Megaloblastic Anemia

Megaloblastic AnemiaBYDR. Hayam HebahAssociate Professor of Internal MedicineAL Maarefa CollegeObjectives:BackgroundCausesB12Folic acidManagement.

BACKGROUND:Megaloblastosis describes a heterogeneous group of disorders that share common morphologic characteristics: large cells with an arrest in nuclear maturation. Nuclear maturation is immature relative to cytoplasmic maturity. Cells seen in bone marrow aspirates and in peripheral smears have been called megaloblasts. Megaloblastic changes are most apparent in rapidly dividing cells such as blood cells and gastrointestinal cells.PATHOPHYSIOLOGY:The common feature in megaloblastosis is a defect in DNA synthesis in rapidly dividing cells. To a lesser extent, RNA and protein synthesis are impaired. B12 helps to synthesize thiamine, thus deficiency leads to problems with DNA replication

Causes of Megaloblastic AnemiaB12 deficiencyFolate deficiencyPernicious anemiaOTHER CAUSES OF MEGALOBLASTOSIS:*Medications(antimetabolite drugs as azathioprine)*Direct interference of DNA synthesis by:-- HIV infections --myelodysplastic disorders.*Liver disease with inadequate cholesterol esterification*Alcohol abuse independent of folate (MCV 100-105)*Post-splenectomy

8VITAMIN B12 AND FOLIC ACID-PHYSIOLOGIC CONSIDERATIONS

Vitamin B12 Folic acidSources meat, fish green vegetables, yeast Daily requirement 2-5 ug 50-100 ug Body stores 3-5 mg (liver) 10-12mg (liver) Places of absorption ileum duodenum and proxymalsegment of small intestine

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Vitamin B12 (cobalamin)

The primary sources of cobalamin (Clb), a cobalt-containing vitamin, are meat, fish, and dairy products and not vegetables and fruit.Cobalamin is the only water-soluble vitamin stored in the body. About 3 mg of cobalamin are stored, of which 1 mg is stored in the liver. Hence, it takes 3-5 years to develop a vitamin B-12 deficiency after a total gastrectomy. In contrast, significant amounts of folate are not stored. Clinical evidence of folate deficiency can occur within a month after folate intake is stopped

B12 MetabolismBind to cobalophilin (cobalamine binding protein) in saliva and gastric secretionBind to IF (from parietal cell) in the duodenumCbl-IF complex bind to receptor (cubilin) at distal ileum for mucosal absorption1% B12 can be absorbed without IF (megadose of B12 for IF deficiency )14MEGALOBLASTIC ANEMIAS Causes of Vit.B12 deficiency(1)

1. Malabsorption a) Inadequate production of intrinsic factor- pernicious anemia (autoimmune destruction of gastric parietal cells)- gastrectomy, partial or total b) Inadequate releasing vit. B12 from food - (partial gastrectomy, atrophic gastritis and achlorhydria (mainly in elderly patients), - chronic pancreatic insufficiency (the alkaline environment in the small intestine is insufficient for release of cobalamin from R-proteins and binding to intrinsic factor)c) Terminal ileum disease (sprue, celiac disease, ilea resection, Crohn disease, Imerslund syndrome)14(Causes of Vit.B12 deficiency(2d) Competition for intestinal B12 : - bacterial overgrowth: jejunal diverticula, intestinal stasis and obstruction due to strictures, blind-loop syndrome- Fish tapeworm Diphyllobothrium latum , found in Canada, Alaska, and the Baltic Sea.2-Inadequate intake

Dietary cobalamin deficiency rarely causes megaloblastic anemia, except in vegetarians

