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From the Editor’s Desk...

      Selection of the month

      Recurrent autoimmune hepatitis following liver transplantation

      The impact of recurrent autoimmune hepatitis (AIH) post-liver transplantation (LT) on patient or graft survival is not well characterised. In this large, international, and multi-centre study, Montano-Loza and coworkers aimed to identify the frequency of and risk factors associated with recurrent AIH after LT, and the impact of recurrent disease on patient and graft survival. Seven hundred and thirty-six patients (77% female, mean age, 42±1 years) with AIH who underwent LT from January 1987 to June 2020, were enrolled from 33 centres spanning North America, South America, Europe and Asia. AIH recurred in 20% of the patients after 5 years and 31% after 10 years. Age at LT ≤42 years, use of mycophenolate mofetil post-LT, donor and recipient sex mismatch, and high level of IgG pre-LT were associated with a higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression analysis, recurrent AIH was significantly associated with graft loss and death.
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      Experimental and translational hepatology

      Post-translational protein modification as a novel therapeutic target in cholangiocarcinoma

      The heterogeneity of cholangiocarcinoma (CCA) has already led to the development of personalised therapies, up to now largely based on distinct genomic mutations in patient subgroups. Olaizola and coworkers now demonstrate in CCA patient samples and rodent models that a post-translational protein modification, namely NEDDylation, drives tumorigenesis in CCA and impacts on tumour-stroma interactions. Intriguingly, pharmacological inhibition of NEDDylation via pevonedistat inhibits cholangiocarcinogenesis in experimental models, indicating that this protein modification process may represent a potential therapeutic target in patients with CCA.

      Molecular mechanisms of immune evasion and anti-PD1 resistance in liver cancer

      Immunotherapy has now become part of the first-line systemic therapy in hepatocellular carcinoma (HCC), but using immunotherapies such as anti-PD1 antibodies as a monotherapy is not effective in most patients. Based on their finding that the zinc finger protein ZFP64 is frequently upregulated in tumour tissues from patients with anti-PD1-resistant HCC, Wei and coworkers used cell and animal models to demonstrate that the PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance in liver cancer. Activation of this pathway shifts the polarisation of tumour-associated macrophages, thereby enabling immune evasion by tumours. Importantly, sensitivity to anti-PD1 could be restored by Gö6976, a protein kinase inhibitor, and lenvatinib, a multi-kinase inhibitor, which could be the basis for new combinatorial therapies against HCC.

      Mitochondrial fatty acid oxidation modulates the profibrogenic activation of HSCs

      The activation of hepatic stellate cells (HSCs) leading to their transdifferentiation towards matrix-producing myofibroblasts is a key event in liver fibrosis. Fondevila and coworkers now demonstrate in a series of sophisticated experiments involving HSC-specific mice deficient for the mitochondrial protein carnitine palmitoyltransferase 1A (CPT1A) that this energy-consuming process of HSC activation depends on mitochondrial fatty acid metabolism. CPT1A, known as the rate-limiting enzyme in medium- and long-chain fatty acid beta-oxidation may therefore represent an interesting target for fibrosis treatment aimed at specifically blocking the fibrogenic activation of HSCs.

      Viral hepatitis

      Duration and cost-effectiveness of HCC surveillance after HCV eradication

      Although successful treatment of patients with hepatitis C resulting in sustained virologic response (SVR) represents a “cure” from the standpoint of persistent infection, the subsequent risk of HCC persists and remains an important contributor to liver-related morbidity and mortality in the post-direct-acting antiviral (DAA) era. The objective of the study by Mueller, Chen and coworkers was to evaluate the cost-effectiveness of bi-annual surveillance for HCC in patients cured of hepatitis C and the optimal age to stop surveillance. The authors developed a microsimulation model of the natural history of HCC in individuals with advanced fibrosis or cirrhosis who achieved virological cure with oral DAAs and compared bi-annual HCC surveillance using ultrasound and alpha-fetoprotein for varying durations of surveillance (from 5 years to lifetime) vs. no surveillance. Their data show that ultrasound-based bi-annual screening for liver cancer is cost-effective up to age 70 in those with cirrhosis and up to age 60 in those with stable advanced fibrosis.

