GC097 Many Members Of The Family Have Anaemia (file 1)
A clinical scenario in which multiple family members present with anaemia, suggesting an inherited haemoglobinopathy or hereditary red blood cell disorder such as thalassaemia, sickle cell disease, or hereditary spherocytosis.
Inherited Diseases of Haemoglobins — Diagnosis and Treatment
Big Idea: This lecture covers hereditary haemoglobin disorders — the conditions you think of when a patient presents with a family history of anaemia and a microcytic blood picture. The two major categories are thalassaemias (quantitative defect — reduced globin chain production) and haemoglobinopathies (qualitative defect — structurally abnormal globin). Understanding these from first principles — the structure of haemoglobin, the genetics of globin gene clusters, and the pathophysiology of chain imbalance — is essential because these are among the most common genetic disorders worldwide and are directly examinable as MCQs, SAQs, and minicases. [1]
How it fits: This is GC 097, File 1 (the Medicine/clinical haematology component by Prof Eric Tse). It is the clinical counterpart to File 2 (Pathology by Dr Jason So, which covers laboratory diagnosis more heavily). Together they constitute the full "Many members of the family have anaemia" teaching session. Related lectures include GC 076 (Pallor — nutritional anaemia, anaemia of chronic disease) and the Block A haematology sessions on inherited/haemolytic/aplastic anaemia.
Learning Objectives (inferred from slides):
- Understand the structure of haemoglobin and the genetic basis of globin chain production.
- Classify hereditary haemoglobin disorders into thalassaemias and haemoglobinopathies.
- Describe the clinical syndromes of α- and β-thalassaemia (major, intermedia, trait).
- Differentiate thalassaemia trait from iron deficiency anaemia.
- Know the key haemoglobinopathies and their functional consequences.
- Apply principles of family screening and prenatal diagnosis.
The haemoglobin molecule consists of two α-globin chains and two β-globin chains (in adult HbA), each containing a haem group with a central iron atom in the ferrous (Fe²⁺) state. [1][2]
Why this matters from first principles:
- Each haemoglobin tetramer (α₂β₂) can bind four O₂ molecules — one per haem.
- The iron must be in the ferrous (Fe²⁺) state to bind oxygen reversibly. If it becomes ferric (Fe³⁺), the result is methaemoglobin, which cannot deliver O₂ to tissues.
- The globin protein wraps around the haem, protecting the iron from oxidation and giving the molecule its cooperative O₂-binding properties (the sigmoid curve).
Normal adult haemoglobin types:
| Haemoglobin | Structure | % in Adults | Notes |
|---|---|---|---|
| HbA | α₂β₂ | ~96–97% | Major adult Hb |
| HbA₂ | α₂δ₂ | ~2–3% | Elevated in β-thal trait |
| HbF | α₂γ₂ | < 1% | Fetal Hb, higher O₂ affinity |
Understanding these proportions is critical because haemoglobin pattern studies (HPLC / Hb electrophoresis) measure HbA₂ and HbF levels to diagnose thalassaemias.
Abnormal haemoglobins are caused by mutations of genes encoding the globin chains. These may result in: (1) decreased production of globin chains → thalassaemia, or (2) globin chains with abnormal function → haemoglobinopathy. [1]
| Feature | Thalassaemia | Haemoglobinopathy |
|---|---|---|
| Nature of defect | Quantitative — reduced/absent globin chain output | Qualitative — structurally abnormal globin chain |
| Mechanism of disease | Chain imbalance → excess unpaired chains precipitate → ineffective erythropoiesis + haemolysis | Abnormal protein function → sickling, instability, altered O₂ affinity, metHb |
| Examples | α-thal, β-thal | HbS, HbC, HbE, Hb Köln, Hb with ↑/↓ O₂ affinity |
| Inheritance | Autosomal recessive (co-dominant expression for carrier states) | Autosomal recessive (HbS) or dominant (some unstable Hbs) |
Key Conceptual Point
Thalassaemia = not enough of a normal chain. Haemoglobinopathy = enough of an abnormal chain. Some variants (e.g. HbE) are "thalassaemic haemoglobinopathies" — they produce an abnormal chain in reduced quantity, combining features of both.
