Citations

Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction–associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction–associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.

Background and Aims: Transforming growth factor-beta 1 (TGFβ1) induces HSC activation into metastasis-promoting cancer-associated fibroblasts (CAFs), but how the process is fueled remains incompletely understood. We studied metabolic reprogramming induced by TGFβ1 in HSCs. Approaches and Results: Activation of cultured primary human HSCs was assessed by the expression of myofibroblast markers. Glucose transporter 1 (Glut1) of murine HSC was disrupted by Cre recombinase/LoxP sequence derived from bacteriophage P1 recombination (Cre/LoxP). Plasma membrane (PM) Glut1 and glycolysis were studied by biotinylation assay and the Angilent Seahorse XFe96 Analyzer. S.c. HSC/tumor co-implantation and portal vein injection of MC38 colorectal cancer cells into HSC-specific Glut1 knockout mice were performed to determine in vivo relevance. Transcriptome was obtained by RNA sequencing of HSCs and spatialomics with MC38 liver metastases. TGFβ1-induced CAF activation of HSCs was accompanied by elevation of PM Glut1, glucose uptake, and glycolysis. Targeting Glut1 or Src by short hairpin RNA, pharmacologic inhibition, or a Src SH3 domain deletion mutant abrogated TGFβ1-stimulated PM accumulation of Glut1, glycolysis, and CAF activation. Mechanistically, binding of the Src SH3 domain to SH3 domain–binding protein 5 led to a Src/SH3 domain–binding protein 5/Rab11/Glut1 complex that activated Rab11-dependent Glut1 PM transport under TGFβ1 stimulation. Deleting the Src SH3 domain or targeting Glut1 of HSCs by short hairpin RNA or Cre recombinase/LoxP sequence derived from bacteriophage P1 recombination suppressed CAF activation in mice and MC38 colorectal liver metastasis. Multi-omics revealed that Glut1 deficiency in HSCs/CAFs suppressed HSC expression of tumor-promoting factors and altered MC38 transcriptome, contributing to reduced MC38 liver metastases. Conclusion: The Src SH3 domain–facilitated metabolic reprogramming induced by TGFβ1 represents a target to inhibit CAF activation and the pro-metastatic liver microenvironment.

INTRODUCTION: Management of hepatic encephalopathy relies on self-titration of lactulose. In this feasibility trial, we assess an artificial intelligence–enabled tool to guide lactulose use through a smartphone application. METHODS: Subjects with hepatic encephalopathy on lactulose captured bowel movement pictures during lead-in and intervention phases. During the intervention phase, daily feedback on lactulose titration was delivered through the application. Goals were determined according to number of bowel movement and Bristol Stool Scale reports. RESULTS: Subjects completed the study with more than 80% satisfaction. In the lead-in phase, less compliant subjects achieved Bristol Stool Scale goal on 62/111 (56%) of days compared with 107/136 (79%) in the intervention phase ( P = 0.041), while the most compliant subjects showed no difference. Severe/recurrent hepatic encephalopathy group achieved Bristol Stool Scale goal on 80/104 (77%) days in the lead-in phase and 90/110 (82%) days in the intervention phase ( P = NS), compared with 89/143 (62%) days and 86/127 (68%) days in the stable group. DISCUSSION: Dieta application is a promising tool for objective Bowel Movement/Bristol Stool Scale tracking for hepatic encephalopathy and may potentially be used to assist with lactulose titration.

ABSTRACT Alcohol-associated liver disease (ALD) is the most common cause of advanced hepatic disease and frequent indication for liver transplantation worldwide. With harmful alcohol use as the primary risk factor, increasing alcohol use over the past decade has resulted in rapid growth of the ALD-related healthcare burden. The spectrum of ALD ranges from early asymptomatic liver injury to advanced disease with decompensation and portal hypertension. Compared with those with other etiologies of liver disease, patients with ALD progress faster and more often present at an advanced stage. A unique phenotype of advanced disease is alcohol-associated hepatitis (AH) presenting with rapid onset or worsening of jaundice, and acute on chronic liver failure in severe forms conveying a 1-month mortality risk of 20%–50%. The model for end stage disease score is the most accurate score to stratify AH severity (>20 defined as severe disease). Corticosteroids are currently the only available therapeutic with proven efficacy for patients with severe AH, providing survival benefit at 1 month in 50%–60% of patients. Abstinence of alcohol use, a crucial determinant of long-term outcomes, is challenging to achieve in ALD patients with concurrent alcohol use disorder (AUD). As patients with ALD are rarely treated for AUD, strategies are needed to overcome barriers to AUD treatment in patients with ALD and to promote a multidisciplinary integrated care model with hepatology, addiction medicine providers, and social workers to comprehensively manage the dual pathologies of liver disease and of AUD. Liver transplantation, a definitive treatment option in patients with advanced cirrhosis, should be considered in selected patients with AH, who are unresponsive to medical therapy and have a low risk of relapse to posttransplant alcohol use. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the American College of Gastroenterology Practice Parameters Committee.

