A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study.

BACKGROUND AND AIMS: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. APPROACH AND RESULTS: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 µg (TXR 140 ), CVC 150 mg (CVC), TXR 140 µg + CVC 150 mg (TXR 140 + CVC), or TXR 90 µg + CVC 150 mg (TXR 90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; -13%, TXR 90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + CVC, -1.0 kg; and CVC, -0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR 140 , CVC, TXR 140 + CVC, and TXR 90 + CVC groups, respectively. CONCLUSIONS: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Rational combination therapy for NASH: Insights from clinical trials and error.

So far without an approved therapy, non-alcoholic steatohepatitis (NASH) remains at the beginning of its therapeutic cycle, whereby many pharmacological agents are initially developed as monotherapies. Given the complex pathogenesis of NASH, the prevailing opinion is that combination therapy will be key to its treatment and that therapeutic efforts should be aimed at developing combinations rather than monotherapies. However, the development of combination therapies is associated with multiple challenges, which we attempt to describe here, and which extend beyond the perceived biological rationale of combining two different mechanisms of action. Important hurdles include predicting the added benefit of a specific combination regimen over monotherapies, given the limited data provided by early phase trials. Regulatory requirements for approving a combination span from preclinical models, through initial demonstration of the efficacy of the combination, to complex late-stage therapeutic trials. Development pathways for combination therapies are, in this paradigm, highly demanding in terms of patient and sponsor resources. In light of recent, negative, late-stage trials of monotherapies, well-designed combination development programmes could be essential to avoid additional failures that may hold back therapeutic research and access to treatment for patients. Enthusiasm for combination therapies should be maintained but realistically balanced against the complexity of demonstrating their therapeutic value.

Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): Beyond insulin resistance.

While the association of metabolic dysfunction-associated steatotic liver disease (MASLD) with obesity and insulin resistance is widely appreciated, there are a host of complex interactions between the liver and other endocrine axes. While it can be difficult to definitively distinguish direct causal relationships and those attributable to increased adipocyte mass, there is substantial evidence of the direct and indirect effects of endocrine dysregulation on the severity of MASLD, with strong evidence that low levels of growth hormone, sex hormones, and thyroid hormone promote the development and progression of disease. The impact of steroid hormones, e.g. cortisol and dehydroepiandrosterone, and adipokines is much more divergent. Thoughtful assessment, based on individual risk factors and findings, and management of non-insulin endocrine axes is essential in the evaluation and management of MASLD. Multiple therapeutic options have emerged that leverage various endocrine axes to reduce the fibroinflammatory cascade in MASH.

Liver Transplantation 2023: Status Report, Current and Future Challenges.

Liver transplantation offers live-saving therapy for patients with complications of cirrhosis and stage T2 hepatocellular carcinoma. The demand for organs far outstrips the supply, and innovations aimed at increasing the number of usable deceased donors as well as alternative donor sources are a major focus. The etiologies of cirrhosis are shifting over time, with more need for transplantation among patients with alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease and less for viral hepatitis, although hepatitis B remains an important indication for transplant in countries with high endemicity. The rise in transplantation for alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease has brought attention to how patients are selected for transplantation and the strategies needed to prevent recurrent disease. In this review, we present a status report on the most pressing topics in liver transplantation and future challenges.

