Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

46.Introduction to Hypothyroidism

Lewis E. Braverman

Robert D. Utiger

Hypothyroidism is the most common clinical disorder of thyroid function. It is most often caused by some disorder of the thyroid gland that leads to a decrease in thyroidal production and secretion of thyroxine (T4) and triiodothyronine (T3), in which case it is referred to as primary or thyroidal hypothyroidism. Primary hypothyroidism is invariably accompanied by increased thyrotropin (TSH) secretion. Much less often hypothyroidism is caused by decreased thyroidal stimulation by TSH, which is referred to as central, secondary, or hypothyrotropic hypothyroidism. Central hypothyroidism may be caused by pituitary or hypothalamic disease, the latter causing deficiency of thyrotropin-releasing hormone (TRH). It is usually accompanied by low or inappropriately normal serum TSH concentrations, but a few patients have high serum TSH concentrations because they secrete TSH that is immunoreactive but biologically inactive. Although most of the daily production of T3 occurs in extrathyroidal tissue, and extrathyroidal T3 production is decreased and serum T3concentrations are low in patients with nonthyroidal illness, the decrease in T3 production in these patients is accompanied by few if any clinical manifestations of hypothyroidism (see section on Nonthyroidal Illness in Chapter 11). The rare patients with generalized resistance to thyroid hormone may have some residual signs of past hypothyroidism, but usually there are few if any symptoms or signs of hypothyroidism when the condition is recognized (see Chapter 81).

Hypothyroidism is sometimes referred to as myxedema, but the two terms are not interchangeable. Myxedema is the nonpitting edema caused by the accumulation of glycosaminoglycans in subcutaneous and other interstitial tissue that occurs in hypothyroid patients. It is most often present in long-standing or severe primary hypothyroidism (and is rarely seen today).

Primary hypothyroidism may result from diseases or treatments that destroy thyroid tissue or interfere with thyroid hormone biosynthesis (Table 46.1). Worldwide, iodine deficiency is the most common cause of hypothyroidism. In areas where iodine intake is adequate, the most common causes are chronic autoimmune thyroiditis, which occurs in both goitrous and atrophic forms, and radiation-induced hypothyroidism. The latter may be caused by radioactive iodine treatment of hyperthyroidism or external radiation therapy directed to the neck in patients with lymphoma or head and neck cancer. Although central hypothyroidism is rare, some of its causes (e.g., pituitary or hypothalamic tumors) may have disabling and even potentially fatal effects independent of the thyroid deficiency. For this reason, and because primary hypothyroidism may not be due to permanent thyroid destruction, an attempt should always be made to determine the cause of hypothyroidism in an individual patient.


Primary hypothyroidism

   Destruction of thyroid tissue

     Chronic autoimmune thyroiditis—atrophic and goitrous forms

     Radiation—131I therapy for thyrotoxicosis, external radiotherapy to the head and neck for nonthyroid malignant disease

     Subtotal and total thyroidectomy

     Infiltrative diseases of the thyroid (amyloidosis, scleroderma)

   Defective thyroid hormone biosynthesis

     Iodine deficiency

     Drugs with antithyroid actions—lithium, iodine, and iodine-containing drugs and radiographic contrast agents

     Congenital defects in thyroid hormone biosynthesis

     Thyroid dysgenesis

   Central hypothyroidism

     Pituitary disease

     Hypothalamic disease

   Transient hypothyroidism

     Silent (painless) thyroiditisa

     Subacute thyroiditis

     After withdrawal of thyroid hormone therapy in euthyroid patients

aIncluding postpartum thyroiditis.

The clinical manifestations of hypothyroidism are largely independent of its cause. It affects persons of all ages and both sexes, although the majority of patients are women, whatever the cause of the hypothyroidism. It may be overt or subclinical. The former is defined as high serum TSH concentrations and low serum free T4 concentrations, and the latter as high serum TSH and normal serum free T4 concentrations. Many but not all patients with overt hypothyroidism have some symptoms and signs of hypothyroidism, but the spectrum is broad; at one extreme are those patients who have no or very few symptoms and signs of hypothyroidism, and at the other extreme are those with myxedema coma (see Chapter 65) (1). Patients with subclinical hypothyroidism have few or no symptoms or signs of hypothyroidism (see Chapter 78).

