Figure 24-8 A patient with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one of the features of this disorder. In Graves

disease, one of the most important causes of hyperthyroidism, accumulation of loose connective tissue behind the eyeballs also adds to the protuberant appearance of the eyes.

TABLE 24-3-- Causes of Hypothyroidism

Primary

Developmental (thyroid dysgenesis: PAX-8, TTF-2, TSH-receptor mutations)

Thyroid hormone resistance syndrome (TRb mutations)

Postablative

••Surgery, radioiodine therapy, or external radiation

Autoimmune hypothyroidism

••Hashimoto thyroiditis *

Iodine deficiency *

Drugs (lithium, iodides, p-aminosalicylic acid) *

Congenital biosynthetic defect (dyshormonogenetic goiter) *

Secondary

Pituitary failure

Tertiary

Hypothalamic failure (rare)

*Associated with enlargement of thyroid ("goitrous hypothyroidism"). Hashimoto thyroiditis and postablative hypothroidism account for the majority of cases.

exogenous irradiation, such as external radiation therapy to the neck.

Autoimmune hypothyroidism is the most common cause of goitrous hypothyroidism in iodine-sufficient areas of the world. The vast majority of cases of autoimmune hypothyroidism are

due to Hashimoto thyroiditis. Circulating autoantibodies, including anti-TSH receptor autoantibodies, are commonly found in Hashimoto thyroiditis. Some patients with hypothyroidism

have circulating anti-TSH antibodies, but they usually do not have the goitrous enlargement or lymphocytic infiltrate characteristic of Hashimoto thyroiditis. In the past, many of these

patients were classified as having primary "idiopathic" hypothyroidism, but the disease is now recognized as a type of autoimmune disorder of the thyroid, occurring either in isolation or

in conjunction with other autoimmune endocrine manifestations.

Drugs given intentionally to decrease thyroid secretion (e.g., methimazole and propylthiouracil) can cause hypothyroidism, as can agents used to treat nonthyroid conditions (e.g.,

lithium, p-aminosalicylic acid).

Inborn errors of thyroid metabolism are an uncommon cause of goitrous hypothyroidism (dyshormonogenetic goiter). Any one of the multiple steps leading to thyroid hormone synthesis

may be deficient: (1) iodide transport defect, (2) organification defect, (3) dehalogenase defect, and (4) iodotyrosine coupling defect. Organification of iodine involves binding of

oxidized iodide with tyrosyl residues in thyroglobulin, and this process is deficient in patients with Pendred syndrome, wherein goitrous hypothyroidism is accompanied by sensorineural

deafness.

Thyroid hormone resistance syndrome is a rare autosomal-dominant disorder caused by inherited mutations in the thyroid hormone receptor (TR), which abolish the ability of the

receptor to bind thyroid hormones.[11] Patients demonstrate a generalized resistance to thyroid hormone, despite high circulating levels of T3 and T4 . Since the pituitary is also resistant

to feedback from thyroid hormones, TSH levels tend to be high as well. In rare instances, there may be complete absence of thyroid parenchyma (thyroid agenesis), or the gland may be

greatly reduced in size (thyroid hypoplasia). Mutations in the TSH receptor are a newly recognized cause of congenital hypothyroidism associated with a hypoplastic thyroid gland.[12]

Recently, mutations in two transcription factors that are expressed in the developing thyroid and regulate follicular differentiation—thyroid transcription factor-2 (TTF-2)[13] and Paired

Homeobox-8 (PAX-8) [14] —have been reported in patients with thyroid agenesis. Thyroid agenesis caused by TTF-2 mutations is usually associated with a cleft palate.

Secondary hypothyroidism is caused by TSH deficiency, and tertiary (central) hypothyroidism is caused by TRH deficiency. Secondary hypothyroidism can result from any of the causes

of hypopituitarism. Frequently, the cause is a pituitary tumor; other causes include postpartum pituitary necrosis, trauma, and nonpituitary tumors, as was previously discussed. Tertiary

(central) hypothyroidism can be caused by any disorder that damages the hypothalamus or interferes with hypothalamic-pituitary portal blood flow, thereby preventing delivery of TRH

to the pituitary. This can result from hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases. Classic clinical manifestations of hypothyroidism include

cretinism and myxedema.

