SECTION 10
Endocrinology 56.
Suspecting and Managing an Adrenal patient Sameer Aggarwal
303
57.
Practical Approaches to a Person with Abnormal TSH Suresh Damodharan, Benzy Susan Joseph
307
C H A P T E R
56
Suspecting and Managing an Adrenal patient
Adrenal disorders can present in variety of ways.
ADRENAL HYPERANDROGENISM
The primary adrenal androgens are dehydroepiandrosterone (DHEA) and DHEA sulfate. The adrenal glands are a prominent source of androgen. Excess adrenal androgen secretion is a well-recognized cause of virilization in infants and children, and an occasional cause of hirsutism and virilization in women. Prepubertal children — In prepubertal children of both sexes, androgen excess from any source increases height velocity, somatic development, and skeletal maturation. Epiphyseal fusion may occur prematurely, leading to short adult height. Other findings vary with the sex of the child: ●
●
In prepubertal boys, increases in androgen exposure causes virilization manifested by penile enlargement, growth of hair in androgen-dependent areas, deepening of the voice, and development of other secondary sexual characteristics (eg, isosexual precocious puberty). In prepubertal girls, androgen excess causes hirsutism, acne, and clitoromegaly (eg, heterosexual precocious puberty).
Pubertal children — In pubertal boys, androgen excess increases the rate of progression of puberty and skeletal maturation, which can lead to premature epiphyseal fusion, thereby decreasing adult height. In pubertal girls, androgen excess causes virilization, primary or secondary amenorrhea, and increased skeletal maturation. As in boys, concurrent hypercortisolism may cause gonadal suppression and stunt linear growth. Adults — In adult men, adrenal androgen excess has little effect (ie, hair growth or muscle mass do not increase; however, acne and hirsutism in early puberty may occur). It does, however, inhibit gonadotropin secretion so that testes size, testicular testosterone secretion, and spermatogenesis may decrease. In adult women, increased adrenal androgen production causes hirsutism, acne, male pattern baldness, menstrual irregularities, oligomenorrhea or amenorrhea, infertility, and even frank virilization. As in men, hypercortisolism in women inhibits pituitary-gonadal secretion, causing oligomenorrhea or amenorrhea and infertility, but not signs of androgen excess.
Sameer Aggarwal
The treatment and prognosis of patients with adrenal hyperandrogenism vary with the underlying cause. Premature adrenarche — Premature adrenarche is an incomplete, benign, slowly progressive form of premature puberty that is an extreme variant of normal or nearly normal. It is a form of androgen excess, most often manifest as premature pubarche, that is characterized by a serum steroid pattern typical of adrenarche (DHEAS level above 40 µg/dl ) and is otherwise unexplained.No treatment is needed besides reassurance. Pubertal development usually begins at the expected time. When associated with obesity or insulin resistance, appropriate advice for diet and lifestyle changes should be given. Children with an unusual amount of sexual hair, evidence of true pubertal development (breast development in girls, testicular enlargement in boys), or significantly advanced bone age should undergo further evaluation. When associated with late onset congenital adrenal hyperplasia, oral contraceptives or glucocorticoid replacement is given. Classic 21-hydroxylase deficiency results in one of two clinical syndromes: a salt-losing form and the simple virilizing form. Girls with both forms present as neonates with ambiguous genitalia. Boys present as neonates with a salt-losing adrenal crisis (salt-losing form) (hyponatremia, hyperkalemia, and failure to thrive) or as toddlers with signs of puberty (simple virilizing form). ●
Reproductive abnormalities are common in females and include structural abnormalities due to androgen excess in utero and anovulatory menstrual cycles.
●
In adult men, testicular masses (adrenal rests), Leydig cell dysfunction, and abnormal semen analyses may be seen.
●
Nonclassic or late-onset 21-hydroxylase deficiency may present as hirsutism and menstrual irregularity in young women, early pubarche or sexual precocity in school age children, or there may be no symptoms.
Glucocorticoid replacement is necessary in all infants and children who have classic 21-hydroxylase deficiency. In infants and children, this is usually administered ashydrocortisone in a dose of 10 to 15 mg/m2 body surface area/day. Mineralocorticoid replacement is necessary in all pediatric patients who have classic 21-hydroxylase deficiency.
304
ADRENAL INSUFFICIENCY
ENDOCRINOLOGY
Common causes are autoimmune disease, metastasis, infection, drugs or congenital adrenal hyperplasia. Adrenoleukodystrophy and adrenomyeloneuropathy, an X-linked disorder, should be considered in any boy or young man with adrenal insufficiency. Congenital adrenal hypoplasia should be suspected in neonates with salt wasting and hyperpigmentation. Boys with X-linked forms may also have a failure of puberty (DAX-1). 46,XY individuals with sex reversal or ambiguous genitalia may have steroidogenic factor 1 (SF-1) mutations. Familial glucocorticoid deficiency presents in infancy with low cortisol and high corticotropin (ACTH) but normal mineralocorticoid production. IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, genital abnormalities) and Triple A syndrome (adrenal insufficiency, achalasia, alacrima and neurologic abnormalities) should be suspected in the context of their additional syndromic features. The most common clinical features of chronic primary adrenal insufficiency are chronic malaise, lassitude, fatigue ,weakness, anorexia, and weight loss. Other clinical manifestations are gastrointestinal symptoms, nausea, vomiting,pain abdomen, diarrhea,salt craving, joint pains, hypotension, electrolyte abnormalities (hyponatremia and hyperkalemia ), hypoglycemia and hyperpigmentation. Adrenal crisis is a life-threatening emergency that requires immediate treatment with steroids like hydrocortisone. Fludrocortisone is given as mineralocorticoid replacement.
