Why would a patient with sepsis have low hemoglobin (Hb) levels but high ferritin levels?

Why Hemoglobin is Low but Ferritin is High in Sepsis

In sepsis, low hemoglobin with markedly elevated ferritin reflects inflammatory anemia (anemia of chronic disease), where systemic inflammation causes functional iron deficiency—iron becomes trapped in macrophages and unavailable for erythropoiesis, while ferritin rises as both an acute phase reactant and marker of iron sequestration. 1

Pathophysiological Mechanisms

Iron Sequestration and Hepcidin Activation

• Inflammation-driven hepcidin elevation is the central mechanism: Interleukin-6 (IL-6) and other inflammatory cytokines stimulate hepatic production of hepcidin, which blocks iron release from macrophages and enterocytes 1
• Iron becomes functionally unavailable despite adequate total body stores, creating a paradox where ferritin is high (indicating iron storage) but serum iron is low 2
• This represents an evolutionary host defense mechanism—sequestering iron deprives pathogens of this essential nutrient 2

Ferritin as a Dual Marker

• Ferritin serves two roles in sepsis: (1) acute phase reactant that rises with inflammation, and (2) marker of iron trapped within the reticuloendothelial system 1
• Non-survivors of sepsis demonstrate significantly higher ferritin levels compared to survivors, with ferritin correlating with disease severity 1
• Extremely elevated ferritin (>4,420 ng/mL) may indicate macrophage activation-like syndrome, associated with 46.7% ICU mortality and profound host response derangement 3

Hemoglobin Suppression Mechanisms

• Multiple pathways contribute to anemia: (1) blunted erythropoietin responsiveness despite elevated EPO levels, (2) direct suppression of erythroid progenitors by inflammatory cytokines, (3) shortened red blood cell survival, and (4) hemolysis 2, 4
• Hemoglobin correlates negatively with IL-6 and hepcidin levels—the more severe the inflammation, the lower the hemoglobin 1
• Sepsis-induced hemolysis occurs through complement activation, disseminated intravascular coagulation, capillary stopped-flow, glucose restriction to RBCs, membrane property changes, and direct pathogen effects 4

Clinical Significance and Prognostic Value

Mortality Prediction

• Hepcidin demonstrates superior predictive value for 28-day mortality with 87.3% specificity (AUC 0.808), outperforming other inflammatory anemia markers 1
• The sTfR/log ferritin ratio (soluble transferrin receptor to log ferritin) is significantly lower in non-survivors, reflecting more severe functional iron deficiency 1
• Free hemoglobin concentration is twice as high in non-survivors versus survivors, serving as an independent predictor of death (odds ratio 6.1) 5

Pattern Recognition

• Expect this triad in septic patients: low hemoglobin, low serum iron, elevated ferritin, elevated hepcidin, and elevated IL-6 1
• These parameters change significantly within the first week of ICU admission and persist as long as inflammation continues 1, 2

Management Implications

Transfusion Strategy

• Maintain restrictive transfusion approach: Transfuse only when hemoglobin falls below 7.0 g/dL, targeting 7.0-9.0 g/dL once tissue hypoperfusion resolves 6, 7
• The TRISS trial demonstrated no mortality benefit from liberal transfusion (threshold 9.0 g/dL) versus restrictive (threshold 7.0 g/dL) in septic shock patients, with significantly fewer units transfused in the restrictive arm 7
• Exception: Patients with active myocardial ischemia, acute coronary syndrome, or severe hypoxemia require individualized higher thresholds 6, 8

Avoid Erythropoietin

• Do not administer erythropoietin for sepsis-associated anemia—it provides no mortality benefit and does not improve clinical outcomes (Grade 1B recommendation) 6, 8
• Despite elevated endogenous EPO levels in sepsis, the bone marrow remains relatively unresponsive due to inflammatory suppression 2

Critical Pitfall

• Never interpret high ferritin as indicating iron overload requiring phlebotomy or iron chelation in acute sepsis—this represents sequestered, functionally unavailable iron 2
• The elevated ferritin does not indicate need for iron supplementation either, as iron is present but trapped 1

Special Populations at Risk

• Hematologic malignancy patients show disproportionate risk: 33.3% of community-acquired pneumonia patients with ferritin >4,420 ng/mL had hematologic malignancies versus 5.1% of controls 3
• These patients demonstrate exaggerated host response abnormalities including dysregulation of inflammation, cytokine responses, endothelial activation, and coagulation pathways 3