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HIS > HIS06 Classification And Laboratory Diagnosis Of Anaemia I > Flashcards

HIS06 Classification And Laboratory Diagnosis Of Anaemia I Flashcards

1
Q

Adult haemoglobin

A

Haem (Prophyrin + Iron) + Globin (2α2β)

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2
Q

Anaemia

A

Definition: Low Hb concentration

Formula: Hb (gram) / Volume of blood (dL or L)
1. Low Hb mass
2. Expansion of plasma volume

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3
Q

Reference intervals for Hb concentration

A

Normally 13.3-17.1 g/dL

For different people: Specific reference interval
Determined by:
1. Age
- newborn (high as 19-20)
- children (low as 9-10)

  1. Sex
    - female < male
  2. Race
  3. Altitude
    - high altitude —> low oxygen tension —> high Hb concentration
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4
Q

Reasons of anaemia

A

Upset of balance between production and loss

Production:
- Erythropoiesis

Loss:
- Haemolysis
- Excessive bleeding

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5
Q

***Anaemia under pathological classification

A
  1. Production defect (Bone marrow failure)
  2. Destruction (Haemolysis, ↓ life span of RBC)
  3. Sequestration
  4. Dilution (Increase in plasma volume relative to RBC mass)
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6
Q

***Production defect

A

Inadequate / Ineffective RBC production

Marrow problem:
1. Loss of HSC / Production site
- **Aplastic anaemia (damage of HSC by autoimmune, drugs etc. —> Pancytopenia)
- **Marrow infiltrative lesions

  1. ***Myelodysplastic syndrome
    - Oncogenic mutation on common myeloid progenitor cells —> excessive apoptosis in mature cells —> Cytopenia in PB

Renal problem:
3. Low erythropoietin (***Chronic renal failure) / Lack of humoral stimulation

Raw material problem:
4. Iron
- ***Iron deficiency
- Inability to use Iron (Sideroblastic anaemia)

  1. Folate / B12
    - Deficiency (***Megaloblastic anaemia: impaired nucleotide synthesis —> abnormal maturation)
    - Inability to use Folate (antifolate drugs) / B12 (congenital transcobalamin II deficiency)

Other problem:
6. Globin metabolism / ***Thalassaemia
- underproduction of α/β globin chains —> globin chain imbalance —> abnormal Hb formation —> RBC precursor die in bone marrow

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7
Q

***Destruction of RBC: Haemolytic anaemia

A

Intrinsic (within RBC)
1. **Membrane defect
2. **Enzyme defect (e.g. G6PDD) (Red cell enzymopathy)
3. ***Hb defect (Haemoglobinopathy)

Extrinsic (outside RBC)
1. Ab-mediated (Alloimmune, Autoimmune, Drug-induced)
2. **Mechanical damage (*Microangiopathic haemolytic anaemia, mechanical heart valves)
3. Burn
4. Toxin
5. Infection

Interaction between intrinsic / extrinsic factors —> Paroxysmal Nocturnal Haemoglobinuria

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8
Q

***Sequestration

A

***Hypersplenism / Splenomegaly
—> Trapping / Pooling of RBC, platelets (normally 1/3 trapped), WBC
—> Cannot be released into circulation

Causes:
- **Portal hypertension (Liver cirrhosis, Hep B)
- **Haematological diseases
(- Infectious mononucleosis)

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9
Q

***Dilution (Increase in plasma volume relative to RBC mass)

A
  • Pregnancy
  • Fluid resuscitation after acute blood loss
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10
Q

***Summary: Anaemia under pathological classification

A
  1. Production defect (Bone marrow failure)
    - Inadequate RBC production
    —> Aplastic anaemia (damage of HSC by autoimmune, drugs etc. —> Pancytopenia)
    —> Iron deficiency anaemia
    —> Low erythropoietin (Chronic renal failure) / Lack of humoral stimulation
    —> Bone marrow lesions
    —> Sideroblastic anaemia (Inability to use Iron)
  • Ineffective RBC production
    —> Myelodysplastic syndrome
    (Oncogenic mutation on common myeloid progenitor cells —> excessive apoptosis in mature cells)
    —> Megaloblastic anaemia
    (Folate B12 deficiency —> impaired nucleotide synthesis —> abnormal maturation)
    —> Thalassaemia
    (underproduction of α/β globin chains —> globin chain imbalance —> abnormal Hb formation —> RBC precursor die in bone marrow)

