What is the appropriate workup for a adult patient with moderately elevated ferritin (iron storage protein) and no significant medical history?

Workup for Moderately Elevated Ferritin

The single most important initial test is a fasting transferrin saturation (TS), as over 90% of elevated ferritin cases are NOT due to iron overload but rather secondary causes like inflammation, metabolic syndrome, liver disease, or malignancy. 1

Initial Laboratory Evaluation

Order these tests simultaneously:

• Fasting transferrin saturation (TS) - the key discriminator between true iron overload (TS ≥45%) and secondary causes (TS <45%) 1
• Complete metabolic panel including AST, ALT to assess hepatocellular injury 1
• Complete blood count with differential to evaluate for anemia, polycythemia, or hematologic malignancy 1
• Inflammatory markers: CRP and ESR to detect occult inflammation 1
• Creatine kinase (CK) to evaluate for muscle necrosis 1

Diagnostic Algorithm 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

• C282Y homozygotes with elevated iron stores confirm HFE hemochromatosis and can proceed to therapeutic phlebotomy 1
• Consider liver biopsy if ferritin >1000 μg/L AND any of: elevated AST, hepatomegaly, age >40 years, or platelet count <200,000/μL (this combination predicts cirrhosis in 80% of C282Y homozygotes) 1
• Screen first-degree relatives if hereditary hemochromatosis is confirmed 1

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

Focus on identifying the underlying condition causing ferritin elevation as an acute-phase reactant: 1

Evaluate for common secondary causes:

• Metabolic syndrome/NAFLD: Check fasting glucose, lipid panel, assess for obesity, hypertension 1
• Chronic alcohol consumption: Detailed alcohol history (increases iron absorption and causes hepatocellular injury) 1
• Liver disease: Viral hepatitis B and C serologies if risk factors present 1
• Malignancy: Age-appropriate cancer screening, assess for B symptoms, lymphadenopathy, unexplained weight loss 1, 2
• Infection: Evaluate for active infection as ferritin rises acutely with inflammation 1
• Inflammatory/rheumatologic conditions: If CRP/ESR elevated, consider underlying autoimmune disease 1

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L:

• Low risk of organ damage (94% negative predictive value for advanced liver fibrosis) 1
• Focus on treating underlying secondary cause 1

Ferritin 1000-10,000 μg/L:

• Higher risk of advanced fibrosis/cirrhosis IF iron overload is present 1
• Requires additional evaluation with platelet count and liver enzymes 1
• Consider liver biopsy if ferritin >1000 μg/L with elevated liver enzymes or platelet count <200,000/μL 1

Ferritin >10,000 μg/L:

• Rarely represents simple iron overload 1
• Consider Adult-Onset Still's Disease if persistent fever present - measure glycosylated ferritin fraction (<20% is 93% specific for AOSD) 1
• Consider hemophagocytic lymphohistiocytosis/macrophage activation syndrome if cytopenias, fever, splenomegaly, elevated triglycerides present 1
• Urgent specialist referral to evaluate for life-threatening conditions 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone - ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 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
• Do not order HFE genetic testing if TS <45% - this wastes resources and leads to unnecessary anxiety 1
• Do not initiate phlebotomy therapy without confirmed iron overload (TS ≥45% plus genetic confirmation or liver biopsy evidence) 1
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 1

Management Approach

Treat the underlying condition, not the elevated ferritin itself: 1

• Metabolic syndrome/NAFLD: Weight loss, exercise, management of diabetes/hypertension 1
• Alcoholic liver disease: Alcohol cessation 1
• Inflammatory conditions: Disease-specific anti-inflammatory therapy 1
• Malignancy: Oncologic treatment 1
• Iron overload (TS ≥45% with genetic confirmation): Therapeutic phlebotomy 1