I have a seminar based on the main topic "Approach to patient with pallor (anaemia)". Explain in detail the clinical features including the complications of different types of anaemia. Use all the information from the given document only.

Approach to Patient with Pallor (Anaemia) — Clinical Features & Complications

Based exclusively on the provided Davidson's document

Overview

Around 30% of the total world population is anaemic. The classification of anaemia by the size of the red cells (MCV) indicates the likely cause. Anaemias can be broadly divided by MCV into:

Microcytic (↓MCV <76 fL) — defective haemoglobinisation (e.g. iron deficiency, thalassaemia, sideroblastic anaemia)
Macrocytic (↑MCV >100 fL) — defective DNA synthesis (e.g. B12/folate deficiency, cytotoxic drugs, myelodysplasia) or elevated plasma lipids
Normocytic — anaemia of chronic disease, haemolysis (early)

1. Iron Deficiency Anaemia

Causes

Blood loss: Gastrointestinal loss (most common in men and post-menopausal women) — occult gastric/colorectal malignancy, gastritis, peptic ulceration, IBD, diverticulitis, polyps, angiodysplasia; hookworm and schistosomiasis worldwide. Menstrual blood loss, pregnancy, breastfeeding in women of child-bearing age. Rarely: chronic haemoptysis or haematuria.
Malabsorption: Achlorhydria (older patients, proton pump inhibitors), previous gastric surgery, coeliac disease
Physiological demands: Infancy, puberty, pregnancy (iron diverted to fetus, placenta, increased maternal red cell mass, lost at parturition)

Clinical Features

Iron deficiency produces a microcytic, hypochromic anaemia. Symptoms and signs arise from the anaemia itself (fatigue, breathlessness, pallor) as well as from tissue iron deficiency.

Investigations (Box 25.30)

Test	Iron Deficiency Anaemia
Ferritin	↓
Iron	↓
TIBC	↑
Transferrin saturation	↓ (< 16%)
Soluble transferrin receptor	↑

Management

Unless the patient has angina, heart failure or evidence of cerebral hypoxia, transfusion is not indicated
Oral ferrous sulphate 200 mg 3 times daily (195 mg elemental iron/day) for 3–6 months to replete stores
Haemoglobin rises by ~10 g/L every 7–10 days; reticulocyte response within a week
Parenteral iron (ferric isomaltose or ferric carboxymaltose) for malabsorption, chronic gut disease or oral intolerance

2. Anaemia of Chronic Disease (ACD / Anaemia of Inflammation)

Causes

Occurs in the setting of chronic infection, chronic inflammation or neoplasia.

Clinical Features

Mild anaemia — haemoglobin in the range 85–115 g/L
Usually normocytic, normochromic (MCV may be reduced in long-standing inflammation)
Serum iron is low, but iron stores are normal or increased (ferritin normal or elevated)
Not related to bleeding, haemolysis or marrow infiltration

Pathogenesis

The key regulatory protein is hepcidin, produced by the liver in response to pro-inflammatory cytokines (especially IL-6). Hepcidin binds to ferroportin on intestinal enterocytes and macrophages, internalising ferroportin and thereby blocking iron export into the blood. Iron remains trapped inside cells as ferritin — hence ferritin is normal or high despite significant anaemia.

Diagnosis (Box 25.30)

Test	ACD
Ferritin	↑/Normal
Iron	↓
TIBC	↓
Transferrin saturation	↓
Soluble transferrin receptor	↓/Normal

Management

Treat the underlying disorder
Trial of oral iron may help in difficult situations (positive response only in true iron deficiency)
Trials of higher-dose intravenous iron are underway to bypass the hepcidin-induced blockade

3. Megaloblastic Anaemia

Results from deficiency of vitamin B12 or folic acid, or from disturbances in folic acid metabolism.

