Search

Cirrhosis and its complications may affect gut microbiota (GM) composition. Transjugular intrahepatic portosystemic shunt (TIPS) represents the most effective treatment for portal hypertension (PH). We aimed to evaluate whether TIPS placement modifies GM composition and metabolic function.A compositional and functional GM analysis was prospectively performed in 13 cirrhotic patients receiving TIPS. Patients receiving systemic or non-absorbable antibiotics for any indications were excluded. Fecal samples were collected before and three months after TIPS. GM was analyzed by 16S ribosomal RNA sequencing. Small- and medium-chain fatty acids (SCFAs and MCFAs, respectively) were measured by gas chromatography/mass spectrometry.TIPS placement resulted in a mean 48% reduction in portal-caval pressure gradient. No recurrence of PH related complications was observed. After TIPS, increased levels of Flavonifractor spp. (p = 0.049), and decreased levels of Clostridiaceae (p = 0.024), these latter linked to abdominal infections in cirrhotic patients, were observed. No differences were found in the SCFAs signature while analysis of MCFA profiles showed a decreased abundance of pro-inflammatory isohexanoic (p0.01), 2-ethylhexanoic (p0.01) and octanoic acids (p0.01) after TIPS.Correction of PH following TIPS results in modifications of GM composition which could be potentially beneficial and reduces the levels of fecal pro-inflammatory MCFAs.

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.

Body composition predicts mortality in patients with cirrhosis. The impact of sex on this association is unknown. We investigated the impact of sex on this association in patients with cirrhosis assessed for liver transplantation.This single-centre retrospective cohort study included adults assessed for liver transplantation. Nutritional status was assessed using the Royal Free Hospital-Global Assessment (RFH-GA). Body composition at the third lumbar vertebrae was determined. SarcopeniaThe cohort comprised 628 patients, including 199 females and 429 males. Both groups were similar in terms of baseline liver disease severity by Model for End-stage Liver Disease (MELD) (p = .98) and nutritional status (p = .24). SarcopeniaThis study demonstrates that male patients were susceptible to low muscle mass, whereas female patients were not. Future research in this patient population should minimize sex-related bias and present data for both groups separately.

In patients affected by myelofibrosis with hepatic myeloid metaplasia (HMM), portal hypertension (PHT) complications may develop. In this case series, we analysed the efficacy and safety of transjugular portosystemic shunt (TIPS) in the treatment of PHT-related complications and its effects on the nutritional status. Six patients were evaluated and the average follow-up period after TIPS was 33 (IQR 5) months. None of the patients developed hepatic failure, nor any recurrence of variceal bleeding was recorded. No additional paracentesis or endoscopic prophylactic treatment for PHT-related complications were required. In all subjects, the average dose of diuretics was almost halved three months after TIPS. Three patients died during the follow-up, but none for liver-related causes. All patients showed an improvement in the global nutritional status. In conclusion, TIPS represent an effective and safe treatment option for patients affected by complications of PHT secondary to HMM and drives to an improvement of the nutritional status.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p

ElastPQ is a point shear wave elastography technique used to non-invasively assess liver fibrosis. We compared liver stiffness measurements (LSM) by ElastPQ and fibroscan transient elastography (F-TE) in a cohort of patients with non-alcoholic fatty liver disease (NAFLD). We further evaluated the performance of ElastPQ in a subgroup of patients with available liver histology.We included patients with NAFLD who presented in a dedicated multidisciplinary clinic. Anthropometric parameters, blood tests and elastography measurements were obtained using F-TE and ElastPQ as part of routine clinical care.We enrolled 671 patients with NAFLD, mean age 55.8 ± 13 years, body mass index (BMI) 31.5 ± 5.7 kg/mElastPQ shows an excellent correlation with F-TE in patients with NAFLD, which was better for lower LSM. The optimal cut-off values of ElastPQ are lower than those of F-TE for individual stages of fibrosis. ElastPQ has similar diagnostic accuracy to F-TE for all stages of fibrosis.

Background and aims There are several short-term prognostic scores for alcoholic hepatitis (AH) that combine demographical and biochemical parameters. The extent of liver fibrosis may also be relevant to the prognosis of AH with potential added value. We evaluated collagen proportionate area (CPA) as a predictor of short and long-term mortality in AH. Methods We retrospectively included patients with biopsy-verified AH. Clinical, laboratory and outcome data were collected. CPA and five AH scores were calculated: Maddrey's DF, MELD, GAHS, ABIC, and the Lille Model. Predictors of short and long-term all-cause mortality were assessed using Cox regression analysis. Results We included 140 patients with AH. In total, 67 (48%) patients died after a median follow-up of 66 (IQR 102) months, with 17 (12%) dying within the first 90-days. CPA was not a predictor of 90-days mortality and had no additional value to the prognostic AH scores on short-term mortality. However, CPA predicted long-term mortality independently of prognostic AH scores. Importantly, CPA and abstinence from alcohol were independent predictors of long-term mortality in patients alive 90 days after the biopsy. Conclusion CPA predicts long-term mortality in patients with AH independently of abstinence from alcohol but has no prognostic value on short-term mortality.

Introduction The impact of sarcopenia in patients undergoing transjugular intrahepatic portosystemic shunt (TIPSS) insertion for refractory ascites is unknown. Methods All adult patients who underwent TIPSS insertion for refractory ascites between 2010 and 2018 were included. Skeletal muscle index at L3 was used to determine sarcopenia status. Results One hundred seven patients were followed for 14.2 months. Sarcopenia was present in 57% of patients. No patient had history of pre-TIPSS hepatic encephalopathy (HE). De novo HE occurred in 30% of patients. On multivariate analysis, only platelet count and L3-SMI predicted de novo HE. On multivariate analysis, age and model for end-stage liver disease with sodium predicted mortality, whereas L3-SMI and sarcopenia did not. In patients with repeat imaging, L3-SMI improved significantly post-TIPSS compared with baseline. Discussion Sarcopenia should not be considered as a contraindication to TIPSS insertion in refractory ascites because it is not associated with de novo HE or increased mortality.

