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2.2 Haematology > Megaloblastic Anaemia > Flashcards

Megaloblastic Anaemia Flashcards

1
Q

What exactly is megaloblastic anaemia?

A

Production of fewer but larger red blood cells, thus a decreased ability to carry O2

MCV > 98 fL

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2
Q

How many people have macrocytic anaemia

A

Between 2.5-4% of people

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3
Q

What percentage of people with macrocytosis actually have anaemia?

A

up to 60% of people

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4
Q

What might macrocytosis without anaemia indicate

A

Early folate/vitamin B12 deficiency

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5
Q

What might cause macrocytic anaemia
(10)

A

Alcoholism
Folate/Vitamin B12 deficiency
Drugs - chemo drugs
Reticulocytosis due to haemolysis or bleeding
Myelodysplasia,
Liver disease
Hypothyroidism
Haemorrhage
COPD
Splenectomy

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6
Q

What other than macrocytes might be seen in megaloblastic anaemia?

A

Hyper-segmented lobed nueutrophils

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7
Q

How can you tell the difference between megaloblastic anaemia and nonmegaloblastic anamia

A

Megaloblastic anaemia -> oval shaped (macroovalocytes) and hypersegmented neutrophils

Nonmegaloblastic haemolytic anaemia with polychromatophilic round macrocytes and normally segmented neutrophils. Schistocytes also present.

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8
Q

What are some clinical features of megaloblastic anaemia

A

Insidious onset with gradually progressive symptoms and signs of anaemia (pale and low haemoglobin)

Many asymptomatic patients are diagnosed when FBC is performed for another reason and reveals macrocytosis

Cracking at side of the mouth common

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9
Q

How is megaloblastic anaemia classified?

A

As a nuclear maturation defect

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10
Q

What are megaloblasts and how do they form?
(4)

A

Large blasts

Early megaloblast -> intermediate megaloblast -> late megaloblast -> macrocyte

Defect in DNA synthesis retards proliferation and maturation of all haemopoietic cells

Bone marrow is hypercellular

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11
Q

What happens in sever megaloblastic anaemia?

A

pancyopenia

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12
Q

What are the lab results of megaloblastic anaemia?
(3)

A

MCV up
MCH up
MCHC Normal or low

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13
Q

Comment on the bone marrow in megaloblastic anaemia
(5)

A

Most characteristic finding is dissociation between nuclear and cytoplasmic development in the erythroblasts

The erythroblast nucleus maintains a primitive appearance despite maturation and haemoglobinisation of the cytoplasm

fully haemoglobinised (orthochromatic) erythroblasts, which retain nuclei, are seen

Giant and abnormally shaped metamyelocytes and enlarged hyperpolypoid megakaryocytes are characteristic

Many of these abnormal immature cells die in BM resulting in ineffective erythropoiesis

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14
Q

List some clinical consequences of vitamin B12 deficiency
(5)

A

Metabolic pathways reliant on Vitamin B12 are widely distributed so there are many pathological conditions associated with deficiency

Any or all of these pathologies may arise in Vitamin B12 deficiency

Haematological: Megaloblastic Anaemia

Neurological: Due to demyelination include peripheral neuropathy, ataxia, loss of sensation

Psychological: Depression, psychosis, memory loss, confusion or irritability

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15
Q

Write about Vitamin B12 and folate metabolism
(7)

A

Vitamin B12 (Cyanocobalamin) is required as a co-factor for a number of essential metabolic pathways

Co-factor in the formation of succinyl-CoA

Succinyl CoA is required at early stage of haem synthesis

Co-factor along with folate to convert homocysteine to methionine

Methionine is required for myelin synthesis

As a cofactor to convert folate (methyl tetrahydrofolate) into tetrahydrofolate

Tetrahydrofolate is required for DNA synthesis

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16
Q

What is Vitamin B12 called?

A

Cyanocobalamin

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17
Q

What is Vitamin B12 a co-factor in?

A

Formation of Succinyl CoA
Co-factor along with folate to convert homocysteine to methionine
Co-factor to convert folate (methyl tetrahydrofolate) into tetrahydrofolate

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18
Q

What is Succinyl Co A needed for?

A

Required at early stage of haem synthesis

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19
Q

What does methionine do

A

Required for myelin synthesis

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20
Q

What is tetrahydrate required for?