(Iron: Deficiency / Inability to use Iron
Folate / B12: Deficiency / Inability to use Folate (antifolate drugs) / B12 (congenital transcobalamin II deficiency))

  1. Destruction (Haemolysis, ↓ life span of RBC)
    - Intrinsic
    —> membrane defect
    —> enzyme defect (e.g. G6PDD) (Red cell enzymopathy)
    —> Hb defect (Haemoglobinopathy)
  • Extrinsic
    —> Ab-mediated (Alloimmune, Autoimmune, Drug-induced)
    —> mechanical damage (Microangiopathic haemolytic anaemia, mechanical heart valves)
    —> burn
    —> toxin
    —> infection

Interaction between intrinsic / extrinsic factors —> Paroxysmal Nocturnal Haemoglobinuria

  1. Sequestration
    - Hypersplenism / Splenomegaly
    —> Trapping / Pooling of RBC, platelets (normally 1/3 trapped), WBC
    —> Cannot be released into circulation
    Causes:
    - **Portal hypertension (Liver cirrhosis, Hep B)
    - **    Haematological diseases
  2. Dilution (Increase in plasma volume relative to RBC mass)
    - Pregnancy
    - Fluid resuscitation after acute blood loss
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11
Q

Haemopoiesis

A

1 stem cell —> 10^6 mature cells

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12
Q

Red cell breakdown

A
  • Mainly extravascularly in **tissue macrophage (*Reticuloendothelial system)
  • Breakdown products recycled / excreted
  • Process happen continuously in regulated manner
  1. Globin —> Amino acids
  2. Haem —> Iron —> binds to Transferrin —> recycled
  3. Haem —> Protoporphyrin —> Unconjugated bilirubin (insoluble) —> Bilirubin glucuronides (Liver) —> Stercobilinogen (faeces) / Urobilinogen (reabsorbed, kidney)

Intravascular haemolysis:
- **G6PDD
- **Microangiopathic haemolytic anaemia
- AutoAb attack
- Sign of intravascular haemolysis: ***Haemosiderinuria

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13
Q

Normal life span of RBC

A
  • 120 days (short ∵ no nucleus)

Determined by:
1. Normal **membrane structure
2. Normal **Hb structure
3. Adequate supply of **ATP (normal enzyme system)
4. Adequate supply of **Reducing power (normal enzyme system against oxidative stress)

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14
Q

Anaemia is NOT a disease!!!

A

Anaemia: Manifestation of an underlying disease

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15
Q

Clinical features of Anaemia

A

Low Hb concentration —> Impaired O2 transport —> Tissue hypoxaemia —> Body compensation / decompensation

  1. ***Pallor
  2. ***Fatigue (hypoxaemia)
  3. ***Palpitation (cardiac compensation)
  4. ***SOB (respiratory compensation —> breathe faster)

Variation in patient presentation:
Severity depends on:
1. Extent of Hb lowering
2. Rapidity of onset
3. Adequacy / Capacity of cardiopulmonary compensation

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16
Q

Pallor

A

Less Hb in RBC

Detected in:
1. Conjunctiva (accurate)
2. Periphery pallor (not very accurate, subject to change in temperature —> vasoconstriction in cold)
- palm, nail bed, tongue, lips etc.

17
Q

***Complete blood count - Confirming diagnosis of Anaemia

A

Complete blood count (CBC) / Complete blood picture / Full blood count

  • Most frequently performed test in medical laboratories
  • Fully automated

Approach:

  1. Remember simple investigations first
  2. Get most information from least number of tests:

Parameters

  1. Red cell indices
    - Hb
    - MCV
    - MCH
    - Red cell count
    - RDW
    - MCHC
  2. Reticulocyte count
  3. WBC, platelets
  4. Peripheral blood smear
    - Size
    - Shape
    - Number
    - Colour
    - Disposition
    - Inclusion
18
Q

***Mean Cell Volume (MCV)

A
  • Mean volume of RBC —> Average size of BRC
  • Directly / Indirectly measured by machine (automatic blood cell analyser)
  • MOST useful red cell index (other than Hb)

Classifications of anaemia by MCV:
1. Microcytic
- **Fe deficiency
- **Thalassaemia
(- Both)

