Aralık 2016

65-68

Elmas KASAP¹, Ufuk DEMİRCİ2, Tahir BURAN¹, Hakan YÜCEYAR¹

Departments of ¹Gastroenterology and ²Internal Medicine, Celal Bayar University School of Medicine, Manisa, Turkey

Giriş ve Amaç: Helicobacter pylori birçok gastrik hastalığın nedenidir. Otoimmün karaciğer hastalıklarına diğer hastalıklar ile ilişkisiz olan çeşitli üst gastrointestinal sistem mukozal bulguları eşlik edebilir. Çalışmamızdaki amacımız retrospektif olarak otoimmun karaciğer hastalıklarında üst gastrointestinal endoskopi bulgularını taramak ve Helicobacter pylori ile ilişkisini araştırmaktır. Gereç ve Yöntem: Bu çalışmaya 99 otoimmün karaciğer hastası ve 110 kontrol grubu hastası dahil edilmiştir. Her hastanın antrumdan ve gastrik yüzeyden alınan endoskopik biyopsileri incelenmiş ve Helicobacter pylori varlığı değerlendirilmiştir. Hastalar daha öncesinde asit süpresyon, antibiyotik ya da steroid dışı inflamatuvar baskılayıcı ajan tedavisi almış ise ve veya çeşitli nedenler ile gastrik biyopsi alınmamış ise çalışmaya dahil edilmedi.Bulgular: Helicobacter pylori otoimmün hepatit hastalarında %60, primer biliyer siroz hastalarında %57 ve kontrol grubunda %63 saptandı. Üç grup arasında belirgin bir farklılık yoktu. Patolojik endoskopik bulgular otoimmün hepatit hastalarında %45, primer biliyer siroz hastalarında %52 ve kontrol grubunda %43 saptandı. Sonuç: Helicobacter pylori otoimmün hastalar ile kontrol grubu arasında benzer bulundu. Endoskopik antral gastrit otoimmün hepatit hastalarında yüksek saptansa da otoimmün karaciğer hastalarında dispeptik gruba göre belirgin bir endoskopik bulgu farklılığı saptanmadı.

Otoimmün karaciğer hastalığı, otoimmün hepatit, primer biliyer siroz, Helicobacter pylori, gastrik lezyon

Immune system dysregulation causes the clinical manifestations seen in autoimmune disorders. While there are several underlying causes, the most common are bacterial and viral infections, particularly in individuals with a susceptible genetic disposition. Environmental factors and infections can also contribute to the clinical manifestations (1). Autoimmune hepatic diseases include autoimmune hepatitis (AH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis. These diseases are all associated with intestinal inflammation, although several other autoimmune diseases often coexist (2). The role of Helicobacter pylori (H. pylori) in non-hepatic autoimmune disorders has been clearly demonstrated to involve immune system dysregulation (e.g., immune thrombocytopenic purpura and atrophic gastritis) (3). H. pylori causes several upper gastrointestinal system pathologies, including gastric ulcers, duodenal ulcers, gastric adenocarcinoma, autoimmune gastritis, and malt lymphoma. The role of H. pylori in these disorders has been the subject of many studies (4). The seroprevalence of H. pylori is significantly higher in autoimmune disorders such as Graves’s disease and Hashimoto’s disease than in control groups, with detection of the CagA antigen in most patients positive for H. pylori (5). Although previous studies have investigated the prevalence of H. pylori in autoimmune hepatic diseases, its prevalence in the upper gastrointestinal system has not been previously investigated. (6). Therefore, in this study, we aimed to determine the prevalence of H. pylori in gastrointestinal pathologies resulting from autoimmune hepatic diseases in comparison to controls with functional dyspepsia.

