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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 11 4062-4067
Copyright © 1999 by The Endocrine Society

Original Studies

High Prevalence of Manifestations of Gastric Autoimmunity in Parietal Cell Antibody- Positive Type 1 (Insulin-Dependent) Diabetic Patients1

Christophe E. M. De Block, Ivo H. De Leeuw, Luc F. Van Gaal and the Belgian Diabetes Registry

Department of Endocrinology-Diabetology, University of Antwerp, University Hospital Antwerp (C.E.M.D.B., I.H.D.L., L.F.V.G.), B-2650 Edegem; and the Belgian Diabetes Registry, B-1090 Brussels, Belgium

Address all correspondence and requests for reprints to: Christophe De Block, M.D., Department of Endocrinology-Diabetology, University of Antwerp, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail: christophe.deblock{at}uia.ua.ac.be


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Previous studies have shown a high prevalence of gastric parietal cell antibodies (PCA) in type 1 diabetes, which can be accompanied by (sub)clinical autoimmune gastric disease. This study aimed to determine the grade of associated autoimmunity and to assess the pattern of prevalence of PCA by gender, age, duration of disease, age at onset of diabetes, and human leukocyte antigen (HLA) type in an adult type 1 diabetic population. Furthermore, to examine the clinical significance of being PCA positive, manifestations of gastric autoimmune disease were studied in PCA-positive and PCA-negative patients.

The population studied consisted of 497 type 1 diabetics (men/women, 252/245; mean age, 40.8 ± 12.1 yr; mean duration of disease, 16.4 ± 10.4 yr; mean age at onset, 26.9 ± 13.5 yr; mean hemoglobin A1c, 8.1 ± 1.6%). Associated autoantibodies were present in 39% and PCA were present in 20.9% of the subjects, particularly in older patients. Gender, duration, and age at onset of diabetes did not influence the appearance of PCA. Antithyroid peroxidase antibodies (aTPO) were more frequent in PCA-positive patients than in those without PCA (33.6% vs. 22.4%; P = 0.025), suggesting an association between gastric and thyroid autoimmunity. We could demonstrate an association between PCA and the HLA DR5 haplotype (P = 0.001) as well, but not with HLA DR3 and/or DR4. In the PCA-positive group, iron deficiency anemia was detected in 15.4%, and pernicious anemia was found in 10.5% of subjects. These autoimmune gastric manifestations were significantly more prevalent in PCA-positive diabetics than in PCA-negative subjects, in whom the percentages were 6.9% and 0.5%, respectively (P = 0.01 and P < 0.0001). PCA were prevalent in 84.6% of patients with pernicious anemia. A gastroscopic and anatomopathoplogical examination performed in a subgroup of 30 patients with gastric symptoms revealed atrophic gastritis in 13 of 14 PCA-positive patients and in 9 of 16 PCA-negative subjects (P = 0.04). PCA were present in 59.1% of patients with atrophic gastritis.

In conclusion, a high prevalence of parietal cell antibodies and associated autoimmune gastric disease is present in PCA-positive type 1 diabetics, recommending its screening. Early detection of PCA and iron deficiency anemia, pernicious anemia, and atrophic gastritis and the subsequent care could reduce the morbidity of type 1 diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TYPE 1 (insulin-dependent) diabetes mellitus is the consequence of a selective destruction of insulin-secreting ß-cells of the pancreatic islets of Langerhans. Environmental factors, genetic susceptibility, and, most important, autoimmune factors are involved in the pathogenesis of type 1 diabetes (1, 2, 3, 4). The appearance of insulitis and autoantibodies against the ß-cell document the autoimmune destruction (5, 6, 7, 8, 9, 10). In addition, these patients show an increased prevalence of associated organ-specific autoimmune aggression against other endocrine tissues (thyroid and adrenal glands) as well as against nonendocrine tissues (gastric and enteral mucosa). Indeed, antithyroid peroxidase (aTPO), antigastric parietal cell (PCA), and antiadrenal (AAA) antibodies are 4–5 times more frequent in type 1 diabetics than in a nondiabetic population (11, 12, 13, 14, 15, 16). This chronic autoimmune aggression can lead to organ dysfunction; in the case of gastric autoimmunity to atrophic gastritis (17), pernicious anemia (18, 19), and iron deficiency anemia (20, 21, 22). Early detection of these autoantibodies and organ-specific dysfunction in type 1 diabetic patients is of extreme importance, as they all can severely compromise the prognosis of the diabetic patient.

