Anemia of chronic disease (anemia of inflammation)

Pathophysiology

• A form of iron-restricted erythropoiesis: iron is present in the body but not available for use.
• Central axis: chronic inflammation raises IL-6, which drives hepatic hepcidin. Hepcidin blocks ferroportin, so iron release into the circulation falls: iron is trapped in macrophages and enterocytes (functional iron deficiency despite adequate stores). Hemosiderin-laden macrophages accumulate.
• Additional contributors: suppressed EPO production, blunted EPO responsiveness, and shortened RBC lifespan.
• Immuno-protective rationale: hepcidin-driven iron sequestration minimizes iron availability to pathogens.
• Causes: chronic infection (TB, HIV, osteomyelitis, endocarditis), inflammatory disease (RA, SLE, IBD, vasculitis), malignancy, CKD, congestive heart failure.

Diagnosis

• CBC: usually normocytic normochromic; mild microcytosis can develop but is not inevitable, and marked microcytosis suggests concurrent iron deficiency.
• Iron studies: ↑ or normal ferritin (acute phase reactant), ↓ serum iron, ↓ TIBC (key differentiator from iron deficiency), ↓ transferrin saturation.
• Concurrent iron deficiency: may coexist with AOCD, especially with long-standing inflammation plus blood loss (for example, IBD). Ferritin <100 in the setting of inflammation suggests concurrent iron deficiency.
• Soluble transferrin receptor (sTfR): measures erythropoietic activity and is elevated in iron deficiency, so it (or the sTfR/log ferritin index) helps unmask concurrent iron deficiency. Caveat: sTfR is not a reliable iron-status indicator in patients with hemolytic anemias (increased erythropoiesis raises it independent of iron status).

Iron-study patterns: AOCD vs iron deficiency

Treatment

• Treat the underlying disease: this is the most important step.
• Iron: not routine for pure anemia of inflammation, but treat iron-restricted erythropoiesis even with adequate stores, e.g. CKD (KDIGO: consider iron if TSAT ≤30% and ferritin ≤500); IV iron is preferred in hemodialysis; in nondialysis CKD and other inflammatory states oral or IV iron is chosen by severity, response, and tolerability (high hepcidin can impair oral absorption).
• ESAs (erythropoietin, darbepoetin):
  • CKD anemia: target Hb 10 to 11 (avoid ≥13; CHOIR showed increased cardiovascular/death events at higher Hb; TREAT showed increased stroke with a neutral primary CV composite; CREATE showed no significant CV difference (but more dialysis starts)).
  • Cancer chemotherapy-induced anemia: use only with non-curative intent; start only if Hb <10 and titrate to the lowest Hb needed to avoid transfusion; risk of thromboembolism and reduced tumor response in some studies. Avoid in cancer treated with curative intent.
• HIF-PHI (hypoxia-inducible factor prolyl hydroxylase inhibitors): roxadustat is approved for CKD anemia in the EU, Japan, and China; the FDA declined US approval (CRL Aug 2021 over thrombosis, vascular access thrombosis, and MACE safety concerns).
• Daprodustat (Jesduvroq): oral HIF-PHI; FDA approved Feb 1, 2023 for anemia of CKD in adults on dialysis for at least 4 months (the first US-approved HIF-PHI); voluntarily withdrawn from the US market by GSK in 2024 for business reasons (not safety or efficacy). ASCEND-D (Singh, NEJM 2021) showed non-inferiority to ESAs for Hb and MACE in dialysis patients. NOT approved for non-dialysis CKD (ASCEND-ND showed a thromboembolic signal). Boxed warning: increased risk of death, MI, stroke, VTE, and vascular access thrombosis (HF hospitalization is a separate warning); avoid Hb targets >11.
• Vadadustat (Vafseo): oral HIF-PHI, FDA approved Mar 2024 for anemia of CKD in adults on dialysis for at least 3 months (INNO2VATE); boxed warning for death, MI, stroke, VTE, and vascular access thrombosis; not approved for non-dialysis CKD.

High yield

• IL-6 to ↑ hepcidin to blocked ferroportin is the pathophysiologic axis; iron is trapped in macrophages (iron-restricted erythropoiesis).
• AOCD pattern: ↑ or normal ferritin, ↓ iron, ↓ TIBC, ↓ transferrin saturation.
• Iron deficiency pattern: ↓ ferritin, ↓ iron, ↑ TIBC, ↓ transferrin saturation, ↑ sTfR.
• Low TIBC vs high TIBC is the fastest way to separate AOCD from iron deficiency.
• sTfR / ferritin index helps detect concurrent iron deficiency in inflammation; unreliable in hemolytic anemias.
• Usually normocytic; mild microcytosis can develop if prolonged, and marked microcytosis suggests concurrent iron deficiency.
• ESAs in CKD: target Hb 10 to 11; higher targets increase cardiovascular risk. Avoid ESAs in curative-intent cancer.