The thyroid gland, located in the anterior neck just below the cricoid cartilage, consists of 2 lobes connected by an isthmus. Follicular cells in the gland produce the 2 main thyroid hormones:

• Tetraiodothyronine (thyroxine, T4)
• Triiodothyronine (T3)

These hormones act on cells in virtually every body tissue by combining with nuclear receptors and altering expression of a wide range of gene products. Thyroid hormone is required for normal brain and somatic tissue development in the fetus and neonate, and, in people of all ages, regulates protein, carbohydrate, and fat metabolism.

T3 is the most active form in binding to the nuclear receptor; T4 has only minimal hormonal activity. However, T4 is much longer lasting and can be converted to T3 (in most tissues) and thus serves as a reservoir for T3. A 3rd form of thyroid hormone, reverse T3 (rT3), has no metabolic activity; levels of rT3 increase in certain diseases.

Additionally, parafollicular cells (C cells) secrete the hormone calcitonin, which is released in response to hypercalcemia and lowers serum calcium levels

Synthesis and Release of Thyroid Hormones

Synthesis of thyroid hormones requires iodine. Iodine, ingested in food and water as iodide, is actively concentrated by the thyroid and converted to organic iodine (organification) within follicular cells by thyroid peroxidase. The follicular cells surround a space filled with colloid, which consists of thyroglobulin, a glycoprotein containing tyrosine within its matrix. Tyrosine in contact with the membrane of the follicular cells is iodinated at 1 (monoiodotyrosine) or 2 (diiodotyrosine) sites and then coupled to produce the 2 forms of thyroid hormone.

• Diiodotyrosine + diiodotyrosine → T4
• Diiodotyrosine + monoiodotyrosine → T3

T3 and T4 remain incorporated in thyroglobulin within the follicle until the follicular cells take up thyroglobulin as colloid droplets. Once inside the thyroid follicular cells, T3 and T4 are cleaved from thyroglobulin.

Free T3 and T4 are then released into the bloodstream, where they are bound to serum proteins for transport. The primary transport protein is thyroxine-binding globulin (TBG), which has high affinity but low capacity for T3 and T4. TBG normally carries about 75% of bound thyroid hormones.

The other binding proteins are

• Thyroxine-binding prealbumin (transthyretin), which has high affinity but low capacity for T4
• Albumin, which has low affinity but high capacity for T3 and T4

About 0.3% of total serum T3 and 0.03% of total serum T4 are free and in equilibrium with bound hormones. Only free T3 and free T4 are available to act on the peripheral tissues.

All reactions necessary for the formation and release of T3 and T4 are controlled by thyroid-stimulating hormone (TSH), which is secreted by pituitary thyrotropic cells. TSH secretion is controlled by a negative feedback mechanism in the pituitary: Increased levels of free T4 and T3 inhibit TSH synthesis and secretion, whereas decreased levels increase TSH secretion. TSH secretion is also influenced by thyrotropin-releasing hormone (TRH), which is synthesized in the hypothalamus. The precise mechanisms regulating TRH synthesis and release are unclear, although negative feedback from thyroid hormones inhibits TRH synthesis.

Most circulating T3 is produced outside the thyroid by monodeiodination of T4. Only one fifth of circulating T3 is secreted directly by the thyroid.

Laboratory Testing of Thyroid Function

Thyroid-stimulating hormone (TSH) measurement

TSH measurement is the best means of determining thyroid dysfunction. Normal results essentially rule out hyperthyroidism or hypothyroidism, except in patients with central hypothyroidism due to disease in the hypothalamus or pituitary gland or in rare patients with pituitary resistance to thyroid hormone. Serum TSH can be falsely low in very sick people. The serum TSH level also defines the syndromes of subclinical hyperthyroidism (low serum TSH) and subclinical hypothyroidism (elevated serum TSH), both of which are characterized by normal serum T4, free T4, serum T3, and free T3 levels.

Results of Thyroid Function Tests in Various Clinical Situations

Thyroxine (T4) measurement

Total serum T4 is a measure of bound and free hormone. Changes in levels of thyroid hormone–binding serum proteins produce corresponding changes in total T4, even though levels of physiologically active free T4 are unchanged. Thus, a patient may be physiologically normal but have an abnormal total serum T4 level. Free T4 in the serum can be measured directly, avoiding the pitfalls of interpreting total T4 levels.

Free T4 index is a calculated value that corrects total T4 for the effects of varying amounts of thyroid hormone–binding serum proteins and thus gives an estimate of free T4 when total T4 is measured. The thyroid hormone–binding ratio or T4 resin uptake is used to estimate protein binding. Free T4 index is readily available and compares well with direct measurement of free T4.

