Anemia of Chronic Disease (Anemia of Inflammation)
Normocytic (sometimes microcytic) anemia driven by hepcidin-mediated iron sequestration in chronic inflammation.
Also known as: ACD, anemia of inflammation, AOCD, AI
Overview
Mild-to-moderate anemia occurring in the setting of chronic infection, inflammation, autoimmune disease, malignancy, or CKD. Characterized by adequate or increased iron stores but impaired iron utilization due to inflammation-driven hepcidin elevation.
Epidemiology
Second most common anemia worldwide after iron deficiency; most common anemia in hospitalized patients and the elderly. Prevalence rises with age and burden of comorbid disease.
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Inflammatory cytokines (IL-6 chief among them) stimulate hepatic production of hepcidin, which binds ferroportin on enterocytes and macrophages and triggers its internalization. The result is reduced intestinal iron absorption and trapping of iron within reticuloendothelial macrophages. Erythropoietin production is blunted, and erythroid progenitors become less responsive to EPO. Red cell lifespan is mildly shortened.
Clinical presentation
Symptoms
Often asymptomatic or symptoms attributed to the underlying disease
Fatigue, reduced exercise tolerance, dyspnea on exertion
Worsening of preexisting angina or heart failure
Signs / physical exam
Pallor, tachycardia
Findings of underlying chronic disease (synovitis, lymphadenopathy, hepatosplenomegaly, uremic features)
Classic findings
Mild normocytic anemia (Hb 9-11) with low serum iron, low TIBC, and normal or elevated ferritin in a patient with chronic inflammation.
Differential diagnosis
Iron deficiency anemia — Low ferritin, high TIBC, high RDW; both can coexist — combined ACD + IDA shows ferritin 30-100 ng/mL and sTfR/log ferritin ratio >2
Anemia of CKD — Overlapping mechanism; EPO deficiency dominates as GFR <60; treat with ESA and iron repletion
Myelodysplastic syndrome — Elderly, macrocytic or dimorphic, cytopenias, dysplastic features on smear/marrow
Hypothyroidism — Normocytic or macrocytic anemia; elevated TSH
Drug-induced marrow suppression — Chemotherapy, methotrexate, antiretrovirals, linezolid; temporal relation to drug
Diagnostic workup
Diagnostic criteria
Mild-to-moderate anemia + identifiable chronic inflammatory state + low serum iron + low TIBC + normal/elevated ferritin.
Labs
CBC — Hb usually 8-11 g/dL; MCV normal (sometimes mildly low)
Iron studies — low serum iron, low TIBC, transferrin saturation 10-20%, ferritin normal or elevated (>100 ng/mL)
Reticulocyte count low (inadequate response)
CRP, ESR elevated reflecting inflammation
Soluble transferrin receptor normal (rises in true iron deficiency); sTfR/log ferritin index helps distinguish ACD vs ACD + IDA
BUN/creatinine to assess CKD contribution
Targeted workup for underlying cause (ANA, RF, SPEP, age-appropriate cancer screening if no other source)
Imaging
Driven by suspected underlying condition; no specific imaging for ACD itself
Diagnostic algorithm
flowchart TD
A[Chronic inflammation/<br/>infection/malignancy/CKD] --> B[IL-6 release]
B --> C[Hepatic hepcidin ↑]
C --> D[Ferroportin<br/>internalization]
D --> E[Decreased GI<br/>iron absorption]
D --> F[Iron trapped in<br/>macrophages]
E --> G[Iron-restricted<br/>erythropoiesis]
F --> G
B --> H[Blunted EPO<br/>production/response]
H --> G
G --> I[Normocytic anemia<br/>Low Fe, Low TIBC<br/>Normal/high ferritin]
Pathophysiology of anemia of chronic disease — hepcidin as the central regulator.
Treatment
First-line
Treat the underlying disease — most effective intervention
Optimize comorbidities (HF, diabetes, CKD)
Iron repletion only if concurrent iron deficiency documented (combined picture). Prefer IV iron in CKD and IBD due to oral absorption impairment from hepcidin
Second-line / adjunct
Erythropoiesis-stimulating agents (ESAs) — epoetin alfa, darbepoetin alfa — for symptomatic anemia in CKD (target Hb 10-11 g/dL, not >11.5) and chemotherapy-induced anemia (palliative settings only; AVOID in curative-intent cancer therapy due to mortality and thromboembolism signal)
HIF prolyl hydroxylase inhibitors — roxadustat, daprodustat — oral alternative for CKD anemia (availability varies)
Transfusion for severe symptomatic anemia or hemodynamic compromise
Complications
Reduced quality of life, fatigue, impaired functional status
Worsened cardiovascular outcomes in HF and CKD
ESA-related: hypertension, thromboembolism, pure red cell aplasia (rare anti-EPO antibodies), tumor progression in some malignancies
PANCE pearls
If ferritin <100 ng/mL in a patient with active inflammation or CKD, suspect coexisting iron deficiency and consider a trial of iron.
sTfR/log ferritin index: >2 suggests iron deficiency (with or without ACD); <1 suggests pure ACD.
ESAs should not be used to target Hb >11.5 g/dL in CKD — higher targets associated with stroke and cardiovascular events (CHOIR, TREAT trials).
Never start an ESA without first checking and repleting iron stores; ESA response requires available iron.
In cancer-related ACD, ESAs are restricted to chemotherapy-induced anemia in non-curative settings due to mortality concerns.
References
KDIGO 2012 — KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease
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