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Megaloblastic Anemia - Comment

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1. Folate, Cobalamin and Megaloblastic anemia Grerk Sutamtewagul, M.D. PGY-3 Morning Report 7/30/2013
2. Key Concepts * Folate and Cobalamin (vitamin B12) play key roles in the metabolism of all cells, particularly proliferating cells. * Folate in its tetrahydro form is a transporter of one-carbon fragments which is an important step in biosynthesis of purines, thymidine, and methionine. * Cobalamin is required for 2 reactions: intramitochondrial conversion of methylmalonyl coenzyme A to succinyl CoA and cytosolic conversion of homocysteine to methionine.
3. Key Concepts * The Megaloblastic anemia of cobalamin deficiency results from an intracellular folate deficiency. * Absorption of cobalamin is a highly complex process involving haptocorrin binder, intrinsic factor (from gastric parietal cells), receptor- mediated endocytosis, transcobalamin (serum transporter). * Most common cause of folate deficiency usually nutritional in origin: alcoholics, elderly, patient with hyperalimentation, hemolytic anemia, hemodialysis, tropical/non-tropical sprue.
4. Key Concepts * The most common cause of cobalamin deficiency is pernicious anemia (autoimmune destruction of gastric parietal cell). * Pernicious anemia increases risk of gastric cancer by 2-3 times. * Other causes of cobalamin deficiency include gastric resection, stasis of intestinal content (blind loops, strictures, hypomotility), terminal ileum resection/disease, vegan diet.
5. Key Concepts * "Acute" megaloblastic anemia: * Nitrous oxide * Severe hemolytic anemia * Other causes of megaloblastic anemia: * Drugs (hydroxyurea, nucleoside analogues) * Certain inborn errors of metabolism
6. Folate
7. Folate * Source: vegetables, fruits, liver, folate fortification (in the US) * Daily requirement: 50 mcg minimum, RDA: 0.4 mg * Increased requirement in * Hemolytic anemia, Leukemia * Other malignant diseases * Alcoholism * Growth * Pregnancy and lactation (3-6 times)
8. Folate Metabolism * Tetrahydrofolate is an intermediate in reactions involving the transfer of one- carbon units. * Metabolic systems requiring folate coenzymes * Serine-Glycine conversion * Thymidylate synthesis * Histidine catabolism * Methionine synthesis * Purine synthesis * Pyrimidine synthesis
9. Folate Metabolism * Intracellular folates exist primarily as polyglutamate conjugates (75%). * Intracellular Folylmonoglutamates leak out of the cells at a fairly rapid rate whereas Polyglutamates do not. Polyglutamate form is more active and will retain in the cell.
10. Folate deficiency * Dietary deficiency * Impaired absorption * Increased requirement
11. Folate deficiency * Dietary deficiency * Inadequate dietary intake (before 1990s) – decreased dramatically after folate fortification * Infant raised with goat milk * Excessive cooking * Impaired absorption * Non-tropical sprue (Celiac disease) * Tropical sprue * Other intestinal disorders: scleroderma, amyloidosis, DM, systemic bacterial infection
12. Folate deficiency * Increased requirement * Hemodialysis (folate loss in dialysate) * Pregnancy (transfer to growing fetus) * Difficult to diagnose due to physiologic anemia and macrocytosis (mean MCV 104). * Serum and rbc folate fall steadily even in well nourished women. * Hypersegmented neutrophil is a reliable clue. * Increased cell turnover: Hemolytic anemia, chronic exfoliative dermatitis, psoriasis
13. Diagnosis of Folate deficiency * History and laboratory finding indicating folate deficiency * Absence of the neurological signs of cobalamin deficiency * Full response to physiologic dose of folate
14. Laboratory Findings * Serum Folate * Earliest specific finding * Correlate well (and varies) with recent intake (within few days) * RBC Folate * Better indicator of tissue folate status * Remain unchanged for 2-3 months * Also falls in cobalamin deficiency – not use for differentiate folate from cobalamin deficiency * Serum Homocysteine * Increase homocysteine may precede a fall in folate level but is non-specific.
15. Laboratory Findings * Macrocytosis * Differential diagnosis of macrocytosis without megaloblastic anemia * Alcoholism * Liver disease * Hypothyroidism * Aplastic anemia * Certain myelodysplasia * Pregnancy * Reticulocytosis
16. Cobalamin
17. Cobalamin * Vitamin B12 (cyanocobalamin – therapeutic form) * 4 Forms of cobalamin in animal cell metabolism: cyanocobalamin, hydroxocobalamin, adenosylc obalamin, and methylcobalamin (major circulating form)
18. Source of Cobalamin * Animals cannot produce cobalamin. * Animals depend on microbial synthesis or animal product intake for cobalamin supply. * Cobalamin has not been found in plants. * Species from the following genera are known to synthesize B12: Acetobacterium, Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium,Corynebacterium, Flavobacterium, Lactobacillus, Micromonospora, Mycobacterium, Nocardia, Propionibacterium, Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces, Streptococcus and Xanthomonas.
19. Body composition of cobalamin * Total body cobalamin is around 2-5 mg. * 1 mg is in the liver. * Daily loss of cobalamin is 0.1% of total body pool. Several years is required to develop deficiency state.
