Antony AC. Megaloblastic Anemias. Hoffman R, Benz EJ Jr, Silberstein LE, Heslop HE, Weitz JI, Anastasi J. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA: Elsevier; 2013. 473-504.
Wang YH, Yan F, Zhang WB, et al. An investigation of vitamin B12 deficiency in elderly inpatients in neurology department. Neurosci Bull. 2009 Aug. 25(4):209-15. [QxMD MEDLINE Link].
Hoffbrand AV. Megaloblastic Anemias. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill Education; 2015.
Singh NN. Vitamin B-12 Associated Neurological Diseases. Medscape Drugs & Diseases. Available at https://emedicine.medscape.com/article/1152670-overview. October 22, 2018; Accessed: April 29, 2021.
Leishear K, Ferrucci L, Lauretani F, et al. Vitamin B12 and homocysteine levels and 6-year change in peripheral nerve function and neurological signs. J Gerontol A Biol Sci Med Sci. 2012 May. 67(5):537-43. [QxMD MEDLINE Link].
Castoro C, Le Moli R, Arpi ML, Tavarelli M, Sapuppo G, Frittitta L, et al. Association of autoimmune thyroid diseases, chronic atrophic gastritis and gastric carcinoid: experience from a single institution. J Endocrinol Invest. 2016 Jul. 39 (7):779-84. [QxMD MEDLINE Link].
Dali-Youcef N, Andres E. An update on cobalamin deficiency in adults. QJM. 2009 Jan. 102(1):17-28. [QxMD MEDLINE Link].
Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B(6), Folate, Vitamin B(12), Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academies Press; 1998.
Filioussi K, Bonovas S, Katsaros T. Should we screen diabetic patients using biguanides for megaloblastic anaemia?. Aust Fam Physician. 2003 May. 32(5):383-4. [QxMD MEDLINE Link].
Ben Salem C, Sakhri J, Hmouda H. Drug-Induced Megaloblastic Anemia. N Engl J Med. 2016 Feb 18. 374 (7):696. [QxMD MEDLINE Link].
Gomber S, Dewan P, Dua T. Homocystinuria: a rare cause of megaloblastic anemia. Indian Pediatr. 2004 Sep. 41(9):941-3. [QxMD MEDLINE Link].
Borgna-Pignatti C, Azzalli M, Pedretti S. Thiamine-responsive megaloblastic anemia syndrome: long term follow-up. J Pediatr. 2009 Aug. 155(2):295-7. [QxMD MEDLINE Link].
Molloy AM, Kirke PN, Brody LC, Scott JM, Mills JL. Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr Bull. 2008 Jun. 29(2 Suppl):S101-11; discussion S112-5. [QxMD MEDLINE Link].
U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009 May 5. 150(9):626-31. [QxMD MEDLINE Link].
Sharma K, Wijarnpreecha K, Merrell N. Diphyllobothrium latum Mimicking Subacute Appendicitis. Gastroenterology Res. 2018 Jun. 11 (3):235-237. [QxMD MEDLINE Link]. [Full Text].
Kaur S, Goraya JS. Dermatologic findings of vitamin B₁₂ deficiency in infants. Pediatr Dermatol. 2018 Nov. 35 (6):796-799. [QxMD MEDLINE Link].
Oishi K, Diaz GA, Adam MP, Ardinger HH, Pagon RA, Wallace SE, et al. Thiamine-Responsive Megaloblastic Anemia Syndrome. 2017 May 4. [QxMD MEDLINE Link]. [Full Text].
Tsui E, Tauber J, Barbazetto I, Gelman SK. LONG-TERM MULTIMODAL IMAGING OF OCULAR FINDINGS ASSOCIATED WITH THIAMINE-RESPONSIVE MEGALOBLASTIC ANEMIA. Retin Cases Brief Rep. 2020 Summer. 14 (3):247-250. [QxMD MEDLINE Link].
Yan X, Gao R, Hu Y, Jin J. Pernicious anemia associated with cryptogenic cirrhosis: Two case reports and a literature review. Medicine (Baltimore). 2018 Sep. 97 (39):e12547. [QxMD MEDLINE Link]. [Full Text].
Khera S, Pramanik SK, Patnaik SK. Transcobalamin deficiency: vitamin B₁₂ deficiency with normal serum B₁₂ levels. BMJ Case Rep. 2019 Oct 30. 12 (10):[QxMD MEDLINE Link].
Del Bo' C, Riso P, Gardana C, Brusamolino A, Battezzati A, Ciappellano S. Effect of two different sublingual dosages of vitamin B₁₂ on cobalamin nutritional status in vegans and vegetarians with a marginal deficiency: A randomized controlled trial. Clin Nutr. 2018 Feb 15. [QxMD MEDLINE Link].
Andres E, Fothergill H, Mecili M. Efficacy of oral cobalamin (vitamin B12) therapy. Expert Opin Pharmacother. 2010 Feb. 11(2):249-56. [QxMD MEDLINE Link].
Miller JW. Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications. Adv Nutr. 2018 Jul 1. 9 (4):511S-518S. [QxMD MEDLINE Link].
Moleiro J, Mão de Ferro S, Ferreira S, Serrano M, Silveira M, Dias Pereira A. Efficacy of Long-Term Oral Vitamin B12 Supplementation after Total Gastrectomy: Results from a Prospective Study. GE Port J Gastroenterol. 2018 Apr. 25 (3):117-122. [QxMD MEDLINE Link]. [Full Text].
Dary O. Nutritional interpretation of folic acid interventions. Nutr Rev. 2009 Apr. 67(4):235-44. [QxMD MEDLINE Link].
Lawrence MA, Chai W, Kara R, Rosenberg IH, Scott J, Tedstone A. Examination of selected national policies towards mandatory folic acid fortification. Nutr Rev. 2009 May. 67 Suppl 1:S73-8. [QxMD MEDLINE Link].
Varela-Moreiras G, Murphy MM, Scott JM. Cobalamin, folic acid, and homocysteine. Nutr Rev. 2009 May. 67 Suppl 1:S69-72. [QxMD MEDLINE Link].
Mayo Clinic. Folate (folic acid). Mayoclinic.com. Available at https://www.mayoclinic.org/drugs-supplements-folate/art-20364625. Accessed: July 5, 2018.
Lahner E, Capasso M, Carabotti M, Annibale B. Incidence of cancer (other than gastric cancer) in pernicious anaemia: A systematic review with meta-analysis. Dig Liver Dis. 2018 Aug. 50 (8):780-786. [QxMD MEDLINE Link].
Uhl W, Nolting A, Gallemann D, Hecht S, Kovar A. Changes in blood pressure after administration of hydroxocobalamin: relationship to changes in plasma cobalamins-(III) concentrations in healthy volunteers. Clin Toxicol (Phila). 2008 Jul. 46(6):551-9; discussion 576-7. [QxMD MEDLINE Link].
McEvoy GK (ed). American Hospital Formulary Service - Drug Information 2018. Bethesda, MD: American Society of Health-System Pharmacists Inc.; 2018.

