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Block 4 - Heamatology > Lecture 3 - Megaloblastic Anaemia > Flashcards

Lecture 3 - Megaloblastic Anaemia Flashcards

1
Q

Microcytic anemia

A
  • iron deficiency
  • thalassaemia
  • sideoblastic anaemia
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2
Q

Normocytic anemi

A
  • acute bleeding
  • hemolysis
  • Chronic disease
  • Metabolic, including renal failure
  • endocrine dysfunction
  • stem cell disorders
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3
Q

Macrocytic anemia

A
  • megaloblastic anaemia
  • alcohol + liver disease
  • hypothyroidism
  • reticulocytosis
  • drugs
  • bone marrow disorders
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4
Q

Macrocytic anemia

A
  • MCV > 100fl, hb low

- megaloblastic or non-megaloblastic types

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5
Q

Non-megaloblastic macrocytic anemia

A
  • MCV
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6
Q

Megaloblastic anaemia caused by impaired DNA synthesis

A
  • deficiency of vit B12 or folate
  • abnormalities of vit B12 or folate metabolism: transcobalamin deficiency or NO exposure, antifolate drugs
  • other defects of DNA synthesis: congenital enzyme deficiency or drugs
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7
Q

Vitamin B12 : cobalamin

A
  • water soluble vitamin
  • only synthesized by bacteria
  • only found in animal products
  • not affected by cooking
  • total body stores: 2-5mg (half in liver), sufficient for 3/4 years
  • in plasma 20% bount to TCII - active form
  • 80% bound to TCI and TCIII, TCI=R protein, produced by salivary glands
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8
Q

Functions of vit B12

A
  • essential coenzyme for methionine synthase, which has a role in DNA synthesis
  • essential coenzyme for MCM which catalyses the formation of succinyl coA from methylmalonic acid
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9
Q

Causes of Vit B12 deficiency

A

1)inadequate intake

2) digestion and absorption problems:
- inadequate release of B12 from food due to absent/reduced enzymes and/or acid
- inadequate production of functional IF: pernicious anaemia, gastrectomy
- terminal ileal disease: coeliac disease, ileal resection, Crohn’s disease
- competition for intestinal B12: bacterial overgrowth or fish tapeworm

3) Transport abnormalities: deficiency in TCII

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10
Q

Folate

A
  • water soluble vitamin (B9),
  • found in most foods, highest in liver and yeast, also in green vegetables and nuts
  • easily destroyed by cooking
  • body stores (mostly in liver) = 5=10 mg, lasts only 3-4 months
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11
Q

Folic acid fortification

A
  • since 2009, folic acid must be added to wheat flour for bread making in Australia
  • not if organic, unpackaged or non-wheat based bread
  • also added to other foods
  • prevalence of folate deficiency has fallen by 77%
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12
Q

Folate absorption

A
  • folate in food travels to upper small intestine
  • at the jejunal microvilli: enzymatic deconjugation to form methyl-THF
  • absorption via active carrier mediated transport and concentration dependent diffusion
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13
Q

Folate transport

A
  • in plasma, methyl THF is bound to albumin (weak) or soluble folate receptor (strong)
  • rapidly cleared from plasma by entering liver and other cells via membrane transport proteins
  • inside the cell, folate is polyglutamated and unable to diffuse back to plasma
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14
Q

Folate function

A
  • coenzyme in transfer of carbon molecules between compounds
  • methyl THF used in methylation of homocysteine to form methionine
  • THF acts as intermediate acceptor of 1 carbon units for synthesis of purines and pyrimidines
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15
Q

Causes of folate deficiency

A
  • inadequate intake
  • malabsorption: small bowel disease, alcohol abuse, phenytoin
  • increased requirements: pregnancy and lactation, infancy, haemolytic anaemia, hyperthyroidism, malignancy
  • defective utilisation: inhibition of DHFR
  • hereditary: folate malabsorption, metabolic defects
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16
Q

Concequences of B12 and folate deficiency

A

1) B12 deficiency results in
- increased homocysteine levels
- reduced methionine levels
- reduced formation of THF - also caused by folate deficiency

17
Q

Reduced THF causes

A

1) impaired DNA syntehsis, affecting all rapidly growing tissues
- bone marrow: megaloblastic anaemia
- epithelial surfaces: GIT symptoms
- developing foetus: neural tube defects

18
Q

How does B12 deficiency result in neurological damage

A
  • MMA accumulation destabilises myelin
  • role for methionine deficiency
  • only B12 deficiency, not folate, results in neurological damage in adults
19
Q

