19 Endocrinology

SECTION 19

Endocrinology 182. Panhypopituitarism

Minal Mohit

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183.

Vitamin D: In Health and Clinical Practice BK Mahavarkar, Anoosha Bhandarkar

845

184.

Subclinical Hypothyroidism Gayatri Ghanekar, Manoj Chadha

849

185.

Subclinical Hyper and Hypo Thyroidism - When to Treat Ankit Shrivastav

852

186.

Hypothyroidism.....Beyond Thyroid !

Alaka Deshpande

856

187.

Obesity- Tackling the Epidemic with an Individual-Centric Approach Anupam Prakash

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Panhypopituitarism

C H A P T E R

182 INTRODUCTION

Panhypopituitarism is a condition of inadequate or absent production of the anterior pituitary hormones. It is frequently the result of other problems that affect the pituitary gland and either reduce or destroy its function or interfere with hypothalamic secretion of the varying pituitary-releasing hormones. Hypopituitarism refers to the deficiency of one or more pituitary hormones. It is associated with increased morbidity and mortality.

Clinical manifestations are influenced by the cause, severity, and rate of onset of pituitary hormone deficiency.

Adult patients with hypopituitarism receive substitutive hormone treatment for growth hormone, secondary glucocorticoid, sex steroid, and thyroid hormone deficiency.

EPIDEMIOLOGY

Limited information is available on the epidemiology of hypopituitarism. A Swedish survey estimates the prevalence of hypopituitarism to be 175 cases per

Minal Mohit

million. A Spanish study has reported a prevalence of hypopituitarism of 290 and 450 cases per million from two cross-sectional surveys in 1992 and 1999, respectively, and a corresponding incidence of 60 per million per year.

MORTALITY

Mortality is increased in hypopituitarism. Data from six epidemiologic studies, comprising patients aged between 46 and 52 years who were followed for 10 to 13 years, report increased mortality with standardized mortality rates (SMRs) from 1.2 to 2.2. The higher mortality arises from cardiovascular and cerebrovascular disease and appears to be greater in women (Figure 1). Craniopharyngiomas carry a worse prognosis than pituitary adenomas, and radiotherapy has been identified as a factor that increases mortality. GH deficiency has been implicated as a major contributor to excess mortality in hypopituitarism because it is the only defect not replaced in the studies of hypopituitarism. However, the contribution to overall mortality of other risk factors, such as radiotherapy and suboptimal replacement therapies for other hormone deficits, is the subject of ongoing investigation.

CAUSES

Major causes of hypopituitarism are shown in (Table 1). The most common cause is a pituitary adenoma or treatment with pituitary surgery or radiotherapy.

PITUITARY AND HYPOTHALAMIC MASS LESIONS

Pituitary microadenomas, though found commonly (1.5% - 27%) at autopsy, are very rarely associated with hypopituitarism and tend to run a benign course.

Macroadenomas are less common but are more frequently associated with pituitary hormone deficiencies; some 30% of patients with pituitary macroadenomas have one or more anterior pituitary hormone deficiencies. The causative mechanism of hypopituitarism is compression of the portal vessels in the pituitary stalk, secondary to the expanding tumor mass directly or to increased intrasellar pressure, which explains the potential reversibility of pituitary dysfunction after surgery in some patients.

Fig. 1: Standard mortality rates (SMR) and 95% confidence intervals (CI) in individual studies on patients with nonmalignant pituitary diseases not associated with excess adrenocorticotropic hormone (ACTH) or growth hormone (GH) secretion, and in the weighted meta-analysis (bottom line). Results are shown for men (open boxes) and women (black boxes) separately. (From Nielsen EH, Lindholm J, Laurberg P. Excess mortality in women with pituitary disease: a meta-analysis. Clin Endocrinol 67:693–697, 2007.)

Derangement of central endocrine regulation also occurs with parapituitary space-occupying lesions such as craniopharyngiomas, Rathke’s cleft cysts, arachnoid cysts, chondromas, chordomas, suprasellar meningiomas, astrocytomas of the optic nerve, and primary tumors of the third ventricle.

PITUITARY SURGERY

The incidence and degree of hypopituitarism after surgery depend on the size of the original tumor, the degree of infiltration, and the experience of the surgeon.

There is a possible deterioration of postoperative

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Table 1: Causes of Hypopituitarism Neoplastic: Tumors involving the hypothalamicpituitary (HP) axis Pituitary adenoma Craniopharyngioma Glioma (hypothalamus, third ventricle, optic nerve) Surgery: for HP axis tumors

ENDOCRINOLOGY

Radiotherapy HP axis tumors Brain tumors Head and neck cancer Acute lymphoblastic leukemia Autoimmune Lymphocytic hypophysitis Vascular Sheehan’s syndrome Pituitary apoplexy

Fig. 2: The incidence of growth hormone (GH) deficiency in children receiving 27 to 32 Gy or ≥35 Gy of cranial irradiation for a brain tumor in relation to time from irradiation (dxt).

This illustrates that the speed at which individual pituitary hormone deficits develop is dose dependent; the higher the radiation dose, the earlier GH deficiency occurs. (Courtesy the Department of Medical Illustrations, Withington Hospital, Manchester, England.)

Intrasellar carotid artery aneurysm Subarachnoid hemorrhage Granulomatous disease Sarcoidosis Tuberculosis Histiocytosis X Wegener’s granulomatosis Genetic (table 2) Combined pituitary hormone deficiencies Isolated pituitary hormone deficiencies Developmental Midline cerebral and cranial malformations Traumatic Head injury Perinatal trauma Infection Encephalitis Pituitary abscess Iron-overload states Hemochromatosis Hemosiderosis (thalassemia) Idiopathic pituitary function, and assessment of pituitary function should be performed promptly after surgery. But on the other hand, surgery for pituitary adenomas may also be associated with significant recovery of pituitary function.

Postoperative improvement is more likely if no tumor is found on postoperative imaging, or if the tumor is not invasive. The pituitary hormone most likely to recover is thyroid-stimulating hormone (TSH), followed in order

Fig. 3: Life-table analysis indicating probabilities of initially normal hypothalamic-pituitary-target gland axes remaining normal after radiotherapy (3750 to 4250 cGy). Growth hormone (GH) secretion is the most sensitive of the anterior pituitary hormones to the effects of external radiotherapy, and thyroidstimulating hormone (TSH) secretion is the most resistant.

In two thirds of patients, gonadotropin deficiency develops before adrenocorticotropic hormone (ACTH) deficiency. FSH, Follicle-stimulating hormone; LH, luteinizing hormone. (From Littley MD, Shalet SM, Beardwell CG, et al: Hypopituitarism following external radiotherapy for pituitary tumors in adults.

Q J Med 70:145–160, 1989.) by adrenocorticotropic hormone (ACTH), gonadotropins, and GH. Recovery of pituitary function occurs early, within 8 weeks after surgery.

Table 2: Genetic Causes of Hypopituitarism Combined

Hormone Deficiencies

Pit-1 (POU1F1, GHF1)

GH, TSH, PRL

PROP-1

GH, LH/FSH, TSH, ACTH, PRL

HESX1 (Rpx)

GH, LH/FSH, TSH, ACTH, ADH

LHX3/LHX4

GH, LH/FSH, TSH, PRL

PITX2

GH, PRL

hGH

GH

GHRH receptor gene

GH

KAL

FSH/LH

GnRH receptor gene

FSH/LH

DAX1/AHC

FSH/LH

TBX19 (Tpit)

ACTH

TSH-β gene

TSH

TRH receptor gene

TSH

RADIOTHERAPY

Deficiency of one or more anterior pituitary hormones is almost invariable when the hypothalamic-pituitary axis lies within the fields of radiation. Hypopituitarism also develops in patients who received radiation therapy for nasopharyngeal carcinomas, parasellar tumors, and primary brain tumors, as well as in children who underwent prophylactic cranial irradiation for acute lymphoblastic leukemia or total body irradiation (TBI) for a variety of tumors and other diseases.

The radiobiological impact of an irradiation schedule is dependent on the total dose, the number of fractions, and the duration and length of follow-up (Figure 2).

Somatotrophs are the most sensitive to radiation damage (Figure 3). Endocrine testing should be performed on a yearly basis for at least 10 years and again at 15 years.

GENETIC CAUSES

Mutations in genes encoding for the KAL, HESX-1, Prop1, and Pit-1transcription factors result in deficiency of one or more anterior pituitary hormones. Mutations in early appearing transcription factors tend to cause more extensive hormone deficiencies (Table 2).

TRAUMATIC BRAIN INJURY

Traumatic brain injury (TBI) is an under-appreciated cause of hypopituitarism. It was first reported in 1918.

Meta-analysis of 19 studies, which included more than 1000 patients, demonstrated a pooled prevalence of hypopituitarism following TBI of 27.5%. Prevalence of diabetes insipidus is 26% in the acute phase and is decreased to 6.9% among long-term survivors. Risk factors of traumatic hypopituitarism include basal skull fracture, diffuse axonal injury, raised intracranial pressure, and

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LYMPHOCYTIC HYPOPHYSITIS

Lymphocytic hypophysitis, an immune-mediated diffuse infiltration of the anterior pituitary with lymphocytes and plasma cells, occurs predominantly in women and often is first evident in pregnancy or after delivery. The classic presentation is peripartum hypopituitarism, often with a pituitary mass and visual failure, whereas in later stages, the gland may atrophy, leaving an empty sella.

PITUITARY APOPLEXY

Pituitary apoplexy is the abrupt destruction of pituitary tissue that results from infarction or hemorrhage into the pituitary, usually into an underlying pituitary tumor.

Severe headache accompanies a variable degree of visual loss or cranial nerve palsy. Consequent pituitary hormone deficiencies may develop rapidly. In Sheehan’s syndrome, pituitary infarction occurs secondary to severe postpartum hemorrhage and ensuing circulatory failure.

GRANULOMATOUS DISEASES

Granulomatous diseases, including sarcoidosis, tuberculosis, and Langerhans cell histiocytosis, can affect the hypothalamic-pituitary axis and cause hypopituitarism, including diabetes insipidus.

CLINICAL FEATURES

Presentation of hypopituitarism can be nonspecific. It is affected by degree, type, and rate of onset of the pituitary hormone deficiency. Local pressure effects or hormonal hypersecretion may complicate the clinical picture.

Hypopituitarism arising from an expanding mass lesion or from irradiation produces a characteristic evolution of pituitary failure caused by an initial loss of GH secretion, followed by LH and FSH, and finally by failure of ACTH and TSH secretion. The onset of symptoms is insidious, typically occurring with mild headaches, lethargy, fatigue, disinterest, weight gain, low mood, and declining libido—symptoms mimicking depression.

Rarely, anorexia and weight loss may arise from ACTH deficiency and may be mistaken for and lead to extensive investigations for occult malignancy. Progressive mass expansion causes increasingly severe headaches or visual symptoms from chiasmal compression. The symptoms and signs of individual hormone deficiency are listed in Table 3. The features of isolated deficiencies of each axis are described below.

GH DEFICIENCY

Adults with GH deficiency, whether dating from childhood or acquired in later adult life, have a range of metabolic, body compositional, and functional abnormalities Table 4.

GONADOTROPIN DEFICIENCY

In male patients, the clinical features of gonadotropin deficiency differ according to whether the deficiency was acquired before or after pubertal age. If acquired before pubertal age, clinical examination reveals a small penis, small testes, and eunuchoid proportions (span exceeds a height of 5 cm). Hypogonadism acquired postpubertally

CHAPTER 182

Isolated

Gene Defect

prolonged stay in the intensive care unit. All patients should undergo screening for hypopituitarism between 3 and 6 months after injury.

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Table 3: Symptoms and Signs of Hormone Deficiencies

Table 4: Syndrome of Adult Growth Hormone Deficiency

Hormone Deficiency

Symptoms and Signs

Symptoms

Growth hormone

Please refer to Table 13-6 in the section Growth Hormone Deficiency.

• Increased body fat

ENDOCRINOLOGY

Gonadotropins

In men: poor libido/ impotence, infertility, small soft testes, reduced facial/body hair

• Reduced muscle bulk • Reduced strength and physical fitness • Reduced sweating • Impaired psychological well-being -

Depressed mood

-

Anxiety

-

Reduced physical stamina

-

Reduced vitality and energy

Growth retardation in children; decrease in energy; constipation; sensitivity to cold, dry skin, weight gain

-

Increased social isolation

Adrenocorticotropic hormone

Weakness, tiredness, dizziness on standing, pallor, hypoglycemia

• Poor muscular development

Prolactin

Failure of lactation

Antidiuretic hormone

Polyuria, polydipsia, nocturia, hypotension

In women: amenorrhea/ oligomenorrhea dyspareunia, infertility, breast atrophy Thyroid-stimulating hormone

is associated with a reduction in testicular size, loss of facial and body hair, and thinning of the skin, leading to the characteristic finely wrinkled facial skin of the “aging youth.” Other effects include a decrease in skeletal muscle mass, bone mineral density, sexual function, libido, and general well-being. Azoospermia is an almost inevitable consequence of hypogonadotropic hypogonadism. Partial LH deficiency may result in low circulating testosterone levels and gynecomastia with preserved testicular size and fertility, as intratesticular testosterone levels remain high enough to maintain spermatogenesis.

