Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC.

Statins, the most widely used lipid-lowering drugs, are increasingly recognized to have pleiotropic effects including anti-inflammatory and antiangiogenic properties as well as effects on fibrogenesis and liver endothelial function. Given these pathophysiological effects, there is a growing interest in clinical use of statins in persons with cirrhosis. In this review, we summarize available data regarding the safety, adverse effects, and pharmacokinetics of statins in cirrhosis. We review clinical evidence, derived primarily from retrospective cohort and population-based studies, on the association between statin use and reduction in risk for hepatic decompensation and mortality in persons with established cirrhosis. We also review evidence to date regarding the effects of statins on portal hypertension and in chemoprevention of HCC. Finally, we highlight ongoing prospective randomized controlled trials that we expect will expand our understanding of the safety, pharmacokinetics, and efficacy of statins in cirrhosis and guide clinical practice.

Two-Step Strategy, FIB-4 Followed by Magnetic Resonance Elastography, for Detecting Advanced Fibrosis in NAFLD.

BACKGROUND & AIMS: A two-step strategy combining a serum marker and magnetic resonance elastography (MRE) for detecting advanced fibrosis (stage 3-4) among patients with nonalcoholic fatty liver disease (NAFLD) has been proposed, but its diagnostic accuracy has not been evaluated. In this multicenter study, we aimed to investigate the diagnostic accuracy of a two-step strategy including Fibrosis-4 (FIB-4) followed by MRE. METHODS: In this multicenter study, 806 patients with biopsy-proven NAFLD who underwent contemporaneous MRE were enrolled and randomly assigned to training and validation cohorts. As a first step, patients with FIB-4 <1.3 were defined as test negative regardless of MRE. As a second step, among patients with FIB-4 ≥1.3, MRE <3.6 and ≥3.6 kPa were defined as test negative and positive. The primary outcome was the diagnostic accuracy for advanced fibrosis comparing MRE alone versus the two-step strategy. RESULTS: Area under the receiver characteristic curves of MRE alone and the two-step strategy were 0.840 and 0.853 in the training cohort (P = .4) and 0.867 and 0.834 in the validation cohort (P = .2), respectively, and the diagnostic accuracy was comparable between the 2 methods. In the entire cohort, negative predictive value (NPV) and positive predictive value (PPV) of MRE for advanced fibrosis were 92.2% and 73.7%, respectively, whereas NPV at the first and second step and PPV at the second step were 90.9%, 84.4%, and 77.0%, respectively. CONCLUSIONS: The diagnostic accuracy of the two-step strategy was comparable to MRE and could reduce cost by reducing excessive MRE. Therefore, the two-step strategy could be used as a screening method in a large population.

Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Gut metagenome-derived signature predicts hepatic decompensation and mortality in NAFLD-related cirrhosis.

BACKGROUND: There are limited data on the diagnostic accuracy of gut microbial signatures for predicting hepatic decompensation in patients with cirrhosis. AIMS: To determine whether a stool metagenome-derived signature accurately detects hepatic decompensation and mortality risk in cirrhosis secondary to non-alcoholic fatty liver disease (NAFLD) METHODS: Shotgun metagenomic sequencing was performed on faecal samples collected at study entry from a prospective cohort of adults with NAFLD-related cirrhosis. A Random Forest machine learning algorithm was utilised to identify a metagenomic signature of decompensated cirrhosis (defined by ascites, hepatic encephalopathy or variceal haemorrhage) and subsequently validated in an external cohort. A Cox proportional hazards regression model was used to examine predictors of all-cause mortality. RESULTS: In all, 25 adults with NAFLD-related cirrhosis (training cohort) were included. Among the 16 participants with decompensated cirrhosis, 33% had ascites, 56% had hepatic encephalopathy and 22% had experienced a variceal haemorrhage (not mutually exclusive). We identified a stool metagenomic signature comprising 13 discriminatory species that reliably distinguished decompensated NAFLD-related cirrhosis (diagnostic accuracy, 0.97, 95% confidence interval [CI] 0.96-0.99). Diagnostic accuracy of the 13-species signature remained high after adjustment for lactulose (area under the curve [AUC] 0.99) and rifaximin use (AUC 0.93). The discriminative ability of 13-species metagenomic signature was robust in an independent test cohort (AUC 0.95, 95% CI 0.81-1.00). The 13-species metagenomic signature (hazard ratio [HR] 1.54, 95% CI 1.10-2.15, p = 0.01) was a stronger predictor of mortality than the Model for End-Stage Liver Disease score (HR 1.25, 95% CI 1.03-1.53, p = 0.03). CONCLUSIONS: This study provides evidence for a gut metagenome-derived signature with high diagnostic accuracy for hepatic decompensation that predicts risk of mortality in NAFLD-related cirrhosis.

