Vitamin B12 and Folic Acid Deficiency

Question 1

What is vitamin B12 and what types of food is it commonly found in?

Answer 1

Cobalamin (vitamin B12) is a bacterial product that is ingested and stored by animals.
It is found in meat, cheese, salmon, cod, milk, eggs

Question 2

What is Vitamin B12 needed for?

Answer 2

DNA synthesis

Integrity of the nervous system (involved in myelination)

Question 3

Broadly speaking, what can cause Vitamin B12 deficiency?

Answer 3

Dietary deficiency (vegans) 
Decreased absorption

Question 4

What types of food have lots of folic acid?

Answer 4

Leafy green vegetables

Question 5

Broadly speaking, what can cause folic acid deficiency?

Answer 5

Dietary deficiency
Increased demand for folate
Impaired absorption

Question 6

What is folic acid required for?

Answer 6

DNA synthesis

Homocysteine metabolism

Question 7

Describe the passage of vitamin B12 from entry into the GI tract tothe hepatic portal circulation.

Answer 7

It enters the stomach and binds to transcobalamin 1 (R protein –produced by the salivary glands)
The gastric parietal cells (at the bottom of the stomach) produce intrinsic factor
The B12 moves into the duodenum, bound to transcobalamin 1, and then pancreatic enzymes displace B12 from transcobalamin 1 The free B12 then binds to intrinsic factor
The B12-intrinsic factor complex continues all the way to the terminal ileum where it binds to specific receptors and is absorbed The B12 then goes into the portal circulation and binds to transcobalamin 2 making active B12

Question 8

Describe the absorption of folic acid.

Answer 8

Folic acid enters the GI tract as polyglutamates
The acidic pH of the stomach hydrolyses the polyglutamates to monoglutamates
The folic acid is absorbed as pteroglutamates
It is then methylated in the luminal cells to form methyl tetrahydroflorate

Question 9

In what reaction is B12 a co-factor?

Answer 9

The conversion of homocysteine to methionine

Enzyme = methionine synthetase

Question 10

State some clinical features of B12 and folate deficiency.

Answer 10

Anaemia (macrocytic and megaloblastic) 
Jaundice (due to ineffective erythropoiesis) 
Angular Cheilosis  
Glossitis  
Sterility  
Weight loss and change of bowel habit

Question 11

State some causes of macrocytic anaemia.

Answer 11

Vitamin B12/Folate deficiency
Liver disease and alcoholism
Hypothyroidism
Haematological disorders:
 Myelodysplasia (production of one or all types of blood cells by the bone marrow is disrupted)
 Aplastic anaemia (failure of blood cell production resulting in pancytopenia)
 Reticulocytosis (in response to haemolytic anaemia or bleeding)
Drugs that interfere with DNA synthesis
Prolonged nitrous oxide anaesthesia

Question 12

How can you differentiate between the blood film of someone with B12/Folate deficiency and someone with liver disease or alcoholism causing macrocytosis?

Answer 12

B12/Folate deficiency = OVAL macrocytes

Liver disease and alcoholism = ROUND macrocytes

Question 13

What is a reticulocyte?

Answer 13

A young red blood cell with no nucleus

Question 14

What two things do you look at when determining the maturity of a red blood cell?

Answer 14

Chromatin – how open is it?

Colour of the cytoplasm – how blue is it?

Question 15

What is meant by ‘megaloblastic changes’?

Answer 15

These are changes seen in the red blood cell precursors in the bone marrow.
Megaloblastic change is when there is asynchronous maturation of the nucleus and cytoplasm.
You get an immature, open nucleus with mature cytoplasm.

Question 16

Broadly speaking, what are megaloblastic changes the result of?

Answer 16

Defective DNA synthesis

Question 17

Which of the causes of macrocytic anaemia also show megaloblastic changes in the bone marrow?

Answer 17

B12/Folate deficiency
Myelodysplasia
Drugs that interfere with DNA synthesis

Question 18

In megaloblastic anaemia, you see changes in the red blood cellsand the white blood cells. Describe these changes.

Answer 18

Red blood cells
 Asynchrony between maturation of nucleus and cytoplasm (immature nucleus and mature cytoplasm)
 Increase in size of red cell precursors at all stages of maturation
 Increase in bone marrow activity because haemopoiesis is ineffective (dysplastic)
 Phagocytosis of dysplastic red blood cells
White blood cells
 Giant metamyelocytes (due to asynchronous maturation)
 Hypersegmented neutrophils

Question 19

Which groups are at particular risk of dietary folate deficiency?

