Clinical practice guidelines recommend hepatocellular cancer (HCC) surveillance in patients with cirrhosis from any etiology and those with chronic hepatitis B virus (HBV) infection and additional risk factors. However,...Clinical practice guidelines recommend hepatocellular cancer (HCC) surveillance in patients with cirrhosis from any etiology and those with chronic hepatitis B virus (HBV) infection and additional risk factors. However, HCC incidence varies across groups. Several risk stratification models using clinical factors and/or biomarkers have been derived to facilitate tailored HCC surveillance. Although risk stratification models are used for patients with hepatitis B, few have been sufficiently validated in patients with cirrhosis. Indeed, many unanswered questions related to the development, validation, and impact evaluation of risk stratification models must be addressed before widespread implementation can be recommended. The National Cancer Institute's Translational Liver Cancer (TLC) Consortium was established to advance research focused on risk stratification and early detection of liver cancer. The TLC convened a multidisciplinary group, including clinicians, scientists, biostatisticians, and technology experts from the United States, Asia, and Europe, to provide a framework for the development, validation, and implementation of risk stratification models. The framework defines 4 phases of risk stratification model development and validation: phase 1-development and internal validation, phase 2-decision rule development, phase 3-external validation, and phase 4-impact evaluation. The group also defined a set of recommendations to improve the rigor of development and validation of HCC risk stratification strategies. This framework can inform best practices and highlight necessary steps for endorsement by practice guidelines and regulatory agencies, highlighting a path toward implementation in clinical practice.
Guo Q, Satthawiwat N, Sano A
… +13 more, Meroueh C, Hamdi A, Dai X, Warasnhe K, Washington AM, Starlinger PP, Krivonos A, Cao S, Kostallari E, Jonker JW, van de Sluis B, Hamdan FH, Ibrahim SH
BACKGROUND AND AIMS: Liver sinusoidal endothelial cells (LSECs) acquire a proinflammatory phenotype in metabolic dysfunction-associated steatohepatitis (MASH), characterized by enhanced expression of adhesion molecules a...BACKGROUND AND AIMS: Liver sinusoidal endothelial cells (LSECs) acquire a proinflammatory phenotype in metabolic dysfunction-associated steatohepatitis (MASH), characterized by enhanced expression of adhesion molecules and inflammatory mediators, a process termed lipotoxic endotheliopathy. However, the molecular drivers of this transformation remain incompletely defined. APPROACH AND RESULTS: We employed complementary models of lipotoxicity and MASH, including palmitate-treated primary human LSECs (in vitro), cultured precision-cut liver slices (PCLS) from MASH mice and normal human liver treated with MASH-inducing media (ex vivo), and diet-induced MASH models (in vivo). GeoMx digital spatial profiling of human MASH livers revealed enriched proinflammatory and fibrogenic signaling between LSECs and myeloid cells. Among the top upregulated genes and ligand-receptor pairs was ICAM1, whose expression correlated with disease severity and was increased in human MASH by immunostaining. ATAC-seq on primary mouse LSECs showed enhanced chromatin accessibility at the Icam1 promoter in MASH. Chromatin immunoprecipitation confirmed enrichment of the active epigenetic mark H3K27ac and BRD4 binding at the ICAM1 promoter in human LSECs under lipotoxic stress. Mechanistically, we identified the GSK3β/c-Jun/BRD4 axis as a key regulator of ICAM1 induction in LSECs. In vivo, ICAM1-neutralizing antibody or endothelial-specific epigenetic suppression reduced hepatic inflammation, injury, and fibrosis in MASH mice. CONCLUSIONS: ICAM1 is epigenetically upregulated in LSECs during lipotoxic stress and promotes myeloid cell recruitment in MASH. Targeting the epigenetic regulation of ICAM1 may offer a novel therapeutic strategy for treating human MASH.
