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The use of artificial intelligence is rapidly increasing in medicine to support clinical decision making mostly through diagnostic and prediction models. Such models derive from huge databases (big data) including a large variety of health-related individual patient data (input) and the corresponding diagnosis and/or outcome (labels). Various types of algorithms (e.g. neural networks) based on powerful computational ability (machine), allow to detect the relationship between input and labels (learning). More complex algorithms, like recurrent neural network can learn from previous as well as actual input (deep learning) and are used for more complex tasks like imaging analysis and personalized (bespoke) medicine. The prompt availability of big data makes that artificial intelligence can provide rapid answers to questions that would require years of traditional clinical research. It may therefore be a key tool to overcome several major gaps in the model of advanced chronic liver disease, mostly transition from mild to clinically significant portal hypertension, the impact of acute decompensation and the role of further decompensation and treatment efficiency. However, several limitations of artificial intelligence should be overcome before its application in clinical practice. Assessment of the risk of bias, understandability of the black boxes developing the models and models' validation are the most important areas deserving clarification for artificial intelligence to be widely accepted from physicians and patients.

JC virus is a member of the Polyomavirus family, infects humans worldwide, and 90% of the population carry antibodies to the virus by adult life. The initial infection is asymptomatic, but it may become persistent. JC virus DNA is frequently present in the upper and lower gastrointestinal tracts of healthy adults. Chronic idiopathic intestinal pseudo-obstruction, one of the most severe gastrointestinal motility disorders, is a condition characterized by a clinical picture mimicking small bowel occlusion with related symptoms and signs in the absence of demonstrable mechanical obstruction. Because of the known neuropathic capability of this virus, and its frequent presence in the gut, it has been proposed that JCV might be detectable in tissues of patients with chronic idiopathic intestinal pseudo-obstruction, and possibly be involved in the pathogenesis of this disease, because the virus may actively infect the enteroglial cells of the myenteric plexuses of the patients with chronic idiopathic intestinal pseudo-obstruction. We report two cases of upper idiopathic intestinal pseudo-obstruction associated with JCV infection.

Transition from compensated to decompensated cirrhosis, defined by overt clinical signs, represents a turning point in the clinical course of the disease. In fact, while compensated cirrhosis is a silent disease characterized by long survival, decompensated cirrhosis is associated with symptoms markedly reducing the quality of life and with a median survival of 2–4 years. Therefore, identifying predictors of decompensation and investigating potential interventions for its prevention is a major objective. Mechanisms and incidence of decompensation, together with its predictors, are summarized here, with regard to the etiology of the disease. In a total of 92 studies including 105 cohorts and 152,320 patients, the mean ± SD 5-year decompensation rate was 24.5 ± 13.6%. The 5-year decompensation rate was significantly different across different etiologies, ranging from 12.8% for biliary etiologies to 33.6% in alcoholic liver disease (p

Background & Aims Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. Methods In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. Conclusions In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. Lay summary While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

There is a universal agreement that the occurrence of clinical complications, such as ascites, hepatic encephalopathy, gastrointestinal bleeding, and jaundice mark the transition from the compensated to the decompensated stage of cirrhosis. Decompensation is associated with a substantial worsening of patient prognosis and is therefore considered the most important stratification variable for the risk of death. However, this classification is an oversimplification, as it does not discriminate between the prognostic subgroups that characterise the course of decompensation, which depends on the type and number of decompensating events. A deeper insight into the clinical course of decompensated cirrhosis is provided by observational studies characterising acute decompensation (AD), which occurs mostly in patients who have already experienced decompensating events. Decompensation presents as AD in a portion of patients while in many others it presents as a slow development of ascites or mild grade 1 or 2 hepatic encephalopathy, or jaundice, not requiring hospitalisation. Thus, we propose that decompensation of cirrhosis occurs through 2 distinct pathways: a non-acute and an acute (which includes acute-on-chronic liver failure) pathway. Moreover, while non-acute decompensation is the most frequent pathway of the first decompensation, AD mostly represents further decompensation.

Traditionally, the complications of cirrhosis, namely variceal bleeding, ascites and hepatic encephalopathy, were thought to result predominantly from circulatory dysfunction and altered organ perfusion arising as a result of portal hypertension. Over the past 20 years, large, international prospective studies have indicated the importance of systemic inflammation and organ immunopathology as additional determinants of organ dysfunction in cirrhosis, which not only manifests in the liver, brain, circulation and the kidneys, but also the immune system, gut, muscles, adrenal glands, reproductive organs, heart and lungs. This review provides an overview of the traditional and emerging concepts around the initiation and maintenance of organ dysfunction in cirrhosis and proposes a new paradigm based upon a better understanding of acute decompensation of cirrhosis. The interaction between the traditional concepts and the emerging perspectives remains a matter of great interest and the basis for future research.

