Excerpt from Pernicious Anemia

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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.

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