Steatotic liver disease (SLD) is a leading cause of liver-related morbidity and mortality worldwide. Obesity, insulin resistance, and chronic alcohol intake are its major risk factors, but genetic differences strongly in...Steatotic liver disease (SLD) is a leading cause of liver-related morbidity and mortality worldwide. Obesity, insulin resistance, and chronic alcohol intake are its major risk factors, but genetic differences strongly influence disease susceptibility. Human genetic studies have identified key genetic modifiers of SLD risk, thereby deepening our understanding of disease pathogenesis. All major SLD-associated variants localize to genes involved in hepatic lipid metabolism, underscoring the fundamental role of lipid imbalance in SLD development. Nearly all risk and protective variants are associated with the full spectrum of SLD-from steatosis and steatohepatitis to cirrhosis and hepatocellular carcinoma-with effects on progression proportional to their impact on hepatic triglyceride (TG) levels. These findings have challenged the earlier notion that hepatic steatosis is benign. Furthermore, most variants exert similar effects on metabolic dysfunction-associated SLD (MASLD) and alcohol-associated liver disease (ALD), pointing to shared pathogenic mechanisms of these 2 SLD etiologies. The effects of genetic variants are strongly influenced by nongenetic factors, such as obesity, insulin resistance, and alcohol intake. The advent of GLP-1 receptor agonists for treating obesity and insulin resistance has transformed the therapeutic landscape for SLD. These agents are predicted to become the first-line therapy for SLD, even among individuals at the highest genetic risk. In addition, genetic studies have paved the way for the development of several targeted therapies. Here, we review the major insights into SLD pathogenesis gleaned from over 20 years of human genetic studies, and their implications for the treatment and prevention of SLD.
Nahon P, Ziol M, Pan L
… +28 more, Portal JJ, Oberti F, Aube C, Blanc JF, Trillaud H, Merle P, Rode A, Assenat E, Guiu B, Lequoy M, Cornelis F, Bouattour M, Talib Z, Tibi A, Zeng Q, Bouda Y, Ganne-Carrié N, Sutter O, Sutton A, Guyot E, Barget N, Zucman-Rossi J, Campani C, Bamba-Funck J, Calderaro J, Nault JC, Vicaut E, Seror O
BACKGROUND AND AIMS: Irreversible electroporation (IRE) is a non-thermal ablation technique suited for difficult-to-treat hepatocellular carcinoma (HCC) with 1-year local recurrence (LR) rates above 50%. We hypothesized...BACKGROUND AND AIMS: Irreversible electroporation (IRE) is a non-thermal ablation technique suited for difficult-to-treat hepatocellular carcinoma (HCC) with 1-year local recurrence (LR) rates above 50%. We hypothesized that peri-procedural immunotherapy could synergize with IRE to decrease local recurrence. APPROACH AND RESULTS: NIVOLEP is a multicenter phase 2 trial evaluating nivolumab combined with IRE in patients with BCLC A HCC. Patients received 2 neoadjuvant nivolumab infusions, IRE with curative intent, and 12 monthly adjuvant nivolumab infusions. Tumor biopsies were performed at baseline and during IRE. The primary endpoint was 1-year local recurrence-free survival (LRFS). In all, 62 HCC nodules (mean size: 30.0 mm) from 43 patients (mean age: 71 y, 88% male, 81% cirrhosis) were considered. All patients received neoadjuvant nivolumab; 35 underwent curative IRE (8 others: 4 IRE failures, 3 HCC progressions, 1 death). After neoadjuvant nivolumab, radiological or pathological response was observed in 24.2% and 26.3% nodules, respectively. One-year LRFS was 70.6% (95% CI: 55.3-85.9), and 2-year overall survival was 74.2% in the intention-to-treat analysis. Grade 3 or 4 adverse events related to nivolumab occurred in 2 patients; 1 patient died due to nivolumab. RNA-sequencing analysis of the tumor after neoadjuvant nivolumab showed an enrichment of pathways associated with leukocyte migration, T cell activation, and CD8+ T and B-cell infiltration associated with pathological response. Circulating protein variations were associated with pathological or radiological responses and local recurrence. CONCLUSIONS: Neoadjuvant and adjuvant nivolumab in BCLC A HCC patients eligible for IRE lead to pathological response related to immune activation and show anti-tumoral effect.