3. Thalassaemias — Genetics
α-globin genes are located on chromosome 16. There are 4 α-globin gene loci (two on each chromosome 16). α-thalassaemia is mainly caused by deletions, though point mutations may also occur. [1]
Why deletions predominate: The α-globin gene cluster contains highly homologous duplicated genes (α1 and α2). During meiosis, misalignment of these homologous sequences leads to unequal crossing-over, which deletes one or both α genes — this is much more likely than a point mutation destroying function.
β-globin genes are located on chromosome 11. There are 2 β-globin gene loci (one on each chromosome 11). β-thalassaemia is mainly caused by point mutations, though deletions may also occur. [1]
β⁰ mutations: no β-chain produced. β⁺ mutations: β-chain production much reduced. [1]
Why point mutations predominate: The β-globin gene is a single-copy gene on each chromosome 11 — there is no nearby homologous duplicate to facilitate unequal crossing-over. Instead, hundreds of different point mutations (in promoters, splice sites, coding regions, poly-A signals) can each reduce or abolish β-chain output.
| Feature | α-Thalassaemia | β-Thalassaemia |
|---|---|---|
| Chromosome | 16 | 11 |
| Number of gene loci | 4 (αα/αα) | 2 (β/β) |
| Predominant mutation type | Deletions | Point mutations |
| Mutation nomenclature | Number of genes deleted (1–4) | β⁰ (zero output) vs β⁺ (reduced output) |
4. Clinical Syndromes of Thalassaemia
Clinical syndromes: Thalassaemia major, thalassaemia intermedia, and thalassaemia trait. [1]
The clinical severity is determined by the degree of chain imbalance — the more globin genes affected, the worse the disease.
| Syndrome | Genes deleted | Genotype | Hb level | Abnormal Hb | Clinical features |
|---|---|---|---|---|---|
| Silent carrier | 1 | -α/αα | Normal | None detectable | Asymptomatic; MCV may be borderline low |
| α-thal trait | 2 | --/αα (cis) or -α/-α (trans) | 10–13 g/dL | None detectable | Mild microcytic anaemia; no significant symptoms |
| HbH disease (intermedia) | 3 | --/-α | 6–10 g/dL | HbH (β₄) | Moderate anaemia, mild jaundice, mild-moderate splenomegaly |
| Hb Bart's hydrops fetalis (major) | 4 | --/-- | Incompatible with life | Hb Bart's (γ₄) | Dies in utero or shortly after birth; severe hydrops |
α-thalassaemia major = hydrops fetalis (Hb Bart's — 4γ globin). Dies in utero or after birth. May survive if active measures are taken. [1]
α-thalassaemia intermedia = HbH disease (4β globin). [1]
Why HbH (β₄) and Hb Bart's (γ₄) form: When α-chains are deficient, excess β-chains (in adults) or γ-chains (in fetuses) have no α partner and instead form homotetramers. These tetramers are functionally useless (very high O₂ affinity → won't release O₂ to tissues) and are unstable (precipitate → Heinz bodies → haemolysis).
Cis vs Trans deletion — Clinical Significance
Two-gene deletion α-thal trait can be cis (--/αα, both deletions on same chromosome, common in Southeast Asians/Chinese) or trans (-α/-α, one deletion on each chromosome, common in Africans/Mediterraneans). Clinically they look the same. BUT: cis carriers can pass on the "--" chromosome → their children are at risk of HbH disease or Hb Bart's hydrops if the partner also carries a deletion. Trans carriers can only pass on "-α" → much lower risk of severe disease. This is why Hb Bart's hydrops is common in Southeast Asia but rare in Africa.