When the etiopathogenesss of autoimmune disorders are examineds it often appears that such disorders have multiple causes, with the principle cause being unclear. Although it is believed that an underlying background of genetic susceptibility is often involved, these disorders also have a shared pathogenesis involving the loss of self-tolerance. The coexistence of autoimmune diseases that have common etiopathogenetic features is often expected (1,3). AH, PBC, and primary sclerosing cholangitis all represent autoimmune hepatic diseases. Intestinal inflammation frequently accompanies these conditions. AH and primary sclerosing cholangitis are often observed along with inflammatory bowel diseases and patients with PBC often have celiac disease. T helper 17 and memory lymphocytes are frequently blamed for this comorbidity, supporting the notion of coexisting autoimmune disorders (2). It is believed that several triggers lead to the loss of self-tolerance in patients, a principal example being environmental factors such as bacterial or viral infections (6). Infections in individuals who have genetic susceptibility can trigger several mechanisms, including molecular similarity, epitope spread, polyclonal activation, immune complex formation, MHC-II activation in non-immune cells, proinflammatory cytokine releases and direct inflammatory damage, which can all contribute to the development of autoimmune diseases (6,8). H. pylori infection has been studied for 30 years. Although found in many regions of the world, it is believed that stomach-dwelling H. pylori first infected people during the migration from East Africa 58,000 years ago (9). More than half of the worldwide population carries H. pylori. Based on data from the TURHEP study, a recent urea breath test study and the largest study performed in Turkey to date, the prevalence of H. pylori in Turkish adults is 82.5% (10). No relationship has been established linking AH and H. pylori prevalence and previous evidence regarding a possible link between PBC and H. pylori was found to be subject to variation (6). In a retrospective analysis by Shapira et al. of 69 patients with PBC, the frequency of H. pylori positivity was significantly higher than that of the control group (51% in patients with PBC and 31% in the control group) (11). Ram et al also found a similar anti-HP antibody ratio in patients with autoimmune diseases. 54.4% of 68 patients with PBC were positive for anti-HP antibodies (versus 38.9% in the control group) (12). On the other hand, an analysis of 149 patients with PBC found similar seroprevalence rates between the patient and control groups (13). In a meta-analysis of 21 studies on cirrhosis, H. Pylori prevalence in cirrhotic patients in Europe was 88.9%, while it was much less in Asia (31.8%). In the same study, according to data on Europeans when compared to Asians, H. pylori prevalence was significantly higher than that of the control group. Differences between these studies may be due to the use of different methods or a significantly higher H. Pylori prevalence in patients versus control groups in some studies (14). We found H. Pylori-positive rates of 60%, 57%, and 63% in patients with AH, PBC, and functional dyspepsia, respectively, with no statistically significant difference between the three groups. The lower H. pylori prevalence seen in our data compared to that seen in the previously mentioned community-based study may be attributed to the hypothesis that autoimmune hepatic diseases may reduce H. pylori prevalence via gastric acid levels. Moreover, gastric acid levels may be affected by currently unexplained mechanisms resulting from immune processes. It has been shown that gastrin levels may decline because of pentagastrin stimulation; thus, gastric acid levels may be low in patients with portal fibrosis or portal hypertension associated with hepatic cirrhosis (15). It has also been suggested that peptic ulcer occurrence in liver diseases is associatedwith other reasons because of low H. pylori prevalence in this population compared with the overall population (16). According to previous studies, the prevalence of peptic ulcers in cirrhotic patients (5–20%) is higher than that in the general population (2-4%). In some studies, this high prevalence is dedicated to increase of H. pylori prevalence. Kim et al found a similar high peptic ulcer prevalence (24.3%) as other studies in 288 cirrhotic patients. However, in this study, we did not find that H. pylori played a major role. In a study by Nam et al investigating the effect of H. pylori on gastric pH in cirrhotic patients, gastric pH was found to be higher in cirrhotic patients, similar to the results of the study by Kim et al. In that study, most of the cirrhotic patients had hypochloridi. There was no connection between H. pylori and blood or gastric NH3 ratio (18). Our data demonstrated no significant differences compared with the control group when peptic ulcer frequency (2–6%) was examined in patients with autoimmune disorders. With a high worldwide prevalence, H. pylori is known to play an important role in several diseases of the gastrointestinal system, including peptic ulcers, non-cardiac stomach cancer, malt lymphoma, and some autoimmune diseases (immune thrombocytopenic purpura, Hashimoto’s thyroid, and atrophic gastritis) (3,19,20). Our data, in support of many previous studies, does not establish a clear relationship between H. pylori and autoimmune liver disease. In addition, when compared to control patients with functional dyspepsia, the pathogenesis of the upper gastrointestinal system does not appear to be different. Future studies are needed to elucidate the relationship and etiopathogenesis between autoimmune liver diseases and H. pylori

