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Megaloblastic anemia

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Common anemia...multisystem involvement..covers all systemic manifestations..fallacies and advances

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Megaloblastic anemia

  1. 1. MEGALOBLASTIC ANEMIA Ajay Kumar Yadav PGY3,Medicine IOM-TUTH, Kathmandu 2075/05/18
  2. 2. LAYOUT • Vitamin deficiencies • Historical background • Vitamin B12 • Folic acid • Clinical presentations • Diagnostic approach • Treatment
  5. 5. HISTORICAL BACKGROUND Vitamin B12 structure was demonstrated by Hodgkin, who was awarded a Nobel Prize for her crystallographic work. Castle demonstrated that gastric juice contains an “intrinsic factor” (IF) In 1926 Minot and Murphy using the then new technique of reticulocyte assessment, showed that the manifestations could be reversed by eating prodigious amounts of liver. In 1880, Ehrlich identified megaloblasts Neuropathy was noted by Osler and Gardner in 1877 First description of pernicious anemia : puzzling illness with anemia, debilitation, languor, and, finally, torpor and death by Addison in 1849.
  7. 7. STRUCTURE • Cobalt atom at the center of a corrin ring. • In nature, vitamin B12 exists as 2 forms • 2-deoxyadenosyl (ado) Cobalamin • Located in mitochondria • Co-factor for the enzyme methyl-malonyl CoA mutase. • Methyl Cobalamin • Found in human plasma and in cell cytoplasm. • Co-factor for methionine synthase.
  8. 8. DIETARY SOURCES AND REQUIREMENT • Cobalamin is synthesized solely by microorganisms. • The only source for humans is food of animal origin, e.g., meat, fish, and dairy products. • Vegetables, fruits, and other foods of nonanimal origin are free from cobalamin unless they are contaminated by bacteria. • Daily requirements are also about 1–3 μg (avg 2.4 mcg ) in adult ,0.4 mcg in infancy and 1.8 mcg in preadolescence. • Body stores are of the order of 2–3 mg, sufficient for 3–4 years if supplies are completely cut off.
  9. 9. ABSORBTION • Two mechanisms  Passive  Occurs equally through buccal, duodenal, and ileal mucosa  Rapid but extremely inefficient, with <1% of an oral dose being absorbed.  Active : normal physiological phenomenon  Occurs through the ileum  Efficient and mediated by gastric intrinsic factor (IF). • Dietary cobalamin is released from protein complexes by enzymes in the stomach, duodenum, and jejunum  combines rapidly with a salivary glycoprotein aka haptocorrins (HCs)  In the intestine, the haptocorrin is digested by pancreatic trypsin and the cobalamin is transferred to IF.
  10. 10. TRANSPORT • The IF-cobalamin complex passes to the ileum, where IF attaches to a specific receptor (cubilin) on the microvillus membrane of the enterocytes  cobalamin-IF complex enters the ileal cell, where IF is destroyed  appears in portal blood attached to TC II after a delay of about 6 hr. • TC II is synthesized by liver and by other tissues, including macrophages, ileum, and vascular endothelium. It normally carries only 20–60 ng of cobalamin per liter of plasma and readily gives up cobalamin to marrow, placenta, and other tissues, which it enters by receptor-mediated endocytosis • Between 0.5 and 5 μg of cobalamin enter the bile each day.
  11. 11. FOLIC ACID
  12. 12. STRUCTURE , SOURCE AND REQUIREMENT • Folic (pteroylglutamic) acid is a yellow, crystalline, water-soluble substance. • Partly or completely reduced to di- or tetrahydrofolate (THF) derivatives. • Usually contain a single carbon unit • 70–90% of natural folates - folate-polyglutamates. • Dietary source : The highest concentrations are found in liver, yeast, spinach, other greens, and nuts (>100 μg/100 g). • Folate is easily destroyed by heating. • Total body folate in the adult is ~10 mg, with the liver containing the largest store. • The recommended dietary folate equivalent intake is 400 mcg daily for adults ,600 mcg for pregnant women and 500 mcg for lactating women.
