What is hemochromatosis?

What is Hemochromatosis

Hemochromatosis is a genetic disorder of iron metabolism in which mutations in genes regulating hepcidin production or function lead to excessive intestinal iron absorption and progressive iron accumulation primarily in the liver, heart, pancreas, and joints. 1

Pathophysiology and Genetic Basis

The disease results from deficiency or impairment in hepcidin synthesis or function due to pathogenic variants in genes regulating hepcidin production, which leads to increased intestinal iron absorption and iron release from macrophages, resulting in an expanded circulating iron pool reflected by increased transferrin saturation. 1

• HFE-related hemochromatosis accounts for approximately 85-90% of clinically affected patients and is caused by homozygosity for the C282Y mutation in the HFE gene on chromosome 6p21.3. 2, 3
• The HFE protein acts in association with beta2-microglobulin and transferrin receptor 1 to regulate iron uptake from plasma transferrin by the duodenum, the proposed mechanism by which body iron levels are sensed. 4
• Non-HFE hemochromatosis is much rarer and results from mutations in HAMP, HJV, TFR2, or SLC40A1 genes. 5, 6

Clinical Manifestations and Organ Damage

Iron deposition occurs in a characteristic pattern that distinguishes hemochromatosis from other iron overload conditions:

• Hepatic involvement is the primary manifestation, with iron deposition initially affecting peri-portal hepatocytes but not Kupffer cells, and spleen iron overload is typically absent. 1, 7
• If untreated, progressive iron accumulation leads to liver fibrosis, cirrhosis, and hepatocellular carcinoma. 1
• Cardiac complications include dilated cardiomyopathy, conduction abnormalities, heart failure, cardiac fibrosis, and increased risk of myocardial infarction. 8, 1
• Endocrine manifestations include diabetes mellitus, hypogonadotrophic hypogonadism, and hypothyroidism. 1
• Musculoskeletal symptoms typically involve arthralgia of the second and third metacarpophalangeal joints, chondrocalcinosis, and osteoporosis. 1

Diagnostic Hallmarks

The diagnosis relies on specific biochemical and genetic criteria:

• Transferrin saturation ≥45% is the earliest and most sensitive marker, reflecting the expanded circulating iron pool. 2, 1
• Elevated serum ferritin (>300 µg/L in males, >200 µg/L in females) indicates increased iron stores. 1, 2
• Genetic confirmation through HFE mutation analysis demonstrating C282Y homozygosity establishes the diagnosis of HFE-related hemochromatosis. 2, 1
• At early disease stages, hepatic iron deposition primarily affects peri-portal hepatocytes, distinguishing it from secondary iron overload where Kupffer cells are typically involved. 1

Epidemiology and Penetrance

• The C282Y/C282Y genotype occurs in approximately 1 in 250 individuals of European descent, but fully expressed disease with end-organ manifestations is seen in fewer than 10% of these individuals. 1
• Males are affected significantly more frequently than females, and disease prevalence increases with age. 1
• Only approximately 70% of C282Y homozygotes are found to have elevated ferritin levels indicative of increased iron stores in population screening studies. 1
• An estimated 40-70% of persons with the C282Y homozygous genotype will develop clinical evidence of iron overload, with a smaller proportion dying from complications. 9

Treatment and Prognosis

Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy, and other complications. 1

• Adequate medical therapy can reverse iron overload cardiomyopathy when diagnosed before end-stage heart failure occurs. 1
• Treatment targets for phlebotomy are ferritin <50 µg/L during the induction phase and <100 µg/L during the maintenance phase. 1
• Without treatment, death may occur from cirrhosis, primary liver cancer, diabetes, or cardiomyopathy. 9

Key Clinical Distinctions

Common pitfalls in understanding hemochromatosis include:

• Hemochromatosis refers specifically to genetic iron overload with increased transferrin saturation and hepcidin deficiency, whereas hemosiderosis refers to iron overload from exogenous sources such as chronic blood transfusions. 1
• Typical symptoms include weakness, fatigue, and greyish-brown skin discoloration, though most contemporary diagnoses are made incidentally through routine laboratory screening rather than through overt end-organ disease. 1
• Transferrin saturation can also be increased in patients with advanced cirrhosis, low transferrin, acute liver failure, or acute liver injury, which may be confused with hemochromatosis. 1