BACKGROUND AND AIMS: Epigenetic plasticity is a major challenge in cancer-targeted therapy. However, the molecular basis governing this process has not yet been clearly defined. Despite the considerable success of PARP inhibitors (PARPi) in cancer therapy, the limited response to PARPi, especially in hepatocellular carcinoma (HCC), has been a bottleneck in its clinical implications. Herein, we investigated the molecular basis of the histone methyltransferase KMT5C that governs PARPi sensitivity and explored a potential therapeutic strategy for enhancing PARPi efficacy. APPROACH AND RESULTS: We identified KMT5C, a tri-methyltransferase of H4K20, as a targetable epigenetic factor that promoted liver tumor growth in mouse de novo MYC/Trp53-/- and xenograft liver tumor models. Notably, induction of KMT5C by environmental stress was crucial for DNA repair and HCC cell survival. Mechanistically, KMT5C interacted with the pivotal component of homologous recombination repair, RAD51, and promoted RAD51/RAD54 complex formation, which was essential for the activation of DSBs repair. This effect depended on the methyltransferase activity of KMT5C. We further demonstrated that the function of KMT5C in promoting HCC progression was dependent on RAD51. Importantly, either a pharmacological inhibitor (A196) or genetic inhibition of KMT5C sensitized liver cancer cells to PARPi. CONCLUSIONS: KMT5C played a vital role in promoting liver cancer progression by activating the DNA repair response. Our results revealed a novel therapeutic approach using the KMT5C inhibitor A196, concurrent with olaparib, as a potential HCC therapy.

Albumin is the most abundant protein in the human body and is synthetized exclusively by the liver. Therefore, serum albumin levels are reduced in acute and/or chronic liver disease. In cirrhosis, low levels of albumin predict the outcome. In advanced cirrhosis, the quality of albumin is decreased due to high oxidative stress and a proinflammatory state. Therefore, the administration of i.v. albumin would seem to be of pathophysiological relevance and benefit. Yet, the questions that remain are who, when, how much, and how often. While albumin infusion is recommended after large-volume paracentesis, at diagnosis of spontaneous bacterial peritonitis, in acute kidney injury, and in hepatorenal syndrome, the amount and schedule of albumin to be administered require refinement, particularly given complications related to volume overload that have become increasingly apparent. Other indications for albumin such as infections other than spontaneous bacterial peritonitis, hyponatremia, HE, prevention of poor outcomes in hospitalized, and in outpatients with cirrhosis are still debated. The results of studies in these settings are either negative, controversial, or inconclusive. This sheds some doubts regarding the use of albumin as a "one size fits all" strategy. The indication and patient selection are crucial and not always intuitive. The amount and frequency also seem to play a role in the success or failure of albumin. This review will critically discuss the evidence and underline areas where there are indications for albumin use and others where evidence is still insufficient and will have to await the development/results of randomized controlled trials.

BACKGROUND AIMS: Human genetic variation is thought to guide the outcome of hepatitis C virus (HCV) infection but model systems within which to dissect these host genetic mechanisms are limited. Norway rat hepacivirus (NrHV), closely related to HCV, causes chronic liver infection in rats but causes acute self-limiting hepatitis in typical strains of laboratory mice, which resolves in two weeks. The Collaborative Cross (CC) is a robust mouse genetics resource comprised of a panel of recombinant inbred strains, which model the complexity of the human genome and provide a system within which to understand diseases driven by complex allelic variation. APPROACH RESULTS: We infected a panel of CC strains with NrHV and identified several that failed to clear virus after 4 weeks. Strains displayed an array of virologic phenotypes ranging from delayed clearance (CC046) to chronicity (CC071, CC080) with viremia for at least 10 months. Body weight loss, hepatocyte infection frequency, viral evolution, T-cell recruitment to the liver, liver inflammation and the capacity to develop liver fibrosis varied among infected CC strains. CONCLUSIONS: These models recapitulate many aspects of HCV infection in humans and demonstrate that host genetic variation affects a multitude of virus and host phenotypes. These models can be used to better understand the molecular mechanisms that drive hepacivirus clearance and chronicity, the virus and host interactions that promote chronic disease manifestations like liver fibrosis, therapeutic and vaccine performance, and how these factors are affected by host genetic variation.

BACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for hepatocellular carcinoma (HCC). Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 HCC patients, in which 17 patients received anti-PD-1 therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly 60 publicly-available multi-omics datasets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mice models. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS: We identified three FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

BACKGROUND AIMS: HCC is an aggressive cancer with a poor clinical outcome. Understanding the mechanisms that drive tumor initiation is important for improving treatment strategy. This study aimed to identify functional cell membrane proteins that promote HCC T initiation. APPROACH RESULTS: Tailor-made siRNA library screening was performed for all membrane protein-encoding genes that are upregulated in human HCC (n = 134), with sphere formation as a surrogate readout for tumor initiation. Upon confirmation of membranous localization by immunofluorescence and tumor initiation ability by limiting dilution assay in vivo, LanC-like protein-1 (LANCL1) was selected for further characterization. LANCL1 suppressed intracellular reactive oxygen species (ROS) and promoted tumorigenicity both in vitro and in vivo. Mechanistically, with mass spectrometry, FAM49B was identified as a downstream binding partner of LANCL1. LANCL1 stabilized FAM49B by blocking the interaction of FAM49B with the specific E3 ubiquitin ligase TRIM21, thus protecting FAM49B from ubiquitin-proteasome degradation. The LANCL1-FAM49B axis suppressed the Rac1-NADPH oxidase-driven ROS production, but this suppression of ROS was independent of the glutathione transferase function of LANCL1. Clinically, HCCs with high co-expression of LANCL1 and FAM49B were associated with more advanced tumor stage, poorer overall survival, and disease-free survival. In addition, anti-LANCL1 antibodies targeting the extracellular N-terminal domain were able to suppress the self-renewal ability, as demonstrated by the sphere formation ability of HCC cells. CONCLUSIONS: Our data showed that LANCL1 is a cell surface protein and a key contributor to HCC initiation. Targeting the LANCL1-FAM49B-Rac1-NADPH oxidase-ROS signaling axis may be a promising therapeutic strategy for HCC.

BACKGROUND AIMS: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. APPROACH RESULTS: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over two rounds a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. Priorities were revised between rounds and in R2 panelists also ranked the priorities within six domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2 the mean percentage of 'agree' responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% 'agree'). The highest ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. CONCLUSIONS: This consensus driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reducing fatty liver disease prevalence and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

BACKGROUND: Whilst resection remains the only curative option for perihilar cholangiocarcinoma (PHC), it is well known that such surgery is associated with a high risk of morbidity and mortality. Nevertheless, beyond facing life-threatening complications, patients may also develop early disease recurrence, defining a "futile" outcome in PHC surgery. The aim of this study is to predict the high-risk category (futile group) where surgical benefits are reversed and alternative treatments may be considered. METHODS: The study cohort included prospectively maintained data from 27 Western tertiary referral centers: the population was divided in a development and a validation cohort. The Framingham Heart Study methodology was used to develop a preoperative scoring system predicting the "futile" outcome. RESULTS: A total of 2271 cases were analysed: among them, 309 were classified within the "futile group" (13.6%). ASA score ≥ 3 (OR 1.60; p = 0.005), bilirubin at diagnosis ≥ 50 mmol/L (OR 1.50; p = 0.025), Ca 19-9 ≥ 100 U/mL (OR 1.73; p = 0.013), preoperative cholangitis (OR 1.75; p = 0.002), portal vein involvement (OR 1.61; p = 0.020), tumor diameter ≥ 3 cm (OR 1.76; p < 0.001) and left sided resection (OR 2.00; p < 0.001) were identified as independent predictors of futility. The point system developed, defined three (i.e., low, intermediate, and high) risk classes, which showed good accuracy (AUC 0.755) when tested on the validation cohort. CONCLUSION: The possibility to accurately estimate, through a point system, the risk of severe postoperative morbidity and early recurrence, could be helpful in defining the best management strategy (surgery vs. non-surgical treatments) according to preoperative features.

