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Anemia & vitamins

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Vitamins and Anemia:
Your body needs vitamins ( nutrients found in most foods) for many reasons, including producing healthy red blood cells. If your body is deficient in certain key vitamins, you can develop a type of anemia ( a condition in which your blood is low on healthy red blood cells ) called vitamin deficiency anemia.

Red blood cells carry oxygen from your lungs to all parts of your body. Without enough healthy red blood cells, your body can't get the oxygen it needs to feel energized. To produce red blood cells, your body needs iron and certain vitamins along with adequate protein and calorie intake.

Vitamin deficiency anemia can also lead to other health problems. Fortunately, you can usually correct vitamin deficiency anemia with supplements and dietary changes.

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Anemia & vitamins

  1. 1. Isfahan University of Medical Science, School of Vitamins & Cofactors Anemia & Vitamins Pharmacy Department of Clinical BiochemistryJune 26, 2012 Total slides : 120 1
  2. 2. A n e m ia & Vit aminsBy:A.N. Emami Razavi
  3. 3. Vitamins & Cofactors Anemia & Vitamins Which vitamin deficiency do you think involved in anemia? Which vitamin deficiency do you think not involved in anemia?June 26, 2012 Total slides : 120 3
  4. 4. Vitamins & Cofactors Anemia & Vitamins O u t lin e s  A n e m ia  In t r o d u c t io n t o v it a m in s a n d a n e m ia  T h ia m in & a n e m ia  R ib o f la v in & a n e m ia  N ia c in & a n e m ia  P a n t o t h e n ic a c id & a n e m ia  P y r id o x in e & a n e m ia  C o b a la m in & a n e m ia  F o lic a c id & a n e m ia  V it a m in A & a n e m ia  V it a m in K & a n e m ia  V it a m in E & a n e m ia  V it a m in C & a n e m ia  B io t in & a n e m ia  O r o t ic a c id & a n e m ia  O t h e r v it a m in s & a n e m iaJune 26, 2012 Total slides : 120 4
  5. 5. AnemiaAnemia & Vitamins
  6. 6. Vitamins & Cofactors Anemia & Vitamins Definition of Anemia  A deficiency in the size or number of red blood cells or in the amount of hemoglobin a red blood cell contains  Decrease in blood hemoglobin below a person’s physiological need  Hemoglobin concentration below 95th percentile of healthy reference populationJune 26, 2012 Total slides : 120 6
  7. 7. Vitamins & Cofactors Anemia & Vitamins Causes of Anemia  Lack of required nutrients  Loss of blood  Chronic Disease  Genetic Abnormalities  Inadequate production of red blood cellsJune 26, 2012 Total slides : 120 7
  8. 8. Vitamins & Cofactors Anemia & Vitamins Signs and symptoms of Anemia Anemia occurs in many types, but the main symptom of most anemias is fatigue. Thats true for vitamin deficiency anemias, which can also result in:  Pale skin  Sore mouth and tongue  Shortness of breath  Loss of appetite  Diarrhea  Numbness or tingling in your hands and feet  Muscle weakness  Mental confusion or forgetfulness  Vitamin deficiencies usually develop slowly, over several months to years. Vitamin deficiency symptoms may be subtle at first, but they increase as the deficiency worsensJune 26, 2012 Total slides : 120 8
  9. 9. Vitamins & Cofactors Anemia & Vitamins Classification of Anemia Based on cell size (MCV)  Macrocytic (large) MCV 100+ fl (femtoliters)  Normocytic (normal) MCV 8-99 fl  Microcytic (small) MCV<80 fl Based on hemoglobin content (MCH)  Hypochromic (pale color)  Normochromic (normal color)June 26, 2012 Total slides : 120 9
  10. 10. Vitamins & Cofactors Anemia & Vitamins Types of Anemia  Anemia due to B12 deficiency  Anemia due to folate deficiency  Anemia due to iron deficiency  Hemolytic anemia  Hemolytic anemia due to G-6-PD deficiency  Idiopathic aplastic anemia  Idiopathic autoimmune hemolytic anemia  Immune hemolytic anemia  Megaloblastic anemia  Pernicious anemia  Secondary aplastic anemia  Sickle cell anemiaJune 26, 2012 Total slides : 120 10
  11. 11. Vitamins & Cofactors Anemia & Vitamins Introduction to vitamins and anemia  Your body needs vitamins ( nutrients found in most foods) for many reasons, including producing healthy red blood cells. If your body is deficient in certain key vitamins, you can develop a type of anemia ( a condition in which your blood is low on healthy red blood cells ) called vitamin deficiency anemia.  Red blood cells carry oxygen from your lungs to all parts of your body. Without enough healthy red blood cells, your body cant get the oxygen it needs to feel energized. To produce red blood cells, your body needs iron and certain vitamins along with adequate protein and calorie intake.  Vitamin deficiency anemia can also lead to other health problems. Fortunately, you can usually correct vitamin deficiency anemia with supplements and dietary changes.June 26, 2012 Total slides : 120 11
  12. 12. Thiamin & Anemia Anemia & Vitamins
  13. 13. Vitamins & Cofactors Anemia & Vitamins TRMA  Thiamine-responsive megaloblastic anemia (TRMA) with diabetes and deafness is an autosomal recessive disorder; reported in less than 30 families.  Megaloblastic anemia occurs between infancy and adolescence. The anemia is corrected with pharmacologic doses of thiamine (vitamin B1) (25-75 mg/day compared to US RDA of 1.5 mg/day). However, the red cells remain macrocytic. The anemia can recur when thiamine is withdrawn. Progressive sensorineural hearing loss has generally been early and can be detected in toddlers, is irreversible, and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence.June 26, 2012 Total slides : 120 13
