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From the Editor’s Desk…

      Selection of the month

      A third dose of the BNT162b2 mRNA vaccine significantly improves immune response among liver transplant recipients

      Immune responses of solid organ transplant recipients to 2 doses of the BNT162b2 mRNA anti-SARS-CoV-2 vaccine are impaired. Davidov and co-workers evaluated the immune response of 61 liver transplant (LT) recipients to a third dose of the vaccine. The humoral immune response rate improved significantly, with 56% of patients showing a response before the third vaccine compared to 98% after the third vaccine. The cellular response in 12 evaluated patients improved significantly (p = 0.008). The geometric mean of anti-receptor binding domain IgG levels, neutralizing antibody levels, and T-cell count also increased significantly after the third dose. Hence, the immune response improved significantly among LT recipients after a third dose of the BNT162b2 mRNA anti-SARS-CoV-2 vaccine. Further studies are needed to evaluate immune response durability and determine the optimal number and schedule of booster vaccines.
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      Experimental and translational hepatology

      Targeting mitochondrial dysfunction prevents NASH progression

      Mitochondrial dysfunction is associated with the progression of non-alcoholic steatohepatitis (NASH) and may be partly a consequence of insufficient mitochondrial protein homeostasis, which is controlled by several chaperones and proteases such as mitochondrial matrix caseinolytic protease P (ClpP). Choi and coworkers report reduced hepatic CIpP levels in human NASH and mouse models of NASH. The knock-down of ClpP in hepatocytes and in vivo induces mitochondrial dysfunction, oxidative stress, inflammation and steatosis, while the overexpression or pharmacological induction attenuates diet-induced NASH and decreases fibrosis. This study thereby provides insight into the mechanistic role of mitochondrial dysfunction in NASH and indicates CIpP as a potential target against NASH progression.

      Stiffness-induced angiocrine signalling in liver sinusoidal endothelial cells

      Liver sinusoidal endothelial cells (LSECs) can release inflammatory and angiocrine mediators, which may regulate liver fibrosis and portal hypertension. Using primary human and mouse LSECs as well as LSEC-specific knock-out mice, Greuter, Yaqoob and coworkers identify that matrix stiffness regulates glycolytic enzymes in LSECs, which control angiocrine signalling, including via the chemokine CXCL1. Endothelial cell-specific inhibition of glycolysis attenuates neutrophil infiltration and development of portal hypertension in vivo, indicating that glycolytic enzymes could represent promising (and druggable) targets in early liver disease to prevent inflammation and portal hypertension.

      Disrupted ER–mitochondria interactions promote hepatic insulin resistance and steatosis

      Cellular organelles including endoplasmic reticulum (ER) and mitochondria can crosstalk in hepatocytes at interfaces, e.g. via mitochondria-associated membranes (MAMs). Using dietary and genetic interventions in a non-alcoholic fatty liver disease (NAFLD) mouse model, Beaulant and coworkers demonstrate that ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, while nutritional changes or a synthetic linker targeting MAMs can prevent overnutrition-induced glucose intolerance. Similar observations in liver biopsies of obese patients with and without type 2 diabetes indicate that ER-mitochondria communication could be a marker and trigger of insulin sensitivity in humans.

      Counteracting NASH by hepatic lipoprotein secretion?

      While fat vacuoles accumulate in hepatocytes due to increased lipogenesis and free fatty acid uptake in fatty liver, the secretion of lipoproteins such as VLDL may counteract fat accumulation. Jiang and coworkers studied vacuole membrane protein 1 (VMP1) that regulates hepatic phospholipids and lipoprotein secretion. Hepatic VMP1 is decreased in human NAFLD/non-alcoholic steatohepatitis (NASH). In mouse models, hepatocyte-specific deletion of VMP1 severely aggravates steatosis and NASH, while VMP1 overexpression improves diet-induced NAFLD. These data identify an important endogenous mechanism by which the liver counteracts NASH progression, indicating that this pathway should be further explored as a therapeutic target.

      Metformin can salvage immune checkpoint inhibitor therapy in NASH-related HCC

      NASH may negatively affect the efficacy of immune checkpoint inhibitor therapy, e.g. via anti-PD1, against hepatocellular carcinoma (HCC). Wabitsch and coworkers tested the influence of different NASH models on T-cell responses and anti-PD-1 treatment for liver cancer in mice. All different NASH conditions impaired motility, metabolic function and response of hepatic CD8+ T cells to anti-PD-1 treatment, which blunted their efficacy against HCC tumour cells implanted into the fatty liver. Intriguingly, metformin treatment rescued the efficacy of anti-PD-1 or anti-PD-L1 therapy against liver tumours in murine NASH, possibly via the metabolic reprogramming of CD8+ T cells. The data indicate novel strategies to improve immune checkpoint inhibitor therapy against NASH-related HCC in humans.

      Viral hepatitis

      A risk prediction model for HCC after HBsAg seroclearance

      After spontaneous HBsAg seroclearance, the risk of HCC remains. The study by Yang and coworkers aimed to evaluate incidence and risk factors for HCC and establish a novel prediction model for HCC development after HBsAg seroclearance. Age at HBsAg seroclearance, presence of cirrhosis, family history of HCC, and more-than-moderate alcohol consumption were independently predictive of HCC, and these 4 independent variables were used to develop a prediction model. The time-dependent AUROCs of the score for HCC prediction at 5, 10, and 15 years were 0.799, 0.835, and 0.817, respectively. The authors conclude that this novel prediction model may serve as a useful reference for decision-making in HCC surveillance for patients after HBsAg clearance.

      Efficacy and safety of vebicorvir administered in virologically suppressed patients with chronic HBV infection

      New therapies are needed to provide deeper suppression of HBV replication with the goal of achieving durable, off-treatment virologic response. To address this need, vebicorvir (VBR), an investigational HBV core inhibitor, was developed to interfere with multiple steps of the HBV viral-replication cycle, reducing HBV DNA, pregenomic RNA, and the transcriptional activity of covalently closed circular DNA. A phase II trial evaluated the efficacy and safety of this investigational core inhibitor in 73 virologically suppressed non-cirrhotic patients on nucleos(t)ide reverse transcriptase inhibitors (NrtIs). In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline receiving VBR+NrtI achieved DNA target not detected at Week 24 compared to PBO+NrtI. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Yuen and coworkers conclude that VBR added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

      Autoimmune hepatitis

      CD8 T cell-enriched immune infiltrate with activated SARS-CoV-2-specific CD8 T cells in vaccine-associated hepatitis

      Autoimmune hepatitis episodes have been described following SARS-CoV-2 infection and vaccination, but their pathophysiology remains unclear. Boettler, Csernalabics and coworkers report the case of a 52-year-old male presenting with bimodal episodes of acute hepatitis, each occurring 2-3 weeks after BNT162b2 mRNA vaccination. Analysis of the hepatic tissue revealed an immune infiltrate quantitatively dominated by activated cytotoxic CD8 T cells with panlobular distribution. An enrichment of CD4 T cells, B cells, plasma cells and myeloid cells was also observed compared to controls. The intrahepatic infiltrate showed enrichment for CD8 T cells with SARS-CoV-2-specificity compared to the peripheral blood. The authors conclude that COVID-19 vaccination can elicit a distinct T cell-dominant immune-mediated hepatitis.

      NAFLD/NASH

      Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with NASH

      Given the complex pathogenesis of NASH, combination pharmacotherapies are a rational approach. Alkhouri et al. tested semaglutide alone or in combination with cilofexor (a farnesoid X receptor agonist at 2 different doses) or firsocostat (an acetyl-CoA carboxylase inhibitor) or triple therapy for 6 months in 108 patients with NASH randomised into 5 groups. Despite similar reductions in body weight among groups (-7% to -9.6%) some efficacy parameters favoured the combination arms. All combination arms had a slightly larger reduction in liver fat content (-9.8 to -11% vs. -8% for semaglutide alone). Changes in ALT (-32 IU/L to -40 IU/L vs. -13 IU/L) as well as normalisation of ALT (86-100% vs. 50%) were also significantly greater in the combination groups than in the semaglutide monotherapy arm. Overall reduction in liver stiffness were similar even though more patients achieved a 25% reduction in the combination arms. Reductions in ELF and Fibrotest were noted without differences between arms. There were no unexpected side effects. Despite the use of semaglutide, LDL increases were seen in the cilofexor groups and triglycerides increases in arms containing firsocostat. Despite its limitations, i.e. not being placebo controlled, being of short duration, and being conducted in a relatively small sample, this study hints to some benefit of combinatorial approaches for NASH.

      Rare ATG7 genetic variants predispose patients to severe fatty liver disease

      The effect of pathogenic but rare variants on the severity of NAFLD is not well known. Heading a large Italian consortium with UK collaboration, Baselli et al. present the results of whole exome sequencing in 301 patients with NASH and advanced fibrosis or HCC. They identified a loss-of-function variant in the autophagy-related 7 gene (ATG7) that was enriched in patients with severe NAFLD. In the UK Biobank cohort, the ATG7 variant increased the risk of cirrhosis (odds ratio [OR] 3.3) and HCC (OR 12). They also identified other rare variants of the catalytic domain of the same gene (increasing the risk of severe NAFLD by an OR of 14) as well as a second loss of function variant. The latter increased the risk of severe NAFLD, hepatocellular ballooning and AST levels in the UK Biobank with a larger effect size in severely obese individuals where it also increased the risk of HCC. The rare and low-frequency ATG7 loss-of-function variants described here act as modifiers of NAFLD progression by impairing autophagy and facilitating ballooning and inflammation.
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      Cirrhosis and liver failure

      An RCT comparing 20% albumin to plasmalyte in patients with cirrhosis and sepsis-induced hypotension

      In this study, Maiwall, Kumar and co-authors considered the choice of resuscitation fluid in patients with cirrhosis and sepsis-induced hypotension (SIH), which was still unclear. The authors compared the efficacy and safety of 20% albumin, which is known to have greater oncotic properties, to plasmalyte in reversing SIH. Critically-ill cirrhotic patients were evaluated and underwent open-label randomisation to either 20% albumin (0.5–1.0 mg/kg over 3 hours; n = 50) or plasmalyte (30 ml/kg over 3 hours, n = 50). In the intention-to-treat analysis, albumin was superior to plasmalyte in achieving the primary endpoint of mean arterial pressure >65 mmHg (62% vs. 22%, p <0.001). A faster decrease in arterial lactate (p = 0.03), a reduced need for dialysis (48% vs. 62%; p = 0.06) and a longer time to dialysis were found in the albumin group. Nevertheless, the 28-day mortality was not different between the 2 groups (58% vs. 62%, p = n.s.). Eleven (22%) patients in the albumin group needed to discontinue therapy because of adverse effects, compared to none in the plasmalyte group. Therefore, the authors concluded that albumin infusion is superior to plasmalyte in transiently improving haemodynamics in patients with cirrhosis and SIH, but close monitoring is warranted since it is more often associated with adverse effects.
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      Increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death