In this article we report the results of a study on type 1 diabetes and associated gastric autoimmunity and compare them to literature data. This cross-sectional study aimed to determine the grade of autoimmunity and assess the pattern of prevalence of PCA by age, sex, duration, age at onset of diabetes, and human leukocyte antigen (HLA) DR haplotype. Furthermore, manifestations of gastric autoimmunity were studied to assess the clinical significance of being PCA positive.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The population studied consisted of 497 unselected type 1 diabetic adults, regularly attending the out-patient clinic of the Department of Endocrinology-Diabetology of the University Hospital of Antwerp (Antwerp, Belgium). They all fulfilled the criteria for the diagnosis of diabetes established by the expert committee on the diagnosis and classification of diabetes mellitus (1). At the onset of type 1 diabetes all subjects presented with hyperglycemia, ketonuria, and metabolic decompensation. In addition, fasting as well as 2 h postprandial C peptide levels were very low at the moment of this study (mean ± SD, 0.09 ± 0.07 and 0.12 ± 0.10 pmol/mL, respectively; normal, 0.25–1.00 pmol/mL; C-PEPsp-RIA-CT, Biosource Technologies, Inc. Europe S.A., Nivelles, Belgium). No patient in this series had Addison’s disease or hypoparathyroidism, excluding polyglandular autoimmune syndromes 1 and 2 (23). The 497 patients (252 men and 245 women) had a mean age of 40.8 ± 12.1 yr and a mean duration of disease of 16.4 ± 10.4 yr, and diabetes was diagnosed at a mean age of 26.9 ± 13.5 yr. The level of glycemic control, measured by hemoglobin A1c (HbA1c), averaged 8.1 ± 1.6%. None of these parameters statistically differred between men and women (see Table 1Go).


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  		Table 1. Diabetes profile, prevalence of associated organ-specific autoantibodies, and autoimmune gastric manifestations in 497 type 1 diabetic men and women

 
HbA1c levels (glycated hemoglobin) were determined by high performance liquid chromatography (VARIANT Hemoglobin A1c Reorder Pack, catalog no. 270-0003, Bio-Rad Laboratories, Inc., Richmond, CA; normal, 4.8–6%). A mean of 4 annual determinations of HbA1c were used to determine the degree of overall metabolic control.

aTPO were assayed with a specific immunological test (Immutest, Henning, Berlin, Germany). Values greater than 100 U/mL were considered positive. Thyroid function was estimated by TSH (normal, 0.15–5.5 µU/mL) and freeT4 (free tetraiodothyronine; normal, 11–24 pmol/L) levels. To detect PCA, indirect immunofluorescence (fluorescein isothiocyanate staining) was used with rat gastric mucosa as substrate (MeDiCa kit, Medical Diagnostics California, Carlsbad, CA). A titer higher than 1:20 was regarded as positive. Determining PCA by enzyme-linked immunosorbent assay is about 10-fold more sensitive and about equally specific compared to the indirect immunofluorescence method, as demonstrated by Karlsson et al. (24). However, data obtained with both techniques correlate well. In our study, AAA were also determined by indirect immunofluorescence, using kits from the same company (MeDiCa kit). Thus, for practical reasons the more routinely used immunofluorescence technique was performed in this study. AAA were determined by means of indirect immunofluorescence, using unfixed frozen sections of monkey adrenal tissue as substrate, with titers higher than 1:10 being scored as positive (MeDiCa kit, catalog no. 6001-AG). Antiintrinsic factor was assayed with the enzyme-linked immunosorbent assay technique, using purified intrinsic factor from pig gastric mucosa as substrate (Malakit); a titer higher than 1.1 was considered positive. Pernicious anemia was defined as a megaloblastic anemia with positive antiintrinsic factor and/or PCA.