BACKGROUND AND AIMS: OCE-205 is a mixed agonist-antagonist selective for the vasopressin 1a (V1a) receptor with no vasopressin 2 (V2) receptor activity. Safety and efficacy of OCE-205 were evaluated in patients with hepa...BACKGROUND AND AIMS: OCE-205 is a mixed agonist-antagonist selective for the vasopressin 1a (V1a) receptor with no vasopressin 2 (V2) receptor activity. Safety and efficacy of OCE-205 were evaluated in patients with hepatorenal syndrome-acute kidney injury (HRS-AKI). APPROACH AND RESULTS: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted at 23 North American centers. Patients received a continuous infusion of OCE-205 at 8, 15, 30, or 50 µg/h or placebo. The primary endpoint was time to confirmed clinical improvement, defined as serum creatinine (sCr) <1.5 mg/dL with an absolute reduction of ≥0.3 mg/dL for 2 days. Following terlipressin's approval, this study was stopped early due to a lack of equipoise in conducting a placebo-controlled trial. Baseline characteristics between OCE-205 (n=37) versus placebo (n=10) groups were sCr 2.6 versus 2.3 mg/dL, MELD 27.9 versus 25.8, alcohol-associated cirrhosis 51.4% versus 60.0%. The primary endpoint was met in 48.6% versus 30.0% ( p =0.48 by Log-rank test and NS by Bayesian analysis). Bradycardia was the most common adverse event (21.6% vs. 0%). Most events were asymptomatic, requiring no intervention. No new/unexpected safety findings, no events of ischemia, and no related events of respiratory failure occurred. CONCLUSIONS: OCE-205 was well tolerated, with no evidence of excessive vasoconstriction or related events of ischemia or respiratory failure at any dose level. OCE-205 had a predictable, capped maximal efficacy that improved HRS-AKI in numerically more patients than placebo, though it was underpowered for statistical significance. OCE-205 warrants additional investigation as a novel HRS therapy with a favorable benefit-risk profile.
Gao Y, Wang X, Wang Z
… +68 more, Kong F, Yao L, Liu W, Shang J, Yu Y, Zhao W, Hou J, Dang S, Yuan S, Hu G, Zhong B, Chen H, Chen S, Dong X, Xie X, Liu Z, Zhang Z, Song X, Mao Q, Jiang Y, Meng C, Ge F, Su Z, Mao Q, Bai Y, Yu L, Tan Y, Fan H, Jiao Z, Fu X, Hong L, Xu Y, Yan X, Liu J, Gao Y, Gao H, Chen G, Qu H, Cui H, Wu S, Lu X, Liu Z, Liu F, Li X, Sun S, Ding G, Han T, Wang X, Zhao W, Xiang M, Chen X, He W, Lu S, Zeng W, Hu Q, Zhang D, Jin W, Wang D, Wang Y, Zhang C, Wen X, Gao Z, Lv L, Yu K, Li G, Zhang G, Wu G, Niu J
BACKGROUND AND AIMS: Pradefovir mesylate is a novel liver-targeting prodrug of adefovir developed using HepDirect technology. We report that the phase 3 trial is to compare the efficacy and safety of pradefovir versus te...BACKGROUND AND AIMS: Pradefovir mesylate is a novel liver-targeting prodrug of adefovir developed using HepDirect technology. We report that the phase 3 trial is to compare the efficacy and safety of pradefovir versus tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB). APPROACH AND RESULTS: This ongoing randomized, double-blind, non-inferiority, phase 3 study was conducted at 58 sites in China. Patients with CHB were randomly assigned (2:1) to receive either 45 mg daily pradefovir or 300 mg daily TDF with a matching placebo. The primary efficacy endpoint was defined as the proportion of patients whose HBV DNA level was <29 IU/mL at week 48. All participants who received at least 1 dose of the study drug were included in efficacy and safety analyses with pre-specified renal and bone endpoints at week 96. A total of 1170 patients were screened during the study, and 908 patients received the study drug. At week 48, viral suppression (HBV DNA <29 IU/mL) rates of pradefovir were non-inferior to TDF in HBeAg-positive [-1.8% (95% CI: -9.7 to 6.1)] and HBeAg-negative [2.6% (95% CI: -5.1 to 10.3)] patients, using a non-inferiority margin of -12%. By week 96, HBeAg-positive patients showed significantly greater HBsAg decline (≥1 log 10 IU/mL) with pradefovir (39.3% vs. 29.9%). Pradefovir demonstrated a more favorable safety profile at week 96, including significantly fewer drug-related adverse events (58.6% vs. 71.9%), improved bone/renal safety, and a lower incidence of elevated creatine phosphokinase-MB. CONCLUSIONS: Pradefovir should be a highly recommended treatment option for adult patients with CHB.