  14. 14. Vitamins & Cofactors Anemia & Vitamins Diagnosis/testing  The diagnosis of TRMA is based on an obligate triad of clinical features described above. Examination of the bone marrow reveals megaloblastic anemia with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).  SLC19A2, which encodes the high-affinity thiamine transporter, is the only gene known to be associated with TRMA. All individuals with the diagnostic phenotypic triad evaluated by sequence analysis have identifiable mutations in the SLC19A2 gene. Sequence analysis of SLC19A2 DNA is available clinically.June 26, 2012 Total slides : 120 14
  15. 15. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 15
  16. 16. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 16
  17. 17. Vitamins & Cofactors Anemia & Vitamins Biochemical mechanism  The underlying biochemical mechanisms responsible for these conspicuous changes are, however, not very well defined and remain somewhat speculative and controversial.  There are basically 2 current theories, both rooted in the concept that nucleotide synthesis is impaired as that in folate and cobalamin (vitamin B12) deficiency.June 26, 2012 Total slides : 120 17
  18. 18. Vitamins & Cofactors Anemia & Vitamins  In one theory, lack of deoxythymidine triphosphate (dTTP) retards the elongation of newly formed replicating segments of DNA, resulting in fatally fractured pieces that trigger premature apoptosis.  In the other theory, build-up of deoxyuridine triphosphate (dUTP) resulting from failure of conversion of dU to thymidine causes an inordinate accumulation of dUTP, which can then substitute for missing dTTP in the machinery of DNA polymerase activity. Mis-incorporation of dUTP results in excision of the faulty segment followed by misrepair while the famine for dTTP persists, and thus ensues a futile cycle of excision-misrepair. This, too, results in apoptosis, the final common pathway of ineffective hematopoiesis in megaloblastic anemia.June 26, 2012 Total slides : 120 18
  19. 19. Vitamins & Cofactors Anemia & Vitamins Role of thiamin in ribose 5-phosphate synthesis  Through tracking the stable 13C-labeled glucose in fibroblasts from patients with TRMA, Boros and colleagues concluded that the underlying lesion in this condition resides in the pentose cycle, specifically the transketolase enzyme, which requires thiamine pyro-phosphate as a cofactor.  Through a consideration of the several interconnected pathways of glycolysis, the tricarboxylic acid cycle, and ribose synthesis, the authors defined substrate flux in TRMA and normal wild-type fibroblasts grown in both low- and high- thiamine medium.June 26, 2012 Total slides : 120 19
  20. 20. Vitamins & Cofactors Anemia & Vitamins  They concluded that defective high-affinity thiamine transport in TRMA leads to a critical reduction in de novo generation of ribose with consequent cell-cycle arrest that triggers precocious apoptosis. Their results clearly demonstrate a selective and time-dependent loss of ribose synthesis in TRMA patients that is most marked under thiamine-deprived culture conditions and is partially restored by thiamine supplementation, explaining the clinical responsiveness of TRMA patients to high doses of thiamine.June 26, 2012 Total slides : 120 20
  21. 21. Vitamins & Cofactors Anemia & Vitamins Thiamin and pyruvate dehydrogenase complexJune 26, 2012 Total slides : 120 21
  22. 22. Vitamins & Cofactors Anemia & Vitamins Role of the TCA cycle in anabolismJune 26, 2012 Total slides : 120 22
  23. 23. Vitamins & Cofactors Anemia & Vitamins Diagnosis  To establish the extent of disease in an individual diagnosed with thiamine-responsive megaloblastic anemia syndrome (TRMA), the following evaluations are recommended:  Peripheral blood count and bone marrow analysis for evidence of megaloblastic anemia  Serum folate concentration, serum vitamin B12 concentration, and serum iron studies to exclude other entities  Fasting serum glucose concentration, oral glucose tolerance test (OGTT), and urine analysis to diagnose diabetes mellitus  Hearing test  Ophthalmologic evaluation  Cardiac evaluation, including echocardiographyJune 26, 2012 Total slides : 120 23
  24. 24. Vitamins & Cofactors Anemia & Vitamins Treatment  Early administration of pharmacologic doses of oral thiamine (25-75 mg/day compared to US RDA of 1.5 mg/day) ameliorates the megaloblastic anemia and the diabetes mellitus. It may prevent further deterioration of hearing function.  Whether treatment with thiamine from birth, or even prenatally, could reduce the hearing defect is a matter of conjecture.June 26, 2012 Total slides : 120 24
  25. 25. Riboflavin & Anemia Anemia & Vitamins
  26. 26. Vitamins & Cofactors Anemia & Vitamins  Riboflavin deficiency has been associated with the development of normochromic ,normocytic anaemia .  It may be one of the most common vitamin deficiencies among the people of developing nations.  This anemia is associated with reticulocytopenia; leukocytes and platelets are generally normal.  Administration of riboflavin to deficient patients causes reticulocytosis, andJune 26, 2012 Total slides : 120 26
  27. 27. Vitamins & Cofactors Anemia & Vitamins Biochemical mechanism  Effects on iron absorption:  A FMN-dependent oxidoreductase (NADPH-ferrihemoprotein reductase) catalyses the removal of iron from storage ferritin (by reducing heme-thiolate-dependent monooxygenases).  Riboflavin affects iron absorption by maintaining the absorptive capacity of gastrointestinal villi .  Effects on heme metabolism  Protoporphyrinogen oxidase at the iner mitochondrial membrain contains one FAD moiety per homodimer ,oxidizes protoporphyrinogen-IX to protoporphyrin-IX.  NADPH dehydrogenase (EC1.6.99.1) reduces biliverdin to bilirubin in the liver and also may protect against oxidative damage.June 26, 2012 Total slides : 120 27