Clinical characteristics and management of patients with nonalcoholic steatohepatitis in a real-world setting: analysis of the Ipsos NASH therapy monitor database.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is the more severe, inflammatory type of nonalcoholic fatty liver disease (NAFLD). NASH, a leading indication for liver transplantation, is growing in prevalence. The extent of liver fibrosis, ranging from fibrosis stage (FS) of none (F0) to cirrhosis (F4), is a strong predictor of health outcomes. There is little information on patient demographics and clinical characteristics by fibrosis stage and NASH treatment outside of academic medical centers. METHODS: We conducted a cross-sectional observational study using Ipsos' syndicated NASH Therapy Monitor database, consisting of medical chart audits provided by sampled NASH-treating physicians in the United States in 2016 (n = 174) and 2017 (n = 164). Data was collected online. RESULTS: Of 2,366 patients reported on by participating physicians and included in the analysis, 68% had FS F0-F2, 21% had bridging fibrosis (F3), and 9% had cirrhosis (F4). Common comorbidities were type 2 diabetes (56%), hyperlipidemia (44%), hypertension (46%), and obesity (42%). Patients with more advanced fibrosis scores (F3-F4) had higher comorbidity rates than patients with F0-F2. Commonly used diagnostic tests included ultrasound (80%), liver biopsy (78%), AST/ALT ratio (43%), NAFLD fibrosis score (25%), transient elastography (23%), NAFLD liver fat score (22%), and Fatty Liver Index (19%). Most commonly prescribed medications were vitamin E (53%), statins (51%), metformin (47%), angiotensin converting enzyme inhibitors (28%), and beta blockers (22%). Medications were commonly prescribed for reasons other than their known effects. CONCLUSION: Physicians in this study, drawn from a spectrum of practice settings, relied on ultrasound and liver biopsy for diagnosis and vitamin E, statins, and metformin for pharmacological treatment of NASH. These findings imply poor adherence to guidelines in the diagnosis and management of NAFLD and NASH. Nonalcoholic steatohepatitis (NASH) is a liver disease caused by excess fat in the liver which can lead to liver inflammation and scarring (fibrosis), ranging from stage F0 (no scarring) to F4 (advanced scarring). The stage of liver scarring can predict the likelihood of future health problems, including liver failure and liver cancer. However, we do not fully understand how patient characteristics may vary at different stages of liver scarring. We looked at medical information from physicians treating patients diagnosed with NASH to understand how patient characteristics might differ based on the severity of their liver scarring. The majority (68%) of patients were stage F0-F2, with 30% having advanced scarring (F3-F4). In addition to NASH, many patients also had type 2 diabetes, high cholesterol, high blood pressure, and obesity. Patients with more advanced scarring (F3-F4) were more likely to have these diseases than patients with less severe disease (F0-F2). Diagnosis of NASH by participating physicians was based on tests including imaging (ultrasound, CT scan, MRI), liver biopsy, blood tests, and whether patients had other conditions that would put them at risk for NASH. The medications that the doctors prescribed most often to their patients included vitamin E and drugs to treat high cholesterol, high blood pressure, or diabetes. Medications were frequently prescribed for reasons other than their known effects. By understanding how patient characteristics vary by stages of liver scarring and how NASH is currently managed may help guide the evaluation and treatment of NASH when NASH-specific therapies become available.

Complexity of ballooned hepatocyte feature recognition: Defining a training atlas for artificial intelligence-based imaging in NAFLD.

