Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS: We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS: Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION: Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

Point-of-Care Noninvasive Prediction of Liver-Related Events in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Individual risk prediction of liver-related events (LRE) is needed for clinical assessment of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) patients. We aimed to provide point-of-care validated liver stiffness measurement (LSM)-based risk prediction models for the development of LRE in patients with NAFLD, focusing on selecting patients for clinical trials at risk of clinical events. METHODS: Two large multicenter cohorts were evaluated, 2638 NAFLD patients covering all LSM values as the derivation cohort and 679 more advanced patients as the validation cohort. We used Cox regression to develop and validate risk prediction models based on LSM alone, and the ANTICIPATE and ANTICIPATE-NASH models for clinically significant portal hypertension. The main outcome of the study was the rate of LRE in the first 3 years after initial assessment. RESULTS: The 3 predictive models had similar performance in the derivation cohort with a very high discriminative value (c-statistic, 0.87-0.91). In the validation cohort, the LSM-LRE alone model had a significant inferior discrimination (c-statistic, 0.75) compared with the other 2 models, whereas the ANTICIPATE-NASH-LRE model (0.81) was significantly better than the ANTICIPATE-LRE model (0.79). In addition, the ANTICIPATE-NASH-LRE model presented very good calibration in the validation cohort (integrated calibration index, 0.016), and was better than the ANTICIPATE-LRE model. CONCLUSIONS: The ANTICIPATE-LRE models, and especially the ANTICIPATE-NASH-LRE model, could be valuable validated clinical tools to individually assess the risk of LRE at 3 years in patients with NAFLD/NASH.

Heterologous adenovirus-vector/messenger RNA regimen is associated with improved severe acute respiratory syndrome coronavirus 2 humoral response in liver transplant recipients.

Knowledge of the immunogenicity of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in liver transplant recipients (LTRs) is mainly limited to messenger RNA (mRNA)-based types. We aimed to evaluate the humoral response in LTRs and to address the use of different doses of mycophenolate (MMF) on the probability of developing anti-spike immunoglobulin G (IgG). In this prospective cohort study, SARS-CoV-2 anti-spike IgG, neutralizing antibodies (NAs), and nucleocapsid protein (N) were evaluated in LTRs and healthy volunteers 21-90 days after receiving the second vaccine dose of either ChAdOx1 (AstraZeneca), rAd26-rAd5 (Sputnik V), inactivated BBIBP-CorV (Sinopharm), or the heterologous combination rAd26/mRNA-1273 (Sputnik V/Moderna). We collected information regarding clinical data and vaccine side effects. After excluding three LTRs due to a positive N test, 120 LTRs and 27 controls were analyzed. No significant differences were found among groups. Overall, 24 (89%) controls and 74 (62%) LTRs were positive for anti-spike IgG (p = 0.007). Among LTRs, those immunized with rAd26/mRNA-1273 presented significantly higher positive serology and NAs when compared with the homologous regimens (91% vs. 55%, p = 0.001; and 1182 IU/ml vs. 446 IU/ml, p = 0.002; respectively). In the multivariate analysis, humoral response was significantly reduced in LTRs who received higher doses of MMF (odds ratio [OR], 0.1; 95% confidence interval [CI], 0.03-0.3; p < 0.001) and with increased BMI (OR, 0.4; 95% CI, 0.2-0.7; p = 0.005); and it was significantly higher in those immunized with rAd26/mRNA-1273 (OR, 13.1; 95% CI, 2.3-72.9; p = 0.003). In LTRs anti-spike IgG concentrations showed a very good correlation with NA titers (R2 = 0.949; 95% CI, 0.919-0.967; p < 0.001). No serious adverse events were reported in either group. Conclusion: In LTRs, rAd26/mRNA-1273 was independently associated with higher antibody response. Future studies are necessary to evaluate whether combining different vaccine platforms and MMF reduction may lead to a better booster response.

Noninvasive assessment oesophageal varices: impact of the Baveno VI criteria.