  1. Normocytic
    - **Renal failure
    - **    Anaemia of chronic disease (mostly, sometimes microcytic if severe enough)
  2. Macrocytic
    - **Megaloblastic anaemia
    - **    Haemolysis (Normocytic / **Macrocytic if severe ∵ marked reticulocytosis)
    - **    Aplastic anaemia (Normocytic / Macrocytic)
    - ***Myelodysplasia (Normocytic / Macrocytic: many subtypes)

(4. Dimorphic)

19
Q

Mean Cell Haemoglobin (MCH)

A

Same trend with MCV

20
Q

***Red Cell Distribution Width (RDW)

A
  • Differences in red cell sizes
  • Useful to differentiate between Fe deficiency anaemia and Thalassaemia trait
  • Low MCV, **normal RDW
    —> **    Thalassaemia trait (∵ genetic —> every RBC same size)
  • Low MCV, **high RDW
    —> **    Fe deficiency (∵ acquired)
    —> ***Severe Thalassaemia (∵ severe disruption of normal Hb structure)
21
Q

Mean Cell Haemoglobin Concentration (MCHC)

A
  • Derived from Hb, MCV, Red cell count
  • MCHC = Hb / (MCV x RBC) (i.e. total cell volume)
  • High value: sensitive indicator of **Agglutination / **Spherocytosis

Agglutination:
- RBC clump together
- RBC number read falsely by machine as low number
—> ↓ RBC —> ↑ MCHC

***Spherocytosis (Sphere-shaped RBC, loss of central pallor in RBC, smaller in size):
- due to damaged RBC membrane
—> loss of SA / volume ratio
—> fold into sphere
—> ↓ MCV —> ↑ MCHC
+
—> More Hb packed in smaller RBC —> ↑ MCHC

22
Q

***Reticulocyte count significance

A

Reticulocyte:
- Young red cells
- **Large, **Light-blue staining cells (RNA but no nucleus)
- **Polychromasia (more than 1 colour in peripheral blood, Red = RBC, Blue = Reticulocyte)
—> indicates **Marrow compensation (Functioning marrow + Adequate erythropoietin + Adequate raw materials: Fe, B12, Folate)

Reticulocytosis (前提Kidney normal, BM function normal, Adequate raw material):

  • Hypoxaemia sensed by kidney —> Erythropoietin —> stimulate production of RBC from BM
  • ***MCV ↑ (due to larger reticulocyte)

Example:
- ***Haemolytic anaemia

23
Q

WBC / Platelet abnormalities

A

Isolated anaemia: suggest Limited defect

Pancytopenia: suggest Generalised defect e.g. Bone marrow disorder

Combined pattern of RBC + WBC + Platelet may suggest diagnosis
—> Cell lineages affected

24
Q

***Peripheral blood smear / Blood film

A

RBC morphology (Normal variation in size and shape):
- Should not be examined out of **clinical context
- **Morphology of other cell lines
- Clinical history, physical examination findings and other available investigation results need to be taken into account
- Assimilate all information into a presumptive diagnosis
- Guide to further confirmative / supportive investigations

  1. ***Size
    - Anisocytosis (unequal RBC size)
    - Microcytosis, Macrocytosis
  2. **Shape
    - **    Poikilocytosis (variation in RBC shape)
    —> sickle, target, spherocyte, schistocyte, elliptocyte, acanthocyte, crenated (liver, renal failure)
  3. ***Number
    - Anaemia / Polycythaemia
  4. ***Colour
    - Normochromic
    - Polychromasia
    - Hypochromasia
    —> Central pallor diameter should NOT > 1/3 of total diameter of RBC
    —> Not enough Hb
  5. Disposition
    - Rouleaux formation (>=4 RBC clump together due to ↑ globulin production —> e.g. Plasma cell myeloma)
    - Agglutination
  6. Inclusion
    - Howell-Jolly body (nucleus remnant in RBC —> Hyposplenism —> spleen could not filter abnormal RBC)
    - Pappenheimer body (Hyposplenism)
    - Basophilic stippling
    - Organism (Malaria)
25
Q

***Other relevant investigations

A
  1. ***Iron profile - serum iron, TIBC, ferritin
  2. ***Vit B12 (total / active B12) + Folate level
  3. **Haemolysis —> **Bilirubin, LDH, Haptoglobin, Reticulocyte count, Urine haemosiderin (if suspect intravascular haemolysis)
  4. ***Renal function test
  5. Direct anti-globulin test (DAT)
  6. Hb pattern study
  7. Bone marrow examination
26
Q