3. Inadequate utilisationDrugs: PAS, Neomycin, Colchicin, Nitrous oxide in the Zollinger-Ellison syndrome, the acid environment also prevents binding of cobalamin to intrinsic factor.Disorders of the terminal ileum can result in cobalamin deficiency. Because the terminal ileum is the site of uptake of cobalamin-IF complexes, tropical sprue, inflammatory bowel disease, lymphoma, and ileal resection can lead to cobalamin deficiency.Blind loop syndrome can result in cobalamin deficiency. Bacterial colonization can occur in intestines deformed by strictures, surgical blind loops, scleroderma, inflammatory bowel disease, or amyloidosis. Bacteria then compete with the host for cobalamin.A partial list of medications that can cause cobalamin deficiency includes: purine analogs (6-mercaptopurine, 6-thioguanine, acyclovir), pyrimidine analogues (5-fluorouracil, 5-azacytidine, zidovudine), ribonucleotide reductase inhibitors (hydroxyurea, cytarabine arabinoside)drugs that affect cobalamin metabolism (p-aminosalicylic acid, phenformin, metformin).Causes of B12 DeficiencyGastrectomy/Bariatric surgeryIleal resection or bypassIleal disease (TB, lymphoma, amyloid, post-radiation, Crohns)Enteropathies (protein losing, chronic diarrhea, celiac sprueFish tapeworm (Diphyllobothrium latum) infectionBacterial overgrowthHIV infectionChronic alcoholismSjogrens syndromePancreatic Exocrine InsufficiencyStrict vegan dietInherited Trans-Cbl II or IF deficiencydecreased uptake of IF-Cbl (juvenile megaloblastic anemia) - also presents with proteinuriaHomocysteinuria, severe abnormalities of methionone synthesis, abnormal lysosomal exporterDecreased absorption from medicationNeomycinMetformin up to 10-25%PPINitric oxide (inhibits methionine synthase)

Pernicious AnemiaAutoantibody to Intrinsic Factor detectable in 100 with or without anemiaHypersegmented neutrophilsPancytopenia of uncertain causeUnexplained neurologic s/sAlcoholicsMalnourished, particularly the elderlyVegans if no history of supplementationDiabetics on metformin with new onset neuropathy

Lab work out:Reticulocyte counts are inappropriately low, representing lack of production of RBCs due to massive intramedullary hemolysisLDH is usually markedly increasedPeripheralsmear morphology:MacroovalocytesSingle and multiple Howell-Jolly bodies, nuclear fragment, may be seen in RBCs. Cabot rings, remnants of mitotic spindles, may also be present in RBCs.Nucleated RBCs and megaloblastshypersegmented neutrophilspancytopeniaCabot rings in RBCs

Megaloblastic anemiaMegaloblastic BM

Hypersegmented PMNBone marrow aspirationBone marrow aspiration is usually not needed to make the diagnosis of vitamin B-12 deficiency. However, it can help rule out myelodysplasia and assess iron stores.The bone marrow is hypercellular with erythroid hyperplasiaGiant bands, neutrophil precursers, can be present. Megakaryocytes may be large and hyperlobulated.

Primary Tests for B-12 and Folate Deficiencies

Serum B-12 (cobalamin)Reference range: 200-900 pg/mLBorderline: 180-250 pg/mLAssociated with anemia and neuropathy: < 180 mg/LDiagnostic of B-12 deficiency: < 150 mg/L

Serum folateReference range: 2.5-20 ng/mL5 ng/mLFolate deficiency likely (overlap with normal): < 2.5 ng/mL

RBC folate:

Lab tests to confirm and distinguish B-12 and folate deficienciesFolate deficiencyB12 deficiencyhomocysteineMMAIntrinsic factor(IF)blocking and parietal cell and antibodiesIF antibodies, type 1 and type 2, occur in 50% of patients with pernicious anemiaParietal cell antibody occurs in 90% of patients. with pernicious anemia. Both tests are non Specific.

(Schilling test) not done now.

