Hypothyroidism and Thyroiditis

13
Hypothyroidism and Thyroiditis

GREGORY A. BRENT AND ANTHONY P. WEETMAN
CHAPTER OUTLINE
Hypothyroidism, 404 Thyroiditis, 431
KEY POINTS
• A utoimmunity is responsible for over 90% of noniatrogenic • T he quantity of levothyroxine required to normalize TSH in an
hypothyroidism in iodine-sufficient areas. athyreotic patient results in a slightly higher serum free thyrox-
• A variety of genetic factors contribute to susceptibility in auto- ine (T4) concentration than is present in normal individuals.
immune thyroiditis, but epidemiologic data suggest a strong in- • The current approach to thyroid replacement using levothyrox-
fluence of environmental factors to explain the recent increase ine alone, although not a perfect replication of normal physiol-
in prevalence. ogy, is satisfactory for virtually all patients.
• The risk of progression from subclinical to overt hypothyroidism • Levothyroxine requirements are increased in malabsorption due
is most closely related to the magnitude of serum thyrotropin to bowel diseases and impaired gastric acid secretion or adsorp-
(thyroid-stimulating hormone [TSH]) elevation and the presence tion of levothyroxine to coadministered medications.
of antithyroid peroxidase (TPO) antibodies. • Athyreotic patients who are planning a pregnancy should be
• In some patients with autoimmune hypothyroidism, a tran- advised to increase the dose of levothyroxine by around 30% as
sient exacerbation of thyroiditis or a fluctuation in the balance soon as the diagnosis is confirmed; the increased dose require-
between TSH receptor-blocking and receptor-stimulating auto- ment persists throughout pregnancy, but dosage can return to
antibodies may result in episodes of thyrotoxicosis. normal within a few weeks after delivery.
• Hypothyroidism due to direct thyroidal inflammation or activa-
tion of autoimmune destruction has been associated with a
number of drugs, including tyrosine kinase inhibitors (TKIs).
Hypothyroidism Conditions associated with reduced thyroid hormone action are

rare and include abnormalities of thyroid hormone metabolism
Reduced production of thyroid hormone is the central feature and defects in nuclear signaling.6 Consumptive hypothyroid-
of the clinical state termed hypothyroidism.1,2 Permanent loss or ism, identified in an increasing number of clinical settings, is the
destruction of the thyroid through processes such as autoim- result of accelerated inactivation of thyroid hormone by the type 3
mune destruction, referred to as Hashimoto disease,3 or irradia- iodothyronine deiodinase (D3).7 Defects of activation of the pro-
tion injury is described as primary hypothyroidism (Table 13.1). hormone, T4, to the active form, triiodothyronine (T3), have also
Hypothyroidism due to transient or progressive impairment of been identified.8 Polymorphisms in genes regulating thyroid hor-
hormone biosynthesis is typically associated with compensatory mone production and activation may influence thyroid hormone
thyroid enlargement. Central or secondary hypothyroidism due to action in some tissues.9,10 Resistance to thyroid hormone (RTH),
insufficient stimulation of a normal gland is the result of hypotha- the result of defects in the thyroid hormone nuclear receptor (TR)
lamic or pituitary disease or defects in the TSH molecule.4 Tran- or nuclear cofactors, is associated with elevated circulating lev-
sient or temporary hypothyroidism can be observed as a phase els of thyroid hormone. Some tissues, depending on the level of
of subacute thyroiditis.5 Primary hypothyroidism is the cause in expression of the mutant receptor and other forms of local com-
approximately 99% of cases of hypothyroidism, with less than 1% pensation, have evidence of reduced thyroid hormone action.11
being due to TSH deficiency or other causes. Central hypothy- Estimates of the incidence of hypothyroidism vary depend-
roidism is discussed in Chapter 11. ing on the population studied.12,13 In the United States, 0.3%
Reduced action of thyroid hormone at the tissue level, despite have overt hypothyroidism, defined as an elevated serum TSH
normal or increased thyroid hormone production from the thy- concentration and reduced free thyroxine concentration (FT4),
roid gland, can also be associated with clinical hypothyroidism. and 4.3% have what has been described as subclinical or mild
404
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Chapter 13 Hypothyroidism and Thyroiditis 405
TABLE 13.1 C
auses of Hypothyroidism in some racial and ethnic groups.17 Neonatal screening programs
for congenital hypothyroidism identify hypothyroidism (almost
Primary Hypothyroidism all primary) in almost 1 in 3000 newborns.18
Acquired
Hashimoto thyroiditis Clinical Presentation
Iodine deficiency (endemic goiter)
Drugs blocking synthesis or release of T4 (e.g., lithium, ethionamide, Hypothyroidism can affect all organ systems, and these manifesta-
sulfonamides, iodide) tions are largely independent of the underlying disorder but are a
Drug-induced thyroid destruction (e.g., interferon alpha, interleukin 2, function of the degree of hormone deficiency. The following sec-
tyrosine kinase inhibitors, blockers of CTLA4 or PD1) tions discuss the pathophysiology of each organ system at various
Amiodarone (reversible or permanent) levels of thyroid hormone deficiency, from mild to severe. The
Goitrogens in foodstuffs or as endemic substances or pollutants term myxedema, formerly used as a synonym for hypothyroidism,
Thyroid infiltration (amyloidosis, hemochromatosis, sarcoidosis, Riedel refers to the appearance of the skin and subcutaneous tissues in
struma, cystinosis, scleroderma)
Postablative thyroiditis due to 131I, surgery, or therapeutic irradiation for
the patient in a severely hypothyroid state (Fig. 13.1). Hypothy-
nonthyroidal malignancy roidism of this severity is rarely seen today, and the term should be
Transient hypothyroidism following painless thyroiditis (including post- reserved to describe the physical signs.
partum) or painful subacute thyroiditis
Skin and Appendages
Congenital Hypothyroidism causes an accumulation of hyaluronic acid that
Iodide transport or utilization defect (NIS or pendrin mutations) alters the composition of the ground substance in the dermis and
Iodotyrosine dehalogenase deficiency other tissues.19,20 This material is hygroscopic, producing the
Organification disorders (TPO deficiency or dysfunction) mucinous edema that is responsible for the thickened features and
Defects in thyroglobulin synthesis or processing
Thyroid agenesis or dysplasia
puffy appearance (myxedema) with full-blown hypothyroidism.
TSH receptor defects Myxedematous tissue is characteristically boggy and nonpitting
Thyroidal Gs protein abnormalities (pseudohypoparathyroidism type 1a) and is apparent around the eyes, on the dorsa of the hands and
Idiopathic TSH unresponsiveness feet, and in the supraclavicular fossae (see Fig. 13.1). It causes
enlargement of the tongue and thickening of the pharyngeal and
Consumptive Hypothyroidism laryngeal mucous membranes.
Rapid destruction of thyroid hormone due to D3 expression in large A clinically similar deposit may occur in patients with Graves
hemangiomas or hemangioendotheliomas disease, usually over the pretibial area (infiltrative dermopathy or
Defects of Thyroxine to Triiodothyronine Conversion pretibial myxedema), but it can be differentiated histologically.21
In addition to having a puffy appearance, the skin in hypothyroid-
Selenocysteine insertion sequence–binding protein 2 (SECISBP2) defect
ism is pale and cool as a result of cutaneous vasoconstriction. Ane-
Central Hypothyroidism mia may contribute to the pallor; hypercarotenemia gives the skin
Acquired a yellow tint but does not cause scleral icterus (see Fig. 13.1). The
Pituitary origin (secondary)
secretions of the sweat glands and sebaceous glands are reduced,
Hypothalamic disorders (tertiary) leading to dryness and coarseness of the skin, which in extreme
Bexarotene (retinoid X receptor agonist) cases may resemble that seen in patients with ichthyosis.
Dopamine or severe illness Wounds of the skin tend to heal slowly. Easy bruising is due
to an increase in capillary fragility. Head and body hair is dry
Congenital and brittle, lacks luster, and tends to fall out. Hair may be lost
TSH deficiency or structural abnormality from the temporal aspects of the eyebrows, although this is not
TSH receptor defect specific for hypothyroidism (see Fig. 13.1B). Growth of hair is
Resistance to Thyroid Hormone retarded so that haircuts and shaves are required less often. The
Generalized
nails are brittle and grow slowly. Topical T3 has been shown to
“Pituitary” dominant accelerate wound healing and stimulate hair growth in a euthy-
roid mouse model, demonstrating a role for thyroid hormone in
NIS, Sodium-iodide symporter; TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone these processes.20
(thyrotropin). Histopathologic examination of the skin reveals hyperkerato-
sis with plugging of hair follicles and sweat glands. The dermis is
edematous, and the connective tissue fibers are separated by an
increased amount of metachromatically staining, periodic acid–
hypothyroidism.13 Although a number of clinical manifestations Schiff (PAS)–positive mucinous material. This material consists
have been associated with this early or mild phase of hypothy- of protein complexed with two mucopolysaccharides: hyaluronic
roidism, we will use the term subclinical to describe this group, acid and chondroitin sulfate B. The hygroscopic glycosaminogly-
as is used in most clinical studies. Subclinical hypothyroidism is cans are mobilized early during treatment with thyroid hormone,
defined as an elevated serum TSH level with a normal serum FT4 leading to an increase in urinary excretion of nitrogen and hexos-
concentration.14,15 Subclinical hypothyroidism can progress to amine as well as tissue water.19
overt hypothyroidism and be associated with manifestations that, Patients with hypothyroidism due to Hashimoto thyroiditis
in some patients, may benefit from treatment.16 The incidence may also have skin lesions with loss of pigmentation characteristic
of hypothyroidism is higher among women, in the elderly, and of the autoimmune skin condition vitiligo. This feature is not a
406 SE C T I O N I I I Thyroid
A B
• Fig. 13.1 (A and B) Typical appearance with moderately severe primary hypothyroidism or myxedema.
Note dry skin and sallow complexion; the absence of scleral pigmentation differentiates the carotenemia
from jaundice. Both individuals demonstrate periorbital myxedema. (B) This patient illustrates the loss of
the lateral aspect of the eyebrow, sometimes termed Queen Anne sign. That finding is not unusual in the
age group that is commonly affected by severe hypothyroidism and should not be considered to be a
specific sign of the condition.
manifestation of reduced thyroid hormone action but reflects the no change, or improvement, in anginal symptoms with T4 treat-
common association of autoimmune endocrine disease and this ment.26 Electrocardiographic changes include sinus bradycardia,
skin condition, which is recognized as a component of autoim- prolongation of the PR interval, low amplitude of the P wave and
mune polyendocrine syndromes.22,23 QRS complex, alterations of the ST segment, and flattened or
inverted T waves. Pericardial effusion is probably responsible for
Cardiovascular System the low amplitude in severe hypothyroidism. Systolic time inter-
The cardiac output at rest is decreased because of reduction in vals are altered; the preejection period is prolonged, and the ratio
both stroke volume and heart rate, reflecting loss of the inotropic of preejection period to left ventricular ejection time is increased.
and chronotropic effects of thyroid hormones. Peripheral vascular Echocardiographic studies have revealed resting left ventricular
resistance at rest is increased, and blood volume is reduced. These diastolic dysfunction in overt and, in some studies, subclinical
hemodynamic alterations cause narrowing of pulse pressure, pro- hypothyroidism.27 These findings normalize when the hypothy-
longation of circulation time, and decrease in blood flow to the roidism is treated.
tissues.24,25 The reduction in cutaneous circulation is responsible Serum levels of homocysteine, creatine kinase, aspartate ami-
for the coolness and pallor of the skin and the sensitivity to cold. notransferase, and lactate dehydrogenase may be increased in
In most tissues, the decrease in blood flow is proportional to the hypothyroidism.25,28 Typically the isoenzyme patterns suggest
decrease in oxygen consumption, so the arteriovenous oxygen that the source of the increased creatine kinase and lactate dehy-
difference remains normal. The hemodynamic alterations at rest drogenase is skeletal, not cardiac, muscle. All levels return to nor-
resemble those of congestive heart failure. However, in hypothy- mal with therapy. Sequential cardiac biopsies in a hypothyroid
roidism, cardiac output increases and peripheral vascular resistance patient with heart failure showed that messenger RNA (mRNA)
decreases normally in response to exercise unless the hypothyroid levels from genes regulated by thyroid hormone and important
state is severe and of long standing. for the strength of myocardial contraction were normalized after
In severe primary hypothyroidism the cardiac silhouette T4 treatment.29
is enlarged (Fig. 13.2), and the heart sounds are diminished in The combination of large heart, hemodynamic and electro-
intensity. These findings are the result largely of effusion into the cardiographic alterations, and serum enzyme changes has been
pericardial sac of fluid rich in protein and glycosaminoglycans, but termed myxedema heart. In the absence of coexisting organic heart
the myocardium may also be dilated. Pericardial effusion is rarely disease, treatment with thyroid hormone corrects the hemody-
of sufficient magnitude to cause tamponade. namic, electrocardiographic, and serum enzyme alterations of
Angina pectoris may first appear or worsen during treatment myxedema heart and restores heart size to normal (see Fig. 13.2).
of the hypothyroid state with thyroid hormone, although most Hypothyroidism is consistently associated with elevations
patients with hypothyroidism and coronary artery disease have of total and low-density lipoprotein (LDL) cholesterol, which
A B
• Fig. 13.2 (A and B) Chest roentgenograms in a patient with myxedema heart disease. The patient had
signs of severe congestive heart failure and was given thyroid hormone alone. Within 4 months, the heart
had returned to normal size (B) and there was no evidence of underlying heart disease.
improve with T4 replacement.30 The higher the original serum Alimentary System
TSH concentration and elevation of serum LDL, the greater the Although most patients experience a modest gain in weight, appe-
magnitude of reduction in LDL cholesterol after T4 therapy. Lipo- tite is usually reduced. The weight gain that occurs is caused partly
protein fractionation has shown that the cholesterol elevation is by retention of fluid by the hydrophilic glycoprotein deposits in
predominantly due to the less atherogenic large LDL particles. the tissues but generally does not exceed 10% of body weight.
A subset of younger (<50 years) male hypothyroid patients had Peristaltic activity is decreased and, together with the decreased
elevated serum triglycerides and C-reactive protein that improved food intake, is responsible for the frequent complaint of constipa-
with T4 treatment.31 Most studies have shown that serum high- tion. The latter may lead to fecal impaction (myxedema mega-
density lipoprotein (HDL) levels are not influenced by thyroid colon). Gaseous distention of the abdomen (myxedema ileus), if
status. accompanied by colicky pain and vomiting, may mimic mechani-
Hypothyroidism has been shown to be a risk factor for athero- cal ileus.38
sclerosis and cardiovascular disease by several studies, although Elevations in the serum levels of carcinoembryonic antigen,
others have not shown this association.32 The Whickham Study which may occur on the basis of hypothyroidism alone, add to the
showed no increase in cardiovascular mortality rate in patients impression that an obstruction is present. Ascites in the absence
with subclinical hypothyroidism followed for more than 20 of another cause is unusual in hypothyroidism, but it can occur,
years.12 A prospective study in the United States, following men usually in association with pleural and pericardial effusions. Like
and women age 65 or older for more than 10 years, showed no pericardial and pleural effusions, the ascitic fluid is rich in protein
influence of hypothyroidism (overt or subclinical) on cardio- and glycosaminoglycans.
vascular outcome or mortality rate.33 Cardiovascular outcome Achlorhydria after maximal histamine stimulation may be
studies suggest that improvement from treatment of hypothy- present in patients with primary hypothyroidism. Circulating
roidism, especially subclinical hypothyroidism, is primarily in antibodies against gastric parietal cells have been found in about
those who are middle age and not older individuals (older than one-third of patients with primary hypothyroidism and may be
65 years of age).15,34,35 secondary to atrophy of the gastric mucosa. Hypothyroid patients
with positive parietal cell antibodies have a higher T4 requirement
Respiratory System compared with antibody-negative patients.39 Among Swedish
Hypothyroidism affects breathing by actions on the central celiac disease patients there was a 4.4-fold increased risk for hypo-
regulation of respiration as well as the innervation and func- thyroidism compared with the general population.40 Overt perni-
tion of the respiratory muscles, upper airways, and tongue.36 cious anemia is reported in about 12% of patients with primary
Pleural effusions usually are evident only on radiologic exami- hypothyroidism. The coexistence of pernicious anemia and other
nation but in rare instances may cause dyspnea. Lung volumes autoimmune diseases with primary hypothyroidism reflects the
are usually normal, but maximal breathing capacity and diffus- fact that autoimmunity plays the central role in the pathogenesis
ing capacity are reduced. In severe hypothyroidism, myxedema- of these diseases (see Chapter 43).22
tous involvement of respiratory muscles and depression of both Hypothyroidism has complex effects on intestinal absorp-
the hypoxic and the hypercapnic ventilatory drives may cause tion. Although the rates of absorption for many substances are
alveolar hypoventilation and carbon dioxide retention, which in decreased, the total amount absorbed may be normal or even
turn can contribute to the development of myxedema coma. An increased because the decreased bowel motility may allow more
increased prevalence of obstructive sleep apnea is seen in hypo- time for absorption. Malabsorption is occasionally overt.
thyroid patients, and it is usually reversed with restoration of a Liver function test results are usually normal, but levels of ami-
euthyroid state.37 notransaminases may be elevated, probably because of impaired
clearance.41 The gallbladder contracts sluggishly and may be dis- The presence of extensor plantar responses or diminished vibra-
tended. In a population study of those without diagnosed thy- tion sense should alert the physician to the possibility of coexisting
roid disease, men (but not women) with an elevated TSH had pernicious anemia with combined system disease. Electroencepha-
a 3.8-fold increased risk of cholelithiasis.42 Hypothyroidism is lographic changes include slow alpha-wave activity and general loss
being recognized as a predisposing factor for nonalcoholic fatty of amplitude. The concentration of protein in the cerebrospinal
liver disease.43 fluid is often increased, but cerebrospinal fluid pressure is normal.
Atrophy of the gastric and intestinal mucosa and myxedema- Histopathologic examination of the brain in patients with
tous infiltration of the bowel wall may be demonstrated on histo- untreated hypothyroidism reveals that the nervous system is
logic examination. The colon may be greatly distended, and the edematous with mucinous deposits in and around nerve fibers.
volume of fluid in the peritoneal cavity is usually increased. The In patients with cerebellar ataxia, neural myxedematous infiltrates
liver and pancreas are normal. of glycogen and mucinous material are present in the cerebellum.
There may be foci of degeneration and an increase in glial tissue.
Central and Peripheral Nervous Systems The cerebral vessels show atherosclerosis, but this finding is much
Thyroid hormone is essential for the development of the central more common if the patient has had coexistent hypertension.
nervous system.18,44,45 Deficiency in fetal life or at birth impairs Hypothyroidism has been associated with several neurologic
neurologic development, including hypoplasia of cortical neurons conditions, although a strong etiologic link has not been estab-
with poor development of cellular processes, retarded myelina- lished. Epidemiologic studies have shown an association between
tion, and reduced vascularity. If the deficiency is not corrected Alzheimer disease and hypothyroidism.50 It is difficult to convinc-
in early postnatal life, the damage is irreversible. Deficiency of ingly demonstrate this association because the incidence of thy-
thyroid hormone beginning in adult life causes less severe mani- roid disease in the elderly population is high and, like dementia,
festations that usually respond to treatment with the hormone. increases with age. A mechanistic link is suggested by the obser-
Cerebral blood flow is reduced, but cerebral oxygen consumption vation of amyloid deposition in Down syndrome, a condition
is usually normal; this finding is in accord with the conclusion associated with an increased incidence of Hashimoto disease, and
that the oxygen consumption of isolated brain tissue in vitro, thyroid hormone regulates amyloid gene processing in a number
unlike that of most other tissues, is not stimulated by administra- of cellular and animal models. Subclinical hyperthyroidism, how-
tion of thyroid hormones. In severe cases, decreased cerebral blood ever, has also been associated with Alzheimer disease.51 There is an
flow may lead to cerebral hypoxia. increase in cerebrospinal fluid reverse T3 levels in Alzheimer dis-
All intellectual functions, including speech, are slowed in ease patients, all with normal circulating thyroid hormone levels,
thyroid hormone deficiency.46 Loss of initiative is present and suggesting the potential for altered thyroid hormone metabolism
memory defects are common, lethargy and somnolence are prom- in the brain.52 The impact of normalizing T3 levels in the brain,
inent, and dementia in elderly patients may be mistaken for senile however, is not known. A corticosteroid-responsive encephalopa-
dementia.47 Positron emission tomography (PET) brain scans of thy is associated with chronic Hashimoto thyroiditis but may be
hypothyroid patients before and after T4 therapy demonstrate linked to autoimmunity rather than a process mediated specifi-
reversible reduced glucose uptake in specific brain areas, such as the cally by low thyroid hormone levels or thyroid autoantibodies.53
limbic system, which also correlates with behavioral and psychiat-
ric symptoms.48 Psychiatric disorders are common and are usually Muscular System
of the paranoid or depressive type and may induce agitation (myx- Stiffness and aching of muscles are common in hypothyroidism
edema madness).47 Headaches are frequent. Cerebral hypoxia due and are worsened by cold temperatures.49 Delayed muscle con-
to circulatory alterations may predispose to confusional attacks traction and relaxation cause slowness of movement and delayed
and syncope, which may be prolonged and lead to stupor or coma. tendon jerks.45 Muscle mass may be reduced or enlarged due to
Other factors predisposing to coma in hypothyroidism include interstitial myxedema. Muscle mass may be slightly increased, and
exposure to severe cold, infection, trauma, hypoventilation with the muscles tend to be firm. Rarely, a profound increase in muscle
carbon dioxide retention, and depressant drugs. mass with slowness of muscular activity may be the predominant
Epileptic seizures have been reported and tend to occur in manifestation (the Kocher-Debré-Sémélaigne, or Hoffmann, syn-
myxedema coma. Night blindness is due to deficient synthesis drome). Myoclonus may be present. The electromyogram may be
of the pigment required for dark adaptation. Hearing loss of the normal or may exhibit disordered discharge, hyperirritability, and
perceptive type is frequent due to myxedema of the eighth cranial polyphasic action potentials.
nerve and serous otitis media. Perceptive deafness may also occur On histopathologic examination, the muscles appear pale and
in association with a defect in the organic binding of thyroidal swollen. The muscle fibers may show swelling, loss of normal stria-
iodide (Pendred syndrome; see Chapter 11), but in these instances tions, and separation by mucinous deposits. Type I muscle fibers
it is not due to hypothyroidism per se. tend to predominate.
Thick, slurred speech and hoarseness are due to myxedema-
tous infiltration of the tongue and larynx, respectively.45 Body Skeletal System: Calcium and Phosphorus Metabolism
movements are slow and clumsy, and cerebellar ataxia may occur. Thyroid hormone is essential for normal growth and matura-
Numbness and tingling of the extremities are frequent; in the fin- tion of the skeleton, and growth failure is due both to impaired
gers these symptoms may be due to compression by glycosami- general protein synthesis and to a reduction in growth hormone,
noglycan deposits in and around the median nerve in the carpal but especially of insulin-like growth factor 1 (Fig. 13.3).54 The
tunnel (carpal tunnel syndrome).49 The tendon reflexes are slow, thyroid hormone receptor isoforms α and β have specific roles in
especially during the relaxation phase, producing the characteris- bone maturation. Before puberty, thyroid hormone plays a major
tic “hung-up reflexes”; this phenomenon is due to a decrease in role in the maturation of bone. Deficiency of thyroid hormone
the rate of muscle contraction and relaxation rather than a delay in early life leads to both a delay in development and an abnor-
in nerve conduction. mal, stippled appearance of the epiphyseal centers of ossification
(epiphyseal dysgenesis) (Fig. 13.4). Impairment of linear growth

leads to dwarfism, in which the limbs are disproportionately short
in relation to the trunk, but cartilage growth is unaffected (see
Fig. 13.3). Children with prolonged hypothyroidism, even after
adequate treatment, do not reach predicted height based on mid-
parental height calculations.55
Urinary excretion of calcium is decreased, as is the glomerular
filtration rate, whereas fecal excretion of calcium and both urinary
and fecal excretion of phosphorus are variable. Calcium balance is
also variable, and any changes are slight. The exchangeable pool of
calcium and its rate of turnover are reduced, reflecting decreased
bone formation and resorption. Because levels of parathyroid
hormone are often slightly increased, some degree of resistance
to its action may be present; levels of 1,25-dihydroxyvitamin D
(1,25[OH]2D) are also increased.
Levels of calcium and phosphorus in serum are usually normal,
but calcium may be slightly elevated. The alkaline phosphatase
level is usually below normal in infantile and juvenile hypothy-
roidism. Bone density may be increased. The radiologic appear-
ance of the skeleton in cretinism and juvenile hypothyroidism is
discussed subsequently.
Renal Function: Water and Electrolyte Metabolism

