INTRODUCTION

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Background

Pernicious anemia is a chronic illness caused by impaired absorption of vitamin B-12 because of a lack of intrinsic factor (IF) in gastric secretions.

Pernicious anemia occurs as a relatively common adult form of anemia that is associated with gastric atrophy and a loss of IF production and as a rare congenital autosomal recessive form in which IF production is lacking without gastric atrophy.

The disease was named pernicious anemia because it was fatal before treatment became available, first as liver therapy and, subsequently, as purified vitamin B-12. The term pernicious is no longer appropriate, but it is retained for historical reasons.

While the term pernicious anemia is reserved for patients with vitamin B-12 deficiency due to a lack of production of IF in the stomach, vitamin B-12 absorption is complex and other causes of vitamin B-12 deficiency exist and are described briefly in this article.

Pathophysiology

Classic pernicious anemia is caused by the failure of gastric parietal cells to produce sufficient IF to permit the absorption of adequate quantities of dietary vitamin B-12. Other disorders that interfere with the absorption and metabolism of vitamin B-12 can produce cobalamin (Cbl) deficiency, with the development of a macrocytic anemia and neurological complications.

Cbl is an organometallic substance containing a corrin ring, a centrally located cobalt atom, and various axial ligands (see Image 1). The basic structure known as vitamin B-12 is solely synthesized by microorganisms, but most animals are capable of converting vitamin B-12 into the 2 coenzyme forms, adenosylcobalamin and methylcobalamin. The former is required for conversion of L-methylmalonic acid to succinyl coenzyme A (CoA), and the latter acts as a methyltransferase for conversion of homocysteine to methionine. When either Cbl or folate is deficient, thymidine synthase function is impaired. This leads to megaloblastic changes in all rapidly dividing cells because DNA synthesis is diminished. In erythroid precursors, macrocytosis and ineffective erythropoiesis occur.

Dietary Cbl is acquired mostly from meat and milk and is absorbed in a series of steps, which require proteolytic release from foodstuffs and binding to a gastric protein secreted by parietal cells that is known as IF. Subsequently, recognition of the IF-Cbl complex by specialized ileal receptors must occur for transport into the portal circulation to be bound by transcobalamin II (TC II), which serves as the plasma transporter.

The Cbl-TC II complex binds to cell surfaces and is endocytosed. The transcobalamin (TC) is degraded within a lysozyme, and the Cbl is released into the cytoplasm. An enzyme-mediated reduction of the cobalt occurs with either cytoplasmic methylation to form methylcobalamin or mitochondrial adenosylation to form adenosylcobalamin. Defects of these steps produce manifestations of Cbl dysfunction. Most defects become manifest in infancy and early childhood and result in impaired development, mental retardation, and a macrocytic anemia. Certain defects cause methylmalonic aciduria and homocystinuria (see Image 2).

Pernicious anemia probably is an autoimmune disorder with a genetic predisposition. Pernicious anemia is more common than is expected in families of patients with pernicious anemia, and the disease is associated with human leucocyte antigen (HLA) types A2, A3, and B7 and type A blood group.

Antiparietal cell antibodies occur in 90% of patients with pernicious anemia but in only 5% of healthy adults. Similarly, binding and blocking antibodies to IF are found in most patients with pernicious anemia. A greater association than anticipated exists between pernicious anemia and other autoimmune diseases, which include thyroid disorders, type I diabetes mellitus, ulcerative colitis, Addison disease, infertility, and acquired agammaglobulinemia. An association between pernicious anemia and Helicobacter pylori infections has been postulated but not clearly proven.

Cbl deficiency may result from dietary insufficiency of vitamin B-12; disorders of the stomach, small bowel, and pancreas; certain infections; and abnormalities of transport, metabolism, and utilization (see the summary of causes of Cbl deficiency below). Deficiency may be observed in strict vegetarians. Breastfed infants of vegetarian mothers also are affected. Severely affected infants of vegetarian mothers who do not have overt Cbl deficiency have been reported. Meat and milk are the main source of dietary Cbl. Because body stores of Cbl usually exceed 1000 mcg and the daily requirement is about 1 mcg, strict adherence to a vegetarian diet for more than 5 years usually is required to produce findings of Cbl deficiency.

