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MBBS VI - SpC - Medicine > Haematology - Anaemia: IDA, Thalassemia, Megaloblastic anemia, Polycythemia > Flashcards

Haematology - Anaemia: IDA, Thalassemia, Megaloblastic anemia, Polycythemia Flashcards

1
Q

S/S of anemia

A

Symptoms of anaemia: due to ↓O2 delivery
□ Acute/severe: SOB (esp on exertion), palpitation, dizziness/syncope (may be postural)
□ Chronic/insidious: fatigue, Low exercise tolerance, SOB on exertion, pallor

□ Symptoms from causes, eg. menorrhagia, tarry stool, bone pain, hypovolaemia

□ Complications: cardiac ischaemia, thrombocytopenic bleeding, ↑mortality

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2
Q

S/S of following causes of anemia

  • Uremia
  • Haemolysis
  • Megaloblastic anemia
  • Haematological malignancy
  • Hypersplenism
  • Marrow infiltration
A

□ Uremia: café au lait complexion, uremic fetor, flapping tremor

□ Haemolysis: jaundice, ± mild/moderate splenomegaly

□ Megaloblastic anaemia: premature greying of hair, skin hyperpigmentation, atrophic glossitis, jaundice, oral ulcers, SCD, PN, Psychiatric complications

□ Haematological malignancy: lymphadenopathy, hepatosplenomegaly

□ Hypersplenism: isolated splenomegaly

□ Marrow infiltration: signs of infection elsewhere (leukopenia), mucocutaneous bleeding (thrombocytopenia)

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3
Q

List all Red cell indices

A

Haemoglobin (HGB)

Mean corpuscular volume (MCV)

Mean corpuscular haemoglobin (MCH)

MCH concentration (MCHC)

Red cell distribution width (RDW)

RBC count (RBC)

Haematocrit (HCT)

Reticulocyte count (RET)

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4
Q

Haemoglobin level

  • Normal ref. interval
  • Definition
A

14.0-17.5 g/dL (M) 12.3-15.3 g/dL (F)
Concentration of haemoglobin per unit volume blood

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5
Q

MCV

Normal reference interval

Definition

Clinical relevance

A

80-96 fL

Average volume per RBC

Most important
Classifies anaemia into micro-, normo-, macrocytic

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6
Q

Mean corpuscular haemoglobin

Reference interval

Definition

Clinical relevance

A

28-33 pg/RBC

Average Hb content per RBC

Used to double check MCV as prolonged storage can lead to RBC swelling due to temperature changes

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7
Q

MCHC

Normal reference range

Definition

Clinical relevance

A

33-36 g/dL RBC

Average Hb concentration per RBC

Very high = spherocytosis
Low = Fe def anaemia, thalassaemia

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8
Q

Red cell distribution width

Reference interval

Definition

Clinical relevance

A

12-15% CV

Degree of anisocytosis, i.e. variation in RBC size

Increased in reticulocytosis, Fe def anaemia and severe thalassemia (not in trait)

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9
Q

RBC count

Normal reference interval

Definition

Clinical relevance

A

4.5-5.9×109/L (M)
4.1-5.1×109/L (F)

Number of RBCs per unit volume whole blood

Parallels HGB and HCT except in extreme microcytosis, eg. thalassemia

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10
Q

Haematocrit

Normal reference

Definition

Clinical relevance

A

42-50% (M)
36-45% (F)

Volume of intact RBC per unit volume blood (as percentage)

Usually parallels HGB

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11
Q

Reticulocyte count

Normal reference range

Definition

Clinical relevance

A

0.02-0.11×109/L
0.5-2% total RBC

Percentage of reticulocytes among RBCs

Increase signifies intact marrow compensation + adequate EPO and therefore likely ↑consumption

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12
Q

Causes of Falsely elevated WBC count + anemia

A

falsely high due to circulating nucleated RBCs

Anemia: Severe hemolysis, acute hemorrhage
Acute hypoxia
Hyposplenism
Cancer: myelofibrosis, extramedullary erythropoiesis, marrow infiltration by leukemias

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13
Q

Ddx Thrombocytopenia + anemia

Ddx thrombocytosis + anaemia

A

Thrombocytopenia + anemia: DIC and thrombotic microangiopathies (TMAs), marrow infiltration by hematological malignancies

thrombocytosis + anaemia: chronic Fe deficiency, MPN, inflammatory/neoplastic disease e.g. CML

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14
Q

Describe following picture and give Ddx

A

Microcytosis (MCV<76)

