What is the best management approach for a 32-year-old male with a history of horseshoe kidney and hereditary hemochromatosis (HH) DNA mutation, presenting with iron overload, elevated ferritin, and hypercalcemia?

Management of Hereditary Hemochromatosis with Iron Overload

This 32-year-old male with confirmed hereditary hemochromatosis DNA mutation and significant iron overload (ferritin 681 ng/mL, transferrin saturation 92%) requires immediate initiation of therapeutic phlebotomy to prevent life-threatening complications including cirrhosis, hepatocellular carcinoma, diabetes, and cardiomyopathy. 1

Immediate Assessment Required

Before starting phlebotomy, you must evaluate for advanced liver disease and end-organ damage:

• Assess for cirrhosis risk: With ferritin 681 ng/mL (below the 1000 ng/mL threshold), this patient has <2% risk of cirrhosis if liver enzymes are normal and no other risk factors exist 1
• Check liver enzymes (ALT, AST) and platelet count: If ferritin >1000 ng/mL with elevated transaminases and platelets <200, cirrhosis risk approaches 80% and liver biopsy becomes necessary 1, 2
• Evaluate the hypercalcemia (calcium 10.4): This is unrelated to hemochromatosis and requires separate workup for primary hyperparathyroidism or other causes
• Screen for diabetes, cardiac dysfunction, and hypogonadism: These are major causes of death in untreated hemochromatosis 1

Phlebotomy Protocol - Induction Phase

Begin weekly phlebotomy of 500 mL immediately to achieve rapid iron depletion and prevent progression to irreversible organ damage: 1

• Frequency: Remove 500 mL weekly or every 2 weeks depending on patient tolerance and body weight 1
• Monitor hemoglobin before each session: If hemoglobin drops to <12 g/dL, decrease frequency; if <11 g/dL, temporarily discontinue phlebotomy 1
• Target ferritin: Continue weekly phlebotomy until ferritin reaches 50 ng/mL 1
• Monitor ferritin monthly (or every 4th phlebotomy) during induction; when ferritin drops below 200 ng/mL, check every 1-2 sessions 1
• Duration: Expect 1-3 years of weekly phlebotomy to normalize iron stores given the degree of overload 3

The transferrin saturation of 92% will remain elevated even as ferritin normalizes—this is expected in HFE-related hemochromatosis and should not delay stopping phlebotomy once ferritin targets are met. 1

Maintenance Phase

Once ferritin reaches 50 ng/mL, transition to maintenance therapy: 1

• Target ferritin range: Maintain between 50-100 ng/mL 1
• Frequency: Phlebotomy every 1-4 months as needed to keep ferritin in target range 1
• Monitor ferritin every 6 months during maintenance to adjust treatment schedule 1
• Average iron reaccumulation: Ferritin rises approximately 100 ng/mL per year without treatment 1

Critical Lifestyle Modifications

These dietary restrictions are mandatory to prevent accelerated organ damage: 1

• Avoid all vitamin C supplements: Vitamin C accelerates iron mobilization and can saturate transferrin, increasing free radical damage and cardiac dysrhythmias during phlebotomy 1
• Limit red meat consumption 1
• Restrict alcohol intake: Alcohol is a cofactor for liver disease progression in hemochromatosis 1
• Avoid iron-fortified foods and iron supplements 1
• Avoid raw seafood: Iron-overloaded patients have increased susceptibility to Vibrio vulnificus infection 2

Monitoring for Complications

Survival is normal if treatment begins before cirrhosis or diabetes develop, making surveillance critical: 1

• If cirrhosis is present: Initiate hepatocellular carcinoma surveillance (HCC accounts for 30% of deaths in hemochromatosis) and screen for esophageal varices 1
• Monitor for diabetes, cardiomyopathy, and arthropathy: These may improve with phlebotomy (fatigue, skin pigmentation, insulin requirements) but arthropathy and hypogonadism typically do not respond 1
• Check folate and cobalamin periodically: Supplementation may be needed with numerous venesections 1

Family Screening

Screen all first-degree relatives with iron studies (transferrin saturation and ferritin) plus HFE mutation analysis to detect early disease and prevent complications. 1, 2

Special Consideration: Horseshoe Kidney

The horseshoe kidney is unrelated to hemochromatosis management but requires standard precautions during any procedures and awareness of potential urologic complications. Ensure adequate hydration during phlebotomy sessions.

Common Pitfalls to Avoid

• Do not wait for symptoms: This patient is in the critical 20-40 year age window where iron overload exists without overt disease—delaying treatment risks progression to irreversible cirrhosis 1
• Do not over-treat: Stopping phlebotomy when ferritin reaches 50 ng/mL prevents iron deficiency and iron avidity, which can mimic undertreatment with persistently elevated transferrin saturation 4
• Do not ignore the hypercalcemia: Address this separately as it is not explained by hemochromatosis
• Do not perform liver biopsy unless indicated: With ferritin <1000 ng/mL and presumably normal liver enzymes, biopsy adds unnecessary risk 1