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IntroductionHepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE.MethodsWe prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT).ResultsDuring follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01–1.06), HE (HR 1.67, 95% CI 1.08–2.56), ascites (HR 2.56, 95% CI 1.55–4.23), and sodium levels (HR 0.94, 95% CI 0.90–0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39–18.49) and BMI (HR 0.86, 95% CI 0.75–0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission.ConclusionIn patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by a progressive decline in lung function and a specific histopathologic pattern defined as usual interstitial pneumonia. Early diagnosis and new therapeutic protocols have contributed to a reduction in disease progression. Thus, some patients may develop extrapulmonary diseases including malignancies and chronic pathologies. The aim of this study was to investigate the frequency of intestinal disorders such as polyps, colorectal carcinoma (CRC), and chronic inflammatory bowel disease (IBD) in patients with IPF.From the database of 189 patients with IPF (148 males, 78.3 %; 41 females, 21.7 %) residing in the district of Modena, we identified 44 patients (36 males, 81.8 %; 8 females, 18.2 %) with a histologically confirmed intestinal disease.Intestinal polyps were detected in 41 cases (93.2 %), of which 4 were associated with CRC and 1 with IBD; 1 patient had only CRC (2.3 %), and 2 patients had only IBD (4.5 %). Both males and females developed bowel disease, but males seemed to have a higher number of polyps and high-grade adenomas with a predisposition to malignant transformation.As patients with IPF may present with intestinal diseases that can evolve into malignancies in some cases, they should undergo appropriate follow-up and targeted colorectal screening. Thus, colorectal pathologies should not take a back seat. These preliminary results encourage further research to select suitable patients for specific diagnostic and therapeutic procedures in order to prolong survival and improve the quality of life.

Purpose: Liver stiffness (LS) has been shown to be of use in chronic liver disease patients but its utility in surgical judgment still needs to be proven. A decision-making approach was applied to evaluate whether LS measurement before surgery of hepatocellular carcinoma (HCC) can be useful in avoiding post-hepatectomy liver failure (PHLF). Materials and Methods: Decision curve analysis (DCA) was applied to 202 HCC patients (2008?–?14) with LS measurement prior to hepatectomy to verify whether the occurrence of PHLF grades B/C should be reduced through a decision-making approach with LS. Results: Within 90 days of surgery, 4 patients died (2?%) and grades B/C PHLF occurred in 29.7?% of cases. Ascites and/or pleural effusion, treatable with medical therapy, were the most frequent complications. DCA showed that using the “expected utility theory” LS measurement can reduce up to 39?% of cases of PHLF without the exclusion of any patient from surgery that duly undergoes an uncomplicated postoperative course. LS measurement does not add any information to normal clinical judgment for patients with a low (10?%) risk of PHLF. Conclusion: LS measurement can determine a reduction of PHLF under “expected utility theory” fulfilment. However, the degree of PHLF can be minor and “risk seeking” individuals can accept such a risk on the basis of surgical benefits.

The effects of ursodeoxycholic acid on human placental bile acids and bilirubin transporters in intrahepatic cholestasis of pregnancy are still undefined.To evaluate whether ursodeoxycholic acid affects MRP2, MRP3 and MRP4 expression in the placenta.Forty-three pregnant women were enrolled; fourteen subjects had physiological pregnancies. Intrahepatic cholestasis of pregnancy patients were divided into two groups: (i) 13 received ursodeoxycholic acid (20 mg/kg/day) and (ii) 16 untreated. Total bile acid and bilirubin in serum and cord blood were determined in each subject. Multidrug resistance proteins expression (immunoblot, quantitative real-time PCR) was evaluated in placentas collected at delivery. anova test was used for statistical analysis of data.Ursodeoxycholic acid administration significantly improved maternal serum bile acid and cord blood bilirubin and bile acid levels. MRP2 protein and RNA expression was significantly increased in placentas from treated patients compared to controls (P0.001 and P0.01, respectively). MRP3 protein expression was not significantly different between the groups while RNA expression was significantly decreased in treated patients (P0.01). MRP4 did not show significant differences between the groups.Ursodeoxycholic acid administration induces placental MRP2 expression, and reduces bilirubin and bile acid levels in cord blood.

