Arne Kandulski

Helicobacter pylori infection: A clinical overview

BACKGROUND Helicobcater pylori colonizes the stomach of more than half of the worlds population, and the infection continues to play a key role in the pathogenesis of a number of gastroduodenal diseases. Colonization of the gastric mucosa with Helicobcater pylori results in the development of chronic gastritis in all infected individuals and in a subset of patients chronic gastritis progresses to complications (i.e. ulcer disease, gastric neoplasias, some distinct extragastric disorders). The clinical outcome of the disease is dependent on many variables, including Helicobcater pylori genotype, innate host physiology, genetic predisposition and environmental factors. Helicobcater pylori eradication decreases the incidence of gastroduodenal ulcer and prevents its recurrence. Helicobcater pylori eradication for gastric cancer prevention has been suggested by preclinical research and clinical trials, showing even reversibility of precancerous lesions (atrophic gastritis and intestinal metaplasia) after Helicobcater pylori eradication. AIMS To review the current literature about H. pylori and its related pathologies. CONCLUSION At present, several clinical manifestations are recognized to be causally linked to Helicobcater pylori infection, and most of them can be cured by Helicobcater pylori eradication. Besides the relationship of Helicobcater pylori and gastroduodenal diseases, it has been well established that Helicobcater pylori infection is also involved in some extragastrointestinal diseases.

Naturally Occurring Regulatory T cells (CD4+, CD25high, FOXP3+) in the Antrum and Cardia are Associated with Higher H. pylori Colonization and Increased Gene Expression of TGF-β1

Background: Helicobacter pylori causes gastric inflammation. Despite the induction of H. pylori‐specific B‐ and T cells, the immune response is not sufficient to clear the infection. Regulatory T cells (Treg cells) suppress the activation and proliferation of antigen‐specific T cells and mediate immunologic tolerance. FOXP3 was shown to be expressed in a subset of Treg cells known as ‘naturally occurring Treg cells’. These cells have not been sufficiently studied in context to H. pylori‐induced inflammation in human gastric mucosa.

Proteinase-activated receptor-2 in the pathogenesis of gastroesophageal reflux disease.

OBJECTIVES:The proteinase-activated receptor-2 (PAR-2) is activated by serine proteases and has been demonstrated to induce proinflammatory and neuroinflammatory effects. It is considered to alter transepithelial resistance and mediates visceral hypersensitivity. This study aimed to evaluate the expression of PAR-2 in human esophageal mucosa of patients with gastroesophageal reflux disease (GERD) in relation to mucosal alterations.METHODS:The study included 123 patients with GERD stratified to erosive reflux disease (n=50), non-erosive reflux disease (n=46), and reflux-negative patients as controls (n=27). Endoscopic and histopathological characterization was performed according to the Los Angeles classification and modified Ismail-Beigi criteria, respectively. PAR-2 expression was analyzed by quantitative reverse transcription (RT)-PCR and immunohistochemistry. The gene expression levels of interleukin (IL)-8 were determined by quantitative RT-PCR and correlated to PAR-2 expression in each patient. Performing in vitro studies, esophageal squamous cell lines (KYSE 150, KYSE 450) were incubated, adjusted to different pH (7.0, 6.0, and 5.0), and exposed to bile acids and PAR-2-activation peptide (SLIGKV-NH2).RESULTS:PAR-2 gene expression was 7- to 10-fold upregulated (P<0.0001) in the mucosa of patients with GERD and correlated positively with IL-8 expression and with histomorphological alterations (dilated intercellular spaces, papillary elongation, basal cell hyperplasia (BCH); P<0.01). Immunohistochemistry showed an intense staining of PAR-2 throughout all epithelial layers in patients with GERD compared with controls (P=0.0005). In vitro studies revealed a 1.5- to 20-fold induction of PAR-2 gene expression in esophageal squamous cells by acidified medium (P<0.01), but not by additional bile acids. The activation of PAR-2 leads to expression and secretion of IL-8.CONCLUSIONS:This study provides evidence of the functional importance of PAR-2-mediated pathways in the pathogenesis of GERD and GERD-associated mucosal alterations and inflammatory changes.