Reversible reductions in renal blood flow, glomerular filtration rate,
and tubular reabsorptive and secretory maxima are seen in hypothy-
roidism. Blood urea nitrogen and serum creatinine levels are normal,
but uric acid levels may be increased. Urine flow is reduced, and
• Fig. 13.3 The consequences of untreated congenital hypothyroidism are delay in the excretion of a water load may result in reversal of the
demonstrated in this 17-year-old girl. Her condition had been diagnosed normal diurnal pattern of urine excretion. The delay in water excre-
at birth but, through a series of misunderstandings, was not treated with tion appears to be due to decreased volume delivery to the distal
thyroid hormone. Note her size, the poorly developed nasal bridge, the diluting segment of the nephron as a result of the diminished renal
wide-set eyes, and the ears, which are larger than are appropriate for head perfusion; evidence supporting inappropriate secretion of vasopres-
size. Her tongue is enlarged, and her extremities are inappropriately short sin (syndrome of inappropriate antidiuretic hormone [SIADH]
in relation to her trunk. (Courtesy Dr. Ronald B. Stein.) secretion) is less compelling.56 There is a high prevalence of hypo-
thyroidism in patients with chronic kidney disease, and improve-
ment in renal function has been demonstrated with T4 treatment.57
The impaired renal excretion of water and the retention
of water by the hydrophilic deposits in the tissues result in an
A B
• Fig. 13.4 X-ray films of the skull and hand of the 17-year-old patient illustrated in Fig. 13.3. (A) Skull film
shows that the posterior and anterior fontanels are open and that the sutures are not fused. The deciduous
and permanent teeth are present. (B) Radiograph of the wrist and hand shows the delayed appearance
of the epiphyseal centers of the bones of the hand and the absence of the distal radial epiphysis. The
estimated bone age is 9 months. (Courtesy Dr. Ronald B. Stein.)
increase in total body water, even though plasma volume is hormone is usually normal but may be decreased. The response of
reduced. This increase accounts for the hyponatremia occasion- plasma cortisol to insulin-induced hypoglycemia may be impaired.
ally noted because the level of exchangeable sodium is increased. In severe, long-standing primary hypothyroidism, pituitary
The amount of exchangeable potassium is usually normal in rela- and adrenal function may be secondarily decreased, and adrenal
tion to lean body mass. Serum magnesium concentration may be insufficiency may be precipitated by stress or by rapid replacement
increased, but exchangeable magnesium levels and urinary magne- therapy with thyroid hormone.61 The rate of turnover of aldoste-
sium excretion are decreased. rone is decreased, but the plasma level is normal. Plasma renin
activity is decreased, and sensitivity to angiotensin II is increased,
Hematopoietic System which may contribute to the association of hypertension with
In response to the diminished oxygen requirements and decreased hypothyroidism (see Chapter 16).63,64
production of erythropoietin, the red blood cell mass is decreased;
this is evident in the mild normocytic, normochromic anemia Reproductive Function
that often occurs. Less commonly, the anemia is macrocytic, In both sexes, thyroid hormones influence sexual development and
sometimes from deficiency of vitamin B12. Reference has already reproductive function.65 Infantile hypothyroidism, if untreated,
been made to the high incidence of pernicious anemia (and of leads to sexual immaturity, and juvenile hypothyroidism causes
achlorhydria and vitamin B12 deficiency without overt anemia) a delay in the onset of puberty followed by anovulatory cycles in
in primary hypothyroidism (see Chapter 43). Conversely, overt girls. Paradoxically, primary hypothyroidism may also rarely cause
and subclinical hypothyroidism is present in 12% and 15% of precocious sexual development and galactorrhea, presumably due
patients, respectively, with pernicious anemia. Folate deficiency to “spillover” of elevated TSH stimulating the luteinizing hor-
from malabsorption or dietary inadequacy may also cause mac- mone (LH) receptor and elevated TRH initiating excess prolactin
rocytic anemia. The frequent menorrhagia and the defective release.
absorption of iron resulting from achlorhydria may contribute to In adult women, severe hypothyroidism may be associated
a microcytic, hypochromic anemia. with diminished libido and failure of ovulation. Secretion of pro-
The total and differential white blood cell counts are usually gesterone is inadequate, and endometrial proliferation persists,
normal, and platelets are adequate, although platelet adhesive- resulting in excessive and irregular breakthrough menstrual bleed-
ness may be impaired. If pernicious anemia or significant folate ing. These changes may be due to deficient secretion of LH and
deficiency is present, the characteristic changes in peripheral pulse frequency and amplitude. Rarely, in primary hypothyroid-
blood and bone marrow will be found. The intrinsic clotting ism, secondary depression of pituitary function may lead to ovar-
mechanism may be defective because of decreased concentra- ian atrophy and amenorrhea. Fertility is reduced, and there is an
tions in plasma of factors VIII and IX, which, together with an increase in spontaneous abortion and preterm delivery, although
increase in capillary fragility and the decrease in platelet adhe- many pregnancies are successful.66 Pregnancy complications are
siveness, may account for the bleeding tendency that some- associated with overt and subclinical hypothyroidism, although
times occurs.38,58,59 the impact has varied among different studies.67 A randomized
prospective study of levothyroxine treatment in pregnant women
Pituitary and Adrenocortical Function with thyroid peroxidase antibody (TPOAb) positivity but nor-
In long-standing primary hypothyroidism, hyperplasia of the thy- mal range TSH has shown that the increased incidence of pre-
rotropes may cause the pituitary gland to be enlarged. This feature term delivery and spontaneous abortions is reversed by treatment,
can be detected radiologically as an increase in the volume of the although this result remains to be confirmed.66,68 Primary ovarian
pituitary gland.60 Rarely, the pituitary enlargement compromises failure can also be seen in patients with Hashimoto thyroiditis
the function of other pituitary cells and causes pituitary insuffi- as part of an autoimmune polyendocrine syndrome.22,23 Hypo-
ciency or visual field defects. Patients with severe hypothyroidism thyroidism in men may cause diminished libido, erectile dysfunc-
may have increased serum prolactin levels, stimulated by the elevation, and oligospermia. A significant fraction of men with both
tion in thyrotropin-releasing hormone (TRH) and proportional hypothyroidism and hyperthyroidism have moderate to severe
to the level of serum TSH elevation, and galactorrhea may develop erectile dysfunction, which improves with treatment of the thy-
in some patients. Treatment with thyroid hormone normalizes the roid disease.69
serum prolactin and TSH levels and causes disappearance of galac- Values for plasma gonadotropins are usually in the normal
torrhea, if present. range in primary hypothyroidism; in postmenopausal women,
In rodents, thyroid hormone directly regulates growth hor- levels are usually somewhat lower than in euthyroid women of the
mone synthesis. Growth hormone is not directly regulated by thy- same age but are nevertheless within the menopausal range. This
roid hormone in humans, but thyroid status influences the growth feature provides a valuable means of differentiating primary from
hormone axis.61 Hypothyroid children have delayed growth and secondary hypothyroidism.
the response of growth hormone to provocative stimuli may be The metabolism of both androgens and estrogens is altered
subnormal. Individuals affected with RTHα have delayed growth in hypothyroidism. Secretion of androgens is decreased, and
and short stature, indicating the consequences of interference with the metabolism of testosterone is shifted toward etiochola-
thyroid hormone signaling through thyroid hormone receptor nolone rather than androsterone. With respect to estradiol and
alpha.62 estrone, hypothyroidism favors metabolism of these steroids via
As a result of the decreased rate of turnover of cortisol due 16α-hydroxylation over that via 2-oxygenation, with the result
to decreased hepatic 11β-hydroxysteroid dehydrogenase type that formation of estriol is increased and that of 2-hydroxyestrone
1 (11βHSD1), the 24-hour urinary excretion of cortisol and and its derivative, 2-methoxyestrone, is decreased. The sex hor-
17-hydroxycorticosteroids is decreased, but the plasma cortisol mone–binding globulin in plasma is decreased, with the result
level is usually normal (see Chapter 15). The response of uri- that the plasma concentrations of both testosterone and estra-
nary 17-hydroxycorticosteroid to exogenous adrenocorticotropic diol are decreased, but the unbound fractions are increased. The
alterations in steroid metabolism are corrected by restoration of An elevation in serum LDL cholesterol has been associated, in
the euthyroid state.70 most studies, with both overt and subclinical hypothyroidism.30
According to most studies, serum HDL and triglyceride levels are
Catecholamines not influenced by hypothyroidism.73 The reduction in LDL with
The plasma cyclic adenosine monophosphate (cAMP) response to T4 therapy is generally related to the original magnitude of LDL
epinephrine is decreased in hypothyroidism, suggesting a state of and TSH elevation; the higher the initial levels, the greater the
decreased adrenergic responsiveness. The fact that the responses reduction in LDL that is observed. A typical reduction in LDL is
of plasma cAMP to glucagon and parathyroid hormone are also 5% to 10% of the original level.
decreased suggests that thyroid hormones have a general modu- The role of adipocytokines, such as leptin, adiponectin, and
lating influence on cAMP generation.71 The reduced adrenergic resistin, in metabolic regulation has been increasingly recognized
responsiveness associated with hypothyroidism has been linked to as well as the potential for interaction with thyroid hormone.75
all steps of catecholamine signaling, including receptor and post- Rodent studies have shown that leptin regulates central adaptation
receptor actions, resulting in an impaired cAMP response. Direct between the starved and fed state and that falling leptin levels,
measurement of norepinephrine in abdominal fat of hypothyroid associated with starvation, lead to a suppression of the thyroid
patients shows reduced levels, and there is reduced production of axis. Hypothyroidism in rodents is associated with reduced leptin
glycerol in response to adrenergic agonist stimulation.72 Augmen- and increased resistin levels. Leptin infusion into the cerebral ven-
tation of α2-receptor signaling has also been proposed as a factor tricles reverses some of the metabolic changes seen with hypothy-
reducing catecholamine responsiveness. roidism, including improved glucose disposal and reduced skeletal
muscle fat.78 Human studies, however, have not shown consistent
Energy Metabolism: Protein, Carbohydrate, and Lipid changes in adipocytokines in hypothyroidism.79
Metabolism
The decrease in energy metabolism and heat production is reflected Current Clinical Picture
in a low basal metabolic rate, decreased appetite, cold intolerance, In the adult, the onset of hypothyroidism is usually so insidious
and slightly low basal body temperature.73–75 Both the synthesis that the typical manifestations may take months or years to appear
and the degradation of protein are decreased, the latter especially and go unnoticed by family and friends. The gradual development
so, with the result that nitrogen balance is usually slightly positive. of the hypothyroid state is due to slow progression both of thy-
The decrease in protein synthesis is reflected in retardation of both roid hypofunction and of the clinical manifestations after thyroid
skeletal and soft tissue growth. failure is complete. This course is in contrast with the more rapid
Permeability of capillaries to protein is increased, accounting development of the hypothyroid state when replacement therapy is
for the high levels of protein in effusions and in cerebrospinal discontinued in a patient with treated primary hypothyroidism or
fluid. In addition, the albumin pool is increased because of the when the thyroid gland of a normal subject is surgically removed.
greater decrease in albumin degradation compared to albumin In such patients, manifestations of frank hypothyroidism are usu-
synthesis. A greater than normal fraction of exchangeable albumin ally present by 6 weeks and myxedema appears by 3 months.
is in the extravascular space. The total concentration of serum pro- Hypothyroidism continues to be diagnosed at earlier stages.1,2,80
teins may be increased. Based on the most recent data, subclinical or early hypothyroid-
Hypothyroidism is associated with a reduction in glucose dis- ism is seen approximately 14 times more commonly than overt
posal to skeletal muscle and adipose tissue.76 Thyroid hormone has hypothyroidism. Early symptoms are variable and relatively non-
been shown to stimulate expression of the insulin-sensitive glucose specific. The reason for the increased prevalence of hypothyroid
transporter (GLUT4), and the levels of this transporter are reduced patients presenting with minimal symptoms is largely the avail-
in hypothyroidism. Hypothyroidism is also, however, associated ability of sensitive and specific laboratory tests that allow rec-
with reduced gluconeogenesis. The net effect of these influences is ognition of the primary form of the disease long before severe
usually a minimal effect of hypothyroidism on serum glucose levels. symptoms have developed. There should thus be a low thresh-
Thyroid hormone downregulates expression of prohormone pro- old to test patients for suspected primary hypothyroidism with a
cessing enzymes, which therefore have increased activity in hypo- serum TSH determination. Patients with significant biochemical
thyroidism. Degradation of insulin therefore is slowed, and the abnormalities of hypothyroidism may not score high on indices of
sensitivity to exogenous insulin may be increased. In a patient with symptoms and signs.81
preexisting diabetes mellitus who develops hypothyroidism, insulin With respect to physical signs of hypothyroidism, the presence
requirements may be reduced. A further influence on glucose uptake of coarse skin, periorbital puffiness that obscures the curve of the
may occur at the tissue level. Polymorphisms in the 5′-deiodinase malar bone (see Fig. 13.1), cold skin, and delayed ankle reflex
type 2 (D2) gene, which may affect local T3 production, have been relaxation phase are all signs that should lead to appropriate diag-
shown to be associated with impaired glucose disposal.77 nostic tests.
Both the synthesis and the degradation of lipid are depressed Acute hypothyroidism in the previously hyperthyroid patient
in hypothyroidism. Degradation, however, is reduced to a greater seen after radioiodine therapy may also be characterized by pain-
extent, with a net effect of accumulation of LDL and triglycer- ful cramping of large muscle groups, as discussed in Chapter 12
ides.30,73 The decrease in the lipid degradation rate may reflect regarding Graves disease.
the decrease in postheparin lipolytic activity as well as reduced
LDL receptors. Plasma free fatty acid levels are decreased, and the Hypothyroidism in Infants and Children
mobilization of free fatty acids in response to fasting, catechol- Severe hypothyroidism is seldom apparent at birth, perhaps due
amines, and growth hormone is impaired. Impaired lipolysis of to the partial protection afforded by transplacental transfer of
white fat in hypothyroid patients at baseline and in response to maternal thyroid hormones, hence the requirement for systematic
catecholamine reflects impaired free fatty acid mobilization.71,72 screening for congenital hypothyroidism.18 Congenital hypothy-
All of these abnormalities are relieved by treatment. roidism can be due to complete thyroid agenesis, ectopic thyroid,
or incomplete thyroid development. Mutations in genes impor- a family history of thyroid disease.82 The clinical manifestations
tant for thyroid development have been identified in a number of of hypothyroidism in children are intermediate, between those of
patients and in some cases may explain associated abnormalities infantile and those of adult hypothyroidism, in that the devel-
in development of other structures, such as the heart, because of opmental retardation is not as severe as that of cretinism, and
their spatial association during development. The age at which the manifestations of full-blown adult myxedema are rarely seen.
symptoms appear depends on the degree of impairment of thy- Growth and sexual development are affected predominantly. If left
roid function (see Figs. 13.3 and 13.4). Severe hypothyroidism in untreated, linear growth is severely retarded and sexual maturation
infancy is termed cretinism. As the age at onset increases, the clini- and the onset of puberty are delayed.55,83 On radiologic examina-
cal picture of cretinism merges imperceptibly with that of juvenile tion, epiphyseal dysgenesis may be present, and epiphyseal union
hypothyroidism. Retardation of mental development and growth, is always delayed, resulting in a bone age that is younger relative
the hallmark of cretinism, becomes manifest only in later infancy, to chronologic age.
and the former is largely irreversible. Consequently, early recog-
nition is crucial and has been achieved by universal population Laboratory Evaluation
screening in the developed world by measuring serum T4 or TSH
concentrations routinely in filter paper blood spots from neo- Primary and Central Hypothyroidism
nates. During the first few months of life, symptoms and signs of A decrease in secretion of the thyroid hormones is common to all
hypothyroidism include feeding problems, failure to thrive, con- varieties of hypothyroidism, except for disorders of thyroid hor-
stipation, a hoarse cry, somnolence, and jaundice. In succeeding mone metabolism or action, such as consumptive hypothyroidism
months, especially in severe cases, protuberance of the abdomen, and resistance to thyroid hormone (see later). In patients with pri-
dry skin, poor growth of hair and nails, and delayed eruption of mary thyroid disease—the cause of hypothyroidism in more than
the deciduous teeth become evident. Retardation of mental and 99% of the patients—there is a significant increase in basal serum
physical development is manifested by delay in reaching the nor- TSH concentration. A strategy for evaluating the patient suspected
mal milestones of development, such as holding up the head, sit- of hypothyroidism involves a TSH determination (Table 13.2). If
ting, walking, and talking. the suspicion of hypothyroidism is strong, if a goiter is present,
Thyroid hormone plays a major role in bone development, or if central hypothyroidism is part of the differential diagnosis,
and thyroid hormone receptors are expressed in osteoclasts and an FT4 assay should be included (see Chapter 11). If hypothy-
osteoblasts.54 The primary targets of thyroid hormone have been roidism is thought to be unlikely but must be excluded, only a
identified in the epiphyseal plates. Impairment of linear growth TSH determination is required because primary hypothyroidism
in congenital hypothyroidism results in dwarfism, with the limbs is almost always the cause. If TSH is elevated, an FT4 assay can be
disproportionately short in relation to the trunk (see Fig. 13.3). added to the same determination (Fig. 13.5). As hypothyroidism
Delayed closure of the fontanels causes the head to be large in rela- progresses, the serum TSH increases further, the serum FT4 falls,
tion to the body. The naso-orbital configuration remains infantile. and finally at the most severe stage serum T3 concentrations may
Maldevelopment of the femoral epiphyses results in a waddling become subnormal (see Table 13.2). The persistence of a normal
gait. The teeth are malformed and susceptible to caries. The char- serum T3 is in part due to preferential synthesis and secretion of
acteristic appearance includes a broad and flat nose, widely set T3 by residual functioning thyroid tissue under the influence of
eyes, periorbital puffiness, large protruding tongue, sparse hair, the increased plasma TSH. In addition, the efficiency of conver-
rough skin, short neck, and protuberant abdomen with an umbili- sion of T4 to T3 by D2 is increased as the serum T4 level falls.84
cal hernia. Mental deficiency is usually severe. Consequently, the serum T3 concentration may remain within the
Radiologic examination of the skeleton is diagnostic. The skull normal range.
shows a poorly developed base, delayed closure of the fontanels, The principal differential diagnosis is between primary and
widely set orbits, and a short and flat nasal bone. The pituitary central hypothyroidism (see Chapter 9).85 The serum TSH con-
fossa may be enlarged. Shedding of deciduous teeth and eruption centration is the critical laboratory determination that in general
of permanent teeth are delayed (see Fig. 13.4). allows recognition of the cause of the disease when the serum
The radiologic picture of epiphyseal dysgenesis is virtually FT4 is reduced. An exception is the individual with a recent
pathognomonic of hypothyroidism in infancy and childhood and history of thyrotoxicosis (and suppressed TSH) in whom a low
may involve any center of endochondral ossification, depending on FT4 level may be associated with a reduced TSH level for several
the age at onset of the hypothyroid state; it is usually best seen in months after treatment of the thyrotoxicosis. In patients with
the femoral and humeral heads and the navicular bone of the foot. primary hypothyroidism, the absence of TPOAb raises a pos-
The centers of ossification appear late, so bone age is retarded in sible diagnosis of transient hypothyroidism following an undi-
relation to chronologic age; when they eventually appear, instead agnosed episode of painful subacute thyroiditis, also referred to
of a single center, multiple small centers are scattered throughout a as postviral, de Quervain, granulomatous, or pseudotuberculous
misshapen epiphysis (see Fig. 13.4). These small centers of ossifica- thyroiditis.
tion eventually coalesce and form a single center with an irregular The differentiation of hypothyroidism due to intrinsic thy-
outline and a stippled appearance (stippled epiphysis). Epiphyseal roid failure from hypothyroidism due to diminished TSH secre-
dysgenesis is evident only in centers that normally ossify at a time tion from hypothalamic or pituitary disease (central or secondary
after the onset of the hypothyroidism. After a normal metabolic hypothyroidism) is the most critical decision point in this path-
state is restored by treatment, centers destined to ossify at a later way (see Fig. 13.5).4 A low thyroid hormone level with a normal
age develop normally. or low TSH level should lead to an evaluation for the possibility
Hypothyroidism that begins in childhood is usually Hashi- of failure of other endocrine systems that require trophic pituitary
moto disease and can be transient in this age group. Subclinical hormones for normal function (see Table 13.1) (see Chapters 8
hypothyroidism is also seen in children and adolescents, and in and 9). In some patients with central hypothyroidism, the basal
one study those affected were more likely to be obese and have serum TSH concentration (and the response to TRH) may even
TABLE 13.2 Laboratory Evaluation of Patients With be somewhat elevated, but the TSH has reduced biologic potency
Suspected Hypothyroidism or Thyroid even though it is immunologically reactive.4
Enlargementa In patients with an elevated TSH level and a reduced FT4,
the presence of TPOAb generally points to autoimmune thyroid
TSH, Free T4 TPOAb Diagnosis disease (Hashimoto disease) as the cause of the hypothyroidism
(see Fig. 13.5). On the other hand, the absence of TPOAb raises
TSH >10 mU/L
the possibility of less common causes of hypothyroidism such as
Low + Primary hypothyroidism due to transient hypothyroidism, infiltrative thyroid disorders, and exter-
autoimmune thyroid disease
nal irradiation, as discussed later (see Table 13.1), although rarely
Low-normal + Primary “subclinical” hypothyroidism patients with Hashimoto disease will not have detectable thyro-
(autoimmune) globulin or TPOAb.
Low or − Recovery from systemic illness
Measurement of radioactive iodine uptake (RAIU) is rarely
low-normal required in the evaluation of hypothyroidism. Tests that use radio-
External irradiation, drug-induced, iodine to assess the function of the thyroid gland display a variable
congenital hypothyroidism pattern, depending on the underlying thyroid disorder. The diag-
Iodine deficiency nostic value of a low RAIU is limited because of the relatively high
dietary iodine intake in North America, reducing uptake of the
Seronegative autoimmune thyroid tracer dose of radioiodine, and variation in iodine intake from day
disease
to day in the same individual. National surveys of dietary iodine
Rare thyroid disorders (amyloidosis, intake had shown a progressive reduction in iodine intake over
sarcoidosis, etc.) the past several decades, but the intake has now stabilized.86 The
Recovery from subacute granulomatous
RAIU may be normal or even increased when hypothyroidism
thyroiditis results primarily from a biochemical defect in thyroid hormone
synthesis rather than thyroid cell destruction leading to compensa-
Normal +, − Consider TSH or T4 assay artifacts tory thyroid enlargement. Specific functional patterns in relation
Elevated − Thyroid hormone resistance to the causes of hypothyroidism are discussed later. Nonetheless,
measurement of RAIU is almost never required in the diagnostic
Blockade of T4 to T3 conversion (amio- evaluation of the hypothyroid patient.
darone) or a congenital 5′-deiodinase
deficiency Differential Diagnosis
Consider assay artifacts The clinical picture of fully developed hypothyroidism is quite
characteristic, but the abnormalities can be overlooked, even by
TSH 5–10 mU/L
experienced clinicians, if the diagnosis is not considered. Despite
Low, + Early primary autoimmune hypothyroid- the availability of inexpensive and specific tests, it is still surprising
low-normal ism
how often what is retrospectively obvious, severe, primary hypo-
Low, − Milder forms of nonautoimmune thyroidism is not recognized. A high index of suspicion is required
low-normal hypothyroidism (see earlier) to avoid this oversight.
Central hypothyroidism with impaired For the milder forms of hypothyroidism, the clinical presenta-
TSH bioactivity tion overlaps to a significant extent with other conditions. The fact
that these disorders often occur in older patients is partly respon-
Elevated − (+) Consider thyroid hormone resistance sible for the diagnostic uncertainty.2 In some cases, slowing of
T4 to T3 conversion blockade (e.g., mental and physical activity, dry skin, and loss of hair may mimic
amiodarone) similar findings in hypothyroidism. Furthermore, older people
often become hypothermic with cold exposure. In patients with
TSH 0.5–5 mU/L chronic renal insufficiency, anorexia, torpor, periorbital puffiness,
Low, − (+) Central hypothyroidism sallow complexion, and anemia (e.g., see Fig. 13.1) may suggest
low-normal hypothyroidism and may call for specific testing. Distinguishing
Salicylate or phenytoin therapy
nephrotic states from hypothyroidism by clinical examination
Desiccated thyroid or T3 replacement alone may be even more difficult. In this disorder, waxy pallor,
TSH <0.5 μU/L edema, hypercholesterolemia, and hypometabolism may suggest
hypothyroidism. In addition, the total serum T4 concentration
Low, − (+) “Post-hyperthyroid” hypothyroidism (131I
low-normal or surgery) may be decreased if significant thyroid-binding globulin is lost in
the urine but the FT4 and TSH would be normal. In patients with
Central hypothyroidism pernicious anemia, psychiatric abnormalities, pallor, and numb-
T3 or desiccated thyroid excess ness and tingling of the extremities may mimic similar findings
in hypothyroidism. Although there is a clinical and immunologic
Following excess levothyroxine with- overlap between primary hypothyroidism and pernicious anemia,
drawal this association is not invariable (see Chapter 43). The presence
aInitial tests: serum TSH, serum free T4, TPO, or TgAb. of hypothyroidism is often suspected in patients who are severely
TgAb, Anti-thyroglobulin antibody; TPOAb, thyroid peroxidase autoantibody; TSH, thyroid- ill, especially in the elderly.34,87 In such patients, the total T4 con-
stimulating hormone (thyrotropin); +, present; −, not present. centration may be decreased, often markedly so, but the FT4 is
generally normal unless the patient is severely ill (see Chapter 11).
Symptoms and signs suggesting hypothyroidism
Serum TSH and

free T4 or free T4I
TSH normal or low

TSH increased Free T4 low or low normal
Free T4 low or No phenytoin
low normal No salicylates
No recent thyrotoxicosis
Primary hypothyroidism Central hypothyroidism
TPO antibody MRI
Present Absent Abnormal Normal
? Transient Congenital TRH,

