Current Burden of and Geographic Disparities in Liver Mortality and Access to Liver Transplant.

Importance: Liver disease is a leading cause of mortality in the US. Liver transplant can be a lifesaving procedure for patients with severe liver disease. Objective: To assess temporal trends and geographic variance in liver-related mortality (LRM) and liver transplant in the US. Design, Setting, and Participants: In this cohort study, the frequencies and geographic variance of LRM in 2018 and 2021 were obtained in a cross-sectional analysis of the Underlying Cause of Death data available on the Centers for Disease Control and Prevention's Epidemiologic Research database. The number of livers donated and transplanted according to the state of residence of each donor and recipient were obtained from the United Network for Organ Sharing. Main Outcomes and Measures: Liver-related mortality in 2018 and 2021, overall and by state, as well as the liver transplant rate according to state of residence of recipient and donor. Results: Overall LRM in the US was 93 418 in 2021, with a crude rate of 28.1 per 100 000 individuals, an increase of 19.1% compared with rates seen immediately prior to the COVID-19 pandemic in 2018 (77 282 [23.6 per 100 000 individuals]). Liver-related mortality in 2021 varied several-fold between states, from 18.4 per 100 000 individuals per year in Utah to 65.9 per 100 000 individuals per year in New Mexico. The mean number of liver-related deaths per transplant from all donor sources (in state and out of state) was 7.2 in the lowest LRM quintile compared with 21.5 in the highest (95% CI, 12.1-16.6; SE, 1.1; P < .001). Ten states had no liver transplant center. Paradoxically, residents of states with the highest LRM had a much lower rate of liver transplant (at any location) from organs procured from in-state residents than states with the lowest LRM quintile (13.0% vs 35.2% in-state donors; 95% CI, 14.1%-30.3%; SE, 3.9%; P < .001). Conclusions and Relevance: This study suggests that rates of LRM have increased dramatically since the COVID-19 pandemic and vary several-fold between states. Rates of liver transplant are paradoxically lowest among residents living in states with the highest LRM. These findings highlight apparent geographic disparities in access to liver transplant that allocation policy cannot address.

Evaluating the burden of illness of metabolic dysfunction-associated steatohepatitis in a large managed care population: The ETHEREAL Study.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH; formerly nonalcoholic steatohepatitis) is the inflammatory form of metabolic dysfunction-associated steatotic liver disease (formerly nonalcoholic fatty liver disease). MASH is a progressive disease associated with increased risk for many hepatic and extra-hepatic complications such as cirrhosis, hepatocellular carcinoma, the requirement for liver transplantation, and cardiovascular (CV)-related and kidney-related complications. It is important to understand the clinical and economic burden of MASH. OBJECTIVES: To assess and compare the clinical and economic burdens of MASH in adults with the non-MASH population in a real-world setting. METHODS: This observational, retrospective study used the Healthcare Integrated Research Database (HIRD), which contains health care claims data for commercially insured and Medicare Advantage health plan members across the United States. All-cause, CV-related, and liver-related medical costs and health care resource utilization were evaluated in patients with at least 2 diagnoses of MASH during the patient identification period (October 1, 2016, to April 30, 2022) and compared with a non-MASH cohort 1:1 matched on age, Quan Charlson Comorbidity Index, region of residence, and health plan type and length of enrollment. Generalized linear regression with negative binomial and γ distribution models were used to compare health care resource utilization and medical costs, respectively, while controlling for confounders. Covariate-adjusted all-cause, CV-related, and liver-related hospitalization rate ratios and medical cost ratios were assessed and compared for the MASH and matched non-MASH cohorts. RESULTS: A total of 18,549 patients with MASH were compared with 18,549 matched patients in the non-MASH cohort. After adjusting for covariates, MASH was associated with significantly higher rates of hospitalization and higher medical costs compared with the non-MASH cohort. When compared with the non-MASH cohort, patients with MASH had 1.22 (95% CI = 1.15-1.30; P < 0.0001) times higher rates of all-cause hospitalization, 1.13 (95% CI = 1.03-1.24; P = 0.008) times higher rates of CV-related hospitalization, and 7.22 (95% CI = 4.91-10.61; P < 0.0001) times higher rates of liver-related hospitalization. Similarly, all-cause medical costs were 1.26 (95% CI = 1.22-1.30; P < 0.0001) times higher, CV-related medical costs were 1.66 (95% CI = 1.59-1.73; P < 0.0001) times higher, and liver-related medical costs were 7.79 (95% CI = 7.42-8.17; P < 0.0001) times higher among patients with MASH. CONCLUSIONS: Compared with those of the non-MASH cohort with similar age, Quan Charlson Comorbidity Index, health plan, region of residence, and duration of enrollment, patients with MASH had significantly higher all-cause, CV-related, and liver-related hospitalizations and medical costs.

