IBD: From conventional immunosuppression to biological therapy.

Background Inflammatory bowel diseases (IBD) are chronic recurrent inflammatory diseases with partly understood etiology and pathogenesis. The course of IBD, both ulcerative colitis (UC) and Crohn`s disease (CD) is characterized by periods of relapse and remission with the possible occurrence of extraintestinal manifestations. Summary During the last decades therapeutic goals in IBD evolved towards endoscopic remission and mucosal healing creating the need for early administration of disease-modifying agents (DMA). DMA includes conventional immunosuppressants (thiopurines, methotrexate), biological drugs (anti-TNF, anti-integrin, and anti-IL12/23 monoclonal antibodies), and small molecules (JAK inhibitors, S1P receptor modulators). Patients with an aggressive course of disease and risk factors for poor prognosis should be treated with biological therapy early. At the same time, conventional immunomodulators should be used in those with a milder course of disease in the absence of risk factors. Key points Challenges in treating IBD patients include choosing effective yet safe drugs and preventing or overcoming the loss of response.

The Importance of Artificial Intelligence in Upper Gastrointestinal Endoscopy.

Recently, there has been a growing interest in the application of artificial intelligence (AI) in medicine, especially in specialties where visualization methods are applied. AI is defined as a computer's ability to achieve human cognitive performance, which is accomplished through enabling computer "learning". This can be conducted in two ways, as machine learning and deep learning. Deep learning is a complex learning system involving the application of artificial neural networks, whose algorithms imitate the human form of learning. Upper gastrointestinal endoscopy allows examination of the esophagus, stomach and duodenum. In addition to the quality of endoscopic equipment and patient preparation, the performance of upper endoscopy depends on the experience and knowledge of the endoscopist. The application of artificial intelligence in endoscopy refers to computer-aided detection and the more complex computer-aided diagnosis. The application of AI in upper endoscopy is aimed at improving the detection of premalignant and malignant lesions, with special attention on the early detection of dysplasia in Barrett's esophagus, the early detection of esophageal and stomach cancer and the detection of H. pylori infection. Artificial intelligence reduces the workload of endoscopists, is not influenced by human factors and increases the diagnostic accuracy and quality of endoscopic methods.

Current Trends in the Management of Helicobacter pylori Infection in Serbia: Preliminary Results from the European Registry on H. pylori Management.

BACKGROUND: Helicobacter pylori (H. pylori) is the most common chronic bacterial infection. Treatment effectiveness remains a subject of debate considering bacterial antimicrobial resistance. Our aim was to analyze the diagnostic methods and eradication treatments for H. pylori infection in Serbia. METHODS: An observational multicenter prospective study was conducted in Serbia, as part of the European Registry on H. pylori Management (Hp-EuReg). Demographics, treatment indication, diagnostic methods, previous eradication attempts, and treatment were collected at AEG-REDCap e-CRF. Modified intention-to-treat (mITT) and per-protocol (PP) effectiveness analyses were performed. Safety, compliance, and bacterial antimicrobial resistance rates were reported. Data were quality checked. RESULTS: Overall, 283 patients were included, with a mean age of 55 ± 15 years. Dyspepsia (n = 214, 77%) was the most frequent treatment indication, and histology (n = 144, 51%) was the most used diagnostic method. Overall eradication rate was 95% (PP) and 94% (mITT). Most prevalent first-line therapy was quadruple PPI + clarithromycin + amoxicillin + metronidazole, with a 96% effectiveness (p < 0.001). Second-line main treatment choice was triple amoxicillin + levofloxacin, with a 95% effectiveness (p < 0.05). Single-capsule Pylera® was the most prescribed third-line therapy, with 100% effectiveness (p < 0.05). Longer treatment duration was associated with a higher eradication rate in first-line therapy (p < 0.05). Clarithromycin and quinolone resistance rates in first-line were 24% and 8.3%, respectively. The overall adverse events' incidence rate was 13.4%, and therapy compliance was 97%. CONCLUSIONS: Considering the high eradication rate, 14-day non-bismuth quadruple concomitant therapy is a reasonable first-line choice, while quinolone-based therapy and single-capsule Pylera® should be considered as rescue therapy options.

