Chuong 26

CMDT 2013

Endocrine Disorders Paul A. Fitzgerald, MD

cc

DISEASES OF THE HYPOTHALAMUS & PITUITARY GLAND ANTERIOR HYPOPITUITARISM ``

EssentialS of diagnosis

Partial or complete deficiency of one or any combination of anterior pituitary hormones. `` Adrenocorticotropic hormone deficiency: reduced adrenal secretion of cortisol, testosterone, and epinephrine; aldosterone secretion remains intact. `` Growth hormone (GH) deficiency: short stature in children; asthenia, obesity, and increased cardiac mortality in adults. `` Prolactin deficiency: inhibition of postpartum lactation. `` Thyroid-stimulating hormone (TSH) deficiency: secondary hypothyroidism. `` Luteinizing hormone (LH) and follicle-­ stimulating hormone (FSH) deficiency: hypogonadism and infertility in men and women. ``

``General Considerations Hypopituitarism can be caused by either hypothalamic or pituitary dysfunction. Patients with hypopituitarism may have single or multiple hormonal deficiencies (Table 26–1).

When one hormonal deficiency is discovered, others may be present.

1. Hypopituitarism caused by mass lesions—Lesions in the hypothalamus, pituitary stalk, or pituitary can cause hypopituitarism. Pituitary adenomas are usually sporadic but are sometimes part of multiple endocrine neoplasia type 1 (MEN 1). Pituitary tumors that arise in MEN 1 usually secrete prolactin (63%), GH (9%), or both (10%) and are more aggressive than sporadic adenomas. Pituitary tumors rarely cause diabetes insipidus.

1093

26

Other types of mass lesions include granulomas (eg, ­g ranulomatosis with polyangiitis [formerly Wegener granulomatosis], tuberculosis), Rathke cleft cysts, apoplexy, metastatic carcinomas, aneurysms, and brain tumors (craniopharyngioma, meningioma, dysgerminoma, glioma, chondrosarcoma, chordoma of the clivus). Autoimmune hypophysitis, postpartum pituitary necrosis (Sheehan syndrome), eclampsia–preeclampsia, sickle cell disease, and African trypanosomiasis are rare causes. Langerhans cell histiocytosis usually presents in youth with diabetes insipidus or hypopituitarism; osteolytic bone lesions are noted on radiographs.

2. Hypopituitarism without mass lesions—This may be congenital in syndromes such as septo-optic dysplasia (de Morsier syndrome). Congenital hypopituitarism also develops in patients with PROP1 and other gene mutations.

Hypopituitarism may also be caused by cranial radiation, surgery, encephalitis, hemochromatosis, or autoimmunity.

It may also occur after coronary artery bypass grafting. At least one pituitary hormone deficiency develops in about 25–30% of survivors of moderate to severe traumatic brain injury (Glasgow Coma Scale ≤ 13/15) and in about 55% of survivors of aneurysmal subarachnoid hemorrhage. Some degree of hypopituitarism occurs in one-third of ischemic stroke patients, most commonly GH deficiency and hypogonadotropic hypogonadism. Mitotane, given for adrenal cortical carcinoma, can suppress TSH secretion and cause reversible secondary hypothyroidism. Therapy with exogenous corticosteroids (parenteral, oral, inhaled, or topical) can suppress adrenocorticotropic hormone (ACTH) secretion and causes functional isolated secondary adrenal insufficiency.

Congenital isolated hypogonadotropic hypogonadism can be caused by various gene mutations that control the production or release of gonadotropin-releasing hormone (GnRH), LH, or FSH. Congenital adrenal hypoplasia (see below) is one cause of isolated hypogonadotropic hypogonadism. It may be autosomal recessive or X-linked; the X-linked form is caused by a mutation in the DAX 1 gene.

Adrenal insufficiency, caused by failure to form the adrenal cortex, can present during infancy or childhood in boys with DAX 1 gene mutations. Prader-Willi syndrome

1094

CMDT 2013

Chapter 26

Table 26–1. Pituitary hormones.

Anterior pituitary Growth hormone (GH)1 Prolactin (PRL) Adrenocorticotropic hormone (ACTH) Thyroid-stimulating hormone (TSH) Luteinizing hormone (LH)2 Follicle-stimulating hormone (FSH) Posterior pituitary Arginine vasopressin (AVP)3 Oxytocin 1

GH closely resembles human placental lactogen (hPL).

2 LH closely resembles human chorionic gonadotropin (hCG).

3 AVP is identical with antidiuretic hormone (ADH).

(see below) is a genetic disorder where genes on the paternal chromosome 15 are deleted or unexpressed. The incidence of this disorder is 1:15,000; both sexes are affected equally. Kallmann syndrome (see below) is caused by various gene mutations that impair the development or migration of GnRH-synthesizing neurons from the olfactory bulb to the hypothalamus. Kallmann syndrome is usually sporadic but may be familial and inherited as X-linked recessive (Kal 1), autosomal dominant (Kal 2, 3, 4, 5, or 6), or autosomal recessive (Kal 3, 4, or 6). Kallmann syndrome has an incidence of 1:10,000 males and 1:50,000 females.

``Clinical Findings A. Symptoms and Signs 1. Gonadotropin deficiency—Also known as hypogonadotropic hypogonadism, gonadotropin deficiency is caused by insufficiencies in LH and FSH, which cause hypogonadism and infertility. Congenital gonadotropin deficiency is characterized by partial or complete lack of pubertal development. (See discussion of primary amenorrhea.) Patients with Kallmann syndrome have hypogonadism and anosmia or hyposmia. Half of these patients have unilateral renal agenesis. Some patients with Kallmann syndrome may also exhibit cryptorchidism, micropenis, color blindness, sensorineural deafness, cerebellar ataxia, cognitive problems, bimanual synkinesis, cleft lip or palate, or high-arched palate. Some affected women have menarche followed by secondary amenorrhea.

Patients with congenital adrenal hypoplasia have congenital normosmic idiopathic hypogonadotropic hypogonadism. Boys with congenital adrenal hypoplasia who survive beyond childhood usually do not enter puberty as a result of their hypogonadotropic hypogonadism.

However, hypogonadotropic hypogonadism and subtle signs of adrenal failure can present in adulthood in males with partial loss-of-function mutations in DAX 1. Patients with Prader-Willi syndrome have variable features of both gonadotropin deficiency and primary gonadal dysfunction; boys have cryptorchidism. Other features of PraderWilli syndrome can include mental retardation, short stature, hyperflexibility, autonomic dysregulation, cognitive impairment, and hyperphagia with obesity.

Acquired gonadotropin deficiency is characterized by the loss of axillary, pubic, and body hair. This occurs gradually but becomes particularly prominent in patients who are also hypoadrenal. Men may note diminished beard growth. Libido is diminished. Women have amenorrhea; men note decreased erections. Most patients are infertile.

Androgen deficiency predisposes patients to osteopenia and muscle atrophy. (See sections on male hypogonadism and secondary amenorrhea.) Advancing age, obesity, and poor health also cause partial male hypogonadism. (See Male Hypogonadism.)

2. TSH deficiency—TSH deficiency causes hypothyroidism with manifestations such as fatigue, weakness, weight change, and hyperlipidemia. Bexarotene is a retinoid chemotherapeutic agent that suppresses TSH secretion and circulating levels of T4 and T3, thereby inducing reversible secondary hypothyroidism. (See Hypothyroidism and Myxedema.)

3. ACTH deficiency—This results in diminished cortisol secretion (see Adrenocortical Hypofunction). Symptoms may include weakness, fatigue, weight loss, and hypotension. Patients with partial ACTH deficiency continue to have some cortisol secretion and may not have symptoms until stressed by illness or surgery. Adrenal mineralocorticoid secretion continues, so manifestations of adrenal insufficiency in hypopituitarism are usually less striking than in bilateral adrenal gland destruction (Addison disease); hyponatremia may occur, especially when ACTH and TSH deficiencies are both present.

4. GH deficiency—When GH deficiency is congenital, it presents with hypoglycemia in infancy and short stature in childhood. GH deficiency in adulthood tends to cause mild to moderate central obesity, increased systolic blood pressure, increased low-density lipoprotein (LDL) cholesterol, and reduced cardiac output. Affected patients may also have reduced muscle and bone mass, reduced physical and mental energy, impaired concentration and memory, and depression. Laron syndrome is an autosomal recessive disorder that is mainly associated with mutations in GH receptor gene. This causes resistance to GH and severe insulin-like growth factor-I (IGF-I) deficiency, resulting in short stature (dwarfism). Affected individuals have a prominent forehead, depressed nasal bridge, small mandible, and central obesity. They may have recurrent hypoglycemic seizures. Partial resistance to GH may cause some cases of idiopathic short stature without features of Laron syndrome.

5. Combined pituitary hormone deficiency and ­panhypopituitarism—The conditions refer to a deficiency of several or all pituitary hormones. Combined pituitary hormone deficiency gradually develops in patients with PROP 1 gene mutations, usually presenting with short stature and growth failure due to GH and TSH deficiency; lack of pubertal development occurs due to deficiencies in FSH and LH. ACTH-cortisol deficiency also gradually develops in patients with PROP 1 gene mutations; these patients typically require corticosteroid ­replacement therapy by age 18 years. In addition to the

Endocrine Disorders manifestations noted above, patients with long-standing hypopituitarism tend to have dry, pale, finely textured skin.

The face has fine wrinkles and an apathetic countenance.

6. Other manifestations—Hypothalamic damage can cause obesity and cognitive impairment. Local tumor effects can cause headache or optic nerve compression with visual field impairment.

B. Laboratory Findings The fasting blood glucose may be low. Hyponatremia is often present due to hypothyroidism or hypoadrenalism.

Hyperkalemia usually does not occur, since aldosterone production is not affected.

For men, an accurate serum total testosterone measurement must be obtained. For older men, free testosterone is best measured by calculation, using accurate assays for testosterone and sex hormone binding globulin. Serum gonadotropins (FSH and LH) are obtained if the serum testosterone is low in order to distinguish primary hypogonadism from pituitary dysfunction.

The free thyroxine (FT4) level is low, and TSH is usually not elevated. However, hypothyroidism with a paradoxically increased serum TSH has been reported in some patients with hypothalamic hypopituitarism. Plasma levels of sex steroids (testosterone and estradiol) are low or low normal, as are the serum gonadotropins. Elevated prolactin (PRL) levels are found in patients with prolactinomas, acromegaly, and hypothalamic disease.

ACTH deficiency usually causes functional atrophy of the adrenal cortex within 2 weeks of pituitary destruction.

Therefore, the diagnosis of secondary hypoadrenalism can usually be confirmed with cosyntropin testing. For the cosyntropin test, patients should be either taking no corticosteroids or a short-acting corticosteroid (such as hydrocortisone), which is held after midnight on the morning of the test. At 8 am, blood is drawn for serum cortisol, ACTH, and dehydroepiandrosterone (DHEA); then 0.25 mg of cosyntropin (synthetic ACTH1–24) is administered intramuscularly or intravenously. Another blood sample is obtained 45 minutes after the cosyntropin injection to remeasure serum cortisol levels. A stimulated serum cortisol of < 20 mcg/dL (550 nmol/mL) indicates adrenal insufficiency. With gradual pituitary damage and early in the course of ACTH deficiency, patients can have a stimulated serum cortisol of ≥ 20 mcg/dL but a baseline 8 am serum cortisol < 5 mcg/dL (137.5 nmol/L), which is suspicious for adrenal insufficiency. Serum DHEA levels are usually low in patients with adrenal deficiency, helping confirm the diagnosis. A baseline ACTH level is low or normal in secondary hypoadrenalism, distinguishing it from primary adrenal disease. For patients with symptoms of secondary adrenal insufficiency (hyponatremia, hypotension, pituitary tumor) but borderline cosyntropin testing, treatment can be instituted empirically. The cosyntropin test may be repeated at a later date. Insulin tolerance testing and metyrapone testing are usually unnecessary.

Deficiency of epinephrine occurs with secondary adrenal insufficiency, since high local concentrations of cortisol are required to induce the production of the enzyme

CMDT 2013

1095

­ henylethanolamine N-methyltransferase (PNMT) in the p adrenal medulla that catalyzes the conversion of norepinephrine to epinephrine.

The diagnosis of GH deficiency is difficult since normal GH secretion is pulsatile and serum GH levels are nearly undetectable for most of the day. Also, adults normally tend to produce less GH as they age. Therefore, GH deficiency is often inferred by symptoms of GH deficiency in the presence of pituitary destruction or other pituitary hormone deficiencies. GH deficiency is present in 96% of patients with three or more other pituitary hormone deficiencies. GH stimulates the production of IGF-I. Unfortunately, serum IGF-I is not sensitive for GH deficiency since IGF-I levels are in the normal range in about 50% of adults with GH deficiency. Low serum IGF-I levels are not specific for GH deficiency; however, a very low level of IGF-I (< 84 mcg/L) is indicative of GH deficiency, except in conditions that naturally suppress serum IGF-I (eg, malnutrition, prolonged fasting, oral estrogen, hypothyroidism, uncontrolled diabetes mellitus, liver failure). In GH deficiency, exercise-stimulated serum GH levels remain at < 5 ng/mL and usually fail to rise; however, by age 40 years, most normal adults have lost their GH response to exercise.

Provocative GH-stimulation tests are commonly used but are poor tests for GH deficiency. The insulin hypoglycemia test is now rarely used. Other GH stimulation tests require the administration of intravenous arginine and growth hormone–releasing hormone (GHRH) and oral clonidine or carbidopa/levodopa (combination) in patients pretreated with propranolol or estrogen. However, these tests do not discriminate well between normal individuals and patients with presumed GH deficiency (patients with three or more other pituitary hormone deficiencies). Also, normal overweight adults (body mass index [BMI] ≥ 25 kg/m2) typically have blunted peak GH levels after arginine-GHRH administration.

Despite the limitations of intravenous GHRH/arginine stimulation testing, some insurance companies insist that patients have an abnormal test before covering the costs of GH replacement therapy. However, the latter test has a sensitivity of only 66% for GH deficiency. Therefore, when patients have a serum IGF-I < 84 mcg/L or three other pituitary hormone deficiencies, the likelihood of GH deficiency is so high that symptomatic patients should have a therapeutic trial of GH therapy.

The differential diagnosis of GH deficiency is congenital GH resistance with deficiency of IGF-I; at its worst, IGF-I deficiency results in Laron dwarfism that is resistant to GH therapy.

Patients with hypopituitarism without an established etiology should be screened for hemochromatosis with a serum iron and transferrin saturation or ferritin since hemochromatosis can cause hypopituitarism.

C. Imaging MRI provides the best visualization of pituitary and hypothalamic tumors. Thickening of the pituitary stalk can be caused by sarcoidosis or hypophysitis.

1096

CMDT 2013

Chapter 26

``Differential Diagnosis The failure to enter puberty may simply reflect delayed puberty, also known as constitutional delay in growth and puberty. Reversible hypogonadotropic hypogonadism may occur with serious illness, malnutrition, anorexia nervosa, or morbid obesity. Men typically develop partial secondary hypogonadism with aging. The clinical situation and the presence of normal adrenal and thyroid function allow ready distinction from hypopituitarism.

Profound hypogonadotropic hypogonadism develops in men who receive GnRH analog therapy (leuprolide) for prostate cancer; it usually persists following cessation of therapy. Hypogonadotropic hypogonadism usually develops in patients receiving opioid therapy, including highdose methadone or long-term intrathecal infusion of opioids; both GH deficiency and secondary adrenal insufficiency occur in 15% of such patients. Secondary adrenal insufficiency may persist for many months following high-dose corticosteroid therapy.

Severe illness causes functional suppression of TSH and T4. Hyperthyroxinemia reversibly suppresses TSH. Administration of triiodothyronine (Cytomel) suppresses TSH and T4. Bexarotene, used to treat cutaneous T cell lymphoma, suppresses TSH secretion, resulting in temporary central hypothyroidism. Corticosteroids or megestrol treatment reversibly suppresses endogenous ACTH and cortisol secretion.

GH deficiency normally occurs with aging. Physiologic GH deficiency that develops in obese patients may return to normal with sufficient weight loss.

``Complications Among patients with craniopharyngiomas, diabetes insipidus is found in 16% preoperatively and in 60% postoperatively. Hyponatremia often presents abruptly during the first 2 weeks following pituitary surgery. Visual field impairment may occur. Hypothalamic damage may result in morbid obesity as well as cognitive and emotional problems. Con­ ventional radiation therapy results in an increased incidence of small vessel ischemic strokes and second tumors.

Patients with untreated hypoadrenalism and a stressful illness may become febrile and die in shock and coma.

Adults with GH deficiency have experienced an increased cardiovascular morbidity. Rarely, acute hemorrhage may occur in large pituitary tumors, manifested by rapid loss of vision, headache, and evidence of acute pituitary failure (pituitary apoplexy) requiring emergency decompression of the sella.

``Treatment Transsphenoidal removal of pituitary tumors will sometimes reverse hypopituitarism. Postoperative hyponatremia often occurs; serum sodium must be checked frequently for 2 weeks after pituitary surgery. Hypogonadism due to PRL excess usually resolves during treatment with dopamine agonists. Endocrine substitution therapy must be given before, during and, often, permanently after such procedures.

GH-secreting tumors may respond to octreotide (see section on acromegaly). Radiation therapy with x-ray,

gamma knife, or heavy particles may be necessary but increases the likelihood of hypopituitarism.

The mainstay of substitution therapy for pituitary insufficiency remains lifetime hormone replacement.

A. Corticosteroids Hydrocortisone tablets, 15–35 mg/d orally in divided doses, should be given. Most patients do well with 10–20 mg in the morning and 5–15 mg in the late afternoon. Patients with partial ACTH deficiency (basal morning serum cortisol above 8 mg/dL [220 mmol/L]) require hydrocortisone replacement in lower doses of about 5 mg orally twice daily. Some patients feel better taking prednisone, 3–7.5 mg/d orally. A mineralocorticoid is rarely needed. To determine the optimal corticosteroid replacement dosage, it is necessary to monitor patients carefully for manifestations of overreplacement (Cushing syndrome) or underreplacement. A serum white blood cell count (WBC) with a relative differential can be useful, since a relative neutrophilia and lymphopenia can indicate overreplacement with corticosteroid, and vice versa.

Additional corticosteroids must be given during states of stress, eg, during infection, trauma, or surgical procedures.

For mild illness, corticosteroid doses are doubled or tripled. For trauma or surgical stress, hydrocortisone is given in doses of 50 mg intramuscularly or intravenously every 6 hours and then reduced to normal doses as the stress subsides. Patients with adrenal insufficiency are advised to wear a medical alert bracelet describing their condition and treatment.

Patients with secondary adrenal insufficiency due to treatment with corticosteroids at supraphysiologic doses require their usual daily dose of corticosteroid during surgery and acute illness; supplemental hydrocortisone is not usually required.

B. Thyroid Levothyroxine is given to correct hypothyroidism only after the patient is assessed for cortisol deficiency or is already receiving corticosteroids. (See Hypothyroidism.)

The typical maintenance dose is about 1.6 mcg/kg body weight. However, dosage requirements vary widely, averaging 125 mcg daily with a range of 25–300 mcg daily. The optimal replacement dose of thyroxine for each patient must be carefully assessed clinically on an individual basis.

Serum FT4 levels usually need to be in the high-normal range for adequate replacement. Assessment of serum TSH is useless for monitoring patients, since levels are always low with TSH deficiency.

C. Sex Hormones Hypogonadotropic hypogonadism often develops in patients with hyperprolactinemia; it may be reversed with treatment of the hyperprolactinemia. (See Hyperprolactinemia.)

Androgen replacement is discussed in the section on male hypogonadism. Estrogen replacement is discussed in the section on female hypogonadism. Patients with idiopathic hypogonadotropic hypogonadism, who have received several years of hormone replacement therapy

Endocrine Disorders (HRT), may have a trial off hormonal therapy to assess whether spontaneous sexual maturation may have occurred.

Women with hypopituitarism and secondary adrenal insufficiency whose serum DHEA levels are < 400 ng/mL may be treated with compounded DHEA in doses of about 25–50 mg/d orally. DHEA therapy tends to increase pubic and axillary hair and may modestly improve libido, alertness, stamina, and overall psychological well being after 6 months of therapy.

To improve spermatogenesis, human chorionic gonadotropin (hCG) (equivalent to LH) may be given at a dosage of 2000–3000 units intramuscularly three times weekly and testosterone replacement is discontinued. The dose of hCG is adjusted to normalize serum testosterone levels. After 6–12 months of hCG treatment, if the sperm count remains low, hCG injections are continued along with injections of FSH: follitropin-β (synthetic recombinant FSH) or urofollitropins (urine-derived FSH). An alternative for patients with an intact pituitary (eg, Kallmann syndrome) is the use of leuprolide (GnRH analog) by intermittent subcutaneous infusion. With either treatment, testicular volumes double within 5–12 months, and spermatogenesis occurs in most cases. With persistent treatment and the help of intracytoplasmic sperm injection for some cases, the total pregnancy success rate is about 70%.

Clomiphene, 25–50 mg orally daily, can sometimes stimulate a man’s own pituitary gonadotropins (when his ­pituitary is intact), thereby increasing testosterone and sperm production.

For fertility induction in females, ovulation may be induced with clomiphene, 50 mg daily for 5 days every 2 months. Follitropins and hCG can induce multiple births and should be used only by those experienced with their administration. (See Hypogonadism.)

D. Human Growth Hormone (hGH) Symptomatic adults with severe GH deficiency (serum IGF-I < 85 mcg/L) may be treated with a subcutaneous recombinant human growth hormone (rhGH) injection starting at a dosage of about 0.2 mg/d (0.6 international units/d), administered three or four times weekly. The dosage of rhGH is increased every 2–4 weeks by increments of 0.1 mg (0.3 international units) until side effects occur or a sufficient salutary response and a normal serum IGF-I level are achieved. A sustained-release injectable suspension of depot GH is available (Nutropin Depot). It can be given twice monthly and is therefore more convenient than standard rhGH preparations. In a study of 20 Brazilian GH-deficient adults, depot GH, given in doses of 13.5 mg subcutaneously twice monthly over 6 months, improved body morphology and lipid profiles but was associated with an increase in carotid plaque. If the desired effects (eg, improved energy and mentation, reduction in visceral adiposity) are not seen within 3–6 months at maximum tolerated dosage, rhGH therapy is discontinued.

During pregnancy, rhGH may be safely administered to women with hypopituitarism at their usual pregestational dose during the first trimester, tapering the dose

CMDT 2013

1097

during the second trimester, and discontinuing rhGH during the third trimester.

Oral estrogen replacement reduces hepatic IGF-I production. Therefore, prior to commencing rhGH therapy, oral estrogen is changed to a transdermal or transvaginal estradiol.

Side effects of rhGH therapy may include peripheral edema, hand stiffness, arthralgias, myalgias, headache, pseudotumor cerebri, gynecomastia, carpal tunnel syndrome, tarsal tunnel syndrome, hypertension, and proliferative retinopathy. Side effects are more common in older patients, those with greater weight and higher BMI, and those with adult-onset GH deficiency. Such symptoms usually remit promptly after a sufficient reduction in dosage. Excessive doses of rhGH could cause acromegaly; patients receiving long-term therapy require careful clinical monitoring. Serum IGF-I levels should be kept in the normal range and periodic determinations of serum IGF-I levels are helpful in guiding therapeutic dosing.

GH should not be administered during critical illness since, in one study, administration of very high doses of rhGH to patients in an intensive care unit was shown to increase overall mortality. There is no role for GH replacement in the somatopause of aging.

IGF-I (mecasermin) is available to treat patients with Laron syndrome.

E. Other Treatment Selective transsphenoidal resection of pituitary adenomas can often restore normal pituitary function. Cabergoline, bromocriptine, or quinagolide may reverse the hypogonadism seen in hyperprolactinemia. (See Disorders of Prolactin Secretion.) Disseminated Langerhans cell histiocytosis may be treated with bisphosphonates to improve bone pain; treatment with 2-chlorodeoxyadenosine (cladribine) has been reported to produce remissions.

``Prognosis The prognosis depends on the primary cause. Hypopi­ tuitarism resulting from a pituitary tumor may be reversible with dopamine agonists or with careful selective resection of the tumor. Spontaneous recovery from hypopituitarism associated with pituitary stalk thickening has been reported. Patients can also recover from functional hypopituitarism, eg, hypogonadism due to starvation or severe illness, suppression of ACTH by corticosteroids, or suppression of TSH by hyperthyroidism. Spontaneous reversal of isolated idiopathic hypogonadotropic hypogonadism occurs in about 10% of patients after several years of hormone replacement therapy.

Functionally, most patients with hypopituitarism do very well with hormone replacement. Men with infertility who are treated with hCG/FSH or GnRH are likely to resume spermatogenesis if they have a history of sexual maturation, descended testicles, and a baseline serum inhibin level over 60 pg/mL. Women under age 40 years, with infertility due to hypogonadotropic hypogonadism, can usually have successful induction of ovulation.

1098

CMDT 2013

Chapter 26

Binder G et al; South German Working Group for Pediatric Endocrinology. Effects of dehydroepiandrosterone therapy on pubic hair growth and psychological well-being in adolescent girls and young women with central adrenal insufficiency: a double-blind, randomized, placebo-controlled phase III trial.

J Clin Endocrinol Metab. 2009 Apr;94(4):1182–90. [PMID: 19126625] Bry-Gauillard H et al. Congenital hypogonadotropic hypogonadism in females: clinical spectrum, evaluation, and genetics. Ann Endocrinol (Paris). 2010 May;71(3):158–62.

[PMID: 20363464] Chanson P et al. Comparative validation of the growth ­hormone-releasing hormone and arginine test for the diagnosis of adult growth hormone deficiency using a growth hormone assay conforming to recent international recommendations. J Clin Endocrinol Metab. 2010 Aug; 95(8):3684–92. [PMID: 20484474] Clemmons DR. The diagnosis and treatment of growth hormone deficiency in adults. Curr Opinion Endocrinol Diabetes Obes. 2010 Aug;17(4):377–83. [PMID: 20588115] Grossman AB. The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(6):4855–63.

[PMID: 20525912] Root AW. Reversible isolated hypogonadotropic hypogonadism due to mutations in the neurokinin B regulation of gonadotropin-releasing hormone release. J Clin Endocrinol Metab. 2010 Jun;95(6):2625–9. [PMID: 20525912] Santhanam P et al. Diagnostic predicament of secondary adrenal insufficiency. Endocr Pract. 2010 Jul–Aug;16(4):689–9.

[PMID: 20439244] ­Tessnow AH et al. The changing face of Sheehan’s syndrome. Am J Med Sci. 2010 Nov;340(5):402–6. [PMID: 20944496]

Diabetes insipidus ``

EssentialS of diagnosis

Antidiuretic hormone (ADH) deficiency causes central diabetes insipidus with polyuria (2–20 L/d) and polydipsia. `` Hypernatremia occurs if fluid intake is inadequate. ``

``General Considerations Diabetes insipidus is an uncommon disease characterized by an increase in thirst and the passage of large quantities of urine of low specific gravity (usually < 1.006 with ad libitum fluid intake). The urine is otherwise normal. It is caused by a deficiency of vasopressin or resistance to vasopressin.

Primary central diabetes insipidus (without an identifiable lesion noted on MRI of the pituitary and hypothalamus) accounts for about one-third of all cases of diabetes insipidus. Many such cases appear to be due to autoimmunity against hypothalamic arginine vasopressin (AVP)secreting cells; pituitary stalk thickening can often be detected on pituitary MRI scanning. The cause may also be genetic. Familial diabetes insipidus occurs as a dominant genetic trait with symptoms developing at about 2 years of age. Diabetes insipidus also occurs in Wolfram syndrome, a rare autosomal recessive disorder that is also known by

the acronym DIDMOAD (diabetes insipidus, type 1 diabetes mellitus, optic atrophy, and deafness). DIDMOAD manifestations usually present in childhood but may not occur until adulthood, along with depression and cognitive problems. Diabetes insipidus can also occur in the preleukemic phase of acute myelogenous leukemia associated with myelodysplasia. Secondary central diabetes insipidus is due to damage to the hypothalamus or pituitary stalk by tumor, hypophysitis, anoxic encephalopathy, surgical or accidental trauma, infection (eg, encephalitis, tuberculosis, syphilis), sarcoidosis, or multifocal Langerhans cell (eosinophilic) granulomatosis (“histiocytosis X”). Metas­ tases to the pituitary are more likely to cause diabetes insipidus (33%) than are pituitary adenomas (1%).

Vasopressinase-induced diabetes insipidus may be seen in the last trimester of pregnancy and in the puerperium. A circulating enzyme destroys native vasopressin; however, synthetic desmopressin is unaffected. Nephrogenic diabetes insipidus is a disorder caused by a defect in the kidney tubules that interferes with water reabsorption. These patients have normal secretion of vasopressin, and the polyuria is unresponsive to it. Congenital nephrogenic diabetes insipidus is present from birth and is due to defective expression of renal vasopressin V2 receptors or vasopressinsensitive water channels. It occurs as a familial X-linked trait; adults often have hyperuricemia as well. Acquired forms of vasopressin-resistant diabetes insipidus are usually less severe and are seen in pyelonephritis, renal amyloidosis, myeloma, potassium depletion, Sjögren syndrome, sickle cell anemia, or chronic hypercalcemia. The disorder may occur also as a corticosteroid effect or as an acute side effect of diuretics. Certain drugs (eg, demeclocycline, lithium, foscarnet, or methicillin) may induce nephrogenic diabetes insipidus. The recovery from acute tubular necrosis may also be associated with transient nephrogenic diabetes insipidus.

(See Kidney Disorders.)

``Clinical Findings A. Symptoms and Signs The symptoms of the disease are intense thirst, especially with a craving for ice water, and polyuria, the volume of ingested fluid varying from 2 L to 20 L daily, with correspondingly large urine volumes. Partial diabetes insipidus presents with less intense symptoms and should be suspected in patients with unremitting enuresis. Most patients with diabetes insipidus are able to maintain fluid balance by continuing to ingest large volumes of water. However, diabetes insipidus may present with hypernatremia and dehydration in patients without free access to water, or with a damaged hypothalamic thirst center and altered thirst sensation. Diabetes insipidus is aggravated by administration of high-dose corticosteroids, which increases renal free water clearance. Vasopressin-induced diabetes insipidus during pregnancy is often associated with oligohydramnios, preeclampsia, or hepatic dysfunction.

B. Laboratory Findings The diagnosis of diabetes insipidus as a cause of polyuria or hypernatremia requires clinical judgment. There is no

Endocrine Disorders single diagnostic laboratory test. Evaluation for diabetes insipidus should include an accurate 24-hour urine collection that is measured for volume and creatinine. A urine volume of < 2 L/24 h (in the absence of hypernatremia) essentially rules out diabetes insipidus. Serum is assayed for glucose, urea nitrogen, calcium, potassium, sodium, and uric acid. Hyperuricemia occurs in many patients with diabetes insipidus, since reduced vasopressin stimulation of the renal V1 receptor causes a reduction in the renal tubular clearance of urate.

A supervised “vasopressin challenge test” may be given: Desmopressin acetate is given in an initial dose of 0.05–0.1 mL (5–10 mcg) intranasally (or 1 mcg subcutaneously or intravenously), with measurement of urine volume for 12 hours before and 12 hours after administration.

Serum sodium must be obtained immediately in the event of symptoms of hyponatremia. The dosage of desmopressin is doubled if the response is marginal.

Patients with central diabetes insipidus notice a distinct reduction in thirst and polyuria; serum sodium stays normal except in some salt-losing conditions.

In nonfamilial central diabetes insipidus, MRI of the pituitary and hypothalamus and of the skull is done to look for mass lesions. The pituitary stalk may be thickened, which may be a manifestation of Langerhans cell histiocytosis, sarcoidosis, or lymphocytic hypophysitis. When nephrogenic diabetes insipidus is a diagnostic consideration, measurement of serum vasopressin is done during modest fluid restriction; typically, the vasopressin level is high.

``Differential Diagnosis Central diabetes insipidus must be distinguished from polyuria caused by psychogenic polydipsia, diabetes mellitus, Cushing syndrome or corticosteroid treatment, lithium, hypercalcemia, hypokalemia, and the nocturnal polyuria of Parkinson disease. It must also be distinguished from vasopressinase-induced diabetes insipidus and nephrogenic diabetes insipidus.

``Complications If water is not readily available, the excessive output of urine will lead to severe dehydration. Patients with an impaired thirst mechanism are very prone to hypernatremia, particularly since they usually also have impaired mentation and forget to take their desmopressin. All the complications of the primary disease may eventually become evident. In patients who are receiving desmopressin acetate therapy, there is a danger of induced water intoxication.

``Treatment Mild cases of diabetes insipidus require no treatment other than adequate fluid intake. Reduction of aggravating factors (eg, corticosteroids, which directly increase renal free water clearance) will improve polyuria.

Desmopressin acetate is the treatment of choice for central diabetes insipidus. It is also useful in diabetes insipidus associated with pregnancy or the puerperium, since desmopressin is resistant to degradation by the circulating vasopressinase.

CMDT 2013

1099

Desmopressin is given orally in a starting dose of 0.05 mg twice daily and increased to a maximum of 0.4 mg every 8 hours, if required. Oral desmopressin is particularly useful for patients with sinusitis from the nasal preparation.

Gastrointestinal symptoms, asthenia, and mild increases in hepatic enzymes can occur with the oral preparation.

The nasal preparation (100 mcg/mL solution) is given every 12–24 hours as needed for thirst and polyuria. It may be administered via metered-dose nasal inhaler containing 0.1 mL/spray or via a plastic calibrated tube. The starting dose is 0.05–0.1 mL every 12–24 hours, and the dose is then individualized according to response. Nasal desmopressin may cause nasal irritation.

Desmopressin can also be given intravenously, intramuscularly, or subcutaneously in doses of 1–4 mcg every 12–24 hours as needed to treat thirst or hypernatremia.

Desmopressin may cause hyponatremia, which is uncommon if minimum effective doses are used and the patient allows thirst to occur periodically. Desmopressin can sometimes cause emotional changes, such as depression or agitation and there is an increased risk of suicide among patients starting desmopressin treatment. Erythromelalgia occurs rarely. All desmopressin preparations, including tablets, are subject to heat degradation and should be refrigerated.

Both central and nephrogenic diabetes insipidus respond partially to hydrochlorothiazide, 50–100 mg/d orally (with potassium supplement or amiloride). Nephrogenic diabetes insipidus may respond to combined treatments of indomethacin-hydrochlorothiazide, ­indomethacin-desmopressin, or indomethacin-amiloride. Indo­methacin, 50 mg orally every 8 hours, is effective in acute cases.

Psychotherapy is required for most patients with psychogenic polydipsia. Thioridazine and lithium are best avoided if psychiatric drug therapy is needed, since they cause polyuria.

``Prognosis Central diabetes insipidus appearing after pituitary surgery usually remits after days to weeks but may be permanent if the upper pituitary stalk is cut.

Chronic central diabetes insipidus is ordinarily more an inconvenience than a dire medical condition. Treatment with desmopressin allows normal sleep and activity.

Hypernatremia can occur, especially when the thirst center is damaged, but diabetes insipidus does not otherwise reduce life expectancy, and the prognosis is that of the underlying disorder.

Alexandrov N et al. Gestational diabetes insipidus: a review of an underdiagnosed condition. J Obstet Gynaecol Can. 2010 Mar; 32(3):225–31. [PMID: 20500966] Ananthakrishnan S. Diabetes insipidus in pregnancy: etiology, evaluation, and management. Endocr Pract. 2009 Jul–Aug; 15(4):377–82. [PMID: 19454377] Kristof RA et al. Incidence, clinical manifestations, and course of water and electrolyte metabolism disturbances following transsphenoidal pituitary adenoma surgery: a prospective observational study. J Neurosurg. 2009 Sep;111(3):555–62.

[PMID: 19199508] Loh JA et al. Disorders of water and salt metabolism associated with pituitary disease. Endocrinol Metab Clin North Am. 2008 Mar;37(1):213–34. [PMID: 18226738]

1100

CMDT 2013

Chapter 26

ACROMEGALY & GIGANTISM ``

EssentialS of diagnosis

Pituitary tumor.

Excessive growth of hands, feet, jaw, and internal organs; or gigantism before closure of epiphyses. `` Amenorrhea, headaches, visual field loss, weakness. `` Soft, doughy, sweaty handshake. `` Elevated IGF-I. `` Serum GH not suppressed following oral glucose. `` ``

``General Considerations GH exerts much of its growth-promoting effects by stimulating the release of IGF-I from the liver and other tissues.

Acromegaly is nearly always caused by a pituitary adenoma. These tumors may be locally invasive, particularly into the cavernous sinus. Less than 1% are malignant. Most are macroadenomas (over 1 cm in diameter). Acromegaly is usually sporadic but may rarely be familial. The disease may also be associated with endocrine tumors of the parathyroids or pancreas (MEN 1). Acromegaly may also be seen in McCune–Albright syndrome and as part of Carney syndrome (atrial myxoma, acoustic neuroma, lentigines, adrenal hypercortisolism). Acromegaly is rarely caused by ectopic secretion of GHRH or GH secreted by a lymphoma, hypothalamic tumor, bronchial carcinoid, or pancreatic tumor.

``Clinical Findings A. Symptoms and Signs Excessive GH causes tall stature and gigantism if it occurs in youth, before closure of epiphyses. Afterward, acromegaly develops. The term “acromegaly,” meaning extremity enlargement, seriously understates the manifestations. The hands enlarge and a doughy, moist handshake is characteristic. The fingers widen, causing patients to enlarge their rings.

Carpal tunnel syndrome is common. The feet also grow, particularly in shoe width. Facial features coarsen since the bones and sinuses of the skull enlarge; hat size increases. The mandible becomes more prominent, causing prognathism and malocclusion. Tooth spacing widens. Older photographs of the patient can be a useful comparison.

Macroglossia occurs, as does hypertrophy of pharyngeal and laryngeal tissue; this causes a deep, coarse voice and sometimes makes intubation difficult. Obstructive sleep apnea may occur. A goiter may be noted. Hypertension (50%) and cardiomegaly are common. At diagnosis, about 10% of acromegalic patients have overt heart failure, with a dilated left ventricle and a reduced ejection fraction.

Weight gain is typical, particularly of muscle and bone.

Insulin resistance is usually present and frequently causes diabetes mellitus (30%). Arthralgias and degenerative arthritis occur. Overgrowth of vertebral bone can cause

spinal stenosis. Colon polyps are common, especially in patients with skin papillomas. The skin may also manifest hyperhidrosis, thickening, cystic acne, skin tags, and areas of acanthosis nigricans.

GH-secreting pituitary tumors usually cause some degree of hypogonadism, either by cosecretion of PRL or by direct pressure upon normal pituitary tissue. Decreased libido and erectile dysfunction are common. Women with acromegaly may experience irregular menses or amenorrhea; those who become pregnant have an increased risk of gestational diabetes and hypertension. Secondary hypothyroidism sometimes occurs; hypoadrenalism is unusual.

Headaches are frequent. Temporal hemianopia may occur as a result of the optic chiasm being impinged by a suprasellar growth of the tumor.

B. Laboratory Findings For screening purposes, a random serum IGF-I can be obtained. If it is normal for age, acromegaly is ruled out.

For further evaluation, the patient should be fasting for at least 8 hours (except for water), not acutely ill, and should not have exercised on the day of testing. Assay for the following: IGF-I (increased to over five times normal in most acromegalic patients), PRL (cosecreted by many GH-secreting tumors), glucose (diabetes is common in acromegaly), liver enzymes and blood urea nitrogen (BUN) (liver failure or kidney disease can misleadingly elevate GH), serum calcium (to screen for hyperparathyroidism), serum inorganic phosphorus (frequently elevated), serum free T4, and TSH (secondary hypothyroidism is common in acromegaly; primary hypothyroidism may increase PRL; hyperthyroidism may occur as a result of excess TSH).

Glucose syrup (75 g) is then administered orally, and serum GH is measured 60 minutes afterward; acromegaly is excluded if the serum GH is < 1 ng/mL (immunoradiometric assay [IRMA] or chemiluminescent assays). For ultrasensitive GH assays, GH should be suppressed to < 0.3 ng/mL to exclude acromegaly. The serum IGF-I and glucose-suppressed GH are usually complementary tests; however, disparities between GH and IGF-I levels occur in up to 30% of patients.

C. Imaging MRI shows a pituitary tumor in 90% of acromegalic patients. These tumors ordinarily involve the sella and cavernous sinus; rare ectopic tumors may arise in the sphenoid bone. MRI is generally superior to CT scanning, especially in the postoperative setting. Radiographs of the skull may show an enlarged sella and thickened skull.

Radiographs may also show tufting of the terminal phalanges of the fingers and toes. A lateral view of the foot shows increased thickness of the heel pad.

``Differential Diagnosis Active acromegaly must be distinguished from familial coarse features, large hands and feet, and isolated prognathism and from inactive (“burned-out”) acromegaly in which there has been a spontaneous remission due to infarction of the pituitary adenoma. GH-induced gigantism

Endocrine Disorders must be differentiated from familial tall stature and from aromatase deficiency. (See Osteoporosis.)

Misleadingly high serum GH levels can be caused by exercise or eating just prior to the test; acute illness or agitation; liver failure or kidney disease; malnourishment; diabetes mellitus; or concurrent treatment with estrogens, β-blockers, or clonidine. During normal adolescence, serum IGF-I is usually elevated and GH may fail to be suppressed.

``Complications Complications include hypopituitarism, hypertension, glucose intolerance or frank diabetes mellitus, cardiac enlargement, and cardiac failure. Carpal tunnel syndrome may cause thumb weakness and thenar atrophy. Arthritis of hips, knees, and spine can be troublesome. Cord compression may be seen. Visual field defects may be severe and progressive. Acute loss of vision or cranial nerve palsy may occur if the tumor undergoes spontaneous hemorrhage and necrosis (pituitary apoplexy). Colon polyps are more likely to develop in patients with acromegaly.

``Treatment Pituitary microsurgery is the treatment of choice for patients with acromegaly. Many patients have an apparent surgical cure and a remission in all clinical symptoms but continue to have a mildly elevated serum GH or IGF-I postoperatively. If no residual tumor is apparent on MRI, the patient may elect to be monitored closely, rather than embark on adjuvant medical therapy that is expensive and carries its own risks (see below).

A. Pituitary Microsurgery Endoscopic transnasal, transsphenoidal pituitary microsurgery removes the adenoma while preserving anterior pituitary function in most patients. Surgical remission is achieved in about 70% of patients followed over 3 years. GH levels fall immediately; diaphoresis and carpal tunnel syndrome often improve within a day after surgery. Transsphenoidal surgery is usually well tolerated, but complications occur in about 10% of patients, including infection, cerebrospinal fluid leak, and hypopituitarism. Transsphenoidal pituitary surgery may be difficult in patients with McCune–Albright syndrome because of fibrous dysplasia of the skull base.

Fluid and electrolyte disturbances occur in most patients postoperatively. Diabetes insipidus can occur within 2 days postoperatively but is usually mild and self-correcting.

Hyponatremia can occur abruptly 4–13 days postoperatively in 21% of patients; symptoms may include nausea, vomiting, headache, malaise, or seizure. It is treated with fluid restriction and salt supplements. It is prudent to monitor serum sodium levels postoperatively. Dietary salt supplements for 2 weeks postoperatively may help prevent this complication.

Corticosteroids are administered perioperatively and tapered to replacement doses over 1 week; hydrocortisone is discontinued and cosyntropin stimulation test is performed about 6 weeks after surgery. At that time, a serum T4 can be checked (to screen for secondary hypothyroidism) and the patient is screened for secondary hypogonadism (see above).

CMDT 2013

1101

B. Medications Patients who do not have a clinical or biochemical remission after surgery may be treated with a dopamine agonist (eg, cabergoline), somatostatin analogs, pegvisomant, or a combination of these medications. Cabergoline may be used first, since it is an oral medication. Cabergoline therapy is most successful for tumors that secrete both PRL and GH but can also be effective for patients with normal serum PRL levels. Therapy with cabergoline will shrink one-third of such tumors by more than 50%. The initial dose is 0.25 mg orally twice weekly, which is gradually increased to a maximum dosage of 1 mg twice weekly, if tolerated by the patient based on serum GH and IGF-I levels. Side effects of cabergoline include nausea, fatigue, constipation, abdominal pain, and dizziness. Long-term therapy with dopamine agonists (cabergoline, bromocriptine, or pergolide) for pituitary tumors has not caused the cardiac valve problems that can occur when much higher doses are used for Parkinson disease.

Octreotide and lanreotide are somatostatin analogs that are given by subcutaneous injection. Octreotide (Sandostatin LAR depot) is given at a dose of 20–40 mg intragluteally monthly. Lanreotide acetate (Somatuline Depot) is given by subcutaneous intragluteal injection at a dosage of 60–120 mg monthly. Whichever preparation is used, the dosage can be adjusted to achieve serum GH levels under 2 ng/mL. Such long-acting somatostatin analogs can achieve serum GH levels under 2 ng/mL in 79% of patients and normal serum IGF-I levels in 53% of patients.

Headaches often improve, and tumor shrinkage of about 30% may be expected. Acromegalic patients with pretreatment serum GH levels exceeding 20 ng/mL are less likely to respond to octreotide or lanreotide therapy. Side effects are experienced by about one-third of patients and include injection site pain, loose acholic stools, abdominal discomfort, or cholelithiasis. All somatostatin analogs are expensive and must be continued indefinitely or until other treatment has been effective.

Pegvisomant is a GH receptor antagonist that blocks hepatic IGF-I production. Pegvisomant therapy produces symptomatic relief and normalizes serum IGF-I levels in over 90% of patients. The starting dosage is 10 mg subcutaneously daily. The maintenance dosage can be increased by 5–10 mg every 4–6 weeks, based on serum IGF-I levels and liver transaminase levels; the maximum dosage is 40 mg subcutaneously daily. Pegvisomant does not shrink GH-secreting tumors. Patients need to be monitored carefully with visual field examinations, GH levels, and MRI scanning of the pituitary. Side effects of pegvisomant, including hepatitis and liver injury, have occurred in a patient with Gilbert syndrome. Other adverse effects include edema, flulike syndrome, nausea, and hypertension. Lipohypertrophy can occur at injection sites, so injection sites must be diligently rotated and inspected.

In acromegalic diabetics, hypoglycemic drugs are reduced to avoid hypoglycemia during pegvisomant therapy.

The effectiveness of pegvisomant is reduced by coad­ ministration of opioids. Pegvisomant is detected in some GH assays, which could overestimate serum GH levels.

Pegvisomant is extremely expensive.

1102

CMDT 2013

Chapter 26

C. Stereotactic Radiosurgery Acromegalic patients who have not had a complete remission with transsphenoidal surgery or medical therapy may be treated with stereotactic radiosurgery administered by gamma knife, heavy particle radiation, or adapted linear accelerator. Gamma knife radiosurgery is preferred, since it has become more widely available and normalization of serum IGF-I has been reported in up to 80% of treated patients. Radiosurgery precisely radiates the pituitary tumor in a single session and reduces radiation to the normal brain. However, it cannot be used for pituitary tumors with suprasellar extension due to the risk of damaging the optic chiasm. Radiosurgery can be used for pituitary tumors invading the cavernous sinus, since cranial nerves III, IV, V, and VI are less susceptible to radiation damage.

Radiosurgery can also be used for patients who have not responded to conventional radiation therapy. Following any pituitary radiation therapy, patients are advised to take lifelong daily low-dose aspirin because of the increased risk of small-vessel stroke.

Caron P et al. Acromegaly and pregnancy: a retrospective multicenter study of 59 pregnancies in 46 women. J Clin Endo­ crinol Metab. 2010 Oct;95(10):4680–7. [PMID: 20660047] Giustina A et al. Current management practices for acromegaly: an international survey. Pituitary. 2011 Jun;14(2):125–33.

[PMID: 21063787] Jane JA Jr et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab. 2011 Sep; 96(9):2732–40. [PMID: 21715544] Katznelson L. Approach to the patient with persistent acromegaly after pituitary surgery. J Clin Endocrinol Metab. 2010 Sept;95(9):4114–23. [PMID: 20823464] Rowland NC et al. Radiation treatment strategies for acromegaly.

Neurosurg Focus. 2010 Oct;29(4):E12. [PMID: 20887122] Sandret L et al. Place of cabergoline in acromegaly: a meta-­ analysis. J Clin Endocrinol Metab. 2011 May;96(5):1327–35.

[PMID: 21325455] Sherlock M et al. Medical therapy in acromegaly. Nat Rev Endocrinol. 2011 May;7(5):291–300. [PMID: 21448141]

HYPERPROLACTINEMIA

``Prognosis Patients with acromegaly have increased morbidity and mortality from cardiovascular disorders and progressive acromegalic symptoms. Those who are treated and have a random serum GH under 1.0 ng/mL or a glucose-­ suppressed serum GH under 0.4 ng/mL with a normal age-adjusted serum IGF-I level have reduced morbidity and mortality. Transsphenoidal pituitary surgery is successful in 80% of patients with tumors < 2 cm in diameter and GH levels < 50 ng/mL. Extrasellar extension of the pituitary tumor, particularly cavernous sinus invasion, reduces the likelihood of surgical cure.

Adjuvant medical therapy has been quite successful in treating patients who are not cured by pituitary surgery.

Postoperatively, normal pituitary function is usually preserved. Soft tissue swelling regresses but bone enlargement is permanent. Hypertension frequently persists despite successful surgery. Conventional radiation therapy (alone) produces a remission in about 40% of patients by 2 years and 75% of patients by 5 years after treatment. Gamma knife or cyberknife radiosurgery reduces GH levels an average of 77%, with 20% of patients having a full remission after 12 months. Patients with pituitary adenomas that abut the optic chiasm can be treated with cyberknife radiosurgery, controlling tumor growth and preserving vision in most patients. Heavy particle pituitary radiation produces a remission in about 70% of patients by 2 years and 80% of patients by 5 years. Radiation therapy eventually produces some degree of hypopituitarism in most patients. Conventional radiation therapy may cause some degree of organic brain syndrome and predisposes to small strokes. Patients must receive lifelong follow-up, with regular monitoring of serum GH and IGF-I levels. Serum GH levels over 5 ng/mL and rising IGF-I levels usually indicate a recurrent tumor.

Hypopituitarism may occur, due to the tumor itself, pituitary surgery, or radiation therapy. Hypopituitarism may develop years following radiation therapy, so patients must have regular clinical monitoring of their pituitary function.

``

EssentialS of diagnosis

Women: Oligomenorrhea, amenorrhea; galactorrhea; infertility. `` Prolactin normally elevated during pregnancy. `` Men: Hypogonadism; decreased libido and erectile dysfunction; infertility. `` Elevated serum PRL. `` CT scan or MRI often demonstrates pituitary adenoma. ``

``General Considerations Non-gestational elevations in serum PRL can be caused by numerous conditions (Table 26–2). PRL-secreting pituitary tumors are more common in women than in men and are usually sporadic but may rarely be familial as part of MEN 1. Most are microadenomas (< 1 cm in diameter) that do not grow even with pregnancy or oral contraceptives. However, some giant prolactinomas (over 3 cm in diameter) can spread into the cavernous sinuses and suprasellar areas; rarely, they may erode the floor of the sella to invade the sinuses.

``Clinical Findings A. Symptoms and Signs Hyperprolactinemia may result in hypogonadotropic hypogonadism and reduced fertility. Men usually have erectile dysfunction and diminished libido; gynecomastia sometimes occurs but rarely with galactorrhea. Women may note oligomenorrhea or amenorrhea, although some women continue to menstruate normally. Galactorrhea, defined as lactation in the absence of nursing, is common.

During pregnancy, clinically significant enlargement of a microprolactinoma (diameter < 1 cm) occurs in < 3%;

Endocrine Disorders

Table 26–2. Causes of hyperprolactinemia.

Physiologic Causes

Pharmacologic Causes

Pathologic Causes

Exercise Idiopathic Macroprolactinemia (”big prolactin”) Pregnancy Puerperium Sleep (REM phase) Stress (trauma, surgery) Suckling

Amoxapine Amphetamines Anesthetic agents Antipsychotics (conventional and atypical) Butyrophenones Cimetidine and ranitidine (not famotidine or nizatidine) Estrogens Hydroxyzine Methyldopa Metoclopramide Opioids Nicotine Phenothiazines Protease inhibitors Progestins Reserpine Risperidone Selective serotonin reuptake inhibitors Testosterone Tricyclic antidepres sants Verapamil

Acromegaly Chronic chest wall stimulation (postthoracotomy, postmastectomy, herpes zoster, breast problems, chest acupuncture, nipple rings, etc) Cirrhosis Hypothalamic disease Hypothyroidism Kidney disease (especially with zinc deficiency) Multiple sclerosis Optic neuromyelitis Pituitary stalk section Prolactin-secreting tumors Pseudocyesis (false pregnancy) Spinal cord lesions Systemic lupus erythematosus

clinically significant enlargement of a macroprolactinoma (diameter ≥ 1 cm) occurs in about 30%.

Pituitary prolactinomas may cosecrete GH and cause acromegaly (see above). Large tumors may cause headaches, visual symptoms, and pituitary insufficiency.

Aside from pituitary tumors, some women secrete an abnormal form of prolactin that appears to cause peripartum cardiomyopathy (see Chapter 10). Suppression of prolactin secretion with dopamine agonists can reverse the cardiomyopathy.

B. Laboratory Findings Evaluate for conditions known to cause hyperprolactinemia, particularly pregnancy (serum hCG), hypothyroidism (serum FT4 and TSH), kidney disease (BUN and serum creatinine), cirrhosis (liver function tests) and hyperparathyroidism (serum calcium). Men are evaluated for hypogonadism with determinations of serum total and free testosterone, LH, and FSH. Women who have amenorrhea are assessed for hypogonadism with determinations of serum estradiol, LH, and FSH. Patients with pituitary macroadenomas (> 3 cm in diameter) should have PRL measured on serial dilutions of serum, since IRMA assays may otherwise report falsely low titers, the “high-dose hook effect.” Patients with macroprolactinomas or manifestations of possible hypopituitarism should be evaluated for

CMDT 2013

1103

hypopituitarism as described above. An assay for macroprolactinemia should be considered for patients with hyperprolactinemia who are relatively asymptomatic and have no apparent cause for hyperprolactinemia.

C. Imaging Patients with hyperprolactinemia not induced by drugs, hypothyroidism, or pregnancy should be examined by pituitary MRI. Small prolactinomas may thus be demonstrated, but clear differentiation from normal variants is not always possible. In the event that a woman with a macroprolactinoma becomes pregnant and elects not to take dopamine agonists during her pregnancy, MRI is usually not performed since the normal pituitary grows during pregnancy. However, if visual-field defects or other neurologic symptoms develop in a pregnant woman, a limited MRI study should be done, focusing on the pituitary without gadolinium contrast.

``Differential Diagnosis The causes of hyperprolactinemia are shown in Table 26–2.

Chronic nipple stimulation, nipple piercing, augmentation or reduction mammoplasty, and mastectomy may stimulate PRL secretion. The pituitary tumor of acromegaly can cosecrete GH and PRL. Hyperprolactinemia may also be idiopathic. Increased pituitary size is a normal variant in young women. About 10% of hyperprolactinemic patients are found to be secreting macroprolactin, a relatively inactive “big prolactin”; pituitary MRI is normal in 78% of cases.

The differential diagnosis for galactorrhea includes the small amount of breast milk that can be expressed from the nipple in many parous women that is not cause for concern. Nipple stimulation from nipple rings, chest surgery, or acupuncture can cause galactorrhea; serum PRL levels may be normal or minimally elevated. Some women can have galactorrhea with normal serum PRL levels and no discernible cause (idiopathic). Normal breast milk may be various colors besides white. Bloody galactorrhea requires an evaluation for breast malignancy.

``Treatment Medications known to increase PRL should be stopped if possible. Hyperprolactinemia due to hypothyroidism is corrected by thyroxine.

Women with microprolactinomas who have amenorrhea or are desirous of contraception may safely take oral contraceptives or estrogen replacement—there is minimal risk of stimulating enlargement of the microadenoma.

Patients with infertility and hyperprolactinemia may be treated with a dopamine agonist in an effort to improve fertility. Women with amenorrhea who elect to receive no treatment have an increased risk of developing osteoporosis; such women require periodic bone densitometry.

Pituitary macroprolactinomas (> 10 mm in diameter) have a higher risk of progressive growth, particularly during treatment with estrogen or testosterone replacement therapy or during pregnancy. Therefore, patients with macroprolactinomas should not be treated with sex HRT unless they are in remission with dopamine agonist medication or surgery. Pregnant women with macroprolactinomas

1104

CMDT 2013

Chapter 26

should continue to receive treatment with dopamine agonists throughout the pregnancy to prevent tumor growth.

If dopamine agonists are not used during pregnancy in a woman with a macroprolactinoma, visual-field testing is required each trimester. During pregnancy, measurement of prolactin is not useful surveillance for tumor growth due to the fact that prolactin increases greatly during normal pregnancy.

A. Dopamine Agonists Dopamine agonists are the initial treatment of choice for patients with giant prolactinomas and those with hyperprolactinemia desiring restoration of normal sexual function and fertility. Cabergoline is usually the best tolerated ergotderived dopamine agonist. The beginning dosage is 0.25 mg orally once weekly for 1 week, then 0.25 mg twice weekly for the next week, then 0.5 mg twice weekly. Further dosage increases may be required monthly, based on serum PRL levels, up to a maximum of 1.5 mg twice weekly.

Bromocriptine (1.25–20 mg/d orally) is an alternative drug.

Women who experience nausea with oral preparations may find relief with deep vaginal insertion of cabergoline or bromocriptine tablets; vaginal irritation sometimes occurs.

Quinagolide (Norprolac; not available in the United States) is a non-ergot-derived dopamine agonist for patients intolerant or resistant to ergot-derived medications; the starting dosage is 0.075 mg/d orally, increasing as needed and tolerated to a maximum of 0.6 mg/d. Patients whose tumor is resistant to one dopamine agonist may be switched to another in an effort to induce a tolerable remission.

Dopamine agonists are given at bedtime to minimize side effects of fatigue, nausea, dizziness, and orthostatic hypotension. These symptoms usually improve with dosage reduction and continued use. Erythromelalgia is rare. Dopamine agonists can cause a variety of psychiatric side effects that are not dose related and may take weeks to resolve once the dopamine agonist is discontinued. Therefore, dopamine agonists should be used judiciously in psychiatric patients whose antipsychotic medications have caused hyperprolactinemia.

Long-term therapy with dopamine agonists (cabergoline, bromocriptine, or pergolide) for pituitary tumors has not caused the cardiac valve problems that can occur when much higher doses are used for Parkinson disease.

With dopamine agonist treatment, 90% of patients with prolactinomas experience a fall in serum PRL to 10% or less of pretreatment levels; about 80% of treated patients achieve a normal serum PRL level. Shrinkage of a pituitary adenoma occurs early, but the maximum effect may take up to a year.

Nearly half of prolactinomas—even massive tumors— shrink more than 50%. Such shrinkage of giant prolactinomas can result in spinal fluid rhinorrhea. Discontinuing therapy after months or years usually results in the reappearance of hyperprolactinemia and galactorrhea-amenorrhea.

After 2 years of cabergoline therapy, the percentage of patients who maintain a normal serum prolactin after withdrawal of the drug are as follows: 32% with idiopathic hyperprolactinemia, 21% with microprolactinomas, and 16% with macroprolactinomas.

Because dopamine agonists usually restore fertility promptly, many pregnancies have resulted; no teratogenicity

has been noted with any of the dopamine agonists. However, women with microadenomas may have treatment withdrawn during pregnancy. Macroadenomas may enlarge significantly during pregnancy; if therapy is withdrawn, such patients must be monitored clinically with serum PRL determinations and with computer-assisted visual fields. Women with macroprolactinomas who have responded to dopamine agonists may safely receive oral contraceptive agents as long as they continue receiving therapy.

B. Surgical Treatment Transsphenoidal pituitary surgery may be urgently required for large tumors undergoing apoplexy or those severely compromising visual fields. It is also used electively for patients who do not tolerate or respond to dopamine agonists.

Pituitary transsphenoidal surgery is generally well-tolerated, with a surgical mortality rate of < 0.5%. Complications, such as cerebrospinal fluid leakage, meningitis, stroke, or visual loss, occur in about 3% of cases; sinusitis, nasal septal perforation, or infection complicates about 6.5% of surgeries.

Postoperative hyponatremia occurs quite commonly, and it is advisable to monitor serum sodium levels for the first 2 weeks postoperatively. For pituitary microprolactinomas, skilled neurosurgeons are successful in normalizing prolactin in 87% of patients; the 10-year recurrence rate is 13%. Pituitary function can be preserved in over 95% of cases. However, the surgical success rate for macroprolactinomas is much lower, and the complication rates are higher. Craniotomy is rarely indicated, since even large tumors can usually be decompressed via the transsphenoidal approach.

Fluid and electrolyte disturbances occur in most patients postoperatively. Diabetes insipidus can occur within 2 days postoperatively but is usually mild and selfcorrecting. Hyponatremia can occur abruptly 4–13 days postoperatively in 21% of patients; symptoms may include nausea, vomiting, headache, malaise, or seizure. It is treated with fluid restriction and salt supplements. It is prudent to monitor serum sodium levels postoperatively. Dietary salt supplements for 2 weeks postoperatively may help prevent this complication.

C. Radiation Therapy Radiation therapy is reserved for patients with macroadenomas that are growing despite treatment with dopamine agonists. A single gamma knife or cyberknife treatment is preferable for certain patients whose optic chiasm is clear of tumor, since it is generally safer and more convenient than conventional radiation therapy. Conventional radiation therapy must be given over 5 weeks and carries a high risk of eventual hypopituitarism. Other possible side effects include some degree of memory impairment and an increased longterm risk of second tumors and small vessel ischemic strokes.

After radiation therapy, patients are advised to take low-dose aspirin daily for life to reduce their stroke risk.

D. Chemotherapy Some patients with aggressive pituitary macroadenomas or carcinomas are not surgical candidates and do not respond to dopamine agonists or radiation therapy. Temozolomide

Endocrine Disorders may be administered, 150–200 mg/m2 orally daily for 5 days of each 28-day cycle; after three cycles, treatment efficacy is determined by prolactin measurement and MRI scanning. A minority of such patients respond to temozolomide.

Coker F et al. Antidepressant-induced hyperprolactinaemia: incidence, mechanisms and management. CNS Drugs. 2010 Jul;24(7):563–74. [PMID: 20527996] Dekkers OM et al. Recurrence of hyperprolactinemia after withdrawal of dopamine agonists: systematic review and metaanalysis. J Clin Endocrinol Metab. 2010 Jan;95(1):43–51.

[PMID: 19880787] Kars M et al. Update in prolactinomas. Neth J Med. 2010 Mar;68(3):104–12. [PMID: 20308704] Klibanski A. Clinical practice. Prolactinomas. N Engl J Med. 2010 Apr 1;362(13):1219–26. [PMID: 20357284] Melmed S et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Feb;96(2):273–88. [PMID: 21296991] Milano W et al. Recent clinical aspects of hyperprolactinemia induced by antipsychotics. Rev Recent Clin Trials. 2011 Jan;6(1):52–63. [PMID: 20868350]

cc

DISEASES OF THE THYROID GLAND

CMDT 2013

1105

of total T4, resin T3 uptake (RT3U), and free thyroxine index (FT4I). It is particularly important to determine “free” serum levels (FT4 and FT3) in conditions associated with high circulating levels of thyroxine-binding globulin, such as during therapy with oral estrogen. Ultrasensitive assays for serum TSH have largely replaced older TSH assays. Table 26–3 shows the appropriate use of thyroid tests.

HYPOTHYROIDISM & MYXEDEMA ``

EssentialS of diagnosis

Weakness, fatigue, cold intolerance, constipation, weight change, depression, menorrhagia, ­hoarseness. `` Dry skin, bradycardia, delayed return of deep tendon reflexes. `` Anemia, hyponatremia, hyperlipidemia. `` FT level is usually low.

4 `` TSH elevated in primary hypothyroidism. ``

THYROID TESTING

``General Considerations

Assays for FT4, total triiodothyronine (T3), and free triiodothyronine (FT3) have largely supplanted measurements

Hypothyroidism is common, affecting over 1% of the general population and about 5% of individuals over age

Table 26–3. Appropriate use of thyroid tests.

