(Acta Paediatr Jpn 1990; 32: 31 1
314)
Pernicious Anemia in a Patient with Hypogammaglobulinemia Hiroyuki Moriuchi, M.D.,’ Toshimitsu Takayanagi, M.D.,’ Shiro Yamasaki, M.D.; Makoto Yasui, M.D.? Koichi Mori, M.D.? Masanori Yanai, M.D.,3 Tadamichi Yanagi, M.D.? and Yoshiro Tsuji, M.D.3 1
Division of Pediatrics, Sasebo Kyosai Hospital, 2Division of Pediatrics, Sasebo City Hospital, 3Departmentof Pediatrics, Nagasaki University School of Medicine
A 19-year-old male with pernicious anemia and hypogammaglobulinemia (common variable immunodeficiency: CVID) is reported in comparison with classical pernicious anemia. This case was characterized by an earlier onset of anemia, the absence of autoantibodies to intrinsic factor or gastric parietal cells and involvement of the pyloric antrum as well as the gastric corpus. It is suggested that dysregulation of cellular immunity produces the autoimmune lesion in the gastric mucosa, including the pyloric antrum, in a patient with CVID, and that some of such cases develop pernicious anemia. Key Words
Pernicious anemia, Hypogammaglobulinemia, Gastrin
Introduction Autoimmunity to the gastric mucosa is implicated in the pathogenesis of classical pernicious anemia and autoantibodies to intrinsic factor and gastric parietal cells are frequently found in patients with classical pernicious anemia [ 1-21 . Pernicious anemia has also been reported in patients with hypogammaglobulinemia in whom such autoantibodies are absent [3-91. The association of these two diseases may be apparently paradoxical but has stimulated a good deal of interest and speculation. At least in these patients, and probably also in others,
cellular autoimmunity may be more important in producing pernicious anemia than humoral au toan tibodies [ 10- 181 . Cowling et al have characterized the disorder of pernicious anemia with hypogammaglobulinemia and have differentiated it from “classical pernicious anemia” by the absence of autoantibodies and the involvement of the pyloric antrum, and have termed it the “pernicious-anemia-like syndrome with immunoglobulin deficiency” (PA-LS-ID) [7] . We report here a 19-year-old Japanese male with PA-LS-ID, who is the first case from Asia, all documented cases so far being white or black.
Case report Received October 11,1989 Revised January 30, 1990 Accepted February 23, 1990 Correspondence address: Hiroyuki Moriuchi, M.D., Virus Research Center, Sendai National Hospital, 2-8-8 Miyagino, Miyagino-ku, Sendai 983, Japan
The patient was diagnosed as a case of common variable immunodeficiency (CVID) at the age of 11 years. He had had a history of recurrent bacterial
312 (86)Moriuchietal infections including pneumonia, otitis media and meningitis since the age of 3 years, and immunological assessment at 1 1 years (Table) showed the following: significant decrease of the serum immunoglobulins (IgG 9.9 mg/dl, IgM trace IgA, IgD and IgE not detectable); no detectable anti-B isohemagglutinins in the serum (his blood was type A); normal levels of complement; normal leukocyte function including chemotaxis, phagocytosis, bactericidal activity assay, and normal nitroblue tetrazolium dye reduction test; peripheral blood T cells (as determined by sheep red cell rosettes) 78%, B cells (as determined by surface membrane immunoglobulin-bearing lymphocytes) 16%; normal lymphocyte response to phytohemagglutinin; negative delayed hypersensitivity skin test for tuberculin (PPD, 0.05 pg; Nihon BCG, Japan), streptokinase-streptodornase (Varidase, 5 U/SK; Lederle), and Gzndida albicans extracts (1 :1,000; Torii, Japan); negative DNCB (2, 4-dinitro-1-chlorobenzene) patch test. Treatment with