In Search for Reasons behind Helicobacter pylori Eradication Failure-Assessment of the Antibiotics Resistance Rate and Co-Existence of Helicobacter pylori with Candida Species.

Helicobacter pylori eradication is characterized by decreasing successful eradication rates. Although treatment failure is primarily associated with resistance to antibiotics, other unknown factors may influence the eradication outcome. This study aimed to assess the presence of the antibiotics resistance genes in H. pylori and the presence of Candida spp., which are proposed to be endosymbiotic hosts of H. pylori, in gastric biopsies of H. pylori-positive patients while simultaneously assessing their relationship. The detection and identification of Candida yeasts and the detection of mutations specific for clarithromycin and fluoroquinolones were performed by using the real-time PCR (RT-PCR) method on DNA extracted from 110 gastric biopsy samples of H. pylori-positive participants. Resistance rate to clarithromycin and fluoroquinolone was 52% and 47%, respectively. Antibiotic resistance was associated with more eradication attempts (p < 0.05). Candida species were detected in nine (8.18%) patients. Candida presence was associated with older age (p < 0.05). A high rate of antibiotic resistance was observed, while Candida presence was scarce, suggesting that endosymbiosis between H. pylori and Candida may not be a major contributing factor to the eradication failure. However, the older age favored Candida gastric mucosa colonization, which could contribute to gastric pathologies and microbiome dysbiosis.

Abnormal Liver Blood Tests: Hepatologist Approach.

BACKGROUND: Available data suggest that the prevalence of chronic liver disease (CLD) and primary liver cancer is rising in Europe and represents a major public health problem. Predictions are showing that these trends will continue to rise in the upcoming years. SUMMARY: Alcohol-related liver disease, nonalcohol fatty liver disease, and viral hepatitis B and hepatitis C are the leading causes of liver cirrhosis and primary liver cancer in Europe. Drug-induced liver injury represents a major cause of acute hepatitis, while liver transplantation is the second most common solid organ transplantation in the world. Patients with CLD have increasing rates of hospitalization, longer hospital stays, and more adverse outcomes compared to the other chronic conditions. Direct targeting of risk factors can prevent complications of advanced liver disease and improve outcome. Patients with CLD should be referred to a hepatologist for assessment of the stage of liver disease, for specific treatment and screening for hepatocellular carcinoma. Moreover, patients with unknown etiology of abnormal liver blood tests should be referred to a hepatologist for assessment of liver disease, as well as for prevention and treatment of complications of cirrhosis and/or portal hypertension. Key Messages: CLD is amenable to prevention and treatment, while disease management strategies need to improve in order to reduce the burden of liver disease and deaths due to end-stage liver diseases.

Chronic Constipation: Gastroenterohepatologist's Approach.

BACKGROUND: Constipation is a common problem in gastroenterological practice. The prevalence of constipation is about 16%. Constipation can be primary or secondary. SUMMARY: The diagnostic and therapeutic approach to patients with constipation begins with a detailed history and physical examination. In selected cases, the use of additional diagnostic procedures is very important. This includes the use of laboratory, endoscopic, and radiological examinations, as well as advanced physiological testing (anorectal manometry, balloon expulsion test, colonic transit studies, and defecography). Constipation therapy can be both nonoperative and operative. Nonoperative therapy includes the application of a lifestyle measures, pharmacotherapy and biofeedback therapy. Key Messages: Two key things when taking a medical history and physical examination are to rule out the existence of alarm symptoms/signs and to rule out secondary constipation (primarily drug-induced). Therapy begins with lifestyle modification, and in case of failure, bulk or osmotic laxatives are used. In case of failure, the use of lubiprostone is indicated, as well as linaclotide. Surgical treatment of constipation is reserved for cases of refractory constipation, with delayed intestinal transit.

