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Introduction to Haematology > Megaloblastic Anaemia > Flashcards

Megaloblastic Anaemia Flashcards

1
Q

what are megaloblastic anaemias?

A

A group of anaemias in which there is delayed maturation of the erythroblast nucleus in relation to the cytoplasm

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2
Q

what deficiencies usually cause megaloblastic anaemia?

A

vitamin b12 or folate

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2
Q

what is an erythroblast?

A

an immature erythrocyte, still containing a nucleus

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3
Q

what causes megaloblastic anaemias?

A

asynchronous maturation of the nucleus due to defective synthesis - seen in the bone marrow

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4
Q

how could megaloblastic anaemia also be caused if not deficiency?

A

abnormalities of vitamin b12 or folate metabolism
defects of DNS synthesis- rare

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5
Q

what are vitb12 and folate crucial in

A

DNA synthesis

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6
Q

what is the scientific name for vitb12

A

cobalamin

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7
Q

where is vit b12 synthesised

A

by micro-organisms animals must consume it through the diet

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8
Q

where is b12 found

A

food of animal origin - 50% of young vegans have subnormal levels of b12

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9
Q

what is the major storage site for vit b12?

A

the liver

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10
Q

how much b12 does the body store?

A

3-4 years worth - short term dietary deficiency not problematic

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11
Q

what is the process of b12 absorption?

A

b12 is consumed with dietary proteins
salivary glands secrete R-Protein
parietal cells in stomach secrete intrinsic factor
chief cells in stomach secrete pepsin
pepsin catabolises dietary proteins and separates the b12
R-protein (from the mouth) binds free b12
b12, R-protein and IF move into the duodenum
pancreas starts to secrete digestive enzymes (lipases, proteases etc)
pancreatic proteases catabolise R-protein and free up the b12
free b12 is now able to bind to IF

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12
Q

what must b12 be attached to for it to be absorbed?

A

IF

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13
Q

what do receptors on enterocytes recognise?

A

the B12-IF complex

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14
Q

What does IF protect the b12 from?

A

catabolism by intestinal bacteria

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15
Q

what % of b12 can be absorbed in the absence of IF?

A

1%

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16
Q

where are b12-IF complexes absorbed?

A

the terminal ileum

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17
Q

what happens to b12 once it has been absorbed?

A

it passes into the portal blood. it attaches to transcobalamin which delivers b12 to the bone marrow and other tissues. Megaloblastic anaemia can also result from transcobalamin deficiency but vitb12 in take is normal.

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18
Q

what happens tol b12-transcobalamin in the bone marrow/tissues

A

binds to a receptor and is endocytosed

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19
Q

properties of folate

A

humans are able to synthesise folate
require pre-formed folate in the diet-mostly in green leafy vegetables foliage

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20
Q

where is the major storage site for folate

A

liver

21
Q

how are dietary folates absorbed?

A

dietary folates are absorbed as methyl tetrahydrofolate (Methyl THF) in the upper small intestine
folate binding proteins are present on cell surfaces to facilitate entry into the cell
once inside the cell they are converted to folate polyglutamates

22
Q

what is b12 an essential co-factor for?

A

the enzyme methionine synthetase which is needed for the conversion of methyl THF to THF. This reaction also involves the methylation of homocysteine to form methionine.

23
Q

what does a lack of b12 do

A

prevents demethylation of methyl-THF preventing formation of the THF polyglutamates

24
Q

what does a lack of folate do

A

prevents formation of the THF polyglutamates

25
Q

what do deficiencies in either b12/folate result in

A

a decrease in DNA synthesis and delayed maturation of the nucleus in relation to the cytoplasm. As there is a high turnover of cells in the bone marrow, this site is where the problems become obvious.

26
Q

clinical features of megaloblastic anaemia?

A

tired all the time
shortness of breath (particularly on exercise)
weakness
pallor of mucous membranes
slight jaundice
glossitis
nervous system disturbances - impaired vision, gait disturbance
psychiatric disturbances - mood swings, irrational behaviour

27
Q

lab findings of macrocytic anaemia?