      End-of-treatment HBcrAg and HBsAb levels identify durable functional cure after Peg-IFN-based therapy in patients with CHB

      HBsAg loss with or without seroconversion to HBsAb is considered a functional cure and the ideal endpoint of antiviral therapy for chronic hepatitis B (CHB). A series of randomized controlled trials reported that sequential pegylated interferon alfa (Peg-IFN-ɑ) treatment in virally suppressed patients with CHB undergoing long-term nucleos(t)ide analogue therapy significantly increased the rate of HBsAg loss. The study by Huang, Wu and coworkers aimed to identify biomarkers associated with a durable functional cure and to dissect the potential immunological mechanisms. Lower HBcrAg and higher HBsAb levels at the end of Peg-IFN-ɑ treatment were associated with sustained cellular and humoral immune responses and can be used to identify patients likely to achieve durable functional cure post Peg-IFN-based therapy. These patients showed maintained proportions of HBV envelope-specific CD8+ T and B cells, a markedly increased proportion of T follicular helper cells after Peg-IFN-ɑ discontinuation, and significantly higher proportions of HBV polymerase-specific CD8+ T and CD86+CD19+ B cells at the end of follow-up.

      Heparanase-1 is upregulated by HCV and favours its upregulation

      Chronic HCV infection evolves through stages of fibrosis, cirrhosis and may lead to liver decompensation or HCC. How HCV induces liver cancer is not yet fully understood since it is a non-integrative virus, but epidemiological observations suggest that HCV could fuel liver carcinogenesis by creating an oxidative, inflammatory microenvironment characterised by concomitant wound repair processes. Gallard, Lebsir and coworkers investigated the impact of HCV on liver extracellular matrix with a focus on heparanase-1 (HPSE). HPSE expression was assessed in liver biopsies infected or not by HCV and in Huh7.5 cells using quantitative reverse-transcription PCR, immunoblotting and immunofluorescence. HCV propagation led to significant HPSE induction, in vivo and in vitro. HPSE enhanced infection when exogenously expressed or supplemented as a recombinant protein. HPSE favoured HCV release by enhancing CD63 synthesis and exosome secretion, but not by stimulating HCV entry or genome replication. The authors also showed that virus-induced oxidative stress was involved in HPSE induction, most likely through NF-κB activation.
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      Absence of chronicity in infants born to immunized mothers with occult HBV infection in Taiwan

      HBsAg carrier rates have fallen below 2% in young Taiwanese born in the universal vaccination era, where occult hepatitis B infection (OBI) develops in approximately 5% of individuals. Ming-Wei Lai and coworkers investigated whether mothers with OBI could transmit HBV to their babies. Eleven babies born to 10 mothers with OBI were recruited. Three babies were HBsAg-reactive, and 2 were positive for HBV DNA. Two transiently transmitted babies harboured variants originating from their mother’s HBV quasispecies. All infants received complete hepatitis B vaccines. At 12 months of age, none of the babies were positive for HBsAg or HBV DNA. The authors concluded that it is possible for mothers with OBI to transmit HBV to their babies, however, viremia cleared 1 year after completing the hepatitis B vaccination series.

