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Hypothyroidism

  • Anil Bhansali
  • Yashpal Gogate

Abstract

A 28-year-old-lady presented with headache for the last 1 year. It was holocranial, continuous, mild in intensity, and not associated with vomiting, seizures, focal neurological deficits, or visual defects. There was history of weight gain, fatigue, and generalized bodyache for the last 2 years. She also had secondary amenorrhea of 1 year duration. She received treatment for migraine without any relief. Subsequently, neuroimaging revealed a sellar mass with suprasellar extension (26 × 18 × 15 mm) with a hypointense area. Her visual acuity and visual field examination did not reveal any abnormality. She was referred for surgical intervention. The preoperative workup included hormonal evaluation which revealed serum T3 0.4 ng/ml (0.8–1.8), T4 1.4 μg/dl (4.8–12.6), and TSH 328 μIU/ml (0.45–4.2), prolactin 112 ng/ml (5–25), 0800h cortisol 280 nmol/l (171–536), serum osmolality 270 mosm/kg, and urine osmolality 350 mosm/kg. She was diagnosed to have nonfunctioning pituitary tumor with hypothyroidism and was referred to endocrinology for opinion. On further evaluation, she had dry and coarse skin, periorbital puffiness, hoarse voice, delayed deep-tendon reflexes, and galactorrhea. She had no goiter. Additional investigations revealed antithyroid peroxidase antibody 600 IU/ml (<34), LH 11 mIU/ml (2.4–12.6), FSH 13 mIU/ml (3.5–13.5), and estradiol 30 pg/ml (12.5–166), and ultrasound pelvis showed bilateral polycystic ovaries. She was diagnosed to have autoimmune thyroid disease (Hashimoto’s thyroiditis) with primary hypothyroidism, thyro-lactotrope hyperplasia, hyperprolactinemia, and secondary polycystic ovarian disease. She was started with levothyroxine 25 μg per day and the dose was escalated weekly to 150 μg per day. She was supplemented with hydrocortisone 20 mg per day in divided doses. After 6 weeks of therapy, she had resolution of symptoms, but did not resume menstruation. Her serum T4 was 6.4 μg/dl, TSH 36 μIU/ml, prolactin 35 ng/ml, and 0800h cortisol after omission of hydrocortisone for 24 h 384 nmol/L; hence, hydrocoritosone was tapered and same dose of levothyroxine was continued. At 3 months of follow-up, she resumed her cycles and galactorrhea resolved. Repeat MRI showed regression of sellar–suprasellar mass (14 × 12 × 11 mm) with normalization of TSH and prolactin.

Keywords

Celiac Disease Subclinical Hypothyroidism Autoimmune Thyroid Disease Primary Hypothyroidism Overt Hypothyroidism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

9.1 Case Vignette

A 28-year-old-lady presented with headache for the last 1 year. It was holocranial, continuous, mild in intensity, and not associated with vomiting, seizures, focal neurological deficits, or visual defects. There was history of weight gain, fatigue, and generalized bodyache for the last 2 years. She also had secondary amenorrhea of 1 year duration. She received treatment for migraine without any relief. Subsequently, neuroimaging revealed a sellar mass with suprasellar extension (26 × 18 × 15 mm) with a hypointense area. Her visual acuity and visual field examination did not reveal any abnormality. She was referred for surgical intervention. The preoperative workup included hormonal evaluation which revealed serum T3 0.4 ng/ml (0.8–1.8), T4 1.4 μg/dl (4.8–12.6), and TSH 328 μIU/ml (0.45–4.2), prolactin 112 ng/ml (5–25), 0800h cortisol 280 nmol/l (171–536), serum osmolality 270 mosm/kg, and urine osmolality 350 mosm/kg. She was diagnosed to have nonfunctioning pituitary tumor with hypothyroidism and was referred to endocrinology for opinion. On further evaluation, she had dry and coarse skin, periorbital puffiness, hoarse voice, delayed deep-tendon reflexes, and galactorrhea. She had no goiter. Additional investigations revealed antithyroid peroxidase antibody 600 IU/ml (<34), LH 11 mIU/ml (2.4–12.6), FSH 13 mIU/ml (3.5–13.5), and estradiol 30 pg/ml (12.5–166), and ultrasound pelvis showed bilateral polycystic ovaries. She was diagnosed to have autoimmune thyroid disease (Hashimoto’s thyroiditis) with primary hypothyroidism, thyro-lactotrope hyperplasia, hyperprolactinemia, and secondary polycystic ovarian disease. She was started with levothyroxine 25 μg per day and the dose was escalated weekly to 150 μg per day. She was supplemented with hydrocortisone 20 mg per day in divided doses. After 6 weeks of therapy, she had resolution of symptoms, but did not resume menstruation. Her serum T4 was 6.4 μg/dl, TSH 36 μIU/ml, prolactin 35 ng/ml, and 0800h cortisol after omission of hydrocortisone for 24 h 384 nmol/L; hence, hydrocoritosone was tapered and same dose of levothyroxine was continued. At 3 months of follow-up, she resumed her cycles and galactorrhea resolved. Repeat MRI showed regression of sellar–suprasellar mass (14 × 12 × 11 mm) with normalization of TSH and prolactin.
Fig. 9.1

(a) T1W CEMR coronal image showing sellar–suprasellar mass with hypointense area (necrosis) within it, suggestive of thyro-lactotrope hyperplasia. (b) T1W CEMR coronal image showing marked regression of sellar–suprasellar mass after levothyroxine therapy

9.2 Stepwise Analysis

Primary hypothyroidism presents with classical myxedematous features and the diagnosis is straightforward in most of the cases. However, at times the diagnosis is delayed for a long duration, particularly when patients have subtle features or present with unusual manifestations. The index patient presented with headache and was initially diagnosed to have nonfunctioning pituitary tumor with hypothyroidism. On analysis of complete profile of the patient, a diagnosis of primary hypothyroidism with hyperprolactinemia was considered, and the sellar–suprasellar mass was attributed to thyro-lactotrope hyperplasia, rather than nonfunctioning pituitary tumor with hypothyroidism. This was based on very high levels of TSH, which is characteristic of long-standing untreated primary hypothyroidism, while patients with nonfunctioning pituitary tumor usually have low or normal TSH. It is important to differentiate between these two disorders to avoid inadvertent surgical intervention in a patient with thyro-lactotrope hyperplasia, which usually responds to levothyroxine therapy. Thyro-lactotrope hyperplasia is commonly seen in young women (20–30 years of age) with long-standing, severe, and untreated primary hypothyroidism. Serum TSH levels are invariably high (100–1,000 μIU/ml) and is accompanied with low serum T4. Although patients with TSH-secreting adenoma also have high TSH, with imaging features indistinguishable from thyro-lactotrope hyperplasia, presence of high serum T4 favors the diagnosis of TSH-secreting adenoma. Thyro-lactotrope hyperplasia is due to increased TRH drive because of lack of T4-mediated negative feedback on the hypothalamo–pituitary axis, which stimulates not only thyrotropes but also lactotropes. Hyperprolactinemia is seen in 23–50% of patients with primary hypothyroidism. The index patient had hypocortisolism which may be due to corticotrope dysfunction secondary to thyro-lactotrope hyperplasia or “lazy adrenal syndrome” because of hypometabolic state associated with primary hypothyroidism. Menorrhagia is the usual menstrual irregularity in patients with primary hypothyroidism, but amenorrhea is common in those with concurrent hyperprolactinemia, central hypogonadism due to mass effect, or secondary polycystic ovarian syndrome. The most common cause of primary hypothyroidism in majority of patients is Hashimoto’s thyroiditis, as was evident in our patient. The treatment strategy in a patient of primary hypothyroidism with thyro-lactotrope hyperplasia includes levothyroxine supplementation either as conventional “step-up” protocol or uncustomary “step-down” approach. In the “step-up” protocol, levothyroxine is started at low dose and is escalated slowly. On the contrary, in “step-down” approach, high-dose levothyroxine (400–600 μg) is administered to achieve rapid reduction in thyrotrope hyperplasia; however, the results with this approach have been variable. Hydrocortisone supplementation is advised along with levothyroxine to avoid adrenal crisis in a patient with long-standing untreated hypothyroidism, as after initiation of levothyroxine there is an increase in metabolic clearance of cortisol which precedes the rise in cortisol synthesis. Serum T4 returns to normal earlier than TSH and it requires 3–6 months for TSH to normalize. Regression of thyro-lactotrope hyperplasia usually occurs within 2–12 months; however, failure to regress after optimal therapy with normalization of TSH suggests either long-standing thyrotrope hyperplasia or the presence of double adenoma (e.g., thyrotrope hyperplasia with nonfunctioning pituitary adenoma).