Test Screening

For hypothyroidism

For hyperthyroidism

Serum thyroid-stimulating hormone (TSH) (sensitive assay)

Most sensitive test for primary hypothyroidism and hyperthyroidism

Free thyroxine (FT4)

Excellent test

Serum TSH

High in primary and low in secondary hypothyroidism

Antithyroglobulin and antithyroperoxidase antibodies

Elevated in Hashimoto thyroiditis

Serum TSH (sensitive assay)

Suppressed except in TSH-secreting pituitary tumor or pituitary hyperplasia (rare)

Triiodothyronine (T3) or free triiodothyronine (FT3)

Elevated

123

Increased uptake; diffuse versus ”hot” areas on scan

Antithyroglobulin and antimicrosomal antibodies

Elevated in Graves disease

Thyroid-stimulating immunoglobulin; TSH receptor antibody (TSH-R Ab [stim])

Usually (65%) positive in Graves disease

I uptake and scan

For thyroid nodules

Comment

Fine-needle aspiration (FNA) biopsy

Best diagnostic method for thyroid cancer

123

Cancer is usually ”cold”; less reliable than FNA biopsy

I uptake and scan

99m

Vascular versus avascular

Ultrasonography

Useful to assist FNA biopsy. Useful in assessing the risk of malignancy (multinodular goiter or pure cysts are less likely to be malignant). Useful to monitor nodules and patients after thyroid surgery for carcinoma.

Tc scan

1106

CMDT 2013

Chapter 26

60 years. Thyroid hormone deficiency affects almost all body functions. The degree of severity ranges from mild and unrecognized hypothyroid states to striking myxedema. The fluid retention seen in myxedema is caused by the interstitial accumulation of hydrophilic mucopolysaccharides, which leads to lymphedema. Hyponatremia is the result of impaired renal tubular sodium reabsorption due to reductions in Na+–K+-ATPase.

Hypothyroidism may be due to failure or resection of the thyroid gland itself or deficiency of pituitary TSH (see Hypopituitarism, above). The condition must be distinguished from the functional hypothyroidism that occurs in severe nonthyroidal illness, which does not require treatment with thyroxine (see Euthyroid Sick Syndrome).

Maternal hypothyroidism during pregnancy results in offspring with IQ scores that are an average 7 points lower than those of euthyroid mothers.

Goiter may be present with thyroiditis, iodide deficiency, genetic thyroid enzyme defects, drug goitrogens (lithium, iodide, propylthiouracil or methimazole, phenylbutazone, sulfonamides, amiodarone, interferon-α, interferon-β, interleukin-2), food goitrogens in iodidedeficient areas (eg, turnips, cassavas) or, rarely, peripheral resistance to thyroid hormone or infiltrating diseases (eg, cancer, sarcoidosis). A hypothyroid phase occurs in subacute (de Quervain) viral thyroiditis following initial hyperthyroidism. Hashimoto thyroiditis is the most common cause of hypothyroidism (see Thyroiditis section).

Goiter is usually absent when hypothyroidism is due to destruction of the gland by surgery, radiation therapy (to the head, neck, chest, and shoulder region), or 131I. Chemotherapy can reduce thyroid function, causing hypothyroidism. Sunitinib, a protein-tyrosine kinase inhibitor used to treat gastrointestinal stromal malignancies, causes transient primary hypothyroidism in about 50% of treated patients.

Amiodarone, because of its high iodine content, causes clinically significant hypothyroidism in about 15–20% of patients who receive it. Hypothyroidism occurs most often in patients with preexisting autoimmune thyroiditis and in patients who are not iodine-deficient. The T4 level is normal or low, and the TSH is elevated, usually over 20 ng/dL. Another 17% of patients have milder elevations of TSH and are asymptomatic. Low-dose amiodarone is less likely to cause hypothyroidism. Cardiac patients with amiodaroneinduced symptomatic hypothyroidism are treated with just enough thyroxine to relieve symptoms. Hypothyroidism usually resolves over several months if amiodarone is discontinued. Hypothyroidism may also develop in patients with a high iodine intake from other sources, especially if they have underlying lymphocytic thyroiditis.

Hepatitis C is associated with an increased risk of autoimmune thyroiditis, with 21% of affected patients having antithyroid antibodies and 13% having hypothyroidism.

The risk of thyroid dysfunction is even higher when patients are treated with interferon. Interferon-α and interferon-β treatment can induce thyroid dysfunction (usually hypothyroidism, sometimes hyperthyroidism) in 6% of patients.

Spontaneous resolution occurs in over 50% of cases once interferon is discontinued.

``Clinical Findings A. Symptoms and Signs 1. Common manifestations—Mild hypothyroidism often escapes detection without screening (ie, serum TSH).

Common symptoms of hypothyroidism include weight gain, fatigue, lethargy, depression, weakness, dyspnea on exertion, arthralgias or myalgias, muscle cramps, menorrhagia, constipation, dry skin, headache, paresthesias, carpal tunnel syndrome, cold intolerance, and Raynaud syndrome. Physical findings can include bradycardia; diastolic hypertension; thin, brittle nails; thinning of hair; peripheral edema; puffy face and eyelids; and skin pallor or yellowing (carotenemia). Delayed relaxation of deep tendon reflexes may be present. Patients often have a palpably enlarged thyroid (goiter) that arises due to elevated serum TSH levels or the underlying thyroid pathology, such as Hashimoto thyroiditis.

2. Less common manifestations—Less common symptoms of hypothyroidism include diminished appetite and weight loss, hoarseness, decreased sense of taste and smell, and diminished auditory acuity. Some patients may complain of dysphagia or neck discomfort. Although most menstruating women have menorrhagia, some women have scant menses or amenorrhea. Physical findings may include thinning of the outer halves of the eyebrows; thickening of the tongue; hard pitting edema; and effusions into the pleural and peritoneal cavities as well as into joints.

Galactorrhea may also be present. Cardiac enlargement (“myxedema heart”) and pericardial effusions may occur.

Psychosis (myxedema madness) can occur from severe hypothyroidism or from toxicity of other drugs whose metabolism is slowed in hypothyroidism. Hypothermia and stupor or myxedema coma, which is often associated with infection (especially pneumonia), may develop in patients with severe hypothyroidism. Pituitary enlargement due to hyperplasia of TSH-secreting cells, which is reversible following thyroid therapy, may be seen in longstanding hypothyroidism.

Some hypothyroid patients with Hashimoto thyroiditis have symptoms that are not due to hypothyroidism but rather to other autoimmune disease. Some autoimmune conditions that occur more commonly in patients with Hashimoto thyroiditis include Addison disease, hypoparathyroidism, diabetes mellitus, pernicious anemia, Sjögren syndrome, vitiligo, biliary cirrhosis, and celiac disease.

Celiac disease occurs in at least 5% of patients with hypothyroidism due to Hashimoto thyroiditis. Affected patients often have weight loss and gastrointestinal symptoms. However, many patients with celiac disease have minimal gastrointestinal symptoms but may have systemic manifestations such as fatigue, depression, osteoporosis or osteomalacia, iron deficiency anemia, short stature, delayed puberty, amenorrhea, or reduced fertility. Intestinal malabsorption may cause vitamin deficiencies with bruising due to vitamin K deficiency, hyperkeratosis due to vitamin A deficiency, bone pain due to vitamin D deficiency, or neuropathy and ataxia due to vitamin E or vitamin B12 deficiency.

Endocrine Disorders B. Laboratory Findings Hypothyroidism is a common disorder and thyroid function tests should be obtained for any patient with the nonspecific symptoms or signs of hypothyroidism. The single best screening test for hypothyroidism is the serum TSH (Table 26–3). Serum TSH is increased with primary hypothyroidism but is low or normal with pituitary insufficiency. The FT4 may be low or low-normal. Other laboratory abnormalities may often be seen: increased serum LDL cholesterol, triglycerides, lipoprotein (a), liver enzymes, and creatine kinase; increased serum PRL; and hyponatremia, hypoglycemia, and anemia (with normal or increased mean corpuscular volume). Semen analysis shows an increase in abnormal sperm morphology. In patients with autoimmune thyroiditis, titers of antibodies against thyroperoxidase and thyroglobulin are high; serum antinuclear antibodies (ANA) may be present and are not usually indicative of lupus.

The normal range for ultrasensitive TSH levels is generally stated to be 0.4–4.0 mU/L. However, the normal range of TSH varies with age such that newborns have a much higher normal range; children and elderly patients have a mildly higher normal range. Over 95% of normal adults have serum TSH concentrations under 3.0 mU/L. There is a high risk of finding antithyroid antibodies in patients with serum TSH in the upper range of normal, but most such patients are asymptomatic. TSH may be mildly elevated in some euthyroid individuals, especially elderly women (10% incidence). Such patients with normal FT4 levels are considered to have “subclinical hypothyroidism,” but can have subtle manifestations of hypothyroidism (eg, fatigue, depression, hyperlipidemia) that may improve with thyroid hormone replacement. Patients who are completely asymptomatic with a mildly elevated serum TSH and normal serum FT4 do not require levothyroxine replacement; in fact, mildly decreased thyroid function was associated with familial longevity in the Leiden Longevity Study. About 18% of patients with subclinical hypothyroidism later become definitely hypothyroid; many such patients have Hashimoto thyroiditis.

C. Imaging Radiologic imaging is usually not necessary for patients with hypothyroidism. However, on CT or MRI, a goiter may be noted in the neck or in the mediastinum (retrosternal goiter). An enlarged thymus is frequently seen in the mediastinum in cases of autoimmune thyroiditis. In primary hypothyroidism with elevated serum TSH levels, MRI of the head will frequently show an enlargement of the pituitary gland from thyrotrophe hyperplasia; such enlargement can be mistaken for a pituitary tumor.

``Differential Diagnosis Many clinical manifestations of hypothyroidism (see above) are common in the general population without thyroid illness. The differential diagnoses are the conditions and drugs that can cause aberrations in laboratory tests, resulting in a low serum T4 or T3 or high serum TSH in

CMDT 2013

1107

Table 26–4. Factors that may cause aberrations in laboratory tests that may be mistaken for primary hypothyroidism.1 Low Serum T4 or T3 Laboratory error Acute psychiatric problems Cirrhosis Nephrotic syndrome Familial thyroid-binding globulin deficiency Severe illness Drugs Androgens Asparaginase Carbamazepine Chloral hydrate Corticosteroids Diclofenac (T3) Didanosine Fenclofenac 5-Fluorouracil Halofenate Mitotane Naproxen (T3) Nicotinic acid Oxcarbazepine Phenobarbital Phenytoin (total T4 may be as low as 2 mcg/dL) Salicylates—large doses (T3 and T4) Sertraline Stavudine T3 therapy (T4)

High Serum TSH Laboratory error Autoimmune disease (assay interference) Heterophile antibodies Anti-mouse antibodies Strenuous exercise (acute) Sleep deprivation (acute) Recovery from nonthyroidal illness (transient) Acute psychiatric admissions (14% transient) Elderly—especially women (10%, mild elevations)

1

True primary hypothyroidism may coexist.

T4, levothyroxine; T3, triiodothyronine; TSH, thyroid-stimulating hormone.

the absence of hypothyroidism (Table 26–4). The pituitary is often quite enlarged in primary hypothyroidism, due to reversible hyperplasia of TSH-secreting cells; the concomitant hyperprolactinemia seen in hypothyroidism can lead to the mistaken diagnosis of a TSH-secreting or PRLsecreting pituitary adenoma.

Euthyroid sick syndrome should be considered in patients with abnormal thyroid function tests (eg, low serum T4 and low levels of FT4) without thyroid disease; conditions that can result in this syndrome include severe illness, caloric deprivation, or major surgery. Patients who have undergone major surgery may have accelerated peripheral metabolism of serum T4 to reverse T3 (rT3). Furthermore, in most patients who are critically ill, there is a circulating inhibitor of thyroid hormone binding to serum thyroxinebinding proteins (TBPs). This causes the RT3U to be misleadingly low, causing the computed FT4I to be very low.

The presence of a very low serum T4 in severe nonthyroidal illness indicates a poor prognosis. Serum TSH tends to be suppressed in severe nonthyroidal illness, making the diagnosis of concurrent primary hypothyroidism quite difficult, although the presence of a goiter suggests the diagnosis.

1108

CMDT 2013

Chapter 26

Cardiac complications may occur as a result of preexistent coronary artery disease and congestive heart failure, which may be exacerbated by levothyroxine therapy. Patients with severe hypothyroidism have an increased susceptibility to bacterial pneumonia. Megacolon has been described in long-standing hypothyroidism. Organic psychoses with paranoid delusions may occur (“myxedema madness”).

Rarely, adrenal crisis may be precipitated by thyroid therapy.

Hypothyroidism is a rare cause of infertility, which may respond to thyroid medication. Pregnancy in a woman with untreated hypothyroidism often results in miscarriage. Sellar enlargement and even well-defined TSH-secreting tumors may develop in untreated cases. These tumors decrease in size after replacement therapy is instituted.

Myxedema crisis refers to severe, life-threatening hypothyroidism. The manifestations of hypothyroidism are present and more severe. Affected patients have impaired cognition, ranging from confusion to somnolence to coma (myxedema coma). Convulsions and abnormal central nervous system signs may occur. Patients have severe hypothermia, hypoventilation, hyponatremia, hypoglycemia, and hypotension. Rhabdomyolysis and acute kidney injury may occur. Myxedema coma is most often seen in elderly women who have had a stroke or who have stopped taking their thyroxine medication. It is often induced by an underlying infection; cardiac, respiratory, or central nervous system illness; cold exposure; or drug use. The mortality rate from myxedema coma is high. Myxedematous patients are unusually sensitive to opioids and average doses may result in death. Patients with severe myxedema may have hyponatremia that is severe and refractory to treatment.

prescribe mixed T4/T3 preparations such as Armour thyroid, but levothyroxine alone renders patients clinically euthyroid as long as it is given in sufficient doses (see below).

Otherwise healthy young and middle-age adults with hypothyroidism may be treated initially with levothyroxine in doses of 25–75 mcg orally daily. The lower doses are used for very mild hypothyroidism, while higher doses are given for more symptomatic hypothyroidism. Women who are pregnant with significant hypothyroidism may begin therapy with levothyroxine at higher doses of 100–150 mcg orally daily. The levothyroxine dosage may be increased according to clinical response and serum TSH, initially trying to keep the serum TSH level between 0.4 mU/L and 2.0 mU/L. The levothyroxine dose required to render patients clinically euthyroid varies considerably, with higher doses required during pregnancy and with certain medications (see below). Since food interferes slightly with the absorption of levothyroxine, it is advisable to take levothyroxine with water in the morning after an overnight fast. The selected time should become a regular daily habit for the patient. After beginning daily administration, significant increases in serum T4 levels are seen within 1–2 weeks, and near-peak levels are seen within 3–4 weeks.

Patients with coronary disease or those who are over age 60 years are treated with smaller initial doses of levothyroxine, 25–50 mcg orally daily; higher initial doses may be used if such patients are severely hypothyroid. The dose can be increased by 25 mcg every 1–3 weeks until the patient is euthyroid. Patients with hypothyroidism and known ischemic heart disease may begin thyroxine therapy following restoration of coronary perfusion by coronary artery angioplasty or bypass.

Myxedema crisis requires larger initial doses of levothyroxine intravenously, since myxedema itself can interfere with levothyroxine intestinal absorption. Levothyroxine sodium 400 mcg is given intravenously as a loading dose, followed by 50–100 mcg intravenously daily; the lower dose is given to patients with suspected coronary insufficiency. In patients with myxedema coma, liothyronine (T3, Triostat) can be given intravenously in doses of 5–10 mcg every 8 hours for the first 48 hours. The hypothermic patient is warmed only with blankets, since faster warming can precipitate cardiovascular collapse. Patients with hypercapnia require intubation and assisted mechanical ventilation. Infections must be detected and treated aggressively. Patients in whom concomitant adrenal insufficiency is suspected are treated with hydrocortisone, 100 mg intravenously, followed by 25–50 mg every 8 hours.

``Treatment

B. Monitoring & Optimizing Treatment of Hypothyroidism

The clinician must decide whether such severely ill patients (with a low serum T4 but no elevated TSH) might have hypothyroidism due to pituitary insufficiency. Patients without symptoms of prior brain lesion or hypopituitarism are very unlikely to suddenly develop hypopituitarism during an unrelated illness. Patients with diabetes insipidus, hypopituitarism, or other signs of a central nervous system lesion may be given T4 empirically.

True secondary hypothyroidism due to direct dopamine suppression of TSH-secreting cells may develop in patients receiving prolonged dopamine infusions.

Certain antiseizure medications cause low serum FT4 levels by accelerating hepatic conversion of T4 to T3; serum TSH levels are normal.

``Complications

Before therapy with thyroid hormone is commenced, the hypothyroid patient requires at least a clinical assessment for adrenal insufficiency and angina, for which the patient would require evaluation and treatment.

A. Beginning Treatment for Hypothyroidism Levothyroxine is the preferred preparation for treating hypothyroid patients. However, patients (as a group) receiving levothyroxine replacement do not have the same sense of well-being as their peers. In response, some clinicians

Every hypothyroid patient requires regular clinical assessments that must include interim histories and physical examinations. Clinical judgment is critical to determine the optimal levothyroxine dose for each patient. Laboratory assays supplement clinical judgment. An elevated serum TSH usually indicates the need for a higher dose of levothyroxine (see below). Unfortunately, normal serum TSH and FT4 levels do not accurately determine that the patient is euthyroid (see below). The patient should be prescribed sufficient levothyroxine to restore a clinically euthyroid state,

Endocrine Disorders while maintaining the serum T3 within the reference range.

For most patients with hypothyroidism, a stable maintenance dose of levothyroxine can usually be found.

Levothyroxine doses may need to be titrated upward after patients commence taking medications that increase the hepatic metabolism of levothyroxine (eg, carbamazepine, phenobarbital, primidone, phenytoin, rifabutin, rifampin, sunitinib, and imatinib [Gleevec]). Amiodarone can cause an increase or decrease in thyroxine dose requirements, making it necessary to closely monitor serum TSH and adjust the thyroxine dosage accordingly in these patients.

Malabsorption of thyroxine can be caused by coadministration of binding substances, such as iron preparations (including iron found in multivitamins), fiber, raloxifene, sucralfate, aluminum hydroxide antacids, sevelemer, orlistat, calcium and magnesium supplements, and soy milk or soy protein supplements. Bile acid-binding resins, such as cholestyramine and colesevelam, can bind T4 and impair its absorption even when administered 5 hours before the T4. Proton pump inhibitors reduce gastric acidity, which interferes slightly with the absorption of levothyroxine. Gastrointestinal disorders can interfere with thyroxine absorption, including celiac disease, inflammatory bowel disease, lactose intolerance, Helicobacter pylori gastritis, and atrophic gastritis.

Different thyroxine preparations vary in their bioavailability by up to 14%. Such differences in the bioavailability of different T4 formulations may have a subtle but significant clinical impact. It is therefore recommended that patients always continue to take the same brand name of thyroxine or the same manufacturer’s generic thyroxine.

There is no standardized optimal dose of levothyroxine, so each patient’s dose must be based on careful clinical assessment. Although serum TSH levels can be helpful in determining optimal dosing, it is important to consider clinical response and to not rely entirely on serum TSH levels to determine the patient’s optimal thyroxine dosage.

Women with hypothyroidism typically require increased doses of T4 during therapy with oral estrogen as well as during pregnancy (see below). Conversely, T4 dosage requirements for women often decrease with delivery, cessation of oral estrogen, and menopause.

1. During pregnancy—Administering adequate levothyroxine to a hypothyroid woman is critical. The fetus is at least partially dependent on maternal T4 for central nervous system development—particularly in the second trimester.

It is therefore important to carefully monitor hypothyroid women with serum TSH (FT4I or FT4 concentrations in hypopituitarism) determinations every 4–6 weeks and to increase T4 replacement progressively as required (see Chapter 19).

There is considerable individual variation in the requirement for additional T4 replacement during pregnancy. An increase in levothyroxine requirement has been noted as early as the fifth week of pregnancy. Therefore, for women receiving replacement thyroxine, it is prudent to increase levothyroxine dosages by approximately 30% as soon as pregnancy is confirmed. By mid pregnancy, women require an average of 47% increase in their levothyroxine dosage.

The increased T4 dosage requirements during pregnancy are believed to be due to several factors: (1) Rising estrogen

CMDT 2013

1109

levels during pregnancy increase thyroxine binding glob­ ulin (TBG) serum concentrations, reducing FT4 levels.

(2) Placental deiodinase promotes the turnover of T4.

(3) Supplemental iron and prenatal multivitamins containing iron can bind to oral T4 and reduce its intestinal absorption. Similarly, supplemental calcium can also reduce T4 absorption. Therefore, it is important that patients take their T4 replacement at least 4 hours before or after such dietary supplements. Postpartum, T4 replacement requirements ordinarily return to prepregnancy levels.

Serum TSH levels normally drop while FT4I rises during the first trimester of pregnancy. This probably results from high levels of hCG (with structural homology to TSH) that stimulates thyroid hormone production. Most women with a low serum TSH in the first trimester are euthyroid. Serum FT4I is helpful in evaluating the thyroid status of pregnant women, particularly in the first trimester. Following delivery, levothyroxine dose requirements decline.

2. Elevated serum TSH levels—This usually indicates underreplacement with levothyroxine. However, before increasing the T4 dosage, it is important to confirm that the patient is indeed taking the medication as directed and does not have angina. It is also important to consider the following: A high TSH in a patient receiving standard replacement doses of T4 may indicate malabsorption of levothyroxine due to concurrent administration with binding substances (see above) or with food (instead of fasting).

Malabsorption of T4 can also occur in short bowel syndrome; therapy with medium chain triglyceride oil may improve absorption. Impaired absorption of T4 can also be caused by diarrhea of any cause or malabsorption due to concurrent celiac disease (sprue), regional enteritis, liver disease, or pancreatic exocrine insufficiency. Serum TSH may be elevated transiently in acute psychiatric illness and during recovery from nonthyroidal illness. Autoimmune disease can cause false elevations of TSH by interfering with the assay. A high TSH can also be caused by thyrotropin-secreting pituitary tumors. TSH may be increased by phenothiazines and atypical antipsychotics.

3. Normal serum TSH levels—Patients are treated with sufficient levothyroxine to achieve normal serum TSH levels of 0.4–2.0 mU/L. Patients who continue to feel hypothyroid despite a normal serum TSH may have a suboptimal serum T3; they may respond well to higher replacement doses of levothyroxine.

4. Low or suppressed serum TSH levels—Serum TSH levels (using a sensitive assay) that are below the reference range (0.4–4.0 mU/L) are considered “low” (0.04–0.4 mU/L) or “suppressed” (≤ 0.03 mU/L). It has generally been assumed that since TSH is a sensitive test for hyperthyroidism in Graves disease, a low serum TSH in patients taking levothyroxine reliably indicates overreplacement; that assumption is proving incorrect. Certainly, if a patient taking levothyroxine has a suppressed serum TSH and manifestations of hyperthyroidism, the dosage of levothyroxine must be reduced. However, many patients with low serum TSH levels exhibit no symptoms of hyperthyroidism. For such patients, it is important to determine whether hypopituitarism or severe nonthyroidal illness is present, which can result

1110

CMDT 2013

Chapter 26

in low serum TSH levels without hyperthyroidism. TSH can also be reduced by certain medications, such as nonsteroidal anti-inflammatory drugs; opioids; nifedipine; verapamil; and high-dose, short-term administration of corticosteroids.

Absent such conditions, a clinically euthyroid patient with a suppressed serum TSH should be given a lower dosage of levothyroxine. Patients who exhibit hypothyroid symptoms on the reduced dosage of levothyroxine may have the higher dose resumed.

Some hypothyroid patients receiving levothyroxine have hypothyroid-type symptoms, particularly persistent fatigue or weight gain, despite having low serum TSH levels. Such patients require careful assessment for concurrent ­illnesses such as adrenal insufficiency, hypogonadism, ­anemia, celiac disease, or depression. If such conditions are not present or are treated and hypothyroid-type symptoms persist despite low-normal or low TSH levels, a serum T3 level (FT3 in pregnancy and women receiving oral estrogens) is often helpful. If the serum T3 level is low or low normal, the patient may benefit from an increase in levothyroxine dosage; if a definite clinical benefit is achieved, the higher dose is continued. Patients with a low serum TSH (0.04–0.4 mU/L) on replacement levothyroxine do not have any long-term increased risk of cardiovascular disease, dysrhythmias, or fractures. However, patients with suppressed serum TSH (≤ 0.03 mU/L) do have an increased risk of such side effects and long-term monitoring for atrial arrhythmias and osteoporosis is recommended.

``Prognosis Hypothyroidism caused by interferon-α resolves within 17 months of stopping the drug in 50% of patients. Patients with mild hypothyroidism caused by Hashimoto thyroiditis have a remission rate of 11%. With early treatment of hypothyroidism, striking transformations take place both in appearance and mental function. Return to a normal state is usually the rule, but relapses will occur if treatment is interrupted. On the whole, response to thyroid treatment is most satisfactory. However, untreated hypothyroid patients with myxedema crisis have a mortality rate approaching 100%. Even with optimal treatment, patients with myxedema crisis have a mortality rate of 20–50%.

Kim BW et al. For some: L-thyroxine replacement might not be enough: a genetic rationale. J Clin Endocrinol Metab. 2009 May;94(5):1521–3. [PMID: 19420275] Liwanpo L et al. Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab. 2009 Dec;23(6):781–92. [PMID: 19942153] Nygaard B et al. Effect of combination therapy with thyroxine (T4) and 3,5,3’-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomized cross-over study. Eur J Endocrinol. 2009 Dec;161(6):895–902.

[PMID: 19666698] O’Reilly DS. Thyroid hormone replacement: an iatrogenic problem.

Int J Clin Pract. 2010 Jun;64(7):991–4. [PMID: 20584231] Padmanabhan H. Amiodarone and thyroid dysfunction. South Med J. 2010 Sep;103(9):922–30. [PMID: 20689491] Reid SM et al. Interventions for clinical and subclinical hypothyroidism in pregnancy. Cochrane Database Syst Rev. 2010 Jul 7;(7):CD007752. [PMID: 20614463]

HYPERTHYROIDISM (Thyrotoxicosis) ``

EssentialS of diagnosis

Sweating, weight loss or gain, anxiety, palpitations, loose stools, heat intolerance, irritability, fatigue, weakness, menstrual irregularity. `` Tachycardia; warm, moist skin; stare; tremor. `` In Graves disease: goiter (often with bruit); ophthalmopathy. `` Suppressed TSH in primary hyperthyroidism; increased T4, FT4, T3, FT3. ``

``General Considerations The term “thyrotoxicosis” refers to the clinical manifestations associated with serum levels of T4 or T3 that are excessive for the individual (hyperthyroidism). Serum TSH levels are suppressed in primary hyperthyroidism. However, certain drugs and conditions can affect laboratory tests and lead to the erroneous diagnosis of hyperthyroidism in euthyroid individuals (Table 26–5). The causes of hyperthyroidism are many and diverse, as described below.

A. Graves Disease Graves disease (known as Basedow disease in Europe) is the most common cause of thyrotoxicosis. It is an autoimmune disorder affecting the thyroid gland, characterized by an increase in synthesis and release of thyroid hormones.

Graves disease is much more common in women than in men (8:1), and its onset is usually between the ages of 20 and 40 years. It may be accompanied by infiltrative ophthalmopathy (Graves exophthalmos) and, less commonly, by infiltrative dermopathy (pretibial myxedema). The thymus gland is typically enlarged and serum ANA levels are usually elevated, reflecting the underlying autoimmunity.

Graves disease has a familial tendency, and many patients have a family history of Graves disease or hypothyroidism from Hashimoto thyroiditis. Histocompatibility studies have shown an association with group HLA-B8 and HLADR3. The pathogenesis of the hyperthyroidism of Graves disease involves the formation of autoantibodies that bind to the TSH receptor in thyroid cell membranes and stimulate the gland to hyperfunction. Such antibodies are called thyroid-stimulating immunoglobulins (TSI) or TSH receptor antibodies (TSHrAb).

Dietary iodine supplementation can trigger Graves ­disease. An increased incidence of Graves disease occurs in countries that have embarked on national programs to fortify commercial salt with potassium iodide; the increase in Graves disease lasts about 4 years. Similarly, patients being treated with potassium iodide or amiodarone (which contains iodine) have an increased risk of developing Graves disease.

Patients with Graves disease have an increased risk of other systemic autoimmune disorders. Affected patients are at increased risk for Sjögren syndrome, pernicious anemia,

Endocrine Disorders

Table 26–5. Factors that can cause aberrations in laboratory tests that may be mistaken for spontaneous clinical primary hyperthyroidism.1 High Serum T4 or T3

Low Serum TSH

Laboratory error Collecting serum in vial with gel barrier for T3 Acute psychiatric problems (30%) Acute medical illness (eg, acute intermittent porphyria) AIDS (increased thyroid-binding globulin) Autoimmunity Hepatitis: acute or chronic active Primary biliary cirrhosis Pregnancy (especially with morning sickness) Hyperemesis gravidarum Familial thyroid-binding abnormalities Familial generalized resistance to thyroid (Refetoff syndrome) Drugs Amiodarone Amphetamines Clofibrate Estrogens (oral) Heparin (dialysis method) Heroin Thyroid hormone therapy Methadone Perphenazine Tamoxifen

Laboratory error Autonomous thyroid or thyroid nodule Acute corticosteroid administration Elderly euthyroid Nonthyroidal illness (severe) Pregnancy (especially with morning sickness) hCG-secreting trophoblastic tumors Drugs Thyroid hormone Amphetamines Dopamine Dopamine agonists Calcium channel blockers (nifedipine, verapamil)

1

True clinical hyperthyroidism may coexist. hCG, human chorionic gonadotropin; NSAIDs, nonsteroidal antiinflammatory drugs; T4, levothyroxine; T3, triiodothyronine; TSH, thyroid-stimulating hormone.

Addison disease, alopecia areata, vitiligo, celiac disease, autoimmune diabetes mellitus type 1, hypoparathyroidism, myasthenia gravis, and cardiomyopathy.

B. Toxic Multinodular Goiter and Thyroid Adenomas Autonomous toxic adenomas of the thyroid may be single (Plummer disease) or multiple (toxic multinodular goiter).

Jod-Basedow disease, or iodine-induced hyperthyroidism, may occur in patients with multinodular goiters after intake of large amounts of iodine in the diet or in the form of radiographic contrast materials or drugs, especially amiodarone. This condition is not associated with infiltrative ophthalmopathy or dermopathy.

C. Subacute (de Quervain) Thyroiditis Subacute thyroiditis typically presents with a moderately enlarged, tender thyroid, and hyperthyroidism. It is thought to be due to a viral infection. If the gland is nontender, the disorder is called “silent thyroiditis.” Hyperthyroidism is

CMDT 2013

1111

followed by hypothyroidism. Patients taking lithium may rarely experience thyrotoxicosis due to silent thyroiditis.

Symptoms mimic a manic episode such that the diagnosis is often missed.

D. Thyrotoxicosis Factitia Thyrotoxicosis factitia is due to ingestion of excessive amounts of exogenous thyroid hormone. Isolated epidemics of thyrotoxicosis have been caused by consumption of ground beef contaminated with bovine thyroid gland.

E. Struma Ovarii Thyroid tissue is contained in about 3% of ovarian dermoid tumors and teratomas. This thyroid tissue may autonomously secrete thyroid hormone due to a toxic nodule or in concert with the woman’s thyroid gland in Graves disease or toxic multinodular goiter.

F. Pituitary Tumor TSH hypersecretion by the pituitary may be caused by a tumor or thyrotrophe cell hyperplasia and is a rare cause of hyperthyroidism. Serum TSH is elevated or normal in the presence of true thyrotoxicosis. Pituitary hyperplasia may be detected on MRI scan as pituitary enlargement without a discrete adenoma being visible. This condition appears to be due to a diminished feedback effect of T4 upon the pituitary. Some cases are familial. Prolonged untreated hypothyroidism causes pituitary enlargement due to thyrotrophe hyperplasia; thyrotrophe tumors are rare.

G. Thyroiditis Hashimoto thyroiditis may cause transient hyperthyroidism during the initial destructive phase. This is also seen in some patients receiving interferon-α, interferon-β, and interleukin-2. Postpartum thyroiditis refers to Hashimoto thyroiditis that occurs in the first 6 months after delivery. It is common, occurring postpartum in 5–10% of women in the United States. Hyperthyroidism results from the release of stored thyroid hormone following damage to the thyroid.

Thyroiditis and hyperthyroidism can also develop in patients receiving sunitinib chemotherapy.

H. Pregnancy and Trophoblastic Tumors The prevalence of hyperthyroidism in pregnancy—most commonly due to Graves disease—is about 0.2%. Struma ovarii is rare. Newborns have an increased risk of intrauterine growth retardation, prematurity, and transient thyrotoxicosis from transplacental transfer of thyrotropin receptor antibody (TRAb).

Although hCG generally has a low affinity for the thyroid’s TSH receptors, very high serum levels of hCG may cause sufficient receptor activation to cause thyrotoxicosis.

Mild gestational hyperthyroidism may occur during the first 4 months of pregnancy, when hCG levels are very high.

Pregnant women are more likely to have thyrotoxicosis and hyperemesis gravidarum if they have high serum levels of asialo-hCG, a subfraction of hCG with greater affinity for TSH receptors.

1112

CMDT 2013

Chapter 26

High levels of hCG can also cause thyrotoxicosis in some cases of molar pregnancy, choriocarcinoma, and testicular malignancies.

I. Thyroid Carcinoma Metastatic functioning thyroid carcinoma is a rare cause of thyrotoxicosis. Hyperthyroidism can be induced by recombinant human thyroid-stimulating hormone (rhTSH) that is given prior to radioiodine therapy or scanning. (See Thyroid Cancer section.)

J. Iodine-Induced Hyperthyroidism Iodine-induced hyperthyroidism is also known as JodBasedow disease. The recommended iodine intake for nonpregnant adults is 150 mcg/d. Higher iodine intake can precipitate hyperthyroidism, particularly in patients with nodular goiters, autonomous thyroid nodules, or asymptomatic Graves disease. Iodine-induced hyperthyroidism also occurs in patients with no detectable underlying thyroid disorder. Common sources of excess iodine include intravenous iodinated radiocontrast dye, certain foods (eg, kelp, nori), topical iodinated antiseptics (eg, povidine iodine), and medications (eg, potassium iodide or amiodarone). Intravenous iodinated radiocontrast dye can also precipitate thyrotoxicosis by inducing a destructive subacute thyroiditis that may be painful and is similar to type 2 amiodarone-induced thyrotoxicosis.

K. Amiodarone-Induced Thyrotoxicosis Amiodarone is a widely used antiarrhythmic drug. The half-life of amiodarone and its metabolites is about 100 days. By weight, amiodarone is 37% iodine and thyroid dysfunction develops in about 15–20% of patients taking amiodarone. In the United States, amiodarone-induced thyrotoxicosis develops in about 3% of patients taking the drug; the incidence of amiodarone-induced thyrotoxicosis is higher in Europe and in iodine-deficient geographic areas (20%). Hyperthyroidism can occur 4 months to 3 years after initiation of amiodarone and may develop several months after amiodarone has been discontinued.

Type 1 amiodarone-induced thyrotoxicosis is caused by active elaboration of excessive thyroid hormone and may occur by either of two mechanisms: (1) Free iodine may cause toxic multinodular goiter in iodine-deficient patients with preexisting autonomous thyroid nodules. Thyroid radioactive iodine (RAI) uptake ranges from low to high.

(2) Excessive free iodine can trigger an immunologic attack on the thyroid; this may cause Graves disease, commonly with diffuse thyroid enlargement and antithyroid peroxidase antibodies (70%). Color flow Doppler sonography shows increased vascularity and blood flow velocity. Thyroidal radioiodine uptake may be low, normal, or increased.

Type 2 amiodarone-induced thyrotoxicosis is caused by destructive thyroiditis, which releases stored thyroid hormone from damaged cells; hyperthyroidism can last 1–3 months and may be followed by hypothyroidism. On ultrasound, the thyroid gland is normal in size, and on color flow Doppler sonography there is no increase in vascularity. Thyroidal radioiodine uptake is usually very low (< 3%).

``Clinical Findings A. Symptoms and Signs Thyrotoxicosis due to any cause produces many different manifestations of variable intensity among different individuals. Patients may complain of nervousness, restlessness, heat intolerance, increased sweating, pruritus, fatigue, weakness, muscle cramps, frequent bowel movements, or weight change (usually loss). There may be palpitations or angina pectoris. Women frequently report menstrual irregularities.

Signs of thyrotoxicosis also include fine resting finger tremors, moist warm skin, fever, hyperreflexia, fine hair, and onycholysis. Chronic thyrotoxicosis may cause osteoporosis. Clubbing and swelling of the fingers (acropachy) develop in a small number of patients.

In patients with Graves disease, physical examination usually reveals a diffusely enlarged thyroid, frequently asymmetric, often with a bruit. However, some patients have no palpable thyroid enlargement. The thyroid gland in subacute thyroiditis is usually moderately enlarged and tender. In patients with toxic multinodular goiter, the thyroid usually has palpable nodules.

Cardiopulmonary manifestations of thyrotoxicosis commonly include a forceful heartbeat, premature atrial contractions, and sinus tachycardia. Patients often have exertional dyspnea. Atrial fibrillation or atrial tachycardia occurs in about 8% of patients with thyrotoxicosis, more commonly in men, the elderly, and those with ischemic or valvular heart disease. The ventricular response from the atrial fibrillation may be difficult to control. Thyrotoxicosis itself can cause a thyrotoxic cardiomyopathy, and the onset of atrial fibrillation can precipitate congestive heart failure. Echocardiogram reveals pulmonary hypertension in 49% of patients with hyperthyroidism; of these, 71% have pulmonary artery hypertension while 29% have pulmonary venous hypertension. Hemodynamic abnormalities and pulmonary hypertension are reversible with restoration of euthyroidism.

Graves eye manifestations, which can occur with hyperthyroidism of any etiology, include upper eyelid retraction (Dalrymple sign), lid lag with downward gaze (von Graefe sign), and a staring appearance (Kocher sign).

Ophthalmopathy is clinically apparent in 20–40% of patients with Graves disease and type 1 amiodaroneinduced thyrotoxicosis, but in no other conditions causing hyperthyroidism. It usually consists of conjunctival edema (chemosis), conjunctivitis, and mild exophthalmos (proptosis). About 5–10% of patients experience more severe exophthalmos, with the eye being pushed forward by increased retro-orbital fat and eye muscles that have been thickened by lymphocytic infiltration. Such patients can experience diplopia from extraocular muscle entrapment.

There may be weakness of upward gaze (Stellwag sign).

The optic nerve may be compressed in severe cases, causing progressive loss of color vision, visual fields, and visual acuity. Corneal drying may occur with inadequate lid closure. Eye changes may sometimes be asymmetric or unilateral. The severity of the eye disease is not closely correlated with the severity of the thyrotoxicosis. Some patients with Graves ophthalmopathy are clinically euthyroid.

Endocrine Disorders Exophthalmometry should be performed on all patients with Graves disease to document their degree of exophthalmos and detect progression of orbitopathy. The protrusion of the eye beyond the orbital rim is measured with a prism instrument (Hertel exophthalmometer). Maximum normal eye protrusion varies between kindreds and races, being about 22 mm for blacks, 20 mm for whites, and 18 mm for Asians.

The differential diagnosis for Graves ophthalmopathy includes diplopia caused by coexistent ocular myasthenia gravis, which is more common in Graves disease and is usually mild, often with selective eye involvement.

Acetylcholinesterase receptor antibody (AChR Ab) levels are elevated in only 36% of such patients, and a thymoma is present in 9%. Orbital lymphoma can also masquerade as Graves ophthalmopathy.

Graves dermopathy (pretibial myxedema) occurs in about 3% of patients with Graves disease, usually in the pretibial region. It is more common in patients with high levels of serum thyroid-stimulating immunoglobulin and in those with severe Graves ophthalmopathy. Glycosaminoglycans accumulation and lymphoid infiltration occur in affected skin, which becomes erythematous with a thickened, rough texture. Elephantiasis of the legs is a rare complication.

Thyroid acropachy is an extreme and unusual manifestation of Graves disease. It presents with digital clubbing, swelling of fingers and toes, and a periosteal reaction of extremity bones. It is ordinarily associated with ophthalmopathy and thyroid dermopathy. Most patients are smokers. The presence of thyroid acropachy is an indication of the severity of the autoimmunity; most patients have high serum titers of thyroid-stimulating immunoglobulin. Patients with thyroid acropachy are at greater risk for having concurrent Graves dermopathy and severe ophthalmopathy. However, acropachy itself does not usually cause clinical complaints.

Tetany is a rare presenting feature. In hyperthyroidism, the renal excretion of magnesium is increased and hypomagnesemia is common. Severe magnesium depletion causes hypoparathyroidism that can result in hypocalcemia.

Hyperthyroidism during pregnancy shares many of the features of normal pregnancy: tachycardia, warm skin, heat intolerance, increased sweating, and a palpable thyroid. Pregnancy can have a beneficial effect on the thyrotoxicosis of Graves disease. However, there is an increased risk of thyroid storm, preeclampsia–eclampsia, congestive heart failure, premature delivery, and abruptio placentae.

TSI (or TSHrAb) crosses the placenta; if maternal serum TSI (or TSHrAb) levels reach > 500% in the third trimester, the risk of transient neonatal Graves disease in the newborn is increased.

Hypokalemic periodic paralysis occurs in about 15% of Asian or Native American men with thyrotoxicosis. It usually presents abruptly with symmetric flaccid paralysis (and few thyrotoxic symptoms), often after intravenous dextrose, oral carbohydrate, or vigorous exercise. Attacks last 7–72 hours.

B. Laboratory Findings Serum FT4, T3, FT3, T4, thyroid resin uptake, and FT4 index are all usually increased. Sometimes the FT4 level may be

CMDT 2013

1113

normal but with an elevated serum T3 (T3 toxicosis). Serum T3 can be misleadingly elevated when blood is collected in tubes using a gel barrier, which causes certain immunoassays (eg, Immulite but not Axsym analyzers) to report serum total T3 levels that are falsely elevated in 24% of normal patients. Serum T4 or T3 can be elevated in other nonthyroidal conditions (Table 26–5).

Serum TSH is suppressed in hyperthyroidism, except in the very rare cases of pituitary inappropriate secretion of thyrotropin. Serum TSH may be misleadingly low in other nonthyroidal conditions (Table 26–5). The term “subclinical hyperthyroidism” is used to describe asymptomatic individuals with a low serum TSH but normal serum levels of FT4 and T3; progression to symptomatic thyrotoxicosis occurs at a rate of 1–2% per year in patients without a goiter and at a rate of 5% per year in patients with a multinodular goiter.

Hyperthyroidism can cause other laboratory abnormalities, including hypercalcemia, increased alkaline phosphatase, anemia, and decreased granulocytes.

Hypokalemia and hypophosphatemia occur in thyrotoxic periodic paralysis.

Problems of diagnosis occur in patients with acute psychiatric disorders; about 30% of these patients have elevated serum T4 levels without clinical thyrotoxicosis. The TSH is not usually suppressed, distinguishing psychiatric disorder from true hyperthyroidism. T4 levels return to normal gradually.

In Graves disease, serum TSI (or TSHrAb) is usually detectable (65%). Antithyroglobulin or antithyroperoxidase antibodies are usually elevated but are nonspecific.

Serum ANA and anti-double-stranded DNA antibodies are also usually elevated without any evidence of lupus erythematosus or other collagen-vascular disease.

With subacute thyroiditis, patients often have an increased erythrocyte sedimentation rate (ESR) but antithyroid antibodies are usually not present in the plasma, and tests for TSI (or TSHrAb) are negative. Patients with iodine-induced hyperthyroidism also have undetectable serum TSI (or TSHrAb), an absence of serum anti-­ thyroperoxidase antibodies, and an elevated urinary iodine concentration. In thyrotoxicosis facticia, serum thyroglobulin levels are low, distinguishing it from other causes of hyperthyroidism.

With hyperthyroidism during pregnancy, women have an elevated FT4 while the TSH is suppressed. However, apparent lack of full TSH suppression can be seen due to misidentification of hCG as TSH in certain assays. Although the total T4 is elevated in most pregnant women, values over 20 mcg/dL are encountered only in hyperthyroidism. The T3 resin uptake, which is low in normal pregnancy because of high TBG concentration, is normal or high in thyrotoxic persons. Pregnancy can have a beneficial effect on the thyrotoxicosis of Graves disease, with decreasing antibody titers and decreasing FT4 levels as the pregnancy advances.

Since high levels of T4 and FT4 are normally seen in patients taking amiodarone, suppressed TSH (sensitive assay) must be present along with a greatly elevated T4 (> 20 mcg/dL) or T3 (> 200 ng/dL) in order to diagnose hyperthyroidism. (Note: Hypothyroidism occurs in an additional 6% of patients receiving amiodarone after

1114

CMDT 2013

Chapter 26

2–39 weeks of therapy.) In type 1 amiodarone-induced thyrotoxicosis, the presence of proptosis, thyroid-­ stimulating immunoglobulin is diagnostic. In type 2 amiodarone-induced thyrotoxicosis, serum levels of interleukin-6 (IL-6) are usually quite elevated.

C. Imaging RAI should never be administered to pregnant women. In others, RAI scanning and uptake may be helpful to determine the cause for hyperthyroidism. RAI uptake and scanning is not necessary for patients with obvious Graves disease who have elevated serum thyroid-stimulating immunoglobulin or associated Graves ophthalmopathy. Women with hyperthyroidism due to Graves disease should ideally have the RAI scan extended to include the pelvis in order to screen for concomitant struma ovarii (rare). A high RAI uptake is seen in Graves disease and toxic nodular goiter.

Patients with type 1 amiodarone-induced thyrotoxicosis have RAI uptake that is usually detectable but typically below the normal range, although some patients may have elevated RAI uptake. A low RAI uptake is characteristic of subacute thyroiditis and iodine-induced hyperthyroidism.

Low RAI uptake is also seen with interleukin-2 therapy and after neck surgery for hyperparathyroidism. In type 2 ­amiodarone-induced thyrotoxicosis, thyroid RAI uptake is usually below 3%.

Thyroid ultrasound can be helpful in patients with hyperthyroidism, particularly in patients with palpable thyroid nodules. Color flow Doppler sonography is helpful to distinguish type 1 amiodarone-induced thyrotoxicosis, with its increased blood flow velocity and vascularity, from type 2 amiodarone-induced thyrotoxicosis (reduced vascularity).

MRI and CT scanning of the orbits are the imaging methods of choice to visualize Graves ophthalmopathy affecting the extraocular muscles. Imaging is required only in severe or unilateral cases or in euthyroid exophthalmos that must be distinguished from orbital pseudotumor, tumors, and other lesions.

``Differential Diagnosis True thyrotoxicosis must be distinguished from those conditions that elevate serum T4 and T3 or suppress serum TSH without affecting clinical status (see Table 26–5).

Some states of hypermetabolism without thyrotoxicosis—notably severe anemia, leukemia, polycythemia, and cancer—rarely cause confusion. Pheochromocytoma is often asso­ciated with hypermetabolism, tachycardia, weight loss, and profuse sweating. Acromegaly may also produce tachycardia, sweating, and thyroid enlargement. Appropriate laboratory tests will easily distinguish these entities.

Cardiac disease (eg, atrial fibrillation, angina) refractory to treatment suggests the possibility of underlying (“apathetic”) hyperthyroidism. Other causes of ophthalmoplegia (eg, myasthenia gravis) and exophthalmos (eg, orbital tumor, pseudotumor) must be considered. Thyrotoxicosis must also be considered in the differential diagnosis of muscle weakness and osteoporosis. Diabetes mellitus and Addison disease may coexist with thyrotoxicosis.

``Complications Hypercalcemia, osteoporosis, and nephrocalcinosis may occur. Decreased libido, erectile dysfunction, diminished sperm motility, and gynecomastia may be noted in men with hyperthyroidism. Other complications include cardiac arrhythmias and heart failure, thyroid crisis, ophthalmopathy, dermopathy, and thyrotoxic hypokalemic periodic paralysis (see below.)

``Treatment A. Graves Disease The treatment of Graves disease involves a choice of methods rather than a method of choice.

1. Propranolol—Propranolol is generally used for symptomatic relief until the hyperthyroidism is resolved. It effectively relieves the tachycardia, tremor, diaphoresis, and anxiety that occur with hyperthyroidism due to any cause.

It is the initial treatment of choice for thyroid storm. The periodic paralysis seen in association with thyrotoxicosis is also effectively treated with β-blockade. It has no effect on thyroid hormone secretion. Treatment is usually begun with propranolol ER 60 mg orally once or twice daily, with dosage increases every 2–3 days to a maximum daily dose of 320 mg. Propranolol ER is initially given every 12 hours for patients with severe hyperthyroidism, due to accelerated metabolism of the propranolol; it may be given once daily as hyperthyroidism improves.

2. Thiourea drugs—Methimazole or propylthiouracil is generally used for young adults or patients with mild thyrotoxicosis, small goiters, or fear of isotopes. Carbimazole is another thiourea that is converted to methimazole in vivo and is available outside the United States. Elderly patients usually respond particularly well. These drugs are also useful for preparing hyperthyroid patients for surgery and elderly patients for RAI treatment. The drugs do not permanently damage the thyroid and are associated with a lower chance of posttreatment hypothyroidism (compared with RAI or surgery). When thiourea therapy is discontinued, there is a high recurrence rate for hyperthyroidism (about 50%). A better likelihood of long-term remission is seen in patients with small goiters or mild hyperthyroidism and those requiring small doses of thiourea. Patients whose thyroperoxidase and thyroglobulin antibodies remain high after 2 years of therapy have been reported to have only a 10% rate of relapse. Thiourea therapy may be continued long-term for patients who are tolerating it well.

Agranulocytosis occurs in about 0.3% of patients taking methimazole and about 0.4% of patients taking propylthiouracil. Agranulocytosis usually occurs in the first 60 days of therapy, and it develops in a few patients after 5 months of therapy. There is a genetic tendency to develop agranulocytosis with thiourea therapy; if a close relative has had this adverse reaction, other therapies should be considered for the patient. Patients are warned that if a sore throat or febrile illness develops, they should seek medical attention and have a WBC determined immediately. The agranulocytosis is generally reversible; recovery is not

Endocrine Disorders improved by filgrastim (granulocyte colony-stimulating factor [G-CSF]). Periodic surveillance of the WBC during treatment has been advocated, but the onset of agranulocytosis is generally abrupt.

Other side effects common to thiourea drugs include pruritus, allergic dermatitis, nausea, and dyspepsia. Anti­ histamines may control mild pruritus without discontinuation of the drug. Since the two thiourea drugs are similar, patients who have had a major allergic reaction from one should not be given the other.

Primary hypothyroidism may occur. The patient may become clinically hypothyroid for 2 weeks or more before TSH levels rise, having been suppressed by the preceding hyperthyroidism. Therefore, the patient’s changing thyroid status is best monitored clinically and with serum levels of FT4. Rapid growth of the goiter usually occurs if prolonged hypothyroidism is allowed to develop; the goiter may sometimes become massive but usually regresses rapidly with reduction or cessation of thiourea therapy or with thyroid hormone replacement.

A. Methimazole—Methimazole is generally preferred over propylthiouracil since methimazole is more convenient to use and is less likely to cause fulminant hepatic necrosis.

Methimazole therapy is also less likely to cause 131I treatment failure. Rare complications peculiar to methimazole include serum sickness, cholestatic jaundice, loss of taste, alopecia, nephrotic syndrome, and hypoglycemia. Methimazole is given orally in initial doses of 30–60 mg once daily. Some patients with very mild hyperthyroidism may respond well to smaller initial doses of methimazole (10–20 mg daily).

Methimazole may also be administered twice daily to reduce the likelihood of gastrointestinal upset. Methimazole use in pregnancy has been associated with a possibly increased risk of fetal anomalies such as aplasia cutis, esophageal atresia, and coanal atresia. However, methimazole may be used if the patient cannot tolerate propylthiouracil (see below). If methimazole is used during pregnancy or breastfeeding, the dose should not exceed 20 mg daily. The dosage is reduced as manifestations of hyperthyroidism resolve and as the FT4 level falls toward normal. For patients who have elected to receive 131I therapy, methimazole is discontinued 4 days prior to receiving the 131I and is resumed at a lower dose 3 days afterwards to avoid recurrence of hyperthyroidism.

About 4 weeks after 131I therapy, methimazole may be discontinued if the patient is euthyroid.

B. Propylthiouracil—Propylthiouracil has been the drug of choice during breastfeeding since it is not concentrated in the milk as much as methimazole. Propylthiouracil is also favored during pregnancy, possibly causing fewer problems in the newborn. Rare complications peculiar to propylthiouracil include arthritis, lupus, aplastic anemia, thrombocytopenia, and hypoprothrombinemia. Acute hepatitis occurs rarely and is treated with prednisone but may progress to liver failure. Propylthiouracil is given orally in initial doses of 300–600 mg daily in four divided doses. The dosage and frequency of administration are reduced as symptoms of hyperthyroidism resolve and the FT4 level approaches normal. During pregnancy, the dose of propylthiouracil is kept below 200 mg/d to avoid goitrous

CMDT 2013

1115

hypothyroidism in the infant; the patient may be switched to methimazole in the second trimester.

3. Iodinated contrast agents—These agents provide effective temporary treatment for thyrotoxicosis of any cause. Iopanoic acid (Telepaque) or ipodate sodium (Bilivist, Oragrafin) is given orally in a dosage of 500 mg twice daily for 3 days, then 500 mg once daily. These agents inhibit peripheral 5′-monodeiodination of T4, thereby blocking its conversion to active T3. Within 24 hours, serum T3 levels fall an average of 62%. For patients with Graves disease, methimazole is begun first to block iodine organification; the next day, ipodate sodium or iopanoic acid may be added. The iodinated contrast agents are particularly useful for patients who are very symptomatically thyrotoxic (see Thyroid Storm). They offer a therapeutic option for patients with T4 overdosage, subacute thyroiditis, and amiodarone-induced thyrotoxicosis and for those intolerant to thioureas and for newborns with thyrotoxicosis (due to maternal Graves disease). Treatment periods of 8 months or more are possible, but efficacy tends to wane with time. In Graves disease, thyroid RAI uptake may be suppressed during treatment but typically returns to pretreatment uptake by 7 days after discontinuation of the drug, allowing 131I treatment.

4. Radioactive iodine (131I, RAI)—The administration of 131 I is an excellent method of destroying overactive thyroid tissue (either diffuse or toxic nodular goiter). There are ample data to conclude that patients who are treated with RAI in adulthood do not have an increased risk of subsequent thyroid cancer, leukemia, or other malignancies.

Similarly, individuals who were treated with RAI as teenagers have not shown any increased risk of malignancy in a 36-year retrospective study. Children born to parents previously treated with 131I show normal rates of congenital abnormalities.

Because fetal radiation is harmful, RAI should not be given to pregnant women. A sensitive pregnancy test (serum β-hCG) should be obtained on all women of reproductive age prior to 131I therapy.

Most patients may receive 131I while being symptomatically treated with propranolol ER, which is then reduced in dosage as hyperthyroxinemia resolves. However, some patients (those with coronary disease, the elderly, or those with severe hyperthyroidism) are usually rendered euthyroid with a thiouracil drug (see above) while the dosage of propranolol is reduced. A higher rate of 131I treatment failure has been reported in patients with Graves disease who have been receiving methimazole or propylthiouracil.

However, therapy with 131I will usually be effective if the methimazole is discontinued at least 4 days before RAI therapy and if the therapeutic dosage of 131I is adjusted (upward) according to RAI uptake on the pretherapy scan.

Prior to 131I therapy, patients are instructed against receiving intravenous iodinated contrast or ingesting large quantities of dietary iodine, but severe restriction of dietary iodine is not usually necessary.

Following 131I treatment for hyperthyroidism, Graves ophthalmopathy appears or worsens in 15% of patients (23% in smokers and 6% in nonsmokers) and improves in

1116

CMDT 2013

Chapter 26

none, whereas during treatment with methimazole, ophthalmopathy worsens in 3% and improves in 2% of patients. Among patients receiving prednisone following 131 I treatment, preexistent ophthalmopathy worsens in none and improves in 67%. Therefore, patients with Graves ophthalmopathy who are to be treated with radioiodine should be considered for prophylactic prednisone (20–40 mg/d) for 2 months following administration of 131I, particularly in patients who have severe orbital involvement.

Smoking increases the risk of having a flare in ophthalmopathy following 131I treatment and also reduces the effectiveness of prednisone treatment. Therefore, patients who smoke are strongly encouraged to quit prior to 131I treatment.

FT4 levels may sometimes drop within 2 months after 131 I treatment, but then rise again to thyrotoxic levels, at which time thyroid RAI uptake is low. This phenomenon is caused by a release of stored thyroid hormone from injured thyroid cells and does not indicate a treatment failure. In fact, serum FT4 then falls abruptly to hypothyroid levels.

There is a high incidence of hypothyroidism in the months to years after 131I, even when small doses are given.

Patients with Graves disease treated with 131I also have an increased lifetime risk of developing hyperparathyroidism, particularly when radioiodine therapy was administered in childhood or adolescence. Lifelong clinical follow-up is mandatory, with measurements of serum TSH, FT4, and calcium when indicated.

5. Thyroid surgery—Thyroidectomy may be performed for pregnant women whose thyrotoxicosis is not controlled with low doses of thioureas, and for women who desire to become pregnant in the very near future. Surgery is also an option for nodular goiters, when there is a suspicion for malignancy.

The Hartley–Dunhill operation is the procedure of choice for patients with Graves disease having surgery; this operation consists of a total resection of one lobe and a subtotal resection of the other lobe, leaving about 4 g of thyroid tissue. Subtotal thyroidectomy of both lobes is often used, but ultimately results in a 9% recurrence rate for hyperthyroidism. Total thyroidectomy of both lobes poses an increased risk of hypoparathyroidism and damage to the recurrent laryngeal nerves.

Patients are ordinarily rendered euthyroid preoperatively with a thiourea drug. Ipodate sodium or iopanoic acid (500 mg orally twice daily) may be used in addition to a thiourea to accelerate the decline in serum T3. Propranolol ER is given orally at initial doses of 60–80 mg twice daily and increased every 2–3 days until the heart rate is < 90 beats per minute. Propranolol is continued until the serum T3 (or free T3) is normal preoperatively. Thyroid vascularity is reduced by preoperative treatment with either ipodate sodium or iopanoic acid (500 mg twice orally daily for 3 days) or iodine (eg, Lugol solution, two or three drops orally daily for several days). If a patient undergoes surgery while thyrotoxic, larger doses of propranolol are given perioperatively to reduce the likelihood of thyroid crisis.

Morbidity includes possible damage to the recurrent laryngeal nerve, with resultant vocal cord paralysis. If both recurrent laryngeal nerves are damaged, airway obstruction

may develop, and the patient may require intubation and tracheostomy. Hypoparathyroidism also occurs, which means that calcium levels must be checked postoperatively.

When a competent, experienced neck surgeon performs a thyroidectomy, surgical complications are uncommon.

Thyroid surgery should be performed as an inpatient, with at least an overnight observational period.

B. Toxic Solitary Thyroid Nodules Toxic solitary thyroid nodules are usually benign but may rarely be malignant. If a nonsurgical therapy is elected, the nodule should be evaluated with a fine-needle aspiration biopsy (FNA). Hyperthyroidism caused by a single hyperfunctioning thyroid nodule may be treated symptomatically with propranolol ER and methimazole or propylthiouracil, as in Graves disease (see above). Patients who tolerate methimazole well may elect to continue it for long-term therapy. The dose of methimazole should be adjusted to keep the TSH slightly suppressed, so the risk of TSHstimulated growth of the nodule is reduced. For patients under age 40 years and for healthy older patients, surgery is usually recommended; patients are made euthyroid with a thiourea preoperatively and given several days of iodine, ipodate sodium, or iopanoic acid before surgery as in Graves disease (see above). Transient postoperative hypothyroidism resolves spontaneously. Permanent hypothyroidism occurs in about 14% of patients by 6 years after surgery. Patients with a toxic solitary nodule who are over age 40 years or in poor health may be offered 131I therapy. If the patient has been receiving methimazole preparatory to 131I, the TSH should be kept slightly suppressed in order to reduce the uptake of 131I by the normal thyroid. Nevertheless, permanent hypothyroidism occurs in about one-third of patients after 8 years of 131I therapy. The nodule remains palpable in 50% and may grow in 10% of patients after 131I.

C. Toxic Multinodular Goiter Hyperthyroidism caused by a toxic multinodular goiter may also be treated with propranolol ER and methimazole, as in Graves disease. Methimazole does reverse hyperthyroidism, but there is a 95% recurrence rate if it is stopped.

Definitive treatment for large multinodular goiters is surgery, prior to which patients are rendered euthyroid.

Surgery is particularly indicated to relieve pressure symptoms or for cosmetic indications. Patients with toxic multinodular goiter are prepared for surgery the same as those with Graves disease. Patients who are to receive 131I treatment are rendered nearly euthyroid with methimazole, which is stopped at least 4 days before RAI treatment.

Meanwhile, the patient follows a low-iodine diet; this is done to enhance the thyroid gland’s uptake of RAI, which may be relatively low in this condition (compared to Graves disease). Relatively high doses of 131I are usually required; recurrent thyrotoxicosis and hypothyroidism are common, so patients must be monitored closely. Peculiarly, in about 5% of patients with diffusely nodular toxic goiter, the administration of 131I therapy may induce Graves disease. Also, Graves eye disease has occurred rarely following 131 I therapy for multinodular goiter.

Endocrine Disorders D. Subacute (de Quervain) Thyroiditis Patients with hyperthyroidism due to subacute thyroiditis are treated symptomatically with oral propranolol ER at initial doses of about 60–80 mg twice daily and increased every 2–3 days until the heart rate is < 90 beats per minute.

Ipodate sodium or iopanoic acid, 500 mg orally daily, promptly corrects elevated T3 levels and is continued for 15–60 days until the serum FT4 level normalizes. The condition subsides spontaneously within weeks to months.

Thioureas are ineffective, since thyroid hormone production is actually low in this condition. RAI is ineffective, since the thyroid’s iodine uptake is low. Since periods of hypothyroidism may occur following the initial inflammatory episode, patients should have close clinical follow-up, with serum FT4 measurement when necessary. Prompt treatment of the transient hypothyroidism may reduce the incidence of recurrent thyroiditis. Pain can usually be managed with non-aspirin nonsteroidal anti-inflammatory drugs.

E. Hashimoto Thyroiditis (Hashitoxicosis) Rarely, hyperthyroidism develops as a result of release of stored thyroid hormone during severe Hashimoto thyroiditis. Serum thyroperoxidase or thyroglobulin antibodies are usually high, but RAI uptake is low, thus distinguishing it from Graves disease. This is especially common in postpartum women, in whom it may be transient. Treatment is with propranolol ER. Ipodate sodium or iopanoic acid may also be used as described above. Patients are monitored carefully for the development of hypothyroidism and treated.

F. Hyperthyroidism during Pregnancy and Lactation There may be a slightly increased risk of fetal anomalies associated with methimazole in the first trimester.

Therefore, pregnant women with hyperthyroidism are treated with propylthiouracil in the first trimester and then may be switched to methimazole. Either thiourea should be given in the smallest dose possible, permitting mild subclinical hyperthyroidism to occur since it is usually well tolerated. Both propylthiouracil and methimazole cross the placenta and can induce hypothyroidism, with fetal TSH hypersecretion and goiter. Thyroid hormone administration to the mother does not prevent hypothyroidism in the fetus, since T4 and T3 do not freely cross the placenta. Fetal hypothyroidism is rare if the mother’s hyperthyroidism is controlled with small daily doses of propylthiouracil (50–150 mg/d orally) or methimazole (5–15 mg/d orally).

Thyroidectomy is reserved for women who are allergic or resistant to antithyroid drugs (usually due to noncompliance) or who have very large goiters. Fetal ultrasound at 32 weeks gestation can visualize any fetal goiter, so fetal thyroid dysfunction can be diagnosed and treated.

Both methimazole and propylthiouracil are secreted in breast milk, but not in amounts that affect the infant’s thyroid hormone levels. No adverse reactions to these drugs (eg, rash, hepatic dysfunction, leukopenia) have been reported in breast-fed infants. Recommended doses are 20 mg orally daily or less for methimazole and 450 mg

CMDT 2013

1117

orally daily or less for propylthiouracil. It is recommended that the medication be taken just after breast-feeding.

G. Treatment of Other Causes of Hyperthyroidism Patients with thyrotoxicosis from thyrotrophe pituitary hyperplasia are treated with propranolol ER as described above. Definitive treatment is with RAI or thyroid surgery.

