Hypothyroidism as a clinical syndrome was described in 1874 by Gull under the name of myxedema in view of the swollen skin (edema) and its excessive content of mucin (myx-). In 1883, Semon noted striking similarities between patients with myxedema and patients who had undergone total thyroidectomy. The Clinical Society of London nominated a committee to investigate this matter. In 1888, the committee reported in what has become a classic paper ³ that cretinism, myxedema, and postthyroidectomy changes all were due to loss of thyroid function. In 1891, Murray reported cure of myxedema by hypodermic injections of sheep thyroid extract. Simply eating ground or dried animal thyroid tissue proved equally effective. The active principle of thyroid extract was isolated by Kendall on Christmas Day, 1914, and was named thyroxine. Harrington elucidated the precise constitution of thyroxine in 1926 and was able to synthesize it. Desiccated thyroid remained the usual treatment for hypothyroidism, however, because thyroxine was more expensive and less efficacious owing to poor absorption of the free acid. As of the 1960s, levothyroxine sodium surplanted gradually desiccated thyroid as the preferred treatment modality for hypothyroidism.

Primary hypothyroidism is a common disease worldwide, especially in iodine-deficient areas. It also is a prevalent disease in iodine-replete regions. The most extensive epidemiologic data have been obtained from a population-based study of subjects 18 years old and older in Whickham County in northeast England (Table 14-1).^4,5 The initial survey was done between 1972 and 1974, with a follow-up 20 years later. The data seem representative of other countries inasmuch as similar figures have been reported from Sweden, Japan, and the United States.⁶ Most striking are the high prevalence (especially of subclinical hypothyroidism), the marked female preponderance, and the increasing occurrence with advancing age. The mean age at diagnosis of hypothyroidism in women is 60 years. Most cases are due to chronic autoimmune thyroiditis (incidence of 3.5 per 1000 women per year), followed by destructive treatment for thyrotoxicosis (incidence of 0.6 per 1000 women per year). The probability of spontaneous hypothyroidism developing in women at a particular time increases with age: from 1.4 per 1000 per year at ages 20 to 25, to 14 per 1000 per year at 75 to 80 years. Risk factors for progression to overt hypothyroidism include the presence of thyroid autoantibodies and an already elevated TSH (Table 14-2). The risk correlates directly with the serum concentration of thyroid peroxidase autoantibodies and with the extent of the TSH increase. The probability that hypothyroidism will develop increases even at TSH levels in the high-normal range of 2 to 5 mU/L, independent of age or antibody status.^5,7

Table 14-1

Prevalence and Incidence of Primary Hypothyroidism in Adults as Established in the Whickham Survey

Data from Tunbridge et al⁴ and Vanderpump et al.⁵

Table 14-6

Characteristics and Treatment of Myxedema Coma

Hypothyroxinemia	Large doses of intravenous levothyroxine
Hypothermia	Blankets, no active rewarming
Hypoventilation	Mechanical ventilation
Hypotension	Cautious volume expansion with crystalloid or whole blood
Hyponatremia	Mild fluid restoration
Hypoglycemia	Glucose administration
Hypocortisolemia	Glucocorticoid administration
Precipitating event	Identification and elimination by specific treatment

Pathogenesis

The various causes of hypothyroidism can be classified according to their site of interference (in the hypothalamus-pituitary, in the thyroid gland, or in the peripheral target tissues) and their nature (organic lesions resulting in loss of functional tissue, or functional disturbances resulting in deficient hormone biosynthesis and release) (Table 14-3). Most cases of hypothyroidism are acquired and permanent; congenital hypothyroidism and transient forms of hypothyroidism are in the minority.

Table 14-2

Percentage of Women Acquiring Spontaneous Primary Hypothyroidism During 20 Years of Follow-up in the Whickham Survey

TSH, Thyroid-stimulating hormone.

Data from Vanderpump et al⁵ and Wang and Crapo.⁶

Central Hypothyroidism

Reduced T₄ secretion in central hypothyroidism is due to insufficient stimulation of the thyroid gland by TSH, which is caused by lesions in the pituitary (secondary hypothyroidism) or the hypothalamus (tertiary hypothyroidism resulting from deficient thyrotropin-releasing hormone [TRH] release). The term central hypothyroidism is preferred because lesions sometimes involve both sites, which prevents clear-cut distinction. Although an absent TSH response to exogenous TRH would suggest a pituitary cause, and a delayed response would suggest a hypothalamic cause,⁸ the TSH profiles after TRH are not well correlated to the anatomic site of the lesion. Basal serum TSH values in central hypothyroidism can be low, normal, or even slightly elevated (up to 10 mU/L).^9,10 The apparent paradox of central hypothyroidism in the presence of a normal or increased serum TSH concentration is explained by the reduced biological activity of TSH in these patients related to abnormal sialylation of TSH. Central hypothyroidism also is associated with a decreased nocturnal TSH surge (because of loss of the usual nocturnal increase in TSH pulse amplitude, but not TSH pulse frequency), which might hamper further maintenance of normal thyroid function.^11,12

The prevalence of central hypothyroidism in the general population is unknown; a rough estimate is 0.005%. The sex distribution is about equal, and central hypothyroidism occurs with peaks in childhood and in adults 30 to 60 years old.¹³ Congenital cases are due to pituitary hypoplasia, midline defects such as septo-optic dysplasia (TSH deficiency in 20%), Rathke’s pouch cysts, or rare loss-of-function mutations in genes encoding for TRH receptors, the TSH-β subunit, or pituitary transcription factors. Childhood cases are caused most often by craniopharyngioma (TSH deficiency in 53%) or cranial irradiation for brain tumors (TSH deficiency in 6%).¹⁴ Adult cases most frequently are due to pituitary macroadenomas (hypothyroidism in 10% to 25%) and pituitary surgery or irradiation. TSH deficiency caused by loss of functional tissue usually becomes manifest after the development of growth hormone and gonadotropin deficiency.¹³ TSH deficiency sometimes may disappear after selective adenomectomy.¹⁵ Cranial radiotherapy for brain tumors causes hypothyroidism in 65%, depending on the radiation dose; the onset varies between 1 and 26 years after irradiation.¹⁶

Radiotherapy for pituitary tumors is followed by hypothyroidism in at least 15% (55% when combined with surgery).¹⁷ Less common causes include traumatic brain injury and subarachnoid hemorrhage,¹⁸ ischemic necrosis from postpartum hemorrhage (Sheehan’s syndrome) and severe shock, pituitary apoplexy (hemorrhage in a pituitary adenoma), infiltrative diseases, and lymphocytic hypophysitis.¹⁹ Lymphocytic hypophysitis most likely is an autoimmune disease that occurs predominantly in women during pregnancy and the postpartum period and is characterized by a pituitary mass and hypopituitarism.¹⁹ Despite the many known causes of central hypothyroidism, idiopathic cases are still encountered.

In critically ill patients receiving dopamine, serum TSH and the T₄ production rate decrease by 60% and 56%, respectively, as a result of direct inhibition of pituitary TSH.²⁰ Transient functional inhibition of TSH release is observed after withdrawal of long-term levothyroxine suppressive therapy, which may last 6 weeks.²¹ Glucocorticoid excess dampens pulsatile TSH release, which rarely results in decreased serum FT₄.²² Octreotide therapy does not cause hypothyroidism despite its inhibition of TSH secretion. High doses of bexarotene, a specific retinoid X receptor agonist used in the treatment of cutaneous T cell lymphoma, cause central hypothyroidism by strongly inhibiting TSH secretion.²³