Portal hypertension and ascites are two crucial events in the natural history of liver cirrhosis, whose appearance marks a downward shift in the prognosis of the disease. Over the years, several international and national societies have issued clinical practice guidelines for the diagnosis and management of portal hypertension and ascites. The present document addresses the needs of an updated guidance on the clinical management of these conditions. Accordingly, the AISF Governing Board appointed a multi-disciplinary committee of experts for drafting an update of the most recent EASL Clinical Practice Guidelines. The aim of this work was to adapt the EASL recommendations to national regulations and resources, local circumstances and settings, infrastructure, and cost/benefit strategies to avoid duplication of efforts and optimize resource utilization. The committee defined the objectives, the key issues and retrieved the relevant evidence by performing a systematic review of the literature. Finally, the committee members (chosen on the basis of their specific expertise) identified the guidelines’ key questions and developed them following the PICO format (Population, Intervention, Comparison, Outcomes). For each of the PICO questions, the systematic review of the literature was made on the most important scientific databases (Pubmed, Scopus, Embase)

Background and aims Prevention of decompensation is a primary therapeutic target in patients with compensated cirrhosis (CC). However, a major problem is the large sample size and long follow-up required to demonstrate a significant treatment effect because of the relatively low baseline risk. For this reason, it has been recently suggested that ordinal outcomes may be used in this area to gain power and reduce sample size. The aim of this study was to assess the applicability of ordinal outcomes in cirrhosis. Approach and results An inception cohort of 202 patients with CC (no ascites, gastrointestinal bleeding, encephalopathy, or jaundice) without esophageal varices was included, and 5-year outcome is reported. Etiology was mostly viral and alcoholic, and there were no dropouts. Ordinal outcome was set according to six grades with a previously established prognostic ordinality: grade 1 = no disease progression; grade 2 = development of varices; grade 3 = bleeding alone; grade 4 = nonbleeding single decompensation; grade 5 = more than one decompensating event; and grade 6 = death. At the 60-month time point, patients were distributed in grades 1 through 6 as follows: 129, 43, 2, 7, 5, and 16, respectively. Emulation of a clinical trial performed by dividing patients based on baseline platelet count into two groups (cutoff, 150 × 109 /L) demonstrated a statistically significant outcome difference between groups when using ordinal outcomes not detectable by binary logistic or chi-square or time-to-event analyses. Additionally, using ordinal outcomes in a hypothetical study to prevent decompensation resulted in sample-size estimates 3-to 4-fold lower than using a binary composite endpoint. Conclusions Compared to traditional binary outcomes, the use of ordinal outcomes in trials of cirrhosis decompensation may provide more power and thus may require a smaller sample size.

The clinical course of cirrhosis has been typically described by a compensated and a decompensated state based on the absence or, respectively, the presence of any of bleeding, ascites, encephalopathy or jaundice. More recently, it has been recognized that increasing portal hypertension and several major clinical events are followed by a marked worsening in prognosis, and disease states have been proposed accordingly in a multistate model. The development of multistate models implies the assessment of the probabilities of more than one possible outcome from each disease state. This requires the use of competing risks analysis which investigates the risk of several competing outcomes. In such a situation, the Kaplanâ Meier risk estimates and the Cox regression may be not appropriate. Clinical states of cirrhosis presently considered as suitable for a comprehensive multistate model include: in compensated cirrhosis, early (mild) portal hypertension with hepatic venous pressure gradient (HVPG) >5 and

