Total and Cause-Specific Mortality by Elevated Transferrin Saturation and Hemochromatosis Genotype in Individuals With Diabetes: Two General Population Studies

Abstract

OBJECTIVEMortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation (TS), and also in patients with type 1 diabetes and increased TS from a highly specialized diabetes clinic. Thus, we have recommended targeted screening for TS in specialized diabetes clinics. Whether mortality is also increased in individuals from the general population with diabetes and increased TS is unknown. RESEARCH DESIGN AND METHODSIn two Danish population studies (N = 84,865), we examined mortality according to baseline levels of TS and hemochromatosis genotype (HFE) G → A substitution at nucleotide 845 in codon 282 (C282Y/C282Y) in individuals with diabetes (type 1, N = 118; type 2, N = 3,228; total, N = 3,346). RESULTSThe cumulative survival rate was reduced in individuals with diabetes with TS ‡50% vs. <50% (log-rank; P < 0.0001), with median survival ages of 66 and 79 years, respectively. The hazard ratio (HR) for TS ‡50% vs. <50% was 2.0 (95% CI 1.3-2.8; P = 0.0004) for total mortality overall (and similar for men and women separately); 2.6 (1.3-5.4; P = 0.008) for neoplasms; and 3.4 (2.0-6.0; P = 0.00002) for endocrinological causes. A stepwise increased risk of total mortality was observed for stepwise increasing TS (log-rank test, P = 0.0001), with an HR for TS ‡70% vs. TS <20% of 4.8 (2.0-12; P = 0.0006). The HR for total mortality in individuals with diabetes for C282Y/C282Y versus wild type/wild type was 3.3 (1.04-10; P = 0.04), and for C282Y/C282Y and TS ‡50% versus wild type/wild type and TS <50% was 6.0 (1.5-24; P = 0.01). Six percent of these premature deaths can possibly be avoided by early screening for TS or HFE genotype. CONCLUSIONSIndividuals with diabetes, ascertained in the general population, with increased TS or HFE genotype have a twofold to sixfold increased risk of premature death.

Total and Cause-Specific Mortality by Moderately and Markedly Increased Ferritin Concentrations: General Population Study and Metaanalysis

“…Our results are in accordance with previous evidence that increased transferrin saturation is associated dose-dependently with increased total mortality (23)(24)(25). Another population-based study examined risk of premature death in individuals of mixed ethnicity with serum ferritin Ն200 vs 50 -99 g/L and did not find any association (9 ); however, compared to the present study, that study was smaller (n ϭ 1604), had shorter follow-up (12 years), and had actual HRs for total mortality of 0.7 (0.4 -1.3) and 0.9 (0.4 -2.1) in white women and men, respectively, overlapping with the present HRs.…”

“…Finally, iron supplementation has also been associated with risk of premature death (26 ). The association of increased plasma ferritin with increased risk of cancer and endocrinological mortality is in accordance with previous studies of increased transferrin saturation and cause-specific mortality (24,25 ). The association of increased plasma ferritin with increased risk of cardiovascular mortality is in accordance with a previous study of heterozygosity for hereditary hemochromatosis; however, the finding is contradictory to a previous metaanalysis of ferritin concentrations with coronary heart disease, although that metaanalysis did not cover other cardiovascular diseases or mortality (27 ) and was primarily based on small study populations with shorter follow-up than our study.…”

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

“…Increased transferrin saturation showed a dose-dependent association with an increased total mortality (65). A moderate to marked increase of ferritin concentrations also predicted early death in a dose-dependent linear manner among the general population (65) and among patients with T2D (66). Clinicians must be aware of the importance of preventing, diagnosing in a timely manner, and treating disturbances of iron metabolism in patients with MetS and T2D.…”

Diabetes inHFEHemochromatosis

“…In a 1991 study of Canadian patients with hemochromatosis, diabetes did not increase the risk of death after data were controlled for the presence of cirrhosis [140]. In a large study of Danes reported in 2014, the mortality risk in individuals with diabetes was more than threefold greater in those with HFE p.C282Y/p.C282Y than in those with HFE wt/wt genotypes [141]. …”