Estimation of the Eligible Population For Resmetirom Among Adults in the United States for Treatment of Non-Cirrhotic NASH with Moderate-to-Advanced Liver Fibrosis.

INTRODUCTION: As of March 2024, resmetirom is the first and only therapy approved in the United States (US) for the treatment of adults with non-cirrhotic nonalcoholic steatohepatitis (NASH) with moderate-to-advanced liver fibrosis (MALF) consistent with stages F2/F3 fibrosis. Estimates of the diagnosed, treatment-eligible NASH population are poorly understood due to diagnostic variability. This study provides a contemporary estimate of the size of the US resmetirom treatment-eligible population. METHODS: A dynamic population calculator was developed combining literature, screening guidelines, resmetirom study criteria, and analyses of the NHANES 2017-March 2020 cycle. It computes NASH prevalence, proportion non-cirrhotic NASH with MALF, Year 1 diagnosis, and new diagnoses in Years 2 and 3. NASH prevalence was estimated by applying the American Association of Clinical Endocrinology screening algorithm and recommended NIT cut-offs in the NHANES dataset. The proportion of non-cirrhotic NASH with MALF was informed by analyses of the Forian US integrated medical claims database using NASH and cirrhosis-specific ICD-10-CM codes and FIB-4 scores. NASH diagnosis rates were obtained from published estimates and NHANES responses. Treatment-eligible population growth was projected using published incidence data. Estimates were compared to a NASH budget-impact-analysis (BIA) from the Institute for Clinical and Economic Review (ICER). RESULTS: In the base case, a NASH prevalence of 4.6% was modeled (range 1.3-14.2%). This value was multiplied by the proportion estimated to have non-cirrhotic MALF (i.e., 35%). Published analyses suggest a diagnosis rate of ~ 10% (range 3.3-14.3%) and ~ 16% year-over-year growth in the treatment-eligible population. Assuming a 1-million commercial-member population, the resmetirom treatment-eligible population was estimated as 1255-1699 in Years 1-3 following approval. Sensitivity analyses were conducted and comparison to the ICER BIA was influenced by different diagnosis rates. CONCLUSION: Estimation of the treatment-eligible population for resmetirom depends importantly on NASH diagnosis rates, which are predicted to be < 15% in the 3 years after drug approval. Nonalcoholic steatohepatitis (NASH) is an advanced form of nonalcoholic fatty liver disease. Previously there were no treatments for NASH in the United States (US), but as of March 2024, the US Food and Drug Administration (FDA) approved resmetirom (REZDIFFRA™), a once-daily, oral therapy, in conjunction with diet and exercise, under accelerated approval for the treatment of adults (aged 18 years or older) with non-cirrhotic NASH with moderate-to-advanced liver fibrosis (MALF), consistent with stages F2-F3. It is not well understood how many diagnosed patients with NASH would be eligible for treatment with resmetirom; thus, this study aimed to estimate the size of the US resmetirom treatment-eligible population. To do so, we created a flexible population calculator that considers how many people have NASH, what proportion would be eligible for resmetirom treatment-i.e., have non-cirrhotic NASH with MALF-and of those how many people would be diagnosed. We used published literature, screening guidelines, resmetirom study criteria, and analyses of national surveys to inform our range of estimates. In the main analysis, we modeled a NASH prevalence of 4.6% (range 1.3-14.2%), which was then limited to the proportion estimated to have non-cirrhotic NASH with MALF (i.e., 35%) and diagnosed (i.e., 10%, range 3.3-14.3%). A year-over-year growth of approximately 16% in the treatment-eligible population was modeled in years following approval. Assuming a population of 1 million commercial insurance enrollees, the resmetirom treatment-eligible population was estimated to be 1255-1699 in Years 1-3 following approval. We assessed alternative scenarios and have compared our results to existing models.

Facility design and management. Strategies for high level biocontainment.