ADRENAL TUMORS
Unilateral tumors or masses of the adrenal gland are common. They are categorized as either functional (hormone-secreting) or silent, and as either benign or malignant. ●
●
The majority of adrenocortical tumors are benign, nonfunctioning adenomas that are discovered incidentally on abdominal imaging studies (adrenal incidentalomas). Others are benign hormone-secreting adenomas that cause Cushing’s syndrome, primary aldosteronism or, much less commonly, virilization or feminization. Pheochromocytomas are adrenomedullary, not adrenocortical tumors.
●
Adrenocortical carcinomas (ACCs) are rare, frequently aggressive tumors that may be functional and cause Cushing’s syndrome and/ or virilization, or nonfunctional, and present as an abdominal mass or an incidental finding.
●
At initial presentation, approximately 50 percent of adult patients with ACC have relatively advanced disease stage.
Adults with hormone-secreting ACCs usually present with Cushing’s syndrome alone (45 percent), or a mixed Cushing’s and virilization syndrome, with overproduction
of both glucocorticoids and androgens (25 percent). Fewer than 10 percent present with virilization alone, but the presence of virilization in a patient with an adrenal neoplasm suggests an ACC rather than an adenoma. The clinical symptoms associated with glucocorticoid excess, such as weight gain, weakness, and insomnia, usually develop very rapidly (over three to six months). Patients who have coexisting hypersecretion of adrenal androgens may not experience the typical catabolic effects of glucocorticoid excess (muscle and skin atrophy). Feminization and hyperaldosteronism occur in fewer than 10 percent of cases. Most patients with nonfunctioning tumors (or more precisely with subclinical production of steroids) present with clinical manifestations related to tumor growth (ie, abdominal or flank pain), or with an incidentally found adrenal mass detected on radiographic imaging performed for a different reason; constitutional symptoms Uncommonly, a varicocele or fever and leucocytosis from tumor necrosis or production of chemokines may occur. Children usually present with virilization (84 percent) while isolated glucocorticoid excess (Cushing’s syndrome) is much less common (6 percent). Congenital Adrenal tumors — Surgery is the treatment of choice for all patients with hormone-secreting adrenal tumors. Surgery is the initial treatment for patients with adrenocortical carcinoma. Androgen and estrogen-secreting tumors — Androgensecreting adrenal tumors are usually malignant, but benign tumors have also been described in women. In a report of 21 women with androgen-secreting tumors, malignant tumors (n = 10) were larger at presentation than benign tumors (n = 11; 14 versus 9 cm, respectively). In addition, serum testosterone levels were 2.6-fold higher in the women with malignant tumors. Benign cortisolsecreting adenomas can also produce small amounts of androgens, but the serum androgen levels are usually not elevated. Estrogen-secreting tumors are rare and are usually malignant. In males it can present as feminization with gynecomastia, decreased libido, testicular atrophy; in women it can present with breast tenderness and dysfunctional uterine bleeding. For patients with potentially resectable stage I to III adrenocortical cancer who are surgical candidates, complete open surgical resection is recommended as initial therapy. Suspicious lymph nodes should be resected, but the benefit of routine lymphadenectomy has not been fully established yet. Adjuvant mitotane therapy is recommended for all patients who have a high risk of disease recurrence after complete resection, including all those with high-grade disease (Ki67 >10 percent or mitotic rate greater than 20 per 50 high-power fields [HPF]), incompletely resected disease, intraoperative tumor spillage or fracture, and some large tumors that are low grade but have vascular or capsular invasion.
CUSHING SYNDROME
Various causes of adrenal cushing syndrome are Adrenocortical adenomas and carcinomas – 18 to 20 percent. ●
Primary pigmented nodular adrenocortical disease (PPNAD), also called bilateral adrenal micronodular hyperplasia – less than 1 percent
●
Bilateral macronodular adrenal (BMAH) – less than 1 percent
hyperplasia
Symptoms that are most suggestive of the presence of hypercortisolism include supraclavicular fat pads, skin atrophy, wide purplish striae, and proximal muscle weakness. Adenomas are always cured with unilateral adrenalectomy. Laparoscopic adrenalectomy is the preferred approach for adrenal adenomas. There may be cardiovascular and metabolic benefits to surgery for patients with subclinical Cushing’s syndrome, who often present with adrenal incidentalomas. ACTH-independent bilateral adrenal hyperplasia — There are two forms of ACTH-independent bilateral adrenal hyperplasia: primary pigmented nodular adrenocortical disease (PPNAD, also called micronodular adrenal hyperplasia); and bilateral macronodular adrenal hyperplasia (BMAH). ●
Surgical bilateral adrenalectomy is uniformly effective in PPNAD; subtotal or unilateral adrenalectomy should not be performed since recurrence can occur. Bilateral adrenalectomy is also indicated in most patients with macronodular adrenal hyperplasia. In selected cases with macronodular adrenal hyperplasia and aberrant hormone receptors, pharmacologic blockade on the aberrant receptor can result in long-term normalization of cortisol secretion.