CRETINISM

Cretinism refers to hypothyroidism that develops in infancy or early childhood. The term cretin was derived from the French chrétien, meaning Christian or Christlike, and was applied

to these unfortunates because they were considered to be so mentally retarded as to be incapable of sinning. In the past, this disorder occurred fairly commonly in areas of the world

where dietary iodine deficiency is endemic, such as the Himalayas, inland China, Africa, and other mountainous areas. It has become much less frequent in recent years, owing to the

widespread supplementation of foods with iodine. On rare occasions, cretinism may also result from inborn errors in metabolism (e.g., enzyme deficiencies) that interfere with the

biosynthesis of normal levels of thyroid hormone (sporadic cretinism).

Clinical features of cretinism include impaired development of the skeletal system and central nervous system, manifested by severe mental retardation, short stature, coarse facial

features, a protruding tongue, and umbilical hernia. The severity of the mental impairment in cretinism appears to be related to the time at which thyroid deficiency occurs in utero.

Normally, maternal hormones, including T3 and T4 , cross the placenta and are critical to fetal brain development. If there is maternal thyroid deficiency before the development of the

fetal thyroid gland, mental retardation is severe. In contrast, reduction in maternal thyroid hormones later in pregnancy, after the fetal thyroid has developed, allows normal brain

development.

MYXEDEMA

The term myxedema is applied to hypothyroidism developing in the older child or adult. Myxedema, or Gull disease, was first linked with thyroid dysfunction in 1873 by Sir William

Gull in a paper addressing the development of a "cretinoid state" in adults. The clinical manifestations vary with the age of onset of the deficiency. The older child shows signs and

symptoms intermediate between those of the cretin and those of the adult with hypothyroidism. In the adult, the condition appears insidiously and may take years to reach the level of

clinical suspicion.

Clinical features of myxedema are characterized by a slowing of physical and mental activity. The initial symptoms include generalized fatigue, apathy, and mental sluggishness, which

may mimic depression in the early stages of the disease. Speech and intellectual functions become slowed. Patients with myxedema are listless, cold-intolerant, and frequently

overweight. Reduced cardiac output probably contributes to shortness of breath and decreased exercise capacity, two frequent complaints in patients with hypothyroidism. Decreased

sympathetic activity results in constipation and decreased sweating. The skin in these patients is cool and pale because of decreased blood flow. Histologically, there is an accumulation

of matrix substances, such as glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, and a number of visceral sites. This results in edema, a broadening and coarsening of

facial features, enlargement of the tongue, and deepening of the voice.

Laboratory evaluation plays a vital role in the diagnosis of suspected hypothyroidism because of the nonspecific nature

of symptoms. Measurement of the serum TSH level is the most sensitive screening test for this disorder. The TSH level is increased in primary hypothyroidism due to a loss of feedback

inhibition of TRH and TSH production by the hypothalamus and pituitary, respectively. The TSH level is not increased in patients with hypothyroidism due to primary hypothalamic or

pituitary disease. T4 levels are decreased in patients with hypothyroidism of any origin.

Thyroiditis

Thyroiditis, or inflammation of the thyroid gland, encompasses a diverse group of disorders characterized by some form of thyroid inflammation. These diseases include conditions that

result in acute illness with severe thyroid pain (e.g., infectious thyroiditis, subacute granulomatous thyroiditis) and disorders in which there is relatively little inflammation and the illness

is manifested primarily by thyroid dysfunction (subacute lymphocytic thyroiditis and fibrous [Reidel] thyroiditis).

Infectious thyroiditis may be either acute or chronic. Acute infections can reach the thyroid via hematogenous spread or through direct seeding of the gland, such as via a fistula from the

piriform sinus adjacent to the larynx. Other infections of the thyroid, including mycobacterial, fungal, and Pneumocystis infections, are more chronic and frequently occur in

immunocompromised patients. Whatever the cause, the inflammatory involvement may cause sudden onset of neck pain and tenderness in the area of the gland and is accompanied by

fever, chills, and other signs of infection. Infectious thyroiditis can be self-limited or can be controlled with appropriate therapy. Thyroid function is usually not significantly affected,

and there are few residual effects except for possible small foci of scarring. This section focuses on the more common and clinically significant types of thyroiditis: (1) Hashimoto

thyroiditis (or chronic lymphocytic thyroiditis), (2) subacute granulomatous thyroiditis, and (3) subacute lymphocytic thyroiditis.

Date: 2016-04-22; view: 662