In a teenage girl, hypogonadotropic hypogonadism is associated with primary amenorrhea and absent breast development. In the adult woman, amenorrhea or oligomenorrhea, infertility, breast atrophy, vaginal dryness, and dyspareunia occur; pubic and axillary hair remains unless ACTH deficiency also is present.

ADRENOCORTICOTROPIC HORMONE DEFICIENCY

ACTH deficiency is the most life-threatening component of hypopituitarism. If the onset is abrupt, as in pituitary apoplexy, the clinical picture may be dominated by profound shock in the most serious form. Patients with chronic ACTH deficiency usually present with chronic progressive symptoms of chronic fatigue, anorexia, and weight loss, sometimes mimicking anorexia nervosa or an occult malignancy. Patients on long-term glucocorticoid therapy can develop adrenal atrophy secondary to ACTH suppression. Examination may reveal pallor of the skin, in contrast to the hyperpigmentation of Addison’s disease, and in female patients particularly, loss of secondary sexual hair occurs. In severe ACTH deficiency, particularly in childhood, hypoglycemia can occur: Cortisol deficiency results in increased insulin sensitivity and a decrease

Signs • Overweight • Increased adiposity, especially abdominal • Reduced exercise performance • Thin, dry skin • Depressed affect Investigations • Peak GH response to hypoglycemia <3 µg/L (all patients) • Low IGF-1 (60% of patients) • Hyperlipidemia: high LDL cholesterol, low HDL cholesterol • Elevated fasting insulin • Reduced bone mineral density GH, Growth hormone; IGF, insulin-like growth factor; LDL, lowdensity lipoprotein; HDL,high-density lipoprotein.

in hepatic glycogen reserves. Hyponatremia, although less commonly seen than in Addison’s disease because of preservation of aldosterone secretion, may be the presenting feature of ACTH deficiency, particularly in the elderly.

THYROID-STIMULATING HORMONE DEFICIENCY

Thyroid-stimulating hormone (TSH) deficiency occurs late in most pituitary disorders. Symptoms include fatigue, weakness, inability to lose weight, constipation, and cold intolerance, in keeping with the symptoms of primary hypothyroidism. However, symptoms generally are milder than in primary hypothyroidism, because some residual TSH secretion often is preserved.

ANTIDIURETIC HORMONE DEFICIENCY

Polydipsia and polyuria with nocturia are the classic features of diabetes insipidus resulting from antidiuretic hormone (ADH) deficiency. If the patient is unable to keep up with the fluid loss, hypotension and hypovolemia ensue. The features of diabetes insipidus may be masked by the presence of ACTH deficiency, because of the

consequent hypovolemia and reduced glomerular filtration rate. Only when cortisol replacement therapy is commenced may the polyuria and polydipsia of diabetes insipidus be revealed.

DIAGNOSIS AND ENDOCRINE EVALUATION

Imaging

Endocrine Evaluation

The insulin tolerance test (ITT) evaluates the response of the HPA axis to the potent stressor of hypoglycemia, and it is generally the “gold standard” in the confirmation of secondary adrenal failure. It is also the test of growth hormone reserve in patients with pituitary disease. Following injection of a standard dose of intravenous insulin (0.1 unit/kg),57 cortisol concentrations are measured serially. Upon achievement of adequate hypoglycemia (<2.2 mmol/L), a peak cortisol response of between 500 and 600 nmol/L generally is accepted as adequate.

The endocrine assessment of a patient with suspected hypopituitarism usually involves measurement of both baseline and stimulated hormone levels. Evaluation of baseline function involves prolactin, TSH, thyroxine (T4), cortisol, LH, FSH, and testosterone in men, and estradiol in women. Baseline blood testing reliably identifies hypothyroidism, hypogonadism, and severe hypoadrenalism due to pituitary insufficiency.

The short Synacthen (tetracosactrin) test sometimes is used as a surrogate test of ACTH deficiency on the basis that the adrenal gland will respond to an exogenous bolus of synthetic ACTH when there is a normal endogenous ACTH reserve and the gland is not atrophic. Although it is a good test of adrenal reserve, it does not directly test pituitary ACTH reserve. In a patient with organic pituitary disease, a normal response to Synacthen does not exclude mild or recent ACTH deficiency.

DYNAMIC TESTING

Thyroid-Stimulating Hormone Deficiency

Growth Hormone Deficiency

Three widely accepted approaches for assessing GH secretory status include measuring 1.

peak GH response to a provocative test, which include the insulin tolerance test (ITT); arginine, glucagon, clonidine, and growth hormone-releasing hormone (GHRH) alone or in combination with arginine or pyridostigmine

2.

spontaneous GH secretion, and

3.

serum concentrations of GH-regulated proteins such as insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3).

Adult Gonadotropin Deficiency

In women of postmenopausal age, gonadotropin levels are clearly low or undetectable, whereas in premenopausal women, amenorrhea (or less commonly, oligomenorrhea), in addition to low estradiol levels and low or normal gonadotropin levels, provides sufficient evidence of the diagnosis. In adult men, a similar picture of low testosterone levels and low or inappropriately normal gonadotropin levels is seen.

Adrenocorticotropic Hormone Deficiency

In normal people, the highest plasma cortisol levels are found between 6:00 AM and 8:00AM, and the lowest before midnight. Plasma cortisol and ACTH concentrations are elevated during physical and emotional stress, including acute illness, trauma, surgery, infection, and starvation. If a 9:00 AM cortisol level is less than 100 nmol/L, particularly in an unwell patient, cortisol deficiency is highly likely, whereas a baseline level greater than 500 nmol/L indicates normality; dynamic assessment of the hypothalamic-pituitary-adrenal (HPA) axis is not necessary under these circumstances. A paired plasma

Secondary hypothyroidism is associated with reduced concentration of free or total T4 in association with a serum TSH concentration below the normal range, analogous to the biochemical findings in secondary hypogonadism.

Antidiuretic Hormone Deficiency

The diagnosis of ADH deficiency first requires confirmation of polyuria, which is defined as the excretion of more than 3 L of urine per 24 hours (40 mL/kg/24 hours). The usual first-line investigation is an 8-hour fluid deprivation test.

The test should be performed under strict observation because severe fluid and electrolyte depletion can occur.

Plasma osmolality, urine volume, and osmolarity are measured hourly for 8 hours, after which a synthetic analogue of ADH (desmopressin) is given intramuscularly (IM). The urine osmolality then is remeasured. In a normal subject, ADH is secreted throughout the test, water is absorbed normally, and a subsequent elevation of urine osmolality occurs. In diabetes insipidus, the urine fails to concentrate (normal subjects achieve a urine osmolality at least twice the plasma osmolality) because of a lack of ADH; hence, plasma osmolality increases.

Urine concentrates adequately only after administration of desmopressin. In cases in which the results of a water deprivation test are inconclusive, ADH measurement is helpful. A definitive diagnosis of ADH deficiency can be established by infusing hypertonic saline for 2 hours to increase plasma osmolality to more than 300 mOsm/kg, with regular 20 to 30 minute blood sampling to estimate plasma osmolality and ADH. In nephrogenic diabetes insipidus, ADH values are above the normal reference range, whereas in cranial diabetes insipidus, values are at the lower end of or below the normal reference range.

MANAGEMENT

Treatment for hypopituitarism can be separated into

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MRI is the scanning technique of choice, as it offers higher resolution than CT scanning and is able to demonstrate microadenomas as small as 3 mm in diameter. MRI also has provided insights into the morphologic abnormalities that arise from developmental defects of the pituitary gland. CT is used in situations where MRI is contraindicated, such as when arterial clips or a pacemaker is present. CT has a valuable role in defining bone anatomy in preparation for surgery.

ACTH level will help distinguish between primary and secondary glucocorticoid deficiency: In primary cortisol deficiency (Addison’s disease), the ACTH level will be high, whereas in secondary glucocorticoid deficiency, the ACTH level will be low or inappropriately normal.

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Table 5: Endocrine Replacement Therapy for Hormone Deficiencies

Table 6: Treatment Guidelines for Growth Hormone (GH) Replacement in Adult GH Deficiency

Hormone Deficiency

Pretherapy

Growth hormone

ENDOCRINOLOGY

Gonadotropins (female)

Replacement Hormones and Typical Daily Dose Range (Oral, if Not Stated Otherwise) Please refer to Table 13-7 in the section Growth Hormone Deficiency.

Estrogen: Estradiol valerate: 1-2 mg, transdermal: 25-100 µg or conjugated equineestrogens: 0.6251.25 mg

Pituitary imaging Body composition IGF-1, BSL, lipids Starting dose

0.2 mg/day for men and 0.3 mg/day for women

Adjustments

Small monthly increment, 0.01-0.15 mg/day

Monitor

IGF-1 (dose titration) BSL, lipids Weight, body composition, quality-of-life measures

PLUS Progesterone (examples):

Side effects

Norethisterone, 0.7-1 mg, transdermal: 170-250 µg

Edema, arthralgia, myalgia, paresthesia

Dosage considerations

Avoid weight-based regimens.

or Levonorgestrel, 250 µg, transdermal: 7 µg

Women require more GH than men.

or Medroxyprogesterone acetate, 5 mg Gonadotropins (male)

Adequate replacement of other hormone deficiencies

Elderly require less GH than the young.

Testosterone:

Requirements are greater with oral than with transdermal estrogen therapy in women.

Intramuscular (as testosterone esters): 250 mg every 2-3 wk or Transdermal: 5-7.5 mg or Implant: 600-800 mg every 4-6 mo Thyroid-stimulating hormone

Thyroxine, 75-200 µg/day

Adrenocorticotropic hormone

Glucocorticoid (preferred schedule): Hydrocortisone, 10 mg morning, 5 mg noon, 5 mg evening, to 10 mg t.i.d.

Prolactin

Nil

Antidiuretic hormone

Desmopressin (DDAVP), 300-600 µg (in divided doses); intranasal, 1040 µg (in divided doses)

those therapies directed at the underlying disease process and endocrine replacement therapy Table 5.

HORMONE REPLACEMENT IN HYPOPITUITARISM

Endocrine replacement therapy should aim to mimic the normal hormonal milieu as far as possible, thus improving symptoms while avoiding overtreatment.

GROWTH HORMONE DEFICIENCY

GH secretion is greater in younger individuals than in older ones, and in women than in men. Therefore the starting dose of GH in young men and women is 0.2 and

Contraindications

Malignancy, intracranial hypertension, proliferative retinopathy

BSL, Blood sugar level; IGF-1, insulin-like growth factor-1.

0.3 mg/day, respectively, and in older individuals 0.1 mg/ day (Table 6). Dose determination based on body weight is not recommended because of large interindividual variation in absorption and in sensitivity to GH, as well as the lack of evidence that a larger replacement is required for heavier individuals in adults. GH is administered in the evening to mimic the greater secretion of GH at night.

Dose escalation should be gradual, individualized, and guided by clinical and biochemical response. Long-acting preparations of human GH are under evaluation for longterm safety and efficacy.

Serum IGF-1 is the most useful biochemical marker of GH response, the level of which should be maintained within an age-adjusted normal range. Clinical monitoring should include physical examination, including anthropometric measurements such as waist circumference and skin folds, and careful history, with particular attention to quality-of-life questions, assessment of body composition with dual x-ray absorptiometry and lipid measurements.

GONADOTROPIN DEFICIENCY

In both sexes, sex steroid replacement therapy is important for the maintenance of normal body composition, skeletal health, and sexual function, and it is the most appropriate

form of replacement therapy in patients not desirous of fertility.

Estrogen Replacement

Androgen Replacement

The choice of preparation of androgen replacement depends on local availability and patient preference. IM injection of testosterone can be associated with disturbing fluctuations in sexual function, energy level, and mood, mirroring the changes in testosterone concentrations.

Transdermal testosterone systems, which are an alternative, are available as patch systems (nonscrotal or scrotal) or as the recently introduced testosterone gel. Both formulations are able to maintain physiologic testosterone profiles in most patients, but skin irritation, the need for scrotal shaving, and drying time after gel application are some of the potential drawbacks of both transdermal systems. Testosterone undecanoate has become available as an intramuscular injection, which achieves stable serum testosterone levels over a 10- to 14-week period. This new preparation has essentially replaced testosterone implants as replacement therapy.

Androgen replacement therapy should always be monitored to ensure physiologic mean testosterone levels. Suboptimal replacement doses result in low trough levels, whereas supraphysiologic doses can promote secondary polycythemia and progression of prostate cancer; therefore, regular monitoring of hemoglobin and prostate-specific antigen is recommended.

Gonadotropin and Gonadotropin-Releasing Hormone Therapy

In the hypogonadotropic hypogonadal patient, fertility can be achieved with gonadotropin therapy in both men and women. The choice of therapy lies between gonadotropin replacement and GnRH. The former is the traditional therapeutic approach; initially, LH “activity” is provided by human chorionic gonadotropin (hCG) administered subcutaneously (SC) or IM at a dose of between 1000 and 2000 IU, two to three times weekly.

In women with hypogonadotropic hypogonadism, pregnancy rates up to 80% are reported after therapy with pulsatile GnRH or gonadotropins. Again, the choice of therapy lies between gonadotropin therapy and pulsatile GnRH, but obvious advantages accrue to GnRH therapy if the patient has enough residual gonadotroph function.

