Are you sure the patient has thyrotoxicosis?

Thyrotropin-secreting pituitary adenomas

Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare form of pituitary tumor, comprising less than 1% of all pituitary adenomas. In the author’s experience, 9 of nearly 1,400 patients (~0.65 %) who underwent surgery for pituitary tumors had TSH-secreting lesions. The disorder is characterized by serum elevations of thyroxine (T4) and triiodothyronine (T3), along with either normal or elevated concentrations of TSH. Approximately 25% of TSHomas co-secrete other pituitary hormones, including growth hormone, prolactin, and rarely, gonadotropins. The overwhelming majority of TSHomas are macroadenomas.

Symptoms of thyrotoxicosis are common, including anxiety, nervousness, palpitations, and weight loss, depending on the degree of thyrotoxicosis. In addition, the mass effect of the adenoma may result in both visual field and visual acuity abnormalities (30-40%) due to chiasmal compression. Headaches, due to mass effect, occur in approximately a third of patients. In cases of co-secretion of growth hormone, symptoms of acromegaly occur, and where prolactin is co-secreted in female patients, galactorrhea may be present.

Signs of hyperthyroidism, including tachycardia and goiter, are usual. Indeed, goiter, generally diffuse, is present in nearly all patients. Visual field defects may be present, and if the tumor has been longstanding and large enough to compress the visual apparatus, optic atrophy may be noted.

Gestational trophoblastic tumors

Gestational trophoblastic tumors, including hydatidiform moles and choriocarcinomas, are uncommon causes of hyperthyroidism during pregnancy. The routine use of ultrasound has significantly increased the detection of trophoblastic tumors early in gestation, such that the incidence of hyperthyroidism in such lesions has decreased from greater than 50 % in years past to approximately 5-7% of molar pregnancies currently. The hyperthyroidism is due to the markedly elevated beta human chorionic gonadotropin (hCG) concentrations associated with trophoblastic tissue. hCG has homology with thyroid stimulating hormone (TSH) and is thus is a weak thyroid stimulator.

When hCG levels are high enough (i.e. >200,000 mIU/ml), biochemical and clinical hyperthyroidism may result. At least some of the hCG gas decreased sialic acid content, rendering it a more potent thyroid stimulator.

Extrathyroidal causes of thyrotoxicosis

Extrathyroidal thyrotoxicosis is almost always from the administration of supraphysiologic doses of thyroid hormone and rarely from endogenous causes. Excess administration of thyroid medication is either intentional, when the goal is to suppress TSH secretion in cases of differentiated thyroid cancer, or unintentional, when patients with hypothyroidism are over-replaced with thyroid hormone. Also, some individuals take excess thyroid hormone in order to lose weight, which is not only ineffective but also associated with both potential and real adverse effects.

There are also some rare extrathyroidal causes of thyrotoxicosis, including struma ovarii, functioning metastatic follicular thyroid cancer, and choriocarcinoma of the testis. Struma ovarii is characterized by ectopic thyroid tissue as a major component of an ovarian teratoma and may be either benign or malignant. Approximately 10% of women with struma ovarii are hyperthyroid. I have personally seen only 3 women with thyrotoxicosis due to struma ovarii in my 40-year career. Hyperthyroidism due to follicular thyroid cancer is also very uncommon and occurs in the presence of significant bulky metastases, usually in lungs and bone. Choriocarcinoma is characterized generally by a testicular mass and usually with pulmonary metastases.

Iodine-induced thyrotoxicosis

Introduction: Iodine-induced thyrotoxicosis generally occurs in older individuals with underlying nodular goiter containing areas of functional autonomy. It can occur either after ingesting fairly substantial amounts of iodine, such as when a patient takes the iodine-rich antiarrhythmic drug, amiodarone, or after the administration of iodinated radiocontrast agents. The exposure to exogenous iodine in such individuals results in excess thyroid hormone synthesis and release. Thyrotoxicosis from amiodarone may also result from inflammation of the thyroid, rather than a direct result of iodine excess. This is called type-2 amiodarone-induced thyrotoxicosis, in contrast to the iodine-induced thyrotoxicosis, which is termed type-1 amiodarone-induced thyrotoxicosis.

Symptoms are those typical for thyrotoxicosis, although older or elderly patients may have relatively few symptoms, other than weight loss. Most patients will have an easily palpable multinodular goiter; occasionally, a diffuse goiter is felt.

What else could the patient have?