9.3 Clinical Rounds

  1. 1.

    How to define hypothyroidism?

    Hypothyroidism is a disorder characterized by varied symptoms and/or signs related to decreased metabolism and/or increased glycosaminoglycans (GAG) deposition in soft tissue (myxedematous features) due to decreased production/ action of thyroid hormones and/or thyroid-stimulating hormone (TSH) excess. Symptoms related to decreased metabolism are lethargy, fatigue, bradycardia, cold intolerance, and “aches and pains” and are primarily due to thyroxine (T4) deficiency. Symptoms related to increased GAG deposition are periorbital puffiness, hoarse voice, nonpitting edema, and macroglossia and are predominantly due to thyroid-stimulating hormone (TSH) excess.

     
  1. 2.

    Why are manifestations severe in primary hypothyroidism as compared to secondary hypothyroidism?

    The clinical manifestations are more pronounced in primary hypothyroidism as compared to secondary hypothyroidism. This is attributed to elevated TSH and severe T4 deficiency in primary hypothyroidism resulting in overt myxedematous features. The increase in GAG is predominantly due to the stimulatory effect of TSH and lack of modest inhibitory effect of T4 on hyaluronic acid, fibronectin, and collagen synthesis by fibroblasts. However, in secondary hypothyroidism, low–normal TSH and mild T4 deficiency result in less severe myxedematous features. Mild T4 deficiency in secondary hypothyroidism is due to TSH-independent T4 synthesis which contributes to around 10–15% of circulating T4. Also, the presence of concurrent multiple pituitary hormone deficiencies may mask the features of hypothyroidism.

     
Fig. 9.2

Florid myxedematous manifestations in a patient with primary hypothyroidism

  1. 3.

    What are the causes of hypothyroidism?

    The most common cause of primary hypothyroidism worldwide is environmental iodine deficiency, whereas in iodine-sufficient regions, the most common cause is Hashimoto’s thyroiditis. Hypothyroidism is common in women and the incidence increases with advancing age. The causes of hypothyroidism are mentioned in the table given below.

     

Etiology of hypothyroidism

Primary hypothyroidism

 Iodine deficiency

 Hashimoto’s thyroiditis

 Post-ablative: thyroidectomy, radioiodine therapy, or external irradiation

 Drugs—thioamides, iodides, lithium, amiodarone, interferon-α, interleukin-2, perchlorate, tyrosine kinase inhibitors

Transient hypothyroidism

 Subacute thyroiditis

 Postpartum thyroiditis

Congenital hypothyroidism

 Ectopic thyroid

 Thyroid dysgenesis

 Thyroid dyshormonogenesis

Secondary hypothyroidism

 Pituitary transcription factor defects

 Pituitary tumors

 Pituitary surgery

 Hypophysitis

 Infiltrative disorders of hypothalamo–pituitary region

 CNS insults like head injury, subarachnoid hemorrhage, and radiotherapy

Resistance to thyroid hormone

Consumptive hypothyroidism

 Hemangioma due to ectopic expression of type 3 deiodinase

  1. 4.

    Does ectopic thyroid gland always present as congenital hypothyroidism?

    No. The development of hypothyroidism in a patient with ectopic thyroid gland depends upon the quantity of functioning thyroid tissue. Ectopic thyroid gland is usually devoid of lateral lobes and has a restricted proliferative capacity in response to TSH. Patients with ectopic thyroid gland usually present during childhood with hypothyroidism or obstructive symptoms; however, they may also present during adolescence with hypothyroidism, when thyroid gland fails to proliferate in response to increased metabolic demands. Rarely, autoimmune thyroiditis in an ectopic thyroid gland may lead to hypothyroidism in an adult.

     
Fig. 9.3

Lingual thyroid in an adult with hypothyroidism

  1. 5.

    What is subclinical hypothyroidism?

    Subclinical hypothyroidism is a biochemical abnormality characterized by normal serum free T4 and elevated TSH above the reference range, irrespective of the presence or absence of symptoms. The reference range for normal TSH depends on sensitivity of the TSH assay, normative distribution of TSH, and iodine status of the study population. The most common cause of subclinical hypothyroidism is Hashimoto’s thyroiditis. Approximately, 7–10% of elderly women have subclinical hypothyroidism. Before considering the diagnosis of subclinical hypothyroidism, thyroid function tests should be reconfirmed after 4 to 8 weeks to exclude the possibility of recovery phase of subacute thyroiditis or sick-euthyroid syndrome.

     
  1. 6.

    What is the reason for normal free T 4 with an elevated TSH in subclinical hypothyroidism?

    A log-linear relationship exists between circulating free T4 and TSH and is responsible for the characteristic biochemical profile of subclinical hypothyroidism. Log-linear relationship is explicited as a single-fold reduction in one variable (T4) resulting in tenfold rise in the dependent variable (TSH). Hence, even a modest decrease in free T4, although in reference range, leads to a log-linear rise in TSH.

     
  1. 7.

    What are the causes of normal T4 with elevated TSH apart from subclinical hypothyroidism?

    The causes of normal T4 with elevated TSH apart from subclinical hypothyroidism include recovery phase of thyroiditis, convalescent phase of non-thyroidal illness, resistance to thyroid hormone, TSH receptor mutation, primary adrenal insufficiency, drugs (e.g., metoclopramide), and TSH assay interference by heterophile anti-mouse antibodies. In addition, patients on intermittent levothyroxine (LT4) therapy with primary hypothyroidism may also have a biochemical profile similar to subclinical hypothyroidism. Hence, the diagnosis of subclinical hypothyroidism should only be considered after careful exclusion of these conditions.

     
  1. 8.

    What are the long-term risks of subclinical hypothyroidism?

    Long-term consequences of subclinical hypothyroidism are progression to overt hypothyroidism (3–8% per year) and increased risk of cardiovascular events, heart failure, dyslipidemia, nonalcoholic fatty liver disease, and possibly neuropsychiatric disorders. Treatment with levothyroxine delays the progression to overt hypothyroidism; however, the data regarding improvement in cardiovascular outcomes and nonalcoholic fatty liver disease with levothyroxine replacement are limited and conflicting.

     
  1. 9.

    When to treat subclinical hypothyroidism?

    Patients with subclinical hypothyroidism should be treated if TSH is > 10 μIU/mL because there is an increased risk for heart failure and cardiac events as shown in observational as well as in prospective studies. Patients with TSH between upper limit of normal and 10 μIU/mL, if accompanied with symptoms/signs suggestive of hypothyroidism or have a predisposition for progression to overt hypothyroidism (presence of goiter, positive antithyroid peroxidase antibody, personal history or family history of autoimmune disease) or on drugs (interferon, tyrosine kinase inhibitors, lithium and amiodarone) or have concurrent comorbidities like atherosclerotic cardiovascular disease, heart failure, dyslipidemia, infertility, and refractory anemia, also need to be treated. Those with nonspecific symptoms and neuropsychiatric disorders should be given a trial of levothyroxine for 3–6 months and further continuation of treatment should be based on clinical response.

