Predictors of Re-bleeding and Mortality Among Patients with Refractory Variceal Bleeding Undergoing Salvage Transjugular Intrahepatic Portosystemic Shunt (TIPS).

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) has proven clinical efficacy as rescue therapy for cirrhotic patients with acute portal hypertensive bleeding who fail endoscopic treatment. AIMS: To investigate predictive factors of 6-week and 1-year mortality in patients undergoing salvage TIPS for refractory portal hypertensive bleeding. METHODS: A total of 144 consecutive patients were retrospectively evaluated. Three logistic regression multivariate models were estimated to individualize prognostic factors for 6-week and 12-month mortality. Log-rank test was used to evaluate survival according to Child-Pugh classes and Bureau's criteria. RESULTS: Mean age 51 ± 10 years, 66% male, mean MELD 18.5 ± 8.3, Child-Pugh A/B/C 8%/38%/54%. TIPS failure occurred in 23(16%) patients and was associated with pre-TIPS portal pressure gradient and pre-TIPS intensive care unit stay. Six-week and 12-month mortality was 36% and 42%, respectively. Pre-TIPS intensive care unit stay, MELD, and Child-Pugh score were independently associated with mortality at 6 weeks. Independent predictors of mortality at 12 months were pre-TIPS intensive care unit stay and Child-Pugh score. CONCLUSIONS: In this large cohort of patients undergoing salvage TIPS, MELD and Child-Pugh scores were predictive of short- and long-term mortality, respectively. Pre-TIPS intensive care unit stay was independently associated with TIPS failure and mortality at 6 weeks and 12 months. Salvage TIPS is futile in patients with Child-Pugh score of 14-15.

Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate.

Current expressions based on serum creatinine concentration overestimate kidney function in cirrhosis, leading to significant differences between "true" and calculated glomerular filtration rate (GFR). We compared the performance of the four-variable and six-variable Modification of Diet in Renal Disease and chronic kidney disease epidemiology with "true," or measured, GFR (mGFR) and the impact of this difference on Model for End-Stage Liver Disease (MELD) calculation. We subsequently developed and validated a GFR equation specifically for cirrhosis and compared the performance of the new derived formula with existing GFR formulae. We included 469 consecutive patients who had a transplant assessment between 2011 and 2014. mGFR was measured using plasma isotope clearance according to a technique validated in patients with ascites. A corrected creatinine was derived from the mGFR after application of the Modification of Diet in Renal Disease formula. Subsequently, a corrected MELD was calculated and compared with the conventionally calculated MELD. Stepwise multiple linear regression was used to derive a GFR equation. This was compared with the mGFR in independent external and internal validation sets of 82 and 174 patients with cirrhosis, respectively. A difference >20 mL/minute/1.73 m2 between existing formulae and mGFR was observed in 226 (48.2%) patients. The corrected MELD score was ≥3 points higher in 177 (37.7%) patients. The predicted equation (r2 = 74.6%) was GFR = 45.9 × (creatinine-0·836 ) × (urea-0·229 ) × (international normalized ratio-0·113 ) × (age-0.129 [Corrected November 29, 2016: originally written as "age-129."]) × (sodium0·972 ) × 0.809 (if female) × 0.92 (if moderate/severe ascites). An online calculator is available at http://rfh-cirrhosis-gfr.ucl.ac.uk. The model was a good fit and showed the greatest accuracy compared to that of existing formulae. CONCLUSION: We developed and validated a new accurate model for GFR assessment in cirrhosis, the Royal Free Hospital cirrhosis GFR, using readily available variables; this remains to be tested and incorporated in prognostic scores in patients with cirrhosis. (Hepatology 2017;65:582-591).

Bacterial Infections Change Natural History of Cirrhosis Irrespective of Liver Disease Severity.