| Syndrome | Genotype | Hb level | Key features |
|---|---|---|---|
| β-thal major (Cooley's anaemia) | β⁰/β⁰ or β⁰/β⁺ | Severe (< 7 g/dL without transfusion) | Presents in first year of life; transfusion-dependent for life |
| β-thal intermedia | β⁺/β⁺ (or milder β⁰/β⁺ combinations) | 6–10 g/dL | Moderate anaemia; mild jaundice; mild-moderate splenomegaly; not routinely transfusion-dependent |
| β-thal trait (minor) | β⁰/β or β⁺/β | 10–13 g/dL | Mild/no anaemia; mild/no jaundice; usually no splenomegaly |
β-thalassaemia major (Cooley's anaemia): anaemia in first year of life, transfusion dependent for life. [1]
Why symptoms appear after birth, not before: During fetal life, HbF (α₂γ₂) is the dominant haemoglobin. β-chains are not needed in utero. The switch from γ to β production occurs around 3–6 months of age (the "haemoglobin switch"). This is when β-thal major becomes clinically apparent — the baby can no longer compensate with HbF.
5. Clinical Features in Detail
Pathophysiology of β-thal major (from first principles):
- Absent/severely reduced β-chain production → excess unpaired α-chains.
- Excess α-chains precipitate in erythroid precursors → ineffective erythropoiesis (cells die in the marrow before release) and haemolysis of mature cells.
- Severe anaemia → massive compensatory marrow expansion → skeletal deformities (frontal bossing, maxillary hyperplasia — "chipmunk facies", hair-on-end appearance on skull X-ray).
- Extramedullary haematopoiesis → hepatosplenomegaly.
- Chronic transfusion requirement → iron overload (haemosiderosis/haemochromatosis) → damage to heart (cardiomyopathy — the leading cause of death), liver (cirrhosis), endocrine organs (diabetes, hypogonadism, hypothyroidism, growth failure).
- Increased intestinal iron absorption (driven by ineffective erythropoiesis via low hepcidin) worsens iron overload even without transfusions.
Management of β-thal major:
- Regular transfusions to maintain Hb 9–10.5 g/dL (suppresses ineffective erythropoiesis and prevents skeletal deformity).
- Iron chelation therapy (essential — see below).
- Splenectomy if transfusion requirements become excessive (> 200–220 mL/kg/year of packed RBCs). Post-splenectomy: lifelong penicillin prophylaxis + vaccinations (pneumococcal, meningococcal, Hib).
- Allogeneic haematopoietic stem cell transplant (HSCT) — potentially curative, best outcomes if done early (Pesaro class 1).
- Gene therapy — emerging option.
- Folic acid supplementation — chronic haemolysis increases folate demand.
Iron chelation agents: [5]
| Agent | Route | Key features |
|---|---|---|
| Deferoxamine (Desferal) | SC/IV infusion (8–12h, 5–7 nights/week) | Gold standard; compliance issue; S/E: ototoxicity, retinal changes, growth retardation |
| Deferiprone | Oral (TID) | Good for cardiac iron; S/E: agranulocytosis (requires regular CBC monitoring), arthropathy |
| Deferasirox | Oral (OD) | Convenient; S/E: GI upset, renal/hepatotoxicity |
Moderate degree of anaemia (Hb 6–10 g/dL), mild jaundice, mild to moderate splenomegaly. [1]
Patients are not routinely transfusion-dependent but may need transfusions during intercurrent illness, pregnancy, or aplastic crises (e.g., parvovirus B19 infection).
Iron overload can still develop — partly from increased GI absorption driven by ineffective erythropoiesis, even without transfusions.
Mild to no anaemia (Hb 10–13 g/dL), mild to no jaundice, usually no splenomegaly. [1]
Clinically benign. The main importance is genetic counselling — two carriers can have a child with thalassaemia major.
Six critical clinical points from the lecture slide: [1]
- Differential diagnosis of hypochromic microcytic anaemia — thalassaemia trait is the most important DDx for iron deficiency in a microcytic picture.
- Differential diagnosis of mild splenomegaly — think thalassaemia intermedia/trait alongside hereditary spherocytosis, ITP, AIHA. [6]
- Increased ferritin in some cases — do NOT assume iron deficiency just because the patient is microcytic. Thalassaemia patients may have normal or even elevated iron stores.
- Family screening is needed when one member is diagnosed — autosomal recessive inheritance means siblings and offspring may be carriers or affected.
- For at-risk couples, prenatal diagnosis is needed when pregnancy occurs — chorionic villus sampling or amniocentesis with DNA analysis.
