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Authors: Roberto Toni, M.D.,Ph.D., Anastassios G. Pittas, M.D.
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1. Goal

To review thyroid physiology, understand the evaluation of thyroid function and structure and learn the pathophysiology, symptoms/signs, and treatment of hypothyroidism

2. Learning Objectives

  • To review thyroid hormone physiology including thyroid hormone synthesis, storage, release and feedback control of thyroid function
  • To learn that the most important thyroid function test is a measurement of TSH
  • To learn that nuclear imaging is done to assess thyroid function and ultrasound to assess structure
  • To appreciate that hypothyroidism is a very common condition
  • To learn the symptoms and signs of hypothyroidism and to appreciate that they are non-specific
  • To learn the causes of hypothyroidism and the approach to the differential diagnosis
  • To learn the pathophysiology of the most common causes of hypothyroidism which include Hashimoto's thyroiditis and subacute thyroiditis and the importance of differentiating between the two
  • To learn a rational approach to the evaluation of hypothyroidism
  • To learn the treatment of hypothyroidism (replacement with L-thyroxine)
  • To appreciate that even mild hypothyroidism during pregnancy may have adverse effects on fetal development

3. Review: Thyroid Hormone Physiology

The thyroid gland synthesizes and releases thyroid hormones which have diverse physiologic effects including cardiac, pulmonary, hematopoietic, gastrointestinal, skeletal, neuromuscular and endocrine effects (growth, reproduction, energy metabolism). The synthesis and release of thyroid hormones (see figure 1) involves the following steps: The thyroid follicular cell takes up iodine via a Na-Iodine symporter and traps it intracellularly as follows: Iodine is oxidized and incorporated into tyrosyl residues of thyroglobulin to form monoidotyrosine (MIT) and diiodotyrosine (DIT). Thyroglobulin, a large glycoprotein with multiple tyrosyl molecules, is the storage form of thyroid hormone and is found in the follicular lumen of the thyroid cell. Coupling of iodotyrosine molecules within thyroglobulin forms the thyroid hormones T3 (triiodothyronine) and T4 (tetraiodothyronine). Proteolysis of the thyroglobulin molecule releases MIT, DIT, T3 and T4. MIT and DIT are deiodinated and the liberated iodine is reused. T4, and to a much lesser extent T3, is released from the thyroid. Thyroid hormone synthesis is mediated by an enzyme called thyroperoxidase (TPO) which mediates both the oxidation of iodine and their incorporation into tyrosyl residues. As we will see later, this enzyme is the target in Hashimoto's (autoimmune thyroiditis).

Figure 1. Thyroid hormone synthesis, storage and release
Figure 1.  Thyroid hormone synthesis

Thyroid hormones are transported in serum bound to carrier proteins. The 0.04% of T4 and 0.4% of T3 that is free is the biologically active form that is available for cellular uptake and for binding to thyroid receptors (TR). T3 has a much higher affinity for the TR than T4. Therefore, T3 is considered the active form of thyroid hormone. In fact, the body regulates thyroid activity by converting T4 to T3 by enzymes called deiodinases. Free thyroid hormone is transported through the cell membrane by a specific carrier and binds to a TR in the nucleus. TR belongs to the nuclear receptor superfamily that also includes the receptors for retinoids, vitamin D and fatty acids. TR binds to DNA regardless of whether it is occupied by thyroid hormone or not. However, the biological effects by the unoccupied versus the occupied receptor are very different. In general, binding of TR alone to DNA leads to repression of transcription, whereas binding of the T3-TR complex activates transcription.

Thyroid function is regulated by the hypothalamic-pituitary-thyroid axis, shown in Figure 2. Synthesis and release of T4 and T3 are positively regulated by TSH which, in turn, is positively regulated by TRH. Note the negative feedback by thyroid hormone on TSH secretion by the pituitary (as well as on TRH secretion by the hypothalamus).