PURPOSE OF REVIEW: In 2015, as a consequence of the high development in noninvasive tests, Baveno VI consensus recommended for the first time the use of a prediction rule (liver stiffness <20kPa and platelet count > 150000) to identify patients at low risk of having varices and that could circumvent endoscopy. These became known as the Baveno VI criteria. We review here the data validating Baveno VI criteria and we discuss the attempts of expanding these criteria. RECENT FINDINGS: We report 28 studies assessing the performance of Baveno VI criteria showing a pooled 99% negative predictive value for ruling out high-risk varices. Performance is not affected by the cause of cirrhosis. Different attempts at expanding these criteria show suboptimal performance. Nonelastography-based criteria require further validation. SUMMARY: Baveno VI criteria can be safely used to avoid endoscopy in a substantial proportion of patients with compensated cirrhosis. The progressive change in approach to the management of compensated cirrhosis, progressively focusing on treating portal hypertension with beta-blockers independently of the presence of varices, might render these criteria less relevant.

Sarcopenia HIBA score predicts sarcopenia and mortality in patients on the liver transplant waiting list.

Sarcopenia is a prevalent condition that predicts prognosis in patients awaiting liver transplantation (LT). The gold standard for the diagnosis of sarcopenia is the assessment of the muscular area at L3 with computed tomography (CT) scan (skeletal muscle index [SMI]), but the routine use of CT scan is limited in clinical practice. Thus, we designed a single-center observational study aimed to evaluate the clinical factors associated with the presence of sarcopenia by SMI, and to build a score capable of predicting or excluding the presence of sarcopenia in patients on the LT waiting list (WL). Binary logistic regression analysis was performed to establish the factors independently associated with sarcopenia, and the Sarcopenia Hospital Italiano de Buenos Aires (HIBA) score was built from the resulting model after internal validation analysis by bootstrapping and correction for optimism. The predictive capability of mortality on the WL was evaluated with competing risk regression analysis. A total of 215 patients with cirrhosis on the LT WL were included. The independent factors associated with the presence of sarcopenia were male sex (odds ratio [OR]: 6.09, p < 0.001), body mass index (OR: 0.74, p < 0.001), Child Pugh (OR: 1.44, p < 0.001), and the ratio creatinine/Cystatin C (OR: 0.03, p = 0.007). The Sarcopenia HIBA score constructed with these variables showed an area under the curve of 0.862. During follow-up, 77 (36%) patients underwent LT, 46 (21%) died, and 92 (43%) remained alive. After adjusting for Model for End-Stage Liver Disease-Sodium, Sarcopenia HIBA score was an independent predictor of WL mortality (subhazard ratio: 1.19; 95% confidence interval 1.01-1.40; p = 0.042). Sarcopenia HIBA score is an easy-to-use, objective, and reliable diagnostic and predictive tool that can be useful to improve the prognostic evaluation and allow identifying a group of patients with a higher risk of death while awaiting LT.

North American Practice-Based Recommendations for Transjugular Intrahepatic Portosystemic Shunts in Portal Hypertension.

Complications of portal hypertension, including ascites, gastrointestinal bleeding, hepatic hydrothorax, and hepatic encephalopathy, are associated with significant morbidity and mortality. Despite few high-quality randomized controlled trials to guide therapeutic decisions, transjugular intrahepatic portosystemic shunt (TIPS) creation has emerged as a crucial therapeutic option to treat complications of portal hypertension. In North America, the decision to perform TIPS involves gastroenterologists, hepatologists, and interventional radiologists, but TIPS creation is performed by interventional radiologists. This is in contrast to other parts of the world where TIPS creation is performed primarily by hepatologists. Thus, the successful use of TIPS in North America is dependent on a multidisciplinary approach and technical expertise, so as to optimize outcomes. Recently, new procedural techniques, TIPS stent technology, and indications for TIPS have emerged. As a result, practices and outcomes vary greatly across institutions and significant knowledge gaps exist. In this consensus statement, the Advancing Liver Therapeutic Approaches group critically reviews the application of TIPS in the management of portal hypertension. Advancing Liver Therapeutic Approaches convened a multidisciplinary group of North American experts from hepatology, interventional radiology, transplant surgery, nephrology, cardiology, pulmonology, and hematology to critically review existing literature and develop practice-based recommendations for the use of TIPS in patients with any cause of portal hypertension in terms of candidate selection, procedural best practices and, post-TIPS management; and to develop areas of consensus for TIPS indications and the prevention of complications. Finally, future research directions are identified related to TIPS for the management of portal hypertension.