- When anaemia is more severe than expected from the thalassaemia, investigate for other causes — e.g., concurrent iron deficiency (from menstruation, GI bleeding), folate deficiency, infection.
High-Yield Exam Point
The lecture explicitly states these six points. Expect a question asking "What additional investigations would you order?" when a known thalassaemia carrier presents with unexpectedly low Hb. The answer: look for concurrent iron deficiency (iron studies), folate deficiency, infection (reticulocyte count drops in parvovirus B19 aplastic crisis), or other cause of anaemia.
This table is directly from the lecture and is extremely high-yield: [1]
| Parameter | Thalassaemia Trait | Iron Deficiency Anaemia |
|---|---|---|
| Haemoglobin | 10–13 g/dL | Any level (can be very low) |
| RBC count | Normal or ↑ | Decreased |
| MCV | ↓ but usually not < 65 fL | Any level (can be very low, often < 65 fL) |
| Serum iron | Normal | Decreased |
| TIBC | Normal | Increased |
| % Iron saturation | Normal | Decreased |
Why RBC count is normal/raised in thalassaemia trait: The marrow is compensating and producing red cells at a normal or increased rate; each cell is just small (microcytic) and pale (hypochromic) because it contains less Hb. In IDA, the marrow cannot produce enough cells because iron is the rate-limiting substrate.
Why MCV rarely < 65 fL in thalassaemia trait: With only one β-gene affected (or 1–2 α genes deleted), the reduction in Hb per cell is modest. In severe IDA, iron stores are so depleted that each cell gets dramatically less Hb, shrinking the MCV further.
Mentzer Index (MCV/RBC):
- < 13 → suggests thalassaemia trait
-
13 → suggests IDA (Not on the lecture slide but commonly asked — a useful discriminator.)
Common Exam Trap
A microcytic anaemia with normal iron studies in an asymptomatic patient with positive family history → think thalassaemia trait, not IDA. Do NOT give iron supplements empirically — check iron studies and Hb pattern first. Unnecessary iron loading in a thalassaemia patient can be harmful.
Additional discriminating tests (from supporting sources): [3][7]
| Test | Thalassaemia Trait | IDA |
|---|---|---|
| Serum ferritin | Normal or ↑ | ↓ (but acute phase reactant — can be falsely normal in inflammation) |
| RDW (Red cell distribution width) | Normal or mildly ↑ | Typically ↑ (anisocytosis) |
| HbA₂ (by HPLC) | Elevated > 3.5% in β-thal trait | Normal or low |
| Blood film | Target cells, basophilic stippling | Pencil cells, anisopoikilocytosis |
Haemoglobin pattern study is the MOST USEFUL screening test for thalassaemia in the antenatal period. [4]
8. Haemoglobinopathies
Haemoglobinopathies are predominantly qualitative defects — structurally abnormal haemoglobin molecules with abnormal function. [1]
The lecture lists five functional categories:
HbS: occurs in people with black ancestry. Not found in the Chinese. Sickling of red blood cells when oxygen is decreased. [1]
Mechanism: A single point mutation (β6 Glu→Val) makes the deoxygenated HbS molecule polymerize into rigid fibres → distorts the RBC into a sickle shape → vaso-occlusion + haemolysis.
Triggers for sickling: hypoxia, dehydration, acidosis, cold, infection, high altitude.
Clinical features (for completeness — likely tested as MCQ distractors):
- Vaso-occlusive crises — painful bone crises, acute chest syndrome, stroke, splenic sequestration, priapism.
- Chronic haemolytic anaemia — jaundice, gallstones, aplastic crises (parvovirus B19).
- Functional asplenia — autosplenectomy from repeated infarction → susceptibility to encapsulated organisms.
Clinical Relevance for HKU
HbS is not found in Chinese populations — the lecture explicitly states this. However, it remains examinable because of global prevalence and because understanding the mechanism illustrates general principles of haemoglobinopathy.
