Toh BH. Pathophysiology and laboratory diagnosis of pernicious anemia. Immunol Res. 2017 Feb. 65 (1):326-330. [QxMD MEDLINE Link].
Antony AC. Megaloblastic Anemias. Hoffman R, Benz EJ Jr, Silberstein LE, Heslop HE, Weitz JI, Anastasi J, Salama ME, Abutalib SA, eds. Hematology: Basic Principles and Practice. 7th ed. Philadelphia, PA: Elsevier Saunders; 2018. 514-45.
Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med. 1997 Nov 13. [QxMD MEDLINE Link]. [Full Text].
Lenti MV, Rugge M, Lahner E, Miceli E, Toh BH, Genta RM, et al. Autoimmune gastritis. Nat Rev Dis Primers. 2020 Jul 9. 6 (1):56. [QxMD MEDLINE Link].
Elmadfa I, Singer I. Vitamin B-12 and homocysteine status among vegetarians: a global perspective. Am J Clin Nutr. 2009 May. 89(5):1693S-1698S. [QxMD MEDLINE Link].
Hasbaoui BE, Mebrouk N, Saghir S, Yajouri AE, Abilkassem R, Agadr A. Vitamin B12 deficiency: case report and review of literature. Pan Afr Med J. 2021. 38:237. [QxMD MEDLINE Link]. [Full Text].
Andrès E, Vogel T, Federici L, Zimmer J, Ciobanu E, Kaltenbach G. Cobalamin deficiency in elderly patients: a personal view. Curr Gerontol Geriatr Res. 2008. 848267. [QxMD MEDLINE Link]. [Full Text].
Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med. 1996 May 27. 1097-100. [QxMD MEDLINE Link].
Bizzaro N, Antico A. Diagnosis and classification of pernicious anemia. Autoimmun Rev. 2014 Apr-May. 13(4-5):565-8. [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].
Green R. Vitamin B₁₂ deficiency from the perspective of a practicing hematologist. Blood. 2017 May 11. 129 (19):2603-2611. [QxMD MEDLINE Link]. [Full Text].
Murphy G, Dawsey SM, Engels EA, Ricker W, Parsons R, Etemadi A, et al. Cancer Risk After Pernicious Anemia in the US Elderly Population. Clin Gastroenterol Hepatol. 2015 Jun 14. [QxMD MEDLINE Link].
Chan JC, Liu HS, Kho BC, Lau TK, Li VL, Chan FH, et al. Longitudinal study of Chinese patients with pernicious anaemia. Postgrad Med J. 2008 Dec. 84(998):644-50. [QxMD MEDLINE Link].
Venkatesh P, Shaikh N, Malmstrom MF, Kumar VR, Nour B. Portal, superior mesenteric and splenic vein thrombosis secondary to hyperhomocysteinemia with pernicious anemia: a case report. J Med Case Rep. 2014 Aug 25. 8:286. [QxMD MEDLINE Link]. [Full Text].
Ekabe CJ, Kehbila J, Abanda MH, Kadia BM, Sama CB, Monekosso GL. Vitamin B12 deficiency neuropathy; a rare diagnosis in young adults: a case report. BMC Res Notes. 2017 Jan 28. 10 (1):72. [QxMD MEDLINE Link]. [Full Text].
Kocaoglu C, Akin F, Caksen H, Böke SB, Arslan S, Aygün S. Cerebral atrophy in a vitamin B12-deficient infant of a vegetarian mother. J Health Popul Nutr. 2014 Jun. 32(2):367-71. [QxMD MEDLINE Link]. [Full Text].
Ammouri W, Tazi ZM, Harmouche H, Maamar M, Adnaoui M. Venous thromboembolism and hyperhomocysteinemia as first manifestation of pernicious anemia: a case series. J Med Case Rep. 2017 Sep 2. 11 (1):250. [QxMD MEDLINE Link]. [Full Text].
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. 2017 Nov 23. [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].
Mohamed M, Thio J. Pernicious Anemia. BMJ. 2020. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Devalia V, Hamilton MS, Molloy AM, British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014 Aug. 166 (4):496-513. [QxMD MEDLINE Link]. [Full Text].
Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013 Jan 10. 368(2):149-60. [QxMD MEDLINE Link].
Graber JJ, Sherman FT, Kaufmann H, Kolodny EH, Sathe S. Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with "normal" serum B12 levels. J Neurol Neurosurg Psychiatry. 2010 Dec. 81(12):1369-71. [QxMD MEDLINE Link].
Gilotra M, Gupta M, Singh S, Sen R. Comparison of bone marrow aspiration cytology with bone marrow trephine biopsy histopathology: An observational study. J Lab Physicians. 2017 Jul-Sep. 9 (3):182-189. [QxMD MEDLINE Link]. [Full Text].
Erkurt MA, Aydogdu I, Dikilitas M, Kuku I, Kaya E, Bayraktar N, et al. Effects of cyanocobalamin on immunity in patients with pernicious anemia. Med Princ Pract. 2008. 17(2):131-5. [QxMD MEDLINE Link].
Zhang J, Field CJ, Vine D, Chen L. Intestinal Uptake and Transport of Vitamin B₁₂-loaded Soy Protein Nanoparticles. Pharm Res. 2014 Oct 16. [QxMD MEDLINE Link].
Andres E, Serraj K. Optimal management of pernicious anemia. J Blood Med. 2012. 3:97-103. [QxMD MEDLINE Link]. [Full Text].
Favrat B, Vaucher P, Herzig L, et al. Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial. BMC Fam Pract. 2011 Jan 13. 12:2. [QxMD MEDLINE Link]. [Full Text].
Bunn HF. Vitamin B12 and pernicious anemia--the dawn of molecular medicine. N Engl J Med. 2014 Feb 20. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Pernicious 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).
Pernicious 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).
Pernicious 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 leucocyte 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 6

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; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.

Coauthor(s)

Salem Kim, MD, MPH Physician in Hematology/Oncology, Miami Cancer Institute, Baptist Health South Florida

Salem Kim, MD, MPH is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

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

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

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.

Acknowledgements

David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Troy H Guthrie, Jr, MD Director of Cancer Institute, Baptist Medical Center

Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association

Disclosure: Nothing to disclose.

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

Disclosure: Medscape Salary Employment

Patient Condition	Methylmalonic Acid	Homocysteine
Healthy	Normal	Normal
Vitamin B12 deficiency	Elevated	Elevated
Folate deficiency	Normal	Elevated

Patient Condition	Stage I No Intrinsic Factor	Stage II Intrinsic Factor	Stage III Antibiotic	Stage IV Pancreatic Extract
Healthy	Normal	…	…	…
Pernicious anemia	Low	Normal	…	…
Bacterial overgrowth	Low	Low	Normal	…
Pancreatic insufficiency	Low	Low	Low	Normal
Defect in ileum	Low	Low	Low	Low

Pernicious Anemia Questions & Answers

References

Tables

Contributor Information and Disclosures

What would you like to print?