Serologic HLA DR typing was performed in 280 patients using a two-color fluorescence technique as described by Van Rood et al. (25). The most recently published nomenclature of the HLA system was used (26).

Serum iron, total iron binding capacity, and a peripheral hematogram (hemoglobin, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin) were determined by routine laboratory tests to evaluate iron status. Serum gastrin (normal, <110 pg/mL) was measured using a RIA liquid technique. To collect some preliminary data giving an indication of whether atrophic gastritis is present in a high percentage of PCA-positive subjects, a gastroscopic and anatomopathological examination was performed in a subgroup of 30 patients (PCA+ vs PCA-, 14 vs. 16) with gastric symptoms.

The study was approved by the local ethical committee of the University Hospital of Antwerp. Informed consent was obtained from each patient in accordance with the Helsinki Declaration.

All data from this cross-sectional study were analyzed using the statistical package SPSS version 8.0 (SPSS, Inc., Chicago, IL). The unpaired t test was used for comparison of means and the {chi}2 test or Fisher’s exact test was used to test frequency differences. Multiple logistic regression, stepwise forward, was used to assess the strength and independency of associations and to describe an adequate predictive model. Women were scored 0, and men were scored 1. All tests were performed two-sided. P < 0.05 or less was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Among the 497 patients, 193 (79 men and 114 women) or nearly 4 of 10 patients, showed 1 or more autoantibody positivity. aTPO were present in 123 patients (24.7%); significantly more women (31.8%) than men (17.9%) were aTPO positive [P = 0.0005; odds ratio (OR), 2.15; 95% confidence interval, 1.41–3.27]. This female preponderance was not observed in regard to the prevalence of other associated organ-specific autoantibodies. PCA were found in 104 patients (20.9%), and AAA in 2% of the subjects (see Table 1Go). Figure 1Go shows the age and gender distribution of the study population and the respective prevalences of gastric PCA.



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  		Figure 1. Age and gender distribution of 497 type 1 diabetic patients with respective prevalences of gastric PCA.

 
Exactly 20.9% of the 497 patients showed PCA, with an equal gender distribution. PCA-positive patients were significantly older than PCA-negative diabetics (43.7 ± 12.9 vs. 40.0 ± 11.8 yr; P = 0.004). Diabetes was of longer duration in the PCA-positive group than in the group without PCA, although this difference was not statistically significant. The age at onset did not seem to be related to the appearance of PCA. aTPO were more frequent in PCA-positive (33.6%) than in PCA-negative patients (22.4%; P = 0.025; OR, 1.76), suggesting an association between gastric and thyroid autoimmunity (see Table 2Go).


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  		Table 2. Profile of PCA-positive compared to PCA-negative type 1 diabetic patients

 
The mean level of circulating iron did not differ between patients with or without PCA, mainly because iron-deficient patients were and are receiving supplementation. However, mean levels of gastrin remained significantly higher in patients with PCA than in those without PCA (P < 0.0001), and significantly more PCA-positive (26.9%) than PCA-negative diabetics (7.1%) had hypergastrinemia (gastrin, >110 pg/mL; see Table 2Go). Neither age nor gender were associated with serum gastrin levels. On the other hand, women had significantly lower values of serum iron than men. A hypochromic microcytic anemia was observed and treated in 15.4% of the PCA-positive group compared to 6.9% of the PCA-negative adults (P = 0.01; OR, 2.47).

Four PCA-positive diabetics had an overt pernicious anemia, and seven PCA-positive and two PCA-negative patients showed a latent pernicious anemia. In 84.6% of patients, characterized by this megaloblastic anemia, PCA were present. The prevalence of this form of anemia was significantly higher in PCA-positive (10.5%) than in PCA-negative diabetics (0.5%; see Table 2Go). No differences in gender distribution were found.

Most patients showed the HLA DR3 and/or DR4 haplotype, as expected. No difference in HLA DR type between men and women was detected. We did observe that significantly more PCA-positive diabetics (17%) showed the HLA DR5 haplotype compared to the PCA-negative group (3.5%; P = 0.001). We could not find an association with HLA DR3 and/or DR4 (see Table 2Go).

