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Imported Infectious Diseases - 10 Mark Pathology Answer

Definition

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Classification

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1. Malaria

Pathological Features

• Parasitized red cells - ring forms, trophozoites, schizonts, gametocytes on peripheral smear
• P. falciparum - Maurer's clefts; P. vivax - Schuffner's dots; P. malariae - band forms (trophozoites)
• Haemolytic anaemia - intravascular haemolysis releases haemozoin (malarial pigment)

• Acute: congestion, enlargement, soft consistency ("ague cake")
• Chronic: massive splenomegaly, grey-black pigmentation from haemozoin, fibrosis, hyperplastic RE cells
• Tropical splenomegaly syndrome - exaggerated immunological response

• Hepatomegaly with haemozoin in Kupffer cells
• Centrizonal necrosis in severe falciparum malaria
• Periportal inflammation, haemosiderin deposition

• Cytoadherence - parasitized RBCs adhere to cerebrovascular endothelium via PfEMP1 ligand and ICAM-1 receptors
• Duffy rosettes, sequestration in cerebral capillaries and venules
• Ring haemorrhages - Dürck's granulomas (necrotic foci surrounded by microglia)
• Petechial haemorrhages throughout white matter
• Brain oedema, raised intracranial pressure

• Blackwater fever (P. falciparum) - massive intravascular haemolysis - haemoglobinuria - acute tubular necrosis
• Quartan malarial nephropathy (P. malariae) - immune complex deposition - membranoproliferative glomerulonephritis

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2. Leishmaniasis

Pathological Features

• Massively enlarged spleen (can reach 3-4 kg) - sinusoidal dilatation, RE hyperplasia packed with amastigotes
• Liver - Kupffer cell hyperplasia laden with LD bodies; periportal fibrosis in chronic cases
• Bone marrow - hypercellular; macrophages with amastigotes, plasma cell infiltration
• Lymph nodes - cortical hyperplasia, sinus histiocytosis
• Skin - post-kala-azar dermal leishmaniasis (PKDL) - depigmented macules/nodules after treatment
• Profound anaemia, leukopenia, thrombocytopenia (pancytopenia due to hypersplenism + BM infiltration)
• Serology: hypergammaglobulinaemia, low albumin (reversed A:G ratio)

• Ulcerated skin lesion ("Delhi boil/Oriental sore") - granulomatous inflammation, giant cells, amastigotes in dermal macrophages, central necrosis

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3. Schistosomiasis (Bilharziasis)

Pathological Features

• Pipestem/Symmer's clay pipestem fibrosis - periportal fibrosis around portal tracts due to granulomatous reaction to ova
• Granulomas with eosinophils, giant cells around ova - later fibrosis
• Portal hypertension - splenomegaly, oesophageal varices - preserved hepatocellular function (unlike cirrhosis)
• Liver surface: "hobnail" appearance; cut surface: white pipestem portal tracts

• Sandy patches - calcified dead ova in bladder wall
• Squamous cell carcinoma of bladder - major complication (strong association)
• Obstructive uropathy - hydroureter, hydronephrosis

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4. Viral Haemorrhagic Fevers (VHFs)

Pathological Features

• Ebola/Marburg/Yellow fever: councilman/acidophil bodies (eosinophilic apoptotic hepatocytes), mid-zonal necrosis (Yellow fever - zones 2), pan-lobular necrosis (Ebola)
• Viral inclusions (Ebola - intracytoplasmic)

• Thrombocytopenia due to immune-mediated platelet destruction and BM suppression
• Dengue haemorrhagic fever (DHF) - plasma leakage, dengue shock syndrome
• Liver: hepatocyte apoptosis (Councilman-like bodies), Kupffer cell hypertrophy

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5. Filariasis

Pathological Features (Lymphatic Filariasis)

• Acute: lymphangitis, lymphadenitis with adult worms; eosinophilic infiltration, granuloma formation
• Chronic: obstruction of lymphatics - lymphoedema - elephantiasis (lower limbs, scrotum)
• Histology: filarial granuloma - central degenerated worm, palisading histiocytes, eosinophils, plasma cells, fibrosis
• Tropical pulmonary eosinophilia - microfilariae in lungs - interstitial pneumonitis, eosinophilia

