Mortality and risk of diabetes, liver disease, and heart disease in individuals with haemochromatosis HFE C282Y homozygosity and normal concentrations of iron, transferrin saturation, or ferritin: prospective cohort study

Abstract

Objectives: To test whether haemochromatosis HFE C282Y homozygotes have increased risk of diabetes, liver disease, and heart disease even when they have normal plasma iron, transferrin saturation, or ferritin concentrations and to test whether C282Y homozygotes with diabetes, liver disease, or heart disease have increased mortality compared with non-carriers with these diseases.

Design: Prospective cohort study.

Setting: Three Danish general population cohorts: the Copenhagen City Heart Study, the Copenhagen General Population Study, and the Danish General Suburban Population Study.

Participants: 132 542 individuals genotyped for the HFE C282Y and H63D variants, 422 of whom were C282Y homozygotes, followed prospectively for up to 27 years after study enrolment.

Main outcome measure: Hospital contacts and deaths, retrieved from national registers, covering all hospitals and deaths in Denmark.

Results: Comparing C282Y homozygotes with non-carriers, hazard ratios were 1.72 (95% confidence interval (CI) 1.24 to 2.39) for diabetes, 2.22 (1.40 to 3.54) for liver disease, and 1.01 (0.78 to 1.31) for heart disease. Depending on age group, the absolute five year risk of diabetes was 0.54-4.3% in C282Y homozygous women, 0.37-3.0% in non-carrier women, 0.86-6.8% in C282Y homozygous men, and 0.60-4.80% in non-carrier men. When studied according to levels of iron, transferrin saturation, and ferritin in a single blood sample obtained at study enrolment, risk of diabetes was increased in C282Y homozygotes with normal transferrin saturation (hazard ratio 2.00, 95% CI 1.04 to 3.84) or ferritin (3.76, 1.41 to 10.05) and in C282Y homozygotes with normal levels of both ferritin and transferrin saturation (6.49, 2.09 to 20.18). C282Y homozygotes with diabetes had a higher risk of death from any cause than did non-carriers with diabetes (hazard ratio 1.94, 95% CI 1.19 to 3.18), but mortality was not increased in C282Y homozygotes without diabetes. The percentage of all deaths among C282Y homozygotes that could theoretically be prevented if excess deaths in individuals with a specific disease were eliminated (the population attributable fraction) was 27.3% (95% CI 12.4% to 39.7%) for diabetes and 14.4% (3.1% to 24.3%) for liver disease. Risk of diabetes or liver disease was not increased in H63D heterozygotes, H63D homozygotes, C282Y heterozygotes, or C282Y/H63D compound heterozygotes.

Conclusions: Haemochromatosis C282Y homozygotes with normal transferrin saturation and/or ferritin, not recommended for HFE genotyping according to most guidelines, had increased risk of diabetes. Furthermore, C282Y homozygotes with diabetes had higher mortality than non-carriers with diabetes, and 27.3% of all deaths among C282Y homozygotes were potentially attributable to diabetes. These results indicate that prioritising detection and treatment of diabetes in C282Y homozygotes may be relevant.

Fig 1

Relative risk of diabetes according to haemochromatosis genotypes C282Y and H63D, adjusted for age and sex. Diabetes was defined as any hospital contact with diabetes (inpatient admission, emergency department visit, or outpatient visit) at any time before or after study enrolment. Non-carrier/non-carrier=non-carrier for both C282Y and H63D; H63D/non-carrier=heterozygous for H63D variant; H63D/H63D=homozygous for H63D variant; C282Y/non-carrier=heterozygous for C282Y variant; C282Y/H63D=compound heterozygous for C282Y and H63D variants; C282Y/C282Y=homozygous for C282Y variant. CI=confidence interval

Fig 2

Relative risk of diabetes, liver disease, and heart disease and subcategories of these conditions for C282Y homozygotes (C282Y/C282Y) compared with non-carriers of haemochromatosis variants C282Y and H63D (non-carrier/non-carrier), adjusted for age and sex. Any diabetes was defined as any hospital contact with diabetes; subcategory “diabetes with complication” was defined as any hospital contact with diabetes with complications (eye complications, nephropathy, angiopathy, gangrene, foot ulcer, neurological complication, or other complications due to diabetes). Any liver disease was defined as any hospital contact with liver disease; subcategory “liver cirrhosis” was defined as any hospital contact with liver cirrhosis. Any heart disease was defined as any hospital contact with heart disease; subcategory “heart failure” was defined as any hospital contact with heart failure. For all diagnoses, all types of hospital contacts (inpatient admission, emergency department visits, and outpatient visits) at any time before or after study enrolment were included. CI=confidence interval