A

macrocytosis - MCV > 95 fL (macrocytosis is the earliest sign of b12 deficiency and can be detected even before the onset of anaemia)
Macrocytes are typically oval in shape - ovalocytes
normal RBCS/larger RBCs/oval RBCs - anisocytosis
hypersegmented neutrophils are one of the hallmarks of megaloblastic anaemia - 6 or more lobes - R shift. this results from delayed DNA synthesis but intact segmentation mechanism.
howell-jolly body - nuclear remnants
poikilocytosis - abnormal shaped RFBCs
basophilic stippling - aggregation of ribosomal RNA
increase in serum un-conjugated bilirubin due to marrow cell breakdown
increase in lactic acid dehydrogenase (LDH) due to marrow cell breakdown
normal serum iron and ferritin
25-40% with b12 def have normal MCVs
25-50% of b12 def have normal hb on presentation

28
Q

how is serum vit b12 measured

A

commercially fully automated assays
low in cases of b12 def
normal or borderline in cases of folate deficiency
not considered a robust assay

29
Q

serum folate results

A

low in fol def
normal / raised in b12 def

30
Q

red cell folate results

A

will be low in folate deficiency
not specific to folate deficiency- 60% b12 deficiency cases have low red cell folate
more reliable guide of tissue folate status that the serum folate test

31
Q

in b12 and fol def what is serum homocysteine

A

increased

32
Q

serum methylmalonic acid (MMA) is increased in…

A

b12 deficiency only

33
Q

what can normal levels of MMA and homocysteine rule out

A

clinically significant b12 deficiency with virtual certainty

34
Q

what can cause b12 deficiency

A

lack of b12 absorption
transcobalamin deficiency

35
Q

reasons for lack of b12 absorption

A

congenital lack of intrinsic factor
congenital lack of B12-IF receptors (cause b12 def in childhood but not until all b12 stores derived from the mother ‘in utero’ are all used up i.e. 2yrs)
autoimmune attack on gastric mucosa, IF or parietal cells (pernicious anaemia)

36
Q

reasons for transcobalamin deficiency

A

adequate b12 absorption but poor transport

37
Q

causes of folate deficiency

A

poor dietary intake
pregnancy - increased demand
long term use of antibiotics - interfere with normal absorption
drugs - antagonists of folate metabolism e.g. methotrexate
chronic diseases of digestive tract-interfere with absorption e.g. coeliac, crohn’s, tropical sprue-disease
gastric intestinal surgery

38
Q

b12 absorption test

A

for years the gold standard test to distinguish between malabsorption and poor dietary intake was the SCHILLINGS TEST.
uses radiolabelled b12 to measure absorption of free or IF-bound B12
the test is now becoming rare due to increasing difficulties in obtaining the isotope

39
Q

schilling test step 1

A

pt given IM B12- this will move directly to the liver and saturate all b12 receptors in the liver

pt also given an oral dose of radiolabelled b12 (co-labelled)

radiolabelled b12 should be absorbed in the intestine, move to the liver- but the liver is saturated

Radiolabelled b12 should be excreted in the urine over a 24hr period

if radiolabelled b12 is present in the urine - dietary problem

40
Q

schilling test - step II

A

if results from step I show no radiolabelled b12 in the urine then this suggests an absorption problem

next radiolabelled b12 plus IF is administered

urine is monitored over 24hr period

if radiolabelled b12 is present in the urine then it indicates IF deficiency caused by pernicious anaemia

41
Q

schilling test step III

A

if results from step II show no radio labelled b12 in the urine then it suggests a less common cause

radiolabelled b12 plus antibiotic is administered

urine monitored 24hr period

if radiolabelled b12 is present in the urine - indicates bacterial overgrowth in terminal ileum impeding b12 absorption

42
Q

schilling test - step IV

A

if results from step III show no radiolabelled b12 in the urine

radiolabelled b12 plus pancreatic enzymes are administered

urine is monitored over 24 hr period

if radiolabelled b12 is present then indicates pancreatic insufficiency - r protein remains bound to b12 therefore IF is unable to bind - no absorption by enterocytes e.g. chronic pancreatitis

43
Q

schilling test principels

A

whatever causes the presence of radiolabelled b12 in the urine is what was originally deficient

44
Q

what does it show if u add b12 and u get b12 in urine

A

poor b12 intake

45
Q

what does it show if u add IF and u get b12 in urine

A

IF deficiency

46
Q

what does it show if u add Abx and u get b12 in urine

A

bacterial overgrowth

47
Q

what does it show if u add pancreatic enzymes and u get b12 in urine

A

pancreatic insufficiency

48
Q

other mechanisms that can cause megaloblastic anaemia

A

drugs affecting nuclei acid synthesis - chemotherapy drugs e.g. azathioprine, hydroxycarbamide
inherited causes

49
Q

poor intake of b12 treatment

A

change in diet and/or oral supplementation -concomitant folic acid often given

50
Q

other cause b12 def treatment

A

high dose oral supplementation (small proportion of b12 absorption is independent of IF)
IM injections of b12 -initial high loading dose (5 x 1000mg) then 3 monthly injections

51
Q

treatment for folate def

A

change in diet and/or oral supplementation

Introduction to Haematology (10 decks)

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