Answer 19

Elderly, sick, eating disorders, alcoholics

Question 20

What are the consequences of folate deficiency for DNA synthesis?

Answer 20

Folate deficiency means that you can’t methylate dUMP to dTMP, which affects DNA synthesis.
It also leads to the accumulation of homocysteine (it can’t be converted to methionine without folate)

Question 21

State some physiological and pathological causes of increased folate demand.

Answer 21

Physiological (increased growth) 
 Pregnancy
 Adolescence 
 Premature babies
Pathological (rapid cell turnover) 
 Malignancy 
 Erythroderma (whole body rash)
 Haemolytic anaemia

Question 22

State some causes of malabsorption of folate.

Answer 22

Coeliac Disease
Surgery or inflammatory bowel disease
Drugs

Question 23

How can coeliac disease be diagnosed?

Answer 23

Anti-gliadin (transglutaminase) antibodies

Duodenal biopsy

Question 24

State some tests to identify folate deficiency.

Answer 24

Full blood count
Blood film
Serum folate – useful as a screening test
 Shows diurnal variation
 Affected by recent changes in diet
Red cell folate – useful as confirmatory test

Question 25

What would you expect the serum folate and red cell folate of a patient with B12 deficiency to be and why?

Answer 25

Serum folate = high Red cell folate = LOW This is because B12 is required for the folate to enter the red blood cells

Question 26

What are the three main consequences of folate deficiency?

Answer 26

Megaloblastic anaemia Neural tube defects Increased risk of venous thromboembolism

Question 27

What are the two types of neural tube defects?

Answer 27

Spinal cord = spina bifida | Brain = anencephaly

Question 28

Homocysteine accumulates in folate deficiency. What are the consequences of this?

Answer 28

Very high homocysteine levels are associated independently with:  Atherosclerosis  Premature vascular disease Mildly elevated homocysteine is associated with cardiovascular disease and probably with arterial and venous thrombosis.

Question 29

Which groups of people are at particular risk of vitamin B12 deficiency due to decreased intake?

Answer 29

Vegans

Question 30

State some factors that can affect the absorption of B12.

Answer 30

Autoimmune – pernicious anaemia (lack of intrinsic factor) Surgery – resection of parts of the GI tract Inflammatory bowel conditions – Crohn’s, chronic pancreatitis, bacterial overgrowth, parasitic infection

Question 31

What is the relationship between Hb level and neurological symptoms in B12 deficiency?

Answer 31

Inverse relationship between Hb level and neurological symptoms

Question 32

State some symptoms and signs of B12 deficiency.

Answer 32

Weak, tired, lethargic Symmetrical parasthesia/numbness Muscle weakness Difficulty walking and loss of balance Anaemia and jaundice giving ‘yellow tinge’ Neurology  Loss of vibration and joint position sense but also cutaneous sensation loss  Absent responses and up-going plantar responses in legs Visual impairment Memory impairment Psychiatric disturbance

Question 33

What is the test for B12 deficiency?

Answer 33

``` Serum cobalamin (B12) level PROBLEM: it measures total cobalamin levels (bound to transobalamin 1, 2 and 3) so you see a lot of healthy patients with low transcobalamin This means that the clinical circumstances must be taken into account when interpreting the results. ```

Question 34

What is the role of B12 in DNA synthesis?

Answer 34

Both B12 and folate are needed for the production of dTMP (deoxythymidine), which is a crucial building block in DNA synthesis

Question 35

State new test used to diagnose B12 deficiency.

Answer 35

Plasma homocysteine (high in B12 and folate deficiency)

Question 36

What is pernicious anaemia and what does it result in?

Answer 36

A form of anaemia resulting from the deficiency of B12 It can be caused by autoimmune atrophic gastritic with the loss of intrinsic factor This results in macrocytic/megaloblastic anaemia with or without neurological damage

Question 37

Which antibodies are found in pernicious anaemia?

Answer 37

Anti-intrinsic factor antibodies ( | Anti-gastric parietal cell antibodies

Question 38

How are folate and B12 deficiency treated?

Answer 38

Oral folate or oral cyanobalamin for dietary deficiency or increased demand Parenteral (IM/SC) hydroxycobalamin for malabsorption due to pernicious anaemia or bowel disease