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MBBS II HIS > L07 - Classification and Lab Dx of anaemia > Flashcards

L07 - Classification and Lab Dx of anaemia Flashcards

1
Q

Where does iron absorption occur? What enhances the rate of iron transport?

A

Absorption at duodenum

Enhanced by:

  • Acid, reducing agent that keep iron soluble in ferrous state
  • Iron deficiency
  • Enhanced erythropoiesis
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2
Q

Storage and main source of iron in the body?

A

Normal turnover of senescent or defective RBC through phagocytosis in macrophages of liver, BM and spleen

Stored as ferritin, haemosiderin

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3
Q

List some major and minor causes of iron deficiency?

A 
Major: BLOOD LOSS:
 Gastrointestinal (e.g. bleeding from peptic ulcer / carcinoma of colon) 
 Uterine 
 Urinary 
 Respiratory tracts (less common)

Minor/ Less common:
 Increased demand (premature infants, growth spurts, multiple pregnancy);
 Poor intake (dietary deficiency, mal-absorption)

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4
Q

Clinical features of Iron deficiency?

A
  • Asymptomatic, or;
  • Anaemic symptoms and signs
  • Epithelial changes
  • Pica (abnormal craving to eat non-food substances)
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5
Q

List some epithelial changes related to iron deficiency?

A
  • Glossitis (tongue inflammation)
  • Angular stomatitis
  • Brittle nails
  • Dysphagia
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6
Q

Typical iron status finding in Iron deficiency?

A

Low serum iron (usable iron)

High serum transferrin (compensatory response to increase transport but low transferrin saturation)

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7
Q

Can serum ferritin be used as a marker to identify Iron deficiency? Why?

A

No

Serum ferritin = acute phase reactant: in acute inflammation, serum ferritin level is raised

cannot indicate body iron store

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8
Q

Typical PBS finding of iron deficiency anaemia?

A
  • Hypochromic (no polychromasia/ reticulocytosis)
  • Microcytic
  • PENCIL CELLS
  • Reactive thrombocytosis
  • Anisopoikilocytosis: Size and shape variation (anisocytosis + poikilocytosis)
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9
Q

Bone marrow examination findings in Iron deficiency anaemia?

A

Active erythropoiesis that is poorly haemoglobinised (micronormoblastic)

Decreased / absent marrow iron store

(BM exam not normally indicated for suspected iron deficiency anaemia)

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10
Q

Case presentation:
68M c/o constipation
P/E: Pallor only
Normal LFT and RFT

CBC:
Low MCV, MCH, MCHC
Very low Hb and RBC 
High RDW, PLT
Normal Retic

PBS:
Pencil cells, Hypochromic, Microcytic, Anisopoikilocytosis, Reactive thrombocytosis

Low serum iron, High serum transferrin, low transferrin sat.

Walk through DDx

A
  • Pallor = anaemic
  • Normal LFT and RFT = not likely to be sequestration or inadequate EPO stimulation
  • Microcytic = Iron def. or thalassemia or anemia of chronic disease
  • High RDW = Iron def. or sever thalassaemia
  • Normal Retic = no reticulocytosis/ unable to perform due to raw material def.
  • PBS suggest Iron def (Pencil cells)
  • Iron def. anaemia = must suspect chronic bleeding, likely related to GI due to constipation, common to see colorectal cancer
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11
Q

Why does retic count not rise in Iron deficiency anaemia?

A

Reticulocytosis = reactive compensation for low RBC count

Need 3 factors:

  • Raw material (B12, iron, folate)
  • Intact BM function
  • Normal EPO

> > Iron def. = not enough Fe for reticulocytosis

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12
Q

Define megaloblastic anaemia?

A

Group of anaemias: asynchronous maturation of nucleus (delayed relative to cytoplasm)

Defective DNA synthesis: usually due to deficiency of vitamin B12 +/- folate

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13
Q

Metabolic pathway of folate?

A
  • Absorbed dietary folates = all converted to methyl THF (= monoglutamate) by the small intestine
  • transported in the plasma as THF and enters cell
  • Vitamin B12 (cobalamin) is needed to convert methyl THF to THF to synthesize polyglutamate forms of folate
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14
Q

List 4 causes of folate deficiency?