Background & Aims The electrocardiographic QT interval frequently is prolonged in patients with cirrhosis. Acute gastrointestinal bleeding further prolongs corrected QT (QTc) in patients with cirrhosis, which has been associated with an increased risk of death within 6 weeks. We aimed to confirm these findings and develop a mortality risk index that incorporates QTc. Methods We collected data from 274 patients with cirrhosis and acute gastrointestinal bleeding from any cause admitted to a hospital in Bologna, Italy, from January 2001 through December 2012 (training set). We used logistic regression analysis to identify patient factors associated with death within 6 weeks (6-week mortality). We validated our findings by using data from 200 patients with cirrhosis and gastrointestinal bleeding treated at 2 separate hospitals in Italy, from 2001 through 2016 and 2007 through 2012. Our primary aim was to confirm the prognostic effects of prolonged QTc in a large population of patients and develop a 6-week mortality risk score for acute gastrointestinal bleeding from any cause that incorporates the QTc interval. Results In the training set, QTc greater than 456 ms, the model for end-stage liver disease-sodium (MELD-Na) score, previous bleeding, and serum albumin concentration were associated independently with 6-week mortality. We combined these parameters to create a risk scoring system that we named MELD-Na acute gastrointestinal bleeding (MELDNa-AGIB). In the validation set, the MELDNa-AGIB identified patients who died within 6 weeks with an area under the receiver operating characteristic curve (AUROC) of 0.888; this value was higher than that of the MELD score (AUROC, 0.838; P = .031), MELD score with updated calibration (AUROC, 0.837; P = .029), Child–Turcotte–Pugh score (AUROC, 0.789; P = .004), D'Amico score (AUROC, 0.761; P = .003), and Augustin score (AUROC, 0.792; P = .001), with a net reclassification improvement better than the MELD-Na score (0.266; P = .045). In calibration, the MELDNa-AGIB produced a high score in the Hosmer–Lemeshow test (P = .947), which was superior to that of MELD-Na (P = .146). In the training set, only 6.3% of patients with MELDNa-AGIB scores of 4 or less died within 6 weeks. Among patients with a scores of 9, 16, and 25 or higher, 15.5%, 41.5%, and 81% or more patients died within 6 weeks, respectively. The probability of survival progressively and significantly decreased with increasing scores in the training and validation sets. Conclusions We confirmed QTc as an independent predictor of 6-week mortality in a large population of patients with cirrhosis and acute gastrointestinal bleeding. The combination of QTc, MELD-Na, previous bleeding, and serum albumin (the MELDNa-AGIB score) accurately determines the risk of 6-week mortality, providing timely identification of patients at very high risk of death.

The interest in prognosis research has been steadily growing during the past few decades because of its impact on clinical decision making. However, since the methodology of prognosis research is still incompletely defined, the quality of published prognosis studies is largely unsatisfactory. Seven major domain for risk of bias in prognosis research have been identified, including study participation, attrition, selection of candidate predictors, outcome definition, confounding factors, analysis, and interpretation of results. The methodology for performing prognostic studies is currently aimed at avoiding such potential biases. Amongst methodologic requirements in prognosis research, the following should be considered most relevant: beforehand publication of the study protocol including the full statistical plan; inclusion of patients at a similar point along the course of the disease; rationale and biological plausibility of candidate predictors; complete information; control of overfitting and underfitting; adequate data handling and analysis; publication of the original data. Validation and analysis of the impact that prediction models have on patient management, are key steps for translation of prognosis research into clinical practice. Finally, transparent reporting of prognostic studies is essential for assessing reliability, applicability and generalizability of study results, and recommendations are now available for this aim.

Portal hypertension is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. Portal hypertension results initially from increased intrahepatic vascular resistance. Later, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure. Reducing portal pressure in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve portal pressure. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as non-alcoholic fatty liver disease, etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing portal pressure. For over 35 years, the mainstay of such therapy has been the use of nonselective beta-blockers that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in pre-clinical and early clinical studies and may act alone or synergistically with nonselective beta-blockers in reducing portal pressure in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2 and 3) in patients with cirrhosis and portal hypertension and to prioritize novel targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals and industry partners.

The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical characteristics. While these disease states do not follow a predictable sequence, they correspond to varying mortality risk. Acute-on-chronic liver failure may occur either in decompensated or in compensated cirrhosis and is always associated with a high short-term mortality. The increasing severity of these disease states prompted the concept of clinical states of cirrhosis. A multistate approach has been considered to describe the clinical course of the disease. Such an approach requires the assessment of the probabilities of different outcomes in each state, which compete with each other to occur first and mark the transition towards a different state. This requires the use of competing risks analysis, since the traditional Kaplan-Meier analysis should only be used in two-state settings. Accounting for competing risks also has implications for prognosis and treatment efficacy research. The aim of this review is to summarise relevant clinical states and to show examples of competing risks analysis in multistate models of cirrhosis.