Thyrotropin-secreting pituitary adenomas

As in any thyrotoxic patient, the entire differential diagnosis of thyrotoxicosis needs to be considered. In this particular disorder, however, where the serum TSH is inappropriately elevated, rather than suppressed, the differential diagnosis is quite limited. The main disorder to consider is generalized resistance to thyroid hormone (RTH), an autosomal dominant disorder with similar biochemical findings as TSHomas.

Patients with RTH are not clinically thyrotoxic, however, but may easily be confused clinically with those with TSH-secreting pituitary tumors, since RTH patients often are anxious and have tachycardia and a goiter. In the rare entity of pituitary resistance to thyroid hormone (PRTH), patients are clinically thyrotoxic and have elevated levels of serum TSH, T4, and T4. Other disorders to consider are the few rare forms of abnormal binding of T4 and T3 to plasma proteins, where serum thyroid hormone concentrations are elevated, and TSH levels are normal. Such patients are clinically euthyroid.

Gestational trophoblastic tumors

All causes of gestational hyperthyroidism need to be considered, including patients with gestational transient thyrotoxicosis and hyperemesis gravidarum (both in which serum levels of hCG are usually elevated) and Graves’ disease. Patients with trophoblastic disease, however, lack features of Graves’ disease, including (with some exceptions) diffuse goiter and ophthalmopathy. Gestational transient thyrotoxicosis is typically mild, occurs at the end of the first trimester, and usually resolves several weeks later. Hyperemesis gravidarum also is mild and associated with vomiting.

Extrathyroidal causes of thyrotoxicosis

Taking the history from the patient will provide the diagnosis in the case of exogenous thyroid hormone ingestion. The other diagnoses may not be as easily ascertained, since patients with either struma ovarii or thyroid cancer could have co-existent thyrotoxicosis, such as Graves’ disease, and in the case of follicular cancer, the thyrotoxic state might be assumed to be due to suppressive doses of levothyroxine.

Iodine-induced thyrotoxicosis

A history of recent iodine exposure, in the context of a palpable goiter, is highly suggestive of the disorder. However, thyrotoxicosis due to toxic nodular goiter, Graves’ disease, and thyroiditis need to be considered. If the patient is prescribed thyroid hormone, excess thyroid hormone administration also is in the differential diagnosis.

Key laboratory and imaging tests

Thyrotropin-secreting pituitary adenomas

The hallmarks of TSHomas are elevations of serum T4 and T3, as well as inappropriately “normal” or elevated TSH concentrations. Unique among more than 80% of patients is an elevation in serum alpha-subunit, relative to the serum TSH concentration. In the patient with a suspected pituitary adenoma, a magnetic resonance imaging (MRI) study, with and without contrast, should be obtained. The majority of patients will have a macroadenoma, and in the 9 patients I have personally seen, all had tumors greater than 1 cm in size.

Gestational trophoblastic tumors

The serum TSH level will be suppressed and total and free levels of T4 and T3 are elevated. hCG levels are significantly elevated, generally above 200,000 mIU/ml. Essential in making the diagnosis, in addition to the hCG level, is the pelvic ultrasound, which, if positive, has characteristic features of pregnancy.

Extrathyroidal causes of thyrotoxicosis

Serum total and free T4 levels are elevated and TSH concentrations suppressed in all types of extrathyroidal thyrotoxicosis. Thyroglobulin levels will be markedly elevated with differentiated thyroid carcinoma and low in patients taking excess thyroid hormone. Serum hCG levels will be strikingly elevated (i.e. usually above 200,000 mIU/mL) in men with testicular cancer. The thyroid radioactive iodine uptake will be suppressed in patients taking excess thyroid hormone and in patients with struma ovarii. If struma ovarii is suspected, because of the presence of an ovarian mass, radioiodine will be taken up by the mass and can be imaged. Patients with functioning follicular thyroid cancer will have distant metastases, usually bone, which often take up radioiodine.

Iodine-induced thyrotoxicosis

Serum total and free T4 levels are elevated, and TSH concentrations are suppressed. A 24 hour I-123 uptake and scan should be performed, and if the uptake is either low or nearly suppressed to less than 1 percent/24 hours, the diagnosis of iodine excess is supported. An elevated diffuse uptake suggests Graves’ disease, while an elevated uptake with areas of autonomy suggests toxic nodular goiter.

Other tests that may prove helpful diagnostically

Thyrotropin-secreting pituitary adenomas

The principle diagnostic dilemma rests between patients with TSHomas and RTH, especially if the serum alpha-subunit is not elevated relative to TSH, which is the case in a minority of TSHoma patients and all of RTH patients. TSHomas are autonomous, and resistant to either stimulation with thyrotropin releasing hormone (TRH), and thyroid hormone suppression, whereas patients with RTH have intact feedback mechanisms, albeit at a much higher set point.