Iron deficiency

Sideroblastic aneaemia

Thalassaemia

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15
Q

Describe following picture and give Ddx

A

Macrocytosis (MCV > 100fl)

Vitamin B12/ Folate deficiency

Liver disease, Alcohol

Hypothyroidism

Drugs: Zidovudine, Trimethoprim, Phenytoin, Methotrexate

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16
Q

Describe following picture and give Ddx

A

Target cell (central area of Hemoglobinization)

Liver disease

Thalassemia

Post-splenectomy

Haemoglobin C disease

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17
Q

Describe following picture and give Ddx

A

Spherocytes (no central pallor)

Autoimmune haemolytic anaemia

Post-splenectomy

Hereditary spherocytosis

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18
Q

Describe following picture and give Ddx

A

Red cell fragments (Intravascular hemolysis)

Macroangiopathic hemolysis e.g. TTP

DIC

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19
Q

Describe following picture and give Ddx

A

Nucleated red blood cells (normoblast)

Marrow infiltration

Myelofibrosis

Severe haemolysis

Acute haemorrhage

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20
Q

Describe following picture and give Ddx

A

Howell-Jolly bodies (small nuclear remnants)

Hyposplenism

Post-splenectomy

Dyshaematopoiesis

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21
Q

Describe following picture and give Ddx

A

Polychromasia (reticulocyte present)

Haemolysis

Acute haemorrhage

Increased red cell turnover

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22
Q

Causes of the following poikilocytes

Rouleaux formation

Macro-ovalocytes

Tear-drop RBC

Bite cells

RBC parasite inclusion

Basophilic stippling

A

Rouleaux formation - Paraproteinaemia

Macro-ovalocytes - Megaloblastic anaemia

Tear-drop RBC - Myelofibrosis

Bite cells - G6PD/ oxidative haemolysis

RBC parasite inclusion - Malaria, Babesiosis

Basophilic stippling - Lead poisoning, Dyshaematopoiesis

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23
Q

2 major mechanisms and sub-categories that cause anaemia *****

How to differentiate?

A
  1. Decreased RBC production - Low reticulocyte count
  • Inadequate RBC production by Erythroid hypoplasia in bone marrow
  • Ineffective erythropoiesis by Erythroid hyperplasia in bone marrow
  1. Increased peripheral consumption - High reticulocyte count
  • Increase destruction of circulating RBC (Hyperplastic marrow)
  • Increase blood loss (Hyperplastic marrow)
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24
Q

Causes of inadequate RBC production (erythroid hypoplasia)

A

Failure of trophic mechanism:
□ Chronic renal failure (↓EPO)
□ Hypothyroidism

Inadequate iron: rate-limiting step
□ Iron deficiency anaemia
□ Anaemia of chronic disease (ACD)

Bone marrow suppression:
□ Drugs, esp chemotherapy, cotrimoxazole
□ Irradiation

Bone marrow disorders:
□ Malignant infiltration
□ Aplastic anaemia
□ Pure red cell aplasia (PRCA)

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25
Q

Causes of ineffective erythropoiesis (erythroid hyperplasia)

A

 Megaloblastic anaemia
 α and β-thalassaemia (*usu ↑reticulocyte count)
 Myelodysplastic syndromes
 Sideroblastic anaemia and lead poisoning
 Congenital dyserythropoietic anaemia (CDA)

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26
Q

Causes of peripheral RBC destruction

A

Intrinsic RBC defects:
□ Enzyme deficiencies, eg. G6PD def
□ Hb defects, eg. thalassemia, Hb-pathy
□ Membrane defects, eg. hereditary spherocytosis, elliptocytosis

Extrinsic RBC defects:
□ Mechanical, eg. mechanical heart valve
□ Infections, eg. malaria
□ Immune: warm- or cold-reacting, drug-induced, alloimmune
□ Microangiopathic haemolytic anaemia (MAHA), eg. DIC, TTP

Hypersplenism

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27
Q

Causes of blood loss leading to anaemia

A

 GI bleeding (most common in general)

 Menorrhagia (most common in young F)

 Haematuria (uncommon)

 Trauma and surgery

 Respiratory tract bleeding

 Occult bleeding

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28
Q

Causes of Microcytic anaemia

A

 Iron deficiency anaemia
 Thalassaemia intermedia and major
 Anaemia of chronic disease/inflammation (some)
 Sideroblastic anaemia (congenital and acquired) and lead poisoning

