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.

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.

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.

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: GP Approach.

BACKGROUND: Anemia is a presentation of an underlying disease or deficiency. As stated by the WHO, anemia is defined as hemoglobin (Hb) levels <12.0 g/dL in women and <13.0 g/dL in men. This review of clinical practice aimed to determine the diagnostic approach to anemia in primary care patients. SUMMARY: Nutritional deficiencies, medications, chronic inflammatory conditions, malignancy, renal dysfunction, and bone marrow and inherent disorders contribute to anemia development. Anemia is classified and diagnosed by the values of hematological parameters, underlying pathological mechanism, and patient history. The diagnostic approach of anemia in primary care settings is focused on history, physical examination, laboratory findings including complete blood cell count, reticulocyte count, and peripheral smear examination, fecal occult blood test, and ultrasound findings. KEY MESSAGES: Anemia is the most common hematological disorder that represents a major health burden worldwide. Hb levels alter with gender, ethnicity, and physiological status. Anemia is often multifactorial. The evaluation of a patient with anemia in primary care includes clinical history, physical examination, and laboratory findings with fecal occult blood test and abdominal ultrasound. The wide variations in general practice in European countries are based on different health care systems but also knowledge of GPs that reflect educational and research policy.

Jaundice as a Diagnostic and Therapeutic Problem: A General Practitioner's Approach.

BACKGROUND: Jaundice is a common clinical finding in clinical practice of hepatologists and general practitioners. It occurs when serum bilirubin levels exceed 3 mg/dL. SUMMARY: In this review, we summarize the pathophysiological mechanism of jaundice, clinical approach to the patient with jaundice, and laboratory and imaging techniques. Clinical presentation of jaundice manifests through yellow skin and sclera coloration. Evaluation of every patient includes detailed medical history and examination. In the laboratory, evaluation of enzymes of hepatic inflammation as well as cholestatic enzymes with serum bilirubin must be included. Additional laboratory analysis and imaging modalities are needed in order to differentiate jaundice etiology. Moreover, imaging is available and needed in further evaluation, and treatment is dependent on the underlying cause. KEY MESSAGES: In this review, we will outline the pathophysiological mechanism of jaundice, clinical approach to the patient with jaundice, and diagnostic and treatment approach to these patients.

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.

Accuracy and Pitfalls in the Assessment of Early Gastrointestinal Lesions.

Superficial neoplastic lesions of the digestive tract are usually asymptomatic, and often represent incidental findings on endoscopy. The Paris Classification was developed for the systematic evaluation of superficial lesions of the oesophagus, stomach and colon. The significance of this classification in clinical practice is that it allows the depth of invasion to be estimated. Chromoendoscopy is used to improve the visualization of gastrointestinal lesions. There are 2 types of chromoendoscopy: dye and virtual chromoendoscopy. In addition to chromoendoscopy, advanced endoscopy techniques have great importance in the detection of early gastrointestinal lesions. Although the depth of invasion can be estimated by endoscopy, the final decision regarding therapeutic approach is made on the basis of histopathological examination, as obtained by biopsy or endoscopic resection (ER). Polypectomy, endoscopic mucosal resection, and endoscopic submucosal dissection may be considered ER. For early gastrointestinal lesions with or without limited submucosal infiltration, ER can serve as therapy. In patients with neoplastic lesions localized deeper than the submucosa, or if the location of the lesion carries a high risk of perforation, a full-thickness resection can be performed. Guidelines for assessment and therapy of early oesophageal, gastric and colorectal lesions are currently available.

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.

General Aspects of Primary Cancer Prevention.

BACKGROUND: Cancer is the second leading cause of death worldwide next to cardiovascular diseases. Despite the advancement in screening, early diagnosis, and development in treatment technology in last several decades, cancer incidence overall, particularly that of gastrointestinal (GI) cancers, is far from being controlled, and is expected to increase worldwide. SUMMARY: Although numerous preclinical and population-based clinical studies have already made important progress in restraining the overall cancer incidence and mortality, the full potential of preventive strategy is still far from being realized, and remains at an early stage. There are several major challenges regarding this issue, and one of the crucial challenges is to maintain the balance between risks and benefits. As a result of past investments, primary prevention nowadays include the integration of various activities such as lifestyle changes to reduce risk, screening to detect early lesions, vaccines and preventive therapies aimed to actively interrupt the carcinogenic pathway. Long-term aspirin use seems to have the largest potential effect on the general population on cancer incidence and mortality overall, especially GI cancers. Helicobacter pylori eradication reduces the risk for gastric cancer and is advocated regardless of the symptoms and stage of disease. Metformin and statins are promising in cancer prevention in patients with type 2 diabetes. Vitamin D supplementation is promising in the prevention of colorectal adenoma recurrence. Key Message: However, additional studies are warranted to establish the potential of various agents and to identify more specific and highly targeted new agents for chemoprevention in digestive oncology.