Co-infection with hepatitis B virus (HBV) and hepatitis D virus (HDV) results in hepatitis D, the most severe form of chronic viral hepatitis, frequently leading to liver decompensation and hepatocellular carcinoma. Pegylated interferon alpha, the only treatment option for chronic hepatitis D for many years, has limited efficacy. New treatments are in advanced clinical development, with one recent approval. Diagnosis and antiviral treatment response monitoring are based on detection and quantification of HDV RNA. However, the development of reliable HDV RNA assays is challenged by viral heterogeneity (at least 8 different genotypes and several subgenotypes), intra-host viral diversity, rapid viral evolution, and distinct secondary structure features of HDV RNA. Different RNA extraction methodologies, primer/probe design for Nucleic Acid Tests, lack of automation, and overall dearth of standardization across testing laboratories contribute to substantial variability in performance characteristics of research-based and commercial HDV RNA assays. A WHO standard for HDV RNA, available for about 10 years, has been used by many laboratories to determine the limit of detection of their assays and facilitates comparisons of RNA levels across study centers. Here we review challenges for robust pan genotype HDV RNA quantification, discuss particular clinical needs and the importance of reliable HDV RNA quantification in the context of drug development and patient monitoring. We summarize distinct technical features and performance characteristics of available HDV RNA assays. Finally, we provide considerations for the use of HDV RNA assays in the context of drug development and patient monitoring.

BACKGROUND AND AIMS: Genetic risk factors are major determinants of chronic liver disease (CDL) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD via increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown. Here we aimed to test our working hypothesis that their combined incidence triggers CLD disease progression. APPROACH AND RESULTS: We showed that PiZZ/PNPLA3I148M patients from the European AATD liver consortium and UK Biobank had a trend towards higher liver enzymes, but no increased liver fat accumulation was evident between subgroups. After generating transgenic mice that overexpress the PiZ variant and simultaneously harbor the PNPLA3I148M knockin (designated as PiZ/PNPLA3I148M), we observed that PiZ and PiZ/PNPLA3I148M animals showed increased liver enzymes compared to controls during aging. However, no significant difference between PiZ and PiZ/PNPLA3I148M groups was observed with no increased liver fat accumulation over time. To further study the impact on CLD progression a Western-Styled diet (WSD) was administered, which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3I148M livers compared to controls, but the additional presence of PNPLA3I148M had no impact on liver phenotype. Notably, PiZ variant protected PNPLA3I148M mice from liver damage and obesity after WSD feeding. CONCLUSION: Our results demonstrate that the PNPLA3 polymorphism in the absence of additional metabolic risk factors is insufficient to drive the development of advanced liver disease in severe alpha1-antitrypsin deficiency.

BACKGROUND AIMS: Long-term nucleos(t)ide analogue (Nuc) treatment can reduce hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-related cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in hepatitis B e antigen (HBeAg)-negative HBV-LC patients who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH RESULTS: From two centers, 494 HBeAg-negative HBV-LC patients who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, hepatitis B surface antigen (HBsAg) loss, liver-related mortality/transplantation and overall survival rates were compared between two groups with 1:1 propensity score matching (PSM) of gender, prior treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end-of-therapy (EOT) in finite group or 3-year-on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/year and 10-year 15.7 vs. 26.8%, respectively; Log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7-8 times higher 10-year incidence of HBsAg loss (22.7 vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent protective factor for HCC [adjusted hazard ratio(aHR): 0.593], liver-related mortality/transplantation (aHR: 0.312) and overall mortality (aHR: 0.382). CONCLUSIONS: Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.

BACKGROUND: the role of medications for alcohol use disorder (MAUD) in patients with cirrhosis is not well established. Evidence on the efficacy and safety of these drugs in these patients is scarce. Approach & results: we performed a systematic review and meta-analysis according to PRISMA guidelines on the efficacy of MAUD in patients with cirrhosis. Search was conducted in PubMed, Embase and Scopus, including all studies until May 2022. Population was defined as patients with AUD and cirrhosis. Primary outcome was alcohol abstinence (AA). Safety was a secondary outcome. We performed a random-effects analysis and expressed the results as relative risk (RR) of alcohol consumption. Heterogeneity was measured by I2. Out of 4,095 unique references, 8 studies on 4 different AUD treatments [baclofen (n = 6), metadoxine (n = 1), acamprosate (n = 1) and fecal microbiota transplant (n = 1)] in a total of 794 patients were included. Four were cohort studies and 4 were randomized clinical trials (RCT). Only RCTs were included in the meta-analysis. MAUD were associated with a reduced rate of alcohol consumption [RR = 0.68 (CI 0.48-0.97), P = 0.03], increasing AA by 32% compared to placebo or standard treatment, despite high heterogeneity (I2 = 67%). Regarding safety, out of 165 serious adverse events in patients treated with MAUD, only 5 (3%) were possibly or probably related to study medications. CONCLUSION: MAUD in patients with cirrhosis are effective in promoting AA and have a good safety profile. Larger studies on the effects of MAUD are needed, especially in patients with advanced liver disease.