Pathophysiology

Folate is a substrate and vitamin B12 a co-factor for generating methionine from homocysteine, producing tetrahydrofolate → thymidine monophosphate for DNA synthesis
Deficiency → impaired DNA synthesis → arrested nuclear maturation with normal cytoplasmic development (nucleocytoplasmic asynchrony)
All proliferating cells affected: buccal mucosa, tongue, small intestine, cervix, vagina, uterus, and especially bone marrow
Ineffective erythropoiesis → expanded hypercellular marrow; haemolysis within marrow → raised bilirubin and LDH without reticulocytosis

Clinical Features (Box 25.31)

Symptoms:

Malaise (90%)
Breathlessness (50%)
Paraesthesiae (80%)
Sore mouth (20%)
Weight loss
Impotence
Poor memory, depression, personality change, hallucinations, visual disturbance

Signs:

Smooth tongue
Angular cheilosis
Vitiligo
Skin pigmentation
Heart failure
Pyrexia

Neurological Features of B12 Deficiency (Box 25.33)

Vitamin B12 deficiency — but not folate deficiency — is associated with neurological disease in up to 40% of cases. The main pathological finding is focal demyelination affecting the spinal cord, peripheral nerves, optic nerves and cerebrum.

Peripheral nerves:

Glove and stocking paraesthesiae
Loss of ankle reflexes

Spinal cord (Subacute combined degeneration):

Posterior columns — diminished vibration sensation and proprioception
Corticospinal tracts — upper motor neuron signs

Cerebrum:

Dementia
Optic atrophy
Autonomic neuropathy

Investigations (Box 25.32)

Investigation	Result
Haemoglobin	Often reduced, may be very low
Mean cell volume	Usually raised, commonly >120 fL
Erythrocyte count	Low for degree of anaemia
Blood film	Oval macrocytosis, poikilocytosis, red cell fragmentation, neutrophil hypersegmentation
Reticulocyte count	Low for degree of anaemia
Leucocyte count	Low or normal
Platelet count	Low or normal
Bone marrow	Increased cellularity, megaloblastic changes, giant metamyelocytes, dysplastic megakaryocytes, increased iron stores, pathological non-ring sideroblasts
Serum ferritin	Elevated
Plasma LDH	Elevated, often markedly

If severe, pancytopenia may be present in the peripheral blood.

Causes of Vitamin B12 Deficiency

Dietary deficiency — strict vegans only
Gastric pathology — hypochlorhydria in older patients, gastric surgery (total gastrectomy invariably causes B12 deficiency within 5 years)
Pernicious anaemia — organ-specific autoimmune disorder; atrophic gastric mucosa with loss of parietal cells causing intrinsic factor deficiency; incidence 25/100,000 over age 40; associated with Hashimoto's thyroiditis, Graves' disease, vitiligo, Addison's disease; anti-intrinsic factor antibodies are diagnostic; antiparietal cell antibodies present in >90% of cases
Small bowel pathology — pancreatic exocrine insufficiency, Crohn's disease of terminal ileum, motility disorders/hypogammaglobulinaemia causing bacterial overgrowth, fish tapeworm

Causes of Folate Deficiency (Box 25.34)

Poor intake of vegetables
Malabsorption (coeliac disease, small bowel surgery including bariatric surgery)
Increased demand (haemolysis, pregnancy — most common cause of megaloblastosis worldwide)
Drugs: anticonvulsants (phenytoin), contraceptive pill, cytotoxic drugs (methotrexate)

Management of Megaloblastic Anaemia

If treatment must start before results available, always give both folic acid and vitamin B12 — folic acid alone in B12 deficiency may worsen neurological features
Vitamin B12 deficiency: Hydroxocobalamin 1000 µg IM for 6 doses 2–3 days apart, then maintenance 1000 µg every 3 months for life (malabsorption); if neurological involvement, alternate day dosing until no further improvement
Folate deficiency: Oral folic acid 5 mg daily for 3 weeks (acute); 5 mg once weekly maintenance; prophylactic folic acid in pregnancy prevents megaloblastosis and reduces risk of fetal neural tube defects
Rarely, if severe angina or heart failure present, transfusion may be used — but volume load from transfusion may cause decompensation and severe cardiac failure; exchange transfusion or slow administration of 1 unit of red cells with diuretic cover may be given

4. Haemolytic Anaemia

Haemolysis indicates shortening of the normal red cell lifespan of 120 days. Anaemia occurs only if the rate of destruction exceeds the compensatory increased production rate (bone marrow can increase output 6–8 fold).