Independent risk factors for having PCA were studied with stepwise forward logistic regression analysis. When the model tested age, gender, duration of disease, age at onset, HbA1c, insulin dose, aTPO, AAA, HLA DR1–7, gastrin, iron deficiency anemia, and pernicious anemia as covariates, only gastrin levels (ß = 1.74; P = 0.017) and the HLA DR5 haplotype (ß = 0.003; P = 0.049) were independently associated with PCA positivity. However, this model only included 158 patients. To detect possible associations among data from all 497 patients, insulin dose, AAA, gastrin, and HLA DR1–7 were removed from the previous model. Anti-TPO-positivity (ß = 0.86; P = 0.008), ferriprive anemia (ß = 0.92; P = 0.015), and pernicious anemia (ß = 1.61; P = 0.003) turned out to be associated with PCA positivity. Logistic regression analysis, stepwise forward, was also performed to study risk factors for microcytic hypochromic anemia. PCA (ß = 0.81; P = 0.034), gender (ß = -0.99; P = 0.007), and duration of diabetes (ß = 0.06; P = 0.0005) were associated with microcytic hypochromic anemia when the model tested age, gender, duration, age at onset, HbA1c, PCA, pernicious anemia, and HLA DR1–7 as independent risk factors.

A subgroup of 30 patients (PCA+ vs. PCA-, 14 vs. 16) demonstrating gastric symptoms underwent gastroscopy. Atrophic gastritis was documented by gastroscopic and anatomopathological examination in 73.3% of this subgroup with gastric symptoms. In the PCA-positive group, 13 of 14 patients (92.8%) were detected with atrophic gastritis compared to a significantly lesser number of 9 of 16 diabetics in the PCA-negative group (56.3%; P = 0.0395; OR, 10.11). PCA were prevalent in 59.1% of patients with atrophic gastritis. Gender did not influence the prevalence of atrophic gastritis. In diabetics with atrophic gastritis more patients with iron deficiency anemia were found (36.4%) compared to those without atrophic gastritis (12.5%), although this difference was not statistically significant. Hypergastrinemia was significantly more prevalent in patients with atrophic gastritis (72.7%) than in those who did not have atrophic gastritis (25%; P = 0.034; OR, 8.00).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Type 1 diabetes mellitus is generally accepted as an autoimmune disease, but whether this autoimmune dysfunction is the exclusive cause, a contributing factor, or only a marker of pancreatic ß-cell destruction is still not clear (4). Moreover, triggering factors of this autoimmune response to the ß-cell and to other endocrine and gastrointestinal tissues remain to be clarified (12, 27).

Type 1 diabetic adults have a high grade of associated autoimmunity. In the present study 39% of the patients showed one or more autoantibodies. The prevalence of PCA is high in our study, namely 20.9%, compared to previously reported prevalences ranging between 5–28% in type 1 diabetics and 1.4–12% in nondiabetic controls (11, 14, 17, 19, 28).

PCA positivity was found significantly more at an older age, although multiple logistic regression did not withhold age as an independent risk factor. Neither duration of disease, age at onset of diabetes, nor gender triggered the appearance of these autoantibodies. The association we found between gastric and thyroid autoimmunity has been described previously (16). Regarding the HLA system, Gorsuch et al. reported that thyrogastric autoimmunity did not segregate with the HLA-bound high risk haplotypes of type 1 diabetes mellitus (29). In the present study a positive association was detected between PCA positivity and the HLA DR5, but not DR3 and/or DR4 haplotype. To our knowledge this has not been previously described. We must indicate however that although this is a statistically significant association, the attributable fraction for the allele is low.