Unstable haemoglobin chains that unfold and precipitate. Precipitated haemoglobin = Heinz body. Haemolytic anaemia, which may be triggered and exacerbated by infective episodes. [1]
Mechanism: Amino acid substitutions destabilize the globin fold → spontaneous denaturation → haem falls out → the denatured globin precipitates as Heinz bodies (seen on supravital staining with crystal violet or brilliant cresyl blue). Heinz bodies damage the RBC membrane → splenic pitting and phagocytosis → extravascular haemolysis.
Key point: Distinguish Heinz bodies (precipitated denatured Hb, seen in G6PD deficiency AND unstable Hb variants) from Howell-Jolly bodies (nuclear remnants, seen post-splenectomy/hyposplenism).
Less likely to release the bound oxygen. Causes erythrocytosis. [1]
Why erythrocytosis, not anaemia? The left-shifted O₂ dissociation curve means tissues receive less O₂ at a given PaO₂ → tissue hypoxia → ↑EPO → ↑RBC production. The patient's Hb may be high (polycythaemia) rather than low. This is a diagnostic trap — a patient with apparent polycythaemia who actually has a high-affinity Hb variant, not polycythaemia vera.
SpO₂ will be decreased, with patient relatively asymptomatic. [1]
Why asymptomatic despite low SpO₂? The right-shifted curve means O₂ is more readily released to tissues — actual tissue oxygenation is adequate. The pulse oximeter reads low because it measures the proportion of oxygenated Hb (which is lower at any given PaO₂), but this is a measurement artefact relative to the patient's actual O₂ delivery. These patients may have a mild compensatory anaemia (less Hb needed because each molecule delivers O₂ more efficiently).
Mutations lead to the iron in the haem ring being maintained at a ferric (Fe³⁺) state. Methaemoglobin is blue in colour. Methaemoglobin is increased in the presence of oxidizing agents. [1]
Hereditary vs acquired:
- Hereditary: Mutations in Hb M variants keep iron in Fe³⁺, or deficiency of cytochrome b5 reductase (methaemoglobin reductase) prevents reduction of Fe³⁺ back to Fe²⁺.
- Acquired (more common): Oxidizing drugs/agents (dapsone, nitrites, benzocaine, primaquine, aniline dyes) overwhelm the reductase.
Clinical: Cyanosis that does not respond to supplemental O₂. Chocolate-brown coloured blood that does not turn red on exposure to O₂. SpO₂ characteristically reads ~85% regardless of true PaO₂.
Treatment (acquired): Methylene blue IV (acts as electron carrier to reduce metHb). Contraindicated in G6PD deficiency (methylene blue needs NADPH from HMP shunt to work).
| Investigation | Purpose | Key findings |
|---|---|---|
| CBC with indices | Screen for anaemia, MCV, RBC count | Microcytic hypochromic anaemia; RBC count N/↑ in thal |
| Blood film | Morphology | Target cells, basophilic stippling (thal); sickle cells (HbS); Heinz bodies (unstable Hb) |
| Iron studies | Exclude IDA | Normal in thal trait; low iron/high TIBC in IDA |
| Hb pattern study (HPLC/electrophoresis) | Identify Hb variants and quantify HbA₂, HbF | ↑HbA₂ in β-thal trait; HbH band in α-thal intermedia; abnormal bands in Hbpathies |
| HbH inclusion body test | Detect α-thal | Brilliant cresyl blue staining shows golf-ball-like inclusions in HbH disease |
| DNA/genetic analysis | Confirm specific mutations | Essential for prenatal diagnosis and carrier detection |
| Serum ferritin | Iron stores | Normal/↑ in thal (may be ↑ from ineffective erythropoiesis); ↓ in IDA |
| Reticulocyte count | Marrow response | ↑ in haemolytic states; ↓ in aplastic crisis |
Family screening is needed when one member is diagnosed. For at-risk couples, prenatal diagnosis is needed when pregnancy occurs. [1]
Process:
- Index case identified → screen partner and first-degree relatives with CBC + Hb pattern study.
- If both parents are carriers (e.g., both β-thal trait) → 1 in 4 chance of affected child per pregnancy.
- Prenatal diagnosis: chorionic villus sampling (CVS, 10–12 weeks) or amniocentesis (15–18 weeks) → DNA analysis for specific mutations.
- Pre-implantation genetic diagnosis (PGD) available with IVF.
