What are the common causes of significantly elevated ferritin (iron) levels, specifically a level of severe hyperferritinemia?

Common Causes of Ferritin 1265 μg/L

A ferritin level of 1265 μg/L is most commonly caused by inflammation, chronic liver disease (including alcoholic liver disease and NAFLD), malignancy, or infection—not iron overload—and requires immediate measurement of transferrin saturation to distinguish between these secondary causes and true iron overload disorders. 1, 2

Initial Diagnostic Approach

Measure transferrin saturation (TS) immediately alongside the ferritin level, as ferritin alone cannot distinguish iron overload from inflammatory conditions. 1, 2

If TS ≥45%:

• Consider hereditary hemochromatosis (HFE gene mutations: C282Y homozygosity or C282Y/H63D compound heterozygosity) 1, 2
• Order HFE genetic testing for C282Y and H63D mutations 1, 2
• Consider non-HFE hemochromatosis (mutations in TFR2, SLC40A1, HAMP, HJV genes) if genetic testing is negative 1, 2

If TS <45%:

• Secondary causes are responsible in >90% of cases at this ferritin level 1
• Focus diagnostic workup on the following common etiologies:

Most Common Secondary Causes (>90% of Cases)

Liver Disease

• Chronic alcohol consumption is a leading cause, increasing ferritin through multiple mechanisms including enhanced iron absorption and hepatocellular injury 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome accounts for a substantial proportion of cases 1, 2
• Viral hepatitis B or C should be screened 1, 2
• Check liver enzymes (ALT, AST) to assess for hepatocellular injury 1, 2

Inflammatory Conditions

• Systemic inflammation from any source elevates ferritin as an acute-phase reactant 1, 2
• Check inflammatory markers (CRP, ESR) to detect occult inflammation 1
• Consider rheumatologic diseases (though adult-onset Still's disease typically presents with ferritin >10,000 μg/L) 3, 4

Malignancy

• Solid tumors and lymphomas are common causes 1, 3
• Malignancy was the most frequent cause (24%) in one large series of patients with ferritin >1000 μg/L 3

Infection

• Active infection causes ferritin to rise acutely as part of the inflammatory response 1, 2
• The association is bidirectional: infection causes elevated ferritin, not vice versa 5, 1

Cell Necrosis

• Hepatocellular necrosis or muscle injury releases ferritin 1, 2

Risk Stratification at 1265 μg/L

This ferritin level (1265 μg/L) carries moderate risk and requires further evaluation but does not indicate imminent organ damage:

• Ferritin <1000 μg/L has a 94% negative predictive value for advanced liver fibrosis in hemochromatosis patients 1, 6
• Ferritin 1000-10,000 μg/L (your patient's range) requires additional assessment including platelet count and liver enzymes 1, 6
• In C282Y homozygotes with ferritin >1000 μg/L, elevated liver enzymes, and platelets <200,000/μL, the risk of cirrhosis is 80% 1
• Documented organ damage typically occurs only at ferritin >7500 μg/L with very high transferrin saturation (>88%) 6

Recommended Workup Algorithm

1. Fasting transferrin saturation (morning sample preferred, fasting not required) 5, 2
2. Complete metabolic panel including ALT, AST 1
3. Complete blood count with differential and platelet count 1
4. Inflammatory markers (CRP, ESR) 1
5. Hepatitis B and C screening 1, 2
6. Assess for alcohol use and metabolic syndrome components 1, 2

If TS ≥45%:

• HFE genetic testing (C282Y and H63D) 1, 2
• Consider liver MRI to quantify hepatic iron concentration 5

If TS <45%:

• Treat the underlying condition, not the ferritin number itself 1
• For NAFLD: weight loss and metabolic syndrome management 1
• For inflammatory conditions: disease-specific anti-inflammatory therapy 1

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload 1, 6
• Do not assume iron overload when TS <45%, as secondary causes predominate 1
• Do not overlook liver biopsy consideration if ferritin >1000 μg/L with abnormal liver tests and platelets <200,000/μL 1, 6
• Recognize that ferritin is an acute-phase reactant and can be elevated in many inflammatory conditions without true iron overload 5, 1, 2
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1

When to Refer to Specialist

Refer to gastroenterology, hematology, or iron overload specialist if: 6

• Ferritin >1000 μg/L regardless of transferrin saturation
• Evidence of liver disease with abnormal enzymes
• Confirmed hereditary hemochromatosis requiring therapeutic phlebotomy
• Suspicion of non-HFE hemochromatosis or other rare iron overload disorders