Anaemia Of Chronic Disease
Anaemia of chronic disease is a hypoproliferative anaemia arising in the setting of chronic infection, inflammation, or malignancy, mediated largely by hepcidin-induced iron sequestration and impaired erythropoiesis.
Anaemia of Chronic Disease (ACD)
Anaemia of chronic disease (ACD) — also known as anaemia of inflammation — is a form of anaemia that develops in the setting of chronic infection, chronic inflammatory conditions, autoimmune disease, or malignancy. The hallmark is a functional iron deficiency: the body has adequate total iron stores, but iron is compartmentalised (sequestered) within the reticuloendothelial system (RES) and not made available for erythropoiesis [1][2].
"ACD" → "anaemia" = low haemoglobin, "chronic" = sustained stimulus, "disease" = underlying pathological process driving the anaemia. The name tells you this is never a primary diagnosis — it always sits on top of another condition.
Key Conceptual Point
ACD is not the same as iron deficiency anaemia (IDA). In IDA the iron stores are genuinely depleted. In ACD the iron stores are normal or even increased — they are simply locked away. This distinction drives every downstream difference in investigations and management.
- Second most common cause of anaemia worldwide after iron deficiency anaemia [1].
- Most prevalent in hospitalised patients and the elderly.
- In Hong Kong specifically, the ageing population and high prevalence of chronic hepatitis B/C, chronic kidney disease, rheumatoid arthritis, and malignancies make ACD a daily consideration on the medical wards.
- Prevalence rises steeply with CKD stage: 1% at eGFR 60 → 9% at eGFR 30 → 33–67% at eGFR 15 [3].
- In infective endocarditis, some mild anaemia — anaemia of chronic illness due to the transient suppression of bone marrow — is expected [4].
Risk Factors
| Risk Factor Category | Examples |
|---|---|
| Chronic infections | Tuberculosis, osteomyelitis, chronic hepatitis B/C, HIV, infective endocarditis |
| Chronic inflammatory / autoimmune | Rheumatoid arthritis, SLE, inflammatory bowel disease (Crohn's, UC), vasculitis |
| Malignancy | Solid organ tumours, lymphoma, myeloma |
| Chronic kidney disease | Especially stages 3–5 (inflammation + ↓EPO) |
| Chronic rejection after solid-organ transplantation | Post-renal/liver/heart transplant [1] |
3. Relevant Anatomy & Physiology — Iron Metabolism Primer
Understanding ACD demands a solid grasp of normal iron handling. Let's build this from first principles.
| Compartment | Iron Content | Function |
|---|---|---|
| Haemoglobin (circulating RBCs) | ~2,500 mg (65%) | Oxygen transport |
| Storage (ferritin, haemosiderin in liver, spleen, marrow macrophages) | ~1,000 mg (25%) | Reserve pool |
| Myoglobin | ~300 mg | Muscle O₂ storage |
| Enzymes (cytochromes, catalases) | ~200 mg | Metabolic functions |
| Transport (transferrin-bound in plasma) | ~3–4 mg | Delivery to tissues |
-
Ferroportin — the only known cellular iron exporter in mammals. Found on:
- Duodenal enterocytes (dietary iron absorption)
- Reticuloendothelial macrophages (recycled iron from senescent RBCs)
- Hepatocytes
-
Hepcidin — a 25-amino-acid peptide hormone produced predominantly by the liver.
- Acts as the master negative regulator of iron availability.
- Binds to ferroportin → causes its internalisation and degradation → blocks iron export from both duodenal mucosa and macrophages [1][5].
- Think of hepcidin as the "gatekeeper" or "lock" on the door — when hepcidin is high, iron stays trapped inside cells.
-
Transferrin — the plasma iron-transport protein. Each molecule can carry 2 Fe³⁺ ions.
-
Ferritin — the intracellular iron-storage protein. Serum ferritin is a surrogate marker for total body iron stores but is also a positive acute phase reactant.
-
Soluble transferrin receptor (sTfR) — shed from erythroid precursor membranes; reflects erythropoietic demand for iron. Crucially, it is not affected by inflammation.
Daily iron turnover: ~20–25 mg/day is recycled from old RBCs vs. only ~1–2 mg/day absorbed from the gut. This means macrophage iron recycling is quantitatively far more important than dietary absorption — and this is exactly the pathway ACD sabotages.
Anaemia of chronic disease can be seen in: infections, cancer, autoimmune diseases, chronic rejection after solid-organ transplantation, chronic kidney disease and inflammation [1].
4.1 Causes by Category
| Category | Common Aetiologies (HK-Relevant) |
|---|---|
| Chronic Infection | Chronic hepatitis B (very common in HK, ~8% carrier rate), hepatitis C, TB (still prevalent in HK), HIV, osteomyelitis, infective endocarditis, lung abscess |
| Malignancy | Hepatocellular carcinoma (HCC — major in HK due to HBV), colorectal cancer, lung cancer, nasopharyngeal carcinoma (NPC — "Cantonese cancer"), lymphoma, multiple myeloma |
| Autoimmune / Inflammatory | Rheumatoid arthritis, SLE, inflammatory bowel disease (Crohn's, UC), polymyalgia rheumatica, sarcoidosis |
| Chronic Kidney Disease | CKD stages 3–5 — a dual mechanism (↓EPO + inflammation) |
| Post-Transplant | Chronic allograft rejection (renal, liver, cardiac transplant) |
| Others | Heart failure (chronic inflammation), advanced COPD |
Hong Kong Context
In HK, when you see ACD, think of the "big three" underlying causes: chronic HBV/HCV, CKD, and malignancy (especially HCC and NPC). TB remains a significant cause of occult ACD in the elderly.
5. Pathophysiology
This is the most important section for understanding ACD. The anaemia results from the convergence of three interconnected mechanisms, all driven by chronic immune activation and inflammatory cytokines (IL-6, IL-1, TNF-α, IFN-γ).
Patients with ACD in fact have adequate body iron stores which are compartmentalised in the reticuloendothelial system. It is thought that iron is retained within the reticuloendothelial system and not made available for erythropoiesis, hence anaemia ensues. [2][5]
Step-by-step:
- Chronic inflammation → hepatocytes produce IL-6 → stimulates the liver to synthesise hepcidin (via the JAK2-STAT3 pathway).
- Elevated serum hepcidin binds ferroportin on macrophages and duodenal enterocytes → ferroportin is internalised and degraded [1].
- Iron becomes trapped inside macrophages (cannot be exported to plasma transferrin) and dietary iron absorption is simultaneously blocked.
- Plasma iron falls → transferrin saturation falls → bone marrow erythroid precursors are iron-starved despite abundant total body stores.
Hepcidin blocks ferroportin in two locations → duodenal mucosa and the macrophages [5].
- Inflammatory cytokines (especially TNF-α, IL-1) reduce renal EPO production relative to the degree of anaemia.
- EPO levels in ACD are "inappropriately normal" — i.e., not as high as they should be for the given Hb level (contrast with IDA where EPO is appropriately elevated).
- Additionally, erythroid progenitor cells in the marrow show reduced sensitivity to EPO due to cytokine-mediated interference with EPO receptor signalling.
- Activated macrophages in the RES show enhanced erythrophagocytosis — they destroy circulating RBCs slightly earlier than normal (RBC lifespan shortened from ~120 days to ~80–90 days).
- This alone wouldn't cause significant anaemia, but coupled with impaired production, it tips the balance.
- In CKD, there is genuine loss of EPO-producing peritubular interstitial cells in the kidneys due to fibrosis, on top of the inflammatory mechanisms above.
- This creates a "double hit": anaemia of chronic disease overlapping with renal anaemia [3].
Summary of Pathophysiological Mechanisms
| Mechanism | Mediator | Effect |
|---|---|---|
| Iron sequestration | IL-6 → Hepcidin → ↓Ferroportin | Iron trapped in macrophages; ↓iron absorption |
| Blunted EPO response | TNF-α, IL-1 | ↓EPO production + ↓marrow EPO sensitivity |
| ↓RBC survival | Activated macrophages | Enhanced erythrophagocytosis |
| ↓EPO production (CKD) | Renal fibrosis | Direct loss of EPO-producing cells |
Iron sequestration is actually an innate immune defence mechanism. By withholding iron from the plasma, the body starves invading microorganisms of iron (most bacteria and fungi require iron for growth). This is termed "nutritional immunity." The cost of this defence is anaemia — a collateral consequence of the body prioritising infection control over oxygen-carrying capacity.
6. Classification
- Normochromic normocytic in the vast majority of cases [1][5].
- Some rare cases where you see hypochromic [microcytic] forms — this occurs when:
- The disease is very prolonged and severe.
- There is coexistent true iron deficiency (common scenario — "mixed ACD + IDA").
- Hepcidin-mediated iron restriction has been extreme enough to impair haem synthesis [5].
ACD: Normochromic normocytic. Some rare cases where you see hypochromic forms. [5]
See Aetiology section above (infections, cancer, autoimmune, CKD, transplant rejection).
7. Clinical Features
The clinical presentation of ACD is a composite of:
- Symptoms and signs of anaemia itself (typically mild/insidious)
- Symptoms and signs of the underlying disease (often dominant)
The clinical presentation of anaemia depends on the onset and severity of anaemia. [5]
| Symptom | Pathophysiological Basis |
|---|---|
| Fatigue, decreased exercise tolerance | ↓O₂-carrying capacity → tissue hypoxia → muscles fatigue earlier. Because ACD is chronic and gradual, compensatory mechanisms (↑2,3-DPG, ↑cardiac output) have time to develop, so symptoms are often surprisingly mild for the Hb level. [5] |
| Pale-looking | ↓Hb → ↓colour of blood perfusing skin and mucous membranes [5] |
| Mild exertional dyspnoea | Compensatory ↑minute ventilation to maintain O₂ delivery when Hb is low |
| Palpitations | ↑Heart rate as compensatory mechanism (↑cardiac output = ↑HR × ↑stroke volume) |
| Dizziness / light-headedness | Cerebral hypoperfusion when O₂ delivery falls below threshold |
| Symptoms of the underlying disease | e.g., joint pain and morning stiffness (RA), weight loss and night sweats (malignancy/TB), chronic cough (TB), haematuria/oedema (CKD), fever of unknown origin (infective endocarditis) |
Symptoms related to the cause of anaemia should always be sought — remember that anaemia is not a diagnosis, it reflects an underlying pathology. Always look for: menorrhagia, passage of tarry stool, bone pain [5].
