Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease.

BACKGROUND: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). AIM: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. METHODS: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. RESULTS: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). CONCLUSIONS: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.

Acute kidney injury in severe alcohol-associated hepatitis treated with anakinra plus zinc or prednisone.

BACKGROUND AND AIMS: In a recent trial, patients with severe alcohol-associated hepatitis treated with anakinra plus zinc (A+Z) had lower survival and higher acute kidney injury (AKI) rates versus prednisone (PRED). We characterize the clinical factors and potential mechanisms associated with AKI development in that trial. APPROACH AND RESULTS: Data from 147 participants in a multicenter randomized clinical trial (74 A+Z, 73 PRED) were analyzed. AKI, AKI phenotypes, and kidney injury biomarkers were compared between participants who did/did not develop AKI in the 2 treatment arms. Multivariable competing risk analyses were performed to identify baseline risk factors for incident AKI, with death treated as a competing event. Risk factors considered were age, sex, mean arterial pressure, white blood cell count, albumin, MELD, ascites, HE, and treatment arm. At baseline, no participants had AKI; 33% (n=49) developed AKI during follow-up. AKI incidence was higher in A+Z than in PRED (45% [n=33] versus 22% [n=16], p =0.001). AKI phenotypes were similar between the 2 treatment arms ( p =0.361), but peak AKI severity was greater in A+Z than PRED (stage 3 n=21 [63.6%] vs. n=8 [50.0%], p =0.035). At baseline, urine-neutrophil-gelatinase-associated lipocalin levels were similar between participants who developed AKI in both treatment arms ( p =0.319). However, day 7 and 14 urine-neutrophil-gelatinase-associated lipocalin levels were significantly elevated in participants treated with A+Z who developed AKI versus participants treated with PRED who developed AKI ( p =0.002 and 0.032, respectively). On multivariable competing risk analysis, only A+Z was independently associated with incident AKI (subdistribution hazard ratio 2.35, p =0.005). CONCLUSIONS: AKI occurred more frequently and was more severe in participants treated with A+Z. A+Z-treated participants with AKI had higher urine-neutrophil-gelatinase-associated lipocalin, suggesting that A+Z maybe nephrotoxic in patients with severe alcohol-associated hepatitis.

Utility of Lille Score in Predicting 30-Day Survival in Steroid-Treated Alcohol-Associated Hepatitis.

BACKGROUND/AIMS: In alcohol-associated hepatitis (AH), the Lille score is used to assess futility of steroids. However, the ability of the Lille score to predict 30-day survival in AH is not well-defined. Our aim is to compare the utility of the Lille score in predicting 30-day survival in those with AH treated with steroids. METHODS: Retrospective chart review of 882 patients hospitalized with AH from January 1st, 2012 through December 30th, 2019 was performed. Of these, 201 patients with severe AH met the threshold to receive steroids. Those with data to calculate Lille score < 0.45 on day 4 (n = 29) or 7 (n = 89) who continued steroids were compared to 83 patients with Lille scores ≥ 0.45 on day 4 (n = 18) or 7 (n = 65) who stopped steroids. The primary outcome was 30-day survival. For comparison, a contemporaneous matched control group was also analyzed of 110 patients who were hospitalized with severe AH, but did not receive steroids. RESULTS: In patients with Lille score < 0.45, survival was higher at 30-day when compared to those with Lille score ≥ 0.45 (94.9% vs. 80.72%; p = 0.002). The sensitivity, specificity, positive predictive value and negative predictive value of Lille score (< 0.45) to predict 30-day survival was 95%, 19%, 63%, and 73%, respectively. CONCLUSIONS: In severe AH, those with Lille score < 0.45 at day 4 or 7 have improved 30-day survival compared to those with Lille score ≥ 0.45. In those receiving steroids, Lille score has excellent sensitivity to predict 30-day survival but poor specificity.

Utility of scores to predict alcohol use after liver transplant (lt): take them with a grain of salt.

