Pernicious anemia - genetic insights

Pernicious anemia (PA) is a complex, autoimmune, multi-factorial disease. Rapid progress has been made in the understanding of susceptibility to a spectrum of other autoimmune diseases through genome wide association studies (GWAS). However, PA has been conspicuous by its absence from this work. Here, we examine the evidence that PA has a significant heritable component through epidemiological evidence and its co-occurrence with other autoimmune diseases. Further, we consider how knowledge of the genetic susceptibility to other autoimmune diseases may provide insight into the etiology of PA.     

Diagnosis and classification of pernicious anemia

Pernicious anemia (PA) is a complex disorder consisting of hematological, gastric and immunological alterations. Diagnosis of PA relies on histologically proven atrophic body gastritis, peripheral blood examination showing megaloblastic anemia with hypersegmented neutrophils, cobalamin deficiency and antibodies to intrinsic factor and to gastric parietal cells. Anti-parietal cell antibodies are found in 90% of patients with PA, but have low specificity and are seen in atrophic gastritis without megaloblastic anemia as well as in various autoimmune disorders. Anti-intrinsic factor antibodies are less sensitive, being found in only 60% of patients with PA, but are considered highly specific for PA. The incidence of PA increases with age and is rare in persons younger than 30 years of age. The highest prevalence is seen in Northern Europeans, especially those in the United Kingdom and Scandinavia, although PA has been reported in virtually every ethnic group. Because of the complexity of the diagnosis, PA prevalence is probably underestimated and no reliable data are available on the risk of gastric cancer as the end-stage evolution of atrophic gastritis in these patients.     

Chronic lymphatic leukemia presenting as hemolytic anaemia

In CLL autoimmune phenomena manifest most commonly as autoimmune hemolytic anemia followed by thrombocytopenic purpura and pure red cell aplasia. Here an elderly lady presenting with AIHA as the presenting manifestation of CLL is described.     

Quantitation of red cell-bound immunoglobulins and complement in lymphoma patients

Quantitative ELISA may be useful for determining the amount of red blood cell (RBC)-associated immunoglobulins (Igs) in patients with autoimmune hemolytic anemia (AIHA). In idiopathic AIHA, there is about 20 times more RBC-associated IgG and complement than in normal persons. In patients with low-grade lymphomas (particularly, B-CLL and splenic marginal zone lymphoma) autoimmune hemolysis is a component of their anemia. In high-grade malignant lymphomas (i.e, diffuse large B-cell lymphoma and peripheral T-cell lymphoma), as well as in Hodgkin's disease, autoimmune hemolysis contributes little, if any, anemia. The quantitative ELISA for RBC-associated IgG and complement is useful for following the effects of treatment in patients with immune hemolysis.     

Autoimmune hemolytic anemia associated with postirradiation malignant stromal tumor (leiomyosarcoma) of the jejunum

We describe a patient who presented with autoimmune hemolytic anemia and small bowel obstruction secondary to a malignant stromal tumor (leiomyosarcoma) of the jejunum, 25 years postchemotherapy and radiation treatment for stage IIA Hodgkin's disease. The patient was treated with corticosteroid therapy and surgical resection of the jejunal tumor. We conclude that autoimmune hemolytic anemia may be an unusual presentation for postirradiation sarcoma.     

Effects of Induced Anemia in Normal and Autoimmune Mice

Normal and autoimmune mice were studied with regard to signals eliciting differentiation and division of bone marrow stem cells. The erythropoiesis induced by anemia following serial bleedings was analyzed in young autoimmune New Zealand Black (NZB) mice and non-autoimmune strains. No difference in the response to the stimulus created by anemia was noted between the strains. After serial bleedings as a stimulus to stem cell proliferation, a five-fold increase in numbers of proliferating spleen cells occurred in both NZB and DBA/2 strains; the increased proliferating spleen cells in both strains were non-lymphoid. The bled animals had decreased percentages of B cells. The production of autoantibodies was not significantly altered by the experimentally induced anemia. In contrast, anti-immunoglobulin activation of resting B cells was increased in response to anemia. Young mice which had experimentally induced anemia had several characteristics in common with old autoimmune NZB mice. Both old NZB mice and young anemic animals had splenomegaly, increased numbers of proliferating spleen cells, decrease in splenic Ly 5⁺ cells and an increase in splenic colony forming units (CFUs). The anemic normal strains of animals lacked other characteristics of old NZB mice such as hyperimmunoglobulinemia or autoantibody production or elevated CD5+B cell numbers. This work supports the concept that the increase in spleen cell number, proliferating spleen cells, CFUs and the increased percentages of non-Ly-5 cells (which include erythroid precursors) found in the spleens of old NZB mice may in part result from their autoimmune hemolytic anemia.     