Clinical Pearl
A common exam mistake is to attribute all anaemia in a patient with RA or cancer to "anaemia of chronic disease" without checking for coexistent IDA (e.g., from NSAID-induced GI bleeding in RA, or tumour-related blood loss in colon cancer). Always exclude true iron deficiency even when ACD seems obvious.
| Sign | Pathophysiological Basis |
|---|---|
| Conjunctival / mucosal pallor | ↓Hb concentration → paler blood → visible in vascular beds close to surface (palpebral conjunctivae, oral mucosa, palmar creases). Palmar crease pallor suggests Hb < 7 g/dL. |
| Tachycardia (mild, resting) | Compensatory ↑cardiac output to maintain O₂ delivery |
| Systolic flow murmur | ↓Blood viscosity (due to ↓Hb/haematocrit) → turbulent flow across normal valves → innocent ejection systolic murmur, typically loudest at the left sternal edge/pulmonary area |
| Signs of hyperdynamic circulation | Bounding pulse, wide pulse pressure — again compensatory mechanisms |
| Signs of the underlying condition | RA: symmetrical polyarthropathy, rheumatoid nodules, ulnar deviation. SLE: malar rash, oral ulcers. CKD: oedema, excoriation marks, AV fistula. Malignancy: lymphadenopathy, hepatosplenomegaly, cachexia. TB: wasting, cervical lymphadenopathy. IE: Roth spots, Osler's nodes, Janeway lesions, splinter haemorrhages, splenomegaly, changing murmur [4]. |
| No specific signs of iron deficiency | This is a critical negative finding. In ACD you will not see koilonychia (spoon nails), angular stomatitis, glossitis, or Plummer-Vinson syndrome (oesophageal web) — these are features of true IDA. Their presence should make you think of coexistent IDA. |
Clinical pictures suggesting chronic disease but not iron deficiency → this is the hallmark presentation of ACD [1].
This comparison is extremely high yield for exams:
Iron deficient anaemia vs anaemia of chronic disease [1][5]:
| Feature | Iron Deficiency Anaemia | Anaemia of Chronic Disease |
|---|---|---|
| Clinical picture | Suggesting iron deficiency (tarry stool, menorrhagia, haemorrhoids) | Suggesting chronic disease but not iron deficiency |
| Severity | Could be severe | Generally modest anaemia → most of the times never require transfusion |
| Morphology | Hypochromic microcytic | Normochromic normocytic (rare hypochromic forms) |
| Serum iron | Reduced | Reduced |
| Transferrin / TIBC | Increased | Decreased or no change |
| Transferrin saturation | Reduced | Reduced |
| Ferritin | Reduced | Normal or increased |
| Soluble transferrin receptor (sTfR) | Elevated | Normal |
| Serum hepcidin | Normal | Elevated |
High Yield Exam Point – Best Distinguishing Test
Which of the following is most useful in distinguishing iron deficiency anaemia from anaemia of chronic illness? → TIBC [5]
Serum iron is low in both. Serum ferritin can be confounded by concomitant infection (ferritin is a positive acute phase reactant). TIBC/transferrin goes in opposite directions: ↑ in IDA (body is "hungry" for iron, makes more transferrin) vs ↓ or unchanged in ACD (transferrin is a negative acute phase reactant, suppressed by inflammation) [1][2][5].
Negative acute phase reactants include albumin, prealbumin, transferrin [5].
Positive acute phase reactants include ferritin, ESR, CRP [2].
- Serum ferritin is a positive acute phase reactant [2][5].
- In inflammation, ferritin rises independent of iron stores — driven by cytokines (IL-1, IL-6, TNF-α).
- A "normal" ferritin in a patient with active inflammation may actually be masking true iron deficiency.
- Rule of thumb: if ferritin is normal-low ( < 225 ng/mL), there may be concomitant iron deficiency anaemia [6].
- sTfR is elevated in true iron deficiency (because iron-starved erythroid precursors upregulate transferrin receptors on their surface) but normal in pure ACD.
- The sTfR/log ferritin ratio helps discriminate:
- > 2: suggests true iron deficiency (with or without ACD)
- < 1: suggests pure ACD
- This is particularly useful in the "grey zone" where both ACD and IDA coexist.
- Prussian blue staining of a marrow aspirate for iron stores remains the gold standard for distinguishing IDA from ACD:
- IDA: absent marrow iron stores
- ACD: normal or increased marrow iron stores (iron trapped in macrophages, seen as siderotic granules in macrophages but reduced/absent sideroblasts in erythroid precursors)
- However, this is invasive and rarely done solely for this purpose in clinical practice.
(Full diagnostic algorithm will follow in the next section as requested, but a brief overview of the investigation profile is included here to complete the clinical picture.)
| Investigation | Expected in ACD | Rationale |
|---|---|---|
| Hb | ↓ (typically 8–10 g/dL) | Anaemia |
| MCV | Normal (80–100 fL) | Normocytic |
| MCH/MCHC | Normal | Normochromic |
| Reticulocyte count | Low / inappropriately normal | Hypoproliferative — marrow cannot respond due to iron restriction + blunted EPO |
| Serum iron | ↓ | Iron trapped in RES |
| TIBC / Transferrin | ↓ or normal | Negative acute phase reactant [1][2] |
| Transferrin saturation | ↓ | Low serum iron ÷ low-normal TIBC |
| Ferritin | Normal or ↑ | Positive acute phase reactant + adequate stores [1][2] |
| ESR / CRP | ↑ | Markers of underlying inflammation [2] |
| sTfR | Normal | Not elevated because stores are adequate |
| Hepcidin | ↑ (not routinely available) | Central mediator of iron sequestration [1] |
| Blood film | Normochromic normocytic; no specific features | May see rouleaux (↑ESR) in myeloma/chronic infection |
ACD is associated with reduced concentrations of serum iron, transferrin, TIBC, raised ferritin and erythrocyte sedimentation rate or C-reactive protein. [2]
Serum iron and transferrin → negative acute phase reactants. Ferritin → positive acute phase reactant. [2][6]
When you encounter a normochromic normocytic anaemia (which ACD usually is):
- Confirm it is truly normocytic: check MCV, MCH, MCHC, and blood film.
- Check reticulocyte count: low → hypoproliferative (ACD, renal anaemia, marrow disease). High → haemolysis or blood loss.
- Iron studies: the pattern of ↓Fe, ↓/normal TIBC, normal/↑ferritin, ↑CRP/ESR clinches ACD.
- Always look for the underlying cause: the anaemia is secondary. Investigate based on clinical suspicion (e.g., autoimmune serology, infection workup, malignancy screening, renal function).
- Exclude coexistent IDA: especially in patients on NSAIDs (RA) or with GI malignancy. Check sTfR or sTfR/log ferritin ratio if the picture is mixed.
In CKD, the anaemia has a dual pathogenesis [3]:
- ↓EPO production due to destruction of renal interstitial cells (fibrosis)
- ACD component due to chronic systemic inflammation and uraemia-related immune activation
This produces a normochromic normocytic anaemia [3]. Treatment involves:
- Erythropoiesis-stimulating agents (ESAs) — when Hb < 10 g/dL
- IV iron — to overcome functional iron deficiency (many CKD patients have anaemia of chronic disease due to systemic inflammation → ↓release of iron stores [3])
- Target: Hb 10–11.5 g/dL, transferrin saturation > 30%, ferritin > 500 ng/mL [3]
Functional iron deficiency: adequate iron stores but insufficient iron availability for erythropoiesis. This is essentially ACD superimposed on CKD. Relative iron deficiency may occur with ESA administration when iron release from stores is not rapid enough to support ↑erythropoietic rate driven by ESA → anaemia refractory to ESA with ↓MCV [3].
High Yield Summary
Definition: Anaemia arising in the context of chronic infection, inflammation, malignancy, or CKD. Adequate iron stores but iron compartmentalised in the RES.
Pathophysiology (3+1 mechanisms):
- ↑Hepcidin (IL-6-driven) → degrades ferroportin → iron trapped in macrophages + ↓dietary absorption
- Blunted EPO response (↓production + ↓marrow sensitivity)
- ↓RBC lifespan (enhanced erythrophagocytosis)
- In CKD: direct ↓EPO from renal fibrosis
Morphology: Normochromic normocytic (rarely hypochromic microcytic if severe/prolonged)
Severity: Generally modest (Hb 8–10), rarely requires transfusion
Iron Studies Pattern: ↓Serum iron, ↓/N TIBC, ↓Transferrin saturation, N/↑Ferritin, ↑Hepcidin
Key Distinguishing Test from IDA: TIBC (↑ in IDA, ↓ in ACD)
Acute Phase Reactants:
- Positive: Ferritin, CRP, ESR
- Negative: Serum iron, transferrin, albumin, prealbumin
Always: Identify and treat the underlying cause. Anaemia is not the diagnosis — it is the consequence.
Active Recall - Anaemia of Chronic Disease
[1] Lecture slides: GC 076. Pallor_diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (slides 18, 21) [2] Lecture slides: Chemical Pathology Seminar 7_Iron metabolism.pdf (slide 31) [3] Senior notes: Ryan Ho Urogenital.pdf (p106 — Anaemia in CKD) [4] Senior notes: Block A - Cardiology Interactive Tutorial.pdf (p4 — Infective endocarditis and anaemia of chronic illness) [5] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (pp3, 5, 14) [6] Senior notes: Ryan Ho Chemical Path.pdf (p54 — ACD section)
Differential Diagnosis of Anaemia of Chronic Disease
ACD is never the final diagnosis — it sits on top of an underlying condition. But before you can label something "ACD," you must exclude other causes of anaemia that can look similar or coexist. The key clinical scenario is: a patient with a known chronic illness presents with anaemia. Is this purely ACD, or is something else going on? The differential depends heavily on the MCV and the clinical context.
Since ACD is typically normochromic normocytic [1][5], the primary differential is against other causes of normocytic anaemia. However, because ACD can occasionally be hypochromic microcytic (when severe or prolonged) [1], you also need to consider the microcytic differential. Let's work through both systematically.
3. Differential Diagnosis of Normocytic Anaemia
Normocytic anaemia differential diagnosis: anaemia of chronic disease, anaemia of renal disease, acute blood loss, dimorphic anaemia [5]
These are the "big four" from the GC lecture framework. Let's expand and explain each:
- Normochromic normocytic anaemia occurring in CKD due to lack of erythropoietin from damaged peritubular interstitial cells [3].
- Why it overlaps with ACD: CKD patients frequently have both — genuine EPO deficiency plus an ACD component from chronic inflammation and uraemia [3].
- How to distinguish: check eGFR. If eGFR is low, EPO deficiency is contributing. Note that many CKD patients have anaemia of chronic disease due to systemic inflammation → ↓release of iron stores [3]. So the two are not mutually exclusive — they commonly coexist.
- Prevalence: 1% at eGFR 60, 9% at 30, 33–67% at 15 [3].
- Normocytic initially because you lose whole blood (both plasma and RBCs in proportion) — MCV is usually normal in acute bleeding [7].
- Hb can be normal and unchanged upon initial presentation → since patient is losing BOTH plasma and RBC. May take a few more hours for the Hb to drop → as the fluid moves from the interstitium into the intravascular [space] [7].
- How to distinguish from ACD: history of acute haemorrhage (trauma, GI bleed, post-operative), haemodynamic instability (tachycardia, hypotension), reticulocyte count rises within 3–5 days. In ACD, onset is insidious and reticulocyte count stays low.
- A mixed picture where two populations of RBCs coexist — e.g., microcytic (iron-deficient) + macrocytic (B12/folate-deficient or post-transfusion).
- Distinct population of both large and small red cells, MCV averages out [to normal] [5].
- How to distinguish: look at the RDW (red cell distribution width) — markedly elevated in dimorphic anaemia. Blood film shows anisopoikilocytosis with a bimodal population. This is commonly seen when ACD + IDA coexist, or in patients with combined nutritional deficiencies.
- Not in the GC "normocytic" list above, but must always be considered because haemolytic anaemia can present as normocytic or even slightly macrocytic (due to reticulocytosis — reticulocytes are larger than mature RBCs).