Chronic Autoimmune Thyroiditis

Hypothyroidism secondary to chronic autoimmune thyroiditis is caused mainly by destruction of thyrocytes. The goitrous variant (hypothyroid Hashimoto’s goiter) is characterized by massive lymphocytic infiltration of the thyroid with the formation of germinal centers, oxyphilic changes in thyrocytes called Hürthle or Askanazy cells, and some fibrosis. In the atrophic variant (atrophic myxedema), fibrosis is the predominant feature, along with lymphocytic infiltration. The less common goitrous variant is characterized by a diffuse goiter of firm “rubbery” consistency; the histology remained essentially unaltered after 20 years, and the goiter did not regress despite T₄ treatment in 43% of cases.²⁴ Many patients with chronic autoimmune thyroiditis are euthyroid, and a few have an initial transient hyperthyroid stage (labeled as Hashitoxicosis). Hashimoto’s disease is used by many authors as an umbrella term to indicate autoimmune-mediated destruction of thyrocytes, frequently but not always resulting in hypothyroidism, as opposed to Graves’ disease, in which TSH receptor–stimulating antibodies usually result in hyperthyroidism. The two disease entities overlap and can be viewed as opposite ends of a continuous spectrum of thyroid autoimmunity. Destruction of thyrocytes and development of hypothyroidism in Hashimoto’s disease are mediated by cytotoxic T cells and cytokines (especially interferon-γ and tumor necrosis factor) released by infiltrating T cells and macrophages. Humoral immunity appears less important in this respect, but (a subset of) thyroid peroxidase (TPO) antibodies may contribute via antibody-dependent, cell-mediated cytotoxicity, complement-mediated cytotoxicity, and inhibition of TPO enzymatic activity. TSH receptor–blocking antibodies enhance thyroid atrophy and hypothyroidism, possibly also by inducing apoptosis; their prevalence is low except in Japanese patients.²⁵

Genetic and environmental factors enhance the susceptibility of individuals to develop the disease and may determine the direction of the evolving autoimmune reaction. Autoimmune thyroid disease runs in families (80% of patients have a positive family history) and is four to ten times more common in women. Autoimmune hypothyroidism in whites is weakly associated with HLA-DR and CTLA4 polymorphisms; other, still unidentified genes probably are involved. Iodine intake has been identified as an environmental factor because the prevalence of autoimmune hypothyroidism is higher in iodine-replete than in iodine-deficient areas,²⁶ and the incidence increases after supplemental iodine is introduced. Smoking decreases the risk for developing TPO antibodies and hypothyroidism.²⁷

Reversible Autoimmune Hypothyroidism

Chronic Autoimmune Thyroiditis

Autoimmune hypothyroidism may revert spontaneously into euthyroidism in connection with the disappearance of TSH receptor–blocking antibodies.²⁸ The presence of a goiter and high thyroidal radioiodine uptake increase the likelihood of spontaneous recovery.²⁹ The incidence of spontaneous recovery is about 5%,³⁰ but in Japan—in the face of a high ambient iodine intake—iodide restriction alone restores euthyroidism in one third of patients.²⁹ Autoimmune hypothyroidism, however, is permanent in most patients. Peculiar cases of alternating hypothyroidism and hyperthyroidism are explained by changes in coexisting TSH receptor–blocking and TSH receptor–stimulating antibodies.³¹

Silent and Postpartum Thyroiditis

Silent or painless thyroiditis and postpartum thyroiditis are variant forms of chronic autoimmune thyroiditis. Thyroid histology shows lymphocytic infiltration with no germinal centers or fibrosis. The autoimmune attack is intense (resulting mainly in T cell–mediated destructive thyroiditis) but transient, which explains the characteristic pattern of transient thyrotoxicosis followed by transient hypothyroidism in the recovery stage. Each stage lasts 2 to 8 weeks. Most patients remain asymptomatic and revert spontaneously to euthyroidism. Occurrence is common in the first year after delivery: The incidence of postpartum thyroiditis is 4% to 6% and 25% in patients with type 1 diabetes mellitus.32–34 Several patterns are recognized: Thyrotoxicosis alone occurs in 38%, thyrotoxicosis followed by hypothyroidism occurs in 26%, and hypothyroidism alone occurs in 36%. TPO antibodies in serum of 100 kU/L or greater at 12 weeks’ gestation predict to a certain extent postpartum thyroiditis (positive predictive value 0.50, negative predictive value 0.98).³³ Thyroid antibody titers decrease in the second and third trimesters and increase postpartum. Women with postpartum thyroiditis are at risk for recurrent postpartum thyroiditis after delivery (about 40%) and for permanent hypothyroidism (20% to 30% after 5 years) related to higher antibody titers and absence of a thyrotoxic phase.

Cytokine-Induced Thyroiditis

Treatment for malignant tumors or for hepatitis C or B with interleukin-2 or interferon-α is causally related to the de novo occurrence of TPO antibodies and the development of thyroid dysfunction.35,36 Typical features are similar to features of silent and postpartum thyroiditis and include sudden onset, biphasic pattern of thyrotoxicosis followed by hypothyroidism (although hypothyroidism alone is most frequent), and spontaneous resolution after discontinuation of treatment. The incidence is about 6%; risk factors include female sex and preexisting TPO antibodies.³⁶

Postoperative and Postirradiation Hypothyroidism

Surgery

Total thyroidectomy results in overt hypothyroidism within 1 month. Subtotal thyroidectomy for Graves’ hyperthyroidism is followed by hypothyroidism in 40% after 10 years ³⁷; risk factors include a small thyroid remnant, lymphocytic infiltration, and subsequent exposure to iodine. Most patients become hypothyroid in the first year after surgery; thereafter, the cumulative incidence of hypothyroidism increases by only 1% to 2% per year. Immediate postoperative hypothyroidism does not always indicate permanent hypothyroidism; it may resolve spontaneously by 6 months. Subtotal thyroidectomy for (toxic) nodular goiter carries a much lower risk (about 15%) for postoperative hypothyroidism.

Radioactive Iodine

Radioactive iodine (¹³¹I) treatment for Graves’ hyperthyroidism results in a cumulative incidence of hypothyroidism of 70% after 10 years,³⁷ depending on the dose of ¹³¹I administered. Most cases occur in the first year (spontaneous return to euthyroidism is observed in some patients); thereafter, the annual incidence of hypothyroidism is 0.5% to 2%, also related to persisting chronic autoimmune thyroiditis. Hypothyroidism after ¹³¹I treatment for toxic nodular goiter is less common (6% to 13%).³⁸ ¹³¹I treatment for nontoxic goiter to reduce goiter size carries a cumulative risk of 58% for the development of hypothyroidism in 8 years, the risk being related to the (relatively high) dose of ¹³¹I and the presence of TPO antibodies.³⁹ Hypothyroidism caused by ionizing radiation has been reported in subjects exposed to atomic or hydrogen bomb explosions.

External Irradiation

External radiotherapy of the neck for Hodgkin’s or non-Hodgkin’s lymphoma causes hypothyroidism in 25% to 50% of patients; the risk is related to the radiation dose, the use of iodine-containing contrast agents before radiotherapy, and the duration of follow-up.⁴⁰ The risk is decreased when the thyroid is shielded during mantle field irradiation. External radiotherapy for head and neck cancer has an actuarial risk of 40% for the development of subclinical hypothyroidism and 15% for overt hypothyroidism 3 years after treatment.⁴¹ Another study with a median follow-up of 4.4 years reports a 5-year incidence rate of 48%, with a median time of 1.4 years (range, 0.3 to 7.2 years) to the onset of elevated TSH values.⁴² Total body irradiation with subsequent bone marrow transplantation for acute leukemia or aplastic anemia is associated with (mainly subclinical) hypothyroidism in about 25% and usually occurs after 1 year; it is transient in half of patients.⁴³

Infiltrative and Infectious Diseases

A rare cause of hypothyroidism is thyroidal infiltration by systemic disease.⁴⁴ Hypothyroidism is observed in the course of invasive fibrous thyroiditis of Riedel’s (30% to 40%), cystinosis (86% in adults), progressive systemic sclerosis, and amyloidosis. Infections of the thyroid gland are rare and are associated with preexisting thyroid disease and immunocompromising conditions. Occasionally, damage to the thyroid causes hypothyroidism. In contrast, hypothyroidism in the recovery phase of subacute thyroiditis of de Quervain (related to previous viral infections) is a common event.

Congenital Hypothyroidism

Congenital hypothyroidism can be permanent (incidence 1 in 3100 newborns) or transient. Causes include loss of functional thyroid tissue (thyroid dysgenesis), functional defects in thyroid hormone biosynthesis (related to loss-of-function mutations in genes encoding for the TSH receptor, Na⁺/I⁻ symporter, thyroglobulin, TPO, dual oxidase 2, or dehalogenase 1), and thyroid hormone resistance (mutated TRβ).

