In a patient with hand pain suggestive of early arthropathy, elevated alanine aminotransferase, and high serum ferritin, what does the ferritin level indicate and how should I assess for iron overload versus inflammatory causes?

What is Serum Ferritin?

Serum ferritin is an iron storage protein that reflects total body iron stores, but it is also an acute-phase reactant that rises during inflammation, infection, liver disease, and tissue damage independent of actual iron levels. 1

Dual Nature of Ferritin

Ferritin serves two distinct roles that must be understood to interpret its clinical significance:

As an Iron Storage Marker

• Ferritin reflects both reticuloendothelial system (RES) and parenchymal iron stores, with low levels being highly specific for iron deficiency. 2
• The protein normally accounts for only a trace fraction of total serum iron but maintains a stable concentration proportional to the much larger pool of tissue storage iron. 3
• Low ferritin (<30 μg/L) is diagnostic of iron deficiency, while elevated ferritin with transferrin saturation ≥45% indicates true iron overload. 1, 4

As an Inflammatory Marker

• Ferritin behaves as an acute-phase reactant, rising during inflammation, infection, hepatocellular injury, and cell necrosis completely independent of iron stores. 2, 1, 5
• Serum ferritin arises primarily from damaged cells as a leakage product, making it fundamentally a marker of cellular damage and stress. 5
• The ferritin released during inflammation has lost most of its normal iron content, which explains why elevated ferritin does not always indicate iron overload. 6, 5

Clinical Context: Your Patient with Hand Pain and Elevated ALT

In your specific patient with early arthropathy, elevated ALT, and high ferritin, the ferritin elevation most likely reflects:

Most Probable Causes (>90% of cases)

• Chronic alcohol consumption, inflammation, cell necrosis, tumors, or non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome account for over 90% of hyperferritinemia cases in outpatients. 1
• The combination of elevated ferritin with elevated ALT and hand arthropathy strongly suggests either NAFLD with metabolic syndrome or hereditary hemochromatosis. 1, 7

Critical Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Immediately

• Transferrin saturation (TS) is the single most important test to distinguish true iron overload from secondary causes of hyperferritinemia. 1, 7
• If TS ≥45%, suspect primary iron overload (hereditary hemochromatosis) and proceed immediately to HFE genetic testing for C282Y and H63D mutations. 1, 7
• If TS <45%, iron overload is excluded with >90% certainty, and the elevated ferritin represents inflammation or liver disease. 1, 7

Step 2: Assess for Inflammatory Causes

• Check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to identify occult inflammation. 1, 7
• In inflammatory states, ferritin rises acutely while transferrin saturation often drops, creating a pattern of elevated ferritin with low TS. 1

Step 3: Evaluate Liver Disease

• Order comprehensive metabolic panel including AST, ALT, bilirubin, and albumin to assess hepatocellular injury. 1, 7
• Obtain abdominal ultrasound to evaluate for fatty liver, chronic liver disease, or hepatomegaly. 1
• In NAFLD/metabolic syndrome, ferritin elevation reflects hepatocellular injury and insulin resistance rather than true iron overload. 1, 7

Step 4: Consider Hemochromatosis-Related Arthropathy

• Hand arthropathy affecting the 2nd and 3rd metacarpophalangeal joints is characteristic of hereditary hemochromatosis, occurring in 86.5% of patients. 7
• If TS ≥45% with hand arthropathy, hereditary hemochromatosis is highly likely and requires HFE genetic testing. 1, 7

Risk Stratification by Ferritin Level

• Ferritin <1,000 μg/L has a 94% negative predictive value for advanced liver fibrosis, indicating low risk of organ damage. 1, 7
• Ferritin >1,000 μg/L with elevated liver enzymes or platelet count <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes, warranting liver biopsy consideration. 1, 7
• Ferritin >10,000 μg/L rarely represents simple iron overload and requires urgent specialist referral to evaluate for life-threatening conditions such as adult-onset Still's disease or hemophagocytic lymphohistiocytosis. 1, 7

Common Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload; transferrin saturation must be measured simultaneously. 1, 7
• Do not assume iron overload when TS <45%, as over 90% of elevated ferritin cases with normal TS are due to non-iron causes. 1
• Do not order HFE genetic testing when TS <45%, as this leads to misdiagnosis and unnecessary treatment. 1, 7
• Recognize that ferritin lacks sensitivity for iron deficiency in inflammatory conditions because it rises as an acute-phase reactant. 2, 4

Bottom Line for Your Patient

Order fasting transferrin saturation immediately. If TS ≥45%, proceed to HFE genetic testing and consider hereditary hemochromatosis with characteristic arthropathy. If TS <45%, the elevated ferritin reflects liver disease (likely NAFLD given elevated ALT) or inflammation, and treatment should target the underlying condition rather than the ferritin itself. 1, 7