Triiodothyronine (T3) measurement

Total serum T3 and free T3 can also be measured. Because T3 is tightly bound to TBG (although 10 times less so than T4), total serum T3 levels are influenced by alterations in serum TBG level and by drugs that affect binding to TBG. Free T3 levels in the serum are measured by the same direct and indirect methods (free T3 index) described for T4 and are used mainly for evaluating thyrotoxicosis.

Thyroxine-binding globulin (TBG)

TBG can be measured. It is increased in pregnancy, by estrogen therapy or oral contraceptive use, and in the acute phase of infectious hepatitis. TBG may also be increased by an X-linked abnormality. It is most commonly decreased by illnesses that reduce hepatic protein synthesis, use of anabolic steroids, and excessive corticosteroid use. Large doses of certain drugs, such as phenytoin and aspirin and their derivatives, displace T4 from its binding sites on TBG, which spuriously lowers total serum T4 levels.

Autoantibodies to thyroid peroxidase

Autoantibodies to thyroid peroxidase are present in almost all patients with Hashimoto thyroiditis (some of whom also have autoantibodies to thyroglobulin) and in most patients with Graves disease. These autoantibodies are markers of autoimmune disease but probably do not cause disease. However, an autoantibody directed against the thyroid-stimulating hormone receptor on the thyroid follicular cell is responsible for the hyperthyroidism in Graves disease. Antibodies against T4 and T3 may be found in patients with autoimmune thyroid disease and may affect T4 and T3 measurements but are rarely clinically significant.

Thyroglobulin

The thyroid is the only source of thyroglobulin, which is readily detectable in the serum of healthy people and is usually elevated in patients with nontoxic or toxic goiter. The principal use of serum thyroglobulin measurement is in evaluating patients after near-total or total thyroidectomy (with or without iodine-131 ablation) for differentiated thyroid cancer. Normal or elevated serum thyroglobulin values indicate the presence of residual normal or cancerous thyroid tissue in patients receiving TSH-suppressive doses of L-thyroxine or after withdrawal of L-thyroxine. However, thyroglobulin antibodies interfere with thyroglobulin measurement.

Screening for thyroid dysfunction

Screening every 5 years by measuring serum TSH is recommended for all men ≥ 65 and for all women ≥ 50. Screening is also recommended for all newborns and for pregnant women. For patients with risk factors for thyroid disease, the serum TSH should be checked more often. Screening for hypothyroidism is as cost effective as screening for hypertension, hypercholesterolemia, and breast cancer. This single test is highly sensitive and specific in diagnosing or excluding two prevalent and serious disorders (hypothyroidism and hyperthyroidism), both of which can be treated effectively. Because of the high incidence of hypothyroidism in older adults, screening on an annual basis is reasonable for those > age 70.

Radioactive Iodine Uptake and Imaging

Radioactive iodine uptake can be measured. A trace amount of radioiodine is given orally or intravenously; a scanner then detects the amount of radioiodine taken up by the thyroid. The preferred radioiodine isotope is iodine-123, which exposes the patient to minimal radiation (much less than iodine-131). Thyroid iodine-123 uptake varies widely with iodine ingestion and is low in patients exposed to excess iodine.

The test is valuable in the differential diagnosis of hyperthyroidism (high uptake in Graves disease, low uptake in thyroiditis). It may also help in the calculation of the dose of iodine-131 needed for treatment of hyperthyroidism.

Imaging using a scintillation camera can be done after radioisotope administration (radioiodine or technetium 99m pertechnetate) to produce a graphic representation of isotope uptake. Focal areas of increased (hot) or decreased (cold) uptake help distinguish areas of possible cancer (thyroid cancers exist in < 1% of hot nodules compared with 10 to 20% of cold nodules).

Hashimoto Thyroiditis

Hashimoto thyroiditis is believed to be the most common cause of primary hypothyroidism in North America. It is several times more prevalent among women. Incidence increases with age and in patients with chromosomal disorders, including Down syndrome, Turner syndrome, and Klinefelter syndrome. A family history of thyroid disorders is common.

Hashimoto thyroiditis, like Graves disease, is sometimes associated with other autoimmune disorders, including Addison disease (adrenal insufficiency), type 1 diabetes mellitus, hypoparathyroidism, vitiligo, premature graying of hair, pernicious anemia, connective tissue disorders (eg, rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome), celiac disease, and type 2 polyglandular deficiency syndrome (Schmidt syndrome—a combination of Addison disease with hypothyroidism secondary to Hashimoto thyroiditis and/or type 1 diabetes mellitus). There may be an increased incidence of thyroid tumors, rarely thyroid lymphoma. Pathologically, there is extensive infiltration of lymphocytes with lymphoid follicles and scarring.