Chronic Abdominal Pain: Gastroenterologist Approach.

BACKGROUND: Abdominal pain is a common symptom of gastroenterology examination. Chronic abdominal pain is present for >3 months. SUMMARY: Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal diseases encountered by both gastroenterologists and general practitioners. GERD is usually a chronic disease presented with a set of symptoms including heartburn and/or regurgitation, and less commonly epigastric pain. Epigastric pain syndrome is characterized by the following symptoms: epigastric pain and/or burning. It does not necessarily occur after meal ingestion, may occur during fasting, and can be even improved by meal ingestion. Duodenal ulcers tend to cause abdominal pain that is localized in the epigastric region and commence several hours after eating, often at night. Hunger provokes pain in most of the cases and decreases after meal. Gastric ulcer pain occurs immediately after eating, and consuming food increases pain. Pain is localized in the epigastrium and can radiate to the back. Abdominal pain in irritable bowel syndrome is related to defecation. A typical symptom of chronic pancreatitis is pain that radiates to the back. In Crohn's disease, inflammation causes pain. Key Messages: Pain can occur at different locations with diverse intensity and propagation and is often associated with other symptoms. For any gastroenterologist, abdominal pain is a big challenge.

Dyspepsia Challenge in Primary Care Gastroenterology.

BACKGROUND: The purpose of this review is to take a deep dive into general problems and challenges of diagnosis and treatment of patients with symptoms of dyspepsia in primary care practice. SUMMARY: Primary care physicians become acquainted with a broad range of clinical problems and therefore require a wide span of knowledge in taking care of patients from their first medical examination within the health care system. Dyspepsia and Helicobacter pylori infection are two of the most frequent reasons of digestive-related health care issues, despite that in primary care practice, current recommendations for diagnosis and differential therapy are often not implemented. The "test-and-treat" strategy is the initial management of the condition, reserving gastroscopy for patients refractory to symptomatic treatment and for patients presenting with any of the following alarm signs: age of above 55, dysphagia, anemia, weight loss, frequent vomiting, family history of GI malignancy, or a physical examination with key pathological findings. KEY MESSAGES: Examination and treatment of dyspepsia symptoms is the diagnostic and therapeutic challenge dictated by organizational and economic potentials of the health system, professional resources, and primary health care capabilities to accept and treat patients with dyspepsia and to properly refer those with alarm symptoms and findings indicative of organic disease to a gastroenterologist.

Abnormal Liver Blood Tests: Primary Care Approach.

BACKGROUND: According to recent epidemiological data, annual deaths due to liver disease have increased dramatically, while predictions show that trends will continue to rise in the upcoming years. SUMMARY: Abnormal liver blood tests are one of the most common challenges encountered in the primary care setting. The prevalence of mildly elevated transaminase levels is around 10-20% in the general population. The most common causes for the rising burden of liver disease are nonalcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ARLD), and viral hepatitis. With improvements in the management of viral hepatitis over the last decades, the causes for the rising burden of liver disease are shifting toward ARLD and NAFLD. It is well-known that liver disease usually progresses silently for years or decades until the complications of cirrhosis occur. The majority of patients will not require referral to a specialist but will need further assessment in primary care. They should be evaluated for the etiology of liver disease irrespective of the duration of abnormal liver blood tests or unmarked clinical presentation. The evaluation should include a history of alcohol use, a history of medicines or herbal supplements, testing for viral hepatitis, and assessment for NAFLD, especially in obese patients and patients with type 2 diabetes. Abdominal ultrasound should be performed. Key Messages: The general practitioner may contribute significantly by identifying and screening patients at risk for chronic liver disease, as well as prioritize individuals with symptoms or signs of advanced liver disease to the specialist clinic.

Anemia as a Problem: GEH Approach.