Classic pernicious anemia produces Cbl deficiency due to failure of the stomach to secrete IF (see Image 3). In adults, pernicious anemia is associated with severe gastric atrophy and achlorhydria, which are irreversible. Coexistent iron deficiency is common because achlorhydria prevents solubilization of dietary ferric iron from foodstuffs. Autoimmune phenomena and thyroid disease frequently are observed. Patients with pernicious anemia have a 2- to 3-fold increased incidence of gastric carcinoma.

Summary of causes of Cbl deficiency

• Inadequate dietary intake (ie, vegetarian diet)
• Atrophy or loss of gastric mucosa (eg, pernicious anemia, gastrectomy, ingestion of caustic material, hypochlorhydria, histamine 2 [H2] blockers)
• Functionally abnormal IF
• Inadequate proteolysis of dietary Cbl
• Insufficient pancreatic protease (eg, chronic pancreatitis, Zollinger-Ellison syndrome)
• Bacterial overgrowth in intestine (eg, blind loop, diverticula)
• Disorders of ileal mucosa (eg, resection, ileitis, sprue, lymphoma, amyloidosis, absent IF-Cbl receptor, Imerslünd-Grasbeck syndrome, Zollinger-Ellison syndrome, TCII deficiency, use of certain drugs)
• Disorders of plasma transport of cobalamin (eg, TCII deficiency, R binder deficiency)
• Dysfunctional uptake and use of cobalamin by cells (eg, defects in cellular deoxyadenosylcobalamin [AdoCbl] and methylcobalamin [MeCbl] synthesis)

Frequency

United States

The adult form of pernicious anemia is most prevalent among individuals of either Celtic (ie, English, Irish, Scottish) or Scandinavian origin. In these groups, 10-20 cases per 100,000 people occur per year. Pernicious anemia is reported less commonly in people of other racial backgrounds. Although the disease was once believed to be rare in Native American people and uncommon in black people, recent observations suggest that the incidence was underestimated.

International

Historically, pernicious anemia was believed to occur predominantly in people of northern European descent. During recent years, it has become apparent that occurrence of pernicious anemia in all racial and ethnic groups is more common than was previously recognized.

Mortality/Morbidity

The disease is called pernicious anemia because it was fatal prior to the discovery that it was a nutritional disorder. The megaloblastic appearance of cells led many to speculate that it was a neoplastic disease. The response of patients to liver therapy suggested that a nutritional deficiency was responsible for the disorder. This became obvious in clinical trials once vitamin B-12 was isolated. Presently, patients on appropriate treatment have a normal lifespan.

Race

While the disease originally was believed to be restricted primarily to whites of Scandinavian and Celtic origin, recent evidence shows that it occurs in all races.

Sex

A female predominance has been reported in England, Scandinavia, and among persons of African descent (1.5:1). However, data in the United States show an equal sex distribution.

Age

Adult pernicious anemia usually occurs in people aged 40-70 years. Among white people, the mean age of onset is 60 years, whereas it occurs at a younger age in black people (mean age of 50 y), with a bimodal distribution caused by increased occurrence in young black females. Congenital pernicious anemia is usually manifested in children younger than 2 years.

CLINICAL

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History

The onset of pernicious anemia usually is insidious and vague. The classic triad of weakness, sore tongue, and paresthesias may be elicited but usually is not the chief symptom complex. Usually, medical attention is sought because of symptoms suggestive of cardiac, renal, genitourinary, gastrointestinal, infectious, mental, or neurological disorders, and the patient is found to be anemic with macrocytic cellular indices.