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29
Q

Causes of Normocytic anaemia

A

 Acute bleeding (haemodilution) and early/recovering iron deficiency anaemia
 Anaemia of chronic disease/inflammation (ACD)
 Marrow suppression, eg. cancer, aplastic anaemia, infection
 Chronic renal insufficiency
 Microcytic anaemia masked by reticulocytosis
 Haemolytic anaemia (can be normal or high)

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30
Q

Causes of Macrocytic anaemia

A
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31
Q

Causes of Macrocytic RBC with no anaemia

A

*Causes of macrocytosis without anaemia include

Reticulopenic, macrocytic RBC:
 Hypothyroidism and liver disease due to lipid abnormalities
 Chronic alcoholism
 Drugs interfering with nucleic acid metabolism, eg. zidovudine, methotrexate, trimethoprim, phenytoin, TKIs)

Cell swelling and water retension:
 CO2 retention (e.g. COPD)

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32
Q

Outline investigation pathway for normocytic or microcytic anaemia

A
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33
Q

Outline investigative pathway for Macrocytic anaemia

A
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34
Q

Polycythaemia

Definition

Cut-offs

A

Polycythaemia: defined as abnormal elevation of haemoglobin and/or haematocrit in peripheral blood
□ Increased haemoglobin as defined as >16.5g/dL (M) and >16.0g/dL (F)
□ Increased haematocrit as defined as >49% (M) and >48% (F)

35
Q

Compare relative vs absolute polycythaemia

A

□ Relative polycythaemia: spurious ↑Hb/Hct due to loss of plasma volume (i.e. haemoconcentration)
→ Causes: diuretics, vomiting/diarrhoea, obesity, heavy smoking, Gaisbock syndrome

□ Absolute polycythaemia: true ↑Hb/Hct due to ↑total body RBC mass, which can be divided into
→ Primary polycythaemia due to autonomous production of RBCs
→ Secondary polycythaemia due to ↑serum erythropoietin

36
Q

Causes of Primary absolute polycythaemia

A

Primary (EPO = ↓/0)

Congenital: erythropoietin receptor mutations, congenital methaemoglobinaemia

Polycythemia rubra vera (due to JAK2 mutation)

Other myeloproliferative neoplasms (due to JAK2, MPL, CALR mutations)

37
Q

Causes of secondary absolute polycythaemia

A

Secondary (↑EPO)

Hypoxia-associated ↑EPO:

chronic pulmonary disease, cyanotic heart diseases, obstructive sleep apnoea, high altitude, chronic CO poisoning (incl heavy smoking)

Inappropriately increased erythropoietin:
Renal diseases: renal artery stenosis, hydronephrosis, cysts, post-transplant

EPO-producing tumours: HCC, RCC, haemangioblastoma, phaeochromocytoma, uterine leiomyoma

Performance-enhancing drugs in athletes, eg. recombinant erythropoiesis-stimulatint agents, autologous transplantation, androgens/anabolic steroids

38
Q

Symptoms of primary myeloproliferative neoplasms (giving primary absolute polycythaemia)

A

Symptoms of primary myeloproliferative neoplasms:
→ Hyperviscosity: chest/abd pain, myalgia/weakness, fatigue, headache, ↓VA, slow mentation

→ Thrombosis/bleeding: thrombosis at unusual sites, excessive bleeding/bruising

→ PV-related: unexplained fever, sweats, weight loss, aquagenic pruritus, erythromelalgia, gout

39
Q

Panel of investigations for Polycythaemia

A

□ CBC, PBS: ↑other lineages, immature WBC, leucoerythroblastic picture → suggests MPN
□ Urinalysis, L/RFT: for possible renal diseases and HCC
□ Pulse oximetry for tissue hypoxia
□ Serum EPO: low or absent serum EPO → relatively specific for MPN and PV
□ JAK2 testing for V617F mutation in PV

□ Further screen for 2o causes if JAK2 mutation negative + no clear 2o causes
→ Total red cell mass (by radiolabeling RBCs) to confirm absolute erythrocytosis
→ Sleep study for OSA
→ USG abdomen for abdominal tumours (ectopic EPO)
→ Lung function tests for respiratory diseases

□ Bone marrow aspirate + trephine if suspicious of myeloproliferative neoplasms

40
Q

Causes of hereditary microcytosis/ microcytic anaemia

A

Defects in globin synthesis:
Thalassaemia
Thalassaemic Hbpathies, eg. HbE

Defects of iron metabolism:
Iron-refractory iron deficiency anaemia
DMT1 mutation
Atransferrinaemia