Hepatitis C virus (HCV)-related chronic infection has been associated with a higher incidence of cardiovascular diseases. An altered morphology and function of both left and right heart have been described in HCV patients; however, the causality of the association is still debated. Ninety-eight nonobese and nondiabetic HCV patients (59.5 ± 12.0 years; males 52%) with Fibroscan-Transient Elastography assessed low-moderate liver fibrosis that achieved sustained viral response at 12 and 24 weeks after DAAs (direct-acting antivirals) participated. 56 were matched with 52 control subjects for age, sex and cardiovascular risk factors at baseline. A trans-thoracic echocardiography was performed in each subject at baseline (T0) and repeated in all HCV patients after eradication (6 months later eligibility, T1). TNF-α and IL-10 were measured at baseline and at T1. A concentric remodelling of the left heart in HCV participants was identified, whereas tricuspidal annular plane systolic excursion, right indexed atrial volume, right basal ventricular diameter, inferior vena cava diameter and pulmonary arterial pressure were higher in HCV participants compared to matched controls. After virus eradication, left indexed atrial volume and all right cardiac chambers measures were lower than baseline. A significant reduction of TNF-α was shown at T1, while IL-10 did not change. This study shows a concentric remodelling of the left ventricle and structural modifications in the right sections in HCV patients compared to controls. Virus eradication with DAAs was associated with a reduction of the main right atrioventricular parameters indicating a direct involvement of the HCV in cardiac changes.

Background There is limited evidence linking achievement of biochemical response with outcomes in Autoimmune Hepatitis (AIH), and it is unclear whether normalization of serum immunoglobulin G (IgG) levels influences prognosis. Aims We aimed to investigate factors associated with death or liver transplantation in patients affected by AIH. Methods We undertook a retrospective analysis of all AIH patients attending a tertiary liver unit since 1980. Patients not meeting established diagnostic criteria for AIH or with a follow-up shorter than 18 months were excluded. Results 107 patients meeting inclusion criteria were included in the study. Mean age at diagnosis was 44 years, 29 patients (27.1%) had cirrhosis at baseline. Median follow-up was 79 months, and 70 patients (79.5%) reached biochemical response. Biochemical response was associated with reduced hazard of liver transplant or death (HR 0.07, 95% CI 0.01–0.46), whereas cirrhosis at diagnosis was an independent predictor of liver transplantation or death (Hazard ratio (HR) 11.8, 95%, confidence interval (CI) 1.18–117.4). Lack of normalization of serum IgG levels was associated with reduced 5-year transplant-free survival (95% in patients normalizing, compared to 86%, p = 0.02). Conclusion Normalization of serum IgG levels alone translates in better transplant-free survival in patients with AIH and should be a treatment target along with transaminases.

Background & Aims: Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT. Methods: We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983–2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10–15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models. Results: While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28–0.61; p

Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular (CV) risk. However, it is unclear whether NAFLD contributes independently to the development of CV disease. Our study aimed at assessing the differences in several indices of atherosclerosis, arterial stiffness and cardiac morphology among patients with isolated NAFLD, isolated hypertension (HT) or a combination of the two conditions.A total of 169 participants (mean age = 50.4 ± 10.2 yrs; males = 73.6%) were divided according to the presence of NAFLD and HT into three groups: only NAFLD (55 patients), only HT (49 patients), and NAFLD + HT (65 patients). Exclusion criteria were a BMI≥35 kg/mOvert atherosclerosis was significantly present only in NAFLD + HT patients, but not in patients with isolated NAFLD. This implies that the impact of NAFLD on vascular structure and function could depend on the coexistence of other major CV risk factors, such as HT.

Background/Aims Non-alcoholic fatty liver disease (NAFLD) represents a significant public health issue. Identifying patients with simple steatosis from those with non-alcoholic steatohepatitis (NASH) is crucial since NASH is correlated with increased morbidity and mortality. Serum-based markers, including adipokines and cytokines, are important in the pathogenesis and progression of NAFLD. Here we assessed the usefulness of such markers in patients with NAFLD. Methods This prospective, cross-sectional study included 105 adult patients with varying severity of NAFLD. Twelve serum-based markers were measured by 3 biochip platforms and 2 enzyme-linked immunosorbent assay (ELISA) methods. We also developed a NAFLD individual fibrosis index (NIFI) using the serum-based markers mostly correlated with fibrosis severity. Results Sixty-one out of 105 patients were male (58.1%) with mean age was 53.5 years. Higher Interleukin-6 (IL-6) increased (p = 0.0321) and lower Matrix Metalloproteinase-9 (MMP-9) serum levels (p = 0.0031) were associated with higher fibrosis as measured by Fibroscan® in multivariable regression analysis. Using receiver-operating characteristic (ROC) curve analysis for the NIFI, area under the curve for predicting Fibroscan values ≥ 7.2 kPa was 0.77 (95%CI: 0.67, 0.88, p Conclusions Increasing fibrosis severity in NAFLD is associated with differential expression of IL-6 and MMP-9. NIFI could be valuable for the prediction of advanced NAFLD fibrosis and potentially help avoid unnecessary interventions such as liver biopsy in low-risk patients.

Recently a series of papers was introduced describing on “how to do” certain techniques. More specifically we published on how to perform strain imaging using the transcutaneous and endoscopic ultrasound approach and shear wave elastography (SWE). In the first part we describe how to optimize the examination technique, discussing normal values, pitfalls, artefacts and specific tips for applying SWE to specific organs (liver, breast, thyroid, salivary glands) as part of a diagnostic US examination. In part II, the use of SWE in the pancreas, spleen, kidney, prostate, scrotum, musculoskeletal system, lymph nodes and future developments are discussed.