  28. 28. Vitamins & Cofactors Anemia & Vitamins Effects on other vitamins metabolism that their deficiencies are related to anemia:  Metabolism of vitamin B12  Cobalamin reductase  Aquacobalamin reductase/NADPH  Aquacobalamin reductase/NADH  Metabolism of vitamin B6:  Pyridoxamine-phosphate oxidase interconverts the B6 vitamins pyridoxamine,pyridoxine and pyridoxal, as well as their phosphates.  Metabolism of folic acid:  The FAD-dependent methylen tetrahydrofolate reductase is needed for folate metabolite recycling(with a reduction of its activity higher folate intakes are needed to avoid deficiency).June 26, 2012 Total slides : 120 28
  29. 29. Vitamins & Cofactors Anemia & Vitamins  Metabolism of vitamin B2:  Maintains supplies of vitamin B3 with the help of an enzyme kynurenine mono-oxygenase and vitamin B2 in its FAD form.  Metabolism of vitamin C:  Thioredoxin reductase regenerates reduced glutathione, which is used for dehydroascorbate reductase.  Metabolism of vitamin K:  NADPH dehydrogenase (EC1.6.99.6) and two forms of NAD(P)H dehydrogenase (EC1.6.99.2) reactive vitamin K (dicomarol inhibitable) and also provide important antioxidant protection.  Metabolism of vitamin A:  Retinal dehydrogenase is the enzyme that generates retinoic acid from retinal.June 26, 2012 Total slides : 120 29
  30. 30. Niacin & Anemia Anemia & Vitamins
  31. 31. Vitamins & Cofactors Anemia & Vitamins  Niacine deficiency has produced macrocytic anaemia among human patients with pellagra although this is usually due to an accompanying deficiency in folic acid.  Niacin nutritional deficiency causes hemorrhagic diarrhea, dermatitis, anemia and a severe stomatitis with ulceration of the mouth and tongue (black tongue).June 26, 2012 Total slides : 120 31
  32. 32. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 32
  33. 33. Vitamins & Cofactors Anemia & Vitamins Role of niacin in citric acid cycle NAD+ NADH + H+ Isocitrate Alpha-ketogluterate NAD+ NADH + H+ Alpha-ketogluterate Succinyl CoA NAD+ NADH + H+ Malate OxaloacetateJune 26, 2012 Total slides : 120 33
  34. 34. Pantothenate & Anemia Anemia & Vitamins
  35. 35. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 35
  36. 36. Vitamins & Cofactors Anemia & Vitamins  Rats fed a purified diet low in pantothenic acid developed granulocytopenia and anemia singly or in combination. In the former, the marrow showed marked depletion of granulocytes, particularly of the more mature cells, and a slight increase in erythroid cells. In combined granulocytopenia and anemia the granulocytes of the marrow were still further reduced and the erythroid cells were also depleted. Marked reduction in the number of megakaryocytes occurred both in the granulocytopenic and in the granulocytopenic and anemic rats.  Following treatment with combined folic acid, pantothenic acid, and niacinamide, granulocytopenic rats responded by showing a prompt rise in lymphocyte and polymorphonuclear leukocyte count, marked granulocyte response of the bone marrowJune 26, 2012 Total slides : 120 36
  37. 37. Vitamins & Cofactors Anemia & Vitamins Biochemical mechanism  Pantothenic acid as a part of coenzyme A is essential for Heme formation in hemoglobin.  The production of acetyl-C0A from pyruvate and succinyl- CoA from alpha-ketoglutarate constantly consumes large amounts of CoA.  Succinyl-CoA is needed for D-ALA synthesis the first step in heme production.June 26, 2012 Total slides : 120 37
  38. 38. Pyridoxine & Anemia Anemia & Vitamins
  39. 39. Vitamins & Cofactors Anemia & Vitamins  Vitamin B6 (pyridoxine) deficiency can disturb heme synthesis and lead to normocytic, microcytic or sideroblastic anemia. Treatment of sideroblastic anemia with vitamin B6 has resulted in the restored activity of erythroblastic δ-aminolevulinic acid synthetase (ALAS), the rate-limiting enzyme in heme synthesis, followed by correction of the hematological abnormalities.  Heme biosynethsis begins in the mitochondrion with the formation of 5-aminolevulinic acid. This molecule moves to the cytosol where a number of additional enzymatic transformations produce coproporphyrinogin III. The latter enters the mitochondrion where a final enzymatic conversion produces protophorphyrin IX. Ferrochelase inserts iron into the protophorin IX ring to produce heme.June 26, 2012 Total slides : 120 39
  40. 40. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 40
  41. 41. Vitamins & Cofactors Anemia & Vitamins  In Germany, after treating children hospitalized with iron deficiency anemia for 8 days with iron plus vitamin B6, there was an apparent acceleration of heme synthesis, reflected in Hb concentrations that were higher than observed in children who received only ironJune 26, 2012 Total slides : 120 41
  42. 42. Vitamins & Cofactors Anemia & Vitamins  Vitamin B6 may also inhibit sickling of erythrocytes in sickle-cell anemia (SCA), possibly increasing erythrocyte counts, Hb concentrations and Hct among SCA patients  Vitamin B6 deficiency is rare, but treatment with B6 may be effective in correcting the hematological abnormalities of sideroblastic anemia.June 26, 2012 Total slides : 120 42
  43. 43. Vitamins & Cofactors Anemia & Vitamins  The bone marrow aspirate from a patient with sideroblastic anemia in this photomicrograph was stained with Perls Prussian blue. The arrow indicates a normoblast with a greenish halo of material stained by Perls Prussian blue surrounding the nucleus. Electron microscopic examination would should these to be iron-laden mitochondria.June 26, 2012 Total slides : 120 43
  44. 44. Vitamins & Cofactors Anemia & Vitamins Effect of Vitamin B6 on niacin synthesis TRYPTOPHAN N-FORMYLKYNURENINE KYNURENINE Xanthurenic 3-OH-KYNURENINE Acid Kynureninase (PLP) acetyl CoA 3-OH ANTHRANILIC ACID acetoacetyl QUINOLINIC ACID CoA NIACINJune 26, 2012 Total slides : 120 44