Our retrospective study included 99 patients diagnosed with autoimmune hepatic disease based on liver biopsy or laboratory measurement (antinuclear antibody, anti-mitochondrial antibody, anti-smooth muscle cell antibody or anti-liver kidney antibody) who presented at the Gastroenterology Clinic of Celal Bayar University between 2013 and 2015. Patients were excluded from the study if (i) an upper gastrointestinal endoscopy could not be performed; (ii) they refused a biopsy; (iii) biopsies from the antrum and corpus areas could not be taken with an endoscopy; (iv) they had received acid suppression treatment during the biopsy procedure; (v) they had received H. pylori eradication therapy previously; or (vi) they had received antibiotics or non-steroidal anti-inflammatory treatment during the endoscopy. Additionally, this study included 110 functional dyspepsia patients as the control group, diagnosed based on Roma III criteria (Table 1) (7). Ethics board approval for the study (dated March 23, 2015: no. 144) was received from the Clinical Trials Assessment Committee of the Medical Faculty of Celal Bayar University. Statistical measurements were performed using the Statistical Package for the Social Sciences (SPSS) 15.0 software. Analyses were performed using chi-square and Student’s t-tests. Statistical significance was set at P < 0.05.

Of the 99 patients in the autoimmune hepatic disease group, 71 had AH and 28 had PBC. The AH patients, PBC patients and control subjects had mean ages of 51.2±10.2 years, 49.1±11.3 years, and 53.4±9.8 years, respectively. No significant difference was noted between the autoimmune hepatic disease and control groups with respect to gender (Table 2). The AH, PBC, and control groups did not differ significantly for H. pylori positivity, with H. pylori detected in 60%, 57%, and 63% of subjects, respectively (Table 2). Pathology was determined based on upper gastrointestinal endoscopy in 45% of patients with AH, 52% of patients with PBCs and 43% of the controls, with no statistically significant difference between the groups. Endoscopic pathologies included oesophagitis, endoscopic antral and pangastritis, gastric ulcers, bulbar ulcers, and oesophageal varices. The prevalence of endoscopic antral gastritis was higher in AH patients than in PBC patients (P < 0.06). Oesophageal varices had a greater prevalence in AH and PBC patients than in control group (P < 0.07–0.012) (Table 3).

