What is the cause of an elevated ferritin of 267 ng/mL in a 33‑year‑old woman?

Elevated Ferritin of 267 ng/mL in a 33-Year-Old Woman

A ferritin level of 267 ng/mL in a 33-year-old woman is most commonly caused by inflammation, liver disease (particularly non-alcoholic fatty liver disease/metabolic syndrome), chronic alcohol consumption, or cell necrosis—not iron overload—accounting for over 90% of such cases. 1, 2

Immediate Diagnostic Step: Measure Transferrin Saturation

You must immediately order a fasting transferrin saturation (TS) test to distinguish true iron overload from secondary causes of elevated ferritin. 1, 2 Ferritin alone cannot diagnose iron overload because it rises as an acute-phase reactant during inflammation, infection, liver disease, malignancy, and tissue injury independent of actual iron stores. 1, 2, 3

Interpretation Algorithm Based on Transferrin Saturation

If TS < 45%: Iron overload is excluded with >90% certainty, and secondary causes predominate. 1, 2 This is the most likely scenario given the ferritin level of 267 ng/mL. 1

If TS ≥ 45%: Suspect primary iron overload and proceed immediately to HFE genetic testing for C282Y and H63D mutations to diagnose hereditary hemochromatosis. 1, 2

Most Common Secondary Causes (When TS < 45%)

1. Non-Alcoholic Fatty Liver Disease (NAFLD) / Metabolic Syndrome

• Ferritin elevation in NAFLD reflects hepatocellular injury and insulin resistance rather than true iron overload. 1, 2
• Check liver enzymes (ALT, AST) and consider abdominal ultrasound to evaluate for fatty liver. 1
• Assess for metabolic risk factors: obesity, glucose intolerance, dyslipidemia. 1

2. Chronic Alcohol Consumption

• Alcohol increases intestinal iron absorption and causes hepatocellular injury, leading to elevated ferritin. 1, 2
• Obtain a detailed alcohol consumption history. 1

3. Inflammatory Conditions

• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute-phase reactant. 1, 2
• Check inflammatory markers: C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). 1

4. Cell Necrosis

• Muscle injury, hepatocellular necrosis, or tissue breakdown releases ferritin from lysed cells independent of iron stores. 1, 2
• Check creatine kinase (CK) to evaluate for muscle necrosis. 1

5. Infections

• Active infection causes ferritin to rise acutely as part of the inflammatory response. 1
• Investigate for active infection as a cause of elevated ferritin. 1

6. Malignancy

• Solid tumors, lymphomas, and hepatocellular carcinoma can cause elevated ferritin. 1, 2
• Consider age-appropriate cancer screening if clinically indicated. 1

Risk Stratification by Ferritin Level

Ferritin 267 ng/mL is well below the 1,000 μg/L threshold associated with organ damage risk. 1, 2

• Ferritin < 1,000 μg/L: Low risk of organ damage; negative predictive value of 94% for advanced hepatic fibrosis. 1, 2
• Ferritin 1,000–10,000 μg/L: Increased risk of advanced fibrosis/cirrhosis if iron overload is present. 1, 2
• Ferritin > 10,000 μg/L: Rarely represents simple iron overload; mandates urgent evaluation for life-threatening conditions (hemophagocytic lymphohistiocytosis, adult-onset Still's disease). 1, 4, 2

Recommended Diagnostic Workup

1. Fasting transferrin saturation (most critical test) 1, 2
2. Complete metabolic panel including ALT, AST, alkaline phosphatase, bilirubin 1
3. Inflammatory markers: CRP and ESR 1
4. Complete blood count with differential 1
5. Creatine kinase (if muscle injury suspected) 1
6. Abdominal ultrasound if liver disease suspected (elevated ALT/AST) 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without confirming TS ≥ 45%. 1, 2
• Do not order HFE genetic testing when TS < 45%, as this leads to misdiagnosis and unnecessary phlebotomy. 1
• Do not assume iron overload when TS < 45%; in the general population, iron overload is NOT the most common cause of elevated ferritin. 1
• Recognize that ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 1, 2, 3

Management Strategy

Treat the underlying condition, not the elevated ferritin itself. 1

• If NAFLD/metabolic syndrome: weight loss, metabolic syndrome management 1
• If inflammatory condition: disease-specific anti-inflammatory therapy 1
• If infection: appropriate antimicrobial treatment 1
• Phlebotomy is only indicated for confirmed iron overload with TS ≥ 45% and evidence of end-organ damage. 1

When to Refer to Specialist

Refer to hepatology or hematology if:

• Ferritin rises above 1,000 μg/L despite treatment 1
• TS becomes elevated (≥ 45%) on repeat testing 1
• Clinical evidence of cirrhosis (platelet count < 200,000/μL, elevated bilirubin, hepatomegaly) 1
• Confirmed C282Y homozygosity requiring therapeutic phlebotomy 1