Tuesday, December 13, 2011

pernicious anemia

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 B-12 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 B-12 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.

Cobalamin Therapy

Vitamin B-12 is available for therapeutic use parenterally as either cyanocobalamin or hydroxocobalamin.[5] The 2 forms are equally useful in the treatment of vitamin B-12 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 B-12 for 5-6 weeks, followed by monthly injections.
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 B-12 daily. Even with a total absence of intrinsic factor (IF), about 1% of an oral dose is absorbed, and the daily requirement for vitamin B-12 is 1 µg/d. The oral route may be necessary in patients who have allergic reactions to parenteral administration (rare). If this route is used, obtain serum cobalamin measurements at periodic intervals to ensure that adequate quantities of cobalamin have been absorbed.

Blood Transfusions

Transfusions are rarely required in patients with a megaloblastic anemia that is due to vitamin B-12 deficiency. The likelihood of obtaining a dramatic response to 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.

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.
Curtail strenuous physical activity in patients with severe anemia until they develop an adequate hematologic response after treatment.


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.

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.
Proceed to Medication
Contributor Information and Disclosures
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 Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences

Disclosure: Nothing to disclose.
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, and Southwest Oncology Group

Disclosure: No financial interests None None
Chief Editor
Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies, 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 College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.
Additional Contributors
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: eMedicine Salary Employment
  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. May 2009;89(5):1693S-1698S. [Medline].
  3. 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. Dec 2008;84(998):644-50. [Medline].
  4. 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].
  5. 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].
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. This lasts for about 2 weeks after injection. The hemoglobin (Hgb) concentration increases at a slower rate because many of the reticulocytes are abnormal and do not survive as mature erythrocytes.
Table 1. Serum Methylmalonic Acid and Homocysteine Values Used in Differentiating Between Cobalamin and Folic Acid Deficiency
Patient ConditionMethylmalonic AcidHomocysteine
Vitamin B-12 deficiencyElevatedElevated
Folate deficiencyNormalElevated
Table 2. Schilling Test Results
Patient ConditionStage I


Stage II

Intrinsic Factor

Stage III


Stage IV

Pancreatic Extract

Pernicious anemiaLowNormal
Bacterial overgrowthLowLowNormal
Pancreatic insufficiencyLowLowLowNormal
Defect in ileumLowLowLowLow

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