• General findings: Weight loss of 10-15 pounds occurs in about 50% of patients and probably is due to anorexia, which is observed in most patients. Low-grade fever occurs in one third of newly diagnosed patients and promptly disappears with treatment.
• Anemia: The anemia often is well tolerated in pernicious anemia, and many patients are ambulatory with hematocrit levels in the mid teens. However, the cardiac output is usually increased with hematocrits less than 20%, and the heart rate accelerates. Congestive heart failure and coronary insufficiency can occur, most particularly in patients with preexisting heart disease.
• Gastrointestinal findings: Approximately 50% of patients have a smooth tongue with loss of papillae. This is usually most marked along the edges of the tongue. The tongue may be painful and beefy red. Occasionally, red patches are observed on the edges of the dorsum of the tongue. Patients may report burning or soreness, most particularly on the anterior one third of the tongue. These symptoms may be associated with changes in taste and loss of appetite.
• • Patients may report either constipation or having several semisolid bowel movements daily. This has been attributed to megaloblastic changes of the cells of the intestinal mucosa.
  • Nonspecific gastrointestinal symptoms are not unusual and include anorexia, nausea, vomiting, heartburn, pyrosis, flatulence, and a sense of fullness. Rarely, patients present with severe abdominal pain associated with abdominal rigidity; this has been attributed to spinal cord pathology.
• Nervous system: Neurological symptoms can be elicited in most patients with pernicious anemia, and the most common symptoms are paresthesias, weakness, clumsiness, and an unsteady gait. The 2 latter symptoms become worse in a dark room because they reflect the loss of proprioception in a patient who is unable to rely upon vision for compensation. These neurological symptoms are due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex.
• • Neurological symptoms and findings may be present in the absence of anemia; this is more common in patients taking folic acid or on a high-folate diet.
  • Patients who are older may present with symptoms suggesting senile dementia or Alzheimer disease; memory loss, irritability, and personality changes are commonplace. Megaloblastic madness is less common and can be manifested by delusions, hallucinations, outbursts, and paranoid schizophrenic ideation. Identifying the cause is important because significant reversal of these symptoms and findings can occur with vitamin B-12 administration.
• Genitourinary system: Urinary retention and impaired micturition may occur because of spinal cord damage. This can predispose patients to urinary tract infections.

Physical

The finding of severe anemia in an adult patient whose constitutional symptoms are relatively mild and in whom weight loss is not a major symptom should arouse suspicion of pernicious anemia.

• Typically, patients with pernicious anemia are described as having a stereotypic appearance.
• • Patients have a lemon-yellow waxy pallor with premature whitening of the hair.
  • They appear flabby, with a bulky frame that is generally incongruent with the severe anemia and weakness.
  • While this characterization is useful in patients of northern European descent, it is less helpful among patients of other ethnic groups who develop Cbl deficiency.
• Low-grade fever and mild icterus are commonplace but are usually mild and easily missed.
• A beefy, red, smooth tongue may be observed.
• In patients with dark complexions, blotchy skin pigmentation may be observed.
• Tachycardia often is present and may be accompanied by flow murmurs.
• Abnormal mentation and deterioration of vision and hearing may be observed.
• With severe anemia, dyspnea, tachypnea, and evidence of congestive heart failure may be present.
• Retinal hemorrhages and exudates may accompany severe anemia.
• The liver may be enlarged in association with congestive heart failure.
• A splenic tip is palpable in about 20% of patients.
• A careful neurological assessment is important. In all megaloblastic disorders, hematological and epithelial manifestations occur, but only Cbl deficiency causes neurological deficits. Neurological findings may occur in the absence of anemia and epithelial manifestations of pernicious anemia, making it more difficult to identify the etiology. If left untreated, they can become irreversible.
• • Central nervous system: Suspect pernicious anemia in all patients with recent loss of mental capacities. Somnolence, dementia, psychotic depression, and frank psychosis may be observed, which can be reversed or improved by treatment with Cbl. Perversion of taste and smell and visual disturbances, which can progress to optic atrophy, can likewise result from central nervous system Cbl deficiency.
  • Combined system disease: A history of either paresthesias in the fingers and toes or difficulty with gait and balance should prompt a careful neurological examination. Loss of position sense in the second toe and loss of vibratory sense for a 256-Hz but not a 128-Hz tuning fork are the earliest signs of posterolateral column disease. If untreated, this can progress to spastic ataxia from demyelinization of the dorsal and lateral columns of the spinal cord.