• Subcutaneous nodules (onchocercoma) - adult worms in fibrous capsule
• Ocular pathology: sclerosing keratitis, retinal atrophy due to microfilariae

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6. Trypanosomiasis

African (Sleeping Sickness - T. brucei gambiense/rhodesiense):

• Chancre at bite site - perivascular lymphocytic infiltration
• Lymphadenopathy - Winterbottom's sign (posterior cervical)
• Encephalitis - demyelination, perivascular cuffing, Mott cells (plasma cells with Russell bodies) in brain

American (Chagas Disease - T. cruzi):

• Acute: pseudocysts in myocardium, skeletal muscle, neurons; nests of amastigotes
• Chronic: dilated cardiomyopathy - apical aneurysm (characteristic), conduction system fibrosis
• Megaoesophagus, megacolon - destruction of Auerbach's plexus (myenteric neurons)

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Diagnostic Approach in Pathology

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Summary Table

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Examiner's Note - How to Score Full Marks

1. Definition and classification with examples (1.5 marks)
2. Detailed pathology of at least 3-4 diseases (5 marks) - emphasis on gross and histological features
3. Pathogenesis/mechanism briefly stated (1.5 marks)
4. Diagnostic approach (1 mark)
5. Complications mentioned (1 mark)

Sources: Robbins & Cotran Pathologic Basis of Disease 10e; Muir's Textbook of Pathology; Mandell's Principles and Practice of Infectious Diseases

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Paroxysmal Nocturnal Haemoglobinuria (PNH) - 10 Mark Answer

Definition

It is the only haemolytic anaemia caused by an acquired genetic defect (somatic mutation).

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Molecular Pathogenesis - The PIGA Mutation

The Gene

• PNH results from somatic mutations in the PIGA gene (Phosphatidylinositol Glycan complementation class A)
• PIGA is located on the X chromosome and is subject to lyonisation (random X inactivation)
• Because PIGA is X-linked, a single somatic mutation in the active PIGA allele of any haematopoietic stem cell is sufficient to produce a deficiency state
• All clonal progeny - red cells, white cells, and platelets - are deficient in GPI-linked proteins

• 120 distinct somatic PIGA mutations have been described

The GPI Anchor

1. Transmembrane/integral - via hydrophobic span
2. GPI-linked - via covalent linkage to glycosylphosphatidylinositol (GPI) lipid anchor

Key GPI-Anchored Proteins Lost in PNH

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Why PNH Clones Expand - The Autoimmune Hypothesis

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Three Types of PNH Red Cells (Henry's Classification)

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Clinical Features and Pathology

1. Haemolytic Anaemia (Intravascular)

• Loss of CD59 allows uncontrolled activation of the alternative complement pathway on the RBC surface
• The C5b-9 membrane attack complex (MAC) forms and lyses RBCs intravascularly
• Classically paroxysmal and nocturnal - sleep causes mild CO₂ retention, slight fall in blood pH, increased complement activity
• Importantly: paroxysmal nocturnal haemoglobinuria in the classic sense occurs in only 25% of cases - chronic haemolysis without overt haemoglobinuria is more typical
• Bouts can be triggered by: infection, surgery, blood transfusion, contrast dyes, exercise

• Normocytic/normochromic anaemia with reticulocytosis (often less than expected)
• Hypochromic microcytic change due to chronic iron loss in urine
• Elevated LDH, unconjugated bilirubin, reduced/absent haptoglobin
• Haemoglobinuria (pink/brown urine) - intravascular haemolysis
• Haemosiderinuria (almost constantly present) - Prussian blue stain on urine sediment
• Direct Coombs/DAT: negative (distinguishes from autoimmune haemolytic anaemia)
• Pancytopenia in many patients: neutropenia in 60%, thrombocytopenia in 66%

2. Thrombosis - The Major Cause of Death

• Thrombosis occurs in approximately 40% of PNH patients and is the leading cause of disease-related death
• 85% are venous thromboses, often at unusual sites:
  • Hepatic vein - Budd-Chiari syndrome
  • Portal vein
  • Cerebral venous sinuses
  • Abdominal veins
  • Mesenteric veins