Hashimoto hypothyroidism? Pituitary or TSH deficiency
disease Postviral hypothalamic infiltrative disease
thyroiditis lesion of pituitary,
hypothalamus
T4 T4
~4 months
Reduce T4 by Check
50% for 6 weeks adrenal, prolactin,
Check TSH gonads
Normal Increased
Normal Permanent Treat with surgery

thyroid hypothyroidism or drugs after
correction of
adrenal, thyroid,
T4 other deficiencies
• Fig. 13.5 Strategy for the laboratory evaluation of patients with suspected hypothyroidism. The principal
differential diagnosis is between primary and central hypothyroidism (see Chapter 9). The serum thyro-
tropin (TSH) concentration is the critical laboratory determination that in general allows recognition of the
cause of the disease. An exception is the individual with a recent history of thyrotoxicosis (and suppressed
TSH) in whom a low free thyroxine (T4) level may be associated with a reduced TSH level for several
months after relief of the thyrotoxicosis. In patients with primary hypothyroidism, the absence of thyroid
peroxidase (TPO) antibodies raises a possible diagnosis of transient hypothyroidism following an undi-
agnosed episode of subacute or postviral thyroiditis. In such patients, a trial of levothyroxine in reduced
dosage after 4 months may reveal recovery of thyroid function, thus avoiding permanent levothyroxine
replacement. MRI, magnetic resonance imaging; TRH, thyrotropin-releasing hormone; T4I, thyroxine index.
These features, together with the absence of an elevation of serum in hormone biosynthesis capable of response. In some instances,
TSH, usually serve to differentiate the ill euthyroid patient from however, the compensatory TSH response overcomes the impair-
one with primary hypothyroidism. The serum TSH, however, can ment in hormone biosynthesis, and the patient is euthyroid with
be transiently increased (up to 20 mU/L) during recovery from a goiter. The latter condition is discussed in Chapter 14 regard-
severe illness.88 ing simple or nontoxic goiter. Less commonly, hypothyroidism
Hypothyroidism may develop either because of some extrin- is associated with an atrophic gland or, in the case of a congenital
sic factor or acquired condition or because of a congenital defect abnormality, one that never developed properly. Hypothyroidism
impairing thyroid hormone biosynthesis (see Table 13.1). Inad- occurs in about 20% of patients after surgical lobectomy, with an
equate synthesis of hormone leads to hypersecretion of TSH, increased risk in areas of iodine insufficiency or in patients with
which in turn produces both goiter and stimulation of all steps anti-TPOAb.89
Classification by expressing a number of proinflammatory molecules, such as

chemokines and adhesion molecules, which increase the potential
Immune-Mediated for T-cell binding and cytotoxicity.
Autoimmune Hypothyroidism Apart from the striking activity of TSH receptor blocking anti-
Autoimmunity is responsible for over 90% of noniatrogenic hypo- bodies, which can induce temporary neonatal hypothyroidism fol-
thyroidism in countries with iodine sufficiency. The annual inci- lowing their transfer across the placenta,99,100 the pathogenic role
dence of autoimmune hypothyroidism is around 80 per 100,000 of antibodies in autoimmune hypothyroidism is unclear.101 No
men and 350 per 100,000 women.90 All ages may be affected, neonatal disorders have been associated with the presence of high
although the average age of onset is between 40 and 60 years. thyroglobulin or TPO autoantibodies in mothers, indicating that
The disorder is more frequent in whites and Asians than in Afri- any role in tissue injury is likely to be secondary to an initial phase
can Americans. The initial presentation depends on the stage of of T-cell–mediated damage, which allows the autoantibodies to
disease. Juvenile and adolescent autoimmune thyroiditis may be access their target antigens. Such injury may be mediated through
self-limiting. Hashimoto thyroiditis is the commonest cause of antibody-dependent cell-mediated cytotoxicity, involving natural
goiter in iodine-sufficient regions; atrophic thyroiditis (primary killer (NK) cells, or through complement fixation in the case of
myxedema) presents as hypothyroidism without a goiter. TPO antibodies.102
Circulating autoantibodies against thyroglobulin and TPO Histopathology. The pathologic features of autoimmune
are present in almost all patients with autoimmune hypothyroid- hypothyroidism vary from mild focal thyroiditis to extensive
ism. Up to 20% of patients with autoimmune hypothyroidism lymphocytic infiltration and fibrosis. In classical Hashimoto
have TSH receptor antibodies that block the receptor, rather than thyroiditis (originally termed struma lymphomatosa), the thyroid
stimulating it, as in Graves disease; in rare patients there may be gland may be diffusely enlarged or nodular; the tissue is pale
switching from one type of antibody to the other, resulting in and firm and has a rubbery texture (Fig. 13.7A). Typically there
alternating hypothyroidism and hyperthyroidism.91,92 Less com- is a diffuse lymphocytic infiltration with germinal center for-
monly, patients produce autoantibodies against the sodium-iodide mation and obliteration of thyroid follicles, accompanied by a
symporter (NIS), pendrin, and T4 and T3, but the functional rel- variable degree of fibrosis (see Fig. 13.7B). Destruction of thy-
evance of these antibodies is not known. roid epithelial cells occurs as disease progresses from euthyroid-
Around 15% of women and 3% of men have positive thy- ism to hypothyroidism; in some patients there is follicular cell
roid autoantibodies but no other clinical features of thyroid metaplasia and the formation of Hürthle cells. Rarely, there are
disease; most of them, however, will have histologic evidence of concurrent histologic changes of Graves disease, so-called hashi-
focal thyroiditis. Longitudinal studies have shown that euthyroid toxicosis. In the other broad type of autoimmune hypothyroid-
women with high initial levels of autoantibodies against thyro- ism, termed atrophic thyroiditis or primary myxedema, the gland
globulin or TPO and those whose TSH is within the upper half is atrophied and consists of extensive fibrotic tissue, moderate
of the reference interval are the most likely to progress to overt lymphocytic infiltration, and widespread loss of thyroid follicles,
hypothyroidism.93 but the fibrosis is not as extensive as in Riedel thyroiditis (see
Autoimmune hypothyroidism is commonly found in associa- Fig. 13.7C). The histopathologic changes in painless thyroiditis
tion with a range of autoimmune disorders, including pernicious resemble Hashimoto thyroiditis.
anemia, systemic lupus erythematosus, Addison disease, celiac Although it is now generally thought that these variations rep-
disease, and vitiligo.23,94 A steroid-responsive encephalopathy resent a spectrum of disease arising from a common underlying
(referred to as Hashimoto encephalopathy) has been reported in autoimmune process, a distinct subset of patients with Hashimoto
individuals with positive TPOAb, irrespective of thyroid dysfunc- thyroiditis has been delineated recently in whom there are high
tion, but it is unclear whether there is a true causal relationship, circulating levels of IgG4 and increased numbers of IgG4-posi-
for instance, through immunologic cross-reactivity with brain tive plasma cells in the thyroid. Such IgG4-related thyroiditis is
tissue.53,95 characterized pathologically by a greater degree of stromal fibrosis,
Pathophysiology. The current understanding of autoimmune lymphoplasmacytic infiltration, and hypothyroidism.103
mechanisms has been discussed in Chapter 12, and the main
features associated with autoimmune hypothyroidism are sum- Risk Factors
marized in Fig. 13.6. T-cell–mediated tissue injury is believed to Genetic Susceptibility. The importance of genetic factors in the
be the most important cause of autoimmune thyroid follicular cause of autoimmune hypothyroidism is indicated by the frequent
cell destruction. Perforin-containing cytotoxic CD8+ T cells are presence of thyroid autoantibodies, thyroid disease, and other
abundant in the intrathyroidal lymphocytic infiltrate in Hashi- autoimmune disorders in family members and by twin studies,
moto thyroiditis. These T cells increase during the evolution of which show a high concordance rate (0.55) in monozygotic but
disease and recognize both thyroglobulin and TPO.96 Apoptosis is not dizygotic twins.104 As with all autoimmune endocrinopathies,
an additional pathway for thyroid cell destruction. In Hashimoto human leukocyte antigen (HLA)–D region polymorphisms play
thyroiditis, thyroid follicular cells express both Fas (CD95) and a role in susceptibility, and Hashimoto thyroiditis is associated
Fas ligand (CD95L) and may thus self-destruct when these mol- with HLA-DR3 and to a lesser extent HLA-DR4.105 Polymor-
ecules interact; it is now clear that other decoy death receptors and phisms in the PD1 gene also confer susceptibility, with lesser con-
regulators of apoptosis signaling play an additional role.97 There tributions from polymorphisms in the CD40 gene and the gene
is also an increase in the number of intrathyroidal Th17 lympho- encoding thyroglobulin, as well as other unconfirmed candidate
cytes in Hashimoto thyroiditis, implying a pathogenic role for genes.106,107 It is clear that new analytic approaches are likely to
this proinflammatory T-cell subset.98 The differentiation of Th17 reveal many other genes, which make small etiologic contributions
cells may be enhanced by iodine. Cytokines released by T cells that account for the diversity of clinical presentation. For example,
and other inflammatory cells cause Hürthle cell formation and a combination of novel genetic markers has been described and
thyroid dysfunction. The thyroid cells also respond to cytokines is associated with an increased risk of progression from TPOAb
NK cell Loss of tight junction after injury

mediating ADCC allows thyroid autoantibodies to
access autoantigens, leading to
complement fixation and ADCC
NK
CD8+ cytotoxic
T cell Apoptosis triggered
mediating by Fas-Fas ligand
cytolysis binding and other
death receptors
CD8+
Immune complexes fix