     
  1. 10.

    How to monitor patients with subclinical hypothyroidism?

    Serum TSH should be monitored in patients with subclinical hypothyroidism, who are on treatment with levothyroxine. TSH should be targeted between 0.5 and 2.5 μIU/ml. This is based on normative distribution of TSH in healthy population and estimation of TSH by sensitive chemiluminescence assay. Overtreatment is to be avoided as it may result in decreased bone mineral density and increased risk of atrial fibrillation. Those who are not on treatment should undergo regular surveillance of TSH every 6 months.

     
  1. 11.

    What are the monosymptomatic presentations of hypothyroidism in adults?

    Monosymptomatic presentations of hypothyroidism in adults are weight gain, menorrhagia, infertility, galactorrhea, recurrent miscarriages, multicystic ovaries, pericardial effusion, sinus bradycardia, refractory anemia, dyslipidemia, carpal tunnel syndrome, dementia, ataxia, and depressive disorders. The index of suspicion should be high in these cases as treatment is rewarding.

     
  1. 12.

    What are the causes of weight loss in a patient with hypothyroidism?

    Hypothyroidism is usually associated with weight gain (3–4 kg), but at times it may be associated with weight loss. The causes of weight loss in a patient with hypothyroidism include recovery phase of subacute thyroiditis, secondary hypothyroidism with multiple pituitary hormone deficiencies, hypothyroidism associated with polyglandular endocrine failure, and overtreatment with levothyroxine. In addition, children with concurrent type 1 diabetes or celiac disease may have weight loss despite hypothyroidism.

     
  1. 13.

    What are the causes of tachycardia in a patient with hypothyroidism?

    Hypothyroidism is associated with sinus bradycardia in 10–20% of patients, while tachycardia is rare. The most common cause of tachycardia in patients with hypothyroidism is overtreatment with levothyroxine. The causes of tachycardia in treatment-naive patients are cardiac tamponade, congestive cardiac failure, and concurrent presence of anemia.

     
  1. 14.

    What are the causes of anemia in hypothyroidism?

    Most common type of anemia in patients with hypothyroidism is normocytic and normochromic. The causes of anemia in hypothyroidism are menorrhagia, impaired absorption of micronutrients, and poor oral intake. Menorrhagia in patients with hypothyroidism is caused by coagulation abnormalities, platelet dysfunction, increased capillary fragility, and deficient progesterone secretion. Reduced gastric acid output and decreased gut motility contribute to impaired absorption of iron, vitamin, B12, and folic acid. Erythropoietin deficiency as an adaptive response to decreased oxygen demand also contributes to anemia. Concurrent celiac disease, pernicious anemia (intrinsic factor deficiency), and blind loop syndrome may also result in anemia.

     
  1. 15.

    What are the endocrine causes of pallor without anemia?

    The causes of pallor without anemia from endocrine perspectives are hypothyroidism, secondary hypocortisolism (ACTH deficiency), and hypogonadism. Although these disorders can be associated with anemia, they can cause pallor even without anemia. Cutaneous vasoconstriction in response to hypometabolic state in hypothyroidism, reduced melanin production from melanocytes due to ACTH deficiency in secondary hypoadrenalism, and decreased cutaneous vascularity due to testosterone deficiency in hypogonadism result in pallor without anemia, in these disorders.

     
  1. 16.

    What are the neurological manifestations of hypothyroidism?

    Hypothyroidism is associated with dysfunction of central and peripheral nervous system. The most common neurological manifestation of hypothyroidism is “cerebral slowing” due to decreased cerebral blood flow, impaired glucose metabolism, and alterations in neurotransmitter activity. The uncommon neurological manifestations include dementia and movement disorders like ataxia, hemichorea, and pseudoparkinson like syndrome. Compressive neuropathies (carpal tunnel syndrome, tarsal tunnel syndrome), peripheral neuropathy with thickened nerves, and rarely autoimmune demyelinating neuropathies are other manifestations of peripheral nervous system involvement. In addition, “myxedema madness,” a severe neuropsychiatric manifestation of long-standing untreated primary hypothyroidism, may also be seen rarely. Therefore, all patients with cognitive dysfunction, neuropsychiatric disorders, or entrapment neuropathy must have thyroid function tests.

     
  1. 17.

    What are the musculoskeletal manifestations of hypothyroidism?

    Musculoskeletal involvement in patients with hypothyroidism includes delayed deep-tendon reflexes, proximal myopathy, calf hypertrophy (Kocher–Debre–Semelaigne syndrome in children and Hoffman syndrome in adults), arthralgia, and rarely myoedema. Myopathy is characterized by relative atrophy of type 2 and hypertrophy of type 1 muscle fibers and glycosaminoglycans deposition. These muscular dysfunctions are the result of abnormal glycogen metabolism, impaired mitochondrial oxidation, and defective sarcolemmal activity due to deficiency of thyroxine. Muscle enzyme creatine kinase is usually elevated and electromyogram may show polyphasic action potential. Patients with hypothyroidism are predisposed to rhabdomyolysis which may be precipitated by vigorous exercise or concurrent use of statin and fibrates.

     
Fig. 9.4

Calf muscle hypertrophy in a patient with long-standing untreated primary hypothyroidism (Hoffman syndrome)

  1. 18.

    Why are deep-tendon reflexes delayed in patients with hypothyroidism?

    Deep-tendon reflexes are delayed in patients with hypothyroidism both during contraction phase and relaxation phase; however, the delay is more pronounced in relaxation phase and is myogenic in origin. Selective atrophy of type 2 and compensatory hypertrophy of type 1 muscle fiber (slow twitching), decreased Na+/K+-ATPase activity, reduced expression of myosin ATPase, impaired contractility of actin–myosin complex, and defective sarcolemmal depolarization are the underlying mechanisms for this phenomenon. The other causes of delayed deep-tendon reflexes are diabetes, obesity, pernicious anemia, iron deficiency anemia, hypothermia, and use of drugs (e.g., propranolol and chlorpromazine).

     
  1. 19.

    What are the abnormalities of reproductive system in women with hypothyroidism?

    Women with hypothyroidism may have various abnormalities of reproductive system at different phases of life. Girls in peripubertal period can present with delayed puberty, primary amenorrhea, or menorrhagia and rarely with large multicystic ovaries. Occasionally, these adolescent girls may present with acute abdomen due to ovarian torsion. In young women, hypothyroidism is associated with menstrual irregularities in about 23–30% of patients and these include menorrhagia, oligomenorrhea, and secondary amenorrhea. Premature ovarian failure may also occur in patients with primary hypothyroidism as a manifestation of polyglandular endocrine syndrome.

     
  1. 20.

    How does hypothyroidism influence reproductive system in a woman?

    Reproductive system abnormalities in a woman with hypothyroidism include oligo- or amenorrhea, menorrhagia, and infertility. The mechanisms for these abnormalities are enlisted in the table given below.

     

Clinical features

Mechanism

Oligo- or amenorrhea

Defect in GnRH pulsatility

Impaired LH surge

Hyperprolactinemia

Secondary polycystic ovarian disease

Decreased SHBG

Altered estrogen metabolism

Menorrhagia

Estrogen breakthrough bleed

Defect in hemostasis (factor VII, VIII, IX, XI)

Platelet dysfunction

Increased capillary fragility

Infertility

Defect in GnRH pulsatility

Hyperprolactinemia

Defect in oocyte maturation

Luteal phase defect

Impaired blastocyst formation (T4 deficiency)

  1. 21.

    Why is there hyperprolactinemia with hypothyroidism?

    Hyperprolactinemia is observed in 20–30% of patients with primary hypothyroidism. The causes of hyperprolactinemia in a patient with primary hypothyroidism include increased TRH-mediated prolactin secretion due to loss of negative feedback by T4, decreased dopaminergic tone, and reduced prolactin clearance. If hyperprolactinemia does not resolve despite optimal dose and duration of levothyroxine therapy, a possibility of concurrent prolactinoma should be considered. Hyperprolactinemia can also be associated with secondary hypothyroidism in patients with macroprolactinoma with thyrotrope compression, lymphocytic infundibulitis, and stalk compression by nonfunctioning pituitary adenoma with thyrotrope dysfunction.

