Approach to the Patient with Hypothyroidism

David M. Slovik

Hypothyroidism is a common, readily treatable disorder. Increasingly, patients present with subclinical disease detected either as part of a screening program or as a consequence of an evaluation for another medical problem, such as hypercholesterolemia. Women experience the condition much more often than do men (five- to eightfold greater prevalence). The primary physician should be able to confirm the diagnosis of hypothyroidism, initiate the workup for its underlying etiology, determine when replacement therapy is indicated, and prescribe thyroid hormone with safety and precision.

PATHOPHYSIOLOGY, CLINICAL PRESENTATION, AND COURSE (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17)

Pathophysiology

The basic mechanisms of hypothyroidism can be divided into those that impair thyroid function (primary hypothyroidism) and those that principally involve hypothalamic-pituitary function (secondary hypothyroidism). In primary disease, the hypothalamus responds with an increased output of thyrotropin-releasing hormone (TRH), which triggers pituitary thyrotropin (thyroidstimulating hormone, TSH) secretion. This in turn stimulates thyroid gland enlargement, goiter formation, and thyroid hormone production with the preferential synthesis of triiodothyronine (T₃) over thyroxine (T₄). In secondary hypothyroidism, the TSH response is inadequate, the gland is normal or reduced in size, and both T₄ synthesis and T₃ synthesis are equally reduced.

Primary Hypothyroidism

Primary hypothyroidism may occur as a result of blockade of thyroid TSH receptors, impairment of thyroxine production, or inhibition of thyroxine release.

Hashimoto Thyroiditis.

In Hashimoto thyroiditis, the most common form of hypothyroidism, immune-mediated injury may damage all three components of glandular function. The precipitants of excessive antibody production remain ill defined, but TSH receptors and microsomal enzymes (e.g., peroxidase) are among the targeted antigens. In fact, antimicrosomal antibodies serve as a convenient laboratory marker for the condition (see later discussion). Pathologically, a lymphocytic infiltrate and glandular enlargement are noted; frank nodularity may develop (see Chapter 95). Antibodies directed against glandular antigens can impair the response to TSH and the synthesis and release of hormone. Although most patients with Hashimoto thyroiditis remain euthyroid, a fraction experience transient hyperthyroidism because of the premature release of thyroid hormone (see Chapter 103).

Postpartum Thyroiditis.

Postpartum thyroiditis is believed to be a common variant of Hashimoto thyroiditis (see Chapter 103), affecting up to 5% of women postpartum. Antibody production peaks 3 to 4 months after delivery and then declines. A period of transient hyperthyroidism may be followed by hypothyroidism, but most patients return to euthyroid status. The symptoms of mild hyperthyroidism may be mistakenly attributed to “tension” and are followed by fatigue and depression resulting from the onset of hypothyroidism. The symptoms resolve spontaneously within 2 to 3 months but tend to recur with subsequent pregnancies.

Radiation-Induced Hypothyroidism.

Radiation-induced hypothyroidism is another leading cause of thyroid injury in the United States. It is a common and permanent consequence of iodine-131 therapy and also of external neck irradiation that exceeds 2,500 rad (used to treat lymphoma and head and neck cancers). Onset is within 3 to 6 months of treatment.

Subacute Thyroiditis.

Subacute thyroiditis following a viral upper respiratory infection is a more transient form of thyroid injury. In this condition, the gland is very tender and enlarged, sometimes asymmetrically. An initial release of thyroid hormone may produce a brief period of hyperthyroidism followed by hormone depletion and glandular hypofunction, but spontaneous remission and restoration of normal thyroid function are the rule. Pathologically, a granulomatous giant cell infiltrate and a marked reduction in iodine uptake characterize the condition. The clinical course ranges from weeks to a few months.

Subtotal Thyroidectomy and Antithyroid Drugs.

Subtotal thyroidectomy produces transient hypothyroidism in most patients and permanent hypothyroidism in about half within the 1st year after surgery.

Drugs that have an antithyroid effect produce a rapid but reversible form of hypothyroidism, such as seen with use of the antithyroid agents methimazole and propylthiouracil in the treatment of hyperthyroidism (see Chapter 103). Lithium, interferon-α, and interleukins may trigger clinical hypothyroidism in a small percentage of cases, presumably by exacerbating preexisting autoimmune thyroid disease. Amiodarone is believed to lead to hypothyroidism by its release of iodine. Iodide excess impairs thyroxine synthesis and release, especially in patients with underlying thyroid disease; iodide deficiency inhibits hormone synthesis and, worldwide, accounts for much of the hypothyroidism and goiter seen. Phenytoin, carbamazepine, and rifampin increase clearance of thyroid hormone, leading to increased daily replacement requirements. The tyrosine kinase inhibitor sunitinib appears to be capable of triggering a destructive thyroiditis; risk appears to increase with duration of therapy.

