What is the approach to managing hyperferritinemia?

Approach to Hyperferritinemia

The first step in managing hyperferritinemia is to determine whether it is due to true iron overload or secondary causes by measuring transferrin saturation, which should be followed by appropriate diagnostic testing based on the results. 1

Initial Evaluation

Step 1: Assess Iron Parameters

• Measure fasting transferrin saturation (TS) and serum ferritin simultaneously 1
  • TS < 45%: Likely secondary cause of hyperferritinemia
  • TS > 45%: Possible iron overload disorder

Step 2: Rule Out Common Secondary Causes of Hyperferritinemia

• Inflammation (check C-reactive protein)
• Cell necrosis (check AST, ALT, CK)
• Malignancy (check ESR, consider imaging)
• Alcoholic liver disease (assess alcohol intake)
• Non-alcoholic fatty liver disease (check BMI, lipids, glucose)
• Chronic infections 1

Diagnostic Algorithm Based on Transferrin Saturation

If Transferrin Saturation > 45%:

1. Genetic testing for HFE mutations (C282Y and H63D)

   • C282Y homozygotes: Likely hereditary hemochromatosis
   • C282Y/H63D compound heterozygotes or H63D homozygotes: Investigate other causes first 1

2. Liver assessment:

   • Consider liver biopsy in C282Y homozygotes with:
     • Serum ferritin > 1000 μg/L
     • Elevated liver enzymes
     • Hepatomegaly
     • Age > 40 years 1
   • Alternative: Liver MRI for non-invasive iron quantification 2

3. If negative for common HFE mutations but iron overload confirmed:

   • Consider testing for rare hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) 1

If Transferrin Saturation < 45%:

1. Focus on inflammatory and metabolic causes:

   • Metabolic syndrome/NAFLD (most common cause) 3
   • Malignancy (particularly hematologic) 4
   • Rheumatologic diseases
   • Chronic kidney disease
   • Alcoholic liver disease

2. Consider specialized testing:

   • Glycosylated ferritin measurement to differentiate between inflammation and iron overload 5
   • Liver MRI to rule out iron overload 2

Management Based on Etiology

For Primary Iron Overload (Hemochromatosis):

1. Therapeutic phlebotomy:

   • Initial phase: Remove 450-500 mL blood weekly
   • Monitor hematocrit before each procedure
   • Check serum ferritin every 10-12 phlebotomies
   • Continue until ferritin < 50 μg/L 6
   • Maintenance: Periodic phlebotomy to maintain ferritin 25-50 μg/L 6

2. Dietary modifications:

   • Avoid iron supplements and iron-fortified foods
   • Limit red meat consumption
   • Restrict alcohol intake
   • Avoid vitamin C supplements during treatment 6

For Secondary Hyperferritinemia:

1. Treat the underlying condition:

   • NAFLD: Weight loss, management of metabolic syndrome 3
   • Inflammatory conditions: Treat underlying disease
   • Alcoholic liver disease: Alcohol cessation

2. Avoid unnecessary phlebotomy:

   • Phlebotomy is ineffective when hyperferritinemia is primarily due to inflammation 3

For Transfusional Iron Overload:

1. Iron chelation therapy when:
   • Multiple blood transfusions (>20 units)
   • Serum ferritin >1000 μg/L 6
   • Options include:
     • Deferasirox (monitor for renal/hepatic toxicity) 7
     • Deferoxamine (20-40 mg/kg/day) 6

Monitoring

1. For patients on phlebotomy:

   • Monitor ferritin levels every 3-4 months
   • Target maintenance ferritin: 25-50 μg/L 6

2. For patients on chelation therapy:

   • Monitor serum ferritin every 3 months
   • Regular renal function testing (monthly initially)
   • Liver function tests every 2 weeks initially, then monthly
   • Target ferritin < 1000 μg/L 6, 7

3. Screening for complications:

   • Liver function tests
   • Fasting glucose (diabetes screening)
   • Cardiac evaluation if symptoms suggest cardiomyopathy 6
   • Hepatocellular carcinoma screening in cirrhotic patients

Important Caveats

• Serum ferritin > 1000 μg/L in hereditary hemochromatosis predicts hepatic fibrosis/cirrhosis 1
• In inflammatory conditions, ferritin acts as an acute-phase reactant; values up to 100 μg/L may still indicate iron deficiency 6
• Extremely high ferritin levels (>10,000 μg/L) should raise suspicion for adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or malignancy 4
• Avoid iron chelation in patients with poor renal function (eGFR <40 mL/min/1.73m²) due to risk of acute kidney injury 7
• Monitor closely for hepatic and renal toxicity in patients receiving deferasirox, particularly elderly patients and those with comorbidities 7