  45. 45. Cobalamin & Anemia Anemia & Vitamins
  46. 46. Vitamins & Cofactors Anemia & Vitamins B12 deficiency Anemia This picture shows large, dense, oversized, red blood cells (RBCs) that are seen in megaloblastic anemia. Megaloblastic anemia can occur when there is a deficiency of vitamin B-12. Megaloblastic anemia - view of red blood cellsJune 26, 2012 Total slides : 120 46
  47. 47. Vitamins & Cofactors Anemia & Vitamins CAUSES OF MACROCYTOSIS OTHER MDS LIVER ETOH HEMOL DRUGS B12/ FOLATEJune 26, 2012 Total slides : Total slides : 120 47
  48. 48. Vitamins & Cofactors Anemia & Vitamins Age of onset 35 30 25 20 15 10 5 0 10-20 20-30 30-40 40-50 50-60 60-70 70-80 80-90 90-100June 26, 2012 Total slides : 120 48
  49. 49. Vitamins & Cofactors Anemia & Vitamins Causes  Pernicious anemia  Rare autoimmune disease  Failure to absorb B12 from food  Very common in older patients  Drugs  Metformin  PPI  Dramatic reduction in B12 absorptionJune 26, 2012 Total slides : 120 49
  50. 50. Vitamins & Cofactors Anemia & Vitamins Physiologic roles of vitamin B12  Conversion of propionyl-CoA to methylmalonyl CoA and finally to succinyl-CoA  Transfer of a methyl group from methyl-tetrahydrofolate (methyl-THF) via Cbl to homocysteine to form methionine — This reaction has two important effects: it reduces the plasma concentration of homocysteine which is probably toxic to endothelial cells; and, perhaps more importantly, it demethylates THF  Demethylation is a critical step in DNA synthesisJune 26, 2012 Total slides : 120 50
  51. 51. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 51
  52. 52. Vitamins & Cofactors Anemia & Vitamins Intense erythroid hyperplasia in the marrow but relative reticulocytopeniaJune 26, 2012 Total slides : 120 52
  53. 53. Vitamins & Cofactors Anemia & Vitamins Symptoms  Loss of appetite  Diarrhea  Numbness and tingling of hands and feet  Paleness  Shortness of breath  Fatigue  Weakness  Sore mouth and tongue  Confusion or change in mental status in severe or advanced casesJune 26, 2012 Total slides : 120 53
  54. 54. Vitamins & Cofactors Anemia & Vitamins Exams and Tests A physical exam may show problems with reflexes or positive Babinski reflex. The following tests will be done:  CBC  Bone marrow examination  LDH  Vitamin B12 level  Schilling test  Antibody test  Methylmalonic acid testJune 26, 2012 Total slides : 120 54
  55. 55. Vitamins & Cofactors Anemia & Vitamins Bone marrow aspiration  A small amount of bone marrow is removed during a bone marrow aspiration. The procedure is uncomfortable, but can be tolerated by both children and adults. The marrow can be studied to determine the cause of anemia, the presence of leukemia or other malignancy, or the presence of some "storage diseases" in which abnormal metabolic products are stored in certain bone marrow cells.June 26, 2012 Total slides : 120 55
  56. 56. Vitamins & Cofactors Anemia & Vitamins Schilling test  The Schilling test is performed to evaluate vitamin B12 absorption. B12 helps in the formation of red blood cells, the maintenance of the central nervous system, and is important for metabolism. Normally, ingested vitamin B12 combines with intrinsic factor, which is produced by cells in the stomach. Intrinsic factor is necessary for vitamin B12 to be absorbed in the small intestine. Certain diseases, such as pernicious anemia, can result when absorption of vitamin B12 is inadequate.June 26, 2012 Total slides : 120 56
  57. 57. Vitamins & Cofactors Anemia & Vitamins LDH Alternative Names  Lactate dehydrogenase; Lactic acid dehydrogenase Definition LDH is a blood test that measures the amount of lactate dehydrogenase (LDH). How the Test is Performed  The health care provider draws blood from a vein or from a heel, finger, toe, or earlobe. The laboratory quickly spins (centrifuges) the blood to separate the serum (liquid portion) from the cells. The LDH test is done on the serum.June 26, 2012 Total slides : 120 57
  58. 58. Vitamins & Cofactors Anemia & Vitamins Antibodies test  Your doctor may draw a sample of your blood to check for antibodies to intrinsic factor. In the majority of cases, vitamin B-12 deficiency is due to a lack of intrinsic factor — a protein secreted by the stomach necessary for the absorption of vitamin B-12. The presence of antibodies to intrinsic factor indicates pernicious anemia.June 26, 2012 Total slides : 120 58
  59. 59. Vitamins & Cofactors Anemia & Vitamins Methylmalonic acid test  You may undergo a blood and urine test to measure the presence of a substance called methylmalonic acid. The level of this substance is higher in people with vitamin B-12 deficiency.June 26, 2012 Total slides : 120 59
  60. 60. Vitamins & Cofactors Anemia & Vitamins Treatment  Treatment depends on the specific cause of B12 deficiency anemia.  Pernicious anemia requires lifelong vitamin B12 injections. Those with anemia due to a lack of vitamin B12 may be told to take vitamin supplements and to follow a more balanced diet. It may be treated initially with vitamin B12 injections.  Anemia caused by malabsorption is treated with vitamin B12 injections until the condition improve  Outlook (Prognosis)  Treatment for this form of anemia is usually effectiveJune 26, 2012 Total slides : 120 60
  61. 61. Vitamins & Cofactors Anemia & Vitamins Prevention Anemia caused by a lack of vitamin B12 can be prevented by following a well-balanced diet. B12 injections can prevent anemia after surgeries known to cause vitamin B12 deficiency. Early diagnosis and prompt treatment can limit the severity and complications of this anemia.June 26, 2012 Total slides : 120 61
  62. 62. Folic Acid & Anemia Anemia & Vitamins