Changes in the gut microbiome associated with liver stiffness improvement in nonalcoholic steatohepatitis.

Background: Longitudinal studies are needed to decipher mechanistic links between the gut microbiome and nonalcoholic steatohepatitis (NASH). We examined shifts in the gut microbiome in persons with NASH with improvement in liver stiffness measurement (LSM) by magnetic resonance (MR) elastography. Methods: Gut microbial profiling was performed at baseline and study completion (24 weeks) using 16 S rRNA gene sequencing in 69 adults with biopsy-confirmed NASH and significant fibrosis (stages 2-3) enrolled in a multi-center randomized controlled trial evaluating selonsertib alone or in combination with simtuzumab. Differential abundance of bacterial taxa at baseline and end of study were examined in participants with and without longitudinal improvement in LSM. Gut microbial shifts that correlated with secondary outcomes, including reduction in MR imaging-derived proton density fat faction (MRI-PDFF) and histologic fibrosis regression were evaluated. Fecal samples from 32 healthy adults were profiled and genus-level multidimensional scaling was used to determine if microbial shifts in persons with NASH improvement represented a shift toward a healthy gut microbiome. Results: Shifts in abundance of 36 bacterial taxa including Lactobacillus (log2FC = -4.51, FDR < 0.001), Enterococcus (log2FC = -6.72, FDR < 0.001), and Megasphaera (log2FC = 7.74, FDR < 0.001) were associated with improvement in LSM. Improvement in LSM was associated with microbial shifts toward healthy reference (p = 0.05). Significant shifts in 10 and 12 bacterial taxa were associated with improvement in LSM in addition to MRI-PDFF and fibrosis regression, respectively, indicating consistent taxonomic changes across multiple clinical endpoints. Conclusion: Longitudinal changes in the gut microbiota are observed in adults with NASH and clinical improvement and represent a shift toward a healthy microbiome.

Diagnostic accuracy of two-dimensional shear wave elastography and transient elastography in nonalcoholic fatty liver disease.

INTRODUCTION: Two-dimensional shear wave elastography (2D-SWE) and vibration-controlled transient elastography (VCTE) provide noninvasive assessment of hepatic fibrosis. We compared performance of 2D-SWE and VCTE for fibrosis detection in nonalcoholic fatty liver disease (NAFLD). METHODS: We performed a prospective study of adults with NAFLD who underwent 2D-SWE, VCTE, and liver biopsy analysis (using Nonalcoholic Steatohepatitis Clinical Research Network scoring system). The primary outcome was hepatic fibrosis (stage ⩾ 1); secondary outcomes included dichotomized fibrosis stages. Area under receiver operating characteristic curve (AUROC) analyses were used to compare 2D-SWE and VCTE performance. RESULTS: A total of 114 adults with a median BMI of 31.2 kg/m2 were included. The VCTE was better than 2D-SWE for the detection of fibrosis (AUROC: 0.81 versus 0.72, p = 0.03). The VCTE detected fibrosis stage 2, 3, or 4 with AUROCs of 0.86 (95% CI, 0.80-0.93), 0.91 (95% CI, 0.82-0.99), and 0.96 (95% CI, 0.91-1.00). The 2D-SWE detected fibrosis stage 2, 3, or 4 with AUROCs of 0.84 (95% CI, 0.76-0.92), 0.88 (95% CI, 0.81-0.96), and 0.93 (95% CI, 0.86-0.99). CONCLUSION: In a prospective study including more than 100 adults with NAFLD, we found VCTE to be more accurate than 2D-SWE in detecting fibrosis; these modalities, however, are comparable in assessing for higher stages of fibrosis.