Causes

An increased incidence of pernicious anemia in families suggests a hereditary component to the disease. Patients with pernicious anemia have an increased incidence of autoimmune disorders and thyroid disease, suggesting that an immunological component to the disease exists. Children who develop Cbl deficiency usually have a hereditary disorder, and the etiology of their Cbl deficiency is different from the etiology observed in classic pernicious anemia.

• Congenital pernicious anemia is a hereditary disorder in which an absence of IF occurs without gastric atrophy. Other gastric disorders that cause Cbl deficiency are gastrectomy, gastric stapling, and bypass procedures for obesity and extensive infiltrative disease of the gastric mucosa. Usually, these disorders are associated with a decreased ability to mobilize Cbl from food rather than a malabsorption of Cbl. Thus, a patient with these disorders may exhibit a normal finding on Schilling test (stage I).
• Pancreatic insufficiency can produce Cbl deficiency. Nonspecific R binders chelate Cbl in the stomach, making it unavailable for binding to IF. Pancreatic proteases degrade the R binders and release the Cbl so that it can bind IF. The Cbl-IF complex is formed so that it can bind ileal receptors that enable uptake by absorptive cells. Thus, patients with chronic pancreatitis may have impaired absorption of Cbl.
• Cbl deficiency is reported in the Zollinger-Ellison syndrome. The mechanism is believed to be due to the acidic pH of the distal small intestine such that the Cbl-IF complex cannot effectively bind the ileal receptors.
• Disorders of the ileum cause Cbl deficiency due to loss of the ileal receptors for the Cbl-IF complex. Thus, surgical loss of the ileum or diseases such as tropical sprue, regional enteritis, ulcerative colitis, and ileal lymphoma interfere with Cbl absorption.
• Genetic defects of the ileal receptors for IF (ie, Imerslünd-Grasbeck syndrome) and hereditary transcobalamin I (TC I) deficiency produce Cbl deficiency from birth and are usually discovered early in life.
• Many drugs impair Cbl uptake in the ileum but rarely are a cause of symptomatic vitamin B-12 deficiency because they are not taken long enough to deplete body stores of Cbl (eg, nitrous oxide, cholestyramine, para-aminosalicylic acid, neomycin, metformin, phenformin, colchicine).
• The clinical manifestations of inherited defects of Cbl transport and metabolism are usually observed in infancy and childhood. Thus, they are discussed only briefly in this article.
• Three hereditary disorders affect absorption and transport of Cbl, and another 7 alter cellular use and coenzyme production (see Image 2).
• • The 3 disorders of absorption and transport are TC II deficiency and deficiencies of either IF or IF receptors. These defects produce developmental delay and a megaloblastic anemia, which can be alleviated with pharmacological doses of Cbl. Serum Cbl values are decreased in the IF abnormalities but may be within the reference range in TC II deficiency.
  • The abnormalities of cellular use can be detected by the presence or absence of methylmalonic aciduria and homocystinuria. The presence of only methylmalonic aciduria indicates a block in conversion of methylmalonic CoA to succinyl CoA and results in either a genetic deficit in the methylmalonyl CoA mutase that catalyzes the reaction or a defect in synthesis of its CoA Cbl (Cbl A and Cbl B).
  • The presence of only homocystinuria results either from poor binding of Cbl to methionine synthase (Cbl E) or from producing methylcobalamin from Cbl and S adenosylmethionine (Cbl G). This results in a reduction in methionine synthesis, with pronounced homocystinemia and homocystinuria.
  • Methylmalonic aciduria and homocystinuria occur when the metabolic defect impairs reduction of Cbl III to Cbl II (Cbl C, Cbl D, Cbl F). This reaction is essential for formation of both methylmalonic acid and homocystinuria.
  • Early detection of these rare disorders is important because most patients respond favorably to large doses of Cbl. However, some of these disorders are less responsive than others, and delayed diagnosis and treatment are less efficacious.
• Abnormalities in the intestinal lumen may produce Cbl deficiency. Individuals with blind intestinal loops, stricture, and large diverticula may develop bacterial overgrowth, which sequesters dietary Cbl for their metabolic needs. Tapeworm infestation with Diphyllobothrium latum occurs from eating poorly cooked lake fish that are infected and causes Cbl deficiency because the parasites have a high requirement for Cbl.

