TSH receptor antibodies: risk of recurrence and orbitopathy

TOPIC: Graves-orbitopathy

Title: Patients with severe Graves- ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission.

Authors: Ecktsein AK, Lax H, Losch C, Glowacka D, Plicht M, Mann K, Esser J & Morgenthaler NG.

Reference: Clinical Endocrinology 67: 607-612, 2007



Graves- hyperthyroidism and orbitopathy (GO) are frequently associated. This might be due to the putative pathogenic role of the TSH-receptor antibody (TRAb) in both conditions.


The objective of this retrospective observational study was to investigate the possible relationship between the severity of GO and relapse/remission rate of hyperthyroidism after antithyroid drug (ATD) treatment.

Patients and Methods: One hundred and fifty-eight patients with Graves- disease received ATD therapy for one year and, in case of relapse of hyperthyroidism, a second course of ATD, radioiodine therapy or surgical treatment. GO was defined as mild (N = 65) or severe (N = 93) according to severity and activity scores.


Remission of hyperthyroidism occurred in 27 patients with mild GO versus 7 patients with severe GO (8%, p<0.0001). Eventually, 49% of patients with mild GO and 84% of patients with severe GO (p<0.0001) required ablative therapy for hyperthyroidism. Patients with severe GO had higher TRAb levels than patients with mild GO, both at 6 and 12 months of ATD treatment. Probability of relapse of hyperthyroidism could be predicted in 97% of cases by TRAb levels > 7.5 U/L after 12 months of ATD therapy.


Patients with severe GO and high TRAb levels are unlikely to experience sustained remission of hyperthyroidism after ATD drug treatment.


Treatment of hyperthyroidism due to Graves- disease relies on either ablation of the thyroid by thyroidectomy or radioiodine therapy, or prolonged administration of antithyroid drugs (thionamides). Antithyroid drug (ATD) treatment is effective in controlling thyroid hyperfunction in most instances, but is associated with a high rate of relapse (~ 50-60%) when the drug is withdrawn after 18-24 months of therapy.

Hyperthyroidism due to Graves- disease is frequently accompanied by ocular involvement (Graves- orbitopathy, GO), rarely by dermopathy (pretibial myxedema) or acropachy. GO may be mild (and often self-limiting) or, less frequently, moderate-to-severe, posing problems for eyesight in 3-5% of cases. Moderate-to-severe GO is a major therapeutic challenge, and prevention of eye disease would be preferable to embarking into risky (and not infrequently partially ineffective) treatments.

While it is well established that TSH-receptor antibody (TRAb) is ultimately responsible for Graves- hyperthyroidism, its role in the pathogenesis of the orbitopathy is highly suspected but not proven so far. However, a relationship was been found between TRAb levels and clinical features of the eye disease. TRAb seems to represent an independent risk factor for the development of GO and helps to predict its severity and outcome.

In the present observational study, patients who had severe GO and persistingly high TRAb levels after 12 months of ATD treatment (>7.5 IU/L by a second-generation assay based on the human recombinant TSH receptor) were at high risk of having a relapse of hyperthyroidism after drug withdrawal. Graves- disease encompasses a spectrum of clinical situations from mild hyperthyroidism with no or limited ocular involvement and low-titer TRAb to severe hyperthyroidism with moderate-to-severe GO and high-titer TRAb. Patients reported to relapse in this study belonged to the subset of patients with severe Graves- disease as a whole.

The available evidence indicates that: a) thyroid dysfunction is a risk factor for the occurrence and progression of GO; b) TRAb is also such a risk factor; and c) the presence of severe GO and high TRAb titers makes remission of hyperthyroidism after ATD therapy unlikely. Putting all these considerations together, it might be concluded that ablative therapy (thyroidectomy, radioiodine, or thyroidectomy followed by radioiodine) should be preferred in these high-risk patients and performed early after the onset of Graves- disease and the initial control of hyperthyroidism by ATD. However, large randomized controlled trials are warranted to decide on whether such aggressive approach is superior to a more conservative approach (prolonged ATD therapy). Summary and commentary prepared by Luigi Bartalena (related to Chapters 10, 11, & 12 of TDM) Full paper obtainable at: http://www.blackwell-sinergy.com/doi/pdf/10.111/j.1365-2265.2007.02933.x

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