20. Cobalamin Metabolism * There are only 2 recognized cobalamin- dependent enzymes in human: * Mitochondrial Adenosylcobalamin-dependent Methylmalonyl CoA mutase * Cytosolic Methylcobalamin-dependent N5-Methyltetrahydrofolate-homocysteine methyltransferase
21. Methylmalonyl CoA mutase * Methylmalonyl CoA (from proprionate) is changed to Succinyl CoA and enters Krebs cycle.
22. N5-Methyltetrahydrofolate- homocysteine methyltransferase * Synthesis of Methionine * Also involves in demethylation of N5-methyltetrahydrofolate to tetrahydrofolate which is needed for conjugation to polyglutamate. THF-polyglutamate will retain in the cell. * Nitrous oxide (N2O) can impair methyltransferase Acute megaloblastic anemia
23. Folate-cobalamin relationship * Folate can, at least, temporarily correct megaloblastic anemia from cobalamin deficiency. * Cobalamin cannot correct megaloblastic anemia from folate deficiency. * Megaloblastic anemia from cobalamin deficiency is actually an abnormality in folate metabolism (Folate trap hypothesis).
24. Cobalamin transport Stomach * Peptic digestion liberates cobalamin from foods. * Cobalamin is bound to Haptocorrin(HC)- like protein with more avidity than intrinsic factor in stomach pH. Terminal Ilium * Pancreatic protease releases cobalamin from HC complex. * Cobalamin is then bound to intrinsic factor, forming a complex which is very resistant to digestion. Duodenum * Cobalamin-IF complex undergo receptor-mediated endocytosis via IF receptor, Cubilin. * IF is degraded in the lyzosome, releasing cobalamin into cytoplasm. * Transcobalamin forms complex with cobalamin  blood.
25. Cobalamin transport * Like the folates, the cobalamins undergo appreciable enterohepatic recycling. * If the absorption is intact, a very long time – as long as 20 years – is required for a clinically significant cobalamin deficiency to develop from strictly vegan diet.
26. Cobalamin deficiency - outline * Decreased uptake caused by impaired absorption * Intestinal diseases * Blind Loop syndrome * AIDS * Pancreatic disease * Dietary cobalamin deficiency
27. Cobalamin deficiency – pernicious anemia * Decreased uptake – impaired absorption * Pernicious anemia (most common) * Failure of gastric intrinsic factor production, gastric mucosal atrophy, autoimmune * Age of onset usually > 40 yrs * Anti-intrinsic factor antibody/Anti-Cbl-IF complex are very specific. * Anti-parietal cell Ab (90% in PA, 60% in atrophic gastritis) * Related to other autoimmune diseases: thyrotoxicosis, Hashimoto thyroiditis, DM type 1, Addison disease, postpartum hypophysitis, infertility
28. Cobalamin deficiency - others * Gastrectomy syndrome (total, partial) * Removal of intrinsic factor * Zollinger-Ellison syndrome * High acid prevent a transfer of cobalamin from the HC complex to IF * Diseases of terminal Ileum * Extensive ileal resection * IBD, lymphoma, XRT * Hypothyroidism, medication * Diphyllobothrium latum infestation
29. Cobalamin deficiency – Blind loop syndrome * Blind Loop syndrome * Intestinal stasis from * Anatomic lesions (strictures, diverticula, anastomoses, surgical blind loops) * Impaired motility (scleroderma, amyloidosis) * Treatment: antibiotics Cefalexin 250 mg QID plus Metronidazole 250 mg TID for 10 days
30. Cobalamin deficiency – Laboratory findings * Serum Cobalamin level * Low in most but not all patients with cobalamin deficiency * Low in normal subjects (vegetarian, pregnancy, taking large dose ascorbic acid) * Serum Holotranscobalamin * Functional fraction of serum bound cobalamin * Urine Methylmalonic acid * Very reliable indicator of cobalamin deficiency
31. Cobalamin deficiency – Laboratory findings * Serum Methylmalonic acid and Homocysteine * Elevated MMA and Homocysteine levels are indicators of tissue cobalamin deficiency. * MMA is more sensitive and specific, persists several days after treatment. * MMA elevation is seen only in cobalamin deficiency whereas Homocysteine elevation can be seen in folate/pyridoxine deficiency and hypothyroidism.
32. Megaloblastic Anemias * Disorders caused by impaired synthesis of DNA. * Megaloblastic cells: Erythroid * large cells with immature-appearing nuclei * Increasing hemoglobinization of the cytoplasm * “Nuclear-cytoplasmic asynchrony” * Megaloblastic granulocytic cells * Large giant band neutrophil in bone marrow * Hypersegmented neutrophil in the marrow and blood * Other rapidly dividing cells may also showed cytologic abnormalities.
33. Pathogenesis of Megaloblastic anemia * Ineffective erythropoiesis * Intramedullary destruction of red cell precursors * Hypercellular marrow with apoptosis of late precursors * Ineffective granulopoiesis and thrombopoiesis also present and can result in neutropenia and thrombocytopenia. * Mild hemolysis with shortening of red cell half-life.
34. Clinical features of Megaloblastic anemia * Anemia develops gradually and patient is usually able to adapt to very low Hb level. * Fatigue, palpitation, lightheadedness, shortness of breath
35. Peripheral blood smear of Megaloblastic anemia * Hypersegmented neutrophil
36. Bone marrow smear of Megaloblastic anemia * Erythroid hyperplasia with marked nuclear/cytoplasmic dysynchrony noted at all stages of erythroid maturation * Giant Band neutrophil in the bone marrow

Posted by :  peter88 Post date :  2019-11-05 23:20
Category :  Health & Medicine Views :  356

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