Iron deficiency anaemia

A
  • MOST commonly due to chronic blood loss
  • ↑ Demand
  • Poor intake

Clinical features:
1. No symptom
2. General symptoms and signs of anaemia
3. Epithelial changes (Glossitis, Angular stomatitis, Brittle nails, Dysphagia due to pharyngeal webs)
4. Pica (abnormally craving to eat substance usually not fit for food)

Haematological findings:
- **Hypochromic **Microcytic RBC with Anisopoikilocytosis (High RDW)
- Active erythropoiesis in BM that is poorly haemoglobinised (Micronormoblastic)
- Fe stain shows ↓ / absent BM Fe store (although BM investigation NOT normally indicated in Fe deficiency anaemia)

Iron profile:
- ↓ serum Fe
- ↑ serum Transferrin —> ↓ Transferrin saturation
- ↓ serum Ferritin (but ↑ in acute inflammation ∵ acute phase reactant)

Iron absorption:
- Duodenum
- favoured by acid, reducing agents —> keep Fe soluble —> maintain in Fe2+ rather than Fe3+
- enhanced by Fe deficiency / enhanced erythropoiesis
- transported by binding to Transferrin (2 Fe atoms per molecule)

Internal Fe exchange: Unidirectional
Plasma Transferrin —> Erythron —> Monocyte-macrophage system —> Plasma Transferrin

Fe storage:
- Macrophages of liver, bone, spleen
- derived from phagocytosis of senescent RBC / defective developing RBC
- stored as **Ferritin / **Haemosiderin

Hepcidin:
- protein by liver
- bind and break down Ferroportin (iron transporter at enterocyte + membrane of macrophages in reticuloendothelial system)
—> inhibition of Fe release from macrophage + Fe absorption form GI tract
- **Increased under reactive conditions e.g. Inflammation, Infection
- **abnormally suppressed in Thalassaemia Major / Intermedia —> ***Fe overload

27
Q

Megaloblastic anaemia

A

***Maturation of nucleus is delayed relative to cytoplasm (Asynchronous maturation of nucleus)
—> ∵ Defective DNA synthesis (Folate / B12 deficiency)

Clinical features:
1. Mild jaundice (∵ ↑ Bilirubin)
2. Glossitis, Angular stomatitis
3. B12 neuropathy (can occur without haematological changes) (peripheral neuropathy, subacute combined degeneration of cord (dorsal + lateral columns))

Haematological findings:
- **Oval Macrocyte
- **Hypersegmented neutrophils
- ***Pancytopenia (mild)

Biochemical findings:
- Metabolic assays (raised methylmalonic acid, homocysteine level)
- Indirect **↑ Bilirubin, **↑ LDH

Vitamin B12
- animal products (fish, liver, dairy products)
- B12 in food bound to intrinsic factor by **gastric parietal cells —> complex absorbed in **terminal ileum
- transported in plasma attached to ***Transcobalamin II
—> deliver B12 to BM / other tissues (by receptor-mediated endocytosis)

B12 Biochemical function:
1. Methylcobalamin (Linking between 2 reactions)
- Cofactor in methylation of Homocysteine —(B12)—> Methionine
(by Methionine synthase, Methyl-tetrahydrofolate (THF) as methyl donor)
- Methyl-THF —(B12)—> ***THF —> Folate polyglutamate —> act as coenzyme for DNA synthesis —> dUMP —> dTMP —> incorporated into DNA strand

  1. Deoxyadenosylcobalamin
    - Coenzyme in conversion of Methylmalonyl CoA —> Succinyl CoA

Folate
- Dietary folates all converted to Methyl-THF (monoglutamate) by small intestine and transported
- B12 converts Methyl-THF —> THF —> Folate polyglutamate
- involved in variety of biochemical reactions requiring single Carbon unit transfer (e.g. Deoxythymidine synthesis)

B12 deficiency:
1. Diet (long term vegetarian)
2. Gastric causes (Pernicious anaemia, Post-gastrectomy)
3. Intestinal causes (stagnant loop syndrome, malabsorption syndrome, fish tapeworm)

Pernicious anaemia: organ-specific autoimmune disease
Atrophic changes in gastric mucosa
—> loss of parietal cells
—> loss of intrinsic factor needed for B12 absorption
—> Ab against gastric parietal cells and intrinsic factor detected

