Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
+
+
H K -ATPase Antibodies in Autoimmune Gastritis: Observations on the Development of Pernicious Anemia P. Burman, F. A. Karlsson, L. Lööf, P. B. Szesci & K. Borch +
+
To cite this article: P. Burman, F. A. Karlsson, L. Lööf, P. B. Szesci & K. Borch (1991) H K -ATPase Antibodies in Autoimmune Gastritis: Observations on the Development of Pernicious Anemia, Scandinavian Journal of Gastroenterology, 26:2, 207-214, DOI: 10.3109/00365529109025032 To link to this article: http://dx.doi.org/10.3109/00365529109025032
Published online: 08 Jul 2009.
Submit your article to this journal
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Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [137.189.171.235]
Date: 16 March 2016, At: 19:01
H+,K+-ATPase Antibodies in Autoimmune Gastritis: Observations on the Development of Pernicious Anemia P. BURMAN, F. A. KARLSSON, L. LOOF, P. B. SZESCI & K. BORCH Depts. of Internal Medicine, University Hospital, Uppsala, and Dept. of Surgery, University Hospital, Linkoping, Sweden, and Dept. of Clinical Chemistry, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
Downloaded by [] at 19:01 16 March 2016
Burman P, Karlsson FA, Loof L, Szesci PB, Borch K. H+,K'-ATPase antibodies in autoimmune gastritis: observations on the development of pernicious anemia. Scand J Gastroenterol 1991, 26, 207-214 The prevalence and development of antibodies to H+,K+-ATPasewere investigated with a sensitive enzyme-linked immunosorbent assay in 86 patients with autoimmune atrophic gastritis (type A). Sixty-nine of the patients had pernicious anemia, and 17 had simple atrophic gastritis. Elevated titers were found in 937r of pernicious anemia probands. Women had higher levels than men: 3.24 versus 1.58 U/l ( p = 0.002) (upper reference limit, 0.55 U/l). The antibody levels did not change over 1-4 years, but a gradual decrease in titers over decades was observed. All patients with pernicious anemia had low levels of pepsinogen A , a product of the gastric chief and mucous neck cells (median, 8.5 pg/I; reference range, 10-90 percentile, 64.4195.5 pg/l), and elevated serum gastrin values (>55 pmol/l) were found in 87%. Serum pepsinogen A, but not serum gastrin, correlated with H+,K'-ATPase antibody titers ( r = 0.35, p = 0.01). In the 17 cases with simple atrophic gastritis, H+,K+ATPase antibodies correlated inversely with fundic mucosal gland destruction. The data indicate that H +,K+-ATPaseantibody titers reflect the immune responsiveness of a given patient as well as the antigenic amount, dependent on the degree of mucosal destruction and the duration of the disease. Key words: H+,K+-ATPase antibodies; atrophic gastritis; autoimmunity; parietal cell antibodies; pepsinogen; pernicious anemia; stomach Pia Burman, M . D.,Depl. of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden
Pernicious anemia is the result of an autoimmune destruction of the gastric body mucosa, in which the antrum is usually spared. Circulating parietal cell antibodies are found in 70-90% of affected individuals when assayed by an indirect immunofluorescence technique (1,2). Antibodies to intrinsic factor are found in 40-70% (1,2). LOW levels of serum pepsinogen A and high levels of serum gastrin ( 3 ) reflect tissue damage with a loss of both chief and oxyntic cells and a lack of acid. The histopathologic lesion in the gastric mucosa is similar to that found in severe type-A atrophic gastritis without vitamin B 1 2malabsorption. The
two conditions seem to differ mainly in the capacity to secrete adequate amounts of intrinsic factor. However, in chronic atrophic gastritis without pernicious anemia, circulating antibodies to parietal cells are reported to a lesser extent (30-60%) (2,4), and antibodies to intrinsic factor are found only rarely. We have previously reported that the major parietal cell antigen in pernicious anemia is H+,K+-ATPase, the proton pump of the stomach (5) and found that patient immunoglobulins inhibit this enzyme in vitro (6). A sensitive assay (enzyme-linked immunosorbent assay (ELISA))
P. Burman et al.
208
for the detection of H+,K+-ATPase antibodies has been established (7). The assay is based o n a membrane preparation, rich in H+,K+-ATPase, obtained from porcine gastric mucosa. In this study we determined the prevalence of H+,K+ATPase antibodies in 86 patients with type-A gastritis, of whom 69 had pernicious anemia, and 17 had various degrees of simple atrophy of the body mucosa. Furthermore, we examined the antibody titers with regard to the extent of gastric mucosal involvement, as reflected in the histopathology, gastric gland density, serum gastrin, and pepsinogen A and C levels.