- Laboratory features: anaemia (mildly macrocytic usually) with reticulocytosis, increase in unconjugated bilirubin, LDH, reduced serum haptoglobin, increased methaemalbumin [8].
- How to distinguish from ACD: in haemolysis, the reticulocyte count is high (compensatory erythroid hyperplasia). In ACD, reticulocyte count is low. Additionally, haemolysis markers (↑LDH, ↑unconjugated bilirubin, ↓haptoglobin) are positive in haemolysis but normal in ACD.
- Direct antiglobulin test (Coombs' test) — positive in immune haemolytic anaemia [8].
- Particularly relevant because autoimmune haemolytic anaemia (AIHA) can occur in the same diseases that cause ACD (e.g., SLE, lymphoproliferative neoplasms) — you need to distinguish the two mechanisms [9].
Clinical Pearl – Haemolysis vs ACD
A patient with SLE can have both ACD (from chronic inflammation) and warm AIHA (autoimmune destruction of RBCs). If the reticulocyte count is high and LDH/bilirubin are elevated, think haemolysis — don't just default to "ACD."
- Aplastic anaemia: pancytopenia resulting from bone marrow hypoplasia or aplasia [9]. Normocytic or macrocytic. Distinguished by pancytopenia (not just anaemia) and hypocellular marrow on biopsy.
- Pure red cell aplasia (PRA): only involves the erythroid series [9]. Causes include thymoma, parvovirus B19, lymphoproliferative diseases. Reticulocyte count is very low/absent.
- Marrow infiltration (myelophthisis): cancer metastases, myelofibrosis, granulomatous disease replacing normal marrow. Blood film shows a leucoerythroblastic picture (nucleated RBCs + immature white cells = "teardrops + blasts").
- Myelodysplastic syndrome (MDS): usually macrocytic, but can be normocytic. Dysplastic features on film, variable cytopenias.
- Hypothyroidism: ↓metabolic rate → ↓EPO stimulus → normocytic (or mildly macrocytic) anaemia.
- Hypopituitarism / adrenal insufficiency: ↓trophic hormones → ↓erythropoiesis.
- Distinguished by clinical features (e.g., fatigue, weight gain, cold intolerance) and endocrine investigations (TSH, cortisol).
When ACD presents as hypochromic microcytic (rare but does happen in prolonged/severe disease) [1], the differential shifts to the classic microcytic anaemia causes:
Microcytic anaemia differential diagnosis: thalassaemia, iron deficiency, sideroblastic anaemia [5]
| Condition | Key Distinguishing Features |
|---|---|
| Iron deficiency anaemia (IDA) | Clinical pictures suggesting iron deficiency (tarry stool, menorrhagia). ↓Ferritin, ↑TIBC — opposite direction to ACD [1]. Koilonychia, glossitis, angular stomatitis present. |
| Thalassaemia trait | Family history, ethnicity (common in HK/Southern Chinese). Disproportionately low MCV for degree of anaemia ("MCV too low for Hb"). Target cells on film. Normal/↑iron stores. Hb electrophoresis diagnostic (↑HbA₂ in β-thal trait, ↑HbH inclusions in α-thal). |
| Sideroblastic anaemia | Ring sideroblasts on Prussian blue stain of marrow aspirate. Can be congenital or acquired (MDS). Think of MDS, but very rare [5]. Dimorphic blood film. |
| ACD (microcytic variant) | Chronic disease present. ↓Fe, ↓/N TIBC, N/↑Ferritin, ↑CRP/ESR [2]. No features of IDA on history/examination. |
| Mixed ACD + IDA | Very common in practice (e.g., RA patient on NSAIDs with GI bleeding). Iron studies may be confusing — ferritin is normal-low ( < 225) suggesting concomitant iron deficiency [6]. sTfR elevated. sTfR/log ferritin ratio > 2. |
High Yield – IDA vs ACD vs Thalassaemia
This is the classic exam triad for microcytic anaemia. The single best test to distinguish IDA from ACD is TIBC (goes up in IDA because the body is "hungry" for iron; goes down in ACD because transferrin is a negative acute phase reactant) [5]. Thalassaemia is distinguished by Hb electrophoresis and family history/ethnicity.
This is extremely common in clinical practice and a favourite exam scenario. The classic examples:
- Rheumatoid arthritis patient on NSAIDs → ACD from chronic inflammation + IDA from NSAID-induced GI bleeding.
- The GC interactive tutorial case: A 58-year-old woman with rheumatoid arthritis, Hb 7.5 g/dL, MCV 70 fL, serum iron 3, TIBC 75, transferrin saturation 4%, CRP 8, ESR 70 [10]. This is a mixed picture — the very low MCV (70) and very high TIBC (75) suggest true iron deficiency superimposed on chronic disease.
- Colorectal cancer → ACD from malignancy + IDA from chronic tumour-related blood loss.
- IBD → ACD from inflammation + IDA from mucosal blood loss + possibly B12/folate malabsorption.
Drug history: non-steroidal anti-inflammatory drugs → if non-selective, can result in GI bleeding [10]
How to identify the mixed picture:
| Parameter | Pure ACD | Pure IDA | Mixed ACD + IDA |
|---|---|---|---|
| Ferritin | ↑ / N | ↓↓ | Low-normal (30–225) — misleadingly "normal" |
| TIBC | ↓ / N | ↑↑ | Variable (may be normal) |
| sTfR | Normal | ↑↑ | ↑ |
| sTfR/log ferritin | < 1 | > 2 | > 2 (helps identify coexistent IDA) |
| Marrow iron | Present (in macrophages) | Absent | Present in macrophages but absent sideroblasts |
Another powerful way to approach the differential is by checking the reticulocyte count — this tells you whether the marrow is trying to compensate:
| Reticulocyte Count | Interpretation | Differential |
|---|---|---|
| Low (hypoproliferative) | Marrow cannot respond | ACD, renal anaemia, nutritional deficiency (IDA, B12, folate), marrow failure (aplastic anaemia, MDS), marrow infiltration, endocrine causes |
| High (hyperproliferative) | Marrow is compensating | Haemolytic anaemia (AIHA, G6PD, hereditary spherocytosis), acute blood loss (after 3–5 days), recovery from marrow suppression |
| Condition | MCV | Retics | Serum Fe | TIBC | Ferritin | Key Distinguisher |
|---|---|---|---|---|---|---|
| ACD | N (rarely ↓) | Low | ↓ | ↓/N | N/↑ | Underlying chronic disease, ↑CRP/ESR, ↑hepcidin |
| IDA | ↓ | Low | ↓ | ↑ | ↓ | Source of blood loss or dietary deficiency, koilonychia |
| Thalassaemia trait | ↓↓ | N/↑ | N/↑ | N | N/↑ | Ethnicity, Hb electrophoresis, target cells |
| Renal anaemia | N | Low | Variable | Variable | Variable | ↓eGFR, ↓EPO level |
| AIHA | N/↑ | ↑↑ | N/↑ | N | N/↑ | +ve DAT, ↑LDH, ↓haptoglobin, spherocytes |
| Aplastic anaemia | N/↑ | Very low | N/↑ | N | N/↑ | Pancytopenia, hypocellular marrow |
| Sideroblastic | ↓ | Low | ↑ | N | ↑ | Ring sideroblasts, dimorphic film |
| Acute blood loss | N (initially) | ↑ (after 3–5d) | N→↓ | N→↑ | N→↓ | History of haemorrhage, haemodynamic instability |
- Confirm anaemia: CBC — check Hb, MCV, MCH, MCHC.
- Check reticulocyte count: low → hypoproliferative → supports ACD (or other marrow problems).
- Iron studies: ↓serum iron, ↓/N TIBC, N/↑ferritin pattern = ACD [1][2].
- Inflammatory markers: ↑ESR, ↑CRP — confirms active inflammation [2].
- Exclude coexistent IDA: check sTfR if ferritin is in the "grey zone" (30–225 ng/mL). sTfR/log ferritin > 2 suggests concomitant IDA. If ferritin is normal-low ( < 225), there may be concomitant Fe deficiency anaemia [6].
- Exclude haemolysis: LDH, haptoglobin, unconjugated bilirubin, DAT.
- Exclude renal anaemia: check eGFR.
- Exclude marrow pathology: if pancytopenia or suspicious film → consider bone marrow aspirate/biopsy.
- Identify the underlying cause: this is the most important step — ACD is a signpost, not a destination.
Remember: anaemia is not a diagnosis, it reflects an underlying pathology [5].
| Clinical Scenario | Most Likely Cause of Anaemia | Key Investigation to Distinguish |
|---|---|---|
| RA patient on methotrexate + NSAIDs, Hb 7.5, MCV 70 | Mixed ACD + IDA (NSAID-induced GI bleed) [10] | TIBC (↑ favours IDA component), sTfR, stool occult blood |
| CKD stage 4, Hb 9, MCV 88 | Renal anaemia + ACD | eGFR, EPO level, iron studies, reticulocyte count |
| SLE patient, Hb 8, MCV 95, retics high | Warm AIHA (not ACD!) | DAT, LDH, haptoglobin, unconjugated bilirubin |
| Elderly patient, Hb 10, MCV 85, weight loss, night sweats | ACD (? underlying malignancy or TB) | CT scan, infection workup, marrow biopsy if needed |
| IE patient, Hb 11, MCV 84 | ACD — transient suppression of bone marrow [4] | Blood cultures, echocardiogram, ESR/CRP |
| IBD patient, Hb 9, MCV 75 | Mixed ACD + IDA | Ferritin, TIBC, sTfR, faecal calprotectin [11] |
High Yield Summary – Differential Diagnosis of ACD
-
ACD is a diagnosis of exclusion within the context of a known chronic disease. Always exclude coexistent IDA, haemolysis, renal anaemia, and marrow pathology.
-
MCV framework: ACD is typically normocytic. If microcytic → consider IDA, thalassaemia, sideroblastic anaemia, or mixed ACD+IDA.
-
Reticulocyte count separates hypoproliferative causes (ACD, renal, marrow failure) from hyperproliferative ones (haemolysis, blood loss).
-
Best test to distinguish ACD from IDA: TIBC [5] — ↑ in IDA (hungry for iron), ↓ in ACD (negative acute phase reactant).
-
If ferritin < 225 in the setting of inflammation, suspect coexistent IDA [6].
-
sTfR and sTfR/log ferritin ratio are the best tools for identifying IDA hiding behind ACD (sTfR is NOT affected by inflammation).
-
Always look for the underlying cause — ACD is a red flag for occult infection, malignancy, autoimmune disease, or CKD.
Active Recall - Differential Diagnosis of ACD
References
[1] Lecture slides: GC 076. Pallor_diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (slides 18, 21) [2] Lecture slides: Chemical Pathology Seminar 7_Iron metabolism.pdf (slide 31) [3] Senior notes: Ryan Ho Urogenital.pdf (p106 — Anaemia in CKD) [4] Senior notes: Block A - Cardiology Interactive Tutorial.pdf (p4 — Anaemia of chronic illness in IE) [5] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (pp3, 5, 6) [6] Senior notes: Ryan Ho Chemical Path.pdf (p54 — ACD section) [7] Senior notes: Block A - Coffee ground vomitus tarry stool upper GI bleeding.pdf (p9 — CBC in UGIB) [8] Lecture slides: Haematology Introduction to Haematological investigations (CBP, Clotting).pdf (p32 — Haemolytic anaemia lab features) [9] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (pp3, 6, 7) [10] Senior notes: Block A - Hematology Interactive Tutorial.pdf (p2 — RA case with anaemia) [11] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p654 — IBD diagnosis)
Diagnostic Criteria, Algorithm & Investigations for Anaemia of Chronic Disease
Here's the honest truth: there are no universally accepted formal diagnostic criteria for ACD comparable to, say, the Duke criteria for infective endocarditis or the ACR criteria for SLE. ACD is fundamentally a diagnosis of pattern recognition + exclusion: you recognise the characteristic iron study pattern in the context of a known chronic disease, after excluding other causes of anaemia (particularly IDA, haemolysis, marrow failure, and renal anaemia).