  63. 63. Vitamins & Cofactors Anemia & Vitamins Folate-deficiency anemia  Folate-deficiency anemia is a decrease in red blood cells (anemia) caused by folate deficiency.  The hematologic manifestations of folate deficiency are similar to those of Cbl deficiency but neurologic abnormalities do not occur Symptoms  Tiredness  Headache  Sore mouth and tongue  PallorJune 26, 2012 Total slides : 120 63
  64. 64. Vitamins & Cofactors Anemia & Vitamins Causes  Nutritional deficiency Substance abuse ,Alcoholism Poor dietary intake ,Overcooked foods ,Depressed patients, Nursing homes  Malabsorption Sprue, Inflammatory bowel disease Infiltrative bowel disease,Short bowel syndrome  Drugs (various mechanisms) Methotrexate, Trimethoprim, Ethanol, Phenytoin  Increased requirements Pregnancy, lactation, Chronic hemolysis, Exfoliative dermatitisJune 26, 2012 Total slides : 120 64
  65. 65. Vitamins & Cofactors Anemia & Vitamins Folate metabolism DNA dTMP DHF PG THF PG 5,10 dUMP METHYLENE THF PG THF HOMOCYSTEINE METHIONINE SYNTHASE METHIONINE METHYL THFJune 26, 2012 Total slides : 120 65
  66. 66. Vitamins & Cofactors Anemia & Vitamins Exams and Tests  Low red blood cell folate level.  A complete blood count (CBC) shows anemia and large red blood cells.  A bone marrow examination is rarely necessary, but shows megaloblasts.June 26, 2012 Total slides : 120 66
  67. 67. Vitamins & Cofactors Anemia & Vitamins Treatment  The goal is to treat the cause of the anemia, which may be poor diet or a malabsorption disease.  Oral or intravenous folic acid supplements may be taken on a short-term basis until the anemia has been corrected, or -- in the case of poor absorption by the intestine -- replacement therapy may be lifelong.  Dietary treatment consists of increasing the intake of green, leafy vegetables and citrus fruits. Outlook (Prognosis)  Anemia usually responds well to treatment within 2 months.June 26, 2012 Total slides : 120 67
  68. 68. Vitamins & Cofactors Anemia & Vitamins Possible Complications  Symptoms of anemia can cause discomfort. In a pregnant woman, folate deficiency has been associated with neural tube or spinal defects (such as spina bifida) in the infant.June 26, 2012 Total slides : 120 68
  69. 69. Vit amin A & Anemia Anemia & Vitamins
  70. 70. Vitamins & Cofactors Anemia & Vitamins Vitamin A & anemia  In many developing countries vitamin A deficiency (VAD) is considered to be a major public health problem and concurrently the prevalence of anemia is high in populations affected by VAD.  190-255 millions preschool-aged children throughout the world are vitamin A deficient, with some 3–5 million having xerophthalmia, and 500 000 becoming blind and dying each year. Vitamin A deficiency may be responsible for 25–35% of all early childhood deaths in high risk regions of the developing world, attributed to increased severity of infection in a deficient state.June 26, 2012 Total slides : 120 70
  71. 71. Vitamins & Cofactors Anemia & Vitamins Animal studies Vitamin A-deficient rats indicate:  Losses of hematopoietic tissue in bone marrow.  Splenic accumulation of hemosiderin. Adding of vitamin A to the rats diet:  Regeneration of the bone marrow.  Disappearance of hemosiderin from the spleen.  Enhanced erythroblastic activity.June 26, 2012 Total slides : 120 71
  72. 72. Vitamins & Cofactors Anemia & Vitamins Human studies In human studies:  Positive correlation between serum retinol concentration and Hb level.  The findings suggest that adequate vitamin A status can help maintain adequacy of plasma iron to supply body tissues.  Intake of fortified food items with vitamin A has been resulted in elevation serum iron levels,transferrin saturation and serum ferritin levels.  Result: increasing iron availability to tissues.June 26, 2012 Total slides : 120 72
  73. 73. Vitamins & Cofactors Anemia & Vitamins  Vitamin A appears to be involved in the pathogenesis of anemia through diverse biological mechanisms, such as:  The enhancement of growth and differentiation of erythrocyte progenitor cells  Potentiation of immunity to infection  Reduction of the anemia of infection  Mmobilization of iron stores from tissues.  Epidemiological surveys show that the prevalence of anemia is high in populations affected by vitamin A deficiency in developing countries. Improvement of vitamin A status has generally been shown to reduce anemia.June 26, 2012 Total slides : 120 73
  74. 74. Vitamins & Cofactors Anemia & Vitamins A combination of vitamin A with iron and zinc is more effective than with iron alone.  This could reflect Zn association with increases in plasma vitamin A and retinol-binding protein.  The effect of vitamin A on risk of anemia appears to be more variable in pregnancy than childhood.  Haemoconcentration associated with low vitamin A status can mask anemia.June 26, 2012 Total slides : 120 74
  75. 75. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 75
  76. 76. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 76
  77. 77. Vitamins & Cofactors Anemia & Vitamins  It has been reported that supplementation with vitamin A increases hemoglobin levels and packed cell volumes in humans with low vitamin A status, thereby contributing to the control of nutritional anemia; furthermore, a synergistic interaction exists between vitamin A and iron in combined therapy (Suharno et al., 1993). Some important effects of vitamin A are to support erythropoiesis in the bone marrow and to mobilise iron from body stores (Bloem, 1995; Roodenburg et al., 1996; Semba and Bloem, 2002). However, in rats and chickens vitamin A deficiency (VAD) is accompained by imbalances in water regulation, in particular a decrease in extracellular water, which may lead to hemoconcentration as the VAD proceeds (Sure et al., 1929; McLaren et al., 1965; Nockels and Kienholz, 1967; Corey and Hayes, 1972; Mejı´a et al., 1979a; Roodenburg et al., 1994, 1996).June 26, 2012 Total slides : 120 77