A
  1. Dietary insufficiency (e.g. poverty, elderly, alcoholics)
  2. Malabsorption
  3. Increased demand (e.g. pregnancy, haemolytic anaemia, myeloproliferative disease)
  4. Antifolate agents (e.g. trimethoprim, pyrimethamine, phenytoin (= anticonvulsant))
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15
Q

Metabolic pathway/ absorption and transport of Vit B12?

A
  • Dietary intake
  • Bind to intrinsic factor secreted by gastric parietal cells
  • complex is absorbed in terminal ileum
  • transported in plasma via transcobalamin II: delivers to bone marrow, other tissues by receptor-mediated endocytosis
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16
Q

Physiological function of folate?

A

Many biochemical reactions involving single carbon unit transfer (e.g. deoxythymidine synthesis)

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17
Q

Physiological function of Vit B12?

A

Co-factor/enzyme for 2 biochemical reactions:

1) Methylcobalamin = cofactor in methylation of homocysteine to methionine by methionine synthase
2) Deoxyadenosylcobalamin = coenzyme of mutase to convert methylmalonyl CoA to succinyl CoA

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18
Q

Causes of vit B12 deficiency?

A
  1. Dietary insufficiency (e.g. long-term vegetarians)
  2. Gastric causes: Prenicious anemia, Post-gastrectomy = low intrinsic factor for absorption
  3. Intestinal causes (e.g. stagnant loop syndrome, malabsorption syndrome, fish tapeworm) = malabsorption
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19
Q

Pathogenesis of Pernicious anemia?

A

Organ-specific autoimmune disease – antibodies against:

i) Gastric parietal cells
ii) Intrinsic factor for B12 absorption

> > Cause gastric mucosa atrophy, gastric cause of Vit B12 def. and Megaloblastic anaemia

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20
Q

Clinical features of Megaloblastic anaemia?

A
  1. Mild jaundice (lemon yellow tint)
  2. Epithelial changes: Glossitis, angular stomatitis
  3. Vitamin B12 neuropathy (complications may occur in the absence of haematological changes)
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21
Q

List some clinical features under Vitamin B12 neuropathy?

A

 Peripheral neuropathy*
 Dementia*

 Subacute combined degeneration of cord (affects dorsal and lateral columns)
 Optic atrophy

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22
Q

Typical PBS finding in megaloblastic anaemia?

A

Large, oval, Macrocytic RBC

Hypersegmented neutrophils (6 lobes or more)

Mild pancytopenia

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23
Q

Typical BM findings in megaloblastic anaemia? When is it performed?

A
  • hypercellular marrow, hyperplastic but megaloblastic erythropoiesis
  • megaloblasts, giant metamyelocytes and band forms

BM exam performed if blood film does not show characteristic dysplastic features

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24
Q

Typical biochemical findings for megaloblastic anaemia?

A
  1. Metabolic assay: raised methylmalonic acid and homocysteine levels
  2. Serum: Indirect hyperbilirubinaemia, increased LDH
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25
Q

How to determine if megaloblastic anaemia is caused by Vit B12 or Folate def.?

A
  • Consider clinical features and Medical Hx
  • Serum B12 assay/ Serum and RBC folate assay
  • Check for upper or lower GI causes (pernicious anaemia, malabsorption…etc)
  • Check for autoAb (pernicious anaemia): Anti-parietal cell or Anti-intrinsic factor
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26
Q

Interpret and walk through DDx:

72F, PMH of DM, HT

CBC:
Mild pancytopenia 
Severe anemia 
High MCV, RDW
Normal retic

High LDH, slight high bilirubin

PBS:
Hypersegmented neutrophils + Oval, macrocytic RBC

Active B12 low
Serum folate normal

A

High MCV:

  • Aplastic anaemia/ BM defect
  • Megaloblastic anaemia
  • Severe haemolysis
  • Myelodysplasia

High LDH = haemolysis or premature breakdown

Normal retic: not raised despite severe anemia. Problem with reticulocytosis?
Raw material, BM, EPO?

Raw material missing + Macrocytic + high LDH = suspect megaloblastic or severe haemolysis

PBS: definitive features of megaloblastic anaemia

Active B12 low = B12 def. causing megaloblastic anaemia + low raw material for reticulocytosis

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27
Q

Define hemolytic anemia?