Patients with thyrotoxicosis caused by a thyrotrophe ­pituitary adenoma are treated with propranolol ER and methimazole, followed by transsphenoidal resection of the pituitary tumor, when possible.

Patients with type 1 amiodarone-induced thyrotoxicosis usually require propranolol ER. Therapy with 131I may be successful in some patients with sufficient RAI uptake.

If radioiodine therapy is not an option (due to insufficient RAI uptake), treatment with methimazole is begun. If radioiodine is administered, methimazole may be started several days afterward. After two doses of methimazole, iopanoic acid or sodium ipodate may be added to the regimen to further block conversion of T4 to T3; the recommended dosage for each is 500 mg orally twice daily for 3 days, followed by 500 mg once daily until thyrotoxicosis is resolved. If iopanoic acid or sodium ipodate is not available, the alternative is potassium perchlorate; it is given in doses of ≤ 1000 mg daily (in divided doses) for a course not to exceed 30 days in order to avoid the complication of aplastic anemia. Amiodarone may be withdrawn but this does not have a significant therapeutic effect for several months. Thyroidectomy is reserved for resistant cases.

Patients with type 2 amiodarone-induced thyrotoxicosis usually require propranolol ER. Prednisone is given at an initial dose of about 0.5–0.7 mg/kg; that dose of prednisone is continued for about 2 weeks and then slowly tapered and finally withdrawn after about 3 months.

Iopanoic acid or ipodate sodium may also be used (see above). Withdrawal of amiodarone is not usually necessary.

Methimazole is ineffective. Thyroidectomy is rarely required, since the condition is transient. Most patients become euthyroid within 30–40 days, except in cases of very severe thyrotoxicosis.

Some cases of amiodarone-induced thyrotoxicosis cannot be strictly categorized as either type 1 or type 2.

Such patients usually have negligible radioiodine uptake, so treatment is usually commenced with propranolol ER and a 1-month trial of methimazole. Iopanoic acid or ipodate sodium can be added to methimazole as noted above.

Prednisone is given for severe thyrotoxicosis or when methimazole fails to correct the thyrotoxicosis. Amiodarone is discontinued, when feasible.

H. Treatment of Complications 1. Graves ophthalmopathy—The risk of having a “flare” of ophthalmopathy following 131I treatment for hyperthyroidism is about 6% for nonsmokers and 23% for smokers.

Graves ophthalmopathy can also be aggravated by thiazolidinediones (eg, pioglitazone, rosiglitazone); these oral diabetic agents should be avoided or withdrawn in patients with Graves disease. Patients with mild ophthalmopathy

1118

CMDT 2013

Chapter 26

may be treated with selenium 100 mcg orally twice daily, which slows the progression of the disease. For acute, progressive exophthalmos, intravenous methylprednisolone, begun promptly, is superior to oral prednisone, possibly due to improved compliance. Methylprednisolone is given intravenously, 500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks. If oral prednisone is chosen for treatment, it must be given promptly in daily doses of 40–60 mg/d orally, with dosage reduction over several weeks.

Higher initial prednisone doses of 80–120 mg/d are used when there is optic nerve compression. Prednisone alleviates acute eye symptoms in 64% of nonsmokers, but only 14% of smokers respond well.

Progressive active exophthalmos may be treated with retrobulbar radiation therapy using a supervoltage linear accelerator (4–6 MeV) to deliver 20 Gy over 2 weeks to the extraocular muscles, avoiding the cornea and lens. Prednisone in high doses is given concurrently. Patients who respond well to orbital radiation include those with signs of acute inflammation, recent exophthalmos (< 6 months), or optic nerve compression. Patients with chronic proptosis and orbital muscle restriction respond less well. Retrobulbar radiation does not cause cataracts or tumors; however, it can cause radiation-induced retinopathy (usually subclinical) in about 5% of patients overall, mostly in diabetics.

For severe cases, orbital decompression surgery may save vision, though diplopia often persists postoperatively.

General eye protective measures include wearing glasses to protect the protruding eye and taping the lids shut during sleep if corneal drying is a problem. Methylcellulose drops and gels (“artificial tears”) may also help. Tarsorrhaphy or canthoplasty can frequently help protect the cornea and provide improved appearance. Hypothyroidism and hyperthyroidism must be treated promptly.

2. Cardiac complications— A. Sinus tachycardia—Treatment consists of treating the thyrotoxicosis. A β-blocker (as described above) such as propranolol is used in the interim unless there is an associated cardiomyopathy.

B. Atrial fibrillation—Hyperthyroidism must be treated immediately (see above). Other drugs, including digoxin, β-blockers, anticoagulants, may be required.

Electrical cardioversion is unlikely to convert atrial fibrillation to normal sinus rhythm while the patient is thyrotoxic.

Spontaneous conversion to normal sinus rhythm occurs in 62% of patients with return of euthyroidism, but that likelihood decreases with age. Following conversion to euthyroidism, there is a 60% chance that atrial fibrillation will recur, despite normal thyroid function tests. Those with persistent atrial fibrillation may have elective cardioversion 4 months after resolution of hyperthyroidism.

(1) Digoxin—Digoxin is used to slow a fast ventricular response to thyrotoxic atrial fibrillation; it must be used in larger than normal doses because of increased clearance and an increased number of cardiac cellular sodium pumps requiring inhibition. Digoxin doses are reduced as hyperthyroidism is corrected.

(2) β-Blockers—β-Blockers may also reduce the ventricular rate, but they must be used with caution—particularly

in patients with cardiomegaly or signs of heart failure— since their negative inotropic effect may precipitate congestive heart failure. Therefore, an initial trial of a short-duration β-blocker should be considered, such as esmolol intravenously. If a β-blocker is used, doses of digoxin must be reduced.

(3) Anticoagulants—Anticoagulation is indicated in the following situations: left atrial enlargement on echocardiogram, global left ventricular dysfunction, recent congestive heart failure, hypertension, recurrent atrial fibrillation, or a history of previous thromboembolism. The doses of warfarin required in thyrotoxicosis are smaller than normal because of an accelerated plasma clearance of vitamin K–dependent clotting factors. Higher warfarin doses are usually required as hyperthyroidism subsides.

C. Heart failure—Heart failure due to thyrotoxicosis may be caused by extreme tachycardia, cardiomyopathy, or both. Very aggressive treatment of the hyperthyroidism is required in either case (see Thyroid Crisis, below). The tachycardia from atrial fibrillation is treated with digoxin as above. Intravenous furosemide is typically required.

Oral spironolactone or eplerenone may be helpful. If tachycardia appears to be the main cause of the failure, β-blockers are administered cautiously as described above.

Congestive heart failure may occur as a result of lowoutput dilated cardiomyopathy in the setting of hyperthyroidism. It is uncommon and may be caused by an idiosyncratic severe toxic effect of hyperthyroidism upon certain hearts. Cardiomyopathy may occur at any age and without preexisting cardiac disease. β-Blockers and calcium channel blockers are avoided. Emergency treatment may include afterload reduction, diuretics, digoxin, and other inotropic agents while the patient is being rendered euthyroid. Heart failure usually persists despite correction of hyperthyroidism.

D. Apathetic hyperthyroidism—Apathetic hyperthyroidism may present with angina pectoris. Treatment is directed at reversing the hyperthyroidism as well as providing standard antianginal therapy. Coronary angioplasty or bypass grafting can often be avoided by prompt diagnosis and treatment.

3. Thyroid crisis or “storm”—This disorder, rarely seen today, is an extreme form of thyrotoxicosis that may be triggered by stressful illness, thyroid surgery, or RAI administration. Its manifestations often include marked delirium, severe tachycardia, vomiting, diarrhea, dehydration and very high fever. The mortality rate is high.

A thiourea drug is given (eg, methimazole, 15–25 mg orally every 6 hours or propylthiouracil, 150–250 mg orally every 6 hours). Ipodate sodium (500 mg/d orally) can be helpful if begun 1 hour after the first dose of thiourea.

Iodide is given 1 hour later as Lugol solution (10 drops three times daily orally) or as sodium iodide (1 g intravenously slowly). Propranolol is given (cautiously in the presence of heart failure; see above) in a dosage of 0.5–2 mg intravenously every 4 hours or 20–120 mg orally every 6 hours. Hydrocortisone is usually given in doses of 50 mg orally every 6 hours, with rapid dosage reduction as the clinical situation improves. Aspirin is avoided since it

Endocrine Disorders displaces T4 from TBG, raising FT4 serum levels. Definitive treatment with 131I or surgery is delayed until the patient is euthyroid.

4. Hyperthyroidism from postpartum thyroiditis— Propranolol ER is given during the hyperthyroid phase followed by levothyroxine during the hypothyroidism phase (see Thyroiditis, below).

5. Graves dermopathy—Treatment involves application of a topical corticosteroid (eg, fluocinolone) with nocturnal plastic occlusive dressings.

6. Thyrotoxic hypokalemic periodic paralysis—Sudden symmetric flaccid paralysis, along with hypokalemia and hypophosphatemia can occur with hyperthyroidism. There are often few classic signs of thyrotoxicosis. It is most prevalent in Asian and Native Americans with hyperthyroidism and is 30 times more common in men than women.

Therapy with oral propranolol, 3 mg/kg, normalizes the serum potassium and phosphate levels and reverses the paralysis within 2–3 hours. No intravenous potassium or phosphate is ordinarily required. Intravenous dextrose and oral carbohydrate aggravate the condition and are to be avoided. Therapy is continued with propranolol, 60–80 mg orally every 8 hours (or sustained-action propranolol ER daily at equivalent daily dosage), along with a thiourea drug such as methimazole to treat the hyperthyroidism.

``Prognosis Graves disease may rarely subside spontaneously, particularly when it is mild or subclinical. Graves disease that presents in early pregnancy has a 30% chance of spontaneous remission before the third trimester. The ocular, cardiac, and psychological complications can become serious and persistent even after treatment. Permanent hypoparathyroidism and vocal cord palsy are risks of surgical thyroidectomy. Recurrences are common following thiourea therapy but also occur after low-dose 131I therapy or subtotal thyroidectomy. With adequate treatment and long-term follow-up, the results are usually good. However, despite treatment for their hyperthyroidism, women experience an increased long-term risk of death from thyroid disease, cardiovascular disease, stroke, and fracture of the femur.

Posttreatment hypothyroidism is common. It may occur within a few months or up to several years after RAI therapy or subtotal thyroidectomy. Malignant exophthalmos has a poor prognosis unless treated aggressively.

Subclinical hyperthyroidism refers to a condition in which asymptomatic individuals have a low serum TSH and normal FT4 and T3. Most such patients do well without treatment. In one series, clinical hyperthyroidism developed in only one of seven patients after 2 years. In most patients, the serum TSH may revert to normal within 2 years. Most such patients do not have accelerated bone loss. However, if a baseline bone density shows significant osteopenia, bone densitometry may be performed periodically. In persons over age 60 years, serum TSH is very low (< 0.1 mU/L) in 3% and mildly low (0.1–0.4 mU/L) in 9%.

The chance of developing atrial fibrillation is 2.8% yearly in elderly patients with very low TSH and 1.1% yearly in those with mildly low TSH. Asymptomatic persons with

CMDT 2013

1119

very low TSH are monitored closely but are not treated unless atrial fibrillation or other manifestations of hyperthyroidism develop.

Bahn RS et al. Hyperthyroidism and other causes of thyrotoxicosis: management of guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011 Jun;21(6):593–646. [PMID: 21510801] Bogazzi F et al. Approach to the patient with amiodarone-­ induced thyrotoxicosis. J Clin Endocrinol Metab. 2010 Jun; 95(6):2529–35. [PMID: 20525904] Calvi L et al. Acute thyrotoxicosis secondary to destructive thyroiditis associated with cardiac catheterization contrast dye.

Thyroid. 2011 Apr;21(4):443–9. [PMID: 21385076] Ghandour A et al. Hyperthyroidism: a stepwise approach to management. J Fam Pract. 2011 Jul;60(7):388–95. [PMID: 21731916] Kim TD et al. Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-­ positive chronic myeloid leukemia. Thyroid. 2010 Nov;20(11): 1209–14. [PMID: 20929406] Marococci C et al; European Group on Graves’ Orbitophathy.

Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2011 May 19;364(20):1920–31. [PMID: 21591944] Pantalone KM et al. Approach to a low TSH level: patience is a virtue. Cleve Clin J Med. 2010 Nov;77(11):803–11. [PMID: 21048053] Pramyothin P et al. Clinical problem solving. A hidden solution.

N Engl J Med. 2011 Dec;365(22):2123–7. [PMID: 22129257] Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med. 2011 Feb 10;364(6):542–50. [PMID: 21306240]

THYROIDITIS ``

EssentialS of diagnosis

Acute and subacute forms: thyroid gland swelling, sometimes causing pressure symptoms. `` Chronic form: thyroid gland may or may not be enlarged with rubbery firmness. `` Thyroid function tests variable. `` Serum antithyroperoxidase and antithyroglobulin antibody levels usually elevated in Hashimoto thyroiditis. ``

``General Considerations Thyroiditis may be classified as follows: (1) chronic lymphocytic thyroiditis due to autoimmunity (also called Hashimoto thyroiditis), (2) subacute thyroiditis, (3) suppurative thyroiditis, and (4) Riedel thyroiditis.

Hashimoto thyroiditis is an autoimmune condition and the most common thyroid disorder in the United States.

B-lymphocytes invade the thyroid gland, such that the condition is also known as chronic lymphocytic thyroiditis.

Detectable levels of antithyroid antibodies are usually present: antithyroperoxidase (antimitochondrial) antibodies or antithyroglobulin antibodies, or both. Elevated serum levels of antithyroid antibodies are found in 3% of men and 13% of women. Women over the age of 60 years have a 25%

1120

CMDT 2013

Chapter 26

incidence of elevated serum levels of antithyroid antibodies.

However, only a small subset of individuals with elevated antithyroid antibody levels ever develops thyroid dysfunction. One percent of the population has serum antithyroid antibody titers > 1:6400 and they are at particular risk for thyroid dysfunction. The incidence of Hashimoto thyroiditis varies by kindred, race, and by sex; in persons older than 12 years of age in the United States, elevated levels of antithyroid antibodies are found in 14.3% of whites, 10.9% of Mexican-Americans, and 5.3% of blacks.

Hashimoto thyroiditis tends to be familial and is six times more common in women than in men. Its fre­ quency is increased by dietary iodine supplementation.

Certain drugs (amiodarone, interferon-α, interferon-β, interleukin-2, G-CSF) frequently induce thyroid autoantibodies. Childhood or occupational exposure to head–neck external beam radiation increases the lifetime risk of Hashimoto thyroiditis. Subclinical thyroiditis is extremely common, as evidenced in autopsy series that have found focal thyroiditis in about 40% of women and 20% of men.

Hashimoto thyroiditis often progresses to hypothyroidism, which may be linked to thyrotropin receptor– blocking antibodies, detected in 10% of patients with Hashimoto thyroiditis. Hypothyroidism is more likely to develop in smokers than in nonsmokers, possibly due to the thiocyanates in cigarette smoke. High serum levels of thyroid peroxidase antibody also predict progression from subclinical hypothyroidism to symptomatic hypothyroidism. Although the hypothyroidism is usually permanent, up to 11% of patients experience a remission after several years. There are two possible causes for such remissions: (1) the Hashimoto thyroiditis may improve spontaneously; and (2) thyroid-stimulating immunoglobulin is produced in sufficient quantities to overwhelm the destructive effects of concurrent Hashimoto thyroiditis, causing the thyroid to produce more thyroid hormone.

Rarely, if the thyroid gland goes on to produce excessive thyroid hormone, the result is an autoimmune hyperthyroidism (see Graves disease).

Hashimoto thyroiditis is sometimes associated with other endocrine deficiencies as part of polyglandular autoimmunity (PGA). Adults with type 2 PGA are prone to autoimmune thyroiditis, diabetes mellitus type 1, autoimmune gonadal failure, hypoparathyroidism, and adrenal insufficiency (see Adrenal Insufficiency). Thyroiditis is associated with other autoimmune conditions, such as pernicious anemia, Sjögren syndrome, vitiligo, inflammatory bowel disease, and celiac disease. The incidence of celiac disease in patients with Hashimoto thyroiditis is about 5%.

Hashimoto thyroiditis is very rarely associated with other autoimmune conditions such as myocarditis, hypophysitis, alopecia areata, encephalitis, primary pulmonary hypertension, or membranous nephropathy. Women with gonadal dysgenesis (Turner syndrome) have a 15% incidence of significant thyroid dysfunction by age 40 years. Thyroiditis is also commonly seen in patients with hepatitis C. Painless postpartum thyroiditis refers to autoimmune thyroiditis that occurs soon after delivery in 7.2% of women. There is some evidence that the autoimmunity may be triggered by the accumulation of fetal cells in the maternal thyroid during pregnancy, a condition known as

microchimerism. Women in whom postpartum thyroiditis develops have a 70% chance of recurrence after subsequent pregnancies. It occurs most commonly in women who have high levels of thyroid peroxidase antibody in the first trimester of pregnancy or immediately after delivery. It is also more common in women with other autoimmunity or a family history of Hashimoto thyroiditis.

Painless sporadic thyroiditis is thought to be a subacute form of Hashimoto thyroiditis that is similar to painless postpartum thyroiditis (see above), except that it is not related to pregnancy. It accounts for about 1% of cases of thyrotoxicosis.

Subacute thyroiditis—also called de Quervain thyroiditis, granulomatous thyroiditis, and giant cell thyroiditis—is relatively common. It is believed to be caused by a viral infection and often follows an upper respiratory tract infection. Its incidence peaks in the summer. It accounts for up to 5% of clinical thyroid disease and young and middle-aged women are most commonly affected.

Suppurative thyroiditis refers to a nonviral infection of the thyroid gland. It is usually bacterial. However, mycobacterial, fungal, and parasitic infections can occur, particularly in immunosuppressed individuals. Suppurative thyroiditis is quite rare, since the thyroid is resistant to infection, largely due to its high iodine content. It tends to affect patients with preexistent thyroid disease. Congenital pyriform sinus fistulas are a cause for recurrent suppurative thyroiditis in otherwise normal individuals.

Riedel thyroiditis is also called invasive fibrous thyroiditis, Riedel struma, woody thyroiditis, ligneous thyroiditis, and invasive thyroiditis. It is the rarest form of thyroiditis and is found most frequently in middle-aged or elderly women. It is usually a manifestation of a multifocal systemic fibrosis syndrome.

``Clinical Findings A. Symptoms and Signs In Hashimoto thyroiditis, the thyroid gland is usually diffusely enlarged, firm, and finely nodular. One thyroid lobe may be asymmetrically enlarged, raising concerns about neoplasm. Although patients may complain of neck tightness, pain and tenderness are not usually present. About 10% of cases are atrophic, the gland being fibrotic, particularly in elderly women.

Systemic manifestations are mostly related to ambient levels of thyroid hormone. However, depression and chronic fatigue are more common in such patients, even after correction of hypothyroidism. About one-third of patients have mild dry mouth (xerostomia) or dry eyes (keratoconjunctivitis sicca) of an autoimmune nature related to Sjögren syndrome. It may be associated with myasthenia gravis, which is usually of mild severity, mainly affecting the extraocular muscles and having a relatively low incidence of detectable AChR Ab or thymic disease.

Associated celiac disease can produce fatigue or depression, often in the absence of gastrointestinal symptoms.

Postpartum thyroiditis is typically manifested by hyperthyroidism that begins 1–6 months after delivery and persists for only 1–2 months. Then, hypothyroidism tends to develop in affected women beginning 4–8 months after delivery.

Endocrine Disorders Thyrotoxic symptoms in painless sporadic thyroiditis are usually mild; a small, nontender goiter may be palpated in about 50% of such patients. High serum thyroid peroxidase antibody concentrations are found in only 50% of such patients. The course is similar to painless postpartum thyroiditis.

Subacute thyroiditis presents with an acute, usually painful enlargement of the thyroid gland, often with dysphagia. The pain may radiate to the ears. Patients usually have a low-grade fever and fatigue. The manifestations may persist for weeks or months and may be associated with malaise. If there is no pain, it is called silent thyroiditis.

Thyrotoxicosis develops in 50% of affected patients and tends to last for several weeks. Subsequently, hypothyroidism develops that lasts 4–6 months. Normal thyroid function typically returns within 12 months, but persistent hypothyroidism develops in 5% of patients.

Patients with suppurative thyroiditis usually are febrile and have severe pain, tenderness, redness, and fluctuation in the region of the thyroid gland. In Riedel thyroiditis, thyroid enlargement is often asymmetric; the gland is stony hard and adherent to the neck structures, causing signs of compression and invasion, including dysphagia, dyspnea, pain, and hoarseness. Related conditions include retroperitoneal fibrosis, fibrosing mediastinitis, sclerosing cervicitis, subretinal fibrosis, and biliary tract sclerosis. It may respond to therapy with tamoxifen (see Treatment).

B. Laboratory Findings In Hashimoto thyroiditis with clinically evident disease, there are usually increased circulating levels of antithyroid peroxidase (90%) or antithyroglobulin (40%) antibodies.

Antithyroid antibodies decline during pregnancy and are often undetectable in the third trimester. Once Hashimoto thyroiditis has been diagnosed, monitoring of these antibody levels is not necessary. The serum TSH level is elevated if thyroid hormone is not elaborated in adequate amounts by the thyroid gland.

Patients with Hashimoto thyroiditis have a 15% incidence of having serum antibodies associated with celiac disease (sprue, gluten-sensitive enteropathy). At least 5% of patients with Hashimoto thyroiditis are found to have clinically significant celiac disease. Although most patients with celiac disease have gastrointestinal complaints such as bloating or diarrhea, vague symptoms such as fatigue or ennui may predominate. Serum levels of IgA endomysial antibody or IgA tissue transglutaminase (tTG) antibody may be elevated. However, these antibody levels decline on a low gluten diet. Many patients with mild celiac disease have negative serology and a trial of a gluten-free diet is the most sensitive test.

In subacute thyroiditis, the ESR is markedly elevated while antithyroid antibody titers are low, distinguishing it from autoimmune thyroiditis. In suppurative thyroiditis, both the leukocyte count and ESR are usually elevated.

With hyperthyroidism due to Hashimoto thyroiditis or subacute thyroiditis, serum FT4 levels tend to be proportionally higher than T3 levels, since the hyperthyroidism is due to the passive release of stored thyroid hormone, which is predominantly T4; this is in contrast to Graves disease

CMDT 2013

1121

and toxic nodular goiter, where T3 is relatively more elevated. Because T4 is less active than T3, the hyperthyroidism seen in thyroiditis is usually less severe. Serum levels of TSH are suppressed in hyperthyroidism due to thyroiditis.

C. Imaging Ultrasound in cases of Hashimoto thyroiditis typically shows a gland with characteristic diffuse heterogeneous density and hypoechogenicity. Ultrasonography of the thyroid helps distinguish thyroiditis from multinodular goiter or thyroid nodules that are suspicious for malignancy. It is also helpful in guiding FNA biopsy of small suspicious thyroid nodules.

Color-flow Doppler ultrasonography can help distinguish thyroiditis from Graves disease, since patients with Graves disease have a hypervascular thyroid gland, whereas in thyroiditis there is normal or reduced vascularity.

RAI uptake and scan may be helpful in determining the cause of hyperthyroidism, distinguishing thyroiditis from Graves disease, since patients with subacute thyroiditis exhibit a very low RAI uptake. In patients with chronic Hashimoto thyroiditis (euthyroid or hypothyroid), RAI uptake may be normal or high with uneven uptake on the scan; scanning is not useful in making the diagnosis.

[18F]Fluorodeoxyglucose positron emission tomography (18FDG-PET) scanning frequently shows diffuse thyroid uptake of isotope in cases of thyroiditis. About 3% of all 18FDG-PET scans shows such uptake. However, discrete thyroid nodules can also be discovered on 18FDG-PET scanning and are known as “thyroid PET incidentalomas,” of which 50% are malignant.

D. Fine-Needle Aspiration Biopsy Patients with Hashimoto thyroiditis who have a thyroid nodule should have an ultrasound-guided FNA biopsy, since the risk of papillary thyroid cancer is about 8% in such nodules. When suppurative thyroiditis is suspected, an FNA biopsy with Gram stain and culture is required.

FNA biopsy is usually not required for subacute thyroiditis but shows characteristic giant multinucleated cells.

``Complications Hashimoto thyroiditis may lead to hypothyroidism or transient thyrotoxicosis. Perimenopausal women with high serum levels of antithyroperoxidase antibodies have a higher relative risk of depression independently of ambient thyroid hormone levels.

Pregnant women with Hashimoto thyroiditis have an increased risk of spontaneous miscarriage in the first trimester of pregnancy. Hyperthyroidism may develop in patients with Hashimoto thyroiditis, either due to the emergence of Graves disease or due to the release of stored thyroid hormone, which is caused by inflammation. The latter condition has variably been termed “hashitoxicosis” or “painless sporadic thyroiditis;” it is known as postpartum painless thyroiditis when it occurs in women after delivery.

Patients with Hashimoto thyroiditis have an increased risk of other autoimmune conditions, such as Addison disease, hypoparathyroidism, diabetes, pernicious anemia, biliary cirrhosis, vitiligo, and celiac disease.

1122

CMDT 2013

Chapter 26

In the suppurative forms of thyroiditis, any of the complications of infection may occur; the subacute and chronic forms of the disease are complicated by the effects of pressure on the neck structures: dyspnea and, in Riedel struma, vocal cord palsy. Papillary thyroid carcinoma or thyroid lymphoma may rarely be associated with chronic thyroiditis and must be considered in the diagnosis of uneven painless enlargements that continue in spite of treatment; such patients require FNA biopsy.

``Differential Diagnosis Thyroiditis must be considered in the differential diagnosis of all types of goiters, especially if enlargement is rapid.

The very low RAI uptake in subacute thyroiditis with elevated T4 and T3 is helpful. Thyroid autoantibody tests have been of help in the diagnosis of Hashimoto thyroiditis, but the tests are not specific and may also be positive in patients with multinodular goiters, malignancy (eg, thyroid carcinoma, lymphoma), and concurrent Graves disease. The subacute and suppurative forms of thyroiditis may resemble any infectious process in or near the neck structures. Chronic thyroiditis, especially if the enlargement is uneven and if there is pressure on surrounding structures, may resemble carcinoma, and both disorders may be present in the same gland.

``Treatment A. Hashimoto Thyroiditis If hypothyroidism is present, levothyroxine should be given in the usual replacement doses (0.05–0.2 mg orally daily).

In patients with a large goiter and normal or elevated serum TSH, an attempt is made to shrink the goiter by administering levothyroxine in doses sufficient to drive the serum TSH below the reference range while maintaining clinical euthyroidism. Suppressive doses of T4 tend to shrink the goiter an average of 30% over 6 months. If the goiter does not regress, lower replacement doses of levothyroxine may be given. If the thyroid gland is only minimally enlarged and the patient is euthyroid, regular observation is in order, since hypothyroidism may develop subsequently—often years later. (See Hypothyroidism section.)

In one study involving 21 patients with Hashimoto thyroiditis and subclinical hypothyroidism, simvastatin (20 mg orally daily) improved thyroid function over 8 weeks, possibly by stimulating apoptosis of certain types of lymphocytes. In another study, selenium (200 mcg daily orally for 3 months) reduced the serum levels of anti-­ thyroperoxidase antibodies by 49% versus a 10% reduction in the placebo arm. The long-term effectiveness of simvastatin or selenium therapy on the course of Hashimoto thyroiditis is unknown.

B. Subacute Thyroiditis All treatment is empiric and must be continued for several weeks. Recurrence is common. The drug of choice is ­aspirin, which relieves pain and inflammation. Thyrotoxic symptoms are treated with propranolol, 10–40 mg every 6 hours. Iodinated contrast agents cause a prompt fall in

serum T3 levels and a dramatic improvement in thyrotoxic symptoms. Sodium ipodate (Oragrafin, Bilivist) or iopanoic acid (Telepaque) is given orally in doses of 500 mg orally daily until serum FT4 levels return to normal. Transient hypothyroidism is treated with T4 (0.05–0.1 mg orally daily) if symptomatic.

C. Suppurative Thyroiditis Treatment is with antibiotics and with surgical drainage when fluctuation is marked.

D. Riedel Struma The treatment of choice is tamoxifen, 20 mg orally twice daily, which must be continued for years. Tamoxifen can induce partial to complete remissions in most patients within 3–6 months. Its mode of action appears to be unrelated to its antiestrogen activity. Short-term corticosteroid treatment may be added for partial alleviation of pain and compression symptoms. Surgical decompression usually fails to permanently alleviate compression symptoms; such surgery is difficult due to dense fibrous adhesions, making surgical complications more likely.

``Prognosis Hashimoto thyroiditis is occasionally associated with other autoimmune disorders (diabetes mellitus, Addison disease, pernicious anemia, etc). In general, however, patients with Hashimoto thyroiditis have an excellent prognosis, since the condition either remains stable for years or progresses slowly to hypothyroidism, which is easily treated. Although 80% of women with postpartum thyroiditis subsequently recover normal thyroid function, permanent hypothyroidism eventually develops in about 50% within 7 years.

Permanent hypothyroidism is more common in women who are multiparous or who have had a spontaneous abortion. In subacute thyroiditis, spontaneous remissions and exacerbations are common; the disease process may smolder for months. Papillary thyroid carcinoma carries a relatively good prognosis when it occurs in patients with Hashimoto thyroiditis.

Boelaert K et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease.

Am J Med. 2010 Feb;123(2):183.e1–9. [PMID: 20103030] Desailloud R et al. Viruses and thyroiditis: an update. Virol J. 2009 Jan 12;6:5. [PMID: 19138419] Duntas LH. Environmental factors and autoimmune thyroiditis.

Nat Clin Pract Endocrinol Metab. 2008 Aug;4(8):454–60.

[PMID: 18607401] Eschler DC et al. Cutting edge: the etiology of autoimmune thyroid disease. Clin Rev Allergy Immunol. 2011 Oct;41(2): 190–7. [PMID: 21234711] Li Y et al. Hashimoto’s thyroiditis: old concepts and new insights. Curr Opin Rheumatol. 2011 Jan;23(1):102–7. [PMID: 21124092] Tomer Y. Genetic susceptibility to autoimmune thyroid disease: past, present, and future. Thyroid. 2010 Jul;20(7):715–25.

[PMID: 20604685] Tran HA et al. The natural history of interferon-alpha induced thyroiditis in chronic hepatitis C patients: a long term study.

Thyroid Res. 2011 Jan 8;4(1):2. [PMID: 21214950]

Endocrine Disorders

THYROID NODULES & MULTINODULAR GOITER ``

EssentialS of diagnosis

Single or multiple thyroid nodules are commonly found with careful thyroid examinations. `` Thyroid function tests mandatory. `` Thyroid biopsy for single or dominant nodules or for a history of prior head–neck or chest–shoulder radiation. `` Ultrasound examination useful for biopsy and follow-up. `` Clinical follow-up required. ``

CMDT 2013

1123

to radioactive fallout as a child or teen, a family history of thyroid cancer or a thyroid cancer syndrome (eg, Cowden syndrome, multiple endocrine neoplasia type 2, familial polyposis, Carney syndrome), or a personal history of another malignancy. The risk of malignancy is also higher if there is hoarseness or vocal fold paralysis, and if the thyroid nodule is large, adherent to the trachea or strap muscles, or associated with lymphadenopathy. The presence of Hashimoto thyroiditis does not reduce the risk of malignancy; a nodule of ≥ 1 cm in a gland with thyroiditis carries an 8% chance of malignancy.

``Clinical Findings Table 26–6 illustrates the approach to the evaluation of thyroid nodules based on the index of suspicion for malignancy.

``General Considerations

A. Symptoms and Signs

Thyroid nodules are extremely common. In Germany, neck ultrasound screening of adults found a 20% incidence of thyroid nodules > 1 cm in diameter. Palpable nodules are found in 5% of women and 1% of men in iodine-sufficient areas of the world. Palpable thyroid nodules are even more common in iodine-deficient geographic areas (see Iodine Deficiency Disorder & Endemic Goiter). Each year in the United States, about 275,000 thyroid nodules are detected by palpation, of which 10% are malignant. Palpable thyroid nodules are increasingly prevalent with age. On highresolution thyroid ultrasound, about 50% of palpable “solitary nodules” are found to be just one nodule in a multinodular goiter.

In recent years, an increased general use of scanning (CT, MRI, ultrasound, PET) has led to an increased rate of incidentally detecting nonpalpable thyroid nodules. In fact, thyroid ultrasound detects thyroid nodules in about 20% of randomly screened healthy adults.

Although 90% of thyroid nodules are benign, the presence of a thyroid nodule ≥ 1 cm diameter warrants ­follow-up and further testing for function and malignancy.

An occasional nodule < 1 cm diameter requires follow-up if it has high-risk characteristics on ultrasound or if the patient has had prior head-neck radiation therapy. Thyroid nodules that are incidentally discovered on 18FDG-PET scanning have a 33% risk for being malignant and definitely require biopsy.

Most patients with a thyroid nodule are euthyroid, but there is a high incidence of hypothyroidism or hyperthyroidism. Goiter may be caused by numerous conditions, including multinodular goiter, iodine deficiency, pregnancy (in areas of iodine deficiency), Graves disease, Hashimoto thyroiditis, subacute thyroiditis, or infections.

About 90% of thyroid nodules are benign adenoma, colloid nodule, or cyst but may sometimes be a primary thyroid malignancy or (less frequently) a metastatic neoplasm.

Patients with multiple thyroid nodules have the same overall risk of thyroid cancer as patients with solitary nodules.

The risk of a thyroid nodule being malignant is higher among patients with a history of head–neck radiation, total body radiation for bone marrow transplantation, exposure

Most small thyroid nodules cause no symptoms. They may sometimes be detected only by having the patient swallow during careful inspection and palpation of the thyroid.

A thyroid nodule or multinodular goiter can grow to become visible and of concern to the patient. Particularly large nodular goiters can become a cosmetic embarrassment. Nodules can grow large enough to cause discomfort, hoarseness, or dysphagia. Retrosternal large multinodular goiters can cause dyspnea due to tracheal compression.

Large substernal goiters may cause superior vena cava syndrome, manifested by facial erythema and jugular vein distention that progress to cyanosis and facial edema when both arms are kept raised over the head (Pemberton sign).

Depending on their cause, goiters and thyroid nodules may be associated with hypothyroidism (Hashimoto thyroiditis, endemic goiter) or hyperthyroidism (Graves disease, toxic nodular goiter, subacute thyroiditis, and thyroid cancer with metastases).

B. Laboratory Findings A serum TSH level (sensitive assay) should be obtained for all patients with a thyroid nodule. Patients with a subnormal serum TSH must have further assessment for hyperthyroidism and have a radionuclide thyroid scan (123I or 99m Tc pertechnetate) to determine whether the nodule is hyperfunctioning; hyperfunctioning nodules are rarely malignant. Tests for antithyroperoxidase antibodies and antithyroglobulin antibodies may also be helpful. Very high antibody levels are found in Hashimoto thyroiditis.

However, thyroiditis frequently coexists with malignancy, so suspicious nodules should always be biopsied. Serum calcitonin is obtained if a medullary thyroid carcinoma is suspected in a family member with a history of familial medullary thyroid carcinoma or MEN type 2.

C. Imaging Neck ultrasonography should be performed to measure the size of a nodule and to determine whether a palpable nodule is part of a multinodular goiter. The following ultrasound characteristics of thyroid nodules increase the

1124

CMDT 2013

Chapter 26

Table 26–6. Clinical evaluation of thyroid nodules.1 Clinical Evidence

Low Index of Suspicion

High Index of Suspicion

History

Family history of goiter; residence in area of endemic goiter

Previous therapeutic radiation of head, neck, or chest; hoarseness

Physical characteristics

Older women; soft nodule; multinodular goiter

Young adults, men; solitary, firm nodule; vocal cord paralysis; enlarged lymph nodes; distant metastatic lesions

Serum factors

High titer of antithyroid antibody; hypothyroidism; hyperthyroidism

Elevated serum calcitonin

Fine-needle aspiration biopsy

Colloid nodule or adenoma

Papillary carcinoma, follicular lesion, medullary or anaplastic carcinoma

Uptake of 123I

Hot nodule

Cold nodule

Ultrasonogram

Cystic lesion

Solid lesion

Roentgenogram

Shell-like calcification

Punctate calcification

Response to thyroxine therapy

Regression after 0.05–0.1 mg/d for 6 months or more

Increase in size

Scanning techniques

1

Clinically suspicious nodules should be evaluated with fine-needle aspiration biopsy.

likelihood of malignancy: irregular or indistinct margins, heterogenous nodule echogenicity, intranodular vascular images, microcalcifications, complex cyst, or diameter over 1 cm. Ultrasound is also useful for long-term surveillance of thyroid nodules and multinodular goiter. Ultrasono­ graphy is generally preferred over CT and MRI because of its accuracy, ease of use, and lower cost.

RAI (123I or 131I) scans have limited usefulness in the evaluation of thyroid nodules. Hypofunctioning (cold) nodules have a somewhat increased risk of being malignant but most are benign. Hyperfunctioning (hot) nodules are ordinarily benign but may sometimes be malignant. RAI uptake and scanning is helpful if a patient is found to have evidence of hyperthyroidism. (See Hyperthyroidism) CT scanning is helpful for larger thyroid nodules and multinodular goiter; it can determine the degree of tracheal compression and the degree of extension into the mediastinum.

D. Incidentally Discovered Thyroid Nodules Thyroid nodules are frequently discovered as an incidental finding, with an incidence that depends on the imaging modality: MRI, 50%; CT, 13%; and 18FDG-PET, 2%. When such scanning detects a thyroid nodule, an ultrasound is performed to better determine the nodule’s risk for malignancy and the need for FNA biopsy, and to establish a baseline for ultrasound follow-up. The malignancy risk is about 17% for nodules discovered incidentally on CT or MRI, and 25–50% for nodules discovered incidentally by 18 FDG-PET. For incidentally discovered thyroid nodules of borderline concern, follow-up thyroid ultrasound in 3–6 months may be helpful; growing lesions may be bio­psied or resected.

E. Fine-Needle Aspiration Biopsy Fine-needle aspiration (FNA) biopsy is the best method to assess a thyroid nodule for malignancy. FNA biopsy can be done while patients continue taking anticoagulants or aspirin. For multinodular goiters, the four largest nodules (≥ 1 cm diameter) should be biopsied to minimize the risk of missing a malignancy. For solitary thyroid nodules, FNA biopsy is indicated for the following: (1) nodules > 5 mm diameter with a suspicious appearance on ultrasound; (2) nodules associated with abnormal cervical lymph nodes; (3) nodules ≥ 1 cm diameter that are solid or have microcalcifications; (4) mixed cystic-solid nodules ≥ 1.5 cm diameter with any suspicious features on ultrasound or ≥ 2 cm diameter with benign features on ultrasound; (5) spongiform nodules ≥ 2 cm diameter. Pure cystic nodules are benign and do not require FNA biopsy.

Using ultrasound guidance for FNA biopsy improves the diagnostic accuracy for both palpable and nonpalpable thyroid nodules. The chance of an optimal tissue sampling is also improved by having an experienced clinician perform the FNA biopsy and by having the aspirate interpreted by a skilled cytopathologist.

In one review of thyroid FNA biopsies, about 70% were benign, 5% were malignant, 10% were “suspicious,” and 15% were “nondiagnostic.” Nondiagnostic, bloody, or hypocellular FNA biopsies should be repeated under ultrasound guidance; nodules that continue to have nondiagnostic cytology should be monitored closely; those that are solid or that grow should be resected.

When FNA cytology is “suspicious” for papillary thyroid carcinoma or Hürthle cell neoplasm, the risk of malignancy is 57%. When FNA cytology yields a “suspicious” follicular lesion, the overall risk of the lesion being malignant

Endocrine Disorders is about 20–25%. The risk that a follicular lesion is malignant increases for patients who are much younger or older than age 50. Most patients with suspicious FNA cytology are advised to have surgery.

Cystic nodules yielding serous fluid are usually benign, but the aspirate should be submitted for cytologic testing.

Cystic nodules yielding bloody fluid have a higher chance of being malignant.

False-positive thyroid FNA biopsy results occur at a rate of about 4%. False-negative thyroid FNA biopsy results also occur at an overall rate of about 4%, less commonly when performed under ultrasound guidance and interpreted by cytopathologists. False-negative results delay surgical excision and lead to an increased risk of vascular and capsular invasion by the malignancy. Some false-­ negative FNA biopsy results may not have actually been inaccurate, since truly benign thyroid nodules can later become malignant. Patients who have a negative thyroid FNA should have observational follow-up, ideally with both palpation and ultrasound; nodules that continue to grow should be rebiopsied or excised.

``Treatment All thyroid nodules, including those that are benign, need to be monitored by regular periodic palpation and ultrasound and rebiopsied if growth occurs. A toxic multinodular goiter and hyperthyroidism, associated with the ingestion or intravenous administration of large amounts of iodine, may develop in patients with multinodular goiters. It is therefore prudent to minimize excessive dietary iodine intake and intravenous iodinated contrast.

Patients found to have hyperthyroidism may have a RAI uptake and scan for additional evaluation, especially if 131 I is a therapeutic consideration. Patients with toxic multinodular goiters may also be treated with methimazole, propranolol, or surgery (see Hyperthyroidism section).

A. Levothyroxine Suppression Therapy Patients with elevated levels of serum TSH are treated with levothyroxine replacement. Otherwise, for small benign thyroid nodules, levothyroxine suppression therapy is not recommended. For larger nodules (> 2 cm), if TSH levels are elevated or normal, TSH suppression with levothyroxine (starting doses of 50 mcg orally daily) can be considered. Thyroxine suppression therapy is most successful in iodine-deficient areas of the world and less successful in iodine-sufficient regions. Long-term levothyroxine suppression of TSH tends to keep nodules from enlarging, but only 20% shrink more than 50%. In one 5-year study, thyroid nodule size increased in 29% of patients treated with levothyroxine, compared to growth in 56% of nodules in patients not receiving levothyroxine. Levothyroxine suppression also reduces the emergency of new nodules: 8% with levothyroxine and 29% without levothyroxine.

Levothyroxine suppression therapy is not usually given to patients with cardiac disease, since it increases the risk for angina and atrial fibrillation. Levothyroxine suppression causes a small loss of bone density, particularly in postmenopausal women if the serum TSH is suppressed to

CMDT 2013

1125

< 0.05 mU/L. Such patients are advised to have bone density testing every 3–5 years. Levothyroxine should not be administered if the baseline TSH is low, since that is an indication of autonomous thyroid secretion, such that levothyroxine therapy will be ineffective and liable to cause clinical thyrotoxicosis.

Levothyroxine suppression needs to be carefully monitored, since it carries a 17% risk of inducing symptoms of hyperthyroidism. This can occur due to excessive levothyroxine dosing, the emergence of an autonomous or toxic nodule or Graves disease, or a reduction in thyroid binding globulin seen in early menopause or with discontinuing oral estrogen therapy. Therefore, coronary insufficiency and cardiac arrhythmias are relative contraindications to levothyroxine suppression. All patients receiving levothyroxine suppression therapy should have serum TSH levels monitored regularly, with the dose of levothyroxine adjusted to keep the serum TSH mildly suppressed between 0.2 mU/L and 0.8 mU/L. Thyroid nodules require careful clinical evaluation and thyroid palpation or ultrasound examinations about every 6 months initially. After several years of stability, yearly examinations are sufficient.

B. Potassium Iodide Additional suppression of thyroid nodules may be obtained by adding oral potassium iodide, 150 mcg daily, to levothyroxine suppression therapy (see above) for patients with thyroid nodules ≥ 1 cm in diameter. In a German study, the addition of potassium iodide to levothyroxine further decreased thyroid nodule size over the course of 1 year.

However, the study excluded children; pregnant women; non-whites; and patients with autoimmune thyroid disease, autonomous nodules, consumption of other iodinecontaining medications, dermatitis herpetiformis, or iodine allergy. The long-term risk of administering potassium iodide to iodine-sufficient patients is unknown.

C. Surgery Total thyroidectomy is required for thyroid nodules that are malignant on FNA biopsy (see Thyroid Cancer section).

More limited thyroid surgery is indicated for benign nodules with indeterminate or suspicious cytologic test results, compression symptoms, discomfort, or cosmetic embarrassment. Surgery may also be used to remove hyperfunctioning “hot” thyroid adenomas or toxic multinodular goiter causing hyperthyroidism (see Hyperthyroidism section).

D. Percutaneous Ethanol Injection Thyroid cysts can be aspirated, but cystic fluid recurs in 75% of patients. Percutaneous ethanol injection has been used to shrink pure cysts; it must often be repeated, but the success rate is 80%. Percutaneous ethanol injection can also be used to shrink benign (biopsy proven) thyroid nodules. The complication rate is about 9%, but serious or permanent complications are rare.

E. Radioiodine (131I) Therapy Radioactive 131I is a treatment option for hyperthyroid patients with toxic thyroid adenomas, multinodular goiter,

1126

CMDT 2013

Chapter 26

or Graves disease (see Hyperthyroidism section). It may also be used to shrink benign nontoxic thyroid nodules. Thyroid nodules shrink an average of 40% by 1 year and 59% by 2 years after 131I therapy. Nodules that shrink after 131I therapy generally remain palpable and become firmer; they may develop unusual cytologic characteristics on FNA biopsy. 131I therapy may be used to shrink large multinodular goiter but may rarely induce Graves disease. Hypothyroidism is a risk and may occur years after 131I therapy, so it is advisable to assess thyroid function every 3 months for the first year, every 6 months thereafter, and immediately for symptoms of hypothyroidism or hyperthyroidism.

``Prognosis The great majority of thyroid nodules are benign. Benign thyroid nodules may involute but usually persist or grow slowly. About 90% of thyroid nodules will increase their volume by ≥ 15% over 5 years; cystic nodules are less likely to grow. Cytologically benign nodules that grow are unlikely to be malignant; in one series, only 1 of 78 rebiopsied nodules was found to be malignant. The prognosis for patients with thyroid nodules that prove to be malignant is determined by the histologic type and other factors (see below).

Multinodular goiters tend to persist or grow slowly, even in iodine-deficient areas where iodine repletion usually does not shrink established goiters. Patients with very small, incidentally discovered, nonpalpable thyroid nodules do require follow-up with thyroid ultrasound every 1–2 years but are at low risk for malignancy. Nodules that are malignant have a minor effect on morbidity and mortality.

Bahn RS et al. Approach to the patient with nontoxic multinodular goiter. J Clin Endocrinol Metab. 2011 May;96(5): 1201–12. [PMID: 21543434] Bastin S et al. Role of ultrasound in the assessment of nodular thyroid disease. J Med Imaging Radiat Oncol. 2009 Apr;53(2): 177–87. [PMID: 19527364] Grussendorf M et al. Reduction of thyroid nodule volume by levothyroxine and iodine alone and in combination: a randomized, placebo-controlled trial. J Clin Endocrinol Metab.

2011 Sept;96(9):2786–95. [PMID: 21715542] Kim DW et al. Ultrasound-guided fine-needle aspiration biopsy of thyroid nodules: comparison in efficacy according to nodule size. Thyroid. 2009 Jan;19(1):27–31. [PMID: 19021460] Mihai R et al. One in four patients with follicular thyroid ­cytology (THY3) has a thyroid carcinoma. Thyroid. 2009 Jan;19(1):33–7. [PMID: 18976164]

THYROID CANCER ``

EssentialS of diagnosis

Painless swelling in region of thyroid.

Thyroid function tests usually normal. `` Past history of irradiation to head and neck region may be present. `` Positive thyroid needle aspiration. `` ``

``General Considerations The incidence of papillary and follicular (differentiated) thyroid carcinomas increases with age. The overall female:male ratio is 3:1. The yearly incidence of thyroid cancer has been increasing in the United States, with the number of cases diagnosed annually reaching 37,200, probably as a result of the wider use of CT, MRI, PET, and ultrasound that incidentally find small thyroid malignancies. Thyroid cancer mortality has been stable, accounting for about 1500 deaths in the United States annually.

Thyroid microcarcinoma (≤ 10 mm diameter) is found with the surprising frequency of 35%. Clearly, most thyroid cancers remain microscopic and indolent. However, larger thyroid cancers (palpable or ≥ 1 cm in diameter) are more malignant and require treatment.

Papillary thyroid carcinoma is the most common thyroid malignancy (Table 26–7).

Pure papillary and mixed papillary-follicular carcinoma represent about 80% of all thyroid cancers. It usually presents as a single thyroid nodule, but it can arise out of a multinodular goiter. Papillary thyroid carcinoma is commonly multifocal within the gland, with other foci usually arising de novo rather than representing intraglandular metastases. About 10% of cases present with palpable cervical lymph node metastases from a small thyroid cancer.

Papillary thyroid carcinomas tend to grow slowly and often remain confined to the thyroid and regional lymph nodes for years. However, they may become more aggressive, especially in patients over age 45 years, and most particularly in the elderly. The cancer may invade the trachea and local muscles and may spread to the lungs.

Papillary thyroid carcinoma is caused by genetic mutations or translocations. Activating mutations of the ras oncogene can cause benign thyroid adenomas or nodular goiter. Additional activating mutations in BRAF or TRK genes can lead to papillary carcinoma. About 45% of papillary thyroid carcinomas are caused by over expression of the ret oncogene by the translocation of certain gene promoters to it, producing retPTC-1, retPTC-2, or retPTC-3.

Radiation treatments to the head and neck region tend to cause retPTC-1. Nuclear fallout exposure tends to cause retPTC-3, resulting in more aggressive papillary thyroid carcinomas. Additional loss of the p53 tumor suppressor gene can cause progression of papillary thyroid carcinoma to anaplastic thyroid carcinoma.

Exposure to head and neck radiation therapy poses a particular threat to children who then have an increased lifetime risk of developing thyroid pathology, including papillary thyroid carcinoma; thyroid malignancy may emerge between 10 and 40 years after exposure, with a peak occurrence 20–25 years later. After an explosion at the Chernobyl Nuclear Plant in the Ukraine in 1986, the risk of developing papillary thyroid carcinoma was highest among children who were under age 5 at the time of exposure to radiation; emergence of more aggressive papillary thyroid carcinoma occurred within 6–7 years after exposure.

Papillary thyroid carcinoma can occur in familial syndromes as an autosomal dominant trait, caused by loss of various tumor suppressor genes. Such syndromes (with associated features) include familial papillary carcinoma

1127

CMDT 2013

Endocrine Disorders

Table 26–7. Some characteristics of thyroid cancer.

Papillary

Follicular

Medullary

Undifferentiated

Most common

Common

Uncommon

Uncommon

Average age

42

50

50

57

Females

70%

72%

56%

56%

+ + + + +

+

+ + + + + +

+ + +

Incidence

Invasion Juxtanodal Blood vessels

+

+ + +

+ + +

+ + ++ +

Distant sites

+

+ + +

+ +

+ + + +

123

+

+ + + +

0

0

Mortality

+

+ + to + + +

+ to + + + +

+ + + + + + + +

I uptake

(with papillary renal carcinoma); familial nonmedullary thyroid carcinoma; familial polyposis (with large intestine polyps and gastrointestinal tumors); Gardner syndrome (with small and large intestine polyps, fibromas, lipomas, osteomas); and Turcot syndrome (with large intestine polyps and brain tumors). Older patients with multinodular goiter may rarely develop a papillary thyroid carcinoma.

Papillary carcinoma can sometimes undergo a late anaplastic transformation into an aggressive carcinoma.

Generally speaking, papillary carcinoma is the least aggressive thyroid malignancy. However, the tumor spreads via lymphatics within the thyroid, appearing to be multifocal in 60% of patients and involving both lobes in 30% of patients. About 80% of patients have microscopic metastases to cervical lymph nodes. Unlike other forms of cancer, patients with papillary thyroid carcinoma who have palpable lymph node metastases do not have a particularly increased mortality rate; however, their risk of local recurrence is increased.

Occult metastases to the lung occur in 10–15% of papillary thyroid cancer. About 70% of small lung metastases resolve following 131I therapy; however, larger pulmonary metastases have only a 10% remission rate.

Microscopic “micropapillary” carcinoma (≤ 1 mm and invisible even on thyroid ultrasound) is a variant of normal, being found in 24% of thyroidectomies performed for benign thyroid disease when 2-mm sections were carefully examined. It thus appears that the overwhelming majority of these microscopic foci never become clinically significant. The surgical pathology report of such a tiny papillary carcinoma that is otherwise benign does not justify aggressive follow-up or treatment because a cancer diagnosis is unwarranted and harmful. All that may be required is yearly follow-up with palpation of the neck and mild TSH suppression by thyroxine.

Follicular thyroid carcinoma and its variants (eg, Hürthle cell carcinoma) account for about 14% of thyroid malignancies; follicular thyroid carcinoma is generally more aggressive than papillary carcinoma. Rarely, some follicular carcinomas secrete enough T4 to cause thyrotoxicosis if the tumor load becomes significant. Metastases commonly

are found in neck nodes, bones, and lungs. Most follicular thyroid carcinomas avidly absorb iodine, making possible diagnostic scanning and treatment with 131I after total thyroidectomy. The follicular histopathologic features that are associated with a high risk of metastasis and recurrence are poorly differentiated and Hürthle cell (oncocytic) variants. The latter variants do not take up RAI. Follicular carcinoma results from certain gene mutations or translocations. Aberrant DNA methylation, activation of the ras oncogene, and mutations of the MEN1 gene can result in benign follicular adenomas. Loss of function of PPARγ or the 3P tumor suppressor gene can lead to follicular carcinoma, and additional loss of the p53 tumor suppressor gene can produce anaplastic carcinoma.

Follicular thyroid carcinoma and adenomas develop in patients with Cowden disease, a rare autosomal dominant familial syndrome caused by loss of a tumor suppressor gene; such patients tend to have macrocephaly, multiple hamartomas, early-onset breast cancer, intestinal polyps, facial papules, and other skin and mucosal lesions.

Medullary thyroid carcinoma represents about 3% of thyroid cancers. About one-third of cases are sporadic, one-third are familial, and one-third are associated with MEN type 2. Medullary thyroid carcinoma is often caused by an activating mutation of the ret oncogene on chromosome 10. Mutation analysis of the ret oncogene exons 10, 11, 13, and 14 detects 95% of the mutations causing MEN 2A and 90% of the mutations causing familial medullary thyroid carcinoma. Patients with MEN 2B have activating mutations in exon 16 of the ret oncogene. These germline mutations can be detected by DNA analysis of peripheral WBCs. Therefore, discovery of a medullary thyroid carcinoma makes genetic analysis mandatory. If a gene defect is discovered, related family members must have genetic screening for that specific gene defect. When a family member with MEN 2A or familial medullary thyroid carcinoma does not have an identifiable ret oncogene mutation, gene carriers may still be identified using family linkage analysis. Even when no gene defect is detectable, family members should have thyroid surveillance every 6 months.

Somatic mutations of the ret oncogene can be identified in

1128

CMDT 2013

Chapter 26

the tumors of 30% of patients with sporadic (nonfamilial) medullary thyroid carcinoma. (See Multiple Endocrine Neoplasia.)

Medullary thyroid carcinoma arises from parafollicular thyroid cells that can secrete calcitonin, prostaglandins, serotonin, ACTH, corticotropin-releasing hormone (CRH), and other peptides. These peptides can cause symptoms and can be used as tumor markers. Early local metastases are usually present, usually to adjacent muscle and trachea as well as to local and mediastinal lymph nodes. Eventually, late metastases may appear in the bones, lungs, adrenals, or liver. Medullary thyroid carcinoma does not concentrate iodine.

Anaplastic thyroid carcinoma represents about 2% of thyroid cancers. It usually presents in an older patient as a rapidly enlarging mass in a multinodular goiter. It is the most aggressive thyroid carcinoma and metastasizes early to surrounding nodes and distant sites. Local pressure symptoms include dysphagia or vocal cord paralysis. This tumor does not concentrate iodine.

Anaplastic thyroid carcinoma is caused by certain gene mutations, including inactivating mutations of the p53 tumor suppressor gene, as described above for papillary and follicular thyroid carcinomas.

Other thyroid malignancies together represent about 3% of thyroid cancers. Lymphoma of the thyroid is more common in older women. Thyroid lymphomas are most commonly B cell lymphomas (50%) or mucosa-associated lymphoid tissue (MALT; 23%); other types include ­follicular, small lymphocytic, and Burkitt lymphoma and Hodgkin disease. Thyroidectomy is rarely required. Other cancers may sometimes metastasize to the thyroid, particularly bronchogenic, breast, and renal carcinomas and malignant melanoma.

``Clinical Findings A. Symptoms and Signs Thyroid carcinoma usually presents as a palpable, firm, nontender nodule in the thyroid. Most thyroid carcinomas are asymptomatic, but large thyroid cancers can cause neck discomfort, dysphagia, or hoarseness (due to pressure on the recurrent laryngeal nerve). About 3% of thyroid malignancies present with a metastasis, usually to local lymph nodes but sometimes to distant sites such as bone or lung.

Palpable lymph node involvement is present in 15% of adults and 60% of youths. Metastatic functioning differentiated thyroid carcinoma can sometimes secrete enough thyroid hormone to produce thyrotoxicosis. Anaplastic thyroid carcinoma is more apt to be advanced at the time of diagnosis, presenting with dysphagia, hoarseness, dyspnea, and metastases to the lungs. Occasionally, such carcinomas may be discovered while they are still relatively small and localized.

Medullary thyroid carcinoma frequently causes flushing and persistent diarrhea (30%), which may be the initial clinical feature. Patients with metastases often experience fatigue as well as other symptoms. Cushing syndrome develops in about 5% of patients from secretion of ACTH or CRH. Signs of pressure or invasion of surrounding tissues

are present in anaplastic or large tumors; recurrent laryngeal nerve palsy can occur.

Lymphoma usually presents as a rapidly enlarging, painful mass arising out of a multinodular or diffuse goiter affected by autoimmune thyroiditis, with which it may be confused microscopically. About 20% of cases have concomitant hypothyroidism.

B. Laboratory Findings (FNA biopsy is discussed above in the section on Thyroid Nodules.) Thyroid function tests are generally normal unless there is concomitant thyroiditis. Follicular carcinoma may secrete enough T4 to suppress TSH and cause clinical hyperthyroidism.

Serum thyroglobulin is high in most metastatic papillary and follicular tumors, making this a useful marker for ­recurrent or metastatic disease. Caution must be exercised for the following reasons: (1) Circulating antithyroglobulin antibodies can cause erroneous thyroglobulin determinations. (2) Thyroglobulin levels may be misleadingly ele­ vated in thyroiditis, which often coexists with carcinoma. (3) Certain thyroglobulin assays falsely report the continued presence of thyroglobulin after total thyroidectomy and tumor resection, causing undue concern about possible metas­tases. Therefore, unexpected thyroglobulin levels should prompt a repeat assay in another reference laboratory.

Serum calcitonin levels are usually elevated in medullary thyroid carcinoma, making this a marker for metastatic disease. However, serum calcitonin may be elevated in many other conditions, such as thyroiditis; pregnancy; azotemia; hypercalcemia; and other malignancies, including pheochromocytomas, carcinoid tumors, and carcinomas of the lung, pancreas, breast, and colon.

In patients with medullary thyroid carcinoma, serum calcitonin and carcinoembryonic antigen (CEA) determinations should be obtained before surgery, then regularly in postoperative follow-up: every 4 months for 5 years, then every 6 months for life. In patients with extensive metastases, serum calcitonin should be measured in the laboratory with serial dilutions. Calcitonin levels remain elevated in patients with persistent tumor but also in some patients with apparent cure or indolent disease. Therefore, rising levels of calcitonin (or CEA) are the best indication for recurrence. Serum calcitonin levels > 250 pg/mL are also an indication for recurrent or metastatic medullary thyroid carcinoma. Serum CEA levels are usually elevated with medullary carcinoma, making this a useful second marker; however, it is not specific for this carcinoma.

C. Imaging 1. Ultrasound of the neck—Ultrasound of the neck should be performed routinely on all patients with thyroid cancer for the initial diagnosis and for follow-up.

Ultrasound is useful in determining the size and location of the malignancy as well as the location of any neck metastases.

2. Radioactive iodine scanning—RAI (131I or 123I) thyroid and whole-body scanning is used after thyroidectomy for surveillance as described below, supplanting its previous

Endocrine Disorders use to determine whether a nodule was “cold” as a sign of malignancy.

3. CT and MRI scanning—CT scanning may demonstrate metastases and is particularly useful for localizing and monitoring lung metastases. However, CT scanning is less sensitive than ultrasound for detecting metastases within the neck. Iodinated contrast should never be given prior to RAI scanning or RAI therapy, since the large amounts of iodine in contrast media competitively inhibit the uptake of RAI by the thyroid, greatly reducing the effectiveness of subsequent RAI scanning and therapy. Medullary carcinoma in the thyroid, nodes, and liver may calcify, but lung metastases rarely do so. MRI is particularly useful for imaging bone metastases.

4. PET scanning—PET scanning is particularly useful for detecting thyroid cancer metastases that do not have sufficient iodine uptake to be visible on RAI scans. Metastases are best detected using 18FDG-PET whole-body scanning.

The sensitivity of 18FDG-PET scanning for differentiated thyroid cancer is enhanced if the patient is hypothyroid or receiving thyrotropin, which increases the metabolic activity of differentiated thyroid cancer. Disadvantages of PET scanning include its lack of specificity for thyroid cancer as well as its expense and lack of availability in some locations. 18FDG-PET scanning has prognostic implications, since differentiated thyroid cancer metastases with low standard uptake value (SUV) scores are associated with a better prognosis.

``Differential Diagnosis Neuroendocrine carcinomas may metastasize to the thyroid and be confused with medullary thyroid carcinoma.

False-positive 131I scans are common with normal residual thyroid tissue and have been reported with Zenker diverticulum, struma ovarii, pleuropericardial cyst, gastric pull-up, and 131I-contaminated bodily secretions. Falsenegative 131I scans are common in early metastatic differentiated thyroid carcinoma but occur also in more advanced disease, including 14% of bone metastases.

``Complications The complications vary with the type of carcinoma.

Differentiated thyroid carcinomas may have local or distant metastases. One-third of medullary carcinomas may secrete serotonin and prostaglandins, producing flushing and diarrhea, and may be complicated by the coexistence of pheochromocytomas or hyperparathyroidism. The risks of radical neck surgery include permanent hypoparathyroidism and vocal cord palsy due to recurrent laryngeal nerve damage; permanent hypothyroidism is expected after thyroidectomy and should always be treated adequately.

``Treatment of Differentiated Thyroid Carcinoma A. Surgical Treatment Surgical removal is the treatment of choice for thyroid carcinomas. Neck ultrasound is obtained preoperatively, since

CMDT 2013

1129

suspicious cervical lymphadenoapathy is detected in about 25%. Intraoperative thyroid ultrasound by the surgeon also helps assess the extent of the tumor and lymph node involvement, altering surgical treatment in many cases. For differentiated papillary and follicular carcinoma > 1 cm diameter, total thyroidectomy is performed with limited removal of cervical lymph nodes. For medullary thyroid carcinoma, repeated neck dissections are often required.

For indeterminate nodules, surgery consists of a thyroid lobectomy for an indeterminate “follicular lesion” that is ≤ 4 cm diameter. If malignancy is diagnosed on pathology, a completion thyroidectomy is performed. For indeterminate follicular lesions > 4 cm diameter that are at higher risk for being malignant, a bilateral thyroidectomy is performed as the initial surgery. Higher risk lesions include those with a FNA biopsy that shows marked atypia or that are suspicious for papillary carcinoma and those that occur in patients with a history of radiation exposure or a family history of thyroid carcinoma.

For biopsies that are diagnostic of malignancy, surgery involves lobectomy alone for papillary thyroid carcinomas < 1 cm diameter in patients under age 45 years who have no history of head and neck irradiation and no evidence of lymph node metastasis on ultrasonography. Other patients should have a total or near total thyroidectomy.

The advantage of near-total thyroidectomy for differentiated thyroid carcinoma is that multicentric foci of carcinoma are more apt to be resected. Also, there is less normal thyroid tissue to compete with cancer for 131I administered later for scans or treatment. A central neck lymph node dissection is performed at the time of thyroidectomy for patients with nodal metastases that are clinically evident. A lateral neck dissection is performed for patients with biopsy-proven lateral cervical lymphadenopathy. Neck muscle resections are usually avoided for differentiated thyroid carcinoma. However, patients with the Hürthle cell variant of follicular carcinoma may benefit from a modified radical neck dissection. Metastases to the brain are best treated surgically, since treatment with radiation or RAI is ineffective. Levothyroxine is prescribed in doses of 0.05–0.1 mg orally daily immediately postoperatively (see Thyroxine Suppression and Chemotherapy, below). About 2–4 months after surgery, patients require reevaluation and often require therapy with 131I (see below).