Non-invasive imaging criteria for the diagnosis of hepatocellular carcinoma in non-cirrhotic patients with chronic hepatitis B.

BACKGROUND & AIMS: Criteria defined by the European Association for the Study of the Liver (EASL) and Liver Imaging Reporting and Data System (LI-RADS) enable hepatocellular carcinoma (HCC) diagnosis based on imaging in cirrhosis. Non-cirrhotic patients require biopsy given the lower pre-test probability of HCC. The objective of our study was to assess the performance of EASL and LI-RADS criteria for the diagnosis of HCC in non-cirrhotic patients with chronic HBV infection. METHODS: This was a cross-sectional study performed at a referral center. We included all patients with HBV without cirrhosis with focal liver lesions who underwent contrast-enhanced CT or MRI at our clinic between 2005-2018. Studies were reviewed by 2 radiologists blinded to the diagnosis. RESULTS: We included 280 patients, median age was 56.8 (IQR 48.2-65.45) years and 223 (80%) were male. In 191 (79%) cases the lesion was found as a result of screening. Cirrhosis was excluded based on pathology in 252 (90%) cases. We assessed 338 nodules: 257 (76%) HCC, 40 (12%) non-HCC malignant lesions, and 41 (12%) benign lesions. EASL criteria and LR-5/LR-tumor-in-vein (TIV) categories had a 100% agreement in categorizing lesions as HCC, and 226 nodules (67%) were classified as HCCs. The sensitivity, specificity, positive predictive value, and negative predictive value were 82.1 (76.9-86.6), 81.5 (71.3-89.2), 93.4 (89.3-96.2), and 58.9 (49.2-68.1), respectively. When the pre-test probability of HCC is >70%, estimated as a PAGE-B score above 9, and EASL or LR-5/LR-TIV criteria are met, post-test probability would be >90%. CONCLUSIONS: EASL criteria and LR-5/LR-TIV categories show a positive predictive value in patients with HBV without cirrhosis that is comparable to that seen in patients with cirrhosis. These criteria can be used when the pre-test probability of HCC is >70%. LAY SUMMARY: Current guidelines recommend performing a biopsy to confirm the diagnosis of presumed hepatocellular carcinoma (HCC) in patients without cirrhosis. We showed that specific imaging criteria had a 100% agreement for categorizing lesions as HCC, with a positive predictive value of 93.4%. These imaging criteria could be used to diagnose HCC in HBV patients without cirrhosis with a pre-test probability of HCC of ≥70%, avoiding the need for a liver biopsy.

Non-invasive alloimmune risk stratification of long-term liver transplant recipients.

BACKGROUND & AIMS: Management of long-term immunosuppression following liver transplantation (LT) remains empirical. Surveillance liver biopsies in combination with transcriptional profiling could overcome this challenge by identifying recipients with active alloimmune-mediated liver damage despite normal liver tests, but this approach lacks applicability. Our aim was to investigate the utility of non-invasive tools for the stratification of stable long-term survivors of LT, according to their immunological risk and need for immunosuppression. METHODS: We conducted a cross-sectional multicentre study of 190 adult LT recipients assessed to determine their eligibility to participate in an immunosuppression withdrawal trial. Patients had stable liver allograft function and had been transplanted for non-autoimmune non-replicative viral liver disease >3 years before inclusion. We performed histological, immunogenetic and serological studies and measured the intrahepatic transcript levels of an 11-gene classifier highly specific for T cell-mediated rejection (TCMR). RESULTS: In this cohort, 35.8% of patients harboured clinically silent fibro-inflammatory liver lesions (13.7% had mild damage and 22.1% had moderate-to-severe damage). The severity of liver allograft damage was positively associated with TCMR-related transcripts, class II donor-specific antibodies (DSAs), ALT, AST, and liver stiffness measurement (LSM), and negatively correlated with serum creatinine and tacrolimus trough levels. Liver biopsies were stratified according to their TCMR transcript levels using a cut-off derived from biopsies with clinically significant TCMR. Two multivariable prediction models, integrating ALT+LSM or ALT+class II DSAs, had a high discriminative capacity for classifying patients with or without alloimmune damage. The latter model performed well in an independent cohort of 156 liver biopsies obtained from paediatric liver recipients with similar inclusion/exclusion criteria. CONCLUSION: ALT, class II DSAs and LSM are valuable tools to non-invasively identify stable LT recipients without significant underlying alloimmunity who could benefit from minimisation of immunosuppression. LAY SUMMARY: A large proportion of liver transplant patients with normal liver tests have inflammatory liver lesions, which in 17% of cases are molecularly indistinguishable from those seen at the time of rejection. ALT, class II donor-specific antibodies and liver stiffness are useful in identifying patients with this form of subclinical rejection. We propose these markers as a useful tool to help clinicians determine if the immunosuppression administered is adequate.

