General Symptoms pale skin short breath insomnia dementia fatigue paresthesia loss of concentration palpitations neurological probs Severe B12 Deficiency Symptoms neurological symptoms degeneration of spinal cord presentation of absent reflexes ataxia no sense of touch results in severe irreversible brain nervous system damage and death At Risk Malabsorption atrophic gastritis gastrectomy aclorrhydria no acid in stomach decreased absorptive rea in intestine medications proton pumps and H2 blockers Deacreased intake veggie diets Mutations of TC2 circulating storage about 20 of population injections Treatment oral supplements intramuscular Toxicity none recorded no UL set Sources made by bacteria Meat Fish Poultry ONLY animal products Forms Cobalamin generic for compounds called corrinoids for B12 corrin has cobalt attached to it active in human body methylcobalamin and adenosylcobalamin Meats adenosylcobalamin hydroxocobalamin Milks methylcobalamin hydroxocobalamin Supples Cyanocobalamin hydroxocobalamin Digestion Absorption Eaten in all forms Stomach pepsin and HCL separate cobalamins from polypeptides R proteins cobalophilins haptocorrins made in stomach found in saliva gastric juices binds to vitamins Intrinsic Factors are made released in stomach but fxn in intestine Small Intestine cobalamin released from R protein by pancreatic proteases Intrinsic factor binds to free cobalamin Ileum Huge doses passive diffusion Dietary Doses Cubilins receptors for B12 then B12 IF enter cell by receptor mediated endocytosis Enterohepatic circulation BILE Transport bound to 1 of 3 transocbalamins TC1 circulating storage TC2 carries newly absorbed Co to tissues TC3 delivery from tissues to liver Tissues uptake at tissues receptor fro TC2 goes to receptor mediated endocytosis lysosome degradesTC2 and get free B12 inside cell Storage liver is main site stored as adenosylcobalamin less in muscle kidney brain bone heart spleen in circulating blood as transcobalamin methionine Enzymatic Reactions 2 of them Homocysteine 2 step process formations of methylcobalamin the methlycobalamin donates methyl group to form cobalamin methionine Formation of Succinyl CoA from methylmalonyl SuccinylCoA is a krebs intermediate 5 deoxydenoslycobalamin Excretion Urine very little Bile enteroheptaic circulation can be stored up to 11 years B12 Cobalamin Assessments Main tests Serum B12 serum levels can be falsely high low with conditions or other diseases Methylmalonic Acid high with B12 deficieny can be serum or urine Homocysteine high with B12 deficiency Others DUST Deoxyuridine Supression Test complicated and expensive impaired thymidine synthesis dut to lack of B12 TC2 lack of evidence to determine if it is a better indicator that serum B12 Shilling Test no longer done in US determine problems wwtih absorp related to IF give oral radioactive B12 measures urinary excretion lower than normal urinary excretion probs w absorp Antibodies to IF protein can t fxn antibodies bind to protein then Deficiency In stages 1 serum low levels of holotranscobalamin II cell concentrastions of vitamin diminish 2 3 biochemical deficiency occurs decreased DNA synthesis a Elevated homocysteine in serum b high homocysteine high risk c factor for heart attack low methionine low SAM essential for nerve fxn d Elevated methylmalonic acid in serum 4 Megaloblasic macrocytic anemia most common symp may be caused by pernicious anemia autoimmune conditions anitbodies attack parietal cells low IF production pernicious anemia lack of IF gastric bypass long term antacid At Risk malabsorption diseases medications Phenytoin anticonvulsant Methotrexate cancer only Neural Tube Defects a malformation of any part of the body alone the neural line Spina Bifida Anencephaly total absence of brain tissue Craniorachischisis no skull formation no brain head tissues fused to shoulders Folate Future Moms Recommend supplement before preganancy Sources darky leafy greens spinach soy beans lima beans RDA pregnant 600ug breast feeding 500ug Risk factors unplanned preg social status unmarried smokers Cancer epidemiological studies inverse relationship btw cancer folate Cadio vascular health Depression due to decreased neurons folate cell synthesis Dementia cognitive fxn Toxicity large amounts of folate can mask B12 def if B12 is severe then get neurological damage LU is set for folic acid only and is very high Sources mushrooms green veggies peanuts legumes citrus fruits fortified products 1998 products had to be fortified w 140mg of folic acid 100g of product Folacin term used to describe compounds with similar structure and nutritional props as folate Forms Folic acid synthetic Folate natural Monoglutamates one glutamic acid found in supplements fortified foods transport form Polyglutamates 2 9 glutamates attached found in cells biologically active is tetrahydrofolate THF Structure body can make all three pieces of compound but we can t put them together Digestion Eaten as poly monoglutamates Conjugases cleave poly into mono found in jejunal mucosa brush border Zn dependent pancreatic juice bile Conjugases inhibitiors prevent polys from breaking down into monos legumes cabbage oranges Require Zn Metalloenzyme conjugases Absorption proton coupled folate transporter PCFT genetic defect will cause a secondary B9 deficiency Enterocyte Folic acid and folate NADPH dihyrofolate reductase Dihydrofolate Tetrahydrofolate NADPH dihydrofolate reductase Transport portal system monoglutamates sent to liver Uptake at tissues carries reduced folate carries proton coupled folate transporters FR alpha beta gamma Once inside cell 4 8 glutamates residues are attached turn monos into polys now trapped in cell conversion of coenzyme form B9 Folate Involved in Mechanisms of Action 1 accepts 1 C group from metabolic rxns 2 donates the 1 C for synthesis rxns Amino Acid Metabolism see sheet 1 histidine glutamate 2 glycine serine 3 glycine CO2 NH4 4 homocysteine methionine Methyl Folate Trap B12 removes methyl group from 5 methyl THF if no B12 the methyl group becomes trapped on the THF Purine and Pyrmidine Synthesis Purines adenine and guanine 5 10methyl THF DHF Pyrimidine cytosine thymine uracil 5 10methyl THF Formyl THF Methotrexate binds to reductase enzyme prevents cell division DHF THF Excretion Urine and used in bile but most of bile is reabsorbed Assessment 1 2 N formiminoglutamate FIGLU serum and plasma levels reflect recent dietary intake RBC more indicative of tissue status
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