Iodine Deficiency and Iodine Excess

Hypothyroidism can be caused by iodine deficiency or iodine excess. Inorganic iodide in excess of daily doses of 500 to 1000 µg inhibits organification of iodide, known as the Wolff-Chaikoff effect. Usually, the thyroid gland escapes the Wolff-Chaikoff effect after several weeks because autoregulatory mechanisms inhibit thyroid iodide transport, and the intrathyroidal iodine concentration consequently falls below the level required for inhibition of organification. Failure to escape results in hypothyroidism, which occurs in the presence of underlying thyroid disease, such as chronic autoimmune thyroiditis, previous subacute or postpartum thyroiditis, and ¹³¹I or surgical therapy.⁴⁵ Iodide-induced hypothyroidism may be due to inorganic iodide or organic iodine compounds that are deiodinated in vivo. Sources of iodine excess include an iodine-rich diet (e.g., in Japan with high consumption of seaweed²⁹) and iodine-containing medications, such as potassium iodide, vitamins, kelp, topical antiseptics, radiographic contrast agents, and amiodarone.⁴⁵ The incidence of amiodarone-induced hypothyroidism in areas with high environmental iodine intake is higher than in areas with low iodine intake (22% and 5%)⁴⁶; cases occur predominantly in the first 18 months of amiodarone treatment, especially in women with preexisting thyroid antibodies.⁴⁷

Drug-Induced Hypothyroidism

Drugs that cause hypothyroidism through interference with thyroid hormone production or release in the thyroid gland ⁴⁸ include thiouracils and imidazoles (used as treatment for thyrotoxicosis), lithium, cytokines (see Reversible Autoimmune Hypothyroidism), iodine (see Iodine Deficiency and Iodine Excess), and a variety of environmental and industrial goitrogenic chemicals. Examples of the latter group include naturally occurring goitrogens, such as flavonoids and resorcinol (present in watersheds of the coal-rich and shale-rich regions of Colombia and Kentucky), and industrial pollution with polychlorinated biphenyls. Lithium inhibits thyroidal iodide transport and release of T₄ and T₃. Long-term lithium treatment results in goiter in 50%, subclinical hypothyroidism in about 20%, and hypothyroidism in about 20%; goiter and hypothyroidism usually occur in the first 2 years of treatment, especially in patients with preexisting thyroid antibodies. Tyrosine kinase inhibitors like sunitinib induce hypothyroidism in about 50%; the responsible mechanism is incompletely understood.^49,50

Consumptive Hypothyroidism

Hepatic and cutaneous hemangiomas often express high levels of type 3 iodothyronine-5-deiodinase (D₃), which catalyzes the conversion of T₄ and T₃ into biologically inactive rT₃ and 3,3′-T₂. In infants with large hemangiomas, hypothyroidism can occur as the result of D₃-induced degradation of thyroid hormone at rates that exceed the synthetic capacity of the thyroid gland.51,52 Removal of the tumor restores euthyroidism.

Clinical Features

Systemic manifestations vary considerably, depending on the cause, duration, and severity of the hypothyroid state. The characteristic clinical finding is slowing of physical and mental activity and many organ functions. The characteristic pathologic finding is accumulation of hyaluronic acid and other glycosaminoglycans in interstitial tissue, which is related to loss of the inhibitory effects of thyroid hormone on the synthesis of hyaluronate, fibronectin, and collagen by fibroblasts.⁵³ The hydrophilic properties of glycosaminoglycans lead to a peculiar mucinous nonpitting edema (myxedema) that is most obvious in the dermis but can be present in many organs.

Energy and Nutrient Metabolism

Thyroid hormone deficiency causes slowing of a wide variety of metabolic processes, which results in decreased resting energy expenditure, oxygen consumption, and use of substrates. Reduced thermogenesis is related to the characteristic cold intolerance of hypothyroid patients. The decline in metabolic rate and substrate use contributes to decreased appetite and food intake. Body weight increases on average by 10% because of an increase in body fat and retention of water and salt.

Serum leptin in some but not all studies is slightly low, returning to normal levels after treatment.54,55 Whether thyroid hormone regulates leptin secretion independent of body mass index and body fat remains controversial.^56,57 The other adipocytokines have normal (adiponectin) or slightly low (resistin) serum concentrations.⁵⁵ Hypothyroidism delays glucose absorption from the intestine. Insulin secretion in response to oral glucose is appropriate for the slightly flattened oral glucose tolerance curve. Hepatic gluconeogenesis and glucose use usually remain normal, and blood glucose levels are maintained within normal limits. The occurrence of hypoglycemia in hypothyroid patients should alert the physician to concomitant diseases (e.g., hypopituitarism). The development of hypothyroidism in patients with insulin-dependent diabetes mellitus may require lowering of the insulin dose to counteract the decreased rate of insulin degradation.

Synthesis and degradation of proteins are reduced in hypothyroidism; one of the obvious consequences during childhood is impaired growth. Biosynthesis of fatty acids and lipolysis also are reduced. An increase in total cholesterol in serum occurs, largely as the result of an increase in low-density lipoprotein (LDL)-cholesterol (explained by decreased expression of the T₃-responsive liver LDL receptor, which is involved in LDL clearance), combined with an increase in apolipoprotein B, lipoprotein (a), and possible triglycerides.⁵⁸ An increase in the oxidizability of LDL particles occurs,⁵⁹ along with a decrease in the metabolism of serum remnant-like particles reflecting chylomicrons and very low-density lipoprotein (VLDL) remnants.⁶⁰ HDL2 but not HDL3 is increased modestly with higher apoprotein AI but not AII. The changes in serum lipids result in an atherogenic lipid profile that is reversible upon treatment.

Skin and Appendages

Skin changes are prevalent among hypothyroid patients. The skin is dry, pale, thick, and rough with scales, and it feels cold. Dryness is related to decreased function of sebaceous and sweat glands. Pallor is related to decreased skin blood flow and anemia. Yellowish discoloration of the skin may be present, especially on the palms and soles, because of the deposition of carotene, which is converted to a lesser extent to vitamin A. The thick rough skin with scales is caused by mucinous swelling of the dermis and hyperkeratosis of the stratum corneum in the epidermis. The nonpitting swelling is most marked in the extremities and the face and gives rise to the so-called myxedema face (Fig. 14-2). This classic appearance of primary hypothyroidism is seen less often nowadays, probably because of earlier diagnosis achieved by widespread use of the TSH assay. The hair becomes dull, coarse, and brittle. Hair loss occurs in 50%; it usually is diffuse and involves the scalp, beard, and genital hair and less often the eyebrows. Nail deformities also are common: The nails become thin and brittle, have grooves, and grow more slowly.

FIGURE 14-2 Appearance of a 47-year-old man 12 years (A), 5 years (B), and 3 years (C) before hypothyroidism secondary to atrophic myxedema (D) was diagnosed. Note the typical myxedema face characterized by puffy nonpitting swelling of the skin and coarse facial features. (Reproduced with permission of the patient.)

Nervous System

Thyroid hormones are essential for normal brain development; congenital hypothyroidism, if left untreated, results in mental retardation and neurologic abnormalities. In adult hypothyroid patients, a generalized decrease in regional cerebral blood flow and in cerebral glucose metabolism has been shown.⁶¹ Studies using phosphorus 32 nuclear magnetic resonance spectroscopy of the frontal lobe of adult hypothyroid patients reported reversible alterations in phosphate metabolism.⁶² The low-voltage electroencephalogram, prolonged central motor conduction time, and reduced visual and somatosensory-evoked potential amplitude with longer latency in adult hypothyroid patients are reversible with T₄ treatment. These findings indicate that the adult human brain is a thyroid hormone–responsive organ and provide a biological basis for the prevalent neurobehavioral symptoms and cognitive impairment associated with adult hypothyroidism.^61,63,64

Typically, a hypothyroid patient is slow in movement and thought, is less alert, and is less able to concentrate and memorize. Speech becomes slow and often hoarse. Hearing can be impaired. The patient sleeps longer and may fall asleep during the daytime. Hypothyroidism is listed as one of the rare but treatable causes of dementia.⁶⁵ Patients may accept the limitations in physical and mental activity as part of the unavoidable aging process, but many become anxious or depressed. Rarely, severe anxiety and agitation occur, a condition known as myxedematous madness. Depression develops in more than 40%, most likely related to reduced synthesis and turnover of brain 5-hydroxytryptamine; central 5-hydroxytryptamine activity is reduced in hypothyroid patients.⁶⁶

Thyroid hormone deficiency may give rise to several reversible neurologic syndromes. Cerebellar ataxia may occur, especially in elderly people, and is associated with an unsteady gait and intention tremor. More common (30%) is the carpal tunnel syndrome, which is linked to entrapment of the median nerve by thickening of the connective tissue of tendon sheaths.67,68 Complaints of paresthesias occur in 64%, and signs of sensorimotor axonal neuropathy are observed in 42%.⁶⁷ Hashimoto’s encephalopathy is a vaguely defined condition in which otherwise unexplained clinical manifestations of central nervous system dysfunction are linked to the presence of TPO antibodies; serum TSH can be normal or slightly elevated.⁶⁹ The condition responds to glucocorticoids, but the relationship to thyroid autoimmunity is currently uncertain.