1. Loss of CD59 on platelets → phosphatidylserine externalisation → platelet prothrombinase complex assembly → enhanced thrombin generation
2. Free haemoglobin released during haemolysis scavenges nitric oxide (NO) → loss of NO-mediated vasodilation and platelet inhibition → endothelial injury, platelet activation
3. MAC-mediated endothelial damage

3. Bone Marrow Failure

• Marrow may be hypercellular (erythroid hyperplasia) or hypocellular
• PNH, aplastic anaemia, and myelodysplastic syndrome form a clinical continuum
• ~5% of PNH patients transform to AML or MDS over time

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PNH Clinical Categories

1. Classic PNH - haemolysis and thrombosis dominant, usually >50% PNH clone
2. PNH in the setting of another BM disorder (aplastic anaemia, MDS) - cytopenias predominate
3. Subclinical PNH - small clone (<1%), no haemolysis, found incidentally

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Laboratory Diagnosis

Old Tests (Historical)

• Ham's test (Acidified serum lysis test): Patient's RBCs lysed in acidified normal serum (activates complement) - positive in PNH, negative in normal. Largely abandoned.
• Sucrose haemolysis test (Sugar water test): Low ionic strength sucrose activates complement - less specific. Also abandoned.

Current Gold Standard: Flow Cytometry

• Red cells: stained with anti-CD59, anti-CD55 monoclonal antibodies
• Granulocytes: anti-CD24 (excellent GPI-linked marker)
• Monocytes: anti-CD14 (GPI-linked)
• FLAER (Fluorescein-labelled aerolysin): binds directly to GPI anchor - increasingly used as gold standard, highly sensitive for detecting small clones
• High-sensitivity flow cytometry can detect clones as small as 0.01%

Additional labs

• LDH (elevated - marker of intravascular haemolysis)
• Urine haemosiderin (Prussian blue stain - almost always positive)
• Peripheral smear: normocytic anaemia, variable reticulocytosis
• No schistocytes (distinguishes from TMA/TTP)

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Treatment

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Summary - Key Facts for Exam

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Examiner's Scoring Guide

1. Definition and unique nature (acquired, only haemolytic anaemia with acquired genetic defect) - 1 mark
2. PIGA gene, X-linkage, somatic mutation mechanism - 2 marks
3. GPI anchor biology and which proteins are lost (CD55, CD59, C8BP) - 1.5 marks
4. Pathogenesis of haemolysis, thrombosis, pancytopenia - 2 marks
5. Clinical types of RBCs (I/II/III) and clinical features - 1 mark
6. Lab diagnosis - flow cytometry, FLAER, Ham's test (historical) - 1.5 marks
7. Treatment - eculizumab mechanism, HSCT - 1 mark

Sources: Robbins & Cotran Pathologic Basis of Disease 10e (p. 606); Henry's Clinical Diagnosis and Management by Laboratory Methods; Harrison's Principles of Internal Medicine 22e

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Myelodysplastic Neoplasms (MDS) - Classification and Diagnostic Criteria - 10 Mark Answer

Definition

• Maturation defects and ineffective haematopoiesis
• Peripheral blood cytopenias despite a normo- or hypercellular marrow
• Morphological dysplasia in one or more myeloid cell lines
• Genetic instability with a high risk of transformation to AML (10-40% of cases)

The term "Myelodysplastic Neoplasm" is preferred in the WHO 5th edition (2022) and ICC 2022 classification, reflecting their established neoplastic nature, though "MDS" remains in widespread clinical use.