Pheochromocytoma should be excluded in all patients by measuring 24-hour urinary fractionated metanephrines and catecholamines. Symptoms (self-limited episodes of nonexertional palpitations, diaphoresis, headache, tremor, or pallor) are present in approximately 50 percent of patients with pheochromocytoma, and when present, they are typically paroxysmal. If the adrenal mass is vascular, or there are other features suggestive of pheochromocytoma, the preferred test is plasma fractionated metanephrines. Surgery is recommended for all patients with biochemical documentation of pheochromocytoma after preoperative alpha adrenergic blockade. Subclinical Cushing’s syndrome should be ruled out by performing the 1 mg overnight dexamethasone suppression test (DST). To detect significant glucocorticoid secretory autonomy, the post-overnight DST 8 AM serum cortisol concentration cutoff is >1.8 mcg/dL (>138 nmol/L). An abnormal 1 mg overnight dexamethasone suppression is consistent with adrenocorticotropic hormone (ACTH)independent cortisol production, a finding that should be confirmed with 24-hour urinary free cortisol or 2 day low dose DST.
Surgical resection of adenoma is also recommended for patients with subclinical Cushing’s syndrome who are younger and who have disorders potentially attributable to excess glucocorticoid secretion (eg, recent onset of hypertension, diabetes, obesity, and low bone mass) If the adrenal incidentaloma patient is hypertensive, a plasma aldosterone-to-plasma renin activity ratio and plasma potassium concentration should be obtained to ● Although medical treatment does not cure ACTHscreen for primary aldosteronism. Primary aldosteronism independent micronodular or macronodular may be associated with resistant hypertension, which is adrenal hyperplasia, the adrenal enzyme inhibitors defined as failure to achieve goal blood pressure despite metyrapone or ketoconazole can be given to reduce adherence to an appropriate three-drug regimen including cortisol secretion in an attempt to improve the a diuretic. Although hypokalemia is considered to be a patient’s physical condition before surgery. As with “classic” sign of primary aldosteronism, some patients adrenocortical tumors, ACTH secretion will not with primary aldosteronism due to an adrenal adenoma, increase and override the pharmacologic blockade. and more commonly those with adrenal hyperplasia, are not hypokalemic. ADRENAL INCIDENTALOMA An adrenal incidentaloma is a mass lesion greater than 1 cm in diameter, serendipitously discovered by radiologic examination. This entity is the result of technological advances in imaging such as computed tomography (CT) and magnetic resonance imaging (MRI). All
patients
with
adrenal
incidentalomas
should
For most patients with confirmed unilateral aldosterone hypersecretion (eg, adrenal adenoma or unilateral adrenal hyperplasia), unilateral adrenalectomy is recommended over medical therapy. For patients with bilateral adrenal hyperplasia be treated with medical therapy, not adrenalectomy. For patients with either bilateral adrenal
305
CHAPTER 56
The most common manifestations of Cushing’s syndrome, such as obesity, hypertension, and glucose intolerance, are less suggestive of the presence of hypercortisolism as they are also common in individuals who do not have adrenal hyperfunction.
be evaluated for the possibility of malignancy and subclinical hormonal hyperfunction. A homogeneous adrenal mass < 4 cm in diameter, with a smooth border, and an attenuation value < 10 Hounsfield unit (HU) on unenhanced CT, and rapid contrast medium washout (eg, >50 percent at 10 minutes) is very likely to be a benign cortical adenoma. The imaging characteristics that suggest adrenal carcinoma or metastases include: irregular shape, inhomogeneous density, high unenhanced CT attenuation values (>20 HU), delayed contrast medium washout (eg, <50 percent at 10 minutes), diameter >4 cm, and tumor calcification.
306
hyperplasia or confirmed unilateral adrenal aldosterone hypersecretion (who refuse or are not candidates for surgery), mineralocorticoid receptor antagonist like spironolactone or eplerenone is recommended.
ENDOCRINOLOGY
Surgical resection is recommended for patients with adrenal masses greater than 4 cm in diameter. However, the clinical scenario, imaging characteristics, and patient age frequently guide the management decisions in patients who have adrenal incidentalomas that fall on either side of the 4 cm diameter cutoff. In a patient with a known primary malignancy elsewhere who has a newly discovered adrenal mass that has an imaging phenotype consistent with metastatic disease, performing a diagnostic CT-guided fine-needle aspiration (FNA) biopsy may be indicated, but only after excluding pheochromocytoma with biochemical testing. Adrenal biopsy would not be needed if the patient was already known to have widespread metastatic disease. Excision of a tumor is recommended if the initial imaging phenotype is suspicious. For all adrenal masses larger than 10 cm, including those masses with benign imaging phenotypes, open adrenalectomy rather than a laparoscopic procedure is recommended. For incidentalomas with a benign appearance on imaging, repeat imaging study at 6 to 12 months after initial discovery is recommended. Whether to obtain additional images (eg, at 6, 12, and 24 months after initial discovery) and the type of image obtained (eg, CT, MRI, or ultrasound) should be guided by clinical judgment and imaging phenotype. Removal of any tumor that enlarges by more than 1 cm in diameter during the follow-up period is recommended.
We suggest that overnight DST be repeated annually for four years in cases where initial evaluation is negative, although the yield and cost-effectiveness of such testing is also unknown. Autonomous function (glucocorticoid) not present at baseline may be detected at follow-up testing.
REFERENCES
1.
