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Objective: It is not known to what extent iron overload predicts prognosis in patients with diabetes after diagnosis or whether iron overload is a risk factor independent of the HFE genotype. We investigated total and cause-specific mortality according to increased transferrin saturation (≥ 50 vs. <50%), whether mortality is driven by the HFE genotype, and whether early measurement of transferrin saturation helps to predict mortality outcome., Research Design and Methods: Cohort 1 included patients with late-onset type 1 diabetes (n = 716) with a cross-sectional measurement of transferrin saturation and HFE genotype. Cohort 2 included consecutively recruited patients with any diabetes (n = 6,120), transferrin saturation measurement at referral, and HFE genotype if transferrin saturation was above 50%., Results: In cohort 1, the hazard ratio for total mortality was 2.3 (95% CI 1.3-3.9; P = 0.002) and for cause-specific mortality by neoplasms was 5.8 (2.4-14; P = 0.00007) in patients with transferrin saturation ≥ 50 vs. <50%. Excluding genotypes C282Y/C282Y and C282Y/H63D gave similar results. The hazard ratio for total mortality was 4.0 (1.2-13; P = 0.01) and for cause-specific mortality by neoplasms was 13 (3.6-49; P = 0.0001) in patients with C282Y/C282Y versus wild type. In cohort 2, total mortality was not different in patients with transferrin saturation ≥ 50 vs. <50%. In patients with late-onset type 1 diabetes and transferrin saturation ≥ 50%, the hazard ratio for total mortality was 0.4 (0.2-0.9; P = 0.03) in cohort 2 versus cohort 1., Conclusions: Increased transferrin saturation and HFE genotype C282Y/C282Y predict total mortality in patients with late-onset type 1 diabetes, and increased transferrin saturation after diagnosis is an independent risk factor. Early measurement of transferrin saturation in these patients leading to early intervention improves life expectancy.

Objective: We tested the hypothesis that elevated transferrin saturation is associated with an increased risk of any form of diabetes, as well as type 1 or type 2 diabetes separately., Research Design and Methods: We used two general population studies, The Copenhagen City Heart Study (CCHS, N = 9,121) and The Copenhagen General Population Study (CGPS, N = 24,195), as well as a 1:1 age- and sex-matched population-based case-control study with 6,129 patients with diabetes from the Steno Diabetes Centre and 6,129 control subjects, totaling 8,535 patients with diabetes and 37,039 control subjects., Results: In the combined studies, odds ratios in those with transferrin saturation ≥50% vs. <50% were 2.1 (95% CI 1.3-3.4; P = 0.003) for any form of diabetes; 2.6 (1.2-5.6; P = 0.01) for type 1 diabetes; and 1.7 (1.4-2.1; P = 0.001) for type 2 diabetes., Conclusions: Elevated transferrin saturation confers a two- to threefold increased risk of developing any form of diabetes, as well as type 1 and type 2 diabetes separately.

Summary: Background: Although genotyping studies suggest that hereditary haemochromatosis is one of the most common genetic disorders in white people, it is still thought of as an uncommon disease. Our aim was to test the hypothesis that hereditary haemochromatosis is a disease often overlooked in patients with late-onset type 1 diabetes mellitus, a late manifestation of untreated iron overload. Methods: We did a retrospective study in which we genotyped for the C282Y and H63D mutations in the haemochromatosis gene in 716 unselected Danish patients who developed type 1 diabetes mellitus after age 30 years and 9174 controls from the general Danish population. We also screened for hereditary haemochromatosis by assessment of transferrin saturation. Findings: More patients with diabetes (n=9, relative frequency 1.26%, 95% CI 0.58-2.37) than controls (23, 0.25%, 0.16-0.38) were homozygous for C282Y (odds ratio 4.6, 2.0-10.1, p=0.0001). These patients had unrecognised signs of haemochromatosis. Transferrin saturation and ferritin concentrations ranged from 57% to 102% and 17 mg/L to 8125 mg/L, respectively. Frequency of compound heterozygosity (C282Y/H63D) did not differ between patients with diabetes (eight) and controls (131) (odds ratio 0.8, 95% CI 0.4-1.7). Positive and negative predictive values of transferrin saturation greater than 50%, in identification of C282Y homozygosity, were 0.26 and 1.00, respectively. A saturation of less than 50% therefore excluded C282Y homozygosity, whereas a saturation of more than 50% suggested C282Y homozygosity. Interpretation: Measurement of transferrin saturation followed by genetic testing could prevent liver and heart problems and improve life expectancy in patients with diabetes. Population screening before the onset of diabetes might improve the outlook of patients even further, but will be less cost effective. [ABSTRACT FROM AUTHOR]