In Hong Kong: Antenatal screening programs exist. The 2022 Fourth Summative MCQ Q12 specifically asked about the most useful screening test for thalassaemia in the antenatal period — the answer is Hb pattern study, not just MCV or family history alone (though MCV is used as an initial screen). [4]
12. Past Paper Questions & Exam-Relevant Themes
| Past Paper | Question | Key Point |
|---|---|---|
| 2022 4th Summative MCQ Q12 | "Most useful screening test for thalassaemia in antenatal period?" | Answer: Haemoglobin pattern study (not family history, not Hb level, not MCV alone) [4] |
| 2021 4th Summative MCQ Q28 | "Transfusion-dependent thalassaemia patient with EF 15%, poor drug compliance. Most likely cause of heart failure?" | Answer: Haemochromatosis (iron overload cardiomyopathy from poor chelation compliance) [8] |
| 2020 4th Summative MCQ Q30 | "Pancytopenia with macrocytic anaemia, no hepatosplenomegaly" | Answer: Aplastic anaemia (distinguishing from thalassaemia intermedia — which has splenomegaly and is microcytic) [9] |
-
"A 25-year-old woman of Chinese descent is found to have Hb 11.2 g/dL, MCV 68 fL, RBC count 5.8 × 10¹²/L. Iron studies are normal. What is the most likely diagnosis?" → β-thalassaemia trait (microcytic with normal iron, high RBC count)
-
"How would you distinguish thalassaemia trait from iron deficiency anaemia?" → Iron studies (normal vs low iron/high TIBC), RBC count (N/↑ vs ↓), MCV (usually not < 65 in thal trait), Hb pattern study (↑HbA₂ in β-thal trait)
-
"An infant of Southeast Asian parents is found to have severe hydrops fetalis. What is the diagnosis and underlying haemoglobin?" → Hb Bart's hydrops fetalis (α-thal major); Hb Bart's = γ₄
-
"Why does β-thalassaemia major present at 6 months of age rather than at birth?" → The γ-to-β globin switch occurs around 3–6 months; HbF (α₂γ₂) sustains the fetus but β-chain deficiency becomes manifest only after the switch
SAQ/Minicase Style
Q1: A couple, both carriers of β-thalassaemia trait, are planning to have children. Describe the genetic risk and what prenatal options are available.
Markscheme:
- 25% chance of β-thal major, 50% trait, 25% normal per pregnancy
- Prenatal: CVS at 10–12 weeks or amniocentesis at 15–18 weeks for DNA mutation analysis
- Pre-implantation genetic diagnosis (PGD) with IVF is an option
- Genetic counselling is essential
Q2: List 4 features that help distinguish thalassaemia trait from iron deficiency anaemia.
Markscheme:
- RBC count: normal/↑ in thal trait vs ↓ in IDA
- MCV: usually not < 65 fL in thal trait vs can be very low in IDA
- Iron studies: normal in thal trait vs low iron, high TIBC in IDA
- Hb pattern study: ↑HbA₂ in β-thal trait vs normal/low in IDA
- RDW: normal in thal trait vs ↑ in IDA
Q3: Name the abnormal haemoglobin found in α-thalassaemia major and explain why it is incompatible with life.
Markscheme:
- Hb Bart's (γ₄)
- Very high O₂ affinity — does not release O₂ to tissues
- Cannot support tissue oxygenation → severe tissue hypoxia → hydrops fetalis and death in utero/at birth
| Feature | β-thal trait | α-thal trait | IDA | ACD | Sideroblastic anaemia |
|---|---|---|---|---|---|
| MCV | ↓ | ↓ | ↓↓ | N or ↓ | ↓ or N |
| RBC count | N/↑ | N/↑ | ↓ | ↓ | Variable |
| Serum iron | N | N | ↓ | ↓ | ↑ |
| TIBC | N | N | ↑ | ↓ | N |
| Ferritin | N/↑ | N | ↓ | N/↑ | ↑ |
| HbA₂ | ↑ | N | N (may ↓) | N | N |
| Blood film | Target cells | May be normal | Pencil cells | Non-specific | Ring sideroblasts (BM) |
| RDW | N | N | ↑ | N | ↑ |
- GC 076 (Pallor): Covers the general approach to anaemia, nutritional anaemia, and ACD. Thalassaemia trait is one of the key DDx for microcytic anaemia alongside IDA and ACD. [10]
- GC 097 File 2 (Pathology): Covers the laboratory diagnostic approach — Hb electrophoresis patterns, HbH inclusion body staining, interpretation of HPLC chromatograms.
