Macrocytic anemias.docx

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Biochem. and Medical Genetics
BGEN 3020
Jason Leboe- Mcgowan

Macrocytic anemias B12 and folate are involved in DNA synthesis, therefore, if you are B12 and/or folate def, you cannot make DNA, specifically b/c you have a prob with making DMP (deoxythymidine monophosphate). Therefore, if you cannot make that, you cannot mature the nucleus (immature nuclei do not have a lot of DNA in them, but as you make more DNA, the nuclei become more matured, and the nucleus becomes smaller and more condensed). B/c DNA cannot be made, then you have large nucleus, and all nucleated the cells in your body are big – why they are called MEGAloblastic anemias. A good pathologist can dx B12 and folate def in a cervical pap smear, when looking at the squamous cells (cells look big – any cell with a nucleus has DNA in it, so any cell with DNA will be big – not just the hematopoeitic cells that are huge, ALL nucleated cells in the body are big – ie GI, squamous cells) B12 aka cobalamin; B12 has cobalt in it. Circulating form of folate is methyltetrahydrofolate (tetra = four). Purpose of cobalamin (B12) is to take the methyl group off of methyltetrahydrofolate. Then it’s called tetrahydrofolate. If you don’t get the methyl group off of folate, you will not make DNA. So, if you are B12 def, you can’t get the methyl group off and cannot make DNA. If you are def in folate, you can’t make DNA. Cobalamin adds a methyl to group homocysteine; when you add a methyl group to homocysteine, it becomes methionine. Methionine = aa for 1 carbon transfer rxns. (Methyl = CH ). If3you are B12 or folate def, what are the serum homocysteine levels? High. With a high serum homocysteine, it produces thromboses, including MI’s; it damages endothelial cells, leading to thromboses, and predisposing to MI. So, what is MCC of increased homocysteine? It is NOT homocystinuria (rare auto rec dz), but B12 def or folate def, and folate is MC than B12. Therefore, the MCC of increased homocysteine is folate def, and have an increased incidence of thrombosis and MI. This is why cardiologists order serum homocysteine levels. In folate def, no methyl group to add to homocysteine (so homocysteine increases); with B12 def, no methyl group to add to methionine to make homocysteine therefore methionine increases. Tetrahydrofolate is the start of the cycle, and leads to production of thymidilate synthase – this is where DNA is made. DUMP is converted to DDT, making DNA. Therefore, this substrate is necessary to make DNA. So, it is used in the making of DNA by an enzyme called dihydrofolate reductase which converts oxidized dihydrofolate to tetrahydrofolate. Many drugs block dihydrofolate reductase – methotrexate, TMP-SMX. The drugs block DNA synthesis (ie decreasing DNA synthesis) thereby leading to macrocytic anemia. So, the functional B12 takes the methyl group from tetrahydrofolate and gives it to homocysteine to make methionine. And tetrahydrofolate will start the cycle for making DNA. B12 1. B12 Reactions: B12 is humiliated by having to transfer methyl groups. This is an odd request – so whoever he asked said that they can take care of even chained FA’s, but we have a problem with ODD chained FA’s b/c we can only break down till proprionyl CoA, which leads to dementia and proprioception loss. B12 helps in odd chain FA metabolism. Therefore, it is involved in proprionate metabolism, which is metabolism of an odd chain FA. Proprionate forms methylmalonyl CoA, where B12 comes in and helps convert methylmalonyl CoA to succinyl CoA, which can go into the TCA cycle. In B12 def, certain things will build up, such as proprionate and methylmalonyl CoA. Methylmalonyl CoA becomes methylmalonlylic acid, which is a sensitive and specific test for B12 def. So, with B12 def, get a methylmalonlylic acid test (which will be increased). Reason for neurological problems is b/c proprionate metabolism; without B12, cannot convert odd chain FA’s into succinyl CoA, and they build up, and it screws up myelin (cannot syn myelin) – and leads to demyelination of posterior columns, and of the lateral corticospinal tract, along with dementia. B/c it is a posterior column dz, you will have probs with proprioception, vibration; b/c you knock off the lateral cortical spinal tract, you will get UMN lesions (spasticity, babinski), and then dementia. Will always tell you that you can have B12 def, and correct the anemia with high doses of folate, but cannot correct the neurologic dz. Therefore, must make the specific dx. B/c if you think its folate def and give folate, you will correct the hematologic problem, but not the neurological problem, therefore have B12 def. So, in differential of dementia, include B12 def (along with Alzheimer’s). You don’t have to have anemia with B12, but can have neurological probs. So, with dementia, get a TSH level (to throw out hypothyroidism), and a B12 level to rule out B12 def b/c these are REVERSIBLE causes of dementia. Pure vegan vs. ovo-lactovegan: In ovo-lactovegan taking dairy products (which are animal products), therefore, do not have to take B12 supplements. However, a pure vegan does have to take B12 supplements. 2. Normal sequence of B12 absorption: Have to eat meats or dairy products to get B12. The first thing B12 does is binds to R factor in saliva. R factor protects B12 from destruction by acid in the stomach. Intrinsic factor (IF) made by parietal cells in the body fundus; they also make acid. IF is not destroyed by acid, therefore does not need anything to protect it. So the B12/R factor complex goes into the duodenum, where there is IF waiting for it. R factor must be cleaved of
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