BACKGROUND & AIMS: Histologically assessed hepatocyte ballooning is a key feature discriminating non-alcoholic steatohepatitis (NASH) from steatosis (NAFL). Reliable identification underpins patient inclusion in clinical trials and serves as a key regulatory-approved surrogate endpoint for drug efficacy. High inter/intra-observer variation in ballooning measured using the NASH CRN semi-quantitative score has been reported yet no actionable solutions have been proposed. METHODS: A focused evaluation of hepatocyte ballooning recognition was conducted. Digitized slides were evaluated by 9 internationally recognized expert liver pathologists on 2 separate occasions: each pathologist independently marked every ballooned hepatocyte and later provided an overall non-NASH NAFL/NASH assessment. Interobserver variation was assessed and a 'concordance atlas' of ballooned hepatocytes generated to train second harmonic generation/two-photon excitation fluorescence imaging-based artificial intelligence (AI). RESULTS: The Fleiss kappa statistic for overall interobserver agreement for presence/absence of ballooning was 0.197 (95% CI 0.094-0.300), rising to 0.362 (0.258-0.465) with a ≥5-cell threshold. However, the intraclass correlation coefficient for consistency was higher (0.718 [0.511-0.900]), indicating 'moderate' agreement on ballooning burden. 133 ballooned cells were identified using a ≥5/9 majority to train AI ballooning detection (AI-pathologist pairwise concordance 19-42%, comparable to inter-pathologist pairwise concordance of between 8-75%). AI quantified change in ballooned cell burden in response to therapy in a separate slide set. CONCLUSIONS: The substantial divergence in hepatocyte ballooning identified amongst expert hepatopathologists suggests that ballooning is a spectrum, too subjective for its presence or complete absence to be unequivocally determined as a trial endpoint. A concordance atlas may be used to train AI assistive technologies to reproducibly quantify ballooned hepatocytes that standardize assessment of therapeutic efficacy. This atlas serves as a reference standard for ongoing work to refine how ballooning is classified by both pathologists and AI. LAY SUMMARY: For the first time, we show that, even amongst expert hepatopathologists, there is poor agreement regarding the number of ballooned hepatocytes seen on the same digitized histology images. This has important implications as the presence of ballooning is needed to establish the diagnosis of non-alcoholic steatohepatitis (NASH), and its unequivocal absence is one of the key requirements to show 'NASH resolution' to support drug efficacy in clinical trials. Artificial intelligence-based approaches may provide a more reliable way to assess the range of injury recorded as "hepatocyte ballooning".

Preservation solutions for static cold storage in donation after circulatory death and donation after brain death liver transplantation in the United States.

Static cold preservation remains the cornerstone for storing donor livers following procurement; however, the choice between University of Wisconsin solution (UW) and histidine-tryptophan-ketoglutarate solution (HTK) remains controversial. Recent International Liver Transplantation Society (ILTS) guidelines have recommended avoiding HTK for donation after circulatory death (DCD) grafts based on older reports. We studied the latest US adult graft outcomes in three recent eras (2006-2010, 2011-2015, 2016-2020) comparing HTK and UW among 5956 DCD LTs: 3873 (65.0%) used UW and 1944 (32.7%) used HTK. In a total of 82,679 donation after brain death (DBD) liver transplantations (LTs), 63,511 (76.8%) used UW and 15,855 (19.2%) used HTK. The HTK group had higher 1-year and 5-year graft survival rates of 89.7% and 74.3%, respectively, compared with 85.9% and 70.8% in the UW group in the 2016-2020 era (p = 0.005). This difference remained when adjusted for important potential confounders (hazard ratio, 0.78; 95% confidence interval: 0.60, 0.99). There were no differences between groups among DCD LTs in the earlier eras or among DBD LTs in all eras (all p values > 0.05). The latest US data suggest that HTK is at least noninferior to UW for preserving DCD livers. These data support HTK use in DCD LT and contradict ILTS guidance.

Simultaneous Heart-Liver Transplantation for Congenital Heart Disease in the United States: Rapidly Increasing With Acceptable Outcomes.

BACKGROUND AND AIMS: There are more adults than children living with congenital heart disease (CHD) in the United States, with a growing proportion requiring heart-liver transplantation (HLT). Our aim was to ascertain the frequency, outcomes, and prognostic factors in this patient population. APPROACH AND RESULTS: United Network for Organ Sharing data on adult patients who underwent heart transplantation (HT) from 2009 through March 2020 were analyzed. The primary study outcome was patient survival. Cox proportional-hazards modeling assessed for mortality associations. There were 1,084 HT recipients: 817 (75.4%) CHD HTs only, 74 (6.8%) CHD HLTs, 179 (16.5%) non-CHD HLTs, and 14 (1.3%) heart-liver-kidney transplants. The number of CHD HLTs increased from a prior rate of 4/year to 21/year in 2019. Among patients with CHD, the 5-year survival rates were 74.1% and 73.6% in HTs only and HLTs, respectively (P = 0.865). There was a higher rate of allograft failure attributable to rejection in CHD HTs only compared with CHD HLTs (3.2% versus 0.4%; P = 0.014). Only 25 out of 115 HT-performing hospitals undertook CHD HLTs. Higher-volume centers (averaging one CHD HLT per year) had a 5-year patient survival rate of 83.0% compared with 61.3% in lower-volume centers (P = 0.079). Among HLT recipients, total bilirubin (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.12) and diabetes (HR = 2.97, 95% CI = 1.21-7.31) were independently associated with increased mortality risk, whereas CHD and age were not. CONCLUSIONS: The rate of HLT for adult CHD in the United States is rising dramatically. The survival outcomes between CHD HT only and CHD HLT groups are comparable; however, the HLT group had lower rates of acute rejection. Among HLT recipients, diabetes and elevated bilirubin are associated with increased posttransplant mortality risk. An average of one CHD HLT per year could be considered a minimum quality metric at transplant centers.