Permanent injury to one recurrent laryngeal nerve occurs in between 1–2% and 7% of patients, depending on the experience of the surgeon. Bilateral nerve palsies are rare. Temporary recurrent laryngeal nerve palsies occur in another 5% but often resolve within 6 months.

After total thyroidectomy, temporary hypoparathyroidism occurs in 20% and becomes permanent in about 2%.

The incidence of hypoparathyroidism may be reduced if accidentally resected parathyroids are immediately autotransplanted into the neck muscles. Thyroide­ ctomy requires at least an overnight hospital admission, since late bleeding, airway problems, and tetany can occur. Ambulatory thyroidectomy is potentially dangerous and should not be done. Following surgery, staging (Table 26–8) should be done to help determine prognosis and to plan therapy and follow-up.

1130

CMDT 2013

Chapter 26

Table 26–8. Pathologic tumor-node-metastasis (pTNM) staging and tumor-related approximate survival rates for adults with appropriately treated differentiated (papillary) thyroid carcinoma based upon patient age, primary tumor size and invasiveness (T), lymph node involvement (N), and distant metastases (M).1 Stage

Description

Five-Year Survival

Ten-Year Survival

I

Under 45: any T, any N, no M Over 45: T ≤ 1 cm, no N, no M

99%

98%

II

Under 45: any T, any N, any M Over 45: T > 1 cm limited to thyroid, no N, no M

99%

90%

III

Over 45: T > 4 cm limited to thyroid, no N, no M; or any T limited to thyroid, regional N, no M

95%

75%

IV

Over 45: T local invasion, any N, any M; or T extensive invasion, any N, no M; or any T, any N, distant M

85%

65%

1

Patients having a relatively worse prognosis include those with familial differentiated thyroid carcinoma.

In pregnant women with thyroid cancer, surgery is usually delayed until after delivery, except for fast-growing tumors that may be resected after 24 weeks gestation; there has been no difference in survival or tumor recurrence rates in women who underwent surgery during or after their pregnancy. Differentiated thyroid carcinoma does not behave more aggressively during pregnancy. But there is a higher risk of complications in pregnant women undergoing thyroid surgery, compared to nonpregnant women.

B. Thyroxine Suppression and Chemotherapy Patients who have had a thyroidectomy for differentiated thyroid cancer must take thyroxine replacement for life.

Oral thyroxine should be given in doses that suppress serum TSH without causing clinical thyrotoxicosis. An ultrasensitive TSH assay should be used; serum TSH should be suppressed below 0.1 mU/L for patients with stage II disease and below 0.05 mU/L for patients with stage III–IV disease.

(See Table 26–8.) Although patients receiving thyroxine suppression therapy (TSH < 0.05 mU/L) are at risk for a lower bone density than age-matched controls, the adverse effect upon bone density and fracture risk is relatively minor for patients who remain clinically euthyroid.

Nevertheless, patients receiving thyroxine suppression therapy are advised to have periodic bone densitometry.

Zoledronic acid, an intravenous bisphosphonate, has proven useful for osteolytic metastases from other solid tumors and has been used for patients with thyroid bone metastases, but its effectiveness is unknown.

Thyroid carcinomas are extraordinarily resistant to chemotherapy. Sorafenib and sunitinib are tyrosine kinase inhibitors that have shown some activity against metastatic differentiated thyroid carcinomas that are radioiodine-resistant, with partial responses in 20% and stable disease in 60%.

C. Radioactive Iodine (131I) Therapy Differentiated thyroid cancers variably retain the normal thyroid’s ability to respond to TSH, secrete thyroglobulin, and concentrate iodine. There are two reasons to treat

patients with 131I after thyroidectomy: (1) thyroid remnant ablation and (2) treatment of known or suspected thyroid cancer. 131I is usually administered 2–4 months after surgery. Treatment with 131I is repeated 9–12 months later if surveillance RAI scanning shows evidence of metastatic disease. (See Surveillance, below.)

Before starting 131I therapy, patients follow a low iodine diet for at least 2 weeks. The low iodine diet consists of avoiding the following: iodized table salt, sea salt, fish, shellfish, seaweed, commercial bread, dairy products, processed meats, canned or dried fruit, canned fruit juices, highly salted soups and snack foods, black tea, instant coffee, food coloring with Red Dye #3, egg yolks, multivitamins with iodine, or topical iodine. Patients must not be given amiodarone or intravenous radiologic contrast dyes containing iodine.

1. Thyroid remnant ablation—A small dose of 30 mCi (1110 MBq) 131I is given for “remnant ablation” of residual normal thyroid tissues after surgery for differentiated thyroid cancer. This small dose of 131I is given to patients with no lymph node involvement who are at low risk for metastases. There are several advantages for giving thyroid remnant ablation: (1) There is usually remnant normal tissue that can produce thyroglobulin (a useful tumor marker); (2) Remnant ablation using 131I may destroy microscopic deposits of cancer; (3) The post-therapy scan may visualize metastatic cancer that would otherwise have been invisible.

However, 131I remnant ablation has not been useful for patients with stage I papillary thyroid carcinomas < 1 cm diameter that are unifocal or multifocal. Such very low-risk patients may have close surveillance without receiving remnant ablation.

2. Treatment of metastases—RAI therapy improves survival and reduces recurrence rates for patients with stage III-IV cancer and those with stage II cancer having gross extrathyroidal extension. RAI therapy is also given to patients with stage II cancer who have distant metastases, a primary tumor > 4 cm diameter, or primary tumors 1–4 cm diameter with lymph node metastases or other high-risk features. Brain metastases do not usually respond

Endocrine Disorders to 131I and are best resected or treated with gamma knife radiosurgery (Table 26–8). A post-therapy whole-body scan is performed 2–10 days after 131I therapy.

Staging with RAI scanning or 18FDG-PET/CT scanning assists dosing decisions for 131I therapy. Radioiodine doses of 50–100 mCi are given to patients with large primary tumors or tumors at the surgical margin. Patients with local lymph node involvement typically receive 100 mCi of 131 I; patients with more extensive neck node involvement, regional or distant metastases receive 131I at a dose of 125–200 mCi (4625–7400 MBq). Unfortunately, about 35% of patients with differentiated thyroid carcinoma have poor uptake of 131I into metastases. Patients with asymptomatic, stable, radioiodine-resistant metastases may be carefully monitored for tumor progression.

Some patients have elevated serum thyroglobulin levels but a negative whole-body radioiodine scan and a negative neck ultrasound. In such patients, an 18F-FDG PET/CT scan is obtained. If all scans are negative, empiric therapy with 131I is not useful.

Doses of 131I over 100 mCi (3800 MBq) can cause gastritis, temporary oligospermia, sialadenitis, and xerostomia. RAI therapy can cause neurologic decompensation in patients with brain metastases; it is advisable to treat such patients with prednisone 30–40 mg orally daily for several days before and after 131I therapy. Cumulative doses of 131I over 500 mCi can cause infertility, pancytopenia (4%), and leukemia (0.3%). Pulmonary fibrosis can occur in patients with diffuse lung metastases after receiving cumulative 131I activities of > 600 mCi (22 GBq). The kidneys excrete RAI, so patients receiving dialysis for kidney disease require a dosage reduction to only 20% of the usual dose of 131I. 3. rhTSH-stimulated 131I therapy, thyroglobulin, and scan—Recombinant human thyroid stimulating hormone (rhTSH, Thyrogen) is given to increase the sensitivity of serum thyroglobulin for residual cancer and to increase the uptake of 131I into residual thyroid tissue (thyroid remnant “ablation”) or cancer. Thyrogen must be kept refrigerated and is administered according to the following protocol: Thyroxine replacement is held for 2 days before rhTSH and for 3 days afterward. rhTSH 0.9 mg is administered intragluteally (not intravenously) daily for 2 consecutive days.

On the third day, blood is drawn: serum TSH is assayed to confirm that it is > 30 mcU/mL; serum hCG is measured in reproductive-age women to screen for pregnancy; and serum thyroglobulin is measured as a tumor marker. RAI is then administered at the prescribed dose (see above).

Thyrogen should not be administered to patients with an intact thyroid gland because it can cause severe thyroid swelling and hyperthyroidism. Hyperthyroidism can also occur in patients with significant metastases or residual normal thyroid. Other side effects include nausea (11%) and headache (7%). Thyrotropin has caused neurologic deterioration in 7% of patients with central nervous system metastases.

4. Thyroxine-withdrawal stimulated 131I therapy, thyroglobulin, and scan—Thyroxine withdrawal is sometimes used because of its lower cost, despite the discomforts of becoming hypothyroid. Thyroxine is withdrawn for

CMDT 2013

1131

14 days and the patient is allowed to become hypothyroid; high levels of endogenous TSH stimulate the uptake of RAI and production of thyroglobulin by thyroid cancer or residual thyroid. Just prior to 131I therapy, the following blood tests are obtained: serum TSH to confirm it is > 30 mcU/mL, serum hCG in reproductive-age women to screen for pregnancy, serum thyroglobulin as a tumor marker.

Three days after 131I therapy, thyroxine therapy may be resumed at full replacement dose.

5. Side effects and contraindications—National Cancer Institute surveillance data for thousands of patients with thyroid cancer indicate that patients with differentiated thyroid cancer, treated with only surgery, have a 5% increased risk of developing a second non-thyroid malignancy (especially breast cancer). Patients with thyroid cancer who received 131I therapy have a 20% increased risk of developing a second non-thyroid malignancy (especially leukemia and lymphoma). The greatest risk of second cancers appeared within 5 years of 131I therapy and was most significant for younger patients.

Pregnant women may not receive RAI therapy. Women are advised to avoid pregnancy for at least 4 months following 131I therapy. Men have been found to have abnormal spermatozoa for up to 6 months following 131I therapy and are advised to use contraceptive methods during that time.

``Treatment of Other Thyroid Malignancies Patients with anaplastic thyroid carcinoma are treated with local resection and radiation. Lovastatin has been demonstrated to cause differentiation and apoptosis of anaplastic thyroid carcinoma cells in vitro; however, clinical studies have not been performed. Anaplastic thyroid carcinoma does not respond to 131I therapy and is resistant to chemotherapy.

Patients with thyroid MALT lymphomas have a low risk of recurrence after simple thyroidectomy. Patients with other thyroid lymphomas are best treated with external radiation therapy; chemotherapy is added for extensive lymphoma. Patients with systemic lymphomas involving the thyroid are usually treated with chemotherapy.

Patients with a ret protooncogene mutation should have a prophylactic total thyroidectomy, ideally by age 6 years (MEN 2A) or at age 6 months (MEN 2B). Medullary thyroid carcinoma is best treated with surgery for the primary tumor and metastases. It does not respond to 131I therapy and is generally resistant to chemotherapy. In one study, vandetanib (100 mg orally once daily) produced a partial remission in 16% and stable disease in 53% of patients with locally advanced or metastatic medullary thyroid carcinoma.

A. External Radiation Therapy External radiation may be delivered to bone metastases, especially those without radioiodine uptake. Local neck radiation therapy may also be given to patients with anaplastic thyroid carcinoma. Brain metastases can be treated with gamma knife radiosurgery.

1132

CMDT 2013

Chapter 26

``Surveillance Patients with differentiated thyroid carcinoma must be observed long-term for recurrent or metastatic disease.

Patients with differentiated thyroid carcinoma have traditionally required at least two annual consecutively negative stimulated serum thyroglobulin determinations < 1 ng/mL and normal RAI scans (if done) and neck ultrasound before they are considered to be in remission. The first surveillance occurs with stimulated postoperative serum thyroglobulin, 131I therapy, and post-therapy scanning about 2–4 months after surgery. (See Treatment, above.) At 9–12 months postoperatively, patients usually receive another stimulated serum thyroglobulin and radioiodine scan. Patients with persistent RAI uptake restricted to the thyroid bed need not have repeated 131I therapies if the neck ultrasound appears normal and stimulated serum thyroglobulin is < 2 ng/mL. Further radioiodine or other scans may be required for patients with more aggressive differentiated thyroid cancer, prior metastases, rising serum thyroglobulin levels, or other evidence of metastases.

1. Serum TSH suppression—Patients with differentiated thyroid cancer are treated with thyroxine doses that are sufficient to suppress the serum TSH below the normal range. For intermediate- or high-risk patients, the serum TSH should be suppressed below 0.1 mU/L, while the target TSH for low-risk patients is 0.1–0.5 mU/mL. Patients who are considered cured should nevertheless be treated with sufficient thyroxine to keep the serum TSH < 2 mU/L. Follow-up must include physical examinations and laboratory testing to ensure that patients remain clinically euthyroid with serum TSH levels in the target range. To achieve suppression of serum TSH, the required dose of thyroxine may be such that serum FT4 levels may be slightly elevated; in that case, measurement of serum T3 or free T3 can be useful to ensure the patient is not frankly hyperthyroid.

Thyrotoxicosis can be caused by overreplacement with thyroxine or by the growth of functioning metastases.

2. Serum thyroglobulin—Thyroglobulin is produced by normal thyroid tissue and by most differentiated thyroid carcinomas. It is only after a total or near-total thyroidectomy and 131I remnant ablation that thyroglobulin becomes a useful tumor marker for patients with differentiated papillary or follicular thyroid cancer, particularly for patients who do not have serum antithyroglobulin antibodies.

Detectable thyroglobulin levels do not necessarily indicate the presence of residual or metastatic thyroid cancer.

Conversely, baseline serum thyroglobulin levels are insensitive markers for disease recurrence. However, baseline or stimulated serum thyroglobulin levels ≥ 2 ng/mL indicate the need for a repeat neck ultrasound and further scanning with RAI or 18FDG-PET. If serum thyroglobulin levels remain ≥ 2 ng/mL in the presence of normal scanning, it is prudent to repeat the serum thyroglobulin in a national reference laboratory. In one series of patients with differentiated thyroid cancer following thyroidectomy, there was a 21% incidence of metastases in patients with serum thyroglobulin < 1 ng/mL (while receiving thyroxine for TSH suppression). Therefore, baseline serum thyroglobulin

levels are inadequately sensitive and stimulated serum thyroglobulin measurements should be used and always with neck ultrasound. The usefulness of routinely doing a radioiodine scan (see below) in low-risk patients is controversial but continues to be done in many centers during stimulation following either rhTSH or thyroid hormone withdrawal, according to described protocols.

3. Neck ultrasound—Neck ultrasound should be used in all patients with thyroid carcinoma to supplement neck palpation; it should be performed preoperatively, 3 months postoperatively, and regularly thereafter. Ultrasound is more sensitive for lymph node metastases than either CT or MRI scanning. Small inflammatory nodes may be detected postoperatively and do not necessarily indicate metastatic disease, but follow-up is necessary. Ultrasound-guided FNA biopsy should be performed on suspicious lesions.

4. Radioactive iodine (RAI: 131I or 123I) neck and whole-body scanning—Despite its limitations, RAI scanning has traditionally been used to detect metastatic differentiated thyroid cancer and to determine whether the cancer is amenable to treatment with 131I. RAI scanning is particularly useful for high-risk patients and those with persistent antithyroglobulin antibodies that make serum thyroglobulin determinations unreliable.

The 131I isotope may be used in scanning doses, given < 2 weeks before scheduled 131I treatment to avoid “stunning” metastases such that they take up less of the RAI therapy dose. The radioisotope 123I may also be used and does not stun tumors; it allows single-photon emission computed tomography (SPECT) to better localize metastases. Initial RAI scanning is typically performed about 2–4 months following surgery for differentiated thyroid carcinoma.

Whole-body scanning should be performed for at least 30 minutes for at least 140,000 counts and spot views of the neck should be obtained for at least 35,000 counts.

About 65% of metastases are detectable by RAI scanning, but only after optimal preparation: Patients should ideally have a total or near-total thyroidectomy, since any residual normal thyroid competes for RAI with metastases, which are less avid for iodine. It is reasonable to perform a rhTSH-stimulated scan and thyroglobulin level 2–3 months after the initial neck surgery; if the scan is negative and the serum thyroglobulin is < 2 ng/mL, low-risk patients may not require further scanning but should continue to be monitored with neck ultrasound and serum thyroglobulin levels every 6–12 months. For higher-risk patients, the rhTSH-stimulated thyroglobulin and RAI scan may be repeated about 1 year after surgery and then again if warranted. Serum thyroglobulin and radioiodine scanning are stimulated by either rhTSH or thyroid hormone withdrawal according to the protocols described above for 131I treatment.

The combination of rhTSH-stimulated scanning and thyroglobulin levels detects a thyroid remnant or cancer with a sensitivity of 84%. However, the presence of antithyroglobulin antibodies renders the serum thyroglobulin determination uninterpretable. In about 21% of low-risk patients, rhTSH stimulates serum thyroglobulin to above 2 ng/mL; such patients have a 23% risk of local neck

Endocrine Disorders metastases and a 13% risk of distant metastases. The rhTSH-stimulated radioiodine neck and whole-body scan detects only about half of these metastases because they are small or not avid for iodine. Some patients have persistent radioiodine uptake in the neck on diagnostic scanning but have no visible tumor on neck ultrasound; such patients do not require additional radioiodine therapy, especially if the serum thyroglobulin level is very low.

5. Positron emission tomography scanning—18FDGPET scanning is particularly useful for detecting thyroid cancer metastases in patients with a detectable serum thyroglobulin (especially serum thyroglobulin levels >10 ng/mL and rising) who have a normal whole-body RAI scan and an unrevealing neck ultrasound. The patient should be fasting at least 6 hours prior to 18FDG-PET scanning; water is allowed, but no sweetened beverages. Diabetic patients with blood sugars < 200 mg/dL may be scanned. 18FDG-PET scanning can be combined with a CT scan; the resultant 18 FDG-PET/CT fusion scan is 60% sensitive for detecting metastases that are not visible by other methods. This scan is less sensitive for small brain metastases. 18FDG-PET scanning detects the metabolic activity of tumor tissue; for differentiated thyroid carcinoma, this scan is more sensitive when the patient’s thyroid cancer is stimulated with rhTSH (Thyrogen) as described above. One problem with 18FDGPET scanning is its lack of specificity. False-positives can occur with benign hepatic tumors, sarcoidosis, radiation therapy, suture granulomas, reactive lymph nodes, or inflammation at surgical sites that can persist for months. Falsepositive uptake can also occur in muscles and brown fat.

18 FDG-PET scanning predicts survival better than standard staging; the number, location, and SUVmax of metastases are all significant prognostic factors. (See Prognosis.)

18 FDG-PET scanning is particularly sensitive for detecting medullary thyroid carcinoma metastases, and prescan thyrotropin does not improve the PET scan sensitivity for medullary thyroid carcinoma.

6. Other scanning—Thallium-201 (201Tl) scans may be useful for detecting metastatic differentiated thyroid carcinoma when the 131I scan is normal but serum thyroglobulin is elevated. MRI scanning is particularly useful for imaging metastases in the brain, mediastinum, or bones. CT scanning is useful for imaging and monitoring pulmonary metastases.

``Prognosis Papillary thyroid cancer staging and survival data are shown on Table 26–8. 18FDG-PET scanning independently predicts survival, with patients having few PET-avid metastases and low SUVmax (highest image-pixel standardized uptake value) having a better prognosis. There is generally a good prognosis, particularly for adults under age 45 years, despite the fact that up to 40% of these patients are found to harbor lymph node metastases when extensive lymph node dissections are performed. The following characteristics imply a worse prognosis: age over 45 years, male sex, bone or brain metastases, macronodular (> 1 cm) pulmonary metastases, and lack of 131I uptake into metastases. Younger patients with pulmonary metastases tend to

CMDT 2013

1133

respond better to 131I therapy than do older adults. Certain papillary histologic types are associated with a higher risk of recurrence and reduced survival: tall cell, columnar cell, and diffuse sclerosing types. Brain metastases are detected in 1%; they reduce median survival to 12 months, but the patient’s prognosis is improved by surgical resection.

Patients with a follicular variant of papillary carcinoma have a prognosis somewhere between that of papillary and follicular thyroid carcinoma.

Patients with follicular carcinoma have a cancer mortality rate that is 3.4 times higher than patients with papillary carcinoma. The Hürthle cell variant of follicular carcinoma is even more aggressive. Both follicular carcinoma and its Hürthle cell variant tend to present at a more advanced stage than papillary carcinoma. However, at a given stage, the different types of differentiated thyroid carcinoma have a similar prognosis. Patients with primary tumors > 1 cm in diameter who undergo limited thyroid surgery (subtotal thyroidectomy or lobectomy) have a 2.2-fold increased mortality over those having total or near-total thyroidectomies. Patients who have not received 131 I ablation have mortality rates that are increased twofold by 10 years and threefold by 25 years (over those who have received ablation). The risk of cancer recurrence is twofold higher in men than in women and 1.7-fold higher in multifocal than in unifocal tumors.

Patients with a normal 18FDG-PET scan have a 98% 5-year survival, while those having > 10 metastases have a 20% 5-year survival. Those with a SUVmax of 0.1-4.6 have a 5-year survival of 85%, while those with a SUVmax > 13.3 have a 5-year survival of 20%. Patients with only local metastases have a 5-year survival of 95%, while those with regional (supraclavicular, mediastinal) metastases have a 5-year survival of 70%, and those with distant metastases have a 5-year survival of 35%.

Medullary thyroid carcinoma is more aggressive than differentiated thyroid cancer but is typically fairly indolent.

The overall 10-year survival rate is 90% when the tumor is confined to the thyroid, 70% for those with metastases to cervical lymph nodes, and 20% for those with distant metastases. Patients with sporadic disease usually have lymph node involvement noted at the time of diagnosis, whereas distal metastases may not be noted for years. For patients with medullary thyroid carcinoma who have metastases to lymph nodes, modified radical neck dissection is recommended. Familial cases or those associated with MEN 2A tend to be less aggressive; the 10-year survival rate is higher, in part due to earlier detection.

Medullary thyroid carcinoma that is seen in MEN 2B is more aggressive, arises earlier in life, and carries a worse overall prognosis, especially when associated with a germline M918T mutation. The elderly tend to have more aggressive medullary thyroid carcinomas. Women with medullary thyroid carcinoma who are under age 40 years have a better prognosis. A better prognosis is also obtained in patients undergoing total thyroidectomy and neck dissection; radiation therapy reduces recurrence in patients with metastases to neck nodes. The mortality rate is increased 4.5-fold when primary or metastatic tumor tissue stains heavily for myelomonocytic antigen M-1. Conversely,

1134

CMDT 2013

Chapter 26

tumors with heavy immunoperoxidase staining for calcitonin are associated with prolonged survival even in the presence of significant metastases.

Anaplastic thyroid carcinoma carries a 1-year survival rate of about 10% and a 5-year survival rate of about 5%.

Patients with fully localized tumors on MRI have a better prognosis.

Localized lymphoma carries a 5-year survival of nearly 100%. Those with disease outside the thyroid have a 63% 5-year survival. However, the prognosis is better for those with the MALT type. Patients presenting with stridor, pain, laryngeal nerve palsy, or mediastinal extension tend to fare worse.

Bible KC et al. Efficacy of pazopanib in progressive, radioiodinerefractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010 Oct 11;11(10): 962–72. [PMID: 20851682] Brierley JD. Update on external beam radiation therapy in thyroid cancer. J Clin Endocrinol Metab. 2011 Aug;96(8): 2289–95. [PMID: 21816795] Cabanillas ME et al. Challenges associated with tyrosine kinase inhibitor therapy for metastatic thyroid cancer. J Thyroid Res. 2011;2011:985780. [PMID: 22007339] Cox AE et al. Diagnosis and treatment of differentiated thyroid carcinoma. Radiol Clin North Am. 2011 May;49(3):453–62.

[PMID: 21569904] Jasim S et al. Multiple endocrine neoplasia type 2B with RET protooncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation. Thyroid. 2011 Feb;21(2):189–92. [PMID: 21186952] Johnson NA et al. Imaging surveillance of differentiated thyroid cancer. Radiol Clin North Am. 2011 May;49(3):473–87.

[PMID: 21569906] Kim WG et al. Empiric high-dose 131-iodine therapy lacks efficacy for treated papillary thyroid cancer patients with detectable serum thyroglobulin, but negative cervical sonography and 18F-flurodeoxyglucose positron emission tomography scan. J Clin Endocrinol Metab. 2010 Mar;95(3):1169–73.

[PMID: 20080852] Kojic SL et al. Anaplastic thyroid cancer: a comprehensive review of novel therapy. Expert Rev Anticancer Ther. 2011 Mar;11(3): 387–402. [PMID: 21417853] Pitt SC et al. Medullary, anaplastic, and metastatic cancers of the thyroid. Semin Oncol. 2010 Dec;37(6):567–79. [PMID: 21167376] Tala H et al. Contemporary post surgical management of differentiated thyroid carcinoma. Clin Oncol (R Coll Radiol).

2010 Aug;22(6):419–29. [PMID: 20605708]

IODINE DEFICIENCY DISORDER & ENDEMIC GOITER ``

EssentialS of diagnosis

Common in regions with low-iodine diets.

High rate of congenital hypothyroidism and cretinism. `` Goiters may become multinodular and enlarge. `` Most adults with endemic goiter are found to be euthyroid; however, some are hypothyroid or hyperthyroid. `` ``

``General Considerations About 1 billion people are iodine deficient, having no access to iodized salt and living in areas with iodine-depleted soil.

Severe iodine deficiency increases the risk of miscarriage and stillbirth. About 0.5% of live births in iodine-deficient areas have full-blown cretinism. Moderate iodine deficiency during gestation and infancy cause other manifestations of congenital hypothyroidism, such as deafness and short stature and permanently lowers a child’s IQ by 10–15 points.

Populations in areas of iodine deficiency have a high incidence of goiter. One such area is Pescopagano, Italy, where 60% of adults have goiters. Hyperthyroidism (present or past) occurred in 2.9%; hypothyroidism was overt in 0.2% and subclinical in 3.8%.

Although iodine deficiency is the most common cause of endemic goiter, certain foods (eg, sorghum, millet, maize, cassava), mineral deficiencies (selenium, iron), and water pollutants can themselves cause goiter or aggravate a goiter proclivity caused by iodine deficiency. In iodine-deficient patients, smoking can induce goiter growth. Pregnancy aggravates iodine deficiency and is associated with an increase in size of thyroid nodules and the emergence of new nodules.

Some individuals are particularly susceptible to goiter owing to congenital partial defects in thyroid enzyme activity.

``Clinical Findings A. Symptoms and Signs Endemic goiters may become multinodular and very large.

Growth often occurs during pregnancy and may cause compressive symptoms.

Substernal goiters are usually asymptomatic but can cause tracheal compression, respiratory distress and failure, dysphagia, superior vena cava syndrome, gastrointestinal bleeding from esophageal varices, palsies of the phrenic or recurrent laryngeal nerves, or Horner syndrome.

Cerebral ischemia and stroke can result from arterial compression or thyrocervical steal syndrome. Substernal goiters can rarely cause pleural or pericardial effusions. The incidence of significant malignancy is < 1%.

Some patients with endemic goiter may become hypothyroid. Others may become thyrotoxic as the goiter grows and becomes more autonomous, especially if iodine is added to the diet.

B. Laboratory Findings The serum T4 and TSH are generally normal. TSH falls in the presence of hyperthyroidism if a multinodular goiter has become autonomous in the presence of sufficient amounts of iodine for thyroid hormone synthesis. TSH rises with hypothyroidism. Thyroid RAI uptake is usually elevated, but it may be normal if iodine intake has improved. Serum levels of antithyroid antibodies are usually either undetectable or in low titers. Serum thyroglobulin is often elevated.

``Differential Diagnosis Endemic goiter must be distinguished from all other forms of nodular goiter that may coexist in an endemic region (see above).

Endocrine Disorders

``Prevention Adding iodine to commercial salt prevents iodine deficiency. In the United States, potassium iodide is used. Some tropical countries use potassium iodate, since it is more stable than potassium iodide in hot and humid climates.

Iodized salt contains iodine at about 20 mg per kg salt. The minimum dietary requirement for iodine is about 50 mcg daily, with optimal iodine intake being 150–300 mcg daily.

Iodine sufficiency is assessed by measurement of urinary iodide excretion, the target being more than 10 mcg/dL. Initiating iodine supplementation in an iodine-deficient area greatly reduces the emergence of new goiters but causes an increased frequency of hyperthyroidism during the first year.

``Treatment The addition of potassium iodide to table salt greatly reduces the prevalence of endemic goiter and cretinism but is less effective in shrinking established goiter. Concurrent deficiencies in both vitamin A and iodine increase the risk of endemic goiter and concurrent repletion of both iodide and vitamin A reduces goiter in endemic goiter regions.

Adults with large multinodular goiter may require thyroidectomy for cosmesis, compressive symptoms, or ­thyrotoxicosis. Following partial thyroidectomy in iodinedeficient geographic areas, there is a high goiter recurrence rate, so near-total thyroidectomy is preferred when surgery is indicated. Certain patients may be treated with 131I for large compressive goiters.

``Complications Dietary iodine supplementation increases the risk of auto­ immune thyroid dysfunction, which may cause hypothyroidism or hyperthyroidism. Excessive iodine supplementation increases the risk of goiter. Suppression of TSH by administering thyroxine carries the risk of inducing hyperthyroidism, particularly in patients with autonomous multinodular goiters; therefore, thyroxine suppression should not be started in patients with a low TSH level. Rarely, Graves disease can develop 3–10 months after 131I treatment in patients with large multinodular goiters.

Laurberg P et al. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res Clin Endocrinol Metab.

2010 Feb;24(1):13–27. [PMID: 20172467] Untoro J et al. The challenges of iodine supplementation: a public health programme perspective. Best Pract Res Clin Endocrinol Metab. 2010 Feb;24(1):89–99. [PMID: 20172473] Zimmermann MB. Iodine deficiency. Endocr Rev. 2009 Jun;30(4):376–408. [PMID: 19460960]

cc

diseases of The PARATHYROIDs

Parathyroid hormone (PTH) increases osteoclastic activity in bone, increases the renal tubular reabsorption of calcium, and stimulates the synthesis of 1,25-dihydroxycholecalciferol by the kidney. Meanwhile, PTH inhibits the

CMDT 2013

1135

absorption of phosphate and bicarbonate by the renal tubule. All of these actions cause a net increase in serum calcium.

HYPOPARATHYROIDISM & PSEUDOHYPOPARATHYROIDISM ``

EssentialS of diagnosis

Tetany, carpopedal spasms, tingling of lips and hands, muscle and abdominal cramps, psychological changes. `` Positive Chvostek sign and Trousseau phenomenon. `` Serum calcium low; serum phosphate high; alkaline phosphatase normal; urine calcium excretion reduced. `` Low or low-normal serum PTH in presence of hypocalcemia. `` Serum magnesium may be low. ``

``General Considerations Acquired hypoparathyroidism is most commonly seen following thyroidectomy, when it is usually transient but may be permanent. It may also occur after multiple parathyroidectomies. Hypoparathyroidism may occur transiently after surgical removal of a parathyroid adenoma for primary hyperparathyroidism due to suppression of the remaining normal parathyroids and accelerated remineralization of the skeleton (hungry bone syndrome). Neck irradiation may rarely cause hypoparathyroidism.

Autoimmune hypoparathyroidism may be isolated or combined with other endocrine deficiencies in polyglandular autoimmunity (PGA), which is also known as ­autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). PGA type 1 presents in childhood with at least two of the following manifestations: candidiasis, hypoparathyroidism, or Addison disease. Cataracts, uveitis, alopecia, vitiligo, or autoimmune thyroid disease may also develop. Fat malabsorption occurs in 20% of patients with PGA-1 and may present as weight loss; diarrhea; or malabsorption of vitamin D, a fat-soluble vitamin used to treat the hypoparathyroidism. The fat malabsorption may be due to a deficiency in the jejunal enteroendocrine cells that produce cholecystokinin, causing a reduction in bile acid secretion. Hypoparathyroidism can also occur in systemic lupus erythematosus, caused by antiparathyroid antibodies.

Parathyroid deficiency may also be the result of damage from heavy metals such as copper (Wilson disease) or iron (hemochromatosis, transfusion hemosiderosis), granulomas, Riedel thyroiditis, tumors, or infection.

Functional hypoparathyroidism may also occur as a result of magnesium deficiency (malabsorption, chronic alcoholism), which prevents the secretion of PTH. Cor­ rection of hypomagnesemia results in rapid disappearance

1136

CMDT 2013

Chapter 26

of the condition. Hypermagnesemia can also suppress PTH secretion; it may occur in patients with kidney disease who take magnesium supplements, laxatives, or antacids.

In congenital hypoparathyroidism, parathyroid cells have calcium-sensing receptors (CaSR) that sense the serum calcium concentration and suppress PTH secretion by way of G-protein-coupled mechanisms. Gain-offunction mutations (constitutive activation) of the CaSR gene suppress the parathyroid glands, resulting in hypocalcemia without elevations in serum PTH levels. Such mutations cause “autosomal dominant hypocalcemia with hypercalciuria” from deficient secretion of PTH. The prevalence of autosomal dominant hypocalcemia with hypercalciuria in the population is about 1 in 70,000, and it typically presents in infancy with hypocalcemic seizures.

Hypoparathyroidism, deafness, and renal dysplasia (HDR or Barakat) syndrome is an autosomal dominant condition caused by haploinsufficiency or mutations of the gene GATA3; the condition is autosomal dominant. Hypocalcemia is present from birth but may not be detected until the occurrence of mental retardation or hypocalcemic tetany.

Hypoparathyroidism may also be seen in DiGeorge syndrome, along with congenital cardiac and facial anomalies; hypocalcemia usually presents with tetany in infancy, but some cases are not detected until adulthood.

Familial isolated hypoparathyroidism is caused by mutations in various genes that encode the secretion of PTH or the embryologic development of the parathyroid glands. Mutations in the TBCE gene cause autosomal recessive hypoparathyroidism with other phenotypic abnormalities that are known as the Kenny-Caffey syndrome or the Sanjad-Sakati syndrome. Various mutations in genes that encode mitochondria have maternal inheritance and cause hypoparathyroidism in association with other syndromes: Kearns-Sayre (ophthalmoplegia, retinopathy, cardiomyopathy, diabetes) and MELAS (mitochondrial encephalopathy, lactic acidosis, stroke).

``Clinical Findings A. Symptoms and Signs Acute hypoparathyroidism and hypocalcemia can occur spontaneously or may be precipitated when a patient with untreated hypoparathyroidism receives a proton pump inhibitor. Manifestations of hypocalcemia include tetany, muscle cramps, carpopedal spasm, irritability, altered mental status, convulsions, and stridor; tingling of the circumoral area, hands, and feet is almost always present.

Symptoms of the chronic disease are lethargy, personality changes, anxiety state, blurring of vision due to premature cataracts, Parkinsonism, and mental retardation. Some patients with chronic hypocalcemia are asymptomatic, even with very low levels of serum calcium.

Chvostek sign (facial muscle contraction on tapping the facial nerve in front of the ear) is positive, and Trousseau phenomenon (carpal spasm after application of a sphygmomanometer cuff) is present. Cataracts may occur; the nails may be thin and brittle; the skin is dry and scaly, at times with fungus infection (candidiasis), and there may be loss of eyebrows; and deep tendon reflexes may be hyperactive.

Papilledema and elevated cerebrospinal fluid pressure are occasionally seen. Teeth may be defective if the onset of the disease occurs in childhood.

B. Laboratory Findings Serum calcium is low, serum phosphate high, urinary calcium low, and alkaline phosphatase normal. Serum calcium is largely bound to albumin. In hypoalbuminemia, the serum ionized calcium may be determined, but it has had surprisingly poor clinical utility. Alternatively, the serum calcium level can be corrected for serum albumin level as follows: “Corrected” serum Ca2+ = Serum Ca2+ mg/dL + (0.8 × [4.0 – Albumin g/dL]) PTH levels are low. Hypomagnesemia may exacerbate symptoms and decrease parathyroid function.

C. Imaging Radiographs or CT scans of the skull may show basal ganglia calcifications; the bones may be denser than normal.

Cutaneous calcification may occur.

D. Other Examinations Slit-lamp examination may show early posterior lenticular cataract formation. The electrocardiogram (ECG) shows prolonged QT intervals and T wave abnormalities. Patients with chronic hypoparathyroidism tend to have increased bone mineral density, particularly in the lumbar spine.

``Complications Acute tetany with stridor, especially if associated with vocal cord palsy, may lead to respiratory obstruction requiring tracheostomy. Pseudotumor cerebri has been reported.

Congestive heart failure may rarely occur. The complications of chronic hypoparathyroidism largely depend on the duration of the disease. There may be associated autoimmunity causing sprue syndrome, pernicious anemia, or Addison disease. In long-standing cases, cataract formation and calcification of the basal ganglia are seen. Occasionally, parkinsonian symptoms or choreoathetosis develop.

Ossification of the paravertebral ligaments may occur with nerve root compression; surgical decompression may be required. Seizures are common in untreated patients.

Overtreatment with vitamin D and calcium may produce nephrocalcinosis and impairment of kidney function.

Chronic hypocalcemia can cause heart failure.

``Differential Diagnosis Paresthesias, muscle cramps, or tetany due to respiratory alkalosis, in which the serum calcium is normal, can be confused with hypocalcemia. In fact, hyperventilation tends to accentuate hypocalcemic symptoms.

At times hypoparathyroidism is misdiagnosed as idiopathic epilepsy, choreoathetosis, or brain tumor (on the basis of brain calcifications, convulsions, choked disks) or, more rarely, as “asthma” (on the basis of stridor and dyspnea).

Endocrine Disorders In patients with hypoalbuminemia, serum levels of ionized calcium are normal.

Hypocalcemia may also be due to malabsorption of calcium, magnesium, or vitamin D; patients do not always have diarrhea. Hypocalcemia may also be caused by certain drugs: loop diuretics, plicamycin, phenytoin, alendronate, and foscarnet. In addition, hypocalcemia may be seen in cases of rapid intravascular volume expansion or due to chelation from transfusions of large volumes of citrated blood. It is also observed in patients with acute pancreatitis.

Hypocalcemia may develop in some patients with certain osteoblastic metastatic carcinomas (especially breast, prostate) instead of the expected hypercalcemia. Hypocalcemia with hyperphosphatemia (simulating hypoparathyroidism) is seen in azotemia but may also be caused by large doses of intravenous, oral, or rectal phosphate preparations and by chemotherapy of responsive lymphomas or leukemias.

Hypocalcemia with hypercalciuria may be due to a familial syndrome involving a mutation in the calcium-sensing receptor; such patients have levels of serum PTH that are in the normal range, distinguishing it from hypoparathyroidism. It is transmitted as an autosomal dominant disorder.

Such patients are hypercalciuric; treatment with calcium and vitamin D may cause nephrocalcinosis.

Congenital pseudohypoparathyroidism is a group of disorders characterized by resistance to PTH. There are several subtypes caused by different mutations involving the PTH receptor or its G protein or adenylyl cyclase. Renal tubular resistance to PTH causes hypercalciuria with resultant hypocalcemia. PTH levels are high and the PTH receptors in bone are typically not involved, such that bony changes of hyperparathyroidism may be evident. In pseudohypoparathyroidism type 1a, patients have hypocalcemia and hyperphosphatemia with additional features known as Albright hereditary osteodystrophy: mental retardation, short stature, obesity, round face, short fourth metacarpals, ectopic bone formation, hypothyroidism, and hypogonadism. Patients without hypocalcemia but sharing the phenotypic abnormalities are said to have “pseudopseudohypoparathyroidism.”

1137

CMDT 2013

1. Airway—Be sure an adequate airway is present.

2. Intravenous calcium gluconate—Calcium gluconate, 10–20 mL of 10% solution intravenously, may be given slowly until tetany ceases. Ten to 50 mL of 10% calcium gluconate may be added to 1 L of 5% glucose in water or saline and administered by slow intravenous drip. The rate should be adjusted so that the serum calcium is maintained between 8 mg/dL and 9 mg/dL. 3. Oral calcium—Calcium salts should be given orally as soon as possible to supply 1–2 g of calcium daily. Liquid calcium carbonate, 500 mg/5 mL, may be especially useful.

The dosage is 1–3 g calcium daily. Calcium citrate contains 21% calcium, but a higher proportion is absorbed with less gastrointestinal intolerance.

4. Vitamin D preparations—(Table 26–9.) Therapy should be started as soon as oral calcium is begun. The active metabolite of vitamin D, 1,25-dihydroxycholecal­ ciferol (calcitriol), has a very rapid onset of action and is not long-lasting if hypercalcemia occurs. It is of great use in the treatment of acute hypocalcemia. Therapy is commenced at a dosage of 0.25 mcg orally each morning with upward dosage titration to near normocalcemia. Ultimately, doses of 0.5–2 mcg/d are usually required. Calcifediol (25-hydroxyvitamin D3), another option for treatment, has an intermediate onset and duration of action; the usual starting dose is 20 mcg/d orally.

5. Magnesium—If hypomagnesemia is present (chronic alcoholism, malnutrition, renal loss, drugs such as cisplatin, etc), it must be corrected to treat the resulting hypocalcemia. Acutely, magnesium sulfate is given intravenously, 1–2 g every 6 hours. Long-term magnesium replacement may be given as magnesium oxide tablets (600 mg), one or two per day, or as a combined magnesium and calcium preparation (CalMag, others).

``Treatment

6. Transplantation of cryopreserved parathyroid tissue removed during prior surgery—Transplantation restores normocalcemia in about 23% of cases.

A. Emergency Treatment for Acute Attack (Hypoparathyroid Tetany)

B. Maintenance Treatment

This usually occurs after surgery and requires immediate treatment.

The goal should be to maintain the serum calcium in a slightly low but asymptomatic range (8–8.6 mg/dL). This

Table 26–9. Vitamin D preparations used in the treatment of hypoparathyroidism.

Available Preparations

Daily Dose

Duration of Action

Ergocalciferol ergosterol, (vitamin D2, Calciferol)

Capsules of 50,000 international units; 8000 international units/mL oral solution

2000–200,000 units

1–2 weeks

Cholecalciferol (vitamin D3)

Capsules of 50,000 international units not available commercially in United States; may be compounded

10,000–50,000 units

4–8 weeks

Calcitriol (Rocaltrol)

Capsules of 0.25 and 0.5 mcg; 1 mcg/mL oral solution; 1 mcg/mL for injection

0.25–4 mcg

½–2 weeks

1138

CMDT 2013

Chapter 26

will minimize the hypercalciuria that would otherwise occur and provides a margin of safety against overdosage and hypercalcemia, which may produce permanent damage to kidney function. Patients with mild, asymptomatic hypocalcemia require no therapy. For others, calcium supplementation (1 g/d) is given, along with a vitamin D preparation.

Patients with chronic hypoparathyroidism must usually be treated with some type of vitamin D (Table 26–9).

Monitoring of serum calcium at regular intervals (at least every 3 months) is mandatory. Calcitriol, a short-acting preparation, is given in doses that range from 0.25 mcg/d to 2.0 mcg orally daily. Ergocalciferol (vitamin D2) is derived from plants and is commercially available. The usual dose ranges from 25,000 to 150,000 units/d. It is a slow-acting preparation that is stored in fat, giving it a long duration of action. If toxicity develops, hypercalcemia— treatable with hydration and prednisone—may persist for weeks after it is discontinued. Despite this risk, ergocalciferol usually produces a more stable serum calcium level than do the shorter-acting preparations.

Teriparatide (Forteo) is a recombinant preparation of human PTH 1-34. Teriparatide is effective in treating patients with hypoparathyroidism when given by subcutaneous injection at an initial dose of 0.4 mcg/kg twice daily. The dose is adjusted to produce normal serum calcium levels. The disadvantages of teriparatide therapy include its extremely high cost and the necessity for injections. Furthermore, teriparatide is not approved by the US Food and Drug Administration (FDA) for this indication because prolonged high doses in rats caused osteosarcoma. Therefore, teriparatide therapy is reserved for patients with severe hypoparathyroidism that fails to respond to vitamin D. Target serum calcium levels (albumin-corrected) should be 8.0–8.5 mg/dL; these levels are mildly low to avoid hypercalciuria. It is prudent to monitor urine calcium with “spot” urine determinations and keep the level below 30 mg/dL if possible. Hypercalciuria may respond to oral hydrochlorothiazide, usually given with a potassium supplement.

Caution: Phenothiazine drugs should be administered with caution, since they may precipitate extrapyramidal symptoms in hypocalcemic patients. Furosemide should be avoided, since it may worsen hypocalcemia.

``Prognosis The outlook is good if the diagnosis is made promptly and treatment instituted. Any dental changes, cataracts, and brain calcifications are permanent. Periodic blood chemical evaluation is required, since changes in calcium levels may call for modification of the treatment schedule.

Hypercalcemia that develops in patients with seemingly stable, treated hypoparathyroidism may be a presenting sign of Addison disease.

Despite optimal therapy, patients with hypoparathyroidism have been reported to have an overall reduced quality of life. Affected patients have a high risk of having mood and psychiatric disorders along with a reduced overall sense of well-being.

Bosworth M et al. Clinical inquiries: what is the best workup for hypocalcemia? J Fam Pract. 2008 Oct;57(10):677–9. [PMID: 18842196] Khan MI et al. Medical management of postsurgical hypoparathyroidism. Endocr Pract. 2010 Dec;6:1–19. [PMID: 21134871] Milman S et al. Proton pump inhibitor-induced hypocalcemic seizure in a patient with hypoparathyroidism. Endocr Pract.

2011 Jan–Feb;17(1):104–7. [PMID: 21041166] Puig-Domingo M et al. Successful treatment of vitamin D unresponsive hypoparathyroidism with multipulse subcutaneous infusion of teriparatide. Eur J Endocrinol. 2008 Nov;159(5): 653–7. [PMID: 18703565] Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med. 2008 Jul;359(4):391–403. [PMID: 18650515] Sikjaer T et al. PTH treatment in hypoparathyroidism. Curr Drug Saf. 2011 Apr;6(2):89–99. [PMID: 21524246] Wen HY et al. Parathyroid disease. Rheum Dis Clin North Am. 2010 Nov;36(4):647–64. [PMID: 21092844] Winer KK et al. Long-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium. J Clin Endocrinol Metab. 2010 Jun;95(6):2680–8.

[PMID: 20392870]

HYPERPARATHYROIDISM ``

EssentialS of diagnosis

Frequently detected incidentally by screening.

Renal calculi, polyuria, hypertension, constipation, fatigue, mental changes. `` Bone pain; rarely, cystic lesions and pathologic fractures. `` Serum and urine calcium elevated; urine phosphate high with low to normal serum phosphate; alkaline phosphatase normal to elevated. `` Elevated PTH. `` ``

``General Considerations Primary hyperparathyroidism is the most common cause of hypercalcemia, with a prevalence of 1–4 cases per 1000 persons. It occurs at all ages but most commonly in the seventh decade and in women (74%). Before age 45, the prevalence is similar in men and women.

The disease is caused by hypersecretion of PTH, usually by a single parathyroid adenoma (80%), and less commonly by hyperplasia by two or more parathyroid glands (20%), or carcinoma (≤ 1%). However, when hyperparathyroidism presents before age 30 years, there is a higher incidence of multiglandular disease (36%) and parathyroid carcinoma (5%). The size of the parathyroid adenoma correlates with the serum PTH level.

Hyperparathyroidism is familial in about 10% of cases.

Parathyroid hyperplasia may arise in MEN types 1, 2A, and 2B. In MEN 1, multiglandular hyperparathyroidism is usually the initial manifestation and ultimately occurs in 90% of affected individuals. Hyperparathyroidism in MEN 2A is less frequent that in MEN 1 and is usually

Endocrine Disorders milder. Familial hyperparathyroidism can also occur in the hyperparathyroidism-jaw tumor syndrome, a rare autosomal dominant familial condition in which parathyroid cystic adenomas or carcinomas are associated with ossifying fibromas of the mandible and maxilla as well as renal lesions (cysts, hamartomas, Wilms tumors). Affected individuals usually present with severe hypercalcemia as teenagers or young adults; the pathology is usually a single parathyroid adenoma. (See Table 26–17.)

Hyperparathyroidism results in the excessive excretion of calcium and phosphate by the kidneys. PTH stimulates renal tubular reabsorption of calcium; however, hyperparathyroidism causes hypercalcemia and an increase in calcium in the glomerular filtrate that overwhelms tubular reabsorption capacity, resulting in hypercalciuria. At least 5% of renal calculi are associated with this disease. Diffuse parenchymal calcification (nephrocalcinosis) is seen less commonly. Excessive PTH can cause cortical demineralization that is particularly evident at the wrist and hip; trabecular bone is usually spared as evidenced by relatively higher spinal bone density compared to the wrist. Severe, chronic hyperparathyroidism can cause diffuse demineralization, pathologic fractures, and cystic bone lesions throughout the skeleton, a condition known as osteitis fibrosa cystica.

In chronic kidney disease, hyperphosphatemia and decreased renal production of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) initially produce a decrease in ionized calcium. The parathyroid glands are stimulated (secondary hyperparathyroidism) and may enlarge, becoming autonomous (tertiary hyperparathyroidism). The bone disease seen in this setting is known as renal osteodystrophy. Parathyroid hyperplasia in uremia can result in extremely high serum PTH levels that are associated with uremic vascular calcification. Hypercalcemia often occurs after kidney transplant.

Parathyroid carcinoma is a rare cause of hyperparathyroidism but is more common in patients with serum ­calcium levels ≥ 14.0 mcg/dL. About 50% of parathyroid carcinomas are palpable.

``Clinical Findings A. Symptoms and Signs In the developed world, hypercalcemia of hyperparathyroidism is typically discovered accidentally by routine chemistry panels. Many patients are asymptomatic or have mild symptoms that may be elicited only upon questioning. Parathyroid adenomas are usually so small and deeply located in the neck that they are almost never palpable; when a mass is palpated, it usually turns out to be an incidental thyroid nodule.

Symptomatic patients are said to have problems with “bones, stones, abdominal groans, psychic moans, with fatigue overtones.” The manifestations are categorized as skeletal, urinary tract, and those associated with hypercalcemia.

1. Skeletal manifestations—Hyperparathyroidism causes a loss of cortical bone and a gain of trabecular bone.

Low bone density is typically most prominent at the wrist.

CMDT 2013

1139

Postmenopausal women are prone to asymptomatic vertebral fractures. Although significant bone demineralization is uncommon in mild hyperparathyroidism, osteitis fibrosa cystica may present as pathologic fractures or as “brown tumors” or cysts of the jaw. More commonly, patients have bone pain and arthralgias.

2. Manifestations of hypercalcemia—Mild hypercalcemia may be asymptomatic. However, hypercalcemia usually causes a variety of manifestations whose severity is not entirely predictable by the level of serum calcium or PTH in patients with hyperparathyroidism. In fact, patients with only mild hypercalcemia can have significant symptoms, particularly depression, constipation, and bone and joint pain. Paresthesias, muscular weakness, and diminished deep tendon reflexes are examples of neuromuscular manifestations. Central nervous system manifestations include malaise, fatigue, intellectual weariness, depression, increased sleep requirement, progressing to cognitive impairment, disorientation, psychosis, or stupor. Cardio­ vascular symptoms include hypertension, prolonged P-R interval, shortened Q-T interval, sensitivity to arrhythmic effects of digitalis, bradyarrhythmias, heart block, and asystole. Renal manifestations include polyuria and polydipsia, caused by hypercalcemia-induced nephrogenic diabetes insipidus. Among all patients with newly discovered hyperparathyroidism, calcium-containing kidney stones have occurred or are detectable in about 18%. Patients with asymptomatic hyperparathyroidism have a 7% incidence of asymptomatic calcium nephrolithiasis, compared to 1.6% incidence in age-matched controls. Gastrointestinal symptoms include anorexia, nausea, vomiting, abdominal pain, weight loss, constipation, and obstipation. Pancreatitis occurs in 3%. Pruritus may be present. Calcium may precipitate in the corneas (“band keratopathy”). Calcium may also precipitate in extravascular tissues as well as in small arteries, causing small vessel thrombosis and skin necrosis (calciphylaxis).

3. Hyperparathyroidism during pregnancy—About 67% of women with primary hyperparathyroidism during pregnancy experience complications such as nephrolithiasis, hyperemesis, pancreatitis, muscle weakness, cognitive changes, and hypercalcemic crisis. About 80% of fetuses experience complications of maternal hyperparathyroidism, including fetal demise, preterm delivery, low birth weight, postpartum neonatal tetany, and permanent hypoparathyroidism.

B. Laboratory Findings The hallmark of primary hyperparathyroidism is hypercalcemia, with the serum adjusted total calcium > 10.5 mg/dL (Figure 26–1). The adjusted total calcium = measured serum calcium in mg/dL + [0.8 × (4.0 – patient’s serum albumin in g/dL)]. Serum ionized calcium determinations have not proven very helpful clinically, except in hyperproteinemic states (such as hyperalbuminemia, Waldenström macroglobulinemia, myeloma, or thrombocytosis); in such patients with hyperparathyroidism, the serum ionized calcium is usually > 5.4 mg/dL (1.4 mmol/L).

1140

CMDT 2013

Chapter 26

1000 800 600 Secondary HPT

Intact PTH (ng/L)

400

200 Primary HPT 100 80 60

Pseudohypoparathyroidism

40

20

10 mg/dL mmol/L

Normal Hypoparathyroidism 6 1.5

Nonparathyroid hypercalcemia (including malignancy) 8 2

10

12

Serum calcium

14

16 4

s Figure 26–1. Parathyroid hormone and calcium nomogram. Relationship between serum intact parathyroid hormone (PTH) and serum calcium levels in patients with hypoparathyroidism, pseudohypoparathyroidism, nonparathyroid hypercalcemia, primary hyperparathyroidism (HPT), and secondary hyperparathyroidism. (Used with permission from GJ Strewler, MD.)

The urine calcium excretion may be high or normal (averaging 250 mg/g creatinine) but it is usually low for the degree of hypercalcemia. The serum phosphate is often low (< 2.5 mg/dL). There is an excessive loss of phosphate in the urine in the presence of hypophosphatemia (25% of cases), whereas in secondary hyperparathyroidism due to kidney disease, the serum phosphate may be high. The alkaline phosphatase is elevated only if bone disease is present. The plasma chloride and uric acid levels may be elevated. Vitamin D deficiency is common in patients with hyperparathyroidism, and it is prudent to screen for ­vitamin D deficiency with a serum 25-OH vitamin D determination. Low serum 25-OH vitamin D levels (< 20 mcg/L; < 50 nmol/L) can aggravate hyperparathyroidism and its bone manifestations; vitamin D replacement may be helpful in treating such patients with hyperparathyroidism.

Elevated serum levels of intact PTH (IRMA assay) confirm the diagnosis of hyperparathyroidism. Patients with apparent hyperparathyroidism should be screened for familial benign hypocalciuric hypercalcemia with a 24-hour urine for calcium and creatinine. Patients should discontinue thiazide diuretics prior to this test. Calcium excretion of < 50 mg/24 hours (or < 5 mg/dL on a random urine) is not typical for primary hyperparathyroidism and indicates possible familial benign hypocalciuric hypercalcemia.

Patients with low bone density who have an elevated serum PTH but a normal serum calcium must be evaluated for causes of secondary hyperparathyroidism (eg,

vitamin D or calcium deficiency, hyperphosphatemia, renal failure). In the absence of secondary hyperparathyroidism, patients with an elevated serum PTH but normal serum calcium are determined to have normocalcemic hyperparathyroidism. Such individuals require monitoring, since hypercalcemia develops in about 19% of patients over 3 years of follow-up.

C. Imaging Preoperative sestamibi-iodine subtraction scanning and neck ultrasonography can locate parathyroid adenomas preoperatively in an effort to improve the outcome and limit the invasiveness of neck surgery. Parathyroid imaging is crucial for patients who have had prior neck surgery.

However, the usefulness of preoperative parathyroid localizing imaging studies for first neck explorations remains controversial. Preoperative scanning does not improve the outcome of initial bilateral neck explorations performed by a surgeon with special expertise in parathyroid surgery.

Therefore, preoperative imaging has been used mainly to improve the outcome for limited neck exploration, with only modest success. (See Surgery.) Imaging is not useful for the diagnosis of hyperparathyroidism, which must be made by serum calcium and PTH determinations. Small benign thyroid nodules are discovered incidentally in nearly 50% of patients with hyperparathyroidism who have imaging with ultrasound or MRI.

Endocrine Disorders CT and MRI scanning of the neck are not ordinarily required or useful for initial preoperative parathyroid localizing studies, since these scanning techniques are less sensitive for identifying tiny parathyroid adenomas. However, for repeat neck operations and when ectopic parathyroid glands are suspected, MRI is preferred since it offers better soft tissue contrast than CT scanning and is less adversely affected by postoperative changes in the neck.

Patients with hyperparathyroidism have a high risk of calcium nephrolithiasis. Therefore, it has been suggested that all patients with hyperparathyroidism have ­noncontrast-enhanced CT scanning of the kidneys to determine whether calcium-containing stones are present. For patients with apparently asymptomatic hyperparathyroidism, the presence or absence of calcium nephrolithiasis can be a deciding factor about whether to have parathyroidectomy surgery.

Bone density measurements by dual energy x-ray absorptiometry (DXA) are helpful in determining the amount of bone loss in patients with hyperparathyroidism.

Bone loss occurs mostly in long bones, and DXA should ideally include three areas: lumbar spine, hip, and distal radius.

Bone radiographs are usually normal and are not required to make the diagnosis of hyperparathyroidism. There may be demineralization, subperiosteal resorption of bone (especially in the radial aspects of the fingers), or loss of the lamina dura of the teeth. There may be cysts throughout the skeleton, mottling of the skull (“salt-and-pepper appearance”), or pathologic fractures. Articular cartilage calcification (chondrocalcinosis) is sometimes found.

Patients with renal osteodystrophy may have ectopic calcifications around joints or in soft tissue. Such patients may exhibit radiographic changes of osteopenia, osteitis fibrosa, or osteosclerosis, alone or in combination. Osteosclerosis of the vertebral bodies is known as “rugger jersey spine.”

``Complications Pathologic long bone fractures are more common in patients with hyperparathyroidism than in the general population.

Urinary tract infection due to stone and obstruction may lead to kidney disease and uremia. If the serum calcium level rises rapidly, clouding of sensorium, kidney disease, and rapid precipitation of calcium throughout the soft tissues may occur. Peptic ulcer and pancreatitis may be intractable before surgery. Insulinomas or gastrinomas may be associated, as well as pituitary tumors (MEN type 1). Pseudogout may complicate hyperparathyroidism both before and after surgical removal of tumors. Hypercalcemia during gestation produces neonatal hypocalcemia.

In tertiary hyperparathyroidism due to chronic kidney disease, high serum calcium and phosphate levels may cause disseminated calcification in the skin, soft tissues, and arteries (calciphylaxis); this can result in painful ischemic necrosis of skin and gangrene, cardiac arrhythmias, and respiratory failure. The actual serum levels of calcium and phosphate have not correlated well with calciphylaxis, but a calcium (mg/dL) × phosphate (mg/dL) product over 70 is usually present.

CMDT 2013

1141

``Differential Diagnosis A. Artifact A report of hypercalcemia may be due to laboratory error or excess tourniquet time and should always be repeated.

Hypercalcemia may be due to high serum protein concentrations; in the presence of very high or low serum albumin concentrations, a serum ionized calcium is more dependable than the total serum calcium concentration. Hypercalcemia may also be seen with dehydration; spurious elevations in serum calcium have been reported with severe hypertriglyceridemia, when the calcium assay uses spectrophotometry.

B. Hypercalcemia of Malignancy Many malignant tumors (breast, lung, pancreas, uterus, hypernephroma, paraganglioma, etc) can produce hypercalcemia. In some cases (breast carcinoma especially), bony metastases are present. In others, no metastases to bone can be demonstrated. Most of these tumors secrete PTH-related protein (PTHrP), which has tertiary structural homologies to PTH and causes bone resorption and hypercalcemia similar to those of PTH. The clinical features of the hypercalcemia of cancer can closely simulate hyperparathyroidism. Serum phosphate is often low, but the plasma level of PTH is low. Serum PTHrP may be elevated.

Multiple myeloma is a common cause of hypercalcemia in the older population. Many other hematologic cancers, such as monocytic leukemia, T cell leukemia and lymphoma, and Burkitt lymphoma, have also been associated with hypercalcemia. Multiple myeloma causes kidney dysfunction; resultant increased levels of carboxyl terminal PTH may cause it to be confused with hyperparathyroidism if a carboxyl terminal PTH assay is used.

C. Sarcoidosis and Other Granulomatous Disorders Macrophages and perhaps other cells present in granulomatous tissue have the ability to synthesize 1,25(OH)2D3.

Hypercalcemia has been reported in patients with sarcoidosis, tuberculosis, berylliosis, histoplasmosis, coccidioidomycosis, leprosy, and even foreign-body granuloma.

Increased intestinal calcium absorption and hypercalciuria are more common than hypercalcemia. Serum levels of 1,25(OH)2D3 are elevated. Sarcoid granulomas can also secrete PTHrP.

D. Calcium or Vitamin D Ingestion Ingestion of large amounts of calcium or vitamin D can cause hypercalcemia, especially in patients who concurrently take thiazide diuretics, which reduce urinary calcium loss. Hypercalcemia is reversible following withdrawal of calcium and vitamin D supplements. If hypercalcemia persists, the possibility of associated hyperparathyroidism should be strongly considered.

In vitamin D intoxication, patients may be taking large amounts of vitamin D for unclear reasons, so a thorough review of all medications is important. Hypercalcemia may persist for several weeks. Serum levels of 25-hydroxycholecalciferol (25[OH]D3) are helpful to confirm the

1142

CMDT 2013

Chapter 26

diagnosis. A brief course of corticosteroid therapy may be necessary if hypercalcemia is severe.

E. Familial Benign Hypocalciuric Hypercalcemia Familial benign hypocalciuric hypercalcemia can be easily mistaken for mild hyperparathyroidism. It is a common autosomal dominant inherited disorder (prevalence: 1 in 16,000) caused by a loss-of-function mutation in the gene encoding the CaSR. CaSRs are found on the surface of the parathyroid glands and allow the parathyroid glands to vary PTH secretion according to serum calcium levels.

Reduced function of the CaSR causes the parathyroid glands to falsely “sense” hypocalcemia and inappropriately release slightly excessive amounts of PTH. At the same time, the renal tubule CaSRs are also affected, causing hypocalciuria. Familial benign hypocalciuric hypercalcemia is characterized by hypercalcemia, hypocalciuria (usually < 50 mg/24 h), variable hypermagnesemia, and normal or minimally elevated levels of PTH. These patients do not normalize their hypercalcemia after subtotal parathyroid removal and should not be subjected to surgery.

The condition has an excellent prognosis and is easily diagnosed with a family history and urinary calcium clearance determination.

F. Vitamin D Deficiency Secondary hyperparathyroidism predictably develops in patients with a deficiency in vitamin D. Serum calcium levels are typically in the normal range, but may rise to become borderline elevated with time, due to parathyroid glandular hyperplasia. (See Osteomalacia section.)

G. Adrenal Insufficiency Hypercalcemia is common in untreated Addison disease.

This is partly due to disinhibition of calcium uptake by the renal tubule and gut. Additionally, Addison disease can cause dehydration and hyperproteinemia, resulting in higher levels of nonionized calcium.

H. Immobilization Hypercalcemia Prolonged immobilization at bed rest commonly causes hypercalcemia, particularly in adolescents, critically ill patients, and patients with extensive Paget disease of bone. Hypercalcemia develops in about one-third of acutely ill patients being treated in intensive care units, particularly patients with acute kidney injury. Serum calcium elevations are typically mild but may reach 15 mg/dL. Serum PTH levels are usually slightly elevated, consistent with mild hyperparathyroidism, but may be suppressed or normal.

I. Other Causes of Hypercalcemia Other causes of hypercalcemia are shown in Table 21–8.

Modest hypercalcemia is occasionally seen in patients taking thiazide diuretics or lithium; such patients may have an inappropriately nonsuppressed PTH level with hypercalcemia. Hypercalcemia occurs frequently in

infants with Williams syndrome. Hyperthyroidism causes increased turnover of bone and occasional hypercalcemia.

Bisphosphonates can increase serum calcium in 20% and serum PTH becomes high in 10%, mimicking hyperparathyroidism.