Young WF Jr. Adrenal causes of hypertension: pheochromocytoma and primary aldosteronism. Rev Endocr Metab Disord 2007; 8:309.
2.
Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93:3266.
3.
Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushingâ&#x20AC;&#x2122;s syndrome and pseudo-Cushingâ&#x20AC;&#x2122;s states. Endocr Rev 1998; 19:647.
4.
White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21:245.
5.
Allolio B, Fassnacht M. Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006; 91:2027.
6.
Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 2007; 356:601.
7. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016; 101:364. 8.
Williams RM, Ward CE, Hughes IA. Premature adrenarche. Arch Dis Child 2012; 97:250.
9.
Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984; 59:551.
10. Subramanian K, Erick MR, and Amir HH. Evaluation of patients with adrenal incidentalomas. Curr Opin Endocrinol Diabetes Obes 2013; 20:161-9.
Practical Approaches to a Person with Abnormal TSH
C H A P T E R
57
Suresh Damodharan, Benzy Susan Joseph
INTRODUCTION
The thyroid is distinctive amid the endocrine glands owing to the large store of hormone it contains. The metabolic homeostasis in an adult is maintained by the thyroid gland which is achieved through secretion of two hormones, thyroxine (T4) and triiodothyronine (T3); regulated by thyroid stimulating hormone (TSH), secreted by the anterior pituitary.Thyroxine is obtained from thyroid and triiodothyronine is formed by the conversion of fT4 to fT3. The thyroid produces only 20% of tri-iodothyronine hormone (T3). The other 80% is produced by the conversion of fT4 to fT3 in the liver, kidney and pituitary gland.1 The hypothalamo-pituitary-thyroid (HPT) axis regulates
HYPOTHALAMUS TRH ↓ T4 STIMULATION
CIRCULATING FREE T4 AND T3 + LEVELS/- LEVELS
THYROID HORMONE
PITUITARY GLAND ↑ T4 INHIBITION
TSH
the level of thyroid hormones in the blood by feedback mechanisms. When the thyroid is stimulated by thyrotropin hormone, it leads to increased levels of thyroid hormones (free T4 and free T3). Increased levels of these hormones sendsignals to the pituitary to stop the production of thyrotropin hormone. On the contrary, the pituitary gland is stimulated if there are low levels of free hormones in the blood, thus producing fT3 and fT4 from the thyroid until it reaches the normal level. This is called as the negative feedback mechanism (Figure 1).1, 2
THYROID STIMULATING HORMONE
TSH is the major regulator for the growth and functions of the thyroid (Figure 2). In a healthy adult, the rate of production of TSH is within 100 and 200 mU/ day. In normal serum, TSH is present at concentrations between 0.4 and 4.2 mIU/L. TRH released from the hypothalamus triggers the pituitary to secrete TSH which in turn stimulates the thyroid to release fT3 and fT4. The level is increased in primary hypothyroidism and decreased in primary hyperthyroidism. Serum TSH concentration is used as the first line in the diagnosis of primary hypothyroidism and hyperthyroidism (Table 1). Serum total T4, T3 and fT4, fT3 increases in case of hyperthyroidism and decreases in hypothyroidism. Serum thyrotropin is the most sensitive assay to diagnose thyroid diseases but overtreatment can lead to increased liver function test, exaggerated bone demineralization, changes in the electrocardiogram and atrial fibrillation
HYPOTHYROIDISM
THYROID
Fig. 1: Thyroid hormone regulation cycle, TRH- Thyrotropin releasing hormone
Hypothyroidism is caused by insufficient secretion of thyroid hormones which results from a defect anywhere in the HPT axis. In majority of the cases, hypothyroidism is caused by thyroid and autoimmune thyroid diseases. It is the first manifestation for pituitary or thyroid disease.2
Table1: Concentration of thyroid hormones 1° Hypothyroidism Subclinical Hypothyroidism 2° Hypothyroidism 1° Hyperthyroidism
3
T3 Toxicosis Subclinical Hyperthyroidism
TSH ↑
Free T4 ↓
↑
Normal ↓
↓ or normal ↓ ↓
Free T3 or normal Normal
↑↑
↓ or normal ↑
Normal
↑↑ Normal ↑ ↑
2° Hyperthyroidism
↑ or normal
Normal ↑
Thyroidhormone resistance
↑ or normal
↑
308
INDICATION Decreased or increased metabolism Goitre on physical examination Family history of autoimmune thyroiditis
Order TSH and fT4
ENDOCRINOLOGY
High TSHHypothyroidism
NormalThyroid disease improbable
HIGH fT4
LOW fT4
1.Transient thyroiditis 2. Euthyroid sick syndrome 3. Primary hypothyroidism 4. Thyroid ablation removal
Low TSHHyperthyroidism
1. TSH secreting adenoma 2. TSH resistance 3. Thyroid hormone resistance
NORMAL fT4
Hyperthyroidism 1. Drug interference 2. Subclinical hyperthyroidism 3. Euthyroid sick syndrome 4. T3 Toxicosis
Order Throid stimulating immunoglobulin (TSI) Thyroid peroxidase antibody(TPO) Thyroid stimulating hormone receptor antibody (TRAb)
NORMAL FREE T4 1. Transient thyroiditis 2. Autoimmune thyroiditis 3. Subclinical hypothyroidism 4. Euthyroid sick syndrome
TSI Ab+ TPO+ TRAb+ Thyroiid gland enlargement diffuse Graves ophthalmological disease
CONSIDER T3 by dialysis Thyroid antibodies Total T3 Negative antibodies
HIGH fT4
Graves disease
TPO abTSI Ab-
Toxic nodule