Effects of Mediterranean Diet in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Randomized Controlled Trials.

We conducted a meta-analysis to investigate the effects of the Mediterranean Diet (Med-Diet) on hepatic steatosis and insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Six randomized controlled trials were selected for the meta-analysis (sample size: 250 participants). In the meta-analysis, there was no significant difference in body mass index and waist circumference between the Med-Diet and control groups. Med-Diet significantly reduced fatty liver index (FLI) compared with the control diet (standard mean difference [SMD]: -1.06; 95% CI: -1.95 to -0.17; p = 0.02). Med-Diet significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) compared with the control diet (SMD: -0.34; 95% CI: -0.65 to -0.03; p = 0.03). Similarly, a meta-regression analysis using age showed that Med-Diet significantly reduced FLI and HOMA-IR (95% CI: -0.956 to -0.237, p = 0.001 and 95% CI: -0.713 to -0.003, p = 0.048, respectively). This meta-analysis demonstrated that Med-Diet improved hepatic steatosis and insulin resistance in patients with NAFLD. Thus, Med-Diet is a beneficial pharmaconutritional therapy in patients with NAFLD.

Liver transplantation for alcoholic hepatitis in the United States: Excellent outcomes with profound temporal and geographic variation in frequency.

Medical-refractory severe alcoholic hepatitis (AH) has a high mortality. The national frequency, longer term outcomes and regional practices of AH liver transplantation (LT) in the United States are not well described, despite the increasing mortality from alcohol-associated liver disease. We analyzed the trends in frequency and outcomes of UNOS data on 39 455 adult patients who underwent LT from 2014 to 2019, including AH LT recipients. LTs for AH increased 5-fold, from 28 in 2014 to 138 in 2019, varying 8-fold between UNOS regions. Three transplant centers accounted for 50%-90% of AH LTs within each region. The number of transplant centers performing AH LTs increased from 14 in 2014 to 47 in 2019. AH patients were younger (mean = 39.4 years), had higher MELD scores (mean = 36.8), and were more often on dialysis (46.0%) and in ICU (38.4%), compared to other indications (all P < .05). One- and 5-year graft survivals for AH LT recipients were 91.7% and 81.9%, respectively. The frequency of AH LT is increasing rapidly, with excellent medium-term outcomes. An impact of AH recurrence on patient or graft survival is not apparent in this national analysis. There are marked geographic variations in practices, highlighting the lack of selection criteria standardization.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Living Donor Liver Transplantation in the United States: Evolution of Frequency, Outcomes, Center Volumes, and Factors Associated With Outcomes.