Background: Sensors within smartphones, such as accelerometer and location, can describe longitudinal markers of behavior as represented through devices in a method called digital phenotyping. This study aimed to assess the feasibility of digital phenotyping for patients with alcohol-associated liver disease and alcohol use disorder, determine correlations between smartphone data and alcohol craving, and establish power assessment for future studies to prognosticate clinical outcomes. Methods: A total of 24 individuals with alcohol-associated liver disease and alcohol use disorder were instructed to download the AWARE application to collect continuous sensor data and complete daily ecological momentary assessments on alcohol craving and mood for up to 30 days. Data from sensor streams were processed into features like accelerometer magnitude, number of calls, and location entropy, which were used for statistical analysis. We used repeated measures correlation for longitudinal data to evaluate associations between sensors and ecological momentary assessments and standard Pearson correlation to evaluate within-individual relationships between sensors and craving. Results: Alcohol craving significantly correlated with mood obtained from ecological momentary assessments. Across all sensors, features associated with craving were also significantly correlated with all moods (eg, loneliness and stress) except boredom. Individual-level analysis revealed significant relationships between craving and features of location entropy and average accelerometer magnitude. Conclusions: Smartphone sensors may serve as markers for alcohol craving and mood in alcohol-associated liver disease and alcohol use disorder. Findings suggest that location-based and accelerometer-based features may be associated with alcohol craving. However, data missingness and low participant retention remain challenges. Future studies are needed for further digital phenotyping of relapse risk and progression of liver disease.

Liver sinusoidal endothelial cells (LSECs) are key players in maintaining hepatic homeostasis. They also play crucial roles during liver injury by communicating with liver cell types as well as immune cells and promoting portal hypertension, fibrosis, and inflammation. Cutting-edge technology, such as single cell and spatial transcriptomics, have revealed the existence of distinct LSEC subpopulations with a clear zonation in the liver. The signals released by LSECs are commonly called “angiocrine signaling.” In this review, we summarize the role of angiocrine signaling in health and disease, including zonation in healthy liver, regeneration, fibrosis, portal hypertension, nonalcoholic fatty liver disease, alcohol-associated liver disease, aging, drug-induced liver injury, and ischemia/reperfusion, as well as potential therapeutic advances. In conclusion, sinusoidal endotheliopathy is recognized in liver disease and promising preclinical studies are paving the path toward LSEC-specific pharmacotherapies.

Background: Alcohol-associated hepatitis (AH) is among the deadliest liver diseases, but its incidence is poorly defined. The aim of our study was to define the incidence of AH meeting the National Institute on Alcohol Abuse and Alcoholism criteria and to identify risk factors for AH. Methods: We conducted a retrospective cohort study using the Rochester epidemiology project database on adult patients hospitalized with AH between January 1, 2000 and December 31, 2018. Patients were screened using ICD-9 codes and then included if they met the National Institute on Alcohol Abuse and Alcoholism criteria on manual chart review. Baseline demographics, comorbidities, access to care, liver-related complications, and outcomes were obtained. The HOUsing-based index of SocioEconomic status index was used to measure socioeconomic status. Incidence rates were calculated in cases per 100,000 person-years of follow-up. Results: Among 204 patients, the cumulative AH incidence was 6.8 per 100,000 person-years. Between 2000–2004 and 2015–2018, AH incidence among males increased from 8.4 to 14.7 per 100,000 py, whereas AH incidence among females increased by 7-fold from 0.8 to 5.9 per 100,000 py. Such increases among females were accompanied by increases in comorbid depression and anxiety. The proportion of patients with AH in the lower socioeconomic status quartiles increased from 62.9% between 2000 and 2004 to 73.3% between 2015 and 2019. Conclusions: The incidence of AH is increasing rapidly, especially among females and individuals of lower socioeconomic status. There are areas of unmet need in preventative measures and treatments for comorbid psychiatric disorders in patients at high risk of AH.

Background and Aims: The presence of at-risk NASH is associated with an increased risk of cirrhosis and complications. Therefore, noninvasive identification of at-risk NASH with an accurate biomarker is a critical need for pharmacologic therapy. We aim to explore the performance of several magnetic resonance (MR)-based imaging parameters in diagnosing at-risk NASH. Approach and Results: This prospective clinical trial (NCT02565446) includes 104 paired MR examinations and liver biopsies performed in patients with suspected or diagnosed NAFLD. Magnetic resonance elastography-assessed liver stiffness (LS), 6-point Dixon-derived proton density fat fraction (PDFF), and single-point saturation-recovery acquisition-calculated T1 relaxation time were explored. Among all predictors, LS showed the significantly highest accuracy in diagnosing at-risk NASH [AUCLS: 0.89 (0.82, 0.95), AUCPDFF: 0.70 (0.58, 0.81), AUCT1: 0.72 (0.61, 0.82), z-score test z >1.96 for LS vs any of others]. The optimal cutoff value of LS to identify at-risk NASH patients was 3.3 kPa (sensitivity: 79%, specificity: 82%, negative predictive value: 91%), whereas the optimal cutoff value of T1 was 850 ms (sensitivity: 75%, specificity: 63%, and negative predictive value: 87%). PDFF had the highest performance in diagnosing NASH with any fibrosis stage [AUCPDFF: 0.82 (0.72, 0.91), AUCLS: 0.73 (0.63, 0.84), AUCT1: 0.72 (0.61, 0.83), |z| <1.96 for all]. Conclusion: Magnetic resonance elastography-assessed LS alone outperformed PDFF, and T1 in identifying patients with at-risk NASH for therapeutic trials.