General Features of Haemolysis (Box 25.36)

Hallmarks:

↓ Haemoglobin
↑ Unconjugated bilirubin → mild jaundice
↑ Lactate dehydrogenase
↑ Reticulocytes (reticulocytosis)
↑ Urinary urobilinogen

Additional features of intravascular haemolysis:

↓ Haptoglobin
↑ Methaemalbimin
Positive urinary haemosiderin
Haemoglobinuria (black urine in fulminant cases, e.g. falciparum malaria — "blackwater fever")

Blood film clues:

Spherocytes → autoimmune haemolysis or hereditary spherocytosis
Sickle cells → sickle-cell disease
Red cell fragments → microangiopathic haemolysis
Bite cells → oxidative haemolysis

The compensatory erythroid hyperplasia may give rise to folate deficiency with megaloblastic blood features.

4a. Hereditary Spherocytosis

Autosomal dominant (25% new mutations); incidence ~1:5000 in high-income countries
Most common abnormalities: deficiencies of beta spectrin or ankyrin
Severity variable: most cases asymptomatic compensated chronic haemolytic state

Clinical features:

Spherocytes on blood film, reticulocytosis, mild hyperbilirubinaemia
Pigment gallstones in up to 50% of patients → symptomatic cholecystitis

Crises (complications):

Haemolytic crisis: Increased severity of haemolysis, rare, usually with infection
Megaloblastic crisis: Follows folate deficiency; may be first presentation in pregnancy
Aplastic crisis: Associated with parvovirus (erythrovirus) infection — virus invades red cell precursors and temporarily switches off red cell production → severe anaemia with low reticulocyte count

Management:

Folic acid prophylaxis (5 mg daily) for life
Splenectomy in severe cases (improves but does not normalise red cell survival; delay until after 6 years of age due to risk of sepsis)

4b. Hereditary Elliptocytosis

Heterogeneous group; autosomal dominant or recessive; incidence 1:10,000 in Western countries but more common in equatorial Africa and parts of South-East Asia
Due to functional abnormality of anchor proteins (e.g. alpha spectrin or protein 4.1)
Most cases: asymptomatic blood film abnormality; occasional cases: neonatal haemolysis or chronic compensated haemolytic state
A characteristic variant in South-East Asia (Malaysia, Papua New Guinea) with stomatocytes and ovalocytes has a prevalence up to 30% in some communities because it offers relative protection from malaria

4c. Red Cell Enzymopathies

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

Most common human enzymopathy — affecting 10% of the world's population; geographical distribution parallels the malaria belt. X-linked; affects males and rare homozygous females.

Clinical features (Box 25.38):

Acute drug-induced haemolysis: analgesics (aspirin, phenacetin), antimalarials (primaquine, quinine, chloroquine, pyrimethamine), antibiotics (sulphonamides, nitrofurantoin, ciprofloxacin), miscellaneous (quinidine, probenecid, vitamin K, dapsone)
Chronic compensated haemolysis
Infection or acute illness
Neonatal jaundice (B⁻ enzyme)
Favism: acute haemolysis after ingestion of broad beans (Vicia fava)

Laboratory features during an attack (non-spherocytic intravascular haemolysis):

Bite cells, blister cells, irregularly shaped small cells, polychromasia
Heinz bodies (denatured haemoglobin) visible on supravital stain

Pyruvate Kinase Deficiency

Second most common red cell enzyme defect; autosomal recessive; results in ATP deficiency and chronic haemolytic anaemia; blood film shows characteristic 'prickle cells' resembling holly leaves; enzyme activity only 5–20% of normal.

