From the Editor's Desk...
Authors: Patrizia Burra, Frank Tacke, Vlad Ratziu, Stefan Zeuzem, Bruno Sangro, Paolo Angeli
Journal: Journal of Hepatology (2020)

In acute-on-chronic liver failure (ACLF), the link between systemic inflammation and the development of organ failure has been poorly investigated up to now. Moving from the concept that systemic inflammation is energetically expensive, Moreau and coworkers analysed the blood metabolome in 181 patients with cirrhosis and ACLF, 650 with cirrhosis and acute decompensation (AD) without ACLF, 43 with compensated cirrhosis, and 29 healthy controls. Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. The authors observed that the higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers: tumour necrosis factor α, soluble CD206, and soluble CD163. In patients with cirrhosis and ACLF, intense systemic inflammation is associated with profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures. Liver cancer cells quite strikingly adapt their cellular metabolism to allow unrestrained proliferation. However, some of these metabolic adaptations might be needed by non-malignant hepatocytes during liver regeneration as well. Ding and coworkers thoroughly compared metabolic pathways between hepatocellular carcinoma (HCC) cells/models and normal or regenerating hepatocytes, demonstrating that key proteins in the proline biosynthesis pathway were highly upregulated in HCC models and were associated with poor prognosis in human HCC. Moreover, targeting different enzymes in the proline biosynthesis pathway effectively inhibited tumour growth in HCC cell lines. It will be now important to assess whether these fundamental metabolic pathways represent a therapeutic target in vivo, especially in the context of diseased (e.g., fatty or fibrotic) livers with concomitant regeneration. Uncontrolled proliferation in cancer cells might reflect activation of cellular pathways from early embryonic development. Guan and coworkers analysed human hepatic organoids derived from induced pluripotent stem cells by single-cell RNA sequencing and metabolic profiling. The phosphatidyl-ethanolamine biosynthesis pathway was essential for early liver development, as well as being highly sensitive to the cytotoxic effects of the over-the-counter antihistamine meclizine. These principal findings could be recapitulated in HCC cell lines and a xenograft tumour model, suggesting that thorough analysis of early liver development might enable the discovery of novel anti-cancer drugs for HCC. The relevance of this metabolic pathway as well as the efficacy of meclizine, alone or in combination, for human HCC remain to be determined. Many cancers secrete epithelial mucins, such as MUC13, and express cell surface glycoproteins. Pei and colleagues demonstrate that MUC13 has a critical role in intrahepatic cholangiocarcinoma (iCCA). Using a large set of in vitro and in vivo experiments, MUC13 enhanced proliferation, motility and invasiveness of iCCA cells, mainly by interacting with EGFR and downstream signalling (EGFR/PI3K/AKT). MUC13 expression was also high in human iCCA samples and associated with metastasis. This study indicates a key role of MUC13 in iCCA aggressiveness and pinpoints several up- and downstream pathways for potential interventions. ACLF is associated with high mortality and typically develops after precipitating events, particularly infections, in patients with liver cirrhosis. ACLF is characterised by excessive systemic inflammation, impaired bacterial clearance and diminished regeneration. Xiang and coworkers provide novel mechanistic insight into regeneration in ACLF. They developed a new mouse model of ACLF, consisting of chronic fibrotic injury, aggravated acute toxic damage and systemic Klebsiella pneumoniae infection, and demonstrate that the ability of hepatocytes to proliferate is impaired due to a switch from the STAT3 to the STAT1 pathway in ACLF. Stimulation of the STAT3 pathway by interleukin-22 (IL-22) restored regeneration in this ACLF model. The new ACLF rodent model, as well as this fundamental understanding of how inflammation and regeneration are regulated in ACLF, may open new avenues for innovative therapies. The potential therapeutic benefit of IL-22, however, still requires confirmation in human patients. Hepatocyte cell death is a critical event in the progression of all chronic inflammatory liver diseases including non-alcoholic steatohepatitis (NASH). Necroptosis is a particular form of programmed cell death, distinct from apoptosis and necrosis, that is activated in NASH. Necroptosis is controlled by the activation of RIPK1 and 3 and a downstream pseudokinase, MLKL. Majdi et al. tested the inhibition of necroptosis using a highly specific RIPK1 inhibitor, RIPA56, in a high-fat diet model in mice. RIPK1 inhibition resulted in a dramatic improvement of all NASH lesions including inflammation and fibrosis. In vitro RIPK1 inhibition (but also MLKL inactivation) reduced steatosis by improving mitochondrial function. Moreover, serum levels of RIPK and MLKL were increased in patients with NASH and correlated with the activity of the disease and alanine aminotransferase (ALT) levels. This