Musculoskeletal System

Muscles

Muscle symptoms are prevalent in hypothyroid patients and include myalgia, weakness, stiffness, cramps, and easy fatigability.67,68,70 The biochemical substrate of these complaints is provided in part by an increase in the inorganic phosphate-to-adenosine triphosphate (ATP) ratio in resting muscle and by an important decrease in phosphocreatine in working hypothyroid muscle with a greater decrease in intracellular pH than in controls.⁷¹ Impairment of mitochondrial oxidative metabolism also has been shown in subclinical hypothyroidism.⁷² Transition from white fast type II to red slow type I muscle fibers is involved in the change in muscle bioenergetics, which is probably multifactorial. The histopathology varies; most common is type II fiber atrophy, but fiber hypertrophy may be present along with interstitial edema and sarcoplasmic degeneration.⁷⁰ Rarely, chronic hypothyroid myopathy results in increased volume of muscles (notably in the tongue and extremities), which may cause entrapment syndromes.⁷³ Serum creatine kinase (MM fraction derived from skeletal muscle) is often elevated and correlates with the severity of hypothyroidism. The decreased rate of muscle contractility in hypothyroidism is evident from slow deep tendon reflexes. The half-relaxation time of the Achilles reflex is prolonged in many hypothyroid patients, but substantial overlap is seen in euthyroid subjects.

Joints

Arthralgia and joint stiffness are common complaints. Synovial effusions (usually of the knee) are rare.

Bones

Hypothyroidism leads to decreased bone formation and bone resorption, but bone mineral density is comparable with that of matched controls. Urinary excretion of hydroxyproline and serum alkaline phosphatase and osteocalcin levels can be decreased; serum calcium is usually normal.

Cardiovascular System

Changes in cardiovascular dynamics in hypothyroidism include an increase (of 50% to 60%) in peripheral vascular resistance and a decrease (of 30% to 50%) in cardiac output.74,75 Aortic stiffness is increased.⁷⁶ As a result, mean blood pressure is largely unaltered, although systolic pressure may decrease and diastolic pressure may increase. The increase in systemic vascular resistance is due to endothelial dysfunction and impaired vascular smooth muscle relaxation. The decrease in cardiac output is due to a decrease in stroke volume and heart rate. The pre-ejection time and isovolumetric contraction time are prolonged, and the ventricular relaxation rate during diastole is slower.⁷⁵ The mechanism of reduced cardiac contractility with subnormal systolic and diastolic performance is multifactorial. Changes in T₃-dependent myocardial gene expression are involved, especially in genes that code for calcium regulatory proteins.⁷⁷ Blood volume is decreased. Edema may develop through albumin extravasation as a result of increased capillary permeability; it may give rise to pericardial, pleural, or peritoneal effusions.

Cardiovascular symptoms of hypothyroid patients include dyspnea and decreased exercise tolerance; the hemodynamic response to exercise usually is preserved. Physical examination may reveal a slow pulse rate, diastolic hypertension (in 20%), weak heart sounds, occasionally cardiac enlargement (caused by pericardial effusion or, rarely, by T₄-reversible cardiomyopathy ⁷⁷), and peripheral nonpitting or pitting edema (rarely caused by heart failure except when cardiac disease is preexisting). The electrocardiogram may show bradycardia, low-voltage conduction disturbances, and nonspecific ST-T changes. Symptomatic ischemic heart disease with anginal complaints occurs in about 3%; the reduced need for oxygen in view of the hypometabolic state might give some protection.⁷⁸ The atherogenic profile of serum lipids and the hyperhomocysteinemia⁷⁹ in hypothyroidism suggest a greater prevalence of coronary atherosclerosis in these patients.⁸⁰

Respiratory System

Respiratory symptoms of hypothyroidism include shortness of breath and sleep apnea. Shortness of breath can be caused by the cardiac effects of thyroid hormone deficiency, by weakness of respiratory muscles, by pleural effusion, or by impaired pulmonary function. In most nonobese hypothyroid patients, pulmonary function is nearly normal. Reduced ventilatory drive is observed in 34%; the depressed response to hypercapnia or hypoxia usually is restored rapidly on T₄ treatment.⁸¹ Severe obstructive sleep apnea occurs in 7.7%,⁸² in part as a result of increased size of the tongue and pharyngeal muscles with a slow and sustained muscle contraction; the contribution of reduced ventilatory drive to sleep apnea is less marked but can be substantial in obese patients.

Urogenital System

Kidneys and Fluid Metabolism

Renal plasma flow and glomerular filtration rate are reduced in hypothyroidism in accordance with the changes in cardiovascular hemodynamics. Serum creatinine is increased by 10% to 20%, and hyponatremia sometimes occurs.79,83 Hyponatremia is associated with increased total body water and sodium content in hypothyroidism, which is a result of the increased vascular permeability and extravascular accumulation of hydrophilic glycosaminoglycans. Free water clearance in hypothyroidism is diminished, regardless of the presence of hyponatremia. Plasma arginine vasopressin frequently is increased in hypothyroid patients; arginine vasopressin levels increase normally in response to hypertonic saline, but they are not suppressed normally after water ingestion. The syndrome of inappropriate antidiuresis in hypothyroidism is not fully understood,⁸⁴ but a purely renal vasopressin-independent mechanism seems to be involved,⁸⁵ presumably related to increased expression of aquaporin water channels in the kidney.⁸⁶ The significance of low serum atrial natriuretic peptide concentrations in hypothyroidism is unclear.⁷²

Reproductive System

Juvenile hypothyroidism results in delayed sexual maturation; it seldom results in precocious puberty (explained by spillover of the action of TRH on gonadotropes and the action of TSH on follicle-stimulating hormone receptors 87,88). In adult hypothyroid men, semen analysis is usually normal; erectile dysfunction is common but fully reversible.⁸⁹ Serum sex hormone–binding globulin, free testosterone, follicle-stimulating hormone, and luteinizing hormone levels most often are normal. In adult hypothyroid women, pulsatile gonadotropin release in the follicular phase is normal,⁹⁰ but the ovulatory surge may not occur. Irregular—often anovulatory—cycles occur in 23% (three times as often as in the general population); oligomenorrhea and menorrhagia are most common.⁹¹ Some patients are seen initially with the galactorrhea-amenorrhea syndrome, which is due to hyperprolactinemia induced by thyroid hormone deficiency. Despite restricted fertility, conception may occur with a successful pregnancy outcome. Pregnancy-induced hypertension is two to three times more common in hypothyroid women. The prevalence of an elevated TSH among pregnant women is about 2%.⁹² The IQs of children born to affected mothers are 7 points lower than the IQs of controls.⁹³ The spontaneous abortion rate is higher in hypothyroid mothers who do not receive adequate levothyroxine treatment than in mothers who do.⁹⁴

Gastrointestinal System

Hypothyroidism causes a decrease in electrical and motor activity of the esophagus, stomach, small intestine, and colon. Gastric emptying and intestinal transit times are prolonged.⁹⁵ The decreased motility explains the common complaint of constipation, which may range from mild to severe (rarely with paralytic ileus and intestinal pseudo-obstruction). Small intestinal bacterial overgrowth is common,⁹⁶ but intestinal absorption is mostly normal. Malabsorption may be due to pernicious anemia or celiac disease, both of which frequently are associated with autoimmune hypothyroidism. About 25% of patients with chronic autoimmune thyroiditis have parietal cell antibodies; some patients have achlorhydria and vitamin B₁₂ malabsorption. Myxedematous ascites is rare.