That said, we can construct a practical diagnostic framework based on the GC lecture material and what the examiners expect you to know.
A diagnosis of ACD requires all three of the following:
| Criterion | Explanation |
|---|---|
| 1. Presence of a chronic underlying disease | Infections, cancer, autoimmune diseases, chronic rejection after solid-organ transplantation, chronic kidney disease and inflammation [1] |
| 2. Characteristic laboratory pattern | ↓serum iron, ↓TIBC/transferrin, ↓transferrin saturation, normal or ↑ferritin, ↑ESR/CRP [2] |
| 3. Exclusion of other causes of anaemia | Particularly IDA, thalassaemia, haemolytic anaemia, marrow failure, B12/folate deficiency, renal anaemia (as a sole cause) |
ACD is associated with reduced concentrations of serum iron, transferrin, TIBC, raised ferritin and erythrocyte sedimentation rate or C-reactive protein. [2]
Why No Formal Criteria?
ACD is a pathophysiological diagnosis, not a disease entity with its own code and checklist. It always coexists with something else. The "diagnosis" is really confirming (a) the anaemia pattern is consistent with hepcidin-mediated iron sequestration and (b) there is no additional treatable cause you are missing. This is why the investigation strategy focuses as much on ruling out mimics as on confirming ACD itself.
3. Investigation Modalities — Systematic Approach
Let's walk through every investigation you would order, what you expect to find, and why you order it. I'll organise this into tiers: baseline, iron-specific, advanced iron tests, haemolysis screen, and cause-directed investigations.
| Parameter | Expected in ACD | Interpretation / Why |
|---|---|---|
| Haemoglobin | Decreased — typically 8–10 g/dL | Confirms anaemia. Generally modest anaemia [1] — rarely severe enough to require transfusion. |
| MCV | Normal / decreased — usually 80–100 fL | ACD is typically normochromic normocytic [1]. Can be microcytic in rare/prolonged cases [1]. |
| RDW | Normal / increased | Unlike IDA where RDW is markedly ↑ (because iron depletion is gradual → variable-sized cells). In ACD, cell production is more uniformly suppressed → RDW tends to be normal. May be slightly ↑ if mixed picture. |
| RBC count | Decreased | Reduced erythropoiesis. Compare: in thalassaemia, RBC count is increased / normal despite low Hb — because thalassaemic cells are small but numerous [12][13]. |
| Reticulocyte count | Decreased | This is critical. Low reticulocyte count = hypoproliferative anaemia = the marrow isn't compensating. Why? Because iron restriction + blunted EPO response suppress erythropoiesis. Contrast with haemolysis where reticulocytes are high. |
| WBC | Variable | Depends on underlying disease (may be high in infection/inflammation, low in marrow disease). |
| Platelets | Variable, often mildly ↑ | Reactive thrombocytosis can occur with chronic inflammation (IL-6 stimulates thrombopoiesis). In the GC interactive tutorial RA case: platelet count 410 × 10⁹/L [10]. |
| CRP | Increased | Confirms active inflammation. CRP is a positive acute phase reactant [2]. |
| ESR | Increased | Also confirms inflammation. ESR determined by the three main proteins in the blood — albumin, immunoglobulin, fibrinogen [10]. In the GC RA case: ESR 70 mm/hr [10]. |
Blood Film (Peripheral Blood Smear):
- PBS: normal in pure ACD [14] — no specific morphological abnormality.
- No pencil cells (IDA), no target cells (thalassaemia), no spherocytes (AIHA), no fragments (MAHA).
- May see rouleaux formation if ESR is very high (stacking of RBCs like coins — due to ↑fibrinogen/immunoglobulin).
- The absence of abnormal morphology is itself a useful finding — it narrows the differential.
High Yield – CBC Pattern Comparison Table
This table is reproduced from multiple sources [12][13] and is extremely high yield:
| IDA | Thalassaemia | ACD | |
|---|---|---|---|
| HGB | Decreased | Decreased | Decreased |
| MCV | Decreased | Decreased | Normal / decreased |
| RDW | Increased | Increased / normal | Normal / increased |
| RBC | Decreased | Increased / normal | Decreased |
| Serum Fe | Decreased | Normal / increased | Decreased |
| TIBC, Tf | Increased | Normal | Decreased |
| % Tf saturation | Decreased | Normal | Decreased |
| Serum ferritin | Decreased | Normal / increased | Increased (↑storage) |
| Reticulocyte | Decreased | Increased / normal | Decreased |
| CRP | Normal | Normal | Increased |
The Mentzer index (MCV ÷ RBC count) can help distinguish thalassaemia from IDA: < 13 suggests thalassaemia, > 13 suggests iron deficiency anaemia [10]. This is less useful for ACD since ACD is typically normocytic, but relevant when ACD presents as microcytic.
This is the core diagnostic panel for ACD.
| Test | Expected in ACD | Mechanism / Why |
|---|---|---|
| Serum iron | ↓ | Iron is trapped in macrophages (hepcidin blocks ferroportin). Less iron reaches the plasma. Serum iron and transferrin are negative acute phase reactants [2]. However, serum iron CANNOT be used alone [6] — it fluctuates with diurnal variation, recent meals, and acute illness. |
| TIBC (Total Iron Binding Capacity) | ↓ or normal | TIBC measures the capacity of transferrin to bind iron (= indirect measure of transferrin level). In ACD, transferrin is a negative acute phase reactant → production is suppressed by inflammation → TIBC falls. This is the opposite direction to IDA where TIBC is ↑ (body makes more transferrin to scavenge scarce iron). TIBC is the most useful test to distinguish IDA from ACD [5]. |
| Transferrin saturation (TSAT) | ↓ ( < 20%) | TSAT = serum iron ÷ TIBC × 100. Both numerator (serum iron) and denominator (TIBC) are low, but serum iron falls proportionally more → TSAT is reduced. Transferrin saturation CANNOT be used alone [6]. |
| Serum ferritin | Normal or ↑ | Ferritin reflects iron stores but is also a positive acute phase reactant [2]. In ACD, two forces push ferritin up: (1) adequate/increased iron stores in macrophages, and (2) cytokine-driven synthesis independent of iron. Note that if ferritin is normal-low ( < 225), there may be concomitant Fe deficiency anaemia [6]. |
ACD is associated with reduced concentrations of serum iron, transferrin, TIBC, raised ferritin and erythrocyte sedimentation rate or C-reactive protein [2].
The TIBC Question – Favourite Exam Item
Q: Which of the following is most useful in distinguishing iron deficiency anaemia from anaemia of chronic illness? → TIBC [5]
Why? Because:
- Serum iron is ↓ in both IDA and ACD → not helpful
- Ferritin is confounded by inflammation (positive acute phase reactant) → can be misleading
- TIBC goes in opposite directions: ↑ in IDA (body is "hungry"), ↓ in ACD (transferrin is suppressed)
- Hepcidin could theoretically help but is not routinely available [5]
Clinical Decision Cutoffs for Ferritin [6]:
- Adults: < 34 pmol/L (15 μg/L) → diagnostic of iron deficiency
- Hospitalised elderly: < 100 pmol/L (45 μg/L) → use higher cutoff because inflammation raises ferritin
- Ferritin is the most sensitive and specific marker for iron deficiency in isolation [6], but its reliability drops significantly in the presence of inflammation
These tests are used when you suspect mixed ACD + IDA — the most common diagnostic dilemma in clinical practice.
| Test | Expected in Pure ACD | Expected in ACD + IDA | Why It Helps |
|---|---|---|---|
| Soluble transferrin receptor (sTfR) | Normal | ↑ | sTfR is shed from the surface of erythroid precursors. When precursors are truly iron-starved (IDA), they upregulate transferrin receptors → more sTfR in plasma. In pure ACD, iron stores are adequate so sTfR stays normal. Crucially, sTfR is NOT an acute phase reactant — it is unaffected by inflammation. |
| sTfR / log ferritin ratio | < 1 | > 2 | Combines the two: a high ratio picks up true iron deficiency even when ferritin is falsely elevated by inflammation. This is the best single test for detecting coexistent IDA in ACD. |
| Serum hepcidin | ↑ (elevated) | ↑ or variable | Hepcidin is the central mediator of iron sequestration in ACD. Elevated hepcidin confirms inflammation-driven iron restriction. However, hepcidin is in the "not routinely available" section [5] — important for understanding pathophysiology but not yet a standard clinical test. |
If there is any clinical suspicion of haemolysis (e.g., jaundice, splenomegaly, dark urine, underlying SLE or lymphoproliferative disease), order:
| Test | Expected in ACD | Expected in Haemolysis |
|---|---|---|
| LDH | Normal or mildly ↑ (from underlying disease) | ↑↑ (released from lysed RBCs) |
| Unconjugated bilirubin | Normal | ↑ |
| Haptoglobin | Normal | ↓↓ (consumed binding free Hb) |
| Direct antiglobulin test (DAT / Coombs) | Negative | Positive in immune haemolytic anaemia [8] |
| Reticulocyte count | Low | High (compensatory) |
After confirming a patient has haemolysis, order a DAT to determine whether the patient is undergoing a form of autoimmune mediated destruction [9]. But ensure pre-test probability is reasonable — some healthy individuals have a positive DAT without haemolysis [9].