intravenous injections of immunoglobulin had been initiated at the age of 11 years, and induced brisk clinical improvement. Since the age of 16 he had had chronic diarrhea, gray hair, a sore tongue and numbness, and he was noticed to have anemia at the age of 19 years. Laboratory tests performed at the age of 19 (Table) yielded the following values: hemoglobin 6.3 g/dl, hematocrit 18.1%,erythrocyte count 1.65 x lo6 cells/pl, mean corpuscular volume 110 fl, leukocyte count 3,200 cells/ pl, and platelet count 1.79 x l o 5 cells/pl. The reticulocyte count was 0.04%. Peripheral blood smear showed macrocytic anemia and large neutrophils with hypersegmentation. Bone marrow aspirate revealed erythroid hyperplasia (myeloid/erythroid ratio 2.0), megaloblastic change and absence of plasma cells. The serum vitamin BI2 value was 128 pg/ml (normal range, 300- 1,OOO), and serum folate 6.2 ng/ml (normal range, 2-10). The absorption test of vitamin B I Z (dual radioisotope test: Dicopac, Amersham, England) [19] showed 2.3% excretion without intrinsic factor (normal range, 11-28%) and
Table. Summary of laboratory data Hemoglobin (gldl) Mean corpuscularvolume (fl) Serum vitamin B,, (pglml) Absorption test Of vitamin B 1 z without intrinsic factor (%) with intrinsic factor (%) Intrinsic-factor antibody ~ ~ r ~ ~ ~ antibody ~ ~ a l -
6.3 (13.5-16.5)* 110 (80-94) 128 (300-1000)
fasting level (pg/ml) increasing rate after a meal (7%) Serum ~ m u n o g l o b u ~Gn (mg/dl) A (mg/dl) M [rnddl) -. . Peripheral blood T cell (%) B (%) Delayed hypersensitivity skin test for tuberculin SK-SD Candida albicans extracts DNCB patch test
93 (42-200) 148 (400) 9.9 (640-1 810) trace (60-340) ND (50-300) 78 (62.5-78:9) 16 (5.1-21.5)
2.3 (11 -28) 5.2 (11 -28) ND ND c e u
negative negative negative negative
*The figures in parentheses indicate the range of normal values or the value of the control. ND: not detected, SK-SD: streptokinase-streptodornase, DNCB: 2.4-dinitro-1-chlorobenzene.
5.2% excretion with intrinsic factor. His serum and gastric juice were tested for intrinsicfactor antibody by radioimmunoassay, and for gastric-parietal-cell antibody by the indirect immunofluorescent method. Neither of them was detected. Fasting serum gastrin level was 93pg/ml (normal range, 42-200), and an increase to 139 pg/ml or 148% of the fasting level (control 400%) occurred following a steak meal (150-g steak). Gastic juice analysis revealed histamine-fast achlorhydria. No ova, parasites, protozoa (including Ciardia lamblia) or pathogenic bacteria were found on several examinations of the stools. Biopsy of the gastric mucosa (Figure) showed altrophic gastritis, intestinal metaplasia of the mucosa and destruction of G cells through gastrin staining. His lymphocyte response to human intrinsic factor (Dicopac, Amersham, England) was the same as that of the control. Treatment with vitamin B12 induced brisk hematologic remission and clinical improvement. Family study revealed that his brother, 3 years younger than the patient, was also a case of CVID. Laboratory studies showed
Acta Paediatr Jpn
Pernicious anemia with immunodeficiency (87) 313
Fig. Biopsy of the gastric antrum showing atrophic gastritis, intestinal metaplasia of the mucosa and absence of plasma cells. (Hematoxylin-Eosin)
the following: low levels of serum immunoglobulins (IgG 245 mg/dl, IgA 8 mg/dl, IgM 5 mg/dl and IgE 13 U/ml); complete blood cell count within normal limits; serum vitamin B I 2 level 650 pg/ml; fasting serum gastrin level 78 pg/ml, an increase to 300pg/ml or 385% of the fasting level occurring after a steak meal; normal lymphocyte reponse to human intrinsic factor.