OBJECTIVES: We assessed the prognostic significance of infections in relation to current prognostic scores and explored if infection could be considered per se a distinct clinical stage in the natural history of cirrhosis. METHODS: We included consecutive patients with cirrhosis admitted to a tertiary referral liver unit for at least 48 h over a 2-year period. Diagnosis of infection was based on positive cultures or strict established criteria. We used competing risk analysis and propensity score matching for data analysis. RESULTS: 501 patients (63% male, 48% alcoholic liver disease, median Model of End-stage Liver Disease (MELD)=17) underwent 781 admissions over the study period. Portal hypertensive bleeding and complicated ascites were the commonest reasons of admission. The incidence of proven bacterial infection was 25.6% (60% community acquired and 40% nosocomial). Survival rates at 3, 6, 12, and 30 months were 83%, 77%, 71%, and 62% in patients without diagnosis of infection, vs. 50%, 46%, 41%, and 34% in patients with diagnosis of infection. Overall survival was independently associated with MELD score (hazards ratio (HR) 1.099), intensive care (ITU) stay (HR 1.967) and bacterial infection (HR 2.226). Bacterial infection was an independent predictor of survival even when patients who died within the first 30 days were excluded from the analysis in Cox regression (HR 2.013) and competing risk Cox models in all patients (HR 1.46) and propensity risk score-matched infected and non-infected patients (HR 1.67). CONCLUSIONS: Infection most likely represents a distinct prognostic stage of cirrhosis, which affects survival irrespective of disease severity, even after recovery from the infective episode.

The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis.

UNLABELLED: The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). CONCLUSIONS: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care.

The impact of infection by multidrug-resistant agents in patients with cirrhosis. A multicenter prospective study.

BACKGROUND & AIMS: Bacterial strains resistant to antibiotics are a serious clinical challenge. We assessed the antibiotic susceptibility of bacteria isolated from infections in patients with cirrhosis by a multicentre investigation. RESULTS: Three hundred and thirteen culture-positive infections (173 community acquired [CA] and 140 hospital acquired [HA]) were identified in 308 patients. Urinary tract infections, spontaneous bacterial peritonitis and bacteremias were the most frequent. Quinolone-resistant Gram-negative isolates were 48%, 44% were extended-spectrum beta-lactamase producers and 9% carbapenem resistant. In 83/313 culture-positive infections (27%), multidrug-resistant agents (MDRA) were isolated. This prevalence did not differ between CA and HA infections. MDRA were identified in 17 of 37 patients on quinolone prophylaxis, and in 46 of 166 not on prophylaxis (45% vs 27%; P<.03). In 287 cases an empiric antibiotic therapy was undertaken, in 37 (12.9%) this therapy failed. The in-hospital mortality rate of this subset of patients was significantly higher compared to patients who received an effective broad(er)-spectrum therapy (P=.038). During a 3-month follow-up, 56/203 culture-positive patients (27.6%) died, 24/63 who have had MDRA-related infections (38%) and 32/140 who have had antibiotic-susceptible infections (22.8%) (P=.025). Multivariate analysis disclosed MDRA infection, age, hepatocellular carcinoma, bilirubin, international normalized ratio and the occurrence of portal hypertension-related complications independent predictors of death. CONCLUSIONS: Infection by MDRA is frequent in patients with cirrhosis and the prognosis is severe, especially in patients unresponsive to empiric antibiotic therapy.

Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk factors for HCC development in patients with PBC. DESIGN: Risk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates. RESULTS: Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p<0.0001; IR 6.6 vs 1.4, p<0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p<0.001; IR 18.2 vs 5.4, p<0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p<0.0001). CONCLUSIONS: This uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies.

Development and Validation of a Scoring System to Predict Outcomes of Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy.

