Mortality and co-morbidity among patients with Hemochromatosis and their first-degree relatives

Sammanfattning: Genetic hemochromatosis (GH) is an autosomal recessive disease caused by a C282Y mutation in the HFEgene, and is characterized by excess iron accumulation in multiple organs. Classical manifestations of GH include liver cirrhosis, liver cancer, diabetes mellitus, cardiomyopathy, and arthritis. Heterozygous mutation is common (1/5-1/15), and is associated with increased iron stores. In particular, siblings and twins of GHpatients have higher levels of iron compared to siblings and twins of preclinical GH- patients. Genetic screening of first-degree relatives (FDR) of GH-patients is common practice but little is known about morbidity, premature mortality, or strategies for their management. The aim of this thesis was to investigate the risk of all cause mortality, and morbidity due to cancer, ischemic heart disease (IHD), and joint disease in GH- patients and in their FDR using nationwide, population-based health and census registers. In the study on mortality (study II) a matched population-based cohort study of 3,832 GH-patients and their 14,496 FDRs was performed. 940 patients and 1,978 FDRs died during follow-up. Mortality data was compared with that of population controls and their FDRs. A markedly increased risk for death in patients hospitalized with GH was confirmed, but the risk was only modestly increased in GH-patients identified through other means than hospitalization. Among FDRs, we observed only a marginal increase in risk of death, which did not differ substantially from that of spouses of patients. In the study on risk for cancer (study I) 1,847 GH-patients were identified. During follow-up, 190 cancers were registered. In total, 529 cancers were registered in 5,973 FDRs. Standardized incidence ratio (SIR) was used as our measure of the relative risk (RR). The results for the patients and their FDRs were compared to specific cancer incidence rates from the general population. An elevated risk of primary liver cancer among GH-patients was confirmed. Among the FDRs, only a marginally increased (and historic) occurrence of liver cancer was observed, the histopathologic spectrum of which differed from that of the GH-patients. No support for increased occurrence of other cancers among GH-patients or their FDRs was provided. In the studies on risks for IHD, cardiomyopathy, joint disease, and joint replacement surgery among GHpatients and FDR 3,531; GH-patients and 11,794 FDRs were identified (study III and IV). The results were compared to controls and the FDRs to controls. An increased risk of cardiomyopathy among GH-patients was confirmed. By contrast, we found considerably weaker evidence of any altered risk of IHD among GHpatients and no evidence of any increased risks for cardiomyopathy or IHD among their FDRs. Besides the observation of an increased occurrence of arthropathy among GH-patients, our results indicate that patients were at particularly increased risks for joint replacement surgery. By contrast, there was no consistent pattern of increased or decreased risks of arthropathy, nor of joint replacement surgery, among their FDRs. In conclusion, patients with phenotypic GH are at increased risk for death, and diseases described above. FDRs of patients with GH, however, are neither at increased risk for death nor diseases associated with iron load or the most common diseases in the industrial world, IHD and malignancies. In the absence of other risk factors for liver disease and if their iron load is only moderately elevated this thesis did not find evidence to suggest monitoring these individuals on a regular basis.