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In this issue, Cai Q. et al. evaluated the clinical characteristics of patients with COVID-19 and abnormal liver tests. Clinical records and laboratory results were obtained from 417 patients with laboratory confirmed COVID-19 who were admitted to the only referral hospital in Shenzhen, China. Of 417 patients with COVID-19, 318 (76.3%) had abnormal liver tests and 90 (21.5%) had liver injury during hospitalisation. The presence of abnormal liver tests became more pronounced during hospitalisation. The use of lopinavir/ritonavir was found to lead to increased odds of liver injury. Patients with abnormal liver tests of hepatocellular type or mixed type at admission were at greater risk of progressing to severe disease. The authors stated that the potential detrimental effects on liver injury mainly related to drugs used during hospitalisation, which should be monitored.
An inadvertent gift from mama: How maternal obesity increases liver cancer susceptibility in offspring
The global obesity epidemic affects liver health across generations. Sun and coworkers now demonstrate, in multi-generational obesity models in mice, that maternal obesity caused susceptibility of offspring to diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC). Using sophisticated methods, the authors identified the microRNA miR-27a-3p as crucial for this process. This microRNA was upregulated in obese mouse mothers and passed on to the offspring, where it enhanced liver tumour incidence by regulating the expression levels of Acsl1 and Aldh2 genes. This fascinating over-generational mechanism of obesity-induced HCC susceptibility warrants further studies in human cohorts.
Autophagy and necroptosis are co-regulated and interlinked in hepatocytes during fatty liver disease
Autophagy is a highly conserved intracellular process for the ordered degradation of cellular components in lysosomes, which provides energy and recycled substrates (amino acids, glucose, fatty acids) to the cell. Insufficient autophagy in hepatocytes has been implicated in non-alcoholic fatty liver disease (NAFLD). Wu and coworkers now provide an in-depth series of experimental data revealing a co-regulatory mechanism between necroptosis and autophagy in NAFLD. Mlkl-dependent, but Rip3-independent, signalling contributed to “Western diet”-induced liver injury and inflammation through inhibition of autophagy. This new link from mouse models may provide novel targets for intervening in the pathogenesis of NAFLD.
Gut-liver axis revisited: How intestinal Paneth cells influence angiogenesis and portal hypertension
Paneth cells in the epithelium of the small intestine produce antimicrobial peptides and balance the intestinal microbiota. Hassan and coworkers now demonstrate the involvement of Paneth cells in the haemodynamic changes caused by experimental portal hypertension. Using mouse models with Paneth cell depletion as well as intestinal organoids, this study revealed that Paneth cells produce angiogenic molecules – partly in response to signals from the intestinal microbiota – that impact intestinal and mesenteric angiogenesis and regulate portal hypertension. This study raises the perspective that intestinal cells could be a novel target to alleviate portal hypertension.
Cytotoxic functions of MAIT cells in human liver during acute viral hepatitis
Mucosal-associated invariant T (MAIT) cells are abundantly present “innate-like T cells” in human liver, but their role is poorly understood. Rha and coworkers studied many paired samples from blood and liver in human patients, characterising these cells in healthy liver and demonstrating an as yet unrecognised mechanism of MAIT cell activation in acute viral hepatitis. MAIT cell activation by IL-15 results in an NKG2D-dependent cytotoxicity and contributes to immune-mediated liver injury in acute hepatitis A. MAIT cells might therefore represent an interesting target to either reduce immune-mediated injury in acute hepatitis or to increase the elimination of virus-infected cells.
In this paper Balzano T. et al. tested the hypothesis that chronic hyperammonaemia would induce peripheral inflammation which, in turn, would induce neuro-inflammation and cognitive impairment. The effects of chronic hyperammonaemia, induced by feeding rats with an ammonia-containing diet, on peripheral inflammation, neuro-inflammation and cognitive impairment were analysed before and after the administration of an anti-TNFα agent (Infliximab). Rats with hyperammonaemia showed a rapid and reversible induction of peripheral inflammation, with increased pro-inflammatory PGE2, TNFα and IL-6. Peripheral anti-TNFα treatment prevented peripheral inflammation induction, the increase in IL-1β and TNFα and microglia activation in the hippocampus of the rats, which remained hyperammonaemic. This was associated with prevention of the altered membrane expression of glutamate receptors and of the impairment of spatial memory. The authors stated that peripheral inflammation may be a mechanism by which hyperammonaemia induces cognitive impairment. Thus, they hypothesised that reducing peripheral inflammation could improve cognitive function in patients with hepatic encephalopathy.
