Folate, Vit B12 and Anaemia Flashcards by Mona Raza

What is Vitamin B12 required for?

Nuclear maturation - it is part of the Krebs cycle

It is an essential cofactor in DNA & cell metabolism

Methylation in DNA and fatty acid synthesis

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How do we get vitamin B12?

Solely from the diet, from animal products

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How long do the stores of vitamin B12 last? And how much does the body store?

years

2-5 mg (the liver stores this)
sufficient for at least 10 years

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Where is vitamin B12 absorbed?

In the terminal ileum (requires intrinsic factor)

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Where do we get folate from?

Liver, fruits and green leafy vegetables

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Where is folate absorbed?

Upper small bowel

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How long do the folate stores last?

3 - 4 months (small stores)

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What do folate deficiencies result in?

Macrocytic anaemia

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Which enzyme is dependent upon vitamin B12? And what is the action of this enzyme? Hence, what is the importance of vitamin B12

Methionine synthase

it catalyses the formation of methionine from homocysteine
using 5-methyltetrahydrofolate as a methyl donor, and converting it into tetrahydrofolate

Hence vitamin B12 is linked with folate

Vitamin B12 is important in the methylation of DNA, RNA, and proteins

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What is the second reaction that requires vitamin B12?

Converting Methylmalonyl CoA to Succinyl CoA which will then go down the citric acid cycle
(important in fatty acid breakdown and energy production)

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How is vitamin B12 absorbed?

The dietary vitamin B12 combines with an intrinsic factor (IF)

The intrinsic factor is a carriage protein, which drives vitamin B12 through the small bowel to the terminal ileum

then the IF-Vitamin B12 complex attaches to the receptors in the terminal ileum and vitamin B12 is absorbed

The absorbed vitamin B12 attaches to transcobalamin II (carriage protein) which carries B12 in the plasma to the liver, BM, and tissues where it is needed to make DNA

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A deficiency in which of the following will lead to megaloblastic anaemia:

(a) Intrinsic factor
(b) G6PD
(c) PK
(d) factor 4
(e) haptoglobin

a = Intrinsic factor

vitamin B12 will have nothing to bind to, and hence will not be able to be absorbed in the terminal ileum

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What causes vitamin B12 deficiency?

Diet (inadequate intake)

Infants born to B12 deficient mothers

Malnutrition, famine, poverty

Malabsorption (due to gastrectomy - no stomach or due to pernicious anaemia)

Pernicious anaemia is the autoimmune condition where there are antibodies directed against the parietal cells or against the intrinsic factor itself

Intestinal causes (defects of the ileum, Chron’s disease)

Long-term NO exposure

High concentrations of bacteria and certain parasites can absorb the cobalamin

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Which of the following is the main cause of Vitamin B12 deficiency?

(a) gastrectomy
(b) overgrowth of bacteria & parasites which absorb the cobalamin
(c) inadequate intake
(d) Chron’s disease
(e) Pernicious anaemia

Pernicious anaemia (e)

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What happens in pernicious anaemia

Antibodies are made to IF or the parietal cells
preventing the formation of the IF-B12 complex
This means that the individual will not absorb the vitamin B12

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what cells secrete IF?

gastric parietal cells

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Who is more likely to get pernicious anaemia

(a) 60 year old men with a family history of auto-immune disease
(b) 50 year old women with family history of auto-immune disease
(c) women who have greying hair, blue eyes and blood group A
(d) 60 year old women with a family history of auto-immune disease
(e) neonates

(d) ) 60 year old women with a family history of auto-immune disease

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how does pernicious anaemia look like and why

anaemia with lemon-yellow tint due to jaundice

the progenitor cells aren’t being made properly, and as they are ineffective they are being removed & degraded

this means bilirubin is being generated (breakdown of Hb)

bilirubin gives the yellow jaundice color

Pernicious anaemia is

(a) microcytic anaemia
(b) normocytic anaemia
(c) macrocytic anaemia

Macrocytic

Clinical features of B12 deficiency are:

1) asymptomatic
2) gradual onset anaemia
3) Mild jaundice due to ineffective erythropoiesis due to the lack of vitamin B12
3) neuropathy (degeneration of the spinal cord, demyelination of the dorsal and lateral spinal columns (difficulty walking, tingling of feet)

What does a lack of B12 do to the nervous system?