Autoimmune hemolytic anemia in Gaucher's disease

Summary A 23-year-old Ashkenazi woman with Gaucher's disease developed Coombs-positive warm-type autoimmune hemolytic anemia. Treatment with high-dose steroids resulted in complete remission within 2 weeks. Study of an additional 72 patients with Gaucher's disease revealed another case of Coombs-positive warm-type autoimmune hemolytic anemia; other autoimmune disorders were found in 17 of these patients. The possible association of Coombs-positive hemolytic anemia and Gaucher's disease is discussed.     

Anemia in elderly Koreans

Recently, the geriatric population in Korea has grown to comprise approximately 10% of the total population, and anemia has become a significant problem among elderly patients. Many elderly patients have anemia due to nutritional deficiency, chronic inflammation, or comorbid diseases; however, in a significant fraction of the patients with anemia, the cause remains obscure. Anemia of any degree is recognized as a significant independent contributor to morbidity and mortality in elderly patients. This article summarizes the patterns of anemia in Korean geriatric patients.     

Positive direct antiglobulin tests and immune hemolytic anemia in patients receiving procainamide

To characterize the autoimmune phenomena in patients receiving procainamide, we studied the prevalence of positive direct antiglobulin (Coombs') tests and immune hemolytic anemia in 100 such patients and compared them with 100 age-matched and sex-matched controls. There was a significant increase in the frequency of positive direct antiglobulin tests in patients receiving procainamide (21 vs. 10 per cent, P = 0.05). The mechanism of red-cell sensitization in patients receiving procainamide was the production of red-cell autoantibody, which was serologically indistinguishable from that seen in warm autoimmune hemolytic anemia. In contrast, positive direct antiglobulin tests in control patients were due to the presence of complement components. Red-cell autoantibody production secondary to procainamide was not correlated with a higher-than-expected frequency of antinuclear antibodies or the clinical syndrome of drug-induced lupus erythematosus. In the series of 100 patients receiving procainamide, we identified three cases of immune hemolytic anemia. In two of the three cases, the anemia resolved after the medication was discontinued and did not require steroid therapy. We conclude that procainamide often results in the production of red-cell autoimmune phenomena.     

Cold agglutinin disease after chicken pox. An uncommon complication of a common disease.

Chicken pox, although common, is rarely associated with autoimmune hemolytic anemia. Reported here is the case of an 8-year-old boy who was found to have cold agglutinin disease and severe anemia several days after he contracted chicken pox. The cold agglutinin appeared to be a polyclonal immunoglobulin M antibody with anti-Pr specificity. To our knowledge, this is the fifth reported case of autoimmune hemolytic anemia and the second reported case of cold agglutinin disease with anti-Pr specificity to be associated with chicken pox.     

A case of autoimmune hemolytic anemia associated with an ovarian teratoma

Autoimmune hemolytic anemia associated with an ovarian teratoma is a very rare disease. However, treating teratoma is the only method to cure the hemolytic anemia, so it is necessary to include ovarian teratoma in the differential diagnosis of autoimmune hemolytic anemia. We report herein on a case of a young adult patient who had severe autoimmune hemolytic anemia that was induced by an ovarian teratoma. A 25-yr-old woman complained of general weakness and dizziness for 1 week. The hemoglobin level was 4.2 g/dL, and the direct and indirect antiglobulin tests were all positive. The abdominal computed tomography scan revealed a huge left ovarian mass, and this indicated a teratoma. She was refractory to corticosteroid therapy; however, after surgical resection of the ovarian mass, the hemoglobin level and the reticulocyte count were gradually normalized. The mass was well encapsulated and contained hair and teeth. She was diagnosed as having autoimmune hemolytic anemia associated with an ovarian teratoma. To the best of our knowledge, this is the first such a case to be reported in Korea.     

Hemolytic anemia related to an IgM autoantibody to phosphatidylcholine that binds in vitro to stored and to bromelain-treated human erythrocytes

Both normal and autoimmune mice have IgM natural autoantibodies to bromelain-treated erythrocytes in which phosphatidylcholine (PTC) becomes exposed. At one stage this antibody may participate in the genesis of autoimmune hemolytic anemia in the NZB mouse. We have recently studied a patient with hemolytic anemia who had persistently high serum titers of IgM anticardiolipin antibodies (aCL) that were also demonstrated in a hemolysate of his erythrocytes obtained at the time of the anemia. We affinity-purified the antibody and sought its binding to normal human bromelain-treated erythrocytes (BrE) because of the IgM isotype of the antibody, since cardiolipin is not a constituent of the erythrocyte wall, and because the anionic phospholipids, with which aCL are known to cross-react, are not located at the outer leaflet of the erythrocyte membrane. We found binding of the antibody to HBrE in their hemolysates and by flow cytometry. We also demonstrated that the aCL cross-reacted extensively with PTC, as well as with other anionic or zwitterionic phospholipids. The purified IgM antibody lysed BrE in the presence of complement and also bound to in vitro-aged erythrocytes. Because this patient had no other evidence of systemic lupus erythematosus or any other autoimmune condition, his disease may represent a variant of the recently described primary antiphospholipid syndrome.     