The clinical importance of gastric parietal cell autoantibodies is demonstrated by the association with manifestations of autoimmune gastropathy (see Fig. 2Go). PCA are targeted against the gastric proton pump, the H+/K+-adenosine triphosphatase (30, 31, 32), resulting in decreased gastric acid secretion and decreased iron absorption. This can lead to iron deficiency anemia, which is a common and first, although frequently overlooked, manifestation of autoimmune atrophic gastritis (20, 21, 22). Patients with iron deficiency, mainly PCA-positive subjects detected during an initial screening study (22), were supplemented with iron, resulting in normalization of the serum iron levels, as shown in Table 2Go. Elevated levels of gastrin are also associated with autoimmune gastropathy. However, besides arising from the hypo- or achlorhydric situation in the case of atrophic gastritis, elevated gastrin levels in type 1 diabetics can be caused by hypo- or hyperglycemia, both of which can lead to reduced gastric acid secretion (33, 34). In the present study no correlation was found between levels of gastrin and HbA1c. However, hypergastrinemia was significantly associated with being PCA positive. On the other hand, many type 1 diabetic patients, and not only those with gastroparesis, show a triple increase in fasting and postprandial gastrinemia. Helicobacter pylori infection is another possible reason for hypergastrinemia (35). Although there are indications that H. pylori can trigger autoimmune inflammation, its role in autoimmune gastritis is unknown (36, 37, 38).



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  		Figure 2. Hypothetical diagram of the development of autoimmune atrophic gastritis, iron deficiency anemia, and pernicious anemia.

 
In addition, PCA can inhibit the secretion of intrinsic factor, necessary for the absorption of vitamin B12, leading to latent and finally overt pernicious anemia. Latent pernicious anemia is found in 4% of type 1 diabetics (19). In our study, this was present in 2.6% of the subjects; more in PCA-positive patients than in PCA-negative diabetics. Parietal cell antibodies were prevalent in 84.6% of those with a pernicious anemia, confirming published data, where PCA were prevalent in 75–90% of patients with pernicious anemia (39). It is tempting to speculate that using a more sensitive ELISA technique for assaying PCA would give slightly more positive results in patients with pernicious anemia. As Karlsson et al. reported, the major parietal cell antigen in pernicious anemia is the H+/K+-ATPase acid pump of the stomach (40). However, for practical reasons we used indirect immuno- fluorescense (see Subjects and Methods), and therefore we cannot confirm this assumption. On the other hand, PCA might be so cytotoxic to the gastric mucosa that the result is complete atrophy and progressive destruction of parietal cells, with PCA titers decreasing in final stages of pernicious anemia-associated gastropathy (41). However, this is not well documented. It would be interesting to perform longitudinal studies. It was observed that 3% of older patients with autoimmune atrophic gastritis progress to latent pernicious anemia per yr (39). The respective prevalences of atrophic gastritis and pernicious anemia in the general nondiabetic population are 0.1% and 1%.

Parietal cell antibodies are recognized as a marker of an autoimmune type A gastritis, because they are cytotoxic against the gastric mucosa (17). The autoimmune process results in mucosal atrophy and decreased gastric acid and intrinsic factor secretion, subsequently causing hypergastrinemia and vitamin B12 deficiency (42, 43), as discussed above. In this study the presence of atrophic gastritis was investigated in a subgroup of 30 patients. For ethical reasons, at this point only those patients demonstrating gastric symptoms were studied. Atrophic gastritis was present in a very high percentage (73.3%) of this subgroup, although this may be overestimated because only those with gastric symptoms were studied. Supposing patients without symptoms would have much less incidence of atrophic gastritis, the prevalence of this type of gastritis in the whole type 1 diabetic population would be about 4.5–8%. In the PCA-positive group significantly more were detected with atrophic gastritis than in the group without PCA. The prevalence of PCA in patients with atrophic gastritis was 59.1%. This is in line with data from the literature, where PCA could be found in 60% of patients with atrophic gastritis. The observed associations between PCA and hypergastrinemia, on the one hand, and atrophic gastritis, on the other hand, could be confirmed by our study results. The fact that iron deficiency anemia was not associated with atrophic gastritis is because of the small number of patients in this substudy.

