What is the recommended treatment for a patient with iron saturation suggestive of hereditary hemochromatosis (HH)?

Treatment of Hereditary Hemochromatosis with Elevated Iron Saturation

Initiate weekly therapeutic phlebotomy immediately, removing 500 mL of blood per session until serum ferritin reaches 50-100 μg/L, then transition to lifelong maintenance phlebotomy every 1-4 months to keep ferritin within this target range. 1, 2

Induction Phase Protocol

Begin aggressive iron removal with the following structured approach:

• Remove 500 mL of blood weekly or every 2 weeks depending on patient tolerance and body weight 1, 2
• Check hemoglobin/hematocrit before each phlebotomy session to prevent excessive anemia 1, 2
• Discontinue phlebotomy if hemoglobin falls below 11 g/dL; reduce frequency if hemoglobin is 11-12 g/dL 1
• Allow hemoglobin/hematocrit to fall by no more than 20% from prior level during any single session 1, 2
• Monitor serum ferritin every 10-12 phlebotomies (approximately monthly) during induction 1, 2
• When ferritin decreases below 200 μg/L, measure ferritin every 1-2 sessions to avoid overshooting the target 1
• Stop frequent phlebotomy when serum ferritin reaches 50-100 μg/L 1, 2

The most recent EASL 2022 guidelines note that the 50-100 μg/L target represents the evidence-based standard, though more relaxed targets (up to 200 μg/L for women, 300 μg/L for men) may be tolerated during maintenance in elderly patients who poorly tolerate aggressive depletion. 1 However, these relaxed targets are based primarily on expert opinion rather than clinical studies. 1

Maintenance Phase Protocol

After achieving target ferritin, continue lifelong phlebotomy:

• Perform phlebotomy every 1-4 months to maintain ferritin between 50-100 μg/L 1, 2
• Monitor serum ferritin every 6 months during maintenance to adapt treatment schedule 1
• The iron accumulation rate varies widely among patients, with ferritin rising approximately 100 μg/L per year on average without treatment 1
• Continue checking hemoglobin before each maintenance phlebotomy session 1

Critical Dietary and Supplement Restrictions

Avoid vitamin C supplements entirely, especially during iron depletion:

• Pharmacologic doses of vitamin C accelerate iron mobilization to levels that may saturate circulating transferrin, resulting in increased pro-oxidant and free radical activity 1, 3
• In patients with advanced disease, cardiomyopathy, or cardiac arrhythmias, rapid iron mobilization from vitamin C poses serious risk of sudden death 1, 3
• If vitamin C supplementation is absolutely necessary for other medical reasons after iron depletion is complete, limit to maximum 500 mg daily and only after physician discussion 3

Additional dietary modifications:

• Avoid iron supplementation and iron-fortified foods where possible 1
• Limit red meat consumption 1
• Restrict alcohol intake during iron depletion phase; patients with cirrhosis should abstain completely 1
• Consume citrus fruits and fruit juices in moderation, not in combination with iron-rich foods 1
• Avoid raw shellfish due to risk of Vibrio vulnificus infection 1

No restrictive low-iron diet is necessary, as dietary modification can only affect 2-4 mg/day of iron absorption compared to 250 mg/week removed by phlebotomy. 1

Special Populations and Situations

Patients with cardiac complications require modified approach:

• In patients with cardiomyopathy or arrhythmias, there is increased risk of sudden death with rapid iron mobilization 1
• Consider slower phlebotomy schedule or alternative iron chelation therapy in these high-risk patients 4
• Pretransplantation cardiac evaluation is essential if liver transplantation is being considered 1

Alternative treatment for phlebotomy-intolerant patients:

• Deferoxamine 20-40 mg/kg/day subcutaneously is the traditional chelation option for patients who cannot tolerate phlebotomy due to anemia, severe heart disease, or poor venous access 1, 2, 4
• Deferasirox (oral iron chelator) at starting dose of 10 mg/kg/day can reduce iron burden, though it is associated with dose-dependent adverse effects including diarrhea, headache, and elevations in liver enzymes and creatinine 5

Prognostic Considerations

Early treatment before organ damage is critical for normal life expectancy:

• If iron depletion is accomplished before development of cirrhosis or diabetes mellitus, long-term phlebotomy results in normal life expectancy 1
• Survival is normal in patients when treatment is initiated before cirrhosis or diabetes develops, confirming the importance of early diagnosis and treatment 1
• However, if cirrhosis is present at diagnosis, survival is diminished and patients remain at high risk for hepatocellular carcinoma despite adequate iron depletion 1
• Major causes of death include decompensated cirrhosis, hepatocellular carcinoma, diabetes mellitus, and cardiomyopathy, occurring 10- to 119-fold higher than expected in age- and sex-matched populations 1

Common Pitfalls to Avoid

Overtreatment leading to iron deficiency:

• Symptomatic iron deficiency can develop in patients with hemochromatosis if phlebotomy is too aggressive 1
• Iron avidity from overtreatment may mimic undertreatment with persistently elevated transferrin saturation 6
• Monitor for unexpected changes in ferritin or transferrin saturation, as significant fluctuations are not typical of hemochromatosis and warrant investigation 1

Inadequate monitoring:

• Periodically check plasma folate and cobalamin, especially in patients requiring numerous venesections; supplement if necessary 1
• Transferrin saturation may remain elevated even when ferritin is within target range, and observational data suggest general and joint symptoms may relate to long-term exposure to transferrin >50% regardless of ferritin levels 1