Publications by authors named "Jonathan A Fallowfield"

45 Publications

Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility.

Hepatology 2021 Oct 15. Epub 2021 Oct 15.

Centre for Medical Informatics, Usher Institute, University of Edinburgh.

Background & Aims: Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants, representing new targets for gallstone research and treatment.

Approach & Results: We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1,089 cases, 5,228 controls) and conducted a GWA meta-analysis (43,639 cases,506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (P < 5 * 10 ), of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147, both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared to the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations.

Conclusions: This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
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http://dx.doi.org/10.1002/hep.32199DOI Listing
October 2021

Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in type 2 diabetes: The Edinburgh Type 2 Diabetes Study.

Obes Sci Pract 2021 Oct 6;7(5):497-508. Epub 2021 May 6.

Metabolic Unit Western General Hospital Edinburgh UK.

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 ( = 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   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.
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http://dx.doi.org/10.1002/osp4.484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488456PMC
October 2021

Clinical utility of MRI biomarkers for identifying NASH patients' high risk of progression: A multi-center pooled data and meta-analysis.

Clin Gastroenterol Hepatol 2021 Oct 6. Epub 2021 Oct 6.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Background And Aims: Non-alcoholic fatty liver disease (NAFLD) is increasing in prevalence worldwide. NAFLD is associated with excess risk of all-cause mortality, and its progression to non-alcoholic steatohepatitis (NASH) and fibrosis accounts for a growing proportion of cirrhosis and hepatocellular cancer and thus is a leading cause of liver transplant worldwide. Non-invasive precise methods to identify patients with NASH and NASH with significant disease activity and fibrosis when the disease is still modifiable are crucial. The aim of this study was to examine the clinical utility of cT1 versus MRI liver fat for identification of NASH participants with NAS ≥4 and F ≥2 ("high-risk" NASH).

Methods: Data from five clinical studies (n=543) with participants suspected of NAFLD were pooled or used for individual participant data meta-analysis. The diagnostic accuracy of the MRI biomarkers to stratify NASH patients was determined using Area Under the Receiver Operating Characteristic curve (AUROC).

Results: A stepwise increase in cT1 and MRI liver fat with increased NAFLD severity was demonstrated, and cT1 was significantly higher in NASH participants with fibrosis grade ≥2 (high-risk NASH). The diagnostic accuracy (AUROC [95% CI]) of cT1 to identify those with NASH was 0.78 [CI: 0.74-0.82], for liver fat was 0.78 [CI: 0.73-0.82], and when combined with MRI liver fat was 0.82 [CI: 0.78-0.85]. The diagnostic accuracy of cT1 to identify those with high-risk NASH was good (AUROC: 0.78 [CI: 0.74-0.82]), was superior to MRI liver fat (AUROC: 0.69 [CI: 0.64-0.74]) and was not substantially improved by combining it with MRI liver fat (AUC: 0.79, [CI: 0.75-0.83]). The meta-analysis showed similar performance to the pooled analysis for these biomarkers.

Conclusions: This study demonstrates that quantitative MRI derived biomarkers cT1 and liver fat are suitable for identifying those with NASH, and cT1 is a better non-invasive technology than liver fat to identify NASH patients at greatest risk of disease progression. MRI cT1 and liver fat therefore have important clinical utility to help guide appropriate use of interventions in NAFLD and NASH clinical care pathways.
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http://dx.doi.org/10.1016/j.cgh.2021.09.041DOI Listing
October 2021

Genome-Wide Association Study of NAFLD Using Electronic Health Records.

Hepatol Commun 2021 Sep 17. Epub 2021 Sep 17.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edingburgh, Scotland.

Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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http://dx.doi.org/10.1002/hep4.1805DOI Listing
September 2021

Editorial: metformin for portal hypertension-old dog, new tricks?

Aliment Pharmacol Ther 2021 08;54(3):345-346

Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1111/apt.16484DOI Listing
August 2021

All coffee types decrease the risk of adverse clinical outcomes in chronic liver disease: a UK Biobank study.

BMC Public Health 2021 06 22;21(1):970. Epub 2021 Jun 22.

Primary Care & Population Sciences, Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK.

Background: Chronic liver disease (CLD) is a growing cause of morbidity and mortality worldwide, particularly in low to middle-income countries with high disease burden and limited treatment availability. Coffee consumption has been linked with lower rates of CLD, but little is known about the effects of different coffee types, which vary in chemical composition. This study aimed to investigate associations of coffee consumption, including decaffeinated, instant and ground coffee, with chronic liver disease outcomes.

Methods: A total of 494,585 UK Biobank participants with known coffee consumption and electronic linkage to hospital, death and cancer records were included in this study. Cox regression was used to estimate hazard ratios (HR) of incident CLD, incident CLD or steatosis, incident hepatocellular carcinoma (HCC) and death from CLD according to coffee consumption of any type as well as for decaffeinated, instant and ground coffee individually.

Results: Among 384,818 coffee drinkers and 109,767 non-coffee drinkers, there were 3600 cases of CLD, 5439 cases of CLD or steatosis, 184 cases of HCC and 301 deaths from CLD during a median follow-up of 10.7 years. Compared to non-coffee drinkers, coffee drinkers had lower adjusted HRs of CLD (HR 0.79, 95% CI 0.72-0.86), CLD or steatosis (HR 0.80, 95% CI 0.75-0.86), death from CLD (HR 0.51, 95% CI 0.39-0.67) and HCC (HR 0.80, 95% CI 0.54-1.19). The associations for decaffeinated, instant and ground coffee individually were similar to all types combined.