complement, resulting
in tissue injury
Th1 and Th17 cells and Th1 Th17
macrophages releasing
cytokines, which cause
tissue injury
Macrophage
• Fig. 13.6 Summary of the main mechanisms involved in the pathogenesis of autoimmune hypothyroid-
ism. ADCC, antibody-dependent cell-mediated cytotoxicity; NK, natural killer.
positivity to hypothyroidism, including polymorphism in the effect).115 Evidence accumulated in animal models suggests that
MAGI3 gene.108 increased iodination of thyroglobulin enhances its immunoreac-
Shared genetic susceptibility accounts for the frequent occur- tivity, and iodine may also cause thyroid injury through the gen-
rence of other autoimmune disorders in patients with autoimmune eration of reactive oxygen metabolites.116 There are epidemiologic
hypothyroidism. Around half of women with Turner syndrome data to suggest that selenium deficiency exacerbates autoimmune
are positive for thyroid autoantibodies and a third develop hypo- thyroiditis, but trials of selenium supplementation have been
thyroidism.109 There is also an increase in autoimmune hypothy- inconclusive with regard to clinical benefit.117,118
roidism in children with Down syndrome, which may evolve into Drugs and Smoking. Treatment of patients with cytokines may
Graves disease in some cases.110 precipitate the appearance of autoimmune thyroid disease in the
Nongenetic Risk Factors. Many of the factors that have been form of Hashimoto thyroiditis or Graves disease (see later).119
identified as increasing the risk for Graves disease (pregnancy, A number of novel anticancer treatments, including TKIs (such
drugs, age, sex, iodine, and irradiation) apply equally to autoim- as sunitinib), cytotoxic T-lymphocyte–associated protein 4
mune thyroiditis. These factors are detailed in Chapter 12 but (CTLA4) blockers (such as ipilimumab), and PD1 blockers (such
briefly considered here. Epidemiologic data suggest a strong influ- as pembrolizumab and nivolumab), can also induce autoimmune
ence of environmental factors in Hashimoto thyroiditis, as this thyroiditis.120,121 There is a higher than expected prevalence of
was a rare disease before the 1950s but it is now one of the most autoimmune hypothyroidism in patients treated with lithium.
common autoimmune disorders.111 Anthracene derivatives and other chemicals produce autoim-
Sex and Pregnancy. The female preponderance of autoimmune mune thyroiditis in animals, but the role of environmental toxins
hypothyroidism may be due to sex hormones; skewed X-chromo- in human disease is poorly studied. Smoking is associated with a
some inactivation has also been proposed as an additional explana- decreased risk of autoimmune thyroiditis, but the risk rises tem-
tion. During pregnancy, fetal tolerance is maintained by changes porarily when smoking is stopped.122 Moderate alcohol consump-
in immunoregulation that have the coincidental effect of improv- tion is also protective.123
ing thyroid autoimmunity but then lead to postpartum exacer- Irradiation. Radiation exposure has been shown to induce
bation of the autoimmune process.112 This phenomenon results thyroid autoantibodies and autoimmune thyroid disease in a
in transient postpartum thyroiditis, a form of painless subacute number of studies. These exposures include radiation from the
thyroiditis (see Chapter 12), and in 10% to 50% of these cases atomic bomb detonation in Japan124 and radioactive fallout from
permanent hypothyroidism may appear over the next decade.113 the Chernobyl disaster, which was followed by an increase in the
Those women with hypothyroidism and positive TPO antibodies prevalence of thyroid autoantibodies in exposed children, with a
during the phase of postpartum thyroiditis are most at risk of such small overall increase in the prevalence of hypothyroidism 12 to
an outcome. 14 years later.125 Hodgkin disease survivors have a 17-fold relative
Iodine and Selenium. An excessive intake of iodine can pre- risk of developing hypothyroidism, but this may in part be a direct
cipitate autoimmune thyroiditis in susceptible populations.114 effect of irradiation.126
This form of hypothyroidism should be distinguished from Age. Autoimmune hypothyroidism continues to occur through-
direct blockade of a thyroid gland by iodine (the Wolff-Chaikoff out adult life (except in the very elderly whose longevity may be
A B
C
• Fig. 13.7 Hashimoto thyroiditis. (A) Gross appearance of a cut section of the thyroid lobe demonstrating
the pale color of the tissue due to lymphocytic infiltration, fibrosis, and loss of follicles. (B) Typical histologic
appearance illustrating a germinal center, heavy lymphocytic infiltration, and a partially disrupted thyroid fol-
licle. (C) Fibrous variant showing extensive fibrosis and loss of follicles. (A and C, Courtesy Dr. Vania Nosé,
Brigham and Women’s Hospital, Boston, MA; B, From Nosé V, Asa SL, Erickson LA, et al. Diagnostic
Pathology: Endocrine. Salt Lake City: Amirsys; 2012.)
associated with superior immunoregulation) so that the preva- pyramidal lobe may also be enlarged; rarely, adjacent structures,
lence of the disease increases markedly with age.12,17,87 This fea- such as the trachea, esophagus, and recurrent laryngeal nerves,
ture is similar to other types of autoimmunity and may reflect an may be compressed. Enlargement of regional lymph nodes is
increasing loss of tolerance to self. unusual.
Infection. There is no direct evidence that infection causes Other patients with hypothyroidism present without a
autoimmune thyroiditis in humans, although there is some evi- goiter (atrophic thyroiditis), which is thought to be the end
dence that the hepatitis C virus may precipitate thyroid disease result of autoimmune destruction of the thyroid, although
in susceptible patients.118 In addition, there is follow-up evi- the progression of goitrous Hashimoto thyroiditis to the atro-
dence from patients with painful subacute thyroiditis, following phied state is not commonly seen in the individual patient.
a viral infection (see later), that long-term hypothyroidism occurs The atrophic thyroid is likely the reflection of rapid destruc-
in around 15% of patients and some of these cases may have an tion early in the onset of autoimmune thyroiditis, combined
autoimmune basis. in some patients with TSH receptor antibodies of the blocking
Clinical Picture. Goiter, the hallmark of classic Hashimoto variety, although such antibodies may also occur in those with
disease, usually develops gradually and may be found during rou- a goiter. Generally the disease tends to progress slowly with an
tine examination or by ultrasonography. On occasion, the thyroid increase in fibrous tissue and loss of thyroid follicular cells. A
gland enlarges rapidly and, when accompanied by pain and ten- study of thyroid volume by ultrasound in patients with newly
derness, may mimic painful subacute thyroiditis (see Chapter 12). diagnosed autoimmune hypothyroidism found that there was
Some patients are hypothyroid when first seen. The goiter is gener- a continuum of thyroid size, with atrophy and goiter repre-
ally painless, moderate in size, and firm in consistency and moves senting extremes of the distribution, supporting the idea that
freely on swallowing. The surface can be either smooth or nodular. these are not distinct entities but part of the same underlying
Both lobes are enlarged, but the gland may be asymmetric. The autoimmune process.127
Clinically the untreated goiter remains unchanged or enlarges diffuse nontoxic goiter tends to be softer than that of Hashimoto
gradually over many years. The manifestations of hypothyroid- thyroiditis. Ultrasound examination typically reveals a diffuse and
ism vary and often develop over many years in patients who are patchy heterogeneous echotexture or hypoechoic micronodules
initially euthyroid. Thyroid lymphoma occurs almost exclusively with echogenic septations in Hashimoto thyroiditis. In adoles-
in patients with underlying Hashimoto thyroiditis and should be cents, differentiation of Hashimoto goiter from diffuse nontoxic
suspected if there is rapid and sometimes painful enlargement of goiter is even more difficult because in this age group Hashimoto
the thyroid gland.128 As mentioned earlier, the presence of coex- thyroiditis may not be accompanied by such high levels of thy-
istent Hashimoto thyroiditis may be a favorable prognostic fac- roid autoantibodies. The presence of well-defined nodules usu-
tor in patients with papillary carcinoma, but the risk of papillary ally distinguishes nontoxic multinodular goiter from Hashimoto
carcinoma is probably not increased in Hashimoto thyroiditis.129 thyroiditis.
Occasionally hyperthyroidism due to Graves disease develops Differentiation between euthyroid Hashimoto thyroiditis and
in patients with Hashimoto thyroiditis. In other patients with thyroid carcinoma can sometimes be made on clinical grounds,
early autoimmune thyroiditis, transitory thyrotoxicosis (pain- but an ultrasound examination and aspiration biopsy are neces-
less thyroiditis with thyrotoxicosis) occurs as the result of thy- sary in any case in which there is uncertainty. Lymphoma must
roid cell destruction. In such cases, evidence of ongoing thyroid always be excluded if there is a sudden change in a known Hashi-
hyperfunction is lacking because the thyroid RAIU is depressed. moto goiter; core needle biopsy or open surgical biopsy may be
As described earlier, 50% of women with thyroid autoantibod- required for final diagnosis. Thyroid carcinoma usually occurs as a
ies who are euthyroid in the first trimester of pregnancy develop solitary nodule that is firm or hard, and the gland may be fixed to
postpartum thyroiditis, accompanied by transient thyrotoxicosis, adjacent structures. Compression of the recurrent laryngeal nerve
hypothyroidism, or fluctuation from one state to the other.130 with hoarseness is virtually pathognomonic of thyroid carcinoma
Laboratory Tests. The results of the common tests of thyroid but occurs late in the cancer progression. A history of a recent
function depend on the stage of the disease (see Table 13.2). enlargement of the goiter is more common in thyroid malignan-
Rarely, the tests may suggest thyrotoxicosis with a suppressed TSH cies (either carcinoma or lymphoma) than in Hashimoto thyroid-
and elevated serum T4 and T3 levels, due to either release of stored itis. Enlargement of regional lymph nodes also suggests thyroid
thyroid hormone as a result of rapid tissue destruction or the malignancy but can rarely occur in autoimmune thyroiditis.
relative overproduction of autoantibodies, which stimulate rather Treatment. In euthyroid patients with Hashimoto thyroiditis,
than block the TSH receptor (sometimes called hashitoxicosis). In no treatment is required because the goiter is usually asymptom-
the latter case, the RAIU may be increased, whereas it is decreased atic. Levothyroxine treatment may be indicated in patients when
if there is tissue destruction. Typically, patients with Hashimoto the goiter presses on adjacent structures or is unsightly, and it is
thyroiditis present with a goiter, and blood tests show a normal or most effective in goiters of recent onset. The aim is to keep the
slightly raised TSH, with normal serum T4 and T3 levels. As tissue TSH level in the lower half of the reference interval. In long-stand-
destruction continues, the TSH level rises further, but the abil- ing goiter, treatment with thyroid hormone is usually ineffective,
ity of the thyroid to respond to TSH diminishes, and the RAIU possibly because of fibrosis. Rarely, the goiter may be painful, and
and serum T4 level decline to subnormal values, resulting in overt this symptom may respond to levothyroxine therapy. Glucocorti-
hypothyroidism. This is the typical biochemical finding in atro- coids, such as prednisolone, are usually ineffective. Surgery may be
phic thyroiditis, in which there is no goiter to alert the patient or justified if symptoms or unsightly enlargement persists after a trial
physician to the underlying disorder. The serum T3 level remains of levothyroxine therapy.
normal until late in the disease process, reflecting maximal stimu- Replacement doses of thyroid hormone should be given when
lation of the failing thyroid by the increased serum TSH. The early hypothyroidism is present, appropriate to the degree of hor-
phase of the foregoing sequence, when the serum TSH is increased mone deficiency (see later). There may be a spontaneous return
but T4 and T3 are still normal, is termed subclinical hypothyroidism to euthyroidism in up to 10% of patients after starting levothy-
(see Table 13.2). roxine, associated in some cases with the disappearance of TSH
The diagnosis of autoimmune hypothyroidism is confirmed receptor blocking antibodies. However, it has not been established
by the presence of thyroid autoantibodies in the serum, usually that such remissions are durable and there is no need to routinely
in high levels. TPO and thyroglobulin autoantibodies occur in stop levothyroxine once it has been started. It has recently been
roughly similar frequencies; the presence of both autoantibodies suggested that prednisolone treatment can reverse the hypothy-
is twice as frequent as the isolated individual autoantibodies.131 roidism of IgG4-related thyroiditis, but the long-term outcome in
Thyroid autoantibodies may be absent in rare patients due to assay such cases is not yet known.132
insensitivity or the occurrence of an entirely intrathyroidal auto-
immune process. Sometimes part of a gland with autoimmune Iodine Deficiency (Endemic Goiter)
thyroiditis may look and feel like a firm thyroid nodule, and ultra- The term endemic goiter denotes any goiter occurring in a region
sonography or even aspiration biopsy should be performed to con- where goiter is prevalent.132 As mentioned, endemic goiter almost
firm the diagnosis. always occurs in areas of environmental iodine deficiency.133
Differential Diagnosis. Differentiation of autoimmune hypo- Although this condition is estimated to affect more than 200 mil-
thyroidism from other forms of hypothyroidism is facilitated lion people throughout the world and is of major public health
by the demonstration that high levels of thyroid autoantibodies significance, it is most common in mountainous areas, such as the
occur more commonly than in other thyroid disorders. The fre- Alps, Himalayas, and Andes, or in the Great Lakes and Missis-
quent coexistence of hypothyroidism and Hashimoto thyroiditis sippi Valley regions of the United States, owing to the depletion of
serves to distinguish this disease from nontoxic goiter and thyroid iodine consequent to the persistent glacial run-off in these regions.
neoplasia. The causative role of iodine deficiency in the genesis of endemic
Differentiation of a euthyroid Hashimoto goiter from a mul- goiter is supported by the inverse correlation between the iodine
tinodular goiter is often difficult without ultrasonography, and content of soil and water and the incidence of goiter, the kinetics
of iodine metabolism in patients with the disorder, and a decrease usually has no effect on long-standing goiter or on established
in incidence after iodine prophylaxis. The latter accounts for its mental or skeletal changes, but it should be given in full-replace-
absence in the population residing in the Great Plains region of ment doses if there is evidence of hypothyroidism. This is of
the United States. paramount importance in pregnant women. Surgical treatment is
The occurrence of endemic goiter can vary, even within an indicated if the adjacent structures are compressed or if the goiter
area of known iodine deficiency; the roles of dietary minerals or is either very large or enlarging rapidly.
naturally occurring goitrogens and of pollution of water supplies
have been suggested in instances of this type.134 For example, in Endemic Cretinism
the Cauca Valley of Colombia, waterborne goitrogens have been Endemic cretinism is a developmental disorder that occurs in
implicated, and in many areas of endemic iodine deficiency, regions of severe endemic goiter.133 Both parents of an endemic
consumption of cassava meal, which gives rise to thiocyanate, cretin are usually goitrous, and in addition to the features of spo-
aggravates the iodine-deficient state by inhibiting thyroid iodide radic cretinism described earlier, endemic cretins often have deaf-
transport. Familial clustering of goiters within iodine-insufficient mutism, spasticity, motor dysfunction, and abnormalities in the
areas, usually with an autosomal dominant inheritance, suggests basal ganglia demonstrable by magnetic resonance imaging.
an important genetic component.135 Three types of cretins can be discerned: (1) hypothyroid cretins,
Most abnormalities in iodine metabolism in patients with (2) neurologic cretins, and (3) cretins with combined features of
endemic goiter are consistent with the expected effects of iodine the two. The pathogenesis of neurologic cretinism is obscure but
deficiency (see Chapter 11 regarding iodine metabolism). Thyroid may be due to severe thyroid hormone deficiency during a criti-
iodide clearance rates and RAIU are increased in proportion to cal early phase of central nervous system development in utero.44
the decrease in the urinary excretion of stable iodine. The abso- Some cretins are goitrous, but the thyroid may also be atrophic,
lute iodine uptake is normal or low. In areas of moderate iodine possibly as a consequence of exhaustion atrophy from continuous
deficiency, the serum T4 concentration is usually in the lower overstimulation or the lack of iodine.
range of normal; in areas of severe deficiency, however, values are
decreased. Nevertheless, most patients in these areas do not appear Iodide Excess
to be in a hypothyroid state because of an increase in the synthesis Goiter and hypothyroidism, either alone or in combination, are
of T3 at the expense of T4 and because of an increase in the activity sometimes induced by chronic administration of large doses of
of thyroidal D1 and D2.84 TSH levels are typically in the upper iodine in either organic or inorganic form (see Table 11.7).133,138
range of normal. Iodide-induced goiter was formerly seen in patients with chronic
The incidence and severity of endemic goiter and the meta- respiratory disease who were given potassium iodide as an expec-
bolic state of the goitrous patient depend mainly on the degree of torant. The development of iodide goiter has also been reported
iodine deficiency. In the absence of hypothyroidism, the effects of after a single administration of radiographic contrast medium
the goiter are mainly cosmetic. When the goiter becomes nodu- from which iodide is released slowly over a long period and may
lar, however, hemorrhage into a nodule may cause acute pain and also occur during amiodarone administration. Iodide goiter with-
swelling, mimicking painful subacute thyroiditis or neoplasia. out hypothyroidism may occur endemically, such as on the island
The goiter may also compress adjacent structures, such as the tra- of Hokkaido, Japan, where seaweed products are consumed in
chea, esophagus, and recurrent laryngeal nerves. The borderline large quantities.
nature of the iodine supply in many countries of Western Europe From an analysis of reported cases and from the fact that
is exemplified by the development of compensatory maternal and only a small percentage of patients who receive iodides chroni-
fetal goiter during pregnancy due to the increased requirement for cally develop goiter, it appears that the disorder evolves on a
thyroid hormone during gestation.133 background of underlying thyroid dysfunction.138 Categories of
The incidence of endemic goiter has been greatly reduced in susceptible individuals include the following: patients with Hashi-
many areas by the introduction of iodized salt.133 In the United moto disease, patients with Graves disease especially after treat-
States, table salt is enriched with potassium iodide to a concen- ment with radioiodine, and patients with cystic fibrosis.
tration of 0.01%, which, if the intake of salt is average, would Among these groups, many individuals display a positive
provide an iodine intake of approximately 150 to 300 μg/day, the iodide-perchlorate discharge test, indicating a defect in the thy-
desired amount in an adult (see Table 11.1). The use of iodine- roidal organic iodine-binding mechanism (see Chapter 11 regard-
containing flour in bread products and iodized salt in commer- ing iodine metabolism). However, intrinsic thyroid disease need
cially produced food has been markedly reduced.136 The iodine not be present because a propensity to develop iodide goiter and
content of bread and infant formula is variable within a given hypothyroidism has also been demonstrated in patients who have
product and often does not match the measured content.136 As undergone hemithyroidectomy for a solitary thyroid nodule in
mentioned, iodine intake in the United States has been decreas- whom the remaining lobe was histologically normal.89 In these
ing in recent decades, likely due to reduced iodine in commercial patients, as in those with Hashimoto disease or Graves disease
food products, although iodine intake has now stabilized. Preg- studied prospectively, individuals with the highest basal serum
nant women, however, remain a susceptible population because TSH concentrations, even within the normal range, were those
of their increased iodine requirements.134 Most prescription pre- who developed iodide goiter. Iodinated contrast material, amioda-
natal vitamins do not contain iodine.137 An annual injection of rone, and povidone-iodine are common sources.138
iodized oil is another effective means of administering iodine, and Goiter and hypothyroidism commonly occur in newborns of
endemic goiter can be treated by the addition of iodine to com- women given large quantities of iodine during pregnancy, and
munal drinking water. death from neonatal asphyxia has been reported (see Fig. 11.11).
Administration of iodine has little if any effect on a long-stand- In such cases, the mother is usually free from goiter. Pregnant
ing endemic goiter, but it causes the early endemic hyperplastic women should not receive large doses of iodine (>1 mg/day) over
goiter of iodine deficiency to regress. Similarly, thyroid hormone prolonged periods (>10 days), especially near term. Maternal
amiodarone therapy causes thyroidal dysfunction in up to 20% of of pharmacologic goitrogens is required, however, replacement
newborns.133 It is not known whether iodide goiter in newborns therapy with thyroid hormone causes the goiter to regress.
results from an inherent hypersensitivity of the fetal thyroid or
from the fact that the placenta concentrates iodide several-fold, Goitrogens in Foodstuffs or as Endemic Substances or
or both. Pollutants
As discussed earlier (see Chapter 11, “Regulation of Thy- Antithyroid agents also occur naturally in foods. They are widely
roid Function”), large doses of iodine cause an acute inhibition distributed in the family Cruciferae or Brassicaceae, particularly
of organic binding that abates in the normal individual, despite in the genus Brassica, including cabbages, turnips, kale, kohl-
continued iodine administration (acute Wolff-Chaikoff effect and rabi, rutabaga, mustard, and various plants that are not eaten by
escape).139 Iodide goiter appears to result from a more pronounced humans but that serve as animal fodder.142 It is likely that some
inhibition of organic binding and the failure of the escape phe- thiocyanate is present in such plants (particularly cabbage).143
nomenon. As a consequence of decreased hormone synthesis and Cassava meal, a dietary staple in many regions of the world, con-
the consequent increase in TSH, iodide transport is enhanced. tains linamarin, a cyanogenic glycoside, the preparation of which
Because inhibition of organic binding is a function of the intra- leads to the formation of thiocyanate. Ingestion of cassava can
thyroidal concentration of iodide, a vicious circle, augmented by accentuate goiter formation in areas of endemic iodine deficiency.
this increase in serum TSH, is set in motion. Except for thiocyanate, dietary goitrogens influence thyroid iodine
The disorder usually appears as a goiter with or without hypometabolism in the same manner as do the thionamides, which
thyroidism, although in rare instances iodine may produce hypo- they resemble chemically; their role in the induction of disease in
thyroidism unaccompanied by goiter. Usually the thyroid gland humans is uncertain. Waterborne, sulfur-containing goitrogens of
is firm and diffusely enlarged, often greatly so. Histopathologic mineral origin are believed to contribute to the development of
examination reveals intense hyperplasia. The FT4 concentration endemic goiter in certain areas of Colombia.
is low, TSH concentration is increased, and the 24-hour urinary A number of synthetic chemical pollutants have been impli-
iodine excretion and the serum inorganic iodide concentration are cated as a cause of goitrous hypothyroidism, including polychlo-
increased. The disorder regresses after iodine is withdrawn. Thy- rinated biphenyls and resorcinol derivatives.144 Perchlorate has
roid hormone may also be given to relieve severe symptoms. also been noted in high concentrations in geographic regions in
which explosives and rocket fuel were made. Perchlorate has been
Drugs Blocking Thyroid Hormone Synthesis or Release, detected in water, food, and breast milk, although the amount
Causing Goiter Formation does not appear to be sufficient to disrupt thyroid function. In
Ingestion of compounds that block thyroid hormone synthesis or an area of Chile with a high level of natural perchlorate contam-
