Megaloblastic Anaemia Flashcards
What are Nutritional anaemias?
Nutritional anaemias are essentially anaemias caused by micronutrient deficiencies.
What are Micronutrients and examples?
Micronutrients are needed by the bone marrow to carry out the process of haemopoiesis. They include iron, folic acid, vitamin B6, vitamin B12 (cobalamin), vitamin C, copper, zinc, etc
What is Vitamin B12
1. Alternative name
2. Daily requirements
3. Sources
4. Total body stores (and how long they last)
Alternative name: Cobalamin
Sources:
Foods of animal origin (liver, meat, fish, dairy products)
Vitamin B₁₂ is synthesized in nature by micro-organisms.
It is acquired in humans by eating animals that are able to produce it from their intestinal bacteria.
Daily requirement (adults): 1-2µg.
Total body stores: 2-3mg (sufficient for 2-4years)
Write an essay on the absorption of vitamin B12
Mouth:
In food, vitamin B12 is bound to proteins
There is a protein called R-binder in saliva
Vitamin B12 binds to this R-binder in saliva and they together travel to the stomach
Stomach:
The gastric parietal cells secrete a glycoprotein called Intrinsic factor (IF)
IF binds to vitamin B12 and releases it from the proteins it had bound to earlier
The IF-Vit B12 complex together travel to the terminal ileum
Terminal ileum:
There is a specific receptor for IF called cubulin
IF-Vit B12 complex bind to this receptor
Cubulin-IF-VitB12 complex bind to a second receptor called amnionless
Amnionless facilitates the endocytosis of cubulin-IF-Vit B12 complex into intestinal cells of the terminal ileum
Within the ileal cells, Vit B12 is absorbed and IF destroyed
Transportation of B12
B12 is absorbed into portal blood where it becomes attached to the plasma-binding protein, transcobalamin, TC (previously called transcobalamin II)
TC delivers B12 to bone marrow and other tissues.
Why do patients with myeloproliferative diseases (e.g Chronic myeloid leukaemia) come down with vitamin B12 deficiency?
- Most vitamin B12 in plasma is bound to another transport protein called haptocorrin
- Haptocorrin was previously called transcobalamin I
- Haptocorrin is a glycoprotein largely synthesized by granulocytes (WBCs) and macrophages.
- In myeloproliferative diseases like CML, the WBC count is high
- The higher the WBC count, the higher the haptocorrin levels
- The higher the haptocorrin levels, the higher the amount of vitamin B12 that binds to it, and the lower the amount available for binding to transcobalamin (previously transcobalamin II)
- But there is a problem: Haptocorrin CANNOT deliver B12 to bone marrow and other tissues. Only transcobalamin can do this job.
- So all the vitamin B12 that bind to haptocorrin are “functionally dead”
Discuss the biochemical functions of B12
- Methyl B12 functions in the methylation of DNA, myelin, amines, proteins etc by converting homocysteine to Methionine
Homocysteine is from S-adenosyl homocysteine
Methionine is converted to S-adenosyl methionine
- In the conversion of Propionyl CoA to Methylmalonyl CoA to Succinyl CoA
(Ado) Vit. B12 converts Methylmalonyl CoA to Succinyl CoA
Discuss the causes of Vitamin B12 deficiency
Nutritional:
Especially vegans
Malabsorption:
Gastric causes
Pernicious anaemia
Congenital lack or abnormality of intrinsic factor
Total or partial gastrectomy
Intestinal causes:
Intestinal stagnant loop syndrome - jejunal diverticulosis, blind-loop, stricture, etc.
Chronic tropical sprue
lleal resection and Crohn’s disease
Congenital selective malabsorption with proteinuria (autosomal recessive megaloblastic anaemia)
Fish tapeworm
Causes of mild vitamin B12 deficiency include:
poor diet and other causes of malabsorption of vitamin B12 (my absorption of food B12 caused by a trophic gastritis, particularly in the elderly therapy with proton pump, inhibitors or metformin), severe pancreatitis, gluten-induced enteropathy and HIV infection. These conditions do not usually lead to vitamin B12 deficiency sufficient to cause anaemia or neuropathy.
What is Folate
1. Alternative name
2. Daily requirements
3. Sources
4. Total body stores (and how long do they last)
Alternative name: Folic acid (pteroyl glutamic acid), vitamin B9
Sources:
Wide variety of foods – vegetables (especially green leafy), legumes, fruits, liver, meat, poultry, grains, dairy products
Daily requirement (adults): 100-150µg
Total body stores: 10-12mg (sufficient for about 4months)
Where can folate be absorbed?
upper small intestine (duodenum and jejunum)
Discuss the biochemical functions of folate
Causes of folate deficiency
What is the meeting point of B12 and folate?
The meeting point of vitamin B12 and folate is in the methionine cycle, specifically at the enzyme methionine synthase.
Methionine Synthase Reaction:
5-Methyltetrahydrofolate (5-MTHF) + Homocysteine + Vitamin B12 (cobalamin) → Methionine + Tetrahydrofolate (THF)
Here, vitamin B12 (cobalamin) and 5-MTHF (a folate derivative) work together to:
- Convert homocysteine to methionine
- Regenerate THF from 5-MTHF
Clinical features of megaloblastic anaemia
Features are usually insidious in onset with progressive symptoms and signs of anaemia.
Mild jaundice with a lemon yellow tint: Due to excessive breakdown of haemoglobin from ineffective erythropoiesis.
Epithelial abnormalities: Painful glossitis (beefy –red, sore tongue), angular stomatitis, mild symptoms of malabsorption with weight loss
Clinical features of megaloblastic anaemia in severe cases
In severe cases:
Neural Tube Defects
B12 Neuropathy (Subacute Combined Degeneration of the Cord)
Reduced Osteoblastic Activity (B12 deficiency)
Sterility (can affect either sex)
Morphological abnormalities of cervical, buccal, bladder, and other epithelia.
Cardiovascular disease (Folate deficiency)
Purpura – as a result of thrombocytopenia
Widespread melanin pigmentation
Rarely, some patients can come with psychiatric manifestations