Pulsatile GnRH therapy is more likely than hMG to result in development and ovulation of a single follicle, thereby reducing the risks for ovarian hyperstimulation and multiple gestation. However, in practice, GnRH therapy may not be practicable, and in more than 50% of women with organic pituitary disease, residual gonadotroph function is not sufficient to support this method.

ADRENOCORTICOTROPIC HORMONE REPLACEMENT

The modern approach to glucocorticoid replacement is to mimic physiologic levels, ensuring sufficiency during times of acute illness, and to prevent over-replacement, which is associated with adverse metabolic outcomes.

Patients must be educated to increase the replacement dose twofold to threefold in case of an intercurrent illness or when undergoing surgery. Patients should wear an appropriate Medic-alert bracelet or necklace and should be issued an IM hydrocortisone pack and taught how to self-administer in the event of protracted vomiting.

Hydrocortisone directly replaces the missing hormone.

Cortisone acetate is metabolized to cortisol and has a slower onset of action with longer biological activity. Both prednisolone and dexamethasone have longer half-lives, thus allowing daily administration. Generally, the lowest replacement dose tolerated by the patient is preferred (10 to 20 mg/day). Indeed higher serum concentrations of total cholesterol, low-density lipoprotein, triglycerides, and waist circumference were observed with increasing doses of glucocorticoid levels in a study comparing the metabolic phenotypes of patients with growth hormone deficiency treated with different formulations and doses of glucocorticoids. Doses should be divided to suit individual needs.

THYROID-HORMONE STIMULATING HORMONE DEFICIENCY

Secondary hypothyroidism is treated with thyroxine (T4) replacement therapy, as is primary hypothyroidism.

The normal starting dose in a young patient without evidence of cardiac disease is 1.5 mcg/kg/day. Lower starting doses are used in the elderly and in patients with evidence of ischemic heart disease. In patients with suspected hypopituitarism, thyroxine therapy should

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In women, this can be provided by many standard hormone replacement therapy preparations. Progesterone must be given (cyclically or continuously) in all women with an intact uterus to prevent the possible effect of unopposed estrogen on the endometrium, that is, dysfunctional bleeding or endometrial cancer. The dose of estrogen should not be supraphysiologic (as in the oral contraceptive pill) unless a clear indication, such as strong patient preference, exists, or a patient with partial gonadotropin deficiency still has occasional menstrual cycles, along with a desire for contraception. Although estrogen can be delivered as a tablet, patch, gel, or implant, a nonoral route is recommended because of reduction of insulin-like growth factor (IGF)-1 and fat oxidation by oral estrogen. However, an international surveillance study on 315 hypopituitary women taking estrogen replacement demonstrated significant predominance of oral versus transdermal estrogen use (86% vs. 14%). Women on oral estrogen had a significantly greater waist/hip ratio after GH treatment, with lower IGF-1 levels at the end of the study period on twice the GH dose received by women on transdermal estrogen. Therefore a nonoral route is highly recommended.

Spermatogenesis is unlikely within the first 3 months of therapy. Treatment with hCG alone is continued for 6 months, with regular sperm counts to monitor progress.

If adequate spermatogenesis is not achieved, then FSH in the form of human menopausal gonadotropin (hMG) or a recombinant FSH is added. The dose of FSH is increased if adequate spermatogenesis is not achieved after 6 months of combination therapy. The alternative regimen in patients with idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome is pulsatile GnRH therapy. GnRH is administered SC via a catheter attached to a minipump. This regimen appears to offer few advantages over gonadotropin therapy in men but may cause less gynecomastia. Both regimens may take up to 2 years to achieve adequate spermatogenesis.

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be delayed until ACTH deficiency has been excluded or treated, because the risk for worsening the features of cortisol deficiency is present. Goal of replacement is to be to restore the serum-free T4 concentration to the normal range. Measurement of TSH is unhelpful in the monitoring of T4 replacement therapy in secondary hypothyroidism.

ENDOCRINOLOGY

ANTIDIURETIC HORMONE DEFICIENCY

Desmopressin is the drug of choice for the treatment of ADH deficiency. It is available in a number of preparations, including oral, intranasal, parenteral, and the recently available oral form. Dosages vary as much as 10-fold between individuals, with no apparent relation to age, sex, weight, or degree of polyuria. The drug should be started at low dose and increased gradually until urine output is controlled. Overdosage carries a risk for hyponatremia, and sodium levels should be checked after therapy is commenced or changed.

6.

7.

8.

9.

10.

11.

CONCLUSIONS

Hypopituitarism increases morbidity and mortality in affected patients. The extent to which GH deficiency contributes to such excess morbidity and mortality awaits confirmation from longer-term studies. Adequate and appropriate hormone replacement is mandatory in the treatment of hypopituitary patients. Based on global evidence of efficacy and safety, adults with GH deficiency should also have replacement with GH, a principle consistent with the tenet of hormone replacement for hormone deficiency in the practice of endocrinology.

12.

13.

14.

The modern management of hypopituitarism and GH deficiency should also focus on their prevention.

By restriction of surgery to experienced centers and replacement of conventional radiotherapy with stereotactic surgery, the incidence of long-term hypopituitarism will be significantly reduced. Furthermore, greater use of medical therapy for acromegaly with somatostatin analogues and a GH-receptor antagonist should mean fewer hypopituitary patients in the future.

15.

REFERENCES

19.

1.

2.

3.

4.

5.

J. Larry Jameson, Leslie J. De Groot. Endocrinology Adult and Pediatric, 6th ed. Philadelphia: WB Saunders 2010: 243260 Williams RH. Textbook of endocrinology, 13th ed.

Philadelphia: Elsevier, 2016: 232-299.

Kasper, Fauci et al. Harrison’s Principle of Internal Medicine, 19th ed. New york: Mc Graw Hill 2015: 2255-2259.

Rosen T, Bengtsson BA: Epidemiology of adult onset hypopituitarism in Goteborg, Sweden during 1956–1987.

Presented at the International Symposium on Growth Hormone and Growth Factors, Gothenburg, 1994, pp A3– A60 [Abstract] Nielsen EH, Lindholm J, Laurberg P: Excess mortality in women with pituitary disease: a meta-analysis. Clin Endocrinol (Oxf). 2007; 67:693-697.

16.

17.

18.

20.

21.

Nielsen EH, Lindholm J, Laurberg P, et al.: Nonfunctioning pituitary adenoma: incidence, causes of death and quality of life in relation to pituitary function.Pituitary 2007; 10:6773.

Karavitaki N, Wass JA:: Craniopharyngiomas. Endocrinol Metab Clin North Am 2008; 37:173-193.

Molitch ME, Russell EJ: The pituitary “incidentaloma,”. Ann Intern Med. 1990; 112:925-931 2187392 Arafah BM, Prunty D, Ybarra J, et al.: The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab 2000; 85:1789-1793.

Littley MD, Shalet SM, Beardwell CG, et al.: Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med 1989; 70:145-160.

Darzy KH, Aimaretti G, Wieringa G, et al.: The usefulness of the combined growth hormone (GH)-releasing hormone and arginine stimulation test in the diagnosis of radiationinduced GH deficiency is dependent on the post-irradiation time interval. J Clin Endocrinol Metab 2003; 88:95-102.

Deladoëy J, Flück C, Büyükgebiz A, et al. “Hot spot” in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1999; 84:16451650 10323394.

Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, et al. Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review. JAMA 2007; 298:1429-1438.

Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, et al. Hypopituitarism. Lancet 2007; 369:1461-1470 17467517.

Trainer PJ, Besser M: The Bart’s Endocrine Protocols. 1995 Churchchill Livingstone Karavitaki N, Wass JA: Craniopharyngiomas. Endocrinol Metab Clin North Am 2008; 37:173-193.

Christ ER, Carroll PV, Sonksen PH. The etiology of growth hormone deficiency in human adult. Bengtsson B-A Growth Hormone. 1999 Kluwer Academic Publishers Boston 97-108 De Boer H, Blok GJ, Voerman HJ, et al.: Serum lipid levels in growth hormone deficient men. Metabolism 1994; 43:199203.

Ho KK: GH Deficiency Consensus Workshop participants.

Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol 2007; 157:695-700.

Growth Hormone Research Society: Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998; 83:379381.

Hoffman DM, Ho KKY. Diagnosis of GH deficiency in adults. Juul A Jorgensen JOL Growth hormone in adults. 1996 Cambridge University Press Cambridge 168185.

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Vitamin D: In Health and Clinical Practice BK Mahavarkar, Anoosha Bhandarkar

INTRODUCTION

Kurt Huldschinsky, a century ago, concluded from his experiments that exposure to UV radiation was an “infallible remedy” for rickets in children. The factor whose deficiency was linked to the development of rickets, was later in 1919 found to be cholecalciferol. In the past few decades, painstaking work by researchers worldwide has convincingly demonstrated that vitamin D apart from its calciotropic actions also mediates extra-skeletal effects across a wide range of homeostatic functions.

B.

Non-calciotropic actions: VDRs are found fairly ubiquitously throughout the body in tissues viz., in the small intestine, colon, osteoblasts, activated T and B lymphocytes, pancreatic islet cells, and most organs in the body including brain, heart, skin, gonads, prostate, breast, and mononuclear cells.

The innate ability of the above tissues to convert 25HCC to calcitriol suggest an autocrine or paracrine role of calcitriol not related to calcium metabolism.

The three important modes of non-classical actions of vitamin D are:

a.

Regulation of hormone secretion- Vitamin D is shown to enhance insulin secretion, growth hormone and TSH release, physiological significance of some are yet to be established.

b.

Regulation of immune function- It modulates innate and adaptive immunity, enhances chemotactic and phagocytic responses of macrophages and transcription of antimicrobial proteins such as cathelicidin and defensin and downregulates proinflammatory cytokines. It regulates differentiation of CD4+T cells, and favors less development of selfreactive T-cells and autoimmunity.

VITAMIN D SYNTHESIS

Vitamin D3 (cholecalciferol) is made from 7-dehydrocholesterol in the epidermal layer of the skin under the influence of UV (B) radiation (290-315 nm).

It is also acquired from animal-based foods. Vitamin D2 (ergocalciferol) is derived from plant sources. Vitamin D is activated in two steps of hydroxylation reactions in liver and kidney to active hormone endogenously. The first hydroxylated compound, 25 hydroxy cholecalciferol (25-HCC) and the next 1,25 dihydroxy CC (1,25-HCC) are the well known metabolites of vitamin D. The renal 1α-hydroxylation is closely regulated, being enhanced by parathyroid hormone (PTH), hypocalcemia, and hypophosphatemia and inhibited by hyperphosphatemia, FGF-23 and 1,25-HCC itself. The biologically active form of vitamin D i.e. 1,25-HCC (aka calcitriol) performs many of its biologic functions by acting on high-affinity vitamin D receptor (VDR) located primarily in the nuclei of target cells, which further binds to sites in the DNA called vitamin D response elements (VDREs). Later, a variety of co-regulators attach to this complex resulting in either up- or down-regulation in the expression of vitamin D-responsive genes in a cell specific fashion.

ACTIONS OF VITAMIN D

A.

Classical calciotropic actions: Calcitriol facilitates intestinal calcium absorption and bone formation.

It also interacts with VDR in osteoblasts to stimulate osteoclastogenesis. The mature osteoclast removes calcium and phosphorus from the bone to maintain blood calcium and phosphorus levels. In the kidneys calcitriol together with PTH stimulates calcium reabsorption from the glomerular filtrate.

As serum calcium levels rise, PTH secretion drops and vice versa. Calcitriol suppresses parathyroid gene expression and parathyroid cell proliferation, providing important feedback loops that reinforce the direct action of increased serum calcium levels.

c. Regulation of cellular proliferation and differentiation- Vitamin D causes marked inhibition of cell proliferation, and allow differentiation of epithelial cells including keratinocytes which proves its effectiveness in therapy of psoariasis.

It is shown to slow or prevent tumorogenesis by promoting cellular differentiation, stimulating apoptosis, and reducing angiogenesis.

SOURCES OF VITAMIN D

More than 90% of the vitamin D requirement is met from casual exposure to bright sunlight (between 10 am-3 pm) just for 5 min/day. Sources of vitamin D are mentioned in Table 1.

FACTORS CAUSING LOW VITAMIN D LEVELS

1.

Lesser duration of exposure and odd timing (low ambient UVR level), ageing, chronic hospitalisation, high melanin content in the skin especially among African-americans, extensive clothing cover, decreased dietary intake, winter season, higher latitudes, use of sunscreen, low socio-economic status, exclusive breast feeding.

846

Table 1: Sources of Vitamin D Sources of Vitamin D 1. Natural

UV (B) radiation

Cod liver oil (excellent source)

Fish- Salmon, mackerel, sardine

Egg yolk (variable)

ENDOCRINOLOGY

2. Fortified foods

Milk, orange juice and other juice products

Some breads and cereals

Irradiated mushrooms

2.

Malabsorption syndromes and gastric bypass

3.

Adiposity - low amount of vitamin D presented to the liver for 25-hydroxylation

4.

Renal dysfunction, hepatic disease or some familial enzyme deficiency disorders

5.