  78. 78. Vitamins & Cofactors Anemia & Vitamins Possibly mechanism of vitamin A deficiency anemia Vitamin A deficiency may induce anemia by:  Impairing the differentiation and proliferations of pluripotent haematopoietic cells.  Disturbing renal and hepatic erythropoietin synthesis.  Disturbing GI absorption.  Reducing mobilization of body iron stores..June 26, 2012 Total slides : 120 78
  79. 79. Vit amin K & Anemia Anemia & Vitamins
  80. 80. Vitamins & Cofactors Anemia & Vitamins Vitamin K and hemolytic anemia  Vitamin K is necessary for synthesis in the liver of factor II (prothrombin), factor VII (proconvertin), factor IX (thromboplastin), and factor X. Deficiency of vitamin K or disturbances of liver function may lead to deficiencies of these factors. When the prothrombin level falls to about 10 to 15% of normal, even slight trauma may cause bleeding; when the level is below 10%, spontaneous hemorrhage may occur, in the form of hematoma, hematemesis, hematuria or melena. The mechanism by which vitamin K promotes formation in the liver of clotting factors II, VII, IX, and X is not known.June 26, 2012 Total slides : 120 80
  81. 81. Vitamins & Cofactors Anemia & Vitamins  Newborns should be observed for vitamin K deficiency. The incidence of vitamin K deficiency is higher in breast-fed infants.  In newborns, particularly premature infants, hyperbilirubinemia and hemolytic anemia have been reported. The risk is much less with phytonadione than other vitamin K preparations unless high doses (10 to 20 mg) are given.  In infants (particularly premature babies), excessive doses of vitamin K analogs during the first few days of life may cause hyperbilirubinemia; this in turn may result in severe hemolytic anemia, hemoglobinuria, kernicterus, leading to brain damage or even death.June 26, 2012 Total slides : 120 81
  82. 82. Vitamins & Cofactors Anemia & Vitamins Hemorrhagic Disease of the Newborn: Prophylaxis:  In its 1997 clinical practice guidelines on vitamin K administration, the Canadian Paediatric Society recommends that vitamin K1 be given as a single i.m. injection to all newborns within 6 hours of birth, at a dose of 1 mg for infants with a birthweight of >1 500 g and 0.5 mg if birthweight is £1 500 g.June 26, 2012 Total slides : 120 82
  83. 83. Vitamins & Cofactors Anemia & Vitamins Vitamin K deficiency  Vitamin K deficiency may occur in patients with biliary obstruction or other conditions limiting absorption of vitamin K such as celiac disease, ulcerative colitis, sprue, regional enteritis, cystic fibrosis, intestinal resection, and in patients receiving drugs that may affect liver function or intestinal flora.June 26, 2012 Total slides : 120 83
  84. 84. Vit amin E & Anemia Anemia & Vitamins
  85. 85. Vitamins & Cofactors Anemia & Vitamins Vitamin E & hemolytic anemia  Hemolytic anemia results from the deficiency of the enzyme glucose-6-phosphate dehydrogenase or of glutathione synthetase. Red blood cells become more sensitive to attack by free radicals, because they cannot form lipids in which vitamins can be stored. Increasing the blood level of vitamin E has been found to be useful in this disease. Function : as an antioxidant, scavenging highly reactive free radicals and protecting the PUFAs of cellular membranes from oxidative destruction.June 26, 2012 Total slides : 120 85
  86. 86. Vitamins & Cofactors Anemia & Vitamins Vitamin E and membrane lipid oxidation As part of the antioxidant network, a-tocopherol (a-OH) forms a tocopheroxyl radical (a-TO·) when it intercepts a peroxyl radical (ROO·) in a cell membrane. In the absence of vitamin E, these ROO· can abstract a hydrogen from PUFA (RH) and generate both a hydroperoxide (ROOH) and another carbon-centered radical (R·), which in the presence of oxygen (O2) will form a ROO· and thus a lipid peroxidation chain reac-tion occurs. If a-tocopherol (a-TOH) is present it intercepts the radical 1000 times faster than the radical reacts with PUFA, and both a ROOH and an a- TO· are formed. This a-TO· radical can be detoxified and a-TOH regenerated by intracellular antioxidants including vitamin C, glutathione, and reducing equivalents (NAD(P)H) derived from oxidative metabolism.June 26, 2012 Total slides : 120 86
  87. 87. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 87
  88. 88. Vitamins & Cofactors Anemia & Vitamins Animal studies Animal studies have observed:  The development of severe anemia in primates.  Morphological abnormalities of the bone marrow among primates. Treatment with vitamin E improved blood parameters among these animals.June 26, 2012 Total slides : 120 88
  89. 89. Vitamins & Cofactors Anemia & Vitamins Human studies  Pre term and LBW infants are born with low serum and tissue concentration of vit E.  Vit E deficiency induced anemia in infants has been characterized by red blood hemolysis and oedema that resolves promptly following vit E treatment.  Vit E is routinly given to preterm infants in developed country to protect against the potential oxidative caused by iron supplementation  Increasing tocopherol to PUFA ratio to lower oxidant agents such as iron in infant formula.June 26, 2012 Total slides : 120 89
  90. 90. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 90
  91. 91. Vitamins & Cofactors Anemia & Vitamins Vitamin E & fanconi anemia  a-Tocopherol (AT) decreased the frequency of chromosomal damage (under basal and inhibited G2 repair conditions) and the duration of G2 in FA cells. This antioxidant protective effect, expressed as the decrease in chromatid breaks, was greater in FA cells (50.8%) than in controls (25%).June 26, 2012 Total slides : 120 91