Pyrimidine 5' Nucleotidase Deficiency

Autosomal recessive; as common as PK deficiency in Mediterranean, African and Jewish populations; accumulation of excess ribonucleoprotein results in coarse basophilic stippling associated with a chronic haemolytic state; very sensitive to inhibition by lead (explains why basophilic stippling is a feature of lead poisoning).

4d. Autoimmune Haemolytic Anaemia (AIHA)

Results from red cell autoantibodies (IgG, IgM, rarely IgE or IgA).

Warm autoimmune haemolysis (80% of cases, IgG, bind best at 37°C):

Incidence ~1:100,000 per annum; more common in middle age and females
No underlying cause in up to 50% of cases; remainder secondary to SLE, RA, drugs (methyldopa, mefenamic acid, penicillin, quinidine, fludarabine), lymphoid malignancy (CLL, myeloma, lymphoma), other malignancy, ulcerative colitis, HIV
Spherocytes and polychromasia on blood film
Diagnosis confirmed by direct Coombs (antiglobulin) test
Treatment: prednisolone 1 mg/kg orally (response in 70–80%); transfusion for life-threatening problems (heart failure); second-line: rituximab (anti-CD20); third-line: immunosuppressives or splenectomy

Cold agglutinin disease (20% of cases, IgM, bind best at 4°C):

Chronic: associated with underlying low-grade B-cell lymphoma → low-grade intravascular haemolysis, acrocyanosis (cold, painful blue fingers, toes, ears, nose due to red cell agglutination in small vessels)
Acute/transient: associated with Mycoplasma pneumoniae or infectious mononucleosis
Paroxysmal cold haemoglobinuria: rare in children; Donath–Landsteiner antibody (IgG, anti-P antigen)
MCV may be spuriously high (analysers detect red cell aggregates as single cells)
Management: transfusion support, keep extremities warm; some respond to rituximab

4e. Paroxysmal Nocturnal Haemoglobinuria (PNH)

Rare acquired clonal expansion of haematopoietic stem cells deficient in GPI anchor proteins (including CD55 and CD59) → increased sensitivity of red cells to complement-mediated lysis.

Clinical features:

Episodes of intravascular haemolysis → haemoglobinuria, most noticeable in early morning urine (characteristic red–brown colour)
Increased risk of venous and arterial thrombosis in unusual sites (liver, abdomen)
Associated with hypoplastic bone marrow failure, aplastic anaemia and myelodysplastic syndrome

Management:

Transfusion and folate supplements; prophylaxis/treatment of thrombosis
Standard care: anti-complement C5 monoclonal antibodies eculizumab and ravulizumab (effective in reducing haemolysis, transfusion requirements and thrombotic risk)
All treated patients must be vaccinated against Neisseria meningitidis

5. Haemoglobinopathies

5a. Sickle-Cell Anaemia

Results from a single glutamic acid to valine substitution at position 6 of the beta globin chain; autosomal recessive. Homozygotes produce only HbS (SS disease); heterozygotes have sickle-cell trait (HbAS) — previously thought asymptomatic but may be associated with increased risk of sudden and cardiovascular death in young adults.

When HbS is deoxygenated, molecules polymerise to form tactoids — distorting the red cell membrane into characteristic sickle-shaped cells. Sickling is precipitated by hypoxia, acidosis, dehydration and infection. Irreversibly sickled cells have shortened survival and plug vessels in the microcirculation.

Clinical Features and Complications (Fig. 25.24)

Acute crises:

Crisis	Features
Painful vaso-occlusive crisis (most common)	Plugging of small vessels in bone → acute severe bone pain; hands/feet in children (dactylitis); femora, humeri, ribs, pelvis, vertebrae in adults; systemic response with tachycardia and fever
Stroke	Single most devastating consequence; occurs in 10–15% of children; silent stroke also occurs
Sickle chest syndrome (most common cause of death in adults)	Follows vaso-occlusive crisis; bone marrow infarction → fat emboli to lungs → further sickling and infarction → ventilatory failure if not treated
Sequestration crisis	Thrombosis of venous outflow from an organ → loss of function and acute painful enlargement; spleen most common in children → massive splenic enlargement → severe anaemia, circulatory collapse, death; priapism may occur
Aplastic crisis	Parvovirus B19 infection → severe but self-limiting red cell aplasia → profound anaemia, may cause heart failure; uniquely, reticulocyte count is LOW