BACKGROUND: Anemia is present in almost 5% of adults worldwide and accompanies clinical findings in many diseases. Diseases of the gastrointestinal (GI) tract and liver are a common cause of anemia, so patients with anemia are often referred to a gastroenterologist. SUMMARY: Anemia could be caused by various factors such as chronic bleeding, malabsorption, or chronic inflammation. In clinical practice, iron deficiency anemia and the combined forms of anemia due to different pathophysiological mechanisms are most common. Esophagogastroduodenoscopy, colonoscopy, and the small intestine examinations in specific situations play a crucial role in diagnosing anemia. In anemic, GI asymptomatic patients, there are recommendations for bidirectional endoscopy. Although GI malignancies are the most common cause of chronic bleeding, all conditions leading to blood loss, malabsorption, and chronic inflammation should be considered. From a gastroenterologist's perspective, the clinical spectrum of anemia is vast because many different digestive tract diseases lead to bleeding. Key Messages: The gastroenterological approach in solving anemia's problem requires an optimal strategy, consideration of the accompanying clinical signs, and the fastest possible diagnosis. Although patients with symptoms of anemia are often referred to gastroenterologists, the diagnostic approach requires further improvement in everyday clinical practice.

European Registry on Helicobacter pylori management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients.

OBJECTIVE: The best approach for Helicobacter pylori management remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care. DESIGN: International multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in H. pylori management by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables included demographics, previous eradication attempts, prescribed treatment, adverse events and outcomes. Data monitoring was performed to ensure data quality. Time-trend and geographical analyses were performed. RESULTS: 30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empirical H. pylori treatments were included for analysis. Pretreatment resistance rates were 23% to clarithromycin, 32% to metronidazole and 13% to both. Triple therapy with amoxicillin and clarithromycin was most commonly prescribed (39%), achieving 81.5% modified intention-to-treat eradication rate. Over 90% eradication was obtained only with 10-day bismuth quadruple or 14-day concomitant treatments. Longer treatment duration, higher acid inhibition and compliance were associated with higher eradication rates. Time-trend analysis showed a region-dependent shift in prescriptions including abandoning triple therapies, using higher acid-inhibition and longer treatments, which was associated with an overall effectiveness increase (84%-90%). CONCLUSION: Management of H. pylori infection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations. Only quadruple therapies lasting at least 10 days are able to achieve over 90% eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which was associated with a corresponding increase in effectiveness.

Helicobacter pylori first-line and rescue treatments in patients allergic to penicillin: Experience from the European Registry on H pylori management (Hp-EuReg).

BACKGROUND: Experience in Helicobacter pylori eradication treatment of patients allergic to penicillin is very scarce. A triple combination with a PPI, clarithromycin (C), and metronidazole (M) is often prescribed as the first option, although more recently the use of a quadruple therapy with PPI, bismuth (B), tetracycline (T), and M has been recommended. AIM: To evaluate the efficacy and safety of first-line and rescue treatments in patients allergic to penicillin in the "European Registry of H pylori management" (Hp-EuReg). METHODS: A systematic prospective registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H pylori infection. An e-CRF was created on AEG-REDCap. Patients with penicillin allergy were analyzed until June 2019. RESULTS: One-thousand eighty-four patients allergic to penicillin were analyzed. The most frequently prescribed first-line treatments were as follows: PPI + C + M (n = 285) and PPI + B + T + M (classic or Pylera® ; n = 250). In first line, the efficacy of PPI + C + M was 69%, while PPI + B + T + M reached 91% (P < .001). In second line, after the failure of PPI + C + M, two rescue options showed similar efficacy: PPI + B + T + M (78%) and PPI + C + levofloxacin (L) (71%) (P > .05). In third line, after the failure of PPI + C + M and PPI + C + L, PPI + B + T + M was successful in 75% of cases. CONCLUSION: In patients allergic to penicillin, a triple combination with PPI + C + M should not be generally recommended as a first-line treatment, while a quadruple regimen with PPI + B + T + M seems to be a better option. As a rescue treatment, this quadruple regimen (if not previously prescribed) or a triple regimen with PPI + C + L could be used but achieved suboptimal (<80%) results.