``Treatment A. Asymptomatic Primary Hyperparathyroidism Patients with mild asymptomatic hyperparathyroidism may not need therapy. Such patients are advised to keep active, avoid immobilization, and drink adequate fluids.

For postmenopausal women with hyperparathyroidism, estrogen replacement therapy reduces serum calcium by an average of 0.75 mg/dL and slightly improves bone density.

Affected patients must avoid thiazide diuretics, large doses of vitamin A, and calcium-containing antacids or supplements. Serum calcium and albumin are checked about twice yearly, kidney function and urine calcium once yearly, and three-site bone density (distal radius, hip, and spine) every 2 years. Rising serum calcium should prompt further evaluation and determination of PTH levels.

B. Surgical Parathyroidectomy Parathyroidectomy is recommended for patients with symptomatic hyperparathyroidism, kidney stones, bone disease, and pregnancy.

Some patients with seemingly asymptomatic hyperparathyroidism may be surgical candidates for other reasons such as (1) serum calcium 1 mg/dL (0.25 mmol/L) above the upper limit of normal with urine calcium excretion > 50 mg/24 h (off thiazide diuretics), (2) urine calcium excretion over 400 mg/24 h, (3) creatinine clearance < 60 mL/min, (4) cortical bone density (wrist, hip) ≥ 2.5 SD below normal or previous fragility bone fracture, (5) relative youth (under age 50–60 years), (6) difficulty ensuring medical follow-up, or (7) pregnancy. During pregnancy, parathyroidectomy is performed in the second trimester. Surgery for patients with “asymptomatic” hyperparathyroidism may confer modest benefits in social and emotional function, with improvements in anxiety and phobias being reported in comparison to similar patients who are monitored without surgery.

Preoperative parathyroid imaging has been used in an attempt to allow unilateral minimally invasive neck surgery. The reported success rates vary considerably. The usefulness of preoperative parathyroid imaging was evaluated in a series of 350 patients with sporadic primary hyperparathyroidism. A single gland was predicted by sestamibi in 83%, by ultrasound in 85%, and by concordance of both in 59% of patients. Unilateral neck exploration, directed by these studies, resulted in success rate of only 73%, 77%, and 82%, respectively, despite the intraoperative quick PTH assay predicting success. Even in patients with concordant sestamibi and ultrasound scans, and an intraoperative PTH drop of > 50%, at least one additional abnormal parathyroid gland is left behind in the contralateral neck in 15% of patients.

Without preoperative localization studies, bilateral neck exploration is usually advisable for the following:

Endocrine Disorders (1) patients with a family history of hyperparathyroidism, (2) patients with a personal or family history of MEN, and (3) patients wanting an optimal chance of success with a single surgery. Patients undergoing unilateral neck exploration can have the incision widened for bilateral neck exploration if two abnormal glands are found or if the serum quick PTH falls by < 50% within 10 minutes of the parathyroid resection. Parathyroid glands are not uncommonly supernumerary (five or more) or ectopic (eg, intrathyroidal, carotid sheath, mediastinum). The optimal surgical management for patients with MEN type 1 is subtotal parathyroidectomy that usually results in a cure, although recurrent hyperparathyroidism develops in 18% and the rate of postoperative hypoparathyroidism is high.

Parathyroid hyperplasia is commonly seen with secondary or tertiary hyperparathyroidism associated with uremia. Cinacalcet is an alternative to surgery. When surgery is performed, a subtotal parathyroidectomy is optimal; three and one-half glands are usually removed, and a metal clip is left to mark the location of residual parathyroid tissue.

Parathyroid carcinoma can cause severe hypercalcemia associated with very high serum levels of PTH. Preoperative localizing studies usually detect a large invasive tumor.

Therapy consists of en bloc resection of the tumor and the ipsilateral thyroid lobe. Metastases to local and to distant sites occur in about 50% of patients. Reoperation for neck recurrence is usually necessary. Adjuvant treatment includes radiation therapy. Cinacalcet is administered initially in doses of 30 mg twice daily and increased as needed up to 90 mg four times daily. Intravenous bisphosphonate (zoledronic acid) is used as needed.

Complications—Serum PTH levels fall below normal in 70% of patients within hours after successful surgery, commonly causing hypocalcemic paresthesias or even tetany.

Hypocalcemia tends to occur the evening after surgery or on the next day. Therefore, frequent postoperative monitoring of serum calcium (or serum calcium plus albumin) is advisable beginning the evening after surgery. Once hypercalcemia has resolved, liquid or chewable calcium carbonate is given orally to reduce the likelihood of hypocalcemia. Symptomatic hypocalcemia is treated with larger doses of calcium; calcitriol (0.25–1 mcg daily orally) may be added, with the dosage depending on symptom severity. Magnesium salts are sometimes required postoperatively, since adequate magnesium is required for functional recovery of the remaining suppressed parathyroid glands.

In about 12% of patients having successful parathyroid surgery, PTH levels rise above normal (while serum calcium is normal or low) by 1 week postoperatively. This secondary hyperparathyroidism is probably due to “hungry bones” and is treated with calcium and vitamin D preparations. Such therapy is usually needed only for 3–6 months but is required long-term by some patients.

Hyperthyroidism commonly occurs immediately following parathyroid surgery. It is caused by release of stored thyroid hormone during surgical manipulation of the thyroid. In symptomatic patients, short-term treatment with propranolol may be required for several days.

CMDT 2013

1143

C. Medical Measures 1. Fluids—Hypercalcemia is treated with a large fluid intake unless contraindicated. Severe hypercalcemia requires hospitalization and intensive hydration with intravenous saline. (See Chapter 21.)

2. Bisphosphonates—Intravenous bisphosphonates are potent inhibitors of bone resorption and can temporarily treat the hypercalcemia of hyperparathyroidism. Pamidronate in doses of 30–90 mg (in 0.9% saline) is administered intravenously over 2–4 hours. Zoledronic acid 2–4 mg is administered intravenously over 15 to 20 minutes. These drugs cause a gradual decline in serum calcium over several days that may last for weeks to months. Such intravenous bisphosphonates are used generally for patients with severe hyperparathyroidism in preparation for surgery. Oral bisphosphonates, such as alendronate, are not effective for treating the hypercalcemia or hypercalciuria of hyperparathyroidism. However, oral alendronate has been shown to improve bone mineral density in the lumbar spine and hip (not distal radius) and may be used for asymptomatic patients with hyperparathyroidism who have a low bone mineral density.

3. Vitamin D and vitamin D analogs— A. Primary hyperparathyroidism—For patients with vitamin D deficiency, careful vitamin D replacement may be beneficial to patients with hyperparathyroidism. Aggravation of hypercalcemia does not ordinarily occur. Serum PTH levels may fall with vitamin D replacement in doses of 800–2000 international units daily. Occasionally, larger doses are required to achieve normal 25-OH vitamin D levels.

B. Secondary and tertiary hyperparathyroidism associated with azotemia—Calcitriol, given orally or intravenously after dialysis, suppresses parathyroid hyperplasia of kidney disease. For patients with normal serum calcium levels, it is given orally in starting doses of 0.25 mcg on alternate days or daily. Calcitriol often causes hypercalcemia, so that serum levels of calcium and phosphate must be monitored to ensure that the serum Ca2+ × PO4 product remains ≤ 70. When that occurs, the dose of calcitriol is decreased or the patient is switched to therapy with vitamin D analogs or cinacalcet.

The vitamin D analogs paricalcitol and doxercalciferol suppress PTH secretion and cause less hypercalcemia than calcitriol; however, they are very expensive. The doses are adjusted to keep serum PTH levels between 150 pg/mL and 300 pg/mL. Paricalcitol (Zemplar) is administered intravenously during dialysis three times weekly in starting doses of 0.04–0.1 mcg/kg to a maximum dose of 0.24 mcg/kg three times weekly. Alternatively, paricalcitol may be administered orally at doses of 1–2 mcg daily for serum PTH levels < 500 pg/mL or 2–4 mcg daily for serum PTH levels > 500 pg/mL. Dialysis patients receiving paricalcitol have improved survival compared with patients receiving calcitriol. Doxercalciferol (Hectorol) is administered intravenously three times weekly during hemodialysis to patients with azotemic secondary hyperparathyroidism in starting doses of 4 mcg three times weekly to a maximum dose of 18 mcg three times weekly. Alternatively, doxercalciferol may be administered orally three times weekly at dialysis,

1144

CMDT 2013

Chapter 26

starting with 10 mcg three times weekly at dialysis to a maximum of 60 mcg/wk.

4. Cinacalcet—Cinacalcet hydrochloride is a calcimimetic agent that binds to sites of the parathyroid glands’ extracellular CaSRs to increase the glands’ affinity for extracellular calcium, thereby decreasing PTH secretion. About 50% of azotemic patients with secondary or tertiary hyperparathyroidism are resistant to vitamin D analogs (see above).

Cinacalcet is given orally in starting doses of 30 mg daily to a maximum of 250 mg daily, with dosage adjustments to keep the serum PTH in the range of 150–300 pg/mL. Patients with primary hyperparathyroidism have also been treated successfully with cinacalcet in oral doses of 30–50 mg twice daily, with 73% of patients achieving normocalcemia. Cinacalcet is given to patients with severe hypercalcemia due to parathyroid carcinoma at initial doses of 30 mg orally twice daily and increased progressively to 60 mg twice daily, then 90 mg twice daily to a maximum of 90 mg every 6–8 hours. Cinacalcet is usually well tolerated but may cause nausea and vomiting, which are usually transient. It is very expensive.

5. Other measures—Estrogen replacement, given to postmenopausal women, reduces hypercalcemia slightly. Simi­ larly, raloxifene also reduces the hypercalcemia of hyperparathyroidism, reducing serum calcium levels an average of 0.4 mg/dL. Propranolol may be useful for preventing the adverse cardiac effects of hypercalcemia.

Renal osteodystrophy is caused by secondary or tertiary hyperparathyroidism during kidney disease. It can be prevented or delayed by reducing hyperphosphatemia with phosphate binding medication and dietary phosphate restriction.

``Prognosis Patients with symptomatic hyperparathyroidism usually experience worsening disease (eg, nephrolithiasis) unless they have treatment. Conversely, the majority of completely asymptomatic patients with mild hypercalcemia (serum calcium <11.0 mg/dL) remain stable with follow-up.

However, worsening hypercalcemia, hypercalciuria, and reductions in cortical bone mineral density develop in about one-third of asymptomatic patients. Therefore, asymptomatic patients must be monitored carefully and treated with oral hydration and mobilization.

Surgical removal of apparently single sporadic parathyroid adenomas is successful in 94%. Patients with MEN 1 undergoing subtotal parathyroidectomy may experience long remissions, but hyperparathyroidism frequently recurs.

Despite treatment for hyperparathyroidism, patients remain at increased risk for all-cause mortality, cardiovascular disease, kidney stones, and renal failure. These increased risks are likely the residuals of pretreatment hypertension and nephrolithiasis.

Spontaneous cure due to necrosis of the tumor has been reported but is exceedingly rare. The bones, in spite of severe cyst formation, deformity, and fracture, will heal if a parathyroid tumor is successfully removed. The presence of pancreatitis increases the mortality rate. Acute pancreatitis usually resolves with correction of hypercalcemia,

whereas subacute or chronic pancreatitis tends to persist.

Significant renal damage may progress even after removal of an adenoma.

Parathyroid carcinoma tends to invade local structures and may sometimes metastasize; repeat surgical resections and radiation therapy can prolong life. Aggressive surgical and medical management of parathyroid carcinoma can result in a median overall survival of 14.3 years (range 10.5–25.7 years) from the date of diagnosis. Factors associated with a worsened mortality rate include lymph node or distant metastases, high number of recurrences, and higher serum calcium levels at recurrence.

Bargren AE et al. Can biochemical abnormalities predict symptomatology in patients with primary hyperparathyroidism?

J Am Coll Surg. 2011 Sep;213(3):410–4. [PMID: 21723154] Duntas LH et al. Cinacalcet as alternative treatment of primary hyperparathyroidism: achievements and prospects. Endocrine.

2011 Jun;39(3):199–204. [PMID: 21442382] Harari A et al. Parathyroid carcinoma: a 43-year outcome and survival analysis. J Clin Endocrinol Metab. 2011 Dec;96(12): 3679–86. [PMID: 21937626] Marcocci C et al. Clinical practice. Primary hyperparathyroidism.

N Engl J Med. 2011 Dec 22;365(25):2389–97. [PMID: 22187986] McVeigh T et al. Changing practices in the surgical management of hyperparathyroidism. Surgeon. 2011 Nov 19. [Epub ahead of print] [PMID: 22105046] Morris GS et al. Parathyroidectomy improves functional capacity in “asymptomatic” older patients with primary hyperparathyroidism: a randomized control trial. Ann Surg. 2010 May;251(5):832–7. [PMID: 20395857] Rejnmark L et al. Nephrolithiasis and renal calcifications in primary hyperparathyroidism. J Clin Endocrinol Metab. 2011 Aug;96(8):2377–85. [PMID: 21646371] Sprague SM et al. Control of secondary hyperparathyroidism by vitamin D receptor agonists in chronic kidney disease. Clin J Am Soc Nephrol. 2010 Mar;5(3):512–8. [PMID: 20133492] Vestergaard P et al. Medical treatment of primary, secondary, and tertiary hyperparathyroidism. Curr Drug Saf. 2011 Apr; 6(2):108–13. [PMID: 21524244] cc

METABOLIC BONE DISEASE

The term “metabolic bone disease” denotes those conditions producing diffusely decreased bone density and diminished bone strength. It is categorized by histologic appearance: osteoporosis (bone matrix and mineral both decreased) and osteomalacia (bone matrix intact, mineral decreased). Osteoporosis and osteomalacia often coexist in the same patient.

OSTEOPOROSIS ``

EssentialS of diagnosis

Fracture propensity of spine, hip, pelvis, and wrist from demineralization. `` Serum PTH, calcium, phosphorus, and alkaline phosphatase usually normal. `` Serum 25-hydroxyvitamin D levels often low as a comorbid condition. ``

Endocrine Disorders

``General Considerations Osteoporosis is a skeletal disorder characterized by a loss of bone osteoid that reduces bone integrity, resulting in an increased risk of fractures. In the United States, osteoporosis causes about 2 million fractures annually, including 547,000 vertebral fractures, 300,000 hip fractures, and 135,000 pelvic fractures. White women have a 40% lifetime risk of sustaining one or more osteoporotic fractures. The morbidity and indirect mortality rates are very high. The rate of bone formation is often normal, whereas the rate of bone resorption is increased.

Osteoporosis can be caused by a variety of factors, which are listed in Table 26–10. The most common causes are aging; high-dose corticosteroid administration; alcoholism; and sex hormone deficiency, particularly menopause in women.

Osteogenesis imperfecta is caused by a major mutation in the gene encoding for type I collagen, the major collagen constituent of bone. This causes severe osteoporosis; spontaneous fractures occur in utero or during childhood. Blue sclerae may be present. Certain polymorphisms in the genes encoding type I collagen are common, particularly in whites, resulting in collagen disarray and predisposing to hypogonadal (eg, menopausal) or idiopathic osteoporosis.

``Clinical Findings A. Symptoms and Signs Osteoporosis is usually asymptomatic until fractures occur.

It may present as backache of varying degrees of severity or as a spontaneous fracture or collapse of a vertebra. Loss of height is common. Once osteoporosis is identified, a

Table 26–10. Causes of osteoporosis.1 Hormone deficiency Estrogen (women) Androgen (men) Hormone excess Cushing syndrome or cortico steroid administration Thyrotoxicosis Hyperparathyroidism Immobilization and microgravity Tobacco Alcoholism Malignancy, especially multiple myeloma Medications Excessive vitamin D intake Excessive vitamin A intake Heparin therapy Selective serotonin reuptake inhibitors Rosiglitazone 1

Genetic disorders Aromatase deficiency Type I collagen mutations Osteogenesis imperfecta Idiopathic juvenile and adult osteoporosis Ehlers-Danlos syndrome Marfan syndrome Homocystinuria Miscellaneous Celiac disease Anorexia nervosa Hyponatremia (chronic) Protein-calorie malnutrition Vitamin C deficiency Copper deficiency Liver disease Rheumatoid arthritis Uncontrolled diabetes mellitus Systemic mastocytosis

See Table 26–11 for causes of osteomalacia.

CMDT 2013

1145

carefully directed history and physical examination must be performed to determine its cause (Table 26–10).

B. Laboratory Findings Serum calcium, phosphate, and PTH are normal. The alkaline phosphatase is usually normal but may be slightly elevated, especially following a fracture. Vitamin D deficiency is very common and serum determination of 25-hydroxyvitamin D should be obtained for every individual with low bone density. Serum 25-hydroxyvitamin D levels below 20 ng/mL are considered frank vitamin D deficiency. Lesser degrees of vitamin D deficiency (serum 25-hydroxyvitamin D levels between 20 ng/mL and 30 ng/mL) may also increase the risk for hip fracture.

(See Osteomalacia, below.) Testing for thyrotoxicosis and hypogonadism may be required. Celiac disease may be screened for with serum immunoglobulin A (IgA) endomysial antibody and tissue transglutaminase antibody determinations.

C. Bone Densitometry DXA is used to determine the bone density of the lumbar spine and hip. Bone densitometry should be performed on all patients who are at risk for osteoporosis or osteomalacia or have pathologic fractures or radiographic evidence of diminished bone density. This test delivers negligible radiation, and the measurements are quite accurate. However, bone densitometry cannot distinguish osteoporosis from osteomalacia; in fact, both are often present. Also, the bone mineral density does not directly measure bone quality and is only fairly successful at predicting fractures. Vertebral bone mineral density may be misleadingly high in compressed vertebrae and in patients with extensive arthritis.

DXA also overestimates the bone mineral density of taller persons and underestimates the bone mineral density of smaller persons. Quantitative CT delivers more radiation but is more accurate in the latter situations.

Bone mineral density in typically expressed in g/cm2, for which there are different normal ranges for each bone and for each type of DXA-measuring machine. The “T score” is a simplified way of reporting bone density in which the patient’s bone mineral density is compared to the young normal mean and expressed as a standard deviation score. The World Health Organization has established criteria for defining osteoporosis in postmenopausal white women, based on T score: T score ≥ –1.0: Normal.

T score –1.0 to –2.5: Osteopenia (“low bone density”).

T score < –2.5: Osteoporosis.

T score < –2.5 with a fracture: Severe osteoporosis.

This classification is somewhat arbitrary and there really is no bone mineral density fracture threshold; instead, the fracture risk increases about twofold for each standard deviation drop in bone mineral density. In fact, most women with fragility fractures have bone densities above –2.5. Surveillance DXA bone densitometry is recommended for postmenopausal women with a frequency according to their T scores: obtain DXA every 5 years for

1146

CMDT 2013

Chapter 26

T scores –1.0 to –1.5, every 3–5 years for scores –1.5 to –2.0, and every 1–2 years for scores under –2.0.

The “Z score” is used to express bone density in premenopausal women, younger men, and children, The Z score is a statistical term that is used for expressing an individual’s bone density as standard deviation from agematched, race-matched, and sex-matched means.

``Differential Diagnosis Osteopenia and fractures can be caused by osteomalacia (see below) and bone marrow neoplasia such as myeloma or metastatic bone disease. These conditions coexist in many patients.

``Treatment A. General Measures For prevention and treatment of osteoporosis, the diet should be adequate in protein, total calories, calcium, and vitamin D. Pharmacologic corticosteroid doses should be reduced or discontinued if possible. Thiazides may be useful if hypercalciuria is present. High-impact physical activity (eg, jogging) significantly increases bone density in men and women. Stair-climbing increases bone density in women. Patients who cannot exercise vigorously should be encouraged to engage in other exercise regularly, thereby increasing strength and reducing the risk of falling. Weight training is helpful to increase muscle strength as well as bone density. Measures should be taken to avoid falls at home (eg, adequate lighting, handrails on stairs, handholds in bathrooms). Patients who have weakness or balance problems must use a cane or a walker; rolling walkers should have a brake mechanism. Balance exercises can reduce the risk of falls. Patients should be kept active; bedridden patients should be given active or passive exercises.

The spine may be adequately supported (though braces or corsets are usually not well tolerated), but rigid or excessive immobilization must be avoided. Alcohol and smoking should be avoided.

B. Specific Measures Several treatment options are available, so a regimen is tailored to each patient. Generally, treatment is indicated for all women with osteoporosis (T scores below –2.5) and for all patients who have had fragility fractures. Prophylactic treatment should also be considered for patients with advanced osteopenia (T scores between –2.0 and –2.5).

1. Vitamin D and calcium—Osteoporosis and osteomalacia often coexist (see Osteomalacia section). Sun exposure and vitamin D supplementation are useful in preventing and treating osteomalacia but not osteoporosis. Vitamin D supplementation reduces the incidence of vertebral fractures by 37% and may slightly reduce the incidence of nonvertebral fractures. Oral vitamin D is given in doses of 800-2000 international units daily. Vitamin D supplementation is especially required during winter months and for patients having prolonged hospitalization or nursing home care, for patients with serum levels of 25-hydroxyvitamin D below 20 ng/mL, and those with intestinal malabsorption.

Calcium supplementation does not reduce the fracture risk in otherwise healthy postmenopausal women. One meta-analysis concluded that calcium supplementation is associated with a 27% increased risk of myocardial infarction; however, methodologic shortcomings in that study have raised doubts about its validity. Conversely, the Women’s Health Initiative found that myocardial infarction rates were not significantly higher among postmenopausal women taking calcium. Calcium supplements may increase the risk of calcium-containing kidney stones, unless taken with meals. Some patients experience gastrointestinal upset with calcium supplements. Therefore, calcium supplementation should probably be given only to those patients whose diets are low in calcium. More important is the assurance of adequate vitamin D through sun exposure or oral vitamin D supplementation. If calcium supplementation is given, it should include vitamin D. Calcium supplementation may be given as calcium citrate (0.4–0.7 g elemental calcium per day) or calcium carbonate (1–1.5 g elemental calcium per day).

2. Bisphosphonates—Bisphosphonates all work similarly, inhibiting osteoclast-induced bone resorption. They increase bone density significantly and reduce the incidence of both vertebral and nonvertebral fractures.

Bisphosphonates have also been effective in preventing corticosteroid-induced osteoporosis. To ensure intestinal absorption, oral bisphosphonates must be taken in the morning with at least 8 oz of plain water at least 40 minutes before consumption of anything else. The patient must remain upright after taking bisphosphonates to reduce the risk of esophagitis. These medications are excreted in the urine. However, no dosage adjustments are required for patients with creatinine clearances above 35 mL/min.

There has been little experience giving bisphosphonates to patients with severe kidney disease; if given, the dose would need to be greatly reduced and serum phosphate levels monitored.

Bisphosphonates may be given orally once monthly or weekly. Available oral preparations include alendronate, 70 mg orally once weekly (tablet or solution), and risedronate, 35 mg orally once weekly. Both these medications reduce the risk of both vertebral and nonvertebral fractures. Studies sponsored by the manufacturer of alendronate found that alendronate was significantly more potent than risedronate and equally well tolerated. Another bisphosphonate, ibandronate sodium, is taken once monthly in a dose of 150 mg orally. Once-monthly ibandronate is convenient and reduces the risk of vertebral fractures but not nonvertebral fractures; its effectiveness has not been directly compared with other bisphosphonates. Oral bisphosphonates can cause nausea, chest pain, and hoarseness. Erosive esophagus can occur, particularly in patients with hiatal hernia and gastroesophageal reflux.

For patients who cannot tolerate oral bisphosphonates or for whom oral bisphosphonates are contraindicated, intravenous bisphosphonates are available. Zoledronic acid is a third-generation bisphosphonate and a potent osteoclast inhibitor. It can be given every 12 months in doses of 2–4 mg intravenously over at least 15–30 minutes. Pamidronate can be given in doses of 30–60 mg by

Endocrine Disorders slow intravenous infusion in normal saline solution every 3–6 months.

Bisphosphonate therapy can cause several side effects that are collectively known as the acute-phase response.

Such a response occurs in 42% of patients following the first infusion of zoledronic acid and usually starts within the first few days following the infusion. Among patients receiving their first infusion of zoledronic acid, these adverse side effects have included fever, chills, or flushing (20%); musculoskeletal pain (20%); nausea, vomiting, or diarrhea (8%); nonspecific symptoms, such as fatigue, dyspnea, edema, headache, or dizziness (22%); and eye inflammation (0.6%). The acute-phase response is most commonly seen after the first dose of bisphosphonate (particularly zoledronic acid) and tends to diminish with time. Symptoms are transient, lasting several days and usually resolving spontaneously but typically recurring with subsequent doses. For patients experiencing a severe acute-phase response with zoledronic acid, intravenous pamidronate can substitute for zoledronic acid for subsequent treatment. Additionally, patients who experience an especially severe acute-phase response can be given prophylactic corticosteroids and ondansetron prior to subsequent bisphosphonate infusions.

Osteonecrosis of the jaw is a rare complication of bisphosphonate therapy for osteoporosis. A painful, necrotic, nonhealing lesion of the jaw occurs, particularly after tooth extraction. About 95% of jaw osteonecrosis cases have occurred with high-dose therapy with zoledronic acid or pamidronate for patients with myeloma or solid tumor osteolytic metastases. Only about 5% of cases have occurred in patients receiving oral (or, less frequently, intravenous) bisphosphonate doses for osteoporosis. The incidence of osteonecrosis is estimated to be about 1:100,000 patients treated for osteoporosis and 1:100 patients being treated for cancer. In a prospective 3-year trial of 7714 women who received intravenous zoledronic acid 5 mg/year, there were no cases of osteonecrosis. For patients with painful osteonecrotic exposed bone, treatment is 90% effective (without resolution of the exposed bone) using antibiotics along with 0.12% chlorohexidine antiseptic mouthwash. Patients receiving bisphosphonates must receive regular dental care and try to avoid dental extraction.

Atypical “chalkstick” fractures of the femur occur rarely in patients taking bisphosphonates. Bisphosphonate use for more than 5 years is associated with 2.7-fold risk in subtrochanteric or shaft fractures; but the absolute risk is low at about 1 fracture per 1000 bisphosphonate users yearly. In one study, atypical femoral fractures developed in 4 of 327 patients after receiving at least 24 intravenous bisphosphonate infusions for bone metastases. Atypical fractures are subtrochanteric or diaphyseal, occur with little trauma, and are usually transverse as opposed to the more typical comminuted or spiral femoral shaft fractures.

Bilateral femoral fractures occur in 27%. About 70% of affected patients have had prodromal thigh pain prior to the fracture. The risk for atypical femoral fractures is particularly increased among patients concurrently taking high-dose corticosteroids and those receiving treatment for more than 5 years. Teriparatide may be helpful to promote

CMDT 2013

1147

healing of such fractures. Despite this rare complication, the overall risk of hip fracture is reduced among patients taking bisphosphonates for up to 5 years.

Patients taking oral bisphosphonates have an increased risk of developing esophageal cancer. In North America and Europe, the incidence of esophageal cancer at age 60–79 is about 1 per 1000 population over 5 years; this risk is estimated to increase to about 2 per 1000 with administration of oral bisphosphonates for 5 years or longer.

In patients taking bisphosphonates, hypercalcemia is seen in 20% and serum PTH levels increase above normal in 10%, mimicking primary hyperparathyroidism. Hypo­ calcemia occurs frequently, resulting in secondary hyperparathyroidism.

The half-life of alendronate in bone is 10 years. Therefore, bisphosphonates may be discontinued after a 5-year course of therapy. Repeat bone densitometry may be obtained after 3 years of bisphosphonate therapy. Bone density falls in 18% of patients during their first year of treatment with bisphosphonates, but 80% of such patients have gain in bone density with continued bisphosphonate treatment.

3. Sex hormones—Hypogonadal women who take estrogen replacement therapy (ERT) have a lower risk of developing osteoporosis. Postmenopausal estrogen replacement is valuable as an osteoporosis prevention measure and this should be one factor in the complex decision about whether to take ERT. Low doses of estrogen appear to be adequate to prevent postmenopausal osteoporosis (see Estrogen Replacement Therapy). Once osteoporosis has developed, estrogen replacement is not an effective treatment. Men with hypogonadism may be treated with testosterone (see Male Hypogonadism).

4. Selective estrogen receptor modulators— Raloxifene, 60 mg/d orally, can be used by postmenopausal women in place of estrogen for prevention of osteoporosis.

Bone density increases about 1% over 2 years in postmenopausal women versus 2% increases with estrogen replacement. It reduces the risk of vertebral fractures by about 40% but does not appear to reduce the risk of nonvertebral fractures. Raloxifene produces a reduction in LDL cholesterol but not the rise in high-density lipoprotein (HDL) cholesterol seen with estrogen. It has no direct effect on coronary plaque. Unlike estrogen, raloxifene does not reduce hot flushes; in fact, it often intensifies them. It does not relieve vaginal dryness. Unlike estrogen, raloxifene does not cause endometrial hyperplasia, uterine bleeding, or cancer, nor does it cause breast soreness. The risk of breast cancer is reduced 76% in women taking raloxifene for 3 years. Since it is a potential teratogen, it is relatively contraindicated in women capable of pregnancy.

Raloxifene increases the risk for thromboembolism and should not be used by women with such a history. Leg cramps can also occur.

5. Teriparatide—Teriparatide (Forteo, Parathar) is an analog of PTH. Teriparatide stimulates the production of new collagenous bone matrix that must be mineralized.

Patients receiving teriparatide must have sufficient intake of vitamin D and calcium. When administered to patients

1148

CMDT 2013

Chapter 26

with osteoporosis in doses of 20 mcg/d subcutaneously for 2 years, teriparatide dramatically improves bone density in most bones except the distal radius. Teriparatide may also be used to promote healing of atypical femoral chalkstick fractures associated with bisphosphonate therapy. The recommended dose should not be exceeded, since teriparatide has caused osteosarcoma in rats when administered in very high doses. Patients with Paget disease of bone or patients with open epiphyses or hypercalcemia should not use the drug. Patients with a past history of osteosarcoma or chondrosarcoma should not use this medication. Side eff­ects may include dizziness and leg cramps. Teriparatide is approved only for a 2-year course of treatment.

Teriparatide should be used with caution in patients if they are also taking corticosteroids and thiazide diuretics along with oral calcium supplementation because hypercalcemia may develop.

Following a course of teriparatide, a course of bisphosphonates should be considered in order to retain the improved bone density.

6. Calcitonin—A nasal spray of calcitonin-salmon (Miacalcin) is available that contains 2200 units/mL in 2-mL metered-dose bottles. The usual dose is one puff (0.09 mL, 200 international units) once daily, alternating nostrils. Nasal administration causes significantly less nausea and flushing than the parenteral route. However, nasal symptoms such as rhinitis and epistaxis occur commonly; other less common adverse reactions include flu-like symptoms, allergy, arthralgias, back pain, and headache.

Five years of therapy increases bone 2–3% and reduces the number of new vertebral fractures. Both nasal and parenteral calcitonin have analgesic effects on bone pain from fractures; reduction of pain may be noted within 2–4 weeks after commencing therapy. Calcitonin reduces the incidence of vertebral fractures, but its effect upon nonvertebral fractures has not been established.

osteomalacia. Bisphosphonates and raloxifene can reverse progressive osteopenia and osteoporosis and decrease fracture risk.

Hypogonadal men are also at risk for developing osteoporosis. Testosterone administration can prevent osteoporosis. Men with prostate cancer may not receive testosterone replacement and should be monitored with bone densitometries. Bisphosphonate therapy can reverse progressive osteopenia and osteoporosis in men.

Bolland MJ et al. Effect of calcium supplements on risk of myocardial infarctions and cardiovascular events: metaanalysis.

BMJ. 2010 Jul;341:c3691. [PMID: 20671013] Cauley JA et al. Once-yearly zoledronic acid and days of ­disability, bed rest and back pain: randomised controlled HORIZON pivotal fracture trial. J Bone Miner Res. 2011 May;26(5):984–92. [PMID: 21089141] Charopoulos I et al. The role and efficacy of denosumab in the treatment of osteoporosis: an update. Expert Opin Drug Saf. 2011 Mar;10(2):205–17. [PMID: 21208140] Hollick RJ et al. Role of bisphosphonates in the management of postmenopausal osteoporosis: an update on recent safety anxieties. Menopause Int. 2011 Jun;17(2):66–72. [PMID: 21693503] Howe TE et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD000333. [PMID: 21735380] Mazziotti G et al. Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med. 2010 Oct;123(10):877–84.

[PMID: 20920685] Moen MD et al. Denosumab: a review of its use in the treatment of postmenopausal osteoporosis. Drugs Aging. 2011 Jan;28(1): 63–82. [PMID: 21174488] Puhaindran ME et al. Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am. 2011 Jul 6;93(13):1235–42. [PMID: 21776577] Ryan CS et al. Osteoporosis in men: the value of laboratory testing.

Osteoporos Int. 2011 June;22(6):1845–53. [PMID: 20936403]

7. Denosumab—This is a monoclonal antibody that inhibits the proliferation and maturation of preosteoclasts into mature osteoclast bone-resorbing cells. It does this by binding to the osteoclast receptor activator of nuclear factorkappa B ligand (RANKL). Denosumab is administered in doses of 60 mg subcutaneously every 6 months. It increases bone mineral density more than oral alendronate. It has been relatively well tolerated, with an 8% incidence of flu-like symptoms. It can decrease serum calcium and should not be administered to patients with hypocalcemia. Other side effects include the development of eczema and dermatitis, serious infections, new malignancies, and pancreatitis. Its efficacy is comparable to bisphosphonates. However, its longterm safety remains unknown, so it is reserved for patients with severe osteoporosis who have not tolerated or not responded to bisphosphonates. It is extremely expensive.

OSTEOMALACIA

``Prognosis

``General Considerations

Bone mineral density densitometries can detect whether progressive osteopenia or frank osteoporosis is developing.

Hypogonadal women, especially those not receiving HRT, must ensure sufficient intake of vitamin D to prevent

Defective mineralization of the growing skeleton in childhood causes permanent bone deformities (rickets).

Defective skeletal mineralization in adults is known as osteomalacia. It is caused by any condition that results in

``

EssentialS of diagnosis

Painful proximal muscle weakness (especially pelvic girdle); bone pain and tenderness. `` Decreased bone density from defective mineralization. `` Laboratory abnormalities may include increased alkaline phosphatase, decreased 25-hydroxy­ vitamin D, hypocalcemia, hypocalciuria, hypo­ phosphatemia, secondary hyperparathyroidism. `` Classic radiologic features may be present. ``

Endocrine Disorders inadequate calcium or phosphate mineralization of bone osteoid.

``Etiology (Table 26–11) A. Vitamin D Deficiency and Resistance Vitamin D is predominantly synthesized in the skin during exposure to ultraviolet B light. Vitamin D is also consumed in the diet from plants (ergocalciferol, D2) or animals/fish (cholecalciferol, D3). Both forms of vitamin D are converted in the liver to 25-hydroxyvitamin D (25OHD); 25OHD is subsequently converted in various tissues (mainly kidney) to 1,25-dihydroxyvitamin D (1,25[OH]2D), the active hormone whose production is regulated by serum calcium, phosphorus, and PTH. 1,25(OH)2D binds to cytoplasmic vitamin D receptors, increasing the absorption of dietary calcium from the intestine and increasing the reabsorption of calcium in the renal tubule, thereby reducing calcium loss in the urine. 1,25(OH)2D also stimulates bone osteoblasts to release RANKL that stimulates osteoclasts, which release calcium from bone.

Unexpectedly, vitamin D receptors have been found in most tissues in the body (eg, brain, heart, breast, prostate) that have nothing to do with calcium homeostasis. The function of these vitamin D receptors is unknown. Much of the recent interest in vitamin D has been sparked by

Table 26–11. Causes of osteomalacia.1 Vitamin disorders Decreased availability of vitamin D Insufficient sunlight exposure Nutritional deficiency of vitamin D Malabsorption; aging, excess wheat bran, bariatric surgery, pancreatic enzyme deficiency Nephrotic syndrome Vitamin D–dependent rickets type I Liver disease Chronic kidney disease Kidney transplantation Phenytoin, carbamazepine, valproate, or barbiturate therapy Dietary calcium deficiency Phosphate deficiency Decreased intestinal absorption Nutritional deficiency of phosphorus Phosphate-binding antacid therapy Increased renal loss X-linked hypophosphatemic rickets Tumoral hypophosphatemic osteomalacia Association with other disorders, including paraproteinemias, glycogen storage diseases, neurofibromatosis, Wilson disease, Fanconi syndrome, renal tubular acidosis, and alcoholism Inhibitors of mineralization Aluminum Bisphosphonates Disorders of bone matrix Hypophosphatasia Fibrogenesis imperfecta Axial osteomalacia 1

See Table 26–10 for causes of osteoporosis.

CMDT 2013

1149

epidemiology studies relating an increased prevalence of cancer, diabetes mellitus, cardiovascular disease, and multiple sclerosis to lower serum levels of 25OHD. Such association studies suffer from the fact that healthy individuals have more sun exposure and a better diet, such that low serum 25OHD levels may be the result of the disease rather than the cause of it.

Vitamin D deficiency is the most common cause of osteomalacia and its incidence is increasing throughout the world as a result of diminished exposure to sunlight caused by urbanization, automobile and public transportation, modest clothing, and sunscreen use. Significant vitamin D deficiency (serum 25OHD < 50 nmol/L or < 20 ng/mL) was found in 24.3% of postmenopausal women from 25 countries in the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The incidence varied: < 1% in Southeast Asia, 29% in the United States, and 36% in Italy. Severe vitamin D deficiency (serum 25OHD < 25 nmol/L or < 10 ng/mL) was found in 4% of these women; 3.5% in the United States and 12.5% in Italy. Among US men over age 65 years, 25% have serum 25OHD levels below 20 ng/mL; men over age 75 with such low vitamin D levels have particularly accelerated bone loss. Vitamin D deficiency is particularly common in the institutionalized elderly, with the incidence exceeding 60% in some groups not receiving vitamin D supplementation. Deficiency of vitamin D may arise from insufficient sun exposure, malnutrition, or malabsorption (due to pancreatic insufficiency, cholestatic liver disease, sprue, inflammatory bowel disease, jejunoileal bypass, Billroth type II gastrectomy). Orlistat is a weightloss medication that causes fat malabsorption and reduced serum 25OHD levels. Cholestyramine binds bile acids necessary for vitamin D absorption. Patients with severe nephrotic syndrome lose large amounts of vitamin D–binding protein in the urine, and osteomalacia may also develop.

Anticonvulsants (eg, phenytoin, carbamazepine, valproate, phenobarbital) inhibit the hepatic production of 25OHD and sometimes cause osteomalacia. Phenytoin can also directly inhibit bone mineralization. Serum levels of 1,25(OH)2D are usually normal.

Vitamin D–dependent rickets type I is caused by a rare autosomal recessive disorder with a defect in the renal enzyme 1-α-hydroxylase leading to defective synthesis of 1,25(OH)2D. It presents in childhood with rickets and alopecia; osteomalacia develops in adults with this condition unless treated with oral calcitriol in doses of 0.5–1 mcg daily.

Vitamin D–dependent rickets type II (better known as hereditary 1,25[OH]2D-resistant rickets) is caused by a genetic defect in the 1,25(OH)2D receptor. Patients have hypocalcemia with childhood rickets and adult osteomalacia. Alopecia is common. These patients respond variably to oral calcitriol in very large doses (2–6 mcg daily).

B. Deficient Calcium Intake Rickets and osteomalacia continue to be common problems in many tropical countries despite adequate exposure to sunlight. A nutritional deficiency of calcium can occur in any severely malnourished patient. Some degree of calcium deficiency is common in the elderly, since intestinal

1150

CMDT 2013

Chapter 26

calcium absorption declines with age. Ingestion of excessive wheat bran also causes calcium malabsorption.

C. Phosphate Deficiency Clinical symptoms of phosphate deficiency include severe muscle weakness and bone pain. Phosphate deficiency in childhood causes classic rickets, whereas phosphate deficiency in adulthood causes osteomalacia.

1. Genetic disorders—Fibroblast growth factor-23 (FGF23) is a phosphaturic factor (phosphatonin) that is secreted by bone osteoblasts in response to elevated serum phosphate levels. Families with autosomal dominant hypophosphatemic rickets have a gain-of-function mutation in the gene encoding FGF23 that makes it resistant to proteolytic cleavage, thereby increasing serum FGF23 levels. In X-linked hypophosphatemic rickets, there is a mutation in the gene encoding PHEX endopeptidase, which fails to cleave FGF23, resulting in elevated serum FGF23 levels. An autosomal recessive form of hypophosphatemic rickets is caused by mutations in DMP1, a transcription factor that regulates FGF23 production in bone. All three conditions have high serum FGF23 levels causing hypophosphatemia and bone mineral depletion.

Sodium-phosphate cotransporters (NPT2a or NPT2c) reabsorb phosphate from the proximal renal tubule.

Mutations in the genes encoding them or in NHERF1 cause hypophosphatemia, bone mineral depletion, and calcium-phosphate kidney stones.

2. Tumor-induced osteomalacia—A variety of mesenchymal tumors (87% benign) secrete fibroblast growth factor-23 (FGF23, see above) and cause marked hypophosphatemia due to renal phosphate wasting. Such tumors are usually small and are often difficult to locate. The condition is characterized by hypophosphatemia, excessive ­phosphaturia, reduced or normal serum 1,25(OH)2D concentrations, and osteomalacia. Serum levels of FGF23 are elevated. Such tumors are often small and difficult to find, frequently lying in extremities. Imaging with 111 In-octreotide or 18FDG-PET should include the entire body and may be helpful in localizing these tumors.

3. Other causes of hypophosphatemia—Osteomalacia from hypophosphatemia can be caused by poor nutrition, and severe hypophosphatemia can occur with refeeding after starvation. Other causes of hypophosphatemic osteo­ malacia include alcoholism and chelation of phosphate in the gut by aluminum hydroxide antacids, calcium acetate (Phos-Lo), or sevelamer hydrochloride (Renagel). Excessive renal phosphate losses are also seen in proximal renal tubular acidosis and Fanconi syndrome.

D. Aluminum Toxicity Bone mineralization is inhibited by aluminum. Osteomalacia may occur in patients receiving long-term renal hemodialysis with tap water dialysate or from aluminum-containing antacids used to reduce phosphate levels. Osteomalacia may develop in patients being maintained on long-term total parenteral nutrition if the casein hydrolysate used for amino acids contains high levels of aluminum.

E. Hypophosphatasia Hypophosphatasia, a deficiency of bone alkaline phosphatase effect, is a rare genetic cause of osteomalacia that is commonly misdiagnosed as osteoporosis. The incidence in the United States is about 1 in 100,000 live births; about 1 in 300 adults is a carrier. Many different mutations in the gene (designated ALPL) encoding bone alkaline phosphatase have been described, and transmission can be either autosomal recessive or autosomal dominant. The phenotypic presentation of hypophosphatasia is extremely variable. At its worst extreme, it can present as a stillborn without dentition or calcified bones. At its mildest, hypophosphatasia can present in middle age with premature loss of teeth, foot pain (due to metatarsal stress fractures), thigh pain (due to femoral pseudofractures), or arthritis (due to chondrocalcinosis). Serum alkaline phosphatase (collected in a non-EDTA tube) is low for age in patients with hypophosphatasia. To confirm the diagnosis, a 24-hour urine should be assayed for phosphoethanolamine, a substrate for tissue-nonspecific alkaline phosphatase, whose excretion is always elevated in patients with hypophosphatasia. Prenatal genetic testing, by way of chorionic villus biopsy, is available for the infantile form of hypophosphatasia. There is no proven therapy for hypophosphatasia, except for supportive care. Teriparatide, a useful therapy for osteoporosis, has been administered to some patients with hypophosphatasia, but its long-term efficacy is unknown.

F. Fibrogenesis Imperfecta Ossium This rare condition sporadically affects middle-aged patients, who present with progressive bone pain and pathologic fractures. Bones have a dense “fishnet” appearance on radiographs. Serum alkaline phosphatase levels are elevated. Some patients have a monoclonal gammopathy, indicating a possible plasma cell dyscrasia causing an impairment in osteoblast function and collagen disarray. Remission has been reported after repeated courses of melphalan, corticosteroids, and vitamin D analog over 3 years.

``Clinical Findings The clinical manifestations of defective bone mineralization depend on the age at onset and the severity. In infants and children, vitamin D deficiency can cause severe hypocalcemia with muscle weakness; heart failure; laryngospasm; and rickets with bone pain, fractures, bone deformities, and dental problems. In adults, osteomalacia is typically asymptomatic at first. Eventually, bone pain occurs, along with muscle weakness due to calcium deficiency. Pathologic fractures may occur with little or no trauma. Vitamin D deficiency has also been associated with a possible increased risk of multiple sclerosis, rheumatoid arthritis, diabetes mellitus (types 1 and 2), and other conditions, but the causal relationship is uncertain.

``Diagnostic Tests Serum is obtained for calcium, albumin, phosphate, alkaline phosphatase, PTH, and 25[OH]D3 determinations.

Bone densitometry helps document the degree of osteopenia. Radiographs may show diagnostic features.

Endocrine Disorders In one series of biopsy-proved osteomalacia, alkaline phosphatase was elevated in 94% of patients; the calcium or phosphorus was low in 47% of patients; 25(OH)D3 was low in 29% of patients; pseudofractures were seen in 18% of patients; and urinary calcium was low in 18% of patients.

1,25(OH)2D3 may be low even when 25(OH)D2 levels are normal.

Bone biopsy is not usually necessary but is diagnostic of osteomalacia if there is significant unmineralized osteoid.

``Differential Diagnosis Osteomalacia is often seen together with osteoporosis, and its presence can be inferred by finding low serum levels of 25(OH) vitamin D, low serum calcium, or low serum phosphate. A high serum alkaline phosphatase may be present in severe osteomalacia but not osteoporosis. The relative contribution of the two entities to diminished bone density may not be apparent until treatment, since a dramatic rise in bone density is often seen with therapy for osteomalacia.

Phosphate deficiency must be distinguished from hypophosphatemia seen in hyperparathyroidism.

``Prevention & Treatment To obtain adequate sunshine vitamin D, the face, arms, hands, or back must have sun exposure without sunscreen for 15 minutes at least twice weekly. The main natural food source of vitamin D is fish, particularly salmon, mackerel, cod liver oil, and sardines or tuna canned in oil. Most commercial cow’s milk is fortified with vitamin D at about 400 international units per quart; however, skim milk and other dairy products contain much less vitamin D. Many vitamin supplements contain plant-derived ­vitamin D2, which has less biologic availability than once believed. Over-the-counter multivitamin/mineral supplements contain variable amounts of vitamin D, and vitamin D toxicity has occurred from two different multivitamins sold in the United States. Therefore, it is prudent to recommend that patients take a dedicated vitamin D supplement from a reliable manufacturer.

In sunlight-deprived individuals (eg, veiled women, confined patients, or residents of higher latitudes during winter), the recommended daily allowance should be ­vitamin D3 1000 international units daily. In such individuals, vitamin D3 supplements should be given prophylactically. Patients receiving long-term phenytoin therapy may be treated prophylactically with vitamin D, 50,000 international units orally every 2–4 weeks.

Frank vitamin D deficiency is treated with ergocalciferol (D2), 50,000 international units orally once weekly for 8 weeks. Following that, vitamin D3 (cholecalciferol) supplementation is used at a dose of 2000 international units daily. Vitamin D3 is more effective than vitamin D2 in raising serum levels of 25(OH)D. Some patients require longterm supplementation with ergocalciferol of up to 50,000 international units weekly. In patients with intestinal malabsorption, oral doses of 25,000–100,000 international units of vitamin D3 daily may be required. Some patients with steatorrhea respond better to oral 25(OH)D3 (calcifediol), 50–100 mcg/d. Serum levels of 25(OH)D should be

CMDT 2013

1151

monitored and the dosage of vitamin D adjusted to maintain serum 25(OH)D levels above 30 ng/mL. During treatment with high-dose vitamin D, serum calcium should also be monitored to avoid hypercalcemia.

Beyond increasing the intestinal absorption of calcium, vitamin D supplementation may have additional effects.

Vitamin D supplementation has been associated with improved muscle strength and a reduced fall risk, factors that reduce the risk of bone fracture.

The addition of calcium supplements to vitamin D is probably not necessary for the prevention of osteomalacia in the majority of otherwise well-nourished patients.

However, patients with malabsorption or poor nutrition should receive calcium supplementation. Recommended doses of calcium are as follows: calcium citrate (eg, Citracal), 0.4–0.6 g elemental calcium per day, or calcium carbonate (eg, OsCal, Tums), 1–1.5 g elemental calcium per day.

Calcium supplements are best administered with meals.

In hypophosphatemic osteomalacia, nutritional deficiencies are corrected, aluminum-containing antacids are discontinued, and patients with renal tubular acidosis are given bicarbonate therapy. In patients with sporadic adultonset hypophosphatemia, hyperphosphaturia, and low serum 1,25(OH)2D levels, a search is conducted for occult tumors that may be resected; whole-body MRI scanning may be required.

For those with X-linked or idiopathic hypophosphatemia and hyperphosphaturia, oral phosphate supplements must be given long-term; calcitriol, 0.25–0.5 mcg/d, is given also to improve the impaired calcium absorption caused by the oral phosphate. If necessary, rhGH may be added to the above regimen to reduce phosphaturia.

Patients with hypophosphatasia have been treated with teriparatide with improvement in bone pain and fracture healing.

Araki T et al. Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States. J Clin Endocrinol Metab. 2011 Dec;96(12):3603–8. [PMID: 21917864] Bell DS. Protean manifestations of vitamin D deficiency, part 1: the epidemic of deficiency. South Med J. 2011 May;104(5): 331–4. [PMID: 21606711] Bergwitz C et al. Case records of the Massachusetts General Hospital. Case 33-2011. A 56-year-old man with hypophosphatemia. N Engl J Med. 2011 Oct;365(17):1625–35. [PMID: 22029985] Chehade H et al. Acute life-threatening presentation of vitamin D deficiency rickets. J Clin Endocrinol Metab. 2011 Sep;96(9): 2681–3. [PMID: 21795457] Chong WH et al. The importance of whole body imaging in tumor-induced osteomalacia. J Clin Endocrinol Metab. 2011 Dec;96(12):3599–600. [PMID: 22143830] Heaney RP et al. Vitamin D3 is more potent than vitamin D2 in humans. J Clin Endocrinol Metab. 2011 Mar;96(3):E447–52.

[PMID: 21177785] Hollick MF et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911–30.

[PMID: 21646368] Russell LA. Osteoporosis and osteomalacia. Rheum Dis Clin North Am. 2010 Nov;36(4):665–80. [PMID: 21092845]

1152

CMDT 2013

Chapter 26

PAGET DISEASE OF BONE (Osteitis Deformans) ``

EssentialS of diagnosis

Often asymptomatic.

Bone pain may be the first symptom. `` Kyphosis, bowed tibias, large head, deafness, and frequent fractures. `` Serum calcium and phosphate normal; alkaline phosphatase elevated; urinary hydroxyproline elevated. `` Dense, expanded bones on radiographs. `` ``

may have serum alkaline phosphatase levels within the normal range. A serum bone-specific alkaline phosphatase determination can be useful for patients with a normal serum total alkaline phosphatase level and to distinguish the source of an elevated serum alkaline phosphatase as being from bone (rather than liver). Other markers of bone turnover may be elevated. Serum C-telopeptide (CTx) is usually high. Urinary hydroxyproline is also elevated in active disease. Serum calcium may be elevated, particularly if the patient is at bed rest. A serum 25-OH vitamin D determination should be obtained to screen for vitamin D deficiency, which can also present with an increased ­alkaline phosphatase and bone pain. Also, any vitamin D deficiency should be corrected before prescribing a bisphosphonate.

C. Imaging

``General Considerations Paget disease of bone is a common condition manifested by one or more bony lesions having high bone turnover and disorganized osteoid formation. Involved bones become vascular, weak, and deformed. Paget disease is most common in the United Kingdom but is also common in other areas of the world, particularly in those with British ancestry. It is uncommon in Africa, Asia, and Scandinavia. Paget disease is present in 1–2% of the population of the United States and affects men more commonly than women. It is usually diagnosed in patients over age 40 years and its prevalence doubles with each decade thereafter, reaching an incidence of about 10% after age 80. It is usually discovered incidentally during radiology imaging or because of incidentally discovered elevations in serum alkaline phosphatase. The cause of Paget disease is unknown. However, there is often a genetic component since about 15% of affected patients have a first-degree relative with the disease. Similar familial disorders occur at an earlier age and their genetics has been established.

``Clinical Findings A. Symptoms and Signs Paget disease is often mild and asymptomatic. Only 27% of affected individuals are symptomatic at the time of diagnosis. It can involve just one bone (monostotic) or multiple bones (polyostotic), particularly the skull, femur, tibia, ­pelvis, and humerus. The affected bones are typically involved right away and the disease tends not to involve additional bones during its course. Pain is the usual first symptom. It may occur in the involved bone or in an adjacent joint, which can be involved with degenerative arthritis.

The bones can become soft, leading to bowed tibias, kyphosis, and frequent “chalkstick” fractures with slight trauma. If the skull is involved, the patient may report headaches and an increased hat size. Deafness may occur. Increased vascularity over the involved bones causes increased warmth and can cause vascular “steal” syndromes.

B. Laboratory Findings Serum alkaline phosphatase is usually markedly elevated.

However, some patients with limited monostotic involvement

On radiographs, the initial lesions are typically osteolytic, with focal radiolucencies (“osteoporosis circumscripta”) in the skull or advancing flame-shaped lytic lesions in long bones. Bone lesions may subsequently become sclerotic and have a mixed lytic and sclerotic appearance. The affected bones eventually become thickened and deformed. Tech­ netium pyrophosphate bone scans are helpful in delineating activity of bone lesions even before any radiologic changes are apparent.

``Differential Diagnosis Certain rare familial osteoclastic bone disorders share phenotypic homologies with Paget disease of bone. Familial expansile osteolysis, familial early-onset Paget disease, and familial skeletal hyperphosphatasia are autosomal dominant disorders caused by different tandem duplications of the gene encoding RANK, resulting in its constitutive activation. Juvenile Paget disease is an autosomal recessive disorder caused by an inactivating mutation in the gene encoding osteoprotegerin. The syndrome of Paget disease, inclusion body myopathy, and frontotemporal dementia is caused by a mutation in the gene that encodes valosincontaining protein.

Paget disease must be differentiated from primary bone lesions such as osteogenic sarcoma, multiple myeloma, and fibrous dysplasia and from secondary bone lesions such as metastatic carcinoma and osteitis fibrosa cystica. Fibrogenesis imperfecta ossium is a rare symmetric disorder that can mimic the features of Paget disease; alkaline phosphatase is likewise elevated. If serum calcium is elevated, hyperparathyroidism may be present in some patients as well.

``Complications If immobilization occurs, hypercalcemia and renal calculi may develop. Vertebral collapse may lead to spinal cord compression. The increased vascularity may give rise to high-output cardiac failure. Arthritis frequently develops in joints adjacent to involved bone.

Extensive skull involvement may cause cranial nerve palsies from impingement of the neural foramina.

Involvement of the petrous temporal bone frequently causes hearing loss (mixed sensorineural and conductive)

Endocrine Disorders and occasionally tinnitus or vertigo. Vertebral involvement can cause compression of spinal nerves, resulting in radiculopathy or paralysis. The affected bones have a high blood flow and can thereby cause a vascular “steal” syndrome.

Skull involvement can cause a vascular steal syndrome with somnolence or ischemic neurologic events; the optic nerve may be affected, resulting in loss of vision. Vertebral involvement can cause a vascular steal syndrome with paralysis. Jaw involvement can cause the teeth to spread intraorally and become misaligned.

Osteosarcoma may develop in long-standing lesions but is rare (< 1%). Sarcomatous change is suggested by a marked increase in bone pain, sudden rise in alkaline phosphatase, and appearance of a new lytic lesion.

``Treatment Asymptomatic patients may require only clinical surveillance and no treatment. However, treatment should be considered for asymptomatic patients who have extensive involvement of the skull, long bones, or vertebrae. Patients must be monitored carefully before, during, and after treatment with clinical examinations and serial serum alkaline phosphatase determinations.

A. Bisphosphonates Bisphosphonates are the treatment of choice for Paget disease. Bisphosphonates are usually given cyclically.

Therapy is given until a therapeutic response occurs, as evidenced by normalization of the serum alkaline phosphatase. After a course of therapy, patients are given a break for about 3 months or until the serum alkaline phosphatase begins rising again; another cycle is then commenced.

Patients frequently experience a paradoxical increase in pain soon after commencing bisphosphonate therapy; this is the “first dose effect” and the pain usually subsides with further treatment. Flu-like symptoms occur fairly frequently. Osteonecrosis, particularly of the jaw, is rare but can occur spontaneously or after tooth extraction.

The oral bisphosphonates should all be taken with 8 oz of plain water only; they are relatively contraindicated in patients with a history of esophagitis, esophageal stricture, dysphagia, hiatal hernia, or achalasia. Alendronate, 40 mg orally daily for 3–6 month cycles, must be taken in the morning with water only, at least 30-40 minutes before any other food, liquids, or medications. Patients should not lie down for at least 30 minutes after taking alendronate to reduce the risk of esophagitis. Tiludronate, 400 mg orally daily for 3-month cycles, should not be taken within 2 hours of meals, aspirin, indomethacin, calcium, magnesium, or aluminum-containing antacids. Esophagitis is uncommon, but it is still advisable to avoid recumbency for 30 minutes after dosing; but the drug may be taken in the evening as well as during the day. The most common side effects have been gastrointestinal, including abdominal pain in 13% and ­nausea in 9%. Risedronate, 30 mg orally daily for 2-month cycles, must be taken in the morning with water only, at least 30–40 minutes before any other food, liquids, or medications. Patients should not lie down for at least 30 minutes after taking risedronate to reduce the risk of esophagitis.

CMDT 2013

1153

Parenteral bisphosphonates are particularly useful for patients who cannot tolerate oral bisphosphonates.

Intravenous bisphosphonates can produce clinical improvements that last several months. Serum alkaline phosphatase levels may continue to drop for 6 months after treatment.

They appear to be more effective than oral bisphosphonates but have more systemic side effects. Postinfusion fever, fatigue, myalgia, bone pain, and ocular problems occur commonly and may sometimes be severe. Serious side effects are rare but include uveitis and acute kidney disease. Hypocalcemia is common and may be severe, especially if intravenous bisphosphonates are given along with loop diuretics. It is advisable to administer calcium and vitamin D supplements, especially during the first 2 weeks following treatment. Asthma may occur in aspirin-sensitive patients. Pamidronate, 30–60 mg is infused intravenously over 2–4 hours. Depending on the disease severity, one to three additional doses may be given days or weeks apart.

Zoledronic acid can be given every 6–12 months in doses of 2–5 mg intravenously over 20 minutes. Six months following a single infusion of zoledronic acid, patients had a clinical response rate of 96%, compared with 74% in patients receiving daily oral risedronate. Intravenous zoledronic acid has been demonstrated to be significantly more effective than daily risedronate. Bisphosphonates have significant side effects (see Osteoporosis, above).

B. Nasal Calcitonin-Salmon Calcitonin-salmon, 200 international units/unit dose spray, is administered as one spray daily, alternating nostrils. It is just as effective as the parenteral preparation and is associated with fewer side effects. Nasal irritation may occur, as may occasional epistaxis. However the use of calcitonin has declined dramatically with the introduction of more potent bisphosphonates.

``Prognosis The prognosis in general is good, but sarcomatous changes (in 1–3%) can alter it unfavorably. In general, the prognosis is worse the earlier in life the disease starts. Fractures usually heal well. In the severe forms, marked deformity, intractable pain, and cardiac failure are found. These complications should become rare with prompt bisphosphonate treatment.

Colina M et al. Paget’s disease of bone: a review. Rheumatol Int. 2008 Sep;28(11):1069–75. [PMID: 18592244] Mahmood W et al. Proposed new approach for treating Paget’s disease of bone. Ir J Med Sci. 2011 Mar;180(1):121–4.

[PMID: 21132539] Michou L et al. Emerging strategies and therapies for treat­ ment of Paget’s disease of bone. Drug Des Devel Ther.

2011;5:225–39. [PMID: 21607019] Reid IR et al. Bisphosphonates in Paget’s disease. Bone. 2011 Jul;49(1):89–94. [PMID: 20832512] Roodman GD. Insights into the pathogenesis of Paget’s disease. Ann N Y Acad Sci. 2010 Mar;1192:176–80. [PMID: 20392234] Silverman SL. Paget disease of bone: therapeutic options. J Clin Rheumatol. 2008 Oct;14(5):299–305. [PMID: 18838910]

1154 cc

CMDT 2013

Chapter 26

DISEASES OF THE ADRENAL CORTEX

ACUTE ADRENOCORTICAL INSUFFICIENCY (Adrenal Crisis) ``

EssentialS of diagnosis

Weakness, abdominal pain, fever, confusion, ­ ausea, vomiting, and diarrhea. n `` Low blood pressure, dehydration; skin pigmentation may be increased. `` Serum potassium high, sodium low, BUN high. `` Cosyntropin (ACTH ) unable to stimulate an 1–24 increase in serum cortisol to ≥ 20 mcg/dL. ``

B. Laboratory Findings The eosinophil count may be high. Hyponatremia or hyperkalemia (or both) are usually present. Hypoglycemia is frequent. Hypercalcemia may be present. Blood, sputum, or urine culture may be positive if bacterial infection is the precipitating cause of the crisis.

The diagnosis is made by a simplified cosyntropin stimulation test, which is performed as follows: (1) Synthetic ACTH1–24 (cosyntropin), 0.25 mg, is given intramuscularly. (2) Serum is obtained for cortisol between 30 and 60 minutes after cosyntropin is administered. Normally, serum cortisol rises to at least 20 mcg/dL. For patients receiving corticosteroid treatment, hydrocortisone must not be given for at least 8 hours before the test. Other corticosteroids (eg, prednisone, dexamethasone) do not interfere with specific assays for cortisol.

Plasma ACTH is markedly elevated if the patient has primary adrenal disease (generally > 200 pg/mL).

``General Considerations

``Differential Diagnosis

Acute adrenal insufficiency is an emergency caused by insufficient cortisol. Crisis may occur in the course of treatment of chronic insufficiency, or it may be the presenting manifestation of adrenal insufficiency. Acute adrenal crisis is more commonly seen in primary adrenal insufficiency (Addison disease) than in disorders of the pituitary gland causing secondary adrenocortical hypofunction.

Adrenal crisis may occur in the following situations: (1) during stress, (eg, trauma, surgery, infection, hyperthyroidism, or prolonged fasting) in a patient with latent or treated adrenal insufficiency; (2) following sudden withdrawal of adrenocortical hormone in a patient with chronic insufficiency or in a patient with temporary insufficiency due to suppression by exogenous corticosteroids or megestrol; (3) following bilateral adrenalectomy or removal of a functioning adrenal tumor that had suppressed the other adrenal; (4) following sudden destruction of the pituitary gland (pituitary necrosis), or when thyroid hormone is given to a patient with hypoadrenalism; and (5) following injury to both adrenals by trauma, hemorrhage, anticoagulant therapy, thrombosis, infection or, rarely, metastatic carcinoma; (6) following administration of etomidate, which is used intravenously for rapid anesthesia induction or intubation.

Acute adrenal insufficiency must be distinguished from other causes of shock (eg, septic, hemorrhagic, cardiogenic).

Hyperkalemia is also seen with gastrointestinal bleeding, rhabdomyolysis, hyperkalemic paralysis, and certain drugs (eg, angiotensin-converting enzyme [ACE] inhibitors, spironolactone). Hyponatremia is seen in many other conditions (eg, hypothyroidism, diuretic use, heart failure, cirrhosis, vomiting, diarrhea, severe illness, or major surgery). Acute adrenal insufficiency must be distin­ guished from an acute abdomen in which neutrophilia is the rule, whereas adrenal insufficiency is characterized by a relative lymphocytosis and eosinophilia.

More than 90% of serum cortisol is protein bound and low serum levels of binding proteins result in misleadingly low serum cortisol determinations by most assays. Nearly 40% of critically ill patients, with serum albumin < 2.5 g/dL, have low serum total cortisol levels but normal serum free cortisol or salivary cortisol levels and normal adrenal function.

``Clinical Findings A. Symptoms and Signs The patient complains of headache, lassitude, nausea and vomiting, abdominal pain, and often diarrhea. Confusion or coma may be present. Fever may be 40.6 °C or more.

The blood pressure is low. Recurrent hypoglycemia and reduced insulin requirements may present in patients with preexisting type 1 diabetes mellitus. Other signs may include cyanosis, dehydration, skin hyperpigmentation, and sparse axillary hair (if hypogonadism is also present).

