The non-invasive evaluation of liver involvement in patients with cystic fibrosis: A prospective study.

BACKGROUND AND AIMS: Porto-sinusoidal vascular disease (PSVD) has been described as the prominent pathology in liver explants of patients with cystic fibrosis (CF), but data outside the transplant setting are lacking. We aimed to investigate the prevalence of portal hypertension (PH) in CF-associated liver disease (CFLD) and develop an algorithm to classify liver involvement in CF patients. METHODS: This is a cross-sectional study of consecutive paediatric and adult patients in a tertiary centre between 2018 and 2019, who underwent ultrasound, liver (LSM) and spleen stiffness (SSM) measurement. CFLD was defined according to physical examination, liver tests and ultrasound findings. PSVD was likely if there were PH signs in the absence of advanced chronic liver disease (CF-ACLD, LSM <10 kPa). A historical cohort was used to validate the prognostic significance of the new definitions. RESULTS: Fifty (27.5%) patients met CFLD criteria. At least one sign of PH was found in 47 (26%) patients, but most (81%) had LSM <10 kPa and were likely to have PSVD; only 9 (5%) had CF-ACLD. PSVD and CFLD (LSM <10 kPa) co-existed in most (23/36) cases. In the historical cohort (n = 599 patients), likely PSVD and CFLD+PH were independently associated with a 2-fold and 3.5-fold increase in mortality compared to patients without PH, respectively. In 34 patients with SSM, values <21 and >50 kPa accurately diagnosed specific signs of PH. CONCLUSIONS: PSVD is the prevailing cause of PH in CF patients. We developed a new diagnostic algorithm based on clinical and elastosonography criteria to classify liver involvement in patients with CF.

A Combined Baveno VII and Spleen Stiffness Algorithm to Improve the Noninvasive Diagnosis of Clinically Significant Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease.

INTRODUCTION: A noninvasive diagnosis of clinically significant portal hypertension (CSPH) has important prognostic and therapeutic implications for patients with compensated advanced chronic liver disease. We aimed to validate and improve the available algorithms for the CSPH diagnosis by evaluating spleen stiffness measurement (SSM) in patients with compensated advanced chronic liver disease. METHODS: This is a retrospective study including patients with liver stiffness measurement (LSM) ≥10 kPa, no previous decompensation, and available measurements of hepatic venous pressure gradient, LSM, and SSM by transient elastography referring to our center in Bologna. The diagnostic algorithms were adequate if negative and positive predictive values were >90% when ruling out and ruling in CSPH, respectively; these models were validated in a cohort from Verona. The 5-year decompensation rate was reported. RESULTS: One hundred fourteen patients were included in the derivation cohort. The Baveno VII diagnostic algorithm (LSM ≤15 kPa + platelet count ≥150 × 10 9 /L to rule out CSPH and LSM >25 kPa to rule in CSPH) was validated; however, 40%-60% of the patients remained in the gray zone. The addition of SSM (40 kPa) to the model significantly reduced the gray zone to 7%-15%, maintaining adequate negative and positive predictive values. The diagnostic algorithms were validated in a cohort of 81 patients from Verona. All first decompensation events occurred in the "rule-in" zone of the model including SSM. DISCUSSION: The addition of SSM significantly improves the clinical applicability of the algorithm based on LSM and platelet count for CSPH diagnosis. Our models can be used to noninvasively identify candidates for nonselective beta-blocker treatment and patients at a high risk of decompensation.

Spleen Stiffness Measurements Predict the Risk of Hepatic Decompensation After Direct-Acting Antivirals in HCV Cirrhotic Patients.

