Pathology
MBBS Pathology — high-yield long questions and short notes from Robbins & Cotran and Harsh Mohan, covering general pathology (cell injury, inflammation, haemodynamics, immunopathology, neoplasia), haematology, and systemic pathology of the cardiovascular, respiratory, GI, hepatobiliary, renal, endocrine and other systems, written to the marks with definitions, mechanisms, morphology, classification, clinical correlation and pearls.
12chapters144questions99High-Yield
Definition
Anaemia is a reduction in haemoglobin concentration below the normal range for age and sex, causing reduced oxygen-carrying capacity.
WHO Criteria
- Adult males <13 g/dL; adult females <12 g/dL
- Pregnancy <11 g/dL; children 6–59 months <11 g/dL
- Severity: mild, moderate, severe (<7 g/dL)
Morphological Classification (MCV, MCHC)
- Microcytic hypochromic — iron deficiency, thalassaemia, sideroblastic, chronic disease
- Normocytic normochromic — acute blood loss, haemolysis, aplastic anaemia, chronic disease
- Macrocytic — vitamin B12 and folate deficiency, liver disease, hypothyroidism
Aetiological Classification
- Blood loss — acute or chronic
- Impaired production — deficiency, marrow failure
- Increased destruction — haemolysis
MCV is the practical first branch point in evaluating anaemia. MCV Type Example <80 fL Microcytic Iron deficiency 80–100 fL Normocytic Haemolysis >100 fL Macrocytic B12 deficiency Applied
- Features: pallor, fatigue, dyspnoea, tachycardia, koilonychia, glossitis
- Always identify the underlying cause, not just correct haemoglobin
🔑KEY POINTS TO REMEMBER- Anaemia = haemoglobin below normal for age and sex (WHO criteria).
- Morphological: microcytic, normocytic, macrocytic (by MCV).
- Aetiological: blood loss, impaired production, increased destruction.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Iron-deficiency anaemia is microcytic hypochromic anaemia from inadequate iron for haemoglobin synthesis — the commonest anaemia worldwide.
Causes
- Chronic blood loss — commonest: menorrhagia, hookworm, peptic ulcer, colon carcinoma, piles
- ↑ Demand — pregnancy, infancy, adolescence
- ↓ Intake — poor diet, vegetarian diet
- Malabsorption — coeliac disease, gastrectomy
Laboratory Findings
- ↓ Hb, ↓ MCV, ↓ MCH, ↓ MCHC; ↑ RDW
- Blood film: microcytic hypochromic cells, anisopoikilocytosis, pencil cells, target cells
- ↓ Serum iron, ↑ TIBC, ↓ transferrin saturation, ↓↓ serum ferritin (best single test)
- Marrow: absent iron stores (Perls stain)
Stores are exhausted before the blood picture becomes abnormal. Test Iron deficiency Chronic disease Serum iron Low Low TIBC High Low Ferritin Low Normal/high Applied
- In an adult male or postmenopausal woman, exclude gastrointestinal malignancy
- Treat with oral iron for 3 months after haemoglobin normalises
🔑KEY POINTS TO REMEMBER- Commonest anaemia; usually from chronic blood loss.
- Microcytic hypochromic with ↓ ferritin, ↓ serum iron, ↑ TIBC.
- Ferritin is the best single test; investigate the gut in adults.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Megaloblastic anaemia is macrocytic anaemia caused by impaired DNA synthesis from deficiency of vitamin B12 or folate.
Causes
- Vitamin B12 — pernicious anaemia (intrinsic factor deficiency), strict vegan diet, ileal disease/resection, fish tapeworm, blind loop
- Folate — poor diet, alcoholism, pregnancy, haemolysis, methotrexate, phenytoin
- Impaired DNA synthesis → nuclear-cytoplasmic asynchrony
Findings
- Blood: macro-ovalocytes, hypersegmented neutrophils (>5 lobes), pancytopenia
- Marrow: megaloblasts — large cells with open sieve-like chromatin; giant metamyelocytes
- ↑ LDH and ↑ indirect bilirubin (ineffective erythropoiesis)
- B12 deficiency only: subacute combined degeneration, glossitis, neuropathy
The cytoplasm matures while the nucleus lags, creating megaloblasts. Feature B12 Folate Neuropathy Present Absent Stores last Years Months Schilling test Abnormal Normal Applied
- Never give folate alone in B12 deficiency — worsens neurological damage
- Hypersegmented neutrophils are an early clue
🔑KEY POINTS TO REMEMBER- Megaloblastic anaemia results from B12 or folate deficiency impairing DNA synthesis.
