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Background: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults., Methods: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I., Results: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01)., Conclusions: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD., Competing Interests: Declaration of Competing Interest DT, JS, RBT, KPH and AJ have no conflicts of interest to disclose. PB has accepted speaking fees and honoraria from Vertex pharmaceuticals and advisory board fees from INSMED. VA has accepted speaking fees and honoraria from Vertex pharmaceuticals and Roche diagnostics., (Copyright © 2023. Published by Elsevier B.V.)

Background: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, tolerance has been limited by hepatic toxicity. It is unknown whether there may be particular risk factors for significant drug-induced elevation in transaminases., Objective: We aimed to determine the cause of raised transaminases following the introduction of E/T/I, and whether E/T/I can safely be continued in some individuals with elevated transaminases., Methods: At a large, single, adult CF centre, individuals with transaminases >3 × the upper limit of normal (ULN) since commencing E/T/I underwent clinical assessment to exclude known causes of raised transaminases. Where an alternative cause could not be identified, individuals were discussed with hepatology to advise on further investigations to establish aetiology in addition to calculation of the updated Roussel Uclaf Causality Assessment Method (RUCAM) score to assess causality grading of drug-induced liver injury (DILI) due to E/T/I, and to guide management of ongoing CFTR modulator therapy., Results: Of 337 adults taking E/T/I for a median of 27 months, 19 (5.6%) had transaminases >3 × ULN. In 12 individuals, there was clear evidence of an aetiology unrelated to E/T/I (RUCAM scores -2 to 1 [excluded-unlikely]). Of the remaining cases, two had RUCAM scores in the 'possible' range and one had a RUCAM score in the 'probable' range. Liver biopsy was performed in four individuals, showing hepatic steatosis in one individual, normal histology in one individual, and hepatocyte necrosis suggestive of DILI in two individuals. E/T/I was suspended in those with hepatocyte necrosis, with one permanent discontinuation due to synthetic dysfunction. One individual with hepatocyte necrosis on histology was successfully re-established on E/T/I therapy., Conclusions: Alternative causes were identified in the majority of patients with clinically significant increases in transaminases following E/T/I, highlighting the importance of thorough investigation. Multidisciplinary assessment involving an experienced hepatologist is crucial in cases of diagnostic uncertainty or suggestion of significant DILI, as discontinuation of therapy can have significant consequences for individuals., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking., Methods: Patients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD., Results: 255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy., Conclusions: E/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Donor hepatitis-C (HCV) infection has historically represented a barrier to kidney transplantation (KT). However, direct-acting antiviral (DAA) medications have revolutionised treatment of chronic HCV infection. Recent American studies have demonstrated that DAA regimes can be used safely peri-operatively in KT to mitigate HCV transmission risk. Methods: To formulate this narrative review, a comprehensive literature search was performed to analyse results of existing clinical trials examining KT from HCV-positive donors to HCV-negative recipients with peri-operative DAA regimes. Results: 13 studies were reviewed (11 single centre, four retrospective). Outcomes for 315 recipients were available across these studies. A sustained virological response at 12 weeks (SVR12) of 100% was achieved in 11 studies. One study employed an ultra-short DAA regime and achieved an SVR12 of 98%, while another achieved SVR12 of 96% due to treatment of a missed mixed genotype. Conclusion: HCV+ KT is safe and may allow increased utilisation of organs for transplantation from HCV+ donors, who often have other favourable characteristics for successful donation. Findings from US clinical trials can be applied to the United Kingdom transplant framework to improve organ utilisation as suggested by the NHSBT vision strategy "Organ Donation and Transplantation 2030: meeting the need"., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Doherty, Athwal, Moinuddin, Augustine, Prince, van Dellen and Khambalia.)