Figure 2. Hypothalamic-pituitary-thyroid feedback system for control of thyroid hormone secretion
Figure 2.  Hypothalamic-pituitary-thyroid feedback system for control of thyroid hormone secretion

4. Evaluation of Thyroid Function and Structure

4.1. Serum Thyroid Hormones (T4 and T3)

Thyroid hormones are transported in serum bound to carrier proteins. The 0.04% of T4 and 0.4% of T3 that is free is the biologically active form. Measurement of thyroid hormone levels is done as follows:

  • Serum Total Thyroxin (T4, normal value 4-12 microg/dL). This test measures both free and bound T4. In healthy patients (without abnormalities in thyroid binding proteins), total T4 reflects thyroid hormone activity.
  • Serum Total Triiodothyronine (T3, normal values 80-200 ng/dL). This test measures both free and bound T3.
  • Thyroid Hormone Transport. Thyroid Binding Globulin (TBG) is the major thyroid hormone binding proteins. Other proteins with thyroid hormone binding capacity include transthyretin (thyroxine-binding prealbumin) and albumin. Alterations in thyroid binding proteins (especially TBG) will markedly change the total T4 and total T3 levels. The level of TBG in the blood is not routinely measured (this is a common mistake in clinical practice). Factors that influence thyroid hormone binding and therefore will alter total thyroid hormone levels include:
    • Increased TBG (will increase total thyroid hormone levels)
      1. Congenital (rare)
      2. Estrogen (oral contraceptives, pregnancy, estrogen replacement therapy, feminizing tumors)
      3. Hypothyroidism (increase in available binding sites on TBG
      4. Acute hepatitis (release of TBG from liver)
      5. Intermittent porphyria
      6. Drugs (heroin, methadone, 5-FU)
    • Decreased TBG (will decrease total thyroid hormone levels)
      1. Congenital (rare)
      2. Androgens (testosterone, DHEA-S, anabolic steroids, masculinizing tumors)
      3. Liver failure (decreased synthesis by liver), nephrotic syndrome (loss in urine), or malnutrition
      4. Hyperthyroidism (decrease in available binding sites on TBG)
      5. Sick patients with a variety of acute and chronic illnesses
      6. Drugs (glucocorticoids)
  • Free Thyroid Hormone As the free thyroid hormone is the biologically active, it is important that a measurement of free thyroid levels be done. The proportion of biologically active (free) thyroid hormone can be measured by dialysis (free hormone passes through dialysis membrane while the bound does not). This technique, however, is not widely available and is not commonly used. Generally, most laboratories report an estimate of free T4 which is a calculated Free T4 Index (FT4 I) which is the product of the total T4 and Total Hormone Binding Ratio (THBR). THBR is the new nomenclature for the T3 resin uptake (T3RU) test. THBR seems to be one of the most difficult to understand laboratory tests for the non-endocrinologist (student or physician). The THBR value is inversely related to the serum thyroid hormone binding protein sites available to bind thyroid hormone. For example, THBR is low in the setting of a large number of free binding sites (i.e. excess of thyroid binding proteins during estrogen therapy, reduction in serum T4 due to hypothyroidism). Thus, using the equation:
    T4 x THBR = FT4I

    The estimate of free T4, (FT4I) is adjusted upwards if thyroid binding is low or downward if thyroid binding is high. By using the THBR value, which falls between 0.8 to 1.2, the adjusted free FT4 I has the same range as the total T4. In the majority of healthy patients in the ambulatory setting, the FT4I provides a reliable index of the true free thyroid levels and therefore, the patient's thyroid status. When thyroid hormone binding levels are very high or very low, the estimated FT4I may not accurately reflect free T4 levels.

4.2. Serum TSH (Thyroid Stimulating Hormone)

TSH measurement is one of the most important tools in the diagnosis of thyroid dysfunction. As shown in figure 2, TSH positively regulates thyroid hormone synthesis and release while a a negative feedback exists by thyroid hormone on TSH secretion by the pituitary. The negative feedback relationship between TSH and serum free thyroid hormone is log-linear, namely, small changes in serum free thyroid levels result in substantial changes in the TSH concentration. This concept is very important during biochemical evaluation of thyroid function as the TSH becomes the only test that can detect small changes of thyroid hormone excess or deficiency.

