How to manage elevated ferritin levels due to iron overload?

Management of Elevated Ferritin Due to Iron Overload

For confirmed iron overload, initiate weekly therapeutic phlebotomy (500 mL) targeting a ferritin level of 50-100 μg/L, which prevents end-organ damage including cirrhosis, diabetes, cardiomyopathy, and premature death. 1

Initial Diagnostic Evaluation

The critical first step is distinguishing true iron overload from secondary hyperferritinemia, as 90% of elevated ferritin cases are NOT due to iron overload. 2, 3

Measure both transferrin saturation (TS) and ferritin together:

• If TS ≥45% with elevated ferritin: Proceed to HFE genotype testing for hereditary hemochromatosis (C282Y and H63D mutations). 1, 4, 5
• If TS <45% with elevated ferritin: This suggests secondary causes (inflammation, liver disease, metabolic syndrome, malignancy) rather than primary iron overload. 4, 6

Order HFE genetic testing when TS ≥45%:

• C282Y homozygosity confirms hereditary hemochromatosis and accounts for the majority of cases. 5
• Compound heterozygotes (C282Y/H63D) represent 14-30% of referred patients but rarely develop significant iron overload without additional risk factors. 1, 4

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L with normal liver enzymes:

• In C282Y homozygotes, proceed directly to phlebotomy without liver biopsy. 1, 4
• Risk of advanced fibrosis is very low (negative predictive value 94%). 4

Ferritin >1000 μg/L:

• This is the critical threshold indicating 20-45% prevalence of cirrhosis in C282Y homozygotes. 4
• Strongly consider liver biopsy if: Elevated ALT/AST OR platelet count <200,000/μL. 1
• If ferritin >1000 μg/L with elevated aminotransferases and platelets <200,000/μL, cirrhosis is present in 80% of cases. 5
• Refer to gastroenterologist or hematologist specializing in iron overload. 4, 2

Ferritin >10,000 ng/mL:

• This extreme elevation suggests life-threatening conditions (adult-onset Still's disease, hemophagocytic lymphohistiocytosis, macrophage activation syndrome) requiring urgent specialist referral. 4

Therapeutic Phlebotomy Protocol

Induction phase (de-ironing):

• Remove 500 mL blood weekly or biweekly as tolerated. 1
• Check hemoglobin/hematocrit before each phlebotomy; allow no more than 20% decline from baseline. 1
• Monitor ferritin every 10-12 phlebotomies. 1
• Stop intensive phlebotomy when ferritin reaches 50-100 μg/L. 1

Maintenance phase:

• Continue phlebotomy at intervals (typically 3-4 times yearly) to maintain ferritin 50-100 μg/L. 1, 5
• This target prevents iron reaccumulation while avoiding overchelation. 1

Critical pitfall to avoid: Continuing phlebotomy when ferritin falls below 500 μg/L can cause life-threatening complications. Interrupt therapy if ferritin <500 μg/L and reassess monthly. 7

Alternative Treatments for Secondary Iron Overload

When phlebotomy is contraindicated (dyserythropoiesis, severe anemia):

• Deferoxamine (Desferal): 20-40 mg/kg/day via continuous subcutaneous infusion. 1
• Deferasirox (Exjade): Oral iron chelator, but monitor closely for renal toxicity, hepatotoxicity, cytopenias, and severe skin reactions. 1, 7
• Consider follow-up liver biopsy to confirm adequate iron removal. 1

Phlebotomy is NOT recommended for:

• Mild secondary iron overload in chronic hepatitis C (hepatic iron concentration <2500 μg/g). 1
• Alcoholic liver disease (no evidence of benefit). 1

Phlebotomy shows benefit in:

• Porphyria cutanea tarda (reduces skin manifestations). 1
• NAFLD (improves insulin resistance and ALT levels). 1

Dietary and Lifestyle Modifications

Avoid:

• Vitamin C supplements (increases iron absorption, especially during phlebotomy). 1
• Iron supplements and multivitamins containing iron. 1
• Raw shellfish (risk of Vibrio vulnificus infection in iron-overloaded patients). 1

Dietary iron restriction is unnecessary: The amount of iron absorption affected by diet (2-4 mg/day) is negligible compared to phlebotomy removal (250 mg/week). 1

Monitoring and Surveillance

During treatment:

• Ferritin every 10-12 phlebotomies during induction. 1
• Liver enzymes (ALT, AST) if initially elevated. 4
• Hemoglobin/hematocrit before each phlebotomy. 1

Long-term surveillance for complications:

• Screen for diabetes mellitus, arthropathy, hypogonadism, and cardiac dysfunction. 5, 8
• Cardiac evaluation (ECG/echocardiography) if severe iron overload suspected. 4
• Auditory and ophthalmic testing every 12 months if using iron chelators. 7

MRI for iron quantification:

• Use R2* sequences to non-invasively quantify hepatic iron concentration (correlation 0.74-0.98 with biochemical measurement). 4
• Assess cardiac, pancreatic, and splenic iron in complex cases. 1, 4

Family Screening

First-degree relatives of C282Y homozygotes require:

• Serum ferritin and transferrin saturation. 5
• HFE genetic testing. 4, 5
• Siblings have 25% chance of being affected. 5
• Penetrance is higher in family members than general population. 4

Special Populations

Chronic kidney disease with anemia:

• Despite ferritin 500-1200 ng/mL, IV iron may be beneficial if TS <25% (functional iron deficiency). 1, 4
• Withhold iron when ferritin >1000 ng/mL or TS >50%. 4

Elderly patients:

• Monitor more frequently for toxicity with iron chelators. 7
• Higher risk of serious adverse reactions. 7

Pediatric patients:

• Avoid deferasirox doses 14-28 mg/kg/day when ferritin approaches normal range (risk of volume depletion and renal toxicity). 7

Common Pitfalls to Avoid

• Using ferritin alone without transferrin saturation to diagnose iron overload leads to misdiagnosis of inflammatory conditions. 4
• Overlooking liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests misses cirrhosis. 4
• Continuing phlebotomy when ferritin <500 μg/L causes overchelation complications. 7
• Delaying treatment while awaiting cardiac MRI in symptomatic patients worsens outcomes. 4