In a patient with a negative HFE gene test but elevated ferritin, what other causes should be considered?

Differential Diagnosis of Elevated Ferritin with Negative HFE Gene Testing

When a patient has elevated ferritin but negative HFE gene testing, the most likely causes are secondary hyperferritinemia from chronic alcohol consumption, inflammatory conditions, metabolic syndrome/NAFLD, liver disease, malignancy, or cell necrosis—not iron overload—and the critical next step is measuring transferrin saturation to distinguish true iron overload (TS ≥45%) from these secondary causes (TS <45%). 1

Initial Diagnostic Framework

The key discriminator is transferrin saturation (TS), which must be measured immediately if not already done. 1 Over 90% of elevated ferritin cases are caused by non-iron overload conditions including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD. 1, 2

If Transferrin Saturation ≥45%

• Consider non-HFE hemochromatosis caused by mutations in TFR2, SLC40A1, HAMP, or HJV genes (ferroportin disease, juvenile hemochromatosis, transferrin receptor 2 mutations). 1, 3
• Proceed with genetic testing for these rarer iron overload genes if clinical suspicion is high and ferritin remains elevated. 1
• Consider liver MRI to quantify hepatic iron concentration if TS ≥45%. 1
• Liver biopsy is indicated if ferritin >1000 μg/L with elevated liver enzymes or platelet count <200,000/μL to assess for cirrhosis. 1

If Transferrin Saturation <45%

Iron overload is excluded with >90% certainty, and secondary causes predominate. 1, 4 The following conditions should be systematically evaluated:

Secondary Causes of Hyperferritinemia (TS <45%)

Liver Disease

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury, leading to elevated ferritin. 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation reflecting hepatocellular injury and insulin resistance rather than true iron overload. 1, 2
• Viral hepatitis (B and C) causes abnormal serum iron studies in approximately 50% of patients. 1
• Acute hepatitis and cirrhosis elevate ferritin through hepatocellular necrosis. 1, 2
• Order ALT, AST, and consider abdominal ultrasound to evaluate for fatty liver, chronic liver disease, or hepatomegaly. 1, 2

Inflammatory and Rheumatologic Conditions

• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute-phase reactant. 1, 2
• Adult-onset Still's disease (AOSD) presents with extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20%. 1, 2
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome should be considered if ferritin >5,000-10,000 ng/mL with cytopenias, fever, and multiorgan dysfunction. 1, 2
• Systemic inflammatory response syndrome from any cause. 1
• Check CRP and ESR to detect occult inflammation. 1, 2

Malignancy

• Solid tumors, lymphomas, and hepatocellular carcinoma can all cause marked ferritin elevation. 1, 2, 5
• Malignancy was the most frequent cause (153/627 patients) in one large series of markedly elevated ferritin (>1000 μg/L). 5
• Assess for B symptoms, lymphadenopathy, and consider CT imaging if suspected. 2

Cellular Damage and Necrosis

• Cell necrosis from 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. 2

Metabolic and Endocrine

• Metabolic syndrome with obesity, glucose intolerance, and dyslipidemia. 1, 2
• Diabetes mellitus. 1

Chronic Kidney Disease

• Functional iron deficiency in CKD patients on erythropoiesis-stimulating agents may occur with ferritin 100-700 ng/mL and TS <20%, where IV iron may still be beneficial despite elevated ferritin. 1, 2

Infections

• Active infection causes ferritin to rise acutely as part of the inflammatory response. 1, 2

Risk Stratification by Ferritin Level

Ferritin Level	Clinical Significance	Action Required
<1000 μg/L	Low risk of organ damage; 94% negative predictive value for advanced liver fibrosis. [1]	Evaluate secondary causes; no liver biopsy needed if TS <45% and liver enzymes normal. [1]
1000-10,000 μg/L	Higher risk of advanced fibrosis/cirrhosis if iron overload present; 20-45% prevalence of cirrhosis in C282Y homozygotes. [1]	Consider liver biopsy if TS ≥45% with elevated liver enzymes or platelet count <200,000/μL. [1]
>10,000 μg/L	Rarely represents simple iron overload; suggests life-threatening conditions (AOSD, hemophagocytic lymphohistiocytosis, severe malignancy). [1,2]	Urgent specialist referral required. [1]

Diagnostic Algorithm

1. Measure fasting transferrin saturation if not already done. 1, 4
2. If TS ≥45%: Consider non-HFE hemochromatosis; order genetic testing for TFR2, SLC40A1, HAMP, HJV mutations; consider liver MRI or biopsy. 1, 3
3. If TS <45%: Systematically evaluate secondary causes:
   • Detailed alcohol history 1, 2
   • Liver enzymes (ALT, AST), abdominal ultrasound 1, 2
   • Inflammatory markers (CRP, ESR) 1, 2
   • CBC with differential to assess for malignancy or infection 2
   • Creatine kinase for muscle necrosis 2
   • Metabolic panel, fasting glucose, lipid panel for metabolic syndrome 1
   • Screen for malignancy if clinically indicated 5
   • If ferritin >4000-5000 ng/mL with persistent fever, measure glycosylated ferritin fraction (<20% is 93% specific for AOSD) 1, 2

Specialist Referral Indications

Refer to gastroenterology, hematology, or iron overload specialist when: 1

• Ferritin >1000 μg/L with elevated bilirubin
• Ferritin >10,000 μg/L regardless of other findings
• TS ≥45% on repeat testing despite negative HFE gene
• Clinical evidence of cirrhosis (platelet count <200,000/μL, elevated bilirubin, hepatomegaly)
• Cause of elevated ferritin remains unclear after initial workup 6

Critical Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload. 1, 4, 7
• Do not assume iron overload when TS <45%; in the general population, iron overload is NOT the most common cause of elevated ferritin. 1, 4
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests. 1
• Recognize that ferritin is an acute-phase reactant that rises with inflammation, infection, liver disease, and malignancy independent of iron stores. 1, 2, 7
• Do not initiate phlebotomy unless TS ≥45% confirms true iron overload. 1, 4