Pregnancy.

Early in pregnancy, levothyroxine requirements increase, plateauing at about 20 weeks. Mechanisms include an estradiol-related increase in synthesis of thyroxine-binding globulin and a resultant decline in the concentration of free thyroxine. The increased requirements are not a problem for euthyroid women, who respond with increased thyroxine production, but hypothyroid women may experience worsening hypothyroidism as early as 5 weeks into gestation, a time when fetal development is particularly sensitive to levels of circulating thyroid hormone.

Secondary and Tertiary Hypothyroidism (Central Hypothyroidism)

Secondary hypothyroidism is caused by TSH deficiency and tertiary hypothyroidism by TRH deficiency. Together, they account for less than 1% of all hypothyroidism.

Secondary hypothyroidism occurs most commonly as a result of injury to thyrotropes by a functioning or nonfunctioning pituitary adenoma. Many other forms of sellar or suprasellar disease can produce the same net result, which is inadequate production of TSH leading to an atrophic thyroid gland and hypothyroidism. These include hypophysitis, trauma, postpartum pituitary necrosis, nonpituitary tumors, radiation, and infiltrative disease.

Tertiary hypothyroidism is caused by disorders that injure the hypothalamus or interfere with the hypothalamus-pituitary blood flow. Other hormone-producing cells of the pituitary may also be involved and cause a host of associated endocrinopathies (see Chapters 100 and 101).

Clinical Presentation

Subclinical Hypothyroidism

Along with the ability to detect early disease (see later discussion) comes the designation of subclinical hypothyroidism, defined as an asymptomatic elevation in serum TSH concentration (generally ranging from 5.5 to 10.0 mU/L, depending on the specificity desired) accompanied by thyroid hormone levels within normal limits. The general population prevalence averages 7% for women and 2.5% for men. In about 20% of patients with a TSH concentration greater than 6 mU/L, clinically symptomatic hypothyroidism develops within a period of 5 years; the incidence of clinical disease rises to almost 100% for those with a TSH level greater than 14 mU/L. Patients with high titers of antithyroid antibodies are at greatest risk for becoming overtly hypothyroid, which suggests that Hashimoto thyroiditis plays an important role. The meaning of an isolated TSH between 6 and 10 mU/L is unclear, although some evidence has been found of an increased risk for coronary artery disease resulting from lipid abnormalities.

Clinical Hypothyroidism

The overt symptomatic manifestations of hypothyroidism reflect the decreases in metabolic rate and sensitivity to catecholamines that result from insufficient circulating thyroid hormone. Early symptoms are gradual in onset and may occur before serum free thyroxine levels fall below normal limits, although the TSH level rises as soon as circulating levels of thyroid hormone are sensed to be inappropriately low. The patient typically complains of fatigue, constipation, moderately dry skin, heavy menstrual periods, a slight weight gain, or cold intolerance. These symptoms are followed during the next few months by the development of very dry skin, coarse hair, hoarseness, continued weight gain (although appetite is minimal), and slightly impaired mental activity (e.g., minor diminution in psychomotor activity, visual-perceptual skills, or memory). Later, depression may become evident.

In late stages, hydrophilic mucopolysaccharide accumulates subcutaneously, producing the myxedematous changes that characterize the severe form of the disease. The skin becomes doughy, the face puffy, the tongue large, the expression dull, and mentation slow, even lethargic. Muscle weakness, arthralgias, diminished hearing, and carpal tunnel syndrome are also found. Daytime sleepiness in severely myxedematous patients suggests that obstructive sleep apnea may be occurring. Bradycardia, pericardial effusion, and diastolic hypertension may develop. Dementia may ensue and be only partially responsive to thyroid replacement therapy. Rarely, a picture of “myxedema madness” is encountered.

On examination, a goiter may be evident. If Hashimoto disease is the cause, the goitrous gland may feel rubbery, nontender, and even nodular. In the case of subacute thyroiditis, it will be very tender and enlarged, although not always symmetrically. Diffuse enlargement also occurs with hereditary defects in thyroxine synthesis or the use of iodides, para-aminosalicylic acid, or lithium. An atrophic gland is characteristic of secondary hypothyroidism, although this can be seen in primary hypothyroidism with eventual gland destruction. The heart may show signs of dilation or an effusion. Bowel sounds are diminished, and the relaxation phase of the deep tendon reflexes is slowed or “hung up.”