study reveals the importance of necroptosis for the pathogenesis of NASH, demonstrates that blocking necroptosis can improve NASH and that specific inhibitors should be tested as pharmacological agents for NASH. It also suggests that serum biomarkers for necroptosis should be further investigated as they appear to be correlated with the severity of the disease. Pioglitazone never became a mainstream off-label treatment for NASH because of tolerability issues, mainly weight gain, anaemia, fractures and oedema. A drug devoid of these side effects but retaining the insulin sensitising properties and the histological efficacy of pioglitazone would be ideal. Colca et al. have shown in multiple previous studies that in addition to activating the nuclear receptor PPARγ, thiazolidinediones also inhibit the mitochondrial pyruvate carrier (MPC). This results in insulin sensitising effects, while the side effects seem to result mainly from PPARγ activation. Harrison et al. report the results of a clinical trial testing a second-generation thiazolidinedione, MSDC-0602K, that is primarily an activator of MPC in patients with NASH. This was a 1-year trial testing 3 doses against placebo, with histological endpoints assessed in 392 patients. While MSDC-0602K had clear insulin sensitising effects and led to a small but significant reduction in ALT, there was no histological benefit. The authors detail issues that occurred with the pathological assessment and that might have influenced the negative results. Of concern, there was moderate but real weight gain, thus questioning the selectivity of MSDC-0602K for the MPC target in humans, despite promising animal data. A selective thiazolidinedione modulator that minimises side effects while maintaining histological efficacy is yet to be identified. Few data are reported on the long-term outcome of patients with decompensation of alcohol-associated liver disease. The retrospective study from Degré́ and coworkers is based on prospective databases of patients consecutively admitted for liver decompensation with biopsy proven alcohol-associated steatohepatitis and Maddrey's discriminant function <32. The authors evaluated 5-year survival in 121 patients admitted for ascites, jaundice, or encephalopathy, 84% of whom already had cirrhosis. During the follow-up, 30% of the patients remained abstinent. Survival rates at 1, 6, 12, 24, and 60 months were 96.7 ± 1.6%, 90.1 ± 2.7%, 80.8 ± 3.6%, 69.9 ± 4.3%, and 50.7 ± 4.9%, respectively. The majority of deaths (80%) were liver related. In multivariable analysis, encephalopathy at baseline and alcohol abstinence were predictive of 5-year survival. When the authors stratified patients into 2 categories, with and without encephalopathy at baseline, the 5-year survival rates were 29.7 ± 8.0% and 60.5 ± 5.8%, respectively, when the authors stratified the patients according to non-abstinence and abstinence, the 5-year survival rates were 40.9 ± 5.8% and 74.0 ± 8.0%, respectively. Mortality of patients with alcohol-associated hepatitis, with steatohepatitis, with or without cirrhosis, presenting with an AD, is around 50% at 5 years. New treatment strategies, including measures to ensure abstinence, are required. Neutralising antibodies would form a key component of a protective HCV vaccine. The rational design of immunogens has been hindered by the lack of understanding of the variable epitope immunogenicity, and the association of epitope-specific responses and neutralising activity with the outcome of primary infections. Brasher and coworkers characterised the predominant neutralising and non-neutralising antibody (epitope) targets in patients with acute HCV infection. They found that no epitopes were uniquely targeted by clearers vs. those who developed chronic infection. Samples with broad neutralising antibody activity were enriched for multi-specific responses directed towards epitopes AR3, AR4 and domain D, and did not target non-neutralising domains. Genotype 1 and 3 infections were associated with responses targeted towards different broad neutralising antibody domains. The findings highlight key epitopes that are associated with broadly neutralising antibodies, and the deleterious impact of mounting a response towards some of these domains on neutralising breadth. These findings should guide future efforts to design immunogens aimed at generating neutralising antibodies with a vaccine candidate. Egypt has one of the highest burdens of HCV infection worldwide, and a large treatment programme, but reaching rural communities represents a major challenge. Shiha and coworkers report the feasibility and effectiveness of a comprehensive community-based HCV prevention, testing and treatment model in 73 villages across Egypt. The model comprised community mobilisation facilitated by a network of village promoters to support the education, test and treat campaign, as well as fundraising in the local community. Of 221,855 eligible villagers, 204,749 were screened for HCV antibody and HBsAg, and 33,839 and 763 were positive, respectively. 15,892 villagers were HCV RNA positive, 14,495 received DAA treatment and 14,238 (98.3%) achieved sustained virological response (SVR) at 12 weeks. 