In the past, advanced chronic liver disease was considered irreversible, but with better understanding and improved treatments, it is now recognized that fibrosis is a dynamic process that can regress even when it has reached the stage of cirrhosis. We present the case of a 60-year-old male patient with advanced chronic liver disease due to chronic hepatitis B, whose follow-up liver biopsy revealed significant fibrosis regression after successful antiviral therapy. We confirmed the predominantly regressive pattern using the P-I-R classification, a new histological classification that defines the tissue features as predominantly "Progressive, Intermediate or Regressive" by comparing stroma to parenchymal ratios. Furthermore, we also point out the prognostic value of P-I-R classification, as the patient has remained free of decompensation over time. In this clinical case, we highlight important aspects of the pathophysiology and histopathology of cirrhosis regression, emphasizing its critical prognostic significance. Finally, familiarizing clinicians and pathologists with the application of the P-I-R classification may improve prognostication based on histology in patients with advanced liver disease.

Background & aims: Patients with compensated advanced chronic liver disease (cACLD) and treated type 2 diabetes have an increased risk for liver-related events, but data regarding this population is lacking, particularly, taking into account novel treatments. We assessed the role of Fibrosis-4 index and other variables to predict events. Methods: First hepatic decompensation, liver transplantation (OLT), death, hepatocellular carcinoma (HCC) and bacterial infections over a follow-up period of 28.7 (16-49.4) months were retrospectively identified from 106 patients with treated type 2 diabetes and liver stiffness measurement >10 kPa suggesting ACLD. We identified predictors of events using Cox regression. Additionally, we evaluated treatment effect with add-on GLP-1 receptor agonists (GLP-1-RA) compared to other antidiabetic medications. Results: FIB-4 was associated with hepatic decompensation, OLT and death (HR 1.517, 95%CI 1.226-1.879, p <= 0.001), HCC (HR 1.369, 95%CI 1.046-1.791, p = 0.022) and bacterial infections (HR 1.379, 95%CI 1.118-1.702, p = 0.003). Propensity score adjusted analysis for GLP-1-RA treatment did not show an effect (HR 0.240, 95%CI 0.044-1.315, p = 0.1). Survival was worse in those with more advanced disease defined by FIB-4 > 2.67 (p = 0.02). Conclusion: FIB-4 is a strong prognostic tool to screen patients and refer them to specialists, in cACLD patients and pharmacologically treated type 2 diabetes, irrespective of treatment.

Amphibians are undergoing a dramatic global decline. This massive biodiversity loss, which is critically impacting public and planetary health, has been attributed to multiple causes including infectious diseases. Of the known pathogens associated with obvious diseases in amphibians, herpesviruses have recently raised attention secondary to the discovery of two new species, both associated with skin diseases. Here, we provide the detection and characterization of a novel amphibian herpesvirus associated with a proliferative skin disease, closely resembling that previously described in association with Batravirus ranidallo3 (previously Ranid herpesvirus 3-RaHV3) and Bufonid herpesvirus 1 (BfHV1). The novel virus, tentatively named candidate Batravirus ranidallo5 is genetically related, but distinct from the previously described Batraviruses and it is the first amphibian herpesvirus described in Spain. The full-length genome obtained for this novel herpesvirus is approximately 220 kb and it contains the homologues of herpesvirus hallmark genes, which allows us to propose its unambiguous classification as a herpesvirus. Interestingly, a number of predicted ORFs showed to match closer to fish Alloherpesviruses homologues than Batraviruses. The discovery within a limited time span of three distinct herpesviruses, all associated with obvious skin diseases in Europe is alarming and may have significant implication for amphibian conservation.

