Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

Simple blood tests to diagnose compensated advanced chronic liver disease and stratify the risk of clinically significant portal hypertension.

BACKGROUND AND AIMS: Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO). APPROACH AND RESULTS: Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 [95% CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95% CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95% CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95% CI:0.801-0.910], p = 0.351) and the ANTICIPATE model (AUROC:0.910 [95% CI:0.869-0.952], p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated. CONCLUSIONS: Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.

Oesophageal varices predict complications in compensated advanced non-alcoholic fatty liver disease.

Background & Aims: We aimed to evaluate the impact of oesophageal varices (OV) and their evolution on the risk of complications of compensated advanced chronic liver disease (cACLD) caused by non-alcoholic fatty liver disease (NAFLD). We also assessed the accuracy of non-invasive scores for predicting the development of complications and for identifying patients at low risk of high-risk OV. Methods: We performed a retrospective assessment of 629 patients with NAFLD-related cACLD who had baseline and follow-up oesophagogastroduodenoscopy and clinical follow-up to record decompensation, portal vein thrombosis (PVT), and hepatocellular carcinoma. Results: Small and large OV were observed at baseline in 30 and 15.9% of patients, respectively. The 4-year incidence of OV from absence at baseline, and that of progression from small to large OV were 16.3 and 22.4%, respectively. Diabetes and a ≥5% increase in BMI were associated with OV progression. Multivariate Cox regression revealed that small (hazard ratio [HR] 2.24, 95% CI 1.47-3.41) and large (HR 3.86, 95% CI 2.34-6.39) OV were independently associated with decompensation. When considering OV status and trajectories, small (HR 2.65, 95% CI 1.39-5.05) and large (HR 4.90, 95% CI 2.49-9.63) OV at baseline and/or follow-up were independently associated with decompensation compared with the absence of OV at baseline and/or follow-up. The presence of either small (HR 2.8, 95% CI 1.16-6.74) or large (HR 5.29, 95% CI 1.96-14.2) OV was also independently associated with incident PVT. Conclusion: In NAFLD-related cACLD, the presence, severity, and evolution of OV stratify the risk of developing decompensation and PVT. Impact and implications: Portal hypertension is the main driver of liver decompensation in chronic liver diseases, and its non-invasive markers can help risk prediction. The presence, severity, and progression of oesophageal varices stratify the risk of complications of non-alcoholic fatty liver disease. Easily obtainable laboratory values and liver stiffness measurement can identify patients at low risk for whom endoscopy may be withheld, and can also stratify the risk of liver-related complications.

Non-invasive tools for compensated advanced chronic liver disease and portal hypertension after Baveno VII - an update.

Non-invasive tests (NITs) and liver stiffness measurement (LSM) in particular, have entered clinical practice over 20 years ago as point-of-care tests to diagnose liver fibrosis in patients with compensated chronic liver disease. Since then, NITs use has evolved thanks to a large number of studies in all major etiologies of liver disease, and they have become important tools to stratify the risk of portal hypertension and liver-related events. The Baveno VII consensus workshop provided several novel recommendations regarding the use of well-established and novel NITs in the specific setting of portal hypertension screening, diagnosis and follow-up. The Baveno VII expert panels paid special attention to summarizing the existing data into simple clinical rules able to guide clinicians in their practice. The "rule of five" for LSM is a tool to stratify the risk of liver-related events, and LSM alone or in combination with platelet count, can be used now to rule-in and rule-out compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension, as well as to rule-out high-risk varices. Use of NITs in obese subjects with non-alcoholic fatty liver disease (NAFLD) and patients with viral hepatitis C that has been successfully treated, require specific knowledge. This review will update the reader on these aspects.

Investigational drugs in early clinical development for portal hypertension.