Background and Aims Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) improves survival in patients with cirrhosis with refractory ascites and portal hypertensive bleeding. However, the indication for TIPS in older adult patients (greater than or equal to 70 years) is debated, and a specific prediction model developed in this particular setting is lacking. The aim of this study was to develop and validate a multivariable model for an accurate prediction of mortality in older adults. Approach and Results We prospectively enrolled 411 consecutive patients observed at four referral centers with de novo TIPS implantation for refractory ascites or secondary prophylaxis of variceal bleeding (derivation cohort) and an external cohort of 415 patients with similar indications for TIPS (validation cohort). Older adult patients in the two cohorts were 99 and 76, respectively. A cause-specific Cox competing risks model was used to predict liver-related mortality, with orthotopic liver transplant and death for extrahepatic causes as competing events. Age, alcoholic etiology, creatinine levels, and international normalized ratio in the overall cohort, and creatinine and sodium levels in older adults were independent risk factors for liver-related death by multivariable analysis. Conclusions After TIPS implantation, mortality is increased by aging, but TIPS placement should not be precluded in patients older than 70 years. In older adults, creatinine and sodium levels are useful predictors for decision making. Further efforts to update the prediction model with larger sample size are warranted.

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Background & Aims Hepatocellular carcinoma (HCC) is a frequent complication of liver disease. When feasible, hepatic resection is the first-choice therapy. However, tumor recurrence complicates at least 2/3 hepatic resections at 5 years. Early recurrences are mainly tumor or treatment-related, but predictors of late recurrences are undefined. We aimed to evaluate the factors related to HCC recurrence after curative resection, with liver and spleen stiffness measurement (LSM and SSM) as markers of severity and duration of the underlying liver disease. Methods We enrolled patients with chronic liver disease and primary HCC suitable for hepatic resection. We followed up patients for at least 30 months or until HCC recurrence. We performed uni- and multivariate analyses to evaluate the predictive role of tumor characteristics, laboratory data, LSM and SSM for both early and late recurrence of HCC. Results We prospectively enrolled 175 patients. Early HCC recurrence at multivariate analysis was associated with viral etiology, HCC grading (3 or 4), resection margins Conclusions SSM seems to be the only predictor of late HCC recurrence, since it is directly correlated with the degree of liver disease and portal hypertension, both of which are involved in carcinogenesis. Lay summary The main result of this study is that spleen stiffness measurement, evaluated by transient elastography, seems to be the only predictor of the late recurrence of hepatocellular carcinoma, defined as recurrence after 24 months from liver resection. Indeed, spleen stiffness measurement is directly correlated with the degree of liver disease and portal hypertension, which are both involved in carcinogenesis.

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Post-hepatectomy liver failure (PHLF) is associated with great morbidity and mortality after resection of hepatocellular carcinoma. Previous studies have underlined that advanced age could be a potential factor influencing post-operative complications and long-term survival. In the past, candidates for resection were based on the Child-Pugh classification, the predictive value of which was rather low. The selection of patients undergoing resection in Western countries is based on the assessment of portal hypertension (PH), which is clinically assessed by measurement of the hepatic venous pressure gradient, an invasive and costly process. Thus, there have been several attempts to identify the best non-invasive test (NIT) to accurately predict PHLF. Most biochemical NITs for the prediction of PHLF are focused on evaluation of underlying liver cirrhosis and PH. Amongst them, FIB-4, which also includes the patient’s age, seems to have more robust supporting results. In Europe and the USA., the most tested and reliable NIT for predicting PHLF is the evaluation of liver stiffness measurement, which is also influenced by age. Imaging parameters are promising tools which are used only in specialized centers however, and when available. Liver volume parameters, as well as contrastenhanced data, demonstrate good accuracy in predicting PHLF. In this scenario, the evaluation of sarcopenia and bone mineral density through contextual imaging allows the delineation of PHLF in at-risk elderly patients. Further studies focused on parameters for the evaluation of PHLF in elderly patients are needed.