     
  1. 22.

    When to suspect thyro-lactotrope hyperplasia in a patient with primary hypothyroidism?

    Patients with long-standing, severe untreated primary hypothyroidism are predisposed for the development of thyro-lactotrope hyperplasia. The presence of headache, visual field defects, amenorrhea–galactorrhea, and multiple pituitary hormone deficiencies in a patient with primary hypothyroidism should raise a suspicion of thyro-lactotrope hyperplasia.

     
Fig. 9.5

(a) Adolescent girl with myxedematous appearance, multicystic ovaries, and thyro-lactotrope hyperplasia. (b) CECT pelvis showing bilateral huge multicystic ovaries in the same patient. (c) T1W CEMR coronal image showing sellar–suprasellar mass suggestive of thyro-lactotrope hyperplasia

  1. 23.

    What are the emergencies in a patient with primary hypothyroidism?

    Emergencies in a patient with primary hypothyroidism are usually an outcome of undiagnosed or untreated long-standing disease. They may present with altered sensorium due to hyponatremia, hypoglycemia, myxedema coma, or Hashimoto’s encephalopathy. The cardiac emergencies in patients with hypothyroidism are syncope due to sinus bradycardia, cardiac tamponade due to massive pericardial effusion, and congestive cardiac failure. They may also present as acute abdomen due to ovarian torsion, megacolon, paralytic ileus, and acute cholecystitis. Rarely, they may present as severe myoedema masquerading as tetanus, or rhabdomyolysis precipitated by use of statins or vigorous activity. In addition, hypokalemic periodic paralysis may rarely be a presenting manifestation.

     
  1. 24.

    How was the normative data for TSH derived?

    Normative data for TSH were derived from the study of healthy subjects from iodine-sufficient region with no historical and ultrasonographic evidence of thyroid disease and negative thyroid autoantibodies. To derive the normative data, most of the studies have used third generation TSH assay. The upper limit of TSH reference range in self-reported “healthy” population in NHANES III was 4.5 μIU/ml and the lower limit was 0.45 μIU/ml. The upper limit of TSH was decreased to 4.12 μIU/ml after careful exclusion of subjects with TPO positivity, pregnancy, and use of various drugs that interfere with thyroid function. However, the National Academy of Clinical Biochemistry (NACB) reported the upper limit of TSH as <2.5 μIU/ml in >95% of study population without evidence of any thyroid dysfunction. Recent literature also supports that targeting TSH <2.5 μIU/ml is associated with better improvement in quality of life and lipid profile. Hence, for all practical purposes, serum TSH >4.12 μIU/ml suggests thyroid dysfunction and the treatment goal with LT4 should be targeted to TSH <2.5 μIU/ml. Serum TSH value rises with increasing age by 0.3 μIU/ml for each decade after the age of 40 years; hence, in elderly population, it should be interpreted cautiously.

     
  1. 25.

    What is the screening test for hypothyroidism?

    Estimation of serum TSH is the primary screening modality in patients with suspected hypothyroidism. This is because rise in TSH is the earliest detectable abnormality due to log-linear relationship between free T4 and TSH.

     
  1. 26.

    Is there any correlation between severity of symptoms in patients with primary hypothyroidism and serum TSH levels?

    No. There is a poor correlation between severity of symptoms in patients with primary hypothyroidism and circulating TSH levels. Severity of symptoms of hypothyroidism depends upon serum free T4 levels and the rapidity of development of hypothyroidism. The lack of correlation between serum TSH and symptomatology is due to increased secretion of TSH isomers by thyrotropes, which are immunoreactive but not bioactive and flattening of log-linear relationship at very low levels of serum free T4.

     
  1. 27.

    What are the limitations of TSH as a first-line test in patients with suspected thyroid dysfunction?

    Serum TSH as a first-line test can be misleading in patients with secondary hypothyroidism (normal TSH and low free T4), non-thyroidal illness (normal TSH and low free T4) and in the presence of anti-mouse antibodies (elevated TSH with normal free T4). Further, it may be deceptive in the diagnosis of thyrotropinoma (elevated TSH and free T4) and resistance to thyroid hormone (elevated TSH and free T4).

     
  1. 28.

    What are the causes of elevated TSH without thyroid gland dysfunction?

    The causes of elevated TSH without thyroid gland dysfunction include assay interference by heterophile antibodies, drugs (e.g., metoclopramide, ketoconazole), elevated rheumatoid factor titer, anti-TSH antibody, adrenal insufficiency, and immunoreactive but bioinactive TSH isomers.

     
  1. 29.

    Who should be evaluated for hypothyroidism?

    Hypothyroidism is a common endocrine disorder with multifaceted presentation. In addition to those who have classical symptoms and signs of hypothyroidism, history of prior ablative therapy, or sellar-suprasellar mass evaluation for hypothyroidism should be performed in the disorders/conditions listed in the table given below.

     

Reproductive disorders

Menorrhagia, infertility, galactorrhea, multicystic ovaries, delayed puberty and recurrent fetal loss

Pregnant women with risk factors for hypothyroidisma

Medical disorders

Dyslipidemia, refractory anemia, sinus bradycardia, unexplained pericardial effusion, hyponatremia, and hypoglycemia

Neuropsychiatric disorders

Mood disorders, entrapment neuropathy, ataxia, dementia

Autoimmune disorders

Type 1 diabetes, celiac disease, primary pulmonary hypertension

Drugs

Amiodarone, lithium, tyrosine kinase inhibitors, and interferon therapy

Special situations

Turner’s and Down syndrome

Women with type 2 diabetes aged >50 years

Chronic kidney disease

Past history of head injury

aAge >30 years, presence of goiter, TPO positivity, bad obstetric history, morbid obesity (BMI >40 kg/m2), personal or family history of autoimmune thyroid disease or autoimmune disorders, presence of iodine deficiency, or prior thyroid surgery

  1. 30.

    What is the rationale of screening for hypothyroidism in patients with depression?

    The prevalence of depressive symptoms in patients with subclinical hypothyroidism has been reported to vary from 13 to 63%. Neuropsychiatric symptoms have been correlated with levels of TSH, but treatment with levothyroxine alone does not remit the depressive symptoms. On the contrary, 8–20% of patients with depressive disorders have subclinical hypothyroidism and treatment with levothyroxine in these patients may augment the response to antidepressants. In addition, there are studies demonstrating the usefulness of liothyronine as well as levothyroxine in patients with refractory mood disorders, even with normal thyroid function; however, the data are inconsistent. Therefore, every patient with depression should be evaluated for hypothyroidism and particularly those who are resistant to anti-depressant therapy. However, the use of thyroid hormone supplementation is not recommended in euthyroid patients with depression.

     
  1. 31.

    What is the appropriate time to measure TSH?

    Serum TSH can be measured at any time between 0800h and 1800h as the normative data for TSH has been derived during this period. However, it should preferably be estimated in the morning hours (0800–1000h) as TSH secretion peaks at midnight with nadir occurring between 1000h and 1600h, which approximate 50% of the peak value. Thus, the estimation of TSH in the morning hours may possibly detect higher number of patients with subclinical hypothyroidism as compared to TSH measurement later in afternoon.

     
  1. 32.

    What are the investigations required for the diagnosis of hypothyroidism?

