Natural History and Management ofHFE-Hemochromatosis

Abstract

Advances in our knowledge of hereditary hemochromatosis (HH) over the past 150 years have revealed new insights into this common genetic disorder. Meticulous family and HLA association studies followed ultimately by cloning of the HFE gene have dramatically changed our understanding of the natural history and manifestations of HH. Cross-sectional studies demonstrated that HH had a highly variable clinical and biochemical penetrance in susceptible individuals of northern European descent. "State-of-the-art" large longitudinal population studies have accurately defined the natural history. We now recognize that HH is not as discreet an entity as previously thought because genetic and environmental modifiers of disease penetrance are increasingly identified as influencing the clinical course of HH. While phlebotomy remains the cornerstone of therapy, our diagnostic approach has been refined to incorporate new biochemical, genetic, and noninvasive methods that complement more traditional approaches. This review aims to encapsulate this new knowledge in a framework that addresses commonly raised issues relating to the current natural history, diagnosis, and management of HH patients.

Paraoxonase-1 status in patients with hereditary hemochromatosis

“…Indeed, many patients do not develop severe iron overload or clinical symptoms, and hence, there is a growing interest in investigating the biological mechanisms and consequences of HH phenotypic heterogeneity ( 49,50 ). In a population-based study ( 51 ), only 28.4% of men and 1.2% of women homozygous for C282Y mutation had clinical evidence of disease.…”

Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice

“…Without therapeutic intervention, iron overload leads to multiple organ damage, such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism, and skin pigmentation (24). Phlebotomy is the only treatment option, while iron chelation therapies are extremely rare and controversial (44,45). However, phlebotomy increases erythropoiesis to compensate for blood loss, and Hamp levels are further suppressed by high erythropoietic activity, thereby leading to more dietary iron absorption (23,46).…”

Non-HFE hemochromatosis

“…Venesection (phlebotomy) is the cornerstone of therapy; its goal is to reduce ferritin to low normal range, usually 50-100 µ g/L (52) . This therapeutic strategy is associated with significant improvement in liver and skin manifestations of the disease and it is also related to higher survival (55) .…”