A

DNA synthesis

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21
Q

What are the two key biochemical reactions involving vitamin B12

A

Methionine synthesis
To assist as deoxyadenosylcobalamin in the conversion of methylmalonyl CoA to succinyl CoA

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22
Q

How can vitamin B12 deficiency affect the nerves

A

Can result in varying degrees of neuropathy or nerve damage

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23
Q

What is pernicious anaemia

A

Autoimmune condition whereby you can’t absorb vitamin B12

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24
Q

Write about vitamin B12
(6)

A

Synthesised in nature by micro-organisms

Largest of all vitamins and is water soluble

Wester diets contain between 5 and 30ug/day

Small group of compounds collectively known as the Cobalamins

Found in foods of animal origin such as liver, meat, fish and dairy produce but does not occur in fruit, cereals or vegetables

Animals acquire it by eating food of animal origin

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25
Q

Describe the structure of vitamin B12

A

Cobalt in the centre of a corrin ring which is attached to a nucleotide portion

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26
Q

What are the different phases to vitamin B12 absorption?
(3)

A

Oral Phase
Gastric phase
Intestinal phase

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27
Q

Write about the oral phase of vitamin B12 absorption

A

B12 in proteins ingested

R-binders produced by salivary glands

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28
Q

Write about the gastric phase of B 12 absorption
(3)

A

R binders bind with B12 to form R-B12 complex

Gastric parietal cells secrete pepsin and intrinsic factor

Pepsin breaks down proteins to release the B12 to bind with R binders

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29
Q

Write about the intestinal phase of vitamin B12 absorption
(4)

A

Proteases released by the pancreas split R-B12 complex

Intrinsic factor + B12 => IF-B12 complex

IF-B12 binds to IF receptor on Ileal cells and is taken up into circulation

Transcobalamin transports cobalamin around the body to wherever it is needed

IF

30
Q

What is intrinsic factor?
(2)

A

A glycoprotein that free vitamin B12 combines with

It is synthesised by the gastric parietal cells

31
Q

Write about IF-Vitamin B12 complex and it’s role in absorption
(5)

A

One molecule of Vit B12 binds to one molecule of IF

IF-Vitamin B12 complex binds to a specific surface receptor for IF

Vitamin B12 is internalised into the mucosal cell and passed across into the plasma

Vitamin B12 requires energy for absorption

IF remains within the mucosal cell of the ileum and does not pass across the mucosa

32
Q

What molecule is responsible for transporting vitamin B12

A

Transcobalamin

33
Q

What are the different types of transcobalamin

A

Transcobalamin 1
Transcobalamin 2
Transcobalamin 3

34
Q

What does transcobalamin 1 do?

A

Binds most vitamin B12 in the body

Has little capacity to transfer vitamin B12 to tissues

35
Q

What does transcobalamin 3 do?

A

Released from the granules of neutrophils

Not involved in Vitamin B12 transport

Named incorrectly

36
Q

What happens when the transcobalamin 2/B12 complex has reached its destination

A

Once bound to the receptor of the cell, the complex is internalised

The Vit B12 is liberated and the transcobalamin is degraded by lysosomal enzymes

37
Q

What are the four categories of vitamin B12 deficiency?

A

Nutritional
Biologic competition
Malabsorption
Impaired utilisation

38
Q

What are the three nutritional causes of vitamin B12 deficiency?

A

Vegans
Pregnant women on poor diet
Malnutrition

39
Q

What are the three biologic competition causes of B12 deficiency

A

Intestinal parasite
Leishmaniasis
Bacterial overgrowth

40
Q

What are the eight causes of malabsorption of vitamin B 12

A

Pernicious anaemia
Gastrectomy or gastric bypass
Crohn’s disease
Tropical sprue
Coeliac disease
Surgical resection of ileum
Drugs
Blind loop syndrome

41
Q

What are the two causes of impaired utilisation of vitamin B12

A

TC II deficiency (transcobalamin deficiency)
Nitrous oxide inhalation

42
Q

What is a definition of pernicious anaemia

A

A severe lack of intrinsic factor due to gastric atrophy

43
Q

What causes pernicious anaemia

A

Presence of auto-immune antibodies to gastric parietal cells

Don’t really know why this happens

44
Q

What does pernicious anaemia cause
(4)

A

Most common cause of vitamin B12 deficiency

Loss of gastric secretions including IF

It is a common disease in northern Europeans

Most common in women around 60 years of age, people with a family history of the condition and those with another autoimmune condition

45
Q

Comment on the laboratory investigation of vitamin B12 deficiency
(11)

A

Macrocytosis
MCV > 98fL
Patient presents with anaemia usually
Blood film oval macrocytes
Hypersegmented neutrophils
Reticulocytes decreased on diagnosis, increases on treatment
WCC and Plt count reduced
Vitamin B12 assay low
IF antibodies
Hypercellular bone marrow and large erythroblasts
Plasma bilirubin and lactate dehydrogenase levels increased as a result of marrow cell breakdown

46
Q

How can you tell from blood test results that there is marrow cell breakdown

A

Plasma bilirubin and lactate dehydrogenase levels increased as a result of marrow cell breakdown

47
Q

How is pernicious anaemia treated

A

Vitamin B12 given as an injection directly into muscle which bypasses the need for absorption from the intestine

48
Q

What is folate

A

The naturally-occurring form of the vitamin

49
Q

What is folic acid
(3)

A

The synthetic form used in most supplements and fortified foods

Works the same as folic acid

Folic acid is actually better absorbed than the natural form but they have the same benefits

50
Q

Give some signs of folic acid deficiency
(10)