release may cause goiter with or without hypothyroidism. Apart ination in the water, thyroid function in pregnant women was
from the agents used in the treatment of hyperthyroidism, anti- not different from that in a region with no perchlorate, although
thyroid agents may be encountered either as drugs for the treat- iodine intake is quite high in this area.145
ment of disorders unrelated to the thyroid gland or as natural
agents in foodstuffs. Cytokines
Goiter with or without hypothyroidism can occur in patients Patients with chronic hepatitis C or various malignancies may
given lithium, usually for bipolar manic-depressive psychosis.140 be given interferon-α or interleukin 2.119,146 Such patients may
Like iodide, lithium inhibits thyroid hormone release, and in high experience hypothyroidism, which is often a transient destructive
concentrations it can inhibit organic binding reactions. At least thyroiditis and associated with an initial thyrotoxic phase but in
acutely, iodide and lithium act synergistically in the latter respect. other cases may persist. Graves disease with hyperthyroidism may
The mechanisms underlying the several effects of lithium are also develop, and ablative therapy may be required to treat this
uncertain; what differentiates patients who develop thyroid dis- condition. Women and those who have positive TPOAb prior to
ease during lithium therapy from those who do not is also unclear. treatment are at higher risk for these complications and should be
A promoting effect on underlying autoimmune thyroiditis may be monitored especially carefully during and after a course of treat-
at least one factor because many patients with this combination ment with either of these cytokines.
have autoimmune thyroid disease.
Other drugs that occasionally produce goitrous hypothyroid- Congenital Causes of Goiter
ism include para-aminosalicylic acid, phenylbutazone, aminoglu- Inherited defects in hormone biosynthesis are rare causes of goi-
tethimide, and ethionamide. Like the thionamides, these drugs trous hypothyroidism and account for only about 10% to 15% of
interfere with both the organic binding of iodine and perhaps in the 1 in 3000 newborns with congenital hypothyroidism.18,147,148
later steps in hormone biosynthesis. Although soybean flour is In most instances, the defect appears to be transmitted as an auto-
not an antithyroid agent, soybean products in feeding formulas somal recessive trait. Individuals with goitrous hypothyroidism
formerly resulted in goiter in infants by enhancing fecal loss of are believed to be homozygous for the abnormal gene, whereas
hormone, which, together with the low iodine content of soybean euthyroid relatives with slightly enlarged thyroids are presumably
products, produced a state of iodine deficiency. Feeding formulas heterozygous. In the latter group, appropriate functional testing
containing soybean products are now enriched with iodine. may disclose a mild abnormality of the same biosynthetic step
Cigarette smoking reduces the hypothyroidism in patients that is defective in the homozygous individual. In contrast with
with underlying autoimmune thyroid disease, although the risk nontoxic goiter, which is more common in females than in males,
is transiently increased if smoking is stopped.122 Thiocyanate, these defects, as a group, affect females only slightly more com-
hydroxypyridine, and benzopyrene derivatives found in cigarette monly than males.
smoke may also interfere with thyroid hormone action.141 Although goiter may be present at birth, it usually does not
Both the goiter and the hypothyroidism usually subside after appear until several years later. Therefore the absence of goi-
the antithyroid agent is withdrawn. If continued administration ter in a child with functioning thyroid tissue does not exclude
the presence of hypothyroidism. The goiter is initially diffusely and hypothyroidism is only a complication, the presence of sig-
hyperplastic, often intensely so, suggesting papillary carcinoma, nificant hypothyroidism without evidence of autoimmune thy-
but eventually it becomes nodular. In general, the more severe the roiditis should lead to a consideration of these rare causes of this
biosynthetic defect, the earlier the goiter appears, the larger it is, condition.
and the greater the likelihood of early development of hypothy-
roidism or even cretinism.147 Five specific defects in the pathways Postablative Hypothyroidism
of hormone synthesis have been identified. Postablative hypothyroidism is a common cause of thyroid fail-
Iodide Transport Defect. An iodide transport defect, a result of ure in adults. One type follows total thyroidectomy usually per-
impaired iodide transport by the NIS protein mechanism, is rare formed for thyroid carcinoma. Although functioning remnants
and is reflected in defective iodide transport in the thyroid, salivary may be present, as indicated by foci of radioiodine accumulation,
gland, and gastric mucosa.149,150 Some mutations in such patients hypothyroidism invariably develops. Another etiologic mecha-
produce reduced activity, and others completely inactivate NIS by nism is subtotal resection of the diffuse goiter of Graves disease
preventing the protein from being transported and inserted into or multinodular goiter. Its frequency depends on the amount of
the membrane. With the milder NIS mutations, administration of tissue remaining, but continued autoimmune destruction of the
iodide raises the plasma and intrathyroidal iodide concentration, thyroid remnant in patients with Graves disease may be a factor
permitting the synthesis of normal quantities of hormone. because some studies suggest a correlation between the presence
Defects in Expression or Function of Thyroid Peroxidase. of circulating thyroid autoantibodies in thyrotoxicosis and the
TPO is a protein that is required for normal synthesis of iodo- development of hypothyroidism after surgery. Hypothyroidism
thyronines. Quantitative or qualitative abnormalities of TPO can be manifested during the first year after surgery, but as with
have been identified in 1 in 66,000 infants in the Netherlands. postradioiodine hypothyroidism, the incidence increases with
The most common of the 16 mutations identified in 35 families time. In some patients, mild hypothyroidism appears during the
was a GGCC insertion in exon 8, leading to a premature stop early postoperative period and then may occasionally remit, as also
codon.151 occurs after radioiodine treatment.
Pendred Syndrome. The most common presentation in Hypothyroidism after destruction of thyroid tissue with radio-
patients with Pendred syndrome is a defect in iodine organifica- iodine is common and is the one established disadvantage of this
tion accompanied by sensory nerve deafness.152 The abnormality form of treatment for hyperthyroidism in adults. Its frequency is
is in the PDS gene encoding pendrin, which is involved in the determined in large part by the dose of radioiodine and radioio-
apical secretion of iodide into the follicular lumen (see Fig. 11.1 dine uptake, but it is also influenced by other factors, including
and the discussion regarding iodine metabolism in Chapter 11). age, thyroid gland size, magnitude of thyroid hormone elevations,
Thyroid function is only mildly impaired in this disorder. and use of antithyroid drugs.159 The incidence of postradioio-
Defects in Thyroglobulin Synthesis. Defects in the synthesis of dine hypothyroidism increases with time, approaching 100%.
thyroglobulin due to genetic causes are rare, having been identified Although the FT4 is low in patients with postablative hypothy-
only in a small number of families with congenital hypothyroid- roidism, serum TSH levels may be anomalously low for several
ism.147 Some defects lead to premature termination of translation, months after either surgical or 132I-induced hypothyroidism if
whereas another defect causes deficiency in endoplasmic reticu- TSH synthesis has been suppressed for a long period prior to
lum processing of the thyroglobulin molecule. The complex regu- treatment.
lation and the huge size of this gene make screening for mutations Primary atrophic thyroid failure may also develop in patients
a difficult task, and considerable work is still required to unravel with Hodgkin disease after treatment with mantle irradiation or
the extent of the defects in this gene. after high-dose neck irradiation for other forms of lymphoma
Iodotyrosine Dehalogenase Defect. The pathogenesis of goiter or carcinoma.126 Surgical, radioiodine, or external beam therapy
and hypothyroidism in the iodotyrosine dehalogenase defect is may also lead to a state of subclinical hypothyroidism (see Table
complex. The major abnormality is an impairment of both intra- 13.2).
thyroidal and peripheral deiodination of iodotyrosines, presum-
ably because of the dysfunction of the iodotyrosine DEHAL1B Thyroid Agenesis or Dysplasia
gene (see discussion regarding iodide metabolism in Chapter Developmental defects of the thyroid are often responsible for
11).153,154 the hypothyroidism that occurs in 1 in 3000 newborns.18 These
As a consequence of intense thyroid stimulation and lack of defects may take the form of complete absence of thyroid tissue
intrathyroidal recycling of iodide derived from dehalogenation, or failure of the thyroid to descend properly during embryo-
iodide is rapidly accumulated by the thyroid gland and is rapidly logic development. Thyroid tissue may then be found anywhere
released; monoiodotyrosine (MIT) and diiodotyrosine (DIT) are along its normal route of descent from the foramen cecum at
elevated in plasma and, together with their deaminated deriva- the junction of the anterior two-thirds and posterior third of the
tives, in the urine. Hypothyroidism is presumed to result from tongue (lingual thyroid) to the normal site or below. Absence
the loss of large quantities of MIT and DIT in the urine and to of thyroid tissue or its ectopic location can be ascertained by
secondary iodine deficiency. The goiter and hypothyroidism are scintiscanning.
relieved by administration of high doses of iodine. As indicated, a number of proteins are known to be crucial for
normal thyroid gland development.18 These proteins include the
Thyroid Infiltration Causing Hypothyroidism and Goiter thyroid-specific transcription factor PAX8 as well as thyroid tran-
A number of infiltrative or fibrosing conditions may cause scription factors 1 and 2 (TTF1 and TTF2, respectively). It might
hypothyroidism. Some are often associated with goiter, such be anticipated that defects in one or more of these proteins may
as Riedel struma (see later).155 Others, such as amyloidosis,156 explain abnormalities in thyroidal development. These abnormali-
hemochromatosis,157 or scleroderma,158 may not be. Although ties have been identified in several patients with PAX8 mutations,
the other manifestations of these conditions are usually obvious and a mutation in the human TTF2 gene was associated with
thyroid agenesis, cleft palate, and choanal atresia. Despite a spe- In patients with hypothyroidism that follows an episode of pain-
cific search, no mutations have been found in the TTF1 gene in less subacute thyroiditis, the gland is usually slightly enlarged and
infants with congenital hypothyroidism. somewhat firm, reflecting the underlying scarring and infiltration
associated with that condition.
Thyroid Aplasia Due to Thyrotropin Receptor
Unresponsiveness Consumptive Hypothyroidism
Several families exist in which thyroid hypoplasia, high TSH con- Consumptive hypothyroidism is the term given to an unusual cause
centrations, and a low FT4 level are associated with loss-of-func- of hypothyroidism that has been identified in infants with visceral
tion mutations in the TSH receptor.160 The thyroid gland of these hemangiomas or related tumors.7,163 The first patient reported
patients was in the normal location but did not trap pertechnetate with this syndrome presented with abdominal distention caused
(TcO4−). Somewhat surprisingly, thyroglobulin levels were still by a large hepatic hemangioma with respiratory compromise
detectable. The molecular details of these patients are still under secondary to upward displacement of the diaphragm. However,
study. clinical signs suggested hypothyroidism, which was confirmed
A second type of abnormality that may cause TSH unrespon- by finding a markedly elevated TSH level and undetectable T4
siveness is a mutation in the Gs protein that occurs in pseudo- and T3 levels. The infant’s response to an initial intravenous infu-
hypoparathyroidism type 1A. These patients have inactivating sion of liothyronine (T3) was transient, leading to the decision to
mutations in the α-subunit of the Gs protein and, consequently, use parenteral thyroid hormone replacement to relieve the severe
mild hypothyroidism.161 Other as yet unexplained patients with hypothyroidism. The accelerated degradation of thyroid hormone
elevated TSH levels and hypothyroidism in which the molecular was apparent from the fact that 96 μg of liothyronine plus 50 μg
nature of the defect has not been defined have been reported.162 of levothyroxine were required to normalize the TSH level. The
equivalent dosage of levothyroxine alone is roughly nine times that
Transient Hypothyroidism ordinarily required for treatment of infants with congenital hypo-
Transient hypothyroidism is defined as a period of reduced FT4 thyroidism. The infant succumbed to complications of the hem-
with suppressed, normal, or elevated TSH levels that are eventu- angioma, and a postmortem tumor biopsy showed D3 activity in
ally followed by a euthyroid state. This form of hypothyroidism the tumor at levels eightfold higher than those normally present in
usually occurs in the clinical context of a patient with painful or term placenta. The serum reverse T3 was extremely elevated (400
painless subacute thyroiditis.130 These conditions are reviewed in ng/dL), and the serum thyroglobulin was greater than 1000 ng/
detail in Chapter 12. mL, indicating the presence of a highly stimulated thyroid gland.
The patient reports mild to moderate symptoms of hypothy- Retrospective search revealed two other patients with similar
roidism of short duration, and serum TSH concentrations are pathophysiology in whom the cause of the hypothyroidism had
typically elevated, although not greatly so. The patient often has not been recognized. Significant D3 expression has subsequently
a preceding episode of symptoms consistent with mild or moder- been noted in all proliferating cutaneous hemangiomas studied
ate thyrotoxicosis. If these symptoms cannot be elucidated from to date. The cutaneous hemangiomas of infancy, although they
the history, it may be difficult to distinguish such patients from express D3, are not associated with hypothyroidism owing to their
those with a permanent form of hypothyroidism. In the early small size. Most infantile hemangiomas involute with proprano-
phases of post-thyroiditis hypothyroidism, TSH concentrations lol therapy, but such patients must also receive adequate doses of
may still be suppressed even though the FT4 is low because of the thyroid hormone to prevent the permanent neurologic complica-
delayed recovery of pituitary TSH synthesis, such as in patients tions associated with untreated hypothyroidism during this criti-
with Graves disease or with toxic nodules who have undergone cal phase of neurologic development.164 Subsequent reports have
surgery and who have experienced rapid relief of hypothyroidism identified a similar syndrome in adults, including a patient with
(see Table 13.2). In that situation, the TSH response to hypothy- an epithelioid hemangioendothelioma and an individual with a
roidism may be suppressed for many months; in post-thyroiditis fibrous tumor as well as extensive gastrointestinal stromal tumors
hypothyroidism, this period is rarely longer than 3 to 4 weeks. (GISTs).165 Some of these tumors express D3, or this deiodinase
A significant fraction (50%) of women with autoimmune may be induced during treatment with TKIs (see later).166–169
thyroiditis but normal thyroid function have episodes of hypo-
thyroidism during the postpartum period.130 In some, the pre- Defects in Conversion of Thyroxine to Triiodothyronine
ceding thyrotoxicosis is relatively asymptomatic, which can make The enzymes that convert the precursor T4 to the active form,
an accurate clinical diagnosis difficult. Patients who have had an T3, are 5′-deiodinase 1 (D1) and D2, both of which contain
episode of typical painful subacute thyroiditis, with pain, tender- selenocysteine in their active site.84 A stem loop structure in the
ness, and thyrotoxicosis, are not difficult to recognize. 3′-untranslated region of the mRNA, termed a SECIS element,
Diagnostic evaluation should include a determination of TSH, directs insertion of selenocysteine at the UGA codon, rather
FT4, and TPOAb. Negative or low antibodies argue strongly for a than allowing it to function as a stop codon. Defects in a SECIS-
nonautoimmune cause. This is significant, in that it may be pos- binding protein (selenocysteine insertion sequence–binding pro-
sible for the patient to be treated only temporarily for hypothy- tein 2 [SECISBP2]) were found in two families with an elevated
roidism. In such patients, a trial of a lower levothyroxine dosage FT4, reduced T3, and elevated TSH.170 Affected individuals have
after 3 to 6 months may reveal that thyroid function has recovered growth retardation, compared with unaffected family members.
(see Fig. 13.5). This may also occur in patients with hypothyroid- Polymorphisms in genes associated with thyroid hormone
ism that follows painless subacute thyroiditis (e.g., in the postpar- metabolism have been associated with patterns of thyroid func-
tum period), but it is somewhat less likely to occur because of the tion studies as well as obesity. The D2 polymorphism result-
underlying progressive nature of the autoimmune thyroiditis. ing in a change from threonine (Thr) to alanine (Ala) at codon
In patients with hypothyroidism due to painful subacute thy- 92 (Thr92Ala) has been associated with obesity, reduced glu-
roiditis, the thyroid gland is usually relatively small and atrophic. cose disposal, and lower D2 activity in skeletal muscle.171 This
polymorphism also has a higher frequency in groups with a high is a manifestation of stage 3 illness (see Table 11.10). Although
incidence of obesity and type 2 diabetes such as Mexican Ameri- these agents may be expected to have similar effects when given
cans and Pima Indians.171 The D2 polymorphism has also been long term, they do not, nor does somatostatin have a similar effect
associated with a distinct pattern of gene expression in the cortex, when given for acromegaly, although it does block the response
associated with inflammation and chronic disease, linked to proof TSH to TRH and it has been administered to patients with
longed half-life of the D2 protein in the Golgi.172 thyrotropin-secreting pituitary adenomas.177
Congenital defects in either the stimulation or the synthesis of
Hypothyroidism Due to Drug-Induced Thyroid Destruction TSH or in its structure have been identified as rare causes of con-
Thyroid inflammation or activation of autoimmune thyroid genital hypothyroidism18 and include the consequences of defects
destruction has been associated with a number of drugs.146,173 in several of the homeobox genes, including POU1F1 (formerly
The TKIs, such as sunitinib, have been associated with a high inci- termed Pit1), PROP1, and HESX1. The last gene encodes a factor
dence of hypothyroidism due to thyroid destruction.166,167 Suni- necessary for the development of the hypothalamus, pituitary, and
tinib is used to treat renal cell carcinoma and GISTs and inhibits olfactory portions of the brain. Defects in POU1F1 and PROP1
multiple tyrosine protein kinases, including KIT, PDGF, VEGF, cause hereditary hypothyroidism usually accompanied by defi-
and RET. An abnormal TSH was found in 62% of patients receiv- ciencies in growth hormone and prolactin.178 One patient has
ing sunitinib who were followed for 37 weeks.168 Patients studied been identified with a familial defect in the TRH receptor gene.179
by ultrasound demonstrated no thyroid tissue. Although 40% of All of these conditions are associated with the typical pattern of
hypothyroid patients initially had a suppressed TSH, suggesting central hypothyroidism, a reduced FT4, and inappropriately low
thyroiditis, the long-term course was most consistent with suni- TSH.
tinib-induced follicular cell apoptosis. Thus such patients require Structural defects in TSH have also been described. They
repeated thyroid function testing. These agents have now been include those with a mutation in the CAGYC peptide sequence of
shown to slow disease progression in advanced thyroid cancer the β-subunit, thought to be necessary for its association with the
unresponsive to radioiodine but may increase thyroid hormone α-subunit,180 and defects that produce premature termination of
requirements due to increased D3 expression.174 the TSH β-subunit gene.181 As mentioned, some of these abnor-
malities may be associated with elevations in TSH, suggesting the
Central Hypothyroidism diagnosis of primary hypothyroidism, but the TSH molecule is
Central hypothyroidism is due to TSH deficiency caused by either immunologically, but not biologically, intact.
acquired or congenital hypothalamic or pituitary gland disorders
(see Chapters 8 and 9). The causes of TSH deficiency may be clas- Resistance to Thyroid Hormone
sified as those of pituitary (secondary hypothyroidism) and hypo- The clinical manifestations of resistance to thyroid hormone
thalamic (tertiary hypothyroidism) origins, but this distinction depend on the nature of the mutation.6,11,182 The majority of
is not necessary in the initial separation of primary from central patients with RTH have a mutation in the gene encoding the thy-
hypothyroidism. roid hormone receptor β (TRβ gene, THRB) that interferes with
In many cases, hyposecretion of TSH is accompanied by the capacity of that receptor to respond normally to T3, usually
decreased secretion of other pituitary hormones, with the result by reducing its T3-binding affinity (see Chapter 2 ). A small num-
that evidence of somatotroph, gonadotroph, and corticotroph ber of individuals have been identified with TRα gene (THRA)
failure is also present. Hyposecretion of TSH as the sole demon- mutations, referred to as RTHα1,183 who differ in significant ways
strable abnormality (monotropic deficiency) is less common but from patients with RTH due to THRB mutations.184–186
does occur in both acquired and congenital forms. Hypothyroid- RTH is probably produced by the heterodimerization of the
ism due to pituitary insufficiency varies in severity from instances mutant TRβ with RXR or homodimerization with a normal TRβ
in which it is mild and overshadowed by features of gonadal or TRα. These mutant TRβ-containing dimers compete with
and adrenocortical failure to those in which the features of the wild-type TR-containing dimers for binding to the thyroid hor-
hypothyroid state are predominant. Because a small but signifi- mone response elements (TREs) of thyroid hormone–dependent
cant fraction of thyroid gland function is independent of TSH genes.182 Because these complexes bind corepressor molecules that
(∼10–15%), hypothyroidism due to central causes is less severe cannot be released in the absence of T3 binding, genes containing
than primary hypothyroidism. these TREs are more repressed than they would be normally at
The causes of central hypothyroidism are both acquired and the prevailing concentrations of circulating thyroid hormones (see
congenital. The general subject is discussed in Chapters 8 and 9, Chapter 2).6 Receptors that contain mutations in the activation
and those causes with relatively specific thyroid-related deficien- domain may have a combination of both decreased affinity for T3
cies are mentioned here for completeness. In addition to pituitary and impaired activating potential.
tumors, hypothalamic disorders, and the like, an unusual cause of Thus the mutant TRβ complex can interfere with the func-
secondary hypothyroidism occurs in individuals given bexarotene tion of the wild-type TRs, producing a pattern termed dominant
(a retinoid X receptor [RXR] agonist) for T-cell lymphoma.175,176 negative inhibition with an autosomal dominant pattern of inheri-
This drug suppresses the activity of the human TSH β-subunit pro- tance. At least 400 families have been identified with this condi-
moter in vitro. Serum T4 concentrations are reduced about 50%, tion, and there are probably many more unreported cases. The
and patients experience clinical benefit from thyroid hormone gene frequency estimate is about 1:50,000 for mutations in TRβ
replacement. Dopamine, dobutamine, high-dose glucocorticoids, and the study of the function of the mutant receptors in this disor-
or severe illness may suppress TSH release transiently, leading to der has provided valuable insights into the mechanism of thyroid
a pattern of thyroid hormone abnormalities suggesting central hormone action.182 The frequency of TRα mutations is probably
hypothyroidism.176 As discussed earlier (see Chapter 11 discus- much lower but undefined.
sion regarding changes in thyroid function during severe illness), Patients with RTH usually are recognized because of thy-
this severe state of hypothalamic-pituitary-thyroid suppression roid enlargement, which is present in about two-thirds of these
individuals. Patients usually report a mixture of symptoms of Treatment