ElastPQ is a new elastography technique for non-invasive liver fibrosis staging. However, it does not have validated reliability criteria. We tested the reliability of a different number of measurements in patients with chronic liver disease and explored whether the application of quality criteria improves the diagnostic performance. All patients underwent liver stiffness assessment (LSM) with ElastPQ and Fibroscan (F-TE). The mean, median, standard deviation (SD) and interquartile range (IQR) of 10, 5 and 3 measurements were retrospectively collected for each patient and compared to each other. Liver histology was available in a subset of patients. Overall, 400 patients met the inclusion criteria. Non-alcoholic fatty liver disease (NAFLD) was the most represented etiology (75 %), followed by primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). The correlation of medians was significantly better between 10 and 5 measurements than between 10 and 3. The difference of medians was significant only in the comparison between 10 and 3 measurements. The correlation between ElastPQ and F-TE was equally good for 10 and 5 measurements and significantly improved after an IQR/median ≤ 30 % was applied. The diagnostic performance of ElastPQ was better with the median value of 10 and 5 measurements and improved if LSM values were obtained with IQR/M ≤ 30 %. The median value of 5 valid LSMs suffices for the reliable estimation of liver stiffness using ElastPQ. The quality criterion of IQR/M ≤ 30 % should also be followed when using this technique.ZIEL: ElastPQ ist ein neues elastografisches Verfahren für das nichtinvasive Staging der Leberfibrose, hat aber keine validierten Reliabilitätskriterien. Wir haben die Verlässlichkeit der verschiedenen Messungen bei Patienten mit chronischer Lebererkrankung getestet und untersucht, ob die Anwendung von Qualitätskriterien die diagnostische Leistung verbessert. Bei allen Patienten wurde eine Lebersteifigkeitsuntersuchung (LSM) mit ElastPQ und Fibroscan (F-TE) durchgeführt. Mittelwert, Median, Standardabweichung (SD) und Interquartilsabstand (IQR) von 10, 5 und 3 Messungen wurden retrospektiv für jeden Patienten erhoben und miteinander verglichen. Bei einer Untergruppe der Patienten war eine Leberhistologie verfügbar. Insgesamt erfüllten 400 Patienten die Einschlusskriterien. Die nichtalkoholische Fettleberkrankheit (NAFLD) war die am häufigsten vertretene Ätiologie (75 %), gefolgt von primärer sklerosierender Cholangitis (PSC), primärer biliärer Cholangitis (PBC) und Autoimmunhepatitis (AIH). Die Korrelation der Mediane war signifikant besser zwischen 10 und 5 Messungen als zwischen 10 und 3. Eine Differenz der Mediane war nur signifikant beim Vergleich von 10 und 3 Messungen. Die Korrelation zwischen ElastPQ und F-TE war für 10 und 5 Messungen gleichermaßen gut und verbesserte sich signifikant, wenn IQR/median ≤ 30 % angewendet wurde. Die diagnostische Leistung von ElastPQ war besser mit dem Medianwert von 10 und 5 Messungen und verbesserte sich, wenn LSM-Werte mit IQR/M ≤ 30 % erreicht wurden. Der Medianwert von 5 gültigen LSMs ist ausreichend für die zuverlässige Abschätzung der Lebersteifigkeit mittels ElastPQ. Auch bei dieser Methode sollte das Qualitätskriterium IQR/M ≤ 30 % eingehalten werden.

Defective spleen function increases susceptibility to bacterial infections which can be prevented by vaccine prophylaxis. Splenic hypofunction can be found in a number of autoimmune disorders; however, no data are available regarding autoimmune atrophic gastritis (AAG), autoimmune enteropathy (AIE) and autoimmune liver disease (AILD). Peripheral blood samples from patients with AAG (n = 40), AIE (n = 3) and AILD (n = 40) were collected. Patients affected by autoimmune disorders already known to be associated with splenic hypofunction, i.e. coeliac disease (CD) and ulcerative colitis (UC), were included as disease controls, while splenectomised patients and healthy subjects were evaluated as positive and negative controls, respectively. Counting of erythrocytes with membrane abnormalities, i.e. pitted red cells, was used as an indicator of spleen function (normal upper limit 4%). Defective splenic function was observed in 22 of the 40 patients with AAG (55.0%), in two of the three patients with AIE (66.6%) and in 35 of the 40 patients with AILD (87.5%). As expected, in untreated CD, refractory CD and UC there was a high prevalence of hyposplenism (43.7%, 88.2% and 54.4%, respectively). Due to the high prevalence of splenic hypofunction, patients with AAG, AILD and AIE should undergo pitted red cell evaluation and, if hyposplenic, they should be candidate to vaccine prophylaxis against encapsulated bacteria.

We recently introduced a series of papers describing how to do certain techniques. This article is the first part of a review of shear wave elastography (SWE). It reports the principles and interpretation of the technique and describes how to optimize it. Normal values, pitfalls and artefacts for the examination of liver, breast. thyroid and salivary gland with shear wave elastography are presented. The manuscript provides specific tips for applying SWE as part of a diagnostic US examination.

Background Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years. There are several different treatments to prevent bleeding, including: beta-blockers, endoscopic sclerotherapy, and variceal band ligation. However, there is uncertainty surrounding their individual and relative benefits and harms. Objectives To compare the benefits and harms of different treatments for prevention of first variceal bleeding from oesophageal varices in adults with liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for prevention of first variceal bleeding from oesophageal varices according to their safety and efficacy. Search methods We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers to December 2019 to identify randomised clinical trials in people with cirrhosis and oesophageal varices with no history of bleeding. Selection criteria We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and oesophageal varices with no history of bleeding. We excluded randomised clinical trials in which participants had previous bleeding from oesophageal varices and those who had previously undergone liver transplantation or previously received prophylactic treatment for oesophageal varices. Data collection and analysis We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR), and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute for Health and Care Excellence Decision Support Unit guidance. We performed the direct comparisons from randomised clinical trials using the same codes and the same technical details. Main results We included 66 randomised clinical trials (6653 participants) in the review. Sixty trials (6212 participants) provided data for one or more comparisons in the review. The trials that provided the information included people with cirrhosis due to varied aetiologies and those at high risk of bleeding from oesophageal varices. The follow-up in the trials that reported outcomes ranged from 6 months to 60 months. All but one of the trials were at high risk of bias. The interventions compared included beta-blockers, no active intervention, variceal band ligation, sclerotherapy, beta-blockers plus variceal band ligation, beta-blockers plus nitrates, nitrates, beta-blockers plus sclerotherapy, and portocaval shunt. Overall, 21.2% of participants who received non-selective beta-blockers ('beta-blockers') - the reference treatment (chosen because this was the most common treatment compared in the trials) - died during 8-month to 60-month follow-up. Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates all had lower mortality versus no active intervention (beta-blockers: HR 0.49, 95% CrI 0.36 to 0.67; direct comparison HR: 0.59, 95% CrI 0.42 to 0.83; 10 trials, 1200 participants; variceal band ligation: HR 0.51, 95% CrI 0.35 to 0.74; direct comparison HR 0.49, 95% CrI 0.12 to 2.14; 3 trials, 355 participants; sclerotherapy: HR 0.66, 95% CrI 0.51 to 0.85; direct comparison HR 0.61, 95% CrI 0.41 to 0.90; 18 trials, 1666 participants; beta-blockers plus nitrates: HR 0.41, 95% CrI 0.20 to 0.85; no direct comparison). No trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation had a higher number of serious adverse events (number of events) than beta-blockers (rate ratio 10.49, 95% CrI 2.83 to 60.64; 1 trial, 168 participants). Based on low-certainty evidence, beta-blockers plus nitrates had a higher number of 'any adverse events (number of participants)' than beta-blockers alone (OR 3.41, 95% CrI 1.11 to 11.28; 1 trial, 57 participants). Based on low-certainty evidence, adverse events (number of events) were higher in sclerotherapy than in beta-blockers (rate ratio 2.49, 95% CrI 1.53 to 4.22; direct comparison rate ratio 2.47, 95% CrI 1.27 to 5.06; 2 trials, 90 participants), and in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison rate ratio 1.72, 95% CrI 1.08 to 2.76; 1 trial, 140 participants). Based on low-certainty evidence, any variceal bleed was lower in beta-blockers plus variceal band ligation than in beta-blockers (direct comparison HR 0.21, 95% CrI 0.04 to 0.71; 1 trial, 173 participants). Based on low-certainty evidence, any variceal bleed was higher in nitrates than beta-blockers (direct comparison HR 6.40, 95% CrI 1.58 to 47.42; 1 trial, 52 participants). The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Authors' conclusions Based on low-certainty evidence, beta-blockers, variceal band ligation, sclerotherapy, and beta-blockers plus nitrates may decrease mortality compared to no intervention in people with high-risk oesophageal varices in people with cirrhosis and no previous history of bleeding. Based on low-certainty evidence, variceal band ligation may result in a higher number of serious adverse events than beta-blockers. The evidence indicates considerable uncertainty about the effect of beta-blockers versus variceal band ligation on variceal bleeding. The evidence also indicates considerable uncertainty about the effect of the interventions in most of the remaining comparisons.

Background Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years of diagnosis. Several different treatments are available, which include endoscopic sclerotherapy, variceal band ligation, beta-blockers, transjugular intrahepatic portosystemic shunt (TIPS), and surgical portocaval shunts, among others. However, there is uncertainty surrounding their individual and relative benefits and harms. Objectives To compare the benefits and harms of different initial treatments for secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for secondary prevention according to their safety and efficacy. Search methods We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until December 2019 to identify randomised clinical trials in people with cirrhosis and a previous history of bleeding from oesophageal varices. Selection criteria We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and previous history of bleeding from oesophageal varices. We excluded randomised clinical trials in which participants had no previous history of bleeding from oesophageal varices, previous history of bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those who had acute bleeding at the time of treatment, and those who had previously undergone liver transplantation. Data collection and analysis We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. Main results We included a total of 48 randomised clinical trials (3526 participants) in the review. Forty-six trials (3442 participants) were included in one or more comparisons. The trials that provided the information included people with cirrhosis due to varied aetiologies. The follow-up ranged from two months to 61 months. All the trials were at high risk of bias. A total of 12 interventions were compared in these trials (sclerotherapy, beta-blockers, variceal band ligation, beta-blockers plus sclerotherapy, no active intervention, TIPS (transjugular intrahepatic portosystemic shunt), beta-blockers plus nitrates, portocaval shunt, sclerotherapy plus variceal band ligation, beta-blockers plus nitrates plus variceal band ligation, beta-blockers plus variceal band ligation, sclerotherapy plus nitrates). Overall, 22.5% of the trial participants who received the reference treatment (chosen because this was the commonest treatment compared in the trials) of sclerotherapy died during the follow-up period ranging from two months to 61 months. There was considerable uncertainty in the effects of interventions on mortality. Accordingly, none of the interventions showed superiority over another. None of the trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation may result in fewer serious adverse events (number of people) than sclerotherapy (OR 0.19; 95% CrI 0.06 to 0.54; 1 trial; 100 participants). Based on low or very low-certainty evidence, the adverse events (number of participants) and adverse events (number of events) may be different across many comparisons; however, these differences are due to very small trials at high risk of bias showing large differences in some comparisons leading to many differences despite absence of direct evidence. Based on low-certainty evidence, TIPS may result in large decrease in symptomatic rebleed than variceal band ligation (HR 0.12; 95% CrI 0.03 to 0.41; 1 trial; 58 participants). Based on moderate-certainty evidence, any variceal rebleed was probably lower in sclerotherapy than in no active intervention (HR 0.62; 95% CrI 0.35 to 0.99, direct comparison HR 0.66; 95% CrI 0.11 to 3.13; 3 trials; 296 participants), beta-blockers plus sclerotherapy than sclerotherapy alone (HR 0.60; 95% CrI 0.37 to 0.95; direct comparison HR 0.50; 95% CrI 0.07 to 2.96; 4 trials; 231 participants); TIPS than sclerotherapy (HR 0.18; 95% CrI 0.08 to 0.38; direct comparison HR 0.22; 95% CrI 0.01 to 7.51; 2 trials; 109 participants), and in portocaval shunt than sclerotherapy (HR 0.21; 95% CrI 0.05 to 0.77; no direct comparison) groups. Based on low-certainty evidence, beta-blockers alone and TIPS might result in more, other compensation, events than sclerotherapy (rate ratio 2.37; 95% CrI 1.35 to 4.67; 1 trial; 65 participants and rate ratio 2.30; 95% CrI 1.20 to 4.65; 2 trials; 109 participants; low-certainty evidence). The evidence indicates considerable uncertainty about the effect of the interventions including those related to beta-blockers plus variceal band ligation in the remaining comparisons. Authors' conclusions The evidence indicates considerable uncertainty about the effect of the interventions on mortality. Variceal band ligation might result in fewer serious adverse events than sclerotherapy. TIPS might result in a large decrease in symptomatic rebleed than variceal band ligation. Sclerotherapy probably results in fewer 'any' variceal rebleeding than no active intervention. Beta-blockers plus sclerotherapy and TIPS probably result in fewer 'any' variceal rebleeding than sclerotherapy. Beta-blockers alone and TIPS might result in more other compensation events than sclerotherapy. The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Accordingly, high-quality randomised comparative clinical trials are needed.

Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p 83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS., Jonel Trebicka is supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57, CRC1382), Cellex Foundation and European Union’s Horizon 2020 research and innovation program GALAXY study (No. 668031), LIVERHOPE (No. 731875) and MICROB-PREDICT (No. 825694) and the Cellex Foundation. Joan Genescà is a recipient of a Research Intensification grant from Instituto de Salud Carlos III, Spain. The study was partially funded by grants PI15/00066, and PI18/00947 from Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “Investing in your future”). Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivasis supported by Instituto de Salud Carlos III. Macarena Simón-Talero is a recipient of the grant JR 17/00029 from Instituto de Salud Carlos III

Autoimmune liver diseases (AILDs) are chronic liver pathologies characterized by fibrosis and cirrhosis due to immune-mediated liver damage. In this study, we addressed the question whether mucosal-associated invariant T (MAIT) cells, innate-like T cells, are functionally altered in patients with AILD and whether MAIT cells can promote liver fibrosis through activation of hepatic stellate cells (HSCs). We analyzed the phenotype and function of MAIT cells from AILD patients and healthy controls by multicolor flow cytometry and investigated the interaction between human MAIT cells and primary human hepatic stellate cells (hHSCs). We show that MAIT cells are significantly decreased in peripheral blood and liver tissue of patients with AILD. Notably, MAIT cell frequency tended to decrease with increasing fibrosis stage. MAIT cells from AILD patients showed signs of exhaustion, such as impaired interferon-γ (IFN-γ) production and high ex vivo expression of the activation and exhaustion markers CD38, HLA-DR, and CTLA-4. Mechanistically, this exhausted state could be induced by repetitive stimulation of MAIT cells with the cytokines interleukin (IL)-12 and IL-18, leading to decreased IFN-γ and increased exhaustion marker expression. Of note, repetitive stimulation with IL-12 further resulted in expression of the profibrogenic cytokine IL-17A by otherwise exhausted MAIT cells. Accordingly, MAIT cells from both healthy controls and AILD patients were able to induce an activated, proinflammatory and profibrogenic phenotype in hHSCs in vitro that was partly mediated by IL-17.Our data provide evidence that MAIT cells in AILD patients have evolved towards an exhausted, profibrogenic phenotype and can contribute to the development of HSC-mediated liver fibrosis. These findings reveal a cellular and molecular pathway for fibrosis development in AILD that could be exploited for antifibrotic therapy. (Hepatology 2018;68:172-186).

Background: Approximately 2.5% of all hospitalisations in people with cirrhosis are for spontaneous bacterial peritonitis (SBP). Antibiotics, in addition to supportive treatment (fluid and electrolyte balance, treatment of shock), form the mainstay treatments of SBP. Various antibiotics are available for the treatment of SBP, but there is uncertainty regarding the best antibiotic for SBP. Objectives: To compare the benefits and harms of different antibiotic treatments for spontaneous bacterial peritonitis (SBP) in people with decompensated liver cirrhosis. Search methods: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until November 2018 to identify randomised clinical trials on people with cirrhosis and SBP. Selection criteria: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and SBP. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. Data collection and analysis: Two review authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of SBP, liver transplantation, and other decompensation events. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio with 95% credible intervals (CrIs) based on an available‐case analysis, according to the National Institute of Health and Care Excellence (NICE) Decision Support Unit guidance. Main results: We included a total of 12 trials (1278 participants; 13 antibiotics) in the review. Ten trials (893 participants) were included in one or more outcomes in the review. The trials that provided the information included patients having cirrhosis with or without other features of decompensation of varied aetiologies. The follow‐up in the trials ranged from one week to three months. All the trials were at high risk of bias. Only one trial was included under each comparison for most of the outcomes. Because of these reasons, there is very low certainty in all the results. The majority of the randomised clinical trials used third‐generation cephalosporins, such as intravenous ceftriaxone, cefotaxime, or ciprofloxacin as one of the interventions. Overall, approximately 75% of trial participants recovered from SBP and 25% of people died within three months. There was no evidence of difference in any of the outcomes for which network meta‐analysis was possible: mortality (9 trials; 653 participants), proportion of people with any adverse events (5 trials; 297 participants), resolution of SBP (as per standard definition, 9 trials; 873 participants), or other features of decompensation (6 trials; 535 participants). The effect estimates in the direct comparisons (when available) were very similar to those of network meta‐analysis. For the comparisons where network meta‐analysis was not possible, there was no evidence of difference in any of the outcomes (proportion of participants with serious adverse events, number of adverse events, and proportion of participants requiring liver transplantation). Due to the wide CrIs and the very low‐certainty evidence for all the outcomes, significant benefits or harms of antibiotics are possible. None of the trials reported health‐related quality of life, number of serious adverse events, or symptomatic recovery from SBP. Funding: the source of funding for two trials were industrial organisations who would benefit from the results of the trial; the source of funding for the remaining 10 trials was unclear. Authors' conclusions: Short‐term mortality after SBP is about 25%. There is significant uncertainty about which antibiotic therapy is better in people with SBP. We need adequately powered randomised clinical trials, with adequate blinding, avoiding post‐randomisation dropouts (or performing intention‐to‐treat analysis), and using clinically important outcomes, such as mortality, health‐related quality of life, and adverse events.

Introduction There is an ongoing effort to identify non-invasive surrogates for staging liver disease and detecting clinically significant portal hypertension (CSPH), defined as the presence of gastro-oesophageal varices on endoscopy. The correlation of spleen stiffness measurement (SSM) with portal hypertension measured by hepatic venous pressure gradient has been reported, but data regarding its reliability are controversial. We assessed the ability of liver stiffness measurement (LSM) and SSM performed by point-shear wave elastography (pSWE) to detect CSPH in primary biliary cholangitis (PBC). Methods Predictors of CSPH were evaluated in 53 PBC patients who had an upper-GI endoscopy within 12 months of the elastographic assessment. Demographics, biochemical and ultrasonographic data were prospectively collected. Transient elastography (Fibroscan, Echosens) [F-TE], liver and spleen pSWE (ElastPQ, Philips Affiniti70G), and the most common clinical fibrosis scores were obtained. ROC curves were constructed to establish the performance of elastographic techniques and fibrosis scores in predicting CSPH. Results Mean age 57±12 years, 91% female. OVs were detected in 12 (23%) cases (4 at high-risk of bleeding). Variables significantly associated with CSPH at univariate analysis were: diagnosis of cirrhosis, Child-Pugh, MELD and Mayo risk score, spleen area and longitudinal diameter, platelets, albumin, ALT, INR, F-TE, ElastPQ LSM and SSM, LSPS (LSM*spleen diameter/platelets). SSM remained the only independent predictor of CSPH in all the multivariate models (OR 1.101; 95%CI 1.14–1.20; p F-TE and ElastPQ LSM showed good AUROCs (95%CI): 0.85 (0.72–0.99) and 0.80 (0.62–0.98), with best cut-off 14.3 and 13.8 kPa, respectively. However, specificity (Sp) was In this cohort, the diagnostic performance of ElastPQ SSM in detecting CSPH was superior to the recently validated Baveno VI and Expanded Baveno VI criteria, which showed good Sp (77% and 87%, respectively) but low Se (67%, for both). Conclusions We provide evidence that transient elastography, in particular ElastPQ SSM, can be used as a reliable tool for the detection of CSPH in PBC.

Background Spectrum of liver injury among HIV-positive people is wide; in particular, prevalence of nonalcoholic fatty liver disease (NAFLD) seems to be higher compared with HIV-negative people. Methods We retrospectively evaluated all liver biopsies performed at Royal Free Hospital from 2000 to 2017 in HIV monoinfected patients with abnormal transaminases, to assess the underlying cause of liver disease and to characterize the extent of fibrosis. We furthermore evaluated the diagnostic accuracy of FIB4 and FibroScan as noninvasive tools for fibrosis assessment. Results Ninety-seven patients were included. Most common histological findings were NAFLD (28%), nonspecific changes (26%), and normal histology (13%). Twenty percent of the patients had significant fibrosis and 11% had advanced fibrosis. FIB4, at a cutoff of 1.3, had a specificity of 82% and negative predictive value (NPV) of 95% for exclusion of advanced fibrosis. FibroScan was available in 28% patients and 33% had a liver stiffness ≥7.5 kPa. FibroScan showed a specificity of 77% and NPV of 94% for exclusion of significant fibrosis. Among patients with NAFLD (n = 27), 18% had advanced fibrosis, whereas the majority (56%) did not have any fibrosis. The NPV of FIB4 for advanced fibrosis in these patients was 93%. Conclusions Among HIV-positive patients with elevated transaminases, a surprisingly high number of patients had nonsignificant changes or even normal histological findings. The prevalence of NAFLD was lower than reported in other series. Use of noninvasive tools with a high NPV for significant fibrosis can help reduce the number of required biopsies.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) frequently recurs after liver transplantation. We evaluated risk factors associated with recurrence of PBC and its effects on patient and graft survival in a multicenter, international cohort (the Global PBC Study Group). METHODS: We collected demographic and clinical data from 785 patients (89% female) with PBC who underwent liver transplantation (mean age, 54 ± 9 years) from February 1983 through June 2016, among 13 centers in North America and Europe. Results from biochemical tests performed within 12 months of liver transplantation were analyzed to determine whether markers of cholestasis could identify patients with recurrence of PBC (based on histologic analysis). Patients were followed for a median 6.9 years (interquartile range, 6.1-7.9 years). RESULTS: PBC recurred in 22% of patients after 5 years and 36% after 10 years. Age at diagnosis 3-fold the upper limit of normal) at 6 months after liver transplantation (HR, 1.79; 95% CI, 1.16-2.76; P = .008) were associated with higher risk of PBC recurrence, whereas use of cyclosporine reduced risk of PBC recurrence (HR, 0.62; 95% CI, 0.46-0.82; P = .001). In multivariable Cox regression with time-dependent covariate, recurrence of PBC significantly associated with graft loss (HR, 2.01; 95% CI, 1.16-3.51; P = .01) and death (HR, 1.72; 95% CI, 1.11-2.65; P = .02). CONCLUSIONS: Younger age at the time of diagnosis with PBC or at liver transplantation, tacrolimus use, and biochemical markers of cholestasis after liver transplantation are associated with PBC recurrence. PBC recurrence reduces odds of graft and patient survival. Strategies are needed to prevent PBC recurrence or reduce its negative effects. ispartof: GASTROENTEROLOGY vol:156 issue:1 pages:96-+ ispartof: location:United States status: published