The trans jugular intrahepatic Porto systemic shunt (TIPS) is no longer viewed as a salvage therapy or a bridge to liver transplantation and is currently indicated for a number of conditions related to portal hypertension with positive results in survival. Moreover, the availability of self-expandable polytetrafluoroethylene (PTFE)-covered endoprostheses has dramatically improved the long-term patency of TIPS. However, since the last updated International guidelines have been published (year 2009) new evidence have come, which have open the field to new indications and solved areas of uncertainty. On this basis, the Italian Association of the Study of the Liver (AISF), the Italian College of Interventional Radiology—Italian Society of Medical Radiology (ICIR-SIRM), and the Italian Society of Anesthesia, Analgesia and Intensive Care (SIAARTI) promoted a Consensus Conference on TIPS. Under the auspices of the three scientific societies, the consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Bergamo on June 4th and 5th, 2015. The final statements presented here were graded according to quality of evidence and strength of recommendations and were approved by an independent jury. By highlighting strengths and weaknesses of current indications to TIPS, the recommendations of AISF-ICIR-SIRM-SIAARTI may represent the starting point for further studies.

Background & Aims Two randomized controlled studies have evaluated the effect of recombinant Factor VIIa (rFVIIa) on variceal bleeding in cirrhosis without showing significant benefit. The aim of the present study was to perform a meta-analysis of the two trials on individual patient data with special focus on high risk patients. Methods The primary outcome measure was the effect of rFVIIa on a composite five day endpoint: failure to control bleeding, 5-day rebleeding or death. Analysis was based on intention to treat. High risk was defined as active bleeding on endoscopy while under vasoactive drug infusion and Child-Pugh score >8. Results 497 patients were eligible for the meta-analysis; 308 (62%) had active variceal bleeding at endoscopy (oozing or spurting) and 283 of these had a Child-Pugh score >8. Analysis on the composite endpoint in all patients with bleeding from oesophageal varices did not show any beneficial treatment effect. However, failure rate for the primary composite end-point was significantly lower in treated patients with active bleeding at endoscopy (17%) compared to placebo (26%, p =0.049). This difference was highly significant in patients with Child-Pugh score >8 and active bleeding at endoscopy (rFVIIa 16%, placebo 27%; p =0.023). No significant treatment effect was found at 42days. Five thromboembolic events occurred in rFVIIa treated patients compared to none in placebo treated patients. Conclusions The current meta-analysis shows a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of rebleeding day 1–5 and 5-day mortality in patients with advanced cirrhosis and active bleeding from oesophageal varices at endoscopy. A major drawback of the treatment is a potential increased risk of arterial thrombo-embolic events. This treatment might be considered in patients with lack of control of bleeding after standard treatment.

In 2011 the three major Italian gastroenterological scientific societies (AIGO, the Italian Society of Hospital Gastroenterologists and Endoscopists; SIED, the Italian Society of Endoscopy; SIGE, the Italian Society of Gastroenterology) prepared their official document aimed at analysing medical care for digestive diseases in Italy, on the basis of national and regional data (Health Ministry and Lombardia, Veneto, Emilia-Romagna databases) and to make proposals for planning of care. Digestive diseases were the first or second cause of hospitalizations in Italy in 1999–2009, with more than 1,500,000 admissions/year; however only 5–9% of these admissions was in specialized Gastroenterology units. Reported data show a better outcome in Gastroenterology Units than in non-specialized units: shorter average length of stay, in particular for admissions with ICD-9-CM codes proxying for emergency conditions (6.7 days versus 8.4 days); better case mix (higher average diagnosis-related groups weight in Gastroenterology Units: 1 vs 0.97 in Internal Medicine units and 0.76 in Surgery units); lower inappropriateness of admissions (16–25% versus 29–87%); lower in-hospital mortality in urgent admissions (2.2% versus 5.1%); for patients with urgent admissions due to gastrointestinnal haemorrhage, in-hospital mortality was 2.3% in Gastroenterology units versus 4.0% in others. The present document summarizes the scientific societies’ official report, which constitutes the “White paper of Italian Gastroenterology”

