What are the next steps for a patient with a C282Y homozygous mutation?

Management of C282Y Homozygous Hemochromatosis

For a patient with confirmed C282Y homozygous mutation, initiate therapeutic phlebotomy immediately if they are under age 40 without clinical liver disease or ferritin >1,000 ng/mL; otherwise, perform liver biopsy first to assess for cirrhosis before starting treatment. 1

Risk Stratification and Need for Liver Biopsy

The critical decision point is determining who needs liver biopsy before starting phlebotomy:

Proceed directly to phlebotomy WITHOUT liver biopsy if ALL of the following are met:

• Age <40 years 1
• Serum ferritin ≤1,000 ng/mL 1
• Normal liver enzymes (ALT/AST) 1
• No clinical evidence of liver disease (no hepatomegaly) 1

Liver biopsy IS required if ANY of the following are present:

• Age ≥40 years 1
• Serum ferritin >1,000 ng/mL 1
• Elevated liver enzymes 1
• Clinical evidence of liver disease 1
• Platelet count <200 (predicts cirrhosis in 80% when combined with ferritin >1,000 ng/mL) 2
• Additional risk factors for liver disease, particularly alcohol use 1

The rationale is that hepatic fibrosis was not present in any patient <40 years of age in multiple series, and occurred only at younger ages in those who also abuse alcohol. 1 Patients with ferritin >1,000 ng/mL combined with elevated ALT/AST and platelets <200 have approximately 80% risk of cirrhosis. 2

Therapeutic Phlebotomy Protocol

Induction Phase:

• Remove 500 mL (1 unit) of blood weekly or biweekly 2
• Monitor hemoglobin/hematocrit before each phlebotomy 2
• Check serum ferritin every 10-12 phlebotomies 2
• Continue until serum ferritin reaches 50-100 μg/L (target range) 2

Maintenance Phase:

• Continue phlebotomy to maintain ferritin 50-100 μg/L 2
• Critical pitfall: Monitor transferrin saturation during maintenance, not just ferritin. C282Y homozygotes frequently develop transferrin saturation ≥50% with normal ferritin during maintenance, which indicates presence of non-transferrin bound iron (NTBI) that can cause ongoing organ damage. 3
• In one study, 70 of 92 patients in maintenance with TS ≥50% had detectable NTBI despite normal ferritin in many cases. 3

Monitoring for Complications

Diabetes surveillance is critical because C282Y homozygotes have 1.72-fold increased risk of diabetes even with normal transferrin saturation and ferritin. 4 Most importantly, C282Y homozygotes who develop diabetes have 1.94-fold higher mortality than non-carriers with diabetes, and 27.3% of all deaths among C282Y homozygotes are attributable to diabetes. 4

Monitor for:

• Diabetes: Regular glucose/HbA1c screening, as risk is increased even with normal iron parameters 4
• Liver disease: Periodic liver function tests 5
• Cardiac function: Assess if symptoms develop, though less common in C282Y homozygotes 5
• Joint symptoms: Arthropathy and chondrocalcinosis 5

Family Screening

Screen all first-degree relatives with:

• HFE genetic testing (C282Y and H63D mutations) 1, 2
• Transferrin saturation and serum ferritin 2
• Testing can be postponed until approximately age 20 years, as organ damage is virtually unknown before adult life 1
• For children: Test the spouse/other parent first—if they have no C282Y mutation, offspring can only be heterozygous 1

Lifestyle Modifications

Mandatory dietary restrictions:

• Avoid alcohol completely (accelerates liver damage) 1
• Avoid raw seafood due to Vibrio vulnificus infection risk in iron-overloaded patients 2
• Avoid vitamin C supplements (accelerates iron mobilization and increases oxidative damage) 2, 5

Adjunctive Therapy

Consider proton pump inhibitors for patients requiring frequent maintenance phlebotomies. In a retrospective study, PPIs reduced median phlebotomy frequency from 3.17 to 0.50 per year in C282Y homozygotes. 6 This works by reducing iron absorption through gastric acid suppression.

Prognosis

If diagnosed and treated before cirrhosis develops, life expectancy is normal. 7 However, compliance with maintenance therapy declines at approximately 6.8% annually, with only 84% complying in the first year. 8 Emphasize the importance of lifelong maintenance to prevent re-accumulation of iron and associated complications.