  13. 13. ABSORBTION AND TRANSPORT • Absorbed in upper small intestine. • All dietary folates are converted to 5-methylTHF (5-MTHF) within the small intestinal mucosa before entering portal plasma  achieves peak level in the blood 1 hr after ingestion. • 2/3rd bound to albumin and 1/3rd free form. • About 60–90 μg of folate enters the bile each day and is excreted into the small intestine. • In all body fluids (plasma, CSF, milk, bile), folate is largely, if not entirely, 5-MTHF in the mono glutamate form.
  14. 14. BIOCHEMICAL FUNCTIONS • As coenzymes in the transfer of single-carbon units. • Purine and pyrimidine synthesis necessary for DNA and RNA replication. • As a coenzyme for methionine synthesis, in which methylcobalamin is also involved and in which THF is regenerated. • Methionine, the other product of the methionine synthase reaction, is the precursor for S- adenosylmethionine (SAM), the universal methyl donor involved in >100 methyltransferase reactions . • During thymidylate synthesis, 5,10-methylene-THF is oxidized to DHF (dihydrofolate). The enzyme DHF reductase converts this to THF. • The drugs methotrexate, pyrimethamine, and (mainly in bacteria) trimethoprim inhibit DHF reductase and so prevent formation of active THF from DHF.
  15. 15. BIOCHEMICAL BASIS • Defect in DNA synthesis that affects rapidly dividing cells in the bone marrow. • Failure to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). • Folate is needed as the coenzyme 5,10-methylene-THF for conversion of dUMP to dTMP; the availability of which is reduced in either cobalamin or folate deficiency. • Mis-incorporation of uracil into DNA as consequence of the block in conversion of dUMP to dTMP resulting in DNA breakage arrest of hematopoietic precursor cell in various stages of interphase.
  16. 16. COBALAMIN-FOLATE RELATIONS • Only two reactions in the body are known to require cobalamin. • Methylmalonyl CoA isomerization requires SAM. • Methylation of homocysteine to methionine requires both methylcobalamin and 5-MTHF. • In cobalamin deficiency, MTHF accumulates in plasma, and intracellular folate concentrations fall due to failure of formation of THF : THF starvation or methylfolate trap.
  18. 18. CAUSES Cont..
  20. 20. CLINICAL FEATURES • Asymptomatic : increased MCV • LOA - usually marked , LOW • Diarrhea, or constipation. • Glossitis, angular cheilitis. • Jaundice (unconjugated)- lemon yellow tinge, and reversible melanin skin hyperpigmentation • Pallor, fatigue and other features of anemia – more common. • Mucocutaneous bleed d/t thrombocytopenia and infections d/t leucopenia are less common.
  21. 21. CAUSES OF MACROCYTOSIS(MCV>97 fl) MEGALOBLASTIC ANEMIA  Cobalamin or folate deficiency  Some metabolic disorders (e.g., thiamine-responsive anemia)  Cytotoxic drugs (e.g., hydroxyurea, 5-fluorouracil)
  22. 22. NON-MEGALOBLASTIC CAUSES DRUGS DISORDERS OF RED CELL PRODUCTION IDIOPATHIC NON-HEMATOLOGICAL DISEASE Antiviral drugs  Anticonvulsant drugs  ALCOHOL  Aplastic anemia  Pure red cell aplasia  MDS  Myeloproliferative diseases  Leukemia  Sideroblastic anemia  Fanconi anemia  Diamond-blackfan anemia  Copper deficiency anemia  Pregnancy  Chronic lung disease  Smoking  Cancer  Multiple myeloma  Liver disease  Hypothyroidism  RETICULOCYTOSIS : HEMOLYTIC ANEMIA
  23. 23. GENERAL TISSUE EFFECTS OF VITAMIN B12 AND FOLATE DEFICIENCY • Epithelial Surfaces • After BM, the next most frequently affected tissues are the epithelial cell surfaces of the mouth, stomach, and small intestine and the respiratory, urinary, and female genital tracts. • Complications of Pregnancy • Infertility is common in both men and women (with def. of both ) • Prematurity is common with folate deficiency. • Recurrent fetal loss and neural tube defects ( with def. of both)
  24. 24. • Neural Tube Defects • FA supplement at the time of conception and in the first 12 WOP reduce by ~70% the incidence of NTDs (anencephaly, meningomyelocele, encephalocele, and spina bifida) in the fetus. • Malignancy • Prophylactic FA in pregnancy has been found in some but not all to reduce the subsequent incidence of ALL in childhood. • Lower risk for colorectal cancer.