Defects in porphyrin synthesis:
Inherited sideroblastic anaemia

41
Q

Causes of hereditary microcytosis/ microcytic anaemia

A

Defects in globin synthesis
Thalassaemia
Thalassaemic Hbpathies, eg. HbE

Defects of iron metabolism
Iron-refractory iron deficiency anaemia
DMT1 mutation
Atransferrinaemia

Defects in porphyrin synthesis
Inherited sideroblastic anaemia

42
Q

Causes of acquired microcytosis/ microcytic anaemia

A

Iron deficiency anaemia (IDA)

Anaemia of chronic disease (majority normocytic)

Acquired sideroblastic anaemia due to lead poisoning, alcohol, drugs

Copper deficiency (some)

Zinc toxicity

43
Q

Panel of investigations for microcytosis

A

□ ↑RDW: non-specific

□ RBC count: ↓ in Iron deficiency anaemia (IDA), N/↑ in thalassaemia

□ Iron profile and Hb studies for IDA and thalassaemia respectively

□ Blood smear:
→ Thalassaemia: marked anisopoikilocytosis (↑variation in RBC size/morphology) incl target cells, teardrop cells
→ Fe def: anisopoikilocytosis (↑variation in size and shape), but many have normal-looking RBCs
→ Anaemia of chronic disease: majority have normal sized, shape RBCs, but a subset may have microcytosis (accounts for ↓MCV)
→ Sideroblastic anaemia: ringed sideroblasts with a ring of iron granules surrounding nucleus
→ Lead poisoning: characterized by basophilic stippling (denatured RNA)

□ BM examination: rarely necessary if isolated McHc anaemia

44
Q

Iron deficiency anaemia

Outline the CBC: HBG, MCV, RDW, RBC

Iron profile: (Serum Fe, IBC, %Tf saturation, Serum ferritin)

Reticulocyte count

CRP

A
45
Q

Thalassaemia

Outline the CBC: HBG, MCV, RDW, RBC

Iron profile: (Serum Fe, IBC, %Tf saturation, Serum ferritin)

Reticulocyte count

CRP

A
46
Q

Anaemia of chronic disease

Outline the CBC: HBG, MCV, RDW, RBC

Iron profile: (Serum Fe, IBC, %Tf saturation, Serum ferritin)

Reticulocyte count

CRP

A
47
Q

Hepcidin

  • Function
  • Causes of high hepcidin state
  • Causes of low hepcidin state
A

Function: Internalize ferroportin in gut lumen >> decrease absorption of iron from gut into blood >> decrease serum iron

High hepcidin state:

  • Inflammation/ Infection >> inflammatory cytokines >> Induce hepcidin secretion from liver

Low hepcidin state:

  • Anaemia
  • Hypoxia
  • Low iron stores
48
Q

Factors that decrease iron absorption in GIT

A

High hepcidin state: Infection/ Inflammatory state

Low stomach acid (acid for reduction of iron): Gastrectomy, Long-term PPI use, Autoimmune gastritis

Low reducing agent: e.g. low Vitamin C

Iron overload

Duodenum/ small intestine pathologies/ resection causing malabsorption

49
Q

Describe the recycling and storage of iron in body

A

Internal cycling of iron:
□ Transferrin (Tf): iron transported in plasma bound to transferrin → each Tf binds 2× Fe3+
□ Utilization: used to form erythroid precursors in BM
□ RBC cycling: RBCs broken down by reticuloendothelial system (liver, spleen) and iron returned into plasma as transferrin-bound form

Storage of iron:
□ Form: ferritin and haemosiderin
□ Site: reticulo-endothelial system (RES), i.e. macrophages of liver, bone marrow and spleen → derived almost entirely from phagocytosis of senescent erythrocytes or defective developing red cells

50
Q

Causes of iron deficiency

A

Frank bleeding
*GI bleeding
*Trauma- and surgery-related bleeding
*Severe Haemoptysis
*Menorrhagia

Occult bleeding/iron loss:
Iatrogenic: frequent blood donation, excessive blood taking, haemodialysis
Occult/underestimated bleeding

Functional Iron deficiency - Post- EPO treatment

Urinary and pulmonary haemosiderosis

Malabsorption: H. pylori-related atrophic gastritis, coeliac disease, gastrectomy/gastric bypass, autoimmune gastritis

Inadequate intake (extremely rare, iron store lasts years)

51
Q

Compare absolute and functional iron deficiency

A

Absolute deficiency: absence/severely ↓iron stores in RES

Functional deficiency (iron-restricted erythropoiesis): adequate Fe for normal erythropoiesis but iron is not available for RBC, due to