Statins and Liver Cancer in Cirrhosis: The Most Relevant Questions Are Still Unanswered.

ABSTRACT: Several observational studies have shown an association between statin use and lower incidence of liver cancer. However, several potential biases limit a causal interpretation that could lead to a recommendation of statin prescription to patients with cirrhosis in the absence of a cardiovascular indication. Ongoing randomized trials will soon provide a clearer picture on the efficacy and safety of statins for preventing liver cancer and other complications of cirrhosis.

The Role of Hepatic Venous Pressure Gradient in the Management of Cirrhosis.

Quantifying the degree of portal hypertension provides useful information to estimate prognosis and to evaluate new therapies for portal hypertension. This quantification is done in clinical practice with the measurement of the hepatic venous pressure gradient. This article addresses the applications of measuring portal pressure in cirrhosis, including the differential diagnosis of portal hypertension; estimation of prognosis in cirrhosis, including preoperative evaluation before hepatic and extrahepatic surgery; assessment of the response to drug therapy (mainly in the context of drug development); and assessing the regression of portal hypertension syndrome.

Cirrhosis as new indication for statins.

In the recent years, there have been an increasing number of reports on favourable effects of statins in patients with advanced chronic liver disease. These include reduction in portal pressure, improved liver sinusoidal endothelial and hepatic microvascular dysfunction, decreased fibrogenesis, protection against ischaemia/reperfusion injury, safe prolongation of ex vivo liver graft preservation, reduced sensitivity to endotoxin-mediated liver damage, protection from acute-on-chronic liver failure, prevention of liver injury following hypovolaemic shock and preventing/delaying progression of cirrhosis of any aetiology. Moreover, statins have been shown to have potential beneficial effects in the progression of other liver diseases, such as chronic sclerosing cholangitis and in preventing hepatocellular carcinoma. Because of these many theoretically favourable effects, statins have evolved from being considered a risk to kind of wonder drugs for patients with chronic liver diseases. The present article reviews the current knowledge on the potential applications of statins in chronic liver diseases, from its mechanistic background to objective evidence from clinical studies.

The prognostic role of hepatic venous pressure gradient in cirrhotic patients undergoing elective extrahepatic surgery.

BACKGROUND & AIMS: Surgery in cirrhosis is associated with a high morbidity and mortality. Retrospectively reported prognostic factors include emergency procedures, liver function (MELD/Child-Pugh scores) and portal hypertension (assessed by indirect markers). This study assessed the prognostic role of hepatic venous pressure gradient (HVPG) and other variables in elective extrahepatic surgery in patients with cirrhosis. METHODS: A total of 140 patients with cirrhosis (Child-Pugh A/B/C: 59/37/4%), who were due to have elective extrahepatic surgery (121 abdominal; 9 cardiovascular/thoracic; 10 orthopedic and others), were prospectively included in 4 centers (2002-2011). Hepatic and systemic hemodynamics (HVPG, indocyanine green clearance, pulmonary artery catheterization) were assessed prior to surgery, and clinical and laboratory data were collected. Patients were followed-up for 1 year and mortality, transplantation, morbidity and post-surgical decompensation were studied. RESULTS: Ninety-day and 1-year mortality rates were 8% and 17%, respectively. Variables independently associated with 1-year mortality were ASA class (American Society of Anesthesiologists), high-risk surgery (defined as open abdominal and cardiovascular/thoracic) and HVPG. These variables closely predicted 90-, 180- and 365-day mortality (C-statistic >0.8). HVPG values >16 mmHg were independently associated with mortality and values ≥20 mmHg identified a subgroup at very high risk of death (44%). Twenty-four patients presented persistent or de novo decompensation at 3 months. Low body mass index, Child-Pugh class and high-risk surgery were associated with death or decompensation. No patient with HVPG <10 mmHg or indocyanine green clearance >0.63 developed decompensation. CONCLUSIONS: ASA class, HVPG and high-risk surgery were prognostic factors of 1-year mortality in cirrhotic patients undergoing elective extrahepatic surgery. HVPG values >16 mmHg, especially ≥20 mmHg, were associated with a high risk of post-surgical mortality. LAY SUMMARY: The hepatic venous pressure gradient is associated with outcomes in patients with cirrhosis undergoing elective extrahepatic surgery. It enables a better stratification of risk in these patients and provides the foundations for potential interventions to improve post-surgical outcomes.