Discussion Compared with classical pernicious anemia, our patient was characterized by an earlier onset of anemia, the absence of antibodies to intrinsic factor or parietal cells in either serum or gastric juice and the involvement of the pyloric antrum as well as the gastric corpus, with abnormally low gastrin secretion; in patients with classical pernicious anemia the gastric mucosal lesion is limited to the gastric corpus and the serum gastrin level is elevated. These findings were characteristic features of the patients with PA-LSID et ported by Cowling et a1 [7] . The immunoglobulin deficiency in our patient corresponds best with CVID since he
Vol. 32 No. 3 June 1990
had a normal number of peripheral B cells and some impairment of cellular immunity. It remains uncertain whether CVID represents a single entity, but it often affects cellular immunity, and many cases of CVID are complicated with autoimmune diseases [20]. Some dysregulation of cellular immunity may probably produce these autoimmune diseases as well as humoral immunodeficiency. Interestingly, abnormally low gastin secretion, which reflects the involvement of the pyloric antrum, was found in most cases of CVID with or even without pernicious anemia, while no cases of X-linked agammaglobulinemia have reduced gastrin secretion [21, 221. This suggests that dysregulation of the cellular immunity produces an autoimmune lesion in the gastric mucosa, including the pyloric antrum, in patients with CVID, and that some of them develop pernicious anemia. We could not demonstrate what dysregulation of the cellular immunity occurred in our patient and produced pernicious anemia, since his lymphocyte response to human intrinsic factor was the same as that of the control. Moreover, his brother, who was also diag nosed as a case of W I D , showed no evidence
314 (88) Moriuchi et a1 of such an autoimmune lesion of the gastric mucosa, though possibly he will later develop the same disorder as the patient. To clarify the mechanism, we need further investigations. Acknowledgement We thank Masako Moriuchi for typing the manuscript. References
I . Chanarin I. Pernicious anaemia as an autoimmune disease. Br J Haematol 1972; 23 [Suppl] : 101107. 2. Chanarin 1, James D. Humoral and cellmediated intrinsic factor antibody in pernicious anemia. Lancet 1974;i: 1078-1080. 3. Larsson SO, Hagelquist E, Coester C. Hypogammaglobulinaemia and pernicious anaemia. Acta Haemat (Basel) 1961; 26: 50-64. 4. Lee FI. Jenkins GC, Hughes DTD et al. Pernicious anaemia, myxoedema, and hypogammaglobulinaemia - A family study. Br Med J 1964; 1: 598-602. 5. Conn HO, Binder H, Bums B. Pernicious anaemia and immunologic deficiency. Ann Intern Med 1968;68: 603-612. 6. Twomey JJ, Jordan PH, Laughter AH et al. The gastric disorder in immunoglobulin-deficient patients. Ann Intern Med 1970; 72: 499-504. 7. Cowling DC, Strickland RG. Ungar B et al. Pernicious-anaemia-like syndrome with immunoglobulin deficiency. Med J Aust 1974; 1: 15-17. 8. Nel AE. Primary acquired hypogrammaglobulinaemia complicated by antibody-mediated haemolysis and pernicious anaemia. S Afr Med J 1983;64: 326-328. 9. Wright PE, Sears DA. Hypogammaglobuhemia and pernicious anemia. South Med J 1987;80: 243 -246. 10. Tai C, McGuigan JE. Immunologic studies in pernicious anemia. Blood 1969; 34: 63-71.
