Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression.

Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this 'proof of concept' study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis.

Incidence and prevalence of venous thromboembolism in chronic liver disease: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Historically, bleeding was thought to be a frequent and fatal complication of liver disease. However, thrombosis due to coagulation disorders in cirrhosis remains a real risk. We aim to systematically analyse published articles to evaluate epidemiology of venous thromboembolism (VTE) in chronic liver disease (CLD). METHOD: Electronic search was conducted on Ovid Medline, EMBASE and Scopus from inception to November 2021 to identify studies presenting epidemiology VTE (deep vein thrombosis and pulmonary embolism) in CLD in inpatients and/or community settings. Random-effects meta-analysis was performed to determine pooled per-year cumulative incidence, incidence rate and prevalence. Heterogeneity was measured by I2 test, and, potential sources of heterogeneity by meta-regression and sensitivity analysis. PROSPERO registration-CRD42021239117. RESULTS: Twenty-nine studies comprising 19,157,018 participants were included, of which 15,2049 (0.79%) had VTE. None of the included studies were done in the community. In hospitalised patients with CLD: pooled cumulative incidence of VTE was 1.07% (95% CI 0.80,1.38) per-year, incidence rate was 157.15 (95% CI 14.74,445.29) per 10,000 person-years, and period prevalence was 1.10% (95% CI 0.85,1.38) per year. There was significant heterogeneity and publication bias. Pooled relative risk (RR) of studies reporting incidence rate was 2.11 (95% CI 1.35,3.31). CLD patients (n = 1644), who did not receive pharmacological prophylaxis were at 2.78 times (95% CI 1.11, 6.98) increased risk of VTE compared to those receiving prophylaxis. CONCLUSION: Hospitalised patients with CLD may be at an increased risk of VTE. For every 1000 hospitalised patients with CLD ten have new, and eleven have pre-existing diagnoses of VTE per-year.

Estimating the clinical prevalence of Wilson's disease in the UK.

BACKGROUND & AIMS: The clinical prevalence of Wilson's disease (WD) in the UK remains unknown. The estimated genetic prevalence in the UK, 142/million, is higher than the clinical prevalence (15/million) reported in other European studies. The aim of this study was to estimate the clinical prevalence of WD utilising readily available laboratory and clinical data. METHOD: Patients with WD who attended Nottingham University Hospital NHS Trust (NUH) between 2011 and 2018 were identified using multiple sources of case ascertainment: serum ceruloplasmin, 24-hour urinary copper, 'Wilson' in liver biopsy report, hospital prescription for penicillamine/trientine/zinc and admission coded with ICD-10 Code E83.0 (disorder of copper metabolism). Potential cases were identified using the Leipzig score, diagnosis was confirmed in hospital records and the point prevalence was calculated using the Office for National Statistics mid-2017 population estimates. RESULTS: A total of 1,794 patients were identified from ≥1 source; 19 patients had WD, of whom 11 were from within the study catchment area and alive at the time of point prevalence estimation. Twenty-nine patients had a Leipzig score ≥2 without a diagnosis of WD, but none had WD on screening (n = 16). The overall prevalence of WD was 15.5/million; males 16.9/million and females 14.1/million. CONCLUSION: This is the first UK population-based study to assess the clinical prevalence of WD. The reported clinical prevalence is lower than the UK genetic prevalence, but comparable to the clinical prevalence reported in Europe. The case ascertainment approach used in this study may be cost-effective, and similar practises could be adopted nationally. LAY SUMMARY: Our study estimates the clinical prevalence of Wilson's disease, a rare genetic disorder of copper metabolism, in the UK. The estimated clinical prevalence is this study is markedly lower than the estimated UK genetic prevalence.

Zanubrutinib-induced liver injury: a case report and literature review.