BACKGROUND AIMS: The Sustained Alcohol use post-Liver Transplant (SALT) and the High-Risk Alcohol Relapse (HRAR) scores were developed to predict return to alcohol use after liver transplant (LT) for alcohol associated liver disease (ALD). METHODS: A retrospective analysis of deceased donor LT 10/2018 to 4/2022 was performed. All patients (pts) underwent careful pre-LT psychosocial evaluation. Data on alcohol use, substance abuse, prior rehabilitation, and legal issues were collected. Post-LT, all were encouraged to participate in rehabilitation programs and underwent interval phosphatidylethanol (PeTH) testing. Pts with ALD were stratified by < or > 6 month sobriety prior to listing. Those with <6 month were further stratified as acute alcoholic hepatitis (AH) by NIAAA criteria and non-AH. The primary outcome was utility of the SALT (<5 vs. ≥5) and HRAR (<3 vs. ≥3) scores to predict return to alcohol use (+PeTH) within 1 year after LT. RESULTS: Of the 365 LT, 86 had > 6 month sobriety and 85 had <6 month sobriety; 41 with AH and 44 non-AH. In those with AH, the mean time of abstinence to LT was 58 days, and 71% failed prior rehabilitation. Following LT, return to drinking was similar in the AH (24%) compared to <6M non-AH (15%) and >6M ALD (22%). Only 4% had returned to heavy drinking. The accuracy of both the SALT and HRAR scores to predict return to alcohol was low (accuracy 61-63%) with poor sensitivity (46% and 37%), specificity (67-68%), positive predictive value (22-26%) with moderate negative predictive value (NPV) (81-83%), respectively with higher NPVs (95%) in predicting return to heavy drinking. CONCLUSIONS: Both SALT and HRAR scores had good NPV in identifying patients at low risk for recidivism.

Liver and cardiovascular disease outcomes in metabolic syndrome and diabetic populations: Bi-directional opportunities to multiply preventive strategies.

The incidence and prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are rising globally. MetS and T2DM are associated with significant morbidity and mortality, which is partly related to liver and cardiovascular disease. Insulin resistance is central to MetS and T2DM pathophysiology, and drives ectopic fat deposition in the liver, also known as metabolic dysfunction-associated steatotic liver disease (MASLD). MetS and T2DM are not only risk factors for developing MASLD but are also independently associated with disease progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In addition to the risk of liver disease, MetS and T2DM are independent risk factors for cardiovascular disease (CVD), including coronary artery disease (CAD) and heart failure (HF). Importantly, there is a bidirectional relationship between liver and CVD due to shared disease pathophysiology in patients with MetS and T2DM. In this review, we have described studies exploring the relationship of MetS and T2DM with MASLD and CVD, independently. Following this we discuss studies evaluating the interplay between liver and cardiovascular risk as well as pragmatic risk mitigation strategies in this patient population.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Spontaneous Hepatic Hemorrhage Causing Acute Liver Failure Requiring Liver Transplant.

Spontaneous hepatic hemorrhage (SHH) is a very rare but life-threatening entity that results from a breach in the hepatic parenchyma without any external cause, the most common being hepatocellular carcinoma and hepatic adenoma. We present a case of SHH without any underlying tumor or injury. The cause in our patient remained unclear, but we hypothesize that the patient's SHH was most likely coagulopathy-related.

Emerging therapies for MASLD and their impact on plasma lipids.

Metabolic-dysfunction associated steatotic liver disease (MASLD) affects 1 out of every 3 individuals in the adult population and the disease prevalence is predicted to increase worldwide. Patients with MASLD are also burdened by cardiovascular disease, which is the leading cause of mortality in this population. Complex metabolic derangements such as insulin resistance and atherogenic dyslipidemia affect patients with MASLD. In patients with MASLD, treatment such as pharmacotherapy may be best directed towards improving the adverse concomitant metabolic disorders associated with MASLD, particularly the ones that may contribute to MASLD. Herein, we discuss conventional therapies that target cardiometabolic risk factors which have the potential to improve hepatic injury, and summarize emerging therapies that target hepatic receptors, fibrosis, and fatty acid oxidation in patients with MASLD. Given the relationship between hepatic injury which leads to MASLD, insulin resistance, and ultimately atherogenic dyslipidemia our review uniquely delves into the effects of conventional and emerging therapies for MASLD on plasma lipid parameters.

