The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. ...The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery.
The American, European, and Latin American liver societies have proposed a change in the nomenclature we use to describe alcohol-related liver disease and non-alcoholic fatty liver disease. ...Additionally, a term encompassing both is now advocated: steatotic liver disease, which includes metabolic dysfunction associated steatotic liver disease (MASLD) and MASLD with greater alcohol consumption (MetALD). These classifications offer increased relevance for clinicians, researchers, and patients alike. In this Viewpoint, we discuss the basis for this nomenclature shift and how it was developed. We also explore the challenges that will be faced in the adoption of such change. The proposed change seeks to banish stigma associated with phrasing such as alcoholic and fatty. However stigma, particularly related to the term fatty, is culturally nuanced, and reflects different entities depending on location. If such a change is internationally accepted, there will be wide-reaching effects on practitioners in primary care and metabolic medicine, and on patients. We discuss those effects and the opportunities the nomenclature change could offer, particularly for patients with alcohol and metabolic risk factors who represent a group previously ignored by clinical trials.
Background
Type 2 diabetes (T2D) is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non‐alcoholic ...fatty liver disease (NAFLD). However, the absolute risk of progression is low. So, it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk‐stratification tools are suboptimal and perform worse in people with diabetes.
Aims
To determine whether the addition of complementary biomarker(s) to current NAFLD risk‐stratification tools in people with T2D could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC.
Methods
The Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with T2D (n = 1066, age 60–75 at baseline). Cases of cirrhosis and HCC were identified over 11 years of follow‐up. Biomarkers were measured at baseline and year 1 and association with incident disease was assessed using logistic regression.
Results
Of existing risk‐stratification scores tested, the Fibrosis‐4 (FIB‐4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut‐point ≥ 50 μ g/L) to FIB‐4 (cut‐point ≥ 1.3) maintained a false negative rate of ≤25% and reduced the number of people incorrectly identified as “high risk” for incident disease by ∼50%.
Conclusions
The addition of hyaluronic acid to FIB‐4 reduced the proportion of people inappropriately identified as “high risk” for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with T2D. These findings require a validation in independent cohorts.
Non-invasive quantitation of liver disease using multiparametric magnetic resonance imaging (MRI) could refine clinical care pathways, trial design and preclinical drug development. The aim of this ...study was to evaluate the use of multiparametric MRI in experimental models of liver disease. Liver injury was induced in rats using 4 or 12 weeks of carbon tetrachloride (CCl
) intoxication and 4 or 8 weeks on a methionine and choline deficient (MCD) diet. Liver MRI was performed using a 7.0 Tesla small animal scanner at baseline and specified timepoints after liver injury. Multiparametric liver MRI parameters T1 mapping, T2* mapping and proton density fat fraction (PDFF) were correlated with gold standard histopathological measures. Mean hepatic T1 increased significantly in rats treated with CCl
for 12 weeks compared to controls 1122±78 ms versus 959±114 ms; d=162.7, 95% CI (11.92, 313.4),
=0.038 and correlated strongly with histological collagen content (r
=0.717,
=0.037). In MCD diet-treated rats, hepatic PDFF correlated strongly with histological fat content (r
=0.819,
<0.0001), steatosis grade (r
=0.850,
<0.0001) and steatohepatitis score (r
=0.818,
<0.0001). Although there was minimal histological iron, progressive fat accumulation in MCD diet-treated livers significantly shortened T2*. In preclinical models, quantitative MRI markers correlated with histopathological assessments, especially for fatty liver disease. Validation in longitudinal studies is required.This article has an associated First Person interview with the first author of the paper.
It is not uncommon for clinicians to encounter varying degrees of hepatic steatosis in patients undergoing resection for colorectal liver metastases (CRLM). Magnetic resonance imaging is currently ...the preferred investigation for identification and pre-operative planning of these patients. An objective assessment of liver quality and degree of steatosis is paramount for planning a safe resection, which is seldom provided by routine MRI sequences.