PATIENTS A N D METHODS
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Pa tien ts Sixty-nine patients with pernicious anemia (39 women and 30 men) with a mean age of 56 years (range, 22-78 years) and 17 patients (11 women
and 6 men) with a mean age of 65 years (range, 48-74 years) and with various degrees of atrophic gastritis of the body mucosa were included. The latter patients were detected in routine clinical examinations, and the diagnosis was verified with multiple fundic and antral mucosal biopsies and pentagastrin and Schilling tests. All had hypochylia and normal results in the Schilling test. O n e of these patients also had insulindependent diabetes mellitus. One patient had a father with pernicious anemia and another had a father with gastric cancer. The patients with a diagnosis of pernicious anemia all had a Schilling test result consistent with a lack of intrinsic factor secretion in combination with at least two of the following criteria: subnormal vitamin B levels, macrocytic anemia, megaloblastic bone marrow. histologically verified atrophic fundic gastritis, andachlorhydriaonstimulation with pentagastrin/ histamine. Of the patients with pernicious anemia
Table I. Laboratory findings in patients with simple atrophic gastritis. Individual data and geometric means from 17 patients divided into 3 groups with various scverities of the disease Fundic rnucosal atrophy, grade 1
Patient's sex
F F
Mean 2
F F
F M F M
F F M F M Mean
H',K+-ATPase antibodies (U/U 0.30 0.50
185 115
0.38 2.0 0.75 0.3 0.3 4.1 0.47 8.0 0.3 0.36 2.2 0.55
146 62.5 112 235 354 678 154 49 1 731 63.5 499 113
0.89p
3
= 0.047
Pepsinogen A ( W/I)
1-62
Pepsinogen C (vg/l)
20.5 73
12.5 13.7
38.7
13.1 14.7 11.7 9.4 6.5 15.9 7.7 18.1 9.1 12.9 20.9
-
19.2 22.1 15.6 24.4 36.9 12.4 32 16.1 49.5 31.3
23'8-~
p = 0.049
1i'
F M M
F Mean
Gastrin (p m 4 )
3.2 1.1 10 3.73
10.4 285
14.6 18.2 13.8
9.14
Autoimmune Gastritis
Downloaded by [] at 19:01 16 March 2016
17 had a positive family history for this disease, 9 of the 69 had received treatment because of thyroid disease, and a further 6 also had diabetes mellitus. Endoscopic examination was carried out in all patients by the same examinator (K. Borch), and multiple biopsy specimens were collected from the body and antral mucosa within M 7 years (median, 9.0 years) from the diagnosis of pernicious anemia. Nine of the patients, all women, had small fundic carcinoid tumors, and in another two women early gastric cancer was discovered. Serum samples for the investigation of gastric antibodies, gastrin, and pepsinogen A and C were drawn after an overnight fast. Serial serum samples at intervals of up to 4 years were obtained in 38 patients with pernicious anemia and in 11 patients with simple atrophic gastritis.
209
preparation used consisted of porcine tubulovesicular membranes, prepared by the homogenization of gastric mucosa and followed by sucrose-Ficoll gradient centrifugation, as described by Ljungstrom et al. (8). Flat-bottomed microtiter plates (Nunc, Denmark) were coated with 1 pg membrane protein per well. Sera were diluted 1 : 200 with phosphate-buffered saline with 0.5% Tween 20, and antibody binding was detected with a beta-galactosidase-conjugated rabbit anti-human IgG (Pharmacia, Sweden) as described (7). A patient serum with a high titer of H+,K+-ATPase antibodies was used for constructing standard curves. The absorbance value of a 1 : 1000 dilution was defined as 100 U/ I. The upper normal reference range (mean + 2 SD) in this study, calculated from determinations of the sera of five healthy individuals in each run, was 0.55 U/l. T h e interassay coefficient of Methods H+,K+-ATPase antibodies were determined variation, determined by analysis of a positive by an ELISA. The antigenic H+,K+-ATPase serum. was 22%
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30-45
46-55
56-65
66-70
71-75
76-80
>80
Age of patients (years) Fig. 1 . Titer of H+,K'-ATPase antibodies in sera of 69 patients of various ages with pernicious anemia. The antibodies were quantified with an enzyme-linked immunosorbent assay as described in Methods. The median duration of disease at the time of serum sampling was similar among the various groups of patients.
