Anemia of chronic disease (ACD)

Overview & Pathophysiology

Anemia of chronic disease (ACD), also called anemia of inflammation, is a mild-to-moderate anemia that develops in patients with sustained immune activation (chronic infection, autoimmune disease, malignancy, or CKD). It is the second most common anemia worldwide after iron deficiency.

• Typical picture: mild normocytic, normochromic anemia (MCV 80–100) in a patient with a known chronic illness.
• Can drift to microcytic, hypochromic only if long-standing/severe.
• Hb rarely falls below 8 g/dL on ACD alone — if it does, hunt for a second cause (bleeding, hemolysis, marrow infiltration).

The core lesion is a functional iron deficiency: body iron stores are normal or increased, but the iron is "locked away" and cannot reach the marrow for erythropoiesis.

The inflammation → IL-6 → hepcidin axis

Chronic inflammation drives release of IL-6 (and other cytokines), which signals the liver to make hepcidin — the master regulator of iron. Hepcidin produces three downstream effects:

1. Iron sequestration: hepcidin degrades ferroportin on macrophages → iron is trapped in the reticuloendothelial system → ↑ ferritin (storage form rises).
2. ↓ Gut absorption: hepcidin degrades ferroportin on duodenal enterocytes → less dietary iron enters the blood.
3. ↓ Erythropoiesis: cytokines (IL-1, TNF-α, IFN-γ) blunt the marrow's response to EPO and shorten RBC lifespan.

Net effect: iron is present but unavailable → the marrow cannot make enough hemoglobin → mild anemia. Teleologically, this iron lockdown evolved to starve bacteria of iron during infection — the anemia is a side effect of that defense.

Mnemonic – Hepcidin Hides Iron
"Hepcidin Hides Iron" Hepcidin → degrades ferroportin Holds iron inside macrophages + enterocytes Iron stays high in stores (↑ ferritin) but low in blood (↓ serum iron) The body's "iron-lockdown hormone" during inflammation — meant to starve bacteria of iron, but ends up starving the marrow too.	جملة تذكرية

Etiology

Any disease producing sustained inflammation can cause ACD. The four classic categories — remember "CIA-K":

Mnemonic – Causes of ACD
"CIA-K" = the 4 categories of ACD: Cancer (malignancy) Infection (chronic: TB, osteomyelitis, HIV) Autoimmune (RA, SLE, IBD) Kidney disease (CKD)	جملة تذكرية

Special note on CKD: anemia of CKD overlaps with ACD but adds a second mechanism — the damaged kidney makes less erythropoietin. This is why CKD anemia responds to EPO injections while pure ACD usually does not.

Clinical Presentation

ACD is usually mild and well-tolerated; the anemia itself is frequently asymptomatic and overshadowed by the underlying disease.

• Nonspecific anemia symptoms: fatigue, weakness, pallor, mild exertional dyspnea.
• Onset: gradual over weeks to months after the chronic disease becomes active.
• Severity: Hb usually 9–11 g/dL; Hb < 8 g/dL is unusual — search for a second cause.

Features of the underlying disease dominate the picture:

• Joint pain/stiffness → RA; butterfly rash → SLE.
• Fever, night sweats, weight loss → TB or malignancy.
• Uremic symptoms → CKD.

There are no physical signs specific to ACD. The diagnosis is made by combining a known chronic illness + a characteristic lab pattern (covered next).

Important – فكرة سؤال
A patient with rheumatoid arthritis on long-term therapy presents with fatigue. CBC shows mild normocytic anemia. Which iron-study pattern do you expect? Answer: ↓ serum iron, ↓ TIBC, ↑ ferritin, normal/↓ transferrin saturation. The low TIBC and high ferritin are the two findings that separate ACD from iron deficiency anemia (where TIBC is high and ferritin is low).	تذكر

Diagnostic Approach

ACD is a laboratory diagnosis in a patient with a known chronic disease — there is no single confirmatory test. Build the picture from three blocks of results.

1. CBC

• Mild anemia, Hb 9–11 g/dL.
• MCV usually normal; may become low only in chronic, severe disease.
• Reticulocyte count low or inappropriately normal — the marrow is hypoproliferative.

2. Iron studies — the key step

• Serum iron: ↓ Low
• TIBC (transferrin): ↓ Low
• Ferritin (stores): ↑ High (or normal)
• Transferrin saturation: normal or ↓

3. Inflammatory markers

• ↑ ESR and ↑ CRP support the diagnosis but are non-specific.
• Ferritin is itself an acute-phase reactant — which is exactly why it rises in ACD.

The single highest-yield exam skill is distinguishing ACD from its mimics. Use the master table below; for an external cross-check, see the Iron Studies in Microcytic Anemia comparison table for the ferritin/TIBC/transferrin-saturation pattern across all three conditions.

فخ امتحاني – Exam Trap
أهم ما يميز فقر دم الأمراض المزمنة عن نقص الحديد هو ارتفاع الفيريتين (مخزون الحديد) وانخفاض الـ TIBC. في نقص الحديد، يحدث العكس تماماً.	ملاحظة

Mnemonic – ACD iron studies
"ACD = All Down except Ferritin" ↓ Serum iron ↓ TIBC ↓ Transferrin saturation (or normal) ↑ Ferritin (the odd one out) In IDA it is the mirror image: ferritin goes DOWN and TIBC goes UP.	جملة تذكرية

On the peripheral smear, ACD typically shows normocytic normochromic cells, becoming microcytic/hypochromic only in advanced disease.

Note – ملاحظة
The tricky case is coexisting ACD + IDA (e.g., RA patient with NSAID-induced GI bleed). Ferritin may be falsely "normal." In an inflamed patient, ferritin < 100 ng/mL still suggests true iron deficiency on top of ACD. Most specific clues: transferrin saturation < 20% or a high soluble transferrin receptor (sTfR) — raised in IDA, normal in ACD.	ملاحظة

Management

Management is built around four numbered priorities. The anemia improves as inflammation subsides, so the underlying disease is always the main target.

1. Treat the underlying disease (the definitive fix):
   • Antibiotics for chronic infection (TB, osteomyelitis).
   • DMARDs/immunosuppressants for RA, SLE, IBD.
   • Chemotherapy for malignancy; dialysis/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 fails.
   • If iron deficiency is genuinely present (low ferritin, transferrin saturation < 20%), give IV iron (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 raise thrombosis, stroke, and death risk.
   • ESA resistance: if no response, look for causes of ESA resistance — 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.

Key complications

• Cardiovascular stress: in the elderly or those with heart disease, even mild anemia can worsen angina or heart failure.
• Masked coexisting iron deficiency: ACD can hide a GI bleed (classic RA-on-NSAIDs exam trap) — reduced quality of life and impaired wound healing follow.
• ESA-related thrombosis: EPO therapy can cause hypertension, thromboembolic events, and increased mortality if Hb is pushed above 11–12 g/dL.

ملاحظة مهمة – Management Pearl
في فقر دم الأمراض المزمنة (ACD) لا تعطِ حديد عن طريق الفم بشكل روتيني — الهبسيدين يمنع امتصاصه من الأمعاء. إذا وُجد نقص حديد حقيقي مصاحب (ferritin منخفض)، يُفضّل الحديد عن طريق الوريد. علاج المرض الأساسي هو الحل الجذري.	ملاحظة