Drugs like anticonvulsants, glucocorticoids, rifampicin, ketoconazole, and few antiretroviral drugs

DEFINING VITAMIN D STATUS

The most accurate method of evaluating a person’s vitamin D status is to measure the level of serum 25-HCC. Majority of the groups define vitamin D status as follows:

Table 2: Recommendations of IOM and Endocrine Society Clinical Practice Guidelines Age (yrs) IOM recommendations

0-0.5

RDA (IU/d) UL a (IU/d)

0.5-1

1-3

3-8

8-13

RDA (IU/d) ESCPG Recommendations UL a (IU/d)

1500

18-30

30-50

50-70

2500

3000

>70 800

ß 600 à

ß 400b à 1000

13-18

ß 4000 à

400-1000 c

ß 600-1000 à

ß 1500-2000 à

ß 2000 à

ß 4000 à

ß 10000 à

a – UL is upper limit which indicates the level above which there is risk of adverse events b – reflects adequate intake reference value than RDA, RDA has not been established for infants c – mother’s intake for infant requirement is 4000-6000 IU/d (if infant is not receiving 400 IU/d)

Table 3: Additional recommendations for special groups and deficiency correction RECOMMENDATIONS AS PER ENDOCRINE SOCIETY PRACTICE GUIDELINES a. Dietary requirements of vitamin d in special groups:

Pregnant and lactating women - at least 600 IU/d

Obese children and adults

All patients on anticonvulsant medications,

at least 2-3 times the recommended

glucocorticoids, antifungals such as ketoconazole,

vitamin D for their age group

and medications for AIDS

b. Daily dose for deficiency correction:

0-1yr - 2000 IU/d OR 50k IU once weekly of vitamin D2 or vitamin D3 for 6wks f/b maintenance Rx of 400-1000 IU/d

1-18yrs - 4000IU/d OR 50k IU once weekly for 6wks f/b maintenance Rx of 600-1000 IU/d

>18yrs - 6000 IU/d OR 50k IU once weekly for 8wks f/b maintenance Rx of 1500-2000IU/d

Special groups:

In obese patients, patients with malabsorption syndromes, and patients on medications

affecting vitamin D metabolism require 2-3 times the recommended doses (for both

initial and maintenance) for their age

c. Monitoring the response to therapy: i. In case of deficiency correction, monitoring blood levels of 25-HCC three months after beginning treatment is recommended so as to allow dose adjustments. ii. In patients with extrarenal production of 1,25-HCC, serial monitoring of serum 25-HCC and calcium levels is suggested during treatment with vitamin D to prevent hypercalcemia

847

Table 4: Vitamin D linked disorders and role of vitamin D Vitamin D linked disorders

Comments

Musculoskeletal disorders Rickets

Vitamin D (calcitriol, cholecalciferol ) used in therapy

osteomalacia osteoporosis

myopathy, risk of falls,

risk of fractures

Skin disorders Vitamin D analogs viz., calcipotriene, 1,24-HCC, and maxacalcitol approved

Vitamin D supplementation shown to suppress inflammatory responses, enhance antimicrobial peptide activity and ameliorate clinical signs of the disease

Atopic dermatitis

Endocrine disorders a. Parathyroid 2 hyperparathyroidism (due to severe vitamin D deficiency/ CKD) o

Vitamin D (calcitriol) and its analogs including calcifediol, paricalcitol, doxercalciferol, maxacalcitol and falecalcitriol approved for treatment

Hypoparathyroidism

Cholecalciferol or calcitriol approved for treatment

b. T2 DM

Experimental studies suggest that vitamin D may preserve glucose tolerance by enhancing insulin secretion and sensitivity

Cancer

1,25-HCC keeps cell growth in check and possibly prevents neoplasia. Positive association of low vitamin D status and increased risk of colorectal, breast, prostate and pancreatic cancer in observational studies

Autoimmune disorders a. T1 DM

4 case-control studies revealed a significant 29% risk reduction for type 1DM among vitamin D-supplemented infants compared with controls; No RCTs

b. SLE

A recent RCT concluded that vitamin D supplementation for 12 months showed significant improvement in levels of inflammatory and hemostatic markers, and disease activity

c. Crohn’s disease

Low vitamin D is inversely correlated to disease activity documented by clinical scores and surrogate markers of inflammation(CRP and fecal calprotectin), probably because of low cathelicidin and defensin, and dysregulated mucosal defense

d. Multiple Sclerosis

A RCT showed that vitamin D3 supplementation in optic neuritis and Clinically Isolated Syndrome (CIS) patients with low serum 25-HCC may prevent or delay the onset of a second clinical attack and the subsequent conversion to MS

Respiratory Conditions a. Tuberculosis

An experimental study said that serum low in 25-HCC could not up-regulate induction of cathelicidin leading to ineffective killing of intracellular M. tuberculosis. One RCT gave positive results with vitamin D supplementation on antimycobacterial responses in healthy adult tuberculosis contacts

b. Cystic Fibrosis (CF)

CF patients with vitamin D supplementation pre-emptive to pulmonary exacerbation returned to their baseline lung function much earlier with better clinical outcome than placebo group

Mental disorders Depression

Vitamin D is believed to directly up-regulate tyrosine hydroxylase, the rate limiting enzyme for brain monoamine synthesis and increase monoamine levels

Serum concentration of 25-HCC i.

< 20 ng/mL (50 nmol/L) - deficiency

ii.

20-30 ng/mL (50 to 75 nmol/L) - insufficiency

iii.

> 30ng/mL (75 nmol/L)- sufficiency

iv.

40-60 ng/mL is ideal and that up to 100 ng/mL is safe

v.

> 150ng/mL may cause toxicity (hypervitaminosis D)

CHAPTER 183

Psoariasis

848

[Note: Conversion from ng/mL to nmol/L, multiply by 2.496]

ENDOCRINOLOGY

DIETARY RECOMMENDATIONS

Dietary recommendations made by Institute of Medicine (IOM) and Endocrine Society Clinical Practice Guidelines (ESCPG) on vitamin D intake are mentioned in Table 2.

Additional recommendations made by Endocrine society for special groups and deficiency correction are given in Table 3. The ICMR, 2009 report gives no suggestions for age-specific vitamin D intake, but mainly emphasizes on adequate exposure to sunlight.

[Note: 1mcg (40 IU)/day of Vitamin D3 on a routine basis increases circulating 25-HCC by 1-4 nmol/L (0.4-1.6 ng/ Ml] Vitamin D linked disorders and the proposed therapeutic role of vitamin D are explained in Table 4.

2.

Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health: a review”. Altern Med Rev 2005; 10:94–111.

3.

Martineau AR, Wilkinson R, Wilkinson K, Newton S, Kampmann B, Hall B, Packe G, Davidson R, Eldridge S, Maunsell Z, et al. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med 2007; 176:208–13.

4.

Burkiewicz CJ1, Guadagnin FA, Skare TL, do Nascimento MM, Servin SC, de Souza GD. Vitamin D and skin repair: a prospective, double-blind and placebo controlled study in the healing of leg ulcers. Rev Col Bras Cir 2012; 39:401-7.

5.

Bergman P, Norlin A-C, Hansen S, Björkhem-Bergman L. Vitamin D supplementation to patients with frequent respiratory tract infections: a post hoc analysis of a randomized and placebo-controlled trial. BMC Research Notes 2015; 8:391. doi:10.1186/s13104-015-1378-3

6.

Ganmaa D et al. Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial. Am J Clin Nutr 2012;96:391-6. doi: 10.3945/ ajcn.112.034967. Epub 2012 Jul 3

CONCLUSION

Vitamin D deficiency is a common under-diagnosed condition that has recently been receiving increasing attention in the world. The US Endocrine Society and the IOM recommend screening only in populations who are at specific risk for vitamin D deficiency and patients of hypovitaminosis D. The observation that a multitude of genes may be directly or indirectly regulated by 1,25HCC in a cell-specific fashion has provided a rationale for the non-skeletal health benefits of vitamin D. However, there remains skepticism due to lack of randomized controlled trials to support these benefits. Vigilance in maintaining a normal vitamin D status, i.e., serum 25HCC concentration > 30ng/mL, should be a high priority for overall health and well-being. The effective strategy to prevent vitamin D deficiency as advocated by Expert committees is to obtain sensible exposure to sunlight by outdoor physical activity, ingest foods that contain vitamin D and take vitamin D supplements if necessary.

REFERENCES

1.

Hossein-nezhad A, Holick MF. Vitamin D for health: A global perspective. Mayo Clin Proc 2013; 88:720–755. doi: 10.1016/j.mayocp.2013.05.011

7. Lehouck A et al. High Doses of Vitamin D to Reduce Exacerbations in Chronic Obstructive Pulmonary Disease (COPD): A Randomized Trial, Ann Intern Med 2012; 156:105-14. doi: 10.7326/0003-4819-156-2-201201170-00004 8.

Von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial. Br J Nutr 2010; 103:549-552012

9.

Grossmann RE et al. Pilot study of vitamin D supplementation in adults with cystic fibrosis pulmonary exacerbation: A randomized, controlled trial. Dermatoendocrinol 2012; 4:1917. doi: 10.4161/derm.20332

10. Khoraminya N, Tehrani-Doost M, Jazayeri S, Hosseini A, Djazayery A. Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust NZ J Psychiatry 2013; 47:271-5. doi: 10.1177/0004867412465022. Epub 2012 Oct 23

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Subclinical Hypothyroidism

Case 1: 44y/F, perimenopausal patient has come with irregular menses, emotional lability, facial puffiness on getting up from sleep, weight gain of about 2-3 kg in last 12 months. She was found to have TSH of 7 µIU /ml with normal T3 and T4. There is no family history of thyroid dysfunction and no goiter on examination. No history of significant co morbidities in her. She has been advised to start thyroxin for all these symptoms.

She has ‘googled’ about thyroxin therapy and found that it can be bad for her bones and is seeking second opinion for the same.

Questions 1.

2.

Can these problems be attributed to hypothyroidism? Which symptoms would respond to Thyroxin therapy?

Adverse effects of Thyroxin replacement therapy?

Case 2: 32y/F, married since 2 years, trying to conceive since 1 year. She has regular monthly menses with normal bleeding pattern and amount. No co-morbidities in the patient. Husband’s semen analysis has been reported as normal. Further work up revealed a TSH of 7.9 µIU/ml and normal T4. There was a history of hypothyroidism in her mother for the last 20 years. She has a fairly large Goitre on examination. Her physician started her on daily dose of 50 mcg thyroxin. On follow up, her TSH reduced to 4 µIU /ml.

Questions 1.

Indications for starting treatment in Subclinical hypothyroidism?

2.

How to monitor the treatment?

APPROACH TO SUBCLINICAL HYPOTHYROIDISM

Definition

Subclinical hypothyroidism (SCH) is defined as a clinical scenario characterized by elevated TSH, with normal T4 and T3. Earlier it was also called as preclinical myxedema or early clinical hypothyroidism or compensated euthyroidism. These terms have been abandoned.

However, the upper limit of normal range for TSH is variable depending upon the lab as well as the assay.

Large studies of healthy human volunteers without any underlying thyroid disease or significant risk factors have suggested much lower levels of TSH as normal, compared to traditional values of 4 or 5 µIU/ml. Values of 2.5 µIU/ml (NACB, 2003), 3 µIU/ml (AACE) have been considered as the upper limit of normal range.

Gayatri Ghanekar, Manoj Chadha

Use of age adjusted reference ranges for TSH has also been suggested as these studies reveal increase in normal values of TSH with increasing age. Values of TSH greater than 5 µIU/ml are generally thought to be diagnostic of SCH. In women seeking fertility, TSH level above the normal upper limit of range, which is appropriate for the 1st trimester should be considered as SCH in the presence of normal thyroid hormone levels.

Epidemiology

Prevalence of SCH in general population ranges from 4-15%. Elderly age, women, white race and iodine deficiency are associated with increased prevalence.

Etiology

The causes of subclinical and overt hypothyroidism are similar. Some conditions unrelated to thyroid dysfunction can also give rise to similar biochemical findings.

Chronic autoimmune thyroiditis, inadequately treated overt hypothyroidism and destructive therapy for prior thyrotoxicosis are few common causes. All the causes have been enlisted below in Table 1.

Differential diagnosis

Apart from above mentioned causes, some clinical situations that are associated with similar biochemical picture need to be considered:

Natural history

SCH can either remain stable or progress to overt hypothyroidism (OH). Spontaneous recovery has been noted in a fair number of patients (upto 30% at end of 1 year of follow up).

High TSH (> 10 µIU/ml), anti TPO antibody positivity, high dose external neck radiation or radioactive iodine therapy are associated with progression to OH. Annual progression rates are about 3 to 10% and cumulative

Table 1: Causes of Hypothyroidism Chronic autoimmune thyroiditis Inadequately treated overt hypothyroidism Destructive therapy for prior thyrotoxicosis External neck irradiation Drugs: lithium, iodine containing drugs/ contrast agents Inactivating mutations in TSH receptor gene Pseudohypoparathyroidism type 1a

850

Table 2: Problems faced in treatment of Subclinical Hypothyroidism Thyroid related/ unrelated situations

Lab related issues

Following thyrotoxic phase in thyroiditis

Assay variability

TSH secreting pituitary adenoma (T3 and T4 high)

Heterophile antibodies

Resistance to Thyroid hormones (T3 and T4 may be normal or high)

Macro TSH: anti TSH autoantibodies (1.6% of SCH patients)

Pulsatile secretion, nocturnal surge of TSH

Rheumatoid factor interference

ENDOCRINOLOGY

Recovery from non thyroid illness (transient) Morbid obesity related (High leptin mediated) Metoclopramide, Domperidone Untreated adrenal insufficiency Central hypothyroidism: 25% associated with normal or slightly high, upto 5 µIU/ml progression rates over 10-20 years are 33 to 55%. SCH can remain stable in patients with thyroid surgeries for non thyrotoxic conditions, low dose neck radiation.