| Test | Purpose | Expected Finding if Relevant |
|---|---|---|
| Serum B12 and folate | Exclude megaloblastic anaemia (can coexist) | Low if deficient. Should always order to exclude non-renal cause of anaemia [3]. |
| Renal function (eGFR, creatinine) | Assess for renal anaemia component | If eGFR < 30, EPO deficiency is likely contributing [3]. |
| Thyroid function (TSH) | Exclude hypothyroidism as cause of anaemia | ↑TSH in hypothyroidism |
| Hb electrophoresis / HPLC | Exclude thalassaemia trait (if microcytic) | ↑HbA₂ in β-thal trait; HbH inclusions in α-thal |
| Bone marrow aspirate/biopsy | Rarely needed in suspected ACD alone. Reserved for: unexplained pancytopenia, suspected MDS, aplastic anaemia, myelofibrosis, or when marrow infiltration suspected | In ACD: marrow iron staining shows iron present in macrophages but absent/reduced sideroblasts (iron isn't reaching the erythroid precursors). Gold standard for distinguishing ACD from IDA. |
Remember: anaemia is not a diagnosis, it reflects an underlying pathology [5]. Once ACD is confirmed, investigate the underlying disease if not already known:
| Suspected Cause | Directed Investigations |
|---|---|
| Infection (TB, HBV, HCV, HIV) | Chest X-ray, sputum AFB, HBsAg, anti-HCV, HIV serology, blood cultures |
| Malignancy | CT thorax/abdomen/pelvis, tumour markers (AFP for HCC, CEA for colorectal), PET-CT, tissue biopsy |
| Autoimmune / Inflammatory | ANA, anti-dsDNA, RF, anti-CCP, complement levels. IBD: faecal calprotectin, colonoscopy |
| CKD | eGFR, urine ACR, renal ultrasound |
| Post-transplant rejection | Transplant function tests, DSA levels, protocol biopsy |
This is where clinical practice gets tricky and examiners love to test:
- A ferritin of 15 μg/L → clearly IDA
- A ferritin of 500 μg/L with ↑CRP → clearly ACD
- A ferritin of 80 μg/L with ↑CRP → could be pure ACD with modest stores, OR could be ACD + IDA where inflammation has masked the depletion
Note that if ferritin is normal-low ( < 225), there may be concomitant Fe deficiency anaemia [6]
Resolution strategies:
- sTfR / log ferritin ratio > 2 → IDA is present
- Therapeutic trial of IV iron — if Hb rises appropriately, IDA was contributing
- Bone marrow iron staining — gold standard but invasive; shows absent stainable iron in erythroblasts if IDA component present
Understanding the stages of iron deficiency [6] helps you see why ACD and IDA can overlap:
| Stage | Plasma Fe | TIBC | TSAT | Ferritin | Other | Hb |
|---|---|---|---|---|---|---|
| Depletion of iron stores | N | N | N | LOW | N | N |
| Functional iron deficiency | ↓ | ↑ | ↓ ( < 16%) | ↓ | BM ↓staining | N |
| Iron deficiency anaemia | ↓ | ↑ | ↓ ( < 16%) | ↓ | Hb < 12, MCV < 80 | ↓ |
In ACD, the patient is essentially stuck in a state resembling "functional iron deficiency" — iron is unavailable for erythropoiesis — but for a different reason (hepcidin-mediated sequestration rather than true depletion). This is why serum iron and TSAT are low in both conditions, but ferritin and TIBC diverge.
For CKD patients, the diagnostic approach has specific nuances [3]:
- Screening by CBC when clinically indicated or at least:
- Annually for CKD stage 3 (eGFR 30–60)
- Q6mo for CKD stage 4–5 (eGFR < 30)
- ≥3mo for CKD stage 5 on dialysis or stage 3+ with pre-existing anaemia not on ESA
- ≥1mo for CKD stage 5 on HD with pre-existing anaemia not on ESA [3]
- Diagnosis cutoff: < 13 g/dL for males, < 12 g/dL for females [3]
- Ix: should order reticulocyte count, ferritin/Tf saturation and serum B12/folate to exclude non-renal cause of anaemia [3]
Functional iron deficiency in CKD: adequate iron stores but insufficient iron availability for erythropoiesis. Result: anaemia refractory to ESA with ↓MCV [3].
ACD doesn't just affect the CBC and iron studies — it can confound other investigations:
| Test | Effect of ACD / Chronic Inflammation | Clinical Implication |
|---|---|---|
| HbA1c | Can be falsely high in ACD because ↓erythropoiesis → lower RBC turnover → RBCs circulate longer → more time for glycosylation [15] | A diabetic patient with coexistent ACD/IDA may appear to have worse glucose control than reality. ↓erythropoiesis, lower RBC turnover (e.g. iron deficiency) → falsely high HbA1c [15]. |
| Albumin | ↓ — negative acute phase reactant | Low albumin may reflect inflammation rather than liver dysfunction or malnutrition |
| Total protein / Globulin | Globulin may ↑ (immunoglobulins, acute phase proteins) | ESR determined by three main proteins: albumin, immunoglobulin, fibrinogen [10] |
| Step | Action | Key Finding | Next Step |
|---|---|---|---|
| 1 | CBC + reticulocyte count | Normocytic anaemia, low retics | → Iron studies |
| 2 | Iron studies (Fe, TIBC, ferritin) | ↓Fe, ↓TIBC, N/↑ferritin | → Inflammatory markers |
| 3 | CRP / ESR | ↑ (confirms inflammation) | → Exclude other causes |
| 4 | Haemolysis screen (LDH, haptoglobin, bilirubin, DAT) | All normal | → Check renal function |
| 5 | eGFR, B12, folate, TSH | Normal (or eGFR low = renal component) | → Identify underlying cause |
| 6 | If ferritin 30–225 | Grey zone — possible coexistent IDA | → sTfR or therapeutic iron trial |
| 7 | Cause-directed workup | As clinically indicated | → Treat underlying disease |
High Yield Summary – Diagnosis of ACD
No formal diagnostic criteria exist — ACD is diagnosed by pattern recognition + exclusion.
Three pillars of diagnosis:
- Known underlying chronic disease (infection, cancer, autoimmune, CKD, transplant rejection)
- Characteristic iron pattern: ↓serum iron, ↓TIBC, ↓TSAT, N/↑ferritin, ↑CRP/ESR [2]
- Exclusion of IDA, thalassaemia, haemolysis, marrow failure, B12/folate deficiency
Key distinguishing test: TIBC — ↑ in IDA, ↓ in ACD [5]
Grey zone ferritin (30–225): suspect coexistent IDA → use sTfR/log ferritin ratio ( > 2 = IDA present)
Gold standard for iron stores: bone marrow Prussian blue staining (iron in macrophages but absent sideroblasts in ACD; absent stores in IDA)
CKD-specific: screen annually from stage 3; always check reticulocyte count, ferritin/TSAT, and B12/folate before attributing anaemia to CKD alone [3]
ACD is a hypoproliferative anaemia with low reticulocyte count — if reticulocytes are high, reconsider the diagnosis (think haemolysis or blood loss).
Active Recall - Diagnosis of ACD
References
[1] Lecture slides: GC 076. Pallor_diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (slides 12, 18, 21) [2] Lecture slides: Chemical Pathology Seminar 7_Iron metabolism.pdf (slide 31) [3] Senior notes: Ryan Ho Urogenital.pdf (p106 — Anaemia in CKD) [5] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (pp3, 6) [6] Senior notes: Ryan Ho Chemical Path.pdf (pp53–54) [8] Lecture slides: Haematology Introduction to Haematological investigations (CBP, Clotting).pdf (p32) [9] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p4) [10] Senior notes: Block A - Hematology Interactive Tutorial.pdf (pp2–3); Lecture slides: GC_Interactive tutorial (Haem case 1) student copy.pdf (p2) [12] Senior notes: Ryan Ho Haemtology.pdf (p16 — McHc anaemia table) [13] Senior notes: Ryan Ho Fundamentals.pdf (p385 — McHc anaemia table); Adrian Lui Pediatrics Notes.pdf (p358) [14] Senior notes: Maksim Medicine Notes.pdf (p154 — ACD section) [15] Senior notes: Block A - Polyuria and polydipsia_ glucose metabolism; diabetes mellitus; diabetic ketoacidosis.pdf (p4)
Management of Anaemia of Chronic Disease
Before diving into specific treatments, understand the foundational concept that governs all ACD management:
Anaemia is not a diagnosis — it reflects an underlying pathology [5]. Therefore, the single most important treatment for ACD is treating the underlying disease.
If you cure the infection, control the autoimmune disease, achieve cancer remission, or optimise CKD management, the hepcidin levels normalise → ferroportin is restored → iron is released from macrophages → erythropoiesis recovers → anaemia resolves. Every other intervention (iron, ESAs, transfusion) is supportive while you address the root cause.
Management: treat underlying disease (Fe supplement not particularly useful) [14]
The management of ACD follows a hierarchical approach:
- Treat the underlying disease (always first priority)
- Correct coexistent iron deficiency (if mixed ACD + IDA)
- Consider erythropoiesis-stimulating agents (ESAs) (in selected patients, especially CKD)
- Blood transfusion (only for symptomatic/severe anaemia)
- Emerging therapies (hepcidin antagonists, HIF-PHIs)
3. Treatment Modalities — Detailed
This is not optional — it is the primary treatment for ACD.
| Underlying Cause | Treatment | Expected Effect on ACD |
|---|---|---|
| Infection (TB, HBV, IE, HIV) | Appropriate antimicrobials (anti-TB regimen, antivirals, IV antibiotics for IE) | Resolving infection → ↓IL-6 → ↓hepcidin → ferroportin restored → iron released → anaemia resolves. IE treatment: bactericidal agents, IV, high dose, long duration [4]. |
| Autoimmune/Inflammatory (RA, SLE, IBD) | DMARDs, biologics (anti-TNF, anti-IL-6), corticosteroids | Suppressing inflammation directly reduces hepcidin production. Tocilizumab (anti-IL-6 receptor) is particularly elegant — it blocks the exact cytokine that drives hepcidin production, often dramatically improving ACD in RA. |
| Malignancy | Chemotherapy, surgery, radiotherapy as appropriate | Tumour burden reduction → ↓inflammatory cytokines → ACD improves |
| CKD | Optimise CKD management (ACEI/ARB, SGLT2i, dialysis) | See CKD-specific section below |
Why Anti-IL-6 Therapy Is Uniquely Effective in ACD
Tocilizumab ("tocili" = "anti", "zumab" = humanised monoclonal antibody) blocks the IL-6 receptor. Since IL-6 is the principal cytokine driving hepatic hepcidin synthesis, blocking IL-6 directly lowers hepcidin → releases sequestered iron → corrects ACD. This is why RA patients on tocilizumab often see rapid Hb improvement independent of disease activity changes. It's a beautiful example of pathophysiology-driven therapy.
Fe supplement not particularly useful in pure ACD [14]. Why? Because the problem is not a lack of iron — patients with ACD in fact have adequate body iron stores [2]. Giving more iron to a patient whose ferroportin is already shut down by hepcidin will not help — the iron simply gets added to the already-overloaded macrophage pool.
However, iron therapy IS indicated when:
| Indication | Rationale | Route |
|---|---|---|
| Coexistent IDA (ferritin < 225 in inflamed patient, sTfR/logFerritin > 2) | True depletion of stores on top of sequestration → need to replenish the empty tank [6] | Oral first, IV if intolerant/severe |
| Functional iron deficiency in CKD patients on ESA | Iron release from stores not rapid enough to support ↑erythropoietic rate driven by ESA [3] → marrow needs more iron than the locked-down system can provide | IV iron preferred in CKD |
| CKD anaemia management | Part of the protocolised CKD anaemia pathway | IV iron (especially in haemodialysis patients) |
Oral iron:
- Drug: Ferrous sulphate (FeSO4) 300 mg BD → provides ~65 mg elemental iron per tablet [14]
- Effect: expect Hb ↑ ~1 g/dL every 7–10 days [12]
- Administration: take with vitamin C (enhances absorption), 2h before or 4h after meals
- Side effects: metallic taste, dyspepsia, nausea/vomiting, altered bowel habits, black stools [12]
- Duration: continue until iron profile normalises (~3–6 months) [12]
IV iron:
- Indications: those who cannot tolerate oral iron, severe ongoing blood loss, malabsorption [12], or CKD patients on dialysis
- Drugs: ferric carboxymaltose, iron sucrose, ferric gluconate, iron isomaltoside
- Advantages: effective, rapid correction, ensure good compliance, no GI side effects [12]
- Risks: anaphylaxis (rare but serious — have resuscitation equipment available), transient hypophosphataemia (especially with ferric carboxymaltose), injection site reactions
When NOT to Give Iron in ACD
Pure ACD without coexistent IDA: giving iron is not the answer. The iron stores are already adequate — the problem is hepcidin-mediated sequestration. Adding more iron risks:
- Iron overload over time
- Feeding infection — remember, iron sequestration is the body's defence mechanism to starve pathogens. Giving iron in active infection can worsen outcomes.