Positive antibodies
Thyroid disease improbable
Autoimmune thyroid disease Low T3
T3 hypothyroidism
Normal T3
Improbable hypothyroidism
Fig. 2: Algorithm for abnormal TSH levels In patients with primary hypothyroidism there is a decreased secretion of fT4 and fT3 which leads to a reduction in the serum concentrations of the two hormones eventually resulting in an increased thyrotropin6 secretion. The causes of primary hypothyroidism include
chronic autoimmune thyroiditis, iodine deficiency or excess, iatrogenic causes, transient thyroiditis, congenital thyroid agenesis, subtotal thyroidectomy, subacute granulomatous thyroiditis and drugs like amiodarone and thionamide.2,3
309
HYPOTHYROIDISM
Low fT4
2. Thyroid ablation removal 3. Transient thyroiditis 4. Euthyroid sick syndrome
Normal fT4
1. Autoimmune thyroiditis 2. Subclinical hypothyroidism 3. Transient thyroiditis
1. Thyroid hormone resistance
2. TSH secreting adenoma 3. TSH resistance
Fig. 3: Disease conditions associated with increased serum TSH levels Hypothyroidism can be either subclinical or overt. Subclinical hypothyroidism is characterized by high TSH concentration and normal fT4 and fT3 concentration in the serum. Such patients will be asymptomatic. In overt hypothyroidism, the TSH levels will be high and fT4 levels will be low. Patients with a high serum TSH concentration and a low serum fT4 confirm the diagnosis of hypothyroidism. Treatment of primary hypothyroidism in adults should be based on their disease condition (cardiac and pregnant patients) (Figure 3).3,4 Secondary hypothyroidism can be due to pituitary disorder, Sheehan’s syndrome, trauma and hypophysitis. Patients with macroadenoma are hypothyroid after surgery or radiation. These patients have other types of pituitary hormone deficiency. Tertiary hypothyroidism is attributed to deficiency in TRH to stimulate the pituitary. Most patients with central hypothyroidism have low or normal serum TSH concentrations.3Secondary and tertiary hypothyroidism can be suspected in the following situations such as: •
Known pituitary or hypothalamic disease
•
Mass lesion in the pituitary
•
When symptoms are related to other hormonal deficiencies.
Resistance to thyroid hormone (RTH), a rare syndrome is characterized by diminished response to increased circulating levels of fT4 and fT3 and non suppressed serum TSH. These patients present with short stature, hyperactivity, goiter, learning disability and attention deficit. No treatment is required for most of the patients but if required β-adrenergic blockers can be given.Myxedema coma occurs in patients with severe hypothyroidism and is mainly due to predisposing factors such as cold
Table 2: Manifestations of Hypothyroidism4 Symptoms
Signs
Fatigue, weakness
Slow movement, slow speech
Cold intolerance
Delayed relaxation of tendon reflexes
Dyspnea on exertion
Bradycardia
Weight gain
Carotenemia
Depression, cognitive dysfunction
Coarse skin
Edema
Puffy facies, loss of eyebrows
Constipation
Periorbital edema
Growth failure
Enlargement of the tongue
Hoarseness, Dry skin
Diastolic hypertension
Menorrhagia
Pleural, pericardial effusions
Myalgia and paresthesia Ascites Decreased hearing
Galactorrhea
Arthralgia exposure, infection and trauma. It is characterized by 8 hypothermia, hypoxia, hypoventilation, hypercapnia, hypotension and hyponatremia. These patients can be treated with levothyroxine 300-500mcg IV bolus followed by 50-100 mcg orally daily. If there is no improvement after 48 hours, 10 mcg IV of T3 every 8 hours must be given along with T4.2, 3, 4
CLINICAL MANIFESTATION
Hypothyroidism varies according to the degree, severity, promptness with which it occurs and psychological characteristics of the patient (Table 2).
CHAPTER 57
1. Primary hypothyroidism
High fT4
ENDOCRINOLOGY
310
HASHIMOTOS THYROIDITIS
Hashimotos thyroiditis is a chronic autoimmune thyroiditis which is the most common cause of hypothyroidism. The patient may present with normal thyroid function or overt or subclinical hypothyroidism. Autoimmune thyroid diseases (AITD) occur more in females than in males and increases with age. People with other autoimmune diseases are more prone to develop autoimmune thyroid disease. Patients presenting with chronic thyroiditis are mostly euthyroid. Few patients present with goiter. In such patients, anti-thyroid peroxidase antibodies (TPOAb) are tested.
samples must be taken within a period of 2-3 months to differentiate from non-thyroidal illness.
MANAGEMENT
Treatment in subclinical hypothyroid patients are based on the TSH levels •
TSH>10mU/L- give levothyroxine
•
If TSH is slightly increased (4-10 mU/L) with positive TPO antibodies, check TSH yearly.
•
If the patient is TPO negative, check TSH every 3-5 years
Few studies have shown that women with autoimmune thyroiditis are more prone to increased risk of miscarriage. In such patients thyroxine can be given if TSH is within the range of 2.5-5 mIU//L.4
•
If the patient has symptoms of hypothyroidism and persistent TSH with a serum TSH between 4-10 mU/L, the patient has to be initiated with levothyroxine for 3-6 months.
