Long-term TSH suppression in Graves- hyperthyroidism

Topic: GRAVES- HYPERTHYROIDISM

Title: Continued suppression of serum TSH level may be attributed to TSH receptor antibody activity as well as the severity of thyrotoxicosis and the time to recovery of thyroid hormone in treated euthyroid Graves- patients.

Authors: Chung YJ, Lee BW, Kim J-Y, Jung JH, Min Y-K, Lee M-S, Lee M-K, Kim K-W, Chung JH.

Reference: Thyroid 16: 1251-1257, 2006

Summary

Background

Serum TSH may remain suppressed for weeks or months despite normalization of serum T 4 and T 3 concentrations during antithyroid drug treatment in patients with Graves- hyperthyroidism.

Purpose

To evaluate the relationship between TSH receptor antibodies or other clinical parameters and the continued suppression of serum TSH during antithyroid drug therapy in Graves- disease.

Patients & Methods

One hundred and sixty seven patients with Graves- disease were studied. They had remained euthyroid for at least 12 months after normalization of serum T 3 and T 4 during treatment with antithyroid drugs. Initial therapy with 200-450 mg of propylthiouracil (n=137) or 15-45 mg of methimazole (n=30) resulted in normal serum T 3 and T 4 after 2.8 – 1.6 months in all patients. Antithyroid drugs with dose adjustments were continued for up to 36 months. Recovery of serum TSH was defined as a return of serum TSH to levels >0.30 mU/L. TSH receptor antibodies were measured using a first generation TBII assay: values >15% were considered positive.

Results

At the time of diagnosis, there were no differences in age, sex ratio, serum T 4 and TSH between TBII-positive (N=133) and TBII-negative (N=34) patients, but serum T 3 and I-131 uptake were higher in TBII-positive patients. The interval between onset of treatment and recovery of TSH was 8.7 – 5.9 months. This interval was positively correlated to pretreatment serum T 3 , uptake of I-131, and TBII. The interval until recovery of serum TSH was 9.4 – 6.1 months in TBII-positive and 6.0 – 4.0 months in TBII-negative patients. Recovery of serum TSH at 3, 6, 12, 18, 24, and 30 months, after the normalization of serum T 3 and T 4 were 39%, 62%, 63%, 74%, 88%, and 86% respectively in TBII-positive patients. The corresponding figures in TBII-negative patients were 74%, 91%, 91%, 91%, 94%, and 90% respectively. There was no difference in serum T 3 or T 4 between TBII-positive and TBII-negative patients at 3, 6 and 12 months after normalization of serum T 3 and T 4 , but TSH levels at these time-points were lower in the TBII-positive patients. TBII correlated inversely only with serum TSH.

Conclusions

Continued suppression of serum TSH in patients with Graves- disease during antithyroid drug treatment is related to TBII, pre-treatment severity of hyperthyroidism, and time to normalization of serum T 3 and T 4.

Commentary

Present study confirms and extends previous reports that TBII may be causally related to continuous TSH suppression in treated patients with Graves- hyperthyroidism, despite normal serum T 3 and T 4 concentrations. Evidence supporting a causal relationship is provided by the longer time interval between normalization of serum T 3 / T 4 and normalization of serum TSH in the TBII positive patients, as compared to the TBII-negative patients, and the inverse relation between TBII and TSH, independent of ambient serum T 3 and T 4 concentrations. The mechanism proposed to explain this observation is the binding of TBII to TSH receptors in the pituitary. TSH receptors have been demonstrated in folliculo-stellate cells of the human pituitary. Binding of TSH to these receptors might down-regulate TSH synthesis and release, thereby providing an ultra-short loop feedback in the regulation of TSH. How the folliculo-stellate cells signal to the thyrotroph cells remains to be elucidated. Binding of TBII to the folliculo-stellate TSH receptors might likewise inhibit pituitary TSH release.

The present study also showed that the time period required for normalization of TSH was determined – besides TBII – by pretreatment T 3 levels as well as by the rapidity of normalization of serum T 3 and T 4 . Because pretreatment T 3 was higher in TBII-positive patients, it remains plausible that these two other determinants of TSH recovery time were not independent factors. Nevertheless, the clinical relevance of the present study is that as long as serum TSH is suppressed, dose-adjustments of antithyroid drugs should be guided by serum T 3 and T 3 results and not by serum TSH. Some patients maintain a suppressed TSH for years and, occasionally, one may see patients with clearly decreased FT 4 levels because they receive a dose of antithyroid drugs that is too high in the presence of a TSH that is still suppressed.( Summary and commentary prepared by Wilmar Wiersinga ) Present summary and commentary are related to Chapter N- 11 (Section on Antithyroid Drug Therapy) of TDM