Folate deficiency:
1. Diet (poverty, elderly, alcoholics)
2. Malabsorption
3. Increased demand (pregnancy, haemolytic anaemia, myeloproliferative disease)
4. Antifolate drugs (Trimethoprim, Phenytoin, Pyrimethamine)

B12 / Folate deficiency?
- Vitamin assay: serum total B12 assay / serum active B12 assay / serum and red cell folate assay
- Serum total B12 = B12 bind to **Transcobalamin (active form) + B12 bind to **Haptocorrin (inactive form)

Find out cause of deficiency
1. Tests for malabsorption (upper and lower GI series +/- biopsy)
2. Anti-parietal cell Ab, Anti-intrinsic factor Ab
3. Schilling’s test

28
Q

Haemolytic anaemia

A

Destruction of RBC accelerated —> shortened RBC life span
- may not have anaemia in presence of adequate marrow compensation
—> compensated haemolysis

Extravascular haemolysis: Spleen: Macrophage clearing up damaged/defective RBC, Warm AIHA
Intravascular haemolysis: G6PD deficiency, Microangiopathic haemolytic anaemia, Cold AIHA

Causes:
- Intrinsic / Extrinsic (See previous note)
- Acquired / Inherited

Acquired
1. Immune-mediated
- Ab to RBC surface antigens
—> Spherocytes + ***positive DAT

  1. Microangiopathic
    - mechanical disruption of RBC in circulation
    —> Red cell fragmentation syndromes
    —> Schistocytes
  2. Infection
    - Malaria, Clostridium
    —> cultures, serologies

Hereditary
1. Enzymopathies
- G6PD deficiency
—> Low G6PD activity

  1. Membranopathies
    - Hereditary spherocytosis
    —> Spherocytes, family history, ***negative DAT (vs Warm AIHA)
  2. Hemoglobinopathies
    - Thalassaemia, Sickle cell disease
    —> Hemoglobin electrophoresis, genetic studies

Laboratory findings:
1. Increased Haemoglobin breakdown (↑ Total + ***Unconjugated Bilirubin)

  1. Red cell damage
    - **Spherocytes (Hereditary spherocytosis / Warm AIHA)
    - **    Schistocytes (Microangiopathic haemolytic anaemia)
    - Sickle cell (Sickle cell anaemia)
  2. ***Reticulocytosis (Polychromasia)
  3. Circulating nucleated RBC
  4. Erythroid hyperplasia (in BM)
  5. Intravascular haemolysis
    RBC damaged in circulation
    —> release free Hb (↑ plasma Hb)
    —> Free Hb bind to Haptoglobin first (↓ Haptoglobin)
    —> Haptoglobin used up
    —> Hb bind to Albumin (    ↑ Methaemalbumin, +ve Schumm’s test)
    —> Excess Hb:
  6. ***Haemoglobinaemia
  7. Filter in glomerulus (***Haemoglobinuria —> Dark urine)
  8. Iron deposition in renal tubules (***Haemosiderin) —> re-excreted in urine inside dislodged cells (Haemosiderinuria: Sign of chronic intravascular haemolysis)
29
Q

Hereditary Spherocytosis

A
  • Membrane defect
  • Dominant inheritance
  • wide spectrum of severity
  • Jaundice, Splenomegaly, Anaemia

***Deficiency/Dysfunction of RBC membrane skeletal protein
—> Membrane loss
—> loss of SA / volume ratio
—> fold into sphere
—> ↓ deformability
—> inability to pass through capillaries (esp. in spleen)
—> ∴ Spleen major site of RBC destruction (extravascular haemolysis)

Membrane abnormality associated with ↑ permeability to Na
—> compensated by ↑ activity of ATP dependent Na pump
—> however acidic pH and low glucose environment in Splenic pulp
—> failure of cation pump
—> aggravating membrane loss
—> vicious cycle

Diagnosis:
1. Family history, clinical findings
2. Haematological findings
- Blood film —> Spherocytes
- Reticulocytosis, Bone marrow erythroid hyperplasia
3. **DAT test —> -ve
4. Flow cytometric analysis of **eosin 5’ melamide (EMA) binding on RBC skeletal protein (band 3 protein) —> ↓ binding (i.e. ↓ band 3 protein)
5. Osmotic fragility test (+/- pre-incubation) —> ***↑ osmotic fragility