Alcohol-related liver disease: Clinical practice guidelines by the Latin American Association for the Study of the Liver (ALEH).

Alcohol-related liver disease (ALD) is a major cause of advanced chronic liver disease in Latin-America, although data on prevalence is limited. Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented. ALD comprises a clinical-pathological spectrum that ranges from steatosis, steatohepatitis to advanced forms such as alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma. Besides genetic factors, the amount of alcohol consumption is the most important risk factor for the development of ALD. Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease. The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets. Early forms of ALD are often missed and most clinical attention is focused on AH, which is defined as an abrupt onset of jaundice and liver-related complications. In patients with potential confounding factors, a transjugular biopsy is recommended. The standard therapy for AH (i.e. prednisolone) has not evolved in the last decades yet promising new therapies (i.e. G-CSF, N-acetylcysteine) have been recently proposed. In both patients with early and severe ALD, prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality. A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD. Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence. In selected cases, increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy.

The impact of delayed source control and antimicrobial therapy in 196 patients with cholecystitis-associated septic shock: a cohort analysis

Background: Cholecystitis-associated septic shock carries a significant mortality. Our aim was to determine whether timing of source control affects survival in cholecystitis patients with septic shock. Methods: We conducted a nested cohort study of all patients with cholecystitis-associated septic shock from an international, multicentre database (1996­2015). Multivariable logistic regression was performed to determine associations between clinical factors and in-hospital mortality. The results were used to inform a classification and regression tree (CART) analysis that modelled the association between disease severity (APACHE II), time to source control and survival. Results: Among 196 patients with cholecystitis-associated septic shock, overall mortality was 37%. Compared with nonsurvivors (n = 72), survivors (n = 124) had lower mean admission APACHE II scores (21 v. 27, p < 0.001) and lower median admission serum lactate (2.4 v. 6.8 µmol/L, p < 0.001). Survivors were more likely to receive appropriate antimicrobial therapy earlier (median 2.8 v. 6.1 h from shock, p = 0.012). Survivors were also more likely to undergo successful source control earlier (median 9.8 v. 24.7 h from shock, p < 0.001). Adjusting for covariates, APACHE II (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.06­1.21 per increment) and delayed source control > 16 h (OR 4.45, 95% CI 1.88­10.70) were independently associated with increased mortality (all p < 0.001). The CART analysis showed that patients with APACHE II scores of 15­26 benefitted most from source control within 16 h (p < 0.0001). Conclusion: In patients with cholecystitis-associated septic shock, admission APACHE II score and delay in source control (cholecystectomy or percutaneous cholecystostomy drainage) significantly affected hospital outcomes.

