What are the causes of elevated ferritin levels in males?

Causes of High Ferritin in Males

In males, the most common causes of elevated ferritin levels are non-iron overload conditions including inflammatory liver diseases, metabolic syndrome, and chronic inflammatory conditions, rather than true iron overload disorders. 1

Primary Causes of Hyperferritinemia in Males

Non-Iron Overload Related Causes

• Liver Disorders:

  • Alcoholic liver disease
  • Chronic hepatitis B and C
  • Non-alcoholic fatty liver disease (NAFLD)
  • Metabolic syndrome 1

• Inflammatory Conditions:

  • Chronic inflammatory disorders
  • Acute phase reactions
  • Infections 1

• Malignancies:

  • Lymphomas
  • Other malignant conditions 2

• Metabolic Factors:

  • Insulin resistance (strongly associated with hyperferritinemia) 3
  • Obesity
  • Type 2 diabetes
  • Hypertension 4

Iron Overload Related Causes

• Hereditary Hemochromatosis:

  • HFE gene mutations (C282Y homozygosity most common)
  • Non-HFE hemochromatosis (less common) 1

• Secondary Iron Overload:

  • Multiple blood transfusions
  • Chronic hemolytic anemias
  • Ineffective erythropoiesis 1

Diagnostic Approach

Step 1: Evaluate Ferritin in Context of Transferrin Saturation

• High ferritin with normal transferrin saturation (<45%):

  • Likely non-iron overload cause (inflammatory, metabolic)
  • Negative predictive value of 97% for excluding iron overload in younger patients 1

• High ferritin with elevated transferrin saturation (>45-50%):

  • Suggests possible iron overload
  • Warrants genetic testing for HFE mutations 1

Step 2: Screen for Common Non-Iron Overload Causes

• Check liver enzymes (ALT, AST)
• Assess for metabolic syndrome (BMI, blood pressure, lipids, glucose)
• Check inflammatory markers (CRP)
• Screen for alcohol consumption
• Consider malignancy evaluation if clinically indicated 1

Step 3: Genetic Testing When Appropriate

• HFE genotyping recommended when:
  • Transferrin saturation >45% in females or >50% in males
  • Ferritin >200 μg/L in females or >300 μg/L in males
  • Unexplained persistent elevation of transferrin saturation 1

Clinical Significance of Ferritin Levels

• Mildly elevated (300-500 μg/L):

  • Most commonly due to metabolic syndrome or inflammation
  • Low risk of significant iron overload 3

• Moderately elevated (500-1000 μg/L):

  • May indicate early hemochromatosis in genetically predisposed individuals
  • Often still related to inflammatory conditions 1

• Markedly elevated (>1000 μg/L):

  • In C282Y homozygotes: high risk of significant iron overload and liver fibrosis
  • In non-C282Y individuals: still often due to inflammatory conditions, malignancy 2, 5
  • Ferritin >1000 μg/L with elevated liver enzymes and low platelets predicts cirrhosis in 80% of C282Y homozygotes 1

Important Clinical Considerations

• Hyperferritinemia is more common in males than females across all etiologies
• The prevalence of elevated ferritin varies by ethnicity, with higher rates in certain populations
• Ferritin levels correlate with insulin resistance even in the absence of iron overload 3
• In males with hypertension, increased ferritin is significantly more common (21% vs 0% in normotensive controls) 4
• Extremely high ferritin levels (>10,000 μg/L) may be seen in rare conditions like adult-onset Still's disease or hemophagocytic lymphohistiocytosis 2

Pitfalls to Avoid

• Don't assume elevated ferritin automatically indicates hemochromatosis
• Don't rely on ferritin alone; always check transferrin saturation concurrently
• Don't overlook common metabolic causes in middle-aged, overweight males
• Don't miss rare genetic causes like hereditary hyperferritinemia/cataract syndrome or ferroportin disease in cases that don't fit typical patterns 6
• Don't forget that normal ferritin essentially rules out iron overload, but elevated ferritin has poor specificity for iron overload 1