- Macro-ovalocytes, hypersegmented neutrophils, megaloblastic marrow.
- Only B12 deficiency causes subacute combined degeneration.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Haemolytic anaemia results from premature destruction of red cells with a shortened lifespan (normally 120 days) exceeding marrow compensation.
Classification
- Intracorpuscular (mostly hereditary) — membrane (spherocytosis), enzyme (G6PD, pyruvate kinase), haemoglobin (sickle cell, thalassaemia)
- Extracorpuscular (mostly acquired) — immune (autoimmune, transfusion, Rh disease), infections (malaria), mechanical (prosthetic valve, microangiopathic), toxins, hypersplenism
- PNH is an acquired intracorpuscular exception
Laboratory Features
- ↑ Reticulocyte count; ↑ unconjugated bilirubin, ↑ LDH
- ↓ Haptoglobin; haemoglobinuria and haemosiderinuria (intravascular)
- Marrow erythroid hyperplasia
- Coombs test positive in immune haemolysis
Increased destruction plus a brisk marrow response defines haemolysis. Marker Change Reticulocytes Raised Indirect bilirubin Raised Haptoglobin Reduced Applied
- Clinical triad: anaemia, jaundice, splenomegaly
- Chronic haemolysis → pigment gallstones, aplastic crisis (parvovirus B19)
🔑KEY POINTS TO REMEMBER- Haemolysis = shortened red-cell survival with compensatory reticulocytosis.
- Hereditary defects are intracorpuscular; acquired causes extracorpuscular.
- Labs: ↑ reticulocytes, ↑ bilirubin, ↑ LDH, ↓ haptoglobin; Coombs for immune causes.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Thalassaemias are inherited disorders with reduced or absent synthesis of globin chains, causing microcytic hypochromic haemolytic anaemia.
Types
- β-thalassaemia — ↓ β-chain synthesis (point mutations)
- Major (Cooley anaemia) — homozygous; severe anaemia from 6 months, transfusion-dependent
- Minor (trait) — heterozygous; mild anaemia, often asymptomatic
- α-thalassaemia — gene deletions; 4-gene deletion causes hydrops fetalis
Features & Diagnosis
- Excess unpaired chains precipitate → ineffective erythropoiesis + haemolysis
- Marrow expansion → frontal bossing, ‘hair-on-end’ skull, chipmunk facies
- Hepatosplenomegaly, growth retardation, iron overload from transfusions
- Film: microcytic hypochromic, target cells, nucleated red cells, basophilic stippling
- HbF markedly raised; HPLC/electrophoresis confirms; ↑ HbA2 in trait
Imbalanced globin chains damage red-cell precursors in the marrow. Feature Major Trait Severity Severe Mild Transfusion Dependent Not needed HbA2 Variable Raised Applied
- Treatment: regular transfusion + iron chelation (desferrioxamine); marrow transplant is curative
- Prevention: carrier screening and antenatal diagnosis
🔑KEY POINTS TO REMEMBER- Thalassaemia is reduced globin chain synthesis — β (mutation) or α (deletion).
- Major: severe transfusion-dependent anaemia with skeletal changes and iron overload.
- Raised HbF/HbA2 on HPLC confirms; treat with transfusion plus chelation.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Morphological classification groups anaemias by red-cell indices, chiefly the MCV and MCHC, and guides investigation.
Microcytic Hypochromic (MCV <80 fL)
- Iron-deficiency anaemia — commonest
- Thalassaemia; sideroblastic anaemia
- Anaemia of chronic disease (may be normocytic or microcytic)
- Lead poisoning
Normocytic and Macrocytic
- Normocytic normochromic (80–100 fL) — acute blood loss, haemolytic anaemia, aplastic anaemia, chronic renal disease, chronic disease
- Macrocytic (>100 fL) — megaloblastic (B12, folate) and non-megaloblastic (alcohol, liver disease, hypothyroidism, reticulocytosis)
MCV rapidly narrows a long differential diagnosis. Type MCV Example Microcytic <80 fL Iron deficiency Normocytic 80–100 fL Haemolysis Macrocytic >100 fL B12 deficiency Applied
- Dimorphic picture suggests combined deficiency
- Always correlate with the peripheral blood film
🔑KEY POINTS TO REMEMBER- Classified by MCV: microcytic, normocytic, macrocytic.