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Aetiology and Types

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Pathogenesis

1. Epigenetic Regulators

• DNA methylation: TET2, DNMT3A, IDH1/IDH2
• Histone modification: EZH2, ASXL1
• Dysregulation of the epigenome - transcriptional silencing of differentiation genes

2. RNA Splicing Factors (characteristic of MDS)

• SF3B1 - strongly associated with ring sideroblasts; relatively favourable prognosis
• SRSF2, U2AF1, ZRSR2
• Alter mRNA processing affecting tumour suppressors and oncogenes
• Patients with CHIP + splicing factor mutations are at particularly high risk for MDS

3. Transcription Factors

• RUNX1, ETV6 - loss-of-function mutations impairing normal myelopoiesis
• Note: Common AML translocations [t(8;21), inv(16), t(15;17)] are absent in MDS

TP53 Mutations

• ~10% of MDS cases; correlate with complex karyotype and worst prognosis; biallelic TP53 mutations define a distinct entity

Recurrent Chromosomal Abnormalities

• Monosomy 5 / del(5q) - loss of RPS14 → ineffective erythropoiesis
• Monosomy 7 / del(7q)
• del(20q), del(12p), del(11q), del(9q)
• Trisomy 8 (gain of MYC - stimulates cell growth)
• Isochromosome 17q

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Morphological Features (Dysplasia)

Erythroid Dysplasia

• Megaloblastoid change (nuclear-cytoplasmic asynchrony)
• Ring sideroblasts - iron deposits in mitochondria around nucleus (≥15% of erythroid precursors, or ≥5% if SF3B1 mutation present)
• Nuclear budding, multinucleation, karyorrhexis
• Cytoplasmic vacuolation

Granulocyte Dysplasia

• Pseudo-Pelger-Huet anomaly - bilobed or hyposegmented neutrophils (most characteristic)
• Hypogranular neutrophils (agranular cytoplasm)
• Nuclear hypo- or hypersegmentation
• Abnormal chromatin clumping

Megakaryocyte Dysplasia

• Micromegakaryocytes (small size, single nucleus) - most specific for MDS
• Large megakaryocytes with multiple separate nuclei (separated nuclear lobes)
• Hypolobated/monolobated forms

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Classification

WHO 5th Edition (2022) and ICC (International Consensus Classification) 2022

WHO 5th Edition (2022) MDS Categories

Prior WHO 2016 Classification (Still Widely Tested in Exams)

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Diagnostic Criteria

Minimum Requirements for MDS Diagnosis

1. Cytopenia in ≥1 lineage:
   • Hb <13 g/dL (male) / <12 g/dL (female)
   • ANC <1.8 × 10⁹/L
   • Platelets <150 × 10⁹/L
2. Exclusion of reactive causes of dysplasia (vitamin B12/folate deficiency, copper deficiency, HIV, drugs, alcohol, heavy metal toxicity, hypothyroidism)
3. Stable cytopenia for ≥4 months (unless MDS-defining cytogenetic abnormality present)

MDS-Defining Cytogenetic Abnormalities (Henry's / WHO)

• Monosomy 7 or del(7q)
• del(5q)
• Isochromosome 17q or t(17p)
• Monosomy 13 or del(13q)
• del(11q), del(12p) or t(12p), del(9q)
• idic(X)(q13)

• t(11;16)(q23.3;p13.3)
• t(3;21)(q26.2;q22.1)
• t(1;3)(p36.3;q21.2)
• t(2;11)(p21;q23.3)
• inv(3)(q21.3q26.2) / t(3;3)(q21.3;q26.2)
• t(6;9)(p23;q34.1)

Note: Trisomy 8, del(20q), and loss of Y chromosome are NOT considered MDS-defining as isolated abnormalities - they require concurrent morphological dysplasia.

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Diagnostic Work-up

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Prognosis - IPSS-R Scoring

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Treatment Overview

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Summary Table - Key Distinguishing Features

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Examiner's Scoring Guide

1. Definition, primary vs. secondary, CHIP precursor - 1.5 marks
2. Pathogenesis (3 mutation categories + cytogenetics) - 2 marks
3. Morphological features / dysplasia in each lineage - 1.5 marks
4. Classification (WHO 2016 OR WHO 2022 table with key entities) - 2.5 marks
5. Diagnostic criteria (cytopenias, dysplasia threshold, cytogenetic abnormalities) - 1.5 marks
6. Prognosis/IPSS-R mention + treatment overview - 1 mark