  25. 25. • Cardiovascular Disease • Severe homocystinuria (blood levels ≥100 μmol/L) due to deficiency of one of three enzymes, methionine synthase, MTHFR, or cystathionine synthase. • Premature CVD, CAD,PAD and unexplained and recurrent venous thrombosis. • Prospective RCT with supplements of folic acid, vitamin B12, and vitamin B6 against placebo over a 5-year period • No reduction of first event fatal or nonfatal MI. • No reduction in the risk of recurrent cardiovascular disease after an acute MI • 18% reduction in strokes but no significant prevention of death from any cause.
  26. 26. NEUROLOGICAL DYSFUNCTION • CNS : Demyelination with subsequent axonal disruption and gliosis. • PNS : Axonal degeneration without demyelination. • The classic myelopathic syndrome is subacute combined degeneration, in which posterior and lateral column damage predominates; dorsal, pyramidal, and spinocerebellar tracts are affected. • The earliest changes appear in the cervical or thoracic spine and can be detected by MRI as hyperintensity on T2WI. • Larger, more heavily myelinated fibers tend to be affected most often. • Unlike anemia, neurological dysfunction does not always reverse after cobalamin therapy. Residual deficit persist in 6% of pts.
  27. 27. CLINICAL PRESENTATIONS 1) Young children : Developmental delay ,lethargy , cerebral atrophy, and seizure. 2) Ataxia ( sensory + cerebellar) 3) Pyramidal tract sign : Babinski sign and spasticity 4) Loss of DTR 5) Autonomic dysfunction : Bowel and bladder dysfunction , Impotence.
  28. 28. 6) Visual changes , Optic neuritis 7) Disturbance of smell or taste 8) Dementia • Manifestations tend to be symmetrical • Involvement ascends up the legs, and, eventually, hands are affected as well
  29. 29. HEMATOGICAL FINDINGS • Panmyelosis • N/C disassociation : morphological hallmark. • Giant band cells and metamyelocytes with large and often misshapen nuclei are typical. • Neutrophils with characteristic hypersegmented nuclei appear in the blood early in the course. • 6 lobes in ≥ 1 cell • 5 lobes in ≥ 5 cells.
  30. 30. Cont.. • As megaloblastic anemia worsens, neutropenia and thrombocytopenia develop. • Erythroid macrocytosis is an early change f/b gradual rise in overall MCH and then MCV before the hemoglobin levels fall. • Macro-ovalocytes are especially characteristic of megaloblastic anemia but are not specific.
  31. 31. Cont..
  32. 32. Cont..
  33. 33. BONE MARROW FINDINGS • BM hyperplasia is intense but reticulocytosis does not occur. • Giant and abnormally shaped metamyelocytes and enlarged hyper-polyploid megakaryocytes are characteristic. • Megaloblastoid : Refer to cells with both immature-appearing nuclei and defective hemoglobinization and is usually seen in myelodysplasia.
  34. 34. • CHROMOSOME • BM cells, transformed lymphocytes, and other proliferating cells in the body show a variety of changes – includes • Random breaks, • Reduced contraction, • Spreading of the centromere, and • Exaggeration of secondary chromosomal constrictions and overprominent satellites.