A

Caused by:
1. Increased/accelerated red cell destruction above its normal rate, shorten RBC life span

  1. Failed marrow compensation
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28
Q

Endogenous and pathogenic types of haemolysis?

A
  1. Extravascular haemolysis: macrophages, monocytes in the reticuloendothelial system (liver, spleen) remove damaged / defective red cells from the circulation
  2. Intravascular haemolysis occurs in the vasculature: pro thrombotic states i.e. shearing by mechanical heart valves, microangiopathic haemolytic anaemia (TTP)

Extravascular hemolysis split into intra-/extracorpuscular

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29
Q

Haemolytic anaemias can be classified as?

A
  1. acquired or hereditary

2. intracorpuscular or extracorpuscular

30
Q

List causes of hereditary haemolytic anaemia?

A

All intracorpuscular defects

Abnormal membrane, metabolism, haemoglobin

31
Q

List major causes of acquired haemolytic anaemia? Divide into immune and non-immune causes?

A

All extracorpuscular defects:

a) Immune haemolysis:
i) Alloimmune (HDN, transfusion)
ii) Autoimmune (AHA)
iii) Drug induced

b) Non- immune
i) Mechanical damage (microangiopathic haemolytic anaemia, prosthetic valves)
ii) Toxin
iii) Infection
iv) Burn

(Paroxysmal nocturnal haemoglobinuria (Extremely rare))

32
Q

List 5 lab investigations for haemolytic anaemia?

A
  1. Markers of Hemolysis + Total and unconjugated bilirubin (increased)
  2. PBS: see RBC damage + compensatory erythropoeisis (polychromasia)
  3. BM exam: erythroid hyperplasia
  4. Intravascular haemolysis: Haptoglobin complexes, methae-albumin, Haemoglobinaemia, Haemoglobinuria
    (5. Red cell survival by 51Cr labelling)
33
Q

List some abnormal RBC shapes and cause?

A

Hereditary spherocytosis: spherocytes
Sickle cell anaemia
Microangiopathic haemolysis: schistocytes

Target cell= B-thal
Elliptocyte/ Pencil cell = Iron deficiency anemia
Acanthocyte= liver disease, asplenism
Crenation = Liver disease

34
Q

In intravascular haemolysis, haemoglobin released in plasma is dealt with in what ways?

A
  1. Haptoglobin takes up haemoglobin to form large complex molecules: Cannot pass through renal glomeruli and excreted in urine
    » Decrease Level of free haptoglobin
  2. Haptoglobin saturated: Hb bind to albumin to form methaem-albumin
  3. Methaem-albumin saturation:
    Haemoglobinaemia, Haemoglobinuria, (advanced = haemosiderinuria)
35
Q

Cause of haemosiderinuria?

A

Renal tubules absorb some haemoglobin: iron converted to haemosiderin

> > re-excreted in urine inside dislodged renal tubular epithelial cells

> > haemosiderinuria

sign of chronic intravascular haemolysis

36
Q

Inheritance, Pathogenesis of hereditary spherocytosis?

A

Usually Autosomal Dominant inheritance

Membranopathy**

  • Abnormally increased membrane Na permeability, normally compensated by Na-ATP pump
  • But Low pH, low glucose in spleen environment cause pump failure

> > Dysfunction of membrane proteins, membrane loss, decrease SA:Vol

> > Can’t pass through spleen circulation

37
Q

Presenting features of hereditary spherocytosis?

A

 Jaundice
 Splenomegaly
 Anaemic symptoms

38
Q

Lab tests and expected results for Dx of hereditary spherocytosis? PBS, DAT, Flow, BM?

A
  • PBS spherocytes, reticulocytosis with BM erythroid hyperplasia, High MCHC
  • Coombs’ test negative
  • Flow cytometry: reduced EMA binding to Band 3 protein
  • Family Hx and +ve presentation
39
Q

Inheritance, pathogenesis of G6PD deficiency?

A

X-linked recessive, males affected

G6PD with decreased catalytic activity or decreased stability = cannot make enough NAPDH through Pentose Phosphate Pathway

Low NADPH = Low GSH to protect RBC from oxidative damage

40
Q

Lab Dx of G6PD def.?

A
  1. Screening test (qualitative):
    absence of fluorescence on NADPH in UV light/ failure to reduce methaemoglobin.
  2. G6PD assay (quantitative): Confirms the diagnosis
41
Q

What conditions can mask G6PD def.?