Summary Background Propranolol is recommended for prophylaxis of variceal bleeding in cirrhosis. Carvedilol is a nonselective beta-blocker with a mild anti-alfa-1-adrenergic activity. Several studies have compared carvedilol and propranolol, yielding inconsistent results. Aim To perform a systematic review and meta-analysis of the randomised clinical trials comparing carvedilol with propranolol for hepatic vein pressure gradient reduction. Methods Studies were searched on the MEDLINE, EMBASE and Cochrane library databases up to November 2013. The weighted mean difference in percent hepatic vein pressure gradient reduction and the relative risk of failure to achieve a hemodynamic response (reduction ≥20% of baseline or to ≤12 mmHg) with each drug were used as measures of treatment efficacy. Results Five studies (175 patients) were included. Indication to treatment was primary prophylaxis of variceal bleeding in 76% of patients. There were overall three acute (60–90 min after drug administration) and three long-term (after 7–90 days of therapy) comparisons. The summary mean weighted difference in % of reduction in hepatic vein pressure gradient was: acute −7.70 (CI −12.40, −3.00), long-term −6.81 (CI −11.35, −2.26), overall −7.24 (CI −10.50, −3.97), favouring carvedilol. The summary relative risk of failure to achieve a hemodynamic response with carvedilol was 0.66 (CI 0.44, 1.00). Adverse events were nonsignificantly more frequent and serious with carvedilol. However, quality of trials was mostly unsatisfactory. Conclusions Carvedilol reduces portal hypertension significantly more than propranolol. However, available data do not allow a satisfactory comparison of adverse events. These results suggest a potential for a cautious clinical use.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death with an increasing prevalence worldwide. Early diagnosis of HCC is important since observational studies have reported that, in patients undergoing surveillance, cancer is diagnosed at an earlier stage with increased chances of curative therapies. Anyway, despite the extensive use of screening for HCC, its effectiveness is still a controversial topic since supporting evidence is not unequivocal and some issues need to be explored. Areas covered: The aim of this paper is to review main literature data supporting performance and effectiveness of screening for early detection of hepatocellular carcinoma. Expert commentary: Clinical benefit of screening for HCC is controversial and there are no sufficient data supporting its effectiveness in reducing cancer specific mortality. Since it is unlikely that RCTs will be performed in the future, surveillance should be still reasonably recommended in all at-risk population, until potential data against its effectiveness will be provided. In the future additional and more effective non-invasive tests will be needed, as well as proper surveillance intervals and risk threshold for surveillance enrollment must be assessed and refined by prospective studies.

Competing risks hamper the occurrence of other clinically relevant events or modify the probability that they occur, therefore altering the correspondence between rate and risk for the outcome of interest. When the correspondence between rate and risk is lost, the Kaplan-Meier estimator provides systematically upward biased estimates of the risk. In this situation, the appropriate analysis is the cumulative incidence function (CIF). The use of competing risks analysis allows to build multistate models to describe the course of diseases. Appropriate multistate models in cirrhosis may allow to assess the risk of major events such as hepatocellular carcinoma, decompensation, refractory ascites, liver-related mortality, and other clinically relevant outcomes. A five-state model has been proposed to fit the clinical course of cirrhosis including two states in compensated and three states in decompensated cirrhosis.

Superior mesenteric artery (SMA) syndrome is an infrequent cause of vomiting and weight loss due to compression of the third part of the duodenum by the SMA. We describe the case of a 17-year-old woman, admitted to our department for progressive dysphagia and severe weight loss due to an oesophageal peptic stricture, caused by chronic acid reflux secondary to duodenal compression by the SMA. Symptoms improved after (par)enteral nutrition and repeated oesophageal dilatation, thus supporting the role of intensive medical and endoscopic intervention as an alternative to surgery, at least in some cases.

BACKGROUND AND AIMS: The Cochrane Hepato-Biliary Group (CHBG) is one of the 52 collaborative review groups within The Cochrane Collaboration. The activities of the CHBG focus on collecting hepato-biliary randomized clinical trials (RCT) and controlled clinical trials (CCT), and including them in systematic reviews with meta-analyses of the trials. In this overview, we present the growth of The CHBG Controlled Trials Register, as well as the systematic reviews that have been produced since March 1996. RESULTS: The CHBG register includes almost 11,000 RCT and 700 CCT publications. The earliest RCT in the register were published in 1955, and the earliest CCT in 1945. From 1945 to 1980, there were less than 100 publications each year. From 1981 to 1997, their number increased from over 100 to 600 a year. After 1997, the number of publications seems to have been decreasing. The CHBG has published 199 protocols for systematic reviews and 107 systematic reviews through to August 2009 in which 21% of the RCT and CCT were included. The CHBG reviews have been cited approximately 1200 times. CONCLUSIONS: A large amount of work has been carried out since 1996. However, there is still much to do, as the CHBG register contains a great number of RCT and CCT on topics that have not yet been systematically reviewed.