Spontaneous recovery has been seen in patients without any anti TPO antibodies, in TSH <10 mIU/L and in first 2 years of follow up.

Clinical presentation

No correlation has been observed between symptoms and TSH levels. Most patients get diagnosed based on biochemical findings and few patients complain about symptoms that are mild or non-specific like fatigue, weight gain, constipation, dry skin etc.

Consequences of SCH

Various studies have associated SCH with CVD: CHD, stroke, heart failure, hyperlipidemia, weight gain, fertility problems, neuropsychiatric symptoms, Alzheimer’s disease and increased mortality in general.

Randomized trials

Many available randomized trials have not selected patient population and replacement doses carefully. Few recent trials failed to demonstrate any significant benefit of Thyroxin therapy in these patients. Factors that improve with treatment are total cholesterol and LDL cholesterol concentration and few parameters of myocardial and endothelial function.

OBSERVATIONAL STUDIES

SCH and lipid profile 1.

2.

About 1700 people with TSH 5.1-10 µIU/ml associated with high mean total cholesterol concentration (223 mg/dl vs 216 mg/dl) compared to people with normal TSH. Thyroxin replacement associated with reduction in total cholesterol (about 9 to 15 mg/dl) and LDL (mean 11 mg/dl).

SCH and cardiovascular risk and mortality

Most studies show that TSH above 10 mU/L is associated with increased incidence of coronary artery disease, ischemic heart events, heart failure and stroke.

Men tend to have higher cardiovascular risk if TSH is >10mU/L. However, a contrasting study has shown that there was no increase in cardiovascular mortality or coronary artery disease and in fact, SCH was associated with reduced mortality in age group of 80-85 years!

SCH and neuropsychiatric symptoms

SCH has been associated with increased risk of depression, poor verbal memory and executive functioning defects (reversible with treatment), senile and multiinfarct dementia, increased risk of Alzheimer’s disease in men.

However, most studies did not show any improvement in neuropsychological symptoms.

SCH and reproductive dysfunction

In women, SCH is associated with ovulatory dysfunction and unexplained subfertility especially when associated with positive anti TPO antibody.

Increased chances of miscarriage are also seen in women with SCH and euthyroid women with positive anti TPO antibodies compared to normal.

Fertility improves and pregnancy outcomes are better on treatment of SCH. All associations recommend treatment of SCH in these situations.

Miscellaneous effects of SCH Modest weight gain

Increased risk of common bile duct stones Non alcoholic fatty liver disease Neuromuscular problems

Diagnosis of SCH

As discussed earlier, SCH is diagnosed by the presence of elevated TSH level with normal serum levels of thyroid hormones T3 and T4. In addition to these tests, anti TPO antibodies could be checked to determine the etiology of SCH. In the presence of nodular goiter, Ultrasound of thyroid could be done to look for any suspicious features.

Management of SCH

Treatment of all cases of SCH with thyroxin replacement therapy is a controversial issue.

Points in favour of treatment are reduction in chances of progression to OH, size of goiter, spontaneous abortions and pre term deliveries. Few studies have supported beneficial effects on lipid profile and cardiac dysfunction, better treatment outcomes in iron deficiency anemia, moderate effects on weight loss and neuropsychiatric symptoms.

Whom to treat •

Presence of goiter (likely to progress to OH, 50% goiters reduce in size to some degree)

•

Family history of thyroid disease

•

Those with rising titre of TSH

•

Anti TPO positivity (likely to progress to OH)

•

In females trying to conceive (when normal upper limit of TSH is 2.5mIU/l in first trimester) and those who are pregnant

•

When TSH is greater than 10 µIU/ml (high chances of progression to OH)

•

In patients with dyslipidemia (possible cardio protective effects on lipid profile)

•

In newborn term infants with TSH elevation >10 mIU/l beyond 2 weeks of life (critical period for neurodevelopment)

Whom not to treat •

Morbidly obese patients with modest elevation of TSH (related to high Leptin levels)

•

Very elderly patients with modest elevation of TSH (a normal age related variation in TSH level and it may be protective)

Treatment is with thyroxin. Starting dose of the same is generally slightly lower than full replacement dose

851

MONITORING

After starting the treatment or after changing the dose of thyroxin, TSH levels can be evaluated after 6 weeks and as the TSH goal is achieved and the dose stabilizes, checking once in 6 months is enough.

When no treatment is advised for SCH, repeat testing can be done after 3 months and if the levels are similar, further checking can be done annually.

In pregnant patients, monthly evaluation is advised in first trimester till TSH reaches goal level. Thereafter they are monitored every 4-6 weeks throughout the pregnancy.

In the post-partum period, thyroxin requirements return to pre pregnancy levels. About 6 weeks after delivery, due to restoration of immune function, which is suppressed throughout the pregnancy, there may be a resurgence of auto-immune thyroiditis. Thyroxin requirements may go up at this stage. Hence, monitoring TFTs is indicated even in post partum period till these variations settle down.

In elderly patients and patients with poor cardiac reserve, cautious dosing and monitoring is indicated as the risks of overtreatment in these populations may be serious.

TRIAL OF THYROXIN

In some situations, when clear benefits of treatment are not evident, trial of thyroxin can be given for a period of 3-6 months. Subsequently, if there is no benefit, thyroxin treatment should be stopped and TFTs may be monitored annually. Examples include patients with negative anti TPO antibodies or those with goiter and no decrease in size of the same in spite of treatment.

REFERENCES

1.

Werner and Ingbar’s The Thyroid: a fundamental and Clinical Text: Chapter 47; 10th Edition

2.

William’s Textbook of Endocrinology: Chapter 13; 13th Edition

3.

American Thyroid Society Clinical Practice Guidelines on Treatment of Hypothyroidism (2014)

4.

UpToDate; Subclinical hypothyroidism in Non pregnant adults. Section Ed David Cooper

CHAPTER 184

Points against treatment include lack of strong evidence for clinical benefits in these studies, additional cost, risk of overtreatment in elderly patients (iatrogenic thyrotoxicosis) in terms of cardiac arrhythmias and osteoporosis.

(1.6mcg/kg). Goal is to maintain TSH level in the lower half of normal range (≤2.5 µIU/ml). Subsequently, adjustments in dose by 12.5 to 25 mcg are every 6-8 weeks to keep the TSH in target range.

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185

Subclinical Hyper and Hypo Thyroidism - When to Treat

SUBCLINICAL HYPOTHYROIDISM

Subclinical hypothyroidism is defined as an increased serum TSH in the presence of a normal serum FT4 concentration. Increased refers to values above and normal to values within population-based reference ranges of these hormones. It is however not so simple to diagnose accurately subclinical hypothyroidism in day-to-day practice applying this biochemical definition.

Diagnosis of subclinical hypothyroidism is hampered by uncertainty about what constitutes appropriate reference intervals, and by biologic variation in especially TSH. The upper limit of the TSH reference interval was 4.12 mU/L in the National Health and Nutrition Eamination Survey III (NHANES III) for a large reference population that

Table 1: Abnormalities reported in some but not all studies on subclinical hypothyroidism Symptoms

• hypothyroid symptoms • impaired well-being and quality of life • impaired cognitive functions (working memory) • mood disturbances

Signs

• impaired left ventricle diastolic and systolic function • hypertension • increased systemic vasular resistance • increased central arterial stiffness • impaired endothelium function • increased carotid intima-media thickness • impaired muscle energy metabolism • impaired peripheral nerve conduction latency and amplitude • impaired stapedial reflex

Biochemistry • high serum total and LDL cholesterol • high HOMA index (insulin resistance) • high serum C-reactive protein • low factor VIIa • high serum lactate during exercise • low serum IGF-1, high serum leptin

Ankit Shrivastav

was free of thyroid disease and representative of the U.S. population, in which subjects were excluded who had thyroid antibodies or were taking thyroid medications or other medications affecting thyroid measurements.

It is highly relevant after the biochemical diagnosis to establish a etiological diagnosis to evaluate which condition is responsible for the elevated TSH. The list of possible causes is very long. The most common causes of subclinical hypothyroidism are chronic autoimmune thyroiditis (Hashimoto’s disease), previous 131I therapy or thyroidectomy, and inappropriate dosage of thyroxine or antithyroid drugs. Loss-of-function mutations in the gene encoding for the TSH receptor are relatively common in isolated hyperthyrotropinemia, especially in children and adolescents. Other causes of an elevated TSH are interference of heterophilic TSH antibodies in TSH immunoassys, nonthyroidal illness syndrome (recovery phase), impaired renal function, untreated adrenal insufficiency (Addison’s disease) and obesity.

The prevalence of subclinical hypothyroidism in the general population is rather high in the order of 4% to 8%; it is higher in iodine-replete areas than in iodinedeficient areas.The higher prevalence of subclinical hypothyroidism in females than in males and in older than in younger subjects is in agreement with the higher prevalence of thyroglobulin and thyroid peroxidase (microsomal) antibodies in women and in elderly people.

The natural history of subclinical hypothyroidism is reported in many studies, although it remains difficult to predict whether the increased TSH levels will return spontaneously to within the normal range, will remain stable, or will increase to higher values with development of overt hypothyroidism. In general it can be said that the higher the initial TSH, the higher the risk of progression; the presence of TPO antibodies potentiates the risk. Spontaneous normalization of increased TSH values in subclinical hypothyroidism is a well-known phenomenon, but the reported frequency of normalization differs markedly between studies from 4% up to 52%.

Progression to overt hypothyroidism ranges from 7.8% to 17.8% in various studies. Table 1 depicts some of the abnormalities reported in some studies.

TREATMENT

Many studies on the effect of levothyroxine treatment in subclinical hypothyroidism have yielded inconsistent results (Table 2). The Cochrane meta-analysis did not observe statistically significant improvement in

Table 2: Quality of Evidence on the Strength of Association and Risks/Benefits of Levothyroxine Treatment of Subclinical Hypothyroidism for Patients With a Serum TSH Level of 4.5 to 10.0 mlU/La Strength of association

Benefits of treatment

Progression to overt hypothyroidism

Good

Variableb

Adverse cardiac end points

Insufficientc

No evidence

Elevation in serum total cholesterol and LDL-C levels

Insufficientc

Insufficient

Cardiac dysfunction

Insufficientc

Insufficient

Systemic hypothyroid symptoms

No clear evidence

Insufficient

Psychiatric symptoms

No clear evidence

Insufficient

LDL-C = low-density lipoprotein cholesterol; TSH = thyroidstimulating hormone; bThyroid hormone therapy normalizes the serum TSH level at any TSH concentration. Overt hypothyroidism occurs earlier in untreated patients with a serum TSH level of >10 mlU/L than in those with a serum TSH level of 4.5 to 100 mlU/L; cAvailable data do not distinguish between serum TSH concentrations of 4.5 to 10 mlU/L and of more than 10 mlU/L. Adapted from JAMA? with permission of the American Medical Association. Copyright Š 2004, All rights reserved. a

symptoms, mood or quality of life; one study showed a statistically significant improvement in cognitive function.

A placebo-controlled randomized clinical trial in the UK demonstrated significant improvement in tiredness upon levothyroxine treatment The Cochrane meta-analysis evaluated many parameters of systolic and diastolic heart function. Significant improvement after L-T4 treatment was observed for some parameters, like isovolumic relaxation time, index of myocardial performance, cycle variation index and left ventricular ejection time; systemic vascular resistance was not improved. Some studies report a lower systolic and diastolic blood pressure upon L-T4 treatment of subclinical hypothyroidism. One study reports a 6% reduction in supine mean arterial pressure.

Recent studies also indicate regression of the increased carotid intima-media thickness upon L-T4 treatment.

With respect to serum lipids, an early non-systematic review concluded that normalization of serum TSH in subclinical hypothyroidism decreases serum cholesterol on average by 0.4 mmol/l.

A RCT demonstrated increased cardiopulmonary exercise performance after L-T4 therapy in comparison to no treatment. L-T4 treatment of subjects older than 70 yr with subclinical hypothyroidism did not document

Whether or not subclinical hypothyroidism should be treated was and still is hotly debated; there are strong defenders as well as strong opponents to levothyroxine treatment. A 2004 scientific review by a panel of experts concluded that data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few, and that the consequences of subclinical thyroid disease are minimal ; consequently, the panel recommended against routine treatment of subclinical hypothyroidism, albeit recognizing the possible need for treatment in selected individual cases. The 2007 Cochrane meta-analysis also could find no evidence supporting treatment. Subsequent meta-analyses of long-term follow-up population-based studies seem to indicate that subclinical hypothyroidism is indeed associated with a modest risk on cardiovascular morbidity and mortality (although this may be agedependent), but proof that levothyroxine treatment decreases the risk is lacking. This would require appropriately powered, randomized,placebo- controlled, double-blinded interventional trials with long follow-up.

The debate whether or not to treat, thus continues.Given the current state of affairs with a lack of controlled trials reporting on long-term outcome, the decision whether or not to treat has to be taken in the face of uncertainty.

This is not rare in medical practice, and the physician copes with such problems by an individualized approach taking into account best available circumvential evidence and clinical judgment.