Sources: Robbins & Cotran Pathologic Basis of Disease 10e; Robbins & Kumar Basic Pathology 11e; Henry's Clinical Diagnosis and Management by Laboratory Methods; WHO Classification of Haematolymphoid Tumours 5th ed. (2022)

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Hemophagocytic Syndromes (Hemophagocytic Lymphohistiocytosis - HLH) - 10 Mark Answer

Definition

• Widespread phagocytosis of blood cells and their precursors (haemophagocytosis)
• Severe cytopenias
• Hypercytokinaemia ("cytokine storm")
• Multi-organ failure

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Classification

A. Primary HLH (Familial / Genetic)

1. Familial HLH (FHL) - Most Common

PRF1 and UNC13D variants account for ~30% each of FHL cases.

2. Primary HLH with Partial Albinism

3. X-Linked Lymphoproliferative Disorder (XLP)

• XLP-1: SH2D1A gene → deficient SAP adaptor protein → triggered by EBV infection; impaired NK cell 2B4-mediated cytotoxicity; defective antigen-induced T-cell death
• XLP-2: BIRC4 gene → XIAP deficiency → HLH + colitis; linked to NLRC4 inflammasome dysregulation

4. Other Primary HLH

• Inflammasome activation disorders (NLRC4 gain-of-function)
• Inborn errors of immunity and metabolism

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B. Secondary HLH (Acquired)

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Pathogenesis

The Central Defect

1. Inability to kill infected/abnormal target cells - particularly virus-infected cells (e.g., EBV-infected B cells)
2. Prolonged CTL-target cell engagement - the CTL remains locked in immunological synapse, secreting cytokines instead of lysing
3. Massive IFN-γ secretion by overactivated CD8+ T cells and NK cells - the key proximal driver
4. IFN-γ activates macrophages - producing unbridled macrophage activation
5. Macrophage cytokine storm: TNF-α, IL-6, IL-12, IL-1β, IL-18, CXCL9 - systemic effects resembling sepsis (SIRS)
6. Haemophagocytosis - activated macrophages engulf RBCs, platelets, WBCs and their precursors in BM, liver, spleen, and lymph nodes
7. Vicious cycle: inflamed, non-dying target cells continue stimulating CTLs → further IFN-γ → further macrophage activation

In secondary HLH: heterozygous mutations in FHL genes lower the threshold for HLH, and an overwhelming antigenic stimulus (virus, tumour) drives the same cytokine storm even without complete loss of cytotoxic function.

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Morphological Features

Bone Marrow

• Haemophagocytosis - macrophages engulfing intact RBCs, nucleated erythroid precursors, platelets, and granulocytes (the defining histological finding, though neither sensitive nor specific)
• May progress to hypocellularity in late disease
• Reactive lymphocytes and plasma cells
• Erythroid hyperplasia initially

Liver

• Periportal and sinusoidal lymphohistiocytic infiltrate
• Kupffer cell hyperplasia with haemophagocytosis
• Hepatocyte necrosis (resembles chronic persistent hepatitis on biopsy)
• Cholestasis

Spleen

• Expansion of red pulp by macrophages with haemophagocytosis
• Lymphoid depletion in severe/late disease

Lymph Nodes

• Sinus histiocytosis with haemophagocytosis
• Paracortical expansion by T cells and macrophages

CNS

• Perivascular lymphohistiocytic infiltrate
• Microglial activation
• Demyelination in severe cases

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Clinical Features

Epidemiology

• Primary FHL: incidence 1 in 50,000 live births; median onset 3-6 months; autosomal recessive (equal M:F); more common in consanguineous populations
• Secondary HLH: any age; adults predominantly

Symptoms and Signs

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Diagnostic Criteria - HLH-2004 (Updated 2024)

Note: The 2024 revision removed NK cell activity as a formal criterion (now 5/7 required). Molecular confirmation of a pathogenic FHL gene variant alone is sufficient for diagnosis, independent of clinical criteria.