Meningococcemia may be associated with purpura and adrenal insufficiency secondary to adrenal infarction (Waterhouse–Friderichsen syndrome).

``Treatment A. Acute Phase If the diagnosis is suspected, draw a blood sample for cortisol determination and treat with hydrocortisone, 100–300 mg intravenously, and saline immediately, without waiting for the results. Thereafter, give hydrocortisone phosphate or hydrocortisone sodium succinate, 100 mg intravenously immediately, and continue intravenous infusions of 50–100 mg every 6 hours for the first day. Give the same amount every 8 hours on the second day and then adjust the dosage in view of the clinical picture.

Since bacterial infection frequently precipitates acute adrenal crisis, broad-spectrum antibiotics should be administered empirically while waiting for the results of initial cultures. Hypoglycemia should be vigorously treated while serum electrolytes, BUN, and creatinine are monitored.

B. Convalescent Phase When the patient is able to take food by mouth, give oral hydrocortisone, 10–20 mg every 6 hours, and reduce dosage

Endocrine Disorders to maintenance levels as needed. Most patients ultimately require hydrocortisone twice daily (am, 10–20 mg; pm, 5–10 mg). Mineralocorticoid therapy is not needed when large amounts of hydrocortisone are being given, but as the dose is reduced it is usually necessary to add fludrocortisone acetate, 0.05–0.2 mg orally daily. Some patients never require fludrocortisone or become edematous at doses of more than 0.05 mg once or twice weekly. Once the crisis has passed, the patient must be evaluated to assess the degree of permanent adrenal insufficiency and to establish the cause if possible.

``Prognosis Rapid treatment will usually be lifesaving. However, acute adrenal insufficiency is frequently unrecognized and untreated since its manifestations mimic more common conditions; lack of treatment leads to shock that is unresponsive to volume replacement and vasopressors, resulting in death.

Hahner S et al. Therapeutic management of adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009 Apr;23(2):167–79. [PMID: 19500761] Marik PE. Critical illness-related corticosteroid insufficiency.

Chest. 2009 Jan;135(1):181–93. [PMID: 19136406] Marik PE et al. Requirement of perioperative stress doses of corticosteroids: a systematic review of the literature. Arch Surg. 2008 Dec;143(12):1222–6. [PMID: 19075176] Maxime V et al. Adrenal insufficiency in septic shock. Clin Chest Med. 2009 Mar;30(1):17–27. [PMID: 19186278]

CHRONIC ADRENOCORTICAL INSUFFICIENCY (Addison Disease) ``

EssentialS of diagnosis

Weakness, fatigability, anorexia, weight loss; ­ ausea and vomiting, diarrhea; abdominal pain, n muscle and joint pains; amenorrhea. `` Sparse axillary hair; increased skin pigmentation, especially of creases, pressure areas, and nipples. `` Hypotension, small heart. `` Serum sodium may be low; potassium, calcium, and BUN may be elevated; neutropenia, mild anemia, eosinophilia, and relative lymphocytosis may be present. `` Plasma cortisol levels are low or fail to rise after administration of corticotropin. `` Plasma ACTH level is elevated. ``

``General Considerations Addison disease refers to primary adrenal insufficiency caused by dysfunction or absence of the adrenal cortices. It is distinct from secondary adrenal insufficiency caused by deficient secretion of ACTH. (See Anterior Hypopituitarism.)

CMDT 2013

1155

Addison disease is an uncommon disorder with a prevalence of about 140 per million and an annual incidence of about 4 per million in the United States. Addison disease is characterized by chronic deficiency of cortisol, with consequent elevation of serum ACTH causing skin pigmentation that can be subtle or strikingly dark. Patients with destruction of the adrenal cortices or with classic 21-hydroxylase deficiency also have mineralocorticoid deficiency with hyponatremia, volume depletion, and hyperkalemia. In contrast, mineralocorticoid deficiency is not present in patients with familial glucocorticoid deficiency and Allgrove syndrome (see below).

``Etiology Autoimmune destruction of the adrenals is the most common cause of Addison disease in the United States (accounting for about 80% of spontaneous cases). With such autoimmunity, adrenal function decreases over several years as it progresses to overt adrenal insufficiency. It may occur alone or as part of a polyglandular autoimmune (PGA) syndrome. Type 1 PGA is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome and is caused by a defect in T cellmediated immunity inherited as an autosomal recessive trait. Type 1 PGA usually presents in early childhood with mucocutaneous candidiasis, followed by hypoparathyroidism and dystrophy of the teeth and nails; Addison disease usually appears by age 15 years. Partial or late expression of the syndrome is common. A varied spectrum of associated diseases may be seen in adulthood, including hypogonadism, hypothyroidism, pernicious anemia, alopecia, vitiligo, hepatitis, malabsorption, and Sjögren syndrome.

Type 2 PGA usually presents in young adults age 20–40 years, usually women (female:male ratio is 3:1). The following conditions may be presentations of type 2 PGA: autoimmune adrenal insufficiency, type 1 diabetes mellitus, or autoimmune thyroid disease (usually hypothyroidism, sometimes hyperthyroidism). The combination of Addison disease and hypothyroidism is known as Schmidt syndrome.

Patients may also have vitiligo, alopecia areata, Sjögren syndrome, or celiac sprue. Type 2 PGA is also associated with autoimmune primary ovarian failure; testicular failure (5%); pernicious anemia (4%); and, rarely, autoimmune hypophysitis, encephalitis, or hypoparathyroidism (late-onset).

Tuberculosis as a leading cause of Addison disease is relatively rare in the United States but common where tuberculosis is more prevalent.

Bilateral adrenal hemorrhage may occur during sepsis, heparin-associated thrombocytopenia or anticoagulation, or with antiphospholipid antibody syndrome. It may occur in association with major surgery or trauma, presenting about 1 week later with pain, fever, and shock. It may also occur spontaneously and present with flank pain; MRI may show adrenal enlargement with increased T2-weighted imaging.

Adrenoleukodystrophy is an X-linked peroxisomal disorder causing accumulation of very long-chain fatty acids in the adrenal cortex, testes, brain, and spinal cord. It may present at any age and accounts for one-third of cases of Addison disease in boys. Aldosterone deficiency occurs in 9%. Hypogonadism is common. Psychiatric symptoms

1156

CMDT 2013

Chapter 26

often include mania, psychosis, or cognitive impairment.

Neurologic deterioration may be severe or mild (particularly in heterozygote women), mimics symptoms of multiple sclerosis, and can occur years after the onset of adrenal insufficiency.

Rare causes of adrenal insufficiency include lymphoma, metastatic carcinoma, coccidioidomycosis, histoplasmosis, cytomegalovirus infection (more frequent in patients with AIDS), syphilitic gummas, scleroderma, amyloid disease, and hemochromatosis.

Congenital adrenal insufficiency occurs in several conditions. Familial glucocorticoid deficiency is an autosomal recessive disease that is caused by mutations in the adrenal ACTH receptor (melanocortin 2 receptor, MC2R). It is characterized by isolated cortisol deficiency and ACTH resistance and may present with neonatal hypoglycemia, frequent infections, and dark skin pigmentation. Triple A (Allgrove) syndrome is caused by a mutation in the AAAS gene that encodes a protein known as ALADIN (alachrima, achalasia, adrenal insufficiency, neurologic disorder). It is characterized by variable expression of the following: adrenal ACTH resistance with cortisol deficiency, achalasia, alacrima, nasal voice, autonomic dysfunction, and neuromuscular disease of varying severity (hyperreflexia to spastic paraplegia). Cortisol deficiency usually presents in infancy but may not occur until the third decade of life.

Congenital adrenal hypoplasia causes adrenal insufficiency due to absence of the adrenal cortex; patients may also have hypogonadotropic hypogonadism, myopathy, and high-frequency hearing loss.

Patients with hereditary defects in adrenal enzymes for cortisol synthesis develop congenital adrenal hyperplasia due to ACTH stimulation. The most common enzyme defect is P450c21 (21-hydroxylase). Patients with severely defective P450c21 enzymes manifest deficiency of mineralocorticoids (salt wasting) in addition to deficient cortisol and excessive androgens. Women with milder enzyme defects have adequate cortisol but develop hirsutism in adolescence or adulthood and are said to have “late-onset” congenital adrenal hyperplasia. (See Hirsutism section.) Patients with deficient P450c17 (17 hydroxylase) have varying degrees of adrenocortical deficiency with associated hypertension, hypokalemia, and primary hypogonadism.

Drugs that cause primary adrenal insufficiency include mitotane and abiraterone acetate (Zytiga), which inhibits P450c17 for the treatment of men with prostate cancer but causes adrenocortical deficiency with hypertension and hyperkalemia.

``Clinical Findings A. Symptoms and Signs The symptoms may include weakness and fatigability, weight loss, myalgias, arthralgias, fever, anorexia, nausea and vomiting, anxiety, and mental irritability. Some of these symptoms may be due to high serum levels of IL-6.

Pigmentary changes consist of diffuse tanning over nonexposed as well as exposed parts or multiple freckles; hyperpigmentation is especially prominent over the knuckles, elbows, knees, and posterior neck and in palmar creases. Nail beds may develop longitudinal pigmented bands. Nipples and

areolas tend to darken. The skin in pressure areas such as the belt or brassiere lines and the buttocks also darkens. New scars are pigmented. Some patients have associated vitiligo (10%). Emotional changes are common. Hypoglycemia, when present, may worsen the patient’s weakness and mental functioning, rarely leading to coma. Manifestations of other autoimmune disease (see above) may be present.

Patients tend to be hypotensive and orthostatic; about 90% have systolic blood pressures under 110 mm Hg; blood pressure over 130 mm Hg is rare. Other findings may include a small heart, hyperplasia of lymphoid tissues, and scant axillary and pubic hair (especially in women).

Patients with adult-onset adrenoleukodystrophy may present with neuropsychiatric symptoms, sometimes without adrenal insufficiency.

B. Laboratory Findings The WBC count usually shows moderate neutropenia, lymphocytosis, and a total eosinophil count over 300/mcL. Among patients with chronic Addison disease, the serum sodium is usually low (90%) while the potassium is elevated (65%). Patients with diarrhea may not be hyperkalemic.

Fasting blood glucose may be low. Hypercalcemia may be present. Young men with idiopathic Addison disease are screened for adrenoleukodystrophy by determining plasma very long-chain fatty acid levels; affected patients have high levels.

Low plasma cortisol (< 3 mcg/dL) at 8 am is diagnostic, especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL). The diagnosis is made by a simplified cosyntropin stimulation test, which is performed as follows: (1) Synthetic ACTH1–24 (cosyntropin), 0.25 mg, is given intramuscularly. (2) Serum is obtained for cortisol 45 minutes after cosyntropin is administered.

Normally, serum cortisol rises to at least 20 mcg/dL. For patients receiving corticosteroid treatment, hydrocortisone must not be given for at least 8 hours before the test. Other corticosteroids (eg, prednisone, dexamethasone) do not interfere with specific assays for cortisol.

Serum DHEA levels are under 1000 ng/mL in 100% of patients with Addison disease and a serum DHEA above 1000 ng/mL excludes the diagnosis. However, serum DHEA levels below 1000 ng/mL are not helpful, since about 15% of the general population have such low DHEA levels, particularly children and elderly individuals. Antiadrenal antibodies are found in the serum in about 50% of cases of autoimmune Addison disease. Antibodies to thyroid (45%) and other tissues may be present.

Salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency is usually diagnosed at birth in females due to ambiguous genitalia. Males and patients with milder enzyme defects may present later. The diagnosis of adrenal insufficiency is made as above. The specific diagnosis requires elevated serum levels of 17-OH progesterone.

Elevated plasma renin activity (PRA) indicates the presence of depleted intravascular volume and the need for higher doses of fludrocortisone replacement. Serum epinephrine levels are low in patients with adrenal insufficiency, since these patients do not have the high local concentrations of cortisol that are required to induce the enzyme PNMT in adrenal medulla for the synthesis of epinephrine from norepinephrine.

Endocrine Disorders

CMDT 2013

1157

C. Imaging

``Treatment

When Addison disease is not clearly autoimmune, a chest radiograph is obtained to look for tuberculosis, fungal infection, or cancer as possible causes. CT scan of the abdomen will show small noncalcified adrenals in autoimmune Addison disease. The adrenals are enlarged in about 85% of cases due to metastatic or granulomatous disease.

Calcification is noted in about 50% of cases of tuberculous Addison disease but is also seen with hemorrhage, fungal infection, pheochromocytoma, and melanoma.

A. General Measures

``Differential Diagnosis

Replacement therapy should include a combination of corticosteroids and mineralocorticoids. In mild cases, hydrocortisone alone may be adequate.

Hydrocortisone is the drug of choice. Most addisonian patients are well maintained on 15–30 mg of hydrocortisone orally daily in two divided doses, two-thirds in the morning and one-third in the late afternoon or early evening. Some patients respond better to prednisone in a dosage of about 2–4 mg orally in the morning and 1–2 mg in the evening. Adjustments in dosage are made according to the clinical response. A proper dose usually results in a normal WBC count differential.

The dose of corticosteroid should be raised in case of infection, trauma, surgery, stressful diagnostic procedures, or other forms of stress. The maximum hydrocortisone dose for severe stress is 50 mg intravenously or intramuscularly every 6 hours. Lower doses, oral or parenteral, are used for less severe stress. The dose is reduced back to normal as the stress subsides.

Fludrocortisone acetate has a potent sodium-retaining effect. The dosage is 0.05–0.3 mg orally daily or every other day. In the presence of postural hypotension, hyponatremia, or hyperkalemia, the dosage is increased. Similarly, in patients with fatigue, elevated PRA indicates the need for a higher replacement dose of fludrocortisone. If edema, hypokalemia, or hypertension ensues, the dose is decreased.

DHEA is given to some patients with adrenal insufficiency. In a double-blind clinical trial, patients taking DHEA 50 mg orally each morning experienced an improved sense of well-being, increased muscle mass, and a reversal in bone loss at the femoral neck. DHEA replacement did not improve fatigue, cognitive problems, or sexual dysfunction; however, its placebo effect may be significant in that regard. Older women who receive DHEA should be monitored for androgenic effects. Because over-thecounter preparations of DHEA have variable potencies, it is best to have the pharmacy formulate this with pharmaceutical-grade micronized DHEA.

Patients with secondary adrenal insufficiency (hypopituitarism) lack ACTH and have normal skin pigmentation, in contrast to patients with Addison disease who have ­elevated levels of ACTH that can increase skin pigmentation. Patients with ACTH deficiency have normal mineralocorticoid production and do not develop hyperkalemia.

Addison disease should be considered in any patient with unexplained hypotension, but shock is usually caused by more common conditions such as gastrointestinal bleeding or sepsis. Hyponatremia or hyperkalemia may be seen in numerous other conditions (see Chapter 21). Drospirenone, the progestin component in certain oral contraceptives, may cause hyperkalemia.

Unexplained weight loss, weakness, and anorexia may be mistaken for occult cancer. Nausea, vomiting, diarrhea, and abdominal pain may be misdiagnosed as intrinsic gastrointestinal disease. The hyperpigmentation may be confused with that due to ethnic or racial factors. Weight loss may simulate anorexia nervosa. The neurologic manifestations of Allgrove syndrome and adrenoleukodystrophy (especially in women) may mimic multiple sclerosis. Hemochromatosis also enters the differential diagnosis of skin hyperpigmentation, but it should be remembered that it may truly be a cause of Addison disease as well as diabetes mellitus and hypoparathyroidism. Serum ferritin is increased in most cases of hemochromatosis and is a useful screening test.

About 17% of patients with AIDS have symptoms of cortisol resistance. AIDS can also cause frank adrenal insufficiency.

Hyperkalemia can be caused by isolated hypoaldosteronism and is seen in various conditions. Hyporeninemic hypoaldosteronism can be caused by renal tubular acidosis type IV and is commonly seen with diabetic nephropathy, hypertensive nephrosclerosis, tubulointerstitial diseases, and AIDS (see Chapter 21). Hyperreninemic hypoaldosteronism can be seen in patients with myotonic dystrophy, aldosterone synthase deficiency, and congenital adrenal hyperplasia. Hyperkalemia, hypertension, and hypogonadism may present as delayed adolescence or in adulthood in some patients with congenital adrenal hyperplasia (CYP17 deficiency); cortisol deficiency is also usually present but may not be clinically evident.

``Complications Any of the complications of the underlying disease (eg, tuberculosis) are more likely to occur, and the patient is susceptible to intercurrent infections that may precipitate crisis. Associated autoimmune diseases are common (see above).

Patients with Addison disease must be thoroughly informed about their condition. All infections should be treated immediately and vigorously, with the dose of hydrocortisone increased appropriately (see below). Patients are advised to wear a medical alert bracelet or medal reading, “Adrenal insufficiency—takes hydrocortisone.”

B. Specific Therapy

``Prognosis The life expectancy of patients with Addison disease has been considered reasonably normal, as long as they are very compliant with taking their medications and are knowledgeable about their condition. However, a retrospective Swedish study of 1675 patients with Addison disease found an unexpected increase in all-cause mortality, mostly from cardiovascular disease, malignancy, and infectious causes.

Associated conditions can pose additional health risks. For example, patients with adrenoleukodystrophy or Allgrove

1158

CMDT 2013

Chapter 26

syndrome may suffer from neurologic disease. Patients with adrenal tuberculosis may have a serious systemic infection that requires treatment. Adrenal crisis can occur in patients who stop their medication or who experience stress such as infection, trauma, or surgery without appropriately higher doses of corticosteroids. Patients who take excessive doses of corticosteroid replacement can develop Cushing syndrome, which imposes its own risks.

Many patients with treated Addison disease complain of chronic low-grade fatigue.

Many patients with Addison disease do not feel entirely normal, despite glucocorticoid and mineralocorticoid replacement. This may be due, in part, to the inadequacy of oral replacement to duplicate cortisol’s normal circadian rhythm. Also, patients with Addison disease are deficient in epinephrine, but replacement epinephrine is not available.

Fatigue may also be an indication of suboptimal dosing of medication, electrolyte imbalance, or concurrent problems such as hypothyroidism or diabetes mellitus. However, most patients with Addison disease are able to live fully active lives.

Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab. 2009 Apr;944:1059–67.

[PMID: 19349469] Betterle C et al. Autoimmune Addison’s disease. Endocr Dev. 2011;20:161–72. [PMID: 21164269] Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med. 2009 May 28;360(22):2328–39. [PMID: 19474430] Chakera AJ et al. Addison disease in adults: diagnosis and management. Am J Med. 2010 May;123(5):409–13. [PMID: 20399314] Gurnell EM et al. Long-term DHEA replacement in primary adrenal insufficiency: a randomized, controlled trial. J Clin Endocrinol Metab. 2008 Feb;93(2):400–9. [PMID: 18000094] Koetz K et al. Management of steroid replacement in adrenal insufficiency. Minerva Endocrinol. 2010 Jun;35(2):61–72.

[PMID: 20595936] Neary N et al. Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 2010 Jun; 17(3):217–23. [PMID: 20375886] Speiser PW et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Sep;95(9): 4133–60.

[PMID: 20823466]

``General Considerations The term Cushing “syndrome” refers to the manifestations of excessive corticosteroids, commonly due to supraphysiologic doses of corticosteroid drugs and rarely due to spontaneous production of excessive corticosteroids by the adrenal cortex. Cases of spontaneous Cushing syndrome are rare (2.6 new cases yearly per million population) and have several possible causes.

About 40% of cases are due to Cushing “disease,” by which is meant the manifestations of hypercortisolism due to ACTH hypersecretion by the pituitary. Cushing disease is caused by a benign pituitary adenoma that is typically very small (< 5 mm) and usually located in the anterior pituitary (98%) or in the posterior pituitary (2%). It is at least three times more frequent in women than men.

Excessive ingestion of gamma-hydroxybutyric acid (GHB, Xyrem) can also induce ACTH-dependent Cushing syndrome that resolves after the drug is stopped.

About 10% of cases are due to nonpituitary ACTHsecreting neoplasms (eg, small cell lung carcinoma), which produce excessive amounts of ectopic ACTH. Hypokalemia and hyperpigmentation are commonly found in this group.

About 15% of cases are due to ACTH from a source that cannot be initially located.

About 30% of cases are due to excessive autonomous secretion of cortisol by the adrenals—independently of ACTH, serum levels of which are usually low. Most such cases are due to a unilateral adrenal tumor. Benign adrenal adenomas are generally small and produce mostly cortisol; adrenocortical carcinomas are usually large when discovered and can produce excessive cortisol as well as androgens, with resultant hirsutism and virilization. ACTH-independent macronodular adrenal hyperplasia can also produce hypercortisolism due to the adrenal cortex cells’ abnormal stimulation by hormones such as catecholamines, arginine vasopressin, serotonin, hCG/LH, or gastric inhibitory polypeptide; in the latter case, hypercortisolism may be intermittent and food dependent and serum ACTH may not be completely suppressed. Pigmented bilateral adrenal macronodular adrenal hyperplasia is a rare cause of Cushing syndrome in children and young adults; it may be an isolated condition or part of the Carney complex.

``Clinical Findings CUSHING SYNDROME (Hypercortisolism) ``

EssentialS of diagnosis

Central obesity, muscle wasting, thin skin, hirsutism, purple striae. `` Psychological changes. `` Osteoporosis, hypertension, poor wound healing. `` Hyperglycemia, glycosuria, leukocytosis, lymphocytopenia, hypokalemia. `` Elevated serum cortisol and urinary free cortisol.

Lack of normal suppression by dexamethasone. ``

A. Symptoms and Signs Patients with Cushing syndrome usually have central obesity with a plethoric “moon face,” “buffalo hump,” supraclavicular fat pads, protuberant abdomen, and thin extremities.

Muscle atrophy causes weakness, with difficulty standing up from a seated position or climbing stairs. Patients may also experience oligomenorrhea or amenorrhea (or erectile dysfunction in the male), backache, headache, hypertension, osteoporosis, avascular necrosis of bone, acne, and superficial skin infections. Patients may have thirst and polyuria (with or without glycosuria), renal calculi, glaucoma, purple striae (especially around the thighs, breasts, and abdomen), and easy bruisability. Unusual bacterial or fungal infections are common. Wound healing is impaired. Mental symptoms may range from diminished ability to concentrate to

Endocrine Disorders increased lability of mood to frank psychosis. Patients are susceptible to opportunistic infections.

B. Laboratory Findings Glucose tolerance is impaired as a result of insulin resistance.

Polyuria is present as a result of increased free water clearance; diabetes mellitus with glycosuria may worsen it. Patients with Cushing syndrome often have leukocytosis with relative granulocytosis and lymphopenia. Hypokalemia may be present, particularly in cases of ectopic ACTH secretion.

``Tests for Hypercortisolism The easiest screening test for Cushing syndrome is the dexamethasone suppression test: dexamethasone 1 mg is given orally at 11 pm and serum is collected for cortisol determination at about 8 am the next morning; a cortisol level < 5 mcg/dL (< 135 nmol/L, fluorometric assay) or < 1.8 mcg/dL (< 49 nmol/L, high-performance liquid chromatography [HPLC] assay) excludes Cushing syndrome with some certainty. However, 8% of established patients with pituitary Cushing disease have dexamethasone-suppressed cortisol levels < 2 mcg/dL. Therefore, when other clinical criteria suggest hypercortisolism, further evaluation is warranted even in the face of normal dexamethasone-suppressed serum cortisol. Antiseizure drugs (eg, phenytoin, phenobarbital, primidone) and rifampin accelerate the metabolism of dexamethasone, causing a lack of cortisol suppression by dexamethasone. Estrogens—during pregnancy or as oral contraceptives or ERT—may also cause lack of dexamethasone suppressibility.

Patients with an abnormal dexamethasone suppression test require further investigation, which includes a 24-hour urine collection for free cortisol and creatinine. An abnormally high 24-hour urine free cortisol (or free cortisol to creatinine ratio of > 95 mcg cortisol/g creatinine) helps confirm hypercortisolism. A misleadingly high urine free cortisol excretion occurs with high fluid intake. In pregnancy, urine free cortisol is increased, while 17-hydroxycorticosteroids remain normal and diurnal variability of serum cortisol is normal. Carbamazepine and fenofibrate cause false elevations of urine free cortisol when determined by HPLC. A midnight serum cortisol level > 7.5 mcg/dL is indicative of Cushing syndrome and distinguishes it from other conditions associated with a high urine free cortisol (pseudo-Cushing states). Requirements for this test include being in the same time zone for at least 3 days, being without food for at least 3 hours, and having an indwelling intravenous line established in advance for the blood draw.

Late-night salivary cortisol assays are useful due to the inconvenience of obtaining a midnight blood specimen for serum cortisol. Assays are available that use liquid chromatography-tandem mass spectrometry. Midnight salivary cortisol levels are normally < 0.15 mcg/dL (4.0 nmol/L).

Midnight salivary cortisol levels that are consistently > 0.25 mcg/dL (7.0 nmol/L) are considered very abnormal. The late-night salivary cortisol test has a high sensitivity and specificity for Cushing syndrome, but false-positive and false-negative tests have occurred.

CMDT 2013

1159

Interestingly, hypercortisolism without Cushing syndrome can occur in several conditions, such as severe depression, anorexia nervosa, alcoholism, and familial cortisol resistance.

``Finding the Cause of Hypercortisolism Once hypercortisolism is confirmed, a plasma or serum ACTH is obtained. It must be collected properly in a plastic tube on ice and processed quickly by a laboratory with a reliable, sensitive assay. A level of ACTH below about 20 pg/mL indicates a probable adrenal tumor, whereas higher levels are produced by pituitary or ectopic ACTHsecreting tumors.

``Localizing Techniques In ACTH-independent Cushing syndrome, CT of the adrenals usually detects a mass lesion. Most such lesions are benign adrenal adenomas, but an adrenal carcinoma is suspected in the following circumstances: (1) diameter ≥ 4 cm; (2) nodule growth; or (3) atypical imaging: density on noncontrast CT > 10 Hounsfield units (HU) or CT contrast washout ≥ 60% or relative contrast washout ≥ 40% at 15 minutes after intravenous administration.

In ACTH-dependent Cushing syndrome, MRI of the pituitary demonstrates a pituitary lesion in about 50% of cases. Premature cerebral atrophy is often noted. When the pituitary MRI is normal or shows a tiny (< 5 mm diameter) irregularity that may be incidental, selective catheterization of the inferior petrosal sinus veins draining the pituitary is performed. ACTH levels in the inferior petrosal sinus that are more than twice the simultaneous peripheral venous ACTH levels are indicative of pituitary Cushing disease.

Inferior petrosal sinus sampling is also done during CRH administration, which ordinarily causes the ACTH levels in the inferior petrosal sinus to be over three times the peripheral ACTH level when the pituitary is the source of ACTH. When inferior petrosal sinus ACTH concentrations are not above the requisite levels, a search for an ectopic source of ACTH is undertaken. Location of ectopic sources of ACTH commences with CT scanning of the chest and abdomen, with special attention to the lungs (for carcinoid or small cell carcinomas), the thymus, the pancreas, and the adrenals. In patients with ACTH-dependent Cushing syndrome, chest masses should not be assumed to be the source of ACTH, since opportunistic infections are common, so it is prudent to biopsy a chest mass to confirm the pathologic diagnosis prior to resection.

CT scanning fails to detect the source of ACTH in about 40% of patients with ectopic ACTH secretion. 111In-­ octreotide (OCT, somatostatin receptor scintigraphy) scanning is also useful in detecting occult tumors. A lowdose scan with 6 mCi OCT is used first; a high-dose scan with 12 mCi OCT may be used if the low-dose scan gives equivocal results. 18FDG-PET scanning is not usually helpful. Some ectopic ACTH-secreting tumors elude discovery, necessitating bilateral adrenalectomy. The ectopic source of ACTH should continue to be sought, since it may become detectable by OCT or CT scanning at a later date.

1160

CMDT 2013

Chapter 26

In non-ACTH-dependent Cushing syndrome, a CT scan of the adrenals can localize the adrenal tumor in most cases.

``Differential Diagnosis Alcoholic patients can have hypercortisolism and many clinical manifestations of Cushing syndrome. Pregnant women have elevated serum ACTH levels, increased urine free cortisol, and high serum cortisol levels due to high serum levels of cortisol-binding globulin. Regular use of the “party drug” gamma hydroxybutyrate (GHB, sodium oxybate) has been reported to cause reversible ACTHdependent Cushing syndrome. Depressed patients also have hypercortisolism that can be nearly impossible to distinguish biochemically from Cushing syndrome but without clinical signs of Cushing syndrome. Some adolescents develop violaceous striae on the abdomen, back, and breasts; these are known as “striae distensae” and are not indicative of Cushing syndrome. Cushing syndrome can be misdiagnosed as anorexia nervosa (and vice versa) owing to the muscle wasting and extraordinarily high urine free cortisol levels found in anorexia. Patients with severe obesity frequently have an abnormal dexamethasone suppression test, but the urine free cortisol is usually normal, as is diurnal variation of serum cortisol. Patients with familial cortisol resistance have hyperandrogenism, hypertension, and hypercortisolism without actual Cushing syndrome.

Patients with familial partial lipodystrophy type I develop central obesity and moon facies, along with thin extremities due to atrophy of subcutaneous fat. However, these patients’ muscles are strong and may be hypertrophic, distinguishing this condition from Cushing syndrome.

Patients receiving antiretroviral therapy for HIV-1 infection frequently develop partial lipodystrophy with thin extremities and central obesity with a dorsocervical fat pad (“buffalo hump”) that may mimic Cushing syndrome.

``Complications Cushing syndrome, if untreated, produces serious morbidity and even death. The patient may suffer from any of the complications of hypertension or of diabetes mellitus.

Susceptibility to infections is increased. Compression fractures of the osteoporotic spine and aseptic necrosis of the femoral head may cause marked disability. Nephrolithiasis and psychosis may occur. Following bilateral adrenalectomy for Cushing disease, a pituitary adenoma may enlarge progressively, causing local destruction (eg, visual field impairment) and hyperpigmentation; this complication is known as Nelson syndrome.

``Treatment Cushing disease is best treated by transsphenoidal selective resection of the pituitary adenoma. After pituitary surgery, the rest of the pituitary usually returns to normal function; however, the pituitary corticotrophs remain suppressed and require 6–36 months to recover normal function.

Hydrocortisone or prednisone replacement therapy is necessary in the meantime. Patients who do not have a remission (or who have a recurrence) may be considered for

treatment with cabergoline 0.5–3.5 mg orally twice weekly, which was successful in 40% of patients in one small study.

Laparoscopic adrenalectomy should be offered to unresponsive patients. Another treatment option for patients with ACTH-secreting pituitary tumors is stereotactic pituitary radiosurgery (gamma knife or cyberknife), which normalizes urine free cortisol in two-thirds of patients within 12 months. Conventional radiation therapy results in a 23% cure rate. Pasireotide, a novel multireceptor-­ targeting somatostatin analog that has not yet received approval by the US FDA, is a potential treatment for refractory Cushing disease. Pasireotide (600–900 mcg subcutaneously twice daily) normalizes the urine free cortisol in at least 17% of patients with Cushing disease.

Pituitary radiosurgery can also be used to treat Nelson syndrome, the progressive enlargement of ACTH-secreting pituitary tumors following bilateral adrenalectomy. Patients who are not surgical candidates may be given a trial of ketoconazole in doses of about 200 mg orally every 6 hours; liver enzymes must be monitored for progressive elevation.

Adrenal neoplasms secreting cortisol are resected laparoscopically, if they are < 6 cm diameter. Postoperatively, the contralateral adrenal’s cortisol secretion is deficient, due to ACTH suppression, so postoperative hydrocortisone replacement is required until recovery occurs.

Patients with metastatic adrenocortical carcinoma have detectable cortisol levels following removal of the primary tumor. Metastases may not be visible on scanning. Patients with adrenal carcinoma should be treated postoperatively with mitotane for a course of 2–5 years, since it appears to improve prognosis (see below). Mitotane is given, beginning with 0.5 g twice daily with meals and increasing to 1 g twice daily within 2 weeks. The doses of mitotane are adjusted every 2–3 weeks ideally to reach serum levels of 14–20 mcg/ mL; however, only about half the patients can tolerate mitotane levels above 14 mcg/mL. Mitotane side effects include CNS depression, lethargy, hypogonadism, hypercholesterolemia, hypocalcemia, hepatotoxicity, leukopenia, hypertension, nausea, rash, TSH suppression with hypothyroidism, and primary adrenal insufficiency. Replacement hydrocortisone or prednisone should be started when mitotane doses reach 2 g daily. The replacement dose of hydrocortisone starts at 15 mg in the morning and 10 mg in the afternoon, but must often be doubled or tripled because mitotane increases cortisol metabolism and cortisol binding globulin levels; the latter can artifactually raise serum cortisol levels.

Ketoconazole or metyrapone can help suppress hypercortisolism in unresectable adrenal carcinoma.

Ectopic ACTH-secreting tumors should be located, when possible, and surgically resected. If that cannot be done, laparoscopic bilateral adrenalectomy is usually recommended. Medical treatment with a combination of mitotane (3–5 g/24 h), ketoconazole (0.4–1.2 g/24 h), and metyrapone (3–4.5 g/24 h) often suppresses the hypercortisolism. Octreotide LAR, 20–40 mg injected intramuscularly every 28 days, suppresses ACTH secretion in about one-third of such cases.

Patients who are successfully treated for Cushing ­syndrome typically develop “cortisol withdrawal syndrome,” even when given replacement corticosteroids for adrenal

Endocrine Disorders insufficiency. Manifestations can include hypotension, nausea, fatigue, arthralgias, myalgias, pruritus, and flaking skin.

Increasing the hydrocortisone replacement to 30 mg orally twice daily can improve these symptoms; the dosage is then reduced slowly as tolerated. Patients with Cushing syndrome are prone to develop osteoporosis. Bone densitometry is recommended for all patients and treatment is commenced for patients with osteoporosis. (See Osteoporosis section, above.)

``Prognosis The manifestations of Cushing syndrome regress with time, but patients are often left with residual mild cognitive impairment, muscle weakness, osteoporosis, and sequelae from vertebral fractures. Younger patients have a better chance for recovery and children with short stature may have catch-up growth following cure.

Patients with Cushing syndrome from a benign adrenal adenoma experience a 5-year survival of 95% and a 10-year survival of 90%, following a successful adrenalectomy.

Patients with Cushing disease from a pituitary adenoma experience a similar survival if their pituitary surgery is successful, which can be predicted if the postoperative nonsuppressed serum cortisol is < 2 mcg/dL. However, transsphenoidal surgery incurs a failure rate of about 10–20%, often due to the adenoma’s ectopic position or invasion of the cavernous sinus. Those patients who have a complete remission after transsphenoidal surgery have about a 15–20% chance of recurrence over the next 10 years. Patients with failed pituitary surgery may require pituitary radiation therapy, which has its own morbidity.

Laparoscopic bilateral adrenalectomy may be required; recurrence of hypercortisolism may occur as a result of growth of an adrenal remnant stimulated by high levels of ACTH. The prognosis for patients with ectopic ACTHproducing tumors depends on the aggressiveness and stage of the particular tumor. Patients with ACTH of unknown source have a 5-year survival rate of 65% and a 10-year survival rate of 55%.

In patients with adrenocortical carcinoma, the prognosis depends on the stage of the tumor at the time of surgery.

In patients with stage I–II disease, confined to the adrenal by surgical inspection and scan, the median 5-year survival is about 60% and long-term survival does occur. However, despite apparent complete resection in stage I–III tumors, visible metastases develop in about 40% of patients within 2 years. Adjuvant therapy with mitotane appears to improve the prognosis, with patients receiving mitotane having a 5-year survival of 87% versus 53% in those not receiving mitotane. Patients with advanced stage IV disease at the time of surgery have a poorer prognosis, but debulking surgery and therapy with mitotane may be beneficial.

AbdelMannan D et al. Peri-operative management of Cushing’s disease. Rev Endocr Metab Disord. 2010 Jun;11(2):127–34.

[PMID: 20556520] Doi M et al. Clinical features and management of ectopic ACTH syndrome at a single institute in Japan. Endocr J. 2010; 57(12):1061–9. [PMID: 21076235]

CMDT 2013

1161

Feelders RA et al. Medical treatment of Cushing’s syndrome: adrenal-blocking drugs and ketoconazole. Neuroendocri­ nology. 2010;92(Suppl 1):111–5. [PMID: 20829630] Kamenický P et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 2011 Sep;96(9):2796–804. [PMID: 21752886] Lacroix A. Approach to the patient with adrenocortical carcinoma. J Clin Endocrinol Metab. 2010 Nov;95(11):4812–22.

[PMID: 21051577] Pedroncelli AM. Medical treatment of Cushing’s disease: somatostatin analogues and pasireotide. Neuroendocrinology.

2010;92(Suppl 1):120–4. [PMID: 20829632] Pivonello R et al. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009 Jan;94(1):223–30. [PMID: 18957500] Tritos NA et al. Management of Cushing disease. Nat Rev Endocrinol. 2011 May;7(5):279–89. [PMID: 21301487] Yip L et al. The adrenal mass: correlation of histopathology with imaging. Ann Surg Oncol. 2010 Mar;17(3):846–52.

[PMID: 19960266]

HIRSUTISM & VIRILIZATION ``

EssentialS of diagnosis

Hirsutism, acne, menstrual disorders.

Virilization: increased muscularity, androgenic alopecia, deepening of the voice, clitoromegaly. `` Rarely, a palpable pelvic tumor. `` Urinary 17-ketosteroids and serum DHEAS and androstenedione elevated in adrenal disorders; variable in others. `` Serum testosterone is often elevated. `` ``

``General Considerations Hirsutism is defined as cosmetically unacceptable terminal hair growth that appears in women in a male pattern. Some degree of hirsutism affects about 5–10% of non-Asian women of reproductive age. The amount of hair growth deemed unacceptable depends on a woman’s ethnicity and familial and cultural norms. Hirsutism is quantitated using the Ferriman-Gallwey score in which hirsutism is graded from 0 (none) to 4 (severe) in nine areas of the body with a maximum possible score of 36; scores 8–15 indicate moderate hirsutism, while scores over 15 indicate severe hirsutism.

``Etiology Hirsutism may be idiopathic or familial or be caused by the following disorders: polycystic ovary syndrome (PCOS), steroidogenic enzyme defects, neoplastic disorders; or rarely by medications, acromegaly, or ACTH-induced Cushing disease.

A. Idiopathic or Familial Most women with hirsutism or androgenic alopecia have no detectable hyperandrogenism. Patients often have a

1162

CMDT 2013

Chapter 26

strong familial predisposition to hirsutism that may be considered normal in the context of their genetic background. Such patients may have elevated serum levels of androstenediol glucuronide, a metabolite of dihydrotestosterone that is produced by skin in cosmetically unacceptable amounts.

B. Polycystic Ovary Syndrome (Hyperthecosis, Stein–Leventhal Syndrome) PCOS is a common functional disorder of the ovaries, affecting about 4–6% of premenopausal women in the United States and accounting for at least 50% of all cases of hirsutism associated with elevated testosterone levels. It is familial and transmitted as a modified autosomal dominant trait. Affected women have elevated serum testosterone or free testosterone levels. Affected women have signs of androgen excess, including hirsutism, acne, and malepattern thinning of scalp hair. About 50% of affected women have oligomenorrhea or amenorrhea with anovulation. Despite the syndrome’s name, the presence of ovarian cysts is not helpful diagnostically and is actually a misnomer, since about 30% of women with PCOS do not have cystic ovaries and 25–30% of normal menstruating women have cystic ovaries. Obesity and high serum insulin levels (due to insulin resistance) contribute to the syndrome in 70% of women. The serum LH:FSH ratio is often > 2.0. Both adrenal and ovarian androgen hypersecretion are commonly present. Women with PCOS have a 35% risk of depression, compared with 11% in age-matched controls. Diabetes mellitus is present in about 13% of cases.

Obstructive sleep apnea is particularly common, even in slender women with PCOS. Untreated women with amenorrhea have a slightly increased risk of endometrial carcinoma. Hypertension and hyperlipidemia are often present, increasing the risk of cardiovascular disease. Women frequently regain normal menstrual cycles with aging.

C. Steroidogenic Enzyme Defects Baby girls with “classic” 21-hydroxylase deficiency have ambiguous genitalia and may become virilized unless treated with corticosteroid replacement; about 50% of such patients have clinically evident mineralocorticoid deficiency (salt-wasting) as well.

About 2% of patients with adult-onset hirsutism have been found to have a partial defect in adrenal 21-hydroxylase.

The condition is more common in Ashkenazi Jews, Yupic Alaskans, and natives of La Reunion Island. The phenotypic expression is delayed until adolescence or adulthood; such patients do not have salt-wasting. Polycystic ovaries and adrenal adenomas are more likely to develop in these women.

Some rare patients with hyperandrogenism and hypertension have 11-hydroxylase deficiency. This is distinguished from cortisol resistance by high cortisol serum levels in the latter and by high serum 11-deoxycortisol levels in the former.

Patients with an XY karyotype and a deficiency in 17β-hydroxysteroid dehydrogenase-3 or a deficiency in 5α-reductase-2 may present as phenotypic girls in whom virilization develops at puberty.

D. Neoplastic Disorders Ovarian tumors are very uncommon causes of hirsutism (0.8%) and include arrhenoblastomas, Sertoli-Leydig cell tumors, dysgerminomas, and hilar cell tumors. Adrenal carcinoma is a rare cause of Cushing syndrome and hyperandrogenism that can be quite virilizing. Pure androgensecreting adrenal tumors occur very rarely; about 50% are malignant.

E. Rare Causes of Hirsutism Acromegaly and ACTH-induced Cushing syndrome can cause hirsutism. Porphyria cutanea tarda can cause periorbital hair growth in addition to dermatitis in sun-exposed areas. Maternal virilization during pregnancy may occur as a result of a luteoma of pregnancy, hyperreactio luteinalis, or polycystic ovaries. In postmenopausal women, diffuse stromal Leydig cell hyperplasia is a rare cause of hyperandrogenism. Acquired hypertrichosis lanuginosa is manifested by the appearance of diffuse fine lanugo hair growth on the face and body along with stomatologic symptoms; the disorder is usually associated with an internal malignancy, especially colorectal cancer, and may regress after tumor removal. Pharmacologic causes include minoxidil, cyclosporine, phenytoin, anabolic steroids, diazoxide, and certain progestins.

``Clinical Findings A. Symptoms and Signs Modest androgen excess from any source increases sexual hair (chin, upper lip, abdomen, and chest) and increases sebaceous gland activity, producing acne. Menstrual irregularities, anovulation, and amenorrhea are common. If androgen excess is pronounced, defeminization (decrease in breast size, loss of feminine adipose tissue) and virilization (frontal balding, muscularity, clitoromegaly, and deepening of the voice) occur. Virilization points to the presence of an androgen-producing neoplasm.

Hypertension may be seen in rare patients with Cushing syndrome, adrenal 11-hydroxylase deficiency, or cortisol resistance syndrome.

A pelvic examination may disclose clitoromegaly or ovarian enlargement that may be cystic or neoplastic.

B. Laboratory Testing and Imaging Serum androgen testing is mainly useful to screen for rare occult adrenal or ovarian neoplasms. Some general guidelines are presented here, though exceptions are common.

Serum is assayed for total testosterone and free testosterone. A serum testosterone level > 200 ng/dL or free testosterone > 40 ng/dL indicates the need for pelvic examination and ultrasound. If that is negative, an adrenal CT scan is performed.

Most radioimmunoassays and enzyme-linked immunosorbent assay (ELISA) for testosterone are inaccurate below serum testosterone levels of 300 ng/dL. The more accurate testosterone assays rely upon extraction and chromatography, followed by mass spectrometry or immunoassay. Free testosterone is best measured by calculation, using

Endocrine Disorders accurate assays for testosterone and sex hormone binding globulin.

A serum androstenedione level > 1000 ng/dL also points to an ovarian or adrenal neoplasm.

Patients with milder elevations of serum testosterone or androstenedione usually are treated with an oral contraceptive.

Patients with very elevated serum DHEAS (> 700 mcg/ dL) have an adrenal source of androgen. This usually is due to adrenal hyperplasia and rarely to adrenal carcinoma. An adrenal CT scan is performed.

No firm guidelines exist as to which patients (if any) with hyperandrogenism should be screened for “late-onset” 21-hydroxylase deficiency. The evaluation requires levels of serum 17-hydroxyprogesterone to be drawn at baseline and at 30–60 minutes after the intramuscular injection of 0.25 mg of cosyntropin (ACTH1–24). This test should ideally be done during the follicular phase of a woman’s menstrual cycle. Patients with congenital adrenal hyperplasia will usually have a baseline 17-hydroxyprogesterone level over 300 ng/dL or a stimulated level over 1000 ng/dL. Patients with any clinical signs of Cushing syndrome should receive a screening test. (See Cushing Syndrome.)

Serum levels of FSH and LH are elevated if amenorrhea is due to ovarian failure. An LH:FSH ratio > 2.0 is common in patients with PCOS. On abdominal ultrasound, about 25–30% of normal young women have polycystic ovaries, so the appearance of ovarian cysts on ultrasound is not helpful. Pelvic ultrasound or MRI can usually detect virilizing tumors of the ovary. However, small virilizing ovarian tumors may not be detectable on imaging studies; selective venous sampling for testosterone may be used for diagnosis in such patients.

``Treatment Postmenopausal women with severe hyperandrogenism should undergo laparoscopic bilateral oophorectomy (if CT scan of the adrenals and ovaries is normal), since small hilar cell tumors of the ovary may not be visible on scans.

Girls with classic salt-wasting congenital adrenal hyperplasia and infertility or treatment-resistant hyperandrogenism may be treated with laparoscopic bilateral adrenalectomy.

Any drugs causing hirsutism are stopped.

Spironolactone may be taken in doses of 50–100 mg orally twice daily on days 5–25 of the menstrual cycle or daily if used concomitantly with an oral contraceptive.

Hyperkalemia and other side effects are uncommon.

Finasteride inhibits 5α-reductase, the enzyme that converts testosterone to active dihydrotestosterone in the skin.

Given as 2.5-mg doses orally daily, it provides modest reduction in hirsutism over 6 months—somewhat less than that achieved with spironolactone. Finasteride is ineffective for androgenic alopecia in women. Side effects are rare.

Flutamide inhibits testosterone binding to androgen receptors and also suppresses serum testosterone. It is given orally in a dosage of 250 mg/d for the first year and then 125 mg/d for maintenance. Used with an oral contraceptive, it appears to be more effective than spironolactone in improving hirsutism, acne, and male pattern baldness.

Women with congenital adrenal hyperplasia who take

CMDT 2013

1163

replacement hydrocortisone experience decreased renal cortisol clearance when treated with flutamide, resulting in lower hydrocortisone dosage requirements; corticosteroid replacement doses should be reduced when flutamide is added for treatment of hirsutism. Hepatotoxicity has been reported but is rare.

Oral contraceptives stimulate menses (if that is desired) and reduce acne vulgaris. They are not very effective for hirsutism, but increase serum sex hormone binding globulin and thereby slightly reduce serum free testosterone levels.

Oral contraceptives containing antiandrogen progestins include desogestrel (Azurette, Kariva), drospirenone (Gianvi), or norgestimate (Ortho Tri-Cyclen Lo). Cyproterone is a particularly potent antiandrogen that is not available in the United States but is available as Diane-35 in Canada and the United Kingdom. These preparations may be more effective for treating hirsutism but are associated with an increased risk of deep venous thrombosis.

Metformin may improve menstrual function in women with PCOS and amenorrhea or oligomenorrhea but is less effective than oral contraceptives. Metformin is not effective in promoting fertility or in improving hirsutism in women with PCOS. Metformin therapy is usually given with meals and is started at a dose of 500 mg/d with breakfast for 1 week, then 500 mg with breakfast and dinner for 1 week, then 500 mg with breakfast and 1000 mg with dinner for 1 week, then 850–1000 mg with breakfast and dinner. The most common side effects are dose-related gastrointestinal upset and diarrhea. Patients are advised to take the highest tolerated dosage. Metformin appears to be nonteratogenic. Although metformin reduces insulin resistance, it does not cause hypoglycemia in nondiabetics.

Metformin is contraindicated in renal and hepatic disease.

Simvastatin can reduce hirsutism in women with PCOS. In one study, simvastatin 20 mg orally daily was given to women receiving an oral contraceptive for PCOS. Besides improving their serum lipid profiles, women receiving simvastatin had greater decreases in hirsutism and serum free testosterone levels than the women receiving an oral contraceptive alone.

Clomiphene is the treatment of choice for women with PCOS and infertility. Over 6 months, clomiphene therapy resulted in a 22.5% rate of conception with live births. The rate of pregnancy with multiple fetuses is 6%.

Women with classic congenital adrenal hyperplasia (21-­ hydroxylase deficiency) have hirsutism and adrenal insufficiency that requires glucocorticoid and mineralocorticoid replacement. However, women with partial “late onset” 21-hydroxylase deficiency do not require hormone replacement. Treating such women with dexamethasone risks iatrogenic Cushing syndrome and is not particularly more effective than the other treatments for hirsutism listed below.

Local treatment by shaving or depilatories, waxing, electrolysis, or bleaching should be encouraged. Eflornithine (Vaniqa 13.9%) topical cream retards hair growth when applied twice daily to unwanted facial hair; improvement is noted within 4–8 weeks. However, local skin irritation may occur. Hirsutism returns with discontinuation. Laser therapy (photoepilation) is a fairly effective treatment for facial hirsutism, particularly for women with dark hair and

1164

CMDT 2013

Chapter 26

light skin; longer-wavelength lasers are used for women with darker skin. Complications of laser therapy include skin hypopigmentation (rare) and hyperpigmentation, which occurs in 20% but usually resolves; a paradoxical increase in hair growth occurs infrequently. Repeated laser treatments are usually required.

Topical minoxidil, 2% solution applied twice daily to a dry scalp, may be used to effectively treat women with androgenic alopecia. Hypertrichosis is an unwanted side effect of topical minoxidil, occurring in 3–5% of treated women; it may affect the forehead, cheeks, upper lip, or chin. Hypertrichosis resolves within 1–6 months after the drug is stopped.

Antiandrogen treatments must be given only to nonpregnant women. Women must be counseled to take oral contraceptives, when indicated, and avoid pregnancy, since use during pregnancy causes malformations and pseudohermaphroditism in male infants.

but the peak incidence is between 30 years and 60 years.

Excessive aldosterone production increases sodium retention and suppresses plasma renin. It increases renal ­potassium excretion, which can lead to hypokalemia.

Cardiovascular events are more prevalent in patients with aldosteronism (35%) than in those with essential hypertension (11%). Primary aldosteronism may be caused by an aldosterone-producing adrenal adenoma (Conn syndrome), 40% of which have been found to have somatic mutations in a gene involved with the potassium channel.

Primary aldosteronism is also commonly caused by unilateral or bilateral adrenal hyperplasia. Bilateral aldosteronism may be corticosteroid suppressible, due to an autosomal-dominant genetic defect allowing ACTH stimulation of aldosterone production.

``Clinical Findings A. Symptoms and Signs

Banaszewska B et al. Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial. J Clin Endocrinol Metab. 2007 Feb;92(2):456–61. [PMID: 17105841] Castelo-Branco C et al. Comprehensive clinical management of hirsutism. Gynecol Endocrinol. 2010 Jul;26(7):484–93.

[PMID: 20218823] Escobar-Morreale HF. Diagnosis and management of hirsutism.

Ann NY Acad Sci. 2010 Sep;1205:166–74. [PMID: 20840269] Harrison S et al. Update on the management of hirsutism. Cleve Clin J Med. 2010 Jun;77(6):388–98. [PMID: 20516250] Koulouri O et al. Management of hirsutism. BMJ. 2009 Mar 27;338:b847. [PMID: 19329515] Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med. 2008 Jan;358(1):47–54. [PMID: 18172174] Nouri K et al. Photoepilation: a growing trend in laser-assisted cosmetic dermatology. J Cosmet Dermatol. 2008 Mar;7(1):61–7.

[PMID: 18254814]

PRIMARY ALDOSTERONISM ``

EssentialS of diagnosis

Hypertension that may be severe or drug-resistant.

Hypokalemia (in minority of patients) may cause polyuria, polydipsia, muscle weakness. `` Elevated plasma and urine aldosterone levels and low plasma renin level. ``

``

``General Considerations Primary aldosteronism (hyperaldosteronism) causes hyper­ tension by an inappropriately high aldosterone secretion that does not suppress adequately with sodium loading.

Primary aldosteronism is believed to account for 8% of all cases of hypertension and 20% of cases of resistant hypertension. It may be difficult to distinguish primary aldosteronism from cases of low renin essential hypertension, with which it may overlap. Patients of all ages may be affected,

Patients have hypertension that is typically moderate. Some patients have only diastolic hypertension, without other symptoms and signs. Edema is rarely seen in primary aldosteronism. About 37% of patients have hypokalemia and may consequently have symptoms of muscular weakness (at times with paralysis simulating periodic paralysis), paresthesias with frank tetany, headache, polyuria, and polydipsia.

B. Laboratory Findings Screening for hyperaldosteronism is usually with PRA. About 20% of hypertensive patients have a low PRA, and a significant portion of these patients have primary aldosteronism. Initial screening can also include both aldosterone and plasma renin activity to determine an aldosterone to renin ratio (see below).

Plasma potassium should also be determined in hypertensive individuals. However, hypokalemia, once thought to be the hallmark of hyperaldosteronism, is present in only 37% of affected patients: 50% of those with an adrenal adenoma and 17% of those with adrenal hyperplasia. Proper phlebotomy technique is important to avoid spurious increases in potassium. The blood should be drawn slowly with a syringe and needle (rather than a vacutainer) at least 5 seconds after tourniquet release and without fist-clenching.

Plasma potassium, rather than the routine serum potassium, should be measured in cases of unexpected hyperkalemia, with the separation of plasma from cells within 30 minutes of collection. Besides hypokalemia, many patients with primary aldosteronism have metabolic alkalosis with an elevated serum bicarbonate (HCO–3) concentration.

Testing for primary aldosteronism should be done for all hypertensive patients with hypokalemia, whether spontaneous or diuretic induced. But since only a minority of affected patients have hypokalemia, testing should also be considered for normokalemic hypertensive patients with (1) treatment-resistant hypertension (despite three drugs); (2) severe hypertension: > 160 mm Hg systolic or > 100 mm Hg diastolic; (3) early-onset hypertension; (4) lowrenin hypertension; (5) hypertension with an adrenal mass; and (6) family history of aldosteronism.

Endocrine Disorders For a patient to be properly tested for primary aldosteronism, certain antihypertensive medications should ideally be held. Diuretics should be discontinued for 3 weeks.

Dihydropyridine calcium channel blockers can normalize aldosterone secretion, thus interfering with the diagnosis. β-Blockers suppress PRA in patients with essential hypertension. Antihypertensive medications that have minimal effects on the plasma aldosterone:renin ratio include ACE inhibitors, α-blockers, verapamil, hydralazine, prazosin, doxazosin, and terazosin. However, it may be impractical to hold or change antihypertensive medicines; in such cases, testing should proceed.

During the testing period, the patient should have an unrestricted high sodium intake. The patient should be out of bed for at least 2 hours and seated for 5–15 minutes before the blood draw, which should preferably be obtained between 8 am and 10 am. Renin is measured as either PRA or direct renin concentration. Serum aldosterone should ideally be measured with a tandem mass spectrometry assay.

For patients who have not been receiving diuretics for at least 3 weeks, a plasma renin activity (PRA) that is normal or elevated makes primary aldosteronism very unlikely.

However, a low PRA alone cannot establish the diagnosis of primary aldosteronism, since it occurs in many patients with essential hypertension. An aldosterone:renin ratio is a sensitive screening test. Serum aldosterone (ng/dL):PRA (ng/ mL/h) ratios < 24 exclude primary aldosteronism, whereas ratios between 24 and 67 are suspicious and ratios > 67 are very suggestive of primary aldosteronism. Such elevated ratios are not diagnostic; rather, they indicate the need to document increased aldosterone secretion with a 24-hour urine collection. Another problem with the aldosterone:renin ratio is the use of different units and measurements. For aldosterone, 1 ng/dL converts to 27.7 pmol/L. For renin, a PRA of 1 ng/mL/h (12.8 pmol/L/min) converts to a direct renin concentration of 5.2 ng/L (8.2 mU/L).

When the aldosterone:renin ratio is high, a 24-hour urine collection is assayed for aldosterone, free cortisol, and creatinine. A low PRA (< 5 mcg/L/h) with a urine aldosterone over 20 mcg/24 h indicates primary aldosteronism.

Once primary aldosteronism is diagnosed, unilateral adrenal aldosteronism may be distinguished from bilateral adrenal aldosteronism by adrenal vein sampling and by further biochemical testing. Plasma may be assayed for 18-­ hydroxycorticosterone; a level > 100 ng/dL is seen with adrenal neoplasms, whereas levels < 100 ng/dL are non-­ diagnostic. In addition, a posture stimulation test may be performed, but this requires overnight hospitalization. The test is performed by drawing blood for aldosterone at 8 am while the patient is supine after overnight recumbency and again after the patient is upright for 4 hours. Patients with a unilateral adrenal adenoma usually have a baseline plasma aldosterone level > 20 ng/dL that does not rise. Patients with bilateral adrenal hyperplasia typically have a baseline plasma aldosterone level < 20 ng/dL that rises during upright posture.

The accuracy of the posture stimulation test is about 85%.

C. Imaging All patients with biochemically confirmed primary aldosteronism require a thin-section CT scan of the adrenals to

CMDT 2013

1165

screen for a rare adrenal carcinoma. In the absence of a large adrenal carcinoma, adrenal CT scanning cannot reliably distinguish unilateral from bilateral aldosterone excess, having a sensitivity of 78% and a specificity of 78% for unilateral aldosteronism. Therefore, the decision to perform a unilateral adrenalectomy should not be based solely on an adrenal CT scan. Instead, patients with primary aldosteronism should be considered for a trial of medical therapy with spironolactone or eplerenone. If medical therapy is ineffective or if surgery is desired for an apparent adrenal adenoma, further evaluation for surgical candidacy should be done with laboratory testing. However, since CT scanning and laboratory testing are often inconclusive, adrenal vein sampling is often required.

D. Adrenal Vein Sampling Bilateral selective adrenal vein sampling is the most accurate way to determine whether primary aldosteronism is due to unilateral aldosterone excess, which can be treated by adrenalectomy. It is indicated only to direct the surgeon to the correct adrenal and should be performed only if surgery is contemplated. It is particularly useful for patients who are not hypokalemic, who are over age 40 years, or who have an adrenal adenoma < 1 cm diameter. It is particularly difficult to catheterize the right adrenal vein.

Therefore, the venous samples are assayed for both aldosterone and cortisol during a cosyntropin (ACTH1–24) infusion to be sure that the sampling has included both adrenal veins. The procedure has a sensitivity of 95% and a specificity of 100% but only when performed by an experienced radiologist. The complication rate is 2.5%. Risks can be minimized if the radiologist avoids adrenal venography and limits the use of contrast.

``Screening Hyperaldosteronism is the most common cause of refractory hypertension in youth and middle-aged adults. The Endocrine Society’s Clinical Practice Guidelines recommend screening for hyperaldosteronism in patients who have any of the following: (1) blood pressure > 160/100 mm Hg; (2) drug-resistant hypertension; (3) hypertension with spontaneous or diuretic-induced hypokalemia; (4) hypertension with adrenal incidentaloma; (5) hypertension with a family history of early-onset hypertension or cerebrovascular accident before age 40 years; (6) hypertension and a firstdegree relative with primary aldosteronism.

``Differential Diagnosis The differential diagnosis of primary aldosteronism includes other causes of hypokalemia (see Chapter 21) in patients with essential hypertension, especially diuretic therapy. Chronic depletion of intravascular volume stimulates renin secretion and secondary hyperaldosteronism.

Thus, it is important to discontinue diuretics and ensure adequate hydration and sodium intake when assessing a patient for primary hyperaldosteronism.

Excessive ingestion of real licorice (black and derived from anise) or Sambuca (an Italian liqueur) can cause hyper­ tension and hypokalemia. Real licorice and ­anise-flavored

1166

CMDT 2013

Chapter 26

drinks (sambuca, pastis) contain glycyrrhizinic acid, which has a metabolite that inhibits the adrenal enzyme 11βhydroxysteroid dehydrogenase type 2 that normally inactivates cortisol in the renal tubule. Higher renal tubular cortisol levels activate aldosterone receptors, resulting in renal tubular absorption of sodium and excretion of potassium. Oral contraceptives may increase aldosterone secretion in some patients. Renal vascular disease can cause severe hypertension with hypokalemia; PRA is high, distinguishing it from primary aldosteronism.

Excessive adrenal secretion of other corticosteroids (besides aldosterone) may also cause hypertension with hypokalemia. This occurs with certain congenital adrenal enzyme disorders such as P450c11 deficiency (increased deoxycorticosterone with virilization and deficient cortisol) or P450c17 deficiency (increased deoxycorticosterone, corticosterone, and progesterone but deficient estradiol and testosterone). P450c17 deficiency results from a defect in the 17-hydroxylase enzyme in both the adrenal and ovarian steroidogenic pathways. Presenting signs include hypertension and ambiguous genitalia or primary amenorrhea. Urinary aldosterone secretion is < 20 mcg/24 h and plasma renin is low in both P450c11 and P450c17 deficiencies. Primary cortisol resistance can cause hypertension and hypokalemia; renin and aldosterone are suppressed, while plasma levels of cortisol, ACTH, and deoxycorticosterone are high. Liddle syndrome is an autosomal dominant cause of hypertension and hypokalemia resulting from excessive sodium absorption from the renal tubule; renin and aldosterone levels are low. Thyrotoxicosis and familial periodic paralysis may also present with hypoka­ lemia. Hyperaldosteronism may rarely be due to a malignant ovarian tumor.

also be required. Glucocorticoid-remediable aldosteronism is very rare but may respond well to suppression with lowdose dexamethasone.

``Prognosis The hypertension is reversible in about two-thirds of cases but persists or returns in spite of surgery in the remainder.

The prognosis is much improved by early diagnosis and treatment. Only 2% of aldosterone-secreting adrenal tumors are malignant.

Carey RM. Adrenal disease update 2011. 2011 Dec;96(12): 3583–91. [PMID: 22143828] Choi M et al. K+ channel mutations in adrenal aldosteroneproducing adenomas and hereditary hypertension. Science.

2011 Feb;331(6018):768–72. [PMID: 21311022] Quinkler M et al. Treatment of primary aldosteronism. Best Pract Res Clin Endocrinol Metab. 2010 Dec;24(6):923–32.

[PMID: 21115161] Rossi GP. Diagnosis and treatment of primary aldosteronism.

Rev Endocr Metab Disord. 2011 Mar;12(1):27–36. [PMID: 21369868] Schwartz GL. Screening for adrenal-endocrine hypertension: overview of accuracy and cost-effectiveness. Endocrinol Metab Clin North Am. 2011 Jun;40(2):279–94. [PMID: 21565667] Tomaschitz A et al. Aldosterone to renin ratio—a reliable screening tool for primary aldosteronism? Horm Metab Res. 2010 Jun;43(6):382–91. [PMID: 20225167]

cc PHEOCHROMOCYTOMA

& Paraganglioma

``

``Complications The incidence of cardiovascular complications from hypertension are higher in primary aldosteronism than in idiopathic hypertension. Following unilateral adrenalectomy for Conn syndrome, suppression of the contralateral adrenal may result in temporary postoperative hypoaldosteronism, characterized by hyperkalemia and hypotension.

``Treatment Conn syndrome (unilateral aldosterone-secreting adrenal adenoma) is treated by laparoscopic adrenalectomy, though long-term therapy with spironolactone or eplerenone is an option. Bilateral adrenal hyperplasia is best treated with spironolactone or eplerenone. Spironolactone also has antiandrogen activity and frequently causes breast tenderness, gynecomastia, or reduced libido; it is given at initial doses of 12.5–25 mg orally once daily; the dose may be titrated upward to 200 mg daily. Eplerenone is becoming favored for men, since it does not have antiandrogen effects; however, it has a short half-life and must be given twice daily in oral doses of 25–50 mg. Blood pressure must be monitored daily when beginning these anti-­ mineralocorticoid medications; significant drops in blood pressure have occurred when these drugs are added to other antihypertensives. Other antihypertensive drugs may

EssentialS of diagnosis

”Attacks” of headache, perspiration, palpitations, anxiety. `` Hypertension, frequently sustained but often paroxysmal, especially during surgery or delivery. `` Elevated urinary catecholamines or their metabolites. Normal serum T4 and TSH. ``

``General Considerations Both pheochromocytomas and non–head-neck paragangliomas are tumors of the sympathetic nervous system.