BACKGROUND AND AIMS: Although refractory hepatic hydrothorax (RH) is a serious complication of cirrhosis, waitlisted patients do not receive standardized MELD exemption because of inadequate evidence suggesting mortality above biochemical MELD. This study aimed to examine liver-related death (LRD) associated with RH compared to refractory ascites (RA). METHODS: This was a retrospective cohort study of Veterans with cirrhosis. Eligibility criteria included participants with RH or RA, followed from their first therapeutic thoracentesis/second paracentesis until death or transplantation. The primary outcome was LRD with non-LRD or transplantation as competing risk. RESULTS: Of 2,552 patients with cirrhosis who underwent therapeutic thoracentesis/paracentesis, 177 met criteria for RH and 422 for RA. RH was associated with a significantly higher risk of LRD (aHR 4.63, 95% CI 3.31-6.48) than RA overall and within all MELD-Na strata (<10 aHR 4.08, 95% CI 2.30-7.24, 10-14.9 aHR 5.68, 95% CI 2.63-12.28, 15-24.9 aHR 4.14, 95% CI 2.34-7.34, ≥25 aHR 7.75, 95% CI 2.99-20.12). LRD was higher among participants requiring one (aHR 3.54, 95% CI 2.29-5.48), 2-3 (aHR 4.39, 95% CI 2.91-6.63), and ≥4 (aHR 7.89, 95% CI 4.82-12.93) thoracenteses relative to RA. Although participants with RH and RA had similar baseline MELD-Na, LRD occurred in RH versus RA at a lower MELD-Na (16.5 vs. 21.82, p=0.002) but higher MELD 3.0 (27.85 vs. 22.48, p<0.0001). CONCLUSIONS: RH was associated with higher risk of LRD than RA at equivalent MELD-Na. By contrast, MELD 3.0 may better predict risk of LRD in RH.

Significant quality gaps exist in the management of chronic liver diseases and cirrhosis. Clinical decision support (CDS) systems-information-driven tools based in and launched from the electronic health record-are attractive and potentially scalable prospective interventions that could help standardize clinical care in hepatology. Yet, CDS systems have had a mixed record in clinical medicine due to issues with interoperability and compatibility with clinical workflows. In this review, we discuss the conceptual origins of CDS systems, existing applications in liver diseases, issues and challenges with implementation, and emerging strategies to improve their integration in hepatology care.

INTRODUCTION: The predominantly Progressive, Indeterminate, and predominantly Regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes in an extension study on a randomized controlled trial which originally enrolled 1000 patients with chronic hepatitis B (CHB) and biopsy-proven histological significant fibrosis and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, Indeterminate, and Regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of hepatocellular carcinoma (HCC) was 1.5% for the Regressive cases, 4.3% for the Indeterminate cases, and 22.8% for the Progressive cases (p<0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes and Laennec staging, the post-treatment Progressive had a hazard ratio of 17.77 (vs. post-treatment Regressive; 95% CI: 5.55-56.88) for the incidence of liver related events (decompensation, HCC, death/liver transplantation). CONCLUSIONS: The P-I-R classification can be a meaningful complementary to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.

CRISPR is a gene editing tool adapted from naturally occurring defense systems from bacteria. It is a technology that is revolutionizing the interrogation of gene functions in driving liver disease, especially through genetic screens and by facilitating animal knockout and knockin models. It is being used in models of liver disease to identify which genes are critical for liver pathology, especially in genetic liver disease, hepatitis, and in cancer initiation and progression. It holds tremendous promise in treating human diseases directly by editing DNA. It could disable gene function in the case of expression of a maladaptive protein, such as blocking transthyretin as a therapy for amyloidosis, or to correct gene defects, such as restoring the normal functions of liver enzymes fumarylacetoacetate hydrolase or alpha-1 antitrypsin. It is also being studied for treatment of hepatitis B infection. CRISPR is an exciting, evolving technology that is facilitating gene characterization and discovery in liver disease and holds the potential to treat liver diseases safely and permanently.