It is recommended to confirm the existence of subclinical hypothyroidism in a second blood sample taken about 3-6 months later. This recommendation in current guidelines is given in view of the high chance of spontaneous normalization of the elevated TSH value.It might be useful to already order assay of TPO-Ab and serum lipids in the second sample, because it may be relevant for further management in case subclinical hypothyroidism turns out to be persisitent. If subclinical hypothyroidism is confirmed, a strong case can be made for levothyroxine treatment when TSH values are > 10 mU/L. The observation that subclinical hypothyroidism might have some survival value in the elderly age group has led both guidelines to the recommendation not to treat elderly individuals with TSH values of 4-10 mU/L. In younger subjects with mild to moderate subclinical hypothyroidism (TSH values between 4 and 10 mU/L) one may opt to institute levothyroxine treatment in the presence of symptoms (in

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CHAPTER 185

Clinical condition

any benefit in terms of functional mobility. A non-RCT shows normalization of reduced glomerular filtration rate and increased serum Cystatin-C levels upon L-T4 treatment of subclinical hypothyroidism. A RCT in iron-deficient subjects with subclinical hypothyroidism demonstrated greater increase in hemoglobin levels upon treatment with L-T4 plus iron than in treatment with iron alone. L-T4 treatment of subclinical hypothyroidism in pregnant women improves maternal and fetal outcomes of pregnancy, and is recommended. A RCT in infertile women reports improved outcomes of in vitro fertilization upon L-T4 treatment as compared to placebo treatment.

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view of the chance that symptoms will improve), TPO-Ab (especially in case TPO-Ab concentration is high with the risk of imminent progression to overt hypothyroidism, or cardiovascular risk factors (in the hope based on circumstantial evidence obtained from population-based association studies and some observational intervention studies to diminish the risk of developing cardiovascular events). If these three conditions are absent, most will agree it is better not to treat. In case no treatment is given, follow-up with regular repeat TSH measurements is indicated. However there is certainly a role for clinical judgement in thes patients. Many practitioners will elect to try replacement therapy in patients with SCH who are symptomatic, especizally in patients under age 70, with careful attention to maintaining TSH in the normal range.

SUBCLINCAL HYPERTHYROIDISM

The prevalence of SH in an adult population depends on age, sex, and iodine intake. In a representative sample of U.S. subjects without known thyroid disease, 0.7% had suppressed TSH levels (< 0.1 mU/L), and 1.8% had low TSH levels (< 0.4 mU/L). Similar rates have been reported in studies from Europe, with higher levels in women and older subjects. The differential diagnosis of an isolated low or suppressed TSH level includes exogenous thyroid hormone use, nonthyroidal illness, drug effects, and pituitary/hypothalamic disease, all of which need to be ruled out before the diagnosis of SH can be established in a patient with an isolated low or suppressed TSH level. In addition, mean serum TSH levels are lower in black non-Hispanic Americans, some of whom may have slightly low TSH levels without thyroid disease. Finally, some otherwise healthy older persons may have low serum TSH levels, low normal serum levels of free T4 and total T3, and no evidence of thyroid or pituitary disease, suggesting an altered set point of the pituitary-thyroid axis.

The natural history of SH is variable, with annualized rates of 0.5 – 7% progression to overt hyperthyroidism and 5 – 12% reversion to normal TSH levels. In one study, 51.2% of patients had spontaneously developed a normal TSH when first checked at some time within 5 years (mean time to repeat TSH 13 months). Progression from SH to overt hyperthyroidism appears more likely if the TSH is suppressed (< 0.01 mU/L), rather than low but detectable (0.01 – 0.4 mU/L). Patients with GD rather than a TMNG as the cause of SH may be more likely to spontaneously remit. In patients at high risk of complications from SH, TSH and free T4 should be repeated within 2-6 weeks.

For all other patients, it is important to document that SH is a persistent problem by repeating the serum TSH at 3-6 months, prior to initiating therapy. In clinical series, TMNG is the most common cause of SH, especially in older persons.

The second most common cause of SH is GD, which is more prevalent in younger persons, and is also common in patients who previously received ATD therapy.

Other unusual causes include solitary autonomously functioning nodules, and various forms of thyroiditis, the

latter of which would be more strictly termed ‘‘subclinical thyrotoxicosis.

Since SH is a mild form of hyperthyroidism, it is not surprising that deleterious effects seen in overt hyperthyroidism might also occur in SH. There have been a large number of recent studies elucidating these effects: 1. Overall mortality. A number of longitudinal studies have examined correlations between SH and overall mortality, with variable results. Some studies report increased overall mortality rates in SH subjects , especially older subjects, while others indicate no relation. Limitations of some of these studies include sample sizes, age ranges, length of follow-up, and diagnosis of SH by a single TSH measurement. A recent meta-analysis of individuallevel data from 52,674 participants, pooled from 10 cohorts and providing greater power, concluded that SH confers a 24% increased risk of overall mortality 2.

Cardiovascular disease. A recent large study of 26,707 people followed for 12 years reported increased cardiovascular mortality with SH. Some other, smaller studies have reached similar conclusions , although other smaller studies have failed to find a correlation. , the highest relative risk for atrial fibrillation occurred in younger subjects, possibly because other causes predominate with age, and in subjects with lower TSH levelsyroid A further population-based study found that SH increased the risk for stroke in subjects over age 50 years with a hazard ratio of 3.39 , although a recent meta-analysis of stroke risk in SH found insufficient number of events to draw definitive conclusions.

Complementing these epidemiologic studies, investigations of smaller numbers of subjects with SH have revealed increased heart rate at rest and during exercise, decreased heart rate variability, and increased frequency of atrial and ventricular premature beats, which improve with treatment of SH. Taken together, these data provide a strong argument for the treatment of SH in older subjects to avoid dysrhythmias and possible subsequent stroke. Whether younger patients should be treated for the same preventive indications is less clear. The most recent data provide evidence that relative risks of cardiovascular mortality and atrial fibrillation are elevated in younger, as well as older, patients with SH. However, the absolute risks of these events are very low in younger patients, so the risk/ benefit ratio of treating younger SH patients is not clear. Clinical judgement should be used in these cases, and treatment decisions individualized.

3. Osteoporosis and fractures. Most studies of endogenous SH show decreased bone mineral density in post-menopausal women, but not in men or pre-menopausal women. However, it is not clear that this translates to increased fracture risk..

The most recent and by far the largest individual

Table 3: When to treat SH? Factor

TSH (0.1-0.4 mU/L)a

Yes

Consider treating

Heart disease

Yes

Consider treating

Osteoporosis

Yes

Consider treating

Menopausal, not on estrogens Or bisphosphonates

Yes

Consider treating

Hyperthyroid symptoms

Yes

Consider treating

Age < 65, asymptomatic

Consider treating

Observe

Age > 65 Age <65 with comorbidities

Where 0.4 mUL is the lower limit of the normal range.

a

study to date (231,355 subjects) reported a hazard rate for all major osteoporotic fractures combined (hip, humerus, forearm, spine) of 1.13 (confidence intervals 1.014-1.26). Risk increased with duration of SH, such that after a median follow-up of 7.5 years, 13.5% of subjects with a low TSH level had experienced at least one major osteoporotic fracture, compared to 6.9% of subjects with a normal TSH level. Other studies have not found increased fracture rates in SH subjects.

4.

Mood and cognition. A large body of literature has investigated possible correlations between SH and cognitive decline. Approximately equal numbers of studies report significant associations between SH and measures of cognitive decline and the development of dementia, vs. no associations.

Therefore, at this time, no conclusions regarding this issue can be reached. There appears to be no correlation between SH and depression.

5. Physical functioning.

Four studies have investigated whether SH is associated with selfreported functional capacity or objective measures of physical functioning. Three could find no correlation, while the fourth found a correlation between SH and lower physical performance in men only.

When to treat SH (Table 3)

When TSH is persistently < 0.1 mU/L, treatment of SH should be considered in asymptomatic individuals < 65 years of age. Treatment of SH is controversial, since few intervention studies to show benefit have been performed, especially for clinically important endpoints such as cardiovascular events, atrial fibrillation, and fractures. Additionally, none of these studies included a control arm. Thus the evidence rests only with small uncontrolled studies that have shown improvements in cardiac structure and function, heart rate and the frequency of premature atrial and ventricular beats, bone mineral density, and muscle strength. In 2004, a panel of experts determined that the evidence for benefit was

How to treat SH

If SH is to be treated, the treatment should be based on the etiology of the thyroid dysfunction and follow the same principles as outlined for the treatment of overt hyperthyroidism. The treatment of SH is similar to the treatment of overt hyperthyroidism. RAI is appropriate for most patients, especially in older patients when toxic multi nodular goiter is a frequent cause of SH. There are no data to inform whether elderly patients with SH would benefit from pretreatment with Anti thyroid drugs to normalize thyroid function before Radio active iodine therapy. Given the low risk of exacerbation , the risks of ATD therapy may outweigh any potential small benefit.

A course of ATD therapy is a reasonable alternative to RAI in patients with GD and SH, especially in younger patients, since remission rates are highest in persons with mild disease Some patients with SH due to GD may remit spontaneously without therapy, so that continued observation without therapy is reasonable for younger patients with SH due to GD. A small subset of elderly patients with persistently low TSH and no evidence of true thyroid dysfunction can be followed without intervention, especially when the serum free T4 and total T3 levels are in the lower half of the normal range. Treatment with beta-adrenergic blockade may be sufficient to control the cardiovascularrelated morbidity from SH, especially that of atrial fibrillation. Some patients with SH due to mild GD may remit spontaneously and may be followed without therapy with frequent (every 3-6 months) monitoring of thyroid function. In select patients with SH due to Toxic multi nodular goiter who have compressive symptoms, or in whom there is concern for malignancy, surgery is also an option.

The goal of therapy for SH is to render the patient euthyroid with a normal TSH. Since the rationale for therapy of SH is to a large degree preventive, there are few end points that can be used to document that therapy has been successful. Based on the original indication for treatment, it is reasonable to follow hyperthyroid symptoms or bone density.otherwise, the major end point is a TSH level within the age-adjusted reference range.

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CHAPTER 185

TSH (<0.1 mU/L)

sufficient to warrant therapy of SH in older individuals whose serum TSH level was < 65 years of age. However, younger subjects should be monitored at regular 6-12 month intervals, and treatment should be considered if the TSH persistently decreases to < 0.1 mU/L. In patients with symptoms of hyperthyroidism, a trial of betaadrenergic blockers may be useful to determine whether symptomatic therapy might suffice. A TSH level between 0.1 and 0.4 mU/L on repeated measurement over a 3â&#x20AC;&#x201C; 6-month period is considered persistent, effectively ruling out transient thyroiditis as a cause. The thyroid disorder underlying SH with TSH persistently within this range should be diagnosed before considering treatment to avoid treating patients with transient, functional disorders related to acute illness, drugs, and other causes of low TSH.

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Hypothyroidism.....Beyond Thyroid !

Thyroxine T4 and tri-iodothyronine T3 are the hormones secreted by the thyroid gland. Secretion of these hormones is regulated by thyroid stimulating hormone (TSH) by the pituitary which in turn is regulated by the hypothalamic thyrotropin releasing hormone (TRH). TSH is the ‘set point’ in this hypothalamic-pituitary-thyroid feed back axis.

Both these hormones act on their specific receptors.

During development, these hormones play a crucial role in cell differentiation. In adults, these hormones are critical for the body metabolism maintaining thermogenic and metabolic homeostasis.

Many structural and functional abnormalities can impair the production of these thyroid hormones with its systemic manifestations. It may be due to primary failure of the thyroid gland with low T4 and elevated TSH levels termed as primary hypothyroidism which accounts for 99 % of cases OR it may be due to insufficient stimulation of the normal thyroid gland as a result of the hypothalamic or pituitary disease or a defect in the TSH molecule itself.

This is termed as central hypothyroidism which accounts for less than 1 % of cases.

Till about a decade ago the medicine and endocrinology books enumerated causes of hypothyroidism as---1.

Idiopthic Atrophic hypothyroidism

2.

Ablative : surgical or radioablation

3.

Impairment of biosynthesis of thyroid hormones with compensatory hyperplasia of the thyroid gland –Goitrous hypothyroidism

4.

Transient hypothyroidism :post-partum thyroiditis

5.

Hashimoto’s autoimmune thyroiditis

6.

Central hypothyroidism

7.

Resistance to thyroid hormone --RTH

Alaka Deshpande organ systems and functions which need to be evaluated before initiating thyroid replacement therapy.

Severe hypothyroidism presents with characteristic features of myxedema facies, slow mentation / response, thick hoarse voice, dry skin, constipation and menorrhagia.

However in early stages it may be detected by functional evaluation of a goitre or incidentally in an asymptomatic patient with protean manifestations like hair fall, weight gain etc.

Many studies have documented association between all types of menstrual irregularities and hypothyroidism.

Bad obstetric history, repeated miscarriages, primary and secondary infertility may also be associated with hypothyroidism. Serum TSH estimation as a part of preoperative evaluation and in early pregnancy may detect early asymptomatic cases.

In addition,large number of people voluntarily avail the investigation packages offered by the chain of laboratories.

As a result, many hypothyroid cases are detected in early stages. Treating the elevated TSH report without proper evaluation of the patient has been observed as an increasing trend.

Therefore a study of newly detected hypothyroid cases refered to us was undertaken. The study comprises of 100 consecutive cases in the age group of 15 yrs to 63 yrs. A detailed history including history of galactorrhea along with clinical examination was done.

