Hereditary hemochromatosis is an autosomal recessive disorder that disrupts the 
body's regulation of iron. It is the most common genetic disease in whites. Men 
have a 24-fold increased rate of iron-overload disease compared with women. 
Persons who are homozygous for the HFE gene mutation C282Y comprise 85 to 90 
percent of phenotypically affected persons. End-organ damage or clinical 
manifestations of hereditary hemochromatosis occur in approximately 10 percent 
of persons homozygous for C282Y. Symptoms of hereditary hemochromatosis are 
nonspecific and typically absent in the early stages. If present, symptoms may 
include weakness, lethargy, arthralgias, and impotence. Later manifestations 
include arthralgias, osteoporosis, cirrhosis, hepatocellular cancer, 
cardiomyopathy, dysrhythmia, diabetes mellitus, and hypogonadism. Diagnosis 
requires confirmation of increased serum ferritin levels and transferrin 
saturation, with or without symptoms. Subtyping is based on genotypic 
expression. Serum ferritin measurement is the most useful prognostic indicator 
of disease severity. Liver biopsy is performed to stage the degree of fibrosis 
with severe ferritin elevation or transaminitis, or to diagnose nonclassical 
hereditary hemochromatosis in patients with other genetic defects. Treatment of 
hereditary hemochromatosis requires phlebotomy, and the frequency is guided by 
serial measurements of serum ferritin levels and transferrin saturation. Iron 
avidity can result from overtreatment. If iron avidity is not suspected, it may 
mimic undertreatment with persistently elevated transferrin saturation. Dietary 
modification is generally unnecessary. Universal screening for hereditary 
hemochromatosis is not recommended, but testing should be performed in 
first-degree relatives of patients with classical HFE-related hemochromatosis, 
those with evidence of active liver disease, and patients with abnormal iron 
study results. Screening for hepatocellular carcinoma is reserved for those with 
hereditary hemochromatosis and cirrhosis.