What is the appropriate workup for a patient with elevated ferritin (iron) levels?

Workup for Elevated Ferritin

The most critical first step is to measure fasting transferrin saturation (TS) alongside ferritin, because over 90% of elevated ferritin cases are NOT due to iron overload but rather inflammation, liver disease, malignancy, or metabolic conditions—and TS ≥45% is the key discriminator for true iron overload requiring genetic testing. 1, 2

Initial Laboratory Evaluation

When ferritin is elevated, immediately order the following tests:

• Fasting transferrin saturation (TS) - the single most important test to distinguish iron overload from secondary causes 1, 2
• Complete blood count with differential 2
• Comprehensive metabolic panel including AST, ALT - to assess hepatocellular injury 1, 2
• Inflammatory markers: CRP and ESR - to detect occult inflammation 1, 2
• Creatine kinase (CK) - to evaluate for muscle necrosis 1

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

• Order HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis 1, 2
• C282Y homozygotes with elevated iron stores confirm HFE hemochromatosis and can proceed to therapeutic phlebotomy 1, 2
• Consider liver MRI to quantify hepatic iron concentration if diagnosis remains uncertain 2, 3
• Liver biopsy should be offered to C282Y homozygotes with ferritin >1000 μg/L, elevated AST, hepatomegaly, or age >40 years 1
• Screen first-degree relatives with genetic testing once HFE hemochromatosis is confirmed 1, 2

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

The following conditions account for the vast majority of elevated ferritin 1, 2:

Liver Disease:

• Chronic alcohol consumption - obtain detailed alcohol history 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome - check blood pressure, BMI, cholesterol, triglycerides, fasting glucose 1, 2
• Viral hepatitis B or C - order hepatitis serologies 2
• Acute hepatitis - elevated transaminases suggest hepatocellular necrosis 1, 2

Inflammatory/Infectious Conditions:

• Active infection - ferritin rises acutely as an acute phase reactant 2
• Chronic inflammatory diseases - evaluate based on clinical presentation 1, 2
• Adult-onset Still's disease (AOSD) - consider if ferritin >10,000 μg/L; order glycosylated ferritin fraction (≤20% is 93% specific for AOSD) 2, 4, 5

Malignancy:

• Solid tumors, lymphomas, hepatocellular carcinoma - order CT scan if clinically indicated 1, 2

Other Causes:

• Cell necrosis - check CK for muscle injury 1, 2
• Chronic kidney disease - assess renal function 2

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L:

• Low risk of organ damage (94% negative predictive value for advanced fibrosis) 2
• If C282Y homozygote with elevated TS, can initiate therapeutic phlebotomy without liver biopsy 1, 2

Ferritin 1000-10,000 μg/L:

• Higher risk of advanced fibrosis/cirrhosis if iron overload present 2
• The combination of ferritin >1000 μg/L, elevated aminotransferases, and platelet count <200 predicts cirrhosis in 80% of C282Y homozygotes 2
• Consider liver biopsy in this setting 1, 2

Ferritin >10,000 μg/L:

• Rarely represents simple iron overload 2
• Requires urgent specialist referral to evaluate for life-threatening conditions including AOSD, hemophagocytic lymphohistiocytosis, or severe infection 2, 4, 5

Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload - ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 2
• Do not assume iron overload when TS <45% - in the general population, iron overload is NOT the most common cause of elevated ferritin 2
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests, as this combination warrants histologic assessment for cirrhosis 2
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload and requires evaluation for inflammatory/rheumatologic emergencies 2, 4

Special Considerations

In patients with chronic kidney disease:

• Elevated ferritin with low TS (<20%) may represent functional iron deficiency that responds to IV iron therapy 1, 2
• Consider a trial of weekly IV iron (50-125 mg for 8-10 doses) to differentiate functional iron deficiency from inflammatory block 2

In patients with inflammatory bowel disease:

• Ferritin <30 μg/L indicates iron deficiency 1
• Ferritin >100 μg/L with low TS suggests anemia of chronic disease 1