A New Perspective on the Natural History of Hereditary Hemochromatosis.

A few homozygotes for the C282Y mutation of HFE manifest severe and even fatal iron-storage disease; most have only a modest increase in iron stores, show no clinical manifestations, and have no shortening of lifespan. Screening for hemochromatosis has been advocated so that therapeutic phlebotomy could be offered to the mildly affected subjects, often termed "pre-cirrhotic", presumably protecting them against progression of the disease. The rationale of this approach depends upon the implicit assumption that the natural history of the disease is one of progressive accumulation of iron and consequently ever-increasing tissue damage. In 1998 we began screening for the C282Y homozygous genotype among patients in the Kaiser Permanente Health Appraisal Clinic in San Diego. We have now followed 144 patients from this cohort of 156 C282Y homozygotes with medical records spanning up to 10 years, including 35 patients who declined phlebotomy. Data from this analysis and other sources now suggest that the natural history of the disease might be quite different than has heretofore been assumed. Our revised perspective is based upon both cross-sectional and longitudinal observations. Cross-sectional analysis of levels of serum ferritin, a surrogate for total body iron, shows little or no change with age in C282Y homozygotes. Neither are abnormal liver function tests, which occur in a small minority of homozygotes, age-related. In Denmark, longitudinal analyses of serum ferritin levels in untreated patients show no increase over as much as 20 years. Our own longitudinal data on serum ferritin levels in homozygotes who were not phlebotomized confirm this observation. Longitudinal analyses of abnormal ALT levels in homozygotes show no upward trend over a four-year period. Accordingly, it seems likely that in hemochromatosis the maximum extent of disease has been achieved in most patients by the time they reach adulthood, and that patients who are diagnosed with mild disease are unlikely to show progression.