Background & aims: Systemic inflammation is a driver of decompensation in cirrhosis with unclear relevance in the compensated stage. We evaluated inflammation and bacterial translocation markers in compensated cirrhosis and their dynamics in relation to the first decompensation. Methods: This study is nested within the PREDESCI trial, which investigated non-selective beta-blockers for preventing decompensation in compensated cirrhosis and clinically significant portal hypertension (CSPH: hepatic venous pressure gradient >= 10 mmHg). Blood biomarkers were measured at baseline and at 1 and 2 years in patients who remained compensated and had available samples (n = 164). Values of patients with CSPH were split at each time point by decompensation development in the next time interval after sampling. We also included 54 patients with cirrhosis and subclinical portal hypertension (PH) and 35 controls. We assessed markers of inflammation (interleukin-6 [IL-6], tumor necrosis factor-alpha, von Willebrand factor [vWF], C-reactive protein), macrophage activation (CD14, CD163), intestinal barrier integrity (fatty acid-binding protein [FABP], haptoglobin), and bacterial translocation (lipopolysaccharide [LPS]). Results: IL-6, CD163, and vWF were higher (p <0.01) at baseline in patients with cirrhosis and CSPH compared to those with subclinical PH and controls. IL-6 increased (p <0.05) at 1 year in patients with CSPH, with a greater rise in those who developed decompensation. CD163 was higher (p <0.01) in patients who decompensated at baseline and 1 and 2 years. FABP was elevated (p <0.01) in patients with CSPH compared to subclinical PH and controls at baseline and 1 year, while haptoglobin was lower (p <0.01). LPS was higher (p <0.01) in patients with CSPH than in those with subclinical PH and controls and increased at 1 year regardless of decompensation development. Conclusions: Inflammation and bacterial products are present in the systemic circulation in patients with compensated cirrhosis and CSPH. Progressive inflammation precedes the first decompensation. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background & Aims: Steatotic liver disease can lead to the development of metabolic dysfunction-associated steatohepatitis (MASH), the prevalence of which is rapidly increasing, intensifying the need to find an effective treatment. GTX-11 is a first-in-class drug with anti-inflammatory and antifibrotic properties mediated by the modulation of the transforming growth factor beta pathway. The present study evaluated the effects of GTX-11 on hepatic hemodynamics and liver fibrosis, as well as its underlying mechanisms, in a preclinical model of MASH, and in human precision-cut liver slices (hPCLS). Methods: Male Wistar MASH rats received GTX-11 (1 and 10 mg/kg/day) or vehicle, for 14 days (n = 15/group). In vivo systemic and hepatic hemodynamics, fibrosis, biochemical parameters, and hepatic cells phenotype were analyzed. hPCLS were obtained from human hepatic resections and incubated with the active metabolite of GTX-11 (GTX-11m) (1 μM or 10 μM) or vehicle for 24 h. Gene expression changes were evaluated by RNA sequencing and gene deconvolution analysis was performed (n = 6/group). Results: MASH rats receiving GTX-11 showed a significant dose-dependent reduction in portal pressure compared with the vehicle (-8.4% p = 0.05 and -11.7% p <0.01 for 1 and 10 mg/kg, respectively), associated with lower hepatic fibrosis at 10 mg/kg (-28%, p <0.01). At the cellular level, GTX-11-treated rats showed hepatic stellate cells (HSCs) deactivation and endothelial cells redifferentiation. Transcriptomic analysis from hPCLS revealed that GTX-11m promoted HSCs deactivation and inhibition of pro-fibrogenic pathways, as well as extracellular matrix remodeling. Gene deconvolution analysis confirmed the beneficial effects of GTX-11m on HSCs, promoting their deactivation and rebalance. Conclusions: This study demonstrates for the first time the beneficial effects of GTX-11 on portal hypertension and liver fibrosis in MASH by means of HSCs deactivation and endothelial phenotype restoration. Validation in human liver tissues encourages its clinical evaluation as a possible new treatment for this disease. Impact and implications: Metabolic dysfunction-associated steatohepatitis (MASH) affects >3–6% of the world’s population, and this number continues to increase. Despite its high prevalence, there is currently no specific, generally effective, and safe treatment for the disease. This study demonstrates, for the first time, the therapeutic potential of GTX-11 in treating fibrosis and portal hypertension associated with MASH by deactivating hepatic stellate cells and enhancing endothelial phenotype. These findings highlight GTX-11 as a promising candidate for future therapeutic strategies aimed at reversing liver fibrosis and improving patient outcomes in MASH.