The Polymorphism rs3024505 (C/T) Downstream of the IL10 Gene Is Associated with Crohn's Disease in Serbian Patients with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), manifesting as Crohn's disease (CD) and ulcerative colitis (UC), is characterized by recurring episodes of inflammation in gastrointestinal tract, in which aberrant production of regulatory cytokine interleukin-10 (IL-10) presumably plays important role. Single nucleotide polymorphisms (SNPs) that affect IL-10 production, such as rs1800896 (G/A) at position -1082 and rs1800871 (C/T) at position -819 in the promoter region of the IL10 gene, have been associated with CD and/or UC, but the results were inconsistent. Another SNP that may alter IL-10 production, rs3024505 (C/T) located immediately downstream of the IL10 gene has been recently identified. T allele of rs3024505 was associated with both UC and CD in Western populations, but the studies from East European countries are lacking. Therefore, our aim was to assess the association of rs3024505, rs1800896 and rs1800871 with Serbian IBD patients. To this end, 107 CD and 99 UC patients and 255 healthy controls were genotyped. As a result, T allele of rs3024505 was associated with CD at allelic, genotypic (GT genotype) and haplotypic (GCCT haplotype) level, suggesting potential role of this variant in susceptibility to CD. In contrast, CD patients carrying C allele of rs3024505 had significantly increased risk of anemia and stricturing/penetrating behavior. No association was observed between rs3024505 and UC or SNPs in IL10 promoter region and any form of IBD. In conclusion, rs3024505 SNP flanking the IL10 gene is associated with susceptibility and severity of disease in Serbian CD patients, further validating its role as a potential biomarker in IBD.

Epidemiological trends in stomach-related diseases.

Epidemiology is a study of disease variations by geography, population demographics and time. Temporal influences can manifest themselves as age effects, period effects, cohort effects, seasonal or monthly variations. The acquisition of Helicobacter pylori infection during early childhood and the ensuing risk for the future development of peptic ulcer or gastric cancer represents a typical example for a cohort effect in digestive diseases. The incidence and prevalence of uncomplicated peptic ulcer have decreased in recent years, largely because of the availability of treatment to eradicate H. pylori and the decreasing prevalence of H. pylori infection. Nowadays, gastric and duodenal ulcers tend to occur in older people, who were more likely to have been exposed to H. pylori in their childhood than recently born generations. The overall incidence of gastric cancers is declining; however, there has been a relative increase in the incidence of tumors of the esophagogastric junction and gastric cardia. Thus, by extrapolating the strong, stable and consistent mortality rate declines in recent decades, gastric cancer was projected to become increasingly less important as a cause of death in Europe in the next decades.

Could Capsule Endoscopy Be Useful in Detection of Suspected Small Bowel Bleeding and IBD-10 Years of Single Center Experience.

A retrospective study in patients who underwent video capsule endoscopy (VCE) between 2006 and 2016 was conducted in the Clinic for gastroenterology and Hepatology, University Clinical Center of Serbia. A total of 245 patients underwent VCE. In 198 patients the indication was obscure gastrointestinal bleeding (OGIB), with 92 patients having overt and the other 106 occult bleeding. The remaining 47 patients underwent VCE due to suspected small bowel (SB) disease (i.e., Von Hippel-Lindau syndrome, familial adenomatous polyposis, Peutz Jeghers syndrome, Crohn's disease, prolonged diarrhea, abdominal pain, congenital lymphangiectasia, protein-losing enteropathy, tumors, refractory celiac disease, etc.). VCE identified a source of bleeding in 38.9% of patients (in the obscure overt group in 48.9% of patients, and in the obscure occult group in 30.2% of patients). The most common findings were angiodysplasias, tumors, Meckel's diverticulum and Crohn's disease. In the smaller group of patients with an indication other than OGIB, 38.3% of patients had positive VCE findings. The most common indication is OGIB, and the best candidates are patients with overt bleeding; patients with IBD should be evaluated in this setting.