- Microcytic: iron deficiency, thalassaemia, sideroblastic.
- Macrocytic: megaloblastic (B12/folate) and non-megaloblastic causes.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Sickle-cell anaemia is an inherited haemoglobinopathy caused by a point mutation producing HbS, which polymerises on deoxygenation.
Molecular Basis
- Point mutation in the β-globin gene — glutamate → valine at position 6
- Deoxygenated HbS polymerises → rigid sickle-shaped cells
- Sickled cells cause vaso-occlusion and haemolysis
- Autosomal recessive; trait is protective against falciparum malaria
Clinical Features
- Vaso-occlusive (painful) crisis — bone pain, dactylitis, acute chest syndrome, stroke
- Haemolytic anaemia, jaundice, pigment gallstones
- Autosplenectomy → risk of encapsulated organism infection, Salmonella osteomyelitis
- Aplastic crisis with parvovirus B19
- Diagnosis: sickling test, HPLC/electrophoresis showing HbS
Low oxygen tension triggers polymerisation and the clinical crises. Feature Detail Mutation β6 Glu→Val Crisis trigger Hypoxia, infection, dehydration Prophylaxis Penicillin, vaccines Applied
- Hydroxyurea raises HbF and reduces crises
- Hydration, oxygen and analgesia for painful crises
🔑KEY POINTS TO REMEMBER- Sickle-cell anaemia: β-globin Glu→Val at position 6 producing HbS.
- Deoxygenation causes polymerisation, vaso-occlusion and haemolysis.
- Autosplenectomy increases infection risk; hydroxyurea reduces crises.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Hereditary spherocytosis is an inherited red-cell membrane defect producing spherical cells that are destroyed in the spleen.
Pathogenesis
- Autosomal dominant (usually); commonest inherited membrane disorder
- Defect in spectrin, ankyrin or band 3 cytoskeletal proteins
- Membrane loss → spherical, less deformable cells
- Trapped and destroyed in splenic cords → extravascular haemolysis
Features & Diagnosis
- Anaemia, jaundice, splenomegaly; pigment gallstones
- Aplastic crisis with parvovirus B19
- Film: spherocytes (no central pallor); ↑ reticulocytes, ↑ MCHC
- Osmotic fragility increased; EMA binding test and flow cytometry
- Coombs test negative (distinguishes from autoimmune haemolysis)
Loss of membrane converts biconcave discs into fragile spheres. Test Result Osmotic fragility Increased MCHC Raised Coombs Negative Applied
- Splenectomy is curative for the anaemia (cells remain spherocytic)
- Vaccinate before splenectomy; give folate supplements
🔑KEY POINTS TO REMEMBER- Autosomal dominant defect of spectrin/ankyrin/band 3.
- Spherocytes with ↑ MCHC and ↑ osmotic fragility; Coombs negative.
- Splenectomy is curative for the haemolysis.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked red-cell enzyme defect causing episodic haemolysis under oxidative stress.
Pathogenesis
- G6PD is the first enzyme of the HMP shunt, generating NADPH
- NADPH maintains reduced glutathione to counter oxidants
- Deficiency → haemoglobin oxidised → Heinz bodies
- Splenic removal of Heinz bodies → ‘bite cells’
- Commonest human enzyme deficiency; protective against malaria
Triggers & Diagnosis
- Drugs — primaquine, sulfonamides, nitrofurantoin, dapsone, chloramphenicol
- Infection, fava beans (favism), naphthalene balls
- Acute intravascular haemolysis: jaundice, dark urine, back pain
- Neonatal jaundice
- Diagnosis: G6PD assay (after the acute episode — falsely normal during it)
Without NADPH, red cells cannot neutralise oxidative stress. Finding Detail Inheritance X-linked recessive Film Bite cells, Heinz bodies Trigger Drugs, fava beans Applied
- Test G6PD before primaquine in malaria
- Management is avoidance of triggers; transfuse if severe
🔑KEY POINTS TO REMEMBER- X-linked deficiency of G6PD reduces NADPH and glutathione.
- Oxidant stress → Heinz bodies and bite cells with intravascular haemolysis.
- Triggers: primaquine, sulfonamides, fava beans, infection.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Aplastic anaemia is pancytopenia with a hypocellular marrow due to failure of haematopoietic stem cells.