INTRODUCTION: Advanced chronic liver disease is considered a reversible condition after removal of the primary etiological factor. This has led to a paradigm shift in which portal hypertension (PH) is a reversible complication of cirrhosis. The pharmacologic management of PH is centered on finding targets to modify the natural history of cirrhosis and PH. AREAS COVERED: This paper offers an overview of the use of pharmacological strategies in early clinical development that modify PH. Papers included were selected from searching clinical trial sites and PubMed from the last 10 years. EXPERT OPINION: A paradigm shift has generated a new concept of PH in cirrhosis as a reversible complication of a potentially curable disease. Decreasing portal pressure to prevent decompensation and further complications of cirrhosis that may lead liver transplantation or death is a goal. Therapeutic strategies also aspire achieve total or partial regression of fibrosis, thus eliminating the need for treatment or screening of PH.

Liver-related and extrahepatic events in patients with non-alcoholic fatty liver disease: a retrospective competing risks analysis.

BACKGROUND & AIM: Non-alcoholic fatty liver disease (NAFLD), and especially fibrotic non-alcoholic steatohepatitis, is associated with high risks of liver-related events (LRE) and extrahepatic events (EHE). We evaluated the competitive risk occurrence of LRE and EHE in a large cohort of biopsy-proven NAFLD stratified according to baseline severity of fibrosis. METHODS: Two thousand one hundred thirty-five patients with biopsy-proven NAFLD were enrolled. Observed cumulative incidence functions (CIFs) were used to evaluate the risk of LRE and EHE; cause-specific Cox model and predicted CIFs were fitted to identify predictors of LRE and EHE. A replication cohort of NAFLD patients with liver fibrosis severity estimated by liver stiffness measurement by transient elastography was also enrolled. RESULTS: Observed CIFs indicated that the 60-month probabilities of LRE and EHE were 0.2% and 3% in F0-F1, 2% and 3.8% in F2 and 9.7% and 6.4% in F3-F4 patients, respectively. The cause-specific Cox model indicated that in F0-F1 and F2 patients, age > 50 years (HR 2.7) was the only predictor of LRE, while age > 50 years (HR 2.96), previous cardiovascular events (CVE, HR 2.07), and previous extra-hepatic cancer (HR 2.36) were independent risk factors for EHE. In F3-F4 patients, age > 55 years (HR 1.73), obesity (HR 1.52), PLT < 150 000/mmc (HR 3.66) and log(GGT) (HR 1.77) were associated with LRE, while age > 55 years (HR 1.74) and previous CVE (HR 2.51) were independent predictors of EHE. Predicted CIFs for HE and EHE in F0-F1, F2 and F3-F4 patients stratified the risk of events. The results were externally replicated. CONCLUSION: The likelihood of EHE in NAFLD patients is relevant and increases according to the severity of liver fibrosis, while the risk of LRE is negligible in F0-F1, low but clinically relevant in F2 and high in F3-F4 patients.

FIB-4 Improves LSM-Based Prediction of Complications in Overweight or Obese Patients With Compensated Advanced Chronic Liver Disease.

Liver stiffness measurement (LSM) by transient elastography (TE) is able to stratify the risk of decompensation in patients with compensated advanced chronic liver disease (cACLD).1 Recently, we demonstrated that this holds true also in overweight or obese patients with cACLD due to nonalcoholic steatohepatitis (NASH) studied by the XL probe. An LSM cutoff of ≥21 kPa remained associated with a high risk of complications in this population.2.

Inflammatory activity affects the accuracy of liver stiffness measurement by transient elastography but not by two-dimensional shear wave elastography in non-alcoholic fatty liver disease.

BACKGROUND: In patients with non-alcoholic fatty liver disease (NAFLD), the impact of the severity of steatosis and inflammatory activity on the accuracy of liver stiffness measurement (LSM) by transient elastography (TE) and by two-dimensional shear wave elastography (2D-SWE) in staging liver fibrosis is still debated and scarce. We aimed to focus on this aspect. METHODS: We prospectively studied 104 patients requiring biopsy for the assessment of NAFLD. We used ordinary least squares regression to test for differences in the association between fibrosis and LSM by TE and 2D-SWE when other factors (steatosis and inflammatory activity) are considered. RESULTS: Among 104 patients, 102 had reliable LSM by TE, and 88 had valid LSM by 2D-SWE. The association between fibrosis based on histology and LSM was significantly stronger when 2D-SWE assessed LSM compared to TE (Spearman's correlation coefficient of .71; P < .001 vs .51, P < .001; Z = 2.21, P = .027). Inflammatory activity was an independent predictor of LSM by TE but not of LSM by 2D-SWE. After controlling for fibrosis, age, sex and body mass index, the inflammatory activity and the interaction between inflammatory activity and fibrosis independently explained 11% and 13% of variance in LSM by TE respectively. Steatosis did not affect the association of fibrosis and LSM by either method. CONCLUSION: Inflammatory activity on histology significantly affects LSM by TE, but not LSM by 2D-SWE in NAFLD. LSM by 2D-SWE reflects liver fibrosis more accurately than LSM by TE. Furthermore, the severity of steatosis on histology did not influence the association of LSM and fibrosis by either elastography method.