Sleeve gastrectomy prior to liver transplantation is superior to medical weight loss in reducing posttransplant metabolic complications.

Strategies to optimize the management of obesity-related metabolic complications after liver transplantation (LT) are needed. We examined the effect of pre-LT sleeve gastrectomy (SG), as compared to medical weight loss (MWL), on post-LT outcomes. This is a cohort study of adults (≥18 years) with medically complicated obesity who were eligible for pre-LT SG and underwent LT from January 1, 2006 to June 1, 2016. Logistic regression models evaluated the association of SG on post-LT diabetes and hypertension, defined as new-onset or progressive disease post-LT. Cox regression models evaluated the association of SG on recurrent and de novo nonalcoholic fatty liver disease (NAFLD). Among 70 LT recipients who were eligible for pre-LT SG, 14 (20%) underwent SG and 56 (80%) underwent MWL only. Mean follow-up was 5.2 years post-LT. The SG cohort sustained higher % total body weight loss at 3 years post-LT (28.9% vs. 5.4%, p < .001). In multivariable analyses, SG was associated with significantly lower risk of post-LT diabetes (OR 0.04, 95% CI 0.00-0.41, p = .01), hypertension (OR 0.15, 95% CI 0.04-0.67, p = .01), and recurrent and de novo NAFLD (HR 0.19, 95% CI 0.04-0.91, p = .04). When compared to MWL, SG resulted in sustained weight loss and significantly lower risk of diabetes, hypertension, and recurrent and de novo NAFLD post-LT.

Gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression.

BACKGROUND: Preclinical evidence suggests that modulation of the gut microbiome could represent a new therapeutic target in nonalcoholic fatty liver disease (NAFLD). OBJECTIVES: The aim of this study was to evaluate the most current evidence for liver-specific and metabolic effects of microbiome-targeted therapies (MTTs) in persons with NAFLD. METHODS: We searched multiple electronic databases for randomized controlled trials (RCTs) published from January 1, 2005 to December 1, 2018 that enrolled persons with NAFLD who received MTT rather than placebo or usual care. MTT was defined as antibiotics, probiotics, synbiotics, or fecal microbiota transplantation (FMT). Clinical outcomes were pooled with the use of random-effects models and heterogeneity was assessed with the I2 statistic. A random-effects meta-regression was performed to determine sources of heterogeneity in prevalence estimates between studies. RESULTS: Twenty-one RCTs (1252 participants) were included; 9 evaluated probiotics and 12 evaluated synbiotics, with treatment duration ranging from 8 to 28 wk. No RCTs examined the efficacy of antibiotics or FMT. Probiotics/synbiotics were associated with a significant reduction in alanine aminotransferase activity [ALT, weighted mean difference (WMD): -11.23 IU/L; 95% CI: -15.02, -7.44 IU/L] and liver stiffness measurement (LSM) by elastography (reflecting inflammation and fibrosis) (WMD: -0.70 kPa; 95% CI: -1.00, -0.40 kPa), although analyses showed heterogeneity (I2 = 90.6% and I2 = 93.4%, respectively). Probiotics/synbiotics were also associated with increased odds of improvement in hepatic steatosis, as graded by ultrasound (OR: 2.40; 95% CI: 1.50, 3.84; I2 = 22.4%). No RCTs examined sequential liver biopsy findings. Probiotics (WMD: -1.84; 95% CI: -3.30, -0.38; I2 = 23.6%), but not synbiotics (WMD: -0.85; 95% CI: -2.17, 0.47; I2 = 96.6%), were associated with a significant reduction in body mass index. CONCLUSIONS: The use of probiotics/synbiotics was associated with improvement in liver-specific markers of hepatic inflammation, LSM, and steatosis in persons with NAFLD. Although promising, given the heterogeneity in pooled analyses, additional well-designed RCTs are needed to define the efficacy of probiotics/synbiotics for treatment of NAFLD. This study was registered with PROSPERO as CRD42018091455.

Improving the Quality of Inpatient Ulcerative Colitis Management: Promoting Evidence-Based Practice and Reducing Care Variation With an Inpatient Protocol.