Currently available third generation TSH assays that utilize a sensitive immunochemiluminescent (ICMA) detection system have a detection limit of 0.01 (normal range 0.3-4.2 mU/L).

Serum TSH in patients with primary hyperthyroidism (which accounts for 99.9% of the cases of hyperthyroidism) is low. A very low value (<0.01) is diagnostic of hyperthyroidism while a low value (0.01-0.1) suggests hyperthyroidism. Exceptions include conditions that primarily affect the hypothalamus/pituitary.

Serum TSH is invariably increased in patients with primary hypothyroidism (which accounts for 99% of cases of hypothyroidism) and is one of the most specific tests in medicine; virtually nothing else raises the serum TSH.

Serum TSH is the best SCREENING test for the diagnosis of hypothyroidism or hyperthyroidism in healthy ambulatory individuals. It is the initial test done to assess thyroid function and the only test needed if it is normal. However, if hypothalamic/pituitary disease is suspected or significant alterations in binding proteins are expected, then a measure of free T4 (index or direct assay) is needed together with TSH.

Table 1. Examples of Thyroid Function Tests in various thyroid conditions
CLINICAL CONDITION Total T4 THBR FT4I TSH
Euthyroid, Normal T4binding proteins Normal Normal Normal Normal
Euthyroid, High T4binding proteinsa Normal Normal
Euthyroid, Low T4binding proteinsb Normal Normal
Euthyroid, Normal T4binding proteins, Drug displacing T4 from binding proteinsc
or
Normal

or
Normal
Normal
Hypothyroid, Normal T4binding proteins
Hyperthyroid, Normal T4binding proteins
  • a Clinical conditions associated with elevation in thyroid hormone binding proteins include active hepatitis, pregnancy, drugs (estrogen, raloxifene, tamoxifen, 5-fluorouracil, perphenazine, clofibrate, heroin and methadone), acute intermittent porphyria and hereditary TBG excess.
  • b Clinical conditions associated with reduction in thyroid hormone binding proteins include cirrhosis, nephrotic syndrome, protein losing enteropathies, malnutrition, severe illness, drugs (androgens, glucocorticoids), and hereditary TBG deficiency.
  • c Drugs that can cause displacement of T4 bound to TBG reducing the total T4 level but maintaining a normal free T4 level include salicylates, high dose furosemide with renal failure, certain non-steroidal anti-inflammatory agents (fenclofenac and mefenamic acid), certain anticonvulsants (phenytoin and carbamazepine), and heparin induced elevation in free fatty acids.

4.3. Serum Thyroglobulin (Tg)

Thyroglobulin, a large glycoprotein, is the storage form of thyroid hormone and is found in the follicular lumen of the thyroid cell. Small amounts of Tg continuously leak into the circulation. Serum Tg reflects the mass and function of thyroid tissue (including well-differentiated thyroid cancer). Its primary clinical use is as a tumor marker in patients with thyroid cancer to detect recurrent disease and evaluate efficacy of treatment after thyroidectomy and radioactive iodine. Its clinical value for evaluating thyroid function is limited. However, the demonstration of suppressed serum Tg levels can be useful in differentiating factitious thyrotoxicosis (from exogenous thyroid hormone ingestion) from endogenous hyperthyroidism

4.4. Imaging of Thyroid

4.4.1. Nuclear Imaging of Thyroid

Radionuclide imaging of the thyroid gland provides primarily functional and secondarily structural information about the thyroid gland. It can be very helpful in the differential diagnosis of hyperthyroidism. Radioactive iodine (I-123), administered orally, is often used as the radioisotope and a scan (image) of the thyroid is obtained 4 or 24 hours later. I-123 is actively accumulated by the thyroid follicular cell and covalently incorporated into thyroglobulin (trapped and organified). Given its physiologic behavior, I-123 is the ideal radionuclide agent for thyroid imaging. Alternatively, Technetium-99m pertechnetate (Tc-99m) can be administered intravenously and images are obtained 30-60 minutes later. Although Tc-99m will be taken up by the thyroid follicular cells, it is not incorporated into thyroglobulin and therefore does not absolutely mimic the biological function of iodine. Because Tc-99m scans are easier, faster, more available, and less expensive to perform, they are commonly used instead of I-123 scans. However, if the results of the Tc-99m scan do not match the clinical picture, an I-123 scan should be performed.

