Anaemia of Chronic Disease (ACD) — also known as anaemia of inflammation — is the second most common type of anaemia after iron deficiency anaemia. It typically occurs in the context of:

• Chronic infections (e.g. TB, HIV)

• Inflammatory or autoimmune conditions (e.g. RA, SLE)

• Malignancy

• Chronic kidney disease (CKD)

Pathophysiology of Anaemia of Chronic Disease

Mechanism	Key Pathway	Clinical Impact
Iron dysregulation	↑IL-6 → ↑Hepcidin → ↓iron absorption (gut) + ↑iron sequestration (macrophages)	↓Serum iron, but normal or ↑ferritin
Suppressed erythropoiesis	↑TNF-α, ↑IL-1 → ↓EPO production + ↓bone marrow responsiveness	↓RBC production → normocytic or mild anaemia
Shortened RBC lifespan	Chronic inflammation → ↑RBC phagocytosis by macrophages	Contributes to anaemia
Impaired iron utilisation	Iron stores present but unavailable for erythropoiesis (functional deficiency)	↓Transferrin saturation (TSAT)

In ACD, chronic inflammation — through cytokines like interleukin-6 (IL-6) — stimulates the liver to produce hepcidin, a key regulator of iron homeostasis.

Hepcidin acts by:

• Inhibiting ferroportin, the only known cellular iron exporter, found on enterocytes (gut), hepatocytes (liver), and macrophages.

• This blocks iron absorption from the gut and prevents iron release from macrophages and liver stores.

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As a result, iron becomes sequestered in storage sites, leading to low serum iron despite normal or increased total body iron stores — a state called functional iron deficiency. This limits the availability of iron for erythropoiesis in the bone marrow, contributing to anaemia.

Clinical Presentation of Anaemia of Chronic Disease (ACD)

ACD often presents subtly, with symptoms overlapping those of the underlying chronic condition. In many cases, anaemia is discovered incidentally on blood tests.

⚠Common Symptoms

• Fatigue & weakness – most frequent complaint; may affect daily functioning

• Pallor – often noticed by others

• Shortness of breath – especially on exertion

• Tachycardia – compensatory response to anaemia

• Dizziness or light-headedness – in moderate/severe cases

• Body aches, general malaise – nonspecific, often linked to chronic disease

• Chest pain or increased breathlessness – in severe anaemia or cardiac comorbidity

Note: Symptoms are often milder compared to iron deficiency anaemia and may be masked by the chronic illness itself (e.g., fatigue in rheumatoid arthritis or cancer).

Physical Examination

• Pallor – especially conjunctival or palmar

• Tachycardia – common, especially with exertion

• Signs of underlying disease – e.g., joint swelling (RA), lymphadenopathy (malignancy), or oedema (CKD)

Diagnostic Approach to Anaemia of Chronic Disease (ACD)

Step-by-Step Evaluation

Test	Expected in ACD	Interpretation & Reasoning
Hb (Haemoglobin)	↓ Mild to moderate (80–100 g/L)	Anaemia typically not severe; often incidental finding
MCV	Normal (80–100 fL) or slightly ↓	Normocytic is typical; may be mildly microcytic if long-standing
Serum Iron	↓	Due to hepcidin-mediated iron sequestration
TIBC (Total Iron-Binding Capacity)	↓ or Normal	↓ transferrin due to inflammation (vs ↑ in IDA)
Ferritin	Normal or ↑	Acute-phase reactant; reflects iron stores and inflammation
Transferrin Saturation (TSAT)	↓	Iron present in stores but unavailable for erythropoiesis
Reticulocyte Count	↓ or inappropriately normal	Blunted marrow response to anaemia
CRP / ESR	↑	Supports inflammatory cause
Soluble Transferrin Receptor (sTfR)	Normal	Helpful to distinguish ACD from IDA (↑ in IDA)
Reticulocyte Hb Content	Normal or ↓	↓ suggests IDA; may help when mixed picture suspected

ACD presents as a mild to moderate, normocytic normochromic anaemia, though it may be microcytic in some cases. Key underlying mechanisms include:

• Iron sequestration (↓ serum iron, but normal/↑ ferritin)

• Impaired erythropoiesis

• Reduced RBC lifespan

When evaluating suspected anaemia of chronic disease (ACD), it’s essential to:

• Exclude other causes of anaemia, particularly:

  • Iron deficiency anaemia (IDA) — can coexist with ACD

    • Key tests: ferritin (normal/↑ in ACD, ↓ in IDA) and transferrin saturation (TSAT) (↓ in both, but lower in IDA)

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  • Nutritional deficiencies — check serum B12 and folate

  • Haemolysis — order LDH, bilirubin, haptoglobin, and blood film

  • Bone marrow disorders — consider if anaemia is unexplained or persistent

  • Haemoglobinopathies — use haemoglobin electrophoresis if clinically indicated

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• Consider newer markers to differentiate ACD vs. mixed ACD/IDA:

  • Soluble transferrin receptor (sTfR): normal in ACD, ↑ in IDA

  • sTfR/log ferritin ratio: higher in iron deficiency states

A thorough clinical history, focused examination, and targeted lab testing are critical to avoid missing treatable causes or overlooking co-existing pathologies.

When to Suspect Anaemia of Chronic Disease (ACD) in Primary Care

Step 1: Confirm Anaemia

• Hb ↓ (typically 80–110 g/L)

• MCV: Normal (normocytic) or mildly ↓ (microcytic)

• Reticulocyte count: Low or inappropriately normal

Clue: Mild to moderate anaemia, often with minimal symptoms.