Dyspepsia and IBS Symptoms in Patients with NERD, ERD and Barrett’s Esophagus

Introduction: Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are highly prevalent in the general population as does gastroesophageal reflux disease (GERD). Therefore, it is expected that these conditions may frequently overlap. Objective: We aimed at evaluating the presence ofFD and IBS symptoms in patients with erosive (ERD), non-erosive reflux disease (NERD) and Barrett’s esophagus (BE). Patients and Methods: 71 patients presenting at the reflux disease outpatient clinic were prospectively included in this study. 33 patients had NERD, 25 ERD and 13 BE according to the Montreal classification. All patients with ERD and NERD had typical reflux symptoms, as assessed by a validated GERD questionnaire (RDQ). The diagnosis of functional dyspepsia and IBS symptoms was assessed according to the Rome III criteria. Results: IBS symptoms (bloating, abdominal pain, constipation and diarrhea) were slightly more prevalent in NERD (54.6, 63.6, 21.20, 24.2%, respectively) than in ERD (48.0, 44.0, 12.0, 20.0%, respectively) and in BE (53.9, 23.10, 15,4, 23.1%, respectively), but none of these differences reached statistical significance. NERD patients had more FD symptoms than patients with ERD or BE, but again this difference did not reach statistical significance. Conclusion: Our data show that IBS and FD are common in the entire spectrum of GERD. The presence of these disorders might explain why many patients with GERD are deemed as treatment failures if they have no complete symptom relief with proton pump inhibitors.

Gastroesophageal reflux disease—from reflux episodes to mucosal inflammation

Gastroesophageal reflux disease (GERD) affects 20–30% of the population in Western countries, and is one of the most common clinical problems in daily practice. GERD-associated functional and structural abnormalities are caused by recurrent exposure of the esophagus to acidic and nonacidic refluxate of gastric contents (containing duodenal and intestinal proteases as well as acid and gastric pepsin) from the stomach. Major progress has been made in the understanding of the molecular pathogenesis of GERD-associated mucosal inflammation, suggesting a complex and multifactorial pathogenesis and immune-mediated effects. This Review summarizes the complexity of mucosal pathogenesis, including microscopic changes, mucosal inflammation and GERD-specific molecular mediators, in the context of the clinical features and pathophysiological characteristics of GERD. The abnormal exposure of the esophagus to luminal contents leads to chronic mucosal inflammation that is characterized by the release of IL-8 specifically, as well as other proinflammatory mediators, from the esophageal mucosa. Evidence from animal studies indicates a stepwise inflammatory response by the epithelium, which attracts immune effector cells to infiltrate the mucosa. From bench to bedside, these novel molecular findings might provide new treatment options beyond current acid-suppressive therapy and the principle of inhibition of transient lower esophageal sphincter relaxation.

Helicobacter pylori: diagnosis and treatment.

Purpose of review Multiple diagnostic methods and treatment strategies have been developed to detect and treat the Helicobacter pylori infection. Many of them have stood the test of time; others lost their value with the introduction of new test and treatment modalities. This review focuses on the current diagnostic methods and their clinical implications, as well as on established and novel treatment strategies. Recent findings The increasing antimicrobial resistance has resulted in a decline of the success rate of recommended eradication regimens. The current guidelines recommend as first-line treatment clarithromycin, amoxicillin or metronidazole, and proton pump inhibitor twice daily, but recent studies have demonstrated an increasing eradication failure with these regimens. Several treatment modifications have been adopted regarding duration and combination of substances. Summary The currently recommended first-line treatments are effective and well tolerated. In areas with high antimicrobial resistance rates, new antibiotic combinations and modifications in the sequence of drug administration are proposed as alternative treatment options to standard triple therapy. Future treatment strategies have to focus on regional antimicrobial resistance adopted treatment selection and the development of new antibiotics.