Data from this study and the literature indicate that PCA are good markers of autoimmune gastric manifestations, such as iron deficiency anemia, pernicious anemia, and atrophic gastritis. The well known complications of these three disorders can influence the prognosis of the diabetic patient. Iron deficiency anemia can severely influence cellular immunity, intestinal function, growth, work capacity, cardiopulmonary status, and intellectual performance (44, 45). Pernicious anemia can cause neurologic complications, such as paraesthesia, loss of perception of vibration, and proprioception, which are amenable to vitamin B12 therapy, and is recognized as an early stage of gastric adenocarcinoma (46, 47). Atrophic gastritis itself is also regarded as a possible precursor of gastric adenocarcinoma, which manifests itself only very late in the disease process. Therefore, particularly in anemic patients, screening for PCA and, in case of positivity, additional evaluation, including gastroscopy with biopsy, are needed to take necessary precautions to protect against a bad outcome of these disease processes.

Conclusions

We can conclude that type 1 diabetic patients, particularly at an older age, have a high prevalence of PCA. These PCA can be used as a marker for iron deficiency anemia and hypergastrinemia associated with autoimmune atrophic gastritis and for pernicious anemia. We strongly suggest that physicians faced with a diabetic patient who has anemia and/or gastrointestinal symptoms should measure PCA to help define the pathogenesis of the problem. Based on the high grade of PCA positivity and looking at the adverse impact of these diseases on the health of the diabetic patient in general, screening for PCA and, in case of positivity, an adequate work-up are warranted.


   Acknowledgments
 
We are grateful to the people from different laboratories, particularly Dr. C. Van Campenhout and K. Van Cotthem from the Laboratory of Immunology, Dr. M. Martin from the Laboratory of Nuclear Medicine, and Dr. L. Muylle from the Antwerp blood Transfusion Center. We thankfully acknowledge Prof. Dr. P. Pelckmans and Dr. I. Duysburgh from the Department of Gastroenterology and Hepatology, and Prof. Dr. E. Van Marck and Dr. J.-P. Bogers from the Department of Pathologic Anatomy. We also thank in specific Mr. A. De Block for making and completing the major part of our database. We are indebted to Prof. Dr. F. Gorus of the Vrije Universiteit Brussel, who has contributed to the recruitment of patients.

We thank the members of the Belgian Diabetes Registry: E. Balasse (Brussels), H. Becq (Wilrijk), A. Bodson (Jumet), L. Claeys (Zoersel), M. Coeckelberghs (Antwerp), J.-L. Coolens (Hasselt), W Coucke (Roeselare), E. Couturier (Brussels), R. Craen (Ghent), J.-C. Daubresse (Charleroi), P. Decraene (Bonheiden), I. De Leeuw (Antwerp), C. Delvigne (Antwerp), J. De Schepper (Brussels), M. Du Caju (Antwerp), F. Féry (Brussels), N. Gaham (Braine-l’Alleud), J. Gérard (Liege), C. Gillet (Brussels), J. Guillot (Seraing), C. Herbaut (Mons), B. Keymeulen (Brussels), G. Krzentowski (Jumet), G. Lamberigts (Brugge), M. Letiexhe (Liege), K. Logghe (Roeselare), J. Monballyu (Ekeren), D. Nicolaij (Kortrijk), F. Nobels (Aalst), M.-C. Pelckmans (Lier), A. Purnode (Brussels), M.-P. Roggemans (Brussels), R. Rooman (Antwerp), R. Rottiers (Ghent), A. Scheen (Liege), J. Schutyser (Kortrijk), L. Terriere (Hoboken), J. Teuwen (Kapellen), G. Thenaers (Hasselt), K. Van Acker (Antwerp), P. Van Crombrugge (Aalst), E. Vandenbussche (Herentals), L. Van Gaal (Antwerp), S. Van Imschoot (Brugge), S. Vanneste (Zoersel), P. Van Rooy (Antwerp), and J. Vertommen (Antwerp).


   Footnotes
 
1 This work was supported by a grant from the Belgian Nationaal Fonds voor Wetenschappelijk onderzoek. Back

Received September 23, 1998.

Revised January 28, 1999.

Revised April 28, 1999.

Accepted July 13, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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