Other needed tests:Baseline iron studies and serum ferritin should be obtained since they may predict the need for iron therapy since iron stores can be consumed during cobalamin or folate therapy.Radiographic imaging of the upper and lower GIT may be useful for detecting abnormalities that could cause a blind loop syndromeOther tests that may be considered include :With cobalamin deficiency, evaluate and rule out autoimmune disorders, Zollinger-Ellison syndrome, pancreatic insufficiency, fish tapeworm infestation, Crohn disease, or ileal scarring.With folate deficiency, evaluate evidence for malnutrition and alcoholism, sprue, chronic hemolysis, and exfoliative dermatitis.Megaloblastic anemia

THERAPY:Transfusion therapy should be restricted to patients with severe, uncompensated, and life-threatening anemia.Cobalamin TherapyCobalamin (1000 g) should be given intramuscularly daily for 2 weeks, then weekly until the hematocrit value is normal, and then monthly for life. Oral cobalamin (1000-2000 g) also can be administered. Note the following:Oral cobalamin is indicated in patients with hemophilia to avoid intramuscular injections and bleeding.Intramuscular cobalamin and not oral cobalamin should be used to treat patients with cobalamin-related neurological disorders.One advantage of parenteral over oral cobalamin is that all abnormalities in cobalamin absorption are bypassed.It may be practical to initially administer parenteral cobalamin and then to continue treatment with oral cobalamin. Oral cobalamin is less expensive and is better tolerated by patients.Patients who have undergone either a total or partial gastrectomy should be started on replacement therapy after the surgery to prevent the development of megaloblastosis

Folate Therapy

Folate (3-5 mg) should be administered orally.Folate should be administered prophylactically during pregnancy, lactation, and the perinatal period. Folate is also indicated in patients with chronic hemolytic anemias, psoriasis and exfoliative dermatitis, and during extensive renal dialysis.Folate therapy has been recommended in patients with hyperhomocysteinemia who are at risk for thromboembolic complicationFortification of foods and folic acid supplements have been recommended to reduce the risk of pancreatic, cervical, and colon cancers.Folic acid supplements are indicated in end-stage renal disease. Folate supplementation is indicated in elderly persons

Folate Deficiency TreatmentOral folate 1mg daily for 4 months or until hematologic recoveryRule out B12 deficiency prior to treament as folic acid will not prevent progression of neurologic manifestations of B12 deficiencyRepeat testing for B12 deficiency may be reasonable for those on long-term folic acid therapy if hematologic (macrocytosis or LDH) or neurologic sx persist

Warning

Folate therapy should not be instituted in a patient with megaloblastic anemia if cobalamin deficiency has not been definitively ruled out. The danger is that folic acid will improve the anemia but not the neurological complications of cobalamin deficiency, and the neurological disorder will worsen. Both cobalamin and folate should be initiated if cobalamin deficiency has not been ruled out

Treatment of Other Related ConditionsBlind loop syndrome should be treated with antibiotics.Patients with transcobalamin II (TCII) deficiency may require higher doses of cobalamin.Tropical sprue should be treated with both cobalamin and folate.Acute megaloblastic anemias due to nitrous oxide exposure can be treated with folate and cobalamin.Fish tapeworm infection, pancreatitis, Zollinger-Ellison syndrome, and inborn errors should be treated with appropriate measures.

dietPatients should have diets rich with folic acid. Examples of such foods include asparagus, broccoli, spinach, lettuce, lemons, bananas, melons, liver, and mushrooms. To prevent loss of folate, foods should not be cooked excessively and should not be diluted in large amounts of water. To prevent cobalamin deficiency, vegetarians should include dairy products and eggs in their mealsPrognosisThe prognosis is favorable if the etiology of megaloblastosis has been identified and appropriate treatment has been instituted. However, patients are at risk for hypokalemia and anemia-related cardiac complications during therapy for cobalamin deficiency.Folate deficiency during pregnancy can lead to neural tube defects and other developmental disorders in the fetus. However, folate in prenatal vitamins given during pregnancy has reduced these morbidities