A study of the aetiology of gastritis following gastric surgery. I. Immunofluorescent studies of the gastric mucosa.

The gastritis which follows surgical trauma is probably not of autoimmune origin. Although identical with the gastritis of pernicious anaemia (PA) upon routine histological examination, immunofluorescent examination of post-operative gastritis differs in that IgA-containing plasma cells alone are found, in contrast to the predominantly IgG-containing plasma cells in PA.     

Serum erythropoietin titers in the aged

Erythropoietin (Epo) titers in the aged (from 70 to 89 years) were determined by a radioimmunoassay. Epo levels in normal elderly subjects were not different from levels in the young volunteers. The serum Epo levels in elderly patients with anemia were inversely related to hemoglobin levels; their regression coefficient was not worse than that found in young patients. It is suggested that the reactivity of Epo production to anemia in the aged may not be worse than that reactivity in the young.     

Interferon-Beta-1b Induced Autoimmune Hemolytic Anemia in a Patient with MS: A Case Report

A 26-year-old lady with the diagnosis of multiple sclerosis who had received interferon beta1-b for eleven months was visited in MS clinic of our hospital because of icter and fatigue. Laboratory tests showed anemia, indirect hyperbillirubinemia, increased LDH, positive direct and indirect coomb's tests, and increased reticulocyte count and percentage. Other causes of autoimmune hemolytic anemia (AHA) and pre-existing AHA in the patient were ruled out. After INF discontinuation, symptoms disappeared, hemoglobin increased, and indirect coomb's test became negative. We concluded that autoimmune hemolytic anemia should be considered in all MS patients who receive interferon beta1-b and present with symptoms and signs of anemia.     

Coinfection of hepatitis A virus genotype IA and IIIA complicated with autoimmune hemolytic anemia,prolonged cholestasis,and false-positive immunoglobulin M anti-hepatitis E virus: a case report

A 37-year-old male presented with fever and jaundice was diagnosed as hepatitis A complicated with progressive cholestasis and severe autoimmune hemolytic anemia. He was treated with high-dose prednisolone (1.5 mg/kg), and eventually recovered. His initial serum contained genotype IA hepatitis A virus (HAV), which was subsequently replaced by genotype IIIA HAV. Moreover, at the time of development of hemolytic anemia, he became positive for immunoglobulin M (IgM) anti-hepatitis E virus (HEV). We detected HAV antigens in the liver biopsy specimen, while we detected neither HEV antigen in the liver nor HEV RNA in his serum. This is the first report of hepatitis A coinfected with two different genotypes manifesting with autoimmune hemolytic anemia, prolonged cholestasis, and false-positive IgM anti-HEV.     

Gastric mucosal lymphocyte subpopulations in pernicious anemia and in normal stomach

Gastric mucosal lymphocyte subpopulations were determined by an indirect immunoperoxidase method applied to cryostat sections of gastric biopsies obtained from 12 patients with pernicious anemia (PA group) and from 12 patients whose stomachs were endoscopically and histologically normal (comparison group). T-Cell populations were identified by means of monoclonal antibodies directed against all T cells (UCHT1), T suppressor cells (anti-Leu-2a), and T helper cells (anti-Leu-3a). Non-T cell numbers were estimated indirectly. Concentrations of all T cells, T suppressor cells, T helper cells, and non-T cells were all significantly greater in the PA than in the comparison group. The most striking difference was in non-T cell numbers, which showed an approximately sixfold increase in the PA group. Mean T/non-T cell ratios in PA and comparison groups were significantly different (0.49 and 1.50, respectively). T suppressor/T helper cell ratios were similar in the two groups. There were highly significant positive correlations between numbers of non-T and T helper cells, and non-T and T suppressor cells in PA, but not in comparison groups. If, as seems likely, the majority of non-T cells in these gastritic stomachs were in fact cells of B lineage, these results would be consistent with the hypothesis that gastric mucosal damage in pernicious anemia is mediated primarily by a humoral mechanism, which may involve cytotoxic autoantibodies.     

Biermer's disease and auto-immune haemolytic anaemia

Biermer's disease is an autoimmune atrophic gastritis of the fundus predominantly responsible for a malabsorption of vitamin B12. Despite its association with several autoimmune disorders, few observations have reported an association with autoimmune hemolytic anemia (AIHA). We report a case of Biermer's disease associated with AIHA in a patient of 66 years old.