What is the appropriate work‑up for an elevated ferritin (~300 ng/mL) in a patient with normal complete blood count, normal liver function tests, and anti‑tissue transglutaminase ordered?

Work-Up for Ferritin ~300 ng/mL with Normal CBC and Liver Function Tests

The single most important next step is to order a fasting transferrin saturation (TS) to determine whether this represents true iron overload (TS ≥45%) or secondary hyperferritinemia from inflammation, metabolic disease, or other non-iron causes (TS <45%). 1

Immediate Laboratory Testing

Order transferrin saturation immediately – this test distinguishes primary iron overload from the 90% of cases caused by inflammation, liver disease, metabolic syndrome, or other secondary causes. 1 Ferritin alone cannot make this distinction because it rises as an acute-phase reactant independent of actual iron stores. 1

Additional Initial Labs to Order Concurrently:

• Inflammatory markers (CRP, ESR) – elevated levels point toward inflammatory causes of hyperferritinemia rather than iron overload. 1
• Complete metabolic panel including ALT, AST – hepatocellular injury from NAFLD, alcoholic liver disease, or viral hepatitis commonly elevates ferritin. 1
• Fasting glucose and lipid panel – metabolic syndrome is one of the most common causes of elevated ferritin with normal TS. 1

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
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms HFE-related hemochromatosis. 1
• At ferritin ~300 ng/mL with normal liver enzymes and age considerations, you are well below the 1,000 μg/L threshold that carries 94% negative predictive value for advanced fibrosis. 1
• If C282Y homozygote is confirmed, therapeutic phlebotomy can begin without liver biopsy since ferritin <1,000 μg/L, liver enzymes are normal, and there is no hepatomegaly. 1, 2

If TS <45%: Evaluate Secondary Causes

Iron overload is excluded with >90% certainty when TS <45%. 1 The ferritin elevation reflects one of the following:

• Metabolic syndrome/NAFLD – the most common cause in outpatients, accounting for >40% of cases with elevated ferritin and normal TS. 1 Ferritin reflects hepatocellular injury and insulin resistance, not iron stores. 1
• Chronic alcohol consumption – increases intestinal iron absorption and causes hepatocellular injury. 1
• Inflammatory conditions – rheumatologic diseases, inflammatory bowel disease, or occult infection elevate ferritin as an acute-phase reactant. 1
• Occult malignancy – solid tumors and lymphomas can present with isolated ferritin elevation. 1

Risk Stratification by Ferritin Level

At ferritin ~300 ng/mL, you are in the low-risk category:

• Ferritin <1,000 μg/L has a 94% negative predictive value for advanced hepatic fibrosis in hemochromatosis. 1
• This level does not indicate risk of organ damage (threshold >1,000 μg/L for liver complications). 1
• No liver biopsy is needed at this ferritin level unless TS ≥45% with additional risk factors (age >40, elevated liver enzymes, hepatomegaly, platelet count <200,000/μL). 1

Special Considerations Given Anti-Tissue Transglutaminase Testing

Since anti-tTG has been ordered, consider:

• Celiac disease can present with iron deficiency despite elevated ferritin when inflammation coexists. 3
• If ferritin is elevated with low TS (<20%), this pattern suggests functional iron deficiency where iron is sequestered by inflammation despite seemingly adequate stores. 3
• In inflammatory conditions like celiac disease, a ferritin threshold of <100 μg/L or TS <20% is diagnostic for true iron deficiency, not the standard <30 μg/L cutoff. 3

Common Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without confirming TS ≥45%. 1 Over 90% of elevated ferritin cases are NOT due to iron overload. 1
• Do not order HFE genetic testing when TS <45% – this leads to false-positive results and unnecessary anxiety. 1
• Do not assume normal ferritin excludes iron deficiency in inflammatory states – ferritin can be 50–100 μg/L and still represent iron deficiency when inflammation is present. 3, 4
• Recognize that ferritin 30–100 μg/L with TS <20% in inflammatory conditions represents combined iron deficiency and anemia of chronic disease. 1

Next Steps Summary

1. Order fasting transferrin saturation immediately – this single test determines your entire diagnostic pathway. 1
2. If TS ≥45%: Order HFE genetic testing (C282Y, H63D). 1
3. If TS <45%: Evaluate for metabolic syndrome, NAFLD, chronic alcohol use, inflammatory conditions, and occult malignancy using CRP, ESR, metabolic panel, and clinical history. 1
4. Monitor ferritin and TS together – never interpret ferritin in isolation. 1
5. If ferritin rises above 1,000 μg/L or TS becomes ≥45% on repeat testing, refer to hepatology or hematology. 1