BACKGROUND & AIMS: Approaches to risk stratification for patients with primary biliary cirrhosis (PBC) are limited, single-center based, and often dichotomous. We aimed to develop and validate a better model for determining prognoses of patients with PBC. METHODS: We performed an international, multicenter meta-analysis of 4119 patients with PBC treated with ursodeoxycholic acid at liver centers in 8 European and North American countries. Patients were randomly assigned to derivation (n = 2488 [60%]) and validation cohorts (n = 1631 [40%]). A risk score (GLOBE score) to predict transplantation-free survival was developed and validated with univariate and multivariable Cox regression analyses using clinical and biochemical variables obtained after 1 year of ursodeoxycholic acid therapy. Risk score outcomes were compared with the survival of age-, sex-, and calendar time-matched members of the general population. The prognostic ability of the GLOBE score was evaluated alongside those of the Barcelona, Paris-1, Rotterdam, Toronto, and Paris-2 criteria. RESULTS: Age (hazard ratio = 1.05; 95% confidence interval [CI]: 1.04-1.06; P < .0001); levels of bilirubin (hazard ratio = 2.56; 95% CI: 2.22-2.95; P < .0001), albumin (hazard ratio = 0.10; 95% CI: 0.05-0.24; P < .0001), and alkaline phosphatase (hazard ratio = 1.40; 95% CI: 1.18-1.67; P = .0002); and platelet count (hazard ratio/10 units decrease = 0.97; 95% CI: 0.96-0.99; P < .0001) were all independently associated with death or liver transplantation (C-statistic derivation, 0.81; 95% CI: 0.79-0.83, and validation cohort, 0.82; 95% CI: 0.79-0.84). Patients with risk scores >0.30 had significantly shorter times of transplant-free survival than matched healthy individuals (P < .0001). The GLOBE score identified patients who would survive for 5 years and 10 years (responders) with positive predictive values of 98% and 88%, respectively. Up to 22% and 21% of events and nonevents, respectively, 10 years after initiation of treatment were correctly reclassified in comparison with earlier proposed criteria. In subgroups of patients aged <45, 45-52, 52-58, 58-66, and ≥66 years, age-specific GLOBE-score thresholds beyond which survival significantly deviated from matched healthy individuals were -0.52, 0.01, 0.60, 1.01 and 1.69, respectively. Transplant-free survival could still be accurately calculated by the GLOBE score with laboratory values collected at 2-5 years after treatment. CONCLUSIONS: We developed and validated scoring system (the GLOBE score) to predict transplant-free survival of ursodeoxycholic acid-treated patients with PBC. This score might be used to select strategies for treatment and care.

Patterns of blood component use in cirrhosis: a nationwide study.

BACKGROUND & AIMS: Cirrhosis is a complex acquired disorder of coagulation and frequent indication for transfusion of blood components. We characterised blood component use in patients with cirrhosis and compared this to transfusion guidelines. METHODS: All National Health Service trusts with representation on the British Society of Gastroenterology membership list were invited to take part. Data were collected prospectively on consecutive, unselected, hospitalised admissions with cirrhosis over 28 days. Detailed information was recorded for patients receiving blood components including indication (for bleeding or prophylaxis), type of component, laboratory indices triggering transfusion, complications, thromboembolic events and clinical outcome to day 28. RESULTS: Data on 1313 consecutive patients with cirrhosis were collected from 85 hospitals. A total of 391/1313 (30%) were transfused a blood component; in 238/391 (61%), this was for treatment of bleeding and in 153/391 (39%) for prophylaxis of bleeding. In 48/185 (26%) cases with bleeding, the haemoglobin threshold was >80 g/L prior to red blood cell transfusion. In the prophylaxis group, 238/391 (61%) received transfusion in response to an abnormal haematological value in the absence of any planned procedure. In patients transfused for procedural prophylaxis, 10/34 (29%) received fresh frozen plasma at an International Normalised Ratio lower than the threshold where a benefit would be anticipated. An in-patient thromboembolic event was recorded in 3% (35/1313) and 10% (138/1313) died by day 28. CONCLUSIONS: One-third of hospitalised patients with cirrhosis were transfused. Strategies for Patient Blood Management should include ensuring transfusion practice is consistent with guidelines and greater emphasis on alternatives to transfusion.

Liver cirrhosis.

Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Increasingly, cirrhosis has been seen to be not a single disease entity, but one that can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage. We review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical stages. The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation. The challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible.

Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study.

BACKGROUND & AIMS: Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points. METHODS: We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death). RESULTS: Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P < .0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤ 1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels >1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment. CONCLUSIONS: Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trials.

Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients.