PURPOSE: Little evidence is available regarding the risk of hepatic decompensation (HD) after direct-acting antivirals (DAAs) in patients with advanced chronic liver disease. Our aim was to assess the risk of decompensation and the prognostic role of noninvasive tests, such as liver (LSM) and spleen (SSM) stiffness measurements, in the prediction of decompensation after sustained virologic response (SVR) by DAAs. MATERIALS AND METHODS: A cohort study involving 146 cirrhotic patients treated with DAAs in our tertiary center with LSM and SSM available both before and six months after treatment (SVR24). A historical cohort of 92 consecutive cirrhotic patients with active HCV was used as a control group. A propensity score inverse probability weighting method was used to account for differences between the groups. Time-dependent models for the prediction of decompensation were applied to account for changes in noninvasive tests after therapy. RESULTS: The decompensation incidence in the DAA cohort was 7.07 (4.56-10.96) per 100 person-years (PYs), which was significantly lower than in the active HCV cohort. The DAA therapy was an independent protective factor for HD development (SHR: 0.071, 95 %-CI: 0.015-0.332). SSM ≥ 54 kPa was independently associated with decompensation despite SVR achievement (SHR: 4.169, 95 %-CI: 1.050-16.559), alongside with a history of decompensation (SHR: 7.956, 95 %-CI: 2.556-24.762). SSM reduction < 10 % also predicted the risk of decompensation after SVR24. CONCLUSION: The risk of decompensation was markedly reduced after DAA therapy, but it was not eliminated. Paired SSM values stratified the risk of decompensation after SVR better than other noninvasive tests.

Including Ratio of Platelets to Liver Stiffness Improves Accuracy of Screening for Esophageal Varices That Require Treatment.

BACKGROUND & AIMS: Based on platelets and liver stiffness measurements, the Baveno VI criteria (B6C), the expanded B6C (EB6C), and the ANTICIPATE score can be used to rule out varices needing treatment (VNT) in patients with compensated chronic liver disease. We aimed to improve these tests by including data on the ratio of platelets to liver stiffness. METHODS: In a retrospective analysis of data from 10 study populations, collected from 2004 through 2018, we randomly assigned data from 2368 patients with chronic liver disease of different etiologies to a derivation population (n = 1579; 15.1% with VNT, 50.2% with viral hepatitis, 28.9% with nonalcoholic fatty liver disease, 20.8% with alcohol-associated liver disease, with model for end-stage liver disease scores of 9.5 ± 3.0, and 93.0% with liver stiffness measurements ≥10 kPa) or a validation population (n = 789). Test results were compared with results from a sequential algorithm (VariScreen). VariScreen incorporated data on platelets or liver stiffness measurements and then the ratio of platelets to liver stiffness measurement, adjusted for etiology, patient sex, and international normalized ratio. RESULTS: In the derivation population, endoscopies were spared for 23.9% of patients using the B6C (VNT missed in 2.9%), 24.3% of patients using the ANTICIPATE score (VNT missed in 4.6%), 34.5% of patients using VariScreen (VNT missed in 2.9%), and 41.9% of patients using the EB6C (VNT missed in 10.9%). Differences in spared endoscopy rates were significant (P ≤ .001), except for B6C vs ANTICIPATE and in missed VNT only for EB6C vs the others (P ≤ .009). VariScreen was the only safe test regardless of sex or etiology (missed VNT ≤5%). Moreover, VariScreen secured screening without missed VNT in patients with model for end-stage liver disease scores higher than 10. This overall strategy performed better than a selective strategy restricted to patients with compensated liver disease. Test performance and safety did not differ significantly among populations. CONCLUSIONS: In a retrospective study of data from 2368 patients with chronic liver disease, we found that the B6C are safe whereas the EB6C are unsafe, based on missed VNT. The VariScreen algorithm performed well in patients with chronic liver disease of any etiology or severity. It is the only test that safely rules out VNT and can be used in clinical practice.

Gut microbiota signatures and clinical manifestations in celiac disease children at onset: a pilot study.