      In this prospective study, Alberto Zanetto and co-workers investigated the whole blood platelet aggregation in cirrhosis, and its association with liver-related outcomes. Platelet aggregation was assessed by whole blood aggregometry. In order to overcome the influence of platelet count and compare patients with cirrhosis with thrombocytopenia vs. controls with normal platelet count, we calculated a ratio between platelet aggregation and platelet count (PLT ratio). Patients with cirrhosis were followed prospectively up to transplantation or death. Two-hundred and three patients with cirrhosis were recruited (77% decompensated). The PLT ratio increased with disease severity (Child-Pugh class C>B>A) and was particularly elevated in decompensated patients with severe thrombocytopenia. In the decompensated group of patients, 65 had further decompensation, underwent transplantation, or died during a 6-month follow-up. On a multivariate analysis, PLT ratio and MELD score were independently associated with outcome. The risk of events was 7.5-fold higher in patients with PLT ratio >0.75 vs. patients with PLT ratio <0.025. The prognostic value of PLT ratio >0.75 and its discriminative ability for the composite outcome were confirmed in an independent cohort of hospitalised patients with decompensated cirrhosis. Thus, patients with cirrhosis, in particular those with decompensated cirrhosis, showed a significant increase of PLT ratio and a PLT ratio >0.75 was associated with an 80% probability of further decompensation, transplantation, or liver-related death within 6 months.

      Structured early detection of asymptomatic liver cirrhosis: results of the population-based liver screening programme SEAL

      Labenz, Arslanow and co-workers aimed to evaluate the usefulness of a structured screening procedure in order to detect cirrhosis as early as possible. Participants in the German health check-up after the age of 35 were offered a questionnaire, liver function tests (AST and ALT), as well as a follow-up. In the presence of elevated levels of AST/ALT, the APRI score was calculated, and patients with a score >0.5 were referred to a liver expert in secondary and/or tertiary care. As a final result, 11,859 participants were enrolled, and available for final analysis. The control group consisted of 349,570 members undergoing regular check-up. The SEAL study found 488 individuals with elevated APRI scores (4.12%), and 45 cases of advanced fibrosis/cirrhosis. The standardised incidence of advanced fibrosis/cirrhosis in the screening programme was slightly higher than in controls (3.83‰ vs. 3.36‰). Thus, the comparison of the chance of fibrosis/cirrhosis diagnosis in SEAL vs. in routine care was inconclusive. However, it has to be taken into account that when patients with decompensated cirrhosis at initial diagnosis were excluded from both cohorts in a post hoc analysis, SEAL was associated with a 59% higher chance of early cirrhosis detection than routine care on average. Thus, the implementation of a structured screening programme may increase the rate of early detection of cirrhosis in the general population.

      Hepatic cancer

      Increasing tumour response while preventing toxicity of immunotherapy for HCC

      There is some degree of association between the occurrence of tumour response and immune-mediated adverse events (IMAEs) in patients receiving immune checkpoint inhibitors. Chuah et al. have studied comprehensively (using cytometry by time-of-flight and single-cell RNA sequencing) two small cohorts of patients with HCC treated with a PD-1 inhibitor. They observed that tumour response/prolonged stabilisation, progression-free survival and occurrence of IMAEs were associated with the presence in peripheral blood of clusters of CD11c+ antigen presenting cells (APCs) and CXCR3+CD8+ effector memory T (TEM) cells. Based on predicted cell-cell communications between these TEM cells and other immune cells, they also found distinct pathways – involving TNFR1 and TNFR2 – that could be targeted to uncouple response from irAEs during anti-PD-1 blockade. Indeed, the combination of PD-1 and TNFR2 blockade results in enhanced response without increased IMAEs in the animal HCC model. This combination immunotherapy with dual PD-1 and TNFR2 blockade could therefore enhance response without exacerbating IMAEs and should be explored further.

      Biography

      Patrizia Burra∗ at Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy.

      Biography

      Frank Tacke at Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.

      Biography

      Vlad Ratziu at Insitute for Cardiometabolism and Nutrition, Sorbonne Université and Hospital Pitié Salpêtrière, Paris, France.

      Biography

      Stefan Zeuzem at Department of Medicine I, Goethe University Hospital, Frankfurt, Germany.

      Biography

      Bruno Sangro at Liver Unit, Clinica Universidad Navarra and CIBEREHD, Pamplona, Spain.

      Biography

      Paolo Angeli at Unit of Internal Medicine and Hepatology, University of Padua, Padua, Italy.