UK Health Security Agency is required to investigate the pathogenesis of emerging or re-emerging infections and to test novel interventions, such as vaccines and therapeutics against these and other diseases, such as tuberculosis and Ebola, that have a significant impact on human health world-wide. Research into the causative agents (mainly BSL 3 and 4) using a wide range of animal species as pre-clinical models brings a number of challenges in terms of effective biocontainment to address human safety whilst optimising delivery of scientific objectives and the welfare of the animals. Here we describe the strategies used for high containment of species that include mice, ferrets, hamsters, rabbits and macaques that have been infected with high consequence pathogens. To ensure relevance of these models we frequently challenge by the aerosol route and monitor the development of disease and protective or therapeutic efficacy by methodologies similar to those used in the clinic. We have devised methods of sampling that can inform on pathogenesis and immune function that include lung lavage and medical imaging such as computed tomography and positron emission tomography-computed tomography. Imaging assists our assessment of progression to disease whilst providing refinement in application of early humane endpoints. We have developed directional flow containment systems that provide quantifiable operator protection whilst allowing group housing and a wide range of enrichment strategies appropriate for each species. Furthermore, we have demonstrated our improvements in animal welfare through use of a software-based Animal Welfare Assessment Grid that was developed with help of NC3Rs funding and enables us to quantify the lifetime experience of animals.

The clinical and economic burdens of metabolic dysfunction-associated steatohepatitis.

AIMS: This study aimed to assess and compare the health care resource utilization (HCRU) and medical cost of metabolic dysfunction-associated steatohepatitis (MASH) by disease severity based on Fibrosis-4 Index (FIB-4) score among US adults in a real-world setting. MATERIALS AND METHODS: This observational cohort study used claims data from the Healthcare Integrated Research Database (HIRD) to compare all-cause, cardiovascular (CV)-related, and liver-related HCRU, including hospitalization, and medical costs stratified by FIB-4 score among patients with MASH (identified by International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] code K75.81). Hospitalization and medical costs were compared by FIB-4 score using generalized linear regression with negative binomial and gamma distribution models, respectively, while controlling for confounders. RESULTS: The cohort included a total of 5,104 patients with MASH and comprised 3,162, 1,343, and 599 patients with low, indeterminate, and high FIB-4 scores, respectively. All-cause hospitalization was significantly higher in the high FIB-4 cohort when compared with the low FIB-4 reference after covariate adjustment (rate ratio, 1.63; 95% CI, 1.32-2.02; p < .0001). CV-related hospitalization was similar across all cohorts; however, CV-related costs were 1.26 times higher (95% CI, 1.11-1.45; p < .001) in the indeterminate cohort and 2.15 times higher (95% CI, 1.77-2.62; p < .0001) in the high FIB-4 cohort when compared with the low FIB-4 cohort. Patients with indeterminate and high FIB-4 scores had 2.97 (95% CI, 1.78-4.95) and 12.08 (95% CI, 7.35-19.88) times the rate of liver-related hospitalization and were 3.68 (95% CI, 3.11-4.34) and 33.73 (95% CI, 27.39-41.55) times more likely to incur liver-related costs, respectively (p < .0001 for all). LIMITATIONS: This claims-based analysis relied on diagnostic coding accuracy, which may not capture the presence of all diseases or all care received. CONCLUSIONS: High and indeterminate FIB-4 scores were associated with significantly higher liver-related clinical and economic burdens than low FIB-4 scores among patients with MASH.

MASH is a serious liver disease that can lead to fibrosis, cirrhosis, and other complications. There is a need to understand the impact of disease severity on the burden of MASH. Health care claims data were used to assess the use of medical resources, including hospitalization, and medical costs among patients with 3 different levels of severity of MASH, as assessed via FIB-4 score. FIB-4 is a widely available non-invasive marker of severity. Rates of all-cause, cardiovascular-related and liver-related hospitalization and medical costs were several-fold higher in patients with high disease severity of MASH than those with low disease severity of MASH.

Expert Panel Recommendations: Practical Clinical Applications for Initiating and Monitoring Resmetirom in Patients with MASH/NASH and Moderate to Noncirrhotic Advanced Fibrosis.

