Diabetes Care. 2013 Sep;36(9):2646-54.
Total mortality by elevated transferrin saturation in patients with diabetes.
Ellervik C, Andersen HU, Tybjærg-Hansen A, Frandsen M, Birgens H, Nordestgaard BG, Mandrup-Poulsen T.
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark. firstname.lastname@example.org
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%.
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.
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.
In 2001 we had a publication in the Lancet (1)on the Prevalence of hereditary hemochromatosis in late-onset type 1 diabetes mellitus; the results changed clinical practice at the Steno Diabetes Center in Denmark in that we introduced screening for iron overload in all prevalent and newly referred patients to secure early diagnosis of hereditary hemochromatosis. Thus, in the present publication we have compared survival in those patients who were tested at random (the Lancet publication) with those that were tested at referral to the Steno Diabetes center(2). We showed that 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.
Hereditary hemochromatosis is characterized by life-long iron accumulation in the endocrine pancreas, liver, heart, joints, and other mainly endocrine organs, leading to diabetes(1;3), liver cirrhosis, hepatocellular carcinoma, arthritis, heart failure and various endocrine hypofunctions(4) with onset usually after 30 years of age in men and after menopause in women. Eighty-three percent of cases with hereditary hemochromatosis are explained by polymorphisms in the HFE gene (5). In HFE-related hemochromatosis with a mutated HFE protein the normal regulatory mechanism of iron uptake across the basolateral membrane of the enterocytes to the blood stream is disrupted leading to increased intestinal iron absorption by a complex mechanism involving a recently discovered iron-regulatory hormone called hepcidin. The treatment of hereditary hemochromatosis is with regular phlebotomy.
Non-hereditary hemochromatosis or secondary hemochromatosis may arise from chronic use of iron supplements, chronic liver disease, and especially chronic red blood cell (RBC) transfusion therapy for anemia in patients with ineffective erythropoiesis (6).
Furthermore, a meta-analysis has shown that increased intake of heme-iron is associated with increased risk of diabetes(7).
Previous general population studies have not shown any associations between all-cause mortality and haemochromatosis genotype C282Y/C282Y(8-11); however, in one study heterozygosity for C282Y has been associated with cardiovascular death in postmenopausal women(12).
A recent study in patients with hereditary hemochromatosis (HFE) demonstrated a decline in diabetes prevalence in patients diagnosed after determining that they carried the HFE gene compared to those diagnosed before(13) suggesting that awareness of HFE in general and development of diabetes in those patients in particular will translate into a greater life expectancy.
At the time of the Lancet publication in 2001 as well as now, it was not part of clinical guidelines to assess for hemochromatosis in specialised diabetes clinics or among general practitioners. It was our aim with the Lancet publication to assess whether there was a higher prevalence of patients with hemochromatosis among these patients than seen in the general population. The data confirmed this hypothesis. At that time, it was known from studies of patients with hemochromatosis that early detection(14-16) of the disease would halter or reduce co-morbidities. In 2001 we recommended measurement of transferrin saturation in all diabetic patients with diabetes onset after 30 years of age followed by genetic testing for HFE in cases with a transferrin saturation above 50% to improve life expectancy in patients with diabetes secondary to hereditary hemochromatosis(1). Therefore, we hypothesised/speculated that assessing this group of patients even earlier (i.e. at entry to Steno Diabetes Center) could in the future result in the earlier diagnosis of hemochromatosis and reduced premature death, but we did not have the data to justify that in 2001. In the present publication, we have assessed the recommendation of early measurement of transferrin saturation to prevent premature death in patients with late onset type 1 diabetes. Furthermore, we have investigated total mortality in patients with type 2 diabetes and other diabetes according to transferrin saturation and hemochromatosis genotype; we have shown that individuals with type 2 (17)diabetes, ascertained in the general population, with increased TS or HFE genotype have a 2-6-fold increased risk of premature death when not tested early.
In conclusion: iron overload in general and hereditary hemochromatosis in particular is associated with diabetes and death of diabetes if not diagnosed early. Thus, evidence points toward a potential for reducing body iron and thereby either preventing diabetes secondary to iron overload or improving survival in patients with diabetes; however, this needs to be further tested in randomized clinical trials.
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17. Ellervik C, Mandrup-Poulsen T, Tybjaerg-Hansen A, Nordestgaard BG (2013) Total and cause-specific mortality by elevated transferrin saturation and hemochromatosis genotype in individuals with diabetes – two general population studies. Diabetes Care in press: 10.2337/dc13-1198.