Each hypothyroid case was investigated for.......

CBC Serum FT3, FT4,TSH, Anti-microsomal (TPO) antibody S.Prolactin,S. B 12,Parietal cell antibody ECG, X-ray chest

OBSERVATIONS

In last decade the scenario has changed due to widespread availability of sensitive diagnostic techniques and better understanding of the pathogenesis. Although Hashimoto described ‘struma lymphomatosa’ in 1912; it is only in last 10 to 15 years Auto-Immune Thyroid Disease AITD is universally accepted as the commonest cause of primary hypothyroidism in countries with iodine sufficiency and iodine deficiency as a cause in iodine deficient countries.

There were 89 women and 11 men.Mean age of the group was 44 yrs,26 cases were less than 25 yrs of age.

Being an autoimmune disorder one has to think beyond thyroid for co-existing autoimmune diseases in the patient or his family. Thyroid hormones affect all the

Infertility, scanty menses

09

Schizophrenia /Depression

03

Vague symptoms(hair fall)

25

Reasons for TSH estimation in this series Asymptomatic Goitre

33

Weight gain

11

Pregnancy 09

Voluntary check up

05

Symptomatic hypothy

05

Only 6 women gave history of Galactorrhea. Examination revealed it in 29 additional cases. It can be overlooked unless actively elicited. One was a lactating mother.

Remaining 53 women and 11 men had no evidence of nipple discharge.

S. TSH levels----N range 0.4 to 4.5, TSH > 10 was diagnosed as overt hypothyroidism.

Anti-microsomal (TPO) antibodies—N range 5-34 IU/ml

Proximal weakness

Difficulty in upsquatting was complained by one patient. Examination revealed 16 cases had difficulty in upsquatting suggesting proximal muscle weakness in hypothyroidism. Only 2% patients present with proximal myopathy but it can be found in about 20% cases.

Vit.D levels were also low in these patients. Vit. D plays an important role in balancing TH1 and TH2 cells. Vit. D deficiency has been associated with numerous AIDS.

Antibody levels

Cases (n)

< 34

18

35—100

04

101—300

16

Sen in 39 cases on chest X-ray. The LVEF estimated in these patients was normal on 2-D echocardiography. Six of these cases had minimal pericardial effusion.

301—600

21

Vitilligo

> 601

41

18/100 cases did not have antibodies. 82 cases had raised levels of AMA. Five symptomatic cases had AMA more than 1000 IU however no correlation was found between antiboby levels and severity of the disease. Once detected these antibodies persist.

HYPERPROLACTENEMIA

S. Prolactin level---N 4.79—23.3 in females, males — 0.04 — 15.2 ng/ml.

70 cases including 11 males had S PRL within normal limits.

18 cases had PRL 24 to 60 ng/ml.

Various reports show 27 % of hypothyroid patients have hyperprolactinemia. The cause of hyperprolactinemia in primary hypothyroidism is uncertain but it is well documented. It may result from the enhanced sensitivity of the lactotrophs to thyrotropin releasing hormone (TRH).

Thyroxine replacement therapy controls the galactorrhea and normalizes S. PRL levels if PRL is less than 60 ng/ml.

12 cases had PRL varying from 61 to 300 ng/ml. Of these 12 cases with very high PRL, 8 patients revealed microprolactinoma on MR imaging without any compression.These cases in addition to thyroxine replacement need therapy of hyperprolactenemia with bromocriptin analogs. My patients are treated with thyroxine + cabergolin which normalised PRL levels with disappearance of galactorrhea. Follow up MRI did not show prolactinoma.

Cerebellar Ataxia

Two patients, a 45 yrs woman and 43 yrs old man were found to have cerebellar ataxia. Both of them complained of imbalance, TSH was more than 100, TPO >1000 IU/ml,

857

Cardiomegaly

4 cases had vitilligo which being an autoimmune disorder by itself can coexist in AITD.

Rheumatoid arthritis

It was detected in 4 cases.

S.B 12 levels

Pernicious anemia being an autoimmune disease may be seen in AITD. We measured B 12 conc.in serum of our hypothyroid cases.

S.B12---N 211—946 pg/ml

Parietal Cell Antibody Positive

< 211 pg

54 cases

33 cases

212—311 pg

24 cases

17 cases

312----411 pg

03

00 cases

>411 pg

19

03 cases

54 /100 of our Hypothyroid patients were deficient in Vit B 12. Hematology profile of these cases did not show anemia,macrocytosis.Hematological effects of vit B 12 deficiency are seen at lower levels of B 12 viz.<100 pg /ml.

Dietary history revealed 16 cases were vegeterians. All the cases were subjected for parietal cell antibody test. 53 out of 100 cases showed antibodies against parietal cells necessitating parenteral B12 therapy.A linear relationship between AMA and Parietal cell antibody (PCA) could not be seen however higher the level of AMA, greater were the chances of detecting PCA. One patient with B12>411pg had PCA,on inquiry he revealed being given Inj. B12 by his family physician just before he was refered for AITD. 12 cases deficient in B12 (<211pg)did not have parietal cell antibodies.Two of these cases had TPO around 600 IU/ml.

These cases may have nutritional deficiency.

Recent studies show co-existence of various autoimmune

CHAPTER 186

In this series S.TSH ranged from 17 microunits/ml to more than 500 microunits /ml. All the 5 symptomatic cases had TSH levels were more than 400 microunits/ml.

S.B12 was low but they did not show sensory ataxia. It was cerebellar ataxia. Medical literature documents that on autopsy the cerebellum shows neural myxedematous infiltrates of glycogen and mucinous material.The manifestations are milder in adult hypothyroidism and can be controlled with control of hypothyroidism.

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disorders (AID) in AITD. Relative risk of other AIDs is significantly increased more than 10 fold for pernicious anemia, SLE, Addisonâ&#x20AC;&#x2122;s disease, celiac disease, vitiligo, Rheumatoid arthritis and Type 1 diabetes.

Although the precise pathogenetic mechanisms are unknown, AITD is believed to reflect a multifactorial mode of inheritance between the product of multiple genes conferring susceptibility. Significant clustering of AID within families of AITD cases is reported with 4050 % of patients reporting another family members with thyroid disorder.

Autoimmunity in the thyroid gland appear to be inherited defect in immune surveillance leading to an abnormal regulation of immune responsiveness or alteration of presenting Ag in thyroid. Presence of elevated antithyroid antibody titres are diagnostic of AITD. Thyroperoxidase TPO is a main thyroidal microsomal antigen, the other one being thyroglobulin. Presence of TPO (AMA) Abs in subclinical hypothyroidism predicts progression to overt hypothyroidism at 4.3 % per year v/s 2.6 % per year without TPO antibodies.

B12 deficiency is seen in 54 % of our cases. Khubchandani et al reported it in 64 % cases of hypothyroidism.

Our study correlates B12 Deficiency with parietal cell antibodies which in turn are correlated with high levels of AMA Abs. Though haematological manifestations of B12

deficiency appear at a level of B12 <100pg/ml, presence of parietal cell antibodies indicate that these cases will progress to develop pernicious anemia which is reported in 12 % of AITDs as a coexisting AID. The early detection and parenteral correction of B12 deficiency will prevent pernicious anemia in them. Literature reports incidence of rheumatoid arthritis in 4.8 % of cases. The incidence of other AIDs is variable.

Screening for other AIDs might be indicated if subjects of AITDs present with new or non-specific symptoms.

A growing tendency is observed in the community to treat only the biochemical report of thyroid function without evaluating the patient.

Primary hypothyroidism is beyond thyroid which necessitates clinical examination, appropriate investigations and corrective therapy in addition to thyroxin replacement therapy with regular monitoring.

It is desirable that every hypothyroid case should undergo: S. AMA, ATg antibody test S. Prolactin, S. Vit.D3 S.B12, If low then parietal cell antibody test ECG, X-ray chest.

CBC.

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Obesity- Tackling the Epidemic with an Individual-Centric Approach Anupam Prakash

INTRODUCTION

The 2016 Global Nutrition Report states that the rates of overweight/obese people are rising in every region of the world, and in nearly every country. The global adult obesity prevalence is 13% as against 4.9% in India, and for overweight, prevalence is 39% global and 22% for India, virtually indicating that one in four Indians has a weight problem of abundance. The World Health Organization (WHO) has declared obesity as the largest global chronic health problem in adults which is increasingly turning into a more serious problem than malnutrition. Obesity is a gateway to ill health, and it has become one of the leading causes of disability and death, affecting not only adults but also children and adolescents worldwide. In 2014, more than 1.9 billion adults (18 years and older) were overweight. Of these over 600 million were obese.

42 million children under the age of 5 were overweight or obese in 2013.1 Obesity is defined as a disease process characterised by excessive body fat accumulation with multiple organspecific consequences.2 There are two ingredients integral to this definition- (i) excess body fat, and (ii) multiple organ-specific consequences.

MEASURES OF OBESITY

Body fat content can be measured by several methods,3 these are indicated in Table 1. The anthropometric measures are easy to perform, can be used in the field, but none of them is a true reflection of the content of obesity. Body mass index (BMI) is one of the commonest indices used to determine excess body fat. It is easy to measure using the formula- BMI = (weight in kg)/(height in metres)2, and the criteria applied are universally accepted (Table 2). For the South Asians, the cut-off for abnormally elevated BMI is taken as ≥ 23. However, body mass index can be fallacious specially if the weight of an

Table 1: Methods to measure fat 1. Density-based methods Hydrodensitometry (underwater weighing), Air Displacement plethysmography (ADP) 2. Scanning methods

CT, MRI, DEXA

3. Bioelectrical impedance analysis 4. Anthropometric methods

Skinfold measurements, Waist circumference, Waist-hip ratio

individual is high because of increased muscle mass or oedema. BMI also does not truly reflect visceral adiposity.

Similarly, another commonly used and advocated index is the waist circumference which is a better reflector of central or abdominal obesity. However, it cannot truly assess generalised obesity and can be fallacious in cases of liver disease or ascites. Waist circumference can also not distinguish between visceral adiposity and parietal (subcutaneous fat) adiposity. Waist circumference however can be a valuable adjunct to BMI, and can indicate visceral adiposity even in persons who have normal BMI. A waist circumference ≥ 80cm (females) and ≥ 90 cm (males) is considered to be abnormal, and indicative of abdominal adiposity. Indians have a smaller body size, have excess body fat and greater truncal and abdominal obesity, and have lower average waist circumference.

Therefore, the cut-off for obesity for Indians is BMI ≥ 23, since even at lower BMIs, Indians (South Asians) carry excess morbidity risks than their western counterparts.

Waist to hip circumference is also employed in various clinical settings, however, it requires two measurements and hip circumference measurement can be an awkward thing to perform, be in a population setting or in clinics.

Skin fold thickness measurements are also used in clinical practice, however it requires a trained person for measurement and can have greater inter-observer variability. Though it provides a good measure of the subcutaneous adipose tissue, the visceral adipose tissue is not directly measured. Apart from this, the skin fold callipers is costlier than the non-stretchable tape, weighing machine or the height scale, which are used to measure other anthropometric variables.

Density based methods are very costly, and seldom used

Table 2: Obesity classification according to BMI (WHO 1997) BMI

Classification

Co-morbidity Risk

< 18.5

Underweight

Low, but other problems

18.5-24.9

Healthy weight

Average

25-29.9

Pre-obese state (Overweight)

Increased

30-34.9

Obesity grade I

Moderate

35-39.9

Obesity grade II

Severe

≥ 40

Obesity grade III

Very severe

*For South Asians including Indians, the cut-off for overweight is ≥ 23, and or obesity should be taken as ≥ 27.5

860

Table 3: Health consequences attributed to obesity • Bronchial Asthma • Gastro-esophageal reflux disease (GERD) • Pancreatitis • Osteoarthritis • Sleep disturbance, sleep-disordered breathing, and obstructive sleep apnoea (OSA)

ENDOCRINOLOGY

• Cancers of the - Breast - Ovaries - Endometrium - Gall bladder & Pancreas - Prostate - Colon & Esophagus - Renal cells - Leukemia • Coronary heart disease (CHD) & cerebrovascular disease (CVD) - Dyslipidemia - Hypertension - Venous thromboembolism in combined oral contraceptive users - Stroke - Pulmonary thromboembolism (PTE) - Atrial Fibrillation • Dementia • Depression • Diabetes, Metabolic Syndrome (Nonalcoholic fatty liver disease-NAFLD, polycystic ovarian syndromePCOS) • Reduced fertility & reproduction in both sexes • Pregnancy & birth complications even in research settings. Imaging modalities are often used, and specially have been employed to assess regional fat distributions, as in visceral adiposity or subcutaneous adipose tissue deposits. Bioimpedance analysis which uses the delivery of an electric current is often used in research settings and can be considered to be a good indicator of the body fat tissue, minimising the handicaps of anthropometry and the huge costs of density-based methods or the radiation side-effects of scanning methods.

HEALTH CONSEQUENCES OF EXCESSIVE BODY FAT

Obesity translates in to presence of excess body fat, assessment of which has already been outlined. The health consequences of the presence of excess body fat, is the second component in the definition of obesity.