hyperthyroidism and hypothyroidism. With respect to the heart,
palpitations and tachycardia are more common than a reduced Hypothyroidism, either primary or central, is gratifying to treat
heart rate; however, patients may also demonstrate growth retar- because of the ease and completeness with which it responds to
dation and retarded skeletal maturation.187 This has been attrib- thyroid hormone.81,191 Treatment is nearly always with levothy-
uted to the fact that thyroid hormone effects in the heart and roxine, and the proper use of this medication has been reviewed
bone appear to be primarily dependent on TRα rather than TRβ, extensively.80 A primary advantage of levothyroxine therapy is that
whereas the hypothalamic-pituitary axis is primarily regulated the peripheral deiodination mechanisms can continue to produce
through TRβ. the amount of T3 required in tissues under the normal physiologic
Abnormalities in neuropsychologic development exist, with control.84 If one accepts the principle that replicating the natural
an increased prevalence of attention-deficit/hyperactivity disor- state is the goal of hormone replacement, it is logical to provide
der, which is found in approximately 10% of such individuals.187 the “prohormone” and allow the peripheral tissues to activate it by
Other neuropsychologic abnormalities have also been described. physiologically regulated mechanisms. There is, however, signifi-
Deafness in patients with RTH reflects the important role of TRβ cant interest in combined T4 and T3 therapy.192,193
and thyroid hormone in the normal development of auditory
function. The mixture of symptoms, some suggesting hypothy- Pharmacologic and Physiologic Considerations
roidism and others suggesting hyperthyroidism, may even differ in Levothyroxine has a 7-day half-life; about 80% of the hormone is
individuals within the same family, despite the identical mutation, absorbed relatively slowly (over hours) and it equilibrates rapidly
thus confusing the clinical picture. in its extracellular distribution volume, therefore avoiding large
Because patients may present with symptoms suggesting postabsorptive perturbations in FT4 levels. With its long half-life,
hyperthyroidism, it is important to keep this diagnosis in mind omission of a single day’s tablet has no significant effect and the
in a patient with tachycardia, goiter, and elevated thyroid hor- patient may safely take an omitted tablet the following day. In fact,
mones. RTH is discussed here because a reduced response to the levothyroxine dosage can be calculated almost as satisfactorily
thyroid hormone is the biochemical basis for the condition. on a weekly, as on a daily, basis. Although T4 is well absorbed
However, the laboratory results may be the first clear evidence and does not require fasting, regular ingestion of levothyroxine
that a patient, otherwise thought to have hyperthyroidism, has on an empty stomach results in the least variation in serum TSH
RTH. These tests show the unusual combination of an increased concentration.194
FT4 accompanied by normal or slightly increased TSH levels (see The Food and Drug Administration (FDA) has issued stan-
Table 13.2). Thus the principal differential diagnosis is between dards for single-dose bioequivalence studies in normal volunteers
a TSH-secreting pituitary tumor causing hyperthyroidism and to assess and compare T4 products in the United States.195 The
RTH.188 area under the curve (AUC) confidence interval must fall within
Factors that may assist in the differential diagnosis are as fol- 80% to 125% of the comparison product for a preparation to be
lows: absence of a family history in patients with TSH-producing considered equivalent. The desirability of a pharmacotherapeutic
tumors, normal thyroid hormone levels in family members of measurement, such as TSH level as an end point, has been sug-
individuals with TSH-induced hyperthyroidism due to pituitary gested by many professional organizations.195 The guidelines for
tumor, and the presence of an elevated glycoprotein α-subunit in measured T4 content have narrowed from 90% to 110% to 95%
patients with pituitary tumor but not in those with RTH. to 105% of the stated tablet dose and require that content to be
A definitive diagnosis requires sequencing of the TRβ gene maintained for the entire shelf life.196 The availability in many
demonstrating the abnormality. Mutations in the TRβ gene are countries of a multiplicity of tablet strengths with content ranging
found in about 90% of individuals with a clinical diagnosis. In a from 25 to 300 μg allows precise titration of the daily levothyrox-
few individuals this is not the case, suggesting that there may be ine dosage for most patients with a single daily tablet, improving
mutations in coactivator proteins or one of the RXR receptors, compliance significantly.
which can also present in a similar fashion.189 The typical dose of levothyroxine, approximately 1.6 to 1.8
Treatment is difficult because thyroid hormone analogues μg/kg ideal body weight per day (0.7 to 0.8 μg/lb), generally
designed to suppress TSH, thereby relieving the hyperthyroxin- results in the prescription of between 75 and 125 μg/day for
emia, may lead to worsening of the cardiovascular manifestations women and 125 to 200 μg/day for men. Replacement doses
of the condition.190 Therapy with 3,5,3′-triiodothyroacetic acid need not be adjusted upward in obese patients and should be
(TRIAC) has been used in several patients. The development of based on lean body mass.197 Levothyroxine dose reduction is
analogues of thyroid hormone with TRβ, as opposed to mixed or often required after bariatric surgery, but the dose reduction is
TRα preferential effects, as well as analogues that selectively bind proportional to the reduction in lean body mass.198 This dos-
mutant TRs, may eventually prove useful in treatment. age is about 20% greater than the T4 production rate owing
Individuals with RTHα1 have more subtle changes in thyroid to incomplete absorption of the levothyroxine. In patients
function studies, compared with RTH due to TRβ gene muta- with primary hypothyroidism, these amounts usually result
tions, and a clinical phenotype consistent with hypothyroidism in serum TSH concentrations that are within the normal
in tissue that predominantly expresses the TRα isoform.184,185 range. Because of the 7-day half-life, approximately 6 weeks
Because regulation of TSH is predominantly mediated by TRβ, are required before there is complete equilibration of the FT4
these individuals have a normal serum TSH but a reduced T4/T3 and the biologic effects of levothyroxine. Accordingly, assess-
ratio and low concentration of serum reverse T3, presumably due ments of the adequacy of a given dose or the effects of a change
to reduced activity of the D3 enzyme. Common phenotypic fea- in dosage, with rare exceptions such as pregnancy, should not
tures include growth failure, developmental delays, constipation, be made until this interval has passed. This long half-life also
and delayed bone maturation, with some improvement associated means that it is safe for a patient to take any missed doses of T4
with T4 treatment.186 for up to 1 week after missing tablets.
By and large, levothyroxine products are clinically equivalent, directly from the thyroid gland.84 Studies in thyroidectomized
although problems do occur.199 However, the variation permit- rats, for example, show that it is not possible to normalize T3
ted by the FDA in tablet content can result in slight variations simultaneously in all tissues by an intravenous infusion of T4.207
in serum TSH in patients with primary hypothyroidism even However, it should be recalled from the earlier discussion of T4
when the same brand is used. Using levothyroxine from a single deiodination that the ratio of T3 to T4 in the human thyroid
manufacturer reduces variability that may be relevant for patients, gland is about 0.09 but is 0.17 in the rat thyroid gland.84 Thus
such as elderly, pregnant, and thyroid cancer patients, when close about 40% of the rat’s daily T3 production is derived from the
titration is required. Although the serum TSH level is an indi- thyroid versus about 20% in humans.84 Accordingly, the demon-
rect reflection of the levothyroxine effect in patients with primary stration that T4 alone cannot provide normal levels of T3 in all tis-
hypothyroidism, it is far superior to any other readily available sues in the rat is of interest but is not strictly applicable to thyroid
method of assessing the adequacy of therapy. Return of the serum hormone replacement in humans. Nonetheless, the ratio of T3 to
TSH level to normal is therefore the goal of levothyroxine therapy T4 in the serum of a patient receiving levothyroxine as the only
in the patient with primary hypothyroidism. Some patients may source of T3 is about 20% lower than that in a normal individual.
require slightly higher or lower doses than generally used, owing Similarly, the quantity of levothyroxine required to normalize
to individual variations in absorption, and a number of conditions TSH in an athyreotic patient results in a slightly higher serum
or associated medications may change levothyroxine requirements FT4 concentration than is present in normal individuals. This
in patients with established hypothyroidism (see later). Liquid has been shown in a comparison of thyroid function in the same
preparations of levothyroxine, including preparations in capsules, patient before and after thyroidectomy.208 Although serum T3 was
may be better absorbed in select patients.200 the same level in patients before or after thyroidectomy, a higher
In decades past, desiccated thyroid was successfully used for the serum T4 concentration was necessary when on T4 replacement
treatment of hypothyroidism and still accounts for a small fraction to maintain the same serum T3.208 T4 has an independent mecha-
of the prescriptions written for thyroid replacement in the United nism for TSH suppression, owing to the intracellular generation
States. Although this approach was successful, desiccated thyroid of T3 in the hypothalamic-pituitary-thyroid axis, resulting in a
preparations contain thyroid hormone derived from animal thy- portion of the feedback TSH regulation being independent of the
roids that have twofold to threefold higher ratios of T3 to T4 than plasma T3. A retrospective, cross-sectional study compared thy-
the 1:15 value in normal human thyroglobulin.201 Accordingly, roid function studies in 1800 athyreotic thyroid cancer patients
these preparations may lead to superphysiologic levels of T3 in the on levothyroxine monotherapy compared to control subjects.209
immediate postabsorptive period (2–4 hours) owing to the rapid In these patients, the serum FT4 levels were significantly higher,
release of T3 from thyroglobulin, its immediate and nearly com- and free T3 levels significantly lower, than euthyroid control sub-
plete absorption, and the 1-day period required for T3 to equili- jects. However, these patients came from a region of variable iodine
brate with its 40-L volume of distribution (see Table 11.5).202 A intake, which makes interpretation of the control data difficult.
prospective double-blind randomized crossover study compared Although the concept of combined T4/T3 therapy has been
4 months of levothyroxine monotherapy with desiccated thyroid recognized for many years, a positive study generated a great deal
preparations in the same hypothyroid patients.203 There were no of interest in this approach.210 Patients received 12.5 μg of T3 as
significant differences in outcomes, although among patients who a substitution for 50 μg of their levothyroxine preparation and
had a preference, more preferred desiccated thyroid extract, and scored, on average, somewhat higher on tests of mood than when
these patients lost a modest amount of weight. they were taking levothyroxine alone. The dosage of thyroid hor-
Mixtures of liothyronine and levothyroxine (liotrix) contain mone used in these studies was excessive, as judged by the fact
in a 1-grain (64-μg) equivalent tablet (Thyrolar-1 in the United that 20% of the group had serum TSH values below normal on
States) the amounts of T3 (12.5 μg) and T4 (50 μg) present in either regimen and the test period was only a few months. A large
the most popular desiccated thyroid tablet.204 The levothyroxine number of subsequent studies using a wide range of replacement
equivalency of a 1-grain desiccated thyroid tablet or its liotrix strategies and relative T4/T3 content were performed in different
equivalent can be estimated as follows: The 12.5 μg of liothyronine populations, and none has shown an advantage of combination
(T3) is completely absorbed from desiccated thyroid or from liotrix therapy over T4 alone.211 A study that compared T4 monotherapy
tablets.202 Levothyroxine is approximately 80% absorbed,205 and to T4/T3 combined therapy in hypothyroid patients evaluated
about 36% of the 40 μg of levothyroxine absorbed is converted to the results based on the presence or absence of D2 gene poly-
T3, with the molecular weight of T3 (651) being 84% that of T4 morphisms.212 The hypothyroid patients homozygous for the
(777). Accordingly, a 1-grain tablet should provide about 25 μg D2 polymorphism showed greater improvement in measures of
of T3, which would be approximately equivalent to that obtained well-being while on T4/T3 combination therapy compared to T4
from 100 μg of levothyroxine. This equivalency ratio can be used monotherapy. This study requires replication in a separate popu-
as an initial guide in switching patients from desiccated thyroid lation but may indicate that T4/T3 combination therapy can be
or liotrix to levothyroxine. Although levothyroxine is absorbed in targeted to specific hypothyroid patients who will benefit based on
the stomach and small intestine, normal gastric acid secretion is a genetic profile of genes important for thyroid hormone metabo-
required for complete absorption.206 Patients with impaired acid lism and action.9,193,213
secretion on levothyroxine therapy require a 22% to 34% higher On the other hand, the FT4 index correlated as closely with the
dose of levothyroxine to maintain the desired serum TSH. In resting energy expenditure as TSH levels in a group of patients in
those patients in whom acid secretion was normalized therapeuti- whom small adjustments above or below their ideal replacement
cally, the levothyroxine dose returned to baseline.206 levothyroxine dosage were made.214 The correlation with serum
As indicated earlier, the use of levothyroxine as thyroid hor- T3 was not statistically significant, suggesting that in humans,
mone replacement is a compromise with the normal pathway perhaps as a result of differences in the peripheral metabolism of
of T3 production, in which about 80% of T3 is derived from T4 T4 from that in rodents, the FT4 concentration may be as accu-
5′-monodeiodination and approximately 20% (∼6 μg) is secreted rate as the TSH value as an index of satisfactory thyroid hormone
replacement. The practical difficulty with the design of tablets after 6 weeks; a somewhat longer period may be necessary for
providing combinations of T3 and T4 is that the approximate dose serum TSH levels to return to normal, perhaps up to 3 months.
of 6 μg of T3 provided would need to be released in a sustained In some cases (e.g., myxedema coma [see later]), it is clinically
fashion over 24 hours, as well as replicating the diurnal rhythm appropriate to alleviate hypothyroidism rapidly. For example,
of T3,215 which is quite different from the rapid absorption of T3 patients with severe hypothyroidism withstand acute infections or
with a peak at 2 to 4 hours when given in its conventional form. other serious illnesses poorly, and myxedema coma may develop as
Thus, for the present, it appears that the current approach to thy- a complication. In such circumstances, rapid near repletion of the
roid replacement using levothyroxine alone, although not a per- peripheral hormone pool in the average adult can be accomplished
fect replication of normal physiology, is satisfactory for virtually by a single intravenous dose of 500 μg of levothyroxine. Alter-
all patients. A sustained-release T3 preparation has been developed natively, by virtue of its rapid onset of action, liothyronine (25
and produces more stable levels of serum T3.216 The clinical effects μg orally every 12 hours) can be administered if the patient can
of this more “physiologic” replacement are not known. take medication by mouth. With both approaches, an initial bio-
logic effect is achieved within 24 hours. Parenteral therapy with
Institution of Replacement Therapy levothyroxine is then continued with a dose that is 80% of the
The initial dose of levothyroxine prescribed depends on the degree appropriate oral dose but not in excess of 1.4 μg/kg of ideal body
of hypothyroidism and the age and general health of the patient. weight. Because of the possibility that rapid increases in meta-
Patients who are young or middle aged and otherwise healthy with bolic rate will overtax the existing pituitary-adrenocortical reserve,
no associated cardiovascular or other abnormalities and mild to supplemental glucocorticoid (intravenous hydrocortisone 5 mg/
moderate hypothyroidism (TSH concentrations of 5–50 mU/L) hour) should also be given to patients with severe hypothyroid-
can be given an initial complete replacement dose of about 1.7 μg/ ism receiving high initial doses of thyroid hormones. Finally, in
kg of ideal body weight. The resulting increase in serum T4 con- view of the tendency of hypothyroid patients to retain free water,
centration to normal requires 5 to 6 weeks, and the biologic effects intravenous fluids containing only dextrose should not be given.
of T3 are sufficiently delayed that these patients do not experience When replacement therapy is withdrawn for short periods
adverse effects. At the other extreme, the elderly patient with heart (4–6 weeks) for purposes of evaluating therapy for thyroid cancer,
disease, particularly angina pectoris, without reversible coronary rapid reinstitution of levothyroxine using a loading dose of three
lesions, should be given a small initial dose of levothyroxine (25 times the daily replacement dose for 3 days can usually be given
μg/day), and the dosage should be increased in 12.5-μg incre- unless there are other complicating medical illnesses.
ments at intervals of 2 to 3 months with careful clinical and labo- When hypothyroidism results from administration of iodine-
ratory evaluation. containing or antithyroid drugs, withdrawal of the offending
The goal in the patient with primary hypothyroidism is to agent usually relieves both the hypothyroidism and the accompa-
return serum TSH concentrations to normal, reflecting normal- nying goiter, although it is appropriate to provide interim replace-
ization of that patient’s thyroid hormone supply. This usually ment until the gland recovers its function.138,220 This is especially
results in a mid-normal to high-normal serum FT4. The serum true for amiodarone, which may remain in tissues for up to 1 year.
TSH should be evaluated 6 weeks after a theoretically complete
replacement dose has been instituted to allow minor adjustments Infants and Children
to optimize the individual dose.217 In patients with central hypo- In infants with congenital hypothyroidism, the determining factor
thyroidism, serum TSH is not a reliable index of adequate replace- for eventual intellectual attainment is the age at which adequate
ment, and the serum FT4 should be restored to a concentration treatment with thyroid hormone is begun.18,221 The therapy for
in the upper half of the normal range. T4 dosing based on body infants with congenital hypothyroidism should consist initially of
weight and a serum FT4 in the upper reference range improved raising the serum T4 level to more than 130 nmol/L (10 μg/dL)
markers of thyroid hormone action and was superior to replace- as rapidly as possible and maintaining it at that level for the first
ment with a combination of T4/T3.218 Patients with central hypo- 3 to 4 years of life. This is usually accomplished by administering
thyroidism should also be evaluated and treated for glucocorticoid an initial levothyroxine dose of 50 μg/day, which is higher than
deficiency, if necessary, before institution of thyroid replacement the adult dose on a weight basis and in keeping with the higher
(see Chapter 9). metabolic clearance of the hormone in the infant. The serum TSH
Although the adverse effects of the rapid institution of therapy concentration may not return to normal even with this high dose
are unusual, pseudotumor cerebri has been reported in profoundly because of residual reset of the pituitary feedback mechanism.
hypothyroid juveniles between ages 8 and 12 years who were given After 2 years of age, however, a TSH level in the normal range is
even modest initial levothyroxine replacement.219 This compli- an index of optimal therapy as it is in adults.222
cation appears 1 to 10 months after initiation of treatment and
responds to acetazolamide and dexamethasone. Monitoring Replacement Therapy
The interval between the initiation of treatment and the first Monitoring the adequacy of, and compliance with, thyroid hor-
evidence of improvement depends on the strength of dose given mone therapy in patients with primary hypothyroidism is easily
and the degree of the deficit. An early clinical response in moder- done by measurement of serum TSH.9 This value should be within
ate to severe hypothyroidism is a diuresis of 2 to 4 kg. The serum the normal range for an assay sufficiently sensitive to measure,
sodium (Na+) level increases even sooner if hyponatremia was with confidence, the lower limit of the normal range. The normal
present initially. Thereafter, pulse rate and pulse pressure increase, serum TSH concentration varies between 0.5 and 4 mU/L in most
appetite improves, and constipation may disappear. Later, psycho- second-generation and third-generation assays, and results within
motor activity increases and the delay in the deep tendon reflex this range are associated with the elimination of all clinical and
disappears. Hoarseness abates slowly, and changes in skin and hair biochemical manifestations of primary hypothyroidism, except in
do not disappear for several months. In individuals started on a patients with RTH. Based on analysis of the National Health and
complete replacement dose, the serum FT4 level should normalize Nutrition Examination Survey (NHANES III) reference group,13
a reference TSH range with an upper limit of 2.5 mU/L has been TABLE 13.3 Conditions That Alter Levothyroxine
suggested. This adjustment, however, would identify a large num- Requirements
ber of individuals as having abnormal thyroid function, without
a clear indication of the clinical significance of TSH levels in this Increased Levothyroxine Requirements
range. A more recent analysis, based on age-specific reference Pregnancy
ranges, indicates that older adults, without thyroid autoantibod- Gastrointestinal Disorders
ies, have an increased upper limit TSH (>4.5 mU/L) that is not Mucosal diseases of the small bowel (e.g., sprue)
associated with thyroid disease.223 In related studies, this progres- After jejunoileal bypass and small bowel resection
sive shift with age to higher levels of TSH has been associated with Impaired gastric acid secretion (e.g., atrophic gastritis)
extreme longevity in several populations.224 Diabetic diarrhea
After the first 6 months of therapy, the dose should be reas- Therapy With Certain Pharmacologic Agents
sessed because restoration of euthyroidism increases the metabolic
clearance of T4. A dose that was adequate during the early phases Drugs That Interfere With Levothyroxine Absorption
of therapy may not be so when the same patient is euthyroid Cholestyramine
owing to an acceleration in the clearance of thyroid hormone. Sucralfate
Aluminum hydroxide
Under normal circumstances, the finding of a normal serum Calcium carbonate
TSH level on an annual basis is adequate to ensure that the proper Ferrous sulfate
levothyroxine dose is being taken by the patient. If the serum
TSH level is above the normal range and noncompliance is not Drugs That Increase the Cytochrome P450 Enzyme (CYP3A4)
the explanation, small adjustments, usually in 12-μg increments, Rifampin
can be made with reassessment of TSH concentrations after the Carbamazepine
6 weeks required for full equilibration have passed. In North Estrogen
America, this strategy is simplified by the availability of multiple Phenytoin
Sertraline
tablet strengths, many of which differ by only 12 μg. Most patients ? Statins
can receive the same dose until they reach their seventh or eighth
decade, at which point a downward adjustment of 20% to 30% Drugs That Block T4 to T3 Conversion
may be indicated because thyroid hormone clearance decreases in Amiodarone
the elderly. Conditions That May Block Deiodinase Synthesis
Thyroid hormone requirements may be altered in several situ-
ations (Table 13.3). Most conditions or medications increase the Selenium deficiency
Cirrhosis
levothyroxine requirement in patients receiving maintenance ther-
apy. During pregnancy, the levothyroxine requirement is increased Decreased Levothyroxine Requirements
by 25% to 50% in most hypothyroid women, and a prospective Aging (≥65 years)
study demonstrated that the increased requirement occurs early Androgen therapy in women
in the first trimester.225 The required increment is higher in
athyreotic patients compared to those with autoimmune hypo- T4, Thyroxine; T3, triiodothyronine.
thyroidism.226 Athyreotic patients who are planning a pregnancy
should be advised to increase the dose by around 30% as soon
as the diagnosis is confirmed because the change in requirement
appears soon after implantation.9,113 The increased requirement sucralfate, aluminum hydroxide, calcium carbonate, ferrous sul-
is probably due to a combination of factors, including increases fate, lovastatin, or various resins. Certain medications, notably
in T4-binding globulin and the volume of distribution of T4, an rifampin, carbamazepine, phenytoin, and sertraline, increase the
increase in body mass, and an increase in D3 in the placenta and clearance of levothyroxine by inducing CYP3A4 in the liver.
uterus probably due to estradiol-induced increases in Dio3 gene Estrogen given to postmenopausal women may act in the same
transcription.84 The increased requirement persists throughout way, although the increases in D3 also play a role.229 Soy pro-
pregnancy but returns to normal within a few weeks after delivery. tein and soybean isoflavones have been proposed to interfere
Therefore the dose should be reduced to the original prepregnancy directly with thyroid hormone action as well as synthetic T4
level at the time of delivery. Maternal T4 is critically important to absorption.230 There is no evidence that soy interferes with thy-
the athyreotic fetus and in the normal fetus in the first trimester roid function in euthyroid individuals who are iodine sufficient,
before fetal thyroid function and feedback regulation mature.227 and the effect of soy on T4 absorption in hypothyroid patients is
Maternal hypothyroidism has been associated with fetal loss, pre- modest.230 Amiodarone increases levothyroxine requirements by
term delivery, and intellectual deficit in the offspring.67,113 These blocking conversion of T4 to T3 and perhaps by interfering with
findings are not seen in hypothyroid women on T4 replacement T3–thyroid hormone receptor binding.231 Selenium deficiency
sufficient to normalize their TSH, suggesting that these associa- is rare, but because it is rate limiting in the synthesis of D1 (see
tions are directly related to maternal thyroid hormone status. A Fig. 11.2),84 any significant deficiency, such as may occur in
randomized prospective study in pregnant women with anti- patients receiving diets restricted in protein, may increase levo-
TPOAb and normal range TSH demonstrated the benefit of levothyroxine requirements.
thyroxine treatment to prevent these complications.228 Occasionally in patients who have been treated with radioac-
Other conditions in which levothyroxine requirements are tive iodine for Graves disease or toxic nodular goiter, some degree
increased (see Table 13.3)9,80,146 include malabsorption due to of thyroid hormone secretion persists and, although insufficient
bowel diseases, impaired gastric acid secretion,206 and adsorp- to sustain normal thyroid hormone levels, is autonomous. Such
tion of levothyroxine to coadministered medications such as patients may have a suppressed TSH on what otherwise would
be considered a replacement dose of levothyroxine. The levothy- replacement post-thyroidectomy consistently require a higher
roxine dose in these individuals should be reduced until TSH serum T4 than preoperatively to maintain the same serum T3
levels rise to normal, keeping in mind that several months may concentration.208 The addition of thyroid replacement contain-
be required before TSH secretion recovers after its prolonged sup- ing triiodothyronine continues to be a focus in these patients but
pression. Because of either the delayed effects of radioiodine or the has not been shown to confer long-term relief of symptoms.234
natural history of Graves disease per se, this autonomous T4 secre- Additionally, such patients should be educated as to the relation-
tion may decrease with time, leading to an increase in levothyrox- ship between symptoms of hypothyroidism and the role of thyroid
ine requirements in subsequent years. Rarely, the opposite occurs; hormone in relieving them, and other causes should be sought for
that is, a patient treated with radioiodine develops an increased the symptoms.
TSH level, but after several months of therapy the requirement for
such replacement is either reduced or eliminated. This response Special Aspects of Hypothyroidism
may reflect transient impairment of thyroid function by a combi-
nation of preirradiation antithyroid drug therapy and immediate Subclinical Hypothyroidism
but transient effects of irradiation on the thyroid. In such patients, The term subclinical hypothyroidism was originally used to describe
frequent monitoring of levothyroxine replacement is required to the patient with a low-normal FT4 but a slightly elevated serum
avoid overreplacement. TSH level. Other terms for this condition are mild hypothyroidism,
In North America, based on the recent previously discussed early thyroid failure, preclinical hypothyroidism, and decreased thy-
changes in assessment of levothyroxine bioequivalence, the pos- roid reserve (see Table 13.2). The TSH elevation in such patients is
sibility of a difference in tablet levothyroxine content should be modest, with values typically between 5 and 15 mU/L, although
considered if a new preparation changes the biologic or biochemi- patients with a TSH above 10 mU/L more often have a reduced
cal effects of the same dosage. Although the difference in prepara- FT4 and may have true hypothyroid symptoms. The definition of
tion is unlikely to cause a significant difference in most patients, this syndrome depends significantly on the reference range for a
the change in manufacturer introduces another potential source normal TSH concentration. This syndrome is most often seen in
of variability. patients with early Hashimoto disease and is a common phenom-
enon, occurring in 7% to 10% of older women.14–16
Adverse Effects of Levothyroxine Therapy A number of studies on the effects of thyroid hormone treat-
Although the administration of excessive doses of levothyroxine ment in such patients have used physiologic end points (e.g.,
causes accelerated bone loss in postmenopausal patients, most measurements of various serum enzymes, systolic time intervals,
authorities believe that returning thyroid status to normal does not serum lipids, psychometric testing), and results have been vari-
have adverse effects on bone density.232 Administration of exces- able.14–16 In the most carefully controlled studies, one or another
sive doses also increases cardiac wall thickness and contractility of the parameters has returned to normal in about 25% to 50%
and, in elderly patients, increases the risk of atrial fibrillation.16,25 of patients. A prospective randomized trial of subclinical hypothy-
In some patients, TSH levels remain elevated despite the pre- roidism in elderly males showed no benefit of therapy.236 Among
scription of adequate replacement doses.233 This response is most those men originally enrolled based on an elevated TSH, 62%
often a consequence of poor adherence. The combination of nor- had a normal TSH on subsequent measurement, indicating the
mal or even elevated serum FT4 values and elevated TSH levels importance of repeating a TSH measurement in suspected sub-
can occur if the patient does not take levothyroxine regularly but clinical hypothyroidism. In general, FT4 and TSH levels normal-
ingests several pills the day before testing. The integrated dose ize, but free T3, usually normal at the outset, does not change.
of levothyroxine over prior weeks is best reflected in the serum Modest improvements in cardiac indices and lipid profiles have
TSH level, and nonadherent patients require careful education been noted in most but not all studies, although the benefit on
as to the rationale for treatment. Subtle changes in dietary hab- cardiovascular risk is seen in middle-aged patients.30,34 The asso-
its, such as increasing the ingestion of bran-containing products, ciation of mild hypothyroidism with an increase in risk for ath-
soy, or calcium or proton pump inhibitors, may decrease levo- erosclerotic heart disease has been shown by some studies but not
thyroxine absorption, and their recognition requires a careful others.14,16 The impact of treatment to reduce the risk of athero-
history.80,146,233 In patients on T4 replacement with erratic TSH sclerotic heart disease, other than reduction in risk factors such
levels and consideration of inconsistent adherence with therapy as cholesterol and C-reactive protein, have not yet been studied.
or malabsorption, a protocol has been developed to evaluate such One factor favoring a decision to recommend levothyroxine
patients with weekly supervised dosing of LT4 and monitoring therapy is the likelihood of developing overt hypothyroidism.
of serum TSH and FT4 concentrations.1 Use of weekly dosing of The risk of progression from subclinical to overt hypothyroidism
LT4 should be done very cautiously in older patients or those with (elevated serum TSH and reduced FT4) is most closely related to
known cardiac disease. the magnitude of serum TSH elevation and the presence of anti-
TPOAb. Prospective studies of women with subclinical hypo-
Patients With Hypothyroid Symptoms Despite Restitution thyroidism have shown rates of progression from approximately
of Normal Thyroid Function 3% to 8% per year, with the higher rates seen in individuals with
In patients taking levothyroxine replacement with a normal serum initial TSH concentration greater than 10 and those with posi-
TSH concentration, symptoms consistent with hypothyroidism tive anti-TPOAb.237 Although most individuals progress slowly
may persist.234 A survey of hypothyroid patients on levothyrox- to overt hypothyroidism, rapid progression over weeks to months
ine with normal TSH and control patients included questions has been reported.238 Factors that may predispose to rapid pro-
about symptoms that might be associated with thyroid hormone gression include increased age, high levels of TPOAb, intercur-
deficiency.235 Although a significant fraction of both groups rent systemic infection or inflammation, iodine contrast agents,
reported such symptoms, a greater fraction of patients on levo- and medications such as amiodarone and lithium. The decision to
thyroxine replacement had these symptoms. Patients on thyroxine treat with levothyroxine must also take into account the expense
and inconvenience of a daily medication, which is not acceptable From these studies one may conclude that emergent surgery
to some patients, and the possibility that unintended overdosage should not be postponed in hypothyroid patients but that such
may exacerbate osteoporosis or cause cardiac arrhythmias. Ulti- patients should be rigorously monitored for evidence of carbon
mately the decision to treat must depend on a careful consider- dioxide retention, bleeding, infection, and hyponatremia. These
ation of the individual clinical situation and patient preference. If findings are also relevant to the treatment of hypothyroid individ-
a therapeutic trial is performed, the TSH concentration should be uals with symptomatic coronary artery disease. Considering the
monitored carefully and should not be reduced below normal. If lack of significant increase in perioperative complications in the
no therapy is given, such patients should be monitored at intervals hypothyroid patient, the option of surgery for remediable coro-
of 6 to 12 months both clinically and biochemically. nary artery lesions is open to hypothyroid individuals without the
risk of a myocardial infarction in association with restitution of
Metabolic Insufficiency the euthyroid state (see later).240
Nonspecific symptoms of true hypothyroidism include mild las-
situde, fatigue, slight anemia, constipation, apathy, cold intoler- Heart Disease and Thyroid Hormone Therapy
ance, menstrual irregularities, loss of hair, and weight gain. For
this reason, some patients with such complaints but with nor- Coexisting Coronary Artery Disease and Hypothyroidism
mal laboratory results for thyroid function have been considered In many patients with coronary artery disease and primary hypo-
candidates for levothyroxine therapy. The response to thyroid thyroidism, cardiac function is improved in response to levo-
hormone therapy is sometimes gratifying, at least initially, but thyroxine therapy because of a decrease in peripheral vascular
symptomatic improvement usually disappears after a time unless resistance and improvement in myocardial function. However,
the dose is increased. Eventually, even larger doses fail to alleviate patients with preexisting angina pectoris should be evaluated for
the symptoms, confirming that they do not arise from a deficiency correctable lesions of the coronary arteries and treated appropri-
of thyroid hormone. ately before levothyroxine is administered.240,241 Retrospective
Thus thyroid hormone therapy should be avoided in patients studies indicate that this approach is safer than the institution of
with no biochemical documentation of impaired thyroid function. replacement therapy prior to angiography and angioplasty or even
Furthermore, even in patients with subclinical hypothyroidism, coronary artery bypass grafting (CABG).240
symptoms may be out of proportion to abnormalities in the FT4. In a few patients, lesions may not be remediable, or small-vessel
It is unwise to raise a patient’s expectations that such symptoms disease is severe even after stenting or bypass grafting, so that com-
will be relieved by correction of mild biochemical abnormalities. plete replacement cannot be instituted. Such patients must receive
optimal antianginal therapy combined with β-adrenergic receptor
Thyroid Function Testing in Patients Receiving Replace- blockers in judicious quantities, and complete restitution of the
ment Therapy for Unclear Reasons euthyroid state may not be possible.
Physicians are frequently confronted with patients receiving levo-
thyroxine in whom the basis for the diagnosis cannot be estab- Thyroid Hormone for Compromised Cardiovascular
lished. It may be difficult to document previous clinical findings Function
or laboratory data to determine whether thyroid hormone replace- In addition to the issues raised in patients with combined hypo-
ment is indicated. If serum TSH is in the normal range and pri- thyroidism and coronary artery disease, there is interest in the
mary hypothyroidism is suspected, a simple way of assessing the potential therapeutic use of thyroid hormone in the treatment
need for levothyroxine therapy is to switch levothyroxine to an of patients with cardiomyopathy or those who have undergone
every-other-day dosage or to reduce the daily dose by 50% and CABG or other cardiac procedures.25 As expected, T3 levels
to reevaluate TSH and FT4 after 4 weeks. If there is no significant are reduced in patients with advanced congestive heart failure,
increase in TSH concentration and FT4 remains constant during as with any illness. In one report, 23 patients with advanced
that period, residual thyroid function is present, although it may heart failure (mean ejection fraction, 22%) were given up to
still not be completely normal. To answer this question, levothy- 2.7 μg/kg of liothyronine over 6 hours with an increase in car-
roxine can then be withdrawn and blood tests repeated 4 to 8 diac output and decrease in systemic vascular resistance but
weeks later. without increase in heart or metabolic rate.242 Similar effects
If the initial TSH level is suppressed, indicating overreplace- were seen with a dose of 110 μg liothyronine over 6 hours after
ment, the levothyroxine dose should be reduced until TSH CABG.243
becomes detectable before this trial is instituted. If central hypo- Liothyronine has also been given postoperatively for congeni-
thyroidism is suspected, the FT4 must be monitored. tal heart disease and, again, an improvement in cardiac output
and decrease in vascular resistance occurred without adverse
Emergent Surgery in the Hypothyroid Patient side effects.209 These results suggest that, in certain selected cir-
The perioperative course of patients with untreated hypothyroid- cumstances, liothyronine may be useful as adjunctive therapy in
ism has been evaluated in several studies. In general, such patients patients with congestive heart failure because of its effect of relax-
were not recognized to be hypothyroid or did not require sur- ing vascular smooth muscle.
gery despite the presence of significant hypothyroidism. Com- Although most therapeutic trials of thyroid hormone treat-
plications were uncommon. Perioperative hypotension, ileus, ment have used T3, thyroid hormone analogues have also been
and central nervous system disturbances were more common used.25 The most extensively studied is 3,5-diiodothyropropi-
in hypothyroid patients, and patients with major infections had onic acid (DITPA), an analogue that binds both TRα and TRβ
fewer episodes of fever than did euthyroid control subjects.239 with low affinity. A randomized study of DITPA in heart failure
Other complications were delayed recovery from anesthesia and showed some improved cardiac performance,244 but the study was
abnormal hemostasis, possibly owing to an acquired form of von terminated because of significant metabolic side effects, including
Willebrand disease.59 weight loss.245
intervention make thyroid testing of all pregnant women a reason-