Extraintestinal manifestations of autoimmune pancreatitis.

The term autoimmune pancreatitis (AIP) was first used in Japan in 1995 to describe a newly recognized form of chronic pancreatitis, after the description of Yoshida and colleagues. But Sarles in 1961, first described a form of idiopathic chronic inflammatory sclerosis of the pancreas, suspected to be due to an autoimmune process. AIP has become a widely accepted term because clinical, serologic, histologic, and immunohistochemical findings suggest an autoimmune mechanism. Most affected patients have hypergammaglobulinemia and increased serum levels of IgG, particularly IgG4. Recently published International Consensus Diagnostic Criteria for Autoimmune Pancreatitis include Guidelines of the International Association of Pancreatology, classifying AIP into types 1 and 2, using five cardinal features of AIP, namely imaging of pancreatic parenchyma and duct, serology, other organ involvement, pancreatic histology, and an optional criterion of response to steroid therapy. Extrapancreatic presentations can include sclerosing cholangitis, retroperitoneal fibrosis, sclerosing sialadenitis (Küttner tumor), lymphadenopathy, nephritis, and interstitial pneumonia. Increased IgG4+ plasma cell infiltrate has been reported in sclerosing lesions from other organ sites, including inflammatory pseudotumors of the liver, breast, mediastinum, orbit, and aorta, and it has been observed with hypophysitis and IgG4-associated prostatitis. Abundant IgG4+ plasma cells were also confirmed in Riedel thyroiditis, sclerosing mesenteritis, and inflammatory pseudotumor of the orbit and stomach. Extrapancreatic lesions could be synchronously or metachronously diagnosed with AIP, sharing the same pathological conditions, showing also a favorable result to corticosteroid therapy and distinct differentiation between IgG4-related diseases from the inherent lesions of the corresponding organs.

Ursodeoxycholic acid for primary biliary cirrhosis.