Table 3 outlines the several morbidities that can be associated with the presence of excess fat. It is clear from a glimpse of Table 3, that obesity contributes to or worsens

Table 4: Primary Prevention of Excess weight gain (Overweight and obesity) Reduce • Energy-dense foods in diet • Consumption of ‘fast foods’ • Alcohol intake • Reduce sedentary behaviour including watching television/working or playing on computers /Mobile watching Encourage • Physical activity and outdoor sport activities allergic airway disease, cancers, degenerative diseases, inflammatory diseases, heart and cerebrovascular diseases, diabetes, fertility issues, and also sleep disorders and psychiatric morbidities. Therefore, the consequences can be troublesome and disastrous, and can result in even increased mortality. Hence, the need to control excess fat and maintain body weight.

NON-PHARMACOLOGIC MANAGEMENT OF OBESITY

The first part of management of obesity is spreading awareness about the ill-effects of obesity and preventing weight gain. Table 4 outlines the modalities for prevention of overweight and obesity.

However, once obesity or overweight has set in, the goals of management are different (Table 5).4 One has to realise that losing weight may not be an easy thing to do for many persons. At other times, some patients may be able to lose weight rapidly, but then they are unable to sustain it, and the lost weight comes back, and at times the weight regained is much more than what was lost. To restrict diet and to curb food intake that satisfies the taste buds, is no mean task. Therefore, management of obesity is a tricky situation. It is important to realise that the foremost thing is to aim at abolishing further weight gain. Once weight gain halts, then it is important to concentrate on gradual weight loss. Then, once the patient starts losing weight, then it is important to ensure that there is no weight regain. The last but not the least important goal in the management of overweight and obesity is that the health consequences of obesity should be curtailed, irrespective of the fact whether weight loss has been achieved or not. Reducing morbidities, or controlling morbidities and reducing risk of diseases will result in a better quality of life and also prolong productive life.

Measures adopted to achieve these goals (Table 5) include lifestyle modifications which improve exercise capacity and instil in the patient a new confidence, thus improving the physical and psychological state of the patient’s mind and thus improving patient’s overall quality of life and longevity, as well. It will be pertinent to mention here that simply looking from the point of view of weight or BMI, a person who is overweight or mildly obese is unlikely to have obesity related co-morbidities and a 5-10% weight loss in such a patient will reduce likelihood of cardiovascular disease and metabolic risks. Patients, who

are moderately or severely obese viz. BMI ≥ 30, are likely to have obesity related co-morbidities and in such patients 15-20% weight loss is required for sustained improvement in co-morbidities. A 5-15% weight loss over a period of 6 months is realistic and of proven health benefit. A greater

Table 5: Goals of management in Overweight/obesity • Prevention of excess weight gain • Weight loss • Prevention of weight regain

Achieving weight loss requires a concerted effort comprising of physical activity, dietary change and behavioural modification. It is recommended to have at least 30-45 minutes of brisk walk as a physical activity which may be increased to 45-60 minutes of moderate intensity exercise on at least 5 days a week. This will translate into 225-300 min/week, which will be equivalent to 1800-2500 kcal/week. This should be supplanted by dietary changes incorporating calorie reductions inducing 600 kcal/day energy deficit. The dietary changes will need

Table 6: Three-pronged non-pharmacological strategy for managing overweight/obesity • Increasing Physical activity • Initially at least 150 min/week moderate aerobic exercise • Combine with 1-3 sessions/week resistance exercise (single set exercise, using major muscle groups).

• Reduce sedentary behaviour • Individualise programme keeping in mind physical limitations, if any Dietary advice • Reduce energy intake by 500-1000 kcal/day, although caloric restriction needs to be individualised • Prefer Low energy dense foods (whole grains, cereals, fruits, vegetables & salads) • Consume Low-fat, high fibre diet • Eat more fruits, whole grains, vegetables, salads • Avoid high energy dense foods (foods containing animal fats, other high fat foods, confectionery, sugary drinks) particularly large portions • Avoid Sugary drinks and ‘Fast foods’ • Consume fewer take-aways • Decrease the size of food portions • Avoid snacking between meals • Do not skip breakfast and avoid eating in the night time • Minimise alcohol intake Range of appropriate psychological interventions and strategies includes: • Self monitoring of behaviour and progress (food intake, exercise, weight) • Stimulus control (where the patient is taught how to recognise and avoid triggers that prompt unplanned eating) • Cognitive restructuring (modifying unhelpful thoughts/thinking patterns) • Goal setting • Problem solving strategies • Assertiveness training • Slowing the rate of eating • Reinforcement of changes • Relapse prevention • Strategies for dealing with weight regain • Psychological evaluation, counselling, and treatment, if needed • Education (face-to-ace meetings, group sessions, remote technologies) • Stress reduction • Motivational interviewing

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• Optimising health and reducing risk of disease (whether or not weight loss achieved)

weight loss (20% or more) may be considered for greater degrees of obesity (BMI ≥ 35 kg/m2).4

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Table 7: Medications causing weight gain • Atypical antipsychotoics including clozapine • Beta blockers sp. Ppnl • Insulin, SU, TZD • Lithium • Sodium valproate

ENDOCRINOLOGY

• TCA including amitryptiline to be individualised and the person’s dietary preferences need to be taken in to account.

Table 6 outlines the three important facets of Diet alterations, Physical activity and Behaviour therapy which are required for obese patients aiming for adiposity reduction. It is also important to realise that certain drugs used for treating obesity-related co-morbidities, by themselves induce weight gain. Table 7 mentions certain such drugs. Also, it is pertinent to understand that such drugs should not be initiated or if already prescribed, should be possibly withdrawn or substituted. It is also imperative to understand that smoking cessation also causes weight gain, and in fact, it has been observed that trying to restrict weight gain in this subgroup of patients, can result in poor smoking cessation rates. Therefore, at times, weight loss measures may have to be stopped or delayed, depending on the individual case scenario.

PHARMACOLOGIC MANAGEMENT OF OBESITY

Pharmacotherapy for overweight and obesity should be used only as an adjunct to lifestyle therapy. Addition of pharmacotherapy produces greater weight loss and weight-loss maintenance compared with lifestyle therapy alone. Concurrent initiation of lifestyle therapy and pharmacotherapy should be considered in patients with weight-related complications that can be ameliorated by weight loss.

Orlistat is a potent and selective pancreatic lipase inhibitor, which because of its mode of action causes fat malabsorption. It is administered in dosages of 60-120 mg tid to be taken before each meal. Faecal fat loss and related gastrointestinal symptoms are common. Staining of undergarments and faecal leakage can at times be troublesome, and deficiency of fat-soluble vitamins is known to occur. Orlistat is contraindicated in pregnancy.

Phentermine is a sympathomimetic amine anorectic, approved for short-term (few weeks) weight management.

The maximum adult dose is 37.5 mg once a day to be taken in mid-morning. Caution should be exercised since it can cause rise in blood pressure. It is contraindicated for use in patients with a history of cardiovascular disease and in pregnancy.

Phentermine/Topiramate extended release combination is available in four separate doses (3.75mg phentermine/23mg topiramate ER and 11.25mg/69mg are titration doses, while 7.5mg/46mg and 15mg/92mg are therapeutic doses. Initial dose of 3.75mg/23mg is prescribed as a 2-week course following which it is increased to the

‘mid-range’ maintenance dose of 7.5mg/46mg, which needs to be discontinued or escalated if people have not lost 3% weight after 3 months. At the maximum dose of 15mg/92mg, drug discontinuation should be tapered by taking a dose on alternate days for a week or more, before the treatment is stopped (if weight loss is < 5% of body weight with the maximum dose). Dose-dependent side-effects are known to occur viz. paresthesiae, dry mouth, constipation, dysgeusia, insomnia and dizziness.

Topiramate has teratogenic risk and the preparation is contraindicated in pregnancy.

Lorcaserin- serotonin 2C receptor agonist, in a dose of 10 mg bid, independent of meals can be prescribed for weight management. If the recipient fails to lose ≥5% of his weight 3 months after initiating lorcaserin, medication should be stopped considering the recipient to be a non-responder.

Responder rate at 1 year was 48% compared to placebo (20%), and 68% subjects maintained the weight loss after a further year of lorcaserin treatment. Side-effects include headache, dizziness, nausea, fatigue, constipation, dry mouth and 2.3% had cognitive impairment. Symptomatic hypoglycaemia was reported in diabetes patients and hence, dose adjustments of diabetes medications may be required when prescribing lorcaserin to diabetes patients.

Naltrexone-Bupropion combination (8mg/90mg tablet)Naltrexone is an opioid receptor antagonist while bupropion is a catecholamine reuptake inhibitor. These agents synergistically stimulate central melanocortin pathways and antagonise inhibitory feedback loops that limit weight reduction, leading to improved energy expenditure and reduced appetite. Maximum recommended dose is two tablets bid, and the weight loss effect should be assessed at 12-16 weeks and failure to lose 5% of the baseline body weight should warrant withdrawal of the drug. Side-effects include nausea, headache, vomiting, dizziness and constipation; the former three are the commonest causes for discontinuation.

Liraglutide 3.0 mg, a GLP-1 analogue, is approved for long-term weight management. GLP-1 is a physiological regulator of appetite and energy intake via GLP-1 receptors in the periphery and brain. Liraglutide-induced weight loss is mediated by its effects on appetite regulation (increased satiety, reduced hunger) and reduced energy intake. Common adverse effects are nausea, diarrhoea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain and increased lipase.

NEWER PHARMACOTHERAPEUTIC AGENTS UNDER INVESTIGATION

Bupropion/Zonisamide- Zonisamide is an anticonvulsant drug and its combination with bupropion is being tested in Phase II-III studies wherein the combination has resulted in 7.5% weight loss over baseline, with common adverse effects being headache, insomnia and nausea.5 Beloranib- belongs to a novel drug class that influences metabolism because of its selective methionine aminopeptidase-2 inhibition, resulting in reduced fat

biosynthesis and increased fat oxidation and lipolysis.5 Drug is being tested in Phase II-III trials with results indicating 5-10% weight loss over baseline. Adverse events witnessed were sleep disturbance, nausea and vomiting.

BARIATRIC SURGERY

Although touted as a permanent cure for obesity, it is important to realise that active lifestyle interventions need to be continued even after the bariatric surgery procedure. The decision for this modality needs to be taken up on a case-to-case basis, evaluating the risk and the benefits for the individual. Bariatric surgery should be offered to severely obese patients with BMI â&#x2030;Ľ 40 kg/ m2 in absence of coexisting medical problems and for BMI â&#x2030;Ľ 35 kg/m2 in the presence of one or more severe comorbidities which are expected to improve significantly with weight reduction (viz. mobility problems, arthritis, type 2 diabetes mellitus).2,4 Bariatric surgery should only be offered to patients who have failed to achieve success despite completing a structured weight management programme. Patients who regain excess weight (â&#x2030;Ľ25% of the lost weight) and who do not respond to intensive lifestyle intervention, should be started on liraglutide 1.83.0 mg or phenteramine/topiramate ER, if they are not candidates for re-operation.

REFERENCES

1.

2. Management of obesity- A national clinical guideline.

Scottish Intercollegiate Guidelines Network. Edinburgh.

February 2010, pp. 1-85. Available on www.sign.ac.uk 3.

Sweeting HN. Measurement and definitions of obesity in childhood and adolescence: A field guide for the uninitiated.

Nutr J 2007; 6:32.

4.

Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, et al. AACE/ACE Clinical Practice Guidelines for Comprehensive medical care of patients with ObesityExecutive Summary. Endocr Prac 2016. https://www. aace.com/files/guidelines/ObesityExecutiveSummary.pdf Accessed on Nov. 27, 2016.

5.

Fujioka K. Current and emerging medications for overweight or obesity in people with comorbidities. Diabetes Obes Metab 2015; 17:1021-1032.

CONCLUSION

Obesity has gained pandemic proportions and increased adiposity in any form has adverse impact on morbidity and mortality. Body mass index combined with waist circumference, remain the most effective anthropometric parameters of use in the clinical practice and for taking decisions on when to intervene. Lifestyle management

Yumuk V, Tsigos C, Fried M, et al for the Obesity Management task Force of the European Association for the Study of Obesity. European Guidelines for Obesity Management in Adults. Obes Facts 2015; 8:402-424.

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GLP-1 agonists other than liraglutide have also been tested for their efficacy in inducing weight loss. SGLT2 inhibitors also induce weight loss in diabetics and are independently being investigated for inducing weight loss in obese individuals. Metformin, for a long time has been known to cause weight loss, and off-label has been used as a weight-reduction agent, because of its mode of action and safe side-effect profile.

remains the cornerstone for prevention of obesity and also for its management. Lifestyle measures include dietary modifications, increased physical activity and behavioural modification. Pharmacotherapeutic options can be valuable adjuncts to lifestyle intervention, but are ineffective alone. The long-term efficacy of pharmacotherapeutic agents (orlistat, lorcaserin, liraglutide, phentermine, phentermine-topiramate and naltrexone-bupropion) remains questionable and under investigation. Newer agents bupropion-zonisamide and beloranib are presently being investigated and appear promising. However, many agents have come in the market and have been withdrawn later because of serious adverse effects, rimonabant and sibutramine are some recent withdrawals from the market. Bariatric surgery can also be offered to severely obese patients who have failed to reduce weight despite adopting vigorous lifestyle interventions. Obesity management remains complex, but needs to be addressed with an open mind and an individualised approach, with emphasis on lifestyle interventions.