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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Question 1HematologyMedium
A 64-year-old woman with long-standing rheumatoid arthritis presents with several months of progressive fatigue. She has no melena, hematochezia, or heavy menses. Vitals are normal. Labs show hemoglobin 10.2 g/dL with an MCV of 84 fL, a low serum iron, a LOW total iron-binding capacity, an elevated ferritin, and a low reticulocyte count. Which of the following is the most likely diagnosis?
AHereditary hemochromatosis pattern
BSideroblastic anemia pattern
CIron deficiency anemia pattern
DVitamin B12 deficiency anemia
EAnemia of chronic inflammation
Reveal answer & full explanation
Correct answer: E — Anemia of chronic inflammation
AHereditary hemochromatosis pattern
BSideroblastic anemia pattern
CIron deficiency anemia pattern
DVitamin B12 deficiency anemia
EAnemia of chronic inflammation✓
Why Anemia of chronic inflammation is correct
This patient has anemia of chronic inflammation (anemia of chronic disease).
The core concept is that sustained inflammation from a chronic illness such as rheumatoid arthritis drives interleukin-6, which raises hepcidin; hepcidin traps iron in macrophages and blunts gut absorption, producing a normocytic (sometimes mildly microcytic) anemia with LOW serum iron, LOW TIBC, and HIGH/normal ferritin.
This iron-study pattern plus an inflammatory driver is diagnostic.
Why the others are wrong
Iron deficiency anemia pattern — also shows low serum iron, but TIBC is HIGH and ferritin is LOW because stores are depleted, the opposite of this patient's high ferritin/low TIBC; there is also no blood-loss source.
Sideroblastic anemia pattern — features high serum iron and ferritin with ring sideroblasts and often an elevated transferrin saturation, not a low iron with low TIBC.
Vitamin B12 deficiency anemia — produces a MACROcytic anemia (high MCV) with neurologic signs and hypersegmented neutrophils, not the normocytic pattern here.
Hereditary hemochromatosis pattern — the high ferritin and low TIBC match iron overload, and hemochromatosis can cause fatigue and an arthropathy that mimics rheumatoid arthritis, but serum iron and transferrin saturation are HIGH in hemochromatosis rather than low, and iron overload does not by itself produce anemia.
The low iron/low TIBC/high ferritin triad in an inflammatory disease defines anemia of chronic inflammation.
Question 2HematologyMedium
A 64-year-old woman with poorly controlled rheumatoid arthritis presents with several months of fatigue and reduced exercise tolerance. Her joints are actively swollen and tender, and she has missed recent doses of her DMARD. Hemoglobin is 9.8 g/dL with a normal MCV and a low reticulocyte count. Iron studies show low serum iron, low total iron-binding capacity, transferrin saturation of 15%, and ferritin of 240 ng/mL. C-reactive protein and ESR are markedly elevated, and renal function is normal. Which of the following is the most appropriate initial management?
AOptimize control of her rheumatoid arthritis
BBegin a trial of oral ferrous sulfate therapy
CWithhold further doses of her DMARD therapy
DInitiate subcutaneous epoetin alfa therapy
EAdminister an intravenous iron sucrose infusion
Reveal answer & full explanation
Correct answer: A — Optimize control of her rheumatoid arthritis
AOptimize control of her rheumatoid arthritis✓
BBegin a trial of oral ferrous sulfate therapy
CWithhold further doses of her DMARD therapy
DInitiate subcutaneous epoetin alfa therapy
EAdminister an intravenous iron sucrose infusion
Why Optimize control of her rheumatoid arthritis is correct
This is anemia of chronic disease (anemia of inflammation): mild-to-moderate normocytic anemia, low serum iron, low TIBC, low transferrin saturation, and normal-to-elevated ferritin in a patient with an active inflammatory state.
Inflammatory cytokines (chiefly IL-6) drive hepcidin, which traps iron in macrophages and blunts erythropoiesis. Controlling the underlying disease lowers hepcidin and is the single most effective intervention, so optimizing RA control is the guideline-defined first-line step.
Ferritin of 240 ng/mL with an elevated CRP/ESR makes concurrent iron deficiency unlikely, so no iron or further hematologic agent is needed first.
Why the others are wrong
Initiate subcutaneous epoetin alfa therapy — an erythropoiesis-stimulating agent reserved as second-line for symptomatic CKD or chemotherapy-induced anemia; it carries thromboembolic and cardiovascular risk and should not be started before treating the cause and confirming iron stores.
Begin a trial of oral ferrous sulfate therapy — appropriate for iron deficiency anemia (low ferritin, high TIBC), but here iron stores are adequate and hepcidin impairs intestinal absorption, so oral iron would be ineffective without documented deficiency.
Withhold further doses of her DMARD therapy — DMARD marrow toxicity (classically methotrexate) produces macrocytosis and often pancytopenia rather than this iron-restricted normocytic pattern, and she has already missed doses while her joints are actively inflamed; stopping the DMARD would intensify the inflammatory hepcidin drive and deepen the anemia.
Administer an intravenous iron sucrose infusion — tempting because parenteral iron bypasses the hepcidin block on intestinal absorption that defeats oral iron, but hepcidin also traps iron in macrophages, so much of the infused iron stays sequestered; with a ferritin of 240 ng/mL her stores are adequate, and controlling the inflammation is what releases them.
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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; relative EPO deficiency worsens as GFR falls and alone gives normocytic anemia with normal iron indices, whereas high ferritin + low TSAT + high CRP points to hepcidin-mediated sequestration; 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). IV iron preferred in hemodialysis (KDIGO 2026) and in active IBD (hepcidin impairs oral absorption); oral or IV iron is acceptable in non-dialysis or peritoneal dialysis CKD
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); KDIGO 2026 suggests ESAs rather than HIF-PHIs as first-line, and HIF-PHIs should not be used with active malignancy or a recent cardiovascular or thrombotic event
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, suspect coexisting iron deficiency and consider a trial of iron. CKD uses higher thresholds (KDIGO 2026): start iron in hemodialysis if ferritin ≤500 ng/mL and TSAT ≤30%; in non-dialysis or peritoneal dialysis CKD if ferritin <100 ng/mL with TSAT <40%, or ferritin 100 to <300 ng/mL with TSAT <25%; withhold iron if ferritin >700 ng/mL or TSAT ≥40%.
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 2026 — KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD) (Kidney Int 2026;109(1S):S1-S99)
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