UNLABELLED: The rationale for screening inflammatory serum biomarkers of the hepatic vein pressure gradient (HVPG) is based on the fact that portal hypertension is pathogenically related to liver injury and fibrosis, and that in turn these are associated with the activation of inflammatory pathways. This was a nested cohort study in the setting of a randomized, clinical trial to assess the development of gastroesophageal varices (GEV) (N Engl J Med 2005;353:2254). Patients had cirrhosis and portal hypertension but did not have GEV. A total of 90 patients who had baseline day-1 sera available were enrolled in the present study. The objective of this study was to determine whether inflammatory biomarkers in conjunction with clinical parameters could be used to develop a predictive paradigm for HVPG. The correlations between HVPG and interleukin (IL)-1ß (P=0.0052); IL-1R-α (P=0.0085); Fas-R (P=0.0354), and serum VCAM-1 (P=0.0007) were highly significant. By using multivariate logistic regression analysis and selected parameters (transforming growth factor beta [TGFß]; heat shock protein [HSP]-70; at-risk alcohol use; and Child class B) we could exclude HVPG ≥ 12 mmHg with 86% accuracy (95% confidence interval [CI]: 67.78 to 96.16%) and the sensitivity was 87.01% (95% CI: 69.68 to 96.34%). Therefore, the composite test could identify 86% of compensated cirrhosis patients with HVPG below 12 mmHg and prevent unnecessary esophagogastroduodenoscopy with its associated morbidity and costs in these patients. Our diagnostic test was not efficient in predicting HVPG ≥ 12 mmHg. CONCLUSION: A blood test for HVPG could be performed in cirrhosis patients to prevent unnecessary esophagogastroduodenoscopy.

Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C.

UNLABELLED: The cost-effectiveness of noninvasive tests (NITs) as alternatives to liver biopsy is unknown. We compared the cost-effectiveness of using NITs to inform treatment decisions in adult patients with chronic hepatitis C (CHC). We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes (quality-adjusted life-years; QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four treatment strategies: testing with NITs and treating patients with fibrosis stage≥F2; testing with liver biopsy and treating patients with ≥F2; treat none; and treat all irrespective of fibrosis. We compared all NITs and tested the cost-effectiveness using current triple therapy with boceprevir or telaprevir, but also modeled new, more-potent antivirals. Treating all patients without any previous NIT was the most effective strategy and had an incremental cost-effectiveness ratio (ICER) of £9,204 per additional QALY gained. The exploratory analysis of currently licensed sofosbuvir treatment regimens found that treat all was cost-effective, compared to using an NIT to decide on treatment, with an ICER of £16,028 per QALY gained. The exploratory analysis to assess the possible effect on results of new treatments, found that if SVR rates increased to >90% for genotypes 1-4, the incremental treatment cost threshold for the "treat all" strategy to remain the most cost-effective strategy would be £37,500. Above this threshold, the most cost-effective option would be noninvasive testing with magnetic resonance elastography (ICER=£9,189). CONCLUSIONS: Treating all adult patients with CHC, irrespective of fibrosis stage, is the most cost-effective strategy with currently available drugs in developed countries.

Lack of agreement for defining 'clinical suspicion of rejection' in liver transplantation: a model to select candidates for liver biopsy.

The gold standard to diagnose acute cellular rejection (ACR) after liver transplantation (LT) is histological evaluation, but there is no consensus to select patients for liver biopsy. We aimed to evaluate the agreement among clinicians to select candidates for liver biopsy early after LT. From a protocol biopsy population (n = 690), we randomly selected 100 LT patients in whom the biopsy was taken 7-10 days after LT. The clinical information between LT and protocol biopsy was given to nine clinicians from three transplant centres who decided whether a liver biopsy was needed. The agreement among clinicians to select candidates for liver biopsy was poor: κ = 0.06-0.62, being κ < 0.40 in 76% of comparisons. The concordance between indication for liver biopsy and moderate-severe ACR in the protocol biopsy was κ < 0.30 in all cases. A multivariate model based on the product age-by-MELD (OR = 0.81; P = 0.013), delta eosinophils (OR = 1.5; P = 0.002) and mean tacrolimus trough concentrations <6 ng/ml within the prior 4 days (OR = 11.4; P = 0.047) had an AUROC = 0.84 to diagnose moderate-severe histological ACR. In conclusion, the agreement among clinicians to select patients for liver biopsy is very poor. If further validated the proposed model would provide an objective method to select candidates for liver biopsy after LT.

Interobserver Agreement on Endoscopic Classification of Oesophageal Varices in Children.