30
Q

G6PD deficiency

A

Under oxidative stress —> G6PD deficiency —> ↑ Haemolysis

G6PD required for **NADPH production
—> **Glutathione metabolism
—> protect from oxidative injury

Level of G6PD related to age of RBC (higher in reticulocyte)

**X-linked disorder:
- Presence of genetic variant of enzyme with ↓ catalytic activity / ↓ stability
- **Males affected (minority of heterozygous female may have symptoms as a result of skewed X-inactivation / lyonisation)

Clinical features:
- SOB
- Palpitations
- Jaundice
- Fatigue
- Fever

Laboratory diagnosis:
1. Screening test (qualitative)
- ***Lack of NADPH
—> absence of fluorescence in UV light / failure to reduce methaemoglobin

  1. ***G6PD assay (definitive)
    —> G6PD can be masked by presence of reticulocytosis / recent blood transfusion
    —> re-investigate after haemolytic episode
31
Q

Immune haemolytic anaemia

A

RBC destruction mediated by Ab directed against RBC antigens
- Spherocytosis (warm AIHA)
- RBC agglutination (cold AIHA)

  1. Autoimmune (AutoAb)
    - warm / cold
    - many idiopathic
    - associated with autoimmune disease (e.g. SLE), lymphoproliferative disorder, mycoplasma pneumonia, infectious mononucleosis
    - +ve DAT
  2. Alloimmune (AlloAb)
    - Haemolytic transfusion disorder (ABO incompatible blood transfusion)
    - Haemolytic disease of newborn (Anti-D in Rh D -ve mother —> haemolysis in Rh D +ve infant)
  3. Drug-induced
    - Hapten mechanism: Ab directed against drug-cell membrane complex
    - Immune complex mechanism: drug-Ab complex on RBC surface —> Complement deposition
    - Autoimmune
32
Q

Thalassaemia

A

Hyperproliferative anaemia

Genetic disorder of globin chain synthesis
- ↓ synthesis of particular globin chains
—> imbalance in available globin chains
—> excess chains polymerise but **unstable
—> precipitate
—> **Early destruction of RBC precursors in BM (ineffective erythropoiesis) / ***Shorten RBC life span

Laboratory findings:
- ***Hypochromic Microcytic RBC (defective haemoglobinisation)
- Abnormal globin tetramers (Hb H / Hb Barts) / Normal haemoglobin present in non-physiological amount (e.g. Hb F)
—> Increased O2 affinity
—> Tissue hypoxia (cannot unload O2)

**Laboratory diagnosis of Thalassaemia:
1. CBC, RBC indices
2. Peripheral blood film
- **Hypochromic, Microcytic
- **Reticulocytosis
- Anisocytosis (嚴重先有)
- Poikilocytosis (嚴重先有)
- Normoblasts
- **Target cells
3. β-Thalassaemia —> **Hb F, Hb A2 quantitation by chromatography / electrophoresis
4. α-Thalassaemia —> Detection of **Hb H inclusions
5. Genotyping for complex cases / Prenatal diagnosis

Prevention of Hb Bart’s hydrops fetalis and β-Thalassemia Major
1. Public health education
2. Counselling of specific target groups (couples before / soon after marriage)
3. Carrier detection
4. Antenatal, Prenatal diagnosis

33
Q

α-Thalassaemia

A
  • defective fetal + adult Hb production
  • Fetus: excess γ chains (***Hb Bart’s: γ4)
  • Adult: excess β chains (***Hb H: β4)
    —> may be masked during smear examination by concomitant β-Thalassemia
    —> ∵ cannot produce β-chains
  1. α-Thalassaemia trait (1 / 2 gene deletion)
    - 1 gene deletion: clinically / haematological silent
    - 2 gene deletion:
    —> **normal / slightly ↓ Hb level
    —> **    ↓ MCV (Microcytic), ↓ MCH (Hypochromic)
    —> **↑ RBC count
    - **    HbH inclusions: precipitated out to form blue-green granules when RBC incubated with Brilliant cresyl blue stain (哥爾夫球)
  2. Hb H disease (3 gene deletion)
    - **Chronic anaemia (Low Hb)
    - **    Splenomegaly (to remove RBC)
    - **~ALL patient have normal physical development (small proportion has thalassaemic facies)
    - can be **    Asymptomatic (∵ used to low Hb)
    - generally **NOT transfusion dependent
    - excess β chains —> **    Hb H (5-40% total Hb)
    - small amount of Hb Bart may be present
    - variable features
    - exacerbated by pregnancy / infection
    - Complication: Hypersplenism —> Splenectomy indicated
  3. Hb Bart’s hydrops fetalis (4 gene deletion)
    - no α-chain found
    - incompatible with life (unless start vigorous treatment early in fetal life)
    - excess γ chains —> Hb Bart’s (γ4)
    - edematous fetus due to **heart failure (a result of anaemia) and **liver dysfunction
    —> condition diagnosed with ultrasonography, confirmed with prenatal genetic diagnosis

