What is the cause of elevated ferritin (hyperferritinemia) in a non-drinker without symptoms?

Elevated Ferritin in an Asymptomatic Non-Drinker

Direct Answer

Your patient's ferritin of 1078 μg/L most likely reflects inflammation, metabolic syndrome/fatty liver disease, or hepatocellular injury rather than iron overload, but you must immediately measure transferrin saturation to distinguish between these possibilities. 1

Immediate Next Step

Measure fasting transferrin saturation (TS) alongside a complete metabolic panel including ALT and AST. 1, 2 This single test determines your entire diagnostic pathway, as over 90% of elevated ferritin cases are NOT due to iron overload. 1, 3

Algorithmic Approach Based on Transferrin Saturation

If TS <45% (Most Likely Scenario)

This indicates secondary hyperferritinemia, not iron overload. 1 The most common causes in order of frequency are:

• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome - accounts for the majority of cases in non-drinkers 1, 4
• Occult inflammation - check CRP and ESR 1, 2
• Hepatocellular injury - review ALT/AST levels 1, 2
• Malignancy - most frequent cause in one large series (153/627 patients) 5
• Infection - second most common in hospitalized patients 6
• Cell necrosis - check creatine kinase for muscle injury 1

Management: Treat the underlying condition, NOT the ferritin number itself. 2 For NAFLD, focus on weight loss and metabolic syndrome management. 4

If TS ≥45% (Suggests Iron Overload)

Immediately order HFE genetic testing for C282Y and H63D mutations. 1, 2 This pattern suggests hereditary hemochromatosis or other primary iron overload disorders.

Critical Threshold: Ferritin >1000 μg/L

Your patient's ferritin of 1078 μg/L crosses a critical threshold that changes management:

• In C282Y homozygotes with ferritin >1000 μg/L, the prevalence of cirrhosis is 20-45%. 7, 1
• Consider liver biopsy if ferritin >1000 μg/L AND you find elevated liver enzymes or platelet count <200,000/μL. 7, 2
• If the patient is C282Y homozygous, has normal liver enzymes, and is <40 years old, you can proceed directly to therapeutic phlebotomy without biopsy. 2

What This Level Does NOT Mean

At 1078 μg/L, this ferritin level:

• Does NOT indicate risk of organ damage (threshold is >7500 μg/L for documented liver cell damage) 1
• Has 100% sensitivity but only 70% specificity for cirrhosis in hemochromatosis patients 7
• Has a 94% negative predictive value for advanced fibrosis if <1000 μg/L with normal transaminases 1

Common Pitfalls to Avoid

Never use ferritin alone to diagnose iron overload. 1, 2, 4 Ferritin is an acute phase reactant that rises with inflammation, liver disease, malignancy, and tissue necrosis independent of actual iron stores. 1

Do not overlook liver biopsy in patients with ferritin >1000 μg/L AND abnormal liver tests. 1, 2 This combination warrants histologic assessment for cirrhosis.

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

Specific Laboratory Tests to Order Now

1. Fasting transferrin saturation - the single most important discriminator 1, 2
2. Complete metabolic panel with ALT, AST - assess hepatocellular injury 1, 2
3. CRP and ESR - detect occult inflammation 1, 2
4. Creatine kinase - evaluate for muscle necrosis 1
5. Complete blood count with platelets - if TS ≥45%, platelet count <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes 1

If Hereditary Hemochromatosis is Confirmed

Initiate therapeutic phlebotomy with target ferritin 50-100 μg/L: 2

• Remove 500 mL blood weekly or biweekly
• Check hemoglobin/hematocrit before each phlebotomy
• Allow hemoglobin to fall no more than 20% from baseline
• Check ferritin every 10-12 phlebotomies
• Screen all first-degree relatives with HFE genotyping 1

When to Refer to Specialist

Refer to gastroenterology, hematology, or iron overload specialist if: 1, 3

• Ferritin >1000 μg/L regardless of transferrin saturation
• Cause remains unclear after initial workup
• Evidence of organ damage on evaluation

The Bottom Line for Your Patient

Since your patient is a non-drinker without symptoms and has ferritin 1078 μg/L, the transferrin saturation result will determine everything. If TS <45%, focus on metabolic syndrome and NAFLD as the likely culprits. If TS ≥45%, proceed immediately to HFE genetic testing and consider liver biopsy given the ferritin level just exceeds 1000 μg/L. 1, 2