    Estimation of serum TSH and total T4/free T4 are required for the diagnosis of hypothyroidism. An elevated TSH with low total or free T4 suggests the diagnosis of primary hypothyroidism. The measurement of antithyroid peroxidase antibodies helps in establishing the etiological diagnosis of autoimmune thyroid disease. Fine-needle aspiration cytology and USG are not required unless there is a thyroid nodule or thyroid gland is unusually firm. If serum T4 is low with low/normal/mildly elevated TSH, then the diagnosis of secondary hypothyroidism should be considered and other pituitary hormones should be assessed. A mildly elevated TSH in a patient with secondary hypothyroidism suggests the possibility of concurrent ACTH deficiency, as glucocorticoids inhibit TSH secretion. MR imaging of sella should be performed after confirmation of diagnosis of secondary hypothyroidism to exclude hypothalamo–pituitary disorders.

     
  1. 33.

    What is thyroid peroxidase?

    Thyroid peroxidase (TPO) is a microsomal enzyme involved in oxidation, organification, and coupling, required for thyroid hormone synthesis. TSH is the prime regulator of TPO activity, complemented by intrathyroidal iodine. Congenital deficiency of this enzyme results in thyroid dyshormonogenesis. Antithyroid drugs like carbimazole, methimazole, and propylthiouracil inhibit TPO, thereby suppressing the thyroid hormone biosynthesis. Anti-TPO antibody (also called as anti-microsomal antibody) is a surrogate marker of autoimmune thyroid disease and represents an “epiphenomenon” of thyroid autoimmunity but does not have a causative role.

     
  1. 34.

    Why is estimation of serum T 3 not useful in the diagnosis of hypothyroidism?

    Serum T3 estimation is not useful in the diagnosis of primary hypothyroidism, as it remains within normal range even in patients with overt hypothyroidism because of increased T3 secretion by thyroid gland and augmented peripheral T4 to T3 conversion by peripheral deiodinase type 2 under intense TSH drive.

     
  1. 35.

    What are the regulators of T 4 to T 3 neogenesis?

    Twenty percent of the circulating serum T3 is secreted directly from thyroid gland, while the rest is derived by peripheral T4 to T3 neogenesis, which is regulated by type 2 and type 1 monodeiodinases. However, type 2 monodeiodinase contributes more (60%) to plasma T3 than type 1 monodeiodinase (20%). The activity of type 2 deiodinase is increased by TSH and GH and inhibited by thyroxine and cytokines (TNF-α, IL-6). In addition, propranolol and glucocorticoids inhibit type 2 monodeiodinase, while propylthiouracil and amiodarone inhibit type 1 monodeiodinase.

     
  1. 36.

    How does amiodarone cause hypothyroidism?

    Amiodarone consists of 37% iodine by weight; thus a 200 mg tablet of amiodarone contains 75 mg iodine, which far exceeds the recommended daily allowance of iodine (150 μg). Administration of amiodarone is associated with thyroid dysfunction in 20% of patients. Females, residents of iodine-replete area, and patients with TPO positivity or previous history of ablative treatment for Graves’ disease are at risk for amiodarone-induced hypothyroidism (5–15%), and this is due to permanent “Wolff–Chaikoff’s” effect. However, patients residing in iodine-deficient area are at increased risk for developing amiodarone-induced thyrotoxicosis (10%). Therefore, thyroid function should be performed prior to initiating amiodarone and monitored periodically. Despite normal thyroid function in majority of patients on amiodarone therapy, there is a “cardiac myxedema.” This differential effect is due to amiodarone and its metabolite desethylamiodarone as both act as competitive antagonist to T3 at cardiac cellular level.

     
  1. 37.

    How to manage amiodarone-induced hypothyroidism?

    Amiodarone-induced subclinical/overt hypothyroidism should be treated with levothyroxine without discontinuation of amiodarone. Levothyroxine replacement does not increase the risk of cardiac arrhythmias in this scenario; however, thyroid function should be closely monitored to avoid iatrogenic thyrotoxicosis.

     
  1. 38.

    What are the thyroid dysfunctions in a patient on lithium therapy?

    Lithium therapy is associated with development of goiter (4–60%), subclinical hypothyroidism (34%), and overt hypothyroidism (15%). Females and those with underlying autoimmune thyroid disease are predisposed for lithium-induced thyroid dysfunction. Lithium inhibits the release of thyroid hormones and consequently results in increased TSH, leading to the development of goiter. In addition, lithium therapy per se induces autoimmune thyroid disease. Lithium-induced autoimmune thyroid dysfunction and/or worsening of preexisting autoimmune thyroid disease results in subclinical/overt hypothyroidism. Thyroid function test should be done prior to initiation of lithium therapy and 6–12 monthly thereafter, as lithium-induced thyroid dysfunction can occur anytime during therapy. Lithium-induced hypothyroidism should be managed with levothyroxine without discontinuation of lithium.

     
  1. 39.

    What is the importance of thyroid hormone-binding proteins?

    Circulating T4 predominantly binds with thyroxine-binding globulin (70%) and a small fraction of it binds to albumin (20%) and prealbumin (10%), also known as transthyretin. These binding proteins act as circulating reservoir for thyroid hormones and maintain constant free thyroid hormone level. The role of these binding proteins is interchangeable as in case of thyroxine-binding globulin (TBG) deficiency, transthyretin predominantly binds with T4.

     
  1. 40.

    What are the disorders associated with altered TBG levels?

    Thyroxine-binding globulin (TBG) is an estrogen-dependent globulin. The disorders associated with altered TBG status are enlisted in the table. In all these states, total T4 may be high or low depending on TBG status, but free T4 levels are normal. It should be noted that TBG is increased in patients with hypothyroidism, whereas it is decreased in hyperthyroidism.

     

TBG increased

TBG decreased

Pregnancy

Active acromegaly

Chronic active hepatitis

Nephrotic syndrome

HIV infection

Familial TBG deficiency

Drugs—oral contraceptives, tamoxifen, and methadone

Drugs—androgens, glucocorticoids, and interleukins

  1. 41.

    What are the common errors in the interpretation of thyroid function tests?

     

Thyroid function tests

Clinical scenario

Usual interpretation

Correct diagnosis

Low TSH, low T3 and T4

Graves’ disease on treatment

Hyperthyroidism

Hypothyroidism

Low TSH, high T3 and T4

Rapid weight loss and neck pain

Hyperthyroidism

Subacute thyroiditis

Low–normal TSH, low–normal T3 and T4

Systemic illness

Hypothyroidism

Non-thyroidal illness (sick euthyroid syndrome)

Normal TSH (T3, T4 low normal/low)

Pituitary disorder

Euthyroid

Secondary hypothyroidism

High TSH, normal T3, T4

Hypothyroid on optimal treatment, asymptomatic

Noncompliance with T4

Heterophile antibodies

High TSH, high T3, T4

Euthyroid/ mildly toxic

Lab error

Thyrotropinoma

Resistance to thyroid hormone

  1. 42.

    How to differentiate between subclinical hypothyroidism and recovery phase of subacute thyroiditis?

    Thyroid hormone profile may be similar in patients with subclinical hypothyroidism and recovery phase of subacute thyroiditis. However, recent history of rapid weight loss, neck pain, and palpitations with or without tender goiter supports the diagnosis of subacute thyroiditis, while patients with subclinical hypothyroidism may be asymptomatic or may present with nonspecific symptoms. In clinical practice, many a time patients present with history of recent weight loss with elevated TSH and normal T4; these patients are in the recovery phase of subacute thyroiditis.

     
  1. 43.

    What is “fluctuating thyroid function”?

    “Fluctuating thyroid function” is a clinico-biochemical entity characterized by periods of hypothyroidism and hyperthyroidism in the background of autoimmune thyroid disease. This entity should only be considered after excluding overzealous treatment either with antithyroid drugs or levothyroxine, non-compliance to treatment, and factitious use of levothyroxine. Fluctuating thyroid function represents a spectrum of autoimmune thyroid disease, wherein a balance between TSH receptor-stimulating antibodies and TSH receptor-blocking antibodies determines the clinical presentation as thyrotoxicosis or hypothyroidism, respectively. The presence of goiter is a prerequisite for the development of “fluctuating thyroid function.” These patients should be radio-ablated during the phase of hyperthyroidism to render them permanently hypothyroid, as it is easier to manage thereafter.