Chronic organ damage:

CNS: Cerebrovascular event, subarachnoid bleed, fits
Ocular: Background retinopathy, proliferative retinopathy, vitreous bleeds
Pulmonary: Sickle chest syndrome, infection, pulmonary hypertension, osteomyelitis
Cardiac: Sickle myocardium, cardiomegaly, transfusional iron overload
Skeletal: Vertebral collapse, osteoporosis, avascular necrosis, arthropathy, dactylitis
Splenic: Splenic infarction (recurrent sickling in childhood → no functional spleen in adults)
Hepatic: Hepatic sequestration, cholelithiasis
Renal: Enuresis, haematuria, papillary necrosis, chronic renal failure
Leg ulceration
Pregnancy: Increased rates of placental failure → pre-eclampsia and intrauterine growth retardation, painful crisis, thrombosis

Prognosis (in Africa): Even with standard medical care, approximately 15% die by age 20 years and 50% by age 40 years.

Investigations

Compensated anaemia, usually around 60–80 g/L
Blood film: sickle cells, target cells, features of hyposplenism; reticulocytosis
Haemoglobin electrophoresis: absence of HbA, 2–20% HbF, predominance of HbS

5b. Thalassaemias

Inherited impairment of haemoglobin production — partial or complete failure to synthesise a specific globin chain. Excess chains precipitate, causing red cell membrane damage and reduced red cell survival due to haemolysis.

Beta-Thalassaemia

Thalassaemia major (homozygotes) (Box 25.40):

Profound hypochromic anaemia
Evidence of severe red cell dysplasia
Erythroblastosis
Absence or gross reduction of haemoglobin A
Raised levels of haemoglobin F
Develops profound transfusion-dependent hypochromic anaemia after the first 4–6 months of life

Thalassaemia minor (heterozygotes):

Mild anaemia
Microcytic hypochromic erythrocytes (not iron-deficient)
Some target cells
Punctate basophilia
Raised haemoglobin A₂ fraction
Little or no clinical disability

Management (Box 25.41):

Erythropoietic failure: allogeneic HSCT from HLA-compatible sibling; transfusion to maintain Hb >100 g/L; folic acid 5 mg daily
Iron overload (from transfusions): iron therapy contraindicated; iron chelation therapy required
Splenomegaly causing mechanical problems or excessive transfusion needs: splenectomy

Alpha-Thalassaemia

Common in South-East Asia
1 allele deleted → no clinical effect
2 alleles deleted → mild hypochromic anaemia
3 alleles deleted → haemoglobin H disease (beta-chain tetramer, functionally useless)
4 alleles deleted → stillbirth (hydrops fetalis)

5c. Other Haemoglobinopathies

Haemoglobin C (HbC) disease: clinically silent but associated with microcytosis and target cells on blood film.

Haemoglobin SC disease: compound heterozygotes inheriting one HbS and one HbC gene → behaves like a mild form of sickle-cell disease; associated with reduced frequency of crises but not uncommonly associated with complications in pregnancy and retinopathy.

Summary Table: Differentiating Key Anaemias

Feature	Iron Deficiency	ACD	Megaloblastic	Haemolytic
MCV	↓ (microcytic)	Normal/↓	↑ (macrocytic)	Normal/↑
Reticulocytes	↓	↓	↓ (low for degree)	↑↑
Bilirubin	Normal	Normal	↑ (unconjugated)	↑ (unconjugated)
LDH	Normal	Normal	↑↑	↑
Ferritin	↓↓	↑/Normal	↑	Normal
TIBC	↑	↓	Normal	Normal
Blood film	Hypochromic microcytes	Normocytic	Oval macrocytes, hypersegmented neutrophils	Spherocytes/sickle cells/fragments depending on cause

This is a shared conversation. Sign in to Orris to start your own chat.