BACKGROUND AND AIM: Recent researches have shown an altered gut microbiota in celiac disease (CD) patients compared with healthy controls (HCs). This study aims to evaluate the composition of the microbiota of CD children at onset and the relationship between bacterial abundances and symptoms. METHODS: Celiac disease patients were consecutively enrolled at a pediatric unit referring for suspected CD. HCs were also included in the study. Stool and duodenal samples were collected and evaluated by a high taxonomic fingerprint microbiota array. RESULTS: Thirty-seven subjects enrolled: 21 CD patients and 16 HCs. Fourteen subjects were male (38%). The mean age was 75 months (standard deviation 31.5) for CD patients and 71 months (standard deviation 34.9) for HCs. Duodenal microbiota of CD patients showed a dominance of Enterobacteriaceae and subdominance of Bacteroidetes/Streptococcus. Stool microbiota showed a lower abundance of Bacteroides-Prevotella (P = 0.013), Akkermansia (P = 0.002), and Staphylococcaceae (P = 0.001) in CD patients compared with HC. At symptoms level, an increased mean relative abundance of Bacillaceae and Enterobaeriaceae in patients with abdominal pain (P = 0.007 and P = 0.010) was found. CD patients with diarrhea had reduced mean relative abundance of Clostridium cluster XIVa (P = 0.044) and Akkermansia (P = 0.033) and an increase in Bacillaceae (P = 0.048) and Fusobacterium (P = 0.048). CONCLUSIONS: Gut microbiota of CD children at disease onset is different from that of HC. Pro-inflammatory microbiota imbalances were associated with CD symptoms. Further studies are needed to assess whether dysbiosis is associated with CD early onset and symptoms.

A nomogram based on liver stiffness predicts postoperative complications in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Liver stiffness measurement (LSM), assessed by transient elastography (Fibroscan), has been demonstrated to predict post-hepatectomy liver failure in patients who undergo hepatic resection for hepatocellular carcinoma (HCC). However, other complications are also likely to be related to the underlying grade of liver fibrosis. Herein, we aimed to identify predictors of postoperative complications and to build and develop a novel nomogram able to identify patients at risk of developing severe complications. METHODS: Data from patients who underwent hepatectomy for HCC between 2006 and 2016 at 2 referral centres were retrospectively reviewed. All surgical complications were recorded and scored using the comprehensive complication index (CCI), ranging from 0 (uneventful course) to 100 (death). A CCI ≥26.2 was used as a threshold to define severe complications. RESULTS: During the study period, 471 patients underwent hepatic resection for HCC. Among them, 50 patients (10.6%) had a CCI ≥26.2. Age, model for end-stage liver disease (MELD) score and LSM values, together with serum albumin, were independent predictors of high CCI. The nomogram built on these variables was internally validated and showed good performance (optimism-corrected c-statistic = 0.751). A regression equation to predict the CCI was also established by multiple linear regression analysis: [LSM (kPa) × 0.254] + [age (years) × 0.118] + [MELD score (pt.) × 1.050] - [albumin (g/dl) × 2.395] - 3.639. CONCLUSION: A novel nomogram, combining LSM values, age and liver function tests provided an excellent preoperative prediction of high CCI in patients with resectable HCC. This predictive model could be used as a reference for clinicians and surgeons to help them in clinical decision-making. LAY SUMMARY: Liver stiffness measurement is increasingly being used to assess the degree of liver fibrosis in patients with cirrhosis and/or chronic hepatitis. Using Fibroscan, we developed a novel nomogram to predict severe complications following liver resection for hepatocellular carcinoma, according to the new comprehensive complication index. This tool could be used as a reference for clinicians and surgeons to help them in clinical decision-making.

A novel spleen-dedicated stiffness measurement by FibroScan® improves the screening of high-risk oesophageal varices.

BACKGROUND & AIMS: Several non-invasive tests (NITs) have been developed to diagnose oesophageal varices (EV), including the recent Baveno VI criteria to rule out high-risk varices (HRV). Spleen stiffness measurement (SSM) with the standard FibroScan® (SSM@50Hz) has been evaluated. However, the EV grading could be underestimated because of a ceiling threshold (75 kPa) of the SSM@50Hz. The aims were to evaluate SSM by a novel spleen-dedicated FibroScan® (SSM@100Hz) for EV diagnosis compared with SSM@50Hz, other validated NITs and Baveno VI criteria. METHODS: This prospective multicentre study consecutively enrolled patients with chronic liver disease; blood data, endoscopy, liver stiffness measurement (LSM), SSM@50Hz and SSM@100Hz were collected. RESULTS: Two hundred and sixty patients met inclusion criteria. SSM@100Hz success rate was significantly higher than that of SSM@50Hz (92.5% vs 76.0%, P < .001). SSM@100Hz accuracy for the presence of EV (AUC = 0.728) and HRV (AUC = 0.756) was higher than in other NITs. SSM@100Hz AUC for large EV (0.782) was higher than SSM@50Hz (0.720, P = .027). AUC for HRV with SSM@100Hz (0.780) was higher than with LSM (0.615, P < .001). The spared endoscopy rate of Baveno VI criteria (8.1%) was significantly increased by the combination to SSM@50Hz (26.5%) or SSM@100Hz (38.9%, P < .001 vs others). The missed HRV rate was, respectively, 0% and 4.7% for combinations. CONCLUSIONS: SSM@100Hz is a new performant non-invasive marker for EV and HRV providing a higher accuracy than SSM@50Hz and other NITs. The combination of Baveno VI criteria and SSM@100Hz significantly increased the spared endoscopy rate compared to Baveno VI criteria alone or combined with SSM@50Hz. Clinical trial number: NCT02180113.