Histomorphological differentiation of non-erosive reflux disease and functional heartburn in patients with PPI-refractory heartburn

Proton pump inhibitor (PPI)‐refractory heartburn may be due to persistent gastro‐oesophageal reflux, oesophageal hypersensitivity or functional heartburn (FH). The differentiation between non‐erosive reflux disease (NERD) and FH may be very difficult. However, this differentiation is important for appropriate therapeutic management. Dilated intercellular spaces (DIS), papillary elongation (PE) and basal cell hyperplasia (BCH) can be all assessed by light microscopy. Whether these mucosal abnormalities allow the differentiation of NERD from FH in PPI‐refractory patients is uncertain.

Antibiotic susceptibility of Helicobacter pylori in central Germany and its relationship with the number of eradication therapies.

Objectives Helicobacter pylori eradication rates show a constant decline over the last few years. The main reason for H. pylori treatment failure is the increasing antibiotic resistance. We assessed antibiotic susceptibility of H. pylori in a region of mid-Germany and analyzed the relationship of antibiotic resistance with the number of eradication therapies over a period of 7 years (2005–2012). Methods H. pylori strains were isolated from 436 patients who underwent gastroscopy for different clinical indications. Susceptibility to amoxicillin, clarithromycin, metronidazole, tetracycline, levofloxacin, and rifabutin was determined using the E-test. Results Primary, secondary, and tertiary resistances against clarithromycin were 7.5, 63.2, and 75.4%, respectively. Primary, secondary, and tertiary resistances to levofloxacin were 11.7, 17.6, and 36.4% and to metronidazole were 32.7, 63.2, and 80.1%, respectively. The resistance rates against tetracycline and rifabutin were comparatively low (<5%), even in patients with previous exposure to these antibiotics. Resistance to rifabutin increased to 6.2% in patients who received more than two previous eradication therapies. Amoxicillin resistance was not detectable in all patients. Conclusion In our region, we observed a stable, but constantly increasing, resistance rate to antibiotics commonly used for the treatment of H. pylori infection. Knowledge of the local antibiotic resistance rates is essential for developing successful treatment strategies for H. pylori eradication.

Jackhammer esophagus: high-resolution manometry and therapeutic approach using peroral endoscopic myotomy (POEM).

We present the first report on peroral endoscopic myotomy (POEM) in the treatment of jackhammer esophagus. A 34-year-old female patient was newly diagnosed with a jackhammer esophagus. After failure of medical treatment, the patient underwent POEM procedure for myotomy of the spastic segment. Postoperatively, a mild emphysema and pneumothorax occurred that required drainage and antibiotic therapy until full recovery. Discharge was possible after 5 days. Six months later, she presented with recurrent but mild pain due to a remnant spastic segment proximal to the myotomy. Endoscopic balloon dilation was performed twice within 6 weeks with full symptomatic relief of pain and mild symptoms of dysphagia.

From gastric inflammation to gastric cancer.

The majority of gastric adenocarcinomas are related to chronic inflammation induced by Helicobacter pylori infection. For intestinal-type gastric cancer, a multistep process of mucosal alterations leading from gastritis via glandular atrophy, intestinal metaplasia and dysplasia to invasive carcinoma is well recognized. Ongoing clinical studies focus on a ‘point of no return’. It is defined as a situation when certain alterations are no longer reversible by H. pylori eradication and progression to gastric cancer may continue. H. pylori affects the mucosal as well as the systemic immune response by secretion of cytokines and the recruitment of distinct inflammatory cells. The immune response is characterized by a balance between a Th1-dominated response and the recruitment of antigen-specific regulatory T cells that allow the bacteria to persist in human gastric mucosa. Besides immune-mediated effects, H. pylori induces cellular alterations as well as genetic alterations in genes that are essential for the epigenetic integrity and mucosal homeostasis. These genetic alterations during gastric cancer development are in focus of intensive research and should ultimately allow the identification of risk factors involved in gastric carcinogenesis. The detection of individuals at high risk for gastric cancer would help to design appropriate strategies for prevention and surveillance.