Kamar N, Abravanel F, Marion O
… +15 more, Couat C, Esposito L, Hebral AL, Lavayssière L, Ribes D, Guy P, Lhomme S, Cointault O, Faguer S, Bellière J, Darres A, Guitard J, Médrano C, Del Bello A, Izopet J
BACKGROUND AND AIMS: The awareness regarding HEV infection in solid organ transplant (SOT) has increased over the last few decades after the reports of chronicity and associated complications. The aim of this study was t...BACKGROUND AND AIMS: The awareness regarding HEV infection in solid organ transplant (SOT) has increased over the last few decades after the reports of chronicity and associated complications. The aim of this study was to describe HEV outcome over a long period in a large cohort of patients undergoing SOT. APPROACH AND RESULTS: This retrospective, single-center study analyzed 6452 patients undergoing SOT followed between 2001 and 2024 and systematically screened for HEV in cases of elevated liver enzymes. Since 2016, patients undergoing SOT have also been screened for HEV at 3 and 12 months after transplantation. We assessed the incidence, natural history, treatment, and extrahepatic manifestations. HEV infection was diagnosed in 228 patients (3.53%). The incidence was significantly higher in patients undergoing liver transplant compared to others. At 3 months after HEV documentation, 65.1% developed chronic hepatitis, while 34.9% achieved spontaneous viral clearance. Tacrolimus use was independently associated with chronicity, while mycophenolic acid use was protective. Ribavirin was the main antiviral therapy, achieving a 91.5% sustained virological response rate when treatment was extended until complete serum and stool HEV RNA clearance. A minority of patients required multiple treatment courses or failed therapy, with some developing cirrhosis or dying viremic. Three patients died from decompensated HEV-related cirrhosis. HEV-associated neurological manifestations (2.2%) and glomerular diseases (3.9%) were observed, often resolving with viral clearance. CONCLUSIONS: HEV infection is frequent in SOT recipients, with significant risks of chronicity and extrahepatic complications. Ribavirin remains the cornerstone of treatment, and individualized duration improves outcomes. Screening for HEV is mandatory in patients undergoing SOT with elevated liver enzymes.
BACKGROUND AND AIMS: Ammonia is central in the pathogenesis of HE, but there are no approved treatments targeting ammonia. L -Ornithine Phenylacetate (YAQ007) is a novel drug that effectively reduces ammonia when adminis...BACKGROUND AND AIMS: Ammonia is central in the pathogenesis of HE, but there are no approved treatments targeting ammonia. L -Ornithine Phenylacetate (YAQ007) is a novel drug that effectively reduces ammonia when administered intravenously. This exploratory phase 2a study evaluated the short-term pharmacodynamics, pharmacokinetics, and safety of oral YAQ007 in patients with cirrhosis and a history of overt HE. APPROACH AND RESULTS: In this randomized, open-label, multicenter study, 48 cirrhosis patients (28 male, mean of 57.2 y, Child-Pugh of 8, and MELD score of 10) were randomized (1:1:1:1) to 1 of 3 YAQ007 dosing regimens (2 g three times daily; 4 g twice daily; 4 g three times daily) or rifaximin (550 mg twice daily) for 5 days under inpatient conditions. A decrease of ammonia at day 5 was observed in group C ( p =0.009) and group B ( p =0.002). After multivariable adjustment, treatment group B versus group D, bilirubin, INR, and sodium ( p <0.05) remained significant factors for absolute ammonia reduction. Urinary phenylacetylglutamine excretion increased on day 5 compared with day 1 across all YAQ007 dose groups ( p <0.001). Exposure-response relationships were variable, and a clear dose-response relationship was not demonstrated. Overall, 20 (55.6%) patients who received YAQ007 and 5 (41.7%) who received rifaximin had at least 1 treatment-emergent adverse event, with mainly mild gastrointestinal and neurological symptoms. CONCLUSIONS: In this phase 2a study, oral YAQ007 demonstrated short-term ammonia-lowering activity at doses ≥4 g BID. Given the exploratory design, these findings are hypothesis-generating and support further clinical evaluation.
BACKGROUND AND AIMS: Mitophagy dysfunction in hepatocytes impedes energy homeostasis in the liver and exacerbates metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the novel role o...BACKGROUND AND AIMS: Mitophagy dysfunction in hepatocytes impedes energy homeostasis in the liver and exacerbates metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the novel role of heat shock protein 72 (HSP72), a classic chaperone protein, in controlling mitophagy in the livers of MASLD mice and isolated primary mouse hepatocytes. APPROACH AND RESULTS: Mitophagy and HSP72 expression levels in the livers of MASLD mice and humans were determined. Global or liver-specific Hsp72-/- and HSP72 +/+ mice, or primary mouse hepatocytes, were used to unravel the role of HSP72 in regulating mitophagy and MASLD. Coimmunoprecipitation and LC-MS joint analysis was performed to identify HSP72-interacting protein involving mitophagy; its effect on the ubiquitination level of PTEN-induced kinase 1 (PINK1) and the crucial ubiquitinated site within PINK1 were explored and confirmed. Liver mitophagy was suppressed in MASLD mice and patients as the level of HSP72 decreased. Global or liver-specific deletion of HSP72 specifically exacerbated MASLD and suppressed mitophagy. Restoring HSP72 level in the liver activated mitophagy and ameliorated MASLD. The observations were further confirmed in isolated primary mouse hepatocytes with genetic manipulation of HSP72. Peroxiredoxin 6 (PRDX6) is identified as an interactive protein of HSP72 and is correlated with mitophagy. PRDX6 deletion ubiquitinated PINK1 and inhibited mitophagy, thereby exacerbating MASLD. Instead, restoring PRDX6 efficiently deubiquitinated PINK1, thus activating mitophagy. More importantly, residue Lys318 (K318) of PINK1 was revealed as a priority site for its ubiquitination in response to PRDX6 regulation. CONCLUSIONS: These data suggest that the HSP72/PRDX6 axis is indispensable for PINK1/Parkin-dependent mitophagy to counteract MASLD.