BACKGROUND: Hospitalization for ulcerative colitis is a high-risk period associated with increased risk of Clostridium difficile infection, thromboembolism, and opiate use. The study aim was to develop and implement a quality-improvement intervention for inpatient ulcerative colitis management that standardizes gastroenterology consultant recommendations and improves delivery of evidence-based care. METHODS: All adult patients hospitalized for ulcerative colitis between July 1, 2014, and December 31, 2017, who received intravenous corticosteroids were included. On July 1, 2016, the UCSF Inpatient Ulcerative Colitis Protocol was implemented, featuring standardized core recommendations and a daily checklist for gastroenterology consultant notes, a bundled IBD electronic order set, and an opiate awareness campaign. The composite primary outcome was adherence to all 3 evidence-based care metrics: C. difficile testing performed, pharmacologic venous thromboembolism (VTE) prophylaxis ordered, and opiates avoided. RESULTS: Ninety-three ulcerative colitis hospitalizations occurred, including 36 preintervention and 57 postintervention. Age, gender, disease duration, disease extent, and medication use were similar preintervention and postintervention. C. difficile testing was performed in 100% of hospitalizations. Venous thromboembolism prophylaxis was ordered on 84% of hospital days before intervention compared with 100% after intervention (P ≤ 0.001). Opiates were administered in 67% of preintervention hospitalizations, compared with 53% of postintervention hospitalizations (P = 0.18). The median daily dose of oral morphine equivalents decreased from 12.1 mg before intervention to 0.5 mg after intervention (P = 0.02). The composite outcome of adherence to all 3 metrics was higher after intervention (25% vs. 47%, P = 0.03). CONCLUSIONS: Evidence-based inpatient ulcerative colitis management may be optimized with standardized algorithms that reinforce core principles, reduce care variation, and do not require IBD specialists to implement.

Gut Microbial Metabolism and Nonalcoholic Fatty Liver Disease.

The gut microbiome, the multispecies community of microbes that exists in the gastrointestinal tract, encodes several orders of magnitude more functional genes than the human genome. It also plays a pivotal role in human health, in part due to metabolism of environmental, dietary, and host-derived substrates, which produce bioactive metabolites. Perturbations to the composition and associated metabolic output of the gut microbiome have been associated with a number of chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD). Here, we review the rapidly evolving suite of next-generation techniques used for studying gut microbiome composition, functional gene content, and bioactive products and discuss relationships with the pathogenesis of NAFLD.

Emerging Role of the Gut Microbiome in Nonalcoholic Fatty Liver Disease: From Composition to Function.

The gut microbiome, a diverse microbial community in the gastrointestinal tract, plays a pivotal role in the maintenance of health. The gut microbiome metabolizes dietary and host-derived molecules to produce bioactive metabolites, which have a wide array of effects on host metabolism and immunity. 'Dysbiosis' of the gut microbiome, commonly considered as perturbation of microbiome diversity and composition, has been associated with intestinal and extra-intestinal diseases, including nonalcoholic fatty liver disease (NAFLD). A number of endogenous and exogenous factors, such as nutritional intake and xenobiotic exposure, can alter the gut microbiome. We will review the evolving methods for studying the gut microbiome and how these profiling techniques have been utilized to further our understanding of the gut microbial community composition and functional potential in the clinical spectrum of NAFLD. We will highlight microbiome-host interactions that may contribute to the pathogenesis of NAFLD, with a primary focus on mechanisms related to the metabolic output of the gut microbiome. Finally, we will discuss potential therapeutic implications of the gut microbiome in NAFLD.

Outcomes of Sleeve Gastrectomy in Obese Liver Transplant Candidates.