Metabolic dysfunction-associated steatotic liver disease affects 1 in 4 people in the United States and western Europe, with an important proportion developing metabolic dysfunction-associated steatohepatitis (MASH), the progressive subtype of metabolic dysfunction-associated steatotic liver disease. Cirrhosis caused by MASH is a leading indication for liver transplantation and the most common cause of hepatocellular carcinoma. Hitherto, there have been no specific pharmacotherapies for MASH. The recent conditional approval by the Food and Drug Administration of resmetirom for the treatment of moderate or advanced MASH presents a much-anticipated therapeutic option for patients with noncirrhotic advanced MASH. Specifically, the intended population for resmetirom are patients with MASH and fibrosis stages 2 or 3. The approval of resmetirom also presents important challenges, including how to noninvasively identify patients with fibrosis stages 2-3, and how to exclude patients with more advanced disease who should not be treated until further data emerge on the use of resmetirom in this population. Herein we consider the available literature with regard to identifying the intended population for treatment with resmetirom and in proposing criteria for stopping treatment.

Envisioning how to advance the MASH field.

Since 1980, the cumulative effort of scientists and health-care stakeholders has advanced the prerequisites to address metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent chronic non-communicable liver disease. This effort has led to, among others, the approval of the first drug specific for metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis). Despite substantial progress, MASLD is still a leading cause of advanced chronic liver disease, including primary liver cancer. This Perspective contextualizes the nomenclature change from nonalcoholic fatty liver disease to MASLD and proposes important considerations to accelerate further progress in the field, optimize patient-centric multidisciplinary care pathways, advance pharmacological, behavioural and diagnostic research, and address health disparities. Key regulatory and other steps necessary to optimize the approval and access to upcoming additional pharmacological therapeutic agents for MASH are also outlined. We conclude by calling for increased education and awareness, enhanced health system preparedness, and concerted action by policy-makers to further the public health and policy agenda to achieve at least parity with other non-communicable diseases and to aid in growing the community of practice to reduce the human and economic burden and end the public health threat of MASLD and MASH by 2030.

Cost burden of cirrhosis and liver disease progression in metabolic dysfunction-associated steatohepatitis: A US cohort study.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH), formerly nonalcoholic steatohepatitis, is characterized by fat accumulation and inflammation of the liver and may result in progression to cirrhosis and liver-related events. OBJECTIVE: To characterize the impact of cirrhosis and progression to liver-related events on costs and health care resource use (HCRU) among MASH patients in the United States. METHODS: The study cohort included patients with diagnosed nonalcoholic steatohepatitis (International Classification of Diseases, Tenth Revision, Clinical Modification code K75.81) in Optum's deidentified Clinformatics Data Mart Database (October 2015 to December 2022) and were stratified by baseline cirrhosis status. Among those without cirrhosis at baseline, patients were further stratified by status of progression to cirrhosis during follow-up. Total HCRU and costs per-person per-year (PPPY) were estimated and compared descriptively between the cohorts. In addition, gamma generalized linear models were used to compare costs PPPY between those with vs without cirrhosis at baseline, as well as with vs without progression during follow-up, while adjusting for baseline patient and disease characteristics. Annual costs per person were also longitudinally modeled using gamma generalized linear mixed models to understand longitudinal changes in costs PPPY while accounting for time correlations within individual patients. Lastly, a series of sensitivity analyses were conducted to assess the impact of study design features and clinical variations of total costs PPPY. RESULTS: A total of 28,576 adults were included, and 9,157 (32.0%) had baseline cirrhosis; of the 19,419 without baseline cirrhosis, a total of 4,235 (21.8%) progressed over follow-up. Mean (SD) HCRU and costs PPPY were higher among patients with cirrhosis ($110,403 [$226,037]) than without ($28,340 [$61,472]; P < 0.01) and among those with progression ($58,128 [$102,626]) than without ($20,031 [$39,740]; P < 0.01). Costs remained significantly greater when adjusted for covariates, with a risk ratio (95% CI) of 1.99 (1.89-2.09) when comparing with vs without baseline cirrhosis and 2.28 (2.15-2.42) when comparing with vs without progression over follow-up. Costs increased with each subsequent year, to 21% by year 6 among those with cirrhosis at baseline and 49% among those without baseline cirrhosis who progressed. CONCLUSIONS: The financial burden of MASH is substantial and significantly greater among those with cirrhosis or disease progression. Although patients without cirrhosis incur lower burden, the increase over time is greater and associated with progression. Therapies that slow progression may help alleviate the financial burden, and strategies are needed to identify patients with MASH at risk of progressing to cirrhosis.