Test	ACD Pattern
Serum Iron	↓
Ferritin	Normal or ↑
TIBC	↓ or normal
Transferrin saturation (TSAT)	↓

Step 3: Assess for Inflammation

• CRP / ESR: Elevated

• Known chronic disease? (e.g., RA, CKD, cancer, infection)

Clue: ACD is a diagnosis of context — look for inflammatory or chronic conditions.

Step 4: Exclude Other Common Causes

• Check:

  • Vitamin B12 & folate

  • LDH, bilirubin (for haemolysis)

  • Blood film

• Consider:

  • Soluble transferrin receptor (↑ in IDA, normal in ACD)

  • sTfR/log ferritin ratio (↑ in IDA)

Clue: ACD and IDA often coexist — always rule out true iron deficiency.

When ACD is Likely

• Normocytic or mildly microcytic anaemia

• ↓ Serum iron + ↓ TIBC + normal/↑ ferritin

• Underlying chronic inflammatory condition

• No evidence of bleeding, B12/folate deficiency, or haemolysis.

Basic Principles of ACD Management in Primary Care

1️⃣ Treat the Underlying Cause

• Focus on managing the chronic condition (e.g., RA, CKD, cancer, infection).

• Anaemia often improves as inflammation resolves.

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2️⃣ Supportive Care

• Oral iron is usually ineffective if ferritin is normal or ↑.

• IV iron or ESAs may be considered only after specialist input (e.g., nephrology, haematology).

• Blood transfusion: For severe/symptomatic anaemia (e.g., Hb < 70 g/L), not routine.

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3️⃣ Avoid Mismanagement

• Do not give iron if ferritin is normal/high — suggests iron is present but trapped.

• Always exclude coexisting iron deficiency (esp. in menstruating women or GI symptoms).

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4️⃣ Patient Education

• Reassure: anaemia is often secondary to the chronic condition.

• Explain that dietary iron or supplements are rarely helpful unless true deficiency is confirmed.

Key Takeaways on Anaemia of Chronic Disease (ACD)

• ACD is a common, often overlooked cause of anaemia in patients with chronic inflammatory, infectious, or malignant diseases.

• Diagnosis is clinical, supported by:

  • Normocytic or mildly microcytic anaemia

  • ↓ Serum iron, ↓/normal TIBC, ↑/normal ferritin

  • Low reticulocyte count

  • No evidence of bleeding, haemolysis, or nutritional deficiency

• Management focuses on:

  • Treating the underlying disease

  • Avoiding inappropriate iron therapy unless true deficiency is confirmed

  • Considering specialist referral for IV iron, ESAs, or persistent/severe anaemia

🧠 Follow a structured approach based on clinical context, iron studies, and exclusion of other causes, in line with recommendations from BMJ Best Practice, renal guidelines, and haematology references.

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📚 References

1. BMJ Best Practice. Anaemia of chronic disease. https://bestpractice.bmj.com/topics/en-gb/95

2. Weiss G, Goodnough LT. Anemia of chronic disease. Blood Rev. 2020;34:1–11. PMC7353365

3. NICE Clinical Knowledge Summaries. Anaemia - iron deficiency: Investigations. https://cks.nice.org.uk/topics/anaemia-iron-deficiency/diagnosis/investigations/

4. Cappellini MD, Musallam KM, Taher AT. Diagnosis and management of iron deficiency in the context of ACD. Hematology Am Soc Hematol Educ Program. 2020;2020(1):478–486. ASH Publications

5. UK Kidney Association. Anaemia of Chronic Kidney Disease Guidelines. Updated Feb 2020. https://www.ukkidney.org/sites/default/files/Updated-130220-Anaemia-of-Chronic-Kidney-Disease-1-1.pdf

6. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372:1832–1843. PMC5588399

7. Doncaster & Bassetlaw NHS Foundation Trust. Anaemia Clinical Guidance. https://www.dbth.nhs.uk/wp-content/uploads/2021/09/Anaemia.pdf

8. British Society for Haematology. Laboratory diagnosis of functional iron deficiency. https://b-s-h.org.uk/guidelines/guidelines/laboratory-diagnosis-of-functional-iron-deficiency

9. Cleveland Clinic. Anaemia of Chronic Disease. https://my.clevelandclinic.org/health/diseases/14477-anemia-of-chronic-disease

10. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Anaemia of inflammation and chronic disease. https://www.niddk.nih.gov/health-information/blood-diseases/anemia-inflammation-chronic-disease

11. National Organization for Rare Disorders (NORD). Anaemia of chronic disease. https://rarediseases.org/rare-diseases/anemia-of-chronic-disease/

12. Geeky Medics. Iron Deficiency Anaemia. https://geekymedics.com/iron-deficiency-anaemia/

13. NCBI Bookshelf. Anemia of Chronic Disease. https://www.ncbi.nlm.nih.gov/books/NBK534803/

14. Patient.info. Anaemia of Chronic Disease. https://patient.info/doctor/history-examination/anaemia-of-chronic-disease

15. NHS. Iron Deficiency Anaemia. https://www.nhs.uk/conditions/iron-deficiency-anaemia/

16. Mayo Clinic. Anaemia – Symptoms and Causes. https://www.mayoclinic.org/diseases-conditions/anemia/symptoms-causes/syc-20351360

17. NICE CKS. Anaemia - Iron Deficiency: Signs and Symptoms. https://cks.nice.org.uk/topics/anaemia-iron-deficiency/diagnosis/signs-symptoms/

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