Second-Harmonic Generated Quantifiable Fibrosis Parameters Provide Signatures for Disease Progression and Regression in Nonalcoholic Fatty Liver Disease.

Introduction: The current ordinal fibrosis staging system for nonalcoholic steatohepatitis (NASH) has a limited dynamic range. The goal of this study was to determine if second-harmonic generated (SHG) quantifiable collagen fibrillar properties (qFP) and their derived qFibrosis score capture changes in disease progression and regression in a murine model of NASH, in which disease progression can be induced by a high fat sugar water (HFSW) diet and regression by reversal to chow diet (CD). Methods: DIAMOND mice were fed a CD or HFSW diet for 40 to 52 weeks. Regression related changes were studied in mice with diet reversal for 4 weeks after 48 to 60 weeks of a HFSW diet. Results: As expected, mice on HFSW developed steatohepatitis with stage 2 to 3 fibrosis between weeks 40 and 44. Both the collagen proportionate area and the qFibrosis score based on 15 SHG-quantified collagen fibrillar properties in humans were significantly higher in mice on HFSW for 40 to 44 weeks compared to CD fed mice. These changes were greatest in the sinusoids (Zone 2) with further increase in septal and portal fibrosis related scores between weeks 44 and 48. Diet reversal led to decrease in qFibrosis, septal thickness, and cellularity with greatest changes in Zone 2. Specific qFPs associated with progression only, regression only, or both processes were identified and categorized based on direction of fibrosis change. Conclusion: Complementing recent human studies, these findings support the concept that changes of disease progression and regression can be assessed using SHG-based image quantification of fibrosis related parameters.

A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study.

BACKGROUND & AIMS: Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. METHODS: Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5 g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). RESULTS: Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1ß and endothelial dysfunction markers was also observed in the albumin group. CONCLUSION: In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. CLINICAL TRIALS REGISTRATION: www. CLINICALTRIALS: gov NCT03585257. IMPACT AND IMPLICATIONS: Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.

Evaluation of liver transplant candidates with non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is anticipated to become the leading indication for liver transplantation (LT) in the United States in the near future. LT is indicated in patients with NASH-related cirrhosis who have medically refractory hepatic decompensation, synthetic dysfunction, and hepatocellular carcinoma (HCC) meeting certain criteria. The objective of LT evaluation is to determine which patient will derive the most benefit from LT with the least risk, thus maximizing the societal benefits of a limited resource. LT evaluation is a multidisciplinary undertaking involving several specialists, assessment tools, and diagnostic testing. Although the steps involved in LT evaluation are relatively similar across different liver diseases, patients with NASH-related cirrhosis have unique demographic and clinical features that affect transplant outcomes and influence their LT evaluation. LT candidates with NASH should be assessed for metabolic syndrome and obesity, malnutrition and sarcopenia, frailty, and cardiovascular disease. Interventions that treat cardiometabolic co-morbidities and improve patients' nutrition and functionality should be considered in order to improve patient outcomes in the waitlist and after LT.

Generation of a Diet-Induced Mouse Model of Nonalcoholic Fatty Liver Disease.

The obesity epidemic is driving the increased prevalence of nonalcoholic fatty liver disease (NAFLD) globally. The more aggressive subtype of NAFLD, nonalcoholic steatohepatitis (NASH), can lead to progressive disease and ultimately lead to cirrhosis, liver cancer, and death. There are many unmet needs in the field of NAFLD including understanding of molecular mechanisms driving disease, natural history, risk for liver cancer, and most importantly FDA approved therapeutics. Animal models serve as a tool to aid in answering some of these questions. Here, we describe the diet-induced animal model of NAFLD (DIAMOND), a mouse model with many characteristics that mimic human NASH.

Unannotated small RNA clusters associated with circulating extracellular vesicles detect early stage liver cancer.