We studied two patients who underwent an additional pre-operative multiparametric MRI scan (LiverMultiScan
TM
) as a part of an observational clinical trial (HepaT1ca, NCT03213314) to assess the quality of liver. Outcome was assessed in the form of post-hepatectomy liver failure.
Both patients (Patient 1 and 2) had comparable pre-operative characteristics. Both patients were planned for an extended right hepatectomy with an estimated future liver remnant of approximately 30%. Conventional preoperative contrast MRI showed mild liver steatosis in both patients. Patient one developed post-hepatectomy liver failure leading to prolonged hospital stay compared to patient two who had uneventful post-operative course. Retrospective evaluation of multiparametric MRI scan revealed findings consistent with fibro-inflammatory disease and steatosis (cT1 829 ms, PDFF 14%) for patient 1 whereas patient two had normal parameters (cT1 735 ms, PDFF 2.4%). These findings corresponded with the resection specimen histology.
Multiparametric MRI can objectively evaluate future liver health and volume which may help refine surgical decision-making and improve patient outcomes
Computational quantification reduces observer-related variability in histological assessment of metabolic dysfunction-associated steatotic liver disease (MASLD). We undertook stain-free imaging using ...the SteatoSITE resource to generate tools directly predictive of clinical outcomes. Unstained liver biopsy sections (n = 452) were imaged using second-harmonic generation/two-photon excitation fluorescence (TPEF) microscopy, and all-cause mortality and hepatic decompensation indices constructed. The mortality index had greater predictive power for all-cause mortality (index >.14 vs. </=.14, HR 4.49, p = .003) than the non-alcoholic steatohepatitis-Clinical Research Network (NASH-CRN) (hazard ratio (HR) 3.41, 95% confidence intervals (CI) 1.43-8.15, p = .003) and qFibrosis stage (HR 3.07, 95% CI 1.30-7.26, p = .007). The decompensation index had greater predictive power for decompensation events (index >.31 vs. </=.31, HR 5.96, p < .001) than the NASH-CRN (HR 3.65, 95% CI 1.81-7.35, p < .001) or qFibrosis stage (HR 3.59, 95% CI 1.79-7.20, p < .001). These tools directly predict hard endpoints in MASLD, without relying on ordinal fibrosis scores as a surrogate, and demonstrate predictive value at least equivalent to traditional or computational ordinal fibrosis scores.Computational quantification reduces observer-related variability in histological assessment of metabolic dysfunction-associated steatotic liver disease (MASLD). We undertook stain-free imaging using the SteatoSITE resource to generate tools directly predictive of clinical outcomes. Unstained liver biopsy sections (n = 452) were imaged using second-harmonic generation/two-photon excitation fluorescence (TPEF) microscopy, and all-cause mortality and hepatic decompensation indices constructed. The mortality index had greater predictive power for all-cause mortality (index >.14 vs. </=.14, HR 4.49, p = .003) than the non-alcoholic steatohepatitis-Clinical Research Network (NASH-CRN) (hazard ratio (HR) 3.41, 95% confidence intervals (CI) 1.43-8.15, p = .003) and qFibrosis stage (HR 3.07, 95% CI 1.30-7.26, p = .007). The decompensation index had greater predictive power for decompensation events (index >.31 vs. </=.31, HR 5.96, p < .001) than the NASH-CRN (HR 3.65, 95% CI 1.81-7.35, p < .001) or qFibrosis stage (HR 3.59, 95% CI 1.79-7.20, p < .001). These tools directly predict hard endpoints in MASLD, without relying on ordinal fibrosis scores as a surrogate, and demonstrate predictive value at least equivalent to traditional or computational ordinal fibrosis scores.
Current approaches to staging chronic liver diseases have limited utility for predicting liver cancer risk. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to characterize the cellular ...microenvironment of healthy and pre-malignant livers using two distinct mouse models. Downstream analyses unraveled a previously uncharacterized disease-associated hepatocyte (daHep) transcriptional state. These cells were absent in healthy livers but increasingly prevalent as chronic liver disease progressed. Copy number variation (CNV) analysis of microdissected tissue demonstrated that daHep-enriched regions are riddled with structural variants, suggesting these cells represent a pre-malignant intermediary. Integrated analysis of three recent human snRNA-seq datasets confirmed the presence of a similar phenotype in human chronic liver disease and further supported its enhanced mutational burden. Importantly, we show that high daHep levels precede carcinogenesis and predict a higher risk of hepatocellular carcinoma development. These findings may change the way chronic liver disease patients are staged, surveilled, and risk stratified.
