What is the management approach for a patient with hyperferritinemia and a transferrin saturation of 28%?

Management of Hyperferritinemia with Normal Transferrin Saturation

This patient with ferritin 525 ng/mL and transferrin saturation 28% does NOT have hereditary hemochromatosis and should be evaluated for secondary causes of hyperferritinemia, particularly inflammatory conditions, liver disease, or metabolic syndrome—phlebotomy is NOT indicated.

Why This is NOT Iron Overload

• Transferrin saturation <45% essentially rules out hereditary hemochromatosis and primary iron overload disorders 1
• The American Association for the Study of Liver Diseases states that fasting transferrin saturation <45% with normal or elevated ferritin requires no further evaluation for hemochromatosis 1
• This pattern (elevated ferritin with normal transferrin saturation) indicates ferritin elevation from non-iron causes, as ferritin is an acute phase reactant 2, 3

Diagnostic Approach

Immediate Next Steps

• Check inflammatory markers: CRP and ESR to identify inflammatory conditions 2
• Assess liver function: ALT, AST, and consider hepatic panel 2, 3
• Review medication and alcohol history: Chronic alcohol use commonly causes this pattern 4, 3
• Evaluate for metabolic syndrome: Check fasting glucose, lipid panel, and assess for obesity/insulin resistance 5

Common Causes to Consider

Inflammatory/Metabolic Conditions (most common):

• Chronic inflammatory diseases (rheumatologic conditions) 2
• Metabolic syndrome/dysmetabolic hyperferritinemia 5
• Non-alcoholic fatty liver disease (NAFLD) 1, 2

Liver Disease:

• Alcoholic liver disease (can dramatically elevate ferritin despite disrupting iron metabolism) 4
• Viral hepatitis 1, 2
• Chronic liver disease of any etiology 2

Other Considerations:

• Malignancy (solid tumors or hematologic) 6
• Chronic kidney disease 1, 2
• Recent infection or acute illness 1

What NOT to Do

• Do NOT proceed with HFE genotype testing when transferrin saturation is <45% 1
• Do NOT initiate therapeutic phlebotomy—this patient does not have iron overload requiring iron removal 1, 2
• Do NOT use ferritin alone to diagnose iron overload without considering transferrin saturation 2

Management Strategy

Treat the underlying condition, not the ferritin number 2:

• If inflammatory markers elevated: investigate and treat underlying inflammatory disease 2
• If liver enzymes elevated: evaluate for alcoholic liver disease, NAFLD, or viral hepatitis 2, 3
• If metabolic syndrome present: address weight loss, diabetes control, and cardiovascular risk factors 5

Monitor ferritin levels based on the underlying condition 2:

• Ferritin should decrease as the primary condition improves
• Serial ferritin measurements help track disease activity in inflammatory conditions 2

Critical Thresholds and Red Flags

• Ferritin >1,000 ng/mL warrants more aggressive evaluation for liver disease and consideration of liver biopsy if accompanied by elevated liver enzymes 1, 2
• Ferritin >10,000 ng/mL suggests life-threatening conditions (hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease) requiring urgent specialist referral 2, 6
• This patient's ferritin of 525 ng/mL is moderately elevated but below concerning thresholds for severe pathology 2

Common Pitfall to Avoid

The most common error is assuming all hyperferritinemia represents iron overload 3, 5. Transferrin saturation <45% has high sensitivity for excluding hemochromatosis, though it has lower specificity (can be elevated in acute liver injury) 4. In this case with TS 28%, the ferritin elevation reflects inflammation or metabolic disturbance, not excess iron stores requiring removal 2, 3.