AIMS:Endothelin A (ETA) receptor antagonists may reduce cirrhosis-associated portal hypertension (PH). They are associated with fluid retention, which might be mitigated by sodium-glucose co-transporter 2 inhibitors (SGLT2is). Efficacy, safety and tolerability of combining the selective ETA receptor antagonist zibotentan and the selective SGLT2i dapagliflozin were investigated. METHODS:Patients with compensated cirrhosis (Child-Pugh A) were randomized 1:1 to zibotentan 2.5 mg plus dapagliflozin 10 mg (zibo/dapa) or placebo in a 6-week parallel, double-blind Phase II study. The absolute change in hepatic venous pressure gradient (HVPG) from baseline to week 6 was evaluated in the full analysis set using analysis of covariance. RESULTS:In 28 participants (n = 14 per group), median age was 64 years (range: 37-78), common causes of cirrhosis were metabolic dysfunction-associated steatotic (46%) or alcohol-associated liver disease (39%), and 46% were receiving stable doses of non-selective beta-blockers. Baseline HVPG was 6.5-19 mmHg, and 16/28 had clinically significant portal hypertension. Absolute change in HVPG at week 6 was not different between groups (1.02 mmHg [90% CI -0.31, 2.35]). There was a trend towards decreased HVPG in patients with baseline HVPG ≥12 mmHg receiving zibo/dapa. Systolic and diastolic blood pressure were also reduced by zibo/dapa vs. placebo. Three mild adverse events (peripheral oedema) were reported (zibotentan/dapagliflozin, n = 2; placebo, n = 1). No serious adverse events or drug-induced liver injuries were observed. CONCLUSIONS:Combined zibo/dapa was well tolerated and had a good safety profile in patients with compensated cirrhosis, but had no conclusive effect on HVPG.

The thermal mismatch hypothesis (TMH), the notion that cool- and warm-adapted hosts have higher infection risk during unusually warm and cool spells, respectively, was recently proposed to explain how temperature shifts driven by climate change influence host susceptibility to infections at a global scale.1 Despite substantial support for the TMH in the chytrid fungus (Batrachochytrium dendrobatidis, also commonly referred to as Bd) that is devastating amphibians worldwide,2 it remains unknown whether precipitation mismatches, in addition to temperature ones, affect infection risk. Here, we introduce the thermal-hydric mismatch hypothesis (THMH), which proposes that infection risk is shaped by mismatches resulting from the combined effects of temperature and precipitation. We tested this hypothesis using a large-scale survey of B. dendrobatidis and Ranavirus in over 5,800 adult amphibians across the Iberian Peninsula, a climate change hotspot in Europe that is heavily affected by both pathogens.3,4,5,6 We found that the combined effect of thermal and precipitation mismatches increased infection risk for both pathogens. Cool-and-wet-adapted amphibians were more infected with B. dendrobatidis during warm-and-dry spells, while warm-and-dry-adapted hosts showed higher B. dendrobatidis infection during cool-and-wet spells. For Ranavirus, mismatches occurred under opposite climatic conditions to those of B. dendrobatidis, which is consistent with the limited temporal overlap between the two pathogens, despite their frequent geographical co-occurrence.7 Finally, the fact that thermal mismatches alone did not predict B. dendrobatidis infection, and precipitation mismatches alone did not predict Ranavirus infection, suggests that infection risk in the study region is driven by their combined effects, supporting the THMH proposed here.

