How to evaluate a patient with elevated ferritin (iron storage protein) levels without a recent history of surgery or known injury in primary care?

Workup of Elevated Ferritin in Primary Care

Begin by measuring fasting transferrin saturation (TS) alongside ferritin—if TS is ≥45%, proceed to HFE genetic testing for hereditary hemochromatosis; if TS is <45%, focus on identifying secondary causes including inflammation, liver disease, malignancy, and metabolic syndrome, which account for over 90% of hyperferritinemia cases. 1, 2

Initial Laboratory Assessment

When you encounter elevated ferritin without recent surgery or injury, order the following tests simultaneously:

• Fasting transferrin saturation (must be fasting to avoid false elevations) 1
• Complete metabolic panel including ALT, AST to assess for hepatocellular injury 1
• Inflammatory markers: CRP and ESR to detect occult inflammation 1, 3
• Complete blood count with differential 2
• Creatine kinase (CK) if patient exercises intensively or takes statins, as muscle injury can mimic liver disease 1

Algorithmic Approach Based on Transferrin Saturation

If TS ≥45% (Suggests Iron Overload)

Proceed to HFE genetic testing for C282Y and H63D mutations 1. This pathway indicates possible hereditary hemochromatosis or other primary iron overload disorders.

• C282Y homozygotes: Diagnosis of HFE hemochromatosis is confirmed if iron stores are elevated 1
• Ferritin <1000 μg/L with normal liver enzymes and age <40: Therapeutic phlebotomy can begin without liver biopsy 1
• Ferritin >1000 μg/L, elevated AST, hepatomegaly, or age >40: Consider liver biopsy to assess for cirrhosis, as these patients have 20-45% prevalence of cirrhosis 1, 3, 2

If genetic testing is negative for HFE mutations but TS remains elevated with documented iron overload by MRI or biopsy, consider testing for non-HFE hemochromatosis genes (TFR2, SLC40A1, HAMP, HJV) 1, 2.

If TS <45% (Suggests Secondary Causes)

Iron overload is unlikely—focus on secondary causes 3, 2. Over 90% of hyperferritinemia in outpatients falls into this category 1, 2.

Systematically evaluate for:

• Chronic alcohol consumption: Obtain detailed alcohol history 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome: Check BMI, blood pressure, fasting glucose, lipid panel 1, 2
• Inflammatory conditions: Elevated CRP/ESR suggests rheumatologic disease, infection, or systemic inflammation 1, 3
• Malignancy: Most common cause in one large series (153/627 patients); consider age-appropriate cancer screening, CT imaging if clinically indicated 4
• Hepatocellular injury: Elevated ALT/AST may indicate viral hepatitis (check HBV, HCV), alcoholic liver disease, or drug-induced liver injury 1, 2
• Cell necrosis: Check CK for rhabdomyolysis, especially in patients on statins or who exercise intensively 1

Risk Stratification by Ferritin Level

The absolute ferritin level guides urgency and specialist referral:

• Ferritin <1000 μg/L: Low risk of organ damage; negative predictive value of 94% for advanced liver fibrosis in hemochromatosis 3, 2
• Ferritin 1000-10,000 μg/L: Higher risk if true iron overload; in C282Y homozygotes with elevated liver enzymes and platelets <200,000/μL, 80% have cirrhosis 3, 2
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; consider life-threatening conditions including adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome—requires urgent specialist referral 3, 2, 5, 4

Special Considerations and Common Pitfalls

Critical pitfall: Never use ferritin alone without transferrin saturation to diagnose iron overload 3, 2. Ferritin is an acute-phase reactant that rises with inflammation, infection, malignancy, and liver disease regardless of iron status 1, 5, 6.

NAFLD patients: Elevated ferritin is common and does not automatically warrant iron overload evaluation unless TS is also elevated (>45%) 1. Low-titer autoantibodies (ANA >1:160, ASMA >1:40) are also common in NAFLD and do not indicate autoimmune hepatitis unless accompanied by hypergammaglobulinemia 1.

Acute illness: In patients with vomiting, diarrhea, or decreased oral intake, ferritin may rise as an acute-phase reactant 2. Repeat testing after resolution of acute illness.

When to Refer to Specialist

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

• Ferritin >1000 μg/L regardless of TS, especially with abnormal liver enzymes or evidence of hepatomegaly 3
• Confirmed C282Y homozygosity requiring phlebotomy therapy 1
• Ferritin >10,000 μg/L for urgent evaluation of hyperinflammatory syndromes 3, 2
• Evidence of organ damage: Consider ECG/echocardiography if severe iron overload suspected with cardiac symptoms 3

Management of Secondary Causes

Treat the underlying condition, not the elevated ferritin 3. For example:

• NAFLD: Weight loss, metabolic syndrome management 1
• Alcoholic liver disease: Alcohol cessation 2
• Inflammatory conditions: Disease-specific anti-inflammatory therapy 1
• Malignancy: Oncologic treatment 4

Do not initiate iron chelation or phlebotomy for secondary hyperferritinemia with TS <45% 3, 2.