This rare syndrome consists of hyperthyroidism induced by pregnancy. It is caused by a mutation in the TSH receptor rendering it also specific for human CG(114d). See chapter16a.
THYROTOXICOSIS DUE TO METASTATIC THYROID CARCINOMA
In rare situations metastatic follicular carcinoma may cause thyrotoxicosis. According to Ehrenheim et al (115), Leiter et al. was the first to describe, in 1946, thyrotoxicosis due to functioning metastases in a patient with adenocarcinoma of the thyroid. Ehrenheim et al. reported 20 similar cases, and recently 54 cases reported in the literature were analyzed (115a). The age and sex distribution in such patients is no different from that of other patients with follicular carcinoma, but without thyrotoxicosis. About 85% of patients are older than 40 years and the female: male ratio is 3: 1. The clinical picture of thyrotoxicosis is similar to the general symptoms of other causes of thyrotoxicosis.
There is generally poor efficiency of iodine uptake and thyroid hormone synthesis and excessive hormone production is due to the large mass of metastatic tissue (116). The inefficient thyroid hormone synthesis is at least partly due to relative iodine deficiency in tumor tissue and the presence of abnormal thyroglobulin (117). Other abnormalities may however be present in the complicated process of thyroid hormone synthesis in carcinomatous tissue. For instance, there is evidence that expression of the TSH receptor in carcinomatous thyroid tissue may be absent or low (118) In many cases clinical symptoms are caused by T3 toxicosis with suppressed serum TSH, and normal or low serum T4 (116,117,119). Uptake of radioactive iodine in metastatic tissue may be low in the absence of normal thyroid tissue and is often absent when the thyroid gland is still present. The metastatic pattern of this type of adenocarcinoma is as is usually found in thyroid adenocarcinoma patients, that is predominantly in bone, lung and mediastinum.
Treatment of metastatic functioning thyroid carcinoma consists of administration of radioactive iodine. The usual dose ranges between 3700 - 7400 MBq (100-200 mCi). Exacerbation of thyrotoxicosis, even precipitating thyroid storm, has been reported(120) For this reason radioactive iodine for therapy of a functioning metastatic thyroid carcinoma should be administered with caution and only after adequate preparation of the elderly patient with cardiovascular disease. If normal thyroid tissue is still present, it is often advantageous to irradicate this tissue either by surgery or by radioactive iodine, to ensure more efficient uptake of therapeutic doses of radioactive iodine in the metastatic tissue. Graves' disease and follicular carcinoma occasionally co-occur, and this may not be a coincidence (121-123). There may be an association between Graves' disease and thyroid carcinoma, possibly because of longstanding thyroid stimulation by immunoglobulins (124). Although it has been postulated that thyroid carcinoma in patients with Graves' disease behaves more aggressively (125), this is uncertain (126).
Struma ovarii is a rare tumor occurring in a teratoma or dermoid in the ovary. It is often admixed with a carcinoid tumor, (127) and has been reported to occur in association with multiple endocrine neoplasia type IIA (128). Ovarian strumal carcinoid tumors have been found to synthesize different peptide hormones including calcitonin, ACTH, SRIF, neuron-specific enolase, chromogranin, synaptophysin, serotonin and other peptides (127-129). Struma ovarii is unilaterally localized in about 90% of patients and about 80% are benign (130). Pardo-Mindan and Vazquez (131) reviewed the world literature on malignant struma ovarii until 1983, finding only 18 cases. As differentiation between carcinoid and struma tissue is sometimes difficult, electron microscopic studies in combination with specific immunochemistry may be necessary.
Struma ovarii seldom causes hyperthyroidism. In thyrotoxicosis due to struma ovarii, uptake of radioactive iodine of the thyroid gland is low in the presence of elevated serum thyroid hormones and suppressed TSH. Uptake of radioactive iodine over the ovarian tumor confirms the diagnosis (131a,b). Although one would suspect that in thyrotoxic cases due to struma ovarii the thyroid gland would be reduced in size, the thyroid in several reports was enlarged (130,132). Possibly this could represent the effect of thyroid stimulating antibodies on both tissues. Treatment of struma ovarii, either with euthyroidism or thyrotoxicosis, should be effected by removal of the ovarian tumor. In the case of co-existent thyrotoxicosis, preparation for surgery should be done by administration of antithyroid drugs, sometimes in combination with beta-blocking agents. Because of the co-existing teratoma, it is sometimes difficult to determine if the thyroid tissue in the tumor is benign or malignant. It is not advised to treat patients with thyrotoxic struma ovarii with radioiodide because of the possibility that the tumor is malignant, which cannot be determined on clinical grounds, and secondly because of the unknown radiation effects on the other elements of the teratoma. Doppler flow may aid in the preoperative diagnosis of struma ovarii. Blood flow signals, detected from the center of the echoic lesion, and low resistance to flow may be more common in struma ovarii (132a).
