Other Disorders of the Thyroid
Delbert A. Fisher
NONTHYROIDAL ILLNESS (THE LOW T3 SYNDROME)
Nonthyroidal illness (NTI) was initially characterized as a selective deficiency of serum and tissue T3 (triiodothyronine) in patients dying with severe prolonged illness. This syndrome of low total and free serum T3, normal, low or high total serum T4 (thyroxine), increased T4 sulfate, normal to high free T4, and normal serum thyroid-stimulating hormone (TSH) concentrations has now been reported in a variety of situations. These include the premature neonate (see Chapter 527) patients with protein-calorie malnutrition or anorexia nervosa, fasting subjects, postoperative patients, and patients with a variety of severe acute and chronic illnesses. The latter have included patients with diabetic ketoacidosis, severe trauma, burns, febrile states, cirrhosis, and renal failure. In addition, a number of drugs have been observed to produce a similar syndrome; these drugs include dexamethasone, selected radiographic contrast agents, propylthiouracil, propranolol, and amiodarone. There is no convincing evidence that treatment with thyroid hormones, either T4 or T3, is effective in most patients with nonthyroidal illness. Treatment should be directed to the primary systemic illness. There is some evidence to suggest that treatment may be beneficial in selected clinical conditions such as postoperative cardiac surgery. 
EUTHYROID HYPERTHYROTROPINEMIA
Elevated thyroid-stimulating hormone (TSH) levels with normal thyroid hormone levels are observed in patients with asymptomatic euthyroid hyperthyrotropinemia. This disorder is relatively common and may be transient or permanent. The prevalence of transient hyperthyrotropinemia in Europe approximates 1 in 8000 births, with 50% due to perinatal iodine exposure. Other causes include defects in TSH or the TSH receptor, a mild intrathyroidal synthetic defect, a hemithyroid gland, or a resetting of the TSH feedback control system. Germline inactivating mutations of the TSH receptor gene have been associated with a phenotype of asymptomatic hyperthyrotropinemia. Most were compound heterozygotes with normal heterozygote parents. 
THYROID HORMONE CARRIER PROTEIN ABNORMALITIES
The serum concentrations of T4 and, to a lesser extent, T3 are related to the levels of the three carrier proteins, thyroxine-binding globulin (TBG), transthyretin (TBPA), and albumin. TBG, with the lowest plasma concentration (10–40 mg/L), binds 70% of T4 and about half of total T3. Transthyretin, with a plasma concentration of 100 to 200 mg/L, binds 20% of T4 and about 1% of T3. Albumin with a concentration several thousand-fold greater (20–50 g/L) binds 10% of T4 and about 50% of T3. Genetic defects associated with abnormal levels or hormone-binding affinities of these proteins led to abnormal total T4 and T3 concentrations. Such patients are euthyroid, however, with normal free T4 and T3 levels and normal thyroid-stimulating hormone (TSH) concentrations. The molecular defects include TBG deficiency, high TBG level, high transthyretin levels, and increased albumin binding of T4 referred to as familial dysalbuminemic hyper-thyroxinemia (FDH). The defects are characterized by abnormal T4 levels with normal TSH concentrations in clinically euthyroid patients and are confirmed by direct protein assay and/or thyroid hormone protein-binding assays available in commercial laboratories.
THYROXINE-BINDING GLOBULIN DEFICIENCY
Deficiency of thyroxine-binding globulin (TBG) is transmitted as an X-linked trait, and the prevalence approximates 1 in 5000 individuals. Serum TBG levels are low among affected men and boys, and approximately half-normal among female carriers. 
A variety of structural defects in the TBG molecule account for the variably decreased T4 binding. 
HIGH THYROXINE-BINDING GLOBULIN LEVEL
Persons with increased levels of thyroxine-binding globulin (TBG) have increased total serum T4 concentrations, presumably due to increased hepatic production, with normal free T4 and thyroid-stimulating hormone (TSH) levels; thus, they are euthyroid. The prevalence varies from 1 in 40,000 persons in North America to 1 in 6000 in England. Levels of TBG increase as much as 4.5 times normal among affected boys and men, and female carriers have serum concentrations intermediate between normal values and the high levels among affected men and boys.
HIGH TRANSTHYRETIN
High transthyretin (TBPA) is characterized by an elevated serum T4 not corrected by the use of a free T4 index, but with normal free T4 normal total serum T3 and thyroid-stimulating hormone (TSH) concentrations, and normal TSH and T3 responses to thyrotropin-releasing hormone (TRH). Serum thyroxine-binding globulin (TBG) and albumin levels are normal and the patients are euthyroid, but the serum transthyretin concentration is 2.5 to 3.0 times greater than the level in a normal human serum pool. Inheritance is dominant with serum T4 levels in affected family members 50% above the mean of unaffected relatives. 
FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA
Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasians. FDH is characterized by increased serum T4 concentrations not corrected by the use of the free T4 index correction and with normal free T4, total serum T3, and thyroid-stimulating hormone (TSH) levels. The patients are euthyroid. An increased proportion of thyroxine in affected subjects migrates with albumin by conventional polyacrylamide electrophoresis. The disorder is transmitted as an autosomal-dominant trait.
DIFFUSE NONTOXIC GOITER
A syndrome of euthyroid diffuse goiter has been described during adolescence in nonendemic goiter areas. The prevalence approximates 5% of the population. Many patients with euthyroid goiter have autoimmune thyroiditis, but some have no thyroid autoantibodies and no evidence of thyroid lymphocytic infiltration. A common finding in such patients is a family history of goiter, but detailed tests of thyroid function fail to reveal identifiable defects. Thyroid volume in affected individuals is positively correlated with age, and older patients are more likely to manifest multinodular goiter. The genetic pattern in families is suggestive of an autosomal-dominant mode of transmission with greater expression in the female. Thyroid function tests are normal, and thyroid biopsy in adolescents reveals only “colloid goiter.” The thyroid enlargement may regress spontaneously without therapy.