Morbid obesity (body mass index [BMI] ≥40 kg/m2 ) is a relative contraindication to liver transplantation (LT) at many transplant centers. The safety and efficacy of pre-LT bariatric surgery in morbidly obese LT candidates is unknown. Herein, we describe a cohort study of morbidly obese LT candidates who failed to achieve adequate weight loss through a medically supervised weight loss program and subsequently underwent sleeve gastrectomy (SG) at our institution. In total, 32 LT candidates with a median Model for End-Stage Liver Disease (MELD) score of 12 (interquartile range [IQR], 10-13) underwent SG. All LT candidates had a history of hepatic decompensation, but complications of liver disease were required to be well controlled at the time of SG. Median pre-SG BMI was 45.0 kg/m2 (IQR, 42.1-49.0 kg/m2 ). There were no perioperative deaths or liver-related morbidity. One patient experienced major perioperative morbidity secondary to a gastric leak, which was managed nonoperatively. Median weight loss at 6 and 12 months after SG was 22.0 kg (IQR, 18.9-26.8 kg) and 31.0 kg (IQR, 23.6-50.3 kg), respectively, corresponding to a percentage of excess body weight lost of 33.4% and 52.4%. Within 6 months after SG, 28 (88%) candidates were deemed eligible for LT. Our center's experience highlights the potential option of SG in morbidly obese LT candidates with advanced liver disease who might otherwise be excluded from pursuing LT.

Combined effects of recipient age and model for end-stage liver disease score on liver transplantation outcomes.

BACKGROUND: The proportion of older patients awaiting liver transplantation (LT) is rising. Although increased age and LT-MELD are known to increase the risk of graft loss, no studies have explored whether there is a synergistic effect between LT-age and LT-MELD. METHODS: All US adult, non-Status 1 recipients of primary deceased donor LT from 2/05 to 1/10 without MELD exceptions were included (n=15,677). Recipients were categorized by LT-age [18-59 yr (n=11,966), 60-64 yr (n=2181), 65-69 yr (n=1177), and ≥70 yr (n=343)] and LT-MELD [low (<20, n=5290), mid (20-27, n=5112), and high (≥28, n=5265)]. Adjusted Cox models evaluated the independent and combined effects of LT-age and LT-MELD on graft loss (death or re-LT). RESULTS: LT-age ≥70 yr (HR=1.65, 95% CI 1.08-1.82) and LT-MELD ≥28 (HR=1.46, 95% CI 1.02-1.47) were independently associated with increased risk of graft loss (P<0.001). In a model allowing for the interaction between LT-age and LT-MELD, the risk of graft loss for recipients ≥70 years with MELD ≥28 was higher than predicted by the additive model (HR=2.38, 95% CI 1.73-3.27, P<0.001) resulting in 1-year graft survival of 56%. However, the increased risk of graft loss in recipients ≥70 years was attenuated at lower LT-MELD <28. Furthermore, the interaction term was not significant for any other LT-age and LT-MELD combination. CONCLUSION: Our analyses suggest that recipients should not be excluded solely based on age; however, LT for recipients ≥70 years at high LT-MELD scores should be undertaken cautiously.

The volumetric response of brain metastases after stereotactic radiosurgery and its post-treatment implications.

BACKGROUND: Changes in tumor volume are seen on magnetic resonance imaging within weeks after stereotactic radiosurgery (SRS), but it remains unclear what clinical outcomes early radiological changes portend. OBJECTIVE: We hypothesized that rapid, early reduction in tumor volume post-SRS is associated with prolonged local control and favorable clinical outcome. METHODS: A retrospective review of patients treated with CyberKnife SRS for brain metastases at the University of North Carolina from 2007 to 2009 was performed. Patients with at least 1 radiological follow-up, minimal initial tumor volume of 0.1 cm, no previous focal radiation, and no recent whole-brain radiation therapy were eligible for inclusion. RESULTS: Fifty-two patients with 100 metastatic brain lesions were analyzed and had a median follow-up of 15.6 months (range, 2-33 months) and a median of 2 (range, 1-8) metastatic lesions. In treated metastases in which there was a significant tumor volume reduction by 6 or 12 weeks post-SRS, there was no local progression for the duration of the study. Furthermore, patients with metastases that did not reduce in volume by 6 or 12 weeks post-SRS were more likely to require corticosteroids (P = .01) and to experience progression of neurological symptoms (P = .003). CONCLUSION: Significant volume reductions of brain metastases measured at either 6 or 12 weeks post-SRS were strongly associated with prolonged local control. Furthermore, early volume reduction was associated with less corticosteroid use and stable neurological symptoms.