      Drug-induced liver injury

      Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity

      A new study by Ghallab et al. shed a very original light on acetaminophen toxicity. It all starts with the finding of increased bile acid concentrations in serum of patients with acetaminophen intoxication. In mice, there is a time-dependent increase in bile acid concentrations that precedes the increase in aminotransferases and cell death. Using intravital imaging techniques that enable functional analysis at subcellular resolution, the authors went on to demonstrate that the diameter of the bile canaliculi was strikingly dilated in the pericentral lobular zone while hepatocytes in the periportal zone displayed a very strong uptake of bile acids. This coincides with a loss in mitochondrial potential of hepatocytes and precedes cell death. Canalicular dilation was probably due to altered tight-junction morphology (documented through zonulin1 and claudin3 immunostaining) which occurred very early after acetaminophen ingestion. Collectively, these data suggest that, following acetaminophen overdose, bile acids leak from the bile canaliculi in the pericentral zone into the sinusoidal blood and are then massively taken up by hepatocytes, way above toxic threshold concentrations, thus contributing to hepatocyte cell death. Blocking the sinusoidal bile acid uptake carriers strongly ameliorates acetaminophen-induced hepatotoxicity. These findings could possibly result in new therapeutic options.

      Cirrhosis

      Predicted estimates of resting energy expenditure have limited clinical utility in patients with cirrhosis

      Accurate assessment of energy requirements is needed to optimise dietary intake. Resting energy expenditure (REE), the major component of total energy expenditure, can be measured using indirect calorimetry (mREE) or estimated using prediction equations (pREE). Limon-Miro, Jackson and coworkers assessed the usefulness of predicted estimates of REE in a large cohort of patients with cirrhosis. Individual mREE data were available for 900 patients with cirrhosis and 282 healthy controls. Metabolic status was classified using thresholds based on the mean ±1 SD of the mREE in the healthy controls. Comparisons were made between mREE and pREE estimates obtained using the Harris-Benedict, Mifflin, Schofield and Henry equations. Stepwise regression was used to build 3 new prediction models which included sex, ethnicity, body composition measures, and MELD scores. The mean mREE was significantly higher in patients than controls when referenced to dry body weight without significant differences related to sex. The mean mREE was significantly higher in Caucasian patients than in Asian patients. Overall, 37.1% of the Caucasians and 25.3% of the Asians were classified as hypermetabolic. In the total population, pREE estimates ranged from 501 kcal/24 hr less to 548 kcal/24 hr more than the mREE. Newly derived prediction equations provided better estimates of mREE but still had limited clinical utility. The authors concluded that prediction equations do not provide useful estimates of REE in patients with cirrhosis and, thus, REE should be directly measured.

      Acute kidney disease is common and associated with poor outcomes in patients with cirrhosis and acute kidney injury

      Acute kidney disease (AKD) is the persistence of acute kidney injury (AKI) for up to 3 months. In this study, Patidar and coworkers aimed to define the incidence and outcomes associated with AKD in a nationwide US cohort (n = 6,250) of hospitalised patients with cirrhosis and AKI. KDIGO and ADQI-AKD and Renal-Recovery consensus criteria were used to define AKI and AKD, respectively. The primary outcome was mortality; the secondary outcome was de novo development of chronic kidney disease (CKD). Competing-risk multivariable models were used to determine the independent association of AKD with primary and secondary outcomes. AKD developed in 32% of patients. On multivariable competing risk analysis adjusting for significant confounders, patients with AKD had higher risk of mortality at 90 and 180 days. The incidence of de novo CKD was 37.5% and patients with AKD had higher rates of de novo CKD than patients without AKD (64.0% vs. 30.7%). AKD was independently associated with de novo CKD.

      Hepatic cancer

      AI predicts immune and inflammatory gene signatures directly from HCC histology

      In HCC, response to and survival after immunotherapy with immune checkpoint inhibitors is to some extent associated with the presence of inflammatory and gene signatures. However, genomic analyses have several limitations including availability, timeliness and cost. Using 2 different series of surgically treated patients with HCC, Zeng, Klein and coworkers studied gene expression through RNA sequencing or NanoString technology and then used 3 deep-learning approaches to predict such signatures from digital histological slides obtained from formalin fixed-paraffin embedded samples. In the discovery series, the best model was able to predict upregulation of the immune gene signatures with an AUC of 0.74 to 0.87. In the validation series, the different models had AUCs between 0.81 and 0.91. Pathological analysis of highly predictive tissue areas showed enrichment in inflammatory cells, plasma cells, and neutrophils. This study narrows the gap between pathological and genomic analysis of tumour samples and may help change clinical practice by allowing us to gaze at what the human eye can only glimpse in pathological slides.
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      A meta-analysis that supports the benefits of liver cancer surveillance