Recent modifications in organ allocation policies and increases in chronic liver diseases may have resulted in important changes in living donor liver transplantation (LDLT) in the United States. We examined the trends, outcomes, and factors associated with outcomes in adult LDLT. United Network for Organ Sharing data on 2566 adult LDLT recipients who received transplants from January 1, 2010, through December 31, 2019, were analyzed. LDLT graft and patient survival rates were compared with propensity score-matched deceased donor liver transplantation recipients by the Kaplan-Meier curve estimator. The association between preceding LDLT frequency and subsequent outcomes were assessed by Cox proportional hazards mixed effects modeling. After a stable annual frequency of LDLTs from 2010 to 2014 (~200 per year), the number of LDLTs doubled to 440 in 2019. The 1-year and 5-year graft survival rates for LDLT recipients were 88.4% and 78.1%, respectively, compared with 92.5% and 80.7% in the propensity score-matched donation after brain death recipients (P = 0.005), respectively. Older donor age and recipient diabetes mellitus and life support requirement were significantly associated with graft failure among LDLT recipients (P values <0.05). Average preceding LDLT frequencies of <3 per year, 3 to 20 per year, and >20 per year resulted in 1-year graft survival rates of 82%, 88% to 89%, and 93%, respectively (P values <0.05). There were 3 living donor deaths (0.12%). The frequency of LDLTs has doubled during the past decade, with good outcomes and acceptable donor safety profiles. However, there appear to be varying threshold transplant frequencies (volume/unit time) associated with acceptable (88%-89%) and aspirational (93%) 1-year graft survival rates. These data should be reassuring and encourage LDLT practice as efforts continue to expand the donor pool.

Hepatotoxicity From Immune Checkpoint Inhibitors: A Systematic Review and Management Recommendation.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting immune checkpoint molecules. ICIs are an immunotherapy for the treatment of many advanced malignancies. The advent of ICIs has been a major breakthrough in the field of oncology, a fact recognized by the 2018 Nobel Prize in Physiology or Medicine being awarded for the discovery. The Food and Drug Administration approved the first ICI, ipilimumab, in 2011 for the treatment of metastatic melanoma. Seven ICIs are now used in clinical practice, including nivolumab and pembrolizumab for treatment of advanced hepatocellular carcinoma. ICIs are increasingly used across the spectrum of hepatobiliary neoplasia. The utility of ICI therapy has been limited by immune-related adverse reactions (irAEs) affecting multiple organ systems. Hepatotoxicity is an important irAE, occurring in up to 16% of patients receiving ICIs. Optimizing outcomes in patients receiving ICI therapy requires awareness of and familiarity with diagnosing and management of ICI-induced immune-mediated hepatotoxicity (IMH), including approaches to treatment and ICI dose management. The aim of this review article is to (1) provide a comprehensive, evidence-based review of IMH; (2) perform a systematic review of the management of IMH; and (3) present algorithms for the diagnosis and management of IMH.

Knockout of sulfatase 2 is associated with decreased steatohepatitis and fibrosis in a mouse model of nonalcoholic fatty liver disease.

Sulfatase 2 (SULF2) is a heparan sulfate editing enzyme that regulates the milieu of growth factors and cytokines involved in a variety of cellular processes. We used a murine model of diet-induced steatohepatitis to assess the effect of SULF2 downregulation on the development of nonalcoholic steatohepatitis (NASH) and liver fibrosis. Wild-type B6;129 mice (WT) and Sulf2-knockout B6;129P2-SULF2Gt(PST111)Byg mice (Sulf2-KO) were fed a fast-food diet (FFD) rich in saturated fats, cholesterol, and fructose or a standard chow diet (SC) ad libitum for 9 mo. WT mice on FFD showed a threefold increase in hepatic Sulf2 mRNA expression, and a 2.2-fold increase in hepatic SULF2 protein expression compared with WT mice on SC. Knockout of Sulf2 led to a significant decrease in diet-mediated weight gain and dyslipidemia compared with WT mice on FFD. Knockout of Sulf2 also abrogated diet-induced steatohepatitis and hepatic fibrosis compared with WT mice on FFD. Furthermore, expression levels of the profibrogenic receptors TGFßR2 and PDGFRß were significantly decreased in Sulf2-KO mice compared with WT mice on FFD. Together, our data suggest that knockout of Sulf2 significantly downregulates dyslipidemia, steatohepatitis, and hepatic fibrosis in a diet-induced mouse model of NAFLD, suggesting that targeting of SULF2 signaling may be a potential therapeutic mechanism in NASH.NEW & NOTEWORTHY We report for the first time that in wild-type (WT) mice, fast-food diet (FFD) induced a threefold increase in hepatic Sulf2 mRNA and a 2.2-fold increase in sulfatase 2 (SULF2) protein expression compared with WT mice on standard chow diet (SC). We showed that knockout of SULF2 ameliorates FFD-induced obesity, hyperlipidemia, steatohepatitis, and fibrosis. These data, along with work from other laboratories, suggest that SULF2 may be critical to the ability of the liver to progress to nonalcoholic steatohepatitis and fibrosis in conditions of overnutrition.