  35. 35. • INEFFECTIVE HEMATOPOIESIS • Increase in unconjugated bilirubin d/t death of nucleated RBCs in the marrow (ineffective erythropoiesis). • Raised urine urobilinogen, • Reduced haptoglobins, • Positive urine hemosiderin, • Raised LDH.
  36. 36. CLINICAL DEF. Vs SUB-CLINICAL DEF. CHARACTERISTICS CLINICAL DEFICIENCY SUB-CLINICAL DEFICIENCY Biochemical abnormalities  Often severe  Usually mild Clinical abnormalities  Megaloblastic anemia is present in >75% of cases  Neurologic or cognitive changes are present in >50% of cases  Electrophysiologic (neurologic) abnormalities are usually present  Anemia is absent  Neurologic changes are absent  Mild electrophysiologic changes are sometimes present Cobalamin absorption status  IF-related malabsorption causes >90% of cases  Normal absorption is uncommon (e.g., veganism)  IF-related malabsorption is usually absent  Most persons have normal absorption
  37. 37. CHARACTERISTICS CLINICAL DEFICIENCY SUB-CLINICAL DEFICIENCY Diagnostic criteria  Almost always one or more clinical abnormalities  At least one abnormal biochemical finding  No clinical signs of cobalamin deficiency  Ideally, at least two abnormal biochemical findings should be demonstrated Likelihood of progression of deficiency  Very high because of the usual presence of IF-related malabsorption  Unknown, but probably small Need for cobalamin therapy  Urgent in all cases  Unknown Medical implications  Clinical deficiency indicates that medical management is needed  None known, but if SCCD is found during medical evaluation it must be evaluated medically
  38. 38. DIAGNOSIS
  40. 40. TREATMENT
  41. 41. • INDICATIONS  Well-documented megaloblastic anemia or other hematologic abnormalities and  Neuropathy d/t to the deficiency.
  42. 42. VITAMIN B12 DOSE • Replenishment of body stores should be complete with six 1000-μg IM injections of hydroxocobalamin given at 3- to 7-day intervals. • For maintenance therapy, 1000 μg hydroxocobalamin IM once every 3 months is satisfactory. • When absorption is normal, oral cyanocobalamin can usually be used, and doses of 2 to 5 μg do not substantially exceed IF capacity.
  43. 43. FOLATE DOSE • 5 mg of FA daily. • Duration : 4 months • Long-term folic acid therapy is required when the underlying cause of the deficiency cannot be corrected and the deficiency is likely to recur, e.g., in chronic dialysis or hemolytic anemias. • Folinic Acid (5-Formyl-THF) • Stable form of fully reduced folate. • Given orally or parenterally to overcome the toxic effects of methotrexate or other DHF reductase inhibitors, e.g., trimethoprim or cotrimoxazole.
  44. 44. REVERSAL OF PRESENTING SYMPTOMS  The patient often begins to feel better within a day, before anemia improves.  New reticulocytes appear in 2 to 3 days.  Although neutrophil hyper-segmentation persists for 2 weeks or more, WBC and platelet count rise in the 1st week if they had been decreased.  Peak reticulocytosis occurs at 7 to 10 days.  The blood count becomes fully normal before 8 weeks have elapsed.  Neurologic improvement becomes noticeable in the first few weeks.
  45. 45. MONITORING THE RESPONSE • Homocysteine and MMA levels begin to fall within a few days of therapy and can be used to monitor response. • Monitoring vitamin levels, whether cobalamin, holo-TC II, or serum folate, has little value because plasma levels rise passively regardless of therapeutic effectiveness. • Reticulocyte response can be assessed best at the end of the first week, and completeness of hematologic response after 8 weeks. • The extent of neurologic improvement cannot always be predicted. • The likelihood of full reversal with cobalamin is inversely related to the duration of symptoms before therapy was started and the extent of the original dysfunction. Whatever reversal can be expected is usually completed by 6 months.
  46. 46. REFERENCE • Wintrobe’s clinical hematology 13th edition • Harrison 19th edition • UpToDate 2018
  47. 47. THANK YOU