In secondary hypothyroidism, signs of accompanying ovarian and adrenal insufficiency (e.g., loss of axillary and pubic hair, amenorrhea, postural hypotension) may be seen as a consequence of concurrent loss of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and adrenocorticotropic hormone (ACTH) production. Myxedematous changes tend to be less marked than with primary hypothyroidism, and the gland is smaller.

Laboratory Manifestations

As noted earlier, in primary hypothyroidism, TSH elevation may precede clinical manifestations. The earliest development is an increase in TRH, followed by the TSH response. At this stage, thyroid hormone levels may still be reported as “within normal limits,” although in reality, they are reduced from baseline. Only later does free thyroxine fall to overtly abnormal levels.

Hypercholesterolemia—an increase in low density lipoprotein (LDL) cholesterol and a reduction in high density lipoprotein (HDL) cholesterol—is often noted. Hypothyroidism is associated with a number of anemic states. The most common is a mild normochromic normocytic anemia. In addition, a microcytic anemia may ensue from iron deficiency secondary to heavy menstrual bleeding. Furthermore, a macrocytic picture that clears on administration of exogenous thyroid hormone is sometimes encountered. A true megaloblastic anemia resulting from vitamin B₁₂ deficiency occurs in about 10% of hypothyroid patients with a macrocytic smear; the relation between hypothyroidism and pernicious anemia is unresolved, but an autoimmune mechanism is postulated.

In severe cases of myxedema, dilutional hyponatremia occurs as a result of inadequate renal blood flow. A warning of impending myxedema coma is a rise in arterial carbon dioxide tension, which takes place as the respiratory drive weakens.

DIFFERENTIAL DIAGNOSIS

The causes of hypothyroidism can be categorized according to whether they impair the thyroid gland (primary hypothyroidism) or the hypothalamic-pituitary axis (secondary hypothyroidism) (Table 104-1). Primary disease is far more prevalent
than is secondary disease. Autoimmune thyroiditis (Hashimoto thyroiditis) accounts for most of the cases of hypothyroidism seen in the United States. Other causes of thyroid injury include idiopathic thyroid atrophy, previous radioactive iodine (iodine-131) therapy, and thyroidectomy. Women are more frequently affected than are men. The prevalence of hypothyroidism increases with age. As much as 5% of the elderly population manifests evidence of hypothyroidism, most of it resulting from thyroiditis. Less common causes include neck irradiation, iodide administration, and the use of drugs, including lithium, amiodarone, and antithyroid medications. Pituitary insufficiency can result in secondary hypothyroidism. Rarely, hypothalamic disease is the source of difficulty.

TABLE 104-1 Differential Diagnosis of Hypothyroidism

Primary Hypothyroidism
	Hashimoto thyroiditis
	Postpartum disease (transient)
	Postirradiation disease
	Subtotal thyroidectomy
	Subacute thyroiditis (transient)
	Antithyroid drugs (lithium, PAS, PTU, methimazole, iodide excess)
	Iodide deficiency
	Infiltrative disease (hemochromatosis, amyloidosis, scleroderma)
	Biosynthetic defect, hereditary
Secondary Hypothyroidism
	Pituitary macroadenoma
	Empty sella syndrome
	Infarction
	Infiltrative disease (e.g., sarcoidosis)
	Surgery or radiation-induced injury
PAS, para-aminosalicylic acid; PTU, propylthiouracil.

WORKUP (7,12,14,17, 18, 19, 20, 21, 22, 23, 24 and 25)

Screening for Hypothyroidism

The test of choice to screen for hypothyroidism is a serum TSH determination, the most sensitive and cost-effective of available tests. Modern TSH assays provide a very sensitive means of detecting hypothyroidism, often long before the patient becomes overtly symptomatic. Measurement of thyroid hormone levels is indicated if the TSH is elevated but not for screening because the test sensitivity is lower and the cost is no less.

Despite the ease and effectiveness of detection, considerable controversy remains regarding the value of adding a TSH determination to the periodic health examination. The frequency of hypothyroidism is low in men, and the impact of treatment on asymptomatic patients is unclear. Nonetheless, patients in subgroups with an increased prevalence of hypothyroidism might be reasonable candidates for screening, and for them, a TSH determination should at least be considered. These include women older than 50 years (especially if they are hyperlipidemic) and patients with goiter, Hashimoto thyroiditis (presence of antithyroid antibodies), recent radioiodine or external neck irradiation, or recent thyroid surgery. In addition, the prevalence of hypothyroidism is high among patients with autoimmune disorders, patients with mental dysfunction admitted to geriatric units, and women older than age 40 with such nonspecific complaints as fatigue. Universal early antenatal screening of pregnant women remains controversial, with available data showing no benefit from screening and treatment with regard to childhood cognitive function; current consensus guidelines do not endorse the practice.

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