Slightly abnormal liver function test results are common ⁹⁷ but usually fully reversible (except when caused by associated autoimmune liver disease). Hypotonia of the gallbladder may occur.

The decrease in growth hormone secretion in hypothyroidism is related to an increase in hypothalamic somatostatinergic tone ¹⁰² and results in low insulin-like growth factor (IGF-1) serum concentrations. It may cause dramatic growth retardation in hypothyroid children. Serum IGF-2, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 are also decreased, whereas IGFBP-2 is increased; these changes are reversed with T₄ treatment.¹⁰³

Moderate hyperprolactinemia occurs in 8% of hypothyroid patients, especially in young women, but is not related to the severity of thyroid hormone deficiency.¹⁰⁴ It may cause galactorrhea and amenorrhea, particularly in long-standing hypothyroidism. Increased expression of hypothalamic TRH due to diminished negative feedback exerted by T₃ might explain the (reversible) hyperprolactinemia in hypothyroidism.

Hypothyroidism in the presence of a pituitary mass does not always indicate central hypothyroidism. The hypersecretion of TSH in primary hypothyroidism is accompanied by hyperplasia and hypertrophy of pituitary thyrotrophs. Rarely, this alteration may cause a distinct pituitary macroadenoma in severely hypothyroid patients with high TSH levels (even with impaired vision) that shrinks after thyroid hormone therapy.¹⁰⁵

Parathyroid

Thyroid hormone deficiency reduces the activity of osteoclasts and osteoblasts (only the latter possess nuclear T₃ receptors), which results in a slow rate of bone resorption and formation in the bone structural unit. Because of decreased bone resorption, serum calcium levels are decreased slightly, followed by an increase in parathyroid hormone and 1,25-dihydroxyvitamin D and an increase in intestinal calcium absorption. Calcium losses in urine and feces are decreased.

Adrenal Cortex

Metabolic clearance and, to a lesser extent, production of cortisol are decreased in hypothyroidism ¹⁰⁶; serum cortisol and 24-hour urinary cortisol remain within normal limits. The adrenal response to exogenous adrenocorticotropic hormone and the pituitary response to hypoglycemia or metyrapone usually are maintained or slightly decreased. Some patients with chronic autoimmune thyroiditis have associated autoimmune adrenalitis. Hypocortisolemia by itself may cause slightly elevated TSH levels that return to normal with glucocorticoid replacement, illustrating the negative feedback of cortisol on TSH secretion.¹⁰⁷

Hypothyroidism decreases angiotensinogen production in the liver and serum angiotensin-converting enzyme and plasma renin activity. Serum aldosterone remains normal: The decrease in clearance is neutralized by a decrease in secretion.⁷⁴ The effects of these changes in the renin-angiotensin-aldosterone system are minimal and are not responsible for the hypertension in hypothyroid patients.

Sympathoadrenal System

Serum norepinephrine concentrations are increased in hypothyroid patients because of an increased production rate; epinephrine production is not affected. The increased central sympathetic output seems to be compensatory for the reduced response to catecholamines in target tissues such as the heart.¹⁰⁸ Mechanisms involved include a reduced number of β-adrenergic receptors and postreceptor defects, which contributes to impaired lipolysis, glycogenolysis, and gluconeogenesis.

Diagnosis

Two phases can be distinguished in the diagnosis of hypothyroidism. First, it should be ascertained whether a thyroid hormone deficiency exists (syndromal diagnosis). Thereafter, the cause of the demonstrated thyroid hormone deficiency should be looked for (nosologic diagnosis). Diagnosis of the hypothyroid syndrome starts with the history and physical examination and ends—in the case of sufficient clinical suspicion—with an assay of TSH and FT₄ in serum. One of the rationales for clinical examination is to increase the pretest likelihood of hypothyroidism so that fewer patients need hormone tests; because of the higher prevalence of hypothyroidism in the remaining patients, the diagnostic accuracy of hormone tests increases. The rationale for a nosologic diagnosis is to look for cases of potentially reversible hypothyroidism and increase awareness of the possible existence of other conditions associated with a specific cause.

Syndromal Diagnosis

Clinical Assessment

Statistical methods based on the frequency of symptoms and signs in patients and controls have been applied to the clinical diagnosis of hypothyroidism. The Billewicz score consists of points given in a weighted manner for the presence or absence of 17 symptoms and signs.¹⁰⁹ Application of this score to patients suspected of having hypothyroidism increases the pretest probability of hypothyroidism by 15% to 19%.¹¹⁰ A simpler score is derived by awarding 1 point each for the presence of 12 symptoms and signs (Table 14-4)¹¹¹; because of a high frequency in euthyroid controls, cold intolerance and pulse rate had predictive values less than 70% and were excluded from the score. The score was higher in older than in younger control women; correction for age is done by adding 1 point for women younger than age 55. The positive predictive value for hypothyroidism is 96.9% with a score of 6 or more points; the negative predictive value for exclusion of hypothyroidism is 94.2% with a score of 2 points or less. Sixty-two percent of all overt hypothyroid and 24% of subclinical hypothyroid patients are classified as clinically hypothyroid by this new score; the corresponding figures with the Billewicz score are 42% and 6%. Receiver operating curves of both scores, however, are similar.

Table 14-3

Causes of Hypothyroidism

Central (Hypothalamic/Pituitary) Hypothyroidism

Loss of functional tissue

Tumors (pituitary adenoma, craniopharyngioma, meningioma, dysgerminoma, glioma, metastases)

Trauma (surgery, irradiation, head injury)

Vascular (ischemic necrosis, hemorrhage, stalk interruption, aneurysm of internal carotid artery)

Infections (abscess, tuberculosis, syphilis, toxoplasmosis)

Infiltrative (sarcoidosis, histiocytosis, hemochromatosis)

Chronic lymphocytic hypophysitis

Congenital (pituitary hypoplasia, septo-optic dysplasia, basal encephalocele)

Functional defects in TSH biosynthesis and release

Mutations in genes encoding for TRH receptor, TSHβ, or pituitary transcription factors POUIFI, PROPI, LHX3, HESX1

Drugs: dopamine, glucocorticoids, levothyroxine withdrawal, bexarotene

Primary (Thyroidal) Hypothyroidism

Loss of functional thyroid tissue

Chronic autoimmune thyroiditis

Reversible autoimmune hypothyroidism (silent and postpartum thyroiditis, cytokine-induced thyroiditis)

Surgery and irradiation (¹³¹I or external irradiation)

Infiltrative and infectious diseases, subacute thyroiditis

Thyroid dysgenesis

Functional defects in thyroid hormone biosynthesis and release

Congenital defects in thyroid hormone biosynthesis

Iodine deficiency and iodine excess

Drugs: antithyroid agents, lithium, natural and synthetic goitrogenic chemicals, tyrosine kinase inhibitors

Peripheral (Extrathyroidal) Hypothyroidism

Mutations in genes encoding for MCT8, SECISBP2, or TRβ

Consumptive hypothyroidism

MCT8, Monocarboxylate transporter 8; SECISBP2, selenocysteine insertion sequence-binding protein 2; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone; TRβ, thyroid hormone receptor β.

The clinical diagnosis of hypothyroidism can be easy but also difficult because of the nonspecific nature of the symptoms and signs and the marked diversity of findings.¹¹² It is incompletely understood why the clinical manifestations of thyroid hormone deficiency vary considerably among patients. Chilliness, paresthesias, weight gain, and muscle cramps occur less frequently in elderly patients, who also have fewer clinical signs than younger patients.¹¹³ Smokers have more severe manifestations of hypothyroidism.¹¹⁴

Biochemical Assessment

The ideal diagnostic test for hypothyroidism would be one that accurately measures the effect of thyroid hormone deficiency on target tissues. Peripheral tissue function tests, such as serum cholesterol and creatine kinase, lack sufficient sensitivity and specificity to be of much use. Serum TSH is the best assay for detection of hypothyroidism. By using the flow diagram presented in Fig. 14-3, the following results can be obtained:

FIGURE 14-3 Flow diagram for the biochemical diagnosis of hypothyroidism. FT₄, Free thyroxine; TSH, thyroid-stimulating hormone.

