What is the treatment for iron overload?

Treatment of Iron Overload

Phlebotomy is the gold standard treatment for iron overload when bone marrow function is preserved, removing 400-500 mL of blood weekly or twice weekly until ferritin reaches 50-100 μg/L, followed by maintenance phlebotomy 3-4 times yearly for men and 1-2 times yearly for women. 1

Initial Assessment Before Treatment

Before initiating therapy, you must evaluate several key parameters:

• Obtain serum ferritin level to confirm iron overload (target >1000 μg/L for transfusional overload) 2
• Measure serum creatinine in duplicate and calculate eGFR using appropriate prediction equations (CKD-EPI or MDRD for adults, Schwartz for pediatrics) 2
• Check serum transaminases and bilirubin to assess hepatic function 2
• Perform baseline auditory and ophthalmic examinations before chelation therapy 2
• Obtain urinalysis and serum electrolytes to evaluate renal tubular function 2

Primary Treatment: Therapeutic Phlebotomy

Phlebotomy should be your first-line approach for patients with hereditary hemochromatosis, porphyria cutanea tarda, African iron overload, and post-transplant iron overload when bone marrow function is intact. 3

Induction Phase Protocol

• Remove 400-500 mL of blood (containing 200-250 mg of iron) per session 4, 1
• Perform phlebotomy weekly or twice weekly as tolerated during the initial depletion phase 4, 1
• Target ferritin level of 50-100 μg/L (some sources suggest <50 ng/mL for optimal outcomes) 1, 5
• Monitor hemoglobin, ferritin, and hematocrit before each session 4, 1
• Check serum ferritin every 10-12 phlebotomies initially, then more frequently as levels approach target 1, 5

Maintenance Phase Protocol

Once target ferritin is achieved:

• Men require maintenance phlebotomy 3-4 times per year 4, 1
• Women require maintenance phlebotomy 1-2 times per year 4, 1
• Monitor ferritin every 3-6 months during maintenance 1

Clinical Benefits of Phlebotomy

Early aggressive phlebotomy provides substantial mortality and morbidity benefits:

• Improvements in cardiac function and resolution of refractory arrhythmias occur when started early in disease 4, 1
• Survival returns to normal population levels when treatment begins before development of cirrhosis and diabetes 1
• Reduction in morbidity and mortality has been demonstrated specifically in African iron overload 3

Alternative Treatment: Iron Chelation Therapy

Chelation therapy is reserved for patients who cannot tolerate phlebotomy due to significant anemia, hemodynamic instability, malignancy, or transfusion-dependent conditions with secondary iron overload. 4, 1

When to Use Chelation Instead of Phlebotomy

• Patients with transfusion-dependent anemias (thalassemia, sickle cell disease, myelodysplastic syndromes) 4, 3
• Patients with significant anemia where phlebotomy would worsen clinical status 4
• Patients with hemodynamic instability 4
• Patients with ineffective erythropoiesis 3

Deferoxamine (Parenteral Chelator)

Deferoxamine remains the most established chelator with documented long-term survival benefits in transfusion-dependent patients:

• Administer 40 mg/kg/day subcutaneously over 8-12 hours nightly, 5-7 nights weekly 1, 3
• Maximum dose is 60 mg/kg/day 1
• For cardiac iron overload with heart failure, use high-dose intravenous deferoxamine for rapid iron removal 4
• Documented improvements in left ventricular ejection fraction (52% to 63%, P=0.03) and cardiac MRI T2* values in prospective studies 4

The major limitation is poor compliance due to parenteral administration, high cost, and need for frequent dosing. 4

Deferasirox (Oral Chelator)

Deferasirox is FDA-approved for chronic transfusional iron overload in patients ≥2 years old:

• Starting dose is 14 mg/kg/day orally once daily for patients with eGFR >60 mL/min/1.73 m² 2
• Contraindicated in patients with eGFR <40 mL/min/1.73 m² 2
• Adjust dose in 3.5 or 7 mg/kg increments every 3-6 months based on ferritin trends 2
• Maximum dose is 28 mg/kg/day (doses above this are not recommended) 2
• Take on empty stomach or with light meal (<7% fat content, ~250 calories) 2

Monitor serum creatinine weekly for first month, then monthly, due to risk of acute renal failure. 2 Monitor transaminases and bilirubin every 2 weeks during first month, then monthly. 2

Clinical efficacy data shows mean LIC reduction of -5.9 mg Fe/g dry weight and mean ferritin reduction of -332.8 μg/L over 1 year in MDS patients. 2 In cardiac iron overload, cardiac T2 improved from 11.98 ms to 17.12 ms* over 3 years. 2

Deferiprone (Oral Chelator)

Deferiprone has less consistent efficacy than deferoxamine and is available in the USA only through FDA treatment use program:

• Long-term efficacy and safety not fully established 4
• Combination therapy with deferoxamine plus deferiprone showed superior myocardial iron reduction compared to deferoxamine alone in randomized controlled trial 4

Target for Chelation Therapy

• Reduce hepatic iron concentration to <15,000 μg/g dry weight to significantly reduce clinical disease risk 3
• Monitor using hepatic iron concentration rather than serum ferritin, as ferritin is unreliable in secondary iron overload due to inflammation 3

Special Population: Cardiac Iron Overload

Risk stratify patients using cardiac MRI T2 values* to guide treatment intensity:

• T2 >20 ms (green zone)*: Low risk for imminent heart failure 4
• T2 10-20 ms (yellow zone)*: Intermediate risk, cardiac deposition likely present 4
• T2 <10 ms (red zone)*: High risk of cardiac decompensation, requires immediate aggressive chelation therapy plus standard heart failure medications (ACE inhibitors, diuretics, β-blockers) 4

Effective chelation therapy may delay development of clinically significant cardiac iron overload in green and yellow zone patients. 4

Dietary and Lifestyle Modifications

While dietary changes have limited impact on total body iron, certain modifications are advisable:

• Minimize alcohol consumption, which increases iron absorption 4, 1
• Avoid iron supplements and multivitamins containing iron 4, 1
• Avoid vitamin C supplements >500 mg/day, which enhance iron absorption 1, 5
• Avoid raw shellfish due to infection risk in patients with cirrhosis 1

Dietary iron restriction alone is insufficient as only 0.5-1.0 mg of excess iron is absorbed daily, far less than the 200-250 mg removed per phlebotomy session. 4

Monitoring During Treatment

For Phlebotomy Patients

• Hemoglobin and hematocrit before each session 4, 1
• Serum ferritin every 10-12 phlebotomies initially 1, 5
• Liver function tests regularly 1
• Hepatocellular carcinoma screening in patients with cirrhosis 1, 3

For Chelation Patients

• Serum creatinine weekly for first month, then monthly (more frequently if increased risk) 2
• Transaminases and bilirubin every 2 weeks for first month, then monthly 2
• Serum ferritin monthly, with dose adjustments every 3-6 months 2
• Hepatic iron concentration for accurate assessment in secondary iron overload 3

Common Pitfalls to Avoid

• Do not use phlebotomy in patients with alcoholic liver disease or chronic hepatitis C with mild iron overload, as it may not be beneficial 3
• Avoid excessive phlebotomy that could cause anemia and worsen fatigue 5
• Do not rely on serum ferritin alone in secondary iron overload due to inflammatory confounding; use hepatic iron concentration 3
• Never exceed deferasirox dose of 28 mg/kg/day due to safety concerns 2
• Reduce deferasirox dose when ferritin falls below 1000 μg/L at 2 consecutive visits, especially if dose >17.5 mg/kg/day 2