The radiotracer uptake is increased whenever the thyroid is under increased stimulus, e.g., a raised serum TSH, stimulating antibody of Graves' disease, or when the thyroid becomes autonomous ("hot" nodule or toxic multinodular goiter). A decreased uptake occurs when there is little or no thyroid stimulus (e.g. decreased TSH in hypopituitarism, or exogenous thyroid hormone administration), when thyroid cells are damaged so that the uptake mechanism is defective (e.g. subacute thyroiditis, chronic destructive Hashimoto's thyroiditis), or when excess iodine "swamps" the radioactive tracer. Although thyroid functional scans are helpful in the differential diagnosis of hyperthyroidism and in determining the function of a thyroid nodule, they are not helpful in the diagnosis of hypothyroidism and should not be used for this indication. The appearance of the thyroid scan and uptake for the most common causes of thyrotoxicosis can be found in Table 3 of the lecture Hyperthyroidism. Nuclear thyroid imaging is also used occasionally to determine whether a thyroid nodule is functional or not.. Nodules that concentrate radioactivity are called functioning and may be "warm" (same activity as the adjacent thyroid tissue) or "hot" (all activity is located in the nodule = hyperfunctioning). The nonfunctioning nodules are called "cool" or "cold", depending on the concentration of activity within the nodule as compared to the rest of the thyroid. The scan cannot determine if the nodule is malignant as most (>95%) thyroid nodules are "cool" or "cold". The vast majority (>90%) of "cool" or "cold" nodules are not cancer (see lecture on goiter and thyroid cancer).

4.4.2. Other Imaging of Thyroid

Ultrasound, CT and MRI are structural imaging modalities that provide no functional information about the thyroid gland and they have NO role in the initial evaluation of thyroid dysfunction. Ultrasound is the imaging modality of choice for evaluation of thyroid structure (e.g. evaluation of thyroid nodules). CT or MRI may be used to visualize a large substernal goiter and to evaluate tracheal compression

5. Hypothyroidism

5.1. Epidemiology/Pathophysiology

The incidence of hypothyroidism varies based on sex, age and geographic/environmental factors (most important being dietary iodide), but over 5-10% of individuals over 65 may have hypothyroidism. Hypothyroidism can occur as a result of a defect within the thyroid gland itself (primary hypothyroidism) or from a deficiency of TSH secretion (secondary hypothyroidism) or TRH secretion (tertiary or hypothalamic hypothyroidism). Thyroid insufficiency can also arise from peripheral tissue resistance to thyroid hormone.

5.1.1. Primary Hypothyroidism

Primary hypothyroidism is due to defect within the thyroid gland. This is by far the most common cause accounting for 98% of cases of hypothyroidism.

5.1.1.1. Chronic Thyroiditis (Hashimoto's)

Chronic thyroiditisis almost always due to Hashimoto's thyroiditis which is the most common cause of hypothyroidism. The etiology of Hashimoto's thyroiditis is autoimmune destruction of the thyroid gland. Similar to other autoimmune conditions, Hashimoto's is more common in women with age. There is a strong familial component. Thyroid destruction is irreversible and slowly progressive. Thyroid antibodies (anti-thyroglobulin and/or anti-TPO antibodies) are present in the majority of patients. Autoimmune thyroiditis may coexist with other autoimmune disease such as pernicious anemia, rheumatoid arthritis, and diabetes mellitus. "Burnt out" Graves' disease also belongs in this category.