Non-selective β-blocker (NSBB) therapy is the treatment of choice for primary prophylaxis of cirrhotic patients with high-bleeding risk esophageal varices (HRV). The hemodynamic response to NSBB is assessed by the measurement of the hepatic venous pressure gradient (HVPG). Recently, liver and spleen stiffness measurements (LSM and SSM) were proposed as non-invasive surrogates of HVPG. We aimed to evaluate LSM and SSM changes for assessing hemodynamic response in these patients. Cirrhotic patients with HRV were prospectively enrolled and evaluated at our Department before starting NSBB and after 3 months. Correlation between changes (delta) of HVPG after NSBB treatment and those of LSM or SSM by transient elastography was performed. From the initial 59 patients considered for the study, 20 were finally included in the analysis. Fifteen (15) patients reached hemodynamic response to NSBB according to HVPG. Changes in LSM did not correlate with changes in HVPG (r = 0.107, p value = 0.655), unlike changes in SSM (r = 0.784, p value

AIM To investigate changes in spleen stiffness measurements (SSMs) and other non-invasive tests (NITs) after treatment with direct-acting antivirals (DAAs) and identify predictors of SSM change after sustained virological response (SVR). METHODS We retrospectively analysed 146 advanced-chronic liver disease (ACLD) patients treated with DAA with available paired SSM at baseline and SVR24. Liver stiffness (LSM), spleen diameter (SD), platelet count (PLT) and liver stiffness-spleen diameter to platelet ratio score(LSPS) were also investigated. LSM ≥ 21 kPa was used as a cut-off to rule-in clinically significant portal hypertension (CSPH). SSM reduction > 20% from baseline was defined as significant. RESULTS SSM significantly decreased at SVR24, in both patients with and without CSPH; in 44.8% of cases, SSM reduction was > 20%. LSPS significantly improved in the entire cohort at SVR24; SD and PLT changed significantly only in patients without CSPH. LSM significantly decreased in 65.7% of patients and also in 2/3 patients in whom SSM did not decrease. The independent predictor of decreased SSM was median relative change of LSM. CSPH persisted in 54.4% patients after SVR. Delta LSM and baseline SSM were independent factors associated with CSPH persistence. CONCLUSION SSM and other NITs significantly decrease after SVR, although differently according to the patient’s clinical condition. SSM faithfully reflects changes in portal hypertension and could represent a useful NIT for the follow-up of these patients.

none 13 no Published Online First: 12 September 2016 OBJECTIVE: The engagement of the gut microbiota in the development of symptoms and complications of diverticular disease has been frequently hypothesised. Our aim was to explore colonic immunocytes, gut microbiota and the metabolome in patients with diverticular disease in a descriptive, cross-sectional, pilot study. DESIGN: Following colonoscopy with biopsy and questionnaire phenotyping, patients were classified into diverticulosis or symptomatic uncomplicated diverticular disease; asymptomatic subjects served as controls. Mucosal immunocytes, in the diverticular region and in unaffected sites, were quantified with immunohistochemistry. Mucosa and faecal microbiota were analysed by the phylogenetic platform high taxonomic fingerprint (HTF)-Microbi.Array, while the metabolome was assessed by 1H nuclear magnetic resonance. RESULTS: Compared with controls, patients with diverticula, regardless of symptoms, had a >70% increase in colonic macrophages. Their faecal microbiota showed depletion of Clostridium cluster IV. Clostridium cluster IX, Fusobacterium and Lactobacillaceae were reduced in symptomatic versus asymptomatic patients. A negative correlation was found between macrophages and mucosal Clostridium cluster IV and Akkermansia. Urinary and faecal metabolome changes in diverticular disease involved the hippurate and kynurenine pathways. Six urinary molecules allowed to discriminate diverticular disease and control groups with >95% accuracy. CONCLUSIONS: Patients with colonic diverticular disease show depletion of microbiota members with anti-inflammatory activity associated with mucosal macrophage infiltration. Metabolome profiles were linked to inflammatory pathways and gut neuromotor dysfunction and showed the ability to discriminate diverticular subgroups and controls. These data pave the way for further large-scale studies specifically aimed at identifying microbiota signatures with a potential diagnostic value in patients with diverticular disease. Barbara, Giovanni; Scaioli, Eleonora; Barbaro, Maria Raffaella; Biagi, Elena; Laghi, Luca; Cremon, Cesare; Marasco, Giovanni; Colecchia, Antonio; Picone, Gianfranco; Salfi, Nunzio; Capozzi, Francesco; Brigidi, Patrizia; Festi, Davide Barbara, Giovanni; Scaioli, Eleonora; Barbaro, Maria Raffaella; Biagi, Elena; Laghi, Luca; Cremon, Cesare; Marasco, Giovanni; Colecchia, Antonio; Picone, Gianfranco; Salfi, Nunzio; Capozzi, Francesco; Brigidi, Patrizia; Festi, Davide