     
  1. 44.

    How to treat primary hypothyroidism?

    The treatment of choice in patients with hypothyroidism is levothyroxine and is initiated at a dose of 1.6 μg/kg ideal body weight, particularly in younger individuals and in those who have undergone recent thyroid surgery. Lean body mass is the best predictor of daily requirements of levothyroxine. However, because of practical constraints in estimating lean body mass, the dose of levothyroxine is calculated based on ideal body weight. In patients with long-standing hypothyroidism, in those with cardiovascular disease, and in elderly individuals, it seems prudent to initiate levothyroxine therapy at a lower dose with gradual increment thereafter. Levothyroxine is preferred over liothyronine as levothyroxine is a prohormone and its supplementation ensures sustained and stable T3 neogenesis. In addition, levothyroxine has a longer half-life (7 days) and is associated with lesser fluctuations in serum T4 levels.

     
  1. 45.

    Why should levothyroxine dose be escalated slowly?

    Long-standing hypothyroidism is a hypometabolic state and results in upregulation of thyroid hormone receptors; hence, administration of initial high doses of levothyroxine may cause palpitation, tremor, tachycardia, and angina. Occasionally, initiation of high-dose levothyroxine therapy can precipitate adrenal crisis, due to accelerated cortisol catabolism in the backdrop of lazy adrenal syndrome. Therefore, levothyroxine therapy should be built up slowly in patients with long-standing hypothyroidism, in elderly subjects and in those with cardiovascular disease. Similarly, children and adolescents with long-standing hypothyroidism should also be replaced with levothyroxine slowly, as patients in this age group is susceptible for pseudotumor cerebri (due to fluid and electrolyte imbalance), hyperkinetic disorder, and poor scholastic performance with initial full-dose replacement. However, neonates, and pregnant women should be started with full doses of levothyroxine to normalize serum T4 level faster.

     
  1. 46.

    Who are predisposed for adrenal crisis on initiation of levothyroxine therapy?

    Patients with secondary hypothyroidism, long-standing isolated primary hypothyroidism, and primary hypothyroidism with polyglandular endocrine failure are predisposed for the development of adrenal crisis on initiation of levothyroxine therapy. Therefore, in these patients a 0800h sample for serum cortisol should be obtained and glucocorticoid replacement should precede levothyroxine supplementation. A 0800h serum cortisol <100 nmol/L confirms the diagnosis of adrenal insufficiency, while a value >550 nmol/L excludes it. Serum cortisol values in between 100–550 nmol/L require ACTH stimulation test later on. In patients with severe hypothyroidism who are critically ill, a random cortisol should be obtained and empiric intravenous hydrocortisone therapy should be initiated followed by administration of levothyroxine. A random serum cortisol <400 nmol/L suggest adrenal insufficiency, whereas a value >900 nmol/L suggest adequate adrenal reserve. Serum cortisol values in between 400–900 nmol/L requires ACTH stimulation test later on.

     
  1. 47.

    When should levothyroxine be administered?

    Levothyroxine is commonly administered early morning in fasting state as its absorption is interfered by food intake. A few studies have shown that bedtime supplementation of levothyroxine was better in suppressing TSH, as compared to morning dose; however, the participants in these studies had an interval of several hours before the last meal and levothyroxine intake. Therefore, the time of administration in relation with food intake seems to be more important than the time of day. Hence, the appropriate time for levothyroxine administration seems to be 1 h prior to breakfast or 4 h after the last meal.

     
  1. 48.

    How to assess the clinical response after levothyroxine therapy?

    The initial clinical response to levothyroxine therapy is polyuria, increase in heart rate, and weight loss, followed by improvement in appetite and amelioration of constipation (over weeks). Neuropsychiatric manifestations, hoarseness of voice, and cutaneous changes take a longer time to resolve (months). Hyponatremia, if present, is the earliest biochemical abnormality to ameliorate with treatment. Weight loss after optimal therapy with levothyroxine, even in patients with overt hypothyroidism, is around 3–5 kg and is due to excretion of GAG along with water. There is virtually no weight loss in patients with subclinical hypothyroidism with levothyroxine therapy.

     
  1. 49.

    How to treat a patient with coronary artery disease and overt hypothyroidism?

    Treatment of overt hypothyroidism in a patient with concurrent coronary artery disease depends on whether the patient is planned for coronary revascularization procedure or not. If coronary revascularization procedure is planned, then it should be contemplated first followed by initiation of levothyroxine in low doses, with gradual titration over a period of time. However, if the patient is not planned for coronary revascularization, then optimal antianginal therapy including β-blockers should be initiated prior to institution of levothyroxine treatment.

     
  1. 50.

    How to monitor a patient of primary hypothyroidism on levothyroxine therapy?

    In patients with primary hypothyroidism, serum TSH should be monitored after 6 weeks of initiation of levothyroxine therapy, with a target TSH between 0.45 and 4.12 μIU/ml or within laboratory reference range. However, recent literature shows that targeting TSH between 0.45 to <2.5 μIU/ml is associated with better improvement in quality of life and lipid profile. Failure to achieve TSH within target range requires dose adjustment. However, in elderly individuals, target TSH is higher and should be maintained in upper normal reference range, due to age-related increase in TSH. Sample for TSH should be taken in the morning hours and patient should not take levothyroxine tablet prior to sampling.

     
  1. 51.

    What are the conditions where TSH is not useful in monitoring treatment of hypothyroidism?

    The clinical situations where TSH is not useful in monitoring treatment of hypothyroidism are secondary hypothyroidism and in few infants with congenital hypothyroidism during initial months of life (as hypothalamo–pituitary–thyroid axis is reset at a higher level). In addition, TSH is not useful in patients with Graves’ disease who develop hypothyroidism while on antithyroid drugs or after radio-ablation, as TSH normalization takes a longer time. Therefore, in all these situations serum total/free T4 should be monitored and maintained in the upper normal range.

     
  1. 52.

    What are the causes of elevated TSH in a patient with primary hypothyroidism despite “optimal” LT 4 treatment?

    The most common cause of elevated TSH with normal T4 in a patient with primary hypothyroidism on treatment is intermittent administration of levothyroxine, as normalization of serum T4 occurs much faster than TSH. In addition, anti-mouse antibodies (heterophile antibodies) which interferes with TSH assay, presence of bioinactive but immunoreactive TSH, and occurrence of concurrent thyrotrope hyperplasia in a patient with long-standing hypothyroidism may also result in high TSH with normal T4. Rarely, polymorphism in type 2 deiodinase may also lead to persistently high TSH despite optimal levothyroxine therapy. The causes of elevated TSH with low T4 in a patient with hypothyroidism on levothyroxine therapy are poor compliance to treatment, inadequate spacing between the drug and food intake (1 h before breakfast or 4 h after the last meal), and concurrent administration of drugs interfering with levothyroxine absorption like iron, calcium, soya, and proton pump inhibitors. If these conditions have been excluded, then intake of high-fiber diet, celiac disease, inflammatory bowel disease, exocrine pancreatic insufficiency, and autoimmune gastritis should be excluded.

     
  1. 53.

    Is weekly levothyroxine therapy better than daily levothyroxine therapy?

    The need behind weekly levothyroxine therapy is to improve compliance to treatment as 82% of hypothyroid patients report noncompliance with daily dose of levothyroxine. The reasons for noncompliance include need for daily administration in fasting state, recommended lag time of 30–45 min between ingestion of tablet and food intake, and the need to avoid commonly used medications like iron and calcium which interfere with absorption of levothyroxine. To improve compliance, weekly levothyroxine therapy has been suggested. The rationale behind weekly levothyroxine therapy is based on the fact that LT4 has a half-life of 7 days. In a weekly regimen, seven times higher dose than the daily dose of levothyroxine is administered as a single dose once per week. Though administered once weekly, it is not a sustained release preparation of levothyroxine. In a recent study, there was no difference in serum TSH levels achieved with both the regimens, but free T4 levels were significantly higher in the initial 4 h after administration of LT4 with weekly regimen, but this was not accompanied with any symptoms of thyrotoxicosis or cardiac dysfunction. However, the data regarding nadir free T4 levels prior to the administration was not available. Further, the long-term safety data are not available particularly in elderly individuals; therefore, weekly regimen is currently not recommended.