Aim To evaluate prospectively the clinical efficacy and safety of endoscopic hydrostatic balloon dilation in a consecutive cohort of symptomatic intestinal Crohn's disease strictures. Methods Between September 2003 and December 2008 we performed endoscopic balloon dilations in 37 Crohn's disease patients with 39 intestinal symptomatic strictures (4 naive and 35 postoperative). Dilations were performed using a Rigiflex through-the-scope balloon. Clinical success rate was claimed if a patient remained asymptomatic and did not require surgery or further endoscopic dilation, following technical success. Actuarial curves of clinical, endoscopic (redilation) and surgical recurrence were obtained by Kaplan–Meier method. Demographic and disease variables were related to the main outcomes. Results After a mean follow-up of 26.3 months (range, 2–61 months), the long-term global benefit rate was 89% (33/37). The 1–2–3 years cumulative symptom-free rates were respectively: 76%, 55% and 46%. Four patients were operated upon. Technical success predicts a lower rate of surgery. There were no complications related to the endoscopic procedures. Conclusions Endoscopic balloon dilation of symptomatic Crohn's disease strictures may achieve clinical benefit in many patients and is a valid alternative to surgery in the management of the disease. Dilation may be repeated in recurrent intestinal obstructions and appears safe without morbidity.

Portosystemic shunt surgery has played a major role in the evolution of management of portal hypertension. Prophylactic shunts were abandoned in the early 1970s after 4 RCTs showed increased encephalopathy and mortality in operated patients, although bleeding was virtually abolished. The increase in mortality and portal systemic encephalopathy was attributed to the progressive liver function deterioration, induced by the blood diversion from the portal to the systemic circulation [1]. Selective variceal decompression by the distal splenorenal shunt (DSRS) was ideated in the late 1960s to maintain a sufficient portal hepatopetal flow, and therefore preserving liver function, while reducing the risk of variceal bleeding. However, since RCTs and meta-analyses showed no advantage of DSRS over total shunt and sclerotherapy [2], it was confined to the role of rescue therapy for failure of endoscopic therapy for the prevention of rebleeding in patients with relatively well preserved liver function. More recently the trans-jugular intra-hepatic portal systemic shunt (TIPS) has been added to the therapeutic options for portal hypertension and it is currently widely used as a rescue therapy after failure of combined medical and endoscopic therapy for the prevention of recurrent variceal bleeding. In fact, since two meta-analyses showed that TIPS is effective in reducing the risk of variceal rebleeding, but also increases the risk of portal hepatic encephalopathy and does not improve survival, it is not recommended as a first-line treatment for the prevention of recurrent variceal bleeding [3]. Besides the lack of clinical advantage, bare stent TIPS has also the disadvantage of requiring a strict surveillance program with ultrasonography and repeated reinterventions for preserving its patency, with a marked increase of the overall cost over that of the initial procedure. However, the rates of stent dysfunction and reinterventions have been significantly reduced by the use of covered stents. Current AASLD guidelines for the prevention of variceal hemorrhage in cirrhosis recommend that TIPS

Pneumatic dilatation (PD) and Surgical Miotomy (SM) are presently the best treatments for untreated achalasia, with similar efficacy. There is no information on the relative efficacy of PD in younger compared to older patients. Aim of our study was to compare success rate and safety of PD in patients under fifty years old and in those over fifty years old affected by achalasia. Twenty consecutive symptomatic patients were treated in our Unit with graded PD under fluoroscopic view. Five male and 15 female with a median age of 47 years were treated. Twelve patients were less than fifty years old (group I) while 8 were older (group II). Median dysphagia questionnaire score was 14 and13 ingroup I and II respectively. Technical success was achieved in all patients. Seven patients were previously treated through other techniques. In group I all patients achieved a complete remission of symptoms with significant decrease of the dysphagia questionnaire score (3). In group II all patients achieved a complete remission of symptoms with significant decrease of the dysphagia questionnaire score (4.5) but 3 of them repeated the procedure. In boths groups the efficacy of the dilation was radiologically confirmed. Neither early nor late complication were reported in either groups. In our experience PD was an effective and safe procedure both in young and old patients although the older group had more recurrences, all successfully re-dilated.

