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600 Part VI: The Erythrocyte Chapter 41: Folate, Cobalamin, and Megaloblastic Anemias 601

factor production. Many other causes of defective cobalamin absorp- in northern Europeans (especially Scandinavians) as well as Afri-
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tion involve mainly the stomach, or small intestine and to lesser extent, cans, 163,280 but is uncommon in Asians. In Americans of African descent,
the pancreas. the disease tends to begin early, occurs with high frequency in women,
Gastric Disorders in Pernicious Anemia PA is a disease of insid- and often is severe. 163, 254
ious onset that generally begins in middle age or later (usually after age Stomach and Intestine in Pernicious Anemia Gastric mani-
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40 years). In this condition, intrinsic factor secretion fails because of festations of PA include achlorhydria, acquired intrinsic factor defi-
gastric mucosal atrophy. PA is an autoimmune disease. The gastric atro- ciency previously demonstrable by the Schilling test, and an increased
phy of PA probably results from immune destruction of the acid- and incidence of certain malignancies. There is an approximately twofold
pepsin-secreting portion of the gastric mucosa. The term pernicious increase in the incidence of gastric cancer, similar increases in the inci-
anemia sometimes is used as a synonym for cobalamin deficiency, but dence of certain hematologic malignancies, and an increase in the inci-
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it should be reserved for the condition resulting from defective secre- dence of gastric carcinoid. Achlorhydria may precede by many years
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tion of intrinsic factor by an atrophic gastric mucosa caused by an auto- the loss of intrinsic factor secretion and the development of PA. The
immune process primarily directed against the parietal cells and their absence of achlorhydria excludes the diagnosis of PA. H. pylori, a micro-
products. organism that infects the gastric mucosa, is a major cause of gastritis
In patients with PA, antibodies occur that recognize the H / and peptic ulcers. Evidence is conflicting regarding the role of H. pylori
+
K -adenosine triphosphatase (ATPase), which resides in the secretory in PA. In two studies, cultures of gastric biopsies showed a very low
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membrane of the parietal cell and is responsible for acidifying the stom- incidence of H. pylori infection in PA patients. One study reported
ach contents. These antiparietal cell antibodies occur in approximately that anti–H. pylori antibodies were found in only a small fraction of the
60 percent of patients with simple atrophic gastritis and in 90 percent sera from these patients. The other study reported that these antibodies
of patients with PA, but in only 5 percent of a random 30- to 60-year- were present in most of the PA sera, indicating that most of the patients
old population. Antiparietal cell antibodies also occur in a significant described in the study had been infected previously. Whether H. pylori
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percentage of patients with thyroid disease. Conversely, patients with participates in the pathogenesis of PA is an open question. An intriguing
PA have a higher than expected incidence of antibodies against thyroid hypothesis has been advanced that chronic infection with H. pylori may
epithelium, lymphocytes, and renal collecting duct cells. 262 be responsible for triggering an autoimmune reaction directed against
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Antiparietal cell antibodies are not thought to be responsible for the host H /K -ATPase protein as a result of molecular mimicry. 167, 283
the pathogenesis of PA. Rather, studies in mice suggest the gastric atro- Fasting plasma gastrin levels are high in most patients with PA,
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phy in PA is caused by CD4+ T cells whose receptors recognize the whereas somatostatin levels are low. In biopsies from PA stomachs,
H /K -ATPase. Thus, thymectomized BALB/c mice develop an auto- however, fundal gastrin and somatostatin levels were high, correlating
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immune atrophic gastritis similar to that seen in PA patients. CD4+ T with increases in argyrophilic cells in the basal crypts; antral gastrin and
cells from these mice produce atrophic gastritis when injected into nude somatostatin were normal. Gastrin levels are high in simple achlorhy-
mice. 263 dria without PA. 285
Antibodies to intrinsic factor (“type I,” or “blocking,” antibodies) The stomach shows characteristic histologic abnormalities in PA
or the intrinsic factor–cobalamin (Cbl) complex (“type II,” or “binding,” (Fig. 41–14). The mucosa of the cardia and fundus is atrophic, containing
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antibodies) are highly specific to PA patients. Blocking antibodies, few chief (i.e., pepsin-secreting) or parietal cells. The withered mucosa
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which prevent formation of the intrinsic factor–Cbl complex, are found is infiltrated with lymphocytes and plasma cells. In contrast, the antral
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in up to 70 percent of PA sera. Binding antibodies, which prevent the and pyloric mucosa are normal. Gastric atrophy is partly reversible by
intrinsic factor–Cbl complex from binding to its ileal receptors, are found glucocorticoid treatment, with some regeneration and return of intrin-
in about half the sera that contain blocking antibody. Some findings in sic factor secretion, further evidence for the autoimmune nature of
humans support the idea that T cells are responsible for the gastric atro- PA. Clinical response to administration of glucocorticoids or adreno-
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phy in PA. First, lymphocytes from patients with PA are hyperrespon- corticotropic hormone in patients with neurologic disease may reflect
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sive to gastric antigens. Second, the incidence of PA is higher than temporary amelioration of underlying and undiagnosed PA. 288
expected in patients with agammaglobulinemia, even though their sera Megaloblastic changes reversible by cobalamin are seen in the
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contain none of the antibodies typical of PA. 266 gastrointestinal epithelium. Cells recovered by lavage are large and
Other Autoimmune Diseases The coexistence of several other show atypical nuclei resembling early malignant change. Small intes-
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autoimmune diseases and PA is further evidence that PA is an auto- tinal biopsy shows decreased mitoses in crypts, shortening of villi,
immune disease. Antiparietal cell antibodies and PA are unexpectedly megaloblastic changes in epithelial cells, and infiltration in the lam-
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frequent in patients with other autoimmune diseases, including ina propria. These changes may account for the malabsorption of
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autoimmune thyroid disorders (thyrotoxicosis, hypothyroidism, and D-xylose and carotene observed in PA. 291
Hashimoto thyroiditis), type I diabetes mellitus, hypoparathyroid- Recognizing PA may be difficult. PA combines the general features
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ism, Addison disease, postpartum hypophysitis, vitiligo, acquired of megaloblastic anemia and features specific for cobalamin deficiency
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agammaglobulinemia, infertile female patients younger than age 40 with unique clinical features related to its (probable) autoimmune eti-
years, and hypospermia and infertility in males. 273,274 Infertility may, ology and gastric pathology. The disease is easily missed because of its
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however, relate to impairment of DNA synthesis in gonadal cells rather (1) insidious onset, (2) tendency to be masked by the use of multivi-
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than to an autoimmune mechanism. tamin preparations containing folic acid, and (3) many atypical pre-
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Inherited Predisposition to Pernicious Anemia Predisposition sentations, including its presentation as a neurologic disease without
to PA can be inherited. The disease is associated with human leukocyte hematologic findings, 77,294 and its tendency to be overlooked in patients
antigen types A2, A3, B7, and B12, and with blood group A. PA with another autoimmune disease.
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and antiparietal cell antibodies occur more frequently than expected in Antiparietal cell and antiintrinsic factor antibodies are rarely mea-
the families of PA patients. In one study, gastric atrophy was found sured, even though antiintrinsic factor antibodies in particular could be
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in more than 30 percent of the relatives of patients with PA; of these of considerable diagnostic value. In the absence of a reliable method
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relatives, 65 percent had antiparietal cell antibodies and 22 percent to assess vitamin B absorption, following the Schilling test becom-
12
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had antiintrinsic factor antibodies. PA occurs relatively frequently ing obsolete, measurement of antiintrinsic factor antibodies in serum
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