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•snRNA-seq identifies a disease-associated hepatocyte (daHep) transcriptional state•daHeps are absent in healthy livers but prevalent in chronic liver diseases•daHeps display enhanced mutational burden and are likely a pre-malignant intermediary•High daHep levels precede carcinogenesis and predict a higher risk of HCC development
Probing healthy and pre-malignant liver disease by single-nucleus RNA sequencing, Carlessi et al. identify a disease-associated hepatocyte (daHep) state. daHeps are prevalent in liver disease and display a high mutational burden, suggesting they constitute a pre-malignant compartment. Higher frequencies of daHeps predicted an elevated risk for hepatocellular carcinoma development, highlighting their potential as a new prognostic biomarker.
A significant unmet need exists for accurate, reproducible, noninvasive diagnostic tools to assess and monitor portal hypertension (PHT). We report the first use of quantitative MRI markers for the ...haemodynamic assessment of nonselective beta-blockers (NSBB) in PHT. In a randomized parallel feasibility study in 22 adult patients with PHT and a clinical indication for NSBB, we acquired haemodynamic data at baseline and after 4 weeks of NSBB (propranolol or carvedilol) using phase-contrast MR angiography (PC-MRA) in selected intra-abdominal vessels. T1 mapping of liver and spleen was undertaken to assess changes in tissue composition. Target NSBB dose was achieved in 82%. There was a substantial reduction from baseline in mean average flow in the superior abdominal aorta after 4 weeks of NSBB therapy (4.49±0.98 versus 3.82±0.86 L/min, P=0.03) but there were no statistically significant differences in flow in any other vessels, even in patients with >25% decrease in heart rate (47% of patients). Mean percentage change in liver and spleen T1 following NSBB was small and highly variable. In conclusion, PC-MRA was able to detect reduction in cardiac output by NSBB but did not detect significant changes in visceral blood flow or T1. This trial was registered with the ISRCTN registry (ISRCTN98001632).
BackgroundAssociations of coffee consumption with multiple health outcomes have been researched extensively. Coffee consumption, usually reported in cups a day, is a heterogeneous measure due to ...numerous preparation methods and cup sizes, leading to misclassification. This paper develops a new ‘unit’ measure of coffee and uses coffee consumption data from a representative sample of the UK population to assess misclassification when cup volume and preparation type are not taken into account.MethodsA coffee unit measure was created using published estimates of caffeine and chlorogenic acid concentrations, and applied across volumes and preparation types. Four-day food diary data in adults from the UK National Diet and Nutrition Survey (NDNS; 2012–2016) were used to quantify coffee intake. Participant self-reported cups a day were compared with cups a day standardised by (a) 227 mL volume and (b) 227 mL instant coffee equivalents (unit measure), and the degree of misclassification was derived. Sensitivity analyses were conducted to model coffee drinking preferences of different populations and caffeine:chlorogenic acid weighting assumptions of the unit measure.ResultsThe NDNS sample consisted of 2832 adult participants. Coffee was consumed by 62% of participants. Types varied, with 75% of caffeinated coffee cups being instant, 17% filter, 3% latte, 2% cappuccino, 2% espresso and <1% other types. Comparing reported cups to volume-standardised cups, 84% of participants had correct classification, and 73% when using the coffee unit measure, 22% underestimated and 5% overestimated, largely by one cup. Misclassification varied by gender, age and income. Sensitivity analysis highlighted the benefits of using the unit measure over volume alone to cater for different populations, and stability of the unit composition assumption.ConclusionCup volume and preparation type should be taken into account, through the application of a standardised coffee unit measure, when coffee consumption is classified in future research studies.
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