Screening for Primary Hypothyroidism able choice.
The use of screening for hypothyroidism has been addressed by a
number of studies but remains controversial.191 The conclusions Myxedema Coma
depend, to a great extent, on assumptions regarding the effective-
ness and economic value of identifying and treating patients with Myxedema coma is the ultimate stage of severe long-standing hypo-
subclinical hypothyroidism. An evidenced-based medicine review thyroidism.251,252 This state, which almost invariably affects older
of the literature by an expert panel concluded that there was insuf- patients, occurs most commonly during the winter months and is
ficient evidence to support population-based screening.246 Aggres- associated with a high mortality rate. It is usually accompanied by a
sive “case finding,” based on identification of risk factors such as subnormal temperature. Values as low as 23°C have been recorded.
family history, was advocated for pregnant women, women older The external manifestations of severe myxedema, bradycardia, and
than 60 years, and others at high risk. The fraction of patients with severe hypotension are invariably present. The characteristic delay
hypothyroidism missed when a “case finding” strategy is used, in deep tendon reflexes may be lacking if the patient is areflexic.
however, is not known. A updated report from the US Preven- Seizures may accompany the comatose state. Although the patho-
tive Services Task Force concluded that there is still insufficient genesis of myxedema coma is not clear, factors that predispose to its
data to recommend population screening for hypothyroidism in development include exposure to cold, infection, trauma, and cen-
nonpregnant adults.247 Large, randomized, prospective studies of tral nervous system depressants or anesthetics. Alveolar hypoven-
levothyroxine treatment in patients with subclinical hypothyroid- tilation, leading to carbon dioxide retention and narcosis, and
ism to establish benefit, however, have not yet been performed. dilutional hyponatremia resembling that seen with inappropriate
Given the very high incidence of hypothyroidism in older women ADH secretion may also contribute to the clinical state.
and the absence of robust clinical symptoms, an assessment of From the foregoing, it appears that myxedema coma should
TSH levels at 5-year intervals in women older than age 50 years be readily recognized from its clinical signs, but this is not the
seems justified until more extensive studies have been performed. case. Hypothermia of any cause (e.g., to cold exposure) may cause
A second complex issue involves whether women planning preg- changes suggestive of myxedema, including delayed relaxation of
nancy should be screened for the presence of hypothyroidism as a deep tendon reflexes. The importance of diagnosing myxedema
routine part of a prenatal visit.113 This question is raised because of coma is that a delay in therapy worsens the prognosis. Conse-
increasing association of adverse outcomes in pregnancy, even with quently, a rapid serum FT4 and TSH should be obtained when-
subclinical hypothyroidism, including impairment of mental devel- ever this diagnosis is being considered. Otherwise the diagnosis
opment in infants, fetal loss, and preterm delivery.66,67 The preva- should be made on clinical grounds; after serum has been sent for
lence of overt hypothyroidism during pregnancy is approximately thyroid function tests, therapy should be initiated without await-
2%, and screening of all patients has been advocated by several pro- ing the results of delayed confirmatory tests because the mortality
fessional organizations. Thyroid testing in high-risk patients, “case rate may be 20% or higher.
finding,” has been advocated, although a prospective study showed Treatment consists of administration of thyroid hormone
that approximately a third of pregnant women with underlying and correction of the associated physiologic disturbances.251,252
thyroid disease are missed by this testing approach.248 Because of the sluggish circulation and severe hypometabolism,
Isolated maternal hypothyroxinemia in pregnancy, generally absorption of therapeutic agents from the gut or from subcuta-
defined as a FT4 in the lowest 2.5 to 5th percentile, with a normal neous or intramuscular sites is unpredictable, and medications
reference range TSH, has been associated with a range of neu- should be administered intravenously if possible. Administration
rologic deficits, including reduced IQ, reduced cortical volume, of levothyroxine as a single intravenous dose of 500 to 800 μg
language delay, and autism.67 Treatment of hypothyroxinemic repletes the peripheral hormone pool and may cause improvement
women during pregnancy has not been associated with improved within hours. Daily doses of intravenous levothyroxine, 100 μg,
cognitive outcome of the offspring,249,250 and routine treatment is are given thereafter. Hydrocortisone (5–10 mg/hour) should also
not currently recommended.113 be given because of the possibility of relative adrenocortical insuf-
A number of questions are raised regarding the appropriate tim- ficiency as the metabolic rate increases.
ing of testing, whether thyroid autoantibodies should be measured, Alternatively, intravenous liothyronine may be given at a dose
the relative importance of TSH and FT4, the influence of trimes- of 25 μg every 12 hours. Others have used a combination of 200
ter on the normal ranges, and the threshold for intervention. The to 300 μg T4 and 25 μg T3 intravenously as a single dose, followed
association of maternal subclinical hypothyroidism and preterm by 25 μg T3 and 100 μg T4 24 hours later, and then 50 μg T4 daily
delivery is a much more proximal and defined end point to study until the patient regains consciousness. Hypotonic fluids should
compared to intellectual performance in offspring. The morbidity not be given because of the danger of water intoxication owing
and mortality rates from preterm delivery are significant for the to the reduced free water clearance of the hypothyroid patient.
newborn, and these findings are likely to allow for more focused Hypertonic saline and glucose may be required to alleviate severe
intervention studies to determine the response to T4 treatment.66 dilutional hyponatremia and the occasional hypoglycemia.
For the moment, it appears that any patient with a family his- A critical element in therapy is support of respiratory function
tory of autoimmune thyroid disease, with symptoms suggesting by means of assisted ventilation and controlled oxygen adminis-
hypothyroidism, or with thyroid enlargement should be tested for tration. Internal warming by gastric perfusion may be useful, but
thyroid dysfunction prior to pregnancy or as soon after conception external warming should be avoided because it may lead to vascu-
as is feasible. Optimization of levothyroxine therapy for women lar collapse due to peripheral vasodilatation. Further heat loss can
known to have hypothyroidism prior to conception, when pos- be prevented with blankets. An increase in temperature may be
sible, may be the most effective intervention to prevent hypothy- seen within 24 hours in response to levothyroxine. General mea-
roid-related complications of pregnancy. Although the data do not sures applicable to the comatose patient should be undertaken,
yet reach the threshold to mandate universal screening, the ease of such as frequent turning, prevention of aspiration, and attention
testing, associated adverse outcomes, and demonstrated benefit of to fecal impaction and urinary retention.
TABLE 13.4 C
auses of Thyroiditis also discussed in Chapter 12, even though the pain associated with
the typical form of this condition makes the principal differential
Autoimmune thyroiditis diagnosis lie between that and infectious thyroiditis. In that con-
Painless subacute thyroiditis, including postpartum thyroiditis (see text, subacute thyroiditis is also mentioned later.
Chapter 12)
Painful subacute thyroiditis (see Chapter 12)
Acute infectious thyroiditis Acute Infectious Thyroiditis
Riedel thyroiditis
Postirradiation (131I or external-beam therapy) Although the thyroid gland is remarkably resistant to infec-
Sarcoidosis tion, congenital abnormalities of the piriform sinus, underlying
autoimmune disease, or immunocompromise of the host may
lead to the development of an infectious disease of the thyroid
gland, acute infectious thyroiditis.253,254 The cause may be any
Finally, the physician should assess the patient for the presence bacterium, including Staphylococcus, Pneumococcus, Salmonella,
of coexisting disease, especially infection, cardiac disease, or cere- or Mycobacterium tuberculosis. In addition, infections with certain
brovascular disease. The myxedematous patient may be afebrile fungi, including Coccidioides immitis, Candida, Aspergillus, and
despite a significant infection. As soon as the patient is able to take Histoplasma, have been reported.
medication by mouth, treatment with oral levothyroxine should The most common cause of repeated childhood infectious thy-
be instituted. roiditis, particularly in the left lobe, is a consequence of an inter-
nal fistula extending from the piriform sinus to the thyroid.254
Thyroiditis This sinus is the residual connection following the path of migra-
tion of the ultimobranchial body from the fifth pharyngeal pouch
Thyroiditis is a term indicating the presence of thyroid inflamma- to the thyroid gland. The predominance of thyroiditis of the left
tion and thus comprises a large group of diverse inflammatory lobe is explained by the fact that the right ultimobranchial body is
conditions. These conditions include the following: autoimmune often atrophic, whereas this is not the case for the left side. None-
or quasi-autoimmune causes and viral or postviral conditions theless, a patient with a completely normal thyroid gland may
and infections, including those of bacterial and fungal origins; develop bacterial thyroiditis. This is an extremely rare disease even
a chronic sclerosing form of thyroiditis, termed Riedel thyroiditis as a complication of direct puncture of the thyroid gland, such as
(or struma); and miscellaneous causes of various types, including in fine-needle aspiration. In individuals with midline infections,
radiation-induced and granulomatous causes, such as sarcoidosis, persistence of the thyroglossal duct should be considered.
as well as lithium.5
Not only are the causes of thyroiditis extremely varied, their Incidence
clinical presentations may also be diverse and are difficult to cate- Infectious thyroiditis is extremely rare, with no more than a few
gorize in a simple fashion (Table 13.4). Thus, as already discussed, cases being seen in large tertiary care centers.
autoimmune thyroiditis may present with hypothyroidism but
often patients remain euthyroid for long periods after the disease Clinical Manifestations
begins. On the other hand, in a euthyroid patient with Hashi- The clinical manifestations of infectious thyroiditis are domi-
moto disease who becomes pregnant, the postpartum period is nated by local pain and tenderness in the affected lobe or entire
often complicated by an acute form of thyrotoxicosis due to the gland. This is accompanied by painful and difficult swallowing.
transient exacerbation of thyroiditis, often followed by a period of Because of the tendency for referral of pain to the pharynx or ear,
hypothyroidism (see Chapter 12).66 the patient may not recognize the tenderness in the anterior neck.
A similar syndrome has been observed in nonpregnant patients, Depending on the virulence of the organism and the presence of
called painless subacute thyroiditis. It is manifested primarily as thy- septicemia, symptoms such as fever and chills may also accom-
rotoxicosis of sudden onset without localized pain and often with- pany the condition.
out evidence of autoimmune disease. This condition may be viral in The major differential diagnosis lies between an infectious form
origin in some patients; however, the classic presentation of postvi- of thyroiditis and painful subacute thyroiditis. It is instructive to
ral thyroiditis, a condition referred to as painful subacute thyroiditis, compare the principal features of these two diseases to arrive at an
is characterized by extreme thyroid tenderness, with pain radiating accurate diagnosis (Table 13.5). By and large, patients with acute
to the oropharynx and ears, and must be differentiated from acute infectious thyroiditis caused by a bacterium are much sicker than
infectious thyroiditis caused by bacterial or fungal infection.253 patients with painful subacute thyroiditis; they have more severe and
Thus inflammatory conditions of the thyroid present a didactic localized tenderness and are less likely to have laboratory evidence of
dilemma because one must decide whether to discuss these entities thyrotoxicosis, which is present in approximately 60% of patients
as a group with the common denominator of inflammation or to with painful subacute thyroiditis. Ultrasonographic examination
categorize them according to their principal clinical effects, namely, often reveals the abscess in the thyroid gland or evidence of swelling,
thyrotoxicosis or thyroid hormone deficiency. We have chosen and needle aspiration may help pinpoint the responsible organism.
the latter approach and have already discussed autoimmune thy- A gallium scan will be positive as a result of the diffuseness of the
roiditis, the major cause of thyroid gland failure (see Table 13.1). inflammation and, particularly in children with infectious thyroid-
However, patients with acute autoimmune thyroiditis may also itis of the left lobe, a barium swallow showing a fistula connecting
develop thyrotoxicosis, such as in postpartum painless thyroiditis the piriform sinus and left lobe of the thyroid is diagnostic.254
(see Chapter 12 discussion regarding autoimmune thyroiditis).66 Occasionally, pertechnetate scanning is useful in showing nor-
These patients must be differentiated from those with Graves dis- mal function of one lobe of the thyroid gland, which is much
ease. In addition, some patients with painful subacute thyroiditis less common in painful subacute thyroiditis (which more often
have thyrotoxicosis as a major manifestation with varying degrees affects the entire gland). Needle aspiration should be used to drain
of neck discomfort. For that reason, this thyroiditis syndrome is the affected lobe, although occasionally surgical drainage may be
TABLE 13.5 Features Useful in Differentiating required. If a piriform sinus fistula can be demonstrated, it must
Between Acute Infectious Thyroiditis and be removed to prevent recurrence of the problem.
Subacute Thyroiditis Antibiotics should be administered appropriate to the offend-
ing organism. Fungal infections should be treated appropriately,
Acute Subacute especially because many of these individuals are immunocompro-
Thyroiditis Thyroiditis mised. Endemic organisms should be kept in mind as a cause,
(% with (% with in that both Echinococcus and Trypanosomiasis infections of the
Characteristic Feature) Feature) thyroid gland have been reported.
The prognosis is excellent with preservation of thyroid func-
History tion in general, although post-thyroiditis thyroid function tests
Preceding upper respiratory infection 88 17 should be monitored to ascertain that thyroid failure has not
Fever 100 54 occurred.
Symptoms of thyrotoxicosis Uncommon 47
Riedel Thyroiditis
Sore throat 90 36
Riedel chronic sclerosing thyroiditis is rare and occurs primar-
Physical Examination of the Thyroid ily in middle-age women.155,255,256 The etiologic mechanism
Painful thyroid swelling 100 77 is uncertain, and any association with autoimmune thyroid
Left side affected 85 Not specific
disease is probably coincidental.257 The morphologic similari-
ties between the fibrosis of Riedel thyroiditis and IgG4-related
Migrating thyroid tenderness Possible 27 sclerosing disease suggest that these entities are closely related,
Erythema of overlying skin 83 Not usually with thyroiditis representing an initial manifestation of a more
generalized process.258 Retroperitoneal, orbital, and mediastinal
Laboratory Findings fibrosis, as well as rarer fibrotic syndromes, are associated with
Elevated white blood cell count 57 25–50 Riedel thyroiditis.259
Symptoms develop insidiously and are related chiefly to com-
Elevated ESR (>30 mm/hr) 100 85
pression of adjacent structures, including the trachea, esophagus,
Abnormal thyroid hormone levels 5–10 60 and recurrent laryngeal nerves. Systemic evidence of inflamma-
(elevated or depressed) tion is uncommon. The thyroid gland is moderately enlarged,
Alkaline phosphatase, transaminases Rare Common stony hard, and usually asymmetric. The consistency of the gland
increased and the invasion of adjacent structures suggest carcinoma, but
there is no enlargement of regional lymph nodes. Temperature,
Results of Needle Aspiration pulse, and leukocyte count are normal. Severe hypothyroidism is
Purulent, bacteria or fungi present ∼100 0 unusual but does occur, as does loss of parathyroid function. The
Lymphocytes, macrophages, some 0 ∼100
RAIU may be normal or low. Elevated circulating thyroid autoan-
polyps, giant cells tibodies are much less common and are found in lower titers than
in Hashimoto disease.
123I uptake low Uncommon ∼100 Tamoxifen, 10 to 20 mg/day (with or without corticosteroids),
Radiologic Findings has been successful in many of these patients and is thought to
suppress transforming growth factor beta (TGFβ).155 Surgery may
Abnormal thyroid scan 92 —
be required to preserve tracheal and esophageal function, although
Thyroid scan or ultrasound helpful in 75 — the response to tamoxifen will often preclude the necessity for this.
diagnosis Treatment with thyroid hormone relieves the hypothyroidism but
Gallium scan positive ∼100 ∼100 has no effect on the primary process.
Barium swallow showing fistula Common 0
Miscellaneous Causes
CT scan useful Rarely Not indi-
cated Only a few causes of generalized inflammation of the thyroid gland
have been reported. These include inflammation arising after 131I
Clinical Course treatment for Graves disease, a residual thyroid lobe in a patient
Clinical response to glucocorticoid Transient 100 with thyroid cancer of the contralateral lobe, and thyroiditis aris-
treatment ing from external beam therapy for conditions such as Hodgkin
Incision and drainage required 85 No or non-Hodgkin lymphoma, breast carcinoma, or other lesions
of the oropharynx. Anaplastic thyroid carcinoma may rarely be
Recurrence following operative 16 No associated with a diffuse thyroiditis and elevation of thyroid hor-
drainage
mone levels.260 In general, only radioiodine-induced thyroiditis is
Piriform sinus fistula discovered 96 No associated with pain, and glucocorticoid treatment may be useful
in symptomatic therapy.
CT, Computed tomography; ESR, erythrocyte sedimentation rate.
From DeGroot LJ, Larsen PR, Hennemann G. Acute and subacute thyroiditis. In: The Thyroid
and Its Diseases. 6th ed. New York: Churchill Livingstone; 1996:700.
References
The complete list of references is available online at ExpertConsult.com.
References 26. Keating Jr FR, Parkin TW, Selby JB, Dickinson LS. Treatment
of heart disease associated with myxedema. Prog Cardiovasc Dis.
1. Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lan- 1961;3:364–381.
cet. 2017;390(10101):1550–1562. 27. Biondi B. Mechanisms in endocrinology: heart failure and thyroid
2. Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and dysfunction. Eur J Endocrinol. 2012;167(5):609–618.
management. Med Clin North Am. 2012;96(2):203–221. 28. Hussein WI, Green R, Jacobsen DW, Faiman C. Normalization of
3. Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical hyperhomocysteinemia with L-thyroxine in hypothyroidism. Ann
and diagnostic criteria. Autoimmun Rev. 2014;13(4–5):391–397. Intern Med. 1999;131(5):348–351.
4. Beck-Peccoz P, Rodari G, Giavoli C, Lania A. Central hypo- 29. Ladenson PW, Sherman SI, Baughman KL, et al. Reversible altera-
thyroidism—a neglected thyroid disorder. Nat Rev Endocrinol. tions in myocardial gene expression in a young man with dilated
2017;13(10):588–598. cardiomyopathy and hypothyroidism. Proc Natl Acad Sci U S A.
5. Samuels MH. Subacute, silent, and postpartum thyroiditis. Med 1992;89(12):5251–5255.
Clin North Am. 2012;96(2):223–233. 30. Pearce EN. Update in lipid alterations in subclinical hypothyroid-
6. Brent GA. Mechanisms of thyroid hormone action. J Clin Invest. ism. J Clin Endocrinol Metab. 2012;97(2):326–333.
2012;122(9):3035–3043. 31. Pearce EN, Wilson PW, Yang Q, et al. Thyroid function and
7. Luongo C, Trivisano L, Alfano F, Salvatore D. Type 3 deiodinase lipid subparticle sizes in patients with short-term hypothyroid-
and consumptive hypothyroidism: a common mechanism for a rare ism and a population-based cohort. J Clin Endocrinol Metab.
disease. Front Endocrinol (Lausanne). 2013;4:115. 2008;93(3):888–894.
8. Arrojo EDR, Fonseca TL, Werneck-de-Castro JP, Bianco AC. Role 32. Thvilum M, Brandt F, Brix TH, Hegedus L. A review of the evi-
of the type 2 iodothyronine deiodinase (D2) in the control of thyroid dence for and against increased mortality in hypothyroidism. Nat
hormone signaling. Biochim Biophys Acta. 2013;1830(7):3956–3964. Rev Endocrinol. 2012;8(7):417–424.
9. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treat- 33. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovas-
ment of hypothyroidism: prepared by the American Thyroid cular risk, and mortality in older adults. JAMA. 2006;295(9):1033–
Association task force on thyroid hormone replacement. Thyroid. 1041.
2014;24(12):1670–1751. 34. Biondi B, Cooper DS. The clinical significance of subclinical thy-
10. Dayan CM, Panicker V. Novel insights into thyroid hormones roid dysfunction. Endocr Rev. 2008;29(1):76–131.
from the study of common genetic variation. Nat Rev Endocrinol. 35. Kvetny J, Heldgaard PE, Bladbjerg EM, Gram J. Subclinical hypo-
2009;5(4):211–218. thyroidism is associated with a low-grade inflammation, increased
11. Visser WE, van Mullem AA, Visser TJ, Peeters RP. Different causes triglyceride levels and predicts cardiovascular disease in males below
of reduced sensitivity to thyroid hormone: diagnosis and clinical 50 years. Clin Endocrinol (Oxf ). 2004;61(2):232–238.
management. Clin Endocrinol (Oxf ). 2013;79(5):595–605. 36. Schlenker EH. Effects of hypothyroidism on the respiratory system
12. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence and control of breathing: human studies and animal models. Respir
of thyroid disorders in the community: a twenty-year follow-up of Physiol Neurobiol. 2012;181(2):123–131.
the Whickham survey. Clin Endocrinol (Oxf ). 1995;43(1):55–68. 37. Attal P, Chanson P. Endocrine aspects of obstructive sleep apnea. J
13. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, Clin Endocrinol Metab. 2010;95(2):483–495.
T(4), and thyroid antibodies in the United States population (1988 38. Tachman ML, Guthrie Jr GP. Hypothyroidism: diversity of presen-
to 1994): National Health and Nutrition Examination Survey tation. Endocr Rev. 1984;5(3):456–465.
(NHANES III). J Clin Endocrinol Metab. 2002;87(2):489–499. 39. Checchi S, Montanaro A, Pasqui L, et al. L-thyroxine requirement
14. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. in patients with autoimmune hypothyroidism and parietal cell anti-
2012;379(9821):1142–1154. bodies. J Clin Endocrinol Metab. 2008;93(2):465–469.
15. Biondi B. Natural history, diagnosis and management of sub- 40. Elfstrom P, Montgomery SM, Kampe O, et al. Risk of thyroid
clinical thyroid dysfunction. Best Pract Res Clin Endocrinol Metab. disease in individuals with celiac disease. J Clin Endocrinol Metab.
2012;26(4):431–446. 2008;93(10):3915–3921.
16. Franklyn JA. The thyroid—too much and too little across the ages. 41. Burra P. Liver abnormalities and endocrine diseases. Best Pract Res
The consequences of subclinical thyroid dysfunction. Clin Endocri- Clin Gastroenterol. 2013;27(4):553–563.
nol (Oxf ). 2013;78(1):1–8. 42. Volzke H, Robinson DM, John U. Association between thy-
17. Boucai L, Hollowell JG, Surks MI. An approach for development roid function and gallstone disease. World J Gastroenterol.
of age-, gender-, and ethnicity-specific thyrotropin reference limits. 2005;11(35):5530–5534.
Thyroid. 2011;21(1):5–11. 43. Hazlehurst JM, Tomlinson JW. Non-alcoholic fatty liver disease in com-
18. Gruters A, Krude H. Detection and treatment of congenital hypo- mon endocrine disorders. Eur J Endocrinol. 2013;169(2):R27–R37.
thyroidism. Nat Rev Endocrinol. 2012;8(2):104–113. 44. Williams GR. Neurodevelopmental and neurophysiological actions
19. Smith TJ, Bahn RS, Gorman CA. Connective tissue, glycosaminogly- of thyroid hormone. J Neuroendocrinol. 2008;20(6):784–794.
cans, and diseases of the thyroid. Endocr Rev. 1989;10(3):366–391. 45. Wood-Allum CA, Shaw PJ. Thyroid disease and the nervous sys-
20. Safer JD. Thyroid hormone action on skin. Curr Opin Endocrinol tem. Handb Clin Neurol. 2014;120:703–735.
Diabetes Obes. 2012;19(5):388–393. 46. Joffe RT, Pearce EN, Hennessey JV, et al. Subclinical hypothyroid-
21. Somach SC, Helm TN, Lawlor KB, et al. Pretibial mucin. ism, mood, and cognition in older adults: a review. Int J Geriatr
Histologic patterns and clinical correlation. Arch Dermatol. Psychiatry. 2013;28(2):111–118.
1993;129(9):1152–1156. 47. Bauer M, Goetz T, Glenn T, Whybrow PC. The thyroid-brain
22. Wemeau JL, Proust-Lemoine E, Ryndak A, Vanhove L. Thyroid interaction in thyroid disorders and mood disorders. J Neuroendo-
autoimmunity and polyglandular endocrine syndromes. Hormones crinol. 2008;20(10):1101–1114.
(Athens). 2013;12(1):39–45. 48. Bauer M, Silverman DH, Schlagenhauf F, et al. Brain glucose
23. Husebye ES, Anderson MS, Kampe O. Autoimmune polyendo- metabolism in hypothyroidism: a positron emission tomography
crine syndromes. N Engl J Med. 2018;378(12):1132–1141. study before and after thyroid hormone replacement therapy. J Clin
24. Kahaly GJ, Dillmann WH. Thyroid hormone action in the heart. Endocrinol Metab. 2009;94(8):2922–2929.
Endocr Rev. 2005;26(5):704–728. 49. Tagoe CE, Zezon A, Khattri S. Rheumatic manifestations of auto-
25. Danzi S, Klein I. Thyroid hormone and the cardiovascular system. immune thyroid disease: the other autoimmune disease. J Rheuma-
Med Clin North Am. 2012;96(2):257–268. tol. 2012;39(6):1125–1129.
432.e1
432.e2 References
50. Tan ZS, Vasan RS. Thyroid function and Alzheimer’s disease. J 73. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of
Alzheimers Dis. 2009;16(3):503–507. metabolism. Physiol Rev. 2014;94(2):355–382.
51. Kalmijn S, Mehta KM, Pols HA, et al. Subclinical hyperthyroidism 74. Pearce EN. Thyroid hormone and obesity. Curr Opin Endocrinol
and the risk of dementia. The Rotterdam study. Clin Endocrinol Diabetes Obes. 2012;19(5):408–413.
(Oxf ). 2000;53(6):733–737. 75. Iwen KA, Schroder E, Brabant G. Thyroid hormones and the meta-
52. Sampaolo S, Campos-Barros A, Mazziotti G, et al. Increased cere- bolic syndrome. Eur Thyroid J. 2013;2(2):83–92.
brospinal fluid levels of 3,3′5′-triiodothyronine in patients with 76. Crunkhorn S, Patti ME. Links between thyroid hormone action,
Alzheimer’s disease. J Clin Endocrinol Metab. 2005;90(1):198–202. oxidative metabolism, and diabetes risk? Thyroid. 2008;18(2):227–
53. Schiess N, Pardo CA. Hashimoto’s encephalopathy. Ann N Y Acad 237.
Sci. 2008;1142:254–265. 77. Chidakel A, Mentuccia D, Celi FS. Peripheral metabolism of thyroid
54. Williams GR, Bassett JHD. Thyroid diseases and bone health. J hormone and glucose homeostasis. Thyroid. 2005;15(8):899–903.
Endocrinol Invest. 2018;41(1):99–109. 78. Vettor R. The metabolic actions of thyroid hormone and leptin: a
55. Rivkees SA, Bode HH, Crawford JD. Long-term growth in juve- mandatory interplay or not? Diabetologia. 2005;48(4):621–623.
nile acquired hypothyroidism: the failure to achieve normal adult 79. Iglesias P, Alvarez Fidalgo P, et al. Serum concentrations of adi-
stature. N Engl J Med. 1988;318(10):599–602. pocytokines in patients with hyperthyroidism and hypothyroidism
56. Iwasaki Y, Oiso Y, Yamauchi K, et al. Osmoregulation of before and after control of thyroid function. Clin Endocrinol (Oxf ).
plasma vasopressin in myxedema. J Clin Endocrinol Metab. 2003;59(5):621–629.
1990;70(2):534–539. 80. Biondi B, Wartofsky L. Treatment with thyroid hormone. Endocr
57. Rhee CM, Brent GA, Kovesdy CP, et al. Thyroid functional dis- Rev. 2014;35(3):433–512.
ease: an under-recognized cardiovascular risk factor in kidney dis- 81. Zulewski H, Muller B, Exer P, et al. Estimation of tissue hypothy-
ease patients. Nephrol Dial Transplant. 2015;30(5):724–737. roidism by a new clinical score: evaluation of patients with various
58. Federici AB. Acquired von Willebrand syndrome associated with grades of hypothyroidism and controls. J Clin Endocrinol Metab.
hypothyroidism: a mild bleeding disorder to be further investi- 1997;82(3):771–776.
gated. Semin Thromb Hemost. 2011;37(1):35–40. 82. Rapa A, Monzani A, Moia S, et al. Subclinical hypothyroid-
59. Squizzato A, Romualdi E, Buller HR, Gerdes VE. Clinical review: ism in children and adolescents: a wide range of clinical, bio-
thyroid dysfunction and effects on coagulation and fibrinolysis: chemical, and genetic factors involved. J Clin Endocrinol Metab.
a systematic review. J Clin Endocrinol Metab. 2007;92(7):2415– 2009;94(7):2414–2420.
2420. 83. Wojcicka A, Bassett JH, Williams GR. Mechanisms of action
60. Lecky BR, Williams TD, Lightman SL, et al. Myxoedema present- of thyroid hormones in the skeleton. Biochim Biophys Acta.
ing with chiasmal compression: resolution after thyroxine replace- 2013;1830(7):3979–3986.
ment. Lancet. 1987;1(8546):1347–1350. 84. Gereben B, Zavacki AM, Ribich S, et al. Cellular and molecular
61. Kamilaris TC, DeBold CR, Pavlou SN, et al. Effect of altered thy- basis of deiodinase-regulated thyroid hormone signaling. Endocr
roid hormone levels on hypothalamic-pituitary-adrenal function. J Rev. 2008;29(7):898–938.
Clin Endocrinol Metab. 1987;65(5):994–999. 85. Yamada M, Mori M. Mechanisms related to the pathophysiology
62. Moran C, Agostini M, McGowan A, et al. Contrasting phenotypes and management of central hypothyroidism. Nat Clin Pract Endo-
in resistance to thyroid hormone alpha correlate with divergent crinol Metab. 2008;4(12):683–694.
properties of thyroid hormone receptor alpha1 mutant proteins. 86. Caldwell KL, Jones R, Hollowell JG. Urinary iodine concentration:
Thyroid. 2017;27(7):973–982. United States National Health and Nutrition Examination Survey
63. Stabouli S, Papakatsika S, Kotsis V. Hypothyroidism and hyperten- 2001-2002. Thyroid. 2005;15(7):692–699.
sion. Expert Rev Cardiovasc Ther. 2010;8(11):1559–1565. 87. Mariotti S, Franceschi C, Cossarizza A, Pinchera A. The aging thy-
64. Barreto-Chaves ML, Carrillo-Sepulveda MA, Carneiro-Ramos MS, roid. Endocr Rev. 1995;16(6):686–715.
et al. The crosstalk between thyroid hormones and the renin-angio- 88. Lee S, Farwell AP. Euthyroid sick syndrome. Compr Physiol.
tensin system. Vascul Pharmacol. 2010;52(3-4):166–170. 2016;6(2):1071–1080.
65. Mintziori G, Anagnostis P, Toulis KA, Goulis DG. Thyroid dis- 89. Verloop H, Louwerens M, Schoones JW, et al. Risk of hypothy-
eases and female reproduction. Minerva Med. 2012;103(1):47–62. roidism following hemithyroidectomy: systematic review and
66. De Leo S, Pearce EN. Autoimmune thyroid disease during preg- meta-analysis of prognostic studies. J Clin Endocrinol Metab.
nancy. Lancet Diabetes Endocrinol. 2018;6(7):575–586. 2012;97(7):2243–2255.
67. Thompson W, Russell G, Baragwanath G, et al. Maternal thyroid 90. McGrogan A, Seaman HE, Wright JW, de Vries CS. The incidence
hormone insufficiency during pregnancy and risk of neurodevelop- of autoimmune thyroid disease: a systematic review of the litera-
