Is Hemochromatosis an Autoimmune Disorder?
No, hereditary hemochromatosis is not an autoimmune disorder—it is an autosomal recessive genetic disease caused by mutations in iron metabolism genes, most commonly the HFE gene. 1, 2
Genetic Basis and Inheritance Pattern
Hereditary hemochromatosis follows an autosomal recessive inheritance pattern, meaning patients must inherit two mutated copies of the gene (one from each parent) to develop the full disease phenotype. 2
The C282Y mutation in the HFE gene on chromosome 6p accounts for more than 90% of hereditary hemochromatosis cases. 1, 2
Most affected patients are homozygous for C282Y (C282Y/C282Y), which is found in 80.6–90% of clinically diagnosed hemochromatosis patients of European ancestry. 1, 2
Compound heterozygosity (C282Y/H63D) accounts for only 3–5% of cases and has lower penetrance. 1, 2
Pathophysiologic Mechanism
The fundamental defect is inappropriately low hepcidin production, not an autoimmune attack on tissues. 1
The HFE C282Y mutant protein fails to bind properly to the transferrin receptor on enterocytes, resulting in cells that are "programmed" to absorb slightly more dietary iron than the body requires. 1, 3
This leads to excessive intestinal iron absorption over decades, with progressive tissue iron deposition in the liver, heart, pancreas, and joints. 1, 4
The mechanism is a loss of normal iron-sensing function, not immune-mediated tissue destruction. 5
Key Distinguishing Features from Autoimmune Disease
Hemochromatosis presents with normal erythropoiesis and normal hemoglobin/red cell indices, distinguishing it from autoimmune hemolytic anemias. 1, 6
There is no inflammatory infiltrate or antibody-mediated tissue damage—organ injury results purely from toxic iron accumulation in parenchymal cells. 1
The disease is completely preventable and reversible with phlebotomy if detected before end-organ damage occurs, unlike most autoimmune conditions that require immunosuppression. 1, 3
Clinical Penetrance and Expression
Penetrance is incomplete: only 58–70% of C282Y homozygotes develop progressive tissue iron overload, and fewer than 10% progress to end-organ damage such as cirrhosis, diabetes, or cardiomyopathy. 1, 2
Most C282Y homozygotes remain asymptomatic in early life and are identified through screening or family studies. 1
When manifest, the disease typically presents in the fourth to fifth decade with fatigue, arthralgia, hepatomegaly, diabetes, or cardiac symptoms—all due to iron toxicity, not autoimmunity. 1