What is the diagnosis and treatment for hereditary hemochromatosis (HH) due to HFE (Human Ferroportin gene) mutations?

Hereditary Hemochromatosis (HFE-Related)

Diagnosis

Screen with fasting transferrin saturation (TS) and serum ferritin, then confirm with HFE genetic testing for C282Y and H63D mutations in those with elevated iron markers. 1

Step 1: Initial Phenotypic Screening

• Measure fasting transferrin saturation as the primary screening test for suspected iron overload or first-degree relatives over age 20 1
• Add simultaneous serum ferritin to increase diagnostic accuracy 1
• TS <45% with normal ferritin requires no further evaluation 1
• Elevated TS and ferritin proceed to genetic testing 1

This phenotypic approach is cost-effective at $2,700 per case detected, compared to $110,000 per case with direct genetic screening of the general population 1

Step 2: Genetic Confirmation

• Test for C282Y and H63D mutations using PCR on whole blood samples 1
• C282Y homozygosity (C282Y/C282Y) is found in >90% of hemochromatosis patients and confirms the diagnosis 1, 2
• Compound heterozygosity (C282Y/H63D) accounts for 3-5% of cases 1, 2
• H63D homozygosity alone rarely causes clinically significant disease 3

The C282Y mutation has an allelic frequency of 6.2% in European populations, with homozygosity occurring in 0.44-0.5% of individuals of northern European descent 2

Step 3: Risk Stratification for Liver Biopsy

Liver biopsy is NOT needed for most patients but is indicated when: 1

• Age >40 years with confirmed C282Y homozygosity
• Serum ferritin >1,000 ng/mL (accurate predictor of cirrhosis) 1
• Elevated ALT or hepatomegaly suggesting liver disease 1
• Equivocal iron markers requiring clarification 1

Patients <40 years old with no clinical liver disease and ferritin <1,000 ng/mL can proceed directly to phlebotomy without biopsy 1

Treatment

Therapeutic phlebotomy is the primary treatment for all C282Y homozygotes with iron overload. 1, 4

Phlebotomy Protocol

• Initiate phlebotomy immediately in confirmed C282Y homozygotes with elevated iron markers 1
• Treatment before age 40 and before development of cirrhosis or diabetes results in normal life expectancy 1, 4
• Chelating agents can be used as adjunctive therapy 4
• Orthotopic liver transplantation is reserved for patients with advanced cirrhosis 4

Critical Timing Considerations

The disease evolves in predictable stages: 1, 2

• 0-20 years: Clinically insignificant iron accumulation (0-5g storage)
• 20-40 years: Iron overload without disease (10-20g storage)
• >40 years: Risk of organ damage (>20g storage) if untreated

Early diagnosis before age 40 is essential to prevent cirrhosis, hepatocellular carcinoma, diabetes, and cardiomyopathy, which occur 10-119 fold more frequently than in the general population 1

Important Caveats

Incomplete Penetrance

• Not all C282Y homozygotes develop clinical disease: While 100% have elevated transferrin saturation, only 58% develop progressive tissue iron overload 1, 2
• Clinical expression is more common in men than premenopausal women due to menstrual iron loss 4
• Do not assume all homozygotes will develop organ damage, but all require monitoring 2

Family Screening

• Screen all first-degree relatives of confirmed cases with TS and ferritin starting at age 20 1
• Counsel families on autosomal recessive inheritance: Both parents must be carriers for offspring to be at risk 2
• Family screening is more cost-effective than population screening given incomplete penetrance 5

Non-HFE Hemochromatosis

• 7% of iron overload cases lack C282Y or H63D mutations 3
• Consider non-HFE genes (HJV, HAMP, TFR2, SLC40A1) if phenotypic iron overload exists without HFE mutations 6
• Non-HFE cases are more common in Mediterranean and non-European populations 6