Elevated Ferritin in a 48-Year-Old Woman
In a 48-year-old woman with elevated ferritin, the most likely causes are chronic inflammation, metabolic syndrome/non-alcoholic fatty liver disease, chronic alcohol consumption, or hepatocellular injury—not iron overload—and the single most important next step is to measure transferrin saturation to distinguish true iron overload (TS ≥45%) from secondary hyperferritinemia (TS <45%). 1
Understanding Ferritin Elevation
Ferritin serves dual roles: it reflects iron stores but also functions as an acute-phase reactant that rises during inflammation, infection, hepatocellular injury, and tissue necrosis independent of actual iron levels. 2, 1 Over 90% of elevated ferritin cases in outpatients are caused by chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD—not hereditary hemochromatosis. 1
Immediate Diagnostic Algorithm
Step 1: Measure Transferrin Saturation Simultaneously
Never interpret ferritin alone. 1 Order a fasting transferrin saturation (morning sample preferred, fasting not required) alongside ferritin measurement. 1
If TS ≥45%:
- Suspect primary iron overload and proceed immediately to HFE genetic testing for C282Y and H63D mutations 1
- C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis 1
- Consider liver MRI to quantify hepatic iron concentration 1
If TS <45%:
- Iron overload is unlikely; secondary causes predominate 1
- Do not proceed with genetic testing 1
- Focus investigation on inflammatory, metabolic, and hepatic causes 1
Step 2: Evaluate Secondary Causes (When TS <45%)
Order the following laboratory panel:
Inflammatory markers:
- C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to detect occult inflammation 1
- Elevated CRP and ferritin strongly suggest secondary hyperferritinemia from inflammation or metabolic causes 1
Liver function tests:
- AST, ALT, albumin, bilirubin to assess hepatocellular injury 1
- The combination of elevated ferritin with elevated ALT and normal TS strongly suggests NAFLD or metabolic syndrome 1
Complete blood count with differential:
- Assess for anemia, polycythemia, or hematologic malignancy 1
Metabolic screening:
- Lipid profile, fasting glucose, hemoglobin A1c 3
- Phosphatidyl ethanol (PEth) if alcohol use is suspected 3
Imaging:
- Abdominal ultrasound to evaluate for fatty liver, chronic liver disease, or hepatomegaly 1
- Nearly 40% of adults with abnormal liver tests have fatty liver on ultrasound 1
Most Common Causes in a 48-Year-Old Woman
Metabolic Syndrome/NAFLD
This is the most likely diagnosis if TS <45% with elevated ALT. 1 Ferritin elevation reflects hepatocellular injury and insulin resistance rather than iron overload. 1 Management targets weight loss and metabolic control, not the ferritin number itself. 4
Chronic Inflammation
Rheumatologic diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute-phase reactant. 1 Chronic infection or systemic inflammatory conditions also cause persistent elevation. 2, 1
Chronic Alcohol Consumption
Alcohol increases iron absorption and causes hepatocellular injury, leading to elevated ferritin through multiple mechanisms. 1, 5 Check PEth levels and obtain detailed alcohol history. 3
Hepatocellular Injury
Viral hepatitis (B and C), acute hepatitis, or cirrhosis can elevate ferritin independent of iron stores. 1, 5 Hepatocellular injury was the most prevalent diagnosis in hospitalized adults with ferritin >2,000 ng/mL. 6
Malignancy
Solid tumors, lymphomas, and hepatocellular carcinoma can cause marked ferritin elevation. 1 Malignancy was the most frequent condition in patients with ferritin >1,000 μg/L in one large series. 7
Risk Stratification by Ferritin Level
Ferritin <1,000 μg/L:
- Low risk of organ damage 1
- Negative predictive value of 94% for advanced hepatic fibrosis 1
- If TS <45% with normal liver tests, no further investigation needed; follow in primary care 3
Ferritin 1,000–10,000 μg/L:
- Higher risk of advanced fibrosis/cirrhosis if iron overload is present 1
- In C282Y homozygotes, ferritin >1,000 μg/L with elevated aminotransferases and platelet count <200,000/μL predicts cirrhosis in 80% of cases 1
- Consider liver biopsy if ferritin >1,000 μg/L with abnormal liver enzymes or thrombocytopenia 1
Ferritin >10,000 μg/L:
- Rarely represents simple iron overload 1
- Requires urgent specialist referral to evaluate for life-threatening conditions such as hemophagocytic lymphohistiocytosis/macrophage activation syndrome 1
- Average ferritin in HLH/MAS is 14,242 μg/L 7
Special Considerations for Women
Adult-Onset Still's Disease
If ferritin rises above 4,000–5,000 ng/mL with persistent fever, consider adult-onset Still's disease. 1 Measure glycosylated ferritin fraction; <20% is 93% specific for AOSD when combined with 5-fold ferritin elevation. 1
Functional Iron Deficiency
In chronic kidney disease or inflammatory bowel disease, ferritin 100–700 ng/mL with TS <20% may represent functional iron deficiency despite seemingly adequate ferritin levels. 1 This pattern indicates iron is sequestered and unavailable for erythropoiesis. 1
Critical Pitfalls to Avoid
Never diagnose iron overload based on ferritin alone without measuring transferrin saturation. 1 Ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 2, 1, 8
Do not assume iron overload when TS <45%. 1 In the general population, iron overload is not the most common cause of elevated ferritin under these circumstances. 1
Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests. 1 This combination warrants histologic assessment for cirrhosis. 1
Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed. 1
Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload. 1 Hepatocellular injury and infection are more common causes at these levels. 6
When to Refer to Specialist
Refer to hepatology or hematology if: