Carcinoid tumor development in autoimmune gastritis: impact of APCA and autoimmune comorbidities

Authors

Abstract

Aim Autoimmune gastritis (AIG) is associated with the immune-mediated destruction of gastric parietal cells, potentially leading to carcinoid tumors. This study examined factors associated with carcinoid tumor development in patients with AIG, with a particular focus on anti-parietal cell antibody (APCA) positivity, autoimmune comorbidities, and biochemical markers.
Materials and Methods A retrospective single-center prevalence study was conducted on 330 patients with autoimmune gastritis (AIG), categorized into carcinoid tumor-positive (n = 28) and carcinoid tumor-negative (n = 302) groups. Demographic, clinical, and biochemical parameters were compared between the groups. Patients diagnosed with Helicobacter pylori were excluded from the study. Univariate and multivariate logistic regression analyses were used to identify independent predictors.
Results Carcinoid tumors were observed in 28 patients (8.5%). APCA negativity significantly increased the risk of carcinoid tumors (OR, 2.83; 95% CI: 1.10– 7.26, p = 0.030). Autoimmune comorbidities were also significant negative predictors (OR, 3.63; 95% CI: 1.20–12.65, p = 0.044). Lower vitamin B12 levels independently predicted tumor risk (odds ratio [OR], 0.95; 95% CI: 0.91–1.00, p = 0.043). Lower hemoglobin and ferritin levels were significant in the univariate analysis, but not in the multivariate analysis.
Discussion APCA negativity and vitamin B12 deficiency were significantly associated with carcinoid tumors in AIG patients. Vigilant monitoring of these risk factors is essential for early tumor detection. The observation that carcinoid tumor development was reduced in patients with autoimmune comorbidity forms the basis of a new hypothesis: “The protective effect of autoimmunity against cancer.”

Keywords

Introduction

Autoimmune gastritis (AIG) is a chronic inflammatory disease characterized by immune-mediated destruction of gastric parietal cells, primarily affecting the fundus and corpus of the stomach [1, 2, 3]. This process leads to progressive gastric mucosal atrophy, hypochlorhydria, and reduced intrinsic factor secretion, resulting in vitamin B12 deficiency and pernicious anemia [4, 5]. AIG is commonly associated with the presence of anti-parietal cell antibodies (APCA), which target the H+/ K+ ATPase pump, leading to parietal cell loss and subsequent gastric dysfunction [6]. This condition is often asymptomatic in its early stages but may present with dyspeptic symptoms, iron-deficiency anemia, and neurological manifestations due to vitamin B12 deficiency [7]. One of the significant complications of AIG is the increased risk of gastric neoplasia, particularly type 1 gastric carcinoid tumors and intestinal-type adenocarcinoma [8]. Gastric carcinoid tumors in AIG develop due to chronic hypergastrinemia, which results from parietal cell destruction and reduced gastric acid secretion. Elevated gastrin levels stimulate enterochromaffin-like (ECL) cell proliferation, increasing the risk of neoplastic transformation [9, 10]. Previous studies have shown that patients with pernicious anemia and AIG have a threefold increased risk of developing gastric malignancies [8, 11, 12].AIG is frequently associated with other autoimmune diseases, such as Hashimoto’s thyroiditis, celiac disease, type 1 diabetes mellitus, and rheumatoid arthritis [13]. The presence of autoimmune comorbidities may further influence the progression of gastric pathology [14, 15]. However, whether the presence of these conditions contributes to an increased risk of carcinoid tumors remains unclear. In addition to autoimmune mechanisms, biochemical abnormalities, including low vitamin B12, ferritin, and hemoglobin levels, have been implicated in the pathogenesis of gastric atrophy and neoplastic transformation [16, 17, 18]. Vitamin B12 deficiency is of particular interest, as it has been associated with DNA damage and increased cellular oxidative stress, which may contribute to tumorigenesis [19, 20]. Similarly, iron deficiency and anemia have been proposed as potential risk factors for carcinogenesis by promoting chronic mucosal damage and atrophy [7, 21]. Current clinical guidelines emphasize the importance of periodic endoscopic surveillance in patients with AIG, particularly those with advanced atrophy or hypergastrinemia. Monitoring of vitamin B12, iron parameters, and autoimmune markers is also recommended to identify complications at an early stage. Adding these risk-based follow-up strategies into routine care may help prevent delayed diagnosis of gastric neoplasia. While AIG is well recognized as a risk factor for gastric malignancies, the role of APCA positivity, autoimmune comorbidities, and biochemical markers in predicting carcinoid tumor development remains poorly understood. In this study, we aimed to evaluate the prevalence of carcinoid tumors in AIG patients and investigate the associations between APCA status, autoimmune diseases, and key biochemical markers (gastrin, vitamin B12, ferritin, and hemoglobin levels) with carcinoid tumor formation.

Materials and Methods

Study Design and Patients
The data of 6198 patients over 18 years of age who underwent endoscopy for any reason in Ankara University Gastroenterology Department between 2012 and 2022 were retrospectively reviewed. Approximately 4500 of these patients underwent endoscopic biopsy for any reason, and autoimmune gastritis was diagnosed histopathologically in 596 patients. 266 of 596 patients were excluded from the study because of a positive H. pylori test. Only patients with active H. pylori infection confirmed by histopathology and/or rapid urease testing were excluded. Information regarding previous H. pylori infection or eradication therapy was not consistently available in the medical records; therefore, past infection status could not be reliably assessed. The exclusion was thus based solely on active infection at the time of endoscopy. A comprehensive evaluation was conducted on a cohort of 330 patients, encompassing assessments of B12, ferritin, vitamin D, hemoglobin, anti- TPO levels, and APCA status. The patients were divided into two groups: anti-parietal cell antibody (APCA) positive (APCA+) and APCA negative (APCA-). Demographic data, including age, sex, symptoms, and associated autoimmune diseases, were retrieved from the Avicenna Patient Information System and medical records. In addition, APCA positivity, gastrin levels, serum anti-TPO levels, hemoglobin (Hb) levels, ferritin, vitamin B12, and vitamin D levels, as well as the development of gastric carcinoid tumors, were evaluated. Patients with missing data were excluded from the study.
Biochemical Parameters
The biochemical parameters of patients with autoimmune gastritis (AIG) were comprehensively analyzed, comparing seropositive (APCA+) and seronegative (APCA-) groups. Hematological and biochemical parameters were assessed according to routine laboratory reference ranges, following the standards of Ankara University Faculty of Medicine Hospitals. The evaluated biochemical markers included ferritin, vitamin B12, 25-OH vitamin D, gastrin, hemoglobin (Hb), and serum anti-TPO levels. The lower limits were set as follows: ferritin at 11 ng/mL, vitamin B12 at 200 pg/mL, 25-OH vitamin D at 20 µg/L, and serum anti-TPO at 9 IU/mL. Patients with serum anti- TPO levels ≥9 IU/mL were classified as positive. Patients with values exceeding these thresholds were classified as positive for the respective markers. Serum gastrin levels were measured in fasting patients using a chemiluminescent immunoassay (CLIA) method (reference range <100 pg/mL). All samples were collected in the morning after an overnight fast to minimize physiological variation.
Statistical Analysis
Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) for Windows 27.0 (IBM SPSS Inc.). The normality of the variables was assessed using visual methods (histograms and probability plots) and analytical tests (Kolmogorov-Smirnov and Shapiro-Wilk tests). Descriptive statistics were presented as mean ± standard deviation for normally distributed numerical variables, median (minimum-maximum values) for non-normally distributed numerical variables, and frequency tables for categorical variables. Comparisons between groups were performed using Student’s t-test for normally distributed numerical variables, Mann-Whitney U test for non-normally distributed numerical variables, and the chi-square test or Fisher’s exact test for categorical variables. To identify independent risk factors for gastric carcinoid tumor development, a multivariate analysis was conducted. Parameters that were statistically and clinically significant in univariate analyses were included in a logistic regression model. Model fit was assessed using the Hosmer- Lemeshow test (p = 0.64), and statistical significance was defined as p < 0.05. For continuous variables with wide variance, such as vitamin B12, odds ratios were calculated per 10-unit increase to enhance clinical interpretability. Accordingly, the OR values reported in Table 3 reflect the effect of a 10 pg/mL increase in vitamin B12 levels.
Ethical Approval
This study was approved by the Ethics Committee of Ankara University Faculty of Medicine, Ankara, Türkiye (Date: 2023-06- 08, No: İ05-343-23).

