What are the causes and management of elevated ferritin levels?

Causes of High Ferritin

Elevated serum ferritin is most commonly caused by inflammation, chronic alcohol consumption, cell necrosis, tumors, and metabolic syndrome/non-alcoholic fatty liver disease, accounting for over 90% of cases in outpatient settings. 1

Common Causes of Hyperferritinemia

Inflammatory Conditions (Acute Phase Response)

• Infections
• Autoimmune disorders
• Malignancies (most frequent cause in tertiary care settings) 2
• Chronic kidney disease
• Anemia of chronic disease (functional iron deficiency)

Metabolic Disorders

• Metabolic syndrome and obesity 3
• Type 2 diabetes (independently associated with higher ferritin levels) 3
• Non-alcoholic fatty liver disease (NAFLD)

Iron Overload Conditions

• Hereditary hemochromatosis (HFE gene mutations - C282Y homozygosity)
• Secondary iron overload (multiple blood transfusions)
• Ineffective erythropoiesis (thalassemia, sideroblastic anemia)

Liver Disorders

• Alcoholic liver disease
• Viral hepatitis
• Drug-induced liver injury
• Hepatocellular damage (releases stored ferritin)

Other Causes

• Rare genetic disorders (ferroportin disease, aceruloplasminemia)
• Adult-onset Still's disease (extremely high levels >10,000 μg/L)
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome

Diagnostic Approach to Elevated Ferritin

Initial Evaluation

1. Check transferrin saturation (TSAT)

   • TSAT = (serum iron ÷ TIBC) × 100
   • TSAT <20% with high ferritin: suggests inflammation/functional iron deficiency 4
   • TSAT >45% in females or >50% in males: suggests iron overload 1

2. Assess for inflammation

   • Check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
   • Elevated inflammatory markers support inflammation as cause 4

3. Evaluate liver function

   • Check AST, ALT, and CK to assess for cell necrosis 1
   • Check for chronic alcohol consumption history

4. Screen for metabolic disorders

   • Check blood pressure, BMI, cholesterol, triglycerides, and serum glucose 1

Further Testing for Persistent Unexplained Hyperferritinemia

1. Genetic testing for hereditary hemochromatosis

   • HFE gene testing for C282Y and H63D mutations 1, 4
   • C282Y homozygosity confirms HFE-hemochromatosis
   • Other genotypes require investigation for other causes

2. Imaging studies

   • MRI to assess hepatic iron concentration if iron overload suspected

Management Approach

For Inflammatory/Reactive Hyperferritinemia

• Treat the underlying condition (infection, inflammation, malignancy)
• Monitor ferritin and TSAT every 3-6 months 4

For Iron Overload Conditions

• Hereditary hemochromatosis:

  • Therapeutic phlebotomy (remove 400-500 mL weekly until ferritin <50 μg/L)
  • Maintenance phlebotomy to keep ferritin 50-100 μg/L 4

• Secondary iron overload:

  • Consider iron chelation therapy (e.g., deferasirox) if phlebotomy contraindicated 4, 5
  • Monitor for adverse effects including renal dysfunction, hepatotoxicity 5

For Metabolic Syndrome-Related Hyperferritinemia

• Weight loss and lifestyle modifications
• Management of diabetes, hypertension, and dyslipidemia
• Limiting alcohol intake and red meat consumption 4

When to Refer to a Specialist

• Ferritin >1000 μg/L
• Evidence of organ damage
• Unclear cause despite initial workup 6
• Confirmed hereditary hemochromatosis

Pitfalls and Caveats

• Ferritin is an acute phase reactant that increases during inflammation regardless of iron status 4
• Only about 10% of elevated ferritin cases are due to true iron overload 6
• Extremely high ferritin levels (>10,000 μg/L) may suggest hemophagocytic syndrome or adult-onset Still's disease, but can also occur with seemingly indolent conditions 2
• In patients with both inflammation and iron deficiency, ferritin may be falsely normal or elevated despite iron deficiency 7
• Avoid measuring ferritin within 4 weeks of IV iron administration as it interferes with the assay 1