OBJECTIVES: Data regarding agreement on endoscopic features of oesophageal varices in children with portal hypertension (PH) are scant. The aim of this study was to evaluate endoscopic visualisation and classification of oesophageal varices in children by several European clinicians, to build a rational basis for future multicentre trials. METHODS: Endoscopic pictures of the distal oesophagus of 100 children with a clinical diagnosis of PH were distributed to 10 endoscopists. Observers were requested to classify variceal size according to a 3-degree scale (small, medium, and large, class A), a 2-degree scale (small and large, class B), and to recognise red wales (presence or absence, class Red). Overall agreement was considered fair if Fleiss and Cohen κ test was ≥0.30, good if ≥0.40, excellent if ≥0.60, and perfect if ≥0.80. RESULTS: Agreement between observers was fair with class A (κ = 0.34) and class B (κ = 0.38), and good with class Red (κ = 0.49). The agreement was good on presence versus absence of varices (class A = 0.53, class B = 0.48). The agreement among the observers was good in class A when endoscopic features of severe PH (medium and large sizes, red marks) were grouped and compared with mild features (absent and small varices) (κ = 0.58). CONCLUSIONS: Experts working in different centres show a fairly good agreement on endoscopic features of PH in children, although a better training of paediatric endoscopists may improve the agreement in grading severity of varices in this setting.

Transient elastography for diagnosis of stages of hepatic fibrosis and cirrhosis in people with alcoholic liver disease.

BACKGROUND: The presence and progression of hepatic (liver) fibrosis into cirrhosis is a prognostic variable having impact on survival in people with alcoholic liver disease. Liver biopsy, although an invasive method, is the recommended 'reference standard' for diagnosis and staging of hepatic fibrosis in people with liver diseases. Transient elastography is a non-invasive method for assessing and staging hepatic fibrosis. OBJECTIVES: To determine the diagnostic accuracy of transient elastography for diagnosis and staging hepatic fibrosis in people with alcoholic liver disease when compared with liver biopsy. To identify the optimal cut-off values for differentiating the five stages of hepatic fibrosis. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled and Diagnostic Test Accuracy Studies Registers, The Cochrane Library, MEDLINE (OvidSP), EMBASE (OvidSP), and the Science Citation Index Expanded (last search August 2014). SELECTION CRITERIA: Diagnostic cohort and diagnostic case-control study designs that assessed hepatic fibrosis in participants with alcoholic liver disease with transient elastography and liver biopsy, irrespective of language or publication status. The study participants could be of any sex and ethnic origin, above 16 years old, hospitalised or managed as outpatients. We excluded participants with viral hepatitis, autoimmunity, metabolic diseases, and toxins. DATA COLLECTION AND ANALYSIS: We followed the guidelines in the draft Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. MAIN RESULTS: Five retrospective and nine prospective cohort studies with 834 participants provided data for the review analyses. Authors of seven of those studies sent us individual participant data. The risk of bias in the included studies was high in all but three studies. We could identify no serious concerns regarding the applicability of the studies in answering the main study question of our review, namely to use transient elastography to diagnose hepatic fibrosis. We could not identify the optimal cut-off values for the fibrosis stages. The definition of the diagnosis of alcoholic liver disease was not provided in one study and was not clearly defined in two studies, but it was clear in the remaining 11 studies. The study authors used different liver stiffness cut-off values of transient elastography for the hepatic fibrosis stages.There was only one study (103 participants) with data on hepatic fibrosis stage F1 or worse, with a cut-off of 5.9 kPa, and reporting sensitivity of 0.83 (95% confidence interval (CI) 0.74 to 0.90) and specificity of 0.88 (95% CI 0.47 to 1.00). The summary sensitivity and specificity of transient elastography for F2 or worse (seven studies with 338 participants and with cut-offs around 7.5 kPa (range 7.00 to 7.8 kPa)) were 0.94 and 0.89 with LR+ 8.2 and LR- 0.07, which suggests that transient elastography could be useful to rule out the presence of significant hepatic fibrosis, thus avoiding liver biopsy.Due to the wide range of cut-off values (from 8.0 to 17.0 kPa) found in the 10 studies with 760 participants with hepatic fibrosis F3 or worse, we fitted a hierarchical summary receiver operating characteristic (HSROC) model and estimated a summary ROC (SROC) curve. The sensitivity of the 10 studies varied from 72% to 100% and the specificity from 59% to 89%. We performed an additional analysis by including the studies with a cut-off value of around and equal to 9.5 kPa (range 8.0 to 11.0 kPa). The summary sensitivity and specificity of transient elastography (eight studies with 564 participants) were 0.92 and 0.70 with LR+ 3.1 and LR- 0.11, which suggests that transient elastography could also be useful to rule out the presence of severe hepatic fibrosis (F3 or worse), avoiding liver biopsy. We carried out a sensitivity analysis by considering only the studies with a cut-off value equal to 9.5 kPa and the result did not differ.We performed an HSROC analysis and reported an SROC curve for hepatic fibrosis stage F4 (cirrhosis). The HSROC analysis suggested that when the cut-off value changes, there is a wide variation in specificity and a more limited variation in sensitivity. We performed an additional analysis with the studies with the most commonly used cut-off value of 12.5 kPa. The summary sensitivity and specificity of transient elastography (seven studies with 330 participants) were 0.95 and 0.71 with LR+ 3.3 and LR- 0.07, which again suggests that transient elastography could be useful to rule out the presence of cirrhosis, avoiding liver biopsy. AUTHORS' CONCLUSIONS: We identified a small number of studies with a few participants and were unable to include several studies, which raises the risk of outcome reporting bias. With these caveats in mind, transient elastography may be used as a diagnostic method to rule out liver cirrhosis (F4) in people with alcoholic liver disease when the pre-test probability is about 51% (range 15% to 79%). Transient elastography may also help in ruling out severe fibrosis (F3 or worse). Liver biopsy investigation remains an option if the certainty to rule in or rule out the stage of hepatic fibrosis or cirrhosis remains insufficient after a clinical follow-up or any other non-invasive test considered useful by the clinician.The proposed cut-off values for the different stages of hepatic fibrosis may be used in clinical practice, but caution is needed, as those values reported in this review are only the most common cut-off values used by the study authors. The best cut-off values for hepatic fibrosis in people with alcoholic liver disease could not be established yet.In order to diagnose correctly the stage of hepatic fibrosis in people with alcoholic liver disease using transient elastography assessment, the studies should consider a single aetiology. Hepatic fibrosis should be diagnosed with both transient elastography and liver biopsy and in this sequence, and transient elastography cut-off values should be pre-specified and validated. The time interval between the two investigations should not exceed three months, which is the interval mainly valid for people without cirrhosis, and assessment of results should be properly blinded. Only studies with low risk of bias, fulfilling the Standards for Reporting of Diagnostic Accuracy may answer the review question.