Symptoms and Signs

Patients complain of painless enlargement of the thyroid or fullness in the throat. Examination reveals a nontender goiter that is smooth or nodular, firm, and more rubbery than the normal thyroid. Many patients present with symptoms of hypothyroidism, but some present with hyperthyroidism that may be due to thyroiditis.

Diagnosis

• Thyroxine (T4)
• Thyroid-stimulating hormone (TSH)
• Thyroid autoantibodies
• Thyroid ultrasonography

Testing consists of measuring T4, TSH, and thyroid autoantibodies. Early in the disease, T4 and TSH levels are normal and there are high levels of thyroid peroxidase antibodies and, less commonly, of antithyroglobulin antibodies.

Thyroid ultrasonography should be done if there are palpable nodules. Ultrasonography often reveals that the thyroid tissue has a heterogeneous, hypoechoic echotexture with septations that form hypoechoic micronodules.

Hypothyroidism  

Hypothyroidism occurs at any age but is particularly common among older adults, where it may present subtly and be difficult to recognize. Hypothyroidism may be

• Primary: Caused by disease in the thyroid
• Secondary: Caused by disease in the hypothalamus or pituitary

Primary hypothyroidism

Primary hypothyroidism is due to disease in the thyroid; thyroid-stimulating hormone (TSH) is increased. The most common cause is autoimmune. It usually results from Hashimoto thyroiditis and is often associated with a firm goiter or, later in the disease process, with a shrunken fibrotic thyroid with little or no function. The 2nd most common cause is post-therapeutic hypothyroidism, especially after radioactive iodine therapy or surgery for hyperthyroidism or goiter. Hypothyroidism during overtreatment with propylthiouracil, methimazole, and iodide abates after therapy is stopped.

Most patients with non-Hashimoto goiters are euthyroid or have hyperthyroidism, but goitrous hypothyroidism may occur in endemic goiter due to iodine deficiency. Iodine deficiency decreases thyroid hormonogenesis. In response, TSH is released, which causes the thyroid to enlarge and trap iodine avidly; thus, goiter results. If iodine deficiency is severe, the patient becomes hypothyroid, a rare occurrence in the United States since the advent of iodized salt.

Iodine deficiency can cause congenital hypothyroidism. In severely iodine-deficient regions worldwide, congenital hypothyroidism (previously termed endemic cretinism) is a major cause of intellectual disability.

Rare inherited enzymatic defects can alter the synthesis of thyroid hormone and cause goitrous hypothyroidism.

Hypothyroidism may occur in patients taking lithium, perhaps because lithium inhibits hormone release by the thyroid. Hypothyroidism may also occur in patients taking amiodarone or other iodine-containing drugs, in patients taking interferon-alfa, and in patients taking checkpoint inhibitors or some tyrosine kinase inhibitors for cancer. Hypothyroidism can result from radiation therapy for cancer of the larynx or Hodgkin lymphoma. The incidence of permanent hypothyroidism after radiation therapy is high, and thyroid function (through measurement of serum TSH) should be evaluated at 6- to 12-month intervals.

Secondary hypothyroidism

Secondary hypothyroidism occurs when the hypothalamus produces insufficient thyrotropin-releasing hormone (TRH) or the pituitary produces insufficient TSH. Sometimes, deficient TSH secretion due to deficient TRH secretion is termed tertiary hypothyroidism.

Subclinical hypothyroidism

Subclinical hypothyroidism is elevated serum TSH in patients with absent or minimal symptoms of hypothyroidism and normal serum levels of free thyroxine (T4).

Subclinical thyroid dysfunction is relatively common; it occurs in about 15% of older women and 10% of older men, particularly in those with underlying Hashimoto thyroiditis.

In patients with serum TSH > 10 mU/L, there is a high likelihood of progression to overt hypothyroidism with low serum levels of free T4 within the next 10 years. These patients are also more likely to have hypercholesterolemia and atherosclerosis. They should be treated with L-thyroxine, even if they are asymptomatic.

For patients with TSH levels between 4.5 and 10 mU/L, a trial of L-thyroxine is reasonable if symptoms of early hypothyroidism (eg, fatigue, depression) are present.

L-Thyroxine therapy is also indicated in pregnant women and in women who plan to become pregnant to avoid deleterious effects of hypothyroidism on the pregnancy and fetal development. Patients should have annual measurement of serum TSH and free T4 to assess progress of the condition if untreated or to adjust the L-thyroxine dosage.