  92. 92. Vitamins & Cofactors Anemia & Vitamins Effects of vitamin E on heme synthesis  Vitamin E has a stimulatory effect on heme synthesis, apparently through its action on ALAD and on 5- aminolevulinic acid synthetase (ALAS).  Addition of vitamin E to the diets of lead-intoxicated rabbits coused a diminution in the anemia and coproporphyrinuria, which had resulted from plumbism.(Nair et al. , deRosa)June 26, 2012 Total slides : 120 92
  93. 93. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 93
  94. 94. Vitamins & Cofactors Anemia & Vitamins Vitamin E deficiency  Vitamin E deficiency can result from a low intake of fresh fruit and vegetables and other foods rich in vitamin E Deficiency can also occur in those individuals who cannot absorb fat. In addition, damage to the pancreas, bile duct, liver, and surgical removal of the major portion of the digestive tract can cause vitamin E deficiency. The plasma level of vitamin E in normal adults is about 10 mcg/ml; a plasma level of 5 mcg/ml or less is considered and indication of vitamin E deficiency.June 26, 2012 Total slides : 120 94
  95. 95. Vit amin C & Anemia Anemia & Vitamins
  96. 96. Vitamins & Cofactors Anemia & Vitamins Vitamin C effects on anaemia  Vitamin C defciency has been associated with various forms of anemia, but it is still unclear whether vitamin C (ascorbate) is directly involved in hematopoiesis or if anemia arises indirectly through the interactions of vitamin C with folate and iron metabolism. In its role as a reducing agent, vitamin C can facilitate iron absorption from the gastrointestinal tract and enable its mobilization from storage.  Iron and ascorbate form an iron chelate complex that is more soluble in the alkaline environment of the small intestine and, as a result, more easily taken up.June 26, 2012 Total slides : 120 96
  97. 97. Vitamins & Cofactors Anemia & Vitamins  Vitamin C may counteract the inhibition of iron absorption by dietary phytates and tannins.  Ascorbic acid also activates the enzyme folic acid reductase to form THF ,the active form of folate which prevent megaloblastic anemia.  Vitamin C possibly prevent hemolysis resulting from compromised celluar antioxidant defence mechanism.June 26, 2012 Total slides : 120 97
  98. 98. Vitamins & Cofactors Anemia & Vitamins Vitamin C mechanism Ultimately Vitamin C may:  improve absorption of non-heme iron  protect against oxidative damage  counteract the effects of iron absorption inhibitors.  increase serum iron , ferritin and Hb concentrations among children and non-pregnant subjects.June 26, 2012 Total slides : 120 98
  99. 99. Vitamins & Cofactors Anemia & Vitamins Vitamin C deficiency  Vitamin C deficiency is evident when serum ascorbate falls below 11.4 mmol /1. Groups that have been identifed as being at risk of vitamin C deficiency include pregnant and lactating women, infants fed exclusively cows milk, elderly men and smokers.June 26, 2012 Total slides : 120 99
  100. 100. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 100
  101. 101. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 101
  102. 102. Biotin & Anemia Anemia & Vitamins
  103. 103. Vitamins & Cofactors Anemia & Vitamins  Biotin is one of the least-studied vitamins, particularly in relation to mitochondrial function and the extent of its nutritional deficiency in humans.  The most important function of Biotin is to ensure proper growth. Not only does it help produce DNA fatty acids and other essential nucleic acids, it also helps the cells grow and replicate. It also plays a vital role in the production of bone marrow and thus the tissues of the central nervous system and muscles benefit from this vitamin. Vitamin H is also known to be involved in the process that helps transfer carbon dioxide.June 26, 2012 Total slides : 120 103
  104. 104. Vitamins & Cofactors Anemia & Vitamins Effects of biotin on heme synthesis  Biotin is a coenzyme in 5 different biotin-dependent carboxylases (BDC), which catalyze carboxylation reactions : pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCC), 3-methylcrotonyl-CoA carboxylase (MCC), acetyl- CoA carboxylase (ACC)-2, and ACC-1. The first 4 are located in the mitochondria. PC, PCC, and MCC catalyze anaplerotic reactions and replenish tricarboxylic acid (TCA) cycle intermediates .June 26, 2012 Total slides : 120 104
  105. 105. Vitamins & Cofactors Anemia & Vitamins Effects of biotin on heme synthesis  BD has a detrimental effect on the level of TCA cycle intermediates. A deficiency in PC directly decreases production of oxaloacetate. A deficiency in PCC decreases production of succinyl-CoA and causes propionyl-CoA to accumulate, which interacts via a side reaction with oxaloacetate to form methylcitrate. Additionally, low activity of MCC causes methylcrotonyl-CoA to accumulate in the mitochondria where it reacts with glycine and potentially depletes this amino acid from the mitochondrial matrix.  Succinyl-CoA from the TCA cycle and glycine are the precursors for heme biosynthesis. Heme synthesis starts in the mitochondria by condensing succinyl-CoA with glycine to form -aminolevulinate, the first metabolite committed to heme synthesisJune 26, 2012 Total slides : 120 105
  106. 106. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 106