1. TSH normal. Euthyroidism is almost certain, and no additional tests are necessary. The only exception is central hypothyroidism; usually, clinical examination offers sufficient clues to suspect hypothalamic/pituitary disease because isolated TSH deficiency is rare.

2. TSH elevated, FT₄ decreased. Primary hypothyroidism is almost always present. In a few cases, TSH values of 5 to 15 mU/L are associated with central hypothyroidism.

3. TSH elevated, FT₄ normal. The results indicate subclinical hypothyroidism and sometimes nonthyroidal illness.

4. TSH elevated, FT₄ increased. This peculiar combination of test results indicates one of the rare patients with thyroid hormone resistance or thyrotoxicosis caused by a TSH-producing adenoma.

5. TSH decreased, FT₄ decreased. These results are compatible with central hypothyroidism, hypothyroidism after recent therapy for thyrotoxicosis, or nonthyroidal illness.

6. TSH decreased, FT₄ increased or normal. Hypothyroidism is excluded. The results indicate overt thyrotoxicosis, subclinical hyperthyroidism, or rarely, nonthyroidal illness.

Nosologic Diagnosis

The history and physical examination usually provide important clues to the cause of the hypothyroidism. Symptoms and signs of hypopituitarism and pituitary mass effects suggest the presence of central hypothyroidism. Physical examination may reveal a goiter, but many, if not most, hypothyroid patients have no palpable thyroid gland. Goitrous hypothyroidism occurs in goitrous Hashimoto’s disease (with the characteristic firm rubbery consistency), in postpartum and subacute thyroiditis, in iodine deficiency, in iodine excess (small firm goiter), and in drug-induced cases. The most useful laboratory test is the assay of TPO antibodies indicating chronic autoimmune thyroiditis. Thyroid scans usually show low, inhomogeneous uptake of the radioisotope.

Clues for potentially reversible hypothyroidism can be obtained from the history (recent delivery? exposure to iodine excess? use of antithyroid drugs? recent thyroid surgery or ¹³¹I therapy?). In patients with chronic autoimmune thyroiditis, the presence of a goiter, preserved thyroidal radioiodine uptake, and homogeneous distribution of the tracer increase the likelihood of reversible hypothyroidism.²⁹

Recovery of hypothyroidism by elimination of its cause is possible in cases secondary to (antithyroid) drugs or iodine excess. Spontaneous recovery from hypothyroidism in the natural course of the disease is the rule in subacute thyroiditis; it is common in postpartum thyroiditis, occurs less frequently in hypothyroidism that develops in the first 6 months after surgery or ¹³¹I therapy for thyrotoxicosis, and is exceptional (5%) in chronic autoimmune thyroiditis.

Treatment

Most hypothyroid patients need lifelong replacement therapy with T₄. In the few patients with a high likelihood of reversible hypothyroidism, one may refrain from treatment or, if symptoms and signs are severe, prescribe T₄ for a few months. The goal of treatment is restoration of the euthyroid state in all tissues. Gradual disappearance of the systemic manifestations of hypothyroidism can be expected several weeks to months after initiation of therapy; symptoms and signs related to the skin, appendages, and nervous system resolve slowly. Treatment of hypothyroid patients is gratifying because the symptoms and signs are usually fully reversible.

Replacement with Thyroxine

T₄ is prescribed as levothyroxine sodium, which comes in tablets of different strength. The sodium salt increases the gastrointestinal absorption of levothyroxine, which is greater in the fasting (80%) than in the fed state (60%).¹¹⁵ Absorption of T₄ seems to be greater in the evening at 22.00 hours than in the morning at 06.30 hours before breakfast.¹¹⁶ Generic and brand name levothyroxine preparations are most often bioequivalent,¹¹⁷ but altered bioavailability from changes in the formulation of preparations has been reported.¹¹⁸ About 25% of the exogenous T₄ is converted into T₃ and provides 80% of the circulating T₃ pool.¹¹⁵ The half-life of serum T₄ is approximately 7 days, which allows a single daily dose of levothyroxine sodium. Omission of an occasional tablet has little or no clinical relevance.

The initial daily dose of levothyroxine sodium depends on the severity and the duration of the hypothyroid state, the age of the patient, and the coexistence of cardiac disease. In the case of mild hypothyroidism, short duration of hypothyroidism, young age, and no heart disease, one may opt to start with a full replacement dose (on average 1.6 µg/kg/d, but with large interindividual variation).¹¹⁹ In the case of more severe or long-standing hypothyroidism, older age, and especially the presence of ischemic heart disease, it is prudent to start with a low dose (25 to 50 µg daily). Too high a starting dose under these circumstances may be poorly tolerated by the patient, who is accustomed to a low metabolic rate, which is now reversed. The patient may experience agitation, palpitations, and worsening or development of anginal complaints because of the increased need for oxygen. Individualization of the initial dose is recommended, and the same holds true for the rate at which the initial dose is increased until the full replacement dose has been reached. In high-risk cases, the daily levothyroxine sodium dose can be increased by 25 to 50 µg every 4 weeks, and it takes 3 to 6 months before the euthyroid state is restored. The mean replacement dose of levothyroxine sodium is 125 µg daily, in line with the daily production rate of 100 µg of thyroxine in normal subjects; it varies, however, between 50 and 200 µg (Fig. 14-4). The final dose required is a function of body weight (especially lean body mass) and initial TSH value,¹²⁰ but it is not always predictable. The dose should be titrated against serum TSH and FT₄ concentrations. These assays should be done no earlier than 4 to 6 weeks after a change in T₄ dose, when a new steady state has been established. One aims for TSH values in the low normal range, which results in FT₄ values that are significantly higher than values in controls (see Fig. 14-4) and often slightly above the upper normal limit.¹¹⁵ The high T₄ levels under these circumstances serve to maintain serum T₃ (predominantly derived from 5′-deiodination of T₄) in the midnormal range. In patients with central hypothyroidism, one should rely primarily on normalization of serum FT₄, which frequently suppresses serum TSH to less than 0.1 mU/L.¹²¹

FIGURE 14-4 Dosage titration of levothyroxine (L-T4) (top panel) and the free thyroxine (T4) index (bottom panel) as a function of serum thyroid-stimulating hormone (TSH). Values are expressed by month, counting backward from the final dose. The bars represent 1 standard deviation from the mean. (Reprinted from Fish LH, Schwartz HL, Cavanaugh J, et al: Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism: role of triiodothyronine in pituitary feedback in humans. N Engl J Med 316:764–770, 1987. Copyright © 1987, Massachusetts Medical Society. All rights reserved.)

Some patients feel better with a slightly higher dose of levothyroxine sodium and consequently suppressed TSH. This dose can be accepted as long as serum T₃ is still within the normal range and serum TSH is (arbitrarily) not lower than 0.2 mU/L. TSH values of 0.1 mU/L or less carry a risk for atrial fibrillation ¹²² and bone loss¹²³ (especially in postmenopausal women). Long-term levothyroxine therapy at TSH-suppressive doses increases the risk for ischemic heart disease in patients younger than age 65 years.¹²⁴ No or just a slight excess of fractures has been observed in patients maintained with levothyroxine even if TSH is suppressed.^125,126

Lifelong treatment with levothyroxine sodium, when properly monitored, seems to be free of complications. Long-term morbidity and mortality are normal. Cutaneous allergy to the dye used to color the tablets is rarely observed.

Factors Requiring Dose Adjustment

When euthyroidism has been restored by the full replacement dose of levothyroxine, this usually suffices to check the patient’s thyroid state once a year. The main reason for the annual follow-up visit is to enhance compliance with lifelong levothyroxine sodium treatment. Some patients need adjustment of the levothyroxine sodium dose for reasons outlined in Table 14-5.

Table 14-4

Accuracy of 12 Symptoms and Signs in the Diagnosis of Primary Hypothyroidism

^*Add 1 point for women younger than 55 years.

^†Hypothyroid, ≥6 points; intermediate, 3 to 5 points; euthyroid, ≤2 points.

From Zulewski H, Müller B, Exer P, et al: Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 82:771–776, 1997. Copyright © 1997, The Endocrine Society.

