What are the recommended follow-up labs and treatment for a patient with elevated ferritin levels?

Follow-Up Labs and Treatment for Elevated Ferritin Levels

For patients with elevated ferritin levels, the recommended follow-up includes transferrin saturation (TS) measurement, HFE genetic testing, and liver function tests to determine the underlying cause and guide appropriate treatment. 1

Initial Diagnostic Approach

• Measure both serum ferritin AND transferrin saturation (TS) together, as relying on a single test is insufficient for proper evaluation 1
• If either is abnormal (TS ≥45% or ferritin above the upper limit of normal), HFE mutation analysis should be performed 1
• Investigate common causes of non-iron overload hyperferritinemia before pursuing genetic testing, including: 1
  • Chronic alcohol consumption (check history)
  • Inflammation (check C-reactive protein)
  • Cell necrosis (check AST, ALT, CK)
  • Malignancy (check ESR, consider imaging)
  • Non-alcoholic fatty liver disease (check BMI, lipids, glucose)

Risk Stratification Based on Ferritin Level

• Ferritin <1000 μg/L: Low risk of cirrhosis, less urgent evaluation 1
• Ferritin >1000 μg/L with elevated liver enzymes (ALT/AST) and platelet count <200,000: High risk (80%) for cirrhosis in C282Y homozygotes 1
• Ferritin >2000 μg/L: Highly predictive of true iron overload regardless of other factors 2

Additional Testing Based on Initial Results

If HFE Testing Positive (C282Y/C282Y homozygote):

• Assess for liver fibrosis using non-invasive methods like transient elastography (liver stiffness <6.4 kPa rules out advanced fibrosis) 1
• Consider liver biopsy if ferritin >1000 μg/L, elevated liver enzymes, hepatomegaly, or age >40 years 1
• Evaluate for cardiac involvement with ECG and echocardiography if severe iron overload is present 1

If HFE Testing Negative or Inconclusive:

• Check full blood count and iron studies to exclude iron deficiency anemia (which can paradoxically present with elevated ferritin in certain conditions) 1
• Consider other causes of hyperferritinemia including inflammatory conditions, malignancy, and metabolic disorders 3
• For persistently unexplained elevated ferritin, consider referral to a gastroenterologist or hematologist, especially if ferritin >1000 μg/L 4

Treatment Recommendations

For Hereditary Hemochromatosis:

• Therapeutic phlebotomy is the mainstay of treatment for confirmed iron overload 1
• Monitor serum ferritin levels during treatment to guide therapy 1
• For C282Y homozygotes with elevated ferritin, initiate therapeutic phlebotomy 1
• For C282Y/H63D compound heterozygotes with ferritin >1000 μg/L and normal liver enzymes, therapeutic phlebotomy is recommended 1

For Secondary Iron Overload:

• Address underlying cause (alcohol cessation, weight loss for metabolic syndrome, etc.) 1
• For transfusional iron overload, consider iron chelation therapy with deferasirox if phlebotomy is not feasible 5
• Monitor for potential adverse effects of chelation therapy, including renal dysfunction, hepatotoxicity, and cytopenias 5

For Iron Deficiency with Elevated Ferritin:

• Oral iron supplementation for 8-10 weeks with target ferritin ≥50 μg/L 6
• Consider intravenous iron in cases of malabsorption, need for rapid repletion, or failure of oral therapy 6

Family Screening

• Recommend screening for all first-degree relatives of patients with confirmed HFE-related hemochromatosis 1
• For children of an identified proband, HFE testing of the other parent is recommended 1
• If C282Y homozygosity or compound heterozygosity is found in adult relatives and ferritin is increased, therapeutic phlebotomy is indicated 1

Monitoring

• For C282Y homozygotes with normal ferritin, annual follow-up with iron studies is recommended 1
• During iron chelation therapy, monitor renal function, liver function, and blood counts regularly 5
• Avoid measuring iron parameters within 4 weeks of intravenous iron administration as it can interfere with test results 6

Common Pitfalls to Avoid

• Don't assume all elevated ferritin represents iron overload; 90% of cases are due to non-iron overload conditions 4
• Don't rely solely on ferritin without transferrin saturation, as each can be elevated independently 1
• Don't diagnose HFE hemochromatosis based on C282Y homozygosity alone without evidence of increased iron stores 1
• Don't overlook the ferritin/AST ratio, which can be highly predictive of tissue iron overload (sensitivity 83.3%, specificity 78.6%) 2
• Don't miss the opportunity for MRI assessment of liver iron concentration as a non-invasive alternative to liver biopsy in unclear cases 7