The underlying problem in hypothyroidism is slowing of many physiologic processes, and the clinical manifestations reflect that slowing. Some of the more common symptoms and signs of hypothyroidism are listed in Tables 46.2 and 46.3 (2,3,4). These and other symptoms and signs are discussed in more detail in the chapters on the effects of hypothyroidism on different organ systems (see Chapters 52,53,54,55,56,57,58,59,60,61,62,63,64). None of them is a very sensitive or specific indicator of the presence of hypothyroidism (4,5). Indeed, the frequency of any individual symptom is not much higher in patients with overt hypothyroidism than in normal subjects (6). What is more important than the presence or absence of any particular symptom is the presence of multiple symptoms, particularly if of recent onset.






   Mental impairment


   Cold intolerance


   Dry skin

   Decreased perspiration

   Weight gain

   Decreased appetite


   Menstrual disturbances




   Slow movements

   Slow speech



   Dry skin

   Nonpitting edema (myxedema)


   Delayed relaxation of reflexes



Cause of Hypothyroidism

Diffuse or nodular goiter

Chronic autoimmune thyroiditis, Ingestion of antithyroid substances

 Iodine deficiency or excess


Pituitary or hypothalamic tumor

Visual impairment

Pituitary or hypothalamic tumor

Deficiency or excess of pituitary hormones other than TSH

Pituitary or hypothalamic tumor

From the clinical perspective, therefore, hypothyroidism is a syndrome manifested by a collection of symptoms and signs. They are influenced by the age of the patient (7), the rate at which the hypothyroidism developed, and the presence of other disorders. In very young infants, hypothyroidism can result in irreversible mental and physical retardation, unless treatment is initiated within weeks after birth, whereas in children and adults its effects, while they may be profound, are reversible. Older patients tend to have fewer symptoms and signs of hypothyroidism, and those that they do have tend to be less specific (8). In general, patients who develop hypothyroidism rapidly have more symptoms than those in whom it develops slowly. In some patients, particularly those with chronic autoimmune thyroiditis, hypothyroidism may remain subclinical for many years, probably even decades, before becoming overt, testimony both to the indolent nature of the underlying process and the ability of the compensatory increase in TSH secretion that occurs in all patients with any reduction in thyroid secretion to maintain near-normal thyroid hormone secretion if the thyroid gland is not seriously damaged.

We now have excellent tools to confirm the presence of hypothyroidism and to determine whether it is caused by thyroid or hypothalamic-pituitary disease in an individual patient (see Chapter 13). Determining its cause is less easy, but it is usually possible on the basis of history, physical examination, and measurements of thyroid autoantibodies in serum. T4, the major product of the thyroid, can be easily replaced, but it is important to understand that, as shown in Table 46.1, hypothyroidism is not always due to thyroid destruction, and that in such patients the proper treatment is not to provide T4 but to remedy the underlying disorder that led to decreased thyroid hormone synthesis, such as iodine deficiency or excess.


1. Staub J-J, Althaus BU, Engler H, et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral tissues. Am J Med 1992;92:621.

2. Billewicz WZ, Chapman RS, Crooks J, et al. Statistical methods applied to the diagnosis of hypothyroidism. Q J Med 1969;38: 255.

3. Oddie TH, Boyd CM, Fisher DA, et al. Incidence of signs and symptoms in thyroid disease. Med J Aust 1972;2:981.

4. Zulewski H, Muller B, Exer P, et al. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997;82:771.

5. Bemben DA, Hamm RM, Morgan L, et al: Thyroid disease in the elderly. Part 2. Predictability of subclinical hypothyroidism. J Fam Pract 1994;38:583.

6. Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms of hypothyroidism correlate with biochemical disease. J Gen Intern Med 1997;12:544.

7. Griffin JE. Hypothyroidism in the elderly. Am J Med Sci 1990; 299:334.

8. Doucet J, Trivalle C, Chassagne P, et al. Does age play a role in clinical presentation of hypothyroidism? J Am Geriatr Soc 1994; 42:984.