Baveno-VI guidelines recommend that patients with compensated cirrhosis with liver stiffness by transient elastography (LSM-TE)20 kPa and platelets150,000/mm(3) do not need an esophagogastroduodenoscopy (EGD) to screen for varices, since the risk of having varices needing treatment (VNT) is5%. It remains uncertain if this tool can be used in patients with cholestatic liver diseases (ChLDs): primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These patients may have a pre-sinusoidal component of portal hypertension that could affect the performance of this rule. In this study we evaluated the performance of Baveno-VI, expanded Baveno-VI (LSM-TE25 kPa and platelets110,000/mm(3)), and other criteria in predicting the absence of VNT.This was a multicenter cross-sectional study in four referral hospitals. We retrospectively analyzed data from 227 patients with compensated advanced chronic liver disease (cACLD) due to PBC (n = 147) and PSC (n = 80) that had paired EGD and LSM-TE. We calculated false negative rate (FNR) and number of saved endoscopies for each prediction rule.Prevalence of VNT was 13%. Baveno-VI criteria had a 0% FNR in PBC and PSC, saving 39 and 30% of EGDs, respectively. In PBC the other LSM-TE-based criteria resulted in FNRs5%. In PSC the expanded Baveno criteria had an adequate performance. In both conditions LSM-TE-independent criteria resulted in an acceptable FNR but saved less EGDs.Baveno-VI criteria can be applied in patients with cACLD due to ChLDs, which would result in saving 30-40% of EGDs. Expanded criteria in PBC would lead to FNRs5%.

Background & Aims: Spontaneous portosystemic shunts (SPSS) have been associated with hepatic encephalopathy (HE). Little is known about their prevalence among patients with cirrhosis or clinical effects. We investigated the prevalence and characteristics of SPSS in patients with cirrhosis and their outcomes. Methods: We performed a retrospective study of 1729 patients with cirrhosis who underwent abdominal computed tomography or magnetic resonance imaging analysis from 2010 through 2015 at 14 centers in Canada and Europe. We collected data on demographic features, etiology of liver disease, comorbidities, complications, treatments, laboratory and clinical parameters, Model for End-Stage Liver Disease (MELD) score, and endoscopy findings. Abdominal images were reviewed by a radiologist (or a hepatologist trained by a radiologist) and searched for the presence of SPSS, defined as spontaneous communications between the portal venous system or splanchnic veins and the systemic venous system, excluding gastroesophageal varices. Patients were assigned to groups with large SPSS (L-SPSS, ≥8 mm), small SPSS (S-SPSS

The gold standard to assess the presence and severity of portal hypertension remains the hepatic vein pressure gradient, however the recent development of non-invasive assessment using elastography techniques offers valuable alternatives. In this review, we discuss the diagnostic accuracy and utility of such techniques in patients with portal hypertension due to cirrhosis. Areas covered: A literature search focused on liver and spleen stiffness measurement with different elastographic techniques for the assessment of the presence and severity of portal hypertension and oesophageal varices in people with chronic liver disease. The combination of elastography with parameters such as platelet count and spleen size is also discussed. Expert commentary: Non-invasive assessment of liver fibrosis and portal hypertension is a validated tool for the diagnosis and follow-up of patients. Baveno VI recommended the combination of transient elastography and platelet count for ruling out varices needing treatment in patients with compensated advanced chronic liver disease. Assessment of aetiology specific cut-offs for ruling in and ruling out clinically significant portal hypertension is an unmet clinical need. The incorporation of spleen stiffness measurements in non-invasive algorithms using validated software and improved measuring scales might enhance the non-invasive diagnosis of portal hypertension in the next 5 years.

Background Hepatocellular carcinoma (primary liver cancer) is classified in many ways. The Barcelona Clinic Liver Cancer (BCLC) group staging classifies the cancer based on patient's life expectancy. People with very early- or early-stage hepatocellular carcinoma have single tumour or three tumours of maximum diameter of 3 cm or less, Child-Pugh status A to B, and performance status 0 (fully functional). Management of hepatocellular carcinoma is uncertain. Objectives To assess the comparative benefits and harms of different interventions used in the treatment of early or very early hepatocellular carcinoma through a network meta-analysis and to generate rankings of the available interventions according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis and instead assessed the benefits and harms of different interventions versus each other or versus sham or no intervention using standard Cochrane methodology. Search methods We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, and trials registers to September 2016 to identify randomised clinical trials (RCTs) on hepatocellular carcinoma. Selection criteria We included only RCTs, irrespective of language, blinding, or publication status, in participants with very early- or early-stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, portal hypertension, aetiology of hepatocellular carcinoma, size and number of the tumours, and future remnant liver volume. We excluded trials including participants who were previously liver transplanted. We considered interventions compared with each other, sham, or no intervention. Data collection and analysis We calculated the odds ratio, mean difference, rate ratio, or hazard ratio with 95% confidence intervals using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed the risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and the quality of the evidence using GRADE. Main results Eighteen trials met the inclusion criteria for this review. Four trials (593 participants; 574 participants included for one or more analyses) compared surgery versus radiofrequency ablation in people with early hepatocellular carcinoma, eligible to undergo surgery. Fourteen trials (2533 participants; 2494 participants included for various analyses) compared different non-surgical interventions in people with early hepatocellular carcinoma, not eligible to undergo surgery. Overall, the quality of evidence was low or very low for all outcomes for both comparisons. Surgery versus radiofrequency ablation The majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral aetiology. The trials did not report the participants' portal hypertension status or whether they received adjuvant antiviral treatment or adjuvant immunotherapy. The average follow-up ranged from 29 months to 42 months (3 trials). There was no evidence of a difference in all-cause mortality at maximal follow-up for surgery versus radiofrequency ablation (hazard ratio 0.80, 95% confidence interval (CI) 0.60 to 1.08; 574 participants; 4 trials; I2 = 68). Cancer-related mortality was lower in the surgery group (20/115 (17.4%)) than in the radiofrequency ablation group (43/115 (37.4%)) (odds ratio 0.35, 95% CI 0.19 to 0.65; 230 participants; 1 trial). Serious adverse events (number of participants) was higher in the surgery group (14/60 (23.3%)) than in the radiofrequency ablation group (1/60 (1.7%)) (odds ratio 17.96, 95% CI 2.28 to 141.60; 120 participants; 1 trial). The number of serious adverse events was higher in the surgery group (adjusted rate 11.3 events per 100 participants) than in the radiofrequency ablation group (3/186 (1.6 events per 100 participants)) (rate ratio 7.02, 95% CI 2.29 to 21.46; 391 participants; 2 trials; I2 = 0%). None of the trials reported health-related quality of life. One trial was funded by a party with vested interests; three trials were funded by parties without any vested. Non-surgical interventions The majority of participants had cirrhotic livers, and the hepatocellular carcinoma was of viral aetiology. Most trials did not report the portal hypertension status of the participants, and none of the trials reported whether the participants received adjuvant antiviral treatment or adjuvant immunotherapy. The average follow-up ranged from 6 months to 37 months (11 trials). Trial participants, who were not eligible for surgery, were treated with radiofrequency ablation, laser ablation, microwave ablation, percutaneous acetic acid injection, percutaneous alcohol injection, a combination of radiofrequency ablation with systemic chemotherapy, a combination of radiofrequency ablation with percutaneous alcohol injection, a combination of transarterial chemoembolisation with percutaneous alcohol injection, or a combination of transarterial chemoembolisation with radiofrequency ablation. The mortality at maximal follow-up was higher in the percutaneous acetic acid injection (hazard ratio 1.77, 95% CI 1.12 to 2.79; 125 participants; 1 trial) and percutaneous alcohol injection (hazard ratio 1.49, 95% CI 1.18 to 1.88; 882 participants; 5 trials; I2 = 57%) groups compared with the radiofrequency ablation group. There was no evidence of a difference in all-cause mortality at maximal follow-up for any of the other comparisons. The proportion of people with cancer-related mortality at maximal follow-up was higher in the percutaneous alcohol injection group (adjusted proportion 16.8%) compared with the radiofrequency ablation group (20/232 (8.6%)) (odds ratio 2.18, 95% CI 1.22 to 3.89; 458 participants; 3 trials; I2 = 0%). There was no evidence of a difference in any of the comparisons that reported serious adverse events (number of participants or number of events). None of the trials reported health-related quality of life. Five trials were funded by parties without any vested interest; the source of funding was not available in the remaining trials. Authors' conclusions The evidence was of low or very low quality. There was no evidence of a difference in all-cause mortality at maximal follow-up between surgery and radiofrequency ablation in people eligible for surgery. All-cause mortality at maximal follow-up was higher with percutaneous acetic acid injection and percutaneous alcohol injection than with radiofrequency ablation in people not eligible for surgery. There was no evidence of a difference in all-cause mortality at maximal follow-up for the other comparisons. High-quality RCTs designed to assess clinically important differences in all-cause mortality and health-related quality of life, and having an adequate follow-up period (approximately five years) are needed.