5.1.1.2. Subacute Thyroiditis

Subacute thyroiditis (granulomatous, lymphocytic or postpartum thyroiditis) is due to inflammation of the thyroid gland (see lecture on hyperthyroidism). Subacute thyroiditis has distinct clinical phases: there is an initial period of hyperthyroidism followed by a period of hypothyroidism from transient reversible destruction of the thyroid gland with eventual return to euthyroidism. Subacute thyroiditis is usually transient in 90% of patients but it can lead to permanent hypothyroidism, especially the lymphocytic or postpartum type of subacute thyroiditis which are associated with autoimmunity. As the hypothyroid phase of subacute thyroiditis is transient, it is important not to erroneously diagnose these patients with Hashimoto's and commit them to life-long thyroid hormone replacement therapy.

5.1.1.3. Iatrogenic

Post ablative following radioactive iodine administration or after thyroidectomy.

5.1.1.4. Drugs

Lithium, amiodarone (~40% iodine), high intake of iodine such as in seaweed or algae tablets from health food stores. Frequently an associated autoimmune thyroiditis is present in patients who become hypothyroid while taking these medications.

5.1.1.5. Iodide Deficiency

Iodide deficiency is a problem in many less well-developed countries. Goiter is common in these areas; some children develop cretinism.

5.1.1.6. Dyshormonogenesis

Enzymatic defects in thyroid hormone biosynthesis lead to poor hormone secretion and development of goiter. This is a rare cause of hypothyroidism, especially in the adult patient. Failure of the thyroid gland to descend during embryogenenesis may also cause congenital hypothyroidism.

5.1.1.7. Primary and Metastatic Tumor to the Thyroid (rare)

5.1.2. Secondary Hypothyroidism

In adults, it is almost always due to pituitary disease. In this case, TSH secreted by the pituitary may not be as biologically active, but it is picked up by the assay. That explains the finding that TSH is "inappropriately normal" in cases of secondary hypothyroidism. These patients often have other associated pituitary dysfunction.

Selective TSH deficiency is a very rare genetic cause of newborn hypothyroidism. It may also be seen in adults due to autoimmunity against thyrotrophs (cells that produce TSH).

5.1.3. Tertiary Hypothyroidism

Tertiary Hypothyroidism is due to hypothalamic disease (e.g. sarcoidosis, tumors, radiation). See lecture on Pituitary Insufficiency.

5.1.4. Resistance to Thyroid Hormone

Peripheral Resistance to Thyroid Hormone is extremely uncommon. Resistance is due to genetic defects in the thyroid hormone nuclear receptor resulting in abnormal binding and defective gene transcription. Levels of circulating thyroid hormone are elevated, which suggests that TR defect are associated with variable degrees of intracellular resistance to the action of thyroid hormone, partially compensated by excess hormone production.

5.2. Clinical Findings of Hypothyroidism

The most common features of hypothyroidism include fatigue, dry skin, cold intolerance, constipation, menstrual irregularities and possibly weight gain.

5.2.1. Skin and Appendages

Thyroid deficiency results in dry, rough epidermis. Non-pitting puffiness is due primarily to the accumulation of a mixture of mucopolysaccharides, hyaluronic acid and chondroitin sulphate, which are highly hydrophilic and accumulate water (in the lower extremities, this swelling is called myxedema). The skin appears pale and waxy due to vasoconstriction, increase in carotene concentration and anemia. Coarse dry hair and hair loss especially from the temporal aspect of the eyebrows. Decreased activity of sebaceous glands contributes to the dry skin.

5.2.2. Ocular manifestations

Baggy swelling of upper and lower eyelids.

5.2.3. Cardiovascular

Bradycardia, impaired muscular contraction and decreased cardiac output are seen. Cardiomegaly and pericardial effusion may be present. Effusion is the result of increased capillary permeability and is rich in protein and cholesterol. Pleural and peritoneal effusions also may be encountered. Angina may occur due to coronary artery disease upon initiation of thyroid replacement. ECG may show low voltage (P, QRS, T, isoelectric S-T). T may be inverted. Incomplete right bundle branch block common. AST, ALT, LDH, CPK may be elevated reflecting diminished catabolism and probably increased cellular "leakage" of the enzymes. Total and LDL cholesterol are elevated, probably reflecting diminished catabolism. There is evidence to suggest that incidence of coronary atherosclerosis is elevated in hypothyroidism.

