Management of Hyperferritinemia with Normal CBC
The first step is to measure fasting transferrin saturation (TSAT) alongside ferritin, as TSAT <45% effectively rules out primary iron overload and indicates that hyperferritinemia is due to secondary causes requiring targeted treatment rather than phlebotomy. 1, 2
Initial Diagnostic Workup
When encountering elevated ferritin with normal CBC, the diagnostic algorithm proceeds systematically:
Step 1: Measure Transferrin Saturation
- Obtain fasting TSAT immediately (calculated as serum iron/TIBC × 100) 1, 2
- If TSAT <45%, iron overload is unlikely and secondary causes predominate (>90% of cases) 1, 2
- If TSAT ≥45%, proceed to genetic testing for hemochromatosis 1
Step 2: Identify Common Secondary Causes (if TSAT <45%)
Over 90% of hyperferritinemia cases are explained by non-iron overload conditions 1, 2. Systematically evaluate:
- Inflammation: Check CRP, ESR 1
- Liver disease: Check AST, ALT, hepatitis B/C serology, assess for alcohol use and NAFLD/metabolic syndrome (check BMI, blood pressure, glucose, lipids) 1, 2
- Cell necrosis: Check CK for muscle damage 1
- Malignancy: Consider CT imaging if clinical suspicion, especially with very high ferritin (>10,000 μg/L) 1, 2, 3
- Chronic kidney disease: Check creatinine and eGFR 2
Step 3: Consider Rare Inflammatory Conditions
If ferritin is extremely elevated (>5,000-10,000 μg/L) with negative initial workup:
- Adult-onset Still's disease: Look for fever, rash, arthralgia; check glycosylated ferritin if available (<20% supports diagnosis) 1, 2, 3
- Hemophagocytic lymphohistiocytosis: Check for pancytopenia (though you have normal CBC), fever, hepatosplenomegaly 1, 3
- Average ferritin in these rheumatologic syndromes is >14,000 μg/L 3
Management Based on TSAT Results
If TSAT ≥45%: Evaluate for Hemochromatosis
Proceed with HFE genetic testing for C282Y and H63D mutations 1:
- C282Y homozygotes: Confirm diagnosis of HFE hemochromatosis; initiate phlebotomy therapy 1
- C282Y/H63D compound heterozygotes or H63D homozygotes: First investigate other causes of hyperferritinemia before attributing to genetics 1
- Negative HFE testing with confirmed iron overload: Consider non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) after confirming iron excess by MRI or liver biopsy 1, 2
Risk Stratification for Liver Disease in Hemochromatosis
- Ferritin <1,000 μg/L: Very low risk of cirrhosis; liver biopsy not needed if age <40, normal ALT, no hepatomegaly 1
- Ferritin >1,000 μg/L: Consider liver biopsy if elevated AST, hepatomegaly, or age >40 years to assess for cirrhosis 1
- Non-invasive scores (APRI, FIB-4) or transient elastography can help assess fibrosis risk 1
If TSAT <45%: Treat Underlying Condition
Do not initiate iron chelation or phlebotomy 2, 4. Instead:
- Treat identified secondary causes: Manage NAFLD/metabolic syndrome, address alcohol use, treat infections, optimize inflammatory conditions 1, 2, 5
- Monitor ferritin trends: Ferritin should normalize as underlying condition improves 1, 2
- Reassess if ferritin remains elevated: Consider repeat TSAT, liver imaging, or specialist referral if no clear cause identified 2, 5
Critical Pitfalls to Avoid
- Never diagnose iron overload based on ferritin alone without checking TSAT 1, 2
- Do not assume C282Y homozygosity equals hemochromatosis without evidence of increased iron stores 1
- Do not overlook malignancy in patients with very high ferritin (>10,000 μg/L), as this rarely represents simple iron overload 2, 3
- Do not screen for HFE mutations if TSAT is normal, as this leads to unnecessary genetic testing and misdiagnosis 1, 2, 4
Family Screening Considerations
If HFE hemochromatosis is confirmed (C282Y homozygote with iron overload):