BACKGROUND: There is significant uncertainty in the treatment of intermediate‐stage hepatocellular carcinoma which is defined by the Barcelona Clinic Liver Cancer (BCLC) as hepatocellular carcinoma stage B with large, multi‐nodular, Child‐Pugh status A to B, performance status 0 to 2, and without vascular occlusion or extrahepatic disease. OBJECTIVES: To assess the comparative benefits and harms of different interventions used in the treatment of intermediate‐stage hepatocellular carcinoma (BCLC stage B) through a network meta‐analysis and to generate rankings of the available interventions according to their safety and efficacy. However, we found only one comparison. Therefore, we did not perform the network meta‐analysis, and we assessed the comparative benefits and harms of different interventions versus each other, or versus placebo, sham, or no intervention (supportive treatment only) using standard Cochrane methodology. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised clinical trials registers to September 2016 to identify randomised clinical trials on hepatocellular carcinoma. SELECTION CRITERIA: We included only randomised clinical trials, irrespective of language, blinding, or publication status, in participants with intermediate‐stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, size, or number of the tumours (provided they met the criteria of intermediate‐stage hepatocellular carcinoma), of presence or absence of portal hypertension, of aetiology of hepatocellular carcinoma, and of the future remnant liver volume. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various interventions compared with each other or with no active intervention (supportive treatment only). We excluded trials which compared variations of the same intervention: for example, different methods of performing transarterial chemoembolisation. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We calculated the hazard ratio (HR) with 95% confidence intervals (CI) using both fixed‐effect and random‐effects models based on available‐participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and assessed the quality of the evidence using GRADE. MAIN RESULTS: Three randomised clinical trials, including 430 participants, met the inclusion criteria for this review; however, data from two trials with 412 participants could be included in only one primary outcome (i.e. mortality). All three trials were at high risk of bias. All three trials included supportive care as cointervention. The comparisons included in the two trials reporting on mortality were: systemic chemotherapy with sorafenib versus no active intervention; and transarterial chemoembolisation plus systemic chemotherapy with sorafenib versus transarterial chemoembolisation alone. The trials did not report the duration of follow‐up; however, it appeared that the participants were followed up for a period of about 18 to 30 months. The majority of the participants in the trials had cirrhotic livers. The trials included participants with intermediate‐stage hepatocellular carcinoma arising from viral and non‐viral aetiologies. The trials did not report the portal hypertension status of the participants. The mortality was 50% to 70% over a median follow‐up period of 18 to 30 months. There was no evidence of difference in mortality at maximal follow‐up between systemic chemotherapy versus no chemotherapy (hazard ratio 0.85, 95% CI 0.60 to 1.18; participants = 412; studies = 2; I(2) = 0%; very low quality evidence). A subgroup analysis performed by stratifying the analysis by the presence or absence of transarterial chemoembolisation as cointervention did not alter the results. None of the trials reported on serious adverse events other than mortality, health‐related quality of life, recurrence of hepatocellular carcinoma, or length of hospital stay. One of the trials providing data was funded by the pharmaceutical industry, the other did not report the source of funding, and the trial with no data for the review was also funded by the pharmaceutical industry. We found two ongoing trials. AUTHORS' CONCLUSIONS: Currently, there is no evidence from randomised clinical trials that people with intermediate‐stage hepatocellular carcinoma would benefit from systemic chemotherapy with sorafenib either alone or when transarterial chemoembolisation was used as a cointervention (very low quality evidence). We need high‐quality randomised clinical trials designed to measure differences in clinically important outcomes (e.g. all‐cause mortality or health‐related quality of life).