Chapter 562 Hyperthyroidism

Hyperthyroidism results from excessive secretion of thyroid hormone; during childhood, with few exceptions, it is due to Graves disease (Table 562-1). Graves disease is an autoimmune disorder; production of thyroid-stimulating immunoglobulin (TSI) results in diffuse toxic goiter. Germline mutations of the thyroid-stimulating hormone (TSH) receptor resulting in constitutively activating (gain-of-function) mutations are found in both familial (autosomal dominant) and sporadic cases of non-autoimmune hyperthyroidism. These patients, whose disease can appear in the neonatal period or in later childhood, have thyroid hyperplasia with goiter and suppressed levels of TSH. Different activating mutations have been identified in some cases of thyroid adenomas. Hyperthyroidism occurs in some patients with McCune-Albright syndrome as a result of an activating mutation of the α subunit of the G-protein; these patients tend to have a multinodular goiter. Other rare causes of hyperthyroidism that have been observed in children include toxic uninodular goiter (Plummer disease), hyperfunctioning thyroid carcinoma, thyrotoxicosis factitia, subacute thyroiditis, and acute suppurative thyroiditis.

CAUSES OF HYPERTHYROIDISM	PATHOPHYSIOLOGIC FEATURES	INCIDENCE
CIRCULATING THYROID STIMULATORS
Graves disease	Thyroid-stimulating immunoglobulins	Common
Neonatal Graves disease	Thyroid-stimulating immunoglobulins	Rare
Thyrotropin-secreting tumor	Pituitary adenoma	Very rare
Choriocarcinoma	Human chorionic gonadatropin secretion	Rare
THYROIDAL AUTONOMY
Toxic multinodular goiter	Activating mutations in thyrotropin receptor or G-protein	Common
Toxic solitary adenoma	Activating mutations in thyrotropin receptor or G-protein	Common
Congenital hyperthyroidism	Activating mutations in thyrotropin receptor	Very rare
Iodine-induced hyperthyroidism (Jod-Basedow)	Unknown; excess iodine results in unregulated thyroid hormone production	Uncommon in USA and other iodine-sufficient areas
DESTRUCTION OF THYROID FOLLICLES (THYROIDITIS)
Subacute thyroiditis	Probable viral infection	Uncommon
Painless or postpartum thyroiditis	Autoimmune	Common
Amiodarone-induced thyroiditis	Direct toxic drug effects	Uncommon
Acute (infectious) thyroiditis	Thyroid infection (e.g., bacterial, fungal)	Uncommon
EXOGENOUS THYROID HORMONE
Iatrogenic	Excess ingestion of thyroid hormone	Common
Factitious	Excess ingestion of thyroid hormone	Rare
Hamburger thyrotoxicosis	Thyroid gland included in ground beef	Probably rare
ECTOPIC THYROID TISSUE
Struma ovarii	Ovarian teratoma containing thyroid tissue	Rare
Metastatic follicular thyroid cancer	Large tumor mass capable of secreting thyroid hormone autonomously	Rare
Pituitary resistance to thyroid hormone	Mutated thyroid hormone receptor with greater expression in the pituitary compared with peripheral tissues	Rare

Adapted from Cooper DS: Hyperthyroidism, Lancet 362:459–468, 2003.

Suppression of plasma TSH indicates that the hyperthyroidism is not pituitary in origin. Hyperthyroidism due to excess thyrotropin secretion is rare and, in most cases, is caused by pituitary resistance to thyroid hormone. TSH-secreting pituitary tumors have been reported only in adults. In infants born to mothers with Graves disease, hyperthyroidism is almost always a transitory phenomenon; classic Graves disease during the neonatal period is rare. Choriocarcinoma, hydatidiform mole, and struma ovarii have caused hyperthyroidism in adults but have not been recognized as causes in children.

Studies have examined the health and quality of life of subjects with subclinical hyperthyroidism (i.e., with TSH <0.1 mU/L) or who are euthyroid on antithyroid medication. These studies suggest that subclinical hyperthyroidism carries a risk of late-life atrial fibrillation and that treatment of hyperthyroidism with antithyroid medication does not reliably induce remission that is durable when medication is discontinued. There appears to be no difference in long-term quality of life among hyperthyroid patients treated with antithyroid medication, radioiodine ablation, or surgery. Quality of life was diminished relative to control subjects in all three cases (Chapter 562.1).

