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Pernicious Anemia
Updated: Oct 4, 2006
Introduction
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
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.
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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.
Further Reading
Keywords
vitamin B-12 deficiency, cobalamin deficiency, Cbl deficiency, addisonian anemia, Biermer anemia, Hunter-Addison anemia, Lederer anemia, Biermer-Ehrlich anemia, Addison-Biermer disease, macrocytic achylic anemia, malignant anemia, cobalamine deficiency, adenosylcobalamin, methylcobalamin, intrinsic factor, IF, macrocytic anemia, neurological complications, severe gastric atrophy, achlorhydria, gastrectomy, gastric stapling, bypass procedures for obesity, extensive infiltrative disease of the gastric mucosa, Zollinger-Ellison syndrome, tropical sprue, regional enteritis, ulcerative colitis, ileal lymphoma, Imerslünd-Grasbeck syndrome, chronic pancreatitis, sore tongue, smooth tongue with loss of papillae, paresthesias, megaloblastic madness, tapeworm infestation, Diphyllobothrium latum, congenital pernicious anemia, hereditary transcobalamin I deficiency, megaloblastic anemia, homocystinuria, homocystinemia