Chronic liver disease (CLD) is an ignored epidemic. Premature mortality is considerable and in the United Kingdom (UK) liver disease is in the top three for inequitable healthcare alongside heart and respiratory disease. Fifty percentage of patients with CLD are first diagnosed with cirrhosis after an emergency presentation translating to poorer patient outcomes. Traditional models of care have been based in secondary care when the need is at community level. Investigating patients for disease based on their risk factors at a population level in the community will identify its presence early when there is potential reversibility. Innovation is needed in three broad areas to improve clinical care in this area: better access to diagnostics within the community, integrating diagnostics across primary and secondary care and utilizing digital healthcare to enhance patient care. In this article, we describe how the Integrated Diagnostics for Early Detection of Liver Disease (ID-LIVER) project, funded by UK Research and Innovation, is developing solutions in Greater Manchester to approach the issue of diagnosis of liver disease at a population level. The ambition is to build on innovative pathways previously established in Nottingham by bringing together NHS organizations, academic partners and commercial organizations. The motivation is to co-create and implement a commercial solution that integrates multimodal diagnostics via cutting edge data science to drive growth and disrupt the currently inadequate model. The ambitious vision is for this to be widely adopted for early diagnosis and stratification of liver disease at a population level within the NHS., Competing Interests: ING and JM have received investigator led funding research from Gilead Sciences. Gilead had no intellectual input into the study concept or design, interpretation of the results or editing the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bennett, Purssell, Street, Piper Hanley, Morling, Hanley, Athwal and Guha.)

Background: Prescription information for many drugs entering the market lacks dosage guidance for hepatic impairment. Dedicated studies for assessing the fate of drugs in hepatic impairment commonly stratify patients using Child-Pugh score. Child-Pugh is a prognostic clinical score with limitations in reflecting the liver's metabolic capacity., Aims: To demonstrate the need for better drug dosing approaches in hepatic impairment, summarise the current status, identify knowledge gaps related to drug kinetic parameters in hepatic impairment, propose solutions for predicting the liver disease impact on drug exposure and discuss barriers to dosing guidance in those patients., Methods: Relevant reports on dosage adjustment in hepatic impairment were analysed concerning the prediction of the impairment impact on drug kinetics using physiologically-based pharmacokinetic (PBPK) modelling., Results: PBPK models are suggested as a potential framework to understand drug clearance changes in hepatic impairment. Quantifying changes in abundance and activity of drug-metabolising enzymes and transporters, understanding the impact of shunting, and accounting for interindividual variations in drug absorption could help in extending the success of these models in hepatically-impaired populations. These variables might not correlate with Child-Pugh score as a whole. Therefore, new metabolic activity markers, imaging techniques and other scoring systems are proposed to either support or substitute Child-Pugh score., Conclusions: Many physiological changes in hepatic impairment determining the fate of drugs do not necessarily correlate with Child-Pugh score. Quantifying these changes in individual patients is essential in future hepatic impairment studies. Further studies assessing Child-Pugh alternatives are recommended to allow better prediction of drug exposure., (© 2021 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

In vitro to in vivo extrapolation (IVIVE) enables prediction of in vivo clinical outcomes related to drug exposure in various populations from in vitro data. Prudent IVIVE requires scalars specific to the biologic characteristics of the system in each population. This study determined experimentally for the first time scalars in liver samples from patients with varying degrees of cirrhosis. Microsomal and cytosolic fractions were extracted from 13 noncirrhotic and 32 cirrhotic livers (six mild, 13 moderate, and 13 severe, based on Child-Pugh score). Fractional protein content was determined, and cytochrome P450 reductase activity was used to correct for microsomal protein loss. Although the median microsomal protein per gram liver (MPPGL) in mild, moderate, and severe cirrhosis (26.2, 32.4, and 30.8 mg⋅g -1 , respectively) seemed lower than control livers (36.6 mg⋅g -1 ), differences were not statistically significant (Kruskal-Wallis test, P > 0.05). Corresponding values for cytosolic protein per gram liver were 88.2, 67.9, 62.2, and 75.4 (mg⋅g -1 ) for mild, moderate, and severe cirrhosis and control livers, respectively, with statistically lower values for severe versus controls (Mann-Whitney P = 0.006). Cirrhosis associated with cancer showed lower MPPGL (24.8 mg⋅g -1 ) than cirrhosis associated with cholestasis (38.3 mg⋅g -1 , P = 0.003). Physiologically based pharmacokinetic simulations with disease-specific scalars captured cirrhosis impact on exposure to alfentanil, metoprolol, midazolam, and ethinylestradiol. These experimentally-determined scalars should alleviate the need for indirect scaling using functional liver volume. Scaling factors in cirrhosis might be a reflection of the etiology rather than the disease severity. Hence, bundling various cirrhotic conditions under the same umbrella when predicting hepatic impairment impact should be revisited. SIGNIFICANCE STATEMENT: Cirrhosis-specific scalars required for extrapolation from microsomal or cytosolic in vitro systems to liver tissue are lacking. These scalars can help in predicting drug clearance and selection of dosage regimens for cirrhosis populations. Attempts to consider potential changes have been empirical and ignored the potential impact of the cause of cirrhosis. We obtained experimental values for these scalars for the first time and assessed their impact on predicted exposure to various substrate drugs using physiologically-based pharmacokinetics simulations., Competing Interests: A.R.-H. holds shares in Certara, a company focusing on model‐informed drug development, and declares no support from any organization for the submitted work. All other authors declare that they have no conflicts of interest., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Abdominal pain is a common feature in patients with cystic fibrosis (CF) and CF related liver disease (CFLD). Superior mesenteric venous (SMV) thrombosis is an uncommon but important cause of abdominal pain. Management strategies are complicated by an underlying prothrombotic state and increased risk of bleeding from complications of CF and CFLD. This review addresses clinical presentation, detection and management options of an acute SMV thrombus in the context of CF., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Autophagy and the unfolded protein response (UPR) both promote activation of hepatic stellate cells (HSC), however the link between the two stimuli remains unclear. Here we have explored the role of X-box binding protein 1 (XBP1), one of three UPR effector pathways and sought to establish the interdependence between autophagy and the UPR during HSC activation. XBP1 induction accompanied both culture-based HSC activation and ER stress induced by tunicamycin. Ectopic overexpression of XBP1 induced collagen 1-alpha expression in HSCs, which was inhibited by knockdown of ATG7, a critical autophagy mediator. Genome-wide transcriptomic profiling indicated an upregulation of collagen synthesis pathways, but not of the transforming growth factor (TGF)-b pathway, a canonical fibrogenic driver, suggesting that XBP1 activates a specific subset of fibrogenesis pathways independent of TGF-β1. XBP1 target gene signatures were significantly induced in rodent liver fibrosis models (n = 3-5) and in human samples of non-alcoholic fatty liver disease (NAFLD) (n = 72-135). Thus, XBP1-mediated UPR contributes to fibrogenic HSC activation and is functionally linked to cellular autophagy.