BACKGROUND AND AIMS: Cyanobacteria are commonly found in water bodies and their production of hepatotoxins can contribute to liver damage. However, the population health effects of cyanobacteria exposure (CE) are unknown. Our objectives were to determine the effect of chronic exposure to cyanobacteria through proximity to waterbodies with high cyanobacteria counts on the incidence and mortality of liver disease and cancers, as well as to identify location-based risk factors. APPROACH AND RESULTS: Across the contiguous United States, regions with high cyanobacteria counts in waterbodies were identified using satellite remote sensing data. The data was geospatially mapped to county boundaries, and disease mortality and incidence rates analyzed. Distinctive spatial clusters of CE and mortality related to liver diseases or cancer were identified. There was a highly significant spatial association between CE and liver disease and liver cancer, but not between CE and all cancers. Hot spots of CE and mortality were identified along the Gulf of Mexico, eastern Texas, Louisiana, and Florida, and cold spots across the Appalachians. Social vulnerability index was identified as a major location-based determinant by logistic regression, with counties in the fourth or fifth quintiles having the highest prevalence of hot-spots of CE and mortality from liver cancer. CONCLUSIONS: These findings emphasize the importance of environmental exposure to cyanobacteria as a location-based determinant of mortality from liver cancer. Public health initiatives addressing CE may be considered to reduce mortality, particularly in areas of high social vulnerability.

BACKGROUND AND AIMS: To evaluate diagnostic performance of dual elastography (dual-elasto) in continuous differentiation of liver fibrosis and inflammation in a large prospective chronic hepatitis B (HBV) patient cohort. APPROACH: Adults with positive HBsAg for at least 6 months were recruited from 12 medical centers. Participants underwent dual-elasto evaluations. Biopsy was performed 3 days after dual-elasto examination. Four logistic regression models were trained and strung together into series models, Decision trees based on the series models were performed to achieve continuous differentiation of liver fibrosis and inflammation. Influence of inflammation on fibrosis stage was also evaluated. RESULTS: 560 patients were included in the training set and 240 in the validation set. Areas under the receiver operating characteristic curve (AUCs) of the series model were 0.82, 0.86, 0.93, and 0.96 to predict ≥ F1, ≥ F2, ≥F3 and F4 in the validation set, which were significantly higher than those of serum markers and shear wave elastography (all p < 0.05), except for the ≥ F1levels (p = 0.09). AUCs of the series model were 0.93, 0.86, 0.95 and 0.84 to predict inflammation stages ≥ G1, ≥ G2, ≥ G3 and G4, respectively. Decision tress realized five continuous classifications of fibrosis and inflammation. Inflammation could enhance the mild fibrosis stage classification while showed limited influences on severe fibrosis or cirrhosis diagnosis. CONCLUSIONS: Dual elastography demonstrated high performance in the continuous discrimination of fibrosis and inflammation in HBV patients and could be used to diagnose mild fibrosis without influence of inflammation.

BACKGROUND AIMS: Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear. APPROACH AND RESULTS: To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by three distinct stimuli: liver regeneration by partial hepatectomy (PH) and hepatic hyperplasia induced by two direct mitogens, lead nitrate (LN) or triiodothyronine (T3). Following LN treatment, well-established features of cancer metabolic reprogramming including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD+/NADH synthesis and altered amino acid content as well as downregulated oxidative phosphorylation (OXPHOS) occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by PH or T3. CONCLUSION: Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo a cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.

Thyroid hormone action is involved in virtually all physiological processes. It is well known that the liver and thyroid are intimately linked, with thyroid hormone playing important roles in de novo lipogenesis, beta-oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Clinical and mechanistic research studies have shown that thyroid hormone can be involved in chronic liver diseases, including alcoholic or nonalcoholic fatty liver disease and hepatocellular carcinoma. Thyroid hormone action and synthetic thyroid hormone analogs can exert beneficial actions in terms of lowering lipids, preventing chronic liver disease and as liver anticancer agents. More recently, preclinical and clinical studies have indicated that some analogs of thyroid hormone could also play a role in the treatment of liver disease. These synthetic molecules, thyromimetics, can modulate lipid metabolism, particularly in nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. In this review, we first summarize the thyroid hormone signaling axis in the context of liver biology, then we describe the changes in thyroid hormone signaling in liver disease and how liver diseases affect the thyroid hormone homeostasis, and finally we discuss the use of thyroid hormone-analogues for the treatment of liver disease.

