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2.2 Haematology > Megaloblastic Anaemia > Flashcards

Megaloblastic Anaemia Flashcards

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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
Describe the structure of vitamin B12
Cobalt in the centre of a corrin ring which is attached to a nucleotide portion
26
What are the different phases to vitamin B12 absorption? (3)
Oral Phase Gastric phase Intestinal phase
27
Write about the oral phase of vitamin B12 absorption
B12 in proteins ingested R-binders produced by salivary glands
28
Write about the gastric phase of B 12 absorption (3)
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
29
Write about the intestinal phase of vitamin B12 absorption (4)
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
What is intrinsic factor? (2)
A glycoprotein that free vitamin B12 combines with It is synthesised by the gastric parietal cells
31
Write about IF-Vitamin B12 complex and it's role in absorption (5)
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
What molecule is responsible for transporting vitamin B12
Transcobalamin
33
What are the different types of transcobalamin
Transcobalamin 1 Transcobalamin 2 Transcobalamin 3
34
What does transcobalamin 1 do?
Binds most vitamin B12 in the body Has little capacity to transfer vitamin B12 to tissues
35
What does transcobalamin 3 do?
Released from the granules of neutrophils Not involved in Vitamin B12 transport Named incorrectly
36
What happens when the transcobalamin 2/B12 complex has reached its destination
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
What are the four categories of vitamin B12 deficiency?
Nutritional Biologic competition Malabsorption Impaired utilisation
38
What are the three nutritional causes of vitamin B12 deficiency?
Vegans Pregnant women on poor diet Malnutrition
39
What are the three biologic competition causes of B12 deficiency
Intestinal parasite Leishmaniasis Bacterial overgrowth
40
What are the eight causes of malabsorption of vitamin B 12
Pernicious anaemia Gastrectomy or gastric bypass Crohn's disease Tropical sprue Coeliac disease Surgical resection of ileum Drugs Blind loop syndrome
41
What are the two causes of impaired utilisation of vitamin B12
TC II deficiency (transcobalamin deficiency) Nitrous oxide inhalation
42
What is a definition of pernicious anaemia
A severe lack of intrinsic factor due to gastric atrophy
43
What causes pernicious anaemia
Presence of auto-immune antibodies to gastric parietal cells Don't really know why this happens
44
What does pernicious anaemia cause (4)
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
Comment on the laboratory investigation of vitamin B12 deficiency (11)
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
How can you tell from blood test results that there is marrow cell breakdown
Plasma bilirubin and lactate dehydrogenase levels increased as a result of marrow cell breakdown
47
How is pernicious anaemia treated
Vitamin B12 given as an injection directly into muscle which bypasses the need for absorption from the intestine
48
What is folate
The naturally-occurring form of the vitamin
49
What is folic acid (3)
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
Give some signs of folic acid deficiency (10)
Fatigue Depression Loss of appetite Trouble concentrating Forgetfulness Grey hair Poor growth Mouth sores Swollen tongue Spinal cord defects e.g. spina bifida
51
How does folate deficiency affect pregnancy? (5)
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
Write about the action of folate (3)
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
How is folate involved in cell division (4)
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
How is folate absorbed? (4)
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
What happens to polyglutamate forms of folate
Polyglutamate forms are hydrolysed by pteroylpolyglutamatehydrolase (PPH) to monoglutamate form of folate in the intestine
56
What happens to monoglutamate? (2)
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
What are the five classifications of causes of folate deficiency?
Inadequate diet Biologic competition Increased requirement Malabsorption Drug inhibition
58
How can inadequate diet cause folate deficiency?
Low income Elderly people with limited function/income Alcoholics (spirits)
59
How can biological competition cause folate deficiency
Bacterial overgrowth in small intestine
60
How can malabsorption cause folate deficiency? (4)
Ileitis Tropical sprue Non-tropical sprue Blind loop syndrome
61
How can drug inhibition cause folate deficiency? (4)
Oral contraceptives Long term anticoagulant therapy Phenobarbital Antimetabolite chemotherapy
62
How can increased requirement cause folate deficiency?
Disease associated with rapid cell turnover (SCA, THal, leukaemia, pregnancy)
63
Write about the diagnosis of megaloblastic anaemia (9)
Haemoglobin lower MCV increased WCC and platelets may be reduced Oval macrocytes Hypersegmented neutrophils LDH up BIlirubinaemia Haptoglobin low Reticulocyte low
64
What four things provide evidence of ineffective erythropoiesis
LDH up Bilirubinaemia Haptoglobin down Reticulocyte count down
65
What clinical tests are carried out for vitamin B12 deficiency? (4)
Diet history Serum gastrin IF, parietal cell antibodies Endoscopy
66
What five clinical tests are carried out for folate deficiency?
Diet history Test for intestinal malabsorption Anti-transglutaminase and endomysial antibodies Duodenal biopsy Underlying disease
67
Comment on the folate assay
two-step assay for the quantitative determination of folate in human serum, plasma and RBCs
68
Write about the vitamin B12 assay
Two-step assay with an automated sample pretreatment, for determining the presence of vitamin B12 in human serum and plasma
69
How is vitamin B12 deficiency treated
Hydroxycobalamin -> intramuscular - 1000ug every 3 months -> Prophylactic = total gastrectomy or ileal resection
70
How is folate deficiency treated (2)
Folic acid taken orally - 5mg daily for 4 months Prophylactic in pregnancy, sever haemolytic anaemia, dialysis, prematurity
71
What are the preventative measures for megaloblastic anaemia
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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