Anemia of chronic disease (ACD)

Summary

Anemia of chronic disease (ACD), also called anemia of inflammation, is the second most common anemia worldwide (after iron deficiency). It happens when chronic inflammation, infection, or malignancy causes the liver to release hepcidin, which traps iron inside macrophages and blocks its absorption from the gut.

The result is a functional iron deficiency: the body has enough iron, but it cannot reach the bone marrow to make red blood cells.

• Typical picture: mild, normocytic normochromic anemia in a patient with a known chronic disease (RA, SLE, TB, CKD, cancer).
• Key labs: ↓ serum iron, ↓ TIBC, ↑ ferritin, normal/↓ transferrin saturation.
• Treatment: treat the underlying disease. Iron and EPO only in selected cases (e.g., CKD).

The most important exam skill is to differentiate ACD from iron deficiency anemia (IDA) using iron studies — they look similar on CBC but are opposite on ferritin and TIBC.

Definition

Anemia of chronic disease (ACD) is a mild-to-moderate anemia that develops in patients with sustained immune activation — chronic infection, autoimmune disease, malignancy, or chronic kidney disease.

• Usually normocytic, normochromic (MCV 80–100).
• Can become microcytic, hypochromic if the disease is long-standing or severe.
• Hb rarely drops below 8 g/dL on the basis of ACD alone — if it does, look for a second cause (bleeding, hemolysis, marrow infiltration).

The mechanism is not true iron deficiency — body iron stores are normal or increased — but the iron is "locked away" and cannot be used for erythropoiesis.

Etiology

Any disease that produces sustained inflammation can cause ACD. The four classic categories:

Note on CKD: anemia of CKD overlaps with ACD but has an additional mechanism — the failing kidney makes less erythropoietin (EPO). This is why CKD anemia responds to EPO injections while pure ACD usually does not.

Pathophysiology

Chronic inflammation → release of IL-6 (and other cytokines) → liver makes hepcidin → three downstream effects:

1. Iron sequestration: hepcidin degrades ferroportin on macrophages → iron is trapped inside macrophages of the reticuloendothelial system (spleen, liver, marrow). This is why ferritin (storage form) goes up.
2. Decreased gut absorption: hepcidin also degrades ferroportin on duodenal enterocytes → less iron enters the blood from food.
3. Decreased erythropoiesis: cytokines (IL-1, TNF-α, IFN-γ) directly suppress bone marrow response to EPO and shorten RBC lifespan.

The net effect: iron is present but unavailable → the marrow can't make enough hemoglobin → mild anemia.

Teleology (why this exists): bacteria need iron to grow. Locking up iron during infection is an ancient defense mechanism. The "anemia" is a side effect of that defense.

Clinical Features

ACD is usually mild and well-tolerated. Symptoms are often hidden by the underlying disease.

• General anemia symptoms: fatigue, weakness, pallor, mild exertional dyspnea.
• Onset: develops gradually over weeks to months after the underlying disease becomes active.
• Severity: Hb usually 9–11 g/dL. Severe anemia (Hb < 8) is unusual — search for another cause.
• Features of the underlying disease dominate: joint pain (RA), fever and night sweats (TB, malignancy), weight loss (cancer), butterfly rash (SLE), uremic symptoms (CKD).

There are no specific physical signs for ACD itself. The diagnosis is made by combining a known chronic illness + typical lab pattern.

Diagnosis

ACD is a laboratory diagnosis in a patient with a known chronic disease. There is no single confirmatory test — you put the pieces together.

1. CBC

• Mild anemia (Hb 9–11 g/dL).
• MCV usually normal; can become low in chronic, severe cases.
• Reticulocyte count: low or inappropriately normal (marrow is not responding).

2. Iron studies — the key step

Compare with iron deficiency anemia using the iron studies comparison table:

3. Inflammatory markers

• ↑ ESR, ↑ CRP — support the diagnosis but are non-specific.
• Ferritin itself is an acute phase reactant, which is why it goes up.

4. Peripheral smear

Usually normocytic normochromic RBCs. In long-standing cases the smear may look microcytic and hypochromic.

Differential Diagnosis

When you see a normocytic or mildly microcytic anemia, think through these alternatives:

• Iron deficiency anemia (IDA): ferritin LOW, TIBC HIGH. The mirror image of ACD.
• Thalassemia minor: very low MCV (often < 70) with normal/high RBC count, normal iron studies, abnormal Hb electrophoresis (↑ HbA2 in β-thal).
• Sideroblastic anemia: ↑ serum iron, ↑ ferritin, normal TIBC, ringed sideroblasts on marrow.
• Anemia of CKD: overlap with ACD + low EPO. Suspect when creatinine is elevated.
• Multiple myeloma: normocytic anemia + bone pain + renal failure + hypercalcemia + rouleaux formation on smear.
• Aplastic anemia / marrow infiltration: pancytopenia, low reticulocytes.

Management

The cornerstone is to treat the underlying disease. The anemia will improve as inflammation subsides.

1. Treat the cause

• Antibiotics for chronic infection (TB, osteomyelitis).
• Immunosuppressants/DMARDs for RA, SLE, IBD.
• Chemotherapy for malignancy.
• Dialysis and renal optimization for CKD.

2. Iron therapy — only if true iron deficiency coexists

• Do not give oral iron routinely — hepcidin blocks gut absorption, so it doesn't work.
• If iron deficiency is also present (low ferritin, low transferrin saturation), IV iron is preferred (bypasses the gut).

3. Erythropoiesis-stimulating agents (ESAs)

• Indicated mainly for anemia of CKD and selected chemotherapy-induced ACD.
• Target Hb 10–11 g/dL — higher targets increase risk of thrombosis, stroke, and death.
• ESA resistance: if the patient does not respond, look for iron deficiency, ongoing inflammation, or vitamin deficiency.

4. Transfusion

• Reserved for severe symptomatic anemia (Hb < 7–8 g/dL) or acute decompensation.
• Not a long-term solution.

Complications

• Worsening of underlying disease symptoms: fatigue and reduced exercise tolerance limit recovery from chronic illness.
• Cardiovascular stress: in elderly patients or those with heart disease, even mild anemia can worsen angina or heart failure.
• Reduced quality of life and impaired wound healing.
• Diagnostic pitfall: ACD can mask coexisting iron deficiency — missed GI bleed in an RA patient on NSAIDs is a classic exam trap.
• ESA-related risks (when treated with EPO): hypertension, thromboembolic events, increased mortality if Hb is pushed too high (> 11–12 g/dL).

Mnemonics