Nonalcoholic Steatohepatitis After Liver Transplantation.

Currently, nonalcoholic steatohepatitis (NASH) is the second leading indication for liver transplantation (LT), behind alcohol-related liver disease. After transplant, both recurrent and de novo nonalcoholic fatty liver disease are common; however, recurrence rates of NASH and advanced fibrosis are low. Identification of high-risk groups and optimizing treatment of metabolic comorbidities both before and after LT is paramount to maintaining a healthy allograft, especially with the additional consequences of longterm immunosuppression. In addition, NASH LT recipients are at an increased risk of cardiovascular events and malignancy, and their condition warrants a tailored approach to management. The optimal approach to NASH LT recipients including metabolic comorbidities management, tailored immunosuppression, the role of bariatric surgery, and nutritional and pharmacotherapy of NASH are discussed in this review. Overall, aggressive management of metabolic syndrome after LT via medical and surgical modalities and a minimalist approach to immunosuppression is advised.

Asian consensus recommendations on optimizing the diagnosis and initiation of treatment of hepatitis B virus infection in resource-limited settings.

Asia has an intermediate-to-high prevalence of and high morbidity and mortality from hepatitis B virus (HBV) infection. Optimization of diagnosis and initiation of treatment is one of the crucial strategies for lowering disease burden in this region. Therefore, a panel of 24 experts from 10 Asian countries convened, and reviewed the literature, to develop consensus guidance on diagnosis and initiation of treatment of HBV infection in resource-limited Asian settings. The panel proposed 11 recommendations related to diagnosis, pre-treatment assessment, and indications of therapy of HBV infection, and management of HBV-infected patients with co-infections. In resource-limited Asian settings, testing for hepatitis B surface antigen may be considered as the primary test for diagnosis of HBV infection. Pre-treatment assessments should include tests for complete blood count, liver and renal function, hepatitis B e-antigen (HBeAg), anti-HBe, HBV DNA, co-infection markers and assessment of severity of liver disease. Noninvasive tests such as AST-to-platelet ratio index, fibrosis score 4 or transient elastography may be used as alternatives to liver biopsy for assessing disease severity. Considering the high burden of HBV infection in Asia, the panel adopted an aggressive approach, and recommended initiation of antiviral therapy in all HBV-infected, compensated or decompensated cirrhotic individuals with detectable HBV DNA levels, regardless of HBeAg status or alanine transaminase levels. The panel also developed a simple algorithm for guiding the initiation of treatment in noncirrhotic, HBV-infected individuals. The recommendations proposed herein, may help guide clinicians, to optimize the diagnosis and improvise the treatment rates for HBV infection in Asia.

Increasing Utilization and Excellent Initial Outcomes Following Liver Transplant of Hepatitis C Virus (HCV)-Viremic Donors Into HCV-Negative Recipients: Outcomes Following Liver Transplant of HCV-Viremic Donors.