BACKGROUND AND AIMS: Guidelines recommend i.v. albumin after large-volume paracentesis to prevent postparacentesis circulatory dysfunction and acute kidney injury (AKI). However, real-world effects of albumin on paracent...BACKGROUND AND AIMS: Guidelines recommend i.v. albumin after large-volume paracentesis to prevent postparacentesis circulatory dysfunction and acute kidney injury (AKI). However, real-world effects of albumin on paracentesis outcomes in outpatient settings are understudied. We aimed to address this using national data from a well-established cirrhosis cohort. APPROACH AND RESULTS: This was a retrospective cohort study of Veterans with cirrhosis undergoing outpatient paracentesis. Albumin administration and paracentesis volumes were extracted, in addition to hospitalization for AKI within 7 days of outpatient paracentesis. Mixed-effects logistic regression identified factors associated with albumin administration and the association between albumin and incident AKI hospitalization. Among 9467 patients who received 56,941 outpatient paracentesis procedures, i.v. albumin was used 17% of the time. The use was higher with Model for End-Stage Liver Disease-Sodium; (OR: 1.02, 95% CI: 1.02-1.03, p<0.001), lower estimated glomerular filtration rate (OR: 3.06 for <30 vs. ≥90 mL/min/1.73 m2, 95% CI: 2.64-3.54, p<0.001), and HE (OR: 1.22, 95% CI: 1.13-1.33, p<0.001). Albumin administration was associated with lower odds of AKI-related hospitalizations (OR: 0.66, 95% CI: 0.54-0.81, p<0.001), with a greater effect observed in patients with lower estimated glomerular filtration rate (interaction p value=0.03). In a subcohort of 48,401 procedures with available dosing information, higher-dose albumin (≥6-8 g/L removed) was associated with lower odds of AKI hospitalization (OR:: 0.36, 95% CI:: 0.20-0.64, p=0.001) with similar associations noted irrespective of paracentesis volume. CONCLUSIONS: Albumin administration after outpatient paracentesis was associated with a reduced risk of hospitalization with AKI, with a greater effect at lower estimated glomerular filtration rates. Strategies that tailor albumin administration based on intravascular volume and hemodynamics should be prospectively tested.
BACKGROUND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that poses significant public health challenges. Although liver biopsy remains the gold standard for diagnostic and...BACKGROUND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that poses significant public health challenges. Although liver biopsy remains the gold standard for diagnostic and prognostic use in patients with MASH, its invasiveness limits its practical application in routine care and large-scale trials. This narrative review explores the growing role of noninvasive tests in the assessment of disease progression and treatment efficacy in MASH. APPROACH RESULTS: This review represents expert opinion synthesizing current literature on the most widely used noninvasive tests being assessed as front-line biomarkers for identification of patients with MASLD at risk of outcomes and/or in need of pharmacological intervention, and that are being used to assess treatment response in the context of clinical trials, and how they may be translated into clinical practice. Among these, elastography and the enhanced liver fibrosis test are highlighted for their potential to replace liver biopsy in clinical settings and trials. These methods are analyzed for their accuracy and ability to monitor therapeutic response, emphasizing their growing importance in providing reliable measures of clinical improvement as drug-development efforts for MASH intensify. CONCLUSIONS: This synthetic review aims to provide a roadmap for federal regulators updating and potentially revising the requirements for demonstrating histologic improvement in MASH clinical trials, and for practitioners to translate this information into clinical practice. The ultimate goal is to reduce the reliance on liver biopsy while maintaining the rigor necessary to evaluate therapeutic efficacy, thus accelerating the path to approval for new MASH treatments.