Results

The study included 330 patients diagnosed with autoimmune gastritis (AIG), with a mean age of 62.4 ± 12.2 years. The gender distribution consisted of 218 females (66.1%) and 112 males (33.9%). Among the clinical symptoms, dyspepsia was the most prevalent, observed in 219 patients (66.4%), followed by nutritional anemia, which was present in 111 patients (33.6%). Autoimmune comorbidities were significantly less frequent among patients with carcinoid tumors compared with those without tumors (p = 0.016). Regarding associated autoimmune diseases, 102 patients (30.9%) had a concurrent autoimmune disorder, with 50 patients (15.2%) diagnosed with Hashimoto’s thyroiditis, 11 patients (3.3%) with celiac disease, and 23 patients (7.0%) with rheumatologic diseases. In terms of gastric neoplasia, gastric carcinoid tumors were identified in 28 patients (8.5%), whereas 302 patients (91.5%) did not exhibit any carcinoid tumor development. When analyzing serological markers, 275 patients (83.3%) were APCA-positive (APCA+), while 55 patients (16.7%) were APCA-negative (APCA-). The mean gastrin level was 1339.9 ± 938.6 pg/mL, and the serum Anti-TPO level was 239.6 ± 412.3 IU/mL. Hemoglobin (Hb) levels had a mean of 12.6 ± 2.0 g/dL, and ferritin levels were recorded at 24.2 ± 75.0 ng/mL. Vitamin B12 levels had a mean of 253.6 ± 248.9 pg/mL, while vitamin D levels, which were available for 263 patients, averaged 18.4 ± 13.4 µg/L. Comparison of patients with and without carcinoid tumors in autoimmune gastritis (AIG) is shown in Table 1. Comparison of patients with and without APCA in autoimmune gastritis (AIG) is shown in Table 2. APCA positivity was significantly associated with female predominance (68.4% vs. 54.5%, p = 0.048) and higher serum gastrin levels (1434.5 ± 945.1 pg/mL vs. 866.6 ± 749.2 pg/mL, p = 0.001). In addition, serum anti-TPO levels were significantly higher in the APCA-positive group compared with APCA-negative patients (p = 0.046). Although the difference was modest, this finding may reflect the higher prevalence of concomitant thyroid autoimmunity in APCA-positive individuals (Table 2). Factors affecting the likelihood of carcinoid tumor development in patients with autoimmune gastritis (AIG) are shown in Table 3.

Discussion

Our study provides new insights into the relationship between AIG and carcinoid tumor development, particularly regarding APCA positivity, autoimmune comorbidities, and biochemical parameters. The findings highlight that patients with AIG who develop carcinoid tumors exhibit distinct serological and biochemical characteristics, emphasizing the potential pathogenic role of immune dysregulation and nutritional deficiencies in neoplastic progression. One of the most important findings of our study is the significant association between APCA negativity and an increased risk of carcinoid tumor development in AIG patients. There are only a limited number of studies in the literature supporting this relationship [3, 5, 10, 15, 22]. On the contrary, APCA positivity was identified as an independent predictor, suggesting that immune-mediated parietal cell destruction plays a critical role in the neoplastic transformation of enterochromaffin-like (ECL) cells. Ahn et al. reported that APCA-positive AIG patients had an increased risk of ECL cell hyperplasia and carcinoid tumor development due to persistent hypergastrinemia [22]. Conversely, Zhang et al. found no significant difference in carcinoid tumor prevalence between APCA-positive and APCA-negative patients, suggesting that other factors, such as Helicobacter pylori infection or additional genetic predispositions, may modulate tumor risk [3]. Massironi et al. identified a strong association between APCA positivity and carcinoid tumor development, emphasizing the central role of immune-mediated parietal cell damage in ECL cell neoplasia [10]. Wang et al. demonstrated that hypergastrinemia and ECL cell proliferation in APCA-positive AIG patients significantly contributed to tumor development [5]. However, Lenti et al. found no significant correlation between APCA positivity and carcinoid tumor incidence, suggesting that other autoimmune diseases or environmental factors may influence this relationship [15]. These conflicting findings highlight the need for further prospective cohort studies and molecular analyses to clarify the precise role of APCAs in ECL cell neoplasia. Further research with prospective cohorts and molecular analysis is needed to clarify the precise role of APCAs in ECL cell neoplasia. The slightly higher anti-TPO levels in APCA-positive patients further support the well-known association between AIG and autoimmune thyroid disease, although this did not translate into increased carcinoid risk in our cohort. One of the significant findings of our study is the association between autoimmune comorbidities and a decreased risk of carcinoid tumors. Autoimmune gastritis (AIG) is frequently linked to Hashimoto’s thyroiditis, celiac disease, type 1 diabetes mellitus, and rheumatoid arthritis, suggesting a shared immunopathogenic mechanism. Angerilli et al. reported that AIG is commonly associated with other autoimmune diseases, supporting the hypothesis of a common immunological pathway [8]. Sun et al. demonstrated that patients with multiple autoimmune disorders exhibit higher systemic inflammatory activity, which may contribute to increased ECL cell proliferation and subsequent tumorigenesis [23]. However, unlike some earlier studies, our research did not identify any specific autoimmune disease as a predominant risk factor for carcinoid tumor formation. Boutzios et al. found that Hashimoto’s thyroiditis was an independent risk factor for gastric neoplasia [24], whereas our findings suggest that the overall burden of autoimmunity, rather than individual diseases, plays a more significant role in tumorigenesis. One of the most striking observations in our study is the association between vitamin B12 deficiency and an increased risk of carcinoid tumor development. Patients with carcinoid tumors had significantly lower vitamin B12 levels, and this deficiency was found to be an independent predictor of tumor risk. Vitamin B12 plays a crucial role in DNA synthesis, methylation, and cellular homeostasis, and its deficiency has been linked to genomic instability, oxidative stress, and increased cellular proliferation, all of which are key mechanisms in carcinogenesis [16]. Our findings are consistent with previous research demonstrating that patients with B12 deficiency exhibit increased oxidative stress markers and higher rates of gastric neoplastic transformation [18]. However, ferritin and hemoglobin levels, despite being significantly lower in patients with carcinoid tumors in univariate analysis, did not remain statistically significant in multivariate analysis. This suggests that while iron deficiency anemia is common in AIG, it may not be a direct contributor to carcinoid tumor formation. Some studies have proposed that iron deficiency could exacerbate gastric atrophy, leading to a pro-inflammatory state conducive to neoplastic progression, but our findings suggest that vitamin B12 deficiency plays a more dominant role in the pathogenesis [25]. In this cohort, higher mean gastrin levels were observed in carcinoid tumor- positive patients compared to tumor-negative patients, but this difference did not reach statistical significance. This is somewhat unexpected, as hypergastrinemia is a well-established driver of ECL cell proliferation and carcinoid tumor development [7]. Previous studies have shown that gastrin levels above 1000 pg/mL are strongly associated with type 1 gastric carcinoid tumors, yet these results indicate that other factors, such as immune-mediated atrophy and micronutrient deficiencies, may also play critical roles [8]. One possible explanation for the lack of statistical significance is the small sample size of carcinoid tumor-positive patients, which may have limited the power to detect a significant association. Future studies with larger sample sizes and functional analyses of gastrin receptor signaling are warranted to better understand this relationship. Although mean gastrin levels were higher in the carcinoid tumor group, the difference did not reach statistical significance. This is most likely attributable to the small number of tumor-positive cases, which limits statistical power and may prevent the detection of clinically meaningful differences. Given the established biological role of hypergastrinemia in ECL cell proliferation, larger studies are needed to better define the contribution of elevated gastrin levels to carcinoid tumor development.