BACKGROUND AIMS: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood. APPROACH RESULTS: We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident Kupffer cells, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 (Trem2) and osteopontin (Spp1), markers assigned to hepatic bile duct associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, enhanced cholestasis-induced MoMF-Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro, while mAb-mediated neutralization of SPP1 confered protection in experimental PSC. In human PSC patients, serum osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as prognostic biomarker for liver transplant-free survival. CONCLUSIONS: Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as prognostic marker and future therapeutic target in PSC.

BACKGROUND AIM: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining "high-risk" have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. APPROACH AND RESULTS: The derivation cohort included 1554 patients with cirrhosis and acute variceal bleeding who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in endoscopy plus drug patients, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y c-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c-for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 cirrhotic patients with acute variceal bleeding from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). CONCLUSIONS: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.

The field of hepatology has made impressive progress over its ~75 years of existence. Advances in understanding liver function and its dysregulation in disease, genetic determinants of disease, antiviral therapy, and transplantation have transformed the lives of patients. However, there are still significant challenges that require ongoing creativity and discipline, particularly with the emergence of fatty liver diseases, as well as managing autoimmune disease, cancer, and liver disease in children. Diagnostic advances are urgently needed to accelerate risk stratification and efficient testing of new agents with greater precision in enriched populations. Integrated, holistic care models should be extended beyond liver cancer to diseases like NAFLD with systemic manifestations or extrahepatic comorbidities such as cardiovascular disease, diabetes, addiction, and depressive disorders. To meet the growing burden of asymptomatic liver disease, the workforce will need to be expanded by incorporating more advanced practice providers and educating other specialists. The training of future hepatologists will benefit from incorporating emerging skills in data management, artificial intelligence, and precision medicine. Continued investment in basic and translational science is crucial for further progress. The challenges ahead are significant, but with collective effort, the field of hepatology will continue to make progress and overcome obstacles.

BACKGROUND AND AIM: Long-term maintenance of viral control, even HBsAg loss, remains a challenge for chronic hepatitis B (CHB) patients undergoing nucleos(t)ide analogue (NA) discontinuation. This study aimed to investigate the relationship between HBV-specific T-cell responses targeting peptides spanning the whole proteome and clinical outcomes in CHB patients after NA discontinuation. APPROACH AND RESULTS: Eighty-eight CHB patients undergoing NA discontinuation were classified as responders (remained relapse-free up to 96 weeks) or relapsers (relapsed patients who underwent NA retreatment for up to 48 weeks and reachieved stable viral control). HBV-specific T-cell responses were detected at baseline and longitudinally throughout the follow-up. We found responders had a greater magnitude of HBV polymerase (Pol)-specific T-cell responses than relapsers at baseline. After long-term NA discontinuation, simultaneously enhanced HBV Core-induced and Pol-induced responses were observed in responders. Particularly, responders with HBsAg loss possessed enhanced HBV Envelope (Env)-induced responses after short-term and long-term follow-up. Notably, CD4 + T cells accounted for the predominance of HBV-specific T-cell responses. Correspondingly, CD4-deficient mice showed attenuated HBV-specific CD8 + T-cell responses, reduced HBsAb-producing B cells, and delayed HBsAg loss; in contrast, in vitro addition of CD4 + T cells promoted HBsAb production by B cells. Besides, IL-9, rather than PD-1 blockade, enhanced HBV Pol-specific CD4 + T-cell responses. CONCLUSION: HBV-specific CD4 + T-cell responses induced by the targeted peptide possess specificities for long-term viral control and HBsAg loss in CHB patients undergoing NA discontinuation, indicating that CD4 + T cells specific to distinct HBV antigens may endow with divergent antiviral potential.