  • ACD: ↑hepcidin → ↓ferroportin expression → ↓iron release into circulation
  • EPO: release into circulation not rapidly enough to respond to EPO
52
Q

Iron deficiency anaemia

Outline typical CBC, PBS, BM exam results

A

CBC:

  • *McHc anaemia** with ↓RBC count, ↓reticulocyte count
  • *Reactive thrombocytosis** due to ↑stimulation of platelet precursors by ↑EPO

PBS:

hypochromic microcytic red cells with anisopoikilosis
May be dimorphic in concurrent megaloblastic anaemia or iron supplement treatment

BM: not routinely done
Active erythropoiesis but poorly haemoglobinized (micronormoblastic)
Iron stain shows ↓/absent marrow iron stores

53
Q

Iron deficiency anaemia

Describe typical iron profile and limitations of each metric

A

Iron studies:

↓serum iron: influenced by inflammatory state, dietary intake, diurnal variation → NOT diagnostic
↑serum transferrin/TIBC but ↓Tf saturation: <16% compatible with IDA (less specific than ferritin)
↓serum ferritin: diagnostic of IDA (most Spec)
- FN: acute phase reactant → FN if inflammatory state
- FP: very rarely, hypothyroidism, vit C deficiency
↑soluble Tf receptor (sTfR): reflects ↑erythropoiesis

54
Q

Investigations to find cause of Iron Deficiency anaemia

A

□ Hx: bleeding Hx (GI, urine, menses, bleeding disorders), blood donation, RFs for GI cancers, drug Hx (NSAID, anticoagulants), previous scopes

□ P/E: as appropriate, include PR exam

□ Ix: look for occult GI bleeding first
→ FOBT×3 if >50y
→ Stool examination × ova/cyst in tropical areas
→ Upper endoscopy then colonoscopy if either IDA or FOBT+
→ Consider non-GI and small bowel causes if endoscopy –ve

55
Q

Management of Iron deficiency anaemia

Indication for different options, dosing, side effects

A

□ Treat underlying cause

□ Oral iron for majority of patients
Dosing: 150-200mg elemental iron per day until Fe profile normalized (~3-6mo)
Choice: Iron sulphate tablet, ferrum hausmann chewable tablet
Effect: ↑Hb by ~1g/dL every 7-10d with reticulocyte response in 1w
S/E: GI S/E very common → metallic taste, dyspepsia, Nausea and vomiting, altered bowel habits, black stools

□ IV iron if refractory to oral iron, with severe ongoing blood loss or malabsorption

Choice: ferric carboxymaltose, ferric gluconate, ferumoxytol, iron sucrose, iron isomaltoside
Advantage: effective, rapid correction, ensure good compliance, no GI S/E

□ Transfusion if angina, heart failure, cerebral hypoxia or Hb <7g/dL

56
Q

Anaemia of chronic disease

Pathogenesis

A

Pathogenesis: result from body’s normal response to limit availability of iron for invading microbes

□ Dysregulated iron homoeostasis:

Inflammation/ LPS in bacterial infection >> ↑ IL-6 and other cytokines >> Increase transcription and translation of Hepcidin in liver >> Hepcidin internalize ferroprotein in gut mucosa and macrophages in RES >> Decrease GI absorption of Fe and MQ release of Fe

□ Immune effect on erythropoiesis:
→ ↓EPO secretion by kidneys
→ ↓erythropoiesis
→ ↓RBC survival by ↑free radical formation → ↑RBC damage → ↑RBC turnover

57
Q

Diseases asso. with Anaemia of chronic illness

A

□ Systemic inflammatory/ Autoimmune disease, eg. RA, SLE

□ Infections: related to disease severity

□ Cancer, esp haematological malignancies

□ Chronic organ impairment: heart failure, COPD

□ Chronic solid-organ rejection after transplant

□ Chronic Kidney disease/ inflammation

58
Q

Anaemia of chronic disease

CBC, PNS, BM exam and Iron profile typical results

A

□ CBC: Mild NcNc anaemia, can be McHc (<1/4) with low reticulocyte count

□ PBS: relatively uniform population of normocytic RBCs w/o evidence of haemolysis

□ BM: iron stain shows N/↑ iron in MQ, ↓/no iron in erythroid precursors (both –ve in IDA)

□ Iron studies: ↓serum iron, ↓total Tf/TIBC, ↓Tf saturation, N/↑ ferritin

□ ↑CRP/ESR

59
Q

How to differentiate anaemia of chronic illness from concomitant iron deficiency

A

Differentiating from or identifying concomitant Fe deficiency:

