Increased TRAb and/or Low Anti-TPO Titers at Diagnosis of Graves’ Disease are Associated with an Increased Risk of Developing Ophthalmopathy after Onset

Abstract

Patients with low thyroid peroxidase antibodies (anti-TPO) and increased TSH-receptor antibodies (TRAb) at diagnosis of Graves' disease (GD) have been suggested to have an increased risk to develop Graves' ophthalmopathy (GO). The aim was to evaluate if GO development can be predicted.This is an observational study with registration of possible GD and GO risk factors.399 patients with GD were registered 2003-2008 in Malmö, Sweden and out of these 310 were retrospectively followed up to 6 years. The main outcome measures were anti-TPO titer, TRAb titer, smoking habits, radioiodine treatment and GO development.TRAb was assessed with a third generation assay at GD diagnosis in 231 patients. The proportion of patients with GO increased above the median 6.3 IU/L both at diagnosis of GD (p=0.001) and at follow-up (p=0.0001).The distribution of GO patients anti-TPO above or below 20 kIU/L at diagnosis of GD was similar between groups (p=0.239). However at follow-up anti-TPO<20 kIU/L was associated with an increased proportion of newly developed GO as compared to the cohort with anti-TPO>20 kIU/L (p=0.018).87% of patients who developed GO after GD diagnosis had TRAb above 6.3 IU/L and/or anti-TPO below 20 kIU/L. The proportion of GO was doubled in GD patients treated with radioiodine but could not explain the described findingsAnti-TPO<20 kIU/L and/or TRAb>6.3 IE/L at the time of GD diagnosis were associated with an increased risk to develop GO after diagnosis of GD.

Presence of Thyroid-Stimulating Hormone Receptor Antibodies in a Patient with Subacute Thyroiditis followed by Hypothyroidism and Later Graves' Disease with Ophthalmopathy: A Case Report

“…She had high TRAK levels and low or undetectable levels of TPOAbs. This is in agreement with our previous study [15], i.e. that this combination predisposes to endocrine ophthalmopathy [16].…”

The Effect of Radioiodine Treatment on TRAb, Anti-TPO, and Anti-TG in Graves’ Disease

“…The role of anti-TG in the pathogenesis of GD is unclear, but in a previous study examining discontinuation of ATD, it was shown that patients with low levels of anti-TG at the diagnosis of GD had a lower chance to stop the treatment with ATD, indicating a higher activity of GD in these patients [16]. A low level of anti-TPO at the diagnosis of GD has been coupled with an increased risk to develop GO both at diagnosis and during follow-up [8]. …”

“…Tobacco smoking is a risk factor for the development of both GD and Graves’ ophthalmopathy (GO), and in a recent review it is stated that current smoking increases the risk of GD approximately twofold and GO approximately threefold [6]. Independently of smoking, it has also been shown that higher TRAb increase the risk of GO both at and after diagnosis of GD [7, 8]. Treatment of GD with radioiodine is also a risk factor for the development of GO, and the pathophysiological process of GD and GO may be mediated by activating TRAb [9].…”

The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease

“…However, the role of orbital TPO in the pathogenesis of GO remains incompletely understood. The results of the studies assessing the association between TPOAbs and GO are highly inconsistent as some studies negate such an association, whereas others suggest that higher TPOAb serum levels in patients with GD are associated with increased or decreased risk of GO development. The effect of TSH receptor antibodies (TRAbs) in GO is better documented, but GO may develop in TRAb‐negative patients as well.…”