- No clinical benefit — the iron won't reach the erythroid precursors because ferroportin is still blocked.
Exception: CKD patients on ESAs may benefit from IV iron even without absolute iron deficiency, because the ESA-driven erythropoietic demand outstrips the rate of iron release from stores (functional iron deficiency).
What are ESAs? — "Erythropoiesis" (red cell production) + "stimulating" (promoting) + "agents" (drugs). They are recombinant forms of erythropoietin that activate the EPO receptor on erythroid progenitor cells → ↑red cell production.
Why do they work in ACD? Because one mechanism of ACD is blunted EPO response — both reduced production and reduced marrow sensitivity. ESAs overcome this by providing supraphysiological EPO stimulation.
| ESA | Brand Name / Example | Half-life | Dosing |
|---|---|---|---|
| Epoetin alfa/beta | Eprex, NeoRecormon | ~8h (IV), ~24h (SC) | 2–3× per week |
| Darbepoetin alfa | Aranesp | ~25h (IV), ~49h (SC) | Q1–2 weeks |
| Methoxy-PEG epoetin beta | Mircera | ~130h | Q2–4 weeks |
Erythropoiesis-stimulating agents (ESAs), e.g. Mircera [3]
Primary Indication — CKD Anaemia:
Indication: start when Hb < 10 g/dL provided other causes of [anaemia are excluded] [3]
Aim: Hb 10–11.5 g/dL + Tf saturation > 30% + ferritin > 500 ng/mL [3]
Hemoglobin target between 10 to 11, but not greater than 12 g/dL. Iron saturation > 20%. Serum ferritin at least 100 in pre-dialysis patients, 200 in hemodialysis patients [16]
Why not target a higher Hb? Several landmark trials (CHOIR, CREATE, TREAT) showed that targeting Hb > 13 g/dL with ESAs increased cardiovascular events, stroke, and mortality. The sweet spot is Hb 10–11.5 — enough to relieve symptoms without the thrombotic risk.
Other Indications:
- Cancer-related anaemia (chemotherapy-induced): ESAs can reduce transfusion requirements, but carry risks of tumour progression and thromboembolism. Use is limited and controversial — only in patients on active chemotherapy with Hb < 10, and must be discontinued when chemo ends.
- ACD in non-CKD, non-cancer settings: ESAs are not routinely recommended. Treat the underlying disease first. ESAs may be considered in refractory cases where the underlying disease cannot be controlled and the patient remains symptomatically anaemic.
Contraindications / Cautions for ESAs:
| Contraindication / Caution | Reason |
|---|---|
| Uncontrolled hypertension | ESAs can worsen hypertension (↑blood viscosity, direct vasoactive effects). Must control BP before starting. |
| History of pure red cell aplasia (PRCA) due to anti-EPO antibodies | Previous ESA use can rarely trigger antibodies against EPO → PRCA. Rechallenge is contraindicated. |
| Active malignancy (without chemo) | Concern for tumour growth promotion (EPO receptors on some tumour cells) |
| Hb > 12 g/dL | Do not start or continue ESAs above target — ↑cardiovascular risk |
| Acute ischaemic events (MI, stroke) | Risk of thrombosis → defer ESA until stabilised |
ESA Resistance / Hyporesponsiveness:
If a patient on ESA does not achieve target Hb, consider:
- Functional iron deficiency — anaemia refractory to ESA with ↓MCV [3] → give IV iron
- Infection / active inflammation (ongoing hepcidin elevation)
- Occult blood loss
- B12 / folate deficiency
- Aluminium toxicity (dialysis patients)
- Hyperparathyroidism (marrow fibrosis from secondary hyperPTH)
- Anti-EPO antibodies → PRCA
Generally modest anaemia → most of the times never require transfusion [5]
This is important — pure ACD rarely needs transfusion. However, transfusion is indicated when:
| Indication | Threshold | Notes |
|---|---|---|
| Symptomatic anaemia (angina, heart failure, cerebral hypoxia) | Clinical judgement | Transfuse when angina, heart failure, cerebral hypoxia [12] |
| Severe anaemia | Hb < 7 g/dL | Standard restrictive transfusion threshold [12] |
| Acute haemodynamic compromise | Life-threatening | Regardless of Hb level |
For CKD patients specifically: Haemodialysis: transfuse packed cells preferably during dialysis. Peritoneal dialysis: transfuse with extra PD fluid cover, e.g. 4.25% over 2 hours during each unit. CKD with residual urine: give Lasix 20–80 mg IV before transfusion [17]
Risks of transfusion in ACD:
- Transfusion-related iron overload — each unit of packed RBCs contains ~200–250 mg iron. In CKD patients who already have impaired iron export (hepcidin-mediated), repeated transfusions can cause iron accumulation → haemosiderosis.
- Alloimmunisation — particularly problematic if the patient may need a future kidney transplant (anti-HLA antibodies from transfusions can complicate donor matching).
- TACO / TRALI — transfusion-associated circulatory overload or transfusion-related acute lung injury.
These are not yet standard practice for general ACD but are important to know conceptually:
| Agent | Mechanism | Status | Clinical Context |
|---|---|---|---|
| HIF-PHI (Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors) — e.g., roxadustat, daprodustat, vadadustat | Inhibit prolyl hydroxylase → stabilise HIF → ↑endogenous EPO production + ↓hepcidin + ↑iron absorption and mobilisation | Approved for CKD anaemia (roxadustat approved in EU, China, Japan; daprodustat FDA-approved 2023) | Oral agent — advantage over injectable ESAs. Also directly suppresses hepcidin, which is pathophysiologically attractive for ACD. |
| Anti-hepcidin antibodies / hepcidin antagonists | Directly neutralise hepcidin → restore ferroportin function → release sequestered iron | Investigational / clinical trials | Theoretically the most "targeted" therapy for ACD — directly addresses the central pathophysiological defect. |
| Anti-IL-6 / anti-IL-6R therapy (tocilizumab, sarilumab) | Block IL-6 signalling → ↓hepcidin transcription | Approved for RA, GCA, etc. (not specifically for ACD, but ACD improves as a beneficial secondary effect) | Already in clinical use for autoimmune disease; ACD improvement is a well-documented "bonus." |
| Luspatercept | TGF-beta inhibitor — promotes late-stage erythroid maturation | Approved for MDS-related and thalassaemia-related anaemia; studied in myelofibrosis [18] | Supportive for cytopenia in myelofibrosis: long-term transfusion +/- iron chelation, EPO, TGF-beta inhibitor → luspatercept [18] |
HIF-PHI: The Oral Alternative to ESAs
HIF-PHI drugs (roxadustat, daprodustat) work by mimicking the body's response to altitude: they stabilise hypoxia-inducible factor (HIF), which in turn:
- ↑EPO production by the kidneys (or extrarenal sites)
- ↓Hepcidin expression → releases iron from macrophages
- ↑Ferroportin and transferrin expression → improves iron transport
This triple action makes them particularly appealing for ACD/CKD anaemia because they address both the EPO deficiency AND the iron sequestration. They are oral, which is a major practical advantage over injectable ESAs.
Because CKD anaemia is a hybrid of true EPO deficiency + ACD, it has its own structured management pathway:
Symptomatic anaemia: Erythropoietin stimulating agent (e.g. Darbepoetin, Mircera) for refractory anaemia. Replete iron if iron deficiency. Blood transfusion when symptomatic. [17]
| Parameter | Frequency | Target |
|---|---|---|
| Hb | Q2–4 weeks during dose titration; Q1–3 months once stable | 10–11.5 g/dL (CKD); symptom-free in non-CKD |
| Iron studies (ferritin, TSAT) | Q3 months on ESA; more frequently during iron replacement | Ferritin > 100 (pre-dialysis), > 200 (dialysis); TSAT > 20% [16]. Or Tf saturation > 30%, ferritin > 500 ng/mL per KDIGO [3] |
| CRP / ESR | Periodically | Trend of underlying disease activity |
| Reticulocyte count | 1 week after starting ESA or iron | Should rise if therapy is working |
| BP | Every visit on ESA | ESAs can cause/worsen hypertension |
| Common Mistake | Why It's Wrong |
|---|---|
| Giving oral iron for pure ACD | Iron stores are adequate — problem is hepcidin-mediated sequestration, not depletion. Iron won't reach erythroblasts. |
| Targeting Hb > 12 g/dL with ESA | Landmark trials show ↑cardiovascular events, stroke, and mortality. |
| Transfusing for Hb 9 g/dL in a stable, asymptomatic patient | ACD is chronic → compensatory mechanisms (↑2,3-DPG, ↑cardiac output) maintain tissue oxygenation. Only transfuse for symptoms or Hb < 7. |
| Ignoring coexistent IDA | Very common scenario (RA on NSAIDs, cancer with GI bleeding). Must check sTfR if ferritin is in the grey zone. |
| Starting ESA without checking iron status | If iron-deficient, ESA will be ineffective (marrow needs iron to make haemoglobin). Always iron-replete first. |
High Yield Summary – Management of ACD
1. Treat the underlying disease — always the primary and most important intervention. ACD resolves when the inflammatory stimulus is removed.
2. Iron therapy — NOT useful in pure ACD [14]. Only indicated for coexistent IDA or functional iron deficiency in CKD patients on ESA. Oral FeSO4 300mg BD first line; IV iron if intolerant, severe, or CKD on dialysis.
3. ESAs — indicated for CKD anaemia when Hb < 10 g/dL. Target Hb 10–11.5 g/dL — do NOT exceed 12. ESA examples: Darbepoetin, Mircera [3][17]. Must ensure adequate iron status before starting. Monitor for hypertension.
4. Transfusion — most of the time never required [5]. Only for Hb < 7 or symptomatic anaemia (angina, HF, cerebral hypoxia).
5. Anti-IL-6 therapy (tocilizumab) effectively treats ACD in RA by directly reducing hepcidin. HIF-PHIs (roxadustat) are oral alternatives to ESA in CKD with the added benefit of hepcidin suppression.
6. In CKD: iron saturation > 20%, ferritin ≥ 100 (pre-dialysis) / ≥ 200 (dialysis) [16]. Always exclude non-renal causes of anaemia before attributing it to CKD.
Active Recall - Management of ACD
References
[2] Lecture slides: Chemical Pathology Seminar 7_Iron metabolism.pdf (slide 31) [3] Senior notes: Ryan Ho Urogenital.pdf (p106 — Anaemia in CKD) [4] Senior notes: Block A - Cardiology Interactive Tutorial.pdf (p4 — IE treatment principles) [5] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (pp3, 5, 14) [6] Senior notes: Ryan Ho Chemical Path.pdf (p54) [12] Senior notes: Ryan Ho Haemtology.pdf (pp16, 19 — IDA management; AI section) [14] Senior notes: Maksim Medicine Notes.pdf (p154 — ACD management) [16] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (pp23–24 — Renal anaemia guideline) [17] Lecture slides: Handbook of Internal Medicine 2024.pdf (p307 — CKD anaemia management) [18] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p32 — Myelofibrosis treatment)
Complications of Anaemia of Chronic Disease
When thinking about complications of ACD, you need to separate three streams:
- Complications of the anaemia itself — consequences of chronically reduced O₂-carrying capacity
- Complications of the underlying disease — ACD is always secondary; the primary disease carries its own complications
- Complications of treatment — ESAs, iron therapy, and transfusion all have iatrogenic risks
Most ACD complications arise from the first stream, because the anaemia is generally modest [5] — typically Hb 8–10 g/dL — and the body has time to compensate. However, even modest chronic anaemia has important downstream consequences, particularly in patients who already have cardiovascular disease, CKD, or malignancy.