562.1 Graves Disease

Stephen LaFranchi

Epidemiology

Graves disease occurs in approximately 0.02% of children (1 : 5,000). It has a peak incidence in the 11- to 15-yr old; there is a 5 : 1 female to male ratio. Most children with Graves disease have a positive family history of some form of autoimmune thyroid disease. In Japan, familial Graves disease, defined as Graves disease in a 1st-degree relative, occurs in 2-3% of cases.

Etiology

Enlargement of the thymus, splenomegaly, lymphadenopathy, infiltration of the thyroid gland and retro-orbital tissues with lymphocytes and plasma cells, and peripheral lymphocytosis are well-established findings in Graves disease. In the thyroid gland, T helper cells (CD4⁺) predominate in dense lymphoid aggregates; in areas of lower cell density, cytotoxic T cells (CD8⁺) predominate. The percentage of activated B lymphocytes infiltrating the thyroid is higher than in peripheral blood. A postulated failure of T suppressor cells allows expression of T helper cells, sensitized to the TSH antigen, which interact with B cells. These cells differentiate into plasma cells, which produce thyrotropin receptor–stimulating antibody (TRSAb). TRSAb binds to the receptor for TSH and stimulates cyclic adenosine monophosphate, resulting in thyroid hyperplasia and unregulated overproduction of thyroid hormone. In addition to TRSAb, thyrotropin receptor-blocking antibody (TRBAb) may also be produced, and the clinical course of the disease usually correlates with the ratio between the two antibodies.

The ophthalmopathy occurring in Graves disease appears to be caused by antibodies against antigens shared by the thyroid and eye muscle. TSH receptors have been identified in retro-orbital adipocytes and might represent a target for antibodies. The antibodies that bind to the extraocular muscles and orbital fibroblasts stimulate the synthesis of glycosaminoglycans by orbital fibroblasts and produce cytotoxic effects on muscle cells.

In whites, Graves disease is associated with HLA-B8 and HLA-DR3; the latter carries a 7-fold relative risk for Graves disease. Graves disease is also associated with other HLA-D3–related disorders such as Addison disease, type 1 diabetes mellitus, myasthenia gravis, and celiac disease. Systemic lupus erythematosus, rheumatoid arthritis, vitiligo, idiopathic thrombocytopenic purpura, and pernicious anemia have been described in children with Graves disease. In family clusters, the conditions associated most commonly with Graves disease are autoimmune lymphocytic thyroiditis and hypothyroidism. In Japanese children, Graves disease is associated with different HLA haplotypes: HLA-DRB1*0405 and HLA-DQB1*0401.

Clinical Manifestations

About 5% of all patients with hyperthyroidism are <15 yr of age; the peak incidence in these children occurs during adolescence. Although rare, Graves disease has begun between 6 wk and 2 yr of age in children born to mothers without a history of hyperthyroidism. The incidence is about 5 times higher in girls than in boys.

The clinical course in children is highly variable but usually is not so fulminant as in many adults (Table 562-2). Symptoms develop gradually; the usual interval between onset and diagnosis is 6-12 mo and may be longer in prepubertal children compared with adolescents. The earliest signs in children may be emotional disturbances accompanied by motor hyperactivity. The children become irritable and excitable, and they cry easily because of emotional lability. They are restless sleepers and tend to kick their covers off. Their schoolwork suffers as a result of a short attention span and poor sleep. Tremor of the fingers can be noticed if the arm is extended. There may be a voracious appetite combined with loss of or no increase in weight. Recent height measurements might show an acceleration in growth velocity.

Table 562-2 MAJOR SYMPTOMS AND SIGNS OF HYPERTHYROIDISM AND OF GRAVES DISEASE AND CONDITIONS ASSOCIATED WITH GRAVES DISEASE

MANIFESTATIONS OF HYPERTHYROIDISM

Symptoms

Hyperactivity, irritability, altered mood, insomnia, anxiety

Heat intolerance, increased sweating

Palpitations

Fatigue, weakness

Dyspnea

Weight loss with increased appetite (weight gain in 10% of patients)

Pruritus

Increased stool frequency

Thirst and polyuria