Liver transplantation for neuroendocrine tumour liver metastases.

OBJECTIVE: Search and review of available literature were made to define the indications for and timing of liver transplantation for neuroendocrine tumour (NET) liver metastases. METHODS: Electronic bibliographical databases were searched. Prospective and retrospective cohort studies and case-controlled studies were used for qualitative and quantitative synthesis of the systematic review. Reports of patients with liver transplantation alone for NET liver metastases of any origin or combined with resection of extrahepatic tumour deposits were recruited. RESULTS: The number of patients who have undergone liver transplantation for NET liver metastases is 706. The post-transplant 5-year survival rate from the time of diagnosis was approximately 70%. NET patients with metastases confined to the liver and not poorly differentiated are favourable candidates for liver transplantation. Selection of patients based on evolution of tumours over 6 months is not recommended. CONCLUSION: Non-resectable NET liver metastasis resistant to medical treatment and confined to the liver is an accepted indication for liver transplantation.

Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes.

OBJECTIVE: Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA). DESIGN: 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy. RESULTS: No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted. CONCLUSIONS: Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276--Randomised study for immunosuppression regimen in liver transplantation.

Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosis.

BACKGROUND & AIMS: One-year survival in cirrhosis ranges from 1 to 57% depending on the clinical stage. Accurate sub-classification has important prognostic implications but there is no stage beyond cirrhosis using current qualitative histological systems. We compared the performance of all histological semi-quantitative and quantitative methods specifically developed for sub-classifying cirrhosis that have been described to date, with collagen proportionate area (CPA), to evaluate how well they distinguish patients with and without hepatic clinical decompensation at presentation, and in predicting future decompensating events. METHODS: We included consecutive patients with a histological diagnosis of cirrhosis that had a suitable liver biopsy between 2003 and 2007. We used semi-quantitative histological scoring systems proposed by Laennec, Kumar, and Nagula. We also measured quantitatively nodule size, septal width and fibrous tissue expressed in CPA. RESULTS: Sixty-nine patients, mean age 52.3±11years, mean MELD 11.8±5.8, median follow-up 56months. Main aetiologies were alcohol (38%) and hepatitis C (27.5%). Twenty-four patients (34.8%) had had a previous episode of clinical decompensation. Amongst the 45 patients who were compensated, 11 (24%) decompensated on follow-up. In Cox regression, amongst all histological parameters, CPA was the only variable independently associated with clinical decompensation up to the time of biopsy, with an odds ratio that ranged from 1.245 to 1.292. Furthermore, only CPA was significantly associated with future decompensation (OR: 1.117, 95% CI 1.020-1.223; p=0.017). CONCLUSIONS: Cirrhosis can be accurately sub-classified using quantification of fibrosis with CPA, and furthermore CPA is the only independent predictor of clinical decompensation amongst all other histological sub-classification systems described to date.