     
  1. 54.

    What are anti-mouse antibodies?

    Heterophile antibodies are antibodies against specific animal immunoglobulins and human anti-mouse antibodies (HAMA) are the most common among them. These antibodies are produced in humans due to contact with animals or vaccination containing animal immunoglobulins and are IgG in nature. Anti-mouse antibodies interfere with the TSH assays leading to falsely high TSH value in the absence of primary thyroid dysfunction. HAMAs are present in up to 10% of normal individuals and 0.5% have clinically significant titers to interfere with TSH assay. To overcome this interference, newer TSH assays have included blocking reagents like polymerized murine IgG.

     
  1. 55.

    What is the role of iodine supplementation in patients with hypothyroidism?

    Iodine supplementation in patients with hypothyroidism on levothyroxine replacement has no added advantage in improving thyroid function. However, routine iodized salt intake should be continued as iodine has many extra-thyroidal advantages, which include improvement in pregnancy outcome, antioxidant and anticancer properties, and suppression of autoimmunity.

     
  1. 56.

    How to treat a patient with hypothyroidism due to iodine deficiency?

    Levothyroxine is the treatment of choice for hypothyroidism due to iodine deficiency. In fact, therapeutic doses of stable iodine should be avoided in these patients because it may induce Jod–Basedow’s phenomenon, as patients with long-standing iodine deficiency may harbor thyroid nodules. In addition, iodine deficiency-associated hypothyroidism may have concurrent Hashimoto’s thyroiditis and stable iodine treatment in such a scenario may induce iodide myxedema due to permanent Wolff–Chaikoff’s effect. Therefore, inadvertent use of stable iodine (e.g., Lugol’s solution) in the management of hypothyroidism should be avoided. However, iodine supplementation in the form of iodized salt should be continued.

     
  1. 57.

    How to supplement iodine for daily requirement?

    Iodine is an essential element for thyroid health. Iodine is present in alluvium soil and seawater. Therefore, vegetations grown in iodine-rich soil and food of marine origin are ample source of iodine. Because of recurrent floods and consequent soil erosion, iodine is leached away from the soil. Therefore, there is a need to provide iodine through a vehicle which is widely used by the people. This vehicle may be water, milk, salt, wheat flour, or bread. Common salt is universally and consistently consumed; hence, it is the preferred medium to deliver recommended daily allowance for iodine. Potassium iodate (KIO3), the most stable iodine compound, is used to iodize the common salt. The usual concentration of iodide in salt is 15–20 ppm (1 ppm is equivalent to 1 mg per kg). To provide the RDA of 150 μg iodine with strength of 20 ppm, intake of 10 g salt per day is required. This will have 200 μg of KIO3, which will be approximately equivalent to 150 μg of elemental iodine.

     
  1. 58.

    What are the precautions required for the optimal delivery of iodine from iodized salt?

    The following precautions should be observed while using iodized salt. Salt should be purchased within 3 months of manufacturing date, and at time of purchase, it should be crystal clear and white. It should be stored in a dry airtight container along with plastic pack and should be kept away from the furnace. Once the pack is opened, it must be consumed within 4 weeks. Salt should preferably be added on the table rather than during cooking, as iodine quickly sublimates on exposure to heat.

     
  1. 59.

    Does the treatment strategy differ in secondary hypothyroidism?

    In patients with secondary hypothyroidism, assessment of other pituitary hormones is mandatory and glucocorticoid replacement should be initiated prior to levothyroxine therapy, as there is a risk of precipitating adrenal crisis. Requirement of levothyroxine is usually lower in patients with secondary hypothyroidism, as TSH-independent thyroid hormone biosynthesis (15%) continues despite TSH deficiency. However, the requirement of levothyroxine increases with concomitant growth hormone or estrogen replacement. Serum T4 should be monitored in patients with secondary hypothyroidism on levothyroxine therapy and targeted within the upper range of normal. After optimal replacement with glucocorticoids and/or levothyroxine, there may be unmasking of central diabetes insipidus, as both these hormones are counteractive to antidiuretic hormone.

     
  1. 60.

    Is hypothyroidism a contraindication for emergency surgery?

    Hypothyroidism is not a contraindication for emergency surgery. These patients should be supplemented with levothyroxine and can be subjected to emergency surgery even without normalization of serum T4. Perioperatively, these patients should be monitored for hypotension, hyponatremia, hypoglycemia, and paralytic ileus. Postoperatively, they may have difficulty in weaning from ventilator, bleeding diathesis, and central nervous system depression due to anesthetic agents. However, in patients with overt hypothyroidism planned for elective surgery, serum T4 but not essentially TSH should be normalized as it is the circulating T4 which determines the metabolic status and not the TSH. Patients with subclinical hypothyroidism can be taken up for surgery even without levothyroxine supplementation as circulating T4 is normal in them. However, if treatment is indicated for subclinical hypothyroidism, levothyroxine should be initiated, but normalization of TSH prior to surgery is not warranted.

     
  1. 61.

    What are the conditions which require higher doses of levothyroxine?

    Requirement of levothyroxine is increased by 30% in the second trimester of pregnancy and by 50% in third trimester. Similarly, patients on oral contraceptives/hormone replacement therapy also require higher doses. In addition, patients having malabsorption (e.g., celiac disease, jejunal bypass surgery) also need higher doses of levothyroxine. Concomitant use of drugs which are enzyme inducers like rifampicin, carbamazepine, phenytoin, growth hormone, and sertraline also mandates increment of levothyroxine dose. However, drugs interfering with levothyroxine absorption like iron, calcium, proton pump inhibitors, oral bisphosphonates, soya, sucralfate, orlistat, phosphate binders, and aluminum hydroxide need spacing for at least 4–6 h after levothyroxine administration.

     
  1. 62.

    How to treat patients with persistent symptoms of hypothyroidism, despite optimal treatment with levothyroxine?

    All patients may not have complete resolution of symptoms despite optimal replacement with levothyroxine and TSH in the target range. These symptoms include lack of weight loss, fatigue, and mood-related disorders. This is usually because of false perception and undue expectations with levothyroxine therapy or rarely resistance to thyroid hormone predominantly at the peripheral level. Some of these patients may benefit with the combined use of levothyroxine and liothyronine, but the data is not supportive.

     
  1. 63.

    What is the role of selenium in thyroid disease?

    Metallic elements act as a cofactor in most of the biological reactions, but selenium is an exception. Selenium is incorporated co-translationally into polypeptide chain as selenocysteine and forms selenoproteins. Thyroid gland contains more selenium per gram of tissue than any other organ. The important selenoproteins are iodothyronine deiodinases, glutathione peroxidase, and thioredoxin reductase; the latter two are antioxidants. Selenium deficiency contributes to malfunction of these selenoproteins and may contribute to the development of autoimmune thyroid disease, goiter, and endemic cretinism.

     
  1. 64.

    Is routine supplementation of selenium advised?

    Although not robust, some data support that selenium supplementation may reduce anti-TPO antibody levels, decrease the incidence of postpartum thyroiditis, and may be beneficial in thyroid-associated ophthalmopathy. However, selenium use is associated with an increased risk of developing diabetes mellitus. Thus, routine supplementation of selenium is not advised.

     
  1. 65.

    What is myxedema coma?

