What tests should be done in an adult patient with elevated ferritin (iron storage protein) levels and no prior medical history?

What Tests Should Be Done After Elevated Ferritin

The single most important test is fasting transferrin saturation (TS), which must be measured simultaneously with ferritin to distinguish true iron overload (TS ≥45%) from the far more common secondary causes of hyperferritinemia. 1

Initial Essential Laboratory Panel

When ferritin is elevated, immediately order:

• Fasting transferrin saturation (TS) – This is the critical discriminator that determines your entire diagnostic pathway 1, 2
• Complete blood count (CBC) with differential – Evaluates for anemia, polycythemia, or hematologic malignancy 3, 1
• Comprehensive metabolic panel including ALT and AST – Assesses for hepatocellular injury from NAFLD, alcoholic liver disease, or viral hepatitis 1, 2
• Inflammatory markers (CRP and ESR) – Detects occult inflammation, as ferritin is an acute phase reactant 1, 2

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

Proceed immediately to HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis 1, 2. This pattern indicates possible iron overload requiring genetic confirmation 1.

Additional testing in this scenario:

• Liver biopsy or MRI for hepatic iron concentration if ferritin >1000 μg/L with elevated liver enzymes or platelet count <200,000/μL 1, 2
• The combination of ferritin >1000 μg/L, elevated aminotransferases, and platelets <200 predicts cirrhosis in 80% of C282Y homozygotes 1

If TS <45%: Secondary Causes Predominate

Over 90% of elevated ferritin cases with TS <45% are caused by inflammation, chronic alcohol consumption, cell necrosis, tumors, or metabolic syndrome/NAFLD—NOT iron overload 1. In this scenario:

Evaluate for common secondary causes:

• Abdominal ultrasound – Standard workup to evaluate for fatty liver, chronic liver disease, and hepatomegaly 1
• Alcohol consumption history – Chronic alcohol increases iron absorption and causes hepatocellular injury 1
• Creatine kinase (CK) – Checks for muscle necrosis releasing ferritin from lysed cells 1
• Viral hepatitis serologies (Hepatitis B and C) if risk factors present 1

Risk Stratification by Ferritin Level

Ferritin <1000 μg/L

• Low risk of organ damage with 94% negative predictive value for advanced liver fibrosis 1, 2
• If C282Y homozygote with TS ≥45%, can proceed directly to therapeutic phlebotomy without liver biopsy if age <40, normal liver enzymes, and no hepatomegaly 1, 2

Ferritin 1000-10,000 μg/L

• Higher risk requiring additional evaluation 1
• Consider liver biopsy if elevated liver enzymes or platelet count <200,000/μL present 1, 2
• Prevalence of cirrhosis in C282Y homozygotes is 20-45% at this level 2

Ferritin >10,000 μg/L

• Rarely represents simple iron overload – requires urgent specialist referral 1, 4
• Associated with only four causes: hemophagocytic lymphohistiocytosis (HLH), infections, acute hepatitis, and cytokine release syndromes 4
• If ferritin >4000-5000 μg/L with persistent fever, measure glycosylated ferritin fraction (<20% is 93% specific for adult-onset Still's disease) 1, 2

Special Population Considerations

Chronic Kidney Disease

• Functional iron deficiency can occur despite elevated ferritin (500-1200 ng/mL) when TS <25% 1, 2
• Consider soluble transferrin receptor (sTfR) testing to distinguish true iron deficiency from inflammatory iron block 1, 5

Hematologic Malignancy Screening

• Look for aquagenic pruritus and order JAK2 mutation testing if polycythemia vera suspected 3
• Assess for B symptoms and lymphadenopathy – consider CT imaging if lymphoma suspected 3
• Serum protein electrophoresis (SPEP) if multiple myeloma considered, though rarely associated with pruritus 3

Celiac Disease Screening

• Tissue transglutaminase (TTG) antibodies if unexplained iron deficiency coexists with elevated ferritin 3
• Reserve small bowel biopsy for positive serologies requiring pathologic confirmation 3

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload 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 1
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 1, 2
• Recognize that ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 2
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1, 2

When to Refer to Specialist

Immediate referral indicated if:

• Ferritin >10,000 μg/L regardless of other findings 1, 4
• Ferritin >1000 μg/L with abnormal liver tests 1, 2
• TS ≥45% with confirmed C282Y homozygosity requiring therapeutic phlebotomy 1, 2
• Suspicion of HLH, adult-onset Still's disease, or other life-threatening conditions 1, 4