Immunologically-related or incidental coexistence of diabetes mellitus and Graves' disease; discrimination by anti-GAD antibody measurement

Abstract

Coexistence of diabetes mellitus and Graves' disease may be classified into either an immunologically-related or an incidental phenomenon. It has been reported that anti-GAD antibody (GAD-Ab) persists at high levels for longer duration in subjects with type I diabetes and Graves' disease, whereas the prevalence of positive GAD-Ab (1.5%) in 131 non-diabetic subjects with Graves' disease was comparable to that in normal subjects (0.3%, P = 0.2012). Thus, GAD-Ab might be a marker of the immunologically-related coexistence of the two diseases. To test this hypothesis, we investigated characteristics of Japanese subjects having both diseases according to the presence or absence of GAD-Ab. Sixty-one patients having diabetes mellitus and Graves' disease (24 men, 37 women, aged 53±2 years old, mean±SE) were consecutively registered between 1993-1997. The patients were divided into two groups of 14 GAD-Ab positive and 47 negative subjects. In the GAD-Ab positive subjects, earlier (32±3 years old) and abrupt onset (86%) of diabetes and insulin dependency (64%) were documented, as would be expected from the features of type 1 diabetes. Graves' disease often preceded diabetes (57%), presenting typical manifestations (79%). In contrast, older (45±2 years old, P = 0.0031) and gradual onset (87%, P < 0.0001) of diabetes, non-insulin dependency (74%, P < 0.0001), and masked manifestations of Graves' disease (57%, P = 0.0214) were common in the negative subjects. Precedence of diabetes dominated in these subjects (43%, P = 0.0109). Immunological studies showed less frequent HLA-DR 2 locus (0%, P < 0.02) in the GAD-Ab positive subjects. There was also a trend of higher frequency of HLA-DQA1*03 allele and of lower frequency of DQA1*01 allele in these subjects. Allelic frequency of cytotoxic T lymphocyte antigen 4 (CTLA-4) differed between the positive and negative subjects (P = 0.0432). There were distinct clinical and immunological differences between the GAD-Ab positive and negative subjects having both diabetes mellitus and Graves' disease. The present results indicate that GAD-Ab measurement could draw a distinction between the immunologically-related and incidental coexistence of the two diseases.