OBJECTIVE: Surveillance tools for early cancer detection are suboptimal, including hepatocellular carcinoma (HCC), and biomarkers are urgently needed. Extracellular vesicles (EVs) have gained increasing scientific interest due to their involvement in tumour initiation and metastasis; however, most extracellular RNA (exRNA) blood-based biomarker studies are limited to annotated genomic regions. DESIGN: EVs were isolated with differential ultracentrifugation and integrated nanoscale deterministic lateral displacement arrays (nanoDLD) and quality assessed by electron microscopy, immunoblotting, nanoparticle tracking and deconvolution analysis. Genome-wide sequencing of the largely unexplored small exRNA landscape, including unannotated transcripts, identified and reproducibly quantified small RNA clusters (smRCs). Their key genomic features were delineated across biospecimens and EV isolation techniques in prostate cancer and HCC. Three independent exRNA cancer datasets with a total of 479 samples from 375 patients, including longitudinal samples, were used for this study. RESULTS: ExRNA smRCs were dominated by uncharacterised, unannotated small RNA with a consensus sequence of 20 nt. An unannotated 3-smRC signature was significantly overexpressed in plasma exRNA of patients with HCC (p<0.01, n=157). An independent validation in a phase 2 biomarker case-control study revealed 86% sensitivity and 91% specificity for the detection of early HCC from controls at risk (n=209) (area under the receiver operating curve (AUC): 0.87). The 3-smRC signature was independent of alpha-fetoprotein (p<0.0001) and a composite model yielded an increased AUC of 0.93. CONCLUSION: These findings directly lead to the prospect of a minimally invasive, blood-only, operator-independent clinical tool for HCC surveillance, thus highlighting the potential of unannotated smRCs for biomarker research in cancer.

Basic science to clinical trials in non-alcoholic fatty liver disease and alcohol-related liver disease: collaboration with industry.

Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are highly prevalent forms of chronic liver diseases globally, associated with rising all-cause morbidity and mortality. While distinct diseases, NAFLD and ALD share several similarities; both can result in fatty liver disease, steatohepatitis, associated hepatic fibrosis and cirrhosis-related complications, including hepatocellular carcinoma (HCC). Our understanding of the pathophysiology and manifestations of these diseases has advanced significantly, which has established a new foundation to identify therapeutic targets and test new treatments. This review underscores emerging pathogenic pathways that establish a template for target identification and clinical trials. Success is critically dependent upon productive interactions between academic investigators and industry to address unmet therapeutic needs in NAFLD and ALD.

Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma.

Little is known about the mutational landscape of advanced hepatocellular carcinoma (HCC), and predictive biomarkers of response to systemic therapies are lacking. We aimed to describe the mutational landscape of advanced HCC and to identify predictors of primary resistance to systemic therapies using circulating tumor DNA (ctDNA). We prospectively enrolled 121 patients between October 2015 and January 2019. We performed targeted ultra-deep sequencing of 25 genes and Digital Droplet PCR of TERT promoter, including sequential samples throughout treatment. Primary endpoint was progression-free survival (PFS) stratified by mutation profiles in ctDNA. Secondary endpoints were overall survival and objective response rate. The most frequent mutations in ctDNA of advanced HCC were TERT promoter (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%). TP53 and CTNNB1 mutations were mutually exclusive. Patients with mutations in the PI3K/MTOR pathway had significantly shorter PFS than those without these mutations after tyrosine kinase inhibitors (2.1 vs 3.7 months, p < 0.001), but not after immune checkpoint inhibition (CPI). WNT pathway mutations were not associated with PFS, overall survival, or objective response after CPI. Serial profiling of ctDNA in a subset correlated with treatment response. Mutation profiling of ctDNA in advanced HCC shows similar mutation frequencies for known HCC drivers compared to early stages and identifies predictive biomarkers of response to systemic therapies.

Pharmacologic Treatment Strategies for Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is a common form of liver disease, associated with features of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH), the aggressive subtype of NAFLD, can cause progressive fibrosis leading to cirrhosis. With the obesity epidemic, there is an increased health care burden from NASH, one of the most common causes of liver transplantation in the United States. There currently are no Food and Drug Administration-approved medical therapies for NASH. There exists a need for therapeutics to correct the drivers of NASH and to reverse or halt fibrosis progression. This article reviews pharmacologic therapeutics being developed to treat NASH.