Liver Stiffness Measurement Allows Early Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome in Adult Patients Who Undergo Hematopoietic Stem Cell Transplantation: Results from a Monocentric Prospective Study.

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complication affecting patients undergoing hematopoietic stem cell transplantation (HSCT). The survival rate is higher when specific therapy is initiated early; thus, improving early, noninvasive diagnosis of VOD/SOS is an important need. In an adult population undergoing HSCT, we aimed to assess the role of liver stiffness measurement (LSM), evaluated by transient elastography (TE), for diagnosing VOD/SOS. Between April 2016 and March 2018, 78 consecutive adult patients with indications for allogeneic HSCT were prospectively included. LSM was performed before HSCT and at days +9/10, +15/17, and +22/24 post-HSCT. New European Society for Blood and Marrow Transplantation criteria were used to establish VOD/SOS diagnosis. Four patients developed VOD/SOS (5.1%) during the study period, with a median time of +17 days post-HSCT. A sudden increase in LSM compared with previously assessed values and pre-HSCT values, was seen in all patients who developed VOD/SOS. LSM increases occurred from 2 to 12 days before clinical SOS/VOD appearance. The VOD/SOS diagnostic performance of increased LSM over pre-HSCT assessment showed an area under the receiver operating characteristic curve of 0.997 (sensitivity 75%; specificity 98.7%). LSM gradually decreased following successful VOD/SOS-specific treatment. Interestingly, LSM values did not increase significantly in patients experiencing hepatobiliary complications (according to the Common Terminology Criteria) other than VOD/SOS. LSM by TE can be considered a promising method to perform an early, preclinical diagnosis and follow-up of VOD/SOS.

Role of liver and spleen stiffness in predicting the recurrence of hepatocellular carcinoma after resection.

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 <1 cm and being beyond the Milan criteria. HCC late recurrence at univariate analysis was associated with esophageal varices (hazard ratio [HR] 3.321, 95% CI 1.564-7.053), spleen length (HR 3.123, 95% CI 1.377-7.081), platelet/spleen length ratio if <909 (HR 2.170, 95% CI 1.026-4.587), LSM (HR 1.036, 95% CI 1.005-1.067), SSM (HR 1.046, 95% CI 1.020-1.073). HCC late recurrence at multivariate analysis was independently associated only with SSM (HR 1.046, CI 1.020-1.073). Late HCC recurrence-free survival was significantly different according to the SSM cut-off of 70 kPa (p = 0.0002). 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.

How to clarify the Baveno VI criteria for ruling out varices needing treatment by noninvasive tests.

BACKGROUND & AIMS: Baveno VI criteria enabled the screening of varices needing treatment (VNT) without endoscopy but created confusion by not stating the method used to calculate the 5% missed VNT limit, resulting in different calculations across validation studies. We analysed those calculations to clarify their diagnostic meaning. METHODS: (a) Literature review and recalculation of the missed VNT rates according to the three definitions encountered. (b) Contingency table comparison of these latter to determine their diagnostic meanings. (c) Real case analysis. 4/Simulation of variations in the three main statistical descriptors (VNT, missed VNT or spared endoscopies). RESULTS: Missed VNT rates in the three definitions varied five- to 10-fold across 7 papers. The contingency table showed that the definitions based on VNT prevalence and spared endoscopy as reference corresponded, respectively, to sensitivity and negative predictive value (NPV). The whole population-based definition corresponded to diagnostic accuracy (not pertinent in that setting). Real case analysis showed that concerning liver stiffness, the 95% sensitivity and NPV cut-offs for VNT were, respectively, 14.1 and 26.5 kPa. The VNT-based definition offered a more statistically powerful paired comparison between diagnostic tests, whereas the definition based on spared endoscopies was hampered by an unpaired comparison. Case simulation showed that the VNT-based definition was the most sensitive to descriptor variations. CONCLUSION: The definitions of missed VNT rate placing VNT or spared endoscopy as the denominator are appropriate, providing, respectively, sensitivity and NPV for VNT. We privilege the first since it corresponds to the true proportion of missed VNT.