BACKGROUND: Ursodeoxycholic acid is administered to patients with primary biliary cirrhosis, a chronic progressive inflammatory autoimmune-mediated liver disease with unknown aetiology. Despite its controversial effects, the U.S. Food and Drug Administration has approved its usage for primary biliary cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of ursodeoxycholic acid in patients with primary biliary cirrhosis. SEARCH METHODS: We searched for eligible randomised trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, Clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform. The literature search was performed until January 2012. SELECTION CRITERIA: Randomised clinical trials assessing the beneficial and harmful effects of ursodeoxycholic acid versus placebo or 'no intervention' in patients with primary biliary cirrhosis. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. Continuous data were analysed using mean difference (MD) and standardised mean difference (SMD). Dichotomous data were analysed using risk ratio (RR). Meta-analyses were conducted using both a random-effects model and a fixed-effect model, with 95% confidence intervals (CI). Random-effects model meta-regression was used to assess the effects of covariates across the trials. Trial sequential analysis was used to assess risk of random errors (play of chance). Risks of bias (systematic error) in the included trials were assessed according to Cochrane methodology bias domains. MAIN RESULTS: Sixteen randomised clinical trials with 1447 patients with primary biliary cirrhosis were included. One trial had low risk of bias, and the remaining fifteen had high risk of bias. Fourteen trials compared ursodeoxycholic acid with placebo and two trials compared ursodeoxycholic acid with 'no intervention'. The percentage of patients with advanced primary biliary cirrhosis at baseline varied from 15% to 83%, with a median of 51%. The duration of the trials varied from 3 to 92 months, with a median of 24 months. The results showed no significant difference in effect between ursodeoxycholic acid and placebo or 'no intervention' on all-cause mortality (45/699 (6.4%) versus 46/692 (6.6%); RR 0.97, 95% CI 0.67 to 1.42, I² = 0%; 14 trials); on all-cause mortality or liver transplantation (86/713 (12.1%) versus 89/706 (12.6%); RR 0.96, 95% CI 0.74 to 1.25, I² = 15%; 15 trials); on serious adverse events (94/695 (13.5%) versus 107/687 (15.6%); RR 0.87, 95% CI 0.68 to 1.12, I² = 23%; 14 trials); or on non-serious adverse events (27/643 (4.2%) versus 18/634 (2.8%); RR 1.46, 95% CI 0.83 to 2.56, I² = 0%; 12 trials). The random-effects model meta-regression showed that the risk of bias of the trials, disease severity of patients at entry, ursodeoxycholic acid dosage, and trial duration were not significantly associated with the intervention effects on all-cause mortality, or on all-cause mortality or liver transplantation. Ursodeoxycholic acid did not influence the number of patients with pruritus (168/321 (52.3%) versus 166/309 (53.7%); RR 0.96, 95% CI 0.84 to 1.09, I² = 0%; 6 trials) or with fatigue (170/252 (64.9%) versus 174/244 (71.3%); RR 0.90, 95% CI 0.81 to 1.00, I² = 62%; 4 trials). Two trials reported the number of patients with jaundice and showed a significant effect of ursodeoxycholic acid versus placebo or no intervention in a fixed-effect meta-analysis (5/99 (5.1%) versus 15/99 (15.2%); RR 0.35, 95% CI 0.14 to 0.90, I² = 51%; 2 trials). The result was not supported by the random-effects meta-analysis (RR 0.56, 95% CI 0.06 to 4.95). Portal pressure, varices, bleeding varices, ascites, and hepatic encephalopathy were not significantly affected by ursodeoxycholic acid. Ursodeoxycholic acid significantly decreased serum bilirubin concentration (MD -8.69 µmol/l, 95% CI -13.90 to -3.48, I² = 0%; 881 patients; 9 trials) and activity of serum alkaline phosphatases (MD -257.09 U/L, 95% CI -306.25 to -207.92, I² = 0%; 754 patients, 9 trials) compared with placebo or no intervention. These results were supported by trial sequential analysis. Ursodeoxycholic acid also seemed to improve serum levels of gamma-glutamyltransferase, aminotransferases, total cholesterol, and plasma immunoglobulin M concentration. Ursodeoxycholic acid seemed to have a beneficial effect on worsening of histological stage (random; 66/281 (23.5%) versus 103/270 (38.2%); RR 0.62, 95% CI 0.44 to 0.88, I² = 35%; 7 trials). AUTHORS' CONCLUSIONS: This systematic review did not demonstrate any significant benefits of ursodeoxycholic acid on all-cause mortality, all-cause mortality or liver transplantation, pruritus, or fatigue in patients with primary biliary cirrhosis. Ursodeoxycholic acid seemed to have a beneficial effect on liver biochemistry measures and on histological progression compared with the control group. All but one of the included trials had high risk of bias, and there are risks of outcome reporting bias and risks of random errors as well. Randomised trials with low risk of bias and low risks of random errors examining the effects of ursodeoxycholic acid for primary biliary cirrhosis are needed.

Bezafibrate for primary biliary cirrhosis.

