Oesophageal and gastric disease

Question 1

B12 and folate metabolism and deficiency

Answer 1

Vitamin B12

B12 is also called cobalamin.

Source:

• animal products, including meats (esp liver), dairy products, and eggs
• Vitamin B12 supplements methylcobalamin, hydroxocobalamin, adenosylcobalamin, or cyanocobalamin

Absorption/uptake/storage:

• Vitamin B12 in foods is protein-bound. R-binders or haptocorrins (HC) are secreted in the saliva and bind to the vitamin B12 in the stomach.
• B12 is dissociated from proteins by the action of pepsin in the acidic stomach
• Gastric parietal cells produce intrinsic factor
• dissociated B12 binds to intrinsic factor in the stomach
• B12-IF complex is taken up by mucosal receptors in the ileum. A small amount (<1 percent) is absorbed by passive diffusion
• B12 is exported into the bloodstream (across the basolateral membrane) by an ATP-binding cassette protein. It dissociates from IF and becomes bound to transcobalamins
• B12 bound to transcobalamin is taken up by tissue cells throughout the body by receptor-mediated endocytosis (Transcobalamin II is synthesised in the liver, and is the principal transport carrier for B12). Megalin is the specific receptor for transcobalamin-II/B12 complexes, that mediates uptake into tissues.
• Intracellular vitamin B12 is metabolised into adenosylcobalamin or methylcobalamin
• The body stores 2-5mg of B12, half of it in the liver. Hence, B12 deficiency typically does not develop for at least 1-2 years.

B12 deficiency causes:

• Gastric problems: pernicious anemia (Autoantibodies to intrinsic factor or gastric parietal cells); Gastrectomy/bariatric surgery; Gastritis; Autoimmune metaplastic atrophic gastritis
• Small bowel problems: Malabsorption syndrome; Ileal resection or bypass; Inflammatory bowel disease (eg, Crohn disease); Celiac disease; Bacterial overgrowth; Blind loop; Dibothriocephalus latus (fish tapeworm)
• Pancreatitis (leading to pancreatic insufficiency)
• Diet problems: Breastfed infant of a mother with vitamin B12 deficiency; Strict vegan diet; Vegetarian diet in pregnancy
• Drugs that impair absorption: Neomycin; Biguanides (eg, metformin); Proton pump inhibitors (eg, omeprazole); Histamine 2 receptor antagonists (eg, cimetidine); Nitrous oxide (N2O) gas, used for anesthesia or recreationally
• Inherited transcobalamin II deficiency

Folate:

Vitamin B9 or pteroylglutamic acid

Source:

• plant and animal products, especially dark green leafy vegetables and liver
• Naturally occurring folinic acid is the reduced form
• recommended daily intake ranges from 65 mcg of dietary folate equivalents in infants, to 400 mcg of dietary folate equivalents in adults, with higher requirements during pregnancy and lactation (600 and 500 mcg, respectively)

Absorption / uptake / storage:

• Folate polyglutamates are cleaved to monoglutamates
• monoglutamates are absorbed in the jejunum (mainy mediated by proton-coupled folate transporter and folate carrier folate receptors. But passive absorption also occurs)
• Folate enters cells by binding to a folate receptor (Megalin)
• Once inside the cell, folate is again polyglutamated to a biologically active form that cannot diffuse back out of the cell
• Polyglutamated tetrahydro-folate acts as a one-carbon donor for biologic processes, inc synthesis of the purines and pyrimidines used in DNA synthesis.
• Total body folate stores are 500 to 20,000 mcg (0.5 to 20 mg). Deficiency may develop within weeks to months, or more rapidly if demands for folate are increased.

Causes of folate deficiency:

• Inadequate dietary intake
• Increased requirements: Pregnancy and lactation, Chronic hemolytic anemias, Exfoliative skin diseases, Hemodialysis
• Intestinal malabsorption
• Medications: MTX, trimethoprim, phenytoin, valproate, carbamazepine
• Genetic disorders: mutations affecting the proton-coupled folate transporter (PCFT)

B12 and Folate Deficiency

Role of B12 and folate:

• DNA synthesis, RNA synthesis, DNA methylation. Lack of b12/folate means the cell arrests in ‘S’ phase and can lead to apoptosis.
• Haematopoiesis (Hematopoietic precursor cells are among the most rapidly dividing cells in the body)

Deficiency leads to:

• megaloblastic anaemia (macrocytic, due to impaired cell division, this leads to immature or morphologically abnormal nuclei, producing giant metamyelocytes, tear drop red cells, hypersegmented neutrophils)
• neuropsychiatric conditions