Risks and Rewards of Bariatric Surgery in Advanced Chronic Liver Diseases.

The burden of obesity and metabolic syndrome has determined a sharp increase in bariatric surgery (BS) procedures, which lead to marked weight loss, improved metabolic syndrome, reduced cardiovascular risk, and even improvement in nonalcoholic steatohepatitis (NASH). Despite these promising results, BS in patients with chronic liver disease can rarely lead to worsening of liver function, progression to cirrhosis and its complications, and even liver transplantation. On the other hand, since obesity in patients with cirrhosis is a major cofactor for progression to a decompensated stage of the disease and a risk factor for hepatocellular carcinoma, BS has been used to achieve weight loss in this population. In this review, we critically analyze the existing data on outcomes of BS in patients with cirrhosis and the possible mechanisms leading to fibrosis progression and worsening liver function in patients undergoing BS. Finally, we propose a set of measures that could be taken to improve the multidisciplinary management of liver disease in patients undergoing BS, including early recognition of malnutrition and alcohol misuse.

Malnutrition and Alcohol in Patients Presenting with Severe Complications of Cirrhosis After Laparoscopic Bariatric Surgery.

Factors and outcomes associated with decompensation of liver disease and liver failure in obese patients who underwent modern bariatric surgery are unclear. We present here a cohort of seventeen consecutive patients referred because of decompensation of liver disease following laparoscopic bariatric surgery. All patients showed signs of malnutrition (sarcopenia in 76.5%). In ten (58.8%), decompensation was associated with alcohol ingestion, which started after bariatric surgery in six patients. One patient died and three patients required liver transplantation, in one case preceded by transjugular intrahepatic portosystemic shunt (TIPS). However, thirteen patients achieved stabilization or full re-compensation with medical therapy and nutritional support. Our cases underline the risk of alcohol intake and malnutrition after laparoscopic bariatric surgery as causes of severe liver decompensation and underline the need for careful interdisciplinary care of these patients after surgery to early identify and treat alcohol misuse, malnutrition, and liver disease.

Monitoring Occurrence of Liver-Related Events and Survival by Transient Elastography in Patients With Nonalcoholic Fatty Liver Disease and Compensated Advanced Chronic Liver Disease.

BACKGROUND & AIMS: Patients with advanced fibrosis related to nonalcoholic fatty liver disease (NAFLD) are at risk of developing hepatic and extrahepatic complications. We investigated whether, in a large cohort of patients with NAFLD and compensated advanced chronic liver disease, baseline liver stiffness measurements (LSMs) and their changes can be used to identify patients at risk for liver-related and extrahepatic events. METHODS: We performed a retrospective analysis of consecutive patients with NAFLD (n = 1039) with a histologic diagnosis of F3-F4 fibrosis and/or LSMs>10 kPa, followed for at least 6 months, from medical centers in 6 countries. LSMs were made by FibroScan using the M or XL probe and recorded at baseline and within 1 year from the last follow-up examination. Differences between follow up and baseline LSMs were categorized as: improvement (reduction of more than 20%), stable (reduction of 20% to an increase of 20%), impairment (an increase of 20% or more). We recorded hepatic events (such as liver decompensation, ascites, encephalopathy, variceal bleeding, jaundice, or hepatocellular carcinoma [HCC]) and overall and liver-related mortality during a median follow-up time of 35 months (interquartile range, 19-63 months). RESULTS: Based on Cox regression analysis, baseline LSM was independently associated with occurrence of hepatic decompensation (hazard ratio [HR], 1.03; 95% CI, 1.02-1.04; P < .001), HCC (HR, 1.03; 95% CI, 1.00-1.04; P = .003), and liver-related death (HR, 1.02; 95% CI, 1.02-1.03; P = .005). In 533 patients with available LSMs during the follow-up period, change in LSM was independently associated with hepatic decompensation (HR, 1.56; 95% CI, 1.05-2.51; P = .04), HCC (HR, 1.72; 95% CI, 1.01-3.02; P = .04), overall mortality (HR, 1.73; 95% CI, 1.11-2.69; P = .01), and liver-related mortality (HR, 1.96; 95% CI, 1.10-3.38; P = .02). CONCLUSIONS: In patients with NAFLD and compensated advanced chronic liver disease, baseline LSM and change in LSM are associated with risk of liver-related events and mortality.

