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Inappropriately elevated TSH and weight loss
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A 45-year-old Ethiopian man presented to his primary care doctor with several months of weight loss, generalized weakness, fatigue, sweats, heat intolerance, weakness and difficulty climbing stairs caused by shortness of breath. He denied any visual changes but reported daily throbbing frontal headaches. He denied palpitations, tremor, diarrhea and constipation. He denied any galactorrhea or breast pain. A review of systems was otherwise negative.
On physical examination, he was afebrile with a normal pulse and blood pressure; extraocular movements were intact without ophthalmoplegia; cranial nerve exam was within normal limits; thyroid gland was normal in size and texture and was nontender; there were no palpable thyroid nodules; there was no evidence of gynecomastia or galactorrhea; he did not have fine tremor; the relaxation of his deep tendon reflexes were normal.
 Soo Rhee |
 Stephanie L. Lee |
Laboratory testing revealed elevated thyroid function studies with total triiodothyronine (T3) 303 ng/dL (60 ng/dL-181 ng/dL) and free thyroxine (T4) 2.11 ng/dL (0.89 ng/dL-1.8 ng/dL). However, thyroid-stimulating hormone, which should be suppressed, was also elevated with a TSH of 6.1 uU/mL (0.35 uU/mL-5.5 uU/mL). Repeat testing confirmed the high peripheral levels of T3 and T4, high TSH and negative thyroid antibody panel: total T3 315 ng/dL, total T4 15.1 (4.5 mcg/dL-10.9 mcg/dL), T3RU 30.9% (22.5%-37%), free T4 index 4.7 (1.0-4.0), and TSH 8.3 uU/mL. Similar results were found in his records from his prior evaluation at a different institution. Finally, his serum was pre-incubated in a heterophile antibody absorption tube prior to assay, which had no effect on the measured TSH level.
Brain MRI with gadolinium revealed a 1.9-cm × 1.5-cm × 1.8-cm heterogeneously enhancing mass centered within the right side of the pituitary gland. The sella was enlarged, measuring 2 cm with thinning of the anterior and inferior boney margins. There was displacement of the infundibulum to the left. The right carotid artery within the cavernous sinus was displaced rostrally, suggesting mass effect and possible cavernous sinus invasion by the pituitary tumor (figure 1A).
Thyrotropinoma
The combination of high thyroid hormone levels, inappropriately elevated TSH level and pituitary mass on imaging raised the concern of a TSH-secreting pituitary macroadenoma (TSHoma). Additional laboratory data confirmed this diagnosis with an elevated alpha subunit level 7.3 ng/dL (<0.6 ng/dL), elevated alpha subunit to TSH molar ratio 12.0 (<1) and elevated sex hormone-binding globulin level 54 nmol/L (9 nmol/L-45 nmol/L). Other pituitary hormonal evaluation was normal except for a slight increase in serum adrenocorticotropic hormone, with ACTH 79 pg/mL (7 pg/mL-50 pg/mL). However, he had a normal 24-hour urinary-free cortisol collection of 16.8 mcg per 24 hours (4 mcg per 24 hours-50 mcg per 24 hours), which ruled out ACTH-dependent cortisol excess.
The patient was started on beta-blocker therapy and methimazole 10 mg once daily for short-term preoperative management of hyperthyroidism. Additionally, formal visual field testing revealed normal visual fields. The patient had an endoscopic transsphenoidal resection of pituitary macroadenoma.
The beta-blocker and methimazole were stopped in the immediate postoperative period, and subsequent biochemical evaluation revealed a normalization of TSH and peripheral thyroid hormone levels: TSH 2.36 uIU/mL, total T3 76 ng/dL, total T4 9.3 mcg/dL, T3RU 37.1%, free T4 index 3.5.
About one month postoperatively, he had recurrent elevation of TSH that was inappropriate for peripheral thyroid hormone levels that were in the upper range of normal: TSH 5.51 uIU/mL, total T 3 194 ng/dL, total T4 11.7 mcg/dL, T3RU 28.1%, free T4 index 3.3, free T4 1.31 ng/dL. Additionally, postoperative MRI revealed residual adenomatous tissue, with proximity to the right internal carotid artery (figures 1B, 1C).
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Photo courtesy of: Stephanie L.
Lee, MD, PhD |
Octreotide therapy, sandostatin long-acting release therapy, was initiated with the goal of medical control of TSH secretion and tumor growth. His response to two months of therapy has been promising, with a reduction in TSH and peripheral levels into the reference range: TSH 5 uIU/mL; total T3 165 ng/dL; total T4 10.6 mcg/dL; T3RU 28.3%; free T4 index 3; free T4 1.15 ng/dL.
TSH-secreting pituitary adenomas, or thyrotropinomas, account for less than 1% of all pituitary tumors. Most patients with TSH-secreting pituitary adenomas have signs and symptoms of hyperthyroidism. The autonomous TSH secretion by the pituitary adenoma is refractory to negative feedback from thyroid hormone and results in inappropriately normal or elevated TSH values. Upon diagnosis, these tumors are usually macroadenomas ( >1 cm), often with cavernous sinus invasion and unresectable. The inappropriate elevation of TSH is usually minimal and often less than 20 uU/dL.