Downloaded by [] at 19:01 16 March 2016
210
P. Burman et al.
Parietal cell antibodies were also assessed by an indirect immunofluorescence technique, using cryostat sections of rat gastric mucosa as antigen (National Bacteriological Laboratory, Stockholm). Intrinsic factor antibodies were quantified by the charcoal adsorption test (9). Serum gastrin was analyzed by a radioimmunoassay in routine use at the Dept. of Clinical Chemistry, University Hospital, Uppsala, Sweden (reference range, 6 . 5 pmol/l). Pepsinogens A and C were determined by a doubleantibody solid-phase radioimmunoassay (10, 11). Reference ranges in individuals with endoscopically and histologically normal gastroduodenal mucosa were 64.4-195.5 yg/l and 6.9-23.6 pg/I, respectively. Multiple biopsy specimens from fundic and antral gastric mucosa were routinely stained with hematoxylin-eosin and Alcian blue at pH 2.5 for goblet cells containing acid mucopolysaccharides (intestinal metaplasia) and investigated in light microscopy. The degree of atrophic gastritis was classified in accordance with Whitehead et al. (12) from grade 1 to 3. The relative density of gastric glands in specimens from the fundic mucosa was determined in 38 cases by one examiner (K. Borch), using planimetry (point counting) as previously described (13). Analysis of statistical significance between groups was evaluated with Student's t test after logarithmic transformation of antibody titers and gastrin and pepsinogen levels. Correlations were determined by linear regression analysis.
RESULTS Antibodies to H+,K+-ATPase exceeding the upper reference limit were found in the sera of 93% of the pernicious anemia probands. The group of female patients had higher titers than the male group (median, 3.24; range, 0.7-19 U/ I, versus 1.58; range, 0.3-12 U/l) ( p = 0.002). All sera with normal values were drawn from men. The titers of H+,K+-ATPase antibodies among female and male patients with simple atrophic gastritis were 1.53 (median; range, 0.111) and 0.68 (median; range, 0.3-3.2) U/l, respectively. In 9 of the 17 cases the titers were
above normal (Table I). Intrinsic factor antibodies were present in 20 of 52 sera of pernicious anemia probands but in none of 10 investigated sera of the patients with simple atrophic gastritis. Parietal cell antibodies were found in 74% of the pernicious anemia patients and in 41% of the individuals with simple atrophic gastritis when tested with the immunofluorescence method (not shown). In the pernicious anemia group no relationship was found between the H+,KfATPase antibody titer and the age of the patients (Fig. 1). No consistent titer changes were observed by analysis of serial serum samples drawn over 1 to 4 years (Fig. 2). However, when the material was subdivided according to the duration of the disease, a gradual decline in H+,K+-ATPase antibody titers over decades was observed (Fig. 3)
20.0
10.0
5.0
2.0
1.o
0.5
0.3 1
2
3
4
Time between samples (years) Fig. 2. Titer of H+,K+-ATPaseantibodies in 38 patients with pernicious anemia determined in sera drawn on separate occasions over a 1- to 4-year period.
Autoimmune Gastritis
*
* I
I
20.0
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A
0
10.0
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2
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.-a
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5.0
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(0 (u
u)
Q
2.0
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n
2
cY
1.0
+z
0.5 0
0.3
0
I 0
I
I
0-5
6-10
I
I
11-20
>20
Duration of pernicious anemia (years) Fig. 3 . Titer of H+,K+-ATPaseantibodies in sera drawn from 69 patients at various times after the diagnosis of pernicious anemia. * = p < 0.05.
