Paul C. Adams

Genetic variants for hemochromatosis have been identified in human fossils that are over 4000 years old in Northern Ireland. Iron overload can lead to life-threatening complications, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. In this review, the emphasis is on developments in the diagnosis and treatment of C282Y-linked hemochromatosis. There is a need for earlier diagnosis leading to earlier treatment to prevent morbidity and mortality.

BACKGROUND AND PURPOSE: Brain iron dyshomeostasis is increasingly recognized as an important contributor to neurodegeneration. Hereditary hemochromatosis is the most commonly inherited disorder of systemic iron overload. Although there is an increasing interest in excessive brain iron deposition, there is a paucity of evidence showing changes in brain iron exceeding that in healthy controls. Quantitative susceptibility mapping and R2* mapping are established MR imaging techniques that we used to noninvasively quantify brain iron in subjects with hereditary hemochromatosis. MATERIALS AND METHODS: Fifty-two patients with hereditary hemochromatosis and 47 age- and sex-matched healthy controls were imaged using a multiecho gradient-echo sequence at 3T. Quantitative susceptibility mapping and R2* data were generated, and regions within the deep gray matter were manually segmented. Mean susceptibility and R2* relaxation rates were calculated for each region, and iron content was compared between the groups. RESULTS: We noted elevated iron levels in patients with hereditary hemochromatosis compared with healthy controls using both R2* and QSM methods in the caudate nucleus, putamen, pulvinar thalamus, red nucleus, and dentate nucleus. Additionally, the substantia nigra showed increased susceptibility while the thalamus showed an increased R2* relaxation rate compared with healthy controls, respectively. CONCLUSIONS: Both quantitative susceptibility mapping and R2* showed abnormal levels of brain iron in subjects with hereditary hemochromatosis compared with controls. Quantitative susceptibility mapping and R2* can be acquired in a single MR imaging sequence and are complementary in quantifying deep gray matter iron.

Background: We report long-term survival and development of selected health conditions in Ontario-based referred and screened C282Y homozygotes for hemochromatosis treated by phlebotomy compared with an untreated control group known to be without HFE mutations. Methods: Patient characteristics and outcomes (all-cause mortality, liver cancer, diabetes, cirrhosis, hip or knee joint replacement, and osteoarthritis) were ascertained using a linked health administrative database held at ICES. Outcomes were assessed between groups without the outcome at baseline using Cox proportional hazards regression adjusted for age and sex. All C282Y homozygotes with elevated serum ferritin were treated by phlebotomy to reach serum ferritin of 50 µg/L. Our cohort included 527 C282Y homozygotes (311 men, 216 women, mean age 48 years) and 12,879 control participants (5,667 men and 7,212 women). Results: C282Y homozygotes had an increased risk of all-cause mortality (aHR 1.44 [1.19–1.75], p p p p p p = 0.16) during follow-up (median 17.7 years). Conclusions: C282Y homozygotes experience higher death and complication rates than individuals without HFE mutations, despite treatment by phlebotomy. Diabetes did not increase after phlebotomy therapy.