Background & Aims:Current guidelines recommend intravenous (i.v.) albumin for different indications in decompensated cirrhosis, but iatrogenic hypervolemia following i.v. albumin is increasingly reported. We aimed to characterize intravascular volume status using point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) during passive leg raise (PLR) and i.v. albumin, potentially facilitating clinical management and adjustment of albumin dosage. Methods:This prospective pilot cohort included patients with decompensated cirrhosis requiring i.v. albumin. We assessed changes in minimal and maximal IVC diameters (IVCmin and IVCmax, respectively) and collapsibility index (IVCCI) during PLR and after i.v. albumin. We defined severe intravascular volume overload as IVCmax >2.1 cm and IVCCI <20%. Clinical outcomes were recorded until 3 months after POCUS. Results:We included 81 measurements in 55 patients (70.9% men; median age 62 years; 58.2% alcohol-related cirrhosis; median Child-Pugh score 9 points; 89.1% paracentesis; median 40 g i.v. albumin; 5.5 L ascites). We found a significant increase in IVC diameters both during PLR (change in mean [Δ] IVCmin +20.7%, Δ IVCmax +14.1%, p <0.01) and after i.v. albumin (Δ IVCmin +58.8%, Δ IVCmax +48.2%, p <0.01). There was a significant decrease in IVCCI during PLR (relative Δ -11.1%, p <0.01) and after i.v. albumin (relative Δ -18.0%, p <0.01). Potential severe intravascular volume overload occurred on 17 occasions (21%) after i.v. albumin, more frequently in women than in men (40% vs. 15.7%, p <0.01), and showed higher cumulative incidence rates in variceal bleeding after 1 (16.7% vs. 0%, p = 0.01) and 3 months (18.2% vs. 0%, p = 0.01). Conclusions:Potential severe intravascular volume overload after i.v. albumin was detected in every fifth patient with decompensated cirrhosis. Thus, there is a need to develop strategies for individualizing volume management in patients with decompensated cirrhosis. Impact and implications:Iatrogenic volume overload after albumin infusions in patients with cirrhosis is a potentially harmful side effect, but no policy for monitoring intravascular volume overload using non-invasive tools has been suggested so far. New-onset potential volume overload was detected in almost one out of five men and four out of 10 women and was associated with increases in N-terminal prohormone of brain natriuretic peptide, lower mean arterial pressure during albumin infusion, and higher serum sodium levels. Our results from this proof-of-concept study emphasize the need for larger prospective cohort studies to validate our findings and introduce strategies for individualizing volume management in patients with decompensated cirrhosis.

Background & Aims: Whether non-invasive tests (NITs) can accurately select patients with cirrhosis requiring non-selective betablockers (NSBBs) for clinically significant portal hypertension (CSPH) and prevention of decompensation is unclear. Our aim was to test the performance of NIT-based algorithms for CSPH diagnosis using the prospective PREDESCI cohort. We investigated whether a new algorithm combining NITs with endoscopy could improve performance. Methods: We included patients with compensated cirrhosis and available liver elastography who were screened during the trial. The performance of models based on liver stiffness measurement (LSM) and platelet count was evaluated. An algorithm considering endoscopy for patients with inconclusive results (the "grey zone") was then developed and validated in an independent cohort of 195 patients in whom spleen stiffness was also available. Results: We included 170 patients from the PREDESCI cohort. An LSM >-25 kPa alone (Baveno VII criteria) or combined with an LSM >20 kPa plus thrombocytopenia (AASLD criteria) ruled-in CSPH with positive predictive values of 88% and 89%, respectively. However, 37%-47% patients fell into the grey zone while at high risk of decompensation or death. Performing endoscopy in inconclusive cases identified patients with varices that, when reclassified as high-risk for CSPH, significantly reduced the grey zone to 22%. In this algorithm, 86% of patients with CSPH were correctly classified as high risk. The diagnostic performance was confirmed in the external validation cohort, where combining Baveno VII criteria with spleen stiffness showed similar accuracy to the model using endoscopy. Conclusions: Algorithms based only on LSM and platelet count are suboptimal to identify NSBB treatment candidates. Performing endoscopy in patients with indeterminate findings from NITs improved diagnostic performance and risk stratification. Endoscopy may be substituted by spleen stiffness for stratifying risk in the grey zone. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).