Y
+r
In our material 87% of the pernicious anemia probands and 15 of the 17 patients (88%) with simple atrophic gastritis had a basal serum gastrin level above the normal reference range (
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
+
+
H K -ATPase Antibodies in Autoimmune Gastritis: Observations on the Development of Pernicious Anemia P. Burman, F. A. Karlsson, L. Lööf, P. B. Szesci & K. Borch +
+
To cite this article: P. Burman, F. A. Karlsson, L. Lööf, P. B. Szesci & K. Borch (1991) H K -ATPase Antibodies in Autoimmune Gastritis: Observations on the Development of Pernicious Anemia, Scandinavian Journal of Gastroenterology, 26:2, 207-214, DOI: 10.3109/00365529109025032 To link to this article: http://dx.doi.org/10.3109/00365529109025032
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 6
View related articles
Citing articles: 4 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [137.189.171.235]
Date: 16 March 2016, At: 19:01
H+,K+-ATPase Antibodies in Autoimmune Gastritis: Observations on the Development of Pernicious Anemia P. BURMAN, F. A. KARLSSON, L. LOOF, P. B. SZESCI & K. BORCH Depts. of Internal Medicine, University Hospital, Uppsala, and Dept. of Surgery, University Hospital, Linkoping, Sweden, and Dept. of Clinical Chemistry, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
Downloaded by [] at 19:01 16 March 2016
Burman P, Karlsson FA, Loof L, Szesci PB, Borch K. H+,K'-ATPase antibodies in autoimmune gastritis: observations on the development of pernicious anemia. Scand J Gastroenterol 1991, 26, 207-214 The prevalence and development of antibodies to H+,K+-ATPasewere investigated with a sensitive enzyme-linked immunosorbent assay in 86 patients with autoimmune atrophic gastritis (type A). Sixty-nine of the patients had pernicious anemia, and 17 had simple atrophic gastritis. Elevated titers were found in 937r of pernicious anemia probands. Women had higher levels than men: 3.24 versus 1.58 U/l ( p = 0.002) (upper reference limit, 0.55 U/l). The antibody levels did not change over 1-4 years, but a gradual decrease in titers over decades was observed. All patients with pernicious anemia had low levels of pepsinogen A , a product of the gastric chief and mucous neck cells (median, 8.5 pg/I; reference range, 10-90 percentile, 64.4195.5 pg/l), and elevated serum gastrin values (>55 pmol/l) were found in 87%. Serum pepsinogen A, but not serum gastrin, correlated with H+,K'-ATPase antibody titers ( r = 0.35, p = 0.01). In the 17 cases with simple atrophic gastritis, H+,K+ATPase antibodies correlated inversely with fundic mucosal gland destruction. The data indicate that H +,K+-ATPaseantibody titers reflect the immune responsiveness of a given patient as well as the antigenic amount, dependent on the degree of mucosal destruction and the duration of the disease. Key words: H+,K+-ATPase antibodies; atrophic gastritis; autoimmunity; parietal cell antibodies; pepsinogen; pernicious anemia; stomach Pia Burman, M . D.,Depl. of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden
Pernicious anemia is the result of an autoimmune destruction of the gastric body mucosa, in which the antrum is usually spared. Circulating parietal cell antibodies are found in 70-90% of affected individuals when assayed by an indirect immunofluorescence technique (1,2). Antibodies to intrinsic factor are found in 40-70% (1,2). LOW levels of serum pepsinogen A and high levels of serum gastrin ( 3 ) reflect tissue damage with a loss of both chief and oxyntic cells and a lack of acid. The histopathologic lesion in the gastric mucosa is similar to that found in severe type-A atrophic gastritis without vitamin B 1 2malabsorption. The
two conditions seem to differ mainly in the capacity to secrete adequate amounts of intrinsic factor. However, in chronic atrophic gastritis without pernicious anemia, circulating antibodies to parietal cells are reported to a lesser extent (30-60%) (2,4), and antibodies to intrinsic factor are found only rarely. We have previously reported that the major parietal cell antigen in pernicious anemia is H+,K+-ATPase, the proton pump of the stomach (5) and found that patient immunoglobulins inhibit this enzyme in vitro (6). A sensitive assay (enzyme-linked immunosorbent assay (ELISA))
P. Burman et al.
208
for the detection of H+,K+-ATPase antibodies has been established (7). The assay is based o n a membrane preparation, rich in H+,K+-ATPase, obtained from porcine gastric mucosa. In this study we determined the prevalence of H+,K+ATPase antibodies in 86 patients with type-A gastritis, of whom 69 had pernicious anemia, and 17 had various degrees of simple atrophy of the body mucosa. Furthermore, we examined the antibody titers with regard to the extent of gastric mucosal involvement, as reflected in the histopathology, gastric gland density, serum gastrin, and pepsinogen A and C levels.