Contexte: Le choc septique associé à une cholécystite s'accompagne d'une mortalité significative. Notre but était de déterminer si le moment du contrôle de la source affecte la survie chez les patients atteints de cholécystite qui se trouvent en choc septique. Méthodes: Nous avons procédé à une étude de cohorte nichée regroupant tous les patients ayant présenté un choc septique associé à une cholécystite à partir d'une base de données multicentrique internationale (1996­2015). La régression logistique multivariée a été utilisée pour déterminer les liens entre les facteurs cliniques et la mortalité perhospitalière. Les résultats ont été utilisés pour éclairer une analyse par arbre de classification (CART) qui modélisait le lien entre la gravité de la maladie (APACHE II), le temps nécessaire au contrôle de la source et la survie. Résultats: Parmi 196 patients souffrant d'un choc septique associé à une cholécystite, la mortalité globale a été de 37 %. Comparativement aux patients décédés (n = 72), les survivants (n = 124) présentaient à l'admission des scores APACHE II moyens plus bas (21 c. 27, p < 0,001) et un taux de lactate sérique médian plus bas (2,4 c. 6,8 µmol/L, p < 0,001). Les survivants étaient plus susceptibles de recevoir une antibiothérapie adéquate plus hâtive (médiane 2,8 c. 6,1 h suivant le choc, p = 0,012). Les survivants étaient aussi plus susceptibles de bénéficier plus hâtivement d'un contrôle réussi de la source (médiane 9,8 c. 24,7 h suivant le choc, p < 0,001). L'ajustement pour tenir compte des covariables du score APACHE II (rapport des cotes [RC] 1,13, intervalle de confiance [IC] de 95 % 1,06­1,21 par palier) et le retard du contrôle de la source > 16 h (RC 4,45, IC de 95 % 1,88­10,70) ont été associés indépendamment à une mortalité plus élevée (tous deux p < 0,001). L'analyse CART a révélé que les patients ayant des scores APACHE II de 15­26 ont le plus bénéficié d'un contrôle de la source dans les 16 h (p < 0,0001). Conclusion: Chez les patients présentant un choc septique associé à une cholécystite, le score APACHE II à l'admission et le retard de contrôle de la source (cholécystectomie ou drainage par cholécystotomie percutanée) ont significativement influé sur les résultats hospitaliers.

Alcohol-Related Liver Disease Is Rarely Detected at Early Stages Compared With Liver Diseases of Other Etiologies Worldwide.

BACKGROUND & AIMS: Despite recent advances in treatment of viral hepatitis, liver-related mortality is high, possibly owing to the large burden of advanced alcohol-related liver disease (ALD). We investigated whether patients with ALD are initially seen at later stages of disease development than patients with hepatitis C virus (HCV) infection or other etiologies. METHODS: We performed a cross-sectional study of 3453 consecutive patients with either early or advanced liver disease (1699 patients with early and 1754 with advanced liver disease) seen at 17 tertiary care liver or gastrointestinal units worldwide, from August 2015 through March 2017. We collected anthropometric, etiology, and clinical information, as well as and model for end-stage liver disease scores. We used unconditional logistic regression to estimate the odds ratios for evaluation at late stages of the disease progression. RESULTS: Of the patients analyzed, 81% had 1 etiology of liver disease and 17% had 2 etiologies of liver disease. Of patients seen at early stages for a single etiology, 31% had HCV infection, 21% had hepatitis B virus infection, and 17% had nonalcoholic fatty liver disease, whereas only 3.8% had ALD. In contrast, 29% of patients seen for advanced disease had ALD. Patients with ALD were more likely to be seen at specialized centers, with advanced-stage disease, compared with patients with HCV-associated liver disease (odds ratio, 14.1; 95% CI, 10.5-18.9; P < .001). Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. These patients had significantly more visits to health care providers, with more advanced disease, compared with patients without excess alcohol use. The mean model for end-stage liver disease score for patients with advanced ALD (score, 16) was higher than for patients with advanced liver disease not associated with excess alcohol use (score, 13) (P < .01). CONCLUSIONS: In a cross-sectional analysis of patients with liver disease worldwide, we found that patients with ALD are seen with more advanced-stage disease than patients with HCV-associated liver disease. Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. Early detection and referral programs are needed for patients with ALD worldwide.

Child-Pugh Classification: Time to Abandon?

The Child-Pugh classification is one of the commonest and oldest bedside tools utilized in estimating prognosis in patients with cirrhosis. However, its usage as a risk prediction tool or indeed a decision-making tool should be revisited. In this review, we discuss some inherent issues with the Child-Pugh classification and present a few contexts in which the current usage of Child-Pugh warrants reassessment, elaborating on its utility in acute variceal bleeding, specifically its role in decision-making on early transjugular intrahepatic portosystemic shunt, as well as its use in the context of hepatocellular carcinoma and drug development and dose adjustment.

Depression in cirrhosis - a prospective evaluation of the prevalence, predictors and development of a screening nomogram.