BACKGROUND: Treatment of primary biliary cirrhosis is complicated. There are studies suggesting that bezafibrate, alone or in combination with ursodeoxycholic acid (UDCA), is effective in the treatment of primary biliary cirrhosis, but no systematic review has summarised the evidence yet. OBJECTIVES: To assess the beneficial and harmful effects of bezafibrate in patients with primary biliary cirrhosis. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, Clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. The searches in Chinese Bio-medical Literature Database, China Network Knowledge Information, Chinese Science Journal Database, Chinese Medical Citation Index, Wanfang Database, and full text searches were conducted until January 2011. Manufacturers and authors were contacted. SELECTION CRITERIA: All randomised clinical trials comparing bezafibrate at any dose or regimen in patients with primary biliary cirrhosis with placebo or no intervention, or with another drug. Any concomitant interventions were allowed if received equally by all treatment groups in a trial. DATA COLLECTION AND ANALYSIS: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD), and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Methodological domains were used to assess risk of systematic errors (bias). Trial sequential analysis was used to control for random errors (play of chance). MAIN RESULTS: Six trials with 151 Japanese patients were included. All trials had high risk of bias. Four trials compared bezafibrate plus UDCA with no intervention plus UDCA (referenced as bezafibrate versus no intervention in the remaining text), and two trials compared bezafibrate with UDCA. No patient died and no patient developed liver-related complications in any of the included trials. Bezafibrate was without significant effects on the occurrence of adverse events compared with no intervention (5/32 (16%) versus 0/28 (0%)) (RR 5.40, 95% CI 0.69 to 42.32; 3 trials with 60 patients; I² = 0%) or with UDCA (2/32 (6%) versus 0/37 (0%)) (RR 6.19, 95% CI 0.31 to 122.05; 2 trials with 69 patients; I² = 0%). Bezafibrate significantly decreased the activity of serum alkaline phosphatases compared with no intervention (MD -186.04 U/L, 95% CI -249.03 to -123.04; 4 trials with 79 patients; I² = 34%) and when compared with UDCA (MD -162.90 U/L, 95% CI -199.68 to -126.12; 2 trials with 48 patients; I² = 0%). These results were supported by trial sequential analyses. Bezafibrate compared with no intervention significantly decreased plasma immunoglobulin M (MD -164.00 mg/dl, 95% CI -259.47 to -68.53; 3 trials with 50 patients; I² = 46%) and serum bilirubin concentration (MD -0.19 mg/dl, 95% CI -0.38 to -0.00; 2 trials with 34 patients; I² = 0%). However, the latter two results were not supported by trial sequential analyses. Bezafibrate compared with no intervention had no significant effect on the activity of serum gamma-glutamyltransferase (MD -1.22 U/L, 95% CI -11.97 to 9.52; 4 trials with 79 patients; I² = 42%) and serum alanine aminotransferase (MD -5.61 U/L, 95% CI -24.50 to 13.27; 2 trials with 35 patients; I² = 34%). Bezafibrate compared with UDCA had no significant effect on the activity of serum gamma-glutamyltransferase (MD 38.44 U/L, 95% CI -180.67 to 257.55; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -2.34 U/L, 95% CI -34.73 to 30.06; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -20.23 mg/dl, 95% CI -218.71 to 178.25; 2 trials with 41 patients; I² = 90%) in random-effects model meta-analyses, but bezafibrate significantly decreased the activity of serum gamma-glutamyltransferase (MD -58.18, 95% CI -76.49 to -39.88; 2 trials with 49 patients; I² = 89%), serum alanine aminotransferase (MD -13.94, 95% CI -18.78 to -9.09; 2 trials with 49 patients; I² = 95%), and plasma immunoglobulin M concentration (MD -99.90, 95% CI -130.72 to -69.07; 2 trials with 41 patients; I² = 90%) in fixed-effect model meta-analyses. One patient had bezafibrate withdrawn due to an adverse event compared to no intervention (RD 0.03, 95% CI -0.09 to 0.16; 2 trials with 60 patients; I² = 0%). AUTHORS' CONCLUSIONS: This systematic review did not demonstrate any effect of bezafibrate versus no intervention on mortality, liver-related morbidity, adverse events, and pruritus in patients with primary biliary cirrhosis. Furthermore, we found no significant effects of bezafibrate on mortality, liver-related morbidity, or adverse events when compared with ursodeoxycholic acid, None of the trials assessed quality of life or fatigue. The data seem to indicate a possible positive intervention effect of bezafibrate on some liver biochemistry measures compared with the control group, but the observed effects could be due to systematic errors or random errors. We need more randomised clinical trials on the effects of bezafibrate on primary biliary cirrhosis with low risks of systematic errors and random errors.

Complications of peptic ulcer disease.

There are four major complications of peptic ulcer disease (PUD): bleeding, perforation, penetration, and obstruction. Complications can occur in patients with peptic ulcer of any etiology. Despite improvements in the medical management and the lower overall incidence of PUD, there are conflicting data about the incidence of potentially life-threatening ulcer complications. There are important time trends embedded within this stable overall rate of complications: the dramatic decline in the prevalence of Helicobacter pylori (comparing the cohort born from 1900 to 1920 to cohorts born after 1940); an increased use of nonsteroidal anti-inflammatory drugs, and an increased rate of ulcer complications related to such drug use, especially in the elderly. As a result of these trends, ulcer complications are on the rise in older patients but on the decline in younger individuals. Hemorrhage is the most frequent PUD complication and its incidence is increasing in comparison to perforation and stenosis. Therapeutic endoscopy is considered the treatment of choice for bleeding ulcers, reducing the need for emergent surgical procedures to 10-20% of the cases. In recent years, besides the success of angiographic embolization, the containment of massive hemorrhage must also be taken into account. Transcatheter arterial embolization is also an effective and safe treatment in patients with duodenal ulcers re-bleeding after therapeutic endoscopy or surgery.

Bisphosphonates for osteoporosis in primary biliary cirrhosis.