Symptoms and Signs

Symptoms and signs of primary hypothyroidism are often subtle and insidious. Various organ systems may be affected.

• Metabolic manifestations: Cold intolerance, modest weight gain (due to fluid retention and decreased metabolism), hypothermia
• Neurologic manifestations: Forgetfulness, paresthesias of the hands and feet (often due to carpal tunnel syndrome caused by deposition of proteinaceous ground substance in the ligaments around the wrist and ankle); slowing of the relaxation phase of deep tendon reflexes
• Psychiatric manifestations: Personality changes, depression, dull facial expression, dementia or frank psychosis (myxedema madness)
• Dermatologic manifestations: Facial puffiness; myxedema; sparse, coarse and dry hair; coarse, dry, scaly and thick skin; carotenemia, particularly notable on the palms and soles (caused by deposition of carotene in the lipid-rich epidermal layers); macroglossia due to deposition of proteinaceous ground substance in the tongue
• Ocular manifestations: Periorbital swelling due to infiltration with the mucopolysaccharides hyaluronic acid and chondroitin sulfate, droopy eyelids because of decreased adrenergic drive
• Gastrointestinal manifestations: Constipation
• Gynecologic manifestations: Menorrhagia or secondary amenorrhea
• Cardiovascular manifestations: Slow heart rate (a decrease in both thyroid hormone and adrenergic stimulation causes bradycardia), enlarged heart on examination and imaging (partly because of dilation but chiefly because of pericardial effusion; pericardial effusions develop slowly and only rarely cause hemodynamic distress)
• Other manifestations: Pleural or abdominal effusions (pleural effusions develop slowly and only rarely cause respiratory or hemodynamic distress), hoarse voice, and slow speech

Myxedema in Hypothyroidism

Symptoms can differ significantly in older patients.

Although secondary hypothyroidism is uncommon, its causes often affect other endocrine organs controlled by the hypothalamic-pituitary axis. In a woman with hypothyroidism, indications of secondary hypothyroidism are a history of amenorrhea rather than menorrhagia and some suggestive differences on physical examination.

Secondary hypothyroidism is characterized by skin and hair that are dry but not very coarse, skin depigmentation, only minimal macroglossia, atrophic breasts, and low blood pressure. Also, the heart is small, and serous pericardial effusions do not occur. Hypoglycemia is common because of concomitant adrenal insufficiency or growth hormone deficiency.

Myxedema coma

Myxedema coma is a life-threatening complication of hypothyroidism, usually occurring in patients with a long history of hypothyroidism. Its characteristics include coma with extreme hypothermia (temperature 24° to 32.2° C), areflexia, seizures, and respiratory depression with carbon dioxide retention. Severe hypothermia may be missed unless low-reading thermometers are used. Rapid diagnosis based on clinical judgment, history, and physical examination is imperative, because death is likely without rapid treatment. Precipitating factors include illness, infection, trauma, drugs that suppress the central nervous system, and exposure to cold.

Diagnosis

• Thyroid-stimulating hormone (TSH)
• Free thyroxine (T4)

Serum thyroid-stimulating hormone measurement is the most sensitive test for diagnosing hypothyroidism. In primary hypothyroidism, there is no feedback inhibition of the intact pituitary, and serum TSH is always elevated, whereas serum free T4 is low. In secondary hypothyroidism, free T4 and serum TSH are low (sometimes TSH is normal but with decreased bioactivity).

Many patients with primary hypothyroidism have normal circulating levels of triiodothyronine (T3), probably caused by sustained TSH stimulation of the failing thyroid, resulting in preferential synthesis and secretion of biologically active T3. Therefore, serum T3 is not sensitive for hypothyroidism.

Anemia is often present, usually normocytic-normochromic and of unknown etiology, but it may be hypochromic because of menorrhagia and sometimes macrocytic because of associated pernicious anemia or decreased absorption of folate. Anemia is rarely severe (hemoglobin usually > 9 g/dL or 90 g/L). As the hypometabolic state is corrected, anemia subsides, sometimes requiring 6 to 9 months.

Serum cholesterol is usually high in primary hypothyroidism but less so in secondary hypothyroidism.

In addition to primary and secondary hypothyroidism, other conditions may cause decreased levels of total T4, such as euthyroid sick syndrome and serum thyroxine-binding globulin (TBG) deficiency.

Screening

Screening for hypothyroidism is warranted in select populations (eg, older adults), in which it is relatively more prevalent, especially because its manifestations can be subtle. Screening is done by measuring TSH levels.