  107. 107. Vitamins & Cofactors Anemia & Vitamins Results  Heme level and synthesis were markedly decreased in BD cells , indicating that adequate heme synthesis requires biotin and that BD can cause heme deficiency. Thus, biotin should be considered the 8th member of the group of vitamins and minerals required for adequate heme synthesis . The decrease in iron uptake in BD cells is unexpected, because heme deficiency should be expected to cause a compensatory increase in iron uptake . A possible explanation for the lack of an increase in iron uptake in BD cells is that the heme deficiency caused by BD is due to a decrease in succinyl- CoA, which lowers the production of porphyrins. Porphyrins are intermediates in the biosynthesis of heme. These results suggest that optimal uptake of iron requires that the mechanisms for iron assimilation into heme remain intact. Adequate levels of biotin appear to be essential for adequate iron uptake. Thus, for correcting iron deficiency in humans, it may be important to ensure biotin adequacy.June 26, 2012 Total slides : 120 107
  108. 108. Orotic acid & Anemia Anemia & Vitamins
  109. 109. Vitamins & Cofactors Anemia & Vitamins  Orotic acid plays a central role in the metabolism of folic acid and vitamin B-12, and may enhance the transportation of minerals across cell membranes.  Orotic acid and folate are also involved in DNA synthesis. Many of the vitamin-like effects of orotic acid are undoubtedly due to its role in RNA and DNA synthesis. Our bodies produce OA as an intermediate in the manufacture of the pyrimidine bases uracil, cytosine, and thymine. Together, these pyrimidines constitute half of the bases needed for RNA/ DNA, the other half coming from the purine bases adenine and guanine which are synthesized independently of orotic acid.June 26, 2012 Total slides : 120 109
  110. 110. Vitamins & Cofactors Anemia & VitaminsJune 26, 2012 Total slides : 120 110
  111. 111. Vitamins & Cofactors Anemia & Vitamins Mechanism of OA action  The oral administration of the pyrimidine precursor orotic acid in doses of 3 to 6 Gm. daily to patients with pernicious anemia in relapse produced with some regularity Partial remissions in the manifestations of vitamin B12 deficiency.  The early effects of orotic acid in pernicious anemia resembled those of small amounts of B12. Reticulocytosis appeared 7 to 14 days after the start of therapy.June 26, 2012 Total slides : 120 111
  112. 112. Vitamins & Cofactors Anemia & Vitamins Mechanism of OA action  B12 is concerned with pyrimidine biosynthesis.  The degree of remission that can be produced in patients with pernicious anemia in relapse by the administration of orotic acid suggests, that one major consequence of vitamin B12 deficiency in the human is a defect in pyrimidine biosynthesis and/or incorporation. Other processes, such as purine ring formation, may also be affected. The mechanism by which orotic acid induces partial remissions in pernicious anemia is unknown.June 26, 2012 Total slides : 120 112
  113. 113. Vitamins & Cofactors Anemia & Vitamins Mechanism of OA action  It could serve merely as a metabolite which when supplied from exogenous sources would circumvent a block in its synthesis or in that of a precursor. Increasing the supply of orotic acid could possibly overcome by mass action a defect in the synthetic pathway at a later stage. In view of demonstrated feed-back regulatory mechanisms in pyrimidine synthesis,June 26, 2012 Total slides : 120 113
  114. 114. Other vit amins & Anemia Anemia & Vitamins
  115. 115. Vitamins & Cofactors Anemia & Vitamins PABA Para-aminobenzoic acid, as part of the coenzyme tetrahydrofolic acid, aids in the metabolism and utilization of amino acids and is also supportive of blood cells, particularly the red blood cells. PABA supports folic acid production by the intestinal bacteria.June 26, 2012 Total slides : 120 115
  116. 116. Vitamins & Cofactors Anemia & Vitamins Inositol  Usually considered part of the vitamin B complex. It is thought that along with choline, inositol is necessary for the formation of lecithin within the body. Involved in calcium mobilization.  IP6 regulates the oxygen capacity of red blood cells; it reduces both cholesterol and trigylcerides, as well as preventing heart damage during a heart attack.  Research has shown that IP6 can help prevent sikle cell anemia  Anemia has been reported as a clinical sign of inositol deficiency in salmonids (Halver, 1982). Waagbø et al. (1998) observed a positive correlation between blood hemoglobin concentrations and dietary levels of inositol in Atlantic salmon.June 26, 2012 Total slides : 120 116
  117. 117. Vitamins & Cofactors Anemia & Vitamins adenine  Acts as a co-enzyme with other vitamins to enhance metabolism.  Acts as a precursor for assimilation of other B-vitamins.  Strengthens the immune system response.  Promotes cell formation and normal growth.  Prevents cellular mutation and free radical formation.  Helps to balance blood sugar levels.  Deficiency of adenine associated whit blood and skin disordersJune 26, 2012 Total slides : 120 117
  118. 118. Vitamins & Cofactors Anemia & Vitamins Vitamin DJune 26, 2012 Total slides : 120 118
  119. 119. Vitamins & Cofactors Anemia & Vitamins  The association of hypercalcemia and anemia suggested a neoplastic origin; this idea was rejected when results of additional examinations became available. High vitamin D levels could directly affect hematopoietic cells or act through high calcium levels, which inhibit erythroid colony formation in vitro and erythropoietin production in vitro and in vivo. That calcium is more important than vitamin D itself is supported by the course of our patient, whose anemia subsided after normalization of calcium levels, despite high vitamin D levels.  In addition to the danger of extemporaneous formulations, which carry a higher risk for error than factory-made pills, anemia is another potential complication of vitamin D intoxication.June 26, 2012 Total slides : 120 119
  120. 120. Vitamins & Cofactors Anemia & Vitamins Laetrile  Relationship between laetrile and anemia…  What is your idea?June 26, 2012 Total slides : 120 120
  121. 121. Thank you Questions ?

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