A

Fatigue
Depression
Loss of appetite
Trouble concentrating
Forgetfulness
Grey hair
Poor growth
Mouth sores
Swollen tongue
Spinal cord defects e.g. spina bifida

51
Q

How does folate deficiency affect pregnancy?
(5)

A

Added stress of rapidly growing cells in pregnancy so increased amounts of folate are required

If a woman has folate deficiency prior to pregnancy it will be intensified during gestation and may lead to premature birth and neural tube defects

Neural tube defects decreased by 36% in the US since focusing on folate supplements during pregnancy

Deficiency implicated with pregnancy loss

Restless leg syndrome also a neurological symptom of deficiency

52
Q

Write about the action of folate
(3)

A

Levomefolic acid (5-MTHF) is required for the synthesis of methionine from homocysteine and serine to glycine

Required for the synthesis of thymidine - a purine precursor of DNA

DNA is essential for cell division

53
Q

How is folate involved in cell division
(4)

A

Folate is needed for the synthesis of thymidine which is a precursor for thymine

Deficiency inhibits thymidolyate synthesis which is a rate limiting step of DNA synthesis, as this reaction required the coenzyme 5-MTHF

Therefore all dividing cells are affected by deficiency

i.e. deficiency results in failure to form thymine one of the purine base pair

54
Q

How is folate absorbed?
(4)

A

Absorption occurs in upper small intestine

Polyglutamate forms are hydrolysed by pteroylpolyglutamatehydrolase (PPH) to monoglutamate form of folate in the intestine

Monoglutamate is converted to tetrahydro-folate (THF) within the small intestinal mucosa before entering the portal plasma

Transporter to liver and stored as tetrahydro-folate (THF)

55
Q

What happens to polyglutamate forms of folate

A

Polyglutamate forms are hydrolysed by pteroylpolyglutamatehydrolase (PPH) to monoglutamate form of folate in the intestine

56
Q

What happens to monoglutamate?
(2)

A

Monoglutamate is converted to tetrahydro-folate (THF) within the small intestinal mucosa before entering the portal plasma

Transporter to liver and stored as tetrahydro-folate (THF)

57
Q

What are the five classifications of causes of folate deficiency?

A

Inadequate diet
Biologic competition
Increased requirement
Malabsorption
Drug inhibition

58
Q

How can inadequate diet cause folate deficiency?

A

Low income
Elderly people with limited function/income
Alcoholics (spirits)

59
Q

How can biological competition cause folate deficiency

A

Bacterial overgrowth in small intestine

60
Q

How can malabsorption cause folate deficiency?
(4)

A

Ileitis
Tropical sprue
Non-tropical sprue
Blind loop syndrome

61
Q

How can drug inhibition cause folate deficiency?
(4)

A

Oral contraceptives
Long term anticoagulant therapy
Phenobarbital
Antimetabolite chemotherapy

62
Q

How can increased requirement cause folate deficiency?

A

Disease associated with rapid cell turnover (SCA, THal, leukaemia, pregnancy)

63
Q

Write about the diagnosis of megaloblastic anaemia
(9)

A

Haemoglobin lower

MCV increased

WCC and platelets may be reduced

Oval macrocytes

Hypersegmented neutrophils

LDH up
BIlirubinaemia
Haptoglobin low
Reticulocyte low

64
Q

What four things provide evidence of ineffective erythropoiesis

A

LDH up
Bilirubinaemia
Haptoglobin down
Reticulocyte count down

65
Q

What clinical tests are carried out for vitamin B12 deficiency?
(4)

A

Diet history
Serum gastrin
IF, parietal cell antibodies
Endoscopy

66
Q

What five clinical tests are carried out for folate deficiency?

A

Diet history
Test for intestinal malabsorption
Anti-transglutaminase and endomysial antibodies
Duodenal biopsy
Underlying disease

67
Q

Comment on the folate assay

A

two-step assay for the quantitative determination of folate in human serum, plasma and RBCs

68
Q

Write about the vitamin B12 assay

A

Two-step assay with an automated sample pretreatment, for determining the presence of vitamin B12 in human serum and plasma

69
Q

How is vitamin B12 deficiency treated

A

Hydroxycobalamin -> intramuscular - 1000ug every 3 months ->

Prophylactic = total gastrectomy or ileal resection

70
Q

How is folate deficiency treated
(2)

A

Folic acid taken orally - 5mg daily for 4 months

Prophylactic in pregnancy, sever haemolytic anaemia, dialysis, prematurity

71
Q

What are the preventative measures for megaloblastic anaemia

A

Vegetarians/Vegans should supplement their diet especially in pregnancy or breast feeding

Gastric surgery -> should supplement with large doses of oral vitamin B12, preferably on an empty stomach

Nitrous oxide exposure inactivates vitamin B12 -> its used in anaesthesia may precipitate rapid neuropsychiatric deterioration in vitamin B12 deficient people

2.2 Haematology (38 decks)

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