Longitudinal evaluation of liver stiffness in three pediatric patients with veno-occlusive disease.

Liver stiffness measurement by transient elastography is a non-invasive ultrasound-based technique used mainly for the evaluation of liver fibrosis in patients with chronic liver diseases. Some authors have suggested that it could be useful in the assessment of hepatic complications during hematopoietic stem cell transplant (HSCT), especially veno-occlusive disease (VOD) or sinusoidal obstructive syndrome (SOS). Here, we present the evaluation of liver stiffness in three patients who developed severe hepatic VOD/SOS after HSCT. Liver stiffness measurement values were normal before transplant and afterward until the diagnosis of VOD/SOS when a dramatic increase was observed. After the VOD/SOS specific treatment, the values of stiffness showed a similar pattern of progressive reduction in all the three patients, with normalization after two weeks. In this report, we discuss the role of LSM in the management of patients after the diagnosis of VOD/SOS.

Role of Ultrasound Elastography in the Detection of Fibrotic Bowel Strictures in Patients with Crohn's Disease: Systematic Review and Meta-Analysis.

PURPOSE: To perform a systematic review with meta-analysis to assess whether ultrasound elastography can have a diagnostic role in detecting fibrotic bowel strictures in patients with Crohn's disease. MATERIALS AND METHODS: MEDLINE via the PubMed, Ovid Embase, Scopus and Cochrane Library databases, and abstracts of international conference proceedings were searched up to March 31, 2018. Studies were included if they assessed the performance of abdominal ultrasound elastography in detecting fibrotic bowel strictures in patients with Crohn's disease using histology or the need for surgery after medical treatment as a reference standard. The quality of the studies was assessed using Quality Assessment of Diagnostic Accuracy Studies. RESULTS: 6 studies including a total of 217 patients with Crohn's disease and 231 bowel segments, of which 76 were bowel segments with fibrotic stricture, were selected. Three studies used strain ratio and three studies used strain value as parameters of bowel stiffness. Both the pooled standardized mean strain ratio and the pooled standardized mean strain value were higher in bowel segments with fibrotic strictures than in those without fibrotic strictures with a standardized mean difference of 0.85 (95 % confidence level [CI]: 0 to 1.71; p = 0.05) and 1.0 (95 % CI: -0.11 to 2.10; p = 0.08), respectively. There was a high heterogeneity between studies. All studies were at "high risk" or "unclear risk" of bias. CONCLUSION: Ultrasound elastography could be able to detect fibrotic bowel strictures in patients with Crohn's disease. Well-designed high quality diagnostic studies with a large sample size are needed.

A combined model based on spleen stiffness measurement and Baveno VI criteria to rule out high-risk varices in advanced chronic liver disease.