5.2.4. Pulmonary

Dyspnea is common and respiratory failure may occur in myxedema coma (see below).

5.2.5. Ear, Nose, Throat

Partial deafness may be seen, due to increased mucopolysaccharides in the middle ear. Nasal obstruction and discharge for the same reason. Husky voice due to infiltration, but not paralysis of vocal cords. Enlarged tongue may also contribute to garbled voice and sleep apnea/snoring.

5.2.6. Gastrointestinal

Appetite is reduced. Modest weight gain may be seen due to water retention. Intestinal peristalsis is reduced. Abdominal distention, flatulence, and constipation common. Megacolon (uncommon) with signs of paralytic ileus. Malabsorption syndrome may be seen occasionally. Atrophic gastritis common, resulting in achlorhydria (50% of patients). B12 absorption decreases and pernicious anemia is present in 12% of patients. Parietal antibodies increased in 1/3 of patients.

5.2.7. Nervous System

Thyroid hormone is essential in nervous tissue development. Children born hypothyroid suffer from severe brain damage (cretinism). The earlier the initiation of treatment, the better the results for normal intellectual development. Decreased concentration, lethargy and coma may be seen in adults. Sedatives (morphine, barbiturates, etc.) may precipitate C02 narcosis and coma. Carpal tunnel syndrome may be seen. Reflexes are characteristically slow (relaxation phase) due to decreased muscle function.

5.2.8. Muscles

Stiffness, aching, cramps very common. Enzymes CPK and SGOT may be elevated.

5.2.9. Skeleton

T4 and growth hormone act synergistically to promote skeletal maturation. Lack of thyroid hormone in childhood results in stippled epiphyses (enichyseal dysgenesis). Alkaline phosphatase is decreased in hypothyroid children, as compared to normal. Adults have symptoms reminiscent of degenerative arthritis.

5.2.10. Anemia

There are various types of anemia, most common is mild normochromic, normocytic anemia. Microcytic (from iron deficiency due to impaired intestinal absorption) or macrocytic (B12 or folic acid deficiency) due to concomitant pernicious anemia or malabsorption.

5.2.11. Renal and Electrolytes

Glomerular filtration rate, renal plasma flow, and tubular reabsorption are reduced, but creatinine and BUN are normal. Water excretion is impaired and fluid administration intravenously should be carefully monitored as it may result in water intoxication in patients with myxedema. Na can be decreased in serum and gives rise to a condition similar to that found with the syndrome of inappropriate secretion of ADH (SIADH). Total body water may be increased due to mucopolysaccharide retention of H20.

5.2.12. Myxedema Coma

Myxedema coma (decompensated hypothyroidism) is the end stage of severe long-standing hypothyroidism, in which mental obtundation is profound. This is one of the few endocrine emergencies as the mortality is over 50%. This state often affects the elderly patient, occurs most commonly during the winter, and is usually accompanied by a subnormal temperature. Bradycardia and hypotension are present.

Predisposing factors are always present and include cold, infection, trauma, and CNS depressants. Alveolar hypoventilation leading to C02 retention and narcosis, dilutional hyponatremia resembling inappropriate ADH secretion are common. The clinical diagnosis is often difficult. Elderly patients with various illnesses may resemble patients with myxedema and, after brain stem infarction, they may become comatose and hypothermic. The diagnosis should be made on clinical grounds and therapy initiated without awaiting the results of thyroid function tests.

5.3. Laboratory Evaluation of Hypothyroidism

Hypothyroidism may be suspected by symptoms and signs, but the diagnosis needs to be confirmed biochemically.

