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Pernicious Anemia Differential Diagnoses

  • Author: Paul Schick, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Aug 05, 2015
 
 

Diagnostic Considerations

By definition, pernicious anemia refers specifically to vitamin B-12 deficiency resulting from a lack of production of intrinsic factor (IF) in the stomach. However, vitamin B-12 absorption is a complex process, and other causes of vitamin B-12 deficiency exist. Pernicious anemia must be differentiated from other disorders that interfere with the absorption and metabolism of vitamin B-12 and produce cobalamin deficiency, with the development of a macrocytic anemia and neurologic complications.

Go to Anemia, Iron Deficiency Anemia, and Chronic Anemia for complete information on these topics.

Other conditions to be considered include the following:

  • Cestode infection
  • Neurologic disorders
  • Senility

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

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.

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

References
  1. Hoffman R, Benz EJ, Furie B, Shattil SJ. Hematology: Basic Principles and Practice. Philadelphia, Pa: Churchill Livingstone; 2009.

  2. 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. [Medline].

  3. 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. [Medline]. [Full Text].

  4. Bizzaro N, Antico A. Diagnosis and classification of pernicious anemia. Autoimmun Rev. 2014 Apr-May. 13(4-5):565-8. [Medline].

  5. 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. [Medline].

  6. 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. [Medline].

  7. 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. [Medline]. [Full Text].

  8. 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. [Medline]. [Full Text].

  9. Centers for Disease Control and Prevention. Vitamin B12 Deficiency: Detection and Diagnosis. CDC. Available at http://www.cdc.gov/ncbddd/b12/detection.html. June 29, 2009; Accessed: August 5, 2015.

  10. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013 Jan 10. 368(2):149-60. [Medline].

  11. 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. [Medline].

  12. 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. [Medline].

  13. Zhang J, Field CJ, Vine D, Chen L. Intestinal Uptake and Transport of Vitamin B12-loaded Soy Protein Nanoparticles. Pharm Res. 2014 Oct 16. [Medline].

  14. Andres E, Serraj K. Optimal management of pernicious anemia. J Blood Med. 2012. 3:97-103. [Medline]. [Full Text].

  15. 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. [Medline]. [Full Text].

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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.
Table 1. Serum Methylmalonic Acid and Homocysteine Values Used in Differentiating Between Cobalamin and Folic Acid Deficiency
Patient ConditionMethylmalonic AcidHomocysteine
HealthyNormalNormal
Vitamin B12 deficiencyElevatedElevated
Folate deficiencyNormalElevated
Table 2. Schilling test results
Patient ConditionStage I



No Intrinsic Factor



Stage II



Intrinsic Factor



Stage III



Antibiotic



Stage IV



Pancreatic Extract



HealthyNormal
Pernicious anemiaLowNormal
Bacterial overgrowthLowLowNormal
Pancreatic insufficiencyLowLowLowNormal
Defect in ileumLowLowLowLow
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