Quality of Life in Patients with Primary Biliary Cholangitis: A Single-Center Experience in Serbia.

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic cholestatic autoimmune disease, predominantly affecting middle-aged women, which may progress to end-stage liver disease. We aimed to assess the quality of life (QoL) in patients with PBC given that social, economic, and geographical factor also influence QoL. METHODS: This study included patients with diagnosed PBC according to the European Association for the Study of the Liver guidelines, who were treated for at least 6 months in order to allow adequate time for the initial burden of symptoms to subside. We used the PBC-40 questionnaire validated in the Serbian language. RESULTS: The mean total PBC-40 score was 89.4 ± 29.3. The overall frequency of moderate and severe involvement in each domain was as follows: 84.9% (n = 107) in "Symptoms," 29.3% (n = 36) in "Itch," 76.4% (n = 97) in "Fatigue," 58.1% (n = 72) in "Cognitive," 77.2% (n = 98) in "Social," and 70.9% (n = 90) in "Emotional." There was a statistically significant negative correlation of disease duration and albumin score with the Emotional domain score. Furthermore, this domain showed a significant positive correlation with the Mayo score. CONCLUSION: The present study demonstrates that patients with PBC have significant impairment in QoL with fatigue being the most prevalent symptom. The Social and Emotional domains were also significantly affected in these individuals, particularly in patients with peripheral edema who exhibited worse QoL that those who were euvolemic.

Burden of Gastroduodenal Diseases from the Global Perspective.

PURPOSE OF REVIEW: We reviewed the recent medical literature to show global burden of gastroduodenal disease, potential strategies, and further perspectives. RECENT FINDINGS: Gastrointestinal and liver diseases are growing health problems, and cause more than 8 million deaths per year worldwide; encompass a range of long-term health conditions, such as digestive cancers, gastroesophageal reflux disease, Helicobacter pylori infection, peptic ulcer disease, liver diseases, inflammatory bowel disease, coeliac disease, and functional gastrointestinal disorders. Scientific knowledge demonstrates that the noncommunicable disease burden can be greatly reduced if cost-effective preventive and curative actions, along with interventions for prevention and control of noncommunicable diseases already available, are implemented in an effective and balanced manner. SUMMARY: Future research will have to elaborate on simple methods for preselection of patients at high risk to allow their implementation in strategies and respect all demand of cost-effectiveness. Understanding trends in GI illnesses could be helpful to meet the needs of patients and decrease the disease burden.

Metabolic Syndrome in Inflammatory Bowel Disease: Association with Genetic Markers of Obesity and Inflammation.

Background: This study analyzed poorly understood relationship of two overlapping conditions: metabolic syndrome (MeS) and inflammatory bowel disease (IBD), both associated with inflammation in the visceral adipose tissue. Methods: Newly diagnosed 104 IBD patients, of which 50 Crohn's disease (CD) and 54 ulcerative colitis (UC), and 45 non-IBD controls were examined for MeS-related obesity and lipid markers. Th-17 immune genes IL17A, IL17F, IL23A, and TLR9 mRNAs were measured in intestinal mucosa by qRT-PCR. Subjects were genotyped for obesity-associated FTO variant rs9939609 by polymerase chain reaction-amplification refractory mutation system. Results: CD was associated with MeS (P = 0.01), while both CD and UC were associated with central obesity (P = 10-5, P = 0.002, respectively) and low levels of high-density lipoprotein (HDL) cholesterol (P = 5 × 10-6, P = 6 × 10-6, respectively). IBD lipid profile was characterized by decreased total and HDL cholesterol, while low-density lipoprotein cholesterol was reduced only in CD. Negative correlations were found between total cholesterol and CD activity index (P = 0.005), waist circumference and IL17A as well as IL17F mRNA levels in inflamed CD colon (P = 0.003, P = 0.001, respectively). Carriers of FTO rs9939609 AA genotype showed increased risk of CD (OR 2.6, P = 0.01). Conclusions: MeS, central obesity, and dyslipidemia could be important for IBD pathogenesis. This could influence therapeutic approaches and prevention strategies in high-risk groups.