11. Douglas SD, Goldberg LS, Fudenberg HH et al. Agammaglobulinaemia and coexistent pernicious anaemia. Clin Exp lmmunol 1970; 6: 181-187. 12. Fixa B, Thiele HG, Komarkova 0 et al. Gastric autoantibodies and cell-mediated immunity in pernicious anaemia A comparative study. Scand J Gastroent 1972; 7: 237-240. 13. Gelfand EW, Berkel AI, Godwin HA et al. Pernicious anaemia, hypogammaglobulinaemia, and altered lymphocyte reactivity. Clin Exp Immunol 1972; 11: 187-199. 14. Goldberg LS, Cunningham JE, Terasaki PI. Lymphocytotoxins and pernicious anaemia. Blood 1972; 39: 862-865. 15. Finlayson NDC, Fauconnet MH, and Krohn K. In vitro demonstration of delayed hypersensitivity to gastric antigens in pernicious anemia. Dig Dis 1972; 17: 631-638. 16. Goldstone AH, Calder EA, Barnes EW et al. The effect of gastric antigens on the in vitro migration of leukocytes from patients with atrophic gastritis and pernicious anaemia. Clin Exp Immunol 1973; 14: 501-508. 17. Weisbart RH, Bluestone R, Goldberg LS. Cellular immunity to intrinsic factor in pernicious anemia. J Lab Clin Med 1975; 85: 87-92. 18. James D, Asherson G, Chanalin I et al. Cellmediated immunity to intrinsic factor in autoimmune disorders. Br Med J 1974; 4: 494-496. 19 Bell K, Lee D. Evaluation of a dual radioisotope urinary excretion test in the diagnosis of pernicious anemia. Acta Haemat 1969;42: 183-187. 20. Conley ME, Park CL, Douglas SD. Childhood common variable immunodeficiency with autoimmune disease. J Pediatr 1986; 108: 915-922. 21. Hughes WS, Brooks FP, Conn HO. Serum gastrin levels in primary hypogrammaglobulinemia and pernicious anemia. Ann Intern Med 1972; 77: 746 -750. 22. den Hartog G, van der Meer JWM, Jansen JBMJ et al. Decreased gastrin secretion in patients with late-onset hypogammaglobulinemia. N Engl J Med 1988; 318: 1563-1567.
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Acta Puediatr Jpn
314)
Pernicious Anemia in a Patient with Hypogammaglobulinemia Hiroyuki Moriuchi, M.D.,’ Toshimitsu Takayanagi, M.D.,’ Shiro Yamasaki, M.D.; Makoto Yasui, M.D.? Koichi Mori, M.D.? Masanori Yanai, M.D.,3 Tadamichi Yanagi, M.D.? and Yoshiro Tsuji, M.D.3 1
Division of Pediatrics, Sasebo Kyosai Hospital, 2Division of Pediatrics, Sasebo City Hospital, 3Departmentof Pediatrics, Nagasaki University School of Medicine
A 19-year-old male with pernicious anemia and hypogammaglobulinemia (common variable immunodeficiency: CVID) is reported in comparison with classical pernicious anemia. This case was characterized by an earlier onset of anemia, the absence of autoantibodies to intrinsic factor or gastric parietal cells and involvement of the pyloric antrum as well as the gastric corpus. It is suggested that dysregulation of cellular immunity produces the autoimmune lesion in the gastric mucosa, including the pyloric antrum, in a patient with CVID, and that some of such cases develop pernicious anemia. Key Words
Pernicious anemia, Hypogammaglobulinemia, Gastrin
Introduction Autoimmunity to the gastric mucosa is implicated in the pathogenesis of classical pernicious anemia and autoantibodies to intrinsic factor and gastric parietal cells are frequently found in patients with classical pernicious anemia [ 1-21 . Pernicious anemia has also been reported in patients with hypogammaglobulinemia in whom such autoantibodies are absent [3-91. The association of these two diseases may be apparently paradoxical but has stimulated a good deal of interest and speculation. At least in these patients, and probably also in others,
cellular autoimmunity may be more important in producing pernicious anemia than humoral au toan tibodies [ 10- 181 . Cowling et al have characterized the disorder of pernicious anemia with hypogammaglobulinemia and have differentiated it from “classical pernicious anemia” by the absence of autoantibodies and the involvement of the pyloric antrum, and have termed it the “pernicious-anemia-like syndrome with immunoglobulin deficiency” (PA-LS-ID) [7] . We report here a 19-year-old Japanese male with PA-LS-ID, who is the first case from Asia, all documented cases so far being white or black.