Media Gallery

Megaloblastic anemia. View of red blood cells
Megaloblastic anemia. The structure of cyanocobalamin is depicted. The cyanide (Cn) is in green. Other forms of cobalamin (Cbl) include hydroxocobalamin (OHCbl), methylcobalamin (MeCbl), and deoxyadenosylcobalamin (AdoCbl). In these forms, the beta-group is substituted for Cn. The corrin ring with a central cobalt atom is shown in red and the benzimidazole unit in blue. The corrin ring has 4 pyrroles, which bind to the cobalt atom. The fifth substituent is a derivative of dimethylbenzimidazole. The sixth substituent can be Cn, CC3, hydroxycorticosteroid (OH), or deoxyadenosyl. The cobalt atom can be in a +1, +2, or +3 oxidation state. In hydroxocobalamin, it is in the +3 state. The cobalt atom is reduced in a nicotinamide adenine dinucleotide (NADH)–dependent reaction to yield the active coenzyme. It catalyzes 2 types of reactions, which involve either rearrangements (conversion of l methylmalonyl coenzyme A [CoA] to succinyl CoA) or methylation (synthesis of methionine).
Megaloblastic anemia. Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters correspond to the sites at which abnormalities have been identified, as follows: (1) absence of intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II (TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl E and G), and (f) lysosomal Cbl efflux (Cbl F).
Megaloblastic anemia. Cobalamin (Cbl) is freed from meat in the acidic milieu of the stomach where it binds R factors in competition with intrinsic factor (IF). Cbl is freed from R factors in the duodenum by proteolytic digestion of the R factors by pancreatic enzymes. The IF-Cbl complex transits to the ileum where it is bound to ileal receptors. The IF-Cbl enters the ileal absorptive cell, and the Cbl is released and enters the plasma. In the plasma, the Cbl is bound to transcobalamin II (TC II), which delivers the complex to nonintestinal cells. In these cells, Cbl is freed from the transport protein.
Peripheral smear of blood from a patient with pernicious anemia. Macrocytes are observed, and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leukocyte is present.
Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.
Response to therapy with cobalamin (Cbl) in a previously untreated patient with pernicious anemia. A reticulocytosis occurs within 5 days after an injection of 1000 mcg of Cbl and lasts for about 2 weeks. The hemoglobin (Hgb) concentration increases at a slower rate because many of the reticulocytes are abnormal and do not survive as mature erythrocytes. After 1 or 2 weeks, the Hgb concentration increases about 1 g/dL per week.

of 7

Author

Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine

Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi; Dova<br/>Serve(d) as a speaker or a member of a speakers bureau for: Dova; Sanofi.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Paul Schick, MD † Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Thomas H Davis, MD, FACP Associate Professor, Fellowship Program Director, Department of Internal Medicine, Section of Hematology/Oncology, Geisel School of Medicine at Dartmouth

Thomas H Davis, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Education, American College of Physicians, New Hampshire Medical Society, Phi Beta Kappa, Society of University Urologists

Disclosure: Nothing to disclose.

Megaloblastic Anemia Questions & Answers

References

Tables

Contributor Information and Disclosures

What would you like to print?