DIFFERENTIALS

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Other Problems to be Considered

Neurological disorders
Senility
Alzheimer disease
Cestode infection
Alcoholic cirrhosis

WORKUP

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Lab Studies

• Peripheral blood: The peripheral blood usually shows a macrocytic anemia with a mild leukopenia and thrombocytopenia. The mean cell volume (MCV) and mean cell hemoglobin (MCH) are increased, with a mean corpuscular hemoglobin concentration (MCHC) within the reference range. The leukopenia and thrombocytopenia usually parallel the severity of the anemia (see Images 4-5). The peripheral smear shows oval macrocytes, hypersegmented granulocytes, and anisopoikilocytosis. In severe anemia, red blood cell inclusions may include Howell-Jolly bodies, Cabot rings, and punctate basophilia. The macrocytosis can be obscured by the coexistence of iron deficiency, thalassemia minor, or inflammatory disease.
• Serum: The indirect bilirubin may be elevated because pernicious anemia is a hemolytic disorder associated with increased turnover of bilirubin. The serum lactic dehydrogenase usually is markedly increased. Increased values for other red blood cells, enzymes, and serum iron saturation also are observed. The serum potassium, cholesterol, and skeletal alkaline phosphatase often are decreased.
• Gastric secretions: Total gastric secretions are decreased to about 10% of the reference range. Most patients with pernicious anemia are achlorhydric, even with histamine stimulation. IF is either absent or markedly decreased.
• Serum Cbl levels: The serum Cbl is low in patients with pernicious anemia; however, it may be within the reference range in certain patients with other forms of Cbl deficiency. These include some inborn areas of Cbl deficiency, TC II deficiency, and Cbl deficiency due to nitrous oxide.
• • Conversely, serum Cbl levels may be low in patients who are pregnant, have TC I deficiency, have severe folic acid deficiency, and following large doses of ascorbic acid.
  • Screening of individuals who are older has shown that 10-20% have low serum Cbl levels, and half of these patients have increased levels of homocysteine and methylmalonic acid, indicating a tissue Cbl deficiency.
• Methylmalonic acid and homocysteine (see Table 1): Elevated serum methylmalonic acid and homocysteine levels are found in patients with pernicious anemia. They probably are the most reliable test for Cbl deficiency in patients who do not have a congenital metabolism disorder. In the absence of an inborn error of methylmalonic acid metabolism, methylmalonic aciduria is a sign of Cbl deficiency.

  Table 1. Serum Methylmalonic Acid and Homocysteine Values Used in Differentiating Between Cbl and Folic Acid Deficiency

  Patient Condition	Methylmalonic Acid	Homocysteine
  Healthy	Normal	Normal
  Vitamin B-12 deficiency	Elevated	Elevated
  Folate deficiency	Normal	Elevated

• Schilling test (see Table 2): The Schilling test measures Cbl absorption by increasing urine radioactivity after an oral dose of radioactive Cbl. The test is useful in demonstrating that the anemia is caused by an absence of IF and is not secondary to other causes of Cbl deficiency. Likewise, it is helpful because it is used to identify patients with classic pernicious anemia, even after they have been treated with vitamin B-12.

  Table 2. Schilling Test Results

  Patient Condition	Stage I Water	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