Case report Received October 11,1989 Revised January 30, 1990 Accepted February 23, 1990 Correspondence address: Hiroyuki Moriuchi, M.D., Virus Research Center, Sendai National Hospital, 2-8-8 Miyagino, Miyagino-ku, Sendai 983, Japan
The patient was diagnosed as a case of common variable immunodeficiency (CVID) at the age of 11 years. He had had a history of recurrent bacterial
312 (86)Moriuchietal infections including pneumonia, otitis media and meningitis since the age of 3 years, and immunological assessment at 1 1 years (Table) showed the following: significant decrease of the serum immunoglobulins (IgG 9.9 mg/dl, IgM trace IgA, IgD and IgE not detectable); no detectable anti-B isohemagglutinins in the serum (his blood was type A); normal levels of complement; normal leukocyte function including chemotaxis, phagocytosis, bactericidal activity assay, and normal nitroblue tetrazolium dye reduction test; peripheral blood T cells (as determined by sheep red cell rosettes) 78%, B cells (as determined by surface membrane immunoglobulin-bearing lymphocytes) 16%; normal lymphocyte response to phytohemagglutinin; negative delayed hypersensitivity skin test for tuberculin (PPD, 0.05 pg; Nihon BCG, Japan), streptokinase-streptodornase (Varidase, 5 U/SK; Lederle), and Gzndida albicans extracts (1 :1,000; Torii, Japan); negative DNCB (2, 4-dinitro-1-chlorobenzene) patch test. Treatment with intravenous injections of immunoglobulin had been initiated at the age of 11 years, and induced brisk clinical improvement. Since the age of 16 he had had chronic diarrhea, gray hair, a sore tongue and numbness, and he was noticed to have anemia at the age of 19 years. Laboratory tests performed at the age of 19 (Table) yielded the following values: hemoglobin 6.3 g/dl, hematocrit 18.1%,erythrocyte count 1.65 x lo6 cells/pl, mean corpuscular volume 110 fl, leukocyte count 3,200 cells/ pl, and platelet count 1.79 x l o 5 cells/pl. The reticulocyte count was 0.04%. Peripheral blood smear showed macrocytic anemia and large neutrophils with hypersegmentation. Bone marrow aspirate revealed erythroid hyperplasia (myeloid/erythroid ratio 2.0), megaloblastic change and absence of plasma cells. The serum vitamin BI2 value was 128 pg/ml (normal range, 300- 1,OOO), and serum folate 6.2 ng/ml (normal range, 2-10). The absorption test of vitamin B I Z (dual radioisotope test: Dicopac, Amersham, England) [19] showed 2.3% excretion without intrinsic factor (normal range, 11-28%) and
Table. Summary of laboratory data Hemoglobin (gldl) Mean corpuscularvolume (fl) Serum vitamin B,, (pglml) Absorption test Of vitamin B 1 z without intrinsic factor (%) with intrinsic factor (%) Intrinsic-factor antibody ~ ~ r ~ ~ ~ antibody ~ ~ a l -
6.3 (13.5-16.5)* 110 (80-94) 128 (300-1000)
fasting level (pg/ml) increasing rate after a meal (7%) Serum ~ m u n o g l o b u ~Gn (mg/dl) A (mg/dl) M [rnddl) -. . Peripheral blood T cell (%) B (%) Delayed hypersensitivity skin test for tuberculin SK-SD Candida albicans extracts DNCB patch test
93 (42-200) 148 (400) 9.9 (640-1 810) trace (60-340) ND (50-300) 78 (62.5-78:9) 16 (5.1-21.5)
2.3 (11 -28) 5.2 (11 -28) ND ND c e u
negative negative negative negative
*The figures in parentheses indicate the range of normal values or the value of the control. ND: not detected, SK-SD: streptokinase-streptodornase, DNCB: 2.4-dinitro-1-chlorobenzene.