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Background & Aims Hepatic venous pressure gradient (HVPG) measurement represents the best predictor of clinical decompensation (CD) in cirrhotic patients. Recently data show that measurement of spleen stiffness (SS) has an excellent correlation with HVPG levels. Aim of the present prospective study was to assess SS predictive value for CD compared to HVPG, liver stiffness (LS), and other non-invasive tests for portal hypertension in a cohort of patients with HCV-related compensated cirrhosis. Methods From an initial cohort of 124 patients, 92 underwent baseline LS, SS, HVPG measurements and upper gastrointestinal endoscopy at enrolment and then followed-up for 2years or until the occurrence of the first CD. Univariate and multivariate logistic regression models were used for determining judgement criteria associated parameters. Accuracy of predictive factors was evaluated using c statistic. The final model was internally validated using the bootstrap method. Results During follow-up, 30 out 92 (32.6%) patients developed CD. At univariate analysis varices at enrolment, all non-invasive parameters, HVPG, and model for end-stage liver disease (MELD) resulted clinical predictors of CD. At multivariate analysis only SS ( p =0.0001) and MELD ( p =0.014) resulted as predictive factors. A decision algorithm based on the results of a predictive model was proposed to detect patients with low risk of decompensation. Conclusions This study shows that in compensated cirrhotic patients a SS and MELD predictive model represents an accurate predictor of CD with accuracy at least equivalent to that of HVPG. If confirmed by further studies, SS and MELD could represent valid alternatives to HVPG as prognostic indicator of CD in HCV-related cirrhosis.

The occurrence of de novo hepatocellular carcinoma after liver transplantation is a rare event with only few cases reported in the literature. In a post liver transplantation setting distinguishing between a de novo hepatocellular carcinoma from recurrence should be tested with molecular analysis such as fluorescent in situ hybridization (for sex chromosomes) or microsatellite analysis. Nevertheless, a certain degree of epithelial chimerism between recipient and donor tissues could be responsible for the development of de novo hepatocellular carcinoma of recipient origin. We report two cases of de novo hepatocellular carcinoma after liver transplantation. The first one occurred in a patient receiving transplantation for hepatitis C related cirrhosis and hepatocellular carcinoma. A de novo hepatocellular carcinoma developed five years after transplantation and microsatellite analysis revealed the donor origin of the neoplasia. The second one occurred in a patient who received transplantation for secondary sclerosing cholangitis. Hepatocellular carcinoma was found six years after transplantation. Both microsatellite analysis and fluorescent in situ hybridization revealed the recipient origin of the tumor, potentially due to tissue chimerism.

Background and aims Whether Fibroscan thresholds can be immediately adopted for none, some or all other shear wave elastography techniques has not been tested. The aim of the present study was to test the concordance of the findings obtained from 7 of the most recent ultrasound elastography machines with respect to Fibroscan. Methods Sixteen hepatitis C virus-related patients with fibrosis ≥2 and having reliable results at Fibroscan were investigated in two intercostal spaces using 7 different elastography machines. Coefficients of both precision (an index of data dispersion) and accuracy (an index of bias correction factors expressing different magnitudes of changes in comparison to the reference) were calculated. Results Median stiffness values differed among the different machines as did coefficients of both precision (range 0.54–0.72) and accuracy (range 0.28–0.87). When the average of the measurements of two intercostal spaces was considered, coefficients of precision significantly increased with all machines (range 0.72–0.90) whereas of accuracy improved more scatteredly and by a smaller degree (range 0.40–0.99). Conclusions The present results showed only moderate concordance of the majority of elastography machines with the Fibroscan results, preventing the possibility of the immediate universal adoption of Fibroscan thresholds for defining liver fibrosis staging for all new machines.