Summary: B12 vs folate

A
  • source: animal product vs all food
  • water soluble: yes/yes
  • site of absorption: ileum/ duodenum, jejunum
  • mechanism of absorption: uptake of If-CBl complex/ deconjugation of polyglutamate
  • metabolic function: coenzymes
  • body stores: 3-4 years / 3-4 months
  • dietary deficiemncy: rare
  • Megaloblastic anaemia: Yes
  • neurological disease: Yes/no
20
Q

Clinical presentation of B12 and folate deficiency

A
  • symptoms of anaemia
  • lemon-yellow skin
  • shiny/beefy red tongue
  • malabsorption
  • vaginal atrophy
21
Q

Neurological manifestations of B12 deficiency

A
  • progressive neurological disease due to demyelination
  • peripheral sensory nerves
  • posterior and lateral columns of spinal cord affecting proprioception/vibration and lateral corticospinal tracts mediating motor function
  • optic nerve atrophy
  • CNS disease with cognitive disturbances
22
Q

Blood results of megaloblastic anaemia

A
  • low hb
  • MCV 110-130 fl
  • oval macrocytes
  • aniso/poikilocytosis
  • hypersegmented neutrophils
  • WCC and platelets mostly normal but may be low
  • signs of ineffective erythropoiesis: raised bilirubin, LDH
23
Q

Bone marrow findings

A
  • usually hypercellular
  • erythroblasts: nuclear irregulatiry, increased N:C ratio and delayed nuclear maturation relative to that of the cytoplasm. RBC are so dysfunctional that they auto-hemolyze - raised bilirubin + LDH
  • giant metamyelocytes
  • dysplastic megakaryocytes
24
Q

Think vitamin B12/folate deficiency if

A
  • pancytopenia of uncertain cause
  • oval macrocytes and hypersegmented neutrophils on blood film
  • neurological: unexplained dementia, weakness, ataxia, paraesthesia
  • elderly, alcoholics, malnourished, vegans, people with bariatric surgery
25
Q

Vitamin B12 or folate deficiency diagnosis

A
  • clinical
  • serum B12 level + serum or RBC folate levels (serum for short term, RBC for long term)
  • metabolic intermediates: raised homocysteine and raised MMA
26
Q

Traps when diagnosing vit B12 deficiency

A
  • falsely low levels of vit B12: drugs, reduced TCI lebels in pregnancy and neutropenic state/aplastic anaemia, injerited transcobalamin I deficiency
  • falsely normal/high levels of vit B12 in hepatitis or cirrhosis, chronic renal failure, hypothyroidism, myeloproliferative diseases, TCII deficiency
27
Q

Active B12 level: holotranscobalamin

A
  • now widely available as additional test if low or equivocal serum vit B12 result
  • measures only B12 bound to TCII
  • normal range > 35pmol/L
28
Q

Traps when diagnosing folate deficiency

A

1) serum folate
- can be corrected by one good meel
- unstable so can’t test on specimen older than 1-2 days
- high levels in heamolysed samples
- rises in Vit B12 deficiency

2) RBC folate
- low level doesnt distinguish between folate and B12 deficiency
- reticulocytes have high levels so high results in marked reticulocytosis
- transfusion invalidates results

29
Q

Diagnosis of pernicious anaemia

A
  • severe lack of IF due to autoimmune disease affecting gastric parietal cells
  • peaks in 60s, more common in female
  • associated with other organ specific autoimmune disorders (hypoparathyroidism, addison’s disease, thyroid disease)
  • investigations: serum B12 levels +/- metabolic intermediates plus IF antibodies, gastric parietal cell antibodies and endoscopy
30
Q

Management of megaloblastic anaemia

A
  • treat cause
  • give replacement therapy: initially both: never folic acid alone
  • rarely necessary to transfuse
31
Q

Replacement therapy

A
  • in folate deficiency: folic acid 5 mg daily orally, for 3-4 months
  • in vit B12 deficiency: 1000 mcg IMI daily x 4 doses, then weekly x 4 doses then every 1-3 months
  • continue for life for patients with pernicious anaemia or ileal resection
32
Q

Response to therapy

A
  • reticulocyte response within 2-3 days with a peak at 6-7 days
  • Hb should rise by 10g/L per week
  • bone marrow normoblastic in 48 hours
  • if inadequate response - further investigation
33
Q 
Which one of the following does not cause folate deficiency
A) antiepileptic drugs
B) Veganism
C) gluten sensitivity
D) inflammatin
E) pregnancy
A

B

34
Q

Which one of the following is most commonly characterised by macrocytosis

A
  • anaemia due to poor nutrition
35
Q

Which of the following biochemical abnormalities is seen in severe vit B12 deficiency

  • raised red cell folate concentration
  • reduction in TCII
  • MMA in urine
  • reduced homocysteine in plasma
  • excess deoxynucleotide production
A
  • MMA in urine

Block 4 - Heamatology (23 decks)

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