Pheochromocytomas arise from the adrenal medulla and usually secrete both epinephrine and norepinephrine.

Paragangliomas (“extra-adrenal pheochromocytomas”) arise from sympathetic paraganglia, often metastasize, and secrete norepinephrine or are nonsecretory. Excessive levels of norepinephrine or neuropeptide Y cause hypertension, while epinephrine causes tachyarrhythmias. These tumors may be located in either or both adrenals or anywhere along the sympathetic nervous chain, and rarely in such aberrant locations as the mediastinum, heart, or bladder.

These rare tumors are deceptive and deadly. They are a rare cause of hypertension, being found in < 0.3% of hypertensive individuals. The incidence is higher in patients

Endocrine Disorders with moderate to severe hypertension. About two to three new cases per million population are diagnosed annually.

However, in autopsy cases, the incidence of pheochromocytoma is 250–1300 cases per million, indicating that most cases are not diagnosed during life.

About 25% of patients with pheochromocytomas/­ paragangliomas harbor germline mutations making them prone to develop the tumor. The chance of harboring a germline mutation is nearly 100% in patients with a family history of pheochromocytomas/paragangliomas and 17% in patients without any known family history of pheochromocytomas/paragangliomas.

Pheochromocytomas develop in about 20% of patients with type 2 von Hippel–Lindau (VHL) disease (hemangiomas of the retina, cerebellum, brainstem, and spinal cord; hyperparathyroidism; pancreatic cysts; endolymphatic sac tumors; cystadenomas of the adnexa or epididymis; renal cysts, adenomas, and carcinomas); inheritance is autosomal dominant. Patients with VHL develop pheochromocytomas that are less likely to be extra-adrenal, less likely to be malignant (3.5%), more likely to be bilateral, and more likely to present at an early age. Pheochromocytomas that arise in patients with VHL secrete exclusively norepinephrine and its metabolite normetanephrine. Therefore, individuals who carry type 2 VHL mutations should be screened for pheochromocytoma with plasma normetanephrine levels.

MEN 2A is associated with pheochromocytomas and medullary thyroid carcinoma. MEN 2B is associated with pheochromocytomas, aggressive medullary thyroid carcinoma, mucosal neuromas, and marfinoid habitus. von Recklinghausen neurofibromatosis type 1 (NF-1) is associated with an increased risk of pheochromocytomas/ paragangliomas as well as cutaneous neurofibromas, optic gliomas, vascular anomalies, hamartomas, malignant nerve sheath tumors, and smooth-bordered café au lait spots.

Familial paraganglioma can be caused by mutations in the genes encoding suscinate dehydrogenase (SDH) subunits B, C, or D. Patients with such germline mutations are more apt to have bilateral pheochromocytomas or multicentric paragangliomas.

``Clinical Findings A. Symptoms and Signs (Table 26–12) Pheochromocytomas can be lethal unless they are diagnosed and treated appropriately. Catastrophic hypertensive crisis and fatal cardiac arrhythmias can occur spontaneously or may be triggered by intravenous contrast dye or glucagon injection, needle biopsy of the mass, anesthesia, or surgical procedures. Paroxysms can be triggered by exercise, bending, lifting, or emotional stress.

Certain drugs can precipitate attacks: monoamine oxidase (MAO) inhibitors, caffeine, nicotine, decongestants, amphetamines, cocaine, ionic intravenous contrast, and epinephrine. Bladder paragangliomas may present with paroxysms during micturition.

Paroxysms typically produce hypertension (90%) and such symptoms as severe headache (80%), perspiration (70%), and palpitations (60%); other symptoms may include anxiety (50%), a sense of impending doom, or

CMDT 2013

1167

tremor (40%). Vasomotor changes during an attack cause mottled cyanosis and facial pallor; as the attack subsides, facial flushing may occur as a result of reflex vasodilation.

Epinephrine secretion by an adrenal pheochromocytoma may cause episodic tachyarrhythmias, hypotension, or even syncope. Acute coronary syndrome can be caused by coronary vasoconstriction. Confusion, psychosis, seizures, transient ischemic attacks, or stroke may occur with cerebrovascular vasoconstriction or hemorrhagic stroke. Aortic aneurysms may dissect and rupture. Abdominal pain, nausea, vomiting, and even ischemic bowel can be due to splanchnic vasoconstriction. Large or hemorrhagic abdominal tumors can also cause abdominal pain. Peripheral vasoconstriction can cause Raynaud phenomenon or even gangrene. Patients may experience nervousness and irritability, increased appetite, and loss of weight. Other patients have pulmonary edema and heart failure due to cardiomyopathy. Cytokine release can cause nephrotic syndrome or acute respiratory distress syndrome (ARDS). Although most patients are symptomatic, some patients are normotensive and asymptomatic, particularly when the tumor is nonsecretory or discovered at an early stage.

B. Laboratory Findings Plasma fractionated free metanephrines is the single most sensitive test for secretory pheochromocytomas and paragangliomas. Normal levels rule out pheochromocytoma and paraganglioma with some certainty and the work-up can usually end there. However, misleading elevations in metanephrines or normetanephrines can be caused by factors such as physical or emotional stress, sleep apnea, and MAO inhibitors. Therefore, patients with elevated plasma metanephrines or normetanephrines levels require further evaluation.

Assay of urinary fractionated metanephrines and creatinine effectively confirms most pheochromocytomas that were detected by elevated plasma fractionated metanephrines. A 24-hour urine specimen is usually obtained, although an overnight or shorter collection may be used; patients with pheochromocytomas generally have more than 2.2 mcg of total metanephrine per milligram of creatinine, and more than 135 mcg total catecholamines per gram creatinine. Urinary assay for total metanephrines is about 97% sensitive for detecting functioning pheochromocytomas. Urinary assay for vanillylmandelic acid (VMA) is not usually required.

Some drugs and foods can interfere with certain assays for catecholamines, and stresses can also cause misleading elevations in catecholamine excretion (Table 26–13). About 10% of hypertensive patients have a misleadingly elevated level of one or more tests.

Serum chromogranin A is elevated in 90% of patients with pheochromocytoma and the levels correlate with tumor size, being higher in patients with metastatic disease. Serum chromogranin A levels can be misleadingly elevated in patients with azotemia or hypergastrinemia, and in those treated with corticosteroids or proton pump inhibitors. Serum may also be assayed for neuron-specific enolase; high levels implicate a malignant pheochromocytoma, while normal levels are nonspecific.

1168

CMDT 2013

Chapter 26

Table 26–12. Clinical manifestations of pheochromocytoma and paraganglioma.

Blood pressure

Hypertension: severe or mild, paroxysmal or sustained; orthostasis; hypotension/shock; normotension

Vasospasm

Cyanosis, Raynaud syndrome, gangrene; severe radial artery vasospasm with thready pulse; falsely low blood pressure by radial artery transducer

Multisystem crisis

Severe hypertension/hypotension, fever, encephalopathy, ARDS, renal failure, hepatic failure, death

Cardiovascular

Palpitations, dysrhythmias, chest pain, acute coronary syndrome, cardiomyopathy, heart failure, cardiac paragangliomas

Gastrointestinal

Abdominal pain, nausea, vomiting, weight loss, intestinal ischemia; pancreatitis, cholecystitis, jaundice; rupture of abdominal aneurysm; constipation, toxic megacolon

Metabolic

Hyperglycemia/diabetes, lactic acidosis, fevers

Neurologic

Headache, paresthesias, numbness, dizziness, CVA, TIA, hemiplegia, hemianopsia, seizures, hemorrhagic stroke; skull metastases may impinge on brain structures, optic nerve, or other cranial nerves; spinal metastases may impinge on cord or nerve roots

Pulmonary

Dyspnea; hypoxia from ARDS

Psychiatric

Anxiety attacks or constant anxiety; depression; chronic fatigue; psychosis

Renal

Renal insufficiency, nephrotic syndrome, malignant nephrosclerosis; large tumors often involve the kidneys and renal vessels

Skin

Apocrine sweating during paroxysms, drenching sweats as attack subsides; eczema; mottled cyanosis during paroxysm

Thyroid

Paroxysmal thyroid swelling

Ectopic hormones

ACTH (Cushing syndrome); VIP (Verner-Morrison syndrome); PTHrP (hypercalcemia); erythropoietin (erythrocytosis)

Children

More commonly have sustained hypertension, diaphoresis, visual changes, polyuria/polydipsia, seizures, edematous or cyanotic hands; more commonly harbor germline mutations, multiple tumors, and paragangliomas

Women

More symptomatic than men: more frequent headache, weight loss, numbness, dizziness, tremor, anxiety, and fatigue

Pregnancy

Hypertension mimicking eclampsia; hypertensive multisystem crisis during vaginal delivery; postpartum shock or fever; high mortality

General laboratory

Leukocytosis, erythrocytosis, eosinophilia

ACTH, adrenocorticotropic hormone; ARDS, acute respiratory distress syndrome; CVA, cerebrovascular accident; PTHrP, parathyroid hormone–related protein; TIA, transient ischemic attack; VIP, vasoactive intestinal peptide.

Used, with permission, from Gardner D, Shoback D (editors). Greenspan’s Basic and Clinical Endocrinology. 9th edition, McGraw-Hill, NY, 2011.

Pharmacologic provocative and suppressive tests that evaluate the rise or fall in blood pressure are usually not required or recommended.

Hyperglycemia is present in about 35% of patients but is usually mild. Leukocytosis is common. The ESR is sometimes elevated. PRA may be increased by catecholamines.

Genetic testing should ideally be performed on all patients with pheochromocytoma or paraganglioma. Test­ ing for VHL, ret protooncogene, and SDHB/SDHD mutations is advisable. Family members may then be screened for the specific gene mutation.

C. Imaging 1. CT and MRI scanning—Imaging should not usually replace biochemical testing, since incidental adrenal adenomas are common (2–4% of scans) and can be misleading. When a pheochromocytoma is suspected because of biochemical testing or a genetic condition predisposing to

pheochromocytoma, a CT scan of the abdomen is performed, with thin sections through the adrenals. A noncontrast CT should be followed by a CT scan using nonionic contrast, which reduces the risk of catecholamine release from a pheochromocytoma and a hypertensive crisis. Glucagon should not be used during scanning, since it can provoke hypertensive crisis; similarly, intravenous contrast can precipitate hypertensive crisis, particularly in patients whose hypertension is uncontrolled.

MRI scanning has the advantage of not requiring intravenous contrast dye; its lack of radiation makes it the imaging of choice during pregnancy and childhood.

Both CT and MRI scanning have a sensitivity of about 90% for adrenal pheochromocytoma and a sensitivity of 95% for adrenal tumors over 0.5 cm in diameter. However, both CT and MRI are less sensitive for detecting recurrent tumors, metastases, and extra-adrenal paragangliomas. If no adrenal tumor is found, the scan is extended to include the entire abdomen, pelvis, and chest.

Endocrine Disorders

Table 26–13. Factors potentially causing misleading catecholamine results: High-performance liquid chromatography with electrochemical detection (HPLC-ECD).

Drugs

Foods

Acetaminophen2 Aldomet2 Amphetamines1 Bronchodilators1 Buspirone2 Captopril2 Cimetidine2 Cocaine1 Codeine2 Decongestants1 Ephedrine1 Fenfluramine3 Isoproterenol1 Labetalol1,2 Levodopa2 Mandelamine2 Metoclopramide2 Nitroglycerin1 Phenoxybenzamine Tricyclic antidepressants Viloxazine2

Bananas1 Caffeine1 Coffee2 Peppers2 Pineapples1 Walnuts1

Conditions Amyotrophic lateral sclerosis1 Brain lesions1 Carcinoid1 Eclampsia1 Emotion, severe1 Exercise, vigorous1 Guillain-Barré syndrome1 Hypoglycemia1 Kidney disease3 Lead poisoning1 Myocardial infarct, acute1 Pain, severe1 Porphyria, acute1 Psychosis, acute1 Quadriplegia1 Sleep apnea

1

Increases catecholamine excretion.

May cause confounding peaks on HPLC chromatograms.

3 Decreases catecholamine excretion.

2

2. Nuclear imaging—A whole-body 123I-meta-iodobenzylguanidine (123I-MIBG) scan can localize tumors with a sensitivity of 94% and a specificity of 92%. It is less sensitive for MEN 2A- or MEN 2B-related pheochromocytomas and for metastases. Preoperative 123I-MIBG scanning is not usually required to confirm that a unilateral adrenal mass is a pheochromocytoma in a patient with classic clinical and biochemical presentation. Preoperative whole-body 123I-MIBG scanning can be useful when the CT scan cannot locate a suspected pheochromocytoma, making a paraganglioma more likely; it can also be useful when the CT scan is ambiguous for pheochromocytoma. It is prudent to perform a whole-body 123I-MIBG scan about 3 months postoperatively to determine if metastatic or recurrent tumor is present.

Drugs that reduce 123I-MIBG uptake should be avoided, including tricyclic antidepressants and cyclobenzaprine (6 weeks), amphetamines, nasal decongestants, phenothiazines, haloperidol, diet pills, labetalol, and cocaine (2 weeks).

Somatostatin receptor imaging using 111In-labeled octreotide is only 25% sensitive for detecting an adrenal pheochromocytoma. However, 111In-labeled octreotide scanning is quite sensitive for detecting extra-adrenal pheochromocytomas (paragangliomas) and metastatic pheochromocytomas, sometimes locating tumors that were missed by 123I-MIBG scanning.

PET scanning usually detects tumors using 18F-labeled deoxyglucose (18FDG-PET) or 18F-labeled dopamine (18FDA-PET), and may demonstrate tumors that are not visible on 123I-MIBG scanning. Combining PET scan with

CMDT 2013

1169

noncontrast CT produces a PET/CT fusion scan with exceptional sensitivity.

``Differential Diagnosis Certain conditions mimic pheochromocytoma: thyrotoxicosis, essential hypertension, myocarditis, glomerulonephritis or other renal lesions, eclampsia, and psychoneurosis ­(anxiety attack). Toxemia of pregnancy is associated with hypertension and increased catecholamine production.

Conditions that have manifestations similar to those of pheochromocytoma include the following: essential labile hypertension, renal hypertension, anxiety attacks, thyrotoxicosis, toxemia of pregnancy, acute intermittent porphyria, hypogonadal vascular instability (hot flushes), cocaine or amphetamine use, and clonidine withdrawal. Patients taking nonselective MAO inhibitor antidepressants can have hypertensive crisis after eating foods that contain tyramine (eg, fermented cheeses, aged wines, certain beers, fava beans, vegemite, marmite). Patients with erythromelalgia can have hypertensive crises; their episodic painful flushing and leg swelling are relieved by cold, distinguishing this condition from pheochromocytoma. Pheochromocytomas can cause chest pain and ECG changes that mimic acute cardiac ische­ mia. Renal artery stenosis can cause severe hypertension and may coexist with pheochromocytoma.

False-positive testing for catecholamines and metabolites occurs in about 10% of hypertensives, but levels are usually < 50% above normal and typically normalize with repeat testing.

``Complications All of the complications of severe hypertension may be encountered. In addition, a catecholamine-induced cardiomyopathy may develop. Severe heart failure and cardiovascular collapse may develop in patients during a paroxysm.

Sudden death may occur due to cardiac arrhythmia. ARDS has been reported. Hypertensive crises with sudden blindness or cerebrovascular accidents are not uncommon.

Paroxysms may be spontaneous or precipitated by sudden movement, exertion, manipulation, vaginal delivery, emotional stress, trauma, or surgical removal of the tumor.

Decongestant medications, fluoxetine, and other selective serotonin reuptake inhibitors may induce hypertensive paroxysms and death. Occasionally, the initial manifestation of pheochromocytoma may be hypotension or even shock.

After removal of the tumor, a state of severe hypotension and shock (resistant to epinephrine and norepinephrine) may ensue with precipitation of kidney disease or myocardial infarction. Hypotension and shock may occur from spontaneous infarction or hemorrhage of the tumor.

On rare occasions, a patient dies as a result of the complications of diagnostic tests or during surgery. During surgery, pheochromocytoma cells may be seeded within the peritoneum, resulting in multifocal recurrent tumors.

``Medical Treatment Patients must receive adequate treatment for hypertension and tachyarrhythmias prior to surgery for ­pheochromocytoma/paraganglioma. Patients are advised

1170

CMDT 2013

Chapter 26

to use a portable sphyngomanometer and measure their blood pressures daily and immediately during paroxysms.

Some patients with pheochromocytoma or paraganglioma are not hypertensive and do not require preoperative antihypertensive management. `-Blockers are typically administered preparatory to surgery. Phenoxybenzamine is a long-acting nonselective α-blocker with a half-life of 24 hours; it is given initially in a dosage of 10 mg orally every 12 hours, increasing gradually by about 10 mg/d about every 3 days until hypertension is controlled. Maintenance doses range from 10 mg/d to 120 mg/d. Selective α1-blockers may be used: doxazosin (half-life 22 hours), terazosin (half-life 12 hours), or prazosin (half-life 3 hours). Patients given preoperative phenoxybenzamine experience less intraoperative hypertension but greater post-resection hypotension than patients given preoperative selective α1-blockers. Optimal α-blockade is achieved when supine arterial pressure is below 140/90 mm Hg or as low as possible for the patient to have a standing arterial pressure above 80/45 mm Hg. Calcium channel blockers (nifedipine ER or nicardipine ER) are very effective and may be used with or without α-blockers. They are superior to phenoxybenzamine for long-term use, since they cause less fatigue, nasal congestion, and orthostatic hypotension. For acute hypertensive crisis (systolic blood pressure > 170 mm Hg) a nifedipine 10-mg capsule may be chewed and swallowed.

Nifedipine is quite successful for treating acute hypertension in patients with pheochromocytoma/paraganglioma, even at home; it is reasonably safe as long as the blood pressure is monitored. a-Blockers (eg, metoprolol XL) are often required after institution of α-blockade or calcium channel blockade.

The use of a β-blocker as initial antihypertensive therapy has resulted in an “unopposed alpha” that causes paradoxical worsening of hypertension. Labetalol has combined αand β-blocking activity and is an effective agent but can cause paradoxical hypertension if used as the initial antihypertensive agent. Labetalol can also interfere with catecholamine determinations in some laboratories and reduces the tumor’s uptake of radioisotopes, such that it must be discontinued for at least 4–7 days before diagnostic scanning with 123I-MIBG or 18FDA-PET or 131I-MIBG therapy.

``Surgical Treatment Surgical removal of pheochromocytomas or abdominal paragangliomas is the treatment of choice. For surgery, a team approach—endocrinologist, anesthesiologist, and surgeon—is critically important. Laparoscopic surgery is preferred, but large and invasive tumors require open laparotomy. Patients with small familial or bilateral pheochromocytomas may undergo selective resection of the tumors, sparing the adrenal cortex; however, there is a recurrence rate of 10% over 10 years.

Prior to surgery, blood pressure control should be maintained for a minimum of 4–7 days or until optimal cardiac status is established. The ECG should be monitored until it becomes stable. (It may take a week or even months to correct ECG changes in patients with catecholamine

myocarditis, and it may be prudent to defer surgery until then in such cases.) Patients must be very closely monitored during surgery to promptly detect sudden changes in blood pressure or cardiac arrhythmias.

Intraoperative severe hypertension is managed with continuous intravenous nicardipine (a short-acting calcium channel blocker), 2–6 mcg/kg/min, or nitroprusside, 0.5–10 mcg/kg/min. Prolonged nitroprusside administration can cause cyanide toxicity. Tachyarrhythmia is treated with intravenous atenolol (1 mg boluses), esmolol, or lidocaine.

Autotransfusion of 1–2 units of blood at 12 hours preoperatively plus generous intraoperative volume replacement reduces the risk of postresection hypotension caused by desensitization of the vascular α1-receptors. Shock may therefore occur following removal of the pheochromocytoma. It is treated with intravenous saline or colloid and high doses of intravenous norepinephrine. Intravenous 5% dextrose is infused postoperatively to prevent hypoglycemia.

``Managing Metastatic Pheochromocytoma & Paraganglioma Surgical histopathology for pheochromocytoma or paraganglioma cannot reliably determine whether a tumor is malignant. Therefore, all pheochromocytomas and paragangliomas must be approached as possibly malignant.

Even if no metastases are visible at the time of surgery, they may become apparent years later. So all patients require lifetime follow-up. Therefore, it is essential to recheck plasma fractionated metanephrine levels postoperatively, at least 2–4 weeks after surgery and when the patient has minimal residual pain. It is also prudent to perform a whole-body 123I-MIBG scan about 3 months postoperatively, since previously undetected metastases may become visible. Thereafter, blood pressure and symptoms must be rechecked regularly for life; plasma fractionated metanephrines are also rechecked regularly, at least every 6 months for 5 years, then once yearly for life and immediately if hypertension or symptoms recur or if metastases become evident. Since some metastases are indolent, it is important to tailor treatment to each individual according to their tumor’s aggressiveness. Most surgeons resect the main tumor and larger metastases (debulking). Indolent metastases may be kept under close surveillance. Patients with osteolytic bone metastases may be treated with external beam radiation therapy, which is often helpful in relieving pain and stabilizing local osseous disease. Intravenous zoledronic acid may also be administered to patients with osteolytic bone metastases. Various chemotherapy regimens have been used, but there have been no controlled clinical trials to prove the effectiveness of one regimen over another or whether any regimen actually improves overall survival. The most common chemotherapy regimen combines cyclophosphamide, vincristine, and dacarbazine in cycles that are repeated every 3 weeks. About one-third of patients experience some degree of temporary remission.

Another chemotherapy regimen uses temozolomide, 250 mg/d orally for 5 days, repeating the cycle every 28 days.

Sunitinib, a tyrosine kinase inhibitor, can also produce remissions, given in doses of 50 mg/d for 4 weeks on and then 2 weeks off; alternatively, a dose of 37.5 mg/d can be

Endocrine Disorders given continuously. Each chemotherapy regimen has ­toxicities.

About 60% of patients with metastatic pheochromocytoma or paraganglioma have tumors with sufficient uptake of 123I-MIBG on diagnostic scanning to allow for therapy with high-activity 131I-MIBG. Activities of 125–500 mCi are infused, with many centers administering repeated infusions of 2 mCi/kg to cumulative activities of at least 500–800 mCi. Radioisotope therapy can suppress the bone marrow temporarily. Myelodysplastic syndrome and leukemia can develop several years after 131I-MIBG therapy, with the risk proportional to the cumulative amount of isotope.

ARDS and multisystem failure can occur rarely after 131 I-MIBG therapy, particularly in patients with pretreatment proteinuria.

For inoperable or metastatic secretory tumors, metyrosine reduces catecholamine synthesis but does not impede the progressive growth of metastases; the initial metyrosine dosage is 250 mg four times daily, increased daily by increments of 250–500 mg to a maximum of 4 g/d. Metyrosine causes central nervous system side effects and crystalluria; hydration must be ensured. Metastatic pheochromocytomas may be treated with combination chemotherapy (eg, cyclophosphamide, vincristine, and dacarbazine) or with high doses of 131I-MIBG.

``Prognosis The malignancy of a pheochromocytoma or sympathetic paraganglioma cannot be determined by its size or histologic examination. A tumor is considered malignant if metastases are present; this may take many years to become clinically evident. Therefore, lifetime surveillance is required. Malignancy is more likely for larger tumors and for sympathetic paragangliomas. The prognosis is good for patients with pheochromocytomas that are resected before causing cardiovascular damage. Hypertension usually resolves after successful surgery but may persist or return in 25% of patients despite successful surgery. Although this may be essential hypertension, biochemical reevaluation is then required, looking for a second or metastatic ­pheochromocytoma.

Formerly, the surgical mortality was as high as 30%, but the development of laparoscopic surgical techniques, improved anesthesia, intraoperative monitoring, and preoperative blood pressure control with α-blockers or calcium channel blockers has reduced surgical mortality to < 3%.

Patients with metastatic pheochromocytoma and paraganglioma have an extremely variable prognosis. Patients with a heavy and progressive tumor burden and distant metastases have a worse prognosis; patients with multiple pulmonary metastases have limited survival. Patients harboring SDHB germline mutations often have more aggressive tumors. Those with metastases limited to the abdomen or bone tend to have a better prognosis. Patients who receive surgery and chemotherapy have a median survival of about 44%. Patients undergoing surgery and high-dose 131 I-mIBG therapy have been reported to have a 5-year survival rate of 75%. It is important to note that some patients have an indolent malignancy and prolonged survivals of up to 30 years have been reported with no treatment.

CMDT 2013

1171

Ayala-Ramirez M et al. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab. 2011 Mar;96(3):717–25. [PMID: 21190975] De Jong WH et al. Elevated urinary free and deconjugated catecholamines after consumption of a catecholamine-rich diet. J Clin Endocrinol Metab. 2010 Jun;95(6):2851–5. [PMID: 20382681] Gonias S et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol. 2009 Sep;27(25): 4162–8. [PMID: 19636009] Lenders JW. Biochemical diagnosis of pheochromocytoma and paraganglioma. Ann Endocrinol (Paris). 2009 Jun;70(3): 161–5. [PMID: 19296926] Shao Y et al. Preoperative alpha blockade for normotensive pheochromocytoma: is it necessary? J Hypertens. 2011 Dec; 29(12):2429–32. [PMID: 22025238] Shen WT et al. One hundred two patients with pheochromocytoma treated at a single institution since the introduction of laparoscopic adrenalectomy. Arch Surg. 2010 Sep;145(9): 893–7. [PMID: 20855761] Weingarten TN et al. Comparison of two preoperative medical management strategies for laparoscopic resection of pheochromocytoma. Urology. 2010 Aug;76(2):508.e6–11. [PMID: 20546874]

cc

PANCREATIC & DUODENAL NEUROENDOCRINE TUMORS* ISLET CELL TUMORS ``

EssentialS of diagnosis

Half the tumors are nonsecretory; weight loss, abdominal pain, or jaundice may be presenting signs. `` Secretory tumors cause a variety of manifestations depending on the hormones secreted. ``

``General Considerations The pancreatic islets are composed of several types of cells, each with distinct chemical and microscopic features: the A cells (20%) secrete glucagon, the B cells (70%) secrete insulin, and the D cells (5%) secrete somatostatin or gastrin. F cells secrete “pancreatic polypeptide.”

Pancreatic neuroendocrine tumors constitute < 5% of all pancreatic tumors. Pancreatic neuroendocrine tumors are rare, with an incidence of about 10 per million yearly.

About 40% are functional, producing hormones that are tumor markers, which are important for diagnosis and follow-up. Although most pancreatic and duodenal neuroendocrine tumors arise spontaneously, they may occur as part four different inherited disorders: MEN 1,

∗

Diabetes mellitus and hyperglycemia are discussed in Chapter 27.

1172

CMDT 2013

Chapter 26

von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) and the rare tuberous sclerosis complex (TSC).

Insulinomas are usually benign (about 90%) and secrete excessive amounts of insulin that causes hypoglycemia. Insulinomas also produce proinsulin and C-peptide.

Insulinomas are solitary in 95% of sporadic cases but are multiple in about 90% of cases arising in MEN 1. (See Chapter 27.)

Gastrinomas secrete excessive quantities of the hormone gastrin (as well as “big” gastrin), which stimulates the stomach to hypersecrete acid, thereby causing hyperplastic gastric rugae and peptic ulceration (Zollinger– Ellison syndrome). About 50% of gastrinomas are malignant and metastasize to the liver. Gastrinomas are typically found in the duodenum (49%), pancreas (24%), or lymph nodes (11%). Sporadic Zollinger–Ellison syndrome is rarely suspected at the onset of symptoms; typically, there is a 5-year delay in diagnosis. About 22% of patients have MEN 1. In patients with MEN 1, gastrinomas usually present at a younger age; hyperparathyroidism may occur from 14 years preceding the Zollinger–Ellison diagnosis to 38 years afterward.

Glucagonomas are usually malignant; liver metastases are ordinarily present by the time of diagnosis. They usually secrete other hormones besides glucagon, often gastrin.

Somatostatinomas are very rare and are associated with weight loss, diabetes mellitus, malabsorption, and hypochlorhydria.

VIPomas are rare pancreatic neuroendocrine tumors that produce vasoactive intestinal polypeptide (VIP), a substance that causes profuse watery diarrhea and profound hypokalemia (Verner-Morrison syndrome).

Nonfunctional pancreatic neuroendocrine tumors produce no significant hormones and usually grow to large size prior to detection. They typically present with symptoms caused by mass effect.

Carcinoid pancreatic neuroendocrine tumors are typically indolent but usually metastasize to local and distant sites, particularly to other endocrine organs.

``Clinical Findings A. Symptoms and Signs Presenting symptoms and signs of gastrinomas include abdominal pain (75%), diarrhea (73%), heartburn (44%), bleeding (25%), or weight loss (17%). Endoscopy usually discovers prominent gastric folds (94%).

The 5-, 10-, and 20-year survival rates with MEN 1 are 94%, 75%, and 58%, respectively, while the survival rates for sporadic Zollinger–Ellison syndrome are 62%, 50%, and 31%, respectively. (See Chapter 15.)

Initial symptoms of glucagonoma often include weight loss, diarrhea, nausea, peptic ulcer, or necrolytic migratory erythema. About 35% of patients ultimately develop diabetes mellitus. The median survival is 34 months after diagnosis.

Carcinoid pancreatic neuroendocrine tumors secrete serotonin and can produce an atypical carcinoid syndrome manifested by pain, diarrhea, and weight loss; skin flushing occurs in 39% of patients. Islet cell tumors can secrete ectopic hormones in addition to native hormones, often in

combinations that produce various clinical syndromes.

They may secrete ACTH and cause Cushing syndrome.

B. Imaging Localization of noninsulinoma pancreatic islet cell tumors and their metastases is best done with somatostatin receptor scintigraphy (SRS); SRS detects about 75% of noninsulinomas. CT and MRI are also useful. Insulinomas can usually be located preoperatively by endoscopic ultrasonography.

For insulinomas, preoperative localization studies are less successful and have the following sensitivities: ultrasonography 25%, CT 25%, endoscopic ultrasonography 27%, transhepatic portal vein sampling 40%, arteriography 45%, intraoperative palpation 55%, and intraoperative pancreatic ultrasound 75%. Nearly all insulinomas can be successfully located at surgery by intraoperative palpation and ultrasound. An abdominal CT scan is usually obtained, but extensive preoperative localization procedures, especially with invasive methods, are not required. Tumors may be located in the pancreatic head or neck (57%), body (15%), or tail (19%) or in the duodenum (9%).

``Treatment Direct resection of the tumor (or tumors), which often spread locally, is the primary form of therapy for all types of islet cell neoplasms. In Zollinger–Ellison syndrome, gastrinomas are most commonly found in the duodenum but also in the pancreas. Gastric hyperacidity in Zollinger– Ellison syndrome is treated with a proton pump inhibitor at quadruple the usual doses. Proton pump inhibitors increase serum gastrin, which is the tumor marker for gastrinomas; hypercalcemia also stimulates gastrin release.

Insulinomas must be localized with biphasic thin section helical CT and endoscopic ultrasound. Surgery must be guided, either by preoperative endoscopic ultrasound tattooing or by laparoscopic intraoperative ultrasound.

Surgery is usually successful for sporadic insulinomas.

However, in MEN 1, insulinomas are rarely cured by surgery, with the exception of total pancreatectomy. The hypoglycemia caused by insulinomas may be counteracted by verapamil or diazoxide.

Octreotide LAR is useful in the therapy of islet cell tumors with the exception of insulinoma; subcutaneous injections of 20–30 mg are required every 4 weeks.

Treatment with octreotide LAR improves the symptoms caused by excessive VIP but does not halt tumor growth.

Selective radioembolization of hepatic metastases can be accomplished with the use of yttrium-90(Y)-labeled resin or glass microspheres. The use of streptozocin, doxorubicin, and asparaginase, especially for malignant insulinoma, has produced some encouraging results, though these drugs are quite toxic. Combined chemotherapy with 5-­fluouracil, dacarbazine, and epirubicin has also been effective (see Table 39–12).

The prognosis in these neoplasms is variable. The surgical complication rate is about 40%, with patients commonly developing fistulas and infections. Extensive pancreatic resection may cause diabetes mellitus. The overall 5-year survival is higher with functional tumors (77%) than with

Endocrine Disorders nonfunctional ones (55%) and higher with benign tumors (91%) than with malignant ones (55%).

Batcher E et al. Pancreatic neuroendocrine tumors. Endocr Res. 2011;36(1):35–43. [PMID: 21226566] Ehehalt F et al. Neuroendocrine tumors of the pancreas.

Oncologist. 2009 May;14(5):456–67. [PMID: 19411317] Ekeblad S. Islet cell tumours. Adv Exp Med Biol. 2010;654: 771–89. [PMID: 20217524] Imamura M. Recent standardization of treatment strategy for pancreatic neuroendocrine tumors. World J Gastroenterol.

2010 Sep 28;16(36):4519–25. [PMID: 20857521] Lewis RB et al. Pancreatic endocrine tumors: radiologicclinicopathologic correlation. Radiographics. 2010 Oct; 30(6): 1445–64. [PMID: 21071369] Smith JK et al. Complications after pancreatectomy for neuroendocrine tumors: a national study. J Surg Res. 2010 Sep;163(1): 63–8. [PMID: 20599224] Walter T et al. Evaluation of the combination of 5-fluouracil, dacarbazine, and epirubicin in patients with advanced welldifferentiated neuroendocrine tumors. Clin Colorectal Cancer. 2010 Oct;9(4):248–54. [PMID: 20920998]

cc

DISEASES OF THE TESTES & Male Breast

MALE HYPOGONADISM ``

EssentialS of diagnosis

Diminished libido and erections.

Fatigue, depression, reduced exercise endurance. `` Decreased growth of body hair. `` Testes may be small or normal in size. `` Serum testosterone or free testosterone is decreased. `` Serum gonadotropins (LH and FSH) are decreased or normal in hypogonadotropic hypogonadism; they are increased in testicular failure (hypergonadotropic hypogonadism). `` ``

``General Considerations Male hypogonadism is caused by deficient testosterone secretion by the testes. It may be classified according to whether it is due to (1) insufficient gonadotropin secretion by the pituitary (hypogonadotropic); (2) pathology in the testes themselves (hypergonadotropic); or (3) both (Table 26–14). Partial male hypogonadism may be difficult to distinguish from the physiologic reduction in serum testosterone seen in normal aging, obesity, and illness.

``Etiology A. Hypogonadotropic Hypogonadism (Low Testosterone with Normal or Low LH) A deficiency in FSH and LH may be isolated or associated with other pituitary hormonal abnormalities. (See

1173

CMDT 2013

Table 26–14. Causes of male hypogonadism.

Hypogonadotropic (Low or Normal LH)

Hypergonadotropic (High LH)

Aging Alcohol Chronic illness Congenital syndromes Constitutional delay Cushing syndrome Drugs Estrogen GnRH agonist (leuprolide) Ketoconazole Marijuana Prior androgens Spironolactone Hemochromatosis Hypopituitarism Hypothyroidism Idiopathic Kallmann syndrome 17-Ketosteroid reductase deficiency Major medical or surgical illnesses Malnourishment Obesity (BMI > 30) Prader-Willi syndrome

Aging Antitumor chemotherapy Bilateral anorchia Idiopathic Klinefelter syndrome Leprosy Lymphoma Male climacteric Mumps Myotonic dystrophy Noonan syndrome Orchitis Radiation therapy Sertoli cell-only syndrome Testicular trauma Tuberculosis Uremia

BMI, body mass index; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

Hypopituitarism.) Hypogonadotropic hypogonadism can be primary, with a failure to enter puberty by age 14; the differential diagnosis is isolated hypogonadotropic hypogonadism, hypopituitarism, or simply delayed puberty (constitutional delay of growth and puberty).

Hypogonadotropic hypogonadism may also be acquired.

Causes of acquired hypogonadotropic hypogonadism include pituitary or hypothalamic tumors, granulomatous diseases, lymphocytic hypophysitis, or hemochromatosis.

Other causes of acquired hypogonadotropic hypogonadism include Cushing syndrome, adrenal insufficiency, and thyroid hormone excess or deficiency. Genetic conditions (eg, Kallman syndrome or PROKR2 mutations) account for about 40% of cases of acquired hypogonadotropic hypogonadism that is isolated, severe (serum testosterone < 150 ng/dL), and apparently idiopathic.

The main causes of male partial acquired hypogonadotropic hypogonadism (serum testosterone 150–300 ng/dL) are functional and include obesity, poor health, or normal aging. Spermatogenesis is usually preserved. After age 40, serum total testosterone declines variably by an average of 1–2% per year; serum free testosterone levels decline even faster, since sex hormone binding globulin increases with age. After age 70 years, 28% of men have low serum total testosterone and 68% have low serum free testosterone levels, compared with the levels found in young men. Serum levels of free testosterone are lower in men aged 40–70 compared with younger men, without any increase in serum LH. After age 70, LH levels tend to rise, indicating a contribution of primary gonadal dysfunction with advanced age.

1174

CMDT 2013

Chapter 26

There is considerable clinical and laboratory overlap between patients with partial hypogonadotropic hypogonadism and those with normal aging, obesity, or illness. A multicenter European study concluded that the diagnosis of testosterone deficiency in older men should include a serum testosterone < 320 ng/mL and at least three of the following six symptoms: erectile dysfunction, poor morning erection, low libido, depression, fatigue, and inability to perform vigorous activity. Such men are most likely to benefit from testosterone replacement.

B. Hypergonadotropic Hypogonadism (Testicular Failure with High LH) A failure in testicular secretion of testosterone causes a rise in LH. If testicular Sertoli cell function is deficient, FSH will be elevated. Conditions that can cause testicular failure include viral infection (eg, mumps), irradiation, cancer chemotherapy or radioisotope therapy, autoimmunity, myotonic dystrophy, uremia, XY gonadal dysgenesis, partial 17-ketosteroid reductase deficiency, Klinefelter syndrome, and male climacteric. In men who have had a unilateral orchiectomy for cancer, the remaining testicle can fail even in the absence of radiation or chemotherapy.

Male hypogonadism can also be caused by a congenital partial deficiency in the steroidogenic enzyme CYP17 (17-hydroxylase). CYP17 may be deliberately inhibited by abiraterone acetate (Zytiga), a drug for prostate cancer.

CYP17 inhibition also causes adrenocortical insufficiency, hypertension, and hypokalemia.

Klinefelter syndrome (47,XXY and its variants) is the most common chromosomal abnormality among males, with an incidence of about 1:500. It is caused by the expression of an abnormal karyotype, classically 47,XXY. Other forms are common, eg, 46,XY/47,XXY mosaicism, 48,XXYY, 48,XXXY, or 46,XX males.

The manifestations of Klinefelter syndrome are variable. Testes feel normal during childhood, but during adolescence they usually become firm, fibrotic, small, and nontender to palpation. Although puberty occurs at the normal time, the degree of virilization is variable. About 85% of patients have some gynecomastia at puberty.

Other causes of gynecomastia (Table 26–15) must be excluded. Other common findings include tall stature and abnormal body proportions that are unusual for hypogonadal men (height greater than arm span; crown-pubis length greater than pubis-floor). Patients with multiple X or Y chromosomes are more apt to have mental deficiency and other abnormalities such as clinodactyly or synostosis. They may also exhibit problems with coordination and social skills. Other problems include a higher incidence of breast cancer, chronic pulmonary disease, varicosities of the legs, and diabetes mellitus (8% of patients); impaired glucose tolerance occurs in an additional 19% of patients.

The diagnosis of Klinefelter syndrome is confirmed by karyotyping or by determining the presence of RNA for X-inactive-specific transcriptase (XIST) in peripheral blood leukocytes by polymerase chain reaction.

On semen analysis, most men (about 95%) with classic Klinefelter syndrome have azoospermia, although some

Table 26–15. Causes of gynecomastia.

Idiopathic Physiologic causes Neonatal period Puberty Aging Obesity Endocrine diseases Androgen resistance syndromes Aromatase excess syndrome (sporadic or familial) Diabetic lymphocytic mastitis Hyperprolactinemia Hyperthyroidism Klinefelter syndrome Male hypogonadism Partial 17-ketosteroid reductase deficiency Systemic diseases Androgen insensitivity Chronic liver disease Chronic kidney disease Neurologic disorders Refeeding after starvation Spinal cord injury Neoplasms Adrenal tumors Bronchogenic carcinoma Carcinoma of the breast Ectopic hCG: lung, hepatocellular, gastric, renal carcinomas Pituitary prolactinoma Testicular tumors Drugs (partial list) Alcohol Alkylating agents Amiodarone Anabolic steroids Androgens Bicalutamide

Busulfan Chorionic gonadotropin Cimetidine Clomiphene Cyclophosphamide Diazepam Diethylstilbestrol Digitalis preparations Dutasteride Estrogens (oral or topical) Ethionamide Famotidine (rare) Finasteride Flutamide Goserelin Growth hormone HAART (highly active antiretroviral therapy) Haloperidol Hydroxyzine Isoniazid Ketoconazole Lavender oil (topical) Leuprolide Marijuana Meprobamate Methadone Methyldopa Metoclopramide Metronidazole Mirtazapine Nilutamide Omeprazole Opioids Penicillamine Phenothiazines Progestins Protease inhibitors Proton pump inhibitors (uncommon) Ranitidine (rare) Reserpine Risperidone Somatropin (growth hormone) Soy ingestion Spironolactone Tea tree oil (topical) Testosterone Thioridazine Tricyclic antidepressants Verapamil

sperm production is often present in their early teens. Men with 46,XY/47,XXY mosaicism may have spontaneous fertility. Also, testicular biopsy reveals sperm in up to 50% of affected patients, allowing some of them to be fertile with the use of in vitro fertilization using intracytoplasmic sperm injection (ICSI).

XY gonadal dysgenesis describes several conditions that result in the failure of the testes to develop normally.

Endocrine Disorders SRY is a gene on the Y chromosome that initiates male sexual development. Mutations in SRY result in testicular dysgenesis. Affected individuals lack testosterone, which results in sex reversal: female external genitalia with a blind vaginal pouch, no uterus, and intra-abdominal dysgenetic gonads. Affected individuals are raised as girls and appear normal until their lack of pubertal development and amenorrhea leads to the diagnosis. Intra-abdominal rudimentary testes have an increased risk of developing a malignancy and are usually resected. Patients are considered women and receive estrogen replacement therapy.

C. Androgen Insensitivity Partial resistance to testosterone is a rare condition in which phenotypic males have variable degrees of apparent hypogonadism, hypospadias, cryptorchism, and gynecomastia. Serum testosterone levels are normal.

``Clinical Findings A. Symptoms and Signs Hypogonadism that is congenital or acquired during childhood presents as delayed puberty. Men with acquired hypogonadism have variable manifestations. Most men experience decreased libido. Others complain of erectile dysfunction, poor morning erection, or hot sweats. Men often have depression, fatigue, or decreased ability to perform vigorous physical activity. The presenting complaint may also be infertility, gynecomastia, headache, fracture, or other symptoms related to the cause or result of the hypogonadism. The patient’s history often gives a clue to the cause (Table 26–14).

Physical signs associated with hypogonadism may include decreased body, axillary, beard, or pubic hair; such diminished sexual hair growth is not reliably present except after years of severe hypogonadism. Men in whom hypogonadism develops tend to lose muscle mass and gain weight due to an increase in subcutaneous fat. Examination should include measurements of arm span and height.

Testicular size should be assessed with an orchidometer (normal volume is about 10–25 mL; normal length is usually over 6 cm). Testicular size may decrease but usually remains within the normal range in men with postpubertal hypogonadotropic hypogonadism, but it may be diminished with testicular injury or Klinefelter syndrome. The testes must also be carefully palpated for masses, since Leydig cell tumors may secrete estrogen and present with hypogonadism. The testicles must be carefully examined for evidence of trauma, infiltrative lesions (eg, lymphoma), or ongoing infection (eg, leprosy, tuberculosis).

CMDT 2013

1175

levels are considered low if they are confirmed to be < 320 ng/dL (11 nmol/L). Free testosterone is best measured by calculation, using accurate assays for testosterone and sex hormone binding globulin. Serum free testosterone levels are considered low if they are confirmed to be < 64 pg/mL (220 pmol/L).

Normal ranges for serum testosterone have been derived from nonfasting morning blood specimens, which tend to be the highest of the day. Later in the day, serum testosterone levels can be 25–50% lower. Therefore, a serum testosterone drawn fasting or late in the day may be misleadingly below the “normal range.” Serum testosterone levels in men are highest at age 20–30 years and slightly lower at age 30–40 years; testosterone falls gradually but progressively after age 40 years. Testing for serum free testosterone is especially important for detecting hypogonadism in elderly men, who generally have high levels of sex hormone binding globulin. A low serum testosterone should be verified with a repeat assay and further evaluated with serum LH and FSH levels. LH and FSH tend to be high in patients with hypergonadotropic hypogonadism but low or inappropriately normal in men with hypogonadotropic hypogonadism or normal aging. Patients with low gonadotropins may be further evaluated for other pituitary abnormalities, including hyperprolactinemia.

Testosterone stimulates erythropoiesis in men, causing the normal red blood count range to be higher in men than in women; mild anemia is common in men with hypogonadism, with red blood counts below the normal male range. For men with long-standing male hypogonadism, bone densitometry is recommended. Men with severe osteoporosis may require treatment with bisphosphonates and vitamin D, in addition to testosterone replacement therapy. (See Osteoporosis section.)

B. Laboratory Findings

1. Hypogonadotropic hypogonadism—A serum PRL determination is obtained but may be elevated for many reasons (see Table 26–2). Men with gynecomastia may be screened for partial 17-ketosteroid reductase deficiency with serum determinations for androstenedione and estrone, which are elevated in this condition. X-linked congenital adrenal hypoplasia is a rare condition in which a DAX-1 gene mutation causes hypogonadotropic hypogonadism and azoospermia, which usually presents in adolescence; the associated primary adrenal insufficiency usually presents in childhood, but it may remain undiagnosed into adulthood.

The serum estradiol level may be elevated in patients with cirrhosis and in rare cases of estrogen-secreting tumors (testicular Leydig cell tumor or adrenal carcinoma). Men with no discernible definite cause for hypogonadotropic hypogonadism should be screened for hemochromatosis and have an MRI of the pituitary and hypothalamic region to look for a tumor or other lesion. (See Hypopituitarism.)

The evaluation for hypogonadism begins with a morning serum testosterone or free testosterone measurement (or both) using a reliable assay. Most radioimmunoassays and ELISAs for testosterone are inaccurate when serum testosterone levels are < 300 ng/dL. More accurate testosterone assays rely on extraction and chromatography, followed by mass spectrometry or immunoassay. Serum testosterone

2. Hypergonadotropic hypogonadism—Men with hypergonadotropic hypogonadism have low serum testosterone levels with a compensatory increase in FSH and LH. Klinefelter syndrome can be confirmed by karyotyping or by measurement of leukocyte XIST. Testicular biopsy is usually reserved for younger patients in whom the reason for primary hypogonadism is unclear.

1176

CMDT 2013

Chapter 26

``Treatment Testosterone replacement is reasonable for boys who have not begun puberty by age 14. It is beneficial to most men with hypergonadotropic hypogonadism or severe hypogonadotropic hypogonadism. Men with symptoms of hypogonadism (see above) and a repeatedly low serum testosterone or free testosterone can also benefit from testosterone replacement. For men with borderline low serum testosterone levels and marginal hypogonadal symptoms, the decision to treat should consider the potential benefits versus risks (see below). Such men may be given a trial of testosterone therapy for several months while monitoring their response.

Testosterone therapy should not be administered to men with active prostate or breast cancer, or erythrocytosis. In men over age 50 years, a digital prostate examination and serum prostate-specific antigen (PSA) level should be done before beginning testosterone therapy. Men with symptoms of prostatic hypertrophy, a palpable prostate nodule, or a PSA > 4 ng/mL (> 3 ng/mL in men of African ancestry) should have a urologic evaluation prior to treatment. Serum PSA should be measured yearly during therapy. Similarly, testosterone therapy is not given to men with untreated sleep apnea or congestive heart failure. In men who have coronary risk factors or are over age 65, special attention should be given to improving cardiac risk factors (eg, controlling hypertension or hyperlipidemia) and administering low-dose aspirin while receiving testosterone replacement.

Drug interactions can occur. Testosterone should be administered cautiously to men receiving coumadin, since the combination can increase the INR and risk of bleeding.

Similarly, testosterone therapy can increase serum levels of cyclosporine, tacrolimus, and tolvaptan. Testosterone can predispose to hypoglycemia in diabetic men receiving insulin or oral hypoglycemic agents, so close monitoring of blood sugars is advisable during initiation of testosterone therapy.

Oral androgen therapy with methyltestosterone is not advisable due to the potential for causing liver tumors, peliosis hepatis, and cholestatic jaundice (see below).

A. Formulations of Testosterone Replacement Therapy 1. Topical testosterone—Testosterone is best administered topically. Topical administration yields more stable serum testosterone levels than intramuscular administration. Topical testosterone is usually applied once daily in the morning after showering. Topical testosterone should not be applied to the breast or genitals. Androgel 1% gel is available in 2.5-g packets (25 mg testosterone) and 5-g packets (50 mg testosterone) and in a pump that dispenses 12.5 mg testosterone per pump actuation: the recommended dose is 50–100 mg applied daily to the shoulders.

Androgel 1.6% gel is available in a pump that dispenses 20.25 mg testosterone per pump actuation; the recommended dose is 40.5–81 mg daily. Testim 1% gel is available in 5-g tubes (50 mg testosterone); the recommended dose is 50–100 mg applied daily. Fortesta 2% gel is available in a pump that dispenses 10 mg testosterone per pump

actuation; the recommended dose is 40–70 mg daily.

Testogel is distributed in 5-g sachets (50 mg testosterone); this brand is not available in the United States. Testim, Fortesta, and Testogel may be applied to both shoulders, upper arms, or abdomen. Axiron 2% solution is available in a pump that dispenses 30 mg per actuation; the recommended dose is 30–60 mg applied to each axilla daily.

The skin serves as a reservoir that slowly releases about 10% of the testosterone into the blood; serum testosterone levels reach a steady state in 1–3 days. The serum testosterone level should be determined about 14 days after starting therapy; if the level remains below normal or the clinical response is inadequate, the daily dose may be increased to 1.5 to 2 times the initial dose. After the application of topical testosterone, the hands should be washed. The application site should be allowed to dry for 5–10 minutes before dressing. Before close contact with women or children, a shirt must be worn or the areas of application washed with soap and water to prevent transfer of testosterone to them.

2. Transdermal testosterone —Testosterone transdermal systems (skin patches) are available in two formulations for application to nongenital skin. Testoderm II, 5 mg/d leaves a sticky residue but causes little skin irritation.

Androderm (2 or 4 mg/24 h) patches may be applied at bedtime in doses of 4–8 mg; it adheres more tightly to the skin but may cause more skin irritation. Both produce reliable serum levels of testosterone that are somewhat lower that those achieved with injections. The patch systems also suffer from being rather inconvenient and expensive.

3. Parenteral testosterone—Testosterone cypionate and testosterone enanthate are intramuscular testosterone formulations that are available in solutions containing 200 mg/mL. Their main advantage is low cost. The usual dose is 200 mg every 2 weeks or 300 mg every 3 weeks.

The dose and injection intervals are adjusted according to the patient’s response. These preparations are oil-based and are usually given intramuscularly in the gluteal area.

Testosterone undecanoate (Nebido) is a long-lasting depot testosterone formulation that is administered in doses of 1000 mg (4 mL) by slow intramuscular injection.

The initial injection is followed by another 1000 mg injection 6 weeks later and maintenance doses of 1000 mg every 3 months. A serum testosterone level is measured before the fourth dose; if the serum testosterone remains low, the dosing interval is shortened to every 10 weeks. It is not available in the United States or Canada.

4. Buccal testosterone—Testosterone buccal tablets (Striant) are placed between the upper lip and gingivae.

One or two 30-mg tablets are thus retained and changed every 12 hours. They should not be chewed or swallowed.

5. Oral testosterone—Oral androgen preparations include methyltestosterone and fluoxymesterone. Another oral preparation is testosterone undecanoate; it is not approved in the United States. These oral preparations can cause liver tumors or peliosis hepatis with long-term use. Cholestatic jaundice occurs in 1–2% of patients but usually remits after the medication is discontinued. Oral androgens are not as effective as topical or parenteral testosterone.

Endocrine Disorders B. Benefits of Testosterone Replacement Therapy Testosterone therapy usually benefits men with low serum testosterone and at least three manifestations of hypogonadism as noted above. Testosterone therapy can improve overall mood, sense of well-being, sexual desire, and erectile function. It also increases physical vigor and muscle strength as manifested in measurements of leg-press and chest-press strength. Testosterone replacement also improves exercise endurance and stair climbing ability.

C. Risks of Testosterone Replacement Therapy Testosterone replacement therapy appears to increase the risk of cardiovascular events in men older than age 65 with cardiac risk factors or preexisting angina. This increased risk may be due to the decrease in serum HDL that can occur with testosterone therapy.

Testosterone therapy can aggravate benign prostatic hypertrophy (BPH). However, aggravation of voiding problems is uncommon. In men with BPH, finasteride may be coadministered with testosterone to reduce prostate size. The incidence of prostate cancer does not appear to be increased by testosterone therapy. However, testosterone therapy is contraindicated in the presence of active prostate cancer. Hypogonadal men who have had a prostatectomy for low-grade prostate cancer, and who have remained in complete remission for several years, may have testosterone therapy given cautiously while monitoring sensitive serum PSA levels.

Erythrocytosis develops in some men who are treated with testosterone. Erythrocytosis is more common with intramuscular injections of testosterone enanthate than with transcutaneous testosterone. However, no increase in the incidence of thromboembolic events has been reported.

Testosterone therapy tends to aggravate sleep apnea in older men, likely through central nervous system effects.

Surveillance for sleep apnea is recommended during testosterone therapy and a formal evaluation with nocturnal pulse oximetry recording is recommended for all high-risk patients with snoring, obesity, partner’s report of apneic episodes, nocturnal awakening, unrefreshing sleep with daytime fatigue, or hypertension.

Men who are treated with testosterone frequently experience some increase in acne that is usually mild and tolerated; topical antiacne therapy or a reduction in testosterone replacement dosage may be required. Increases in intraocular pressure have occurred during testosterone therapy.

During the initiation of testosterone replacement therapy, gynecomastia develops in some men, which usually is mild and tends to resolve spontaneously; switching from testosterone injections to testosterone transdermal gel may help this condition.

``Prognosis of Male Hypogonadism If hypogonadism is due to a pituitary lesion, the prognosis is that of the primary disease (eg, tumor, necrosis). The prognosis for restoration of virility is good if testosterone is given.

CMDT 2013

1177

Basaria S et al. Adverse events associated with testosterone administration. N Engl J Med. 2010 Jul 8;363(2):109–22. [PMID: 20592293] Bhasin S et al. Testosterone therapy in men with androgen deficiency syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010 Jun;95(6):2536–59.

[PMID: 20525905] Cunningham GR et al. Clinical review: why is androgen replacement in males controversial? J Clin Endocrinol Metab. 2011 Jan;96(1):38–52. [PMID: 20881265] Dwyer AA et al. The long-term clinical follow-up and natural history of men with adult-onset idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2010 Sep;95(9): 4235–43. [PMID: 20591981] Mäkinen JI et al. Androgen replacement therapy in late-onset hypogonadism: current concepts and controversies. Gerontology.

2011;57(3):193–202. [PMID: 20689266] Traish AM et al. Testosterone deficiency. Am J Med. 2011 Jul;124(7):578–87. [PMID: 21683825] Wu FC et al; EMAS Group. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010 Jul 8;363(2):125–35. [PMID: 20554979]

TESTICULAR TUMORS IN ADULTS (See also Chapter 39) About 95% of testicular tumors are germ cell tumors (seminomas or nonseminomas). Seminomas do not produce α-fetoprotein, but about 5–10% produce some hCG. Nonseminomas, on the other hand, produce increased serum levels of one or both of these markers in about 90% of cases. Men with liver disease may have misleadingly high levels of α-fetoprotein. Most germ cell tumors are sensitive to cisplatin-based combined pre-chemotherapy. Sperm banking is advised.

About 5% of testicular tumors are Leydig or Sertoli cell tumors. Leydig cell tumors tend to produce estrogen (75%) and cause gynecomastia and impotence on that basis; they may sometimes produce androgens that can cause pseudoprecocious puberty in boys. Sertoli cell tumors may also produce estrogen (30%) with feminization; gynecomastia may be due to hCG secretion (25%).

Some testicular tumors may be small and nonpalpable yet may secrete sufficient amounts of hCG or estrogen to cause gynecomastia or impotence. Testicular ultrasound may help reveal small tumors.

After unilateral orchiectomy for testicular cancer, an elevated FSH level prior to further treatment indicates a patient at higher risk for cancer in the remaining testis.

Cryptorchism One or both testes may be absent from the scrotum at birth in about 20% of premature or low-birth-weight male infants and in 3–6% of full term infants. Cryptorchism is found in 1–2% of males after 1 year of age but must be distinguished from retractile testes, which require no treatment. Cryptorchism should be corrected before age 12–24 months in an attempt to reduce the risk of infertility, which occurs in up to 75% of men with bilateral cryptorchism and in 50% of men with unilateral cryptorchism.

1178

CMDT 2013

Chapter 26

Some patients have underlying hypogonadism, including hypogonadotropic hypogonadism.

If the testes are not palpable, ultrasound or MRI can be used to locate them. Alternatively, hCG, 1500 units intramuscularly daily for 3 days, causes a significant rise in testosterone if the testes are present. Therapy with hCG results in a testicular descent rate of about 25%.

Compared to an incidence of 0.002% in normal males, cryptorchid testes increase the lifetime risk of testicular neoplasia to about 0.06%, and intra-abdominal testes, to 5%. Orchiopexy decreases the risk of neoplasia when performed before 10 years of age. Orchiectomy after puberty is an option for intra-abdominal testes.

Husmann DA. Testicular descent: a hypothesis and review of current controversies. Pediatr Endocrinol Rev. 2009 Jun; 6(4):491–5. [PMID: 19550384] Kurpisz M et al. Cryptorchidism and long-term consequences.

Reprod Biol. 2010 Mar;10(1):19–35. [PMID: 20349021] Travis LB et al. Testicular cancer survivorship: research strat­ egies and recommendations. J Natl Cancer Inst. 2010 Aug 4;102(15): 1114–30. [PMID: 20585105] Wood HM et al. Cryptorchidism and testicular cancer: separating fact from fiction. J Urol. 2009 Feb;181(2):452–61. [PMID: 19084853]

Gynecomastia ``

EssentialS of diagnosis

Palpable enlargement of the male breast, often asymmetric or unilateral. `` Glandular gynecomastia characterized by tenderness. `` Fatty gynecomastia typically nontender. `` Must be distinguished from carcinoma or mastitis. ``

``General Considerations Gynecomastia refers to a female-appearing male breast. In practice, it is defined as the presence of palpable glandular breast tissue in males. Pubertal gynecomastia develops in about 60% of boys; the swelling usually subsides spontaneously within a year. Gynecomastia is particularly common in teenagers who are very tall or overweight. Gynecomastia develops in about 50% of athletes who abuse androgens and anabolic steroids. It is seen in Klinefelter syndrome, which affects 1:500 men. (See section on Klinefelter syndrome.) Gynecomastia can develop in HIV-infected patients treated with highly active antiretroviral therapy (HAART), especially in men receiving efavirenz or didanosine; breast enlargement resolves spontaneously in 73% of patients within 9 months. Gynecomastia is common among elderly men, particularly when there is associated weight gain. However, it can be the first sign of a serious disorder.

The causes of gynecomastia are multiple and diverse (Table 26–15).

``Clinical Findings A. Symptoms and Signs The male breasts must be palpated carefully to distinguish true glandular gynecomastia from fatty pseudogynecomastia in which only adipose tissue is felt. The breasts are best examined both seated and supine. Using the thumb and forefinger as pincers, the subareolar tissue is compared to nearby adipose tissue. Fatty gynecomastia is usually diffuse and nontender. Glandular enlargement beneath the areola may be tender. Pubertal gynecomastia is characterized by tender discoid enlargement of breast tissue 2–3 cm in diameter beneath the areola. The following characteristics are worrisome for malignancy: asymmetry; location not immediately below the areola; unusual firmness; or nipple retraction, bleeding, or discharge.

Gynecomastia is graded according to severity: I, mild; II, moderate; III, severe.

B. Laboratory Findings Obtain plasma levels of PRL (see Hyperprolactinemia) and the β-subunit of hCG (β-hCG). Detectable levels of β-hCG implicate a testicular tumor (germ cell or Sertoli cell) or other malignancy (usually lung or liver). Detectable low levels of serum β-hCG (< 5 mU/mL) may be reported in men with primary hypogonadism and high serum LH levels if the assay for β-hCG cross-reacts with LH. Measurements of serum free testosterone and LH are valuable in the diagnosis of primary or secondary hypogonadism. A low serum free testosterone and high LH are seen in primary hypogonadism. High testosterone levels plus high LH levels characterize partial androgen resistance. Serum estradiol is determined but is usually normal; increased levels may result from testicular tumors, increased β-hCG, liver disease, obesity, adrenal tumors (rare), true hermaphroditism (rare), or gain of function mutations affecting the aromatase gene (rare). Many estrogens and substances with estrogenic activity are not detected by estradiol assays. Serum TSH (sensitive) and FT4 levels are also determined. A karyotype (for Klinefelter syndrome) is obtained in men with persistent gynecomastia without obvious cause.

Investigation of unclear cases should include a chest radiograph to search for metastatic or bronchogenic carcinoma. Needle biopsy with cytologic examination may be performed on suspicious areas of male breast enlargement (especially when unilateral or asymmetric) to distinguish gynecomastia from tumor or mastitis.

``Treatment Pubertal gynecomastia often resolves spontaneously within 1–2 years. Drug-induced gynecomastia resolves after the offending drug is removed. Spironolactone can be stopped, with substitution of a selective aldosterone antagonist such as eplerenone. Patients with painful or persistent gynecomastia may be treated with medical therapy, which is usually continued for 9–12 months. Generally, it is prudent to treat patients for gynecomastia only when it becomes a troubling and continuing problem for them.

Endocrine Disorders Selective estrogen receptor modulator (SERM) therapy is much more effective for glandular (“lumpy”) gynecomastia than for diffuse fatty gynecomastia. Raloxifene, 60 mg orally daily, may be somewhat more effective than tamoxifen, 10–20 mg orally daily.

Aromatase inhibitor (AI) therapy, such as anastrozole and letrozole, is reasonably effective for gynecomastia.

Anastrozole, 1 mg orally daily, reduces breast volume significantly in adolescent boys over a 6-month course of therapy. Serum levels of estrogen fall slightly while testosterone levels rise significantly. Concerns about long-term AI therapy in adolescents include the possibility of inducing osteoporosis and delaying epiphyseal fusion, which could cause an increase in adult height.

Testosterone therapy for men with hypogonadism may improve or worsen preexistent gynecomastia.

Radiation therapy has been used prophylactically to prevent gynecomastia in men with prostate cancer being treated with antiandrogen therapy. Low-dose radiation therapy reduces the incidence of gynecomastia from 85% to 52%.

Surgical correction is reserved for patients with persistent or severe gynecomastia, since results can be disappointing. For best results, the procedure should be performed by a plastic surgeon who has experience with this surgery.

Carlson HE. Approach to the patient with gynecomastia. J Clin Endocrinol Metab. 2011 Jan;96(1):15–21. [PMID: 21209041] Devalia HL et al. Current concepts in gynaecomastia. Surgeon.

2009 Apr;7(2):114–9. [PMID: 19408804] Hammond DC. Surgical correction of gynecomastia. Plast Reconstr Surg. 2009 Jul;124(1 Suppl):61e–68e. [PMID: 19568140] Johnson RE et al. Gynecomastia: pathophysiology, evaluation, and management. Mayo Clin Proc. 2009 Nov;84(11):1010–5.

[PMID: 19880691] Mauras N et al. Pharmacokinetics and pharmacodynamics of anastrozole in pubertal boys with recent-onset gynecomastia.

J Clin Endocrinol Metab. 2009 Aug;94(8):2975–8. [PMID: 19470631]

cc

AMENORRHEA & MENOPAUSE (See also Chapter 18) PRIMARY AMENORRHEA Menarche ordinarily occurs between ages 11 and 15 years (average in the United States: 12.7 years). The failure of any menses to appear is termed “primary amenorrhea,” and evaluation is commenced (1) at age 14 years if neither menarche nor any breast development has occurred or if height is in the lowest 3%, or (2) at age 16 years if menarche has not occurred.

