How do you assess and treat a patient with hyperferritinemia, low Transferrin Saturation (TSAT), and hypoferritinemia?

Assessment and Treatment of Hyperferritinemia with Low TSAT and Hypoferritinemia

The combination of high ferritin, low transferrin saturation (TSAT <20%), and low serum iron most likely represents functional iron deficiency or inflammatory iron block, which should be treated with intravenous iron therapy after identifying and addressing the underlying cause. 1

Diagnostic Approach

Initial Evaluation

• Obtain complete iron studies including ferritin, TSAT, serum iron, and total iron binding capacity (TIBC) 2
• Check inflammatory markers (C-reactive protein, ESR) to assess for underlying inflammation 1
• Evaluate for common causes of this pattern:
  • Inflammatory conditions (cancer, chronic kidney disease, heart failure, inflammatory bowel disease) 3
  • Iron-sequestration syndromes 4
  • Malignancy (most frequent cause of markedly elevated ferritin >1000 μg/L) 4

Additional Testing

• Consider soluble transferrin receptor (sTfR) testing, which is elevated in true iron deficiency but not affected by inflammation 1
• Reticulocyte hemoglobin content (CHr or RET-He) can provide direct assessment of iron availability for erythropoiesis 2
• Rule out hemochromatosis with HFE gene testing if ferritin is >1000 μg/L with elevated liver enzymes 2

Treatment Algorithm

For Functional Iron Deficiency (Inflammatory Conditions)

1. First line: Intravenous iron therapy 2, 1

   • Preferred over oral iron due to hepcidin-mediated blockade of intestinal absorption 5
   • Dosing options:
     • Ferric derisomaltose (FDI): 1000 mg infusion or up to 20 mg/kg (not exceeding 1500 mg) 2
     • Ferric carboxymaltose (FCM): Effective even in patients with ferritin >500 ng/mL and low TSAT 2

2. Monitor response:

   • Reassess iron parameters (CBC, ferritin, TSAT) 4-8 weeks after infusion 2
   • Hemoglobin should increase within 1-2 weeks and rise by 1-2 g/dL within 4-8 weeks 2

For Absolute Iron Deficiency with Elevated Ferritin

• Treat underlying inflammatory condition if present 1
• Consider IV iron if TSAT <20% regardless of ferritin level, especially if:
  • Ferritin <100-300 μg/L in inflammatory states 5
  • Patient has symptoms of iron deficiency (fatigue, reduced exercise tolerance) 6

Special Considerations

Diagnostic Thresholds in Inflammatory States

• Traditional iron deficiency thresholds don't apply in inflammatory conditions 5
• In chronic inflammatory diseases, consider:
  • TSAT <20% with ferritin <100 μg/L: definite iron deficiency 5
  • TSAT <20% with ferritin 100-300 μg/L: probable iron deficiency 5
  • TSAT <20% with ferritin >300 μg/L: possible functional iron deficiency 1

Common Pitfalls

• Relying solely on ferritin levels can miss functional iron deficiency, as ferritin is an acute phase reactant 5
• TSAT is less affected by inflammation and may be more reliable for diagnosis and prognosis 3
• Avoid excessive iron supplementation; maintain ferritin <500-800 μg/L to prevent iron overload 1
• Do not measure iron parameters within 4 weeks of IV iron administration as circulating iron interferes with assays 2

Long-term Management

• For patients with ongoing losses or malabsorption, multiple IV iron administrations may be necessary 2
• In the absence of inflammation, the goal ferritin is ≥50 ng/mL 2
• For patients with chronic diseases, routine surveillance of iron status is advisable to detect deficiency early 3

By following this approach, clinicians can effectively diagnose and manage the complex presentation of hyperferritinemia with low TSAT and hypoferritinemia, improving patient outcomes through appropriate iron repletion.