BACKGROUND & AIMS: Recently, Baveno VI guidelines suggested that esophagogastroduodenoscopy (EGD) can be avoided in patients with compensated advanced chronic liver disease (cACLD) who have a liver stiffness measurement (LSM) <20 kPa and platelet count >150,000/mm3. We aimed to: assess the performance of spleen stiffness measurement (SSM) in ruling out patients with high-risk varices (HRV); validate Baveno VI criteria in a large population and assess how the sequential use of Baveno VI criteria and SSM could safely avoid the need for endoscopy. METHODS: We retrospectively analyzed 498 patients with cACLD who had undergone LSM/SSM by transient elastography (TE) (FibroScan®), platelet count and EGDs from 2012 to 2016 referred to our tertiary centre. The new combined model was validated internally by a split-validation method, and externally in a prospective multicentre cohort of 115 patients. RESULTS: SSM, LSM, platelet count and Child-Pugh-B were independent predictors of HRV. Applying the newly identified SSM cut-off (≤46 kPa) or Baveno VI criteria, 35.8% and 21.7% of patients in the internal validation cohort could have avoided EGD, with only 2% of HRVs being missed with either model. The combination of SSM with Baveno VI criteria would have avoided an additional 22.5% of EGDs, reaching a final value of 43.8% spared EGDs, with <5% missed HRVs. Results were confirmed in the prospective external validation cohort, as the combined Baveno VI/SSM ≤46 model would have safely spared (0 HRV missed) 37.4% of EGDs, compared to 16.5% when using the Baveno VI criteria alone. CONCLUSIONS: A non-invasive prediction model combining SSM with Baveno VI criteria may be useful to rule out HRV and could make it possible to avoid a significantly larger number of unnecessary EGDs compared to Baveno VI criteria only. LAY SUMMARY: Spleen stiffness measurement assessed by transient elastography, the most widely used elastography technique, is a non-invasive technique that can help the physician to better stratify the degree of portal hypertension and the risk of esophageal varices in patients with compensated advanced chronic liver disease. Performing spleen stiffness measurement together with liver stiffness measurement during the same examination is simple and fast and this sequential model can identify a greater number of patients that can safely avoid endoscopy, which is an invasive and expensive examination.

Eicosapentaenoic Acid Reduces Fecal Levels of Calprotectin and Prevents Relapse in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: High fecal levels of calprotectin indicate mucosal inflammation and have been shown to predict relapse in patients with ulcerative colitis (UC). Eicosapentaenoic acid (EPA), the major component of n-3 fish oil, has anti-inflammatory properties in patients with chronic inflammatory disorders. We performed a placebo-controlled trial of patients with UC at risk of relapse to determine the ability of the free fatty acid form of EPA (EPA-FFA) to reduce intestinal inflammation, using fecal level of calprotectin as a marker. METHODS: From June 2014 to May 2016, 60 patients with UC with a partial Mayo score < 2 and fecal calprotectin ≥150 µg/g, in stable therapy for at least the 3 previous months, were randomly assigned to groups (1:1) given either EPA-FFA (500 mg, twice daily) or placebo for 6 months. A colonoscopy was performed at baseline. Clinical assessments and measurements of fecal calprotectin were made at baseline, at study months 3 and 6, or the time of clinical relapse. Patients with a relapse of UC underwent a second colonoscopy. The primary end point was a 100-point reduction in fecal levels of calprotectin at 6 months from the baseline value; the secondary end point was maintenance of clinical remission at 6 months. RESULTS: The primary end point was achieved by 19 of 30 patients (63.3%) in the EPA-FFA group vs 4 of 30 patients (13.3%) in the placebo group (odds ratio, 12.0; 95% CI, 3.12-46.24; P < .001). The secondary end point was achieved by 23 of 30 patients (76.7%) in the EPA-FFA group vs 15 of 30 (50%) patients in the placebo group (OR, 3.29; 95% CI, 1.08-9.95; P = .035). No serious adverse events were observed. CONCLUSIONS: In a placebo-controlled trial of 60 patients with UC, we found 6 months' administration of EPA-FFA to reduce fecal levels of calprotectin with no serious adverse events. This agent might be used to induce and maintain symptom-free remission in patients with UC. ClinicalTrials.gov number: NCT02179372.

Gut microbiota, metabolome and immune signatures in patients with uncomplicated diverticular disease.

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.

Sulfasalazine in Prevention of Pouchitis After Proctocolectomy with Ileal Pouch-Anal Anastomosis for Ulcerative Colitis.