Effect of poorly absorbable antibiotics on hepatic venous pressure gradient in cirrhosis: A systematic review and meta-analysis.

BACKGROUND: The effects of poorly/non-absorbable antibiotics on hepatic venous pressure gradient (HVPG) are debated. AIM: To analyze the effects of rifaximin or norfloxacin on HVPG and on markers of bacterial translocation and proinflammatory cytokines. METHODS: We performed a systematic search of randomized clinical trials (RCTs) involving patients with cirrhosis and portal hypertension, assessing the effect of rifaximin or norfloxacin vs control on HVPG. Pooled analyses were based on random-effects models, heterogeneity was assessed by Cochran's Q, I2 statistic and subgroup analyses. RESULTS: Five studies (215 patients) were included. Risk of bias was high in three. We found no significant differences using antibiotics versus control. The summary mean difference in HVPG was of -0.55 mmHg (95%CI:-1.52, 0.42; P = 0.27), with moderate heterogeneity (P = 0.15; I2 = 40%). RCTs with longer therapy (60-90 days) used non-selective-beta-blockers (NSBB) in both antibiotics and control arms. Subgroup analysis showed a significantly greater reduction in HVPG in the combination arm over controls (mean difference -1.46 mmHg [95%CI: -2.63, -0.28; P = 0.01]) with no heterogeneity (P = 0.46; I2 = 0%). Serum lipopolysaccharide-binding protein (LBP) significantly decreased with antibiotics, but with high heterogeneity (P < 0.001; I2 = 92%). CONCLUSIONS: Rifaximin or norfloxacin did not significantly reduce HVPG in patients with cirrhosis and portal hypertension. Studies using antibiotic for longer periods on top of NSBB showed a significant decrease in HVPG.

Noninvasive Markers of Portal Hypertension Detect Decompensation in Overweight or Obese Patients With Compensated Advanced Chronic Liver Disease.

BACKGROUND & AIMS: Some patients with compensated advanced chronic liver disease (cACLD) require use of an extralarge probe for liver stiffness measurement (LSM), owing to overweight or obesity. However, the ability of noninvasive markers of portal hypertension and the controlled attenuation parameter (CAP) to determine which of these patients are at risk for decompensation has not been fully assessed. METHODS: We collected data from 272 patients with cACLD (LSM ≥10 kPa by XL probe; 57% with nonalcoholic steatohepatitis; mean body mass index, 33.8 ± 6.5 kg/m2; median Child-Pugh score, 5; median LSM, 16.8 kPa; mean CAP, 318 ± 66 dB/m) evaluated at 2 academic centers from 2015 through 2018. We collected clinical data on decompensation (ascites, portal hypertension bleeding, jaundice, hepatic encephalopathy) and severe bacterial infections; patients were followed up for a median of 17 months (interquartile range, 11-24 mo). We evaluated associations between these events and LSM, CAP, LSM∗spleen size/platelet count (LSPS), and portal hypertension risk scores. RESULTS: Decompensation occurred in 12 patients and severe bacterial infections developed in 5 patients. LSM, LSPS, and the portal hypertension risk score identified patients with decompensation with area under the receiver operating characteristic curve values of 0.848 (95% CI, 0.720-0.976; P < .0001), 0.881 (95% CI, 0.798-0.954; P < .0001), and 0.890 (95% CI, 0.814-0.966; P < .0001), respectively. In multivariate Cox regression analysis, in patients with nonalcoholic steatohepatitis, LSM and CAP were associated independently with decompensation and severe bacterial infection; CAP ≥ 220 dB/m was associated with a reduced risk of decompensation (hazard ratio, 0.043, 95% CI, 0.004-0.476; P = .01). CONCLUSIONS: LSM, LSPS, and the portal hypertension risk score identify obese or overweight patients with cACLD who are at increased risk of decompensation and severe bacterial infection.