Why the N (Nutrition) was Added in the EAGEN Acronym?

BACKGROUND: Nutrition has been neglected for a long time as an important factor in the pathogenesis of digestive diseases, but also in the treatment, despite Hippocrates long ago insisted "Let food be thy medicine and medicine be thy food." SUMMARY: New insights into the importance of nutrition in the emergence of disease, and especially in the field of prevention of diseases of the digestive tract, impose the need to pay special attention to the nutrition field. The goal of nutrition as one of the focuses of European Association on Gastroenterology, Endoscopy and Nutrition (EAGEN) activities means awareness of the importance and the goal of making nutrition knowledge a part of comprehensive gastroenterologist's continuous education. All the above arguments directed the EAGEN to have nutrition (N) - in the name of the organization - acronym, on an equal basis with clinical gastroenterology (G) and endoscopy (E). Key Messages: "Nomen est omen" - The name is a sign, the name speaks for itself; that is, the best explanation for a name change in the fifth decade of organization's existence and activity, such as pointing to the direction of future activities and priorities.

Assessment of Duodenal Adenomas and Strategies for Curative Therapy.

BACKGROUND: The increasing incidence of duodenal neoplasm has underlined different methods of resection depending on the clinical presentation, endoscopic features and histopathology. In this comprehensive review, we systematically describe the current knowledge concerning the diagnosis and management of duodenal adenomas (DAs) and discuss data considering all possible therapeutic approaches. SUMMARY: Among a variety of duodenal lesions, including neuroendocrine tumors and gastrointestinal stromal tumors, DAs present precancerous lesions of the duodenal papilla or non-ampullary region necessitating removal. DAs can occur sporadically (SDA) as rare lesions or relatively common in polyposis syndromes. The endoscopic resections of DA are associated with an increased degree of complexity due to distinctive anatomical properties of the duodenal wall, luminal diameter and the presence of ampulla with pancreatic and biliary drainage. The endoscopic techniques including cold snare polypectomy (CSP), endoscopic mucosal resection (EMR), and argon plasma coagulation ablation are suggested to be less invasive than surgical treatment, associated with shorter hospital stay and lower cost. According to the current clinical practice, surgery has been accepted as standard therapeutic approach in familial adenomatous polyposis patients with severe polyposis or DA not amenable to endoscopic resection. Key Messages: The strategy for endoscopic resection of DAs depends on the lesion size, morphology, location, and histopathology findings. Small adenomas are most frequently diagnosed and removed by standard CSP techniques, while large laterally spreading lesions and ampullary adenoma are referred for EMR or endoscopic papillectomy respectively. Screening colonoscopy is indicated in patients with SDA. Additional studies for new endoscopic strategies and techniques for curative therapy of DAs are needed to refine future management decisions. Complete resection of DA is considered curative, but nevertheless, long-term endoscopic follow-up is still required to detect and treat any recurrent arising lesions.

Gastrointestinal Tract Disorders in Older Age.

Considering an increase in the life expectancy leading to a rise in the elderly population, it is important to recognize the changes that occur along the process of aging. Gastrointestinal (GI) changes in the elderly are common, and despite some GI disorders being more prevalent in the elderly, there is no GI disease that is limited to this age group. While some changes associated with aging GI system are physiologic, others are pathological and particularly more prevalent among those above age 65 years. This article reviews the most important GI disorders in the elderly that clinicians encounter on a daily basis. We highlight age-related changes of the oral cavity, esophagus, stomach, small and large bowels, and the clinical implications of these changes. We review epidemiology and pathophysiology of common diseases, especially as they relate to clinical manifestation in elderly. Details regarding management of specific disease are discussed in detail if they significantly differ from the management for younger groups or if they are associated with significant challenges due to side effects or polypharmacy. Cancers of GI tract are not included in the scope of this article.