→ Suggestive features: MCV (↓ in IDA, Normal in ACD), Ferritin (↓ in IDA, ↑ in ACD)

→ Differentiating features: sTfR (↑ in IDA, ↓ in ACD), hepcidin (↓ in IDA, ↑ in ACD)

→ Therapeutic trial of iron may be given in difficult situations

60
Q

Alpha thalassaemia

Gene affected and type of gene defect

Pathogenesis and effects

A

Genetics: HBA1/2 code for same α-globin chain in α-gene cluster (ch16)

One person has four genes → α0 (0 α genes) to α4 (4 α genes) presents with a spectrum of varying disease severity

Majority are deletions (90%)

Pathogenesis: mutated HBA1/2 resulting in ↓α-globin synthesis
α-globin required for production of both fetal (α2γ2) and adult (α2β2) Hb → affects both fetus and adults

Effects:

→ Fetus: excess γ chains form Hb Bart’s (γ4)
→ Adults: excess β chains form Hb H (β4)
→ Result: abnormal HbH tetramer unstable → ↑haemolysis

61
Q

Compare the 4 phenotypes of Alpha thalassaemia

Underlying genetic defect

Effect on RBC

A

A-thal. minima (silent carrier) - 1 gene deletion, i.e. αα/α-; no effect on MCV and Hb analysis

A-thal minor (Thal. trait) - 2 gene deletions, i.e. αα/– (SE Asians), α-/α- (Blacks); may have hypochromia/microcytosis with mild anaemia

A-thal intermedia (HbH disease) - 3 gene deletions, i.e. α-/– → excessive HbH (β4); Transfusion-dependent, moderate McHc anaemia

A-thal major (Hb Bart’s hydrops fetalis) - 4 gene deletions, i.e. –/– → Hb Bart’s (γ4) in fetal blood; Severe fetal anaemia culminating in hydrops fetalis (fetal high-output HF)

62
Q

Beta-thalassaemia

Gene affected and type of genetic defect

Pathogenesis

A

Genetics: single HBB gene code for β-globin chain in β-gene cluster (ch11)
Majority due to point mutations instead of deletions

Majority compound heterozygotes → clinical severity depends on combination and nature of mutation in each of the two HBB gene

Pathogenesis:
→ α-globin only required for production of adult HbA, HbA2 → only becomes manifest at ≥6y/o
→ α4 tetramer is unstable, precipitate into inclusion bodies → damage RBC membrane and ineffective erythropoiesis
→ Free α-chains in peripheral RBCs → aggregate and precipitate → ↑haemolysis

Other sources of variability in clinical severity:

  • Genetic determinant of HbF level: HbF can compensate partly for function of HbA
  • Configuration of α cluster: excessive α alleles → ↑imbalance → ↑clinical severity
63
Q

Compare the 3 syndromes of Beta thalassaemia

Underlying genetic defect

Effect on RBC

A

β-thal minor (thal trait)
*β/β+ or β/β0; asymptomatic mild anaemia with marked microcytosis

β-thal intermedia
*β+/β+, β+/β0 (majority)
*transfusion-independent anaemia
(β-thal minor with exacerbating genetic variant (eg. triplicated/quadriplicated α genes, HbE) or β-thal major with alleviating genetic variant are also classed as intermedia)

β-thal major (Cooley’s anaemia)
*β0/β0, β0/β+ or β+/β+ with very low β-chain production (rare)
*lifelong transfusion-dependent anaemia with onset at 6-12mo
*Hemolytic symptoms, progress to high-output HF, FTT, Infection, iron overload…etc

64
Q

Thalassaemia

Manifestations of extramedullary haematopoiesis

A

Splenomegaly due to extramedullary haematopoiesis and haemolysis

  • Common in thal major, some thal intermedia
  • Hypersplenism may exacerbate situation

Hepatomegaly due to extramedullary haematopoiesis and iron overload

  • Early-life symptom, cirrhosis with long iron overload

Nephromegaly

Jaundice, dark urine, pigment gallstones

65
Q

Manifestations of iron overload

A

Childhood onset in those with chronic transfusion w/o chelation, adult onset in those with intermedia or transfusion w/ chelation

Chronic liver disease: hepatomegaly, cirrhosis, HCC

Endocrine and metabolic abnormalities due to iron deposits in endocrine glands
Hypogonadism: delayed puberty, oligo/amenorrhoea, ↓libido, ↓2o sexual features
Hypothyroidism
Insulin resistance during 2nd decade of life and DM (bronze diabetes)

Leaden-grey skin pigmentation

Infection by sideroophilic organisms, eg. L. monocytogenes, Yersinia enterolitica, Salmonella enterica, Klebsiella pneumoniae and E. coli

66
Q

Thalassaemia

Skeletal abnormalities in severe cases?