• • The test is performed by administering 0.5-2.0 mCi of radioactive cyanocobalamin in a glass of water to patients who have fasted. Two hours later, the patient is injected with 1 mg of unlabeled vitamin B-12 to saturate circulating transcobalamins. A 24-hour urine sample is collected, and the radioactivity in the specimen is measured and compared to a standard. Specimens with less than 7% excretion represent abnormal findings and indicate that poor absorption of the oral test dose occurred. If abnormal low values are obtained, a stage II Schilling test is performed. In this test, 60 mg of active hog IF is administered with the oral test dose to determine if this enhances the absorption of vitamin B-12. If poor absorption of vitamin B-12 is normalized, the patient presumably has classic pernicious anemia.
  • If poor absorption is observed in a stage II test, search for other causes of vitamin B-12 malabsorption. Performance of a stage I Schilling test after 5 days of tetracycline therapy is used to exclude a blind loop as the etiology for Cbl deficiency (stage III). Similarly, if administration of trypsin or pancreatic enzyme with the radiolabeled test dose corrects the absorption of vitamin B-12, suspect pancreatic disease (stage IV).
  • False-positive Schilling test results are observed in patients with incomplete 24-hour urine collections or renal insufficiency, false-positive results are observed when inactive IF is used, and false-positive results occur because of neutralization of the IF in the stage II test by any IF antibodies in the stomach and severe ileal megaloblastosis.
  • Occasionally Cbl deficiency and a normal result on stage I Schilling test are observed. These patients can absorb vitamin B-12 in the fasting state but not when it is presented with food. Adding the radiolabeled vitamin B-12 to egg white and testing the absorption usually reveals this cause of Cbl deficiency.
• Clinical trial: The administration of 1000 mcg of vitamin B-12 intramuscularly can be used as a clinical trial for suspected Cbl deficiency. Subjectively, this usually provides a marked sense of well-being in patients who are Cbl deficient within 24 hours after administration. Objectively, this produces a marked reticulocytosis, which is maximal in 5-7 days after the administration of the Cbl, and a correction of the anemia occurs in about 3 weeks (see Image 6).

Procedures

• A bone marrow aspirate and biopsy can be performed for histological examination.

Histologic Findings

The bone marrow biopsy and aspirate usually are hypercellular and show trilineage differentiation. Erythroid precursors are large and often oval (see Image 5). The nucleus is large and contains course motley chromatin clumps, providing a checkerboard appearance. Nucleoli are visible in the more immature erythroid precursors. An imbalance in the rate of maturation of the nucleus relative to the cytoplasm exists, such that disassociation between the maturity of the nucleus and the hemoglobinization of the orthochromic megaloblastic normoblasts occurs. Giant metamyelocytes and bands are present, and the mature neutrophils and eosinophils are hypersegmented. Imbalanced growth of megakaryocytes is evidenced by hyperdiploidy of the nucleus and the presence of giant platelets in the smear. Lymphocytes and plasma cells are spared from the cellular gigantism and cytoplasmic asynchrony observed in other cell lineages.

The bone marrow histology is similar in both folic acid and Cbl deficiency. Significant changes in the histology have been observed within 12 hours after appropriate treatment is initiated. The megaloblastic changes due to Cbl deficiency can be reversed by pharmacological doses of folic acid but not the converse. Folic acid therapy may worsen the neurological consequences of Cbl deficiency despite hematological improvement.

TREATMENT

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Medical Care

• The following goals are the most important in establishing care for these patients:
• • To establish that the patient has Cbl deficiency
  • To determine the cause of the failure to absorb Cbl (A controversy in the field exists; not all hematologists work to establish a precise cause for low vitamin B-12 levels. The nuclear medicine tests are expensive and cumbersome and many simply treat patients if a differential diagnosis of a low–vitamin B-12 state is established.)
  • To treat the patient with adequate doses of Cbl
  • To confirm the diagnosis by documenting that specific therapy is effective
  • To ensure administration of adequate quantities of Cbl for the lifespan of the patient
• Blood transfusions: Transfusions are rarely required in patients with a megaloblastic anemia 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 and/or the patient has coronary insufficiency, a 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.

Consultations

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

Diet

People who are strict vegetarians and, most particularly, people who do not consume eggs, milk, or meat can develop Cbl 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 mcg taken weekly should provide adequate therapy.

Activity

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

MEDICATION

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Vitamin B-12 is available for therapeutic use parenterally as either cyanocobalamin or hydroxocobalamin. Both are equally useful in the treatment of vitamin B-12 deficiency, and they 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; both chemical forms of Cbl provide prompt correction. Cbl is available in a solution for injection in 100- to 1000-mcg/mL dosages.

