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

29.Thyrotoxicosis of Extrathyroid Origin

Elizabeth N. Pearce

Extrathyroidal causes of thyrotoxicosis can be difficult to diagnose. The most common extrathyroidal cause of thyrotoxicosis is thyrotoxicosis factitia. The other causes, functional metastatic thyroid carcinoma and struma ovarii, are extremely rare.



Thyrotoxicosis due to the ingestion of exogenous thyroid hormone is most frequently iatrogenic—either intentionally [as when thyroid-stimulating hormone (TSH)–suppressive doses of sodium thyroxine (T4) are prescribed in order to suppress tumor growth in thyroid cancer patients, or in an attempt to decrease goiter size] or unintentionally (as when overly vigorous T4 therapy is prescribed for hypothyroidism).

Thyrotoxicosis factitia may also result from patients' surreptitious use of thyroid hormones. This usually occurs in the setting of psychiatric illness. Surreptitious thyroid hormone ingestion is more common in those working in medicine-related fields (who have more readily available access to thyroid hormone-containing medications) (1), and may occur at any age (2). Large doses of thyroid hormone may be ingested as a suicide attempt. In addition, some patients may ingest excessive doses of thyroid hormones, sometimes at the advice of their physicians, in an effort to lose weight, or to treat depression, menstrual disorders, or infertility (3).

Patients may also develop thyrotoxicosis from the unintentional ingestion of thyroid hormone. Accidental overdose of thyroid hormone most frequently occurs in children. Several community outbreaks of thyrotoxicosis from exogenous thyroid hormone ingestion have been reported. For example, 121 cases of thyrotoxicosis with low radioactive iodine uptake were documented in southwestern Minnesota and adjacent areas between 1984 and 1985. Subsequent investigations revealed the presence of bovine thyroid material in ground beef processed at a single local slaughtering plant (4). Beef-slaughtering techniques were also likely responsible for a similar community outbreak in Nebraska in 1984 (5). This type of community-wide thyrotoxicosis has been referred to as “hamburger thyroiditis” (3). Inadvertent exposure to thyroid hormone resulting in thyrotoxicosis has also been reported from occupational exposure to cosmetic creams containing iodine and thyroid hormones (6) and from accidental dosing with veterinary T4 preparations (7).

Clinical Presentation and Diagnosis

Diagnosis of thyrotoxicosis resulting from exogenous thyroid hormone ingestion can be difficult and requires a high degree of clinical suspicion, as symptoms, initial laboratory values, and imaging studies are often indistinguishable from those of painless sporadic thyroiditis or other types of thyroiditis associated with low radioactive iodine uptakes. Serum TSH values will be low. Serum triiodothyronine (T3) and T4 levels are variably elevated, depending on the thyroid hormone preparation that has been ingested. T3 poisoning may result in more severe and acute symptoms of thyrotoxicosis than poisoning with other forms of thyroid hormone (8). Because of the TSH suppression, the thyroid gland is small in patients without underlying thyroid disease. Exopthalmos is not present. Radioactive iodine uptake is low to undetectable. A serum thyroglobulin (Tg) measurement is frequently helpful, as serum Tg values are low to undetectable in thyrotoxicosis factitia, but are elevated in all other causes of thyrotoxicosis, such as Graves' disease, toxic nodular goiter, painless sporadic thyroiditis, and subacute thyroiditis (9). If antibodies to Tg are present in the serum, however, serum Tg measurements cannot reliably be used to differentiate thyrotoxicosis factitia from other causes of thyrotoxicosis. Fecal T4 measurements may be used instead in such patients. Fecal T4 measurements are approximately 1 nmol/g in normal healthy subjects, are mildly increased in Graves' disease (about 2 nmol/g), and are markedly elevated in individuals with thyrotoxicosis factitia (over 12 nmol/g) (10). Finally, color-flow Doppler sonography has been used to distinguish Graves' disease or toxic nodular goiter, in which the thyroid is hypervascular, from thyrotoxicosis factitia, in which thyroid hypervascularity is absent (11).


In most cases, the only therapy required is the discontinuation of exogenous thyroid hormone ingestion. Although high doses of thyroid hormone have been reported to cause seizures (12), myocardial infarction (13), or thyroid storm (14), even massive overdoses of thyroid hormone are usually well tolerated, especially by children (1,15). Beta blockers may be helpful in patients with severe symptoms of thyrotoxicosis (1). Antithyroid medications have no role in therapy, since thyrotoxicosis is not the result of endogenous thyroid hormone production. In patients seen acutely after massive thyroid hormone overdose, gastric lavage, induced emesis, and activated charcoal may be employed to prevent thyroid hormone absorption (1). Although conservative therapy is adequate in most cases (15), adjunctive therapies may be required in patients who do not respond to conservative measures, or who are considered to be at high risk for cardiac or neurologic complications. Cholestyramine will facilitate a more rapid decrease in circulating thyroid hormone levels by binding thyroid hormone from the enterohepatic circulation and increasing fecal excretion (16). The iodinated radiocontrast agent iopanoic acid will decrease thyroid hormone toxicity by decreasing the conversion of T4 to T3 (17). As a last resort, plasmapheresis and exchange transfusion may be employed (1).


Definition and Epidemiology

Thyrotoxicosis due to metastatic well-differentiated thyroid carcinoma is extremely rare, but has been described in over 50 case reports since its first description by Leiter et al in 1946 (18,19). Its incidence peaks in the fifth decade, and it is 2 to 3 times more common in women (19).