INVESTIGATION
•
If the patient’s condition improves, treatment can be continued.
•
If the patient presents with positive TPO antibodies and without symptoms, the patient may progress to overt hypothyroidism. Therefore the patient has to undergo a yearly TSH examination.
•
If TPO antibodies are negative, the risk of progression to overt hypothyroidism is lesser. The patient has to go for TSH investigation every 3 years.4
As per the ATA/AACE guidelines, patients with autoimmune thyroiditis can be diagnosed by the following tests. •
Thyroid antibodies-
i.
Anti-thyroglobulin antibodies (TgAb)- positive in 20-25% patients
ii. Anti-microsomal / antibodies (TPOAb)
anti-thyroid
iii.
TSH receptor antibodies (TSHRAb)
•
Total tri-iodothyronine
•
Equilibrium dialysis
peroxidase
TREATMENT
These patients can be treated with levothyroxine based on the TSH value. Appropriate dosage among patients may vary but the mean replacement dosage of levothyroxineis 1.6-1.8mcg/kg of body weight per day. The appropriatemethod of treatment depends on the duration,severity and the presence of other associated disorders. The starting dose in patients who are above 50 years of age or who have cardiac diseases is 25mcg/day. The dose has to be titrated to obtain a euthyroid state. In younger patients, levothyroxine can be started at a dose of 50-100mcg.
SUBCLINICAL HYPOTHYROIDISM
Subclinical hypothyroidism is a common disorder characterized by increased serum TSH levels, normal fT4 andfT3 and may occur in the presence or absence of symptoms. The prevalence is high in females, advanced age and also in those with dietary iodine intake. Subclinical hypothyroidism is usually asymptomatic and can be identified by routine screening of TSH. Regardless of patients being asymptomatic, the risks associated with the condition include cardiovascular effects, progression to overthypothyroidism, hyperlipidemia, and neuropsychiatric effects. Few studies have shown that treatment of subclinical hypothyroidism can reduce these risks in patients with TSH > 10 μIU/ML.Two
HYPOTHYROIDISM IN PREGNANCY
Thyroxine (T4) and tri-iodothyronine (T3) increases in a pregnant woman leading to hypothyroidism. Thyrotropin hormone decreases due to the effect of placental human chorionic gonadotropin (hCG) in the first trimester of pregnancy. Thyroid antibodies develop in most of the pregnant women which is a major risk factor for spontaneous abortion independent of thyroid hormone and TSH levels. Untreated overt hypothyroidism during pregnancy can lead to increased risk of preeclampsia, maternal hypertension, postpartum hemorrhage, cardiac ventricular dysfunction, low birth weight and spontaneous abortion. Slight increase in serum TSH levels may increase the risk of fetal death. TSH measurement should be routinebefore pregnancy or during 1st trimester. Thyroid hormone replacement therapy is the most suitable treatment during pregnancy. Levothyroxine is considered to be the safest drug in pregnancy. These patients should check their TSH every 6 weeks to make sure if the same dosage has to be continued. 4, 5
HYPERTHYROIDISM
Hyperthyroidism occurs as a result of excess action of the thyroid hormone. Thyrotoxicosis occurs when the tissues are exposed to high concentration of thyroid hormone. This can occur during Graves’ disease, pituitary thyrotroph adenoma, pituitary thyroid hormone resistance syndrome, and multinodular goitre. In patients with thyrotoxicosis, TSH will be suppressed and fT4 levels will be elevated. TSH receptor antibodies are useful for assessing risk of thyrotoxicosis of the fetus. If
311
1. Euthyroid sick syndrome 2. Subclinical hyperthyroidism 3. Drug interference 4. T3 Toxicosis
Normal free T4 Hyperthyroidism
Hyperthyroidism
Fig. 4: Conditions associated with decreased TSH levels Table 3: Manifestation of Hyperthyroidism Symptoms
Signs
Nervousness , irritability, anxiety, insomnia
Sinus tachycardia
Palpitation, tachycardia
Fine tremor, hyperkinesia, hyperreflexia
Heat intolerance, increased sweating
Warm, moist skin
Thirst, polyuria
Palmar erythema
Weight loss or gain
Hair loss
Changes in appetite
Muscle weakness, wasting
Oligomenorrhoea, loss of libido, erectile dysfunction
Congestive heart failure, chorea, periodic paralysis
Diarrhoea the diagnosis is still uncertain radionucleotide thyroid scan has to be done. Causes of hyperthyroidism are excess iodine mostly due to trophoblastic disease, toxic adenoma, Plummer’s disease, subacute thyroiditis and toxic adenoma. The complications of hyperthyroidism include hypothyroidism and thyroid storm.5
(TRAb) / thyroid-stimulating immunoglobulins (TSI) •
Radioactive iodine uptake
TREATMENT
•
Carbimazole 10-20 mg every 8-12 hours and once daily dose every 6-8 weeks after achieving the euthyroid status.
•
If the patient experience sweating, tachycardia and tremor, propranolol 40 mg initially has to be given and then slowly titrate the dose to 120 mg/day
DIAGNOSIS
•
Other treatment option- surgery in younger patients and radioactive iodine in patients with recurrent thyrotoxicosis.5, 6, 7
Physical examination includes eye examination, weight, blood pressure, dermatologic examination, pulse rate, cardiac rhythm, thyroid palpation and auscultation.