BACKGROUND AND AIMS: Adolescents constitute a unique waitlist cohort that is distinct from younger children. Model for End-stage Liver Disease (MELD) 3.0, which was developed in an adult population of liver transplant candidates, is planned to replace MELD-Sodium in the current liver allocation system for both adults and adolescents aged 12-17. We evaluated the predictive performance of MELD-Sodium, MELD 3.0, and Pediatric End-stage Liver Disease for 90-day waitlist mortality risk among adolescent liver transplant registrants. APPROACH AND RESULTS: New waitlist registrations for primary liver transplants among individuals aged 12-17 and 18-25 for comparison were identified using Organ Procurement and Transplantation Network (OPTN) data from November 17, 2004, to December 31, 2021. The predictive performance of the current and proposed MELD and Pediatric End-stage Liver Disease scores was assessed using Harrell's concordance ( c ) statistic. There were 1238 eligible listings for adolescents aged 12-17 and 1740 young adults aged 18-25. In the adolescent group, 90-day survival was 97.8%, compared with 95.9% in those aged 18-25 (log-rank p = 0.005), with no significant differences when stratified by sex or indication. Among adolescents, increasing MELD 3.0 was associated with an increased hazard of mortality (HR=1.27, 95% CI: 1.18-1.37), and the c -statistic for 90-day waitlist survival using MELD 3.0 was 0.893 compared with 0.871 using MELD-Sodium and 0.852 using Pediatric End-stage Liver Disease. CONCLUSIONS: The discriminative ability of MELD 3.0 to rank adolescents according to the risk of death within 90 days was robust. Although MELD 3.0 was initially developed and validated in adults, MELD 3.0 may also improve the prediction of waitlist mortality in adolescents and better represent their urgency for liver transplants.

Current recommendations for the surveillance of HCC are based on the semiannual liver ultrasound (with or without serum alpha-fetoprotein) in patients with cirrhosis and in subgroups with chronic hepatitis B infection. However, the sensitivity of this strategy is suboptimal for the detection of early-stage tumors, especially in obese patients, due to interoperator variability and poor adherence. The detection rate of focal liver lesions is excellent with MRI, making it the best alternative candidate for surveillance. However, performing a full contrast-enhanced MRI is unrealistic because of limited availability and health economics. Abbreviated MRI (AMRI) corresponds to the acquisition of a limited number of sequences with a high detection rate. The theoretical benefits of AMRI are a reduced acquisition time (≤10 min) with improved time-effectiveness and cost-effectiveness compared with conventional MRI, and greater accuracy than ultrasound. Numerous protocols may be performed, including T1-weighted, T2-weighted, and DWI sequences, with or without contrast administration. Although published studies report promising per-patient results, they should be interpreted with caution. Indeed, most studies were simulated, retrospectively reviewing a subset of sequences in relatively small populations who underwent a full MRI. They also included groups that were not representative of screening populations. In addition, most were published by Asian groups, with at-risk populations that were different from Western populations. There are no existing longitudinal studies that directly compare the different AMRI approaches or AMRI to ultrasound. Finally, it is possible that 1 approach will not fit all patients and that strategies should be tailored to the risk of HCC, in particular in relation to the cost and availability of AMRI. Several trials are ongoing to evaluate these questions.

Comment in Hepatology. 2023 Aug 1;78(2):E26.

Comment in Hepatology. 2023 Aug 1;78(2):E31-E32.

Comment in Hepatology. 2023 Aug 1;78(2):E35-E36.