BACKGROUND: Pouchitis is the most frequent complication after ileal pouch-anal anastomosis for refractory ulcerative colitis. A non-standardized preventative treatment exists. Sulfasalazine has proved effective in acute pouchitis therapy. AIMS: The aim of this study was to retrospectively evaluate the effect of sulfasalazine in primary prophylaxis of pouchitis after proctocolectomy with ileal pouch-anal anastomosis. METHODS: Data files of patients who underwent total proctocolectomy with ileal pouch-anal anastomosis for refractory ulcerative colitis and/or dysplasia from January 2007 to December 2014, with a follow-up until August 2015, were analyzed. After closure of loop ileostomy, on a voluntary basis, patients received a primary prophylaxis of pouchitis with sulfasalazine (2000 mg per day) continually until acute pouchitis flare and/or drop out due to side effects. RESULTS: Follow-up data were available for 51 of the 55 surgical patients. Median follow-up time was 68 months (range 10-104). Thirty postoperative complications occurred in 25 patients. 45% of patients developed pouchitis. Sulfasalazine prophylaxis was administered in 39.2% of patients; 15% of the these developed pouchitis versus 64.5% (20/31) of the non-sulfasalazine patients (p < 0.001). Pouchitis-free survival curves were 90.55 months in sulfasalazine patients and 44.46 in non-sulfasalazine patients (log-rank test p = 0.001, Breslow p = 0.001). CONCLUSION: Sulfasalazine may be potentially administered in pouchitis prophylaxis after proctocolectomy with ileal pouch-anal anastomosis, but large prospectively controlled trials are needed.

Adding Liver Stiffness Measurement to the Routine Evaluation of Hepatocellular Carcinoma Resectability Can Optimize Clinical Outcome.

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.

Relationship between indocyanine green retention test, decompensation and survival in patients with Child-Pugh A cirrhosis and portal hypertension.

BACKGROUND & AIMS: Indocyanine green retention test (ICG-r15) is a non-invasive marker of functional hepatic reserve. Among patients with compensated cirrhosis, ICG-r15 correlates to the degree of portal hypertension (PH); however, its prognostic relationship with the occurrence of decompensation events still requires clarification. METHODS: ICG-r15 was prospectively measured in 154 patients with compensated cirrhosis. Patients with hepatocellular carcinoma (HCC), Child-Pugh B-C, MELD>15, bilirubin > 2 mg/dl, INR > 1.5 or portal vein thrombosis were excluded. All patients underwent laboratory tests, upper endoscopy and hepatic venous pressure gradient (HVPG). Decompensation, development of HCC, liver transplant and death were recorded and analysed through competing-risk analysis. RESULTS: The study group was composed of 134 patients who were followed for a median of 39 months. During follow-up, 46 patients (34.3%) developed liver decompensation. Hepatocellular carcinoma occurred in 18 patients and two patients died from non-liver-related causes. The 1-, 2- and 3-year cumulative incidences of decompensation were 9.7%, 28.4% and 33.4% respectively. Patients with ICG-r15 < 10% did not experience any decompensation events during follow-up, while the 3-year cumulative incidence of decompensation of patients with ICG-r15 between 10% and 22.9% was 29.2% and that of patients with ICG-r15 ≥ 23% was 70.0% (P < 0.001). ICG-r15 gave the lowest pseudo-log-likelihood value, in comparison to oesophageal varices present, MELD, low platelet count and HVPG. CONCLUSIONS: ICG-r15 appears to be strictly related to liver decompensation, longitudinally confirming the preliminary findings of its correlation with PH among patients with compensated cirrhosis, and can be used for patient prognostication.

Pathophysiology and Therapeutic Strategies for Symptomatic Uncomplicated Diverticular Disease of the Colon.

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.

Gut Microbiota and Celiac Disease.

Recent evidence regarding celiac disease has increasingly shown the role of innate immunity in triggering the immune response by stimulating the adaptive immune response and by mucosal damage. The interaction between the gut microbiota and the mucosal wall is mediated by the same receptors which can activate innate immunity. Thus, changes in gut microbiota may lead to activation of this inflammatory pathway. This paper is a review of the current knowledge regarding the relationship between celiac disease and gut microbiota. In fact, patients with celiac disease have a reduction in beneficial species and an increase in those potentially pathogenic as compared to healthy subjects. This dysbiosis is reduced, but might still remain, after a gluten-free diet. Thus, gut microbiota could play a significant role in the pathogenesis of celiac disease, as described by studies which link dysbiosis with the inflammatory milieu in celiac patients. The use of probiotics seems to reduce the inflammatory response and restore a normal proportion of beneficial bacteria in the gastrointestinal tract. Additional evidence is needed in order to better understand the role of gut microbiota in the pathogenesis of celiac disease, and the clinical impact and therapeutic use of probiotics in this setting.