Increased Dose Requirement

T₄ is absorbed mainly from the small intestine, which explains the higher dose requirements in malabsorption and short-bowel syndromes.¹²⁷ Nonspecific absorption of T₄ by dietary fibers decreases the bioavailability of T₄ and necessitates a higher dose in patients with high intake of dietary fiber (whole-wheat bread, granola, bran).¹²⁸ T₄ and T₃ conjugates are excreted in bile and partially deconjugated in the intestine, with the release of small amounts of T₄ and T₃ for reabsorption. Interference with this enterohepatic circulation of thyroid hormone by bile acid–sequestering agents may cause a slight increase in TSH in levothyroxine-treated patients, but not in normal subjects.¹²⁹ Other drugs, such as sucralfate,¹³⁰ aluminum hydroxide,¹³¹ ferrous sulfate,¹³² raloxifene,¹³³ and calcium carbonate,¹³⁴ also decrease the absorption of T₄. Serum T4 is often above normal in many levothyroxine-treated patients with normal TSH. The effect of these drug interactions is modest and largely can be avoided by taking levothyroxine sodium and the other drug several hours apart.

Considerable weight gain may increase the need for T₄. Estrogen therapy ¹³⁵ and pregnancy¹³⁶ also require additional thyroid hormone in most hypothyroid patients, probably because of increased serum concentrations of T₄-binding globulin. Levothyroxine requirements increase by about 50% in most pregnant women during the first half of pregnancy and plateau by week 16; median onset of TSH increase occurs at 8 weeks’ gestation.¹³⁶ It is prudent to anticipate these events, and assessment of thyroid function in each trimester is recommended. After delivery, the dose used before pregnancy can be reinstituted.

Several antiepileptic and tuberculostatic drugs increase the clearance of T₄ by stimulating the mixed-function oxygenases responsible for hepatic drug oxidation.¹³⁷ Serum TSH increases in levothyroxine-treated hypothyroid patients when amiodarone is administered,¹³⁸ possibly as a result of the inhibition of T₄ conversion into T₃. The mechanism by which other drugs, such as sertraline¹³⁹ and chloroquine,¹⁴⁰ increase T₄ requirements is unknown. The most common reason for persistently elevated TSH values despite apparently adequate replacement doses is poor compliance of the patient with intake of levothyroxine tablets. Noncompliance is a challenge to the treating physician who seeks to solve this difficult management problem; in the process, it is important to not lose the patient’s confidence. One option is to administer levothyroxine under supervision once weekly.¹⁴¹ A slightly larger dose than seven times the normal daily dose may be required; a single weekly dose of 1000 µg of levothyroxine sodium given orally seems to be effective and well tolerated.

Decreased Dose Requirement

Considerable weight loss may decrease the need for levothyroxine. In women receiving long-term levothyroxine replacement therapy, administration of androgens for breast cancer may result—via a decrease in serum T₄-binding globulin—in thyrotoxicosis within 4 weeks; the levothyroxine dose has to be reduced by 25% to 50%.¹⁴² Production and metabolic clearance rates of T₄ are slightly decreased in old age; the net result is no change in the serum FT₄ concentration. The levothyroxine replacement dose decreases in elderly people by about 25% in association with the decrease in lean body mass with age.¹⁴³

Other Thyroid Hormone Preparations

Animal Thyroid Extract

Extracts of animal thyroid glands (primarily cattle) were the first thyroid hormone preparations available. Desiccated thyroid, although effective, is no longer used in view of the lack of precise standardization and the availability of synthetic levothyroxine. After ingestion of desiccated thyroid, elevated serum concentrations of T₃ can occur in the postabsorptive period and cause transient thyrotoxic symptoms, such as palpitations. These effects do not occur after a dose of levothyroxine, which is converted gradually into T₃.

Liothyronine Sodium

After oral liothyronine administration, serum T₃ concentrations reach elevated values within hours, with a decline to basal levels in the next couple of hours. The half-life of liothyronine is approximately 1 day. Liothyronine preparations can be useful in the management of patients with thyroid cancer or myxedema coma.

Combination of Levothyroxine and Liothyronine

Synthetic levothyroxine and liothyronine have been combined in a single tablet in a ratio of 4 : 1. New interest in this kind of formula has been inspired by animal studies showing that the euthyroid state of thyroidectomized rats could be restored in all tissues only by the combination of levothyroxine and liothyronine and not by levothyroxine alone,¹⁴⁴ and likewise by human studies reporting impaired psychological well-being and neurocognitive functioning of hypothyroid patients despite adequate treatment with thyroxine.^145,146 However, a meta-analysis of 11 randomized clinical trials found no differences in the effectiveness of T₄ and T₃ combination therapy versus T₄ monotherapy in terms of bodily pain, depression, anxiety, fatigue, and quality of life.¹⁴⁷

Interference with Coexistent Conditions

Cortisol Deficiency

Treatment for hypothyroidism in patients with glucocorticoid deficiency may provoke adrenal insufficiency because the adrenal is incapable of meeting the increasing demand for cortisol caused by the increased metabolic rate. Glucocorticoids should be given before levothyroxine therapy is started.

Ischemic Heart Disease

Levothyroxine increases the need for oxygen in the myocardium. Worsening or de novo development of anginal complaints should call for tempering of the levothyroxine dose or institution of antianginal drugs. Alternatively, coronary artery bypass surgery or angioplasty is a safe procedure, even when euthyroidism has not yet been restored.101,148

Surgery

Surgery in hypothyroid patients is associated with increased risk for several minor perioperative complications.¹⁰¹ A higher incidence of heart failure and gastrointestinal and neuropsychiatric complications has been reported. Patients have fever less frequently with infection.

Drugs

The metabolism of many drugs is slowed in hypothyroidism, which results in higher sensitivity to a loading dose and a lower maintenance dose. Hypothyroid patients can experience marked respiratory depression after a single small dose of morphine. Restoration of the euthyroid state may require dose adjustments, for example, an increase in the dose of digoxin or insulin. Treatment for adult growth hormone deficiency with recombinant human growth hormone decreases serum FT₄, sometimes into the hypothyroid range.¹⁴⁹

Myxedema Coma

Myxedema coma is a rare, life-threatening clinical condition in patients with long-standing, severe untreated hypothyroidism. The term is largely a misnomer because most patients are not comatose. Rather, the entity represents a form of decompensated hypothyroidism in which a precipitating event leads to functional disorders of the cardiovascular and central nervous systems, which, if not recognized and reversed, frequently have a fatal outcome.¹⁵⁰

Pathogenesis

A normal body core temperature is preserved in compensated hypothyroidism because of neurovascular adaptations, including chronic peripheral vasoconstriction, mild diastolic hypertension, and diminished blood volume. The hypothyroid heart also compensates by performing more work at a given amount of oxygen through better coupling of ATP to contractile events. These adaptations to thyroid hormone deficiency maintain homeostasis, albeit at a precarious balance. A further reduction in blood volume (e.g., secondary to gastrointestinal bleeding or the use of diuretics) may disrupt this precarious balance, which homeostatic mechanisms are no longer able to restore. Likewise, the already compromised ventilatory drive may progress to respiratory failure by intercurrent pulmonary infection. Impairment in central nervous system function can be provoked further by stroke, the use of sedatives, and hyponatremia (a common phenomenon in severe hypothyroidism).

Diagnosis

The three key diagnostic features of myxedema coma are as follows:

1. Altered mental status: from disorientation and lethargy to psychosis and coma

2. Defective thermoregulation: hypothermia or the absence of fever despite infectious disease

3. Precipitating event: cold exposure, infection, drugs (diuretics, sedatives, tranquilizers), trauma, stroke, heart failure, gastrointestinal bleeding

Most cases of myxedema coma occur in elderly women in winter. Early recognition is crucial, but in many cases the condition is diagnosed late, often after inadequate response to treatment for the precipitating event. The presence of cool pale skin and the absence of mild diastolic hypertension are warning signs of impending myxedema coma. Serum FT₄ is low; serum TSH is usually high but sometimes is elevated only slightly because of the effect of intercurrent nonthyroidal illness. Serum creatine phosphokinase most often is extremely elevated.

Treatment

Rapid institution of thyroid hormone replacement therapy and supportive measures (Table 14-6) is essential for a successful outcome; the prognosis remains poor, however, with a mortality of at least 20%. Patients should be monitored closely for vital signs.