A

Due to marrow expansion from ineffective erythropoiesis

  • ‘Chipmunk’ facies
  • Change in body habitus: Convex ribs and limb bones, Shortened limbs
  • Osteopenia/ Osteoporosis
  • Growth impairment/ delay
  • Bony masses (expanding marrow break bone cortex
67
Q

Cardiovascular and pulmonary manifestations of thalassaemia

A

Cardiovascular:

  • Major cause of death in thalassaemia
  • Heart failure
  • Bradyarrhythmia
  • Thromboembolism due to hypercoagulation

Pulmonary:

  • Pulmonary hypertension
  • Asymptomatic pulmonary dysfunction: e.g. restrictive ariway/ obstructive defects, decrease VO2 max…etc
68
Q

Investigations for thalassaemia

A

CBC:

  • McHc anaemia with marked ↓MCV, N/↑ reticulocyte13 and ↑RBC
  • Mentzer index (MCV/RBC count): >13 = IDA, <13 = thalassaemia trait

PBS:

  • profoundly hypochromic microcytic red cells with bizarre RBC morphology (target, pencil cells)

Markers of haemolysis: ↑LDH, ↑unconj bilirubin, ↓haptoglobin, ↑methaemalbumin, DAT –ve

Iron studies: ↑serum iron, ↑Tf sat, ↑ferritin due to iron overload

Haemoglobin studies:

Hb electrophoresis for beta

Supravital stain for alpha (HbH)

DNA-based genotyping

69
Q

Management of thalassemia (severe e.g. thal major/ intermedia with hemolysis)

A

Folate supplementation

Low iron diet, eg. avoid red meat, spinach

Regular transfusion: mainstay of treatment

  • hypertransfusion to maintain stable Hb level and suppress ineffective erythropoiesis
  • use leukodepleted packed cells to ↓FNHTR and TRALI

Iron chelation: for B-thal major

Splenectomy

Allogeneic HSCT

70
Q

Causes of macrocytosis and macrocytic anaemia

A
  • *Abnormal DNA metabolism**
  • *- Vitamin B12 deficiency**
  • *- Folate deficiency**
  • Copper deficiency
  • Drugs, including antiretroviral, cytotoxic agent, immunosuppressant, TKI

Primary marrow disorder

  • Myelodysplastic syndrome (esp in elderly)
  • Congenital dyserythropoietic anaemia
  • Sideroblastic anaemia (some)
  • LGL leukaemia

Reticulocytosis:

  • Haemolytic anaemia
  • Stress-induced erythrocytosis

Lipid abnormalities

  • Liver disease
  • Hypothyroidism

Others:

  • *Alcohol abuse**
  • *Multiple myeloma** and other plasma cell dyscrasia
71
Q

Investigations for macrocytosis

A

CBC:

  • *Severe macrocytosis (MCV >110-115) → almost exclusively megaloblastic anaemia**
  • *≥1 additional cytopenias → Primary BM problem, eg. megaloblastic anaemia, MDS**

PBS:
→ Megaloblastic anaemia: macro-ovalocytes, hypersegmented neutrophils (>5 lobes)
→ Liver disease: target cells
→ Myelodysplastic syndrome: hypolobulated or hypogranular, dysplastic neutrophils

□ Ix for cause:
→ Reticulocyte count: ↑ in haemolysis, ↓ in BM disorders
→ Serum B12 and folate (± copper if gastric bypass) for megaloblastic anaemia
→ TFT for hypothyroidism
→ LFT for liver disease

□ BM examination: only when uncertain diagnosis or pancytopenia

72
Q

Causes of false positive macrocytosis

A

Consider factitious cause, eg. RBC clumping, osmotic swelling with hyperGly or prolonged storage, EDTA tube

73
Q

Megaloblastic anaemia

Cause

Pathogenesis

A

Megaloblastic anaemia: due to delay in maturation of nucleus relative to cytoplasm

□ Result from defective DNA synthesis → delayed M phase entry → continuous ↑cytoplasmic size without mitosis (nuclear-cytoplasmic dyssynchrony)

□ Deficiency in vitamin B12 (vast majority) or folate

74
Q

Source and absorption of Folate

A

Found in leafy vegetables (spinach, broccoli, lettuce), fruits (banana, melon) and animal protein (liver, kidney)

Seldom deficient with any normal diet in developed countries (>50μg/d)