``Etiology of Primary Amenorrhea The causes of primary amenorrhea include hypothalamicpituitary causes, hyperandrogenism, ovarian causes, pseudohermaphroditism, uterine causes, and pregnancy.

CMDT 2013

1179

A. Hypothalamic-Pituitary Causes (with Low or Normal FSH) A genetic deficiency of GnRH and gonadotropins may be isolated or associated with other pituitary deficiencies or diminished olfaction (Kallmann syndrome). Hypothalamic lesions, particularly craniopharyngioma, may be present.

Pituitary tumors may be nonsecreting or may secrete PRL or GH. Cushing syndrome may be caused by corticosteroid treatment, a cortisol-secreting adrenal tumor, or an ACTHsecreting pituitary tumor. Hypothyroidism can delay ­adolescence. Head trauma or encephalitis can cause gonadotropin deficiency. Primary amenorrhea may also be caused by constitutional delay of adolescence, organic illness, vigorous exercise (eg, ballet dancing, running), stressful life events, dieting, or anorexia nervosa; however, these conditions should not be assumed to account for amenorrhea without a full physical and endocrinologic evaluation. (See section on Hypopituitarism.)

B. Hyperandrogenism (with Low or Normal FSH) Excess testosterone may be secreted by adrenal tumors or by adrenal hyperplasia caused by steroidogenic enzyme defects such as P450c21 deficiency (salt-wasting) or P450c11 deficiency (hypertension). Ovarian tumors or polycystic ovaries may also secrete excess testosterone.

Androgenic steroids may also cause this syndrome.

C. Ovarian Causes (with High FSH) Gonadal dysgenesis (Turner syndrome and variants; see below) is a frequent cause of primary amenorrhea. Ovarian failure due to autoimmunity is a common cause. Rare deficiencies in certain ovarian steroidogenic enzymes are causes of primary hypogonadism without virilization: 3β-hydroxysteroid dehydrogenase deficiency (adrenal insufficiency with low serum 17-hydroxyprogesterone) and P450c17 deficiency (hypertension and hypokalemia with high serum 17-hydroxyprogesterone). A whole-body deficiency in P450 aromatose (P450arom) activity produces female hypogonadism associated with polycystic ovaries, tall stature, osteoporosis, and virilization.

D. Pseudohermaphroditism (with High LH) An enzymatic defect in testosterone synthesis may present as a sexually immature phenotypic girl with primary amenorrhea. Complete androgen resistance (testicular feminization) presents as a phenotypic young woman without sexual hair but with normal breast development and primary amenorrhea. In both cases, the uterus is absent and testes are intra-abdominal or cryptorchid.

Intra-abdominal testes are surgically resected. Such patients are treated as normal but infertile, hypogonadal women.

E. Uterine Causes (with Normal FSH) Congenital absence or malformation of the uterus may be responsible for primary amenorrhea, as may an unresponsive or atrophic endometrium. An imperforate hymen is occasionally the reason for the absence of visible menses.

1180

CMDT 2013

Chapter 26

F. Pregnancy (with High hCG)

``Etiology

Pregnancy may be the cause of primary amenorrhea even when the patient denies ever having had sexual intercourse.

The causes of secondary amenorrhea include pregnancy, hypothalamic-pituitary causes, hyperandrogenism, uterine causes, premature ovarian failure, and menopause.

``Clinical Findings A. Symptoms and Signs

A. Pregnancy (High hCG)

Patients with primary amenorrhea require a thorough history and physical examination to look for signs of the conditions noted above. Headaches or visual field abnormalities implicate a hypothalamic or pituitary tumor. Signs of pregnancy may be present. Blood pressure abnormalities, acne, and hirsutism should be noted. Short stature may be seen with an associated GH or thyroid hormone deficiency. Short stature with manifestations of gonadal dysgenesis indicates Turner syndrome (see below).

Olfaction testing screens for Kallmann syndrome. Obesity and short stature may be signs of Cushing syndrome. Tall stature may be due to eunuchoidism or gigantism.

Hirsutism or virilization suggests excessive testosterone.

An external pelvic examination plus a rectal examination should be performed to assess hymen patency and the presence of a uterus.

Pregnancy is the most common cause for secondary amenorrhea in women of childbearing age. The differential diagnosis includes rare ectopic secretion of hCG by a choriocarcinoma or bronchogenic carcinoma.

B. Laboratory and Radiologic Findings The initial endocrine evaluation should include serum determinations of FSH, LH, PRL, testosterone, TSH, FT4, and hCG (pregnancy test). Patients who are virilized or hypertensive require serum electrolyte determinations and further hormonal evaluation. MRI of the hypothalamus and pituitary is used to evaluate teens with primary amenorrhea and low or normal FSH and LH—especially those with high PRL levels. Pelvic duplex/color sonography is very useful.

Girls who have a normal uterus and high FSH without the classic features of Turner syndrome may require a karyotype to diagnose X chromosome mosaicism.

``Treatment Treatment of primary amenorrhea is directed at the underlying cause. Girls with permanent hypogonadism are treated with ERT (see below).

Deligeoroglou E et al. Evaluation and management of adolescent amenorrhea. Ann N Y Acad Sci. 2010 Sep;1205:23–32. [PMID: 20840249] Gamboa S et al. Clinical inquiries. What’s the best way to manage athletes with amenorrhea? J Fam Pract. 2008 Nov;57(11): 749–50. [PMID: 19006626] Rosenberg HK. Sonography of the pelvis in patients with primary amenorrhea. Endocrinol Metab Clin North Am. 2009 Dec;38(4):739–60. [PMID: 19944290]

SECONDARY AMENORRHEA & MENOPAUSE Secondary amenorrhea is defined as the absence of menses for 3 consecutive months in women who have passed menarche. Menopause is defined as the terminal episode of naturally occurring menses; it is a retrospective diagnosis, usually made after 6 months of amenorrhea.

B. Hypothalamic-Pituitary Causes (with Low or Normal FSH) The hypothalamus must release GnRH in a pulsatile ­manner for the pituitary to secrete gonadotropins. GnRH pulses occurring more than once per hour favor LH secretion, while less frequent pulses favor FSH secretion. In normal ovulatory cycles, GnRH pulses in the follicular phase are rapid and favor LH synthesis and ovulation; ovarian luteal progesterone is then secreted that slows GnRH pulses, causing FSH secretion during the luteal phase. Most women with hypothalamic amenorrhea have a persistently low frequency of GnRH pulses.

Secondary “hypothalamic” amenorrhea may be caused by stressful life events such as school examinations or leaving home. Such women usually have a history of normal sexual development and irregular menses since menarche.

Amenorrhea may also be the result of strict dieting, vigorous exercise, organic illness, or anorexia nervosa. Intrathecal infusion of opioids causes amenorrhea in most women.

These conditions should not be assumed to account for amenorrhea without a full physical and endocrinologic evaluation. Young women in whom the results of evaluation and progestin withdrawal test are normal have noncyclic secretion of gonadotropins resulting in anovulation.

Such women typically recover spontaneously but should have regular evaluations and a progestin withdrawal test about every 3 months to detect loss of estrogen effect.

PRL elevation due to any cause (see section on hyperprolactinemia) may cause amenorrhea. Pituitary tumors or other lesions may cause hypopituitarism. Corticosteroid excess of any cause suppresses gonadotropins.

C. Hyperandrogenism (with Low-Normal FSH) Elevated serum levels of testosterone can cause hirsutism, virilization, and amenorrhea. In PCOS, GnRH pulses are persistently rapid, favoring LH synthesis with excessive androgen secretion; reduced FSH secretion impairs follicular maturation. Progesterone administration can slow the GnRH pulses, thus favoring FSH secretion that induces follicular maturation. Rare causes include adrenal P450c21 deficiency, ovarian or adrenal malignancies, ectopic ACTH secretion by a malignancy, and Cushing disease. Anabolic steroids also cause amenorrhea.

D. Uterine Causes (with Normal FSH) Infection of the uterus commonly occurs following delivery or D&C but may occur spontaneously. Endometritis

Endocrine Disorders due to tuberculosis or schistosomiasis should be suspected in endemic areas. Endometrial scarring may result, causing amenorrhea (Asherman syndrome). Such women typically continue to have monthly premenstrual symptoms. The vaginal estrogen effect is normal.

E. Early and Premature Menopause (with High FSH) Early menopause refers to primary ovarian failure that occurs before age 45. It affects approximately 5% of women. About 1% of women experience premature menopause that is defined as ovarian failure before age 40; about 30% of such cases are due to autoimmunity against the ovary. X chromosome mosaicism accounts for 8% of cases of premature menopause. Other causes include surgical bilateral oophorectomy, radiation therapy for pelvic malignancy, and chemotherapy. Women who have undergone hysterectomy are prone to premature ovarian failure even though the ovaries were left intact. Myotonic dystrophy, galactosemia, and mumps oophoritis are additional causes.

Early or premature menopause is frequently familial.

Ovarian failure is usually irreversible.

F. Normal Menopause (with High FSH) Normal menopause refers to primary ovarian failure that occurs after age 45. “Climacteric” is defined as the period of natural physiologic decline in ovarian function, generally occurring over about 10 years. By about age 40 years, the remaining ovarian follicles are those that are the least sensitive to gonadotropins. Increasing titers of FSH are required to stimulate estradiol secretion. Estradiol levels may actually rise during early climacteric.

The normal age for menopause in the United States ranges between 48 and 55 years, with an average of about 51.5 years. Serum estradiol levels fall and the remaining estrogen after menopause is estrone, derived mainly from peripheral aromatization of adrenal androstenedione. Such peripheral production of estrone is enhanced by obesity and liver disease. Individual differences in estrone levels partly explain why the symptoms noted above may be minimal in some women but severe in others.

``Clinical Findings A. Symptoms and Signs Vasomotor instability (hot flushes) is experienced by 80% of women, lasting seconds to many minutes. Hot flushes with drenching sweats may be most severe at night or may be triggered by emotional stress. Women may also experience fatigue, insomnia, headache, diminished libido, or rheumatologic symptoms. Psychological symptoms of the “climacteric” include depression and irritability. Some women continue to menstruate for many months despite symptoms of estrogen deficiency. The acute symptoms of estrogen deficiency noted above tend to gradually decline in severity. However, the median duration of moderate to severe hot flushes is about 10 years. Hot flushes tend to continue longer in thin versus obese women and in black

CMDT 2013

1181

versus white women. The late manifestations of estrogen deficiency include urogenital atrophy with vaginal dryness and dyspareunia; dysuria, frequency, and incontinence may occur. Increased bone osteoclastic activity increases the risk for osteoporosis and fractures. The skin becomes more wrinkled. Increases in the LDL:HDL cholesterol ratio cause an increased risk for arteriosclerosis.

A careful pelvic examination is always required to check for uterine or adnexal enlargement and to obtain a Papanicolaou smear and a vaginal smear for assessment of estrogen effect. Various life stresses, vigorous exercise, and “crash” dieting all predispose to amenorrhea; however, such factors should not be assumed to account for amenorrhea without a complete workup to screen for other causes.

B. Laboratory Findings Since pregnancy is the most common cause of amenorrhea, women of childbearing age are immediately screened with a serum or urine hCG (pregnancy test). An elevated hCG overwhelmingly indicates pregnancy; false-positive testing may occur very rarely with ectopic hCG secretion (eg, choriocarcinoma or bronchogenic carcinoma). Women without an elevated hCG receive further laboratory evaluation including serum PRL, FSH, LH, and TSH. Hyperprolactinemia or hypopituitarism (without obvious cause; see section on Hypopituitarism) should prompt an MRI study of the pituitary region. Routine testing for kidney and liver function (eg, BUN, serum creatinine, bilirubin, alkaline phosphatase, and alanine aminotransferase) is also performed. A serum testosterone level is obtained in hirsute or virilized women. Patients with manifestations of hypercortisolism receive a 1-mg overnight dexamethasone suppression test for initial screening (see section on Cushing syndrome). Nonpregnant women without any laboratory abnormality may receive a 10-day course of a progestin (eg, medroxyprogesterone acetate, 10 mg/d); absence of withdrawal menses typically indicates a lack of estrogen or a uterine abnormality.

``Treatment Therapy of symptomatic hypogonadism generally consists of estrogen replacement therapy (see below). Slow, deep breathing can ameliorate hot flushes. For women with severe hot flushes who cannot take estrogen, gabapentin is quite effective in oral doses titrated up to 200–800 mg every 8 hours. However, gabapentin is frequently associated with side effects such as fatigue, headache, dizziness, and cognitive impairment; such symptoms are most pronounced during the first 2 weeks of therapy but often improve within 4 weeks. An herb, black cohosh, may possibly relieve hot flushes. Tamoxifen and raloxifene offer bone protection but aggravate hot flushes. Treatment or prevention of postmenopausal osteoporosis with bisphosphonates such as alendronate, risedronate, or intravenous zoledronic acid (see section on Osteoporosis) is another therapeutic option.

Women with low serum testosterone levels may experience hypoactive sexual desire disorder (HSDD) that may respond to low-dose testosterone replacement.

1182

CMDT 2013

Chapter 26

``Hormone Replacement Therapy Two large, prospective studies have evaluated the effect of HRT on postmenopausal women. The Women’s Health Initiative (WHI) monitored 16,606 mostly-older postmenopausal women in the United States in a prospective, doubleblinded, placebo-controlled study of postmenopausal HRT. A control group of women taking a daily placebo was compared with (1) women receiving daily conventional-dose oral combined HRT (conjugated equine estrogens [CEE] 0.625 mg/d with medroxyprogesterone acetate 2.5 mg/d) and (2) women, having had a hysterectomy, receiving only CEE 0.625 mg/d. The California Teachers Study prospectively followed up 71,237 postmenopausal women of all ages (mean age 63 years, range 36–94 years) for mortality, breast cancer, and other outcomes.

The WHI and California Teachers Study risk–benefit findings (described below) have dramatically changed postmenopausal HRT. The overall use of HRT has declined.

When HRT is prescribed, lower-dose estrogen regimens are preferred over conventional-dose therapy. Estrogen preparations other than CEE have become increasingly favored.

Transdermal and vaginal estrogen preparations are widely preferred over oral estrogen replacement. Also, the potential adverse effects of progestins are now recognized, such that women taking very low-dose estrogen replacement may not require progestins or may receive progestin therapy only periodically, if at all. For moderate- to high-dose estrogen therapy, progestins are being used in lower doses.

Also, clinicians are now tending to prescribe progesteroneeluting intrauterine devices and oral progestins other than medroxyprogesterone acetate.

A. Benefits of Estrogen Replacement Therapy In the California Teachers Study, HRT in women under age 60 was associated with a dramatic 46% reduction in allcause mortality, particularly cardiovascular disease. This association of HRT and lower mortality may suffer from self-selection bias. Nevertheless, there appears to be a survival advantage of HRT in women under age 60 that diminishes with age; no reduction in mortality was noted in the group of women aged 85–94 years. The reduction in cardiovascular disease among younger postmenopausal women taking HRT may be explained by the reduction in serum levels of atherogenic lipoprotein(a) with HRT, with or without a progestin. Improvement in serum HDL cholesterol is greatest with unopposed estrogen but is also seen with the addition of a progestin.

Estrogen replacement improves or eliminates postmenopausal hot flushes and diaphoretic episodes. Vaginal moisture is improved and libido is enhanced in some women.

Estradiol vaginal rings can improve symptoms of an overactive bladder. Sleep disturbances are common in menopause and can be reversed with estrogen replacement. Some women notice a mild impairment in memory and cognitive function at menopause that can improve with HRT. Sex hormone replacement may also improve the body pain and reduced physical function experienced by some women at the time of menopause. Many women taking HRT experience a significantly improved quality of life. Estrogen

replacement does not prevent facial skin wrinkling; however, it may improve facial skin moisture and thickness, reducing seborrhea and atrophy. Estrogen therapy does not appear to reduce the risk of Alzheimer dementia.

1. Estrogen replacement without progestin ­(unopposed HRT)—Interestingly, the WHI study found that postmenopausal women taking unopposed estrogen had a 23% reduction in breast cancer risk. The WHI study also found that women who received estrogen therapy experienced a reduced number of hip fractures (six fewer fractures/year per 10,000 women) compared with placebo.

Even “microdose” transdermal estradiol (0.014 mg/d) improves bone density. Unopposed oral conjugated estrogens have no discernible effect upon cognitive function, overall mortality, or the risk for heart attacks, or colorectal cancer. Unopposed estrogen replacement improves glycemic control in women with type 2 diabetes mellitus.

Perimenopause-related depression is improved by unopposed estrogen replacement; the addition of a progestin may negate this effect. A 20-year study of 8801 women living in a retirement community found that estrogen use was associated with improved survival. Age-adjusted mortality rates were 56.4 (per 1000 person-years) among nonusers and 50.4 among women who had used estrogen for 15 years or longer.

2. Estrogen replacement therapy with progestins (combined HRT)—Women receiving conventional-dose daily conjugated estrogen and medroxyprogesterone acetate (0.625 mg and 2.5 mg, respectively) for an average of 5.6 years, experienced a lower risk of developing diabetes mellitus (3.5%) versus those taking a placebo (4.2%).

B. Risks of Estrogen Replacement Therapy The risks of estrogen replacement depend on the dose.

Conventional doses (eg, oral conjugated estrogens ≥ 0.625 mg/d or transdermal estradiol ≥ 0.05 mg/d) carry higher risks than lower doses (eg, oral conjugated estrogens, ≤ 0.3 mg/d or transdermal estradiol ≤ 0.025 mg/d). Route of administration also affects risks, since oral estrogens pass through the liver and increase hepatic production of clotting factors (thereby increasing the risks of thrombotic stroke), whereas transdermal or vaginal administration of estrogen does not significantly increase clotting proclivity.

The risks for HRT also depend on whether estrogen is administered alone (unopposed HRT) or with a progestin (combined HRT).

1. Estrogen replacement without progestin ­(unopposed HRT)—Surprisingly, the WHI study found that postmenopausal women who received conventionaldose estrogen-only therapy had a reduced risk of breast cancer (seven fewer cases/year per 10,000 women) compared with a placebo group. However, the California Teachers Study monitored women for a longer period; a group of 37,000 women who had been taking conventional-dose estrogen-only therapy for ≥ 20 years did have a slightly increased risk of breast cancer. Women taking lower-dose unopposed estrogen therapy would be expected to have lower long-term risk of breast cancer.

Endocrine Disorders Conventional-dose unopposed estrogen replacement (0.625–1.25 mg daily) increases the risk of endometrial hyperplasia and dysfunctional uterine bleeding, which often prompts patients to stop the estrogen. However, lower-dose unopposed estrogen confers a much lower risk of dysfunctional uterine bleeding. Recurrent dysfunctional bleeding necessitates a pelvic examination and possibly an endometrial biopsy. There has been considerable concern that unopposed estrogen replacement might increase the risk for endometrial carcinoma. However, a Cochrane Database Review found no increased risk of endometrial carcinoma in a review of 30 randomized controlled trials.

Therefore, lower-dose unopposed estrogen replacement does not appear to confer any increased risk for endometrial cancer.

Long-term conventional-dose unopposed estrogen increases the mortality risk from ovarian cancer, although the absolute risk is small. The annual age-adjusted ovarian cancer death rates for women taking estrogen replacement for ≥ 10 years are 64:100,000 for current users, 38:100,000 for former users, and 26:100,000 for women who had never taken estrogen. Lower-dose estrogen replacement is believed to confer a negligible increased risk for ovarian cancer.

The WHI trial was stopped in 2002 because of an increased risk of stroke among women taking conjugated oral estrogens in doses of 0.625 mg daily; the risk was about 44 strokes per 10,000 person-years versus about 32 per 10,000 person-years in women taking placebo. Transdermal or transvaginal estrogen is not expected to increase the risk of stroke.

Conventional-dose therapy with oral estrogen alone had been thought to increase the risk of deep venous thrombosis and stroke, but the WHI follow-up study found no such increased risk for deep venous thrombosis or stroke. Oral estrogens can cause hypertriglyceridemia, particularly in women with preexistent hyperlipidemia, rarely resulting in pancreatitis. Postmenopausal estrogen therapy also slightly increases the risk of gallstones and cholecystitis. Oral estrogens reduce the effectiveness of GH replacement. These side effects can be reduced or avoided by using non-oral estrogen replacement.

Elderly women, receiving long-term conventional-dose estrogen replacement, experience an increased risk of urinary incontinence. Some women complain of estrogeninduced edema or mastalgia. Estrogen replacement has been reported to lower the seizure threshold in some women with epilepsy. Untreated large pituitary prolactinomas may enlarge if exposed to estrogen.

2. Estrogen replacement with a progestin (combined HRT)—The WHI study found that women who received long-term conventional oral doses of combined HRT (conjugated estrogens 0.625 mg/d plus medroxyprogesterone acetate 2.5 mg/d) had an increased risk of deep venous thrombosis (3.5 per 1000 person-years) compared with women receiving placebo (1.7 per 1000 person-years).

Conventional-dose oral combined HRT results in an increased risk of myocardial infarction (24% or six additional heart attacks per 10,000 women), mostly in older women with high-risk LDL levels or preexistent coronary disease. Most of the risk for myocardial infarction occurs in

CMDT 2013

1183

the first year of therapy. This increased risk is attributable to the progestin component, since the estrogen-only arm of the WHI study found no increased risk of myocardial infarction.

Long-term conventional-dose oral combined HRT increases breast density and the risk for abnormal mammograms (9.4% versus 5.4% for placebo). There is also a higher risk of breast cancer (8 cases per 10,000 women/year versus 6.5 cases per 10,000 women/year for placebo); no increased risk of breast cancer has been found with estrogen-only HRT. This increased risk for breast cancer appears to mostly affect relatively thin women with a BMI < 24.4.

The Iowa Women’s Health Study reported an increase in breast cancer with HRT only in women consuming more than 1 oz of alcohol weekly. No accelerated risk of breast cancer has been seen in users of HRT who have benign breast disease or a family history of breast cancer. Women in whom new-onset breast tenderness develops with combined HRT have an increased risk of breast cancer, compared with women without breast tenderness.

The Women’s Health Initiative Mental Study (WHIMS) followed the effect of combined conventional-dose oral HRT on cognitive function in women 65–79 years old.

HRT did not protect these older women from cognitive decline. In fact, they experienced an increased risk for severe dementia at a rate of 23 more cases/year for every 10,000 women over age 65 years.

In the WHI study, women receiving conventional-dose combined oral HRT experienced an increased risk of stroke (31 strokes per 10,000 women/year versus 26 strokes per 10,000 women/year for placebo). Stroke risk was also increased by hypertension, diabetes, and smoking.

Women taking combined estrogen–progestin replacement do not experience an increased risk of ovarian cancer. They do experience an increased risk of developing asthma.

Progestins may cause moodiness, particularly in women with a history of premenstrual dysphoric disorder. Cycled progestins may trigger migraines in certain women. Many other adverse reactions have been reported, including breast tenderness, alopecia, and fluid retention. Contraindications to the use of progestins include thromboembolic disorders, liver disease, breast cancer, and pregnancy.

C. Hormone Replacement Therapy Agents 1. Transdermal estradiol—Estradiol can be delivered systemically with different systems of skin patches, mists, and gels. Transdermal estradiol works for most women, but some women have poor transdermal absorption or skin reactions to the product.

A. Estradiol patches mixed with adhesive—These systems tend to cause minimal skin irritation. Of the following preparations, the Vivelle-Dot patches are the smallest and least obtrusive. Generic estradiol transdermal (0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 mg/d) is replaced once weekly.

Brand products include Esclim, Vivelle, and Vivelle-Dot (0.025, 0.0375, 0.05, 0.075, or 0.1 mg/d), replaced twice weekly; Alora (0.025, 0.05, 0.075, or 0.1 mg/d), replaced twice weekly; Climara (0.025, 0.0375, 0.05, 0.06, 0.075, or 0.1 mg/d), replaced weekly; FemPatch (0.025 mg/d), replaced

1184

CMDT 2013

Chapter 26

weekly; and Menostar (0.014 mg/d), replaced weekly. This type of estradiol skin patch can be cut in half and applied to the skin without proportionately greater loss of potency.

B. Estradiol patches with drug reservoir—These systems cause significant skin irritation in some women.

Available preparations include Estraderm (0.05 or 0.1 mg/d), applied to the trunk, abdomen, or buttocks and replaced twice weekly.

C. Estradiol patches with progestin mixed with adhesive—These preparations mix estradiol with either norethindrone acetate or levonorgestrel. Combipatch (0.05 mg E and 0.14 mg norethindrone acetate daily or 0.05 mg E and 0.25 mg norethindrone acetate daily) is replaced twice weekly. Climara Pro (0.45 mg E and 0.0125 mg levonorgestrel daily) is replaced once weekly.

The addition of a progestin reduces the risk of endometrial hyperplasia but increases the risk of breast cancer and side effects, compared with estrogen therapy alone.

D. Estradiol gels and mists—EstroGel 0.06% is available in a metered-dose pump that dispenses 0.05 mg estradiol per actuation; estradiol doses are 0.05–0.1 mg/d.

Elestrin 0.06% is available in a metered-dose pump that dispenses 0.5 mg estradiol per activation; estradiol doses are 0.5–1 mg/d. These gels are applied daily to one arm from the wrist to the shoulder after bathing. Divigel 1% gel (0.025, 0.5, 1 g/packet) is applied to upper thigh daily.

Estrasorb 1.7 g pouches (0.025 mg estradiol) is available in doses of 0.025–0.05 mg estradiol applied to the leg daily. Evamist is available as a topical mister that dispenses 1.53 mg estradiol/spray; doses are 1–3 sprays to the forearm daily. To avoid spreading the estradiol to others, the hands should be washed and precautions taken to avoid prolonged skin contact with children. Application of sunscreen prior to estradiol gel has been reported to increase the transdermal absorption of estradiol.

2. Oral estrogen— A. Oral estrogen-only preparations—These preparations include conjugated equine estrogens (CEE 0.3, 0.45, 0.625, 0.9, 1.25 mg), conjugated plant-derived estrogens (eg, Menest, Estratab, 0.3, 0.625, and 2.5 mg), and conjugated synthetic estrogens (eg, Cenestin, 0.3, 0.625, 0.9, and 1.25 mg). Other preparations include ethinyl estradiol (20 and 50 mcg), estradiol (0.5, 1, and 2 mg), estropipate (0.75, 1.5, 3, and 6 mg), and estradiol acetate (eg, Femtrace 0.45, 0.9, and 1.8 mg).

B. Oral estrogen plus progestin preparations— These include CEE with medroxyprogesterone acetate (Prempro 0.3/1.5, 0.45/1.5, 0.625/2.5, and 0.625 mg/5 mg), CEE for 14 days cycled with CEE plus medroxyprogesterone acetate for 14 days (Premphase 0.625/0 and 0.625 mg/5 mg), estradiol with norethindrone acetate (Activella 0.5/0 and 1 mg/0.5 mg), ethinyl estradiol with norethindrone acetate (Femhrt 2.5/5 and 5 mcg/1 mg), and estradiol with norgestimate (Prefest, sequences of estradiol 1 mg/d for 3 days, alternating with a combination of 1 mg estradiol/0.09 mg norgestimate daily for 3 days). Oral contraceptives can also be used for combined HRT.

3. Vaginal estrogen—Urogenital atrophy commonly develops in postmenopausal women and can cause dryness of the vagina, genital itching, burning, dyspareunia, and recurrent urinary tract infections. Urinary symptoms can include urgency and dysuria. Vaginal estrogen is intended to deliver estrogen directly to local tissues and is moderately effective in reducing these symptoms, while minimizing systemic estrogen exposure. Some estrogen is absorbed systemically and can relieve menopausal symptoms. Systemically absorbed estrogen avoids first-pass liver metabolism, causing less hypertriglyceridemia and prothrombotic effects than oral estrogen. Manufacturers recommend that these preparations be used for only 3–6 months in women with an intact uterus, since vaginal estrogen can cause endometrial proliferation. However, most clinicians use them for longer periods. Vaginal estrogen can be administered in three different ways: creams, tablets, and rings.

A. Estrogen vaginal creams—These creams are administered intravaginally with a measured-dose applicator daily for 2 weeks for atrophic vaginitis, then administered one to three times weekly. Available preparations include CEEs (Premarin, 0.626 mg/g cream), dosed as 0.25–0.5 g cream vaginally; dienestrol (Ortho Dienestrol, 10 mg/g cream), 0.25–0.5 g cream vaginally; estradiol (Estrace, 0.1 mg/g cream), 1 g cream vaginally; and estropipate (Ogen, 1.5 mg/g cream), 0.25–0.5 g vaginally.

B. Estradiol vaginal tablets—These tablets are sold prepackaged in a disposable applicator and can be administered deep intravaginally daily for 2 weeks for atrophic vaginitis, then twice weekly. The tablets dissolve into a gel that gradually releases estradiol. Available preparations include vaginal estradiol tablets (Vagifem, 25 mcg/tablet).

C. Estradiol vaginal rings—These rings are inserted manually into the upper third of the vagina, worn continuously, and replaced every 90 days. Only a small amount of the released estradiol enters the systemic circulation.

Vaginal rings do not usually interfere with sexual intercourse. If a ring is removed or descends into the introitus, it may be washed in warm water and reinserted. Available preparations include Estring (2 mg estradiol/ring, releasing 7.5 mcg/d) and Femring (12.4 mg estradiol/ring, releasing 0.05 mg/d, or 24.8 mg estradiol/ring, releasing 0.10 mg/d).

For women with postmenopausal urinary urgency and frequency, even the low-dose Estring can successfully reduce urinary symptoms.

D. Estradiol with progestin vaginal rings—­ NuvaRing contains a mixture of estradiol and etonogestrel.

It is a contraceptive vaginal ring that is placed in the vagina for 3 weeks, removed for 1 week, then replaced.

4. Estradiol intramuscular—Parenteral estradiol should be used only for particularly severe menopausal symptoms when other measures have failed or are contraindicated.

Estradiol cypionate (DepoEstradiol 5 mg/mL) may be administered intramuscularly in doses of 1–5 mg every 3–4 weeks. Estradiol valerate (20 mg/mL) may be administered intramuscularly in doses of 10–20 mg every 4 weeks.

Women with an intact uterus should receive a progestin for the last 10 days of each cycle.

Endocrine Disorders 5. Oral progestins—For a woman with an intact uterus, long-term conventional-dose unopposed systemic estrogen therapy can cause endometrial hyperplasia, which typically results in dysfunctional uterine bleeding and might rarely lead to endometrial cancer. Progestin therapy transforms proliferative into secretory endometrium, causing a menses when given intermittently or no bleeding when given continuously.

The type of progestin preparation, its dosage, and the timing of administration may be tailored to the given situation. Progestins may be given daily, monthly, or at longer intervals. When given episodically, progestins are usually administered for 7–14 day periods. Progestins are available in different formulations: Micronized progesterone (Prometrium, 100 mg/capsule), medroxyprogesterone acetate (Provera, Amen, Cycrin; 2.5, 5.0, and 10 mg/scored tablet), norethindrone acetate (Aygestin, 5 mg/tablet), and norethindrone (Micronor, Nor-QD; 0.35 mg/tablet).

Topical progesterone (20–50 mg/d) may reduce hot flushes in women who are intolerant to oral HRT. It may be applied to the upper arms, thighs, or inner wrists daily. It may be compounded as micronized progesterone 250 mg/ mL in a transdermal gel. Its effects upon the breast and endometrium are unknown.

6. Progestin-releasing intrauterine devices—­ Intrauterine devices (IUDs) that release progestins can be useful for women receiving ERT, since they can reduce the incidence of dysfunctional uterine bleeding and endometrial carcinoma without exposing women to the significant risks of systemic progestins. The Mirena IUD releases levonorgestrel and is inserted into the uterus by a clinician within 7 days of the onset of menses. It remains effective for up to 5 years. Parous women are generally better able to tolerate the Mirena IUD than nulliparous women.

7. Selective estrogen receptor modulators—SERMs (eg, raloxifene, tamoxifen) are an alternative to estrogen replacement for hypogonadal women at risk for osteoporosis who prefer not to take estrogens because of their contraindications (eg, breast or uterine cancer) or side effects.

Raloxifene does not reduce hot flushes, vaginal dryness, skin wrinkling, or breast atrophy; it does not improve cognition. However, in doses of 60 mg/d orally, it inhibits bone loss without stimulating effects upon the breasts or endometrium. Because raloxifene may slightly increase the risk of venous thromboembolism, it should not be used by women at prolonged bed rest or by those prone to thrombosis. In contrast with the use of ERT, concomitant progesterone therapy is not needed, and raloxifene does not increase the risk of development of breast cancer.

Tibolone (Livial) is an SERM whose metabolites have mixed estrogenic, progestogenic, and weak androgenic activity. It is comparable to HRT for the treatment of climacteric-related complaints. It does not appear to significantly stimulate proliferation of breast or endometrial tissue. It depresses both serum triglycerides and HDL cholesterol. Long-term studies are lacking. It is not available in the United States.

8. Phytoestrogens—These substances are found in plants that bind to estrogen receptors. Phytoestrogens, found in

CMDT 2013

1185

soy and red clover extracts, do not appear to significantly improve menopausal hot flushes, cognitive function, bone density, or plasma lipids.

9. Testosterone replacement therapy in women—In premenopausal women, serum testosterone levels decline with age. Between 25 and 45 years of age, women’s testosterone levels fall 50%. After natural menopause, the ovaries remain a significant source for testosterone. In fact, following natural menopause, serum testosterone levels do not fall abruptly and serum free testosterone levels may actually rise. In contrast, very low serum testosterone levels are found in women after bilateral oophorectomy, autoimmune ovarian failure, adrenalectomy, and in hypopituitarism. Testosterone deficiency contributes to hot flushes, loss of sexual hair, muscle atrophy, osteoporosis, and diminished libido, also known as hypoactive sexual desire disorder.

In women, diminished libido is common and multifactorial. Although low serum testosterone levels may contribute to hypoactive sexual desire disorder, hysterectomy and sexual isolation are major causes. Low serum testosterone levels may also cause fatigue, a diminished sense of well-being, and a dulled enthusiasm for life. Androgen replacement may improve these problems.

Testosterone therapy is often effective, while DHEA therapy is not. Selected women may be treated with low-dose testosterone. Methyltestosterone can be taken orally in doses of 1.25–2.5 mg daily. Testosterone can also be compounded as a cream containing 1 mg/mL, with 1 mL applied to the low abdomen daily. Methyltestosterone is also available in combination with conjugated estrogens (eg, Estratest). This formulation is convenient but carries the same disadvantage as oral estrogen—increased risk of thromboembolism.

Tablets contain either 1.25 mg conjugated estrogens with 2.5 mg methyltestosterone or 0.625 mg conjugated estrogens with 1.25 mg methyltestosterone. Estratest is usually started at the lowest strength. It should be given cyclically at the lowest dose that controls symptoms.

Women receiving testosterone therapy must be monitored for the appearance of any acne or hirsutism, and serum testosterone levels are determined periodically if women feel that they are benefitting and long-term testosterone therapy is instituted. Side effects of low-dose testosterone therapy are usually minimal but may include polycythemia, emotional changes, hirsutism, acne, an adverse effect on lipids, and potentiation of warfarin anticoagulation therapy. Testosterone replacement tends to reduce both triglyceride and HDL cholesterol levels.

Hepatocellular neoplasms and peliosis hepatis, rare complications of oral androgens at higher doses, have not been reported with methyltestosterone at lower doses of 2.5 mg orally daily. Androgens should not be given to women with liver disease or during pregnancy or breast-feeding.

Testosterone replacement therapy for women should be used judiciously, since long-term prospective clinical trials are lacking. An analysis of the Nurses’ Health Study found that women who had been taking CEEs plus methyltestosterone experienced an increased risk of breast cancer.

Yearly mammography is recommended for all women over 40 years of age.

1186

CMDT 2013

Chapter 26

D. Other Treatments for Menopausal Hot Flashes Lifestyle changes, such as dressing coolly, keeping the ambient room temperature cool, sleeping with light bedclothes, sipping cold beverages, and stress reduction may help reduce hot flushes. Women may try avoiding known triggers for hot flushes, such as smoking, alcohol, caffeine, and hot spicy foods. Idiosyncratic triggers for hot flushes may be discerned and avoided. Gabapentin can relieve hot flushes when estrogen replacement therapy is contraindicated or not desired and when lifestyle changes are insufficient. Women with moderate to severe postmenopausal hot flushes may obtain relief with gabapentin 600–2400 mg daily in divided doses. Side effects are most prominent in the first 2 weeks of treatment and may include somnolence, unsteadiness, and dizziness.

Canonico M et al. Further evidence for promoting transdermal estrogens in the management of postmenopausal symptoms.

Menopause. 2011 Oct;18(10):1038–9. [PMID: 21946050] Deligeoroglou E et al. Evaluation and management of adolescent amenorrhea. Ann N Y Acad Sci. 2010 Sep;1205:23–32. [PMID: 20840249] Freeman EW et al. Duration of menopausal hot flushes and associated risk factors. Obstet Gynecol. 2001 May;117(5): 1095–104. [PMID: 21508748] Hayes LP et al. Use of gabapentin for the management of natural or surgical menopausal hot flashes. Ann Pharmacother. 2011 Mar;45(3):388–94. [PMID: 21343402] Nappi RE et al. Menopause and sexual desire: the role of testosterone. Menopause Int. 2010 Dec;16(4):162–8. [PMID: 21156854] Nelken RS et al. Randomized trial of estradiol vaginal ring versus oral oxybutynin for the treatment of overactive bladder.

Menopause. 2011 Sep;18(9):926–6. [PMID: 21532512] Rosenberg HK. Sonography of the pelvis in patients with primary amenorrhea. Endocrinol Metab Clin North Am. 2009 Dec;38(4):739–60. [PMID: 19944290] Santoro N. Update in hyper- and hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 2011 Nov;96(11):3281–8.

[PMID: 22058375] Stram DO et al. Age-specific effects of hormone therapy use on overall mortality and ischemic heart disease mortality among women in the California Teachers Study. Menopause. 2011 Mar;18:(3):253–61. [PMID: 20881652] Taylor HS et al. Update in hormone therapy use in menopause.

J Clin Endocrinol Metab. 2011 Feb;96(2):255–64. [PMID: 21296989] Warren MP. Hormone therapy for menopausal symptoms: putting benefits and risks into perspective. J Fam Pract. 2010 Dec;59(12):E1–7. [PMID: 21135919]

TURNER SYNDROME (Gonadal Dysgenesis) ``

EssentialS of diagnosis

Turner syndrome comprises a group of X chromosome disorders that are associated with spontaneous abortion, primary hypogonadism, short stature, and other phenotypic anomalies. It affects 1–2% of fetuses, of which about 97% abort, accounting for about 10% of all spontaneous abortions. Nevertheless, it affects about 1 in every 2500 live female births. Patients with the classic syndrome (about 50% of cases) lack one of the two chromosomes (45,XO karyotype). Other patients with Turner syndrome have X chromosome abnormalities, such as ring X or Xq (X/ abnormal X) or X chromosome deletions affecting all or some somatic cells (mosaicism, XX/XO). Turner syndrome may be diagnosed in infant girls at birth, since they tend to be small and may exhibit severe lymphedema. Evaluation for childhood short stature often leads to the diagnosis.

Girls and women with Turner syndrome have an increased risk of aortic coarctation (11%) and bicuspid aortic valves (16%); these cardiac abnormalities are more common in patients with webbed necks.

1. Classic Turner Syndrome (45,XO Gonadal Dysgenesis) ``Clinical Findings A. Symptoms and Signs Features of Turner syndrome are variable and may be subtle in girls with mosaicism. Typical manifestations in adulthood include short stature, hypogonadism, webbed neck, high-arched palate, wide-spaced nipples, hypertension, and renal abnormalities (Table 26–16). Emotional disorders are common.

Hypogonadism presents as “delayed adolescence” (primary amenorrhea, 80%) or early ovarian failure (20%); girls with 45,XO Turner (blood karyotyping) who enter puberty are typically found to have mosaicism if other ­tissues are karyotyped.

B. Laboratory Findings Hypogonadism is confirmed in girls who have high serum levels of FSH and LH. A blood karyotype showing 45,XO (or X chromosome abnormalities or mosaicism) establishes the diagnosis. GH and IGF-1 levels are normal.

C. Imaging An ultrasound and MRI scan of the chest and abdomen should be done in all patients with Turner syndrome to determine whether cardiac, aortic, and renal abnormalities are present.

``Treatment Short stature with normal GH levels. `` Primary amenorrhea or early ovarian failure. `` Epicanthal folds, webbed neck, short fourth metacarpals. `` Renal and cardiovascular anomalies. ``

Treatment of short stature with daily injections of GH (0.1 unit/kg/d) plus an androgen (eg, oxandrolone) for at least 4 years before epiphyseal fusion increases final height by a mean of about 10.3 cm over the mean predicted height of 144.2 cm. Such GH treatment rarely causes pseudotumor cerebri. After age 12 years, estrogen therapy is begun with

Endocrine Disorders

Table 26–16. Manifestations of Turner syndrome.

Short stature Distinctive facial features Ptosis Micrognathia Low-set ears Epicanthal folds Sexual infantilism due to gonadal dysgenesis with primary amenorrhea (80%) Early ovarian failure with secondary amenorrhea (20%) Webbed neck (40%) Low hairline High-arched palate Cubitus valgus Short fourth metacarpals (50%) Lymphedema of hands and feet (30%) Hypoplastic widely spaced nipples Hyperconvex nails Pigmented nevi Keloid formation (eg, surgical scars or after ear piercing) Recurrent otitis media Renal abnormalities (60%) Horseshoe kidney Hydronephrosis Hypertension (idiopathic or due to coarctation or kidney disease) Gastrointestinal disorders Telangiectasis with bleeding Celiac disease Inflammatory bowel disease Colon carcinoma Liver disease Impaired space-form recognition, direction sense, and mathematical reasoning Cardiovascular anomalies Coarctation of the aorta (10–20%) Partial anomalous pulmonary venous connection Bicuspid aortic valve (with aortic stenosis or insufficiency) Aortic dissection due to coarctation and cystic medial necrosis of the aorta Associated conditions Obesity Diabetes mellitus (types 1 and 2) Dyslipidemia Hyperuricemia Hashimoto thyroiditis Achlorhydria Cataracts, corneal opacities Neuroblastoma (1%) Rheumatoid arthritis

low doses of conjugated estrogens (0.3 mg) or ethinyl estradiol (5 mcg) given on days 1–21 per month. When growth stops, HRT is begun with estrogen and progestin; transdermal estrogen may be used to initiate pubertal development.

``Complications & Surveillance Bicuspid aortic valves are associated with an increased risk of infective endocarditis, aortic valvular stenosis or insufficiency, and ascending aortic aneurysm and dissection.

CMDT 2013

1187

Partial anomalous pulmonary vein connections occur in 13% and can lead to left-to-right shunting of blood. Adults with Turner syndrome have a high incidence of ECG abnormalities.

Women with Turner syndrome have a reduced life expectancy due in part to their increased risk of diabetes mellitus (types 1 and 2), hypertension, dyslipidemia, and osteoporosis.

Diagnostic vigilance and aggressive treatment of these conditions reduce the risk of aortic aneurysm dissection, ischemic heart disease, stroke, and fracture. Patients are prone to keloid formation after surgery or ear piercing.

Yearly ocular examinations and periodic thyroid evaluations are recommended.

Repeat cardiovascular evaluations should be done every 3–4 years. Patients with the classic 45,XO karyotype have a high risk of renal structural abnormalities, whereas those with 46 X/abnormal X are more prone to malformations of the urinary collecting system. The risk of aortic dissection is increased more than 100-fold in women with Turner syndrome, particularly those with pronounced neck webbing and shield chest. Patients with aortic root enlargement are usually treated with β-blockade and serial imaging. Women with Turner syndrome who are able to become pregnant are strongly advised to deliver via cesarean section due to the risk of aortic aneurysm rupture during vaginal delivery.

2. Turner Syndrome Variants A. 46,X (Abnormal X) Karyotype Patients with small distal short arm deletions of the X chromosome (Xp-) that include the SHOX gene often have short stature and skeletal abnormalities but have a low risk of ovarian failure. Transmission of Turner syndrome from mother to daughter can occur. There may be an increased risk of trisomy 21 in the conceptuses of women with Turner syndrome. Patients with deletions of the long arm of the X chromosome (distal to Xq24) often have amenorrhea without short stature or other features of Turner syndrome. Abnormalities or deletions of other genes located on both the long and short arms of the X chromosome can produce gonadal dysgenesis with few other somatic features.

B. 45,XO/46,XX Mosaicism This karyotype results in a modified form of Turner syndrome. Such girls tend to be taller and may have more gonadal function and fewer other manifestations of Turner syndrome.

C. Other Variants 45,XO/46,XY mosaicism can produce some manifestations of Turner syndrome. Patients may have ambiguous genitalia or male infertility with an otherwise normal phenotype.

Germ cell tumors, such as gonadoblastomas and seminomas, develop in about 10% of patients with 45,XO/46,XY mosaicism; most such tumors are benign.

1188

CMDT 2013

Chapter 26

1. MEN 1 (Wermer Syndrome)

Bondy CA. Turner syndrome 2008. Horm Res. 2009 Jan;71 (Suppl 1):52–6. [PMID: 19153507] Conway GS et al. How do you monitor the patient with Turner’s syndrome in adulthood? Clin Endocrinol (Oxf). 2010 Dec; 73(6):696–9. [PMID: 20718775] Davenport ML. Approach to the patient with Turner syndrome.

J Clin Endocrinol Metab. 2010 Apr;95(4):1487–95. [PMID: 20375216] Mazzanti L et al. Developmental syndromes: growth hormone deficiency and treatment. Endocr Dev. 2009;14:114–34.

[PMID: 19293579] Ross JL et al. Growth hormone plus childhood low-dose estrogen in Turner’s syndrome. N Engl J Med. 2011 Mar 31;364(13): 1230–42. [PMID: 21449786] Thomas J et al. Management of cardiovascular disease in Turner syndrome. Expert Rev Cardiovasc Ther. 2009 Dec;7(12): 1631–41. [PMID: 19954324] Zeger MP et al. Prospective study confirms oxandrolone-­ associated improvement in height in growth hormone-treated adolescent girls with Turner syndrome. Horm Res Paediatr.

2011;75(1):38–46. [PMID: 20733274] cc

MEN 1 is a familial multiglandular endocrine tumor syndrome, with a prevalence of 2–10 per 100,000 people. The presentation of MEN 1 is quite variable, even in the same kindred. Parathyroid, enteropancreatic, and pituitary tumors can be present in one individual, though not necessarily at the same time. Nonendocrine tumors also occur, such as subcutaneous lipomas, facial angiofibromas, and collagenomas. In some affected individuals, tumors may start developing in childhood, whereas in others, tumors develop late in adult life.

About 90% of patients with MEN 1 have germline mutations that are inherited as an autosomal dominant trait. Patients with MEN 1 usually have detectable mutations in the menin gene, located on the long arm of chromosome 11 (11q13). MEN 1 gene testing is available at a few centers and is able to detect the specific mutation in 60–95% of cases. If no mutation is detected, genetic linkage analysis can be done if there are several affected members in the kindred. Gene testing permits the rest of the kindred to be tested for the specific gene defect and allows informed genetic counseling.

With close endocrine surveillance of affected individuals, the initial biochemical manifestations (usually hypercalcemia) can often be detected as early as age 14–18 years in patients with a MEN 1 gene mutation, although clinical manifestations do not usually present until the third or fourth decade.

Hyperparathyroidism is the first clinical manifestation of MEN 1 in two-thirds of affected patients, but it may present at any time of life. Patients with the MEN 1 mutation have a > 90% lifetime risk of developing hyperparathyroidism. The hyperparathyroidism of MEN 1 is notoriously difficult to treat surgically, due to multiple gland involvement and the frequency of supernumerary glands and ectopic parathyroid tissue. Typically, three and one-half glands are resected, leaving one-half of the most normal-appearing gland intact. Also, during neck surgery, a thymectomy is performed to resect any intrathymic parathyroid glands or

MULTIPLE ENDOCRINE NEOPLASIA

``

EssentialS of diagnosis

MEN 1: tumors of the parathyroid glands, endocrine pancreas and duodenum, pituitary, adrenal, thyroid; lipomas and facial angiofibromas. `` MEN 2A: medullary thyroid cancers, pheochromocytomas, Hirschsprung disease. `` MEN 2B: medullary thyroid cancers, pheochromocytomas, Marfan-like habitus, mucosal neuromas, intestinal ganglioneuroma, delayed puberty. ``

Syndromes of MEN are inherited as autosomal dominant traits and cause a predisposition to the development of tumors in different tissues, particularly involving endocrine glands (Table 26–17).

Table 26–17. Multiple endocrine neoplasia (MEN) syndromes: Incidence of tumor types.

MEN 1 (Wermer Syndrome)

MEN 2A (Sipple Syndrome)

MEN 2B

Parathyroid

Tumor Type

95%

20–50%

Rare

Pancreatic

54%

Pituitary

42%

Medullary thyroid carcinoma Pheochromocytoma

Rare

Mucosal and gastrointestinal ganglioneuromas Subcutaneous lipoma

30%

Adrenocortical adenoma

30%

Thoracic carcinoid

15%

Thyroid adenoma

55%

Facial angiofibromas and collagenomas

85%

> 90%

80%

20–35%

60%

Rare

> 90%

Endocrine Disorders occult thymic carcinoid tumors. Nevertheless, the surgical failure rate is about 38%, and there is a recurrence rate of about 16%, with hypercalcemia often recurring many years after neck surgery. Aggressive parathyroid resection can cause permanent hypoparathyroidism. Patients with persistent or recurrent hyperparathyroidism should avoid oral calcium supplements and thiazide diuretics; oral therapy with calcimimetic drug, such as cinacalcet, is effective but expensive. The diagnosis and treatment of hyperparathyroidism is described earlier in this chapter.

Enteropancreatic tumors occur in about 75% of patients with MEN 1. Nonsecretory neuroendocrine tumors occur and do not secrete hormones; they tend to be large and very aggressive. Gastrinomas occur in about 35% of patients with MEN 1; they secrete gastrin, thereby causing severe gastric hyperacidity (Zollinger–Ellison syndrome) with peptic ulcer disease or diarrhea. Concurrent hypercalcemia, due to hyperparathyroidism (see above), stimulates gastrin and gastric acid secretion; control of the hypercalcemia often reduces gastric acid secretion and serum gastrin levels. These gastrinomas tend to be small, multiple, and ectopic; they are frequently found outside the pancreas, usually in the duodenum. Gastrinomas of MEN 1 can metastasize to the liver; but in patients with MEN 1, depending upon the kindred, hepatic metastases tend to be less aggressive than those from sporadic gastrinomas. Treatment of patients with gastrinomas in MEN 1 is usually conservative, utilizing long-term high-dose proton pump inhibitor therapy and control of hypercalcemia; surgery is palliative and usually reserved for aggressive gastrinomas and those tumors arising in the duodenum. Zollinger–Ellison syndrome is also discussed in Chapter 15.

Insulinomas cause hyperinsulinism and fasting ­hypoglycemia. They occur in about 15% of patients with MEN 1. Surgery is usually attempted, but the tumors can be small, multiple, and difficult to detect. The diagnosis and treatment of insulinomas are described in Chapter 27.

Glucagonomas (1.6%) secrete glucagon and cause diabetes and migratory necrolytic erythema. VIPomas (1%) secrete VIP and cause profuse watery diarrhea, hypokalemia, and achlorhydria (WDHA, Verner-Morrison syndrome).

Somatostatinomas (0.7%) can cause diabetes mellitus, steatorrhea, and cholelithiasis.

Pituitary adenomas occur in about 42% of patients with MEN 1. They are more common in women (50%) than men (31%) and are the presenting tumor in 17% of patients with MEN 1. These tumors tend to be more aggressive macroadenomas (> 1 cm diameter, 85%) compared to sporadic pituitary tumors (42%). Of MEN 1–associated pituitary tumors, about 62% secrete PRL, 8% secrete GH, 13% secrete both PRL and GH, and 13% are nonsecretory; only 4% secrete ACTH and cause Cushing disease. The diagnosis and treatment of pituitary tumors and Cushing disease were described earlier in this chapter. These pituitary tumors can produce local pressure effects and hypopituitarism.

Adrenal adenomas or hyperplasia occurs in about 37% of patients with MEN 1 and 50% are bilateral. They are generally benign and nonfunctional. In one series, one out of 12 of these patients developed a feminizing adrenal carcinoma. These adrenal lesions are pituitary independent.

CMDT 2013

1189

Nonendocrine tumors occur commonly in MEN 1.

Small facial angiofibromas and subcutaneous lipomas are common. Collagenomas can present as firm dermal nodules. Malignant melanomas have been reported.

The differential diagnosis of MEN 1 includes sporadic or familial tumors of the pituitary, parathyroids, or pancreatic islets. Hypercalcemia (from any cause) may cause gastrointestinal symptoms and increased gastrin levels, simulating a gastrinoma. Routine suppression of gastric acid secretion with H2-blockers or proton pump inhibitors causes a physiologic increase in serum gastrin that can be mistaken for a gastrinoma. H2-blockers and metoclopramide cause hyperprolactinemia, simulating a pituitary prolactinoma.

Variants of MEN 1 also occur. Kindreds with MEN 1 Burin variant have a high prevalence of prolactinomas, late-onset hyperparathyroidism, and carcinoid tumors, but rarely enteropancreatic tumors.

2. MEN 2A (Sipple Syndrome) MEN 2A is a rare familial multiglandular syndrome that is inherited as an autosomal dominant trait. Patients with MEN 2A should have genetic testing for a ret protooncogene (RET) mutation. Their first-degree relatives may then be tested for the specific RET mutation. Patients with MEN 2A may have medullary thyroid carcinoma (> 90%); hyperparathyroidism (20–50%), due to hyperplasia or multiple adenomas in over 70% of cases; pheochromocytomas (20–35%), which are often bilateral; or Hirschsprung disease. The medullary thyroid carcinoma is of mild to moderate aggressiveness. Children harboring an MEN 2A RET gene mutation are advised to have a prophylactic total thyroidectomy by age 6 years.

Siblings or children of patients with MEN 2A should have genetic testing to determine if they have a mutation of the ret protooncogene (RET) on chromosome 10cen10q11.2; this identifies about 95% of affected individuals.

Each kindred has a certain ret codon mutation that correlates with the particular variation in the MEN 2 syndrome, such as the age of onset and aggressiveness of medullary thyroid cancer. The specific mutation as well as case histories of family members should guide the timing for prophylactic thyroidectomy. Before any surgical procedure, MEN 2 carriers should be screened for pheochromocytoma. There is incomplete penetrance, and about 30% of those with such mutations never manifest endocrine tumors.

Patients may be screened for medullary thyroid carcinoma with a serum calcitonin drawn after 3 days of omeprazole, 20 mg orally twice daily; calcitonin levels rise in the presence of medullary thyroid carcinoma to above 80 pg/mL in women or above 190 pg/mL in men.

3. MEN 2B MEN 2B is a familial, autosomal dominant multiglandular syndrome that is caused by a mutation of the ret protooncogene (RET) on chromosome 10. MEN 2B is characterized by mucosal neuromas (> 90%) with bumpy and enlarged lips and tongue, Marfan-like habitus (75%), adrenal pheochromocytomas (60%) that are rarely malignant and often bilateral, and medullary thyroid carcinoma

1190

CMDT 2013

Chapter 26

(80%). Patients also have intestinal abnormalities (75%) such as intestinal ganglioneuromas, skeletal abnormalities (87%), and delayed puberty (43%). Medullary thyroid carcinoma is aggressive and presents early in life. Therefore, infants having a parent with MEN 2B receive genetic screening; those carrying the RET mutation undergo a prophylactic total thyroidectomy by age 6 months.

Table 26–18. Systemic versus topical activity of corticosteroids.1

Daly AF et al. Update on familial pituitary tumors: from multiple endocrine neoplasia type 1 to familial isolated pituitary adenoma. Horm Res. 2009 Jan;71(Suppl 1):105–11. [PMID: 19153518] Pieterman CR et al. Care for patients with multiple endocrine neoplasia type 1: the current evidence base. Fam Cancer. 2011 Mar;10(1):151–71. [PMID: 21061174] Romei C et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010 Aug;163(2):301–8. [PMID: 20516206] Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab. 2010 Jun;24(3):355–70.

[PMID: 20833329] Wohllk N et al. Multiple endocrine neoplasia type 2. Best Pract Res Clin Endocrinol Metab. 2010 Jun;24(3):371–87. [PMID: 20833330]

cc

CLINICAL USE OF corticosteroids

``Mechanisms of Action Cortisol is a steroid hormone that is normally secreted by the adrenal cortex in response to ACTH. It exerts its action by binding to nuclear receptors, which then act upon chromatin to regulate gene expression, producing effects throughout the body.

``Relative Potencies (Table 26–18) Hydrocortisone and cortisone acetate, like cortisol, have mineralocorticoid effects that become excessive at higher

Topical Activity

4–5

1–2

5

1

Prednisone Triamcinolone

OTHER SYNDROMES OF MULTIPLE ENDOCRINE NEOPLASIA Patients with Carney complex develop tumors in the adrenal cortex, pituitary, thyroid, and gonads as well as cardiac myxomas and hyperpigmentation. Patients with Cowden disease develop thyroid abnormalities (66%) such as benign adenomas and follicular adenocarcinomas, along with breast cancer (20–36% in women), and multiple hamartomas that affect the skin and multiple other organs. Patients with McCune-Albright syndrome may develop precocious puberty (particularly girls) due to gonadal hypersecretion, Cushing syndrome caused by multiple adrenal nodules, hyperthyroidism from hypersecretory thyroid nodules, and acromegaly caused by GH-secreting pituitary tumors.

Patients have fibrous dysplasia of bones and hypophosphatemia, with bone fractures being common. Sudden death has been reported. It is caused by a postzygotic somatic mutation in the gene encoding the stimulatory Gs protein, resulting in constitutive activation of affected cells.

Systemic Activity

Triamcinolone acetonide

1

5

40

Dexamethasone

30–120

10

Betamethasone

30

5–10

Betamethasone valerate

—

50–150

Methylprednisolone

5

5

Fluocinolone acetonide

—

40–100

Flurandrenolide

—

20–50

Deflazacort

3–4

—

Hydrocortisone = 1 in potency.

doses. Other synthetic corticosteroids such as prednisone, dexamethasone, and deflazacort (an oxazoline derivative of prednisolone) have minimal mineralocorticoid activity.

Anticonvulsant drugs (eg, phenytoin, carbamazepine, phenobarbital) accelerate the metabolism of corticosteroids other than hydrocortisone, making them significantly less potent. Megestrol, a synthetic progestin, has slight corticosteroid activity that becomes significant when administered in high doses for appetite stimulation.

``Adverse Effects Prolonged treatment with systemic high-dose corticosteroids causes a variety of adverse effects that can be life-threatening. Patients should be thoroughly informed of the major possible side effects of treatment such as insomnia, cognitive and personality changes, weight gain with central obesity, bruising, striae, muscle weakness, polyuria, kidney stones, diabetes mellitus, glaucoma, cataracts, sex hormone suppression, candidiasis and opportunistic infections. High-dose corticosteroids have adverse cardiovascular effects, increasing the risk of hypertension, dyslipidemia, myocardial infarction, stroke, atrial fibrillation or flutter, and heart failure.

Bone fractures (especially spine and hip) ultimately occur in about 40% of patients receiving long-term corticosteroid therapy. Osteoporotic fractures can also occur in patients who receive extensive topical, inhaled, or intermittent oral corticosteroids (eg, prednisone ≥ 10 mg daily and cumulative dose > 1 g). Osteoporotic fractures can occur even in patients receiving long-term corticosteroid therapy at relatively low doses (eg, 5–7.5 mg prednisone daily). Patients at increased risk for corticosteroid osteoporotic fractures include those who are over age 60 or who have a low body mass index, pretreatment osteoporosis, a family history of osteoporosis, or concurrent disease that limits mobility. Avascular necrosis of bone (especially hips) develops in about 15% of patients who

Endocrine Disorders

CMDT 2013

1191

Table 26–19. Management of patients receiving systemic corticosteroids.

Recommendations for prescribing • Do not administer corticosteroids unless absolutely indicated or more conservative measures have failed.

• Keep dosage and duration of administration to the minimum required for adequate treatment.

Monitoring recommendations • Screen for tuberculosis with a purified protein derivative (PPD) test or chest radiograph before commencing long-term corticosteroid therapy.

• Screen for diabetes mellitus before treatment and at each clinician visit.

– Have patient test urine weekly for glucose.

– Teach patient about the symptoms of hyperglycemia.

• Screen for hypertension before treatment and at each clinician visit.

• Screen for glaucoma and cataracts before treatment, 3 months after treatment inception, and then at least yearly.

• Monitor plasma potassium for hypokalemia and treat as indicated.

• Obtain bone densitometry before treatment and then periodically. Treat osteoporosis.

• Weigh daily. Use dietary measures to avoid obesity and optimize nutrition.

• Measure height frequently to document the degree of axial spine demineralization and compression.

• Watch for fungal or yeast infections of skin, nails, mouth, vagina, and rectum, and treat appropriately.

• With dosage reduction, watch for signs of adrenal insufficiency or corticosteroid withdrawal syndrome.

Patient information • Prepare the patient and family for possible adverse effects on mood, memory, and cognitive function.

• Inform the patient about other possible side effects, particularly weight gain, osteoporosis, and aseptic necrosis of bone.

• Counsel to avoid smoking and excessive ethanol consumption.

Prophylactic measures • Institute a vigorous physical exercise and isometric regimen tailored to each patient’s disabilities.

• Administer calcium (1 g elemental calcium) and vitamin D3, 400–800 international units orally daily.

– Check spot morning urines for calcium, and alter dosage to keep urine calcium concentration below 30 mg/dL. – If the patient is receiving thiazide diuretics, check for hypercalcemia, and administer only 500 mg elemental calcium daily.

– Consider a bisphosphonate such as alendronate (70 mg orally weekly) or periodic intravenous infusions of pamidronate or zoledronic acid.

• Avoid prolonged bed rest that will accelerate muscle weakness and bone mineral loss. Ambulate early after fractures.

• Avoid elective surgery, if possible. Vitamin A in a daily dose of 20,000 units orally for 1 week may improve wound healing, but it is not prescribed in pregnancy.

• Avoid activities that could cause falls or other trauma.

• For ulcer prophylaxis, if administering corticosteroids with nonsteroidals, prescribe a proton pump inhibitor (not required for corticosteroids alone). Avoid large doses of antacids containing aluminum hydroxide (many popular brands) because aluminum hydroxide binds phosphate and may cause a hypophosphatemic osteomalacia that can compound corticosteroid osteoporosis.

• Treat hypogonadism.

• Treat infections aggressively. Consider unusual pathogens.

• Treat edema as indicated.

receive corticosteroids at high doses (eg, prednisone ≥ 15 mg daily) for more than 1 month with cumulative prednisone doses of ≥ 10 g.

Bisphosphonates (eg, alendronate, 70 mg orally weekly) prevent the development of osteoporosis among patients receiving prolonged courses of corticosteroids. For patients who are unable to tolerate oral bisphosphonates (due to esophagitis, hiatal hernia, or gastritis), periodic intravenous infusions of pamidronate, 60–90 mg, or zoledronic acid, 2–4 mg, should also be effective. Teriparatide, 20 mcg subcutaneously daily for up to 2 years, is also effective against corticosteroid-induced osteoporosis. (See further discussion in Osteoporosis section.) It is wise to follow an organized treatment plan such as the one outlined in Table 26–19.

Christiansen CF et al. Glucocorticoid use and risk of atrial fibrillation or flutter: a population-based, case-control study. Arch Intern Med. 2009 Oct 12;169(18):1677–83. [PMID: 19822824] Leib ES et al. Official positions for FRAX® clinical regarding ­glucocorticoids: the impact of the use of glucocorticoids on the estimate by FRAX® of the 10 year risk of fracture from Joint Official Positions Development Conference of the Interna­ tional Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®. J Clin Densitom. 2011 Jul–Sep;14(3):212–9. [PMID: 21810527] Strohmayer EA et al. Glucocorticoids and cardiovascular risk factors. Endocrinol Metab Clin North Am. 2001 Jun;40(2): 409–17. [PMID: 21565675] Weinstein RS. Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med. 2011 Jul 7;365(1):62–70. [PMID: 21732837]