BACKGROUND: Zanubrutinib is a Bruton's tyrosine kinase inhibitor that has been recently licensed in refractory mantle cell lymphoma and under assessment in phase 3 clinical trials for other B cell malignancies. To date, there are no reported cases of hepatotoxicity secondary to zanubrutinib. We report the first case of severe liver injury due to zanubrutinib. CASE PRESENTATION: A 56-year-old Caucasian male with a history of relapsed lymphoplasmacytic lymphoma was admitted to the hospital with new-onset jaundice, choluria, and pruritus for 10 days. He had been on zanubrutinib as part of a clinical trial for 30 months. His blood profile showed a severe hepatocellular injury with jaundice (alanine transaminase 2474 IU/L and total bilirubin 141 umol/L with mild coagulopathy). He had an extensive work-up including virology, autoimmune, and metabolic profiles in addition to abdominal ultrasound with no alternative explanation found for his liver injury. Zanubrutinib-induced liver injury was suspected, and causality assessment by the updated Roussel Uclaf Causality Assessment Method score showed a probable causal relationship with zanubrutinib. His liver histology was also consistent with drug-induced liver injury. His liver biochemistry improved following cessation of zanubrutinib and normalised after 8 weeks. CONCLUSION: We report the first case of severe liver injury secondary to zanubrutinib after 30 months of treatment. This case raises clinical awareness regarding zanubrutinib-induced liver toxicity and the importance of drug withdrawal in the event of liver injury.

Long-term outcomes of liver transplant recipients followed up in non-transplant centres: Care closer to home.

INTRODUCTION: Increasing rates of liver transplantation and improved outcomes have led to greater numbers of transplant recipients followed up in non-transplant centres. Our aim was to document long-term clinical outcomes of liver transplant recipients managed in this 'hub-and-spoke' healthcare model. METHODS: A retrospective analysis of all adult patients who underwent liver transplantation between 1987 and 2016, with post-transplant follow-up in two non-transplant centres in the UK (Nottingham) and Canada (Ottawa), was performed. RESULTS: The 1-, 5-, 10- and 20-year patient survival rates were 98%, 95%, 87% and 62%, and 100%, 96%, 88% and 62% in the Nottingham and Ottawa groups, respectively (p=0.87). There were no significant differences between the two centres in 1-, 5-, 10- and 20-year cumulative incidence of death-censored graft-survival (p=0.10), end-stage renal disease (p=0.29) or de novo cancer (p=0.22). Nottingham had a lower incidence of major cardiovascular events (p=0.008). CONCLUSION: Adopting a new model of healthcare provides a means of delivering post-transplant patient care close to home without compromising patient survival and long-term clinical outcomes.

Brain activity underlying the recovery of meaning from degraded speech: A functional near-infrared spectroscopy (fNIRS) study.

The purpose of this study was to establish whether functional near-infrared spectroscopy (fNIRS), an emerging brain-imaging technique based on optical principles, is suitable for studying the brain activity that underlies effortful listening. In an event-related fNIRS experiment, normally-hearing adults listened to sentences that were either clear or degraded (noise vocoded). These sentences were presented simultaneously with a non-speech distractor, and on each trial participants were instructed to attend either to the speech or to the distractor. The primary region of interest for the fNIRS measurements was the left inferior frontal gyrus (LIFG), a cortical region involved in higher-order language processing. The fNIRS results confirmed findings previously reported in the functional magnetic resonance imaging (fMRI) literature. Firstly, the LIFG exhibited an elevated response to degraded versus clear speech, but only when attention was directed towards the speech. This attention-dependent increase in frontal brain activation may be a neural marker for effortful listening. Secondly, during attentive listening to degraded speech, the haemodynamic response peaked significantly later in the LIFG than in superior temporal cortex, possibly reflecting the engagement of working memory to help reconstruct the meaning of degraded sentences. The homologous region in the right hemisphere may play an equivalent role to the LIFG in some left-handed individuals. In conclusion, fNIRS holds promise as a flexible tool to examine the neural signature of effortful listening.