Graves is the most common form of hyperthyroidism. The conditions associated with Graves disease are type 1 17 diabetes mellitus, Addison’s disease, vitiligo, pernicious anemia, myasthenia gravis and coeliac disease.
CLINICAL MANIFESTATION
Signs and symptoms are shown due to excess circulating thyroid hormone in the blood. The severity depends on the magnitude and duration of the thyroid hormone and age of the patient (Table 3). A detailed history must be taken, physical examination must be done and laboratory investigation must be conducted to diagnose hyperthyroidism (Figures 4 and 5).
Laboratory investigations include: •
TSH assay
•
Triiodothyronine and thyroxine
•
Free T3
•
Thyroid autoantibodies-TSH receptor antibodies
GRAVES’ DISEASE
MANAGEMENT (FIGURE 6)
1.
Drug of choice- carbimazole 5mg
2.
Propylthiouracil (PTU)- initial dose is 300-450mg/ day and maintenance dose is 100-150mg/day.
After achieving euthyroid, combine carbimazole with T4 of 100mcg. Antithyroid drugs must be stopped 3-7 days
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High free T4
312
Suppressed TSH levels
Measure TSH levels Elevated TSH Levels
ENDOCRINOLOGY
Measure fT4
Measure fT4 Level
Normal
High
Measure fT3
Primary Hyperthyroidism
Normal
Elevated
High
Thyroid Uptake
T3 toxicosis
Image Pitutary Gland
Low -Subclinical Hyperthyroidism -Resolving Hyperthyroidism -Medication -Pregnancy -Non-Thyroid illness (Acute illness)
High
Measure Thyroglobulin
Decreased
Inappropriate Secretion of TSH
Diffuse Graves' Disease
Increased
Exogeneous Hormone
Thyroditis Iodine Exposure
Nodular Multiple 'Hot' Areas
Toxic Multinodular Goiter
One 'Hot'areas
Toxic Adenoma
Extraglandular Production
Fig. 5: Diagnostic Approach- Hyperthyroidism prior to RAI therapy and should be given only after 3-7 days of RAI treatment. 3.
Radioactive iodine (RAI) is given at a dose of 4-10 mCi orally. Larger doses are used in patients with toxic nodular goitre. They destroy the cells that concentrate iodine and decrease the thyroid hormone production.
4.
Propranolol is usually prescribed at a dose of 2040mg four times a day which reduces symptoms of thyrotoxicosis. They are the adjunctive therapy to RAI.
5.
Thyroidectomy is done if all other therapy fails. It is a difficult procedure but the success rate is high and the cure is rapid in such patients. 7
SUBCLINICAL HYPERTHYROIDISM (FIGURE 7)
•
Atrial fibrillation
• Osteoporosis. The risk of fracture is high in female patients. Thyroid function test must be performed in these patients every 6 months. In elderly patients with atrial fibrillation or osteoporosis, low dose of antithyroid drug therapy or ablation therapy must be initiated.
HYPERTHYROIDISM IN PREGNANCY
Thyrotoxicosis mainly occurs in pregnancy due to Graves disease, gestational hyperthyroidism and trophoblastic neoplasia. In these patients fT3 and fT4 increases and TSH decreases. Symptoms in these patients include hyperemesis gravidarum which is more commonly seen. Other symptoms include tiredness, palpitation, muscle weakness, shortness of breath, heat intolerance and irritability. Inability to gain weight, persistent tachycardia at rest is the sign shown in these patients.
It is a condition in which the serum thyrotropin concentration is low in patients with normal fT4 and fT3. Inorder to treat subclinical hyperthyroidism, the21 Diagnosis in pregnant patients is usually difficult and following has to be considered: can be identified if the patient has pregnancy induced hypertension or congestive heart failure.Pregnant patient • TSH<0.1
313
Persistent Subclinical Hypothyroidism
TSH Levels- >10mu/L
TSH Levels â&#x2030;Ľ4.5mIU/L to 10mIU/L
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Treat
Cardiovascular Risk/ Preexisting NO NONO Cardiovascular Disease
Hypothyroidism Symptoms/ Depression
Only Observational Monitoring of Thyroid Function
Sonographic Appearance of AITD and/Positive TPOAb
YES YESYES Treat
Consider treatment
Short LT4 Course
Cardiovascular Risk and/or Preexisting Cardiovascular Disease
Cardiovascular Risk and/or Preexisting Improved Not improved Cardiovascular Disease Cardiovascular Risk Cardiovascular Risk Cardiovascular Risk and/or Preexisting and/or Preexisting and/or Preexisting Cardiovascular Cardiovascular Stop LT4 Therapy Continue LT4 Therapy Cardiovascular Disease Disease Disease Cardiovascular Risk Cardiovascular Risk Cardiovascular Risk Cardiovascular Risk Fig. 7: Algorithm forCardiovascular persistent hypothyroidism, AITD: Autoimmune thyroid Risk and/ordisease Preexisting and/or Preexisting and/or Preexisting and/or Preexisting and/or Preexisting Cardiovascular Cardiovascular Cardiovascular Cardiovascular with Graves disease present with aggravating symptoms TREATMENT Cardiovascular Disease Disease Disease in the firstDisease half, amelioration of symptoms in the second Propylthiouracil can be given at a dose of 100-150mg Disease and recurrent symptoms in the post partum period. every 8 hours andcarbimazole at aRiskdose of 10-20mg Cardiovascular Cardiovascular Risk Cardiovascular Risk once daily. However, propylthiouracil should be and/or Preexisting Gestational trophoblastic disease (GTD) is a veryand/or rare and/or Preexisting Preexisting prescribed only in the first trimester as it can cause Cardiovascular complication of pregnancy which occurs due to molecular Cardiovascular Cardiovascular 14 hepatotoxicity. Propranolol cannot be given as it can mimicry between TSH and human chorionic gonadotropin Disease Disease Disease