SUBACUTE THYROIDITIS
In children, subacute thyroiditis is a relatively rare and self-limited inflammation of the thyroid that usually follows or is associated with an upper respiratory illness. Patients have been identified with evidence of associated mumps virus infection and others with cat-scratch fever. It is likely that a variety of viral agents may be responsible for this condition. The incidence is similar in males and females. The onset is accompanied by fever and pain that may be local or referred to the angles of the jaws. The thyroid gland may be exquisitely sensitive to palpation or only mildly tender. Characteristically, there is an increase in serum T4 and T3 levels due to release of stored hormone, and signs and symptoms of hyperthyroidism may develop. Thyroidal radioiodine uptake is low or absent, indicating thyroid cell damage. Signs and symptoms of hyperthyroidism usually persist for 1 to 4 weeks. After this time, there is a period of transient hypothyroidism as the thyroid gland recovers. The total course runs 2 to 9 months. Treatment of subacute, painful (viral) thyroiditis includes large doses of acetylsalicylic acid or other anti-inflammatory drugs; in severe cases, corticosteroid medication may be helpful.
SUPPURATIVE THYROIDITIS
Bacterial infections of the thyroid gland are rare in children and are usually associated with an embryologic remnant and/or a left pyriform sinus tract. The left lobe is most often involved. Suppurative thyroiditis may be associated with other head and neck infection. In older children or adolescents, bacterial thyroiditis may be associated with bacteremic spread from distant infection. Children usually present with acute onset of pain, often with dysphagia, and unilateral or bilateral thyroid enlargement, fever, and local tenderness. The gland is initially firm and may progress to abscess formation. Leukocytosis is common, and thyroid function tests are usually normal. Early differentiation from subacute thyroiditis may be difficult, but signs and symptoms of hyperthyroidism are uncommon, and the course is usually limited to 2 to 4 weeks. The common organisms are Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. Rarely, Pasteurella, Echinococcus, or other organisms can be causative. Thin-needle aspiration and culture are helpful in antimicrobial selection.
THYROID NEOPLASIA
A thyroid neoplasm should be suspected whenever a child has a solitary thyroid mass with a consistency differing from that of the rest of the thyroid gland.1-4 A solitary nodule during the first two decades of life has a much greater chance of being malignant than those in older age groups. A frequent predisposing cause for development of differentiated thyroid carcinoma during infancy and childhood during the 1950s was radiation exposure involving the head and neck. The prevalence has been decreasing in North America, presumably due to reduced radiation exposure; cancer prevalence now approximates 20% of thyroid nodules in children. 
The most recent epidemic of radiation-induced thyroid cancer in children followed the Chernobyl nuclear accident in Russia in 1986.7,8 The radiation dose ranged from 0.5 to 600 Rads (0.006–6 Gray), with a mean of 20 Rads (0.2 Gray), in a group of 107 exposed Russian children detected by 1992. The age at exposure ranged from 0 to 11 years, and the age at diagnosis 4 to 16 years. The cancers, predominantly papillary adeno-carcinoma, developed in most cases within 3 to 5 years. However, the number of cases continues to increase.
Seventy percent to 80% of solitary thyroid nodules during childhood prove to be cystic lesions or benign adenomas. The ratio of girls to boys among children with thyroid cancer varies from 1:6 (F/M) for ages 5 to 9 years to 5:2 at ages 15 to 19 years. Thyroid cancer accounts for 1% to 1.5% of all childhood cancer.
Characterization of the histopathologic type as follicular, papillary, or papillary-follicular carcinomas does not alter therapy. Other malignant tumors of the thyroid gland during childhood include medullary carcinoma arising in the parafollicular C cells, poorly differentiated thyroid carcinoma, teratomas, lymphoma, and tumors, such as metastatic carcinomas arising in other tissues. The prognosis is that these tumors may be worse than in well-differentiated adeno-carcinoma of the thyroid; hence, it is important to establish a tissue diagnosis as early as possible and design treatment accordingly.
PAPILLARY-FOLLICULAR CARCINOMA
Well-differentiated papillary thyroid carcinoma (PTC) accounts for 60% to 90% of thyroid cancer in childhood. Most children with papillary follicular thyroid carcinoma present with a mid-neck or lateral neck mass, and most (60–80%) have one or more palpable neck lymph nodes containing metastatic thyroid cells by histologic examination. One third to one half of patients has extracapsular extension and 10% distant metastases, usually to the lungs. Approximately 80% of differentiated thyroid carcinoma is classified as papillary and 20% as papillary-follicular.
The prognosis in children with papillary-follicular carcinoma is far better than in most other types of childhood cancer. The course is usually indolent, with long periods without progression. However, local or distant recurrence is observed in as many as 35% of patients, and constant surveillance is required. Because spread to the lymph nodes has occurred prior to surgery in many patients, the excellent prognosis may be related more to the biologic nature of this form of cancer than to total removal of all cancerous cells during the initial operation. Postoperative thyroid hormone suppression cannot be overemphasized and should be prescribed in doses adequate to suppress serum thyroid-stimulating hormone (TSH) (as assessed by a high-sensitivity TSH assay) but avoid evidence of toxicity. 
Table 530-1. Clinical Features Suggesting Malignancy in Children with a Thyroid Nodule