HScore - Alternative Probabilistic Tool

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Laboratory Work-up

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Treatment

HLH-94 / HLH-2004 Protocol (Primary HLH)

• Dexamethasone (penetrates blood-brain barrier) - suppresses inflammatory cytokines
• Etoposide - potent selective depletion of activated T cells; suppresses cytokine production
• Cyclosporin A - reduces T-cell cytokine production; added in HLH-2004

Novel Targeted Therapies

• Emapalumab (anti-IFN-γ monoclonal antibody) - FDA approved; blocks the central cytokine driver in primary HLH
• Ruxolitinib (JAK1/2 inhibitor) - blocks JAK-STAT signalling downstream of IFN-γ; used especially in secondary/MAS-HLH
• Anakinra (IL-1 receptor antagonist) - used in MAS/sJIA-associated HLH

Secondary HLH

• Treat the underlying trigger - antimicrobials for infection, chemotherapy for malignancy
• MAS: High-dose corticosteroids ± cyclosporin, anakinra; cytotoxic therapy less preferred (risk of worsening the underlying rheumatological disease)

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Prognosis

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Summary Table

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Examiner's Scoring Guide

1. Definition + classification (Primary/Secondary with subtypes) - 2 marks
2. Pathogenesis - perforin-granzyme machinery, IFN-γ, cytokine storm - 2.5 marks
3. Morphological features (BM, liver, spleen) - 1 mark
4. Clinical features - 1 mark
5. HLH-2004 diagnostic criteria (all 8 listed with thresholds) - 2 marks
6. Treatment - HLH-2004 protocol, HSCT, emapalumab - 1.5 marks

Sources: Robbins & Cotran Pathologic Basis of Disease 10e (p. 581); Robbins & Kumar Basic Pathology 11e; Harrison's Principles of Internal Medicine 22e (Chapter 68, 2025)

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Anaemia of Chronic Disease (ACD) / Anaemia of Inflammation (AI) - 10 Mark Answer

Definition

• Mild to moderate anaemia in the setting of chronic infection, inflammation, or malignancy
• Low serum iron despite adequate or increased body iron stores
• Reduced erythropoietin (EPO) response
• Blunted bone marrow erythroid response
• The central mechanism is hepcidin-mediated functional iron deficiency - iron is trapped in reticuloendothelial macrophages and unavailable for erythropoiesis

Up to 40% of all anaemias worldwide have a significant ACD component. It is particularly prevalent in elderly patients.

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Causes / Associated Conditions

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Pathogenesis

1. Hepcidin - The Master Regulator (Central Mechanism)

• Iron overload → stimulates hepcidin (via HJV/hemojuvelin, HFE, TFR2 signalling → BMP/SMAD pathway → hepcidin gene transcription)
• Iron deficiency + hypoxia + erythropoietic drive → suppresses hepcidin → allows iron mobilisation

• Inflammatory cytokines, especially IL-6 → directly stimulate hepatic hepcidin synthesis (via JAK-STAT3 pathway)
• High hepcidin binds to and causes internalisation and degradation of ferroportin (FPN) - the only known mammalian iron exporter
• Ferroportin is expressed on:
  • Duodenal enterocytes (iron absorption)
  • RE macrophages (iron recycling from senescent RBCs)
  • Hepatocytes (iron storage/release)
• Loss of ferroportin at all three sites results in:
  • Blocked intestinal iron absorption
  • Iron trapped in RE macrophages (functional iron deficiency)
  • Reduced iron release from hepatocytes
• Result: serum iron falls despite replete (or increased) total body stores - "functional iron deficiency"

2. Reduced Erythropoietin (EPO) Production and Responsiveness

• Inflammatory cytokines (IL-1β, TNF-α, IFN-γ) directly suppress EPO gene transcription in peritubular renal cells
• Serum EPO is lower than expected for the degree of anaemia
• Additionally, EPO responsiveness of erythroid progenitors is blunted
• IFN-γ and TNF-α inhibit BFU-E and CFU-E colony formation in vitro
• Ceramide (a product of IFN-γ-induced sphingomyelin hydrolysis) acts as an intracellular mediator of erythroid progenitor inhibition

3. Direct Suppression of Erythropoiesis

• IFN-γ, TNF-α, IL-1β, and IL-13 directly inhibit erythroid progenitor proliferation and differentiation in bone marrow
• Reactive oxygen species generated at inflammatory sites damage erythroid precursors
• In malignancy - direct bone marrow infiltration by tumour cells

