What is the appropriate workup for a patient with hyperferritinemia (elevated ferritin level)?

Workup of Abnormally High Ferritin

Measure transferrin saturation (TS) immediately alongside ferritin—this single test determines whether you're dealing with true iron overload (TS ≥45%) or secondary hyperferritinemia (TS <45%), which accounts for over 90% of cases. 1

Initial Laboratory Evaluation

The first step is obtaining a fasting transferrin saturation along with your ferritin level. 2, 1 This combination prevents the most common diagnostic error: assuming elevated ferritin means iron overload. 1

Additional initial labs to order simultaneously: 1

• Complete metabolic panel (AST, ALT, bilirubin, albumin)
• Complete blood count with differential
• Inflammatory markers (CRP, ESR)
• Creatine kinase (to assess for muscle necrosis)

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

Order HFE genetic testing for C282Y and H63D mutations immediately. 2, 1 This is the pathway for hereditary hemochromatosis.

Interpretation of genetic results: 2

• C282Y homozygotes with elevated ferritin = confirmed HFE hemochromatosis → proceed to therapeutic phlebotomy
• C282Y/H63D compound heterozygotes = possible mild iron overload → monitor annually if ferritin normal; treat if elevated
• C282Y heterozygotes or H63D heterozygotes = reassure patient they won't develop progressive iron overload
• Negative HFE testing with confirmed iron overload → consider non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) 1

Risk stratification by ferritin level in confirmed hemochromatosis: 2, 1

• Ferritin <1000 μg/L: Low risk of cirrhosis (94% negative predictive value) → can start phlebotomy without liver biopsy if age <40 and normal liver enzymes
• Ferritin >1000 μg/L with elevated ALT/AST and platelets <200,000/μL: 80% risk of cirrhosis in C282Y homozygotes → liver biopsy strongly recommended before starting treatment

If TS <45%: Secondary Hyperferritinemia (>90% of Cases)

Iron overload is extremely unlikely—do NOT pursue HFE genetic testing or liver biopsy for iron assessment. 1, 3 The ferritin elevation is from one or more secondary causes.

Systematic evaluation of secondary causes: 1

1. Liver disease (most common):

• Check alcohol consumption history thoroughly 1
• Elevated ALT/AST suggests NAFLD, alcoholic liver disease, or viral hepatitis 1
• Order hepatitis B and C serologies if risk factors present 1
• Assess for metabolic syndrome components (BMI, blood pressure, triglycerides, glucose) 1, 4

2. Inflammatory/rheumatologic conditions:

• Elevated CRP/ESR indicates active inflammation 1
• If ferritin >4,000-5,000 μg/L with persistent fever → measure glycosylated ferritin fraction (<20% is 93% specific for adult-onset Still's disease) 1
• Screen for hemophagocytic lymphohistiocytosis if ferritin >5,000 μg/L with cytopenias, fever, splenomegaly 1

3. Malignancy:

• Review CBC for cytopenias or abnormal cell lines 1
• Consider CT imaging if B symptoms or lymphadenopathy present 1
• Solid tumors and lymphomas are common causes 1, 5

4. Infection:

• Ferritin rises acutely as an acute-phase reactant during active infection 1
• Evaluate for occult infection with appropriate cultures and imaging 1

5. Cell necrosis:

• Elevated CK suggests muscle injury 1
• Acute hepatitis causes massive ferritin elevation from hepatocellular necrosis 1

Special Clinical Contexts

Chronic Kidney Disease

In CKD patients on erythropoiesis-stimulating agents, ferritin 100-700 ng/mL with TS <20% may represent functional iron deficiency that responds to IV iron therapy despite the elevated ferritin. 1 Consider a trial of weekly IV iron 50-125 mg for 8-10 doses to distinguish functional iron deficiency from pure inflammatory block. 1

Inflammatory Bowel Disease

Ferritin >100 μg/L with low TS suggests anemia of chronic disease rather than iron deficiency. 1 However, IV iron may still be beneficial in active IBD. 1

Heart Failure

In CHF patients with iron deficiency (ferritin <100 μg/L or ferritin 100-300 μg/L with TS <20%), IV iron improves functional capacity and quality of life even without anemia. 1

Critical Pitfalls to Avoid

Never diagnose iron overload based on ferritin alone without confirming TS ≥45%. 1, 3 Ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 1

Do not overlook liver biopsy in C282Y homozygotes with ferritin >1000 μg/L and abnormal liver tests—this combination predicts cirrhosis in 80% of cases. 2, 1

Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin. 1

If hereditary hemochromatosis is confirmed, screen all first-degree relatives with simultaneous HFE genetic testing and iron studies (ferritin + TS). 2

Follow-Up Strategy

For secondary hyperferritinemia (TS <45%): 1, 4

• Treat the underlying condition (weight loss for NAFLD, disease-specific therapy for inflammatory conditions, oncologic treatment for malignancy)
• Recheck ferritin in 3-6 months after addressing underlying causes
• If ferritin remains <1000 μg/L with normal TS, continue monitoring every 6-12 months
• Refer to hepatology if ferritin exceeds 1000 μg/L or continues rising despite treatment

For confirmed iron overload (TS ≥45% with positive genetics): 2

• Initiate therapeutic phlebotomy
• Monitor ferritin and TS during treatment
• Screen family members

2, 1, 4, 3, 5, 6, 7, 8, 9