Most of the injected doses in excess of 50 mcg rapidly are excreted in the urine. Thus, when starting therapy, repeated doses are recommended in order to replenish body stores. A number of regimens have been recommended. One regimen is daily SC administration for the first week. If significant reticulocytosis provides documentation of the success of therapy, then doses are administered twice weekly for another 4-5 weeks. Then, 100 mcg can be administered monthly. Alternatively, others have advocated weekly injections of 1000 mcg of vitamin B-12 for 5-6 weeks, followed by monthly injections.

Limited studies have shown that adequate therapy can be maintained after the initial parenteral loading doses by ingestion of 250-1000 mcg of vitamin B-12 PO daily because, even with a total absence of IF, about 1% of a PO dose is absorbed and the daily requirement for vitamin B-12 is 1 mcg/d. This route may be necessary in patients who have allergic reactions to parenteral administration (rare). If the PO route is used, obtain serum Cbl measurements at periodic intervals to ensure that adequate quantities of Cbl have been absorbed.

Drug Category: Vitamins

Cbl is an essential vitamin. The inability to absorb adequate quantities of the vitamin from the diet leads to hematological and neurological complications.

FOLLOW-UP

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Further Inpatient Care

• Once therapy is started, hospitalization is only required for patients with severe life-threatening anemia. This may be required until patients develop an adequate hematological response. Patients whose Cbl 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.

Further Outpatient Care

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

In/Out Patient Meds

• Cbl at a dose of 100 mcg/mo by subcutaneous or intramuscular injection is provided as maintenance therapy after the patient has experienced an initial response to treatment. Lifetime compliance is necessary.

Deterrence/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 neurological symptoms.
• Determine whether Cbl deficiency is the etiology in patients who recently developed evidence of mental deterioration.
• Periodically perform studies for Cbl deficiency or prophylactically treat patients with Cbl 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 Cbl, particularly during pregnancy and while nursing a newborn infant.
• Monitor siblings and children of patients with a hereditary abnormality of Cbl deficiency for evidence of the specific defect in Cbl transport or metabolism.

Complications

• If patients are not treated early in the disease, neurological complications can become permanent.
• Severe anemia can cause congestive heart failure or precipitate coronary insufficiency.
• The incidence of gastric adenocarcinoma is 2- to 3-fold greater in patients with pernicious anemia than in the general population of the same age. Presently, periodic gastroscopy and/or barium roentgenographic studies are not advocated in patients who are asymptomatic with treated pernicious anemia because they have not been demonstrated to prolong lifespan.

Prognosis

• Early recognition and treatment of pernicious anemia provides a normal, and usually uncomplicated, lifespan. Delayed treatment permits progression of the anemia and neurological complications. The mental and neurological damage can become irreversible without therapy.

Patient Education

• Compliance in obtaining adequate vitamin B-12 for a lifetime by injection (or possibly orally) is necessary to avoid relapse of pernicious anemia.
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure or significant delay in establishing a diagnosis of Cbl deficiency and in initiating appropriate therapy
• Administration of folic acid rather than vitamin B-12 in patients with Cbl deficiency, which can correct the hematological abnormalities while accelerating the neurological deficits
• Failure to advise patients with pernicious anemia of the importance of continuing Cbl therapy for lifetime

MULTIMEDIA

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Media file 1:  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 [seeImage 2]).
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Media type:  Image

Media file 2:  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).
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Media file 3:  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.
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Media file 4:  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.
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Media file 5:  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.
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Media file 6:  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.
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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Beutler E, Lichtman MA, Coller BS. Williams Hematology. 6th ed. New York, NY:. McGraw-Hill;2001:425-446.
• Hoffman R, Benz EJ Jr, Shattil SJ. Hematology: Basic Principles and Practice. 3rd ed. New York, NY:. Churchill Livingstone;2000:446-484.
• Jandl JH. Blood: Textbook of Hematology. 2nd ed. Boston, Mass:. Little, Brown and Co;1996:251-288.
• Lee GR, Foerster J, Lukens J. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md:. Williams & Wilkins;1999:941-978.
• Scriver CR, Beaudet AL, Sly WS. The Metabolic and Molecular Bases of Inherited Disease. 2nd ed. New York, NY:. McGraw-Hill;1995:3129-3149.

Article Last Updated: Oct 4, 2006