A lack of B12 damages the myelin sheath that surrounds and protect nerves. Without this protection, nerves cease to function properly and conditions such as peripheral neuropathy occur.

Blood count & film features of B12 deficiency

Macrocytic anaemia (high MCV)
Oval macrocytes
Mild reduction in leucocytes and platelets
Hypersegmented neutrophils due to defective DNA production

Biochemical features of B12 deficiency are…

Low serum B12

Normal serum folate

Raised bilirubin & LDH (due to premature RBC destruction)

Lab features of the bone marrow when there is B12 deficiency

megaloblastic erythropoiesis

Megaloblastic anemia is a condition in which the bone marrow produces unusually large, structurally abnormal, immature red blood cells (megaloblasts).

What is treatment for B12 deficiency

Intra-muscular administration of hydroxocobalamin 1000 (ug) 3x per week, for 2 weeks Then 1000 ug of hydroxocobalamin every 3 months for life, unless corrected ``` Oral doses (large) of vitamin B12 canalso be given (1-2 mg daily) but less reliable than intramuscular ```

Why do we need folate?

It is an essential coenzyme which is required for the synthesis of thymidine monophosphate (DNA synthesis) It is reduced to tetrahydrofolate which is important in the synthesis of purines, pyrimidines and the metabolism of amino acids

what causes folate deficiency?

reduced intake in the diet poor absorption increased folate requirements, when there is increased cell turnover such as in pregnancy, lactation, prematurity As well as during haemolytic anaemia, inflammatory conditions and exfoliative dermatitis can also get excess folate loss, during dialysis

History and clinical features include:

diet, drugs, alcohol gradual onset anaemia mild jaundice due to ineffective haemopoiesis

History and clinical features include:

diet, drugs, alcohol gradual onset anaemia mild jaundice due to ineffective haemopoiesis

laboratory features of folate deficiency;

serum folate is low red cell folate is low serum vitamin B12 is normal or low

treatment of folate deficiency

oral folic acid tablets per day for few months corrects the anaemia dietary advice need to replenish stores, however decide whether ongoing folic acid is required or not (depends on the underlying cause)

what is megaloblastic anaemia

it is one of a group of macrocytic anaemias (high MCV) due to reduced B12 & folate

what causes megaloblastic anaemia

due to reduced B12 & folate --> impaired DNA synthesis as nuclear division is inhibited

what characterises megaloblastic anaemia

large RBC precursors in the bone marrow (megaloblasts) the delay in the development of the nuclear chromatin gives an open (lacy) appearance cytoplasmic maturation is dependent on RNA & protein synthesis --> hence, less impaired asynchronous maturation between the nucleus and cytoplasm

Blood film characteristics of megaloblastic anaemia

Macrocytic anaemia (oval macrocytes) Hypersegmented neutrophils (6+)

bone marrow characteristics of megaloblastic anaemia

Mild haemolysis of normoblasts in BM ``` Hypercellular BM (erythroid hyperplasia) as the BM tries to increase erythropoiesis ``` More progenitor cells, ineffective erythropoiesis

Biochemical characteristics of megaloblastic anaemia

Increased bilirubin due to the destruction o abnormal megaloblasts in the BM reduced serum B12 or folate intrinsic factor or parietal cell antibodies

Biochemical characteristics of megaloblastic anaemia

Increased bilirubin due to the destruction o abnormal megaloblasts in the BM reduced serum B12 or folate intrinsic factor or parietal cell antibodies

Biochemical characteristics of megaloblastic anaemia

Increased bilirubin due to the destruction o abnormal megaloblasts in the BM reduced serum B12 or folate intrinsic factor or parietal cell antibodies

Other causes of macrocytic which are not megaloblastic ...

normal erythropoiesis but anaemia with enlarged RBC, large MCV caused by liver disease, alcohol, drugs reticulocytosis hyperthyroidism

Neural tube defects arise from failure of embryonic neural tube closure, how many days post conception?

21-27, when most women are unaware of pregnancy

Neural tube defects caused by...

lack of folate which is important in foetal growth and development, and RNA & RNA as the foetus needs to undergo widespread cell division

Neural tube malformations include

anencephaly (stillborn) encephalocele spina bifida