When the etiopathogenesss of autoimmune disorders are examineds it often appears that such disorders have multiple causes, with the principle cause being unclear. Although it is believed that an underlying background of genetic susceptibility is often involved, these disorders also have a shared pathogenesis involving the loss of self-tolerance. The coexistence of autoimmune diseases that have common etiopathogenetic features is often expected (1,3). AH, PBC, and primary sclerosing cholangitis all represent autoimmune hepatic diseases. Intestinal inflammation frequently accompanies these conditions. AH and primary sclerosing cholangitis are often observed along with inflammatory bowel diseases and patients with PBC often have celiac disease. T helper 17 and memory lymphocytes are frequently blamed for this comorbidity, supporting the notion of coexisting autoimmune disorders (2). It is believed that several triggers lead to the loss of self-tolerance in patients, a principal example being environmental factors such as bacterial or viral infections (6). Infections in individuals who have genetic susceptibility can trigger several mechanisms, including molecular similarity, epitope spread, polyclonal activation, immune complex formation, MHC-II activation in non-immune cells, proinflammatory cytokine releases and direct inflammatory damage, which can all contribute to the development of autoimmune diseases (6,8). H. pylori infection has been studied for 30 years. Although found in many regions of the world, it is believed that stomach-dwelling H. pylori first infected people during the migration from East Africa 58,000 years ago (9). More than half of the worldwide population carries H. pylori. Based on data from the TURHEP study, a recent urea breath test study and the largest study performed in Turkey to date, the prevalence of H. pylori in Turkish adults is 82.5% (10). No relationship has been established linking AH and H. pylori prevalence and previous evidence regarding a possible link between PBC and H. pylori was found to be subject to variation (6). In a retrospective analysis by Shapira et al. of 69 patients with PBC, the frequency of H. pylori positivity was significantly higher than that of the control group (51% in patients with PBC and 31% in the control group) (11). Ram et al also found a similar anti-HP antibody ratio in patients with autoimmune diseases. 54.4% of 68 patients with PBC were positive for anti-HP antibodies (versus 38.9% in the control group) (12). On the other hand, an analysis of 149 patients with PBC found similar seroprevalence rates between the patient and control groups (13). In a meta-analysis of 21 studies on cirrhosis, H. Pylori prevalence in cirrhotic patients in Europe was 88.9%, while it was much less in Asia (31.8%). In the same study, according to data on Europeans when compared to Asians, H. pylori prevalence was significantly higher than that of the control group. Differences between these studies may be due to the use of different methods or a significantly higher H. Pylori prevalence in patients versus control groups in some studies (14). We found H. Pylori-positive rates of 60%, 57%, and 63% in patients with AH, PBC, and functional dyspepsia, respectively, with no statistically significant difference between the three groups. The lower H. pylori prevalence seen in our data compared to that seen in the previously mentioned community-based study may be attributed to the hypothesis that autoimmune hepatic diseases may reduce H. pylori prevalence via gastric acid levels. Moreover, gastric acid levels may be affected by currently unexplained mechanisms resulting from immune processes. It has been shown that gastrin levels may decline because of pentagastrin stimulation; thus, gastric acid levels may be low in patients with portal fibrosis or portal hypertension associated with hepatic cirrhosis (15). It has also been suggested that peptic ulcer occurrence in liver diseases is associatedwith other reasons because of low H. pylori prevalence in this population compared with the overall population (16). According to previous studies, the prevalence of peptic ulcers in cirrhotic patients (5–20%) is higher than that in the general population (2-4%). In some studies, this high prevalence is dedicated to increase of H. pylori prevalence. Kim et al found a similar high peptic ulcer prevalence (24.3%) as other studies in 288 cirrhotic patients. However, in this study, we did not find that H. pylori played a major role. In a study by Nam et al investigating the effect of H. pylori on gastric pH in cirrhotic patients, gastric pH was found to be higher in cirrhotic patients, similar to the results of the study by Kim et al. In that study, most of the cirrhotic patients had hypochloridi. There was no connection between H. pylori and blood or gastric NH3 ratio (18). Our data demonstrated no significant differences compared with the control group when peptic ulcer frequency (2–6%) was examined in patients with autoimmune disorders. With a high worldwide prevalence, H. pylori is known to play an important role in several diseases of the gastrointestinal system, including peptic ulcers, non-cardiac stomach cancer, malt lymphoma, and some autoimmune diseases (immune thrombocytopenic purpura, Hashimoto’s thyroid, and atrophic gastritis) (3,19,20). Our data, in support of many previous studies, does not establish a clear relationship between H. pylori and autoimmune liver disease. In addition, when compared to control patients with functional dyspepsia, the pathogenesis of the upper gastrointestinal system does not appear to be different. Future studies are needed to elucidate the relationship and etiopathogenesis between autoimmune liver diseases and H. pylori

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