Smoking and Liver Disease.

Cigarette smoking is the leading cause of preventable disease and death in the United States, causing approximately 480,000 deaths per year, which is equivalent to 1 in 5 deaths being attributable to tobacco use. The adverse effects of cigarette smoking on the lungs and cardiovascular system are well described; however, the detrimental effects of smoking on the liver are not as well defined. Smoking affects the liver via 3 separate mechanisms: toxic (both direct and indirect), immunologic, and oncogenic. There is an emerging body of evidence of an association between cigarette smoking and progression of fibrosis in chronic liver diseases such as nonalcoholic fatty liver disease and primary biliary cholangitis. Smoking is associated with accelerated development of hepatocellular carcinoma in patients with chronic hepatitis B or C virus infection. Tobacco smoking adversely affects lung function, which increases physical limitations and may preclude liver transplantation. Following liver transplantation, smoking is associated with several adverse outcomes, including increased risk of de novo malignancy, vascular complications, and nongraft-associated mortality. The respiratory illness caused by the novel coronavirus disease 2019 serves as a good example of the complex interplay between the lungs and the liver. It is evident that cigarette smoking has important negative effects on a multitude of liver diseases and that patients' smoking cessation must be prioritized. The data are limited, and more research is needed to better understand how smoking affects the liver. This article summarizes what is known about the pathologic effects of cigarette smoking on common liver diseases.

Liver transplant for hepatocellular carcinoma in the United States: Evolving trends over the last three decades.

Hepatitis C virus infection has been the most common etiology in HCC-related liver transplantation (LT). Since 2014, direct-acting antivirals (DAAs) have dramatically improved HCV cure. We aimed to study the changing pattern of etiologies and impact in outcome in HCC-related LT according to HCV treatment-era through retrospective analysis of the Scientific Registry of Transplant Recipients (SRTR) database (1987-2017). A total of 27 855 HCC-related liver transplants were performed (median age 59 years, 77% male). In the DAA era (2014-2017) there has been a 14.6% decrease in LT for HCV-related HCC; however, HCV remains the most common etiology in 50% of cases. In the same era, there has been a 50% increase in LT for NAFLD-related HCC. Overall survival was significantly worse for HCV-related HCC compared to NAFLD-related HCC during pre-DAA era (2002-2013; P = .031), but these differences disappeared in the DAA era. In addition, HCV patients had a significant improvement in survival when comparing the DAA era with IFN era (P < .001). Independent predictors of survival were significantly different in the pre-DAA era (HCV, AFP, diabetes) than in the DAA era (tumor size). HCV-related HCC continues to be the main indication for LT in the DAA era, but patients' survival has significantly improved and is comparable to that of NAFLD-related HCC.

Gene Expression Predicts Histological Severity and Reveals Distinct Molecular Profiles of Nonalcoholic Fatty Liver Disease.

The heterogeneity of biological processes driving the severity of nonalcoholic fatty liver disease (NAFLD) as reflected in the transcriptome and the relationship between the pathways involved are not well established. Well-defined associations between gene expression profiles and disease progression would benefit efforts to develop novel therapies and to understand disease heterogeneity. We analyzed hepatic gene expression in controls and a cohort with the full histological spectrum of NAFLD. Protein-protein interaction and gene set variation analysis revealed distinct sets of coordinately regulated genes and pathways whose expression progressively change over the course of the disease. The progressive nature of these changes enabled us to develop a framework for calculating a disease progression score for individual genes. We show that, in aggregate, these scores correlate strongly with histological measures of disease progression and can thus themselves serve as a proxy for severity. Furthermore, we demonstrate that the expression levels of a small number of genes (~20) can be used to infer disease severity. Finally, we show that patient subgroups can be distinguished by the relative distribution of gene-level scores in specific gene sets. While future work is required to identify the specific disease characteristics that correspond to patient clusters identified on this basis, this work provides a general framework for the use of high-content molecular profiling to identify NAFLD patient subgroups.