Guideline-based management of metabolic dysfunction-associated steatotic liver disease in the primary care setting.

BACKGROUND: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. Primary care providers play a critical role in the screening, diagnosis, and management of MASLD and/or metabolic dysfunction-associated steatohepatitis (MASH), though they can face challenges in this setting, particularly where healthcare resources are limited and barriers to care exist. To address these challenges, several guidelines have been developed to provide evidence-based recommendations for the clinical assessment and management of patients with MASLD/MASH. AIMS: To provide a unified, simple-to-understand, practical guide for MASLD screening, diagnosis, and management based on current guideline recommendations, for use by primary care providers in daily practice. METHODS: Evidence-based recommendations from several international guidelines were summarized, focusing on the similarities and differences between them. RESULTS: Recommendations are broadly aligned across the guidelines, but several key differences are evident. Practical guidance is provided on screening, identifying target populations for risk stratification, initial evaluation of individuals with suspected MASLD, surveillance, risk stratification and referral, as well as approaches to the management of MASLD and associated comorbidities, with specific considerations for the primary care setting. CONCLUSIONS: Primary care providers are ideally placed to identify at-risk individuals, implement evidence-based interventions to prevent the development of fibrosis and cirrhosis, and effectively manage comorbidities. Equipping primary care providers with the necessary knowledge and tools to effectively manage MASLD/MASH may help to improve patient outcomes and reduce the burden of liver disease.

Prevalence of Nonalcoholic Steatohepatitis and Associated Fibrosis Stages Among US Adults Using Imaging-Based vs Biomarker-Based Noninvasive Tests.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is believed to be the most common chronic liver disease worldwide. Therapies are under development for nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, such that the prevalence of NASH with liver fibrosis, which is likely to require treatment, may be of interest to healthcare decision makers. Noninvasive tests are used in initial screening for NASH, as well as in observational studies of NASH prevalence. However, existing evidence does not address how estimated prevalence varies with different noninvasive tests. This analysis estimated the prevalence of NASH among US adults and assessed variation with different noninvasive tests. Methods: A cross-sectional analysis was conducted using the 2017-March 2020 National Health and Nutrition Examination Survey cycle. Participants with presumed NAFLD (steatosis and without alternative causes of liver disease) were identified, among whom NASH was predicted based on FAST score, Fibrosis-4 (FIB-4), and AST-to-Platelet Ratio Index (APRI) cutoffs across 11 scenarios. Among NASH participants, fibrosis stages were explored based on distribution across the spectrum of liver-stiffness measurements. Results: Among participants with complete data for the analysis (N=6969), prevalence of presumed NAFLD was 25.6%. Within presumed NAFLD, prediction of NASH using imaging-based NIT cutoffs yielded estimated prevalence of 1.3%-4.8% (3.3 million-12.2 million) based on FAST score cutoffs from 0.35-0.67. Using biomarker-based NIT cutoffs yielded estimated prevalence of 0.4%-12.3% (1.0 million-14.5 million) based on FIB-4 cutoffs from 0.90-2.67, and 0.1%-1.9% (0.2-5.0 million) based on APRI cutoffs from 0.50-1.50. Conclusion: Prevalence of NASH among US adults was estimated to range from 1.3% to 4.8% when predicted using imaging-based noninvasive test values for participants with presumed NAFLD, generally aligning with estimates in the literature of prevalence of biopsy-confirmed NASH. Use of biomarker-based noninvasive test values for prediction of NASH yielded a wider range of estimates with FIB-4, and a considerably lower range of estimates with APRI.

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.).

Macrophage RAGE activation is proinflammatory in NASH.

Intrahepatic macrophages in nonalcoholic steatohepatitis (NASH) are heterogenous and include proinflammatory recruited monocyte-derived macrophages. The receptor for advanced glycation endproducts (RAGE) is expressed on macrophages and can be activated by damage associated molecular patterns (DAMPs) upregulated in NASH, yet the role of macrophage-specific RAGE signaling in NASH is unclear. Therefore, we hypothesized that RAGE-expressing macrophages are proinflammatory and mediate liver inflammation in NASH. Compared with healthy controls, RAGE expression was increased in liver biopsies from patients with NASH. In a high-fat, -fructose, and -cholesterol-induced (FFC)-induced murine model of NASH, RAGE expression was increased, specifically on recruited macrophages. FFC mice that received a pharmacological inhibitor of RAGE (TTP488), and myeloid-specific RAGE KO mice (RAGE-MKO) had attenuated liver injury associated with a reduced accumulation of RAGE+ recruited macrophages. Transcriptomics analysis suggested that pathways of macrophage and T cell activation were upregulated by FFC diet, inhibited by TTP488 treatment, and reduced in RAGE-MKO mice. Correspondingly, the secretome of ligand-stimulated BM-derived macrophages from RAGE-MKO mice had an attenuated capacity to activate CD8+ T cells. Our data implicate RAGE as what we propose to be a novel and potentially targetable mediator of the proinflammatory signaling of recruited macrophages in NASH.

