Key Points
ÎÎHereditary hemochromatosis (HH) remains the most common identified
genetic disorder in Caucasians.
ÎÎThe principal defect is a point mutation in the hemochromatosis gene (HFE)
that produces the C282Y protein leading to excess dietary iron absorption.
C282Y homozygotes account for 80%-85% of typical patients with HH with
a small minority who are C282Y/H63D compound heterozygotes.
ÎÎAlthough its geographic distribution is worldwide, HH is seen most
commonly in populations of northern European origin, particularly Nordic or
Celtic ancestry, in which it occurs with a prevalence of approximately 1 per
220-250 individuals.
ÎÎHH may lead to the development of life-threatening complications—
cirrhosis, hepatocellular carcinoma (HCC), diabetes, and heart disease.
ÎÎPhenotypic expression occurs in approximately 70% of C282Y homozygotes,
but fewer than 10% of C282Y homozygotes will develop severe iron
overload accompanied by organ damage and clinical manifestations of
hemochromatosis.
ÎÎIn 2000, The European Association for the Study of Liver Diseases defined
three stages of HH to allow clinicians to categorize patients who have
positive genetic test results:
• Stage 1: Patients with the genetic disorder with no increase in iron stores.
• Stage 2: Patients with the genetic disorder who have phenotypic evidence of iron
overload but who are without tissue or organ damage.
• Stage 3: Patients who have the genetic disorder with iron overload and have iron
deposition to the degree that tissue and organ damage occurs.