Although thyroid carcinomas are almost invariably hypofunctional, even tumors that are relatively inefficient at thyroid hormone production may cause thyrotoxicosis in the presence of an extremely large tumor mass, especially in patients with diffuse metastases. In several reported cases of thyrotoxicosis due to hyperfunctional metastatic thyroid carcinoma, all of whom had concomitant Graves' disease, thyroid-stimulating immunoglobulins in patients' sera likely caused thyrotoxicosis by stimulating tumors' TSH receptors (20,21,22). Finally, an activating single-nucleotide tumor mutation of the TSH receptor gene was detected in a recent case of hyperfunctional metastatic insular thyroid carcinoma (23).

Clinical Presentation and Diagnosis

Patients are most commonly diagnosed simultaneously with thyroid carcinoma and thyrotoxicosis, but a cancer diagnosis has been reported to precede the development of thyrotoxicosis by up to 15 years (19). Symptoms of thyrotoxicosis may be mild or severe, even, rarely, resulting in thyroid storm (24). Patients have predominantly T3 toxicosis (25,26). Serum Tg levels are elevated, differentiating this entity from thyrotoxicosis factitia. Histology in most reported cases has demonstrated follicular thyroid carcinoma (18).

Diagnosis is particularly difficult when patients who are on T4 replacement following thyroidectomy present with thyrotoxicosis. Withdrawal of the T4 for several weeks may help to determine whether the thyrotoxicosis is due to T4 overtreatment or to functional metastases. To establish a definitive diagnosis of hyperfunctioning metastatic thyroid carcinoma, the presence of a hyperfunctioning thyroid gland must be ruled out in patients who are not athyreotic (27). A whole-body 131I thyroid scan will show low uptake in the thyroid area but will show uptake by the functioning metastatic tumor.


Therapy for patients with thyrotoxicosis from metastatic thyroid cancer is similar to that for patients with nonfunctional thyroid carcinoma. Depending on the size and location of metastases, tumor debulking may improve the efficacy of subsequent radioactive iodine treatment (28). Antithyroid medications should be used to make patients euthyroid prior to therapy with surgery or radioactive iodine in order to prevent thyroid storm (29). Iodine-containing medications or radiocontrast agents should be avoided, as they will reduce efficacy of subsequent radioactive iodine therapy, and they have been reported to precipitate worsened thyrotoxicosis (30). Survival rates are similar to those for patients with metastatic follicular thyroid cancer who do not have thyrotoxicosis (18,31).


Definition and Epidemiology

Struma ovarii is defined as an ovarian tumor, usually a cystic teratoma, with differentiation primarily into thyroid cells. It was first described in 1889 (32). Struma ovarii is rare, comprising 0.3% to 1% of all ovarian tumors and 2% to 4% of ovarian teratomas (33,34,35). It may occur more commonly in geographic areas with iodine deficiency (36). Thyrotoxicosis is an unusual manifestation, occurring in approximately 8% of cases (34,37). Five percent to 10% of tumors are bilateral (35,38), and 5% to 10% of tumors are malignant (39). The incidence of struma ovarii peaks at age 50 years (37).

Clinical Presentation and Diagnosis

Women with struma ovarii may present with pelvic pain or abdominal mass. Ascites is present in 17% of cases (37); ascites associated with pleural effusion, the pseudo-Meigs' syndrome, is an uncommon presenting symptom (40). Women with thyrotoxicosis from struma ovarii may present with typical signs and symptoms of thyrotoxicosis, or the thyrotoxicosis may be subclinical. Serum TSH will be suppressed, and serum T3 may be preferentially elevated (38,41). Tg is secreted by both benign and malignant tumors (42,43). Goiter is absent in women without underlying thyroid disease; however, coexistent Graves' disease and struma ovarii have been described (44,45,46). There is minimal or absent thyroid uptake of radioactive iodine in the neck, but a whole-body radioactive iodine scan will reveal uptake in the pelvis (47). Magnetic resonance imaging findings of multilocular cystic ovarian masses with variable signal intensity have been described (48,49). Elevated CA 125 levels have been reported in both benign and malignant lesions (50). The histology of benign lesions is identical to that of normal thyroid tissue. Malignant struma ovarii may have histologic features typical for either follicular or papillary thyroid carcinoma, and diagnosis of malignancy is made using the same criteria as for thyroid carcinomas (51). Metastasis is rare, occurring in only 5% of malignant cases, and is generally to the liver or peritoneum (52).


Because of the potential for malignancy, surgical resection is the initial treatment of choice for women with struma ovarii. Oophorectomy and salpingectomy, either bilateral with total abdominal hysterectomy or unilateral (in cases where there is no capsular invasion or metastasis and where preserved fertility is desired), may be performed (53). Some authors have recommended total abdominal hysterectomy and bilateral salpingo-oophorectomy following completion of childbearing in women with malignant struma ovarii who initially opt for a fertility-sparing procedure (34,42). Successful treatment with laparascopic surgery has recently been described (54). Women who are thyrotoxic should be treated with antithyroid drugs prior to surgery to restore euthyroidism (35). Iopanoic acid may be used to restore euthyroidism if rapid surgical preparation is required (45).

In women with malignancy, ovarian surgery is followed by thyroidectomy so that radioactive iodine ablation can be performed. Thyroidectomy also allows for the differentiation of malignant struma ovarii from thyroid carcinoma that is metastatic to the ovary. Total body radioactive iodine scans and Tg levels (34,39) may be used to assess for recurrence or for the presence of metastases, analogous to their use in thyroid carcinomas. Recombinant human TSH has been used to enhance 131I uptake for scans and therapy (41).


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