TRH is not available in the United States, thus when the diagnosis is unclear (e.g., if the ratio of serum alpha-subunit to TSH is normal), TSH adenomas may be distinguished from RTH by administering T3 (100 mcg/day for 10 days) and measuring TSH levels before and at the end of the 10 day period. Patients with RTH will experience TSH inhibition, whereas those with TSHomas will not. A caveat here is that since the T3 dose is pharmacologic, its use may be contraindicated in the elderly, or in those individuals with comorbid conditions, such as underlying heart disease.

Gestational trophoblastic tumors

If Graves’s disease is still under consideration, serum TSH receptor antibodies may be measured, which are nearly always positive in patients with Graves’ disease and negative in patients with trophoblastic tumors.

Iodine-induced thyrotoxicosis

If there is ambiguity regarding the diagnosis, a spot urine for iodine and creatinine, or a 24 hour urine for iodine may be measured, with a 24 hour urinary iodine of greater than 1000 mcg highly suggestive of iodine excess. Most individuals in the United States excrete less than 300-500 mcg of iodine daily.

Management and treatment of the disease

Thyrotropin-secreting pituitary adenomas

Transsphenoidal surgery with tumor removal is the cornerstone of treatment. Cure varies with the size and invasiveness of the tumor, with outright cure or significant improvement being reported in approximately two-thirds of patients. In such cases, normal T4 and T3 levels can be detected within several weeks. Reoperation is sometimes necessary if there is significant residual tissue seen on MRI imaging.

In patients who have failed surgery, the somatostatin analogue, octreotide (administered subcutaneously 2-3 times daily), has been shown to normalize thyroid function tests in more than 90% of patients. A long-acting form, lanreotide (given intramuscularly once monthly), is nearly equally as effective and much easier to use.

Dopamine agonists, such as bromocriptine and cabergoline, have been used with partial success in patients who co-secrete prolactin, and lanreotide has been used as an adjunct in patients who also secrete growth hormone.

Therapy with thionamide drugs, while temporarily of benefit preoperatively, are not indicated longterm, in part because of the concern for tumor growth with additional TSH stimulation. Octreotide, however, may be indicated preoperatively in patients with significant hyperthyroidism.

Finally, ablative therapy, either in conjunction with surgery or radioactive iodine, is contraindicated since the fundamental defect of the pituitary tumor is still present and may actually increase in size.

Gestational trophoblastic tumors

Treatment of hyperthyroidism due to trophoblastic tumors involves treatment of the tumor itself. With benign hydatidiform moles, evacuation may be sufficient, whereas treatment of choriocarcinoma also involves chemotherapy. In all cases, treatment of the lesion results in a reduction of hCG concentration, and hence, lowering of serum T4 and T3 levels. Thionamide drugs may be added as an adjunct during treatment of choriocarcinoma.

Extrathyroidal causes of thyrotoxicosis

Management of patients taking excess thyroid hormone involves dose adjustments, and when ingestion is surreptitious, counseling. Struma ovarii is treated surgically, and when the hyperthyroidism is clinically significant, thionamide drugs may be added as an adjunct until the patient is euthyroid. Radioiodine has also been used in cases of malignant struma with incomplete tumor removal. Radioiodine is also employed in the treatment of metastatic follicular thyroid cancer; thionamide drugs are also useful in lowering thyroid hormone levels. The thyrotoxicosis associated with testicular cancer may be managed with thionamide drugs until specific chemotherapy for the cancer has had beneficial effect. With all forms of hyperthyroidism, beta-blockers may be used to control symptoms.

Iodine-induced thyrotoxicosis

The cornerstone of management is discontinuation of the exogenous iodine and avoidance of its use in the future. If a patient must undergo another exam with iodinated radiocontrast in the future, methimazole should be administered just prior and several days after iodine exposure to inhibit thyroid iodine uptake. Perchlorate has also been used for this purpose (although it is not readily available in the United States, it can be compounded by a pharmacy using reagent-grade perchlorate).

Hyperthyroid symptoms may be controlled with the use of beta-adrenergic blocking agents, such as propranolol or atenolol. In elderly patients with multiple comorbidities, methimazole administration may be of some benefit. It should be noted that iodine-induced thyrotoxicosis may last anywhere from 4 weeks to over one year, depending on the source of iodine. For example, amiodarone is fat soluble, stored in the liver, and may release iodine for many months.