Bifidobacteria metabolize lactulose to optimize gut metabolites and prevent systemic infection in patients with liver disease.

Progression of chronic liver disease is precipitated by hepatocyte loss, inflammation and fibrosis. This process results in the loss of critical hepatic functions, increasing morbidity and the risk of infection. Medical interventions that treat complications of hepatic failure, including antibiotic administration for systemic infections and lactulose treatment for hepatic encephalopathy, can impact gut microbiome composition and metabolite production. Here, using shotgun metagenomic sequencing and targeted metabolomic analyses on 847 faecal samples from 262 patients with acute or chronic liver disease, we demonstrate that patients hospitalized for liver disease have reduced microbiome diversity and a paucity of bioactive metabolites, including short-chain fatty acids and bile acid derivatives, that impact immune defences and epithelial barrier integrity. We find that patients treated with the orally administered but non-absorbable disaccharide lactulose have increased densities of intestinal bifidobacteria and reduced incidence of systemic infections and mortality. Bifidobacteria metabolize lactulose, produce high concentrations of acetate and acidify the gut lumen in humans and mice, which, in combination, can reduce the growth of antibiotic-resistant bacteria such as vancomycin-resistant Enterococcus faecium in vitro. Our studies suggest that lactulose and bifidobacteria serve as a synbiotic to reduce rates of infection in patients with severe liver disease.

Efficacy and Safety of Sofosbuvir/Velpatasvir Plus Ribavirin in Patients with Hepatitis C Virus-Related Decompensated Cirrhosis.

A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child-Turcotte-Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3-4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated.

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.

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.

The Omicron Sub-Variant BA.4 Displays a Remarkable Lack of Clinical Signs in a Golden Syrian Hamster Model of SARS-CoV-2 Infection.

The ongoing emergence of SARS-CoV-2 virus variants remains a source of concern because it is accompanied by the potential for increased virulence as well as evasion of immunity. Here we show that, although having an almost identical spike gene sequence as another Omicron variant (BA.5.2.1), a BA.4 isolate lacked all the typical disease characteristics of other isolates seen in the Golden Syrian hamster model despite replicating almost as effectively. Animals infected with BA.4 had similar viral shedding profiles to those seen with BA.5.2.1 (up to day 6 post-infection), but they all failed to lose weight or present with any other significant clinical signs. We hypothesize that this lack of detectable signs of disease during infection with BA.4 was due to a small (nine nucleotide) deletion (∆686-694) in the viral genome (ORF1ab) responsible for the production of non-structural protein 1, which resulted in the loss of three amino acids (aa 141-143).

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.

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.

SARS-CoV-2 Disease Severity in the Golden Syrian Hamster Model of Infection Is Related to the Volume of Intranasal Inoculum.

The golden Syrian hamster (Mesocricetus auratus) is now commonly used in preclinical research for the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the assessment of vaccines, drugs and therapeutics. Here, we show that hamsters inoculated via the intranasal route with the same infectious virus dose of prototypical SARS-CoV-2 administered in a different volume present with different clinical signs, weight loss and viral shedding, with a reduced volume resulting in reduced severity of disease similar to that obtained by a 500-fold reduction in the challenge dose. The tissue burden of the virus and the severity of pulmonary pathology were also significantly affected by different challenge inoculum volumes. These findings suggest that a direct comparison between the severity of SARS-CoV-2 variants or studies assessing the efficacy of treatments determined by hamster studies cannot be made unless both the challenge dose and inoculation volume are matched when using the intranasal route. Additionally, analysis of sub-genomic and total genomic RNA PCR data demonstrated no link between sub-genomic and live viral titres and that sub-genomic analyses do not provide any information beyond that provided by more sensitive total genomic PCR.