Causes
- Idiopathic — about 50–65% of cases (immune-mediated)
- Drugs — chloramphenicol, cytotoxics, gold, phenylbutazone, antithyroid drugs
- Chemicals — benzene, insecticides; radiation
- Infections — viral hepatitis, parvovirus B19, EBV, HIV
- Inherited — Fanconi anaemia
Features & Diagnosis
- Anaemia (pallor, fatigue), infections (neutropenia), bleeding (thrombocytopenia)
- No splenomegaly or lymphadenopathy — important negative
- Blood: pancytopenia with low reticulocyte count
- Bone marrow biopsy — hypocellular, replaced by fat; diagnostic
One stem-cell failure produces deficits in all three cell lines. Finding Aplastic anaemia Marrow Hypocellular Reticulocytes Low Spleen Not enlarged Applied
- Treatment: bone marrow transplant (young patients) or immunosuppression (ATG + ciclosporin)
- Supportive: transfusions, antibiotics, growth factors
🔑KEY POINTS TO REMEMBER- Aplastic anaemia = pancytopenia with hypocellular marrow.
- Causes: idiopathic, drugs (chloramphenicol), chemicals, radiation, viruses.
- No splenomegaly; treated by transplant or immunosuppression.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Pernicious anaemia is autoimmune atrophic gastritis causing intrinsic factor deficiency and hence vitamin B12 malabsorption.
Pathogenesis
- Autoimmune destruction of gastric parietal cells
- Anti-parietal cell and anti-intrinsic factor antibodies
- ↓ Intrinsic factor → B12 not absorbed in the terminal ileum
- Achlorhydria; associated with other autoimmune diseases (thyroid, vitiligo)
- Middle-aged and elderly, northern European descent
Features & Diagnosis
- Megaloblastic anaemia with glossitis and lemon-yellow tint
- Subacute combined degeneration — posterior and lateral columns; paraesthesia, ataxia
- ↓ Serum B12; ↑ methylmalonic acid and homocysteine
- Antibodies positive; abnormal Schilling test corrected by intrinsic factor
- ↑ Risk of gastric carcinoma
Losing intrinsic factor blocks B12 uptake regardless of dietary intake. Feature Detail Antibody Anti-intrinsic factor Neurological SACD Long-term risk Gastric carcinoma Applied
- Treat with parenteral B12 lifelong (oral is ineffective)
- Neurological damage may be irreversible if treatment is delayed
🔑KEY POINTS TO REMEMBER- Pernicious anaemia is autoimmune loss of intrinsic factor.
- Causes megaloblastic anaemia plus subacute combined degeneration.
- Treated with lifelong parenteral B12; raises gastric cancer risk.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.Definition
Haemolysis is intravascular when red cells lyse within the circulation, and extravascular when they are removed by macrophages of the spleen and liver.
Intravascular Haemolysis
- Red cells destroyed within vessels
- Free haemoglobin → haemoglobinaemia, haemoglobinuria, haemosiderinuria
- Haptoglobin markedly reduced; ↑↑ LDH
- Causes: ABO-incompatible transfusion, G6PD crisis, PNH, malaria (blackwater fever), prosthetic valve, microangiopathic haemolysis
Extravascular Haemolysis
- Red cells removed by splenic and hepatic macrophages
- Splenomegaly typical; jaundice with ↑ unconjugated bilirubin
- No haemoglobinuria; haptoglobin only mildly reduced
- Causes: hereditary spherocytosis, autoimmune haemolytic anaemia, thalassaemia, sickle-cell disease
Where the cell is destroyed determines the laboratory picture. Feature Intravascular Extravascular Haemoglobinuria Present Absent Haptoglobin Very low Mildly low Splenomegaly Uncommon Common Applied
- Red urine with anaemia suggests intravascular haemolysis
- Splenectomy helps only in extravascular haemolysis
🔑KEY POINTS TO REMEMBER- Intravascular: haemoglobinaemia, haemoglobinuria, very low haptoglobin.
- Extravascular: splenomegaly, unconjugated hyperbilirubinaemia, no haemoglobinuria.
- ABO mismatch is intravascular; spherocytosis is extravascular.
📚SOURCES: Robbins & Cotran Pathologic Basis of Disease; Textbook of Pathology (Harsh Mohan); de Gruchy’s Clinical Haematology in Medical Practice.