    Myxedema coma is a rare, life-threatening disorder usually seen in those with long-standing, untreated primary hypothyroidism. Rarely, patients with secondary hypothyroidism may also present as myxedema coma. It is characterized by altered mental state, hypoventilation, and hypothermia. Other characteristic features include hypotension, hypoxia, hypercapnia, hyponatremia, hypoglycemia, and heart failure. Myxedema coma is commonly seen in elderly women, especially during winter. Cold exposure, infection, drugs (e.g., diuretics, sedatives, and tranquilizers), trauma, stroke, heart failure, and gastrointestinal bleed are the usual precipitating factors. Euthermia in a patient with myxedema coma suggests the presence of infection. Free/total T4 and T3 are characteristically low and TSH is high, although it may not be grossly elevated because of severe systemic illness.

     
  1. 66.

    How to treat myxedema coma?

    Recognition and rapid initiation of treatment is important as myxedema coma is associated with high mortality (20–30%). Maintenance of airway and ventilation, restoration of intravascular volume, and identification and treatment of precipitating events improve outcome. Intravenous T4 is preferred, over oral administration of levothyroxine, as oral levothyroxine may be less effective due to impaired gastrointestinal absorption and paralytic ileus. However, some clinical studies have shown that the route of administration of levothyroxine (oral/intravenous) does not influence the outcome. A bolus of 300–500 μg T4 intravenously followed by 50–100 μg daily is recommended, until oral medications can be initiated. If intravenous T4 is not available, then a 500 μg oral loading dose of levothyroxine followed by 100 μg daily is an alternative option. Use of T4 is advocated because it results in steady and smooth levels of serum T4, but it has a slow onset of action and impaired T4 to T3 conversion in critical illness does not yield the optimal levels of T3 required for metabolic action. Use of T3 is suggested because of its greater biologic activity and rapid onset of action; however, it is associated with wide fluctuations in serum levels and increased risk of cardiovascular events. Because of these advantages and limitations, some prefer the combined use of T4 and T3. However, there is robust clinical data to suggest that use of T4 alone is associated with favorable outcome. Intravenous hydrocortisone in stress doses (100 mg bolus followed by 4 mg/h infusion) should be supplemented in all patients anticipating adrenal crisis after T4 therapy. Glucocorticoids also maintain water and sodium homeostasis. Other supportive measures include passive rewarming with blankets, correction of hypoglycemia, use of appropriate antibiotics, and use of vasopressors in fluid refractory hypotension. Digoxin, diuretics, hypotonic fluids, and active rewarming should be avoided. Poor prognostic factors include advanced age and associated comorbidities like heart failure and sepsis. Outcome is better in levothyroxine naive patients as compared to defaulters, as defaulters have no residual thyroid function.

     
  1. 67.

    How is Hashimoto’s encephalopathy different from myxedema coma?

    Myxedema coma is a complication of long-standing, untreated primary hypothyroidism and is invariably associated with low/undetectable T4, whereas Hashimoto’s encephalopathy (HE) is an immune-mediated cerebral disorder associated with autoimmune thyroiditis and high titers of anti-TPO antibody, usually with normal thyroid function. Hashimoto’s encephalopathy (HE) is steroid responsive, while levothyroxine is the primary treatment of myxedema coma.

     
  1. 68.

    What are the salient features of Hashimoto’s encephalopathy?

    Hashimoto’s encephalopathy is a disorder characterized by altered mental state, seizures, myoclonus, ataxia, memory loss, and hyperreflexia. It is more common in women and in those who have HLA-B8/DRw3 haplotype. These patients are usually euthyroid, but can either be hypothyroid or hyperthyroid. Presence of high titer of anti-TPO antibody and/or anti-thyroglobulin antibody is essential for diagnosis but the antibodies are neither involved in pathogenesis nor does the titer correlate with the severity of disease. The autoantibody against enzyme α-enolase is a specific marker for Hashimoto’s encephalopathy. Elevated cerebrospinal fluid protein concentration and electroencephalographic changes like slowing of background activity, triphasic waves, and frontal intermittent rhythmic delta activity (FIRDA) are seen in 80–90% of the patients, but are not specific. MR imaging is usually normal but may demonstrate cerebral atrophy or nonspecific T2 signal abnormalities in the subcortical white matter. However, due to the lack of a sensitive and specific marker, Hashimoto’s encephalopathy is a diagnosis of exclusion.

     
  1. 69.

    How to treat Hashimoto’s encephalopathy?

    Hashimoto’s encephalopathy is steroid responsive and recently has been renamed as “steroid-responsive encephalopathy with autoimmune thyroiditis (SREAT).” Treatment includes glucocorticoid and in the presence of hypothyroidism, levothyroxine should be added. Other immunosuppressive drugs like azathioprine or cyclophosphamide may be used in patients who either do not respond to steroids or relapse during treatment. The recovery is rapid (days to weeks) and prognosis is usually good, if diagnosed early.

     
  1. 70.

    What are the uses of levothyroxine in non-thyroidal diseases?

    Levothyroxine has been tried in the management of obesity, dyslipidemia, heart failure, and refractory depression even in patients without hypothyroidism. Use of levothyroxine in these non-thyroidal diseases was based on the fact that patients with hypothyroidism who had these abnormalities recovered on treatment with levothyroxine. However, no study has established the efficacy of levothyroxine in patients with these disorders who have normal thyroid function tests. On the contrary, over-replacement may be deleterious and may result in decreased lean mass, osteoporosis, and increased risk of atrial fibrillation.

     
  1. 71.

    What are thyromimetics?

    Thyromimetics are designer drug molecules with tissue-specific actions based on their differential affinity to TRα or TRβ receptors. TRα receptor is expressed in heart and skeletal muscle and regulates heart rate and resting energy expenditure in muscle, respectively. TRβ1 receptor is predominantly expressed in liver and regulates cholesterol and lipoprotein metabolism and can be targeted in the treatment of dyslipidemia and nonalcoholic fatty liver disease. TRβ2 receptor in thyrotropes is involved in T3-mediated feedback regulation and has prompted the use of thyromimetics in the management of resistance to thyroid hormone and in thyrotropinoma.

     
  1. 72.

    Why are infections of thyroid gland uncommon?

    Rich blood supply, profuse lymphatic drainage, adherent thick capsule, and high iodine content of thyroid gland are effective barriers which prevent the lodgment of microorganisms and consequently infection of the thyroid gland. However, tuberculosis and Pneumocystis jirovecii may affect thyroid gland, particularly in those who are immunocompromised.

     
  1. 73.

    Do patients with primary hypothyroidism need screening for other autoimmune endocrine disorders?

    No. The pretest probability of finding other autoimmune endocrine disorder in association with primary hypothyroidism is very low (3%); therefore, screening for other autoimmune endocrine disorder is not recommended.

     

Suggested Reading

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    Braverman LE, Cooper D. Werner & Ingbar’s The Thyroid, 10e A fundamental and clinical text. Wolters Kluwer Health. Lippincott Williams & Wilkins; 2012.Google Scholar
  2. 2.
    Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine Pract. 2012;18(6):988–1028.CrossRefGoogle Scholar
  3. 3.
    Larry JJ, De Groot LJ. Endocrinology. Adult and pediatric. Philadelphia: Elsevier Health Sciences; 2010.Google Scholar
  4. 4.
    Longo D, Anthony F, Dennis K, Stephen H, Jameson J, Loscalzo J. Harrison’s principles of internal medicine 18E EB. McGraw Hill Professional; 2012.Google Scholar
  5. 5.
    Melmed S, Polonsky KS, Reed Larsen P, Kronenberg HM. Williams textbook of endocrinology: expert consult. London: Elsevier Health Sciences; 2011.Google Scholar

Copyright information

© Springer India 2015

Authors and Affiliations

  • Anil Bhansali
    • 1
  • Yashpal Gogate
    • 2
  1. 1.Department of EndocrinologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia
  2. 2.Harmony Health HubNasikIndia

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