5.2% excretion with intrinsic factor. His serum and gastric juice were tested for intrinsicfactor antibody by radioimmunoassay, and for gastric-parietal-cell antibody by the indirect immunofluorescent method. Neither of them was detected. Fasting serum gastrin level was 93pg/ml (normal range, 42-200), and an increase to 139 pg/ml or 148% of the fasting level (control 400%) occurred following a steak meal (150-g steak). Gastic juice analysis revealed histamine-fast achlorhydria. No ova, parasites, protozoa (including Ciardia lamblia) or pathogenic bacteria were found on several examinations of the stools. Biopsy of the gastric mucosa (Figure) showed altrophic gastritis, intestinal metaplasia of the mucosa and destruction of G cells through gastrin staining. His lymphocyte response to human intrinsic factor (Dicopac, Amersham, England) was the same as that of the control. Treatment with vitamin B12 induced brisk hematologic remission and clinical improvement. Family study revealed that his brother, 3 years younger than the patient, was also a case of CVID. Laboratory studies showed
Acta Paediatr Jpn
Pernicious anemia with immunodeficiency (87) 313
Fig. Biopsy of the gastric antrum showing atrophic gastritis, intestinal metaplasia of the mucosa and absence of plasma cells. (Hematoxylin-Eosin)
the following: low levels of serum immunoglobulins (IgG 245 mg/dl, IgA 8 mg/dl, IgM 5 mg/dl and IgE 13 U/ml); complete blood cell count within normal limits; serum vitamin B I 2 level 650 pg/ml; fasting serum gastrin level 78 pg/ml, an increase to 300pg/ml or 385% of the fasting level occurring after a steak meal; normal lymphocyte reponse to human intrinsic factor.
Discussion Compared with classical pernicious anemia, our patient was characterized by an earlier onset of anemia, the absence of antibodies to intrinsic factor or parietal cells in either serum or gastric juice and the involvement of the pyloric antrum as well as the gastric corpus, with abnormally low gastrin secretion; in patients with classical pernicious anemia the gastric mucosal lesion is limited to the gastric corpus and the serum gastrin level is elevated. These findings were characteristic features of the patients with PA-LSID et ported by Cowling et a1 [7] . The immunoglobulin deficiency in our patient corresponds best with CVID since he
Vol. 32 No. 3 June 1990
had a normal number of peripheral B cells and some impairment of cellular immunity. It remains uncertain whether CVID represents a single entity, but it often affects cellular immunity, and many cases of CVID are complicated with autoimmune diseases [20]. Some dysregulation of cellular immunity may probably produce these autoimmune diseases as well as humoral immunodeficiency. Interestingly, abnormally low gastin secretion, which reflects the involvement of the pyloric antrum, was found in most cases of CVID with or even without pernicious anemia, while no cases of X-linked agammaglobulinemia have reduced gastrin secretion [21, 221. This suggests that dysregulation of the cellular immunity produces an autoimmune lesion in the gastric mucosa, including the pyloric antrum, in patients with CVID, and that some of them develop pernicious anemia. We could not demonstrate what dysregulation of the cellular immunity occurred in our patient and produced pernicious anemia, since his lymphocyte response to human intrinsic factor was the same as that of the control. Moreover, his brother, who was also diag nosed as a case of W I D , showed no evidence