Fig 3

Relative risk of diabetes for C282Y homozygotes (C282Y/C282Y) compared with non-carriers for both C282Y and H63D (non-carrier/non-carrier) stratified according to levels of plasma iron, transferrin saturation, and ferritin at study enrolment, adjusted for age and sex. Diabetes was defined as any hospital contact with diabetes (inpatient admission, emergency department visit, or outpatient visit) at any time before or after study enrolment. Analysis excludes individuals (n=11 C282Y homozygotes) with diagnosis of haemochromatosis at study enrolment to exclude that levels of iron, transferrin saturation, or ferritin in blood samples obtained at study enrolment were affected by previous therapeutic phlebotomy. Normal iron was defined as iron 9-34 µmol/L and high iron as >34 µmol/L. Normal transferrin saturation was defined as 10-45% for women aged ≤50 years and 15-45% for women >50 and men regardless of age. High transferrin saturation was defined as >45% for both sexes. Normal ferritin was defined as ferritin 12-200 µg/L for women and 12-300 µg/L for men and high ferritin as >200 µg/L for women and >300 µg/L for men. As very few C282Y homozygotes had low levels of iron, transferrin saturation, or ferritin, individuals with low levels of iron, transferrin saturation, or ferritin were excluded from analysis stratified for specific parameter that was low. Owing to Danish regulations on data privacy, fewer than 3 individuals with diabetes in a column is reported as “<3” but risk estimates were calculated using exact numbers. CI=confidence interval

Fig 4

Graphical curves illustrating risk of diabetes by showing proportion of individuals without diabetes as function of time for C282Y homozygotes (C282Y/C282Y) and non-carriers (non-carrier/non-carrier) with normal levels of iron, transferrin saturation, or ferritin and for C282Y homozygotes and non-carriers with normal levels of both ferritin and transferrin saturation. Curves depict proportion of individuals without diabetes estimated using Cox proportional hazards model on risk of diabetes. Diabetes was defined as any hospital contact with diabetes (inpatient admission, emergency department visit, or outpatient visit) at any time before or after study enrolment. Analysis excludes individuals with diagnosis of haemochromatosis at study enrolment to exclude that levels of iron, transferrin saturation, or ferritin in blood samples obtained at study enrolment were affected by previous therapeutic phlebotomy. Arrows on x axis mark median time from diabetes to study enrolment for individuals with diagnosis of diabetes before study enrolment and median time from study enrolment to diabetes for individuals with diagnosis of diabetes after study enrolment. P values are from log-rank test comparing C282Y homozygotes (C282Y/C282Y) with non-carriers for both C282Y and H63D (non-carrier/non-carrier)

Fig 5

Relative risk of diabetes in C282Y homozygotes (C282Y/C282Y) compared with non-carriers (non-carrier/non-carrier) and risk of death from any cause in C282Y homozygotes and non-carriers with and without diabetes, stratified by whether or not C282Y homozygotes had diagnosis of haemochromatosis at any time before or after study enrolment and, adjusted for age and sex. Diagnoses of diabetes and haemochromatosis were retrieved from Danish National Patient Registry. Diabetes was defined as any hospital contact with diabetes; haemochromatosis was defined as any hospital contact with haemochromatosis. For both diagnoses, all types of hospital contacts (inpatient admission, emergency department visits, and outpatient visits) were included. CI=confidence interval

Fig 6

Relative risk of death from any cause for C282Y homozygotes (C282Y/C282Y) and non-carriers for both C282Y and H63D (non-carrier/non-carrier), adjusted for age and sex, including all individuals irrespective of disease with further stratification according to whether or not individuals had diagnosis of diabetes, liver disease, or heart disease at any time before or after study enrolment. Diabetes was defined as any hospital contact with diabetes, liver disease was defined as any hospital contact with any liver disease, and heart disease was defined as any hospital contact with any heart disease. For all three diagnosis categories, all types of hospital contacts (inpatient admission, emergency department visits, and outpatient visits) at any time before or after study enrolment were included. CI=confidence interval; PAF=population attributable fraction for each disease (diabetes, liver disease, or heart disease) on death from any cause. *Age and sex adjusted hazard ratio (95% CI) for death from any cause comparing C282Y homozygotes with diabetes and non-carriers with diabetes. †Age and sex adjusted hazard ratio (95% CI) for death from any cause comparing C282Y homozygotes with liver disease and non-carriers with liver disease. ‡Age and sex adjusted hazard ratio (95% CI) for death from any cause comparing C282Y homozygotes with heart disease and non-carriers with heart disease