PATIENTS A N D METHODS
Downloaded by [] at 19:01 16 March 2016
Pa tien ts Sixty-nine patients with pernicious anemia (39 women and 30 men) with a mean age of 56 years (range, 22-78 years) and 17 patients (11 women
and 6 men) with a mean age of 65 years (range, 48-74 years) and with various degrees of atrophic gastritis of the body mucosa were included. The latter patients were detected in routine clinical examinations, and the diagnosis was verified with multiple fundic and antral mucosal biopsies and pentagastrin and Schilling tests. All had hypochylia and normal results in the Schilling test. O n e of these patients also had insulindependent diabetes mellitus. One patient had a father with pernicious anemia and another had a father with gastric cancer. The patients with a diagnosis of pernicious anemia all had a Schilling test result consistent with a lack of intrinsic factor secretion in combination with at least two of the following criteria: subnormal vitamin B levels, macrocytic anemia, megaloblastic bone marrow. histologically verified atrophic fundic gastritis, andachlorhydriaonstimulation with pentagastrin/ histamine. Of the patients with pernicious anemia
Table I. Laboratory findings in patients with simple atrophic gastritis. Individual data and geometric means from 17 patients divided into 3 groups with various scverities of the disease Fundic rnucosal atrophy, grade 1
Patient's sex
F F
Mean 2
F F
F M F M
F F M F M Mean
H',K+-ATPase antibodies (U/U 0.30 0.50
185 115
0.38 2.0 0.75 0.3 0.3 4.1 0.47 8.0 0.3 0.36 2.2 0.55
146 62.5 112 235 354 678 154 49 1 731 63.5 499 113
0.89p
3
= 0.047
Pepsinogen A ( W/I)
1-62
Pepsinogen C (vg/l)
20.5 73
12.5 13.7
38.7
13.1 14.7 11.7 9.4 6.5 15.9 7.7 18.1 9.1 12.9 20.9
-
19.2 22.1 15.6 24.4 36.9 12.4 32 16.1 49.5 31.3
23'8-~
p = 0.049
1i'
F M M
F Mean
Gastrin (p m 4 )
3.2 1.1 10 3.73
10.4 285
14.6 18.2 13.8
9.14
Autoimmune Gastritis
Downloaded by [] at 19:01 16 March 2016
17 had a positive family history for this disease, 9 of the 69 had received treatment because of thyroid disease, and a further 6 also had diabetes mellitus. Endoscopic examination was carried out in all patients by the same examinator (K. Borch), and multiple biopsy specimens were collected from the body and antral mucosa within M 7 years (median, 9.0 years) from the diagnosis of pernicious anemia. Nine of the patients, all women, had small fundic carcinoid tumors, and in another two women early gastric cancer was discovered. Serum samples for the investigation of gastric antibodies, gastrin, and pepsinogen A and C were drawn after an overnight fast. Serial serum samples at intervals of up to 4 years were obtained in 38 patients with pernicious anemia and in 11 patients with simple atrophic gastritis.
