What is hereditary hemochromatosis?

Hereditary Hemochromatosis Overview

Hereditary hemochromatosis is an autosomal recessive genetic disorder caused by HFE gene mutations that leads to excessive intestinal iron absorption and progressive iron accumulation primarily in the liver, heart, pancreas, and joints, which if untreated can result in cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy, and arthropathy. 1, 2

Genetic Basis and Inheritance

• The disease is caused by mutations in the HFE gene located on chromosome 6p, with the C282Y mutation being the most common pathogenic variant 2, 3
• Approximately 90% of patients with hereditary hemochromatosis are homozygous for the C282Y mutation (C282Y/C282Y), which is required for full expression of the classic disease phenotype 4, 3
• The condition follows an autosomal recessive inheritance pattern, meaning both copies of the HFE gene must carry mutations for clinical disease to develop 3, 5
• The C282Y mutation has an allelic frequency of approximately 6.2% in European populations, with homozygosity occurring in about 0.44-0.5% of individuals of northern European descent 3
• Compound heterozygosity (C282Y/H63D) accounts for only 3-5% of hemochromatosis cases and has significantly lower penetrance 3

Pathophysiology

• The HFE gene mutations disrupt iron regulation through the hepcidin pathway, leading to decreased hepcidin production 2, 6
• This results in increased intestinal iron absorption and iron release from macrophages, creating an expanded circulating iron pool reflected by elevated transferrin saturation 1
• The body lacks an effective mechanism to excrete excess iron, leading to progressive accumulation in parenchymal cells and eventual cellular dysfunction 5, 7

Clinical Manifestations and Natural History

• Males are affected significantly more frequently than females, and disease prevalence increases with age 1
• Women typically present later than men due to protective effects of menstrual blood loss, with symptoms often appearing after menopause 5, 7
• The disease evolves in stages: clinically insignificant iron accumulation (0-20 years), iron overload without disease (20-40 years), and iron overload with organ damage if untreated 3

Common Organ Involvement:

• Liver: Progressive fibrosis leading to cirrhosis and hepatocellular carcinoma if untreated 1
• Pancreas: Diabetes mellitus from iron deposition in pancreatic beta cells 1, 7
• Joints: Arthropathy, particularly affecting the second and third metacarpophalangeal joints 1
• Heart: Cardiomyopathy and heart failure in severe or early-onset cases 1, 7
• Endocrine system: Hypogonadotrophic hypogonadism, hypothyroidism 1
• Skin: Greyish-brown discoloration (bronze diabetes) 1

Typical Symptoms:

• Weakness and fatigue are the most common presenting symptoms 1
• Many patients are now diagnosed asymptomatically through incidental laboratory findings of elevated liver enzymes, ferritin, or transferrin saturation 7

Diagnostic Approach

Initial Laboratory Testing:

• Transferrin saturation (TS) and serum ferritin should be obtained together as the primary screening tests 2, 4
• Diagnostic thresholds for provisional iron overload: TS >45% in females or >50% in males, with ferritin >200 µg/L in females or >300 µg/L in males 1, 4
• TS ≥45% has high sensitivity for detecting C282Y homozygotes and is typically the earliest abnormality 4

Genetic Testing:

• HFE gene mutation analysis for C282Y and H63D should be performed when TS ≥45% and/or ferritin is elevated 2, 4
• Testing for C282Y and H63D mutations is the most cost-effective diagnostic approach 4
• In patients homozygous for C282Y with elevated TSAT and ferritin, provisional iron overload is sufficient to diagnose hemochromatosis without requiring liver biopsy 1

Assessment of Disease Severity:

• Serum ferritin >1000 µg/L combined with elevated liver enzymes (ALT or AST) and platelet count <200 predicts cirrhosis in approximately 80% of C282Y homozygotes 4
• Liver biopsy should be considered in C282Y homozygotes with ferritin >1000 µg/L, elevated liver enzymes, hepatomegaly, age >40 years, or platelet count <200 to assess for cirrhosis 4
• MRI can be used to quantify hepatic iron concentrations in patients with unclear causes of hyperferritinemia 4
• Cardiac MRI should be performed in patients with signs of heart disease or juvenile forms of hemochromatosis 4

Important Diagnostic Pitfalls

• Ferritin can be falsely elevated due to inflammation, chronic liver disease, malignancy, non-alcoholic fatty liver disease, and metabolic syndrome—these must be excluded before attributing elevated ferritin to hemochromatosis 4
• A normal TS with elevated ferritin may still indicate iron overload in non-HFE hemochromatosis or compound heterozygotes 4
• Not all C282Y homozygotes develop clinical disease—penetrance is variable, with only 58% developing progressive tissue iron overload despite all having elevated transferrin saturation 3

Treatment

Phlebotomy:

• Phlebotomy is the mainstay of treatment and should target ferritin <50 µg/L during the induction phase and <100 µg/L during the maintenance phase 1
• Standard protocol involves removing one unit (approximately 500 mL) of blood weekly or biweekly during induction 4
• Hemoglobin/hematocrit and serum ferritin should be monitored, with ferritin checked every 10-12 phlebotomies 4
• Early diagnosis and treatment by phlebotomy before development of cirrhosis or diabetes results in normal life expectancy 1, 3
• Phlebotomy can improve heart function, reduce abnormal skin pigmentation, and lessen the risk of liver complications 7

Additional Management:

• Chelating agents can be used in combination with phlebotomy 5
• Orthotopic liver transplantation may be performed in patients with advanced cirrhosis 5
• Patients should avoid vitamin C supplements, as these can accelerate iron mobilization and increase toxicity 4
• Patients should avoid alcohol and raw seafood due to increased risk of Vibrio vulnificus infection in iron-overloaded individuals 4

Surveillance and Screening

• Patients with advanced fibrosis should be included in a screening program for hepatocellular carcinoma 1
• Individuals with hereditary hemochromatosis have increased risk of hepatocellular carcinoma, colorectal cancer, and breast cancer 7
• First-degree relatives of patients with hemochromatosis should undergo HFE genetic testing along with phenotype testing (ferritin and TS) 4
• Genetic testing should be offered after 18 years of age to first-degree relatives 7
• Population-wide screening is not recommended due to low penetrance and uncertain benefit in asymptomatic genotype-positive individuals 4

Epidemiology

• Hereditary hemochromatosis is one of the most common genetic disorders in individuals of European descent, particularly those of northern European ancestry 5, 7
• The prevalence shows significant geographic variation across Europe, with highest frequencies in Ireland (12.5% allelic frequency) and lowest in Southern Europe 3
• C282Y homozygosity is found in 80.6% of clinically recognized hemochromatosis patients of European ancestry 3