What is the treatment for hyperferritinemia (elevated serum iron levels)?

Treatment of Hyperferritinemia (Elevated Serum Iron Levels)

Initial Diagnostic Assessment

Before initiating treatment, you must first distinguish true iron overload from inflammatory hyperferritinemia by measuring transferrin saturation, with levels >45% indicating genuine iron overload requiring intervention. 1, 2

Essential Pre-Treatment Workup

• Measure transferrin saturation to confirm iron overload versus inflammatory causes 1, 2
• Order HFE genetic testing if transferrin saturation is elevated to diagnose hereditary hemochromatosis 1, 2
• Obtain baseline liver function tests (ALT, AST, bilirubin) and consider liver biopsy if ferritin >1000 μg/L with elevated transaminases and platelets <200,000, which predicts cirrhosis in 80% of C282Y homozygotes 1
• Check duplicate serum creatinine measurements and calculate eGFR, plus urinalysis to assess renal tubular function 1, 3
• Perform baseline auditory and ophthalmic examinations before starting therapy 1, 3

Primary Treatment: Therapeutic Phlebotomy

For confirmed iron overload, initiate weekly therapeutic phlebotomy removing 400-500 mL of blood (containing 200-250 mg of iron) as the gold standard treatment. 4, 1

Phlebotomy Protocol

• Remove 400-500 mL of blood weekly or twice weekly as tolerated during the initial depletion phase 4, 1
• Check hemoglobin/hematocrit before each session and postpone phlebotomy if hemoglobin falls below 12 g/dL 4, 1, 2
• Discontinue phlebotomy if hemoglobin drops below 11 g/dL and resume only when anemia resolves 4, 1
• Monitor serum ferritin every 10-12 phlebotomies (approximately every 3 months) initially, then more frequently as levels approach target 4, 1, 2
• Continue phlebotomy until ferritin reaches 50-100 μg/L without inducing iron deficiency 4, 1, 2, 5

Maintenance Phase

• After achieving target ferritin of 50-100 μg/L, continue maintenance phlebotomy every 3-6 months to prevent reaccumulation 2, 5
• Maintain serum ferritin between 50-100 μg/L during the maintenance phase 2, 5
• Monitor ferritin every 6 months during maintenance and investigate unexpected fluctuations 5

Alternative Treatment: Chelation Therapy

Chelation therapy is reserved for patients who cannot tolerate phlebotomy due to anemia, malignancy, or hemodynamic instability. 4

Indications for Chelation

• Initiate chelation when ferritin reaches 1000 ng/mL in transfusion-dependent patients requiring ≥2 units/month for >1 year 4
• Consider chelation for patients with life expectancy >1 year who show signs of iron-related organ complications requiring preservation 4
• Use chelation in myelodysplastic syndrome patients with low-risk disease (IPSS low or intermediate-1) who are transfusion-dependent 4

Chelation Agents and Dosing

• Deferoxamine: 20-40 mg/kg body weight per day via subcutaneous or intravenous infusion 4
• Deferasirox (oral): Starting dose of 14 mg/kg/day for patients with eGFR >60 mL/min/1.73 m², adjusted in steps of 3.5-7 mg/kg based on ferritin trends, maximum 28 mg/kg/day 3
• Monitor serum ferritin monthly and adjust dose every 3-6 months based on trends 3
• Reduce dose if ferritin falls below 1000 mcg/L at 2 consecutive visits, especially if dose >17.5 mg/kg/day 3
• Interrupt chelation if ferritin falls below 500 mcg/L and continue monthly monitoring 3

Dietary and Lifestyle Modifications

• Avoid all iron supplements and iron-fortified foods including fortified breakfast cereals 1, 2, 5
• Limit vitamin C supplements to ≤500 mg/day as vitamin C enhances iron absorption and should be avoided during phlebotomy 4, 1, 5
• Restrict alcohol intake during iron depletion phase, with complete abstinence for patients with cirrhosis 1, 5
• Avoid raw shellfish due to risk of Vibrio vulnificus infection in iron-overloaded patients 4, 2

Special Populations and Critical Considerations

Transfusion-Dependent Patients

• MDS patients most likely to benefit include those requiring ≥2 units/month for >1 year, ferritin >1000 ng/mL, low-risk disease, life expectancy >1 year, and candidates for allograft 4
• Continue chelation as long as transfusion therapy continues and iron overload remains clinically relevant 4

Pre-Transplant Patients

• Consider iron chelation before allogeneic stem cell transplant to decrease procedure-related hepatic complications and mortality 4
• Avoid chelation post-transplant during immunosuppressive therapy due to overlapping renal toxicity 4
• Use phlebotomy as preferred method for iron removal >1 year post-transplant with stable hemoglobin 4

Pediatric and Elderly Patients

• Interrupt deferasirox in pediatric patients with acute illnesses causing volume depletion (vomiting, diarrhea, decreased oral intake) and monitor more frequently 3
• Monitor elderly patients more frequently for toxicity as deferasirox has been associated with serious and fatal adverse reactions in this population 3

Monitoring During Treatment

• Monitor hemoglobin and hematocrit at each phlebotomy session 5
• Check serum ferritin monthly during chelation therapy to assess for overchelation 3
• Monitor liver function, renal function, and blood counts monthly during chelation 3
• Perform auditory and ophthalmic testing every 12 months during chelation therapy 3
• Continue HCC screening every 6 months even after successful iron depletion in patients with cirrhosis, as HCC accounts for 30% of hemochromatosis-related deaths 1

Critical Pitfalls to Avoid

• Do not continue aggressive iron removal when ferritin approaches normal range as this can cause life-threatening adverse events, particularly in pediatric patients with volume depletion 3
• Do not use chelation doses >28 mg/kg/day deferasirox as higher doses are not recommended and increase toxicity risk 3
• Do not initiate chelation in patients with life expectancy <1 year unless already showing iron-related organ complications requiring preservation 4
• Do not supplement with vitamin C during phlebotomy as it accelerates iron mobilization and may increase pro-oxidant activity 4

Expected Outcomes

• Phlebotomy improves survival to normal population levels when initiated before development of cirrhosis and diabetes 1
• Hepatic fibrosis reverses in approximately 30% of cases, though established cirrhosis does not reverse 1
• Cardiac function and diabetes control improve with successful iron removal 1
• Elevated liver enzymes normalize with phlebotomy 1