- Block A - Family history of anaemia: Broader coverage including haemolytic anaemia (hereditary spherocytosis, G6PD, AIHA) and aplastic anaemia alongside inherited Hb disorders. [3]
- Block A - Splenomegaly: Thalassaemia intermedia/major and HbH disease cause minimal (1–2 cm) splenomegaly — important for the DDx of splenomegaly by size. [6]
- Complications of thalassaemia major — iron overload: Links to endocrine lectures (hypogonadotropic hypogonadism from pituitary hemosiderosis), cardiology (dilated cardiomyopathy), and hepatology (cirrhosis). [11]
High Yield Summary
Thalassaemias = quantitative ↓ globin chain production. α-thal (Chr 16, 4 loci, mainly deletions) vs β-thal (Chr 11, 2 loci, mainly point mutations with β⁰ = zero output, β⁺ = reduced output).
Clinical spectrum: Major (transfusion-dependent / hydrops fetalis) → Intermedia (Hb 6–10, mild jaundice, splenomegaly) → Trait (Hb 10–13, usually asymptomatic).
α-thal major = Hb Bart's (γ₄) → hydrops fetalis → death without active intervention. β-thal major (Cooley's) → presents ~6 months when γ→β switch occurs → lifelong transfusions + iron chelation.
Thalassaemia trait vs IDA: Key discriminators = RBC count (N/↑ vs ↓), MCV (usually not < 65 vs any), iron studies (normal vs low iron/high TIBC), HbA₂ (↑ in β-thal trait).
Haemoglobinopathies: HbS (sickling, Black ancestry, not Chinese), unstable Hb (Heinz bodies, haemolysis), ↑O₂ affinity (erythrocytosis), ↓O₂ affinity (low SpO₂ but asymptomatic), MetHb (Fe³⁺, cyanosis unresponsive to O₂).
Family screening + prenatal diagnosis for at-risk couples. Hb pattern study is the key screening test. When anaemia is worse than expected from thalassaemia alone → look for concurrent causes.
Active Recall - Inherited Diseases of Haemoglobins
[1] Lecture slides: GC 097. Many members of the family have anaemia (File 1).pdf (all pages) [2] Senior notes: Block A - Many members of the family have anaemia.pdf (Part 1) [3] Senior notes: Block A - Family history of anaemia: inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf [4] Past papers: 2022 Fourth Summative MCQ.pdf (Q12) [5] Senior notes: Maksim Medicine Notes.pdf (Haematology section — iron chelation) [6] Senior notes: Ryan Ho Haemtology.pdf (Splenomegaly classification) [7] Senior notes: Ryan Ho Haemtology.pdf (Microcytic hypochromic anaemia approach) [8] Past papers: 2021 Fourth Summative Assessment MCQ.pdf (Q28) [9] Past papers: 2020 Fourth Summative Assessment MCQ paper.pdf (Q30) [10] Senior notes: Block A - Pallor: diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf [11] Senior notes: Block A - I keep on bumping into people on my side: pituitary tumours; hypopituitarism.pdf (Hemosiderosis and hypogonadotropic hypogonadism in thalassaemia major)
GC096 Why Do I Always Get Sick
A clinical discussion exploring the reasons behind recurrent infections, typically related to immune system dysfunction, chronic stress, sleep deprivation, nutritional deficiencies, or underlying immunodeficiency conditions that increase susceptibility to illness.
GC097 Many Members Of The Family Have Anaemia (file 2)
A clinical teaching scenario in which a hereditary pattern of anaemia across multiple family members prompts evaluation for inherited haemoglobin disorders such as thalassaemia or sickle cell disease, or other genetic causes like hereditary spherocytosis.