Liver transplantation significantly improves the survival and quality of life of patients with end-stage cirrhosis. However, a large proportion of cirrhotic patients still die while on the transplant list because of an insufficient number of donors and because of the lack of an accurate prediction of life expectancy. Although many prognostic models have been proposed in the last two decades to predict mortality in cirrhosis, the Child–Pugh score [1] is by far the most largely used both in clinical practice and in clinical research. Recently, the model for end stage liver disease (MELD) has replaced the Child–Pugh score in the United States for prioritizing liver donor allocation [2]. MELD is considered more reproducible than the Child– Pugh score because it does not include subjective variables such as ascites and encephalopathy. However, obtaining the score requires computing and it is, therefore, much less practical than the Child–Pugh score for individual estimates at the bedside. Moreover, the MELD score has not been proven to be superior to the Child–Pugh score in terms of predictive accuracy [3], and both may be unsatisfactory when applied separately to compensated and decompensated patients [4]. It is in fact well known that life expectancies in compensated and decompensated cirrhosis are strikingly different and it is, therefore, conceivable that prognostic indicators may be different or may have a different weight according to the disease stage [4]. In this article we outline the natural history of cirrhosis and report on a systematic review of the literature regarding predictors of mortality in cirrhosis in order to

Upper gastrointestinal bleeding (UGIB) is a severe and frequent complication of cirrhosis. Recombinant coagulation factor VIIa (rFVIIa) has been shown to correct the prolonged prothrombin time in patients with cirrhosis and UGIB. This trial aimed to determine efficacy and safety of rFVIIa in cirrhotic patients with variceal and nonvariceal UGIB.A total of 245 cirrhotic patients (Child-Pugh13; Child-Pugh A = 20%, B = 52%, C = 28%) with UGIB (variceal = 66%, nonvariceal = 29%, bleeding source unknown = 5%) were randomized equally to receive 8 doses of 100 microg/kg rFVIIa or placebo in addition to pharmacologic and endoscopic treatment. The primary end point was a composite including: (1) failure to control UGIB within 24 hours after first dose, or (2) failure to prevent rebleeding between 24 hours and day 5, or (3) death within 5 days.Baseline characteristics were similar between rFVIIa and placebo groups. rFVIIa showed no advantage over standard treatment in the whole trial population. Exploratory analyses, however, showed that rFVIIa significantly decreased the number of failures on the composite end point (P = 0.03) and the 24-hour bleeding control end point (P = 0.01) in the subgroup of Child-Pugh B and C variceal bleeders. There were no significant differences between rFVIIa and placebo groups in mortality (5- or 42-day) or incidence of adverse events including thromboembolic events.Although no overall effect of rFVIIa was observed, exploratory analyses in Child-Pugh B and C cirrhotic patients indicated that administration of rFVIIa significantly decreased the proportion of patients who failed to control variceal bleeding. Dosing with rFVIIa appeared safe. Further studies are needed to verify these findings.

Source Department of Medicine and Pneumology, V Cervello Hospital, Via Trabucco 180, 90146 Palermo, Italy. lindpas@yahoo.it Abstract BACKGROUND AND METHODS: Host may have a role in the evolution of chronic HCV liver disease. We performed two cross-sectional prospective studies to evaluate the prevalence of cirrhosis in first degree relatives of patients with cirrhosis and the role of two major histocompatibility complex class III alleles BF and C4 versus HCV as risk factors for familial clustering. FINDINGS: Ninety-three (18.6%) of 500 patients with cirrhosis had at least one cirrhotic first degree relative as compared to 13 (2.6%) of 500 controls, (OR 7.38; CI 4.21-12.9). C4BQ0 was significantly more frequent in the 93 cirrhotic patients than in 93 cirrhotic controls without familiarity (Hardy-Weinberg equilibrium: chi2 5.76, P = 0.016) and in 20 families with versus 20 without aggregation of HCV related cirrhosis (29.2% versus 11.3%, P = 0.001); the association C4BQ0-HCV was found almost only in cirrhotic patients with a family history of liver cirrhosis. CONCLUSIONS: Our studies support the value of C4BQ0 as a risk indicator of familial HCV related cirrhosis.