BACKGROUND AND AIMS: Genetics plays a role in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP); however, empirical evidence on familial clustering of ICP is scarce. We aimed to assess the extent of familial recurrence of ICP. APPROACH AND RESULTS: This population-based cohort study included all 668,461 primiparous women who gave birth between 1995 and 2018 in Denmark. Women diagnosed with ICP were included to the index cohort. Kinship with index women was determined with the Danish Civil Registration System. Log-binomial regression was used to calculate the relative recurrence risk (RRR) of ICP in relatives of index women. A total of 6722 (1.0%) primiparous women were diagnosed with ICP. In co-twins (n=57), first-degree (n=2279), second-degree (n=1373), and third-degree (n=1758) relatives of the index women, the incidence of ICP reached 5.3%, 2.6%, 0.7%, and 1.4%, respectively, corresponding to adjusted RRRs of 4.82 (95% CI, 1.60-14.48), 2.54 (1.98-3.26), 0.81 (0.44-1.51), and 1.15 (0.77-1.71), respectively. The first-degree relatives of women who had recurrent ICP or first-trimester ICP seemed to be at higher risks [RRR, 4.30 (2.85-6.48), 3.04 (1.93-4.77), respectively]. A minor increased risk was observed in nonbiological relatives [RRR, 1.35 (1.05-1.73); n=4274, including women's full-brothers' partner and women's husbands' full sisters]. CONCLUSIONS: Co-twins and first-degree relatives of ICP patients were at ~5- and ~2.5-fold increased risk of ICP, respectively. No increased risk was observed in second-degree and third-degree relatives. Recurrent ICP and first-trimester ICP might indicate a higher degree of family clustering. Further investigation is needed to investigate the increased risk of ICP in nonbiological relatives.

BACKGROUND AND AIMS: Beta-blockers have been studied for the prevention of variceal bleeding and, more recently, for the prevention of all-cause decompensation. Some uncertainties regarding the benefit of beta-blockers for the prevention of decompensation remain. Bayesian analyses enhance the interpretation of trials. The purpose of this study was to provide clinically meaningful estimates of both the probability and magnitude of the benefit of beta-blocker treatment across a range of patient types. APPROACH AND RESULTS: We undertook a Bayesian reanalysis of PREDESCI incorporating 3 priors (moderate neutral, moderate optimistic, and weak pessimistic). The probability of clinical benefit was assessed considering the prevention of all-cause decompensation. Microsimulation analyses were done to determine the magnitude of the benefit. In the Bayesian analysis, the probability that beta-blockers reduce all-cause decompensation was >0.93 for all priors. The Bayesian posterior hazard ratios (HR) for decompensation ranged from 0.50 (optimistic prior, 95% credible interval 0.27-0.93) to 0.70 (neutral prior, 95% credible interval 0.44-1.12). Exploring the benefit of treatment using microsimulation highlights substantial treatment benefits. For the neutral prior derived posterior HR and a 5% annual incidence of decompensation, at 10 years, an average of 497 decompensation-free years per 1000 patients were gained with treatment. In contrast, at 10 years 1639 years per 1000 patients were gained from the optimistic prior derived posterior HR and a 10% incidence of decompensation. CONCLUSIONS: Beta-blocker treatment is associated with a high probability of clinical benefit. This likely translates to a substantial gain in decompensation-free life years at the population level.

BACKGROUND AIMS: The current prevalence of fatty liver disease (FLD) due to alcohol-associated (AFLD) and nonalcoholic (NAFLD) origins in US persons with HIV (PWH) is not well defined. We prospectively evaluated the burden of FLD and hepatic fibrosis in a diverse cohort of PWH. APPROACH RESULTS: Consenting participants in outpatient HIV clinics in 3 centers in the US underwent detailed phenotyping, including liver ultrasound and vibration-controlled transient elastography for controlled attenuation parameter and liver stiffness measurement. The prevalence of AFLD, NAFLD, and clinically significant and advanced fibrosis was determined. Univariate and multivariate logistic regression models were used to evaluate factors associated with the risk of NAFLD. Of 342 participants, 95.6% were on antiretroviral therapy, 93.9% had adequate viral suppression, 48.7% (95% CI 43%-54%) had steatosis by ultrasound, and 50.6% (95% CI 45%-56%) had steatosis by controlled attenuation parameter ≥263 dB/m. NAFLD accounted for 90% of FLD. In multivariable analysis, old age, higher body mass index, diabetes, and higher alanine aminotransferase, but not antiretroviral therapy or CD4 + cell count, were independently associated with increased NAFLD risk. In all PWH with fatty liver, the frequency of liver stiffness measurement 8-12 kPa was 13.9% (95% CI 9%-20%) and ≥12 kPa 6.4% (95% CI 3%-11%), with a similar frequency of these liver stiffness measurement cutoffs in NAFLD. CONCLUSIONS: Nearly half of the virally-suppressed PWH have FLD, 90% of which is due to NAFLD. A fifth of the PWH with FLD has clinically significant fibrosis, and 6% have advanced fibrosis. These data lend support to systematic screening for high-risk NAFLD in PWH.