Background: To ensure patient safety, rigorous quality assurance (QA) measures for colonoscopy were introduced for the Bowel Cancer Screening Programme (BCSP) in England. The impact of these high QA measures on patient experience and satisfaction is unknown., Aims: To determine the impact of this high-level QA of colonoscopy on patient satisfaction., Methods: A case controlled study using a retrospective audit & telephone interview patient survey was performed between 1/1/07-01/10/08 on patients that underwent colonoscopy. Data were analyzed by comparing quantitative and qualitative performance colonoscopy indicators in patients within the BCSP with those outside the programme (NON-BCSP)., Participants: 720 patients that had undergone day case colonoscopy., Setting: Accredited BCSP centre: University Hospitals Aintree, UK., Intervention: Comparing patient satisfaction between BCSP to NON-BCSP populations., Results: Uptake was 68% (n=488). Caecal intubation rate (CIR) was higher (99 v 91%; p=0.001), and sedation doses lower in BCSP compared to NON-BCSP (Midazolam dose Median [IQR] (1 [0, 2] v 2 [1, 3] mg; respectively p=0.0001). For patient satisfaction and experience, scores were high and pain scores were low in both groups; with no statistically significant difference between groups. However, willingness to have a repeat procedure was higher in BCSP (p=0.001)., Conclusions: Whilst superior CIR with less sedation within BCSP, overall scores were similar for patient satisfaction, both in and outside the programme. With the higher 'willingness for repeat' within BCSP, a positive impact of higher level of QA is suggested and that good patient experience can be achieved with minimal conscious sedation in expert hands.

Unlabelled: Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression., Conclusion: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis., (Copyright © 2012 American Association for the Study of Liver Diseases.)

The transcription factor SOX9 is crucial for multiple aspects of development. Mutations in SOX9 cause campomelic dysplasia, a haploinsufficiency disorder concordant with the expression profile of SOX9 during embryogenesis. The mechanistic understanding of development has revealed roles for SOX9 in regulating cartilage extracellular matrix (ECM) production and cell proliferation, among others. More recently, it transpires that SOX9 becomes expressed and induces destructive ECM components in organ fibrosis and related disorders. Although commonly absent from the parent cell type, SOX9 is expressed in a wide range of cancers, where it regulates cell proliferation. These data have potential diagnostic, prognostic and therapeutic relevance, suggesting that disease mechanisms might result from re-expressing this developmental transcription factor in ectopic locations., (Copyright © 2010 Elsevier Ltd. All rights reserved.)