4. Shortened Red Cell Survival

• Increased macrophage activation (from inflammation) → accelerated erythrophagocytosis
• Mild extravascular haemolysis - RBC lifespan reduced from 120 days to ~60-90 days
• Cytokines alter RBC membrane deformability
• Iron-restricted erythropoiesis produces hypochromic, poorly deformable red cells

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Integrated Pathogenesis Diagram

CHRONIC INFECTION / INFLAMMATION / MALIGNANCY
              ↓
    ┌─────────────────────────────────┐
    │  Monocytes / Macrophages / T-cells│
    │  Release:  IL-6, IL-1β, TNF-α,  │
    │            IFN-γ                 │
    └─────────────────────────────────┘
         ↓              ↓              ↓              ↓
    IL-6 → Liver    TNF-α/IFN-γ    IFN-γ/TNF-α    Macrophage
    ↑ Hepcidin      ↓ EPO gene     ↓ BFU-E/       activation →
    ↓ Ferroportin   transcription  CFU-E           ↑ Erythro-
    → Fe trapped    ↓ EPO levels   → ↓ BM          phagocytosis
      in RE cells   + ↓ response   erythropoiesis  → ↓ RBC survival
    
                     ALL → ANAEMIA

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Morphological Features

Peripheral Blood

• Normocytic, normochromic anaemia in most cases (MCV 80-90 fL)
• Microcytic, hypochromic in 20-50% of cases (when hepcidin-mediated iron restriction is severe; MCV rarely <70 fL)
• Slight anisocytosis and poikilocytosis
• Reticulocyte count: not elevated (inappropriately low for degree of anaemia)
• Normal WBC and platelets (unless affected by underlying disease)

Bone Marrow

• Normocellular or mildly hypercellular/hypocellular
• Erythroid precursors: delayed Hb synthesis - frayed, hypochromic cytoplasm of late normoblasts
• Decreased sideroblasts (less iron available for developing RBCs)
• Macrophage iron stores normal or INCREASED - iron seen in macrophages on Perls' Prussian blue stain

  This is a key distinguishing feature from IDA where macrophage stores are absent

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Laboratory Findings

Key diagnostic clue: Low iron + Low TIBC + Normal/high ferritin + Normal/high BM stores = ACD Low iron + High TIBC + Low ferritin + Absent BM stores = IDA

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Distinguishing ACD from Iron Deficiency Anaemia

Ferritin >100 μg/L essentially excludes iron deficiency (Goldman-Cecil); values of 12-100 μg/L are indeterminate and require sTfR or BM biopsy.

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Clinical Features

• Anaemia is mild to moderate - Hb typically 8-10 g/dL; rarely <7 g/dL
• Symptoms: fatigue, pallor, exertional dyspnoea - often overshadowed by the underlying disease
• No specific signs (no koilonychia, no angular stomatitis - these suggest IDA)
• Symptoms of the underlying disease predominate
• Anaemia worsens with disease flares and improves with disease control

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Treatment

Primary Approach: Treat the Underlying Disease

• The most effective therapy is control of the inflammatory disorder
• Treating infection, malignancy, or immunosuppressing the rheumatological disease normalises hepcidin and restores erythropoiesis

Specific Interventions

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Summary - Key Concepts

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Examiner's Scoring Guide

1. Definition, nomenclature, epidemiology (second most common worldwide) - 1 mark
2. Causes/associated conditions (infection, autoimmune, malignancy, organ failure) - 1 mark
3. Pathogenesis - hepcidin mechanism (central), EPO suppression, direct erythroid suppression, shortened RBC survival - 3 marks
4. Morphological features - PBS and BM - 1 mark
5. Lab findings table (iron, TIBC, ferritin, sTfR, hepcidin) with comparison to IDA - 2.5 marks
6. Treatment - 1.5 marks

Sources: Henry's Clinical Diagnosis and Management by Laboratory Methods; Brenner & Rector's The Kidney 11e; Goldman-Cecil Medicine International Edition; Tietz Textbook of Laboratory Medicine 7e