Direct-acting antiviral (DAA) therapy has altered the frequency and outcome of liver transplantation (LT) for hepatitis C virus (HCV). The high efficacy and tolerability of DAA therapy has also created a rationale for utilizing HCV-viremic (HCV-RNA-positive) donors, including into HCV-negative recipients. We examined trends in frequency of organ utilization and graft survival in recipients of HCV-viremic donors (HCV-RNA positive as measured by nucleic acid testing [NAT]). Data were collected from the Scientific Registry of Transplant Recipients (SRTR) on adult patients who underwent a primary, single-organ, deceased donor LT from January 1, 2008 to January 31, 2018. Outcomes of HCV-negative transplant recipients (R- ) who received an allograft from donors who were HCV-RNA positive (DNAT+ ) were compared to outcomes for R- patients who received organs from donors who were HCV-RNA negative (DNAT- ). There were 11,270 DNAT- /R- ; 4,748 DNAT- /R+ ; 87 DNAT+ /R- ; and 753 DNAT+ /R+ patients, with 2-year graft survival similar across all groups: DNAT- /R- 88%; DNAT- /R+ 88%; DNAT+ /R- 86%; and DNAT+ /R+ 90%. Additionally, there were 2,635 LTs using HCV antibody-positive donors (DAb+ ): 2,378 DAb+ /R+ and 257 DAb+ /R- . The annual number of DAb+ /R- transplants increased from seven in 2008 to 107 in 2017. In the post-DAA era, graft survival improved for all recipients, with 3-year survival of DAb+ /R- patients and DAb+ /R+ patients increasing to 88% from 79% and to 85% from 78%, respectively. Conclusion: The post-DAA era has seen increased utilization of HCV-viremic donor livers, including HCV-viremic livers into HCV-negative recipients. Early graft outcomes are similar to those of HCV-negative recipients. These results support utilization of HCV-viremic organs in selected recipients both with and without HCV infection.

Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase II trial of selonsertib.

BACKGROUND & AIMS: Non-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH. METHODS: We analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS). RESULTS: Among 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value. CONCLUSIONS: These preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH. LAY SUMMARY: Liver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.

Baseline Factors Associated With Improvements in Decompensated Cirrhosis After Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection.

BACKGROUND & AIMS: Treatment with direct-acting antiviral (DAA) agents can reduce Model for End-Stage Liver Disease and Child-Pugh-Turcotte (CPT) scores in patients with decompensated cirrhosis caused by hepatitis C virus. However, many of these patients still die or require liver transplantation. We collected data on baseline features of patients and aimed to develop a scoring system to predict response to DAA therapy. METHODS: We performed a retrospective analysis of data from 4 trials on the effects of sofosbuvir-based therapy in patients with hepatitis C virus-associated decompensated cirrhosis (502 of CPT class B and 120 of CPT class C). In these trials, patients were given 12 or 24 weeks of treatment with ledipasvir, sofosbuvir, and ribavirin or velpatasvir, sofosbuvir, and/or ribavirin, or 48 weeks of treatment with sofosbuvir and ribavirin. We collected demographic, clinical, treatment response, and laboratory data from patients and tested their associations with patient outcomes at 36 weeks. The primary outcome was factors associated with reduction of CPT score to class A. RESULTS: The presence of ascites or encephalopathy, serum level of albumin <3.5 g/dL or alanine aminotransferase <60 U/L, and body mass index >25 kg/m2 were associated with an increased risk of not achieving a reduction in CPT to class A, independent of sustained viral response to therapy. Serum level of albumin <2.8 g/dL and abnormal level of bilirubin were associated with an increased risk of liver transplantation or death. We developed a scoring system based on 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated significantly with patient outcomes, which we called the "BE3A score." For patients with scores of 4-5, the hazard ratio for reduction of CPT score to class A was 52.3 (95% confidence interval, 15.2-179.7). CONCLUSIONS: We identified 5 baseline factors (body mass index, encephalopathy, ascites, and serum levels of alanine aminotransferase and albumin) associated with a reduction of CPT score to class A in patients with hepatitis C virus-associated decompensated cirrhosis receiving DAA therapy. We developed a predictive score using these factors, called the BE3A score, which can be used as a shared decision-making tool, quantifying the potential benefits of DAA therapy for patients with decompensated cirrhosis.