  • Free T4 levels are low, T3 levels may within normal limits. TSH is raised in primary hypothyroidism which is the most common cause of hypothyroidism. If TSH is not elevated, it is important to look for pituitary or hypothalamic disease. Table 2 describes thyroid function tests in hypothyroidism and figure 3 shows how testing is applied in clinical practice.
  • In older individuals, biochemical screening for hypothyroidism with a single TSH is recommended.
  • Thyroid autoantibodies suggest Hashimoto's thyroiditis
  • LDL may be elevated
Table 2. Thyroid function tests in hypothyroidism
T4 level T3 Level TSH Antibodies
Primary-Hashimoto's Low Normal or Low High Anti-TPO positive in about 90% of patients
Anti-Tg positive in about 90% of patients
Primary-Subacute Low Normal or Low High
Secondary Low Normal or Low Low or "normal"
Tertiary Low Normal or Low Low or "normal"
Figure 3. Evaluation of suspected hypothyroidism in clinical practice
Figure 3.  Evaluation of suspected hypothyroidism in clinical practice

5.4. Therapy of Hypothyroidism

The treatment of hypothyroidism is oral thyroxine (T4).

For primary hypothyroidism the starting dose is usually 25 micrograms T4 and increase gradually to 100-150 mcg/day, especially in the elderly and in patients with underlying coronary artery disease. In young patients, a higher dose (1.6 microg/Kg) may be used as the initial dose. Treatment with thyroid hormone may precipitate adrenal crisis in a patient with primary adrenal insufficiency. Therefore, primary adrenal insufficiency may need to be ruled out (with a cortrosyn - synthetic ACTH - stimulation test) prior to initiating thyroid hormone replacement in a patient with autoimmune hypothyroidism. The TSH level is used as a marker for euthyroidism; TSH within the normal range is the goal of treatment.

In secondary hypothyroidism, thyroid hormone replacement is given as above. However, because of the possibility of coexistent adrenal insufficiency (due to a pituitary or hypothalamic defect that affects ACTH secretion), glucocorticoids should be co-administered or a cortrosyn stimulation test be performed to rule out adrenal insufficiency.

If treatment is initiated for the hypothyroid phase of subacute thyroiditis, treatment should be withdrawn after a few months, as this condition is reversible.

Treatment for myxedema includes supportive therapy (IV fluids with glucose, support of respiratory function, correction of hypothermia by rewarming), intravenous T4 (bolus of T4 100-500 micrograms followed by 50-75 micrograms daily until the patient responds), "stress dose glucocorticoids" and treatment of the underlying precipitating factor. Patients usually respond in 24 hours, but mortality is high.

6. Special Cases of Hypothyroidism

6.1. Congenital Hypothyroidism in Neonates

Congenital hypothyroidism is caused by insufficient circulating thyroid hormone at birth or shortly thereafter. Untreated, it results in irreversible damage to the central nervous system and developmental defects. Its most severe form is cretinism which is characterized by goiter, mental retardation and a variety of developmental defects. Congenital hypothyroidism occurs in 1:3500 births. Because of the lack of conspicuous clinical features at birth, the clinical diagnosis of congenital hypothyroidism is seldom made in time to prevent mental retardation. Congenital hypothyroidism is preventable as infants treated with L-thyroxine before the appearance of clinical features should develop normally.

6.2. Unrecognized Hypothyroidism during Pregnancy and its Effects of Fetal Development

Maternal hypothyroidism during pregnancy may lead to adverse fetal outcomes. Children born to women who had unrecognized or inadequately treated hypothyroidism during pregnancy may have a lower IQ as adolescents. It is controversial whether all pregnant women should be screened for hypothyroidism. However, women with known hypothyroidism prior to pregnancy should have their dose of levothyroxine adjusted to maintain normal thyroid levels before conception and during pregnancy.

7. References

  • Pittas AG and Lee SL. Evaluation of thyroid function in Hall JE, Nieman L, and Nieman L (editors), Handbook of Diagnostic Endocrinology. Humana Press, 2003