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Pernicious Anemia Treatment & Management

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

Approach Considerations

The following goals are the most important in establishing care for patients with pernicious anemia:

  • To establish that the patient has cobalamin deficiency
  • If there is evidence for folic acid deficiency but pernicious anemia has not been ruled out, treat with both folic acid and cobalamin until pernicious anemia has been ruled out. The reason is that folic acid restores blood counts but does not prevent the development of subacute combined system degeneration in patients with pernicious anemia.
  • To determine the cause of the failure to absorb cobalamin (This goal is somewhat controversial. Not all hematologists work to establish the precise cause of low vitamin B12 levels. The nuclear medicine tests are expensive and cumbersome, and as a result, many hematologists simply proceed to treatment once a differential diagnosis of a low vitamin B12 state is established.)
  • To treat the patient with adequate doses of cobalamin
  • To confirm the diagnosis by documenting that specific therapy is effective
  • To ensure administration of adequate quantities of cobalamin for the lifespan of the patient

Once therapy is started, hospitalization is necessary only for patients with severe life-threatening anemia. It may be required until patients develop an adequate hematologic response. Patients whose cobalamin deficiency is due to underlying diseases involving the intestine or pancreas may require additional therapy. Examples of additional therapy are surgical correction of anatomic abnormalities of the gut, producing small bowel bacterial overgrowth, or the treatment of fish tapeworm anemia or pancreatitis.

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

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Cobalamin Therapy

Vitamin B12 is available for therapeutic use parenterally as either cyanocobalamin or hydroxocobalamin.[12] The two forms are equally useful in the treatment of vitamin B12 deficiency, and both are nontoxic (except for rare allergic reactions). Theoretical advantages exist to using hydroxocobalamin because it is retained better in the body and is more available to cells; however, both chemical forms of cobalamin provide prompt correction.

Cobalamin is available in a solution for injection in doses ranging from 100 to 1000 µg. Most of the injected doses in excess of 50 µg are rapidly excreted in the urine. Thus, when therapy is started, repeated doses are recommended in order to replenish body stores.

A number of regimens have been recommended. One regimen begins with daily subcutaneous administration for the first week. If significant reticulocytosis confirms that therapy is successful, doses are then administered twice weekly for another 4-5 weeks. After this period, 100 µg can be administered monthly by subcutaneous or intramuscular injection. Lifetime compliance is necessary. An alternative regimen involves weekly injections of 1000 µg of vitamin B12 for 5-6 weeks, followed by monthly injections.

Cobalamin deficiency–related neurological impairment can vary in clinical presentation, including acute combined system degeneration, peripheral neuropathy, and psychosis. These neuropathies should be treated more aggressively.

Response should be monitored by reticulocyte counts, lactic dehydrogenase (LDH), and an appropriate rise in hemoglobin levels. LDH levels decrease and hemoglobin levels increase by about 1 g/dL/wk. A rise in LDH might indicate a relapse.

Limited studies have shown that adequate therapy can be maintained after the initial parenteral loading doses through oral ingestion of 250-1000 µg of vitamin B12 daily. Even with a total absence of intrinsic factor (IF), about 1% of an oral dose is absorbed, and the daily requirement for vitamin B12 is 1 µg/d. A study by Zhang and colleagues found evidence that using orally ingested soy protein isolate (SPI) nanoparticles as a carrier can improve the intestinal transport and absorption of vitamin B12.[13]

The oral route may be necessary in the rare patients who have allergic reactions to parenteral administration, or in patients receiving anticoagulant or antiplatelet agent therapy, in whom intramuscular injections are contraindicated.[14] If this route is used, obtain serum cobalamin measurements at periodic intervals to ensure that adequate quantities of cobalamin have been absorbed. Oral cobalamin therapy should not be used in patients with neurologic symptoms.

A randomized, placebo-controlled trial of oral cobalamin therapy in 50 patients with borderline serum vitamin B12 levels (125-200 pg/mL) and nonspecific symptoms compatible with subtle vitamin B12 deficiency found that after 1 month, serum methylmalonic acid (MMA) levels were corrected more often in patients receiving oral cobalamin than in those receiving placebo. However, the benefit to the MMA level disappeared after 3 additional months without cobalamin therapy.[15]

A study found that oral cobalamine was more effective than parenteral therapy in some circumstances.[15]

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Blood Transfusions

Transfusions are rarely required in patients with a megaloblastic anemia that is due to vitamin B12 deficiency. The likelihood of obtaining a dramatic response to cobalamin therapy within a few days of initiating treatment makes it unnecessary to subject the patient to the hazards of blood transfusion.

Usually, mild-to-moderate congestive heart failure secondary to anemia abates with bed rest and low-dosage diuretic therapy. However, if the congestive heart failure is severe or the patient has coronary insufficiency, transfusion of packed red blood cells may be necessary.

Transfuse the blood slowly because patients who are transfused for severe anemia often develop circulatory overload. For this reason, low-dose diuretic therapy is often employed with transfusion.

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Dietary Measures and Activity Restriction

People who are strict vegetarians and, most particularly, people who do not consume eggs, milk, or meat can develop cobalamin deficiency. Counsel these people to either change their dietary habits or remain on supplementary vitamin B-12 therapy for their lifetime. An oral tablet of 100-200 µg taken weekly should provide adequate therapy.

Patients with severe anemia should curtail strenuous physical activity until they develop an adequate hematologic response after treatment.

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Prevention

Because an increased familial incidence of pernicious anemia exists, family members should be aware that they are at greater risk of developing this disease and should seek medical attention promptly if they develop anemia or mental and neurologic symptoms. Monitor siblings and children of patients with a hereditary abnormality of cobalamin deficiency for evidence of the specific defect in cobalamin transport or metabolism.

Determine whether cobalamin deficiency is the etiology in patients who recently developed evidence of mental deterioration.

Prophylactically treat patients with cobalamin when they have undergone total gastrectomy, bypass procedures for weight reduction, ileectomy, pancreatectomy, or when they have atrophic gastritis or chronic inflammatory disease of the ileum.

Strict vegetarians should continue supplementary cobalamin, particularly during pregnancy and while nursing a newborn infant.

Elderly people are at risk for developing pernicious anemia due to achlorhydria. Therefore, serum vitamin B-12 levels should be checked. If low or if cobalamin deficiency is suspected, they should be treated with vitamin B-12 supplementation.

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Consultations and Long-Term Monitoring

A consultation with a neurologist may be desirable in patients with unusual neurologic manifestations. Such consultation is most useful in patients without a macrocytic megaloblastic anemia.

Outpatient follow-up of patients with pernicious anemia is required to ensure that they have responded to therapy with cobalamin and that they continue to receive cobalamin on a regular basis for the remainder of their lives. Most patients can be taught to self-administer cobalamin subcutaneously so that they can minimize their visits to the physician.

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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 Condition Methylmalonic Acid Homocysteine
Healthy Normal Normal
Vitamin B12 deficiency Elevated Elevated
Folate deficiency Normal Elevated
Table 2. Schilling test results
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
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