Viral hepatitis
C19orf66 is an interferon-induced inhibitor of HCV replication
Innate immunity is key during the entire natural course of HCV infection, highlighted by the presence of viral immune evasion strategies that attenuate the innate immune response. Transcriptomic analysis of liver biopsies from HCV-infected patients revealed induction of hundreds of interferon (IFN)-stimulated genes (ISGs), suggesting a pivotal role of ISGs in the intrinsic antiviral immune response against HCV. C19orf66 is a multifunctional ISG with potential antiviral activities against several viruses. Kinast and coworkers show that C19orf66 is upregulated in vivo and ex vivo in response to HCV infection and to IFN therapy. Expression of C19orf66 restricted HCV infection, whereas knockout of C19orf66 attenuated IFN-mediated suppression of HCV replication. C19orf66 expression impaired HCV-induced elevation of phosphatidylinositol-4-phosphate and altered the morphology of the viral replication organelle (membranous web). Taken together, the data identify C19orf66 as an IFN-inducible restriction factor with a novel antiviral mechanism specifically targeting HCV replication.
Hepatitis C treatment and long-term hepatic function in advanced decompensated cirrhosis
Direct-acting antiviral (DAA) HCV therapy is used in patients with decompensated cirrhosis with the expectation of improving hepatic function. Little is known about the long-term benefit of successful treatment. Within the HCV-TARGET registry, Verna and coworkers evaluated 642 patients with advanced/decompensated cirrhosis (model for end-stage liver disease [MELD] score ≥10) who initiated NS5A-containing DAA therapy prior to September, 2018. Among patients with available virologic outcomes, 90.5% achieved a sustained virological response; 24% achieved a clinically significant decrease in MELD by ≥3 points during short term follow-up (9-26 weeks after the end of treatment). However, in long-term follow-up (median of 4 years after treatment), mean changes in MELD (-0.30 points), total bilirubin (+0.23 mg/dl) and albumin (+0.36 g/dl) were marginal. Fifty-one patients died and 22 underwent liver transplantation. The authors of the study conclude that patients with advanced cirrhosis must continue to be closely followed and may remain at high risk of decompensation in the long term.
Chronic hepatitis D and hepatocellular carcinoma
Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis but its role in the development of HCC remains debated. Alfaiate and coworkers conducted a systematic review and meta-analysis of epidemiological studies to examine whether CHD is associated with an increased risk of HCC. Ninety-three studies (68 case-control studies including 22,862 patients and 25 cohort studies including 75,427 patients) were included. The overall analysis showed a significantly increased risk of HCC in patients with CHD, despite substantial study heterogeneity. The association was particularly strong in the absence of heterogeneity for prospective cohort studies, and studies with HIV-infected patients. The findings highlight the rationale for improving HDV screening in patients with hepatitis B, and the urgent need for novel and effective antiviral therapies.
The global prevalence of hepatitis D virus infection
There are uncertainties about the epidemic patterns of HDV infection and its contribution to the burden of liver disease. Stockdale and coworkers estimated the global prevalence of HDV infection. They included 282 studies, comprising 376 population samples from 95 countries, which together tested 120,293 HBsAg-positive people for anti-HDV. The estimated anti-HDV prevalence was 4.5% among all HBsAg-positive people and 16.4% among those attending hepatology clinics. Worldwide, 0.16% of the general population, 12.0 million people overall, were estimated to be anti-HDV positive. Prevalence among HBsAg-positive people was highest in Mongolia, the Republic of Moldova and countries in Western and Middle Africa, and was higher in injecting drug users, haemodialysis recipients, men who have sex with men, commercial sex workers, and those with HCV or HIV coinfection.
NAFLD
NAFLD in pregnancy is associated with adverse maternal and perinatal outcomes
While the adverse risks of obesity and gestational diabetes on perinatal outcomes are well established, Sarkar et al. studied whether NAFLD during pregnancy confers additional risks for maternal or perinatal health. They used the 2007-2016 US National Inpatient Sample of more than 18 million normal pregnancies, 5,640 with NAFLD and 115,210 with non-NAFLD chronic liver diseases. They first showed that pregnancies with NAFLD nearly tripled from 2007 to 2015. Then they established that gestational diabetes, gestational hypertension, hypertensive complications (pre-eclampsia, eclampsia, and/or HELLP), caesarean section, and postpartum haemorrhage, as well as pre-term birth, were significantly more common in pregnancies with NAFLD, compared to pregnancies with other CLD or no CLD. On multivariate analysis, NAFLD was independently associated with hypertensive complications, postpartum haemorrhage and pre-term birth. NAFLD should be considered a high-risk obstetric condition, with clinical implications for pre-conception counselling and pregnancy care.