Molecular genetics
- 90% due to deletions of DNA (vast majority removal of both α-genes from α-gene cluster, single α-gene deletions less common)
- 10% due to **non-deletional type (*Hb Constant Spring, Hb Quong Sze) —> more severe S/S, complications

34
Q

β-Thalassemia

A

Reduced (β+) / Absent (βo) synthesis of β-globin chain
- β chain production only becomes predominant in post-natal period
—> severe β-Thalassemia (β-Thalassemia major) manifest only when patient >= 3 months old (大個d先見到Symptoms)

  1. β-Thalassemia Trait / Minor
    - **Heterozygous for βo / β+
    - Asymptomatic
    - slightly ↓ Hb level
    - **    ↓ MCV (Microcytic), ↓ MCH (Hypochromic)
    - **↑ RBC count
    - **    ↑ Hb A2 (MOST important diagnostic feature for heterozygous β-Thalassemia)
    - many have minor ↑ Hb F
  2. β-Thalassemia Major (Cooley’s anaemia)
    - total absence / marked reduction of β-globin chains
    —> excessive α-globin chains precipitate out in RBC precursor cells
    —> extensive intramedullary destruction of RBC precursors (**Ineffective erythropoiesis)
    —> **    marked expansion of BM —> Hyperproliferative anaemia
    - **    ↑ destruction of peripheral RBC (    Haemolytic element)
    - **    ↑ Hb F level —> ***selective survival advantage (explain high level of Hb F)

Blood film:
- Marked RBC Anisocytosis (↑ RDW) + **Poikilocytosis
- **Hypochromic
- ***Numerous nucleated RBC (Normoblast)

Homozygous βo:
- complete absence of Hb A
- small amount of Hb A2
- ***HbF remainder (98%)

Clinical features:
1. Thalassaemic facies
2. Protuberant abdomen (Hepatosplenomegaly)
3. ***Poor musculoskeletal development
4. Complications e.g. Recurrent infections, spontaneous fractures, hypersplenism, leg ulcers, extramedullary haemopoiesis

Treatment:
- **Blood transfusion
- **Iron overload —> Treat with ***Iron chelation therapy (Deferoxamine)

***3 Major genetic modifiers of disease severity (can be modified to milder clinical severity e.g. Thalassemia Intermedia):
—> Nature of β-globin gene defect (whether mutation associated with severe phenotype)
—> Configuration of α-globin gene locus (affect degree of α/β globin gene imbalance)
—> Genetic determinants of Hb F level

  1. Thalassemia Intermedia (Non-transfusion dependent Thalassemia (NTDT))
    - symptomatic but milder than β-Thalassemia Major
    —> β-Thalassemia Intermedia
    —> Hb H disease
    —> Hb E β Thalassemia

Hb E:
- Haemoglobinopathy
- point mutation of β gene at position 26 —> a.a. change from Glutamate to Lysine —> Abnormal Hb (Hb E)
- mRNA of Hb E —> unstable —> **underproduced abnormal Hb —> thalassaemic presentation
- Heterozygous HbE —> Mild Microcytosis, No/Minimal anaemia (some have totally normal CBP)
- Homozygous HbE —> Microcytosis, Mild anaemia
- Compound heterozygous HbE + β-Thalassaemia —> Thalassaemia Intermedia syndrome, **Splenomegaly, other complications

Molecular genetics of β-Thalassaemia
- Point mutations (NOT gene deletions)
- Own unique set of mutations among different races

35
Q

Conditions related to Iron overload

A
  1. ***Heart failure (most common cause of death)
  2. Liver fibrosis
  3. Diabetes
  4. Hypothyroidism, Hypoparathyroidism
  5. Hypogonadism
  6. Osteopenia, Osteoporosis

Treatment:
- SC / Oral Iron chelation therapy

HIS (30 decks)

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