Thyrotoxicosis arises from several etiologies other than Graves' disease. Toxic adenomas are characterized by a single hyperactive nodule in the thyroid leading to clinical and biochemical thyrotoxicosis. Autonomous or toxic adenomas are considered to originate from somatic mutations in the gene of Gsalpha protein or the gene of the thyrotropin receptor. In toxic adenoma only a hot nodule is visible on the thyroid scan. The frequency of toxic nodules varies in different countries. The frequency of toxic adenoma in patients with hyperthyroidism ranges between 1.5 and 44.5% as reported from different surveys. The possibility of developing thyrotoxicosis in a patient with a hot nodule with a diameter of 3 cm or larger is 20% in 6 years. This risk is substantially less in smaller nodules. Also, older patients with a hot nodule are more likely to become toxic as compared to younger patients. Definitive treatment consists of surgical removal of the nodule, administration of 131I or percutaneous administration of ethanol into the nodule. The likelihood of malignancy in a toxic nodule is very low.
Thyrotoxicosis due to painless thyroiditis was uncommon until 1973, but the reported incidence has increased since then. This is an autoimmune thyroiditis due to lymphocytic infiltration of the thyroid and is identical to postpartum thyroiditis. About half of the patients pass through four classical phases consisting of thyrotoxicosis, euthyroidism, hypothyroidism and back to euthyroidism. The other half of the patients do not become hypothyroid or, in a small minority, remain hypothyroid. Biochemically characteristic is the fact that uptake of radioactive iodine is absent in the thyrotoxic phase and the serum thyroglobulin levels are high. Clinical thyrotoxicosis is mild and treatment with beta blocking agents is often sufficient. Sometimes addition of prednisone is necessary. Relapses may be seen. Although complete recovery is the rule, these patients are at high risk of developing hypothyroidism in later years. Permanent follow-up is therefore necessary.
Thyrotoxicosis factitia (thyrotoxicosis due to surreptitious ingestion of thyroid hormone) is primarily a psychiatric disorder. The diagnosis is straightforward if it is suspected. Patients usually deny thyroid hormone tablets ingestion. Characteristically thyroid uptake of radioactive iodine is low or absent and thyroglobulin is not detectable in the serum. Furthermore, the thyroid is usually small or absent on palpation. Treatment of the psychiatric disorder is difficult. Another form of excessive thyroid hormone intake is the "hamburger thyrotoxicosis". Subjects became thyrotoxic and showed characteristic serum abnormalities due to inclusion of thyroid in ground beef.
Thyrotoxicosis may be seen in association with elevated serum hCG activity in 1 - 2 % of normal pregnant women. hCG has low intrinsic thyroid stimulating activity, and hCG acts on the human thyroid cell through the TSH receptor. Desialylation of hCG renders it more biologically active. In hydatidiform mole disease however, high levels are found in patients' serum. When values are above 300,000 U/l, thyrotoxicosis is likely. Surgical removal of the mole renders the patient euthyroid.
Administration of moderate or high doses of iodine may induce thyrotoxicosis in patients with or without apparent pre-existing thyroid disease. Iodine may be derived from iodine solutions, radiographic contrast agents and medications. A notorious iodine containing agent is the anti-arrhythmic drug amiodarone. Due to its structure it may block pathways of thyroid hormone metabolism and action, leading to hypothyroidism, but it can also cause hyperthyroidism due to its iodine content. Amiodarone may also cause disruption of thyroid follicles resulting in thyrotoxicosis due to release of stored iodothyronines.
Inappropriate TSH secretion by a TSH secreting pituitary tumor may cause hyperthyroidism. Treatment of the pituitary tumor will lead to euthyroidism. The prognosis is better in patients with microadenoma. Treatment consists of surgery with postoperative external irradiation. Administration of dopamine antagonists or somatostatin analogues has been shown to be successful as well.
Rarely metastases of follicular carcinoma may result in thyrotoxicosis with suppressed activity of the thyroid gland. Treatment of the metastases with radioactive iodine will ameliorate thyrotoxicosis.
Struma ovarii, in itself a rare tumor occurring in a teratoma or dermoid in the ovarium, rarely causes hyperthyroidism. Most patients with struma ovarii are clinically and biochemically euthyroid. Treatment consists of removal of the tumor by surgery.
Other causes of thyrotoxicosis, such as multinodular goiter, (sub)acute thyroiditis of De Quervain, postpartum thyroiditis and Hashimoto's thyroiditis, partial selective pituitary resistance to thyroid hormone, inherited toxic hyperplasia and gestational hyperthyroidism are considered elsewhere in this volume.