BACKGROUND: Depression is associated with substantial morbidity and mortality in cirrhosis, but is underdiagnosed and undertreated. AIMS: Using the Mini International Neuropsychiatric Interview (MINI) as a gold-standard, to determine prevalence, predictors, and outcomes of depression, and to develop a screening nomogram for use in cirrhosis patients. METHODS: Cirrhotic outpatients 18-80 years of age, not on anti-depressants, were consecutively recruited from liver clinics at three tertiary care hospitals. Baseline health-related quality of life (HRQoL) and frailty were determined by the chronic liver disease questionnaire, EQ-VAS, Clinical Frailty Scale and Fried Frailty Criteria. Depression was identified using the MINI and participants were followed up to 6 months to determine unplanned hospitalization/death. RESULTS: Of 305 patients, 62% were male; mean age 55(10) years; mean MELD 12.5(5), 61% Child Pugh B/C. Prevalence of depression 18% by MINI. Patients with depression had lower baseline HRQoL and higher frailty scores. Five independently predictive factors were used to develop a clinical nomogram for the diagnosis of clinical depression. These included three Hospital Anxiety and Depression Screening tool variables: "I have lost interest in my appearance" (adjusted odds ratio [aOR] 2.2, P = 0.006), "I look forward with enjoyment to things" (aOR 2.0, P = 0.02), "I feel cheerful" (aOR 2.8, P = 0.002), and two demographic variables: younger age (aOR 0.92, P = 0.001) and not being married or in a common-law relationship (aOR 0.30, P = 0.008). CONCLUSIONS: Depression is common in patients with cirrhosis. It has a significant impact on HRQoL and functional status. The developed clinical nomogram is promising for the rapid screening of depression in patients with cirrhosis.

Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients.

BACKGROUND & AIMS: Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies. The pathogenesis of these lesions remains unclear. The aim of this study was to identify the key molecular pathways driving progressive subclinical inflammatory liver allograft damage. METHODS: All liver recipients followed at Hospital Clínic Barcelona who were >10 years post-transplant were screened for participation in the study. Patients with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Sixty-seven patients agreed to participate and underwent blood and serological tests, transient elastography and a liver biopsy. Transcriptome profiling was performed on RNA extracted from 49 out of the 67 biopsies employing a whole genome next generation sequencing platform. Patients were followed for a median of 6.8 years following the index liver biopsy. RESULTS: Median time since transplantation to liver biopsy was 13 years (10-22). The most frequently observed histological abnormality was portal inflammation with different degrees of fibrosis, present in 45 biopsies (67%). Two modules of 102 and 425 co-expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. CONCLUSIONS: A large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients' liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage. LAY SUMMARY: A large proportion of adult liver transplant recipients who survive for a long time exhibit subclinical histological abnormalities. The expression profile (a measurement of the activity of genes) of liver tissue from a large fraction of these patients closely resembles the profile of T cell mediated rejection. Liver allografts showing the highest expression levels of rejection-related genes developed progressive damage over time.

The Use of Statins in Patients With Chronic Liver Disease and Cirrhosis.

PURPOSE OF REVIEW: Statins are drugs developed to treat hypercholesterolemia. Its use in patients with liver disease has been limited because one of its potential and most feared side effects is hepatotoxicity. However, there is robust evidence that supports the safety of statins in this population in the absence of severe liver dysfunction. In this review, we will summarize the efficacy and safety of statins in cirrhosis. RECENT FINDINGS: Statins are effective in the treatment of dyslipidemia in patients with liver disease, because of their pleiotropic properties. These properties are independent of their effect on cholesterol levels, such as improving endothelial dysfunction or having antioxidant, antifibrotic, anti-inflammatory, antiproliferative, antiangiogenic, proapoptotic, or immunomodulation properties. Statins have been studied in other areas such as in treatment of portal hypertension, prevention of hepatocellular carcinoma, and/or protection against ischemia/reperfusion injury. Approved indications for statins in patients with cirrhosis are those of the general population, including dyslipidemia and increased cardiovascular risk. Compensated cirrhosis is not a contraindication. In patients with decompensated cirrhosis, statins should be prescribed with extreme caution at low doses, and with frequent monitoring of creatinine phosphokinase levels in order to detect adverse events in a timely fashion.