[W] How should thyrotoxicosis due to unusual causes be managed?

These are several unusual causes of thyrotoxicosis that should be considered in the differential diagnosis (Table 14). Since effective treatment depends on accurate diagnosis, it is important to clearly identify the etiology in every patient presenting with thyrotoxicosis.

[W1] TSH-secreting pituitary tumors

TABLE 14. UNUSUAL CAUSES OF THYROTOXICOSIS

Disorder

Diagnosis

Primary management

TSH-producing adenoma

Pituitary MRI, alpha-subunit to TSH ratio

Surgical removal

Struma ovarii

Radioiodine uptake over pelvis

Surgical removal

Choriocarcinoma

Elevation in the absence of pregnancy

Surgical removal

Thyrotoxicosis factitia (surreptious LT4 or LT3)

Absence of goiter; suppressed thyroglobulin

Psychosocial evaluation

Functional thyroid cancer metastases

Whole-body radioiodine scanning

Radioiodine ablation, embolization and/or surgical removal

Functional pituitary tumors secreting TSH are rare. In a multicenter review of 4400 pituitary tumors seen over a 25- year period, 43 (1%) were TSH-secreting adenomas (33). The majority of patients present with diffuse goiter and clinical signs of thyrotoxicosis. In addition, serum TSH levels may be elevated or, especially in patients who have not had thyroid ablation, they may be inappropriately normal. Cosecretion of either prolactin or growth hormone occurs in up to 25% of cases; 1%–2% secrete both growth hormone and prolactin, and a similar percentage cosecrete gonadotropins. Most TSH-producing adenomas are larger than 1 cm, and approximately 40% of patients have associated visual field deficits (352).

  • RECOMMENDATION 97

    The diagnosis of TSH-secreting pituitary tumor should be based on an inappropriately normal or elevated serum TSH level associated with elevated free T4 estimates and T3 concentrations, usually associated with the presence of a pituitary tumor on MRI and the absence of a family history or genetic testing consistent with thyroid hormone resistance in a thyrotoxic patient. 1/+00

Distinction between a TSH-secreting adenoma and thyroid hormone resistance is important, since thyroid function test results are similar, yet management is quite different for these two disorders. TSH-secreting adenomas are more likely to have concurrent alpha-subunit elevation (not useful in postmenopausal women due to concurrent gonadotropin elevation), a blunted TSH response to thyrotropin-releasing hormone (TRH) (when available), elevated sex-hormone binding globulin and resting energy expenditure, and clinical evidence of thyrotoxicosis, as well as an anatomic abnormality on MRI of the pituitary.

Technical remarks: Genetic testing for thyroid hormone resistance is commercially available and may be useful in equivocal cases, especially in those patients without family members available for thyroid function testing.

Surgery is generally the mainstay of therapy for TSH-producing pituitary tumors. The patient should be made euthyroid preoperatively. Long-term ATD therapy should be avoided. Preoperative adjunctive therapy with octreotide and dopamine agonist therapy has been examined. Treatment with octreotide results in a >50% reduction in serum TSH values in the majority of patients treated, and a concurrent return to euthyroidism in most (33). A reduction in tumor size has been observed in 20%–50% of patients treated with octreotide (33,352), but less impressive results have been obtained with bromocriptine therapy (352). Sterotactic or conventional radiotherapy has also been used in cases that prove refractory to medical therapy. For patients with TSH-producing adenomas who are considered poor surgical candidates, primary medical therapy with octreotide can be considered.

  • RECOMMENDATION 98

    Patients with TSH-secreting pituitary adenomas should undergo surgery performed by an experienced pituitary surgeon. 1/+00

Technical remarks: Postoperative adjunctive therapy with octreotide and/or external beam radiation therapy may be useful in managing patients with persistent central hyperthyroidism after a debulking procedure for nonresectable TSH-secreting adenomas (33).

[W2] Struma ovarii

  • RECOMMENDATION 99

    Patients with struma ovarii should be treated initially with surgical resection. 1/+00

Struma ovarii, defined as ectopic thyroid tissue existing as a substantial component of an ovarian tumor, is quite rare, representing <1% of all ovarian tumors. Approximately 5%– 10% of patients with struma ovarii present with thyrotoxicosis (353) due to either autonomous ectopic thyroid function or the coexistence of GD, and up to 25% of struma ovarii tumors contain elements of papillary thyroid cancer. Patients previously treated for GD may have persistent or recurrent hyperthyroidism due to the action of TRAb on the ectopic thyroid tissue (354). Treatment of struma ovarii generally involves surgical removal, performed largely due to the risk of malignancy within the struma tissue and of curing the hyperthyroidism. Preoperative treatment with beta-adrenergic-blocking agents and antithyroid drugs is warranted to restore euthyroidism before surgery.

Technical remarks: In cases of suspected metastatic malignant struma ovarii, radioactive iodine is generally given following surgical removal of both the ovarian tumor and the patient’s thyroid to facilitate delivery of isotope to any potential residual malignant cells.

[W3] Choriocarcinoma

  • RECOMMENDATION 100

    Treatment of hyperthyroidism due to choriocarcinoma should include both methimazole and treatment directed against the primary tumor. 1/+00

Patients with choriocarcinoma, including molar pregnancy and testicular cancer, may present with thyrotoxicosis due to the effect of tumor-derived hCG upon the TSH receptor (355,356). This cross-stimulation only occurs at very high levels of hCG, since hCG is only a weak agonist for the TSH receptor. Treatment of hyperthyroidism due to choriocarcinoma involves both treatment directed against the primary tumor and treatment designed to prevent the thyroid from responding to hCG stimulation, such as with antithyroid drugs.

[W4] Thyrotoxicosis factitia

Thyrotoxicosis factitia includes all causes of thyrotoxicosis due to the ingestion of thyroid hormone. This may include intentional ingestion of thyroid hormone either surreptitiously or iatrogenically, as well as unintentional ingestion either accidentally, such as in pediatric poisoning or pharmacy error, or through ingestion of supplements that contain thyroid extracts. Historically, accidental thyroid hormone ingestion has occurred as a result of eating meat contaminated with animal thyroid tissue (”hamburger thyrotoxicosis”) (357). Whereas iatrogenic causes of thyrotoxicosis factitia are easily identified, surreptitious use of thyroid hormone may present a diagnostic quandary. Clues to this diagnosis are an absence of goiter, a suppressed serum thyroglobulin level, and a decreased uptake of radioactive iodine. A disproportionately elevated T3 level suggests that the patient may be ingesting liothyronine or a combination T4/T3 preparation.

[W5] Functional thyroid cancer metastases

Thyrotoxicosis due to functional metastases in patients with thyroid cancer has been described in a handful of cases. Typically, patients have either a very large primary follicular cancer or widely metastatic follicular thyroid cancer, and may have coexisting TRAb as the proximate cause of the thyrotoxicosis (358). More recently, thyrotoxicosis has been reported following multiple injections of recombinant human TSH in patients with metastatic thyroid cancer in preparation for imaging. In general, functioning metastasis are treated with radioactive iodine with the addition of ATDs as needed for persistent hyperthyroidism. Recombinant human TSH should be avoided in these patients.