Absorbed folate converted to methyl tetrahydrofolate (THF) by small intestines then transported inside plasma

Total body stores small → deficiency occur in weeks

75
Q

Source and absorption of Vitamin B12

A

Found in meat, fish, eggs, milk

Seldom deficient (>1μg/d) unless vegan diet

Bound to intrinsic factor (IF) produced by gastric parietal cells → IF-B12 complex absorbed in terminal ileum → transported in plasma while binding with transcobalamin II

Liver has 3-year stores of B12 and recycles B12 via enterohepatic cycling → takes years before deficiency manifest

76
Q

Physiological Function of B12 and folate

A
  1. Methyl B12 serves as co-factor in methylation of homocysteine into methionine with demethylation of methyl THF into THF
  2. THF converts to 5,10-methylene THF, serves as coenzyme for conversion of dUMP into dTMP for DNA synthesis
  3. Deoxyadenosyl B12 also serves as co-enzyme in conversion of methylmalonyl CoA into succinyl CoA
77
Q

Causes of Folate deficiency

A

Dietary insufficiency: usually only in poor, elderly, alcoholics

Malabsorption

High demand due to pregnancy, haemolytic anaemia, myeloproliferative diseases

Antifolate agents, eg. trimethoprim, OCP, pyrimethamine, phenytoin, methotrexate

78
Q

Causes of Vitamin B12 deficiency

A

Dietary insufficiency in long-term vegans

Gastric causes:
Pernicious anaemia
Status post-gastrectomy: 10-20% by 5y

Bowel causes:
SBIO with bacteria consuming B12 due to motility disorder, ↓γ-globulin, stagnant loop
Terminal ileal pathology, eg. Crohn’s disease
Fish tapeworm

79
Q

Pernicious anaemia

Define

Pathogenesis

Risk factors

Complications

Diagnosis

A

Define: Autoimmune disorder with atrophic gastric mucosa and loss of parietal cells

Pathogenesis: anti-IF or anti-parietal cell Ab (a/w chronic atrophic gastritis) attack parietal cells → ↓intrinsic factor production

Risk factors: Autoimmune diseases

Complications: Chronic atrophic gastritis, Gastric Cancer (achlorhydria)

Diagnosis: presence of auto-antibodies - Anti-Intrinsic Factor Ab and Anti-parietal cell antibody

80
Q

Clinical features of megaloblastic anaemia

A
  • Anaemia S/S
  • Jaundice
  • Oral: atrophic glossitis, oral ulcers, angular stomatitis
  • Skin: greying of hair, skin hyperpigmentation

Neuropsychiatric:

  • Subacute combined degeneration of cord: affects dorsal (DC-ML) and lateral columns (CST)
  • Peripheral neuropathy: classically ↑knee jerk (from SCD) + ↓ankle jerk (from PN)
  • depression, irritability, cognitive slowing, dementia, psychosis
81
Q

Investigations for Megaloblastic anaemia

A
  1. CBC: macrocytic anaemia (typically >115fL) with mild leukopenia/thrombocytopenia + ↓RET
  2. PBS: macro-ovalocytes + hypersegmented neutrophils
  3. Markers of haemolysis
  4. Serum B12 level: deficient <200pg/mL
  5. RBC folate: <150ng/mL
  6. Anti-IF, anti-parietal cell Ab for pernicious anemia
  7. Metabolite testing (MMA, homocysteine)
  8. Upper endoscopy for atrophic gastritis and CA stomach
82
Q

Management of Megaloblastic anaemia

A

Management: by replacement of B12 and/or folate

Urgent Folate with B12 supplement for severe anaemia/ symptomatic- Parental or oral

Oral B12 supplement: vegan diet require lifelong replacement

Oral folate supplement: indicated for folate deficiency and other conditions e.g. haemolytic anaemia with poor RBC survival

83
Q

S/S of iron deficiency anaemia

A

S/S anaemia: SOB on exertion, Pallor, Tiredness, Dizziness , Palpitation

Pica: desire for or compulsion to eat substances not fit as food, eg. dirt (geophagia), ice (pagophagia)

Restless leg syndrome (RLS)

Nail changes: brittle nails, koilonychias (spoon-shaped nails)

Epithelial/mucosal changes:
→ Atrophic glossitis with loss of tongue papillae ± tongue pain, dry mouth
→ Cheilosis (angular cheilitis)
→ Oesophageal webs (rare) → termed Plummer-Vinson syndrome when a/w dysphagia

MBBS VI - SpC - Medicine (80 decks)

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