3,192 patients had cirrhosis, and of these 166 (5.2%) were diagnosed with HCC. Georgia, with a 5.4% prevalence of HCV infection, launched the world's first national hepatitis C elimination programme in April 2015 with the goal of a 90% prevalence reduction by 2020. Averhoff and coworkers report on progress and key challenges of this programme in identifying HCV-infected people and linking them to care and treatment. As of December 31, 2018, 1,101,530 adults (39.6% of the adult Georgian population) were screened for HCV antibody, of whom 98,430 (8.9%) tested anti-HCV positive, and 78,484 (79.7%) received viremia testing. Of these, 66,916 people (85.3%) tested positive for active HCV infection. A total of 52,576 people with active HCV infection initiated treatment, 48,879 completed their course of treatment. Of the 35,035 who were tested for sustained virologic response, 34,513 (98.5%) achieved SVR. HCV reinfection following successful antiviral treatment can compromise treatment outcome. Bibliographic databases and conference abstracts were searched by Hajarizadeh and coworkers for studies assessing post-treatment HCV reinfection rate among people with recent drug use (injecting or non-injecting) or those receiving opioid agonist therapy (OAT). Thirty-six studies were included (person-years follow-up = 6,311). The overall rate of HCV reinfection was 5.9/100 person-years among people with recent drug use (injecting or non-injecting), 6.2/100 person-years among people recently injecting drugs, and 3.8/100 person-years among those receiving OAT. In stratified analysis, the reinfection rate was 1.4/100 person-years among people receiving OAT with no recent drug use, 5.9/100 person-years among people receiving OAT with recent drug use, and 6.6/100 person-years among people with recent drug use, not receiving OAT. In meta-regression analysis, longer follow-up was associated with a lower reinfection rate. Overall, HCV reinfection is lower than rates of primary infection that have been reported in the literature in this population and it should not be used as a reason to withhold therapy from people with ongoing injecting drug use. The data also illustrate that harm reduction services are required to reduce the reinfection risk, while regular post-treatment hepatitis C assessment is required for early detection and retreatment. Fontan surgery (FS) is used to treat children with congenital cardiopathies characterised by a single functional ventricle. In FS, the venous blood from the inferior and superior vena cava is diverted directly to the pulmonary arteries, and the systemic and pulmonary circulations are consequently placed in series with the functional single ventricle. Systemic venous congestion is inevitable and leads to advanced chronic liver disease in the long-term. Liver nodules and even HCC have been described in children and adults after FS but the prevalence, characteristics and predictors are largely ignored. Téllez et al. have conducted an international, cross-sectional and observational study in which 152 consecutive patients with FS were thoroughly studied. After an average of 18 years from surgery, liver nodules were detected in 29.6% of patients by US and in 47.7% by MRI or CT. Most nodules (59.7%) were LI-RADS-3, and the characteristic appearance of HCC (early contrast uptake and wash-out) was observed in 8 patients (6.1%). However, the diagnosis of HCC was confirmed in only 2 out of 7 patients that were biopsied, speaking against the use of non-invasive criteria in this setting. Regular screening with ultrasound (US) examination is recommended for patients at significant risk of developing HCC due to chronic liver disease. However, the entire liver volume may not be adequately scanned with US in some patients, particularly those who are obese with fatty liver disease. Park et al. assessed whether non-contrast enhanced MRI could be a good alternative. They analysed the diffusion-weighted imaging and T2-weighted images of almost 400 patients who prospectively underwent 1 to 3 rounds of paired gadoxetic acid-enhanced MRI and US. Forty-eight HCCs were diagnosed in 43 patients. Per-lesion, non-enhanced MRI showed a higher positive predictive value (56.9% vs. 16.7%), negative predictive value (99.1% vs. 96.9%), sensitivity (77.1% vs. 25.0%), and specificity (97.9% vs. 94.5%). The estimated scan time of non-enhanced MRI was very short at <6 minutes, although the values of the entire duration of the MRI study were not provided. No doubt this observation warrants further prospective investigation in larger series, paying attention to cost-effectiveness. Patrizia Burra* at Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy. ∗ Corresponding author. Frank Tacke at Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany. Vlad Ratziu at Insitute for Cardiometabolism and Nutrition, Sorbonne Université and Hospital Pitié Salpêtrière, Paris, France. Stefan Zeuzem at Department of Medicine I, Goethe University Hospital, Frankfurt, Germany. Bruno Sangro at Liver Unit, Clinica Universidad Navarra and CIBEREHD, Pamplona, Spain. Paolo Angeli at Unit of Internal Medicine and Hepatology, University of Padua, Padua, Italy.