Several treatments have been proven to be effective for variceal bleeding in patients with cirrhosis. The aim of this multicenter, prospective, cohort study was to assess how these treatments are used in clinical practice and what are the posttherapeutic prognosis and prognostic indicators of upper digestive bleeding in patients with cirrhosis. A training set of 291 and a test set of 174 bleeding cirrhotic patients were included. Treatment was according to the preferences of each center and the follow-up period was 6 weeks. Predictive rules for 5-day failure (uncontrolled bleeding, rebleeding, or death) and 6-week mortality were developed by the logistic model in the training set and validated in the test set. Initial treatment controlled bleeding in 90% of patients, including vasoactive drugs in 27%, endoscopic therapy in 10%, combined (endoscopic and vasoactive) in 45%, balloon tamponade alone in 1%, and none in 17%. The 5-day failure rate was 13%, 6-week rebleeding was 17%, and mortality was 20%. Corresponding findings for variceal versus nonvariceal bleeding were 15% versus 7% (P = .034), 19% versus 10% (P = .019), and 20% versus 15% (P = .22). Active bleeding on endoscopy, hematocrit levels, aminotransferase levels, Child-Pugh class, and portal vein thrombosis were significant predictors of 5-day failure; alcohol-induced etiology, bilirubin, albumin, encephalopathy, and hepatocarcinoma were predictors of 6-week mortality. Prognostic reassessment including blood transfusions improved the predictive accuracy. All the developed prognostic models were superior to the Child-Pugh score. In conclusion, prognosis of digestive bleeding in cirrhosis has much improved over the past 2 decades. Initial treatment stops bleeding in 90% of patients. Accurate predictive rules are provided for early recognition of high-risk patients.

Background : Increased prevalence of cirrhosis in cirrhotics' families in previous studies. Aims : To compare the prevalence of cirrhosis in cirrhotics' families with that in families of patients with non-hepatic diseases. Methods : Case-control study including 500 index cases with cirrhosis and 500 pair-matched controls with chronic non-hepatic diseases, interviewed about cirrhosis in first-degree relatives and spouses using standardized forms. Results : Ninety-three index cases (88% anti-hepatitis C virus (HCV)-positive) and 13 controls had one or more cirrhotics among first-degree relatives and/or spouses (odds ratio (OR) 7.38, 95% confidence interval (CI) 4.21–12.9); cirrhosis was found in 123/4485 first-degree relatives of the index cases and in 16/4086 of controls (OR 7.17 95% CI 4.25–12.09), in 14/467 spouses of the index cases and in 1/416 spouses of controls (OR 12.8, 95% CI 1.67–97.96). The percentage of secondary cases in the families of 440 anti-HCV-positive and 60 anti-HCV-negative index cases was similar (18.8 and 21.6%, respectively). Almost all the secondary cases in families of anti-HCV-positive index cases and none in families of anti-HCV-negative index cases were anti-HCV-positive. Conclusions : Cirrhosis is significantly more frequent among first-degree relatives and spouses of patients with cirrhosis, mostly HCV-related, than among first-degree relatives and spouses of controls.

Cirrhosis of the liver develops usually slowly during inflammatory diseases which cause progressive accumulation of fibrosis and distortion of the liver structure. There are two major clinical phases of the disease, recognized as clinically distinct entities: compensated and decompensated cirrhosis. Compensated cirrhosis is characterized by a very low mortality, while transition to decompensation is the major outcome for this early disease stage. Following decompensation median survival is approximately 2–4 years. Esophageal varices, ascites, bleeding, jaundice, and encephalopathy allow identification of disease stages with significantly different outcomes. In most patients, sepsis, renal failure, and acute-on-chronic liver failure occur as end stage events anticipating death. Hepatocellular carcinoma may occur along the whole course of cirrhosis and, whenever it occurs, significantly worsens the outcome. The Child-Pugh score or its components, age, portal hypertension, renal function, and the model for end stage liver disease, are among the most widely recognized prognostic indicators of mortality.

Summary Background Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice. Aim To investigate whether clinical complications of cirrhosis may define different prognostic disease stages. Methods Analysis of the database from a prospective inception cohort of 494 patients. Decompensation was defined by ascites, bleeding, jaundice or encephalopathy. Explored potential prognostic stages: 1, compensated cirrhosis without oesophago-gastric varices; 2, compensated cirrhosis with varices; 3, bleeding without other complications; 4, first nonbleeding decompensation; 5, any second decompensating event. Patient flow across stages was assessed by a competing risks analysis. Results Major patient characteristics were: 199 females, 295 males, 404 HCV+, 377 compensated, 117 decompensated cirrhosis. The mean follow-up was 145 ± 109 months without dropouts. Major events: 380 deaths, 326 oesophago-gastric varices, 283 ascites, 158 bleeding, 146 encephalopathy, 113 jaundice, 126 hepatocellular carcinoma and 19 liver transplantation. Patients entering each prognostic stage along the disease course were: 202, stage 1; 216, stage 2; 75 stage 3; 206 stage 4; 213 stage 5. Five-year transition rate towards a different stage, for stages 1–4 was 34.5%, 42%, 65% and 78%, respectively (P