Bloating, abdominal discomfort or pain, disturbed bowel habits are very common symptoms, frequently reported by the patients soon after food ingestion. These symptoms may occur in different clinical conditions, such as functional bowel disorders, food adverse reactions, gluten-related syndromes, which frequently are interrelated. Consequently, in clinical practice, it is necessary to perform a correct diagnosis in order to identify, for the single patient, the most appropriate therapeutic strategy, which may include not only specific drugs, but also, and mainly, life style changes (healthy nutritional behavior and constant physical activity). The aim of this review is to provide to the general physician, according to the available evidence, the most appropriate diagnostic work-ups for recognizing the different clinical scenarios (i.e. food allergy and intolerance, functional bowel diseases, gluten-related syndromes), to identify their clinical interrelationships and to suggest the most appropriate management. In fact, as far as food intolerances are concerned, it is well known that the number of patients who believe that their symptoms are related to food intolerance is increasing and consequently they restrict their diet, possibly causing nutritional deficiencies. Furthermore, there is an increasing use of unconventional diagnostic tests for food intolerance which lack accurate scientific evidence; the application of their results may induce misdiagnosis and unhealthy therapeutic choices. Consequently the recognition of food intolerance has to be performed on the basis of reliable tests within an agreed diagnostic workup.

Colonic diverticulosis imposes a significant burden on industrialized societies. The current accepted causes of diverticula formation include low fiber content in the western diet with decreased intestinal content and size of the lumen, leading to the transmission of muscular contraction pressure to the wall of the colon, inducing the formation of diverticula usually at the weakest point of the wall where penetration of the blood vessels occurs. Approximately 20 % of the patients with colonic diverticulosis develop abdominal symptoms (i.e., abdominal pain and discomfort, bloating, constipation, and diarrhea), a condition which is defined as symptomatic uncomplicated diverticular disease (SUDD). The pathogenesis of SUDD symptoms remains uncertain and even less is known about how to adequately manage bowel symptoms. Recently, low-grade inflammation, altered intestinal microbiota, visceral hypersensitivity, and abnormal colonic motility have been identified as factors leading to symptom development, thus changing and improving the therapeutic approach. In this review, a comprehensive search of the literature regarding on SUDD pathogenetic hypotheses and pharmacological strategies was carried out. The pathogenesis of SUDD, although not completely clarified, seems to be related to an interaction between colonic microbiota alterations, and immune, enteric nerve, and muscular system dysfunction (Cuomo et al. in United Eur Gastroenterol J 2:413-442, 2014). Greater understanding of the inflammatory pathways and gut microbiota composition in subjects affected by SUDD has increased therapeutic options, including the use of gut-directed antibiotics, mesalazine, and probiotics (Bianchi et al. in Aliment Pharmacol Ther 33:902-910, 2011; Comparato et al. in Dig Dis Sci 52:2934-2941, 2007; Tursi et al. in Aliment Pharmacol Ther 38:741-751, 2013); however, more research is necessary to validate the safety, effectiveness, and cost-effectiveness of these interventions.

Risk factors for gallstone formation during weight loss

Aim: To comparatively ate the long term efficacy of Rifaximin and dietary fibers in reducing symptoms and/or complication frequency in symptomatic, uncomplicated diverticular disease. Methods: 307 patients (118 males, 189 females, age range: 40-80 years) were enrolled in the study and randomly assigned to: Rifaximin (400 mg bid for 7 d every month) plus dietary fiber supplementation (at least 20 gr/d) or dietary fiber supplementation alone. The study duration was 24 mo; both clinical examination and symptoms' questionnaire were performed every two months. Results: Both treatments reduced symptom frequency, but Rifaximin at a greater extent, when compared to basal values. Symptomatic score declined during both treatments, but a greater reduction was evident in the Rifaximin group (6.4 ± 2.8 and 6.2 ± 2.6 at enrollment, P = NS, 1.0 ± 0.7 and 2.4 ± 1.7 after 24 mo, P < 0.001, respectively). Probability of symptom reduction was higher and complication frequency lower (Kaplan-Meyer method) in the Rifaximin group (P < 0.0001 and 0.028, respectively). Conclusion: In patients with symptomatic, uncomplicated diverticular disease, cyclic administration of Rifaximin plus dietary fiber supplementation is more effective in reducing both symptom and complication frequency than simple dietary fiber supplementation. Long term administration of the poorly absorbed antibiotic Rifaximin is safe and well tolerated by the patients, confirming the usefulness of this therapeutic strategy in the overall management of diverticular disease. © 2007 The WJG Press. All rights reserved.