Limitations

This study has several strengths, including a well-characterized patient cohort, the comprehensive analysis of biochemical and autoimmune markers, and the use of multivariate analysis to identify independent risk factors. Additionally, our findings contribute to the growing evidence that autoimmune dysregulation and micronutrient deficiencies play critical roles in gastric neoplasia. However, there are some limitations to consider. First, this was a retrospective, single-center study, which may limit the generalizability of our findings. In particular, the number of carcinoid tumor–positive patients (n = 28) was relatively small, which may have reduced the statistical power of the regression analyses. This limitation reflects the naturally low prevalence of type 1 gastric carcinoid tumors in autoimmune gastritis cohorts. Therefore, confirmatory studies with larger, multicenter populations are needed to validate the associations observed in our study. Finally, the role of other potential confounding factors, such as Helicobacter pylori infection and genetic predisposition, was not assessed, which may have influenced the observed results.

Conclusion

In conclusion, APCA negativity and vitamin B12 deficiency emerged as independent risk factors for carcinoid tumor development in autoimmune gastritis. The reduced tumor incidence in patients with concurrent autoimmune disorders may indicate a protective immune mechanism that warrants further research. In contrast, the observation that carcinoid tumor development was reduced in patients with autoimmune comorbidities forms the basis for a new hypothesis: ‘Protective effect of autoimmunity against cancer’. These findings suggest that autoimmune-mediated atrophy, prolonged hypergastrinemia, and nutritional deficiencies contribute to gastric neoplasia. Given the potential clinical implications of these findings, future studies should focus on prospective, multicenter investigations with larger patient cohorts to validate these results. Additionally, further research on the molecular mechanisms linking autoimmune gastritis to ECL cell transformation could provide new insights into potential therapeutic targets for preventing gastric carcinoid tumors in high-risk individuals. From a clinical standpoint, our results suggest that patients who are APCA-negative or have low vitamin B12 levels may represent a higher-risk subgroup requiring more vigilant monitoring. Tailored follow-up strategies incorporating serological and biochemical markers may improve early detection of gastric carcinoid tumors in AIG.

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