Hereditary hemochromatosis and its elusive natural history.

H EREDITARY hemochromatosis (HH) has long been described as a disorder of iron absorption that results in tissue iron deposition and cirrhosis of the liver. It has been assumed that HH results from a genetic trait that, given enough time, will inevitably express itself as increased absorption, transport, and storage of iron ultimately leading to organ damage. Based on this assumption, the approach to diagnosing HH has evolved away from analyzing liver biopsy specimens for signs of iron overload and liver damage to testing for specific genes or earlier phenotypic expression of traits that define increased risk for iron overload and disease. Thus, in the last 20 years, research has focused on determining the specific genetic loci and identifying the best laboratory test(s) to detect the disease early. Based on large studies of blood donors and outpatients, the prevalence of HH has been estimated at 3 to 5 per 1000 people. In 1996, 2 specific gene mutations (known as HFE) on chromosome 6 were identified and found to be associated with HH. Serum iron measures (transferrin saturation [TS] and serum ferritin levels) and genetic tests have been recommended to detect HH during the latent phase so that phlebotomy treatment can be started early to prevent clinical problems. The belief that there is a large population potentially at risk for HH has led to increasing calls for population screening, but this has been accompanied by controversy and disagreement in nearly every aspect of its implementation. The controversy has regrettably divided the clinical and public health communities over fundamental issues. Uncertainty about the natural history and case definition of HH has made itdifficult todeterminewhether clinical disease is inevitable and if so, when it occurs and what its prevalence is. Prevalence estimates are dependent on the case definition or diagnostic standard used, and different standards have vastly different prognostic implications. Classically, liver biopsy specimen analysis that reveals ahepatic iron indexgreater than 1.9* with or without fibrosis or cirrhosis (prevalence, 0.2 per 1000) has served as the gold standard for the diagnosis of HH. (The hepatic iron index, reported inmillimolesof ironper gram of liver per year, is calculated as (iron concentration [in milligrams of iron per gram of dry weight liver]/55.846 [ie, the atomic weight of iron])/the patient’s age in years). With recent advances in our knowledge of HH, some now define HH as synonymous with the presence of the HFE genotypes, particularly C282Y/ C282Y (prevalence, 3 per 1000). Others prefer a phenotypic definition that requires a persistent increase in transport iron, as measured by TS (prevalence, 8-9 per 1000). Still other experts require evidence of increased iron stores as measured by serum ferritin levels (prevalence, 5.2 per 1000). More recently, this definition has been changed to include an elevated serumferritin levelandcirrhosis(prevalence, 0.002 per 1000). The sequelae attributed to HH have traditionally included not only liver disease and an increased risk of hepatoma but also arthritis, cardiomyopathy, skin pigmentation, and diabetes. Recently, it has been reported that individuals with HH are no more likely to have these conditions than persons in the general population. The exception is liver disease, which remains linked to HH. Sharon M. McDonnell, MD, MPH