(HCG). Free T3 and free T4 are found to be in the normal cause growth retardation and respiratory depression in with iodides and Cardiovascular Risk radioiodine are range and the patientis asymptomatic most of the Cardiovascular time. the neonate.Treatment Risk contraindicated in pregnant patients. and/or Preexisting This occurs due to high levels of HCG hormone and it Preexisting and/or resolves as the hormone levels fall.4,5,7 Cardiovascular Breast feeding mothers Cardiovascular should be given lower doses of Disease
Disease
314
Graves' Disease
ENDOCRINOLOGY
Antithyroid medication
Mild- PTU 50 mg 8hrly MMI 10mg 12hrly
4 weeks
Severe- PTU 100-150mg 8hrly MMI 20-30mg 12hrly Test TSH and fT4
TSH<0.5µU/ml fT4- High
TSH<0.5µU/ml fT4 -Normal
TSH<0.5µU/ml fT4- Low
Add T4 or decrease dose
Continue or increase Antithyroid drugs
Monitor every 1-2 months: Reduce dose gradually if fT4, TSH normal 4-8 weeks
Discontinue drugs after 12-18 months.
Fig. 6: Treatment of Graves’ disease, fT4: Free thyroxine, MMI: Methimazole these drugs. Thyroid function test should be conducted every 4-6 weeks.7,8
SICK EUTHYROID SYNDROME
Euthyroid syndrome is a condition in which there is a disregulation in the feedback mechanism and is caused by starvation, severe infection, liver failure etc. In such patients T3 and T4 levels will be abnormal and or 23 suppressed TSH.6
DRUGS CAUSING THYROID DYSFUNCTION
Amiodarone induced thyroid dysfunction occurs more commonly.If the patient has thyroid abnormality, amiodarone can be continued along with an added levothyroxine replacement therapy.Thyroid function test should be checked prior to taking this medication and every 6 months after taking amiodarone.4,5
THYROIDITIS
Thyroiditis is the inflammation of the thyroid caused by a group of disorders like Hashimoto’s thyroiditis,
Table 5: Drugs ↓ TSH Production
↑ TSH Production
Alpha adrenergic blockers Dopamine receptor antagonist Serotonin Antagonists
Opioids
Dopamine analogues
Ephedrine, Theophylline
Glucocorticoids
Haloperidol, chlorpromazine
Somatostatin analogues
Selective Serotonin Reuptake Inhibitors
CONCLUSION
Abnormal TSH is considered as the primary method to differentiate between thyroid disorders. Other supporting investigations include serum fT4,fT3 and thyroid antibodies. Patients with subclinical hypothyroidism and hyperthyroidism need to be treated on the basis of symptoms and risk factors. Other conditions like sick euthyroid syndrome, thyroid resistance and assay interference must be considered while managing patients with abnormal TSH. Algorithm for treating patients with abnormal TSH must be followed and treated based on
315
REFERENCE
1.
Melmed S, Polonsky KS, Larsen PR et al editors. Williams Textbook of Endocrinology. 13th ed. India: RELX India Pvt. Ltd; 2016.
2.
Shargel L, Mutnick AH, Souney PF, Swanson LN editors. Comprehensive Pharmacy Review. 8thed New Delhi: Wolters Kluwer (India) Pvt Ltd; 2013.
3.
Jameson and Groot D editors. Endocrinology: Adult and Pediatric Volume 2. 7th ed. India: Reed Elsevier India Pvt. Ltd; 2016.
4.
Wass J, Owen K, Turner H editors. Oxford handbook of endocrinology and diabetes. 3rd ed. India: Oxford University Press; 2014.
5. Kennedy L and Basu A editors. Problem solving in Endocrinology and Metabolism;UK: Atlas Medical Publishing Ltd; 2007. 6.
Garber JR, Cobin RH, Gharib H, et al. Clinical Practice Guidelines For Hypothyroidism In Adults: Cosponsored By The American Association Of Clinical Endocrinologists And The American Thyroid Association 2012; 18:e9-e15.
7.
Ross DS, Burch HB, Cooper DS, et al. American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis. 2016 Mary Ann Liebert, Inc.DOI: 10.1089/thy.2016.0229.
8.
Sharma S, Sethi GR, et al editors. Standard treatment guidelines. A manual for medical therapeutics. 4th ed. New Delhi: Wolters Kluwer (India) Pvt Ltd; 2015.
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postpartum thyroiditis, subacute thyroiditis (De Quervain’s thyroiditis), silent thyroiditis, acute thyroiditis and radiation induced thyroiditis. Subacute thyroiditis is caused by viral infection and acute thyroiditis is caused by bacteria or any other infectious organism. Main aim is to treat these patients according to the type and clinical presentation.
their investigations and diagnosis.One should consider referral to a tertiary centre endocrinologist if there is challenge in diagnosing and managing the patients.