A

presence of reticulocytosis or recent blood transfusion

42
Q

Antibodies that cause Immune haemolytic anaemia can be divided into which classes?

A
  1. Autoantibodies: Warm or cold type, mostly idiopathic associated with underlying autoimmune diseases
  2. Alloantibodies: HDN or haemolytic transfusion reaction, due to previous sensitization
  3. Drug induced immune haemolytic anaemia
43
Q

Subtypes of drug induced immune haemolytic anaemia?

A

a. hapten mechanism : antibody directed against drug-cell membrane complex
b. immune complex mechanism: drug-antibody complex on red cell surface causes complement deposition
c. autoimmune haemolytic anaemia

44
Q

Describe Coombs’ antiglobulin test and what type of anaemia returns positive results?

A

Positive in autoimmune haemolytic anaemia (AIHA)

Test Ab coated on RBCs

Rabbit IgG with antihuman globulin specificity bind to Fc portion of human IgG on red cells = agglutination

45
Q

General Pathogenesis of Thalassaemia?

A

Hemoglobinopathies: Genetic disorder of globin chain synthesis

> > Imbalance in number of normal chains
Excess chains polymerise and precipitate
early destruction of RBC precursor in BM or shorten lifespan

> > Hypochromic, Microcytic RBC

46
Q

Pathogenesis of α-thalassaemias?

A

Defective alpha- globin chain: 90% defect due to DNA deletion**

In foetus: excess γ chains form γ4 tetramers (Hb Bart’s hydrops fetalis)
In adults: excess β chains form β4 (Hb H), α thalassaemia trait

47
Q

What is the spectrum of α- thalassaemias?

A
  1. Single or 2- gene deletion = α thalassaemia trait
  2. 3- gene deletion = Hb H disease
  3. 4 gene deletion = Hb Bart’s hydrops fetalis
48
Q

Clinical presentation and changes to RBC in α thalassaemia trait ?

A

Single α gene deletion = clinically/ haematologically silent, asymptomatic

2 gene deletion = Normal or slightly reduced Hb with increased RBC count. Hypochromic, microcytic RBC

49
Q

Presentation of Hb H disease?

A

3 gene deletion:
Imbalance of chain production = chronic anaemia
Excess Beta chains polyermize to form Hb H (5%-40%)

Symptoms:

  • Asymptomatic, or;
  • Anaemia (exacerbated by infection, pregnancy)+ Splenomegaly
  • Mostly normal development
50
Q

Treatment of Hb H disease?

A

Generally not transfusion dependent

Common = hypersplenism, require splenectomy

51
Q

Presentation of Hb Bart’s Hydrops fetalis?

A

No alpha chain is found: Excess γ-chains produced in foetal period polymerise to form Hb Bart’s (γ4)

Clinical presentation:

  • Anaemia, Heart failure, edematous fetus
  • Liver dysfunction
52
Q

How to Dx and prevent Hb Bart’s hydrops fetalis?

A

Dx:

  • Ultrasound
  • Confirm with prenatal genetic dx

Prevention:

  • Public health education
  • Antenatal, prenatal dx
  • Detect carrier and genetic counselling
53
Q

Pathogensis of general β-thalassaemias?

A

Reduced (β+) or absent (βo) synthesis of β-globin chain

Majority caused by point mutations (vs a-thalassaemia caused by gene deletion)

54
Q

Why does the clinical presentation of β-thalassaemias occur after birth?

A

β-chain production becomes predominant only in post-natal period

> > severe form (β-thalassaemia major) manifests only when the patient is 3 months old or later

55
Q

What is the spectrum of β-thalassaemias?

A
  1. Individuals heterozygous for βo or β+ thalassaemia
    = Heterozygous β- thalassaemia trait (β-thalassaemia minor)
  2. symptomatic but milder clinical course than β-thalassaemia major = β-thalassaemia intermedia
  3. Total absence / marked reduction of β-globin chains = β-thalassaemia major (Cooley’s anaemia)
56
Q

Clinical presentation of β-thalassaemia minor? CBC finding, dominant Hb type?

