Question: Which of the following genetic profiles is likely to result in a clinically relevant phenotypic pattern of iron overload?

A. C282Y heterzygote, H63D heterozygote

B. C282Y homozygote, H63D negative

C. C282Y negative, H63D homozygote

D. C282Y heterozygote, H63D homozygote

Answer: Hereditary hemochromatosis (HH) is a condition of iron overload that classically stems from a mutation of the HFE gene, although not all cases of genetic iron overload have this particular mutation.    In addition to liver infiltration, which causes fibrosis and can lead to cirrhosis and hepatocellular carcinoma, iron deposition can affect the heart, pancreas and joints.

Oftentimes the concern for HH is raised when a patient presents with abnormal transaminase levels and an elevated ferritin.  A high transferrin saturation (Fe/TIBC) is usually prerequisite.  Since other liver-specific conditions can cause these abnormalities, such as the case with alcohol abuse and high transferrin saturation, or NASH and high ferritin, we like to rely on HFE analysis to make a diagnosis of HH.

There are two combinations of genotypes that are consistent with the diagnosis: C282Y homozygosity, and C282Y heterogygote + H63D heterozygote (called a “compound heterozygote”).  All other combinations are not considered to be phenotypically relevant for iron overload.  That said, it is still unclear as to whether another combination might predispose to more rapid development of fibrosis when a second insult such as alcohol is present.

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