What is the treatment for high iron binding and iron overload?

Treatment of High Iron Binding and Iron Overload

All patients with documented iron overload should undergo regular therapeutic phlebotomy as first-line treatment, removing 400-500 mL of blood weekly until serum ferritin reaches 50-100 μg/L, followed by lifelong maintenance phlebotomy every 3-6 months. 1, 2

Initial Diagnostic Confirmation

Before initiating treatment, confirm iron overload with:

• Transferrin saturation >45% combined with elevated serum ferritin (>200 μg/L in men, >150 μg/L in women) 1
• HFE genetic testing for C282Y and H63D mutations if hereditary hemochromatosis is suspected 1
• Liver biopsy is recommended in C282Y homozygotes if ferritin >1000 μg/L or liver enzymes are elevated to stage fibrosis 1

Primary Treatment: Therapeutic Phlebotomy

Induction Phase

• Remove 400-500 mL of blood weekly (containing 200-250 mg of iron) or twice weekly if tolerated 1, 2
• Check hemoglobin and hematocrit before each session—postpone if anemia develops 2, 3
• Monitor serum ferritin every 10-12 phlebotomies initially, then more frequently as levels approach target 1, 2
• Continue until ferritin reaches 50-100 μg/L 1, 2, 3

Maintenance Phase

• Perform phlebotomy every 3-6 months to maintain ferritin between 50-100 μg/L 2, 3
• Men typically require 3-4 phlebotomies yearly, women 1-2 yearly 2
• Monitor ferritin every 3-6 months during maintenance 2, 3

Critical Caveat

Phlebotomy is contraindicated in patients with significant anemia, hemodynamic instability, or transfusion-dependent conditions 2, 4. These patients require iron chelation instead.

Alternative Treatment: Iron Chelation Therapy

Indications for Chelation

Iron chelation is reserved for patients who:

• Cannot tolerate phlebotomy due to anemia or cardiovascular instability 2, 4
• Have secondary iron overload from ineffective erythropoiesis (thalassemia, myelodysplastic syndrome) 1, 4
• Are transfusion-dependent 4, 5

Deferoxamine Protocol

• Administer 40 mg/kg/day subcutaneously over 8-12 hours nightly, 5-7 nights weekly 2, 4, 5
• Maximum dose: 60 mg/kg/day 2, 5
• Target hepatic iron concentration <15,000 μg/g dry weight 4
• Monitor with hepatic iron concentration measurements, as serum ferritin is unreliable in secondary iron overload due to inflammation 4

Chelation Warnings

• Auditory and ocular toxicity can occur with prolonged use, high doses, or low ferritin levels 5
• Renal toxicity including acute renal failure has been reported—monitor renal function regularly 5
• Avoid in patients with severe renal disease or anuria 5

Secondary Iron Overload: Etiology-Specific Treatment

When Phlebotomy Is Appropriate

• Porphyria cutanea tarda: Use standard phlebotomy regimen 1, 4
• African iron overload: Phlebotomy has demonstrated mortality reduction 1, 4
• Post-transplant iron overload: Phlebotomy if bone marrow function is preserved 1, 4

When Chelation Is Required

• Thalassemia major and other transfusion-dependent anemias: Deferoxamine is treatment of choice 1, 4
• Myelodysplastic syndrome with transfusion dependence: Iron chelation therapy 4

When Treatment May Not Be Beneficial

The AASLD suggests phlebotomy may not benefit patients with alcoholic liver disease or chronic hepatitis C with only mild iron overload 4. This is a critical distinction, as treating secondary iron accumulation in these conditions has not shown clear benefit.

Dietary and Lifestyle Modifications

• Avoid iron supplements and iron-fortified foods 2, 3
• Limit vitamin C supplements to ≤500 mg/day, as vitamin C increases iron availability for absorption 1, 2, 3
• Avoid raw shellfish due to Vibrio vulnificus infection risk, particularly in cirrhotic patients 2, 3
• Minimize alcohol consumption, which worsens liver damage 3
• Maintain a broadly healthy diet without strict iron restriction—dietary iron restriction is impractical as only 0.5-1.0 mg excess iron is absorbed daily 1, 2, 3

Special Population: Cardiac Iron Overload

Patients with cardiac involvement require risk stratification by cardiac MRI T2 measurements* 1:

• T2 >20 ms (low risk)*: Standard phlebotomy or chelation with routine monitoring 1
• T2 10-20 ms (intermediate risk)*: Intensify chelation therapy 1
• T2 <10 ms (high risk)*: Aggressive chelation therapy plus standard heart failure medications (ACE inhibitors, beta-blockers, diuretics) 1

Surveillance for Complications

Hepatocellular Carcinoma Screening

• All patients with cirrhosis from iron overload require lifelong HCC surveillance, even after successful iron depletion 1, 4
• HCC accounts for 30% of hemochromatosis-related deaths and risk persists despite adequate phlebotomy 1
• HCC is exceptionally rare in non-cirrhotic patients, providing strong rationale for early treatment before cirrhosis develops 1

Monitoring During Treatment

• Hemoglobin and hematocrit before each phlebotomy 2, 3
• Liver function tests regularly 2
• Serum ferritin every 10-12 phlebotomies initially, then every 3-6 months during maintenance 1, 2, 3

Prognosis and Treatment Goals

Early treatment before development of cirrhosis and diabetes restores survival to normal population levels 1, 2, 3. Benefits of iron removal include:

• Improved cardiac function and resolution of arrhythmias 1, 2
• Improved diabetic control (reduced insulin requirements) 1
• Reversal of hepatic fibrosis in approximately 30% of cases 1
• Resolution of fatigue, malaise, and skin pigmentation 1

However, established cirrhosis does not reverse, and arthropathy and hypogonadism show minimal improvement with phlebotomy 1. This underscores the critical importance of early diagnosis and treatment initiation.