Most genome-wide association studies (GWASs) in NAFLD assessed hepatic triglyceride content as a reference phenotype but lacked detailed histological classification for other lesions with prognostic value. Anstee et al. performed GWAS in 1,483 European NAFLD cases recruited from several European tertiary care centres and 17,781 genetically matched population controls. A replication Italian cohort of 559 NAFLD cases and 945 controls was also included. A majority (78%) of liver pathology slides were scored by a central pathologist and the remainder but the local one. This study confirmed PNPLA3, TM6SF2 and HSD17B13 variants as the major risk factors for disease susceptibility. A combined genetic risk score based on summing the allele count had a statistically significant relationship with the semi-quantitative steatosis/NAS/fibrosis scores, with the most significant relationship detected for fibrosis stage. This result was replicated in the Italian cohort. They also identified a signal in the gene coding for PYGO1 (a transcription factor that contributes to Wnt signalling) with close to genome-wide significance for steatosis. Additional case-control analyses were undertaken but did not identify other traits with genome-wide significance. This study also confirmed that the newly identified HSD17B13 isoform (lacking the exon 6 in the liver) had a protective effect against NAFLD. Importantly, there were no significant associations of any genotype with disease activity when considered separately from steatosis.
Liver cancer
Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with cirrhosis
Over the last 4 years, there has been intense controversy regarding the possibility that DAAs could increase the chances of newly diagnosed or recurrent HCC in a fraction of patients. The subgroup at risk was allegedly enriched in patients with pre-existing indeterminate liver nodules. Sangiovanni et al. led a prospective multicentre study on 1,285 consecutive cirrhotic patients treated with DAAs, Among cirrhotics without HCC, de novo tumours appeared in 48 patients (yearly incidence 3.1/100 patients-year, 77% in early stages), with a 2-year cumulative incidence of 5.4% in patients with no nodules and 13.6% in patients with undefined/non-malignant nodules (UNMNs). UNMNs, prior ascites and alpha-fetoprotein levels were independently associated with the incidence of de novo HCC on multivariate analysis. Among cirrhotics with HCC in complete response, recurrence occurred in 40 patients (yearly incidence 29.9/100 patients-year, 83% in early stages), with a 2-year cumulative incidence of 42.9%. A peak of instant incidence was observed at 7.7 months. The authors concluded that an early peak of incidence for both de novo HCC in patients with UNMNs and recurrent HCC was observed in cirrhotic patients treated with DAAs, but increased incidence was not associated with increased tumour aggressiveness.
Cirrhosis and liver failure
Changes in frailty are associated with waitlist mortality in patients with cirrhosis: A multicentre cohort study
Lai J.C. et al. aimed to evaluate change in frailty over time (DLFI) and its association with death/delisting for sickness. A total of 1,093 outpatients with cirrhosis without HCC, listed for liver transplantation at 8 centres in the US underwent ambulatory longitudinal frailty testing with the liver frailty index (LFI). A multilevel linear mixed effects regression was used to model and predict DLFI per 3 months based on age, gender, MELDNa, ascites, and hepatic encephalopathy. Patients were categorised into 4 groups by frailty trajectories. The impact of baseline LFI and predicted DLFI on death/delisting, was evaluated with transplantation as the competing risk. After a median follow-up of 11 months, 223 (20%) of the overall cohort of patients died/were delisted for sickness. The cumulative incidence of death/delisting increased by worsening DLFI group. In competing risk regression, a 0.1 unit change in DLFI per 3 months was associated with a 2-fold increased risk of death/delisting. The authors stated that changes in frailty were significantly associated with death/delisting independent of baseline frailty and MELDNa in patients with cirrhosis. Thus, they supported the longitudinal measurement of frailty, using the LFI, and interventional work aimed at reversing frailty in these patients.
Cholestatic disease
Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis
In most liver transplant centres, ursodeoxycholic acid (UDCA) is generally employed after the diagnosis of recurrent primary biliary cholangitis (PBC) has been established. In this longitudinal, retrospective analysis of a very large, multicentre, international cohort Corpechot et al. attempted to understand whether prophylactic administration of UDCA is beneficial. They included 780 patients transplanted for PBC and followed-up for a median of 11 years; 190 patients received preventive UDCA (10-15 mg/kg/d). During follow-up, 30% of patients exhibited PBC recurrence and this accounted for a quarter of liver-related deaths and lower rates of patient and graft survivals. Despite patient baseline differences between those who did or did not receive UDCA and large differences between centres, preventive administration of UDCA was associated with a lower risk of disease recurrence, graft loss, liver-related death, and all-cause death. Interestingly, cyclosporine rather than tacrolimus use added to the preventive effect of UDCA against PBC recurrence, graft loss and all-cause death. These results strongly favour initiation of UDCA therapy soon after LT for PBC, as this may not only prevent PBC recurrence but also reduce its long-term negative impact.
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 University Medicine 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.
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