314 (88) Moriuchi et a1 of such an autoimmune lesion of the gastric mucosa, though possibly he will later develop the same disorder as the patient. To clarify the mechanism, we need further investigations. Acknowledgement We thank Masako Moriuchi for typing the manuscript. References
I . Chanarin I. Pernicious anaemia as an autoimmune disease. Br J Haematol 1972; 23 [Suppl] : 101107. 2. Chanarin 1, James D. Humoral and cellmediated intrinsic factor antibody in pernicious anemia. Lancet 1974;i: 1078-1080. 3. Larsson SO, Hagelquist E, Coester C. Hypogammaglobulinaemia and pernicious anaemia. Acta Haemat (Basel) 1961; 26: 50-64. 4. Lee FI. Jenkins GC, Hughes DTD et al. Pernicious anaemia, myxoedema, and hypogammaglobulinaemia - A family study. Br Med J 1964; 1: 598-602. 5. Conn HO, Binder H, Bums B. Pernicious anaemia and immunologic deficiency. Ann Intern Med 1968;68: 603-612. 6. Twomey JJ, Jordan PH, Laughter AH et al. The gastric disorder in immunoglobulin-deficient patients. Ann Intern Med 1970; 72: 499-504. 7. Cowling DC, Strickland RG. Ungar B et al. Pernicious-anaemia-like syndrome with immunoglobulin deficiency. Med J Aust 1974; 1: 15-17. 8. Nel AE. Primary acquired hypogrammaglobulinaemia complicated by antibody-mediated haemolysis and pernicious anaemia. S Afr Med J 1983;64: 326-328. 9. Wright PE, Sears DA. Hypogammaglobuhemia and pernicious anemia. South Med J 1987;80: 243 -246. 10. Tai C, McGuigan JE. Immunologic studies in pernicious anemia. Blood 1969; 34: 63-71.
11. Douglas SD, Goldberg LS, Fudenberg HH et al. Agammaglobulinaemia and coexistent pernicious anaemia. Clin Exp lmmunol 1970; 6: 181-187. 12. Fixa B, Thiele HG, Komarkova 0 et al. Gastric autoantibodies and cell-mediated immunity in pernicious anaemia A comparative study. Scand J Gastroent 1972; 7: 237-240. 13. Gelfand EW, Berkel AI, Godwin HA et al. Pernicious anaemia, hypogammaglobulinaemia, and altered lymphocyte reactivity. Clin Exp Immunol 1972; 11: 187-199. 14. Goldberg LS, Cunningham JE, Terasaki PI. Lymphocytotoxins and pernicious anaemia. Blood 1972; 39: 862-865. 15. Finlayson NDC, Fauconnet MH, and Krohn K. In vitro demonstration of delayed hypersensitivity to gastric antigens in pernicious anemia. Dig Dis 1972; 17: 631-638. 16. Goldstone AH, Calder EA, Barnes EW et al. The effect of gastric antigens on the in vitro migration of leukocytes from patients with atrophic gastritis and pernicious anaemia. Clin Exp Immunol 1973; 14: 501-508. 17. Weisbart RH, Bluestone R, Goldberg LS. Cellular immunity to intrinsic factor in pernicious anemia. J Lab Clin Med 1975; 85: 87-92. 18. James D, Asherson G, Chanalin I et al. Cellmediated immunity to intrinsic factor in autoimmune disorders. Br Med J 1974; 4: 494-496. 19 Bell K, Lee D. Evaluation of a dual radioisotope urinary excretion test in the diagnosis of pernicious anemia. Acta Haemat 1969;42: 183-187. 20. Conley ME, Park CL, Douglas SD. Childhood common variable immunodeficiency with autoimmune disease. J Pediatr 1986; 108: 915-922. 21. Hughes WS, Brooks FP, Conn HO. Serum gastrin levels in primary hypogrammaglobulinemia and pernicious anemia. Ann Intern Med 1972; 77: 746 -750. 22. den Hartog G, van der Meer JWM, Jansen JBMJ et al. Decreased gastrin secretion in patients with late-onset hypogammaglobulinemia. N Engl J Med 1988; 318: 1563-1567.
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Acta Puediatr Jpn
