1. Ferroportin — the only known cellular iron exporter in mammals. Found on:

   • Duodenal enterocytes (dietary iron absorption)
   • Reticuloendothelial macrophages (recycled iron from senescent RBCs)
   • Hepatocytes

2. 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.

3. Transferrin — the plasma iron-transport protein. Each molecule can carry 2 Fe³⁺ ions.

4. 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.

5. 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.

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:

1. Chronic inflammation → hepatocytes produce IL-6 → stimulates the liver to synthesise hepcidin (via the JAK2-STAT3 pathway).
2. Elevated serum hepcidin binds ferroportin on macrophages and duodenal enterocytes → ferroportin is internalised and degraded ^[1].
3. Iron becomes trapped inside macrophages (cannot be exported to plasma transferrin) and dietary iron absorption is simultaneously blocked.
4. 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].

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.

• 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]

• Generally modest anaemia → most of the times never require transfusion ^[1][5].
• Hb typically 8–10 g/dL (rarely drops below 8 g/dL unless there is a coexistent cause).
• Contrast with IDA which could be severe ^[1].

See Aetiology section above (infections, cancer, autoimmune, CKD, transplant rejection).

ACD fits primarily under decreased RBC production ^[5]:

Anaemia of chronic disease is listed under causes of decreased RBC production alongside nutritional deficiency, bone marrow disorders, marrow suppression, and reduced trophic hormones ^[5].

The clinical presentation of ACD is a composite of:

1. Symptoms and signs of anaemia itself (typically mild/insidious)
2. Symptoms and signs of the underlying disease (often dominant)

The clinical presentation of anaemia depends on the onset and severity of anaemia. ^[5]

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 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]:

• 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.

• The condition we are discussing. Normochromic normocytic, generally modest, iron sequestered in RES ^[1][2].
• Reticulocyte count: low/inappropriately normal (hypoproliferative).
• Iron studies: ↓Fe, ↓/N TIBC, N/↑ferritin.

• 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].

• 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).

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.

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.

ACD is associated with reduced concentrations of serum iron, transferrin, TIBC, raised ferritin and erythrocyte sedimentation rate or C-reactive protein ^[2].

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.

If there is any clinical suspicion of haemolysis (e.g., jaundice, splenomegaly, dark urine, underlying SLE or lymphoproliferative disease), order:

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].

Remember: anaemia is not a diagnosis, it reflects an underlying pathology ^[5]. Once ACD is confirmed, investigate the underlying disease if not already known:

This is not optional — it is the primary treatment for ACD.

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:

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

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.

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:

ESA Resistance / Hyporesponsiveness:

If a patient on ESA does not achieve target Hb, consider:

1. Functional iron deficiency — anaemia refractory to ESA with ↓MCV ^[3] → give IV iron
2. Infection / active inflammation (ongoing hepcidin elevation)
3. Occult blood loss
4. B12 / folate deficiency
5. Aluminium toxicity (dialysis patients)
6. Hyperparathyroidism (marrow fibrosis from secondary hyperPTH)
7. 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:

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:

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

Complications: cardiac ischaemia, ↑thrombocytopenic bleeding, ↑mortality ^[19][20]

Complications: ↑thrombocytopenic bleeding ^[19][20]

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).

Complications: ↑mortality ^[19][20]