What’s the Evidence?/References

Beck-Peccoz, P, Persani, L, Mannavola, D, Campi, I. “TSH-secreting adenomas”. Best Pract Res Clin Endocrinol Metab. vol. 23. 2009. pp. 597-606. (Excellent review on TSH-secreting adenomas from the endocrine literature.)

Brucker-Davis, F, Oldfield, EH, Skarulis, MC. “Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity and treatment outcome in 25 patients followed at the National Institutes of Health”. J Clin Endocrinol Metab. vol. 84. 1999. pp. 476-86. (Summary of a center's experience regarding TSH-secreting adenomas.)

Clarke, MJ, Erickson, D, Castro, MR. “Thyroid-stimulating pituitary adenomas”. J Neurosurg. vol. 109. 2008. pp. 17-22. (Excellent review on TSH-secreting adenomas from the neurosurgical literature.)

Macchia, E, Gasperi, M, Lombardi, M, Morselli, L, Pinchera, A. “Clinical aspects and therapeutic outcome in thyrotropin-secreting pituitary adenomas: a single center’s experience”. J Endocrinol Invest. vol. 32. 2009. pp. 773-9. (Summary of a center's experience regarding TSH-secreting adenomas.)

Refetoff, S, Weiss, RE, Usala, SJ. “The syndrome of resistance to thyroid hormone”. Endocr Rev. vol. 14. 1993. pp. 348(Summary of thyroid hormone resistance.)

Hershman, JM. “The role of human chorionic gonadotropin as a thyroid stimulator in normal pregnancy”. J Clin Endocrinol Metab. vol. 93. 2008. pp. 3305-6. (Provides a summary of the association between HCG and TSH.)

Walkington, L, Webster, J, Hancock, BW, Everard, J, Coleman, RE. “Hyperthyroidism and human chorionic gonadotropin production in gestational trophoblastic disease”. Br J Cancer. vol. 104. 2011. pp. 1665-9. (Provides a summary of the association between HCG and TSH.)

Hershman, JH. “Physiological and pathological aspects of the effect of human chorionic gonadotropin on the thyroid”. Best Pract Res Clin Endocrinol Metab. vol. 18. 2004. pp. 249-65. (Provides a summary of the association between HCG and TSH.)

Gillespie, AM, Lidbury, EA, Tidy, JA, Hancock, BW. “The clinical presentation, treatment and outcome of patients diagnosed with possible ectopic molar gestation”. Int J Gynecol Cancer. vol. 14. 2004. pp. 366(Provides a summary of the association between HCG and TSH.)

Norman, RJ, Green-Thompson, RW, Jialal, I. “Hyperthyroidism in gestational trophoblastic neoplasia”. Clin Endocrinol (Oxf). vol. 15. 1981. pp. 395(Provides a summary of the association between HCG and TSH.)

Goodwin, TM, Montoro, M, Mestman, JH, Pekary, AE, Hershman, JM. “The role of chronic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum”. J Clin Endocrinol Metab. vol. 75. 1992. pp. 1333-7. (Provides a summary of the association between HCG and TSH.)

Hershman, JM. “Human chorionic gonadotropin and the thyroid: hyperemesis gravidarum and trophoblastic tumors”. Thyroid. vol. 9. 1999. pp. 653-7. (Provides a summary of the association between HCG and TSH.)

Mariotti, S, Martino, E, Cupini, C. “Low serum thyroglobulin as a clue to the diagnosis of thyrotoxicosis factitia”. N Engl J Med. vol. 307. 1982. pp. 410(Reviews thyrotoxicosis factitia.)

Kasagi, K, Takeuchi, R, Miyamoto, S, Misaki, T, Inoue, D. “Metastatic thyroid cancer presenting as thyrotoxicosis: report of three cases”. Clin Endocrinol (Oxf). vol. 40. 1994. pp. 429(Reviews thyrotoxicosis associated with metastatic thyroid cancer.)

Fradkin, JE, Wolff, J. “Iodide-induced thyrotoxicosis”. Medicine (Baltimore). vol. 62. 1983. pp. 1-20. (Provides an overview of iodide-induced thyrotoxicosis.)

Stanbury, JB, Ermans, AE, Bourdoux, P. “Iodine-induced hyperthyroidism: occurrence and epidemiology”. Thyroid. vol. 8. 1998. pp. 83-100. (Provides an overview of iodide-induced thyrotoxicosis.)

Lawrence, JE, Lamm, SH, Braverman, LE. “The use of perchlorate for the prevention of thyrotoxicosis in patients given iodine rich contrast agents”. J Endocrinol Invest. vol. 22. 1999. pp. 405-7. (Reviews a treatment option for iodine-induced thyrotoxicosis.)