Beta-blockers in cirrhosis: Evidence-based indications and limitations.

Non-selective beta-blockers (NSBBs) are the mainstay of treatment for portal hypertension in the setting of liver cirrhosis. Randomised controlled trials demonstrated their efficacy in preventing initial variceal bleeding and subsequent rebleeding. Recent evidence indicates that NSBBs could prevent liver decompensation in patients with compensated cirrhosis. Despite solid data favouring NSBB use in cirrhosis, some studies have highlighted relevant safety issues in patients with end-stage liver disease, particularly with refractory ascites and infection. This review summarises the evidence supporting current recommendations and restrictions of NSBB use in patients with cirrhosis.

Guía de práctica clínica para la enfermedad hepática grasa no alcohólica / Clinical practice guideline for nonalcoholic fatty liver disease

Objetivo: brindar una guía de práctica clínica basada en la evidencia más reciente para el diagnóstico y tratamiento de la enfermedad hepática grasa no alcohólica teniendo en cuenta la efectividad y seguridad de las intervenciones dirigidas a pacientes, personal asistencial, administrativo y entes gubernamentales de cualquier servicio de atención en Colombia. Materiales y métodos: esta guía fue desarrollada por un equipo multidisciplinario con apoyo de la Asociación Colombiana de Gastroenterología, el Grupo Cochrane ITS y el Instituto de Investigaciones Clínicas de la Universidad Nacional de Colombia. Se desarrollaron preguntas clínicas relevantes y se realizó la búsqueda de guías nacionales e internacionales en bases de datos especializadas. Las guías existentes fueron evaluadas en términos de calidad y aplicabilidad; una guía cumplió los criterios de adaptación, por lo que se decidió adaptar 3 preguntas clínicas. El Grupo Cochrane realizó la búsqueda sistemática de la literatura. Las tablas de evidencia y recomendaciones fueron realizadas con base en la metodología GRADE. Las recomendaciones de la guía fueron socializadas en una reunión de expertos con entes gubernamentales y pacientes. Resultados: se desarrolló una guía de práctica clínica basada en la evidencia para el diagnóstico y tratamiento de la enfermedad hepática grasa no alcohólica en Colombia. Conclusiones: el diagnóstico y manejo oportuno de la enfermedad hepática grasa no alcohólica contribuirá a disminuir la carga de la enfermedad en Colombia, así como de las enfermedades asociadas.

Objective: To provide a clinical practice guideline with the latest evidence for diagnosis and treatment of nonalcoholic fatty liver disease for patients, caregivers, administrative and government bodies at all levels of care in Colombia. Materials and Methods: This guide was developed by a multidisciplinary team with the support of the Colombian Association of Gastroenterology, Cochrane STI Group and Clinical Research Institute of the Universidad Nacional de Colombia. Relevant clinical questions were developed and the search for national and international guidelines in databases was performed. Existing guidelines were evaluated about quality and applicability. One guideline met the criteria for adaptation, so the group decided to adapt 3 clinical questions. Systematic literature searches were conducted by the Cochrane Group. The tables of evidence and recommendations were made based on the GRADE methodology. The recommendations of the guide were socialized in a meeting of experts with government agencies and patients. Results: An evidence-based Clinical Practice Guidelines for the diagnosis and treatment of nonalcoholic fatty liver disease was developed for the Colombian context. Conclusions: The opportune detection and appropriate management of nonalcoholic fatty liver disease would contribute to the burden of the disease in Colombia.