209
preparation used consisted of porcine tubulovesicular membranes, prepared by the homogenization of gastric mucosa and followed by sucrose-Ficoll gradient centrifugation, as described by Ljungstrom et al. (8). Flat-bottomed microtiter plates (Nunc, Denmark) were coated with 1 pg membrane protein per well. Sera were diluted 1 : 200 with phosphate-buffered saline with 0.5% Tween 20, and antibody binding was detected with a beta-galactosidase-conjugated rabbit anti-human IgG (Pharmacia, Sweden) as described (7). A patient serum with a high titer of H+,K+-ATPase antibodies was used for constructing standard curves. The absorbance value of a 1 : 1000 dilution was defined as 100 U/ I. The upper normal reference range (mean + 2 SD) in this study, calculated from determinations of the sera of five healthy individuals in each run, was 0.55 U/l. T h e interassay coefficient of Methods H+,K+-ATPase antibodies were determined variation, determined by analysis of a positive by an ELISA. The antigenic H+,K+-ATPase serum. was 22%
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56-65
66-70
71-75
76-80
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Age of patients (years) Fig. 1 . Titer of H+,K'-ATPase antibodies in sera of 69 patients of various ages with pernicious anemia. The antibodies were quantified with an enzyme-linked immunosorbent assay as described in Methods. The median duration of disease at the time of serum sampling was similar among the various groups of patients.
Downloaded by [] at 19:01 16 March 2016
210
P. Burman et al.
Parietal cell antibodies were also assessed by an indirect immunofluorescence technique, using cryostat sections of rat gastric mucosa as antigen (National Bacteriological Laboratory, Stockholm). Intrinsic factor antibodies were quantified by the charcoal adsorption test (9). Serum gastrin was analyzed by a radioimmunoassay in routine use at the Dept. of Clinical Chemistry, University Hospital, Uppsala, Sweden (reference range, 6 . 5 pmol/l). Pepsinogens A and C were determined by a doubleantibody solid-phase radioimmunoassay (10, 11). Reference ranges in individuals with endoscopically and histologically normal gastroduodenal mucosa were 64.4-195.5 yg/l and 6.9-23.6 pg/I, respectively. Multiple biopsy specimens from fundic and antral gastric mucosa were routinely stained with hematoxylin-eosin and Alcian blue at pH 2.5 for goblet cells containing acid mucopolysaccharides (intestinal metaplasia) and investigated in light microscopy. The degree of atrophic gastritis was classified in accordance with Whitehead et al. (12) from grade 1 to 3. The relative density of gastric glands in specimens from the fundic mucosa was determined in 38 cases by one examiner (K. Borch), using planimetry (point counting) as previously described (13). Analysis of statistical significance between groups was evaluated with Student's t test after logarithmic transformation of antibody titers and gastrin and pepsinogen levels. Correlations were determined by linear regression analysis.
RESULTS Antibodies to H+,K+-ATPase exceeding the upper reference limit were found in the sera of 93% of the pernicious anemia probands. The group of female patients had higher titers than the male group (median, 3.24; range, 0.7-19 U/ I, versus 1.58; range, 0.3-12 U/l) ( p = 0.002). All sera with normal values were drawn from men. The titers of H+,K+-ATPase antibodies among female and male patients with simple atrophic gastritis were 1.53 (median; range, 0.111) and 0.68 (median; range, 0.3-3.2) U/l, respectively. In 9 of the 17 cases the titers were
above normal (Table I). Intrinsic factor antibodies were present in 20 of 52 sera of pernicious anemia probands but in none of 10 investigated sera of the patients with simple atrophic gastritis. Parietal cell antibodies were found in 74% of the pernicious anemia patients and in 41% of the individuals with simple atrophic gastritis when tested with the immunofluorescence method (not shown). In the pernicious anemia group no relationship was found between the H+,KfATPase antibody titer and the age of the patients (Fig. 1). No consistent titer changes were observed by analysis of serial serum samples drawn over 1 to 4 years (Fig. 2). However, when the material was subdivided according to the duration of the disease, a gradual decline in H+,K+-ATPase antibody titers over decades was observed (Fig. 3)
20.0
10.0
5.0
2.0
1.o
0.5
0.3 1
2
3
4
Time between samples (years) Fig. 2. Titer of H+,K+-ATPaseantibodies in 38 patients with pernicious anemia determined in sera drawn on separate occasions over a 1- to 4-year period.
Autoimmune Gastritis
*
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0.5 0
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6-10
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Duration of pernicious anemia (years) Fig. 3 . Titer of H+,K+-ATPaseantibodies in sera drawn from 69 patients at various times after the diagnosis of pernicious anemia. * = p < 0.05.
Y
+r
In our material 87% of the pernicious anemia probands and 15 of the 17 patients (88%) with simple atrophic gastritis had a basal serum gastrin level above the normal reference range (