2. Complications of Chronic Anaemia Per Se
This is the most clinically significant category of ACD complications. The chain of events follows directly from first principles:
↓Hb → ↓O₂-carrying capacity → compensatory mechanisms → cardiac stress → cardiac damage
| Complication | Mechanism (from first principles) | Clinical Relevance |
|---|---|---|
| Cardiac ischaemia | ↓O₂ delivery to myocardium. The heart is already the organ with the highest O₂ extraction ratio (~70% at rest). When Hb drops, the coronary circulation cannot extract much more O₂ → myocardial supply-demand mismatch → ischaemia, even without coronary artery disease (a form of type 2 MI / demand ischaemia). Complications of anaemia: cardiac ischaemia [19][20]. | Especially dangerous in elderly patients with pre-existing coronary artery disease. Anaemia can unmask previously subclinical IHD. Symptoms associated with cardiac ischaemia can be a presenting feature of acute anaemia [5]. |
| High-output heart failure | Chronic anaemia → compensatory ↑cardiac output (↑heart rate + ↑stroke volume) + ↓blood viscosity → ↓peripheral vascular resistance → hyperdynamic circulation. Over time, this sustained ↑workload leads to eccentric left ventricular hypertrophy (volume overload pattern) → eventually LV dilation and systolic dysfunction. | In CKD patients, normochromic normocytic anaemia is listed as a systemic complication [16], and chronic anaemia contributes to the high cardiovascular mortality in this population. Congestive cardiac failure → systolic HF, HFrEF is a listed complication of CKD anaemia [16]. |
| Left ventricular hypertrophy (LVH) | Chronic volume overload (↑cardiac output) → eccentric LVH. Also, in CKD, concurrent hypertension adds pressure overload → concentric LVH. The combination accelerates cardiac remodelling. | Hypertension, LVH are listed together as CKD complications [16]. Anaemia is an independent risk factor for LVH in CKD. |
| Exacerbation of angina pectoris | ↓O₂ delivery to already-stenosed coronary territories → angina at lower levels of exertion, or new-onset rest angina. | This is why the transfusion threshold is higher in IHD patients (Hb < 8 g/dL rather than < 7) [21]. |
Complications: cardiac ischaemia, ↑thrombocytopenic bleeding, ↑mortality [19][20]
Why Does Chronic Anaemia Cause Heart Failure?
Think of it this way: the heart is a pump. If the blood it pumps is "dilute" (low Hb), it must pump more volume per minute to deliver the same amount of O₂. This is like running a water pump at double speed permanently — eventually it wears out. The chambers dilate (eccentric hypertrophy from volume overload), and contractility deteriorates. This is a high-output failure pattern, distinct from the low-output failure seen in ischaemic heart disease.
| Complication | Mechanism | Clinical Features |
|---|---|---|
| Reduced exercise tolerance / fatigue | ↓O₂ delivery to skeletal muscles → earlier onset of anaerobic metabolism → lactic acid accumulation → fatigue. Chronic anaemia: fatigue, ↓exercise tolerance, SOBOE, pale-looking [5][20]. | These are the most common symptoms but are often overlooked because ACD develops gradually and patients adapt. |
| Cognitive impairment | ↓O₂ delivery to the brain. Particularly relevant in elderly patients who have limited cerebrovascular reserve. | Chronic anaemia in the elderly is associated with ↑risk of dementia, falls, and functional decline. |
| Impaired wound healing | O₂ is a critical substrate for collagen synthesis (prolyl hydroxylase requires O₂) and immune cell function. Chronic tissue hypoxia → delayed healing. | Relevant in surgical patients and those with chronic ulcers. |
| Growth retardation (paediatric) | In children with chronic disease (e.g., juvenile idiopathic arthritis, CKD), chronic anaemia compounds the growth-limiting effects of the underlying disease and steroid therapy. | O₂ is needed for normal cellular proliferation and growth. |
While ACD itself does not directly cause thrombocytopaenia (in fact, reactive thrombocytosis is common), the underlying disease may:
- CKD: uraemic platelet dysfunction (impaired aggregation due to uraemic toxins)
- Liver disease: ↓thrombopoietin production + portal hypertension → splenomegaly → platelet sequestration
- Marrow infiltration: if the underlying malignancy invades marrow → pancytopenia
When anaemia is severe (Hb < 7), even normal platelet function is impaired because RBCs contribute to platelet margination (pushing platelets toward the vessel wall). Fewer RBCs → less margination → impaired primary haemostasis.
- Chronic anaemia is an independent risk factor for mortality in CKD, heart failure, cancer, and critical illness.
- In CKD specifically, the anaemia-LVH-heart failure axis is a major contributor to cardiovascular death — the leading cause of death in CKD patients.
- In cancer patients, anaemia worsens quality of life and may impair response to treatment (tumour hypoxia reduces radiotherapy and chemotherapy efficacy).
ACD doesn't exist in isolation. The underlying disease that causes ACD also brings its own set of problems, and the anaemia often amplifies these:
| Underlying Disease | How ACD Worsens It |
|---|---|
| CKD | Anaemia accelerates LVH, heart failure, and CKD progression (tissue hypoxia → tubulointerstitial injury). Normochromic normocytic anaemia is one of the six major complications of CKD alongside fluid retention, metabolic acidosis, hypertension, secondary hyperparathyroidism, and bone disease [16]. |
| Heart failure | Anaemia increases cardiac workload (compensatory ↑CO) → worsens HF. This creates a vicious cycle: HF → renal hypoperfusion → ↓EPO → anaemia → ↑cardiac workload → worsens HF. This is the cardio-renal-anaemia syndrome (CRA syndrome). |
| Malignancy | Tumour hypoxia (from anaemia) → ↑HIF in tumour cells → ↑VEGF → ↑angiogenesis + ↑metastatic potential. Also ↓response to radiotherapy (O₂ is needed to generate free radicals that damage DNA). Anaemia is an independent predictor of poor prognosis in many cancers. |
| Rheumatoid arthritis | Anaemia adds to fatigue and functional impairment. Combined with joint destruction, this significantly reduces quality of life. |
| Chronic infection (TB, IE) | Anaemia → ↓immune cell function (iron-restricted lymphocyte proliferation) → paradoxically, while iron sequestration is meant to starve pathogens, severe anaemia impairs the cellular immune response itself. IE: some mild anaemia → anaemia of chronic illness → due to the transient suppression of bone marrow [4]. |
The Cardio-Renal-Anaemia Syndrome
This is a particularly high-yield concept: CKD → ↓EPO → anaemia → ↑cardiac output → cardiac remodelling → heart failure → ↓renal perfusion → worsens CKD → worsens anaemia. Three organ systems locked in a downward spiral. Breaking the cycle at the anaemia link (with ESA + iron) can improve both cardiac and renal outcomes.
4. Complications of ACD Treatment
These are iatrogenic complications — caused by the therapies themselves:
| Complication | Mechanism | Prevention/Management |
|---|---|---|
| Hypertension | ↑Blood viscosity (from rising Hb) + direct vasoactive effects of EPO (↑endothelin-1, ↓NO) → ↑SVR. | Monitor BP at every visit. Control BP before starting ESA. Titrate dose to avoid Hb overshoot. |
| Thrombotic events (stroke, MI, DVT/PE) | ↑Hb → ↑blood viscosity → ↑thrombotic risk. Also ESA activates platelets and coagulation cascade. This is why Hb > 12 g/dL on ESA is harmful. | Target Hb 10–11.5 g/dL, never > 12 [3]. Dose reduce or hold ESA if Hb rises too fast ( > 1 g/dL per 2 weeks). |
| Pure red cell aplasia (PRCA) | Rare but devastating. Anti-EPO antibodies develop → neutralise both exogenous and endogenous EPO → severe anaemia with absent reticulocytes. | Suspect if sudden severe anaemia with reticulocyte count near zero on ESA. Confirm with anti-EPO Ab. Stop ESA immediately. Consider immunosuppression. |
| Tumour progression (cancer patients) | Some tumour cells express EPO receptors → exogenous EPO may stimulate tumour growth. | Restrict ESA use in cancer to patients on active chemotherapy only. Discontinue when chemo ends. |
| Seizures | Rapid rise in Hb → ↑blood viscosity → hypertensive encephalopathy. Particularly in CKD patients with pre-existing hypertension. | Gradual Hb correction. Tight BP control. |
| Complication | Mechanism | Notes |
|---|---|---|
| GI side effects (oral iron) | Direct irritant effect on GI mucosa → nausea, constipation, epigastric discomfort, black stools. | Switch to IV if intolerable. Not dangerous but affects compliance. |
| Iron overload (repeated IV iron or inappropriate oral iron in pure ACD) | Each unit of IV iron adds to total body iron. In ACD where stores are already adequate, exogenous iron cannot be utilised → accumulates in liver, heart, endocrine organs → haemosiderosis. Secondary iron overload from parenteral iron overload [6]. | Only give iron when there is genuine deficiency or functional deficiency in CKD. Monitor ferritin and TSAT. |
| Anaphylaxis (IV iron) | Type I hypersensitivity to the iron-carbohydrate complex. Rare but potentially fatal. | Give in a monitored setting. Have resuscitation equipment available. Test dose for older formulations (less needed with newer agents like ferric carboxymaltose). |
| Feeding infection | Exogenous iron may become available to pathogens. Iron sequestration in ACD is a deliberate host defence ("nutritional immunity") — bypassing it with iron supplementation during active infection can worsen outcomes. | Avoid iron supplementation during active, uncontrolled infection unless there is severe symptomatic anaemia requiring it. |
| Hypophosphataemia (ferric carboxymaltose) | Inhibits renal tubular phosphate reabsorption via ↑FGF23. | Monitor phosphate levels. Consider alternative IV iron preparation if recurrent. |
| Complication | Mechanism | Relevance to ACD |
|---|---|---|
| Transfusion-related iron overload | Each unit of packed RBCs contains ~200–250 mg iron. Unlike dietary iron, there is no physiological mechanism to excrete transfused iron. Repeated transfusions → iron accumulates in liver, heart, pancreas → haemosiderosis → organ damage. | Particularly problematic in CKD patients who may need recurrent transfusions over years. |
| Alloimmunisation | Donor RBCs carry HLA and minor RBC antigens → recipient develops antibodies → complicates future transfusions and organ transplantation. | Very important in CKD patients who may need future kidney transplant — each transfusion increases the risk of anti-HLA antibodies that narrow the donor pool [21]. |
| Febrile non-haemolytic reactions | Recipient antibodies against donor WBC antigens → cytokine release → fever, rigors. Febrile reaction 3% [21]. | |
| TACO / TRALI | TACO: volume overload in patients with limited cardiac reserve (CKD, HF). TRALI: donor anti-HLA antibodies activate recipient neutrophils in pulmonary vasculature → non-cardiogenic pulmonary oedema. | Give furosemide before transfusion in CKD patients with residual urine. Transfuse slowly. |
| Infection transmission | Hepatitis B/C, HIV (very rare with modern screening), CMV, bacterial contamination. Hepatitis 1/150–1/5000, AIDS 1/200,000 [21]. |
Iron Overload Considerations in ACD
A common mistake: treating ACD with iron "just in case." In pure ACD, the iron stores are already adequate — patients with ACD in fact have adequate body iron stores which are compartmentalised in the reticuloendothelial system [2]. Adding more iron when ferroportin is blocked simply increases macrophage iron burden → eventually → tissue iron overload → organ damage. Only supplement iron when you have confirmed coexistent IDA (ferritin < 225 with inflammation, sTfR/logFerritin > 2) or functional iron deficiency in CKD on ESA.