A
  • typically asymptomatic, slightly reduced Hb
  • Reduced MCV, MCH with elevated RBC count
  • Single most important diagnostic feature = raised level of Hb A2 (4-7%)*****
  • Many have minor elevations of Hb F (1-3%)
57
Q

Detailed pathogenesis of β-thalassaemia major?

A

Total absence / marked reduction of β-globin chains

> > excessive α-globin chains precipitate out in red cell precursors

  • Ineffective erythropoiesis and extensive intramedullary destruction cause BM expansion
  • Increased destruction of peripheral RBC, excpet high level of Hb F
58
Q

Which type of Hb predominates in B-thalassaemia major?

A

 Complete absence of Hb A

 Small amounts (~2%) of Hb A2

 Remainder (~98%) = Hb F

59
Q

Blood smear finding in B-thalassaemia major?

A

 Marked red cell anisopoikilocytosis

 Most red cells = very hypochromic

 Many Circulating nucleated RBC

60
Q

Clinical presentation of B-thalassaemia major?

A

 Typical thalassaemic facies: chipmunk-like cheeks and a prominent forehead.

 Protuberant abdomen (hepatosplenomegaly)

 Poor musculoskeletal development

61
Q

What are the 3 genetic modifiers of B-thalassemia major severity?

A
  1. Nature of β-globin gene defect (i.e. whether the mutation is associated with a severe phenotype)
  2. Genetic determinants of Hb F level
  3. Configuration of α-globin gene locus (affects degree of α and β globin gene imbalance)
62
Q

Complication and treatment of B-thalassaemia major?

A

Complications:
- Recurrent infections, spontaneous fracture, Hypersplenism, Leg ulcers, Extramedullary haemopoiesis

Treatment = Blood transfusion dependent + Iron chelation therapy

63
Q

Difference between pathogenesis of Warm and Cold AIHA?

A

Warm:

  • auto-Ab IgG on RBC -> reticulo-endothelial system
  • AutoAb bind to RBC best at 37 degrees

Cold:

  • auto-Ab IgM on RBC -> fix C3d complement causes RBC lysis by MAC-> intravascular haemolysis
  • AutoAb bind to RBC best at 30 - 32 degrees
64
Q

What causes Warm vs Cold AIHA?

A

Warm: idiopathic , drugs (e.g. Methyldopa), autoimmune disease, Chronic lymphoid proliferative disease

Cold: chronic lymphoproliferative disorders (CLPD), Infection i.e. mycoplasma

65
Q

What is the RBC likely to be coated with in Warm vs Cold AIHA?

A

Warm = IgG coating spherocytes

Cold = C3d (complement system) causing cold agglutination

Use Direct Antiglobulin Test to confirm presence of Ig/ complement on RBC

66
Q

Does DAT +ve = AIHA?

A

No

  • only showed Ab/complement coated on RBC
  • Occurs in small no. of healthy people and hospitalized patients

DAT +ve only proves haemolysis is immune mediated:
Alloimmune, Autoimmune, Drug- mediated

67
Q

Why is MCV sometimes normal in Haemolytic anaemia even if there is severe RBC destruction?

A

Mostly reticulocytes

Increased detroyed RBC fragments + reticulocyte volume = average normal

68
Q

What are the 2 forms of TTP?

A

Thrombotic thrombocytopenic purpura (TTP) (under microangiopathic haemolytic anaemia)

  • Acquired form: idiopathic, autoimmmune diseases, pregnancy, drugs, HIV infection, malignancies
  • Familial form: ADAMTS13 mutation leading to enzyme deficiency
69
Q

Symptoms of TTP?

A 
fever 
fluctuating neurological signs 
impaired renal function 
red cell fragmentation 
thrombocytopenia
70
Q

Pathogenesis of TTP?

A

Increased Von Willebrand Factor not under control of ADAMTS13 protease (hereditary defect)

Increased platelet plugging in microcirculation&raquo_space; RBC traumatized (acquired)

71
Q

Treatment of TTP?

A

Plasma exchange with fresh frozen plasma to remove autoantibodies, ultra-large VWF multimers and to replace ADAMTS13

Dont give platelet transfusion to patient with severe thrombocytopenia&raquo_space; Attract to VWF massively and worsen

72
Q

What disease must be considered as a DDx if anaemia and thrombocytopenia is present?

A

Microangiopathic haemolytic anaemia

MBBS II HIS (30 decks)

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