The diagnosis of TSH-secreting pituitary adenoma is based on suspicion from clinical presentation, elevated T4 and T3 levels, inappropriately normal or elevated TSH, and imaging consistent with pituitary adenoma.
Most TSH-secreting pituitary adenomas have an elevation of serum alpha-subunit level and a high alpha-subunit to TSH molar ratio. Hormones including TSH, follicle-stimulating hormone, luteinizing hormone and human chorionic gonadotropin are composed of two protein subunits. They all have a common alpha subunit associated with a second protein subunit that is hormone specific, ie, beta subunit of hCG, a common pregnancy test. In TSH-secreting pituitary tumors, there is poorly regulated subunit synthesis that often leads to an excess production of alpha subunits compared with the beta subunit. This results in high absolute alpha-subunit values and high molar ratio of alpha-subunit to TSH.
The alpha-subunit to TSH molar ratio can be calculated with the following formula: [serum alpha-subunit / TSH] × 10. It has been reported that about 10% of TSH-secreting pituitary adenomas will exhibit a normal alpha-subunit value and/or a normal alpha-subunit to TSH molar ratio.
Diagnosis, management
The differential diagnosis includes the presence of heterophile antibodies, including the best recognized one, the human anti-mouse antibodies that interfere with the two-site TSH immunoassay. The two-site immunoassay contains a capture antibody fixed to a solid surface that recognizes TSH, a second antibody that recognizes a different site on the TSH molecule and is tagged with a signaling enzyme.
In the presence of the TSH molecule, the capture and signaling antibodies “sandwich� the TSH molecule. After washing, the only signaling antibodies remaining are those attached to TSH, so the signal reflects the amount of TSH present. Usually, these antibodies are obtained from animals, typically mice. If the patient’s blood has antibodies to mice antigens, then it will bind to both the capture and signaling antibodies, making a bridge and resulting in a false positive result. To correct for this interaction, commercially available blocking tubes have immunoglobulin G, which bind and neutralize many but not all heterophile antibodies. If the bridging antibodies are neutralized, then the assay will read the correct amount of TSH in the tube. Unfortunately, these tubes will not detect all cases of heterophile antibodies, so a negative result does not exclude the diagnosis.
Another maneuver is to use a TSH assay from another manufacturer because the heterophile antibodies do not interfere with all assays.
The syndrome of resistance to thyroid hormone (RTH) should be evaluated in this clinical situation. A T3 suppression test can be conducted to distinguish between TSH-secreting pituitary adenoma and RTH. TSH-secreting pituitary adenomas lose the normal T3 feedback inhibition of TSH secretion, whereas patients with RTH will show some feedback inhibition of the TSH level. Additionally, serum SHBG concentrations are elevated in patients with TSH-secreting pituitary adenoma, reflecting a functional response of the biological activity of excess T4, but will usually be normal in patients with RTH.
Initial management of TSH-secreting pituitary adenomas consists of surgical resection. However, only one-third of cases are cured by surgery alone because of large size and high likelihood of cavernous sinus invasion in most cases.
In the event of recurrence, radiotherapy or medical therapy with octreotide analogues should be considered. Medical therapy with octreotide analogues has been successful in control of biochemical disease and prevention of tumor growth; however, success rates vary among case series reports.
The medical treatment of TSHomas mainly rests on the administration of somatostatin analogues, such as octreotide and lanreotide, which are effective in reducing TSH secretion in more than 90% of patients with consequent normalization of free T4 and free T3 levels and restoration of the euthyroid state.
Failure to recognize the presence of a TSHoma may result in these invasive macro pituitary adenomas to continue to grow and result in compression symptoms such as cranial nerve injury in the cavernous sinus or optic chiasm compression and vision loss.
Because of the drastically different management of TSH-secreting pituitary adenoma, RTH and artificially elevated TSH from heterophile antibodies, patients should have a complete biochemical evaluation that includes measurement of the alpha-subunit, evaluation of the alpha-subunit to TSH molar ratio, exclusion of heterophile antibodies, including anti-human mouse antibodies, and differentiation from RTH. Comprehensive biochemical and radiologic evaluations are necessary to make an informed clinical diagnosis of this rare cause of thyrotoxicosis.
Soo Rhee, MD, is a Fellow in Endocrinology, and Stephanie L. Lee, MD, PhD, is Associate Professor of Medicine and Associate Chief, both in the Section of Endocrinology, Diabetes and Nutrition at Boston Medical Center.
For more information:
- Beck-Peccoz P. Best Pract Res Clin Endocrinol Metab. 2009;23:597-606.
- Refetoff S. Endocr Rev. 1993;14:348-399.
- Brucker-Davis F. J Clin Endocrinol Metab. 1999;84:476-486.