BACKGROUND: Bisphosphonates are widely used for treatment of postmenopausal osteoporosis. Patients with primary biliary cirrhosis often have osteoporosis - either postmenopausal or secondary to the liver disease. No systematic review or meta-analysis has assessed the effects of bisphosphonates for osteoporosis in patients with primary biliary cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of bisphosphonates for osteoporosis in primary biliary cirrhosis. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and full text searches were conducted until November 2011. Manufacturers and authors were contacted for additional studies during the conductance of the review. SELECTION CRITERIA: All randomised clinical trials of bisphosphonates in primary biliary cirrhosis compared with placebo or no intervention, or another bisphosphonate, or any other drug. DATA COLLECTION AND ANALYSIS: Two authors extracted data. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) or risk difference (RD) and of continuous data with mean difference (MD) or standardised mean difference (SMD), all with 95% confidence intervals (CI). Methodological components were used to assess risk of systematic errors (bias). Trial sequential analysis was also used to control for random errors (play of chance). MAIN RESULTS: Six trials were included. Three trials with 106 participants, of which two trials with high risk of bias, did not demonstrate significant effects of bisphosphonates (etidronate or alendronate) versus placebo or no intervention regarding mortality (RD 0.00; 95% CI -0.12 to 0.12, I² = 0%), fractures (RR 0.87; 95% CI 0.29 to 2.66, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04). Two trials with 62 participants with high risk of bias compared one bisphosphonate (etidronate or alendronate) versus another (alendronate or ibandronate) and found no significant difference regarding mortality (RD -0.03; 95% CI -0.14 to 0.07, I² = 0%), fractures (RR 0.95; 95% CI 0.18 to 5.06, I² = 0%), or adverse events (RR 1.00; 95% CI 0.49 to 2.04, I² = 0%). Bisphosphonates had no significant effect on liver-related mortality, liver transplantation, or liver-related morbidity compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates had no significant effect on bone mineral density compared with placebo or no intervention, or another bisphosphonate. Bisphosphonates compared with placebo or no intervention seem to decrease the urinary amino telopeptides of collagen I (NTx) concentration (MD -16.93 nmol bone collagen equivalents/mmol creatinine; 95% CI -23.77 to -10.10; 2 trials with 88 patients; I² = 0%) and serum osteocalcin (SMD -0.81; 95% CI -1.22 to -0.39; 3 trials with 100 patients; I² = 34 %) concentration. The former result was supported by trial sequential analysis, but not the latter. Alendronate compared with another bisphosphonate (ibandronate) had no significant effect on serum osteocalcin concentration (MD -3.61 ng/ml, 95% CI -9.41 to 2.18; 2 trials with 47 patients; I² = 82%) in a random-effects meta-analysis, but it significantly decreased serum osteocalcin (MD -4.40 ng/ml, 95% CI -6.75 to -2.05; 2 trials with 47 patients; I² = 82%), the procollagen type I N-terminal propeptide (MD -8.79 ng/ml, 95% CI -15.96 to -1.63; 2 trials with 47 patients; I² = 38%), and NTx concentration (MD -14.07 nmol bone collagen equivalents/mmol creatinine, 95% CI -24.23 to -3.90; 2 trials with 46 patients; I²=0%) in a fixed-effect model. The latter two results were not supported by trial sequential analyses. There was no statistically significant difference in the number of patients having bisphosphonates withdrawn due to adverse events compared with placebo or no intervention (RD -0.04; 95% CI -0.21 to 0.12; 2 trials with 46 patients; I² = 0%), or another bisphosphonate (RR 0.56; 95% CI 0.14 to 2.17; 2 trials with 62 patients; I² = 0%). One trial with 32 participants and with high risk of bias compared etidronate versus sodium fluoride without finding significant difference regarding mortality, fractures, adverse events, or bone mineral density. Etidronate compared with sodium fluoride significantly decreased serum osteocalcin, urinary hydroxyproline, and parathyroid hormone concentration. AUTHORS' CONCLUSIONS: We did not find evidence to support or refute the use of bisphosphonates for patients with primary biliary cirrhosis. The data seem to indicate a possible positive intervention effect of bisphosphonates on decreasing urinary amino telopeptides of collagen I concentration compared with placebo or no intervention with no risk of random error. There is need for more randomised clinical trials assessing the effects of bisphosphonates for osteoporosis on patient-relevant outcomes in primary biliary cirrhosis.