mental disorders in offspring: a systematic review and meta-analy- ture. Clin Endocrinol (Oxf ). 2008;69(5):687–696.
sis. Clin Endocrinol (Oxf ). 2018;88(4):575–584. 91. McLachlan SM, Rapoport B. Thyrotropin-blocking autoantibod-
68. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment ies and thyroid-stimulating autoantibodies: potential mechanisms
in euthyroid pregnant women with autoimmune thyroid disease: involved in the pendulum swinging from hypothyroidism to hyper-
effects on obstetrical complications. J Clin Endocrinol Metab. thyroidism or vice versa. Thyroid. 2013;23(1):14–24.
2006;91(7):2587–2591. 92. Diana T, Krause J, Olivo PD, et al. Prevalence and clinical rel-
69. Krassas GE, Tziomalos K, Papadopoulou F, et al. Erectile dysfunc- evance of thyroid stimulating hormone receptor-blocking anti-
tion in patients with hyper- and hypothyroidism: how common bodies in autoimmune thyroid disease. Clin Exp Immunol.
and should we treat? J Clin Endocrinol Metab. 2008;93(5):1815– 2017;189(3):304–309.
1819. 93. Walsh JP, Bremner AP, Feddema P, et al. Thyrotropin and thyroid
70. Brenta G, Schnitman M, Gurfinkiel M, et al. Variations of sex antibodies as predictors of hypothyroidism: a 13-year, longitudinal
hormone-binding globulin in thyroid dysfunction. Thyroid. study of a community-based cohort using current immunoassay
1999;9(3):273–277. techniques. J Clin Endocrinol Metab. 2010;123(2):186.e1–e9.
71. Silva JE, Bianco SD. Thyroid-adrenergic interactions: physiological 94. Boelaert K, Newby PR, Simmonds MJ, et al. Prevalence and rela-
and clinical implications. Thyroid. 2008;18(2):157–165. tive risk of other autoimmune diseases in subjects with autoim-
72. Haluzik M, Nedvidkova J, Bartak V, et al. Effects of hypo- and mune thyroid disease. Am J Med. 2010;123(2):e1–e9. 183.
hyperthyroidism on noradrenergic activity and glycerol concentra- 95. Blanchin S, Coffin C, Viader F, et al. Anti-thyroperoxidase anti-
tions in human subcutaneous abdominal adipose tissue assessed with bodies from patients with Hashimoto’s encephalopathy bind to
microdialysis. J Clin Endocrinol Metab. 2003;88(12):5605–5608. cerebellar astrocytes. J Neuroimmunol. 2007;192(1–2):13–20.
References 432.e3
96. Ehlers M, Thiel A, Bernecker C, et al. Evidence of a combined 118. Winther KH, Bonnema SJ, Hegedus L. Is selenium supplementa-
cytotoxic thyroglobulin and thyroperoxidase epitope-specific cellu- tion in autoimmune thyroid diseases justified? Curr Opin Endocri-
lar immunity in Hashimoto’s thyroiditis. J Clin Endocrinol Metab. nol Diabetes Obes. 2017;24(5):348–355.
2012;97(4):1347–1354. 119. Tomer Y. Hepatitis C and interferon induced thyroiditis. J Autoim-
97. Wang SH, Baker JR. The role of apoptosis in thyroid autoimmu- mun. 2010;34(3):J322–J326.
nity. Thyroid. 2007;17(10):975–979. 120. Torino F, Barnabei A, Paragliola R, et al. Thyroid dysfunc-
98. Li D, Cai W, Gu R, et al. Th17 cell plays a role in the patho- tion as an unintended side effect of anticancer drugs. Thyroid.
genesis of Hashimoto’s thyroiditis in patients. Clin Immunol. 2013;23(11):1345–1366.
2013;149(3):411–420. 121. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immu-
99. Brown RS, Bellisario RL, Botero D, et al. Incidence of transient notherapy - immune checkpoint blockade and associated endocri-
congenital hypothyroidism due to maternal thyrotropin receptor- nopathies. Nat Rev Endocrinol. 2017;13(4):195–207.
blocking antibodies in over one million babies. J Clin Endocrinol 122. Wiersinga WM. Smoking and thyroid. Clin Endocrinol (Oxf ).
Metab. 1996;81(3):1147–1151. 2013;79(2):145–151.
100. Leger J, Olivieri A, Donaldson M, et al. European Society for Pae- 123. Carle A, Pedersen IB, Knudsen N, et al. Moderate alcohol con-
diatric Endocrinology consensus guidelines on screening, diagnosis, sumption may protect against overt autoimmune hypothyroid-
and management of congenital hypothyroidism. J Clin Endocrinol ism: a population-based case-control study. Eur J Endocrinol.
Metab. 2014;99(2):363–384. 2012;167(4):483–490.
101. Feingold SB, Smith J, Houtz J, et al. Prevalence and functional 124. Imaizumi M, Usa T, Tominaga T, et al. Radiation dose-response
significance of thyrotropin receptor blocking antibodies in children relationships for thyroid nodules and autoimmune thyroid diseases
and adolescents with chronic lymphocytic thyroiditis. J Clin Endo- in Hiroshima and Nagasaki atomic bomb survivors 55-58 years
crinol Metab. 2009;94(12):4742–4748. after radiation exposure. JAMA. 2006;295(9):1011–1022.
102. Rebuffat SA, Nguyen B, Robert B, et al. Antithyroperoxidase 125. Ostroumova E, Brenner A, Oliynyk V, et al. Subclinical hypo-
antibody-dependent cytotoxicity in autoimmune thyroid disease. thyroidism after radioiodine exposure: Ukrainian-American
J Clin Endocrinol Metab. 2008;93(3):929–934. cohort study of thyroid cancer and other thyroid diseases after
103. Li Y, Zhou G, Ozaki T, et al. Distinct histopathological features of the Chornobyl accident (1998-2000). Environ Health Perspect.
Hashimoto’s thyroiditis with respect to IgG4-related disease. Mod 2009;117(5):745–750.
Pathol. 2012;25(8):1086–1097. 126. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid
104. Brix TH, Kyvik KO, Hegedus L. A population-based study of in survivors of Hodgkin’s disease: data from the childhood cancer
chronic autoimmune hypothyroidism in Danish twins. J Clin survivor study. J Clin Endocrinol Metab. 2000;85(9):3227–3232.
Endocrinol Metab. 2000;85(2):536–539. 127. Carle A, Pedersen IB, Knudsen N, et al. Thyroid volume in
105. Jacobson EM, Huber A, Tomer Y. The HLA gene complex in thy- hypothyroidism due to autoimmune disease follows a unimodal
roid autoimmunity: from epidemiology to etiology. J Autoimmun. distribution: evidence against primary thyroid atrophy and autoim-
2008;30(1–2):58–62. mune thyroiditis being distinct diseases. J Clin Endocrinol Metab.
106. Tomer Y. Mechanisms of autoimmune thyroid diseases: from 2009;94(3):833–839.
genetics to epigenetics. Annu Rev Pathol. 2014;9:147–156. 128. Graff-Baker A, Sosa JA, Roman SA. Primary thyroid lymphoma:
107. Ajjan RA, Weetman AP. The pathogenesis of Hashimoto’s thyroid- a review of recent developments in diagnosis and histology-driven
itis: further developments in our understanding. Horm Metab Res. treatment. Curr Opin Oncol. 2010;22(1):17–22.
2015;47(10):702–710. 129. Jankovic B, Le KT, Hershman JM. Clinical review: Hashimoto’s
108. Medici M, Porcu E, Pistis G, et al. Identification of novel genetic thyroiditis and papillary thyroid carcinoma: is there a correlation? J
loci associated with thyroid peroxidase antibodies and clinical thy- Clin Endocrinol Metab. 2013;98(2):474–482.
roid disease. PLoS Genet. 2014;10(2):e1004123. 130. Stagnaro-Green A, Pearce E. Thyroid disorders in pregnancy. Nat
109. Mortensen KH, Cleemann L, Hjerrild BE, et al. Increased preva- Rev Endocrinol. 2012;8(11):650–658.
lence of autoimmunity in Turner syndrome—influence of age. Clin 131. Unuane D, Velkeniers B, Anckaert E, et al. Thyroglobulin autoan-
Exp Immunol. 2009;156(2):205–210. tibodies: is there any added value in the detection of thyroid auto-
110. Aversa T, Lombardo F, Corrias A, et al. In young patients with immunity in women consulting for fertility treatment? Thyroid.
Turner or Down syndrome, Graves’ disease presentation is often 2013;23(8):1022–1028.
preceded by Hashimoto’s thyroiditis. Thyroid. 2014;24(4):744–747. 132. Watanabe T, Maruyama M, Ito T, et al. Clinical features of a
111. Caturegli P, De Remigis A, Chuang K, et al. Hashimoto’s thyroid- new disease concept, IgG4-related thyroiditis. Scand J Rheumatol.
itis: celebrating the centennial through the lens of the Johns Hopkins 2013;42(4):325–330.
hospital surgical pathology records. Thyroid. 2013;23(2):142–150. 133. Pearce EN, Andersson M, Zimmermann MB. Global iodine nutri-
112. Weetman AP. Immunity, thyroid function and pregnancy: molecu- tion: where do we stand in 2013? Thyroid. 2013;23(5):523–528.
lar mechanisms. Nat Rev Endocrinol. 2010;6(6):311–318. 134. Zimmermann MB. Iodine deficiency. Endocr Rev. 2009;30(4):376–
113. Alexander EK, Pearce EN, Brent GA, et al. 2017 guidelines of the 408.
American Thyroid Association for the diagnosis and management 135. Bottcher Y, Eszlinger M, Tonjes A, Paschke R. The genetics of euthy-
of thyroid disease during pregnancy and the postpartum. Thyroid. roid familial goiter. Trends Endocrinol Metab. 2005;16(7):314–319.
2017;27(3):315–389. 136. Pearce EN, Pino S, He X, et al. Sources of dietary iodine: bread,
114. Aghini Lombardi F, Fiore E, Tonacchera M, et al. The effect of volun- cows’ milk, and infant formula in the Boston area. J Clin Endocrinol
tary iodine prophylaxis in a small rural community: the Pescopagano Metab. 2004;89(7):3421–3424.
survey 15 years later. J Clin Endocrinol Metab. 2013;98(3):1031–1039. 137. Leung AM, Pearce EN, Braverman LE. Iodine content of prenatal
115. Pramyothin P, Leung AM, Pearce EN, et al. Clinical problem-solv- multivitamins in the United States. N Engl J Med. 2009;360(9):
ing. A hidden solution. N Engl J Med. 2011;365(22):2123–2127. 939–940.
116. Sundick RS, Herdegen DM, Brown TR, Bagchi N. The incorpora- 138. Leung AM, Braverman LE. Iodine-induced thyroid dysfunction.
tion of dietary iodine into thyroglobulin increases its immunoge- Curr Opin Endocrinol Diabetes Obes. 2012;19(5):414–419.
nicity. Endocrinology. 1987;120(5):2078–2084. 139. Wolff J, Chaikoff IL. Plasma inorganic iodide as a homeostatic
117. Winther KH, Wichman JE, Bonnema SJ, Hegedus L. Insufficient regulator of thyroid function. J Biol Chem. 1948;174(2):555–564.
documentation for clinical efficacy of selenium supplementation in 140. Lazarus JH. Lithium and thyroid. Best Pract Res Clin Endocrinol
chronic autoimmune thyroiditis, based on a systematic review and Metab. 2009;23(6):723–733.
meta-analysis. Endocrine. 2017;55(2):376–385.
432.e4 References
141. Muller B, Zulewski H, Huber P, et al. Impaired action of thyroid 165. Huang SA, Fish SA, Dorfman DM, et al. A 21-year-old woman
hormone associated with smoking in women with hypothyroidism. with consumptive hypothyroidism due to a vascular tumor express-
N Engl J Med. 1995;333(15):964–969. ing type 3 iodothyronine deiodinase. J Clin Endocrinol Metab.
142. Felker P, Bunch R, Leung AM. Concentrations of thiocyanate and 2002;87(10):4457–4461.
goitrin in human plasma, their precursor concentrations in brassica 166. Brown RL. Tyrosine kinase inhibitor-induced hypothyroidism: inci-
vegetables, and associated potential risk for hypothyroidism. Nutr dence, etiology, and management. Target Oncol. 2011;6(4):217–226.
Rev. 2016;74(4):248–258. 167. Makita N, Iiri T. Tyrosine kinase inhibitor-induced thyroid disor-
143. Chu M, Seltzer TF. Myxedema coma induced by ingestion of raw ders: a review and hypothesis. Thyroid. 2013;23(2):151–159.
bok choy. N Engl J Med. 2010;362(20):1945–1946. 168. Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib
144. Pearce EN, Braverman LE. Environmental pollutants and the thy- treatment for patients with gastrointestinal stromal tumors. Ann
roid. Best Pract Res Clin Endocrinol Metab. 2009;23(6):801–813. Intern Med. 2006;145(9):660–664.
145. Pearce EN, Spencer CA, Mestman JH, et al. Effect of environ- 169. Maynard MA, Marino-Enriquez A, Fletcher JA, et al. Thyroid
mental perchlorate on thyroid function in pregnant women from hormone inactivation in gastrointestinal stromal tumors. N Engl J
Cordoba, Argentina, and Los Angeles, California. Endocr Pract. Med. 2014;370(14):1327–1334.
2011;17(3):412–417. 170. Dumitrescu AM, Liao XH, Abdullah MS, et al. Mutations in
146. Barbesino G. Drugs affecting thyroid function. Thyroid. SECISBP2 result in abnormal thyroid hormone metabolism. Nat
2010;20(7):763–770. Genet. 2005;37(11):1247–1252.
147. Grasberger H, Refetoff S. Genetic causes of congenital hypo- 171. Canani LH, Capp C, Dora JM, et al. The type 2 deiodinase A/G
thyroidism due to dyshormonogenesis. Curr Opin Pediatr. (Thr92Ala) polymorphism is associated with decreased enzyme
2011;23(4):421–428. velocity and increased insulin resistance in patients with type 2 dia-
148. Szinnai G. Genetics of normal and abnormal thyroid development in betes mellitus. J Clin Endocrinol Metab. 2005;90(6):3472–3478.
humans. Best Pract Res Clin Endocrinol Metab. 2014;28(2):133–150. 172. McAninch EA, Jo S, Preite NZ, et al. Prevalent polymorphism in
149. Portulano C, Paroder-Belenitsky M, Carrasco N. The Na+/I- thyroid hormone-activating enzyme leaves a genetic fingerprint
symporter (NIS): mechanism and medical impact. Endocr Rev. that underlies associated clinical syndromes. J Clin Endocrinol
2014;35(1):106–149. Metab. 2015;100(3):920–933.
150. Kogai T, Brent GA. The sodium iodide symporter (NIS): regula- 173. Toulis KA, Anastasilakis AD, Tzellos TG, et al. Selenium supple-
tion and approaches to targeting for cancer therapeutics. Pharmacol mentation in the treatment of Hashimoto’s thyroiditis: a systematic
Ther. 2012;135(3):355–370. review and a meta-analysis. Thyroid. 2010;20(10):1163–1173.
151. Bakker B, Bikker H, Vulsma T, et al. Two decades of screening for 174. Haugen BR, Sherman SI. Evolving approaches to patients
congenital hypothyroidism in The Netherlands: TPO gene muta- with advanced differentiated thyroid cancer. Endocr Rev.
tions in total iodide organification defects (an update). J Clin Endo- 2013;34(3):439–455.
crinol Metab. 2000;85(10):3708–3712. 175. Graeppi-Dulac J, Vlaeminck-Guillem V, Perier-Muzet M, et al.
152. Bizhanova A, Kopp P. Genetics and phenomics of Pendred syn- Endocrine side-effects of anti-cancer drugs: the impact of retinoids
drome. Mol Cell Endocrinol. 2010;322(1-2):83–90. on the thyroid axis. Eur J Endocrinol. 2014;170(6):R253–R262.
153. Iglesias A, Garcia-Nimo L, Cocho de Juan JA, Moreno JC. Towards 176. Haugen BR. Drugs that suppress TSH or cause central hypothyroid-
the pre-clinical diagnosis of hypothyroidism caused by iodotyro- ism. Best Pract Res Clin Endocrinol Metab. 2009;23(6):793–800.
sine deiodinase (DEHAL1) defects. Best Pract Res Clin Endocrinol 177. Comi RJ, Gesundheit N, Murray L, et al. Response of thyrotropin-
Metab. 2014;28(2):151–159. secreting pituitary adenomas to a long-acting somatostatin ana-
154. Moreno JC, Visser TJ. Genetics and phenomics of hypothyroidism logue. N Engl J Med. 1987;317(1):12–17.
and goiter due to iodotyrosine deiodinase (DEHAL1) gene muta- 178. de Moraes DC, Vaisman M, Conceicao FL, Ortiga-Carvalho
tions. Mol Cell Endocrinol. 2010;322(1–2):91–98. TM. Pituitary development: a complex, temporal regulated pro-
155. Hennessey JV. Clinical review: Riedel’s thyroiditis: a clinical review. cess dependent on specific transcriptional factors. J Endocrinol.
J Clin Endocrinol Metab. 2011;96(10):3031–3041. 2012;215(2):239–245.
156. Ozdemir D, Dagdelen S, Erbas T. Endocrine involvement in sys- 179. Collu R, Tang J, Castagne J, et al. A novel mechanism for isolated
temic amyloidosis. Endocr Pract. 2010;16(6):1056–1063. central hypothyroidism: inactivating mutations in the thyrotro-
157. Oerter KE, Kamp GA, Munson PJ, et al. Multiple hormone defi- pin-releasing hormone receptor gene. J Clin Endocrinol Metab.
ciencies in children with hemochromatosis. J Clin Endocrinol 1997;82(5). 1561–1556.
Metab. 1993;76(2):357–361. 180. Hayashizaki Y, Hiraoka Y, Tatsumi K, et al. Deoxyribonucleic acid
158. Shah AA, Wigley FM. Often forgotten manifestations of systemic analyses of five families with familial inherited thyroid stimulating
sclerosis. Rheum Dis Clin North Am. 2008;34(1):221–238; ix. hormone deficiency. J Clin Endocrinol Metab. 1990;71(4):792–796.
159. Brent GA. Clinical practice. Graves’ disease. N Engl J Med. 181. Medeiros-Neto G, Herodotou DT, Rajan S, et al. A circulating,
2008;358(24):2594–2605. biologically inactive thyrotropin caused by a mutation in the beta
160. Biebermann H, Schoneberg T, Krude H, et al. Mutations of the subunit gene. J Clin Invest. 1996;97(5):1250–1256.
human thyrotropin receptor gene causing thyroid hypoplasia and 182. Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to
persistent congenital hypothyroidism. J Clin Endocrinol Metab. thyroid hormone: genetic defects in hormone receptors, cell trans-
1997;82(10):3471–3480. porters and deiodination. Best Pract Res Clin Endocrinol Metab.
161. Spiegel AM, Shenker A, Weinstein LS. Receptor-effector coupling 2007;21(2):277–305.
by G proteins: implications for normal and abnormal signal trans- 183. Refetoff S, Bassett JH, Beck-Peccoz P, et al. Classification and
duction. Endocr Rev. 1992;13(3):536–565. proposed nomenclature for inherited defects of thyroid hormone
162. Xie J, Pannain S, Pohlenz J, et al. Resistance to thyrotropin (TSH) action, cell transport, and metabolism. J Clin Endocrinol Metab.
in three families is not associated with mutations in the TSH 2014;99(3):768–770.
receptor or TSH. J Clin Endocrinol Metab. 1997;82(12):3933– 184. Schoenmakers N, Moran C, Peeters RP, et al. Resistance to thyroid
3940. hormone mediated by defective thyroid hormone receptor alpha.
163. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism Biochim Biophys Acta. 2013;1830(7):4004–4008.
caused by type 3 iodothyronine deiodinase in infantile hemangio- 185. Moran C, Agostini M, Visser WE, et al. Resistance to thyroid hor-
mas. N Engl J Med. 2000;343(3):185–189. mone caused by a mutation in thyroid hormone receptor (TR)alpha1
164. Puttgen KB. Diagnosis and management of infantile hemangio- and TRalpha2: clinical, biochemical, and genetic analyses of three
mas. Pediatr Clin North Am. 2014;61(2):383–402. related patients. Lancet Diabetes Endocrinol. 2014;2(8):619–626.
References 432.e5
186. van Mullem AA, Chrysis D, Eythimiadou A, et al. Clinical pheno- 208. Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine lev-
type of a new type of thyroid hormone resistance caused by a muta- els in athyreotic individuals during levothyroxine therapy. JAMA.
tion of the TRalpha1 receptor: consequences of LT4 treatment. J 2008;299(7):769–777.
Clin Endocrinol Metab. 2013;98(7):3029–3038. 209. Gullo D, Latina A, Frasca F, et al. Levothyroxine monotherapy
187. Weiss RE, Refetoff S. Effect of thyroid hormone on growth. Les- cannot guarantee euthyroidism in all athyreotic patients. PLoS One.
sons from the syndrome of resistance to thyroid hormone. Endocri- 2011;6(8):e22552.
nol Metab Clin North Am. 1996;25(3):719–730. 210. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange Jr AJ. Effects
188. Beck-Peccoz P, Persani L, Mannavola D, Campi I. Pituitary of thyroxine as compared with thyroxine plus triiodothyronine in
tumours: TSH-secreting adenomas. Best Pract Res Clin Endocrinol patients with hypothyroidism. N Engl J Med. 1999;340(6):424–429.
Metab. 2009;23(5):597–606. 211. Grozinsky-Glasberg S, Fraser A, Nahshoni E, et al. Thyroxine-tri-
189. Reutrakul S, Sadow PM, Pannain S, et al. Search for abnormalities iodothyronine combination therapy versus thyroxine monotherapy
of nuclear corepressors, coactivators, and a coregulator in families for clinical hypothyroidism: meta-analysis of randomized con-
with resistance to thyroid hormone without mutations in thyroid trolled trials. J Clin Endocrinol Metab. 2006;91(7):2592–2599.
hormone receptor beta or alpha genes. J Clin Endocrinol Metab. 212. Panicker V, Saravanan P, Vaidya B, et al. Common variation in the
2000;85(10):3609–3617. DIO2 gene predicts baseline psychological well-being and response
190. Weiss RE, Refetoff S. Treatment of resistance to thyroid—primum to combination thyroxine plus triiodothyronine therapy in hypo-
non nocere. J Clin Endocrinol Metab. 1999;84(2):401–404. thyroid patients. J Clin Endocrinol Metab. 2009;94(5):1623–1629.
191. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guide- 213. Bianco AC, Casula S. Thyroid hormone replacement therapy: three
lines for hypothyroidism in adults: cosponsored by the American ‘simple’ questions, complex answers. Eur Thyroid J. 2012;1(2):88–98.
Association of Clinical Endocrinologists and the American Thyroid 214. al-Adsani H, Hoffer LJ, Silva JE. Resting energy expenditure is sen-
Association. Thyroid. 2012;22(12):1200–1235. sitive to small dose changes in patients on chronic thyroid hormone
192. Biondi B, Wartofsky L. Combination treatment with T4 and T3: replacement. J Clin Endocrinol Metab. 1997;82(4):1118–1125.
toward personalized replacement therapy in hypothyroidism? J 215. Russell W, Harrison RF, Smith N, et al. Free triiodothyronine has
Clin Endocrinol Metab. 2012;97(7):2256–2271. a distinct circadian rhythm that is delayed but parallels thyrotropin
193. Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA guidelines: levels. J Clin Endocrinol Metab. 2008;93(6):2300–2306.
the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur 216. Hennemann G, Docter R, Visser TJ, et al. Thyroxine plus low-
Thyroid J. 2012;1(2):55–71. dose, slow-release triiodothyronine replacement in hypothyroid-
194. Bach-Huynh TG, Nayak B, Loh J, et al. Timing of levothyroxine ism: proof of principle. Thyroid. 2004;14(4):271–275.
administration affects serum thyrotropin concentration. J Clin 217. Carr D, McLeod DT, Parry G, Thornes HM. Fine adjustment of
Endocrinol Metab. 2009;94(10):3905–3912. thyroxine replacement dosage: comparison of the thyrotrophin
195. Hennessey JV. Levothyroxine a new drug? Since when? How could releasing hormone test using a sensitive thyrotrophin assay with
that be? Thyroid. 2003;13(3):279–282. measurement of free thyroid hormones and clinical assessment.
196. Burman K, Hennessey J, McDermott M, et al. The FDA revises require- Clin Endocrinol (Oxf ). 1988;28(3):325–333.
ments for levothyroxine products. Thyroid. 2008;18(5):487–490. 218. Slawik M, Klawitter B, Meiser E, et al. Thyroid hormone replace-
197. Santini F, Pinchera A, Marsili A, et al. Lean body mass is a major ment for central hypothyroidism: a randomized controlled trial com-
determinant of levothyroxine dosage in the treatment of thyroid paring two doses of thyroxine (T4) with a combination of T4 and
diseases. J Clin Endocrinol Metab. 2005;90(1):124–127. triiodothyronine. J Clin Endocrinol Metab. 2007;92(11):4115–4122.
198. Fierabracci P, Martinelli S, Tamberi A, et al. Weight loss and varia- 219. Van Dop C, Conte FA, Koch TK, et al. Pseudotumor cerebri asso-
tion of levothyroxine requirements in hypothyroid obese patients ciated with initiation of levothyroxine therapy for juvenile hypo-
after bariatric surgery. Thyroid. 2016;26(4):499–503. thyroidism. N Engl J Med. 1983;308(18):1076–1080.
199. Olveira G, Almaraz MC, Soriguer F, et al. Altered bioavailability 220. Bogazzi F, Tomisti L, Bartalena L, et al. Amiodarone and the thy-
due to changes in the formulation of a commercial preparation of roid: a 2012 update. J Endocrinol Invest. 2012;35(3):340–348.
levothyroxine in patients with differentiated thyroid carcinoma. 221. LaFranchi SH, Austin J. How should we be treating children
Clin Endocrinol (Oxf ). 1997;46(6):707–711. with congenital hypothyroidism? J Pediatr Endocrinol Metab.
200. Vita R, Saraceno G, Trimarchi F, Benvenga S. Switching levothy- 2007;20(5):559–578.
roxine from the tablet to the oral solution formulation corrects the 222. Fisher DA, Schoen EJ, La Franchi S, et al. The hypothalamic-
impaired absorption of levothyroxine induced by proton-pump pituitary-thyroid negative feedback control axis in children with
inhibitors. J Clin Endocrinol Metab. 2014;99(12):4481–4486. treated congenital hypothyroidism. J Clin Endocrinol Metab.
201. Rees-Jones RW, Larsen PR. Triiodothyronine and thyroxine content 2000;85(8):2722–2727.
of desiccated thyroid tablets. Metabolism. 1977;26(11):1213–1218. 223. Surks MI, Boucai L. Age- and race-based serum thyrotropin refer-
202. LeBoff MS, Kaplan MM, Silva JE, Larsen PR. Bioavailability of ence limits. J Clin Endocrinol Metab. 2010;95(2):496–502.
thyroid hormones from oral replacement preparations. Metabolism. 224. Atzmon G, Barzilai N, Hollowell JG, et al. Extreme longevity is
1982;31(9):900–905. associated with increased serum thyrotropin. J Clin Endocrinol
203. Hoang TD, Olsen CH, Mai VQ, et al. Desiccated thyroid extract Metab. 2009;94(4):1251–1254.
compared with levothyroxine in the treatment of hypothyroidism: 225. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magni-
a randomized, double-blind, crossover study. J Clin Endocrinol tude of increases in levothyroxine requirements during pregnancy in
Metab. 2013;98(5):1982–1990. women with hypothyroidism. N Engl J Med. 2004;351(3):241–249.
204. Blumberg KR, Mayer WJ, Parikh DK, Schnell LA. Liothyronine and 226. Loh JA, Wartofsky L, Jonklaas J, Burman KD. The magnitude
levothyroxine in Armour thyroid. J Pharm Sci. 1987;76(4):346–347. of increased levothyroxine requirements in hypothyroid pregnant
205. Hays MT. Localization of human thyroxine absorption. Thyroid. women depends upon the etiology of the hypothyroidism. Thyroid.
1991;1(3):241–248. 2009;19(3):269–275.
206. Centanni M, Gargano L, Canettieri G, et al. Thyroxine in goiter, 227. Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thy-
Helicobacter pylori infection, and chronic gastritis. N Engl J Med. roxine in congenital hypothyroidism due to a total organification
2006;354(17):1787–1795. defect or thyroid agenesis. N Engl J Med. 1989;321(1):13–16.
207. Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale 228. Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res
de Escobar G. Replacement therapy for hypothyroidism with thy- Clin Endocrinol Metab. 2011;25(6):927–943.
roxine alone does not ensure euthyroidism in all tissues, as studied 229. Arafah BM. Increased need for thyroxine in women with hypothyroid-
in thyroidectomized rats. J Clin Invest. 1995;96(6):2828–2838. ism during estrogen therapy. N Engl J Med. 2001;344(23):1743–1749.
432.e6 References
230. Messina M, Redmond G. Effects of soy protein and soybean isofla- 246. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease:
vones on thyroid function in healthy adults and hypothyroid patients: scientific review and guidelines for diagnosis and management.
a review of the relevant literature. Thyroid. 2006;16(3):249–258. JAMA. 2004;291(2):228–238.
231. Figge J, Dluhy RG. Amiodarone-induced elevation of thyroid stim- 247. Rugge JB, Bougatsos C, Chou R. Screening for and treatment of
ulating hormone in patients receiving levothyroxine for primary thyroid dysfunction: an evidence review for the US Preventive Services
hypothyroidism. Ann Intern Med. 1990;113(7):553–555. Task Force. Rockville (MD): U.S. Preventive Services Task Force
232. Gogakos AI, Duncan Bassett JH, Williams GR. Thyroid and Evidence Syntheses, formerly Systematic Evidence Reviews; 2014.
bone. Arch Biochem Biophys. 2010;503(1):129–136. 248. Vaidya B, Anthony S, Bilous M, et al. Detection of thyroid dys-
233. Benvenga S. When thyroid hormone replacement is ineffective? function in early pregnancy: universal screening or targeted high-
Curr Opin Endocrinol Diabetes Obes. 2013;20(5):467–477. risk case finding? J Clin Endocrinol Metab. 2007;92(1):203–207.
234. Jonklaas J. Persistent hypothyroid symptoms in a patient with a 249. Casey BM, Thom EA, Peaceman AM, et al. Treatment of subclini-
normal thyroid stimulating hormone level. Curr Opin Endocrinol cal hypothyroidism or hypothyroxinemia in pregnancy. N Engl J
Diabetes Obes. 2017;24(5):356–363. Med. 2017;376(9):815–825.
235. Saravanan P, Chau WF, Roberts N, et al. Psychological well-being 250. Hales C, Taylor PN, Channon S, et al. Controlled antenatal thyroid
in patients on ‘adequate’ doses of l-thyroxine: results of a large, screening II: effect of treating maternal suboptimal thyroid function on
controlled community-based questionnaire study. Clin Endocrinol child cognition. J Clin Endocrinol Metab. 2018;103(4):1583–1591.
(Oxf ). 2002;57(5):577–585. 251. Fliers E, Wiersinga WM. Myxedema coma. Rev Endocr Metab Dis-
236. Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone ther- ord. 2003;4(2):137–141.
apy for older adults with subclinical hypothyroidism. N Engl J Med. 252. Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med
2017;376(26):2534–2544. Clin North Am. 2012;96(2):385–403.
237. Huber G, Staub JJ, Meier C, et al. Prospective study of the spon- 253. Paes JE, Burman KD, Cohen J, et al. Acute bacterial suppura-
taneous course of subclinical hypothyroidism: prognostic value of tive thyroiditis: a clinical review and expert opinion. Thyroid.
thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endo- 2010;20(3):247–255.
crinol Metab. 2002;87(7):3221–3226. 254. Yolmo D, Madana J, Kalaiarasi R, et al. Retrospective case review
238. Heymann R, Brent GA. Rapid progression from subclinical to symp- of pyriform sinus fistulae of third branchial arch origin commonly
tomatic overt hypothyroidism. Endocr Pract. 2005;11(2):115–119. presenting as acute suppurative thyroiditis in children. J Laryngol
239. Ladenson PW, Levin AA, Ridgway EC, Daniels GH. Complications Otol. 2012;126(7):737–742.
of surgery in hypothyroid patients. Am J Med. 1984;77(2):261–266. 255. Bartholomew LG, Cain JC, Woolner LB, et al. Sclerosing cholan-
240. Sherman SI, Ladenson PW. Percutaneous transluminal coronary gitis: its possible association with Riedel’s struma and fibrous retro-
angioplasty in hypothyroidism. Am J Med. 1991;90(3):367–370. peritonitis. Report of two cases. N Engl J Med. 1963;269:8–12.
241. Hay I, Duick DS, Vlietstra RE, et al. Thyroxine therapy in hypo- 256. Chopra D, Wool MS, Crosson A, Sawin CT. Riedel’s struma asso-
thyroid patients undergoing coronary revascularization: a retro- ciated with subacute thyroiditis, hypothyroidism, and hypopara-
spective analysis. Ann Intern Med. 1981;95(4):456–457. thyroidism. J Clin Endocrinol Metab. 1978;46(6):869–871.
242. Hamilton MA, Stevenson LW, Fonarow GC, et al. Safety and 257. Papi G, LiVolsi VA. Current concepts on Riedel thyroiditis. Am J
hemodynamic effects of intravenous triiodothyronine in advanced Clin Pathol. 2004;121(suppl):S50–S63.
congestive heart failure. Am J Cardiol. 1998;81(4):443–447. 258. Pusztaszeri M, Triponez F, Pache JC, Bongiovanni M. Riedel’s thy-
243. Klemperer JD, Klein I, Gomez M, et al. Thyroid hormone roiditis with increased IgG4 plasma cells: evidence for an underly-
treatment after coronary-artery bypass surgery. N Engl J Med. ing IgG4-related sclerosing disease? Thyroid. 2012;22(9):964–968.
1995;333(23):1522–1527. 259. Fatourechi MM, Hay ID, McIver B, et al. Invasive fibrous thyroid-
244. Goldman S, McCarren M, Morkin E, et al. DITPA (3,5-Diio- itis (Riedel thyroiditis): the Mayo Clinic experience, 1976-2008.
dothyropropionic Acid), a thyroid hormone analog to treat heart Thyroid. 2011;21(7):765–772.
failure: phase II trial veterans affairs cooperative study. Circulation. 260. Heymann RS, Brent GA, Hershman JM. Anaplastic thyroid carci-
2009;119(24):3093–3100. noma with thyrotoxicosis and hypoparathyroidism. Endocr Pract.
245. Ladenson PW, McCarren M, Morkin E, et al. Effects of the thy- 2005;11(4):281–284.
romimetic agent diiodothyropropionic acid on body weight, body
mass index, and serum lipoproteins: a pilot prospective, randomized,
controlled study. J Clin Endocrinol Metab. 2010;95(3):1349–1354.

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13

Hypothyroidism and Thyroiditis

Hypothyroidism Conditions associated with reduced thyroid hormone action are

(epiphyseal dysgenesis) (Fig. 13.4). Impairment of linear growth

Renal Function: Water and Electrolyte Metabolism

Symptoms and signs suggesting hypothyroidism

Serum TSH and

TSH normal or low

Primary hypothyroidism Central hypothyroidism

TPO antibody MRI

Present Absent Abnormal Normal

? Transient Congenital TRH,

Normal Permanent Treat with surgery

Classification by expressing a number of proinflammatory molecules, such as

NK cell Loss of tight junction after injury

Immune complexes fix

individuals. Patients usually report a mixture of symptoms of Treatment

intervention make thyroid testing of all pregnant women a reason-

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