Table 14-5

Conditions Requiring Adjustment of the Replacement Dose of Thyroxine for Hypothyroidism

Increased Dose Requirement

Decreased intestinal absorption of T₄

Malabsorption (e.g., celiac disease) and short-bowel syndrome ¹²⁷

Dietary fiber supplements ¹²⁸

Drugs: bile acid sequestering agents (colestipol, cholestyramine ¹²⁹), α-sucralfate,¹³⁰ aluminum hydroxide,¹³¹ ferrous sulfate,¹³² raloxifene,¹³³ calcium carbonate¹³⁴

Increased need for T₄

Weight gain

Estrogens ¹³⁵

Pregnancy ¹³⁶

Increased clearance of T₄

Phenobarbital, phenytoin, carbamazepine, rifampicin ¹³⁷

Precise mechanism unknown

Amiodarone,¹³⁸ sertraline,¹³⁹ chloroquine¹⁴⁰

Noncompliance ¹⁴¹

Decreased Dose Requirement

Decreased need for T₄

Weight loss

Androgens ¹⁴²

Decreased clearance of T₄

Old age ¹⁴³

No consensus has been reached regarding the most appropriate dose, route of administration, and form (liothyronine or levothyroxine) of thyroid hormone replacement. Too high a dose may provoke cardiac ischemia and arrhythmias. Oral administration may be less efficacious because of reduced gastrointestinal absorption. T₃ abruptly increases metabolism, which carries a risk for cardiac complications, but T₄ may be converted less well into T₃ because of nonthyroidal illness. The severity of the patient’s condition might be considered, but clinical experience indicates that too conservative an approach worsens the outcome. Current recommendations include a starting dose of 300 to 500 µg of levothyroxine given intravenously, followed by 50 to 100 µg of levothyroxine intravenously daily until oral medication can be taken. If no improvement is seen within 24 to 48 hours, liothyronine might be given (e.g., 10 µg given intravenously every 4 hours or 25 µg given intravenously every 8 hours).

Hypothermia is treated just with blankets; active rewarming is dangerous because the peripheral vasodilation induced may provoke vascular collapse. Mechanical respiratory assistance is indicated at the first signs of respiratory failure, and one should not delay endotracheal intubation. Hypoxia is worsened by anemia, a common finding in hypothyroidism. In case of hypotension, transfusion of whole blood may restore blood volume and oxygen-carrying capacity. Digoxin and diuretics should be used cautiously for congestive heart failure. Hypoglycemia might indicate hypopituitarism or primary adrenal insufficiency; however, also in the absence of hypoglycemia or hypocortisolemia, all patients should receive intravenous hydrocortisone (100 to 200 mg daily in divided doses) in view of the blunted cortisol response to stress in severe hypothyroidism. Finally, one should try to identify precipitating factors and eliminate them if possible. Infection (pneumonia or urosepsis) is present in 35% but is not easily detected because fever, tachycardia, and leukocytosis are usually absent. A differential count of leukocytes and cultures should be ordered, and broad-spectrum antibiotics are indicated even if the suspicion of infection is modest.

Subclinical Hypothyroidism and Screening

Subclinical hypothyroidism is defined as an elevated serum TSH concentration in the presence of normal serum FT₄ and T₃. It is a prevalent condition (see Table 14-1) that occurs most often in women and elderly people.⁴ The causes can be endogenous (chronic autoimmune thyroiditis, subacute thyroiditis, postpartum thyroiditis) or exogenous (¹³¹I therapy, thyroidectomy, antithyroid drugs).

The natural course of subclinical hypothyroidism secondary to chronic autoimmune thyroiditis is reasonably well known.⁵ Spontaneous return to normal TSH values occurs in 5% to 6%. Progression to overt hypothyroidism is a common event, especially if thyroid antibodies are present (see Table 14-2); the annual incidence is about 5%.

Systemic Manifestations

The term subclinical hypothyroidism suggests the absence of symptoms and signs of thyroid hormone deficiency, but clinical experience tells otherwise. Nonspecific complaints (fatigue and weight gain), depressive feelings, and mild cognitive disturbances (poor ability to concentrate, poor memory) can be present. Subjects score higher on a clinical scale for hypothyroidism (Fig. 14-5).¹¹¹ Peripheral tissue function tests frequently indicate a limited degree of thyroid hormone deficiency; examples include prolongation of the Achilles tendon reflex relaxation time, prolongation of systolic time intervals, a decrease in cardiac contractility, impairment of muscle energy metabolism, and an increase in LDL cholesterol.¹⁵¹

FIGURE 14-5 Assessment of hypothyroidism by a clinical score in 50 patients with overt hypothyroidism, 80 age-matched controls, 93 patients with subclinical hypothyroidism, 67 hypothyroid patients treated with thyroxine, and an additional 109 euthyroid subjects. T₃, triiodothyronine. (From Zulewski H, Müller B, Exer P, et al: Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 82:771–776, 1997. Copyright © 1997, The Endocrine Society.)

Treatment

Treatment for subclinical hypothyroidism is still debated. A Cochrane analysis of randomized clinical trials found that levothyroxine therapy had no effect on survival, cardiovascular morbidity, symptoms, or quality of life, although lipid profiles and left ventricular function improved.¹⁵² Nevertheless, meta-analyses of population-based studies demonstrate a higher prevalence and incidence of ischemic heart disease and mortality, at least in women and subjects younger than 65 years.^153,154 In view of this, thyroxine therapy might be considered in subjects younger than 65 years if TSH is >10 mU/L and/or TPO antibodies are present. In case TSH is <10 mU/L and TPO antibodies are absent, thyroxine therapy still might be warranted in individuals with a high background for cardiovascular risk, symptoms, pregnancy, and infertility.¹⁵¹ When in doubt because of nonspecific complaints, a trial of T₄ treatment for at least 3 months can be considered.

Set Point

Subclinical hypothyroidism seems to be a misnomer, but how some subjects with subclinical thyroid dysfunction experience clinical symptoms and signs, whereas other subjects are really asymptomatic despite similar serum FT₄ concentrations, remains an unanswered question. Repeated measurements of thyroid function in the same individual over time show a narrow fluctuation around the mean value. Apparently, each individual is characterized by a fixed relationship between serum TSH and FT₄ concentrations; this point can be considered the working point of the pituitary-thyroid axis of that individual. From longitudinal observations in subjects in whom abnormal thyroid function develops, it can be deduced that an intraindividual log-linear relationship exists between TSH and FT₄, as depicted by a straight line ¹¹⁵; the working point moves along this line, upward in the case of hypothyroidism (Fig. 14-6). The position of the working point of an individual determines the changes in thyroid function test results that are maximally allowed within the conventional reference range before they are labeled abnormal. In the example depicted in Fig. 14-6, the subject with subclinical hypothyroidism and a serum FT₄ of 12 mol/L might have an original working point at 18 mol/L (indicating a decrease in serum FT₄ by 33%) or at 15 mol/L (indicating a decrease in serum FT₄ by 20%). It is conceivable that symptoms and signs are present in the former but not in the latter situation.

FIGURE 14-6 The log-linear relationship between thyroid-stimulating hormone (TSH) and free thyroxine (FT₄) of a particular individual is depicted by a straight line; the working point of that individual moves upward along this line if hypothyroidism develops. Variation between individuals is given by the different location of the working point on the same or parallel lines. The upper hatched area represents subclinical hypothyroidism, and the central area encompasses the normal range of TSH and FT₄. For further explanation, see the text.

Screening

In view of the high prevalence of thyroid disease in the general population, the question arises of whether a screening program for adults is justified.⁶ A simple, inexpensive, and accurate screening test is available: the sensitive TSH assay. The disease to be screened (hypothyroidism and thyrotoxicosis) has a high prevalence and can be treated effectively. The burden of disease is limited, however, and it has not been proved that clinical outcome is improved by early diagnosis and treatment in the asymptomatic stage. Nevertheless, a computer-derived decision model concludes that it is cost effective to screen persons in the general community for mild hypothyroidism with a serum TSH combined with a serum cholesterol every 5 years after the age of 35 years.¹⁵⁵ Screening of elderly women is especially cost effective. For the time being, case finding is a suitable alternative, that is, determination of serum TSH in patients (especially pregnant women and older women) who consult the physician because of unrelated problems. A high degree of suspicion of thyroid function disorder is warranted in patients with nonspecific complaints.