One underappreciated "complication" of ACD is the diagnostic confusion it creates:
| Diagnostic Problem | How ACD Confounds It |
|---|---|
| Masking coexistent IDA | Ferritin is a positive acute phase reactant [2] — in ACD, ferritin is elevated by inflammation, masking true iron depletion. If ferritin is normal-low ( < 225), there may be concomitant Fe deficiency anaemia [6]. Missing IDA means missing a potentially treatable (and possibly dangerous) source of blood loss. |
| Falsely elevated HbA1c | ACD → ↓erythropoiesis → ↓RBC turnover → RBCs live longer → more glycosylation → falsely high HbA1c [15]. This can lead to unnecessary escalation of diabetic treatment. |
| Misleading albumin levels | Albumin is a negative acute phase reactant. Low albumin in ACD may be attributed to malnutrition or liver disease when it is actually driven by inflammation. |
| Confounding renal anaemia assessment | In CKD, distinguishing the ACD component from the EPO-deficiency component affects management decisions (ESA dose, iron supplementation strategy). |
ACD is not just a laboratory curiosity — it carries independent prognostic significance:
| Setting | Prognostic Impact |
|---|---|
| CKD | Lower Hb independently predicts ↑cardiovascular events, ↑hospitalisation, ↑mortality, and ↑CKD progression |
| Heart failure | Anaemia is an independent predictor of HF hospitalisation and death (NYHA functional class worsens) |
| Cancer | Anaemia correlates with ↓performance status, ↓response to therapy, ↓overall survival |
| Rheumatoid arthritis | Hb level correlates inversely with disease activity (DAS28) — anaemia is a marker of poorly controlled disease |
| Critical illness | In ICU patients, anaemia of critical illness (a variant of ACD) is associated with ↑length of stay and ↑mortality |
| Category | Key Complications |
|---|---|
| Cardiovascular | Cardiac ischaemia, high-output heart failure, LVH, worsened angina |
| Systemic hypoxia | Fatigue, ↓exercise tolerance, cognitive impairment, impaired wound healing, growth retardation (children) |
| Haematological | ↑Bleeding tendency (when severe), ↑mortality |
| Disease amplification | Worsens CKD progression, HF, cancer outcomes, functional status in RA |
| Cardio-renal-anaemia syndrome | CKD ↔ anaemia ↔ HF → vicious downward cycle |
| Treatment-related | ESA: hypertension, thrombosis, PRCA. Iron: overload, anaphylaxis, feeding infection. Transfusion: iron overload, alloimmunisation, TACO/TRALI |
| Diagnostic confusion | Masked IDA, falsely high HbA1c, misleading albumin, confounded renal anaemia assessment |
High Yield Summary – Complications of ACD
The anaemia itself is usually modest (Hb 8–10), but even mild chronic anaemia has important consequences:
- Cardiac ischaemia — demand ischaemia from ↓O₂ delivery, especially in pre-existing IHD
- High-output heart failure and LVH — chronic volume overload from compensatory ↑cardiac output
- Cardio-renal-anaemia syndrome — vicious cycle of CKD → ↓EPO → anaemia → cardiac stress → ↓renal perfusion
- ↑Mortality — independent predictor in CKD, HF, cancer, and critical illness
- Treatment complications: ESA → hypertension, thrombosis (never target Hb > 12); iron → overload, anaphylaxis, feeding infection; transfusion → alloimmunisation, iron overload, TACO
Key exam pitfall: always check for coexistent IDA — ACD can mask it via elevated ferritin (positive acute phase reactant). Missing IDA means missing a treatable underlying cause (e.g., GI malignancy, NSAID bleed).
Active Recall - Complications of ACD
References
[2] Lecture slides: Chemical Pathology Seminar 7_Iron metabolism.pdf (slide 31) [3] Senior notes: Ryan Ho Urogenital.pdf (p106 — Anaemia in CKD, ESA targets) [4] Senior notes: Block A - Cardiology Interactive Tutorial.pdf (p4 — Anaemia of chronic illness in IE) [5] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (pp3, 14) [6] Senior notes: Ryan Ho Chemical Path.pdf (p54 — ACD and iron overload) [15] Senior notes: Ryan Ho Endocrine.pdf (p79 — HbA1c inaccuracy in Fe deficiency anaemia) [16] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (pp23–24) [19] Senior notes: Adrian Lui Pediatrics Notes.pdf (p352 — Complications of anaemia) [20] Senior notes: Ryan Ho Fundamentals.pdf (p380 — Complications of anaemia) [21] Senior notes: Ryan Ho Critical Care.pdf (p20 — Transfusion indications and risks)
High Yield Summary
Definition: Anaemia arising in the context of chronic infection, inflammation, malignancy, or CKD. Adequate iron stores but iron compartmentalised in the RES.
Pathophysiology (3+1 mechanisms):
- ↑Hepcidin (IL-6-driven) → degrades ferroportin → iron trapped in macrophages + ↓dietary absorption
- Blunted EPO response (↓production + ↓marrow sensitivity)
- ↓RBC lifespan (enhanced erythrophagocytosis)
- In CKD: direct ↓EPO from renal fibrosis
Morphology: Normochromic normocytic (rarely hypochromic microcytic if severe/prolonged)
Severity: Generally modest (Hb 8–10), rarely requires transfusion
Iron Studies Pattern: ↓Serum iron, ↓/N TIBC, ↓Transferrin saturation, N/↑Ferritin, ↑Hepcidin
Key Distinguishing Test from IDA: TIBC (↑ in IDA, ↓ in ACD)
Acute Phase Reactants:
- Positive: Ferritin, CRP, ESR
- Negative: Serum iron, transferrin, albumin, prealbumin
Always: Identify and treat the underlying cause. Anaemia is not the diagnosis — it is the consequence.
High Yield Summary – Differential Diagnosis of ACD
-
ACD is a diagnosis of exclusion within the context of a known chronic disease. Always exclude coexistent IDA, haemolysis, renal anaemia, and marrow pathology.
-
MCV framework: ACD is typically normocytic. If microcytic → consider IDA, thalassaemia, sideroblastic anaemia, or mixed ACD+IDA.
-
Reticulocyte count separates hypoproliferative causes (ACD, renal, marrow failure) from hyperproliferative ones (haemolysis, blood loss).
-
Best test to distinguish ACD from IDA: TIBC [5] — ↑ in IDA (hungry for iron), ↓ in ACD (negative acute phase reactant).
-
If ferritin < 225 in the setting of inflammation, suspect coexistent IDA [6].
-
sTfR and sTfR/log ferritin ratio are the best tools for identifying IDA hiding behind ACD (sTfR is NOT affected by inflammation).
-
Always look for the underlying cause — ACD is a red flag for occult infection, malignancy, autoimmune disease, or CKD.
High Yield Summary – Diagnosis of ACD
No formal diagnostic criteria exist — ACD is diagnosed by pattern recognition + exclusion.
Three pillars of diagnosis:
- Known underlying chronic disease (infection, cancer, autoimmune, CKD, transplant rejection)
- Characteristic iron pattern: ↓serum iron, ↓TIBC, ↓TSAT, N/↑ferritin, ↑CRP/ESR [2]
- Exclusion of IDA, thalassaemia, haemolysis, marrow failure, B12/folate deficiency
Key distinguishing test: TIBC — ↑ in IDA, ↓ in ACD [5]
Grey zone ferritin (30–225): suspect coexistent IDA → use sTfR/log ferritin ratio ( > 2 = IDA present)
Gold standard for iron stores: bone marrow Prussian blue staining (iron in macrophages but absent sideroblasts in ACD; absent stores in IDA)
CKD-specific: screen annually from stage 3; always check reticulocyte count, ferritin/TSAT, and B12/folate before attributing anaemia to CKD alone [3]
ACD is a hypoproliferative anaemia with low reticulocyte count — if reticulocytes are high, reconsider the diagnosis (think haemolysis or blood loss).
High Yield Summary – Management of ACD
1. Treat the underlying disease — always the primary and most important intervention. ACD resolves when the inflammatory stimulus is removed.
2. Iron therapy — NOT useful in pure ACD [14]. Only indicated for coexistent IDA or functional iron deficiency in CKD patients on ESA. Oral FeSO4 300mg BD first line; IV iron if intolerant, severe, or CKD on dialysis.
3. ESAs — indicated for CKD anaemia when Hb < 10 g/dL. Target Hb 10–11.5 g/dL — do NOT exceed 12. ESA examples: Darbepoetin, Mircera [3][17]. Must ensure adequate iron status before starting. Monitor for hypertension.
4. Transfusion — most of the time never required [5]. Only for Hb < 7 or symptomatic anaemia (angina, HF, cerebral hypoxia).
5. Anti-IL-6 therapy (tocilizumab) effectively treats ACD in RA by directly reducing hepcidin. HIF-PHIs (roxadustat) are oral alternatives to ESA in CKD with the added benefit of hepcidin suppression.
6. In CKD: iron saturation > 20%, ferritin ≥ 100 (pre-dialysis) / ≥ 200 (dialysis) [16]. Always exclude non-renal causes of anaemia before attributing it to CKD.
High Yield Summary – Complications of ACD
The anaemia itself is usually modest (Hb 8–10), but even mild chronic anaemia has important consequences:
- Cardiac ischaemia — demand ischaemia from ↓O₂ delivery, especially in pre-existing IHD
- High-output heart failure and LVH — chronic volume overload from compensatory ↑cardiac output
- Cardio-renal-anaemia syndrome — vicious cycle of CKD → ↓EPO → anaemia → cardiac stress → ↓renal perfusion
- ↑Mortality — independent predictor in CKD, HF, cancer, and critical illness
- Treatment complications: ESA → hypertension, thrombosis (never target Hb > 12); iron → overload, anaphylaxis, feeding infection; transfusion → alloimmunisation, iron overload, TACO
Key exam pitfall: always check for coexistent IDA — ACD can mask it via elevated ferritin (positive acute phase reactant). Missing IDA means missing a treatable underlying cause (e.g., GI malignancy, NSAID bleed).
Sideroblastic Anemia
Sideroblastic anemia is a group of anemias characterized by defective heme synthesis leading to mitochondrial iron accumulation in erythroid precursors, forming pathologic ring sideroblasts in the bone marrow.
Aplastic Anaemia
Aplastic anaemia is a bone marrow failure syndrome characterized by pancytopenia and hypocellular marrow resulting from destruction or suppression of haematopoietic stem cells.