The Royal Free Hospital score: a calibrated prognostic model for patients with cirrhosis admitted to intensive care unit. Comparison with current models and CLIF-SOFA score.

OBJECTIVES: Prognosis for patients with cirrhosis admitted to intensive care unit (ICU) is poor. ICU prognostic models are more accurate than liver-specific models. We identified predictors of mortality, developed a novel prognostic score (Royal Free Hospital (RFH) score), and tested it against established prognostic models and the yet unvalidated Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) model. METHODS: Predictors of mortality were defined by logistic regression in a cohort of 635 consecutive patients with cirrhosis admitted to ICU (1989-2012). The RFH score was derived using a 75% training and 25% validation set. Predictive accuracy and calibration were evaluated using area under the receiver operating characteristic (AUROC) and goodness-of-fit χ(2) for the RFH score, as well as for SOFA, Model for End-Stage Liver Disease (MELD), Acute Physiology and Chronic Health Evaluation (APACHE II), and Child-Pugh. CLIF-SOFA was applied to a recent subset (2005-2012) of patients. RESULTS: In-hospital mortality was 52.3%. Mortality improved over time but with a corresponding reduction in acuity of illness on admission. Predictors of mortality in training set, which constituted the RFH score, were the following: bilirubin, international normalized ratio, lactate, alveolar arterial partial pressure oxygen gradient, urea, while variceal bleeding as indication for admission conferred lesser risk. Classification accuracy was 73.4% in training and 76.7% in validation sample and did not change significantly across different eras of admission. The AUROC for the derived model was 0.83 and the goodness-of-fit χ(2) was 3.74 (P=0.88). AUROC for SOFA was 0.81, MELD was 0.79, APACHE II was 0.78, and Child-Pugh was 0.67. In 2005-2012 cohort, AUROC was: SOFA: 0.74, CLIF-SOFA: 0.75, and RFH: 0.78. Goodness-of-fit χ(2) was: SOFA: 6.21 (P=0.63), CLIF-SOFA: 9.18 (P=0.33), and RFH: 2.91 (P=0.94). CONCLUSIONS: RFH score demonstrated good discriminative ability and calibration. Internal validation supports its generalizability. CLIF-SOFA did not perform better than RFH and the original SOFA. External validation of our model should be undertaken to confirm its clinical utility.

Inflammation-based scores do not predict post-transplant recurrence of hepatocellular carcinoma in patients within Milan criteria.

Increased preoperative inflammation scores, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and inflammation-based index (IBI) have been related to post-transplant HCC recurrence. We evaluated the association between inflammation-based scores (NLR, PLR, IBI) and post-LT HCC recurrence as well as tumor necrosis after transarterial embolization. 150 consecutive patients who underwent transplantation for HCC within the Milan criteria between 1996 and 2010 were included; data regarding inflammatory markers, patient and tumor characteristics were analyzed. NLR, PLR, and IBI were not significantly associated with post-LT HCC recurrence or worse overall survival. Increased NLR and PLR were associated with complete tumor necrosis in the subset of patients who received preoperative transarterial embolization (P < 0.05). Cox regression analysis revealed that absence of neoadjuvant transarterial therapy (OR = 4.33, 95% CI = 1.28-14.64; P = 0.02) and no fulfillment of the Milan criteria in the explanted liver (OR = 3.34, 95% CI = 1.08-10.35; P = 0.04) were independently associated with post-LT HCC recurrence inflammation-based scores did not predict HCC recurrence post-LT in our group of patients. NLR and PLR were associated with better response to TAE, as this was recorded histologically in the explanted liver. Histological fulfillment of the Milan criteria and absence of neoadjuvant transarterial treatment were significantly associated with post-LT HCC recurrence.