Contents

Search

megaloblastic anemia

Etiology: interference with DNA synthesis 1) folate deficiency 2) vitamin B12 deficiency a) metformin [8] b) proton pump inhibitors [8] 3) myelodysplastic syndrome 4) genetic disorders 5) drugs that interfere with DNA synthesis a) hydroxyurea (inhibits ribonucleotide reductase) b) methotrexate (inhibits dihydrofolate reductase) c) trimethoprim (inhibits dihydrofolate reductase) 6) other drugs [2] a) nitrous oxide b) oral contraceptives c) phenobarbital d) phenytoin e) primidone f) triamterene Pathology: 1) hypercellular marrow reflects ineffective erythropoiesis a) myeloid/erythroid ratio 1/1 b) up to 90% of erythroid precursors die in the bone marrow c) ineffective erythropoiesis may result in hemolytic anemia 2) presence of megaloblasts is pathognomonic 3) nuclear-cytoplasmic asynchrony in bone marrow cells 4) erythroid, myeloid & platelet precursors may be affected [3] Genetics: - thiamine-responsive megaloblastic anemia syndrome Clinical manifestations: 1) symptoms common to all forms of anemia a) fatigue b) pallor c) exercise intolerance 2) atrophy of mucosal surfaces (less common) a) tongue pain b) mouth pain 3) neurologic symptoms (vitamin B12 deficiency) a) paresthesias b) weakness c) gait disturbance d) personality change e) intellectual decline 4) patients with vitamin B12 deficiency may have no hematologic abnormalities & present with neurologic signs only 5) patients may be profoundly anemic at presentation 6) jaundice from hyperbilirubinemia may be present 7) tongue may be smooth as a result of papillary atrophy 8) malnutrition often accompanies folate deficiency 9) cheilosis Laboratory: 1) complete blood count (CBC) a) mean corpuscular volume is generally increased (> 100 fL), but may be diminished by coexisting iron deficiency b) leukopenia in proportion to degree of anemia c) thrombocytopenia in proportion to degree of anemia 2) peripheral smear a) hypersegmented neutrophils b) anisocytosis c) macrocytosis & ovalocytosis d) may be evidence of hemolytic anemia 3) reticulocyte count generally low 4) serum lactate dehydrogenase may be markedly elevated 5) serum bilirubin: unconjugated (indirect) hyperbilirubinemia 6) serum vitamin B12 a) 10% of elderly have low vit B12 levels without evidence of deficiency (anemia, neuropathy) b) 5-10% of patients with vit B12 deficiency have falsely normal serum vitamin B12 levels c) preferred initial diagnostic test for vitamin B12 deficiency [3] d) measure serum methylmalonic acid if serum vitamin B12 is borderline low (200-300 pg/mL) [3] 7) folate a) serum folate b) erythrocyte folate is a better indicator of tissue folate than serum folate 8) serum methylmalonic acid is elevated with vit B12 deficiency but not folate deficiency 9) serum homocysteine is elevated with both folate & vit B12 deficiency 10) holotranscobalamin II 11) Schilling test 12) bone marrow biopsy (see pathology) 13) flow cytometry 14) see ARUP consult [6] Complications: 1) pernicious anemia is associated with development of gastric cancer 2) cases of concurrent myelodysplastic syndrome have been described [5] Differential diagnosis: 1) vitamin B12 deficiency a) dietary: vegans b) pernicious anemia (autoimmune) c) post surgical: gastrectomy or ileal resection d) Crohn's disease e) bacterial or parasitic overgrowth 2) folate deficiency a) alcoholism b) malnutrition in the elderly c) malabsorption: sprue d) anticonvulsants e) pregnancy: increased utilization 3) chemotherapy: a) methotrexate b) hydroxyurea c) alkylating agents d) cytarabine 4) hereditary 5) hematopoietic malignancy a) myelodysplastic syndrome b) acute erythroid leukemia M6 Management: 1) vitamin B12 deficiency a) intramuscular (IM) vitamin B12 except in vegans with dietary deficiency b) vegans should supplement their diet with oral cobalamin c) cyanocobolamin 1 mg IM weekly for one month, then 1 mg IM monthly for life 2) folate deficiency: a) oral folate 1 mg QD b) malabsorption: folate 1 mg IM/IV QD 3) folate therapy will correct the hematologic manifestations, but not the neurologic manifestations of vitamin B12 deficiency 4) early follow-up to determine response to therapy - improvement to vit B12 deficiency occurs in days to weeks

Interactions

disease interactions

Related

classification (etiology) of megaloblastic anemia folate deficiency folate in serum/plasma homocysteine in serum/plasma hyperhomocysteinemia methylmalonate in serum Schilling test vitamin B12 deficiency

Useful

folic acid; folate; vitamin B9 vitamin B12; cobalamin

Specific

hereditary megaloblastic anemia 1; MGA1 Norwegian type; Imerslund-Grasbeck syndrome pernicious anemia; autoimmune gastritis thiamine-responsive megaloblastic anemia syndrome (Rodgers syndrome)

General

macrocytic anemia

Database Correlations

OMIM 603941 MORBIDMAP 603941

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 577-78
  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 829-39
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16. 18, 19 American College of Physicians, Philadelphia 1998, 2006, 2012, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Schiller G, in: UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
  5. Drabik et al, Ann Hematol 80:243, 2001
  6. ARUP Consult: Megaloblastic Anemia The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/megaloblastic-anemia - Megaloblastic Anemia Testing Algorithm https://arupconsult.com/algorithm/megaloblastic-anemia-testing-algorithm
  7. Galloway M, Hamilton M. Macrocytosis: pitfalls in testing and summary of guidance. BMJ. 2007 Oct 27;335(7625):884-6. PMID: 17962289
  8. NEJM Knowledge+ Hematology