      Despite being recommended in most guidelines, there is still considerable controversy regarding the overall value of HCC surveillance in patients with cirrhosis given the lack of strong randomised controlled data. Singal, Zhang and coworkers performed a systematic review and meta-analysis of 59 cohort studies reported between 2014 and 2020 which assessed the benefits and harms of HCC surveillance in almost 150,000 patients with cirrhosis. Surveillance was associated with improved early-stage detection (RR 1.86), curative treatment receipt (RR 1.83), and overall survival (HR 0.67) after adjusting for lead-time bias. Yet, there was notable heterogeneity in all pooled estimates. Where assessed, the proportion of patients experiencing surveillance-related physical harms (mostly mild) ranged from 8.8% to 27.5% across studies. These results support the practice of HCC surveillance in patients with cirrhosis.

      DePARylation, tumour aggressiveness and potential synergy with immunotherapy

      The modification of chromosomal proteins by poly (ADP-ribose)ylation or PARylation is key in DNA damage repair. While suppression of PARylation by PARP inhibitors impairs DNA repair and induces apoptosis of defective tumour cells, we have more recently learned that dePARylation may also play a fundamental role in DNA damage repair. Yu, Chen, Zhou and coworkers have shown that high expression of PAR glycohydrolase (PARG) was associated with poor prognosis after resection in a large group of patients with HCC and that PARG has an important role in HCC progression and metastasis in preclinical models, acting through DDB1-dependent stabilisation of c-myc protein. Furthermore, PARG downregulation attenuated the expression of several mismatch repair genes induced by c-myc. Interestingly, PARG expression was lower in patients responding to PD-1 inhibitors compared to non-responders, and a PARG inhibitor increased the efficacy of a PD-1 inhibitor in a murine HCC model, opening the door for the therapeutic assessment of such a combination.

      Liver transplantation

      Past COVID-19 and immunosuppressive regimens affect the long-term response to anti-SARS-CoV-2 vaccination in liver transplant recipients

      The long-term immunogenicity of anti-SARS-CoV-2 vaccines in liver transplant (LT) recipients is still poorly known. Toniutto and coworkers aimed to assess the long-term antibody response of the Pfizer-BioNTech® BNT162b2 vaccine in LT recipients compared to controls. LT recipients underwent anti-SARS-CoV-2 anti-receptor binding domain protein IgG (anti-RBD) and anti-nucleocapsid protein IgG antibody (anti-N) measurements at the first and 1, 4 and 6 months after the second vaccination dose. Overall, 143 recipients and 58 controls were enrolled. At baseline, 131/143 (91.6%) LT recipients tested anti-N negative (COVID-19 naïve), and 12/143 (8.4%) tested positive (COVID-19 recovered) compared to negative controls. The median anti-RBD titre 4 months after the second vaccine dose was significantly lower (32 U/ml) in COVID-19 naïve than in controls (852 U/ml, p <0.0001). A higher daily dose of mycophenolate mofetil (MMF), a higher frequency of ascites, and lower serum leukocyte count were independent predictors of anti-RBD negativity at 6 months. The median antibody titre was similar in those taking MMF or not taking MMF 3 weeks after the first and 1, 4 and 6 months after the second vaccine dose, respectively. Therefore, the authors concluded that in COVID-19-naïve LT recipients, the immunogenicity of anti-SARS-CoV-2 vaccination was significantly lower than that in controls, with MMF being the main determinant of vaccination failure.

      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.