Conclusion: The finding that all types of coffee are protective against CLD is significant given the increasing incidence of CLD worldwide and the potential of coffee as an intervention to prevent CLD onset or progression.
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http://dx.doi.org/10.1186/s12889-021-10991-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218514PMC
June 2021

Quantitative multiparametric MRI allows safe surgical planning in patients undergoing liver resection for colorectal liver metastases: report of two patients.

BJR Case Rep 2021 May 12;7(3):20200172. Epub 2021 Jan 12.

Department of Hepatobiliary Surgery, Basingstoke and North Hampshire Hospital, Basingstoke, Hampshire, United Kingdom.

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) 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.
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http://dx.doi.org/10.1259/bjrcr.20200172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171142PMC
May 2021

Reliable computational quantification of liver fibrosis is compromised by inherent staining variation.

J Pathol Clin Res 2021 Sep 2;7(5):471-481. Epub 2021 Jun 2.

University of Edinburgh Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.

Biopsy remains the gold-standard measure for staging liver disease, both to inform prognosis and to assess the response to a given treatment. Semiquantitative scores such as the Ishak fibrosis score are used for evaluation. These scores are utilised in clinical trials, with the US Food and Drug Administration mandating particular scores as inclusion criteria for participants and using the change in score as evidence of treatment efficacy. There is an urgent need for improved, quantitative assessment of liver biopsies to detect small incremental changes in liver architecture over the course of a clinical trial. Artificial intelligence (AI) methods have been proposed as a way to increase the amount of information extracted from a biopsy and to potentially remove bias introduced by manual scoring. We have trained and evaluated an AI tool for measuring the amount of scarring in sections of picrosirius red-stained liver. The AI methodology was compared with both manual scoring and widely available colour space thresholding. Four sequential sections from each case were stained on two separate occasions by two independent clinical laboratories using routine protocols to study the effect of inter- and intra-laboratory staining variation on these tools. Finally, we compared these methods to second harmonic generation (SHG) imaging, a stain-free quantitative measure of collagen. Although AI methods provided a modest improvement over simpler computer-assisted measures, staining variation both within and between laboratories had a dramatic effect on quantitation, with manual assignment of scar proportion being the most consistent. Manual assessment also most strongly correlated with collagen measured by SHG. In conclusion, results suggest that computational measures of liver scarring from stained sections are compromised by inter- and intra-laboratory staining. Stain-free quantitative measurement using SHG avoids staining-related variation and may prove more accurate in detecting small changes in scarring that may occur in therapeutic trials.
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http://dx.doi.org/10.1002/cjp2.227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363922PMC
September 2021

Safety and immunogenicity of COVID-19 vaccination in patients with non-alcoholic fatty liver disease (CHESS2101): A multicenter study.

J Hepatol 2021 08 24;75(2):439-441. Epub 2021 Apr 24.

CHESS-COVID-19 Group, The Third People's Hospital of Zhenjiang City, Zhenjiang, China.

Background & Aims: The development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD.

Methods: This multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination.

Results: A total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0-48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m (IQR 23.8-28.1 kg/m). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained.

Conclusions: The inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD.

Lay Summary: The development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease.
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http://dx.doi.org/10.1016/j.jhep.2021.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185617PMC
August 2021

Correlations Between MRI Biomarkers PDFF and cT1 With Histopathological Features of Non-Alcoholic Steatohepatitis.

Front Endocrinol (Lausanne) 2020 27;11:575843. Epub 2021 Jan 27.

Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States.

Introduction: Late stage clinical trials in non-alcoholic steatohepatitis (NASH) are currently required by the FDA to use liver biopsy as a primary endpoint. The well-reported limitations with biopsy, such as associated risks and sampling error, coupled with patient preference, are driving investigation into non-invasive alternatives. MRI-derived biomarkers proton density fat fraction (PDFF) and iron-corrected T1 mapping (cT1) are gaining traction as emerging alternatives to biopsy for NASH. Our aim was to explore the correlations between cT1 and PDFF (from Liver®), with the histological components on the NAFLD-NASH spectrum in a large cohort of cross-sectional data, in order to calibrate the measurement to histology, and to infer what might constitute a clinically meaningful change when related to the FDA's criteria.

Materials And Methods: In a retrospective analysis of data combined from three previously published observational NASH studies, in which adult participants who underwent liver biopsy on suspicion of NAFLD or NASH and had an MRI scan measuring cT1 and PDFF (Liver®, Perspectum Ltd, UK), associations between imaging biomarkers and histology were tested using Spearman's rank correlation coefficient (r), and further exploration of the relationships between the imaging variables and histology were performed using linear regression.

Results: N = 264 patients with mean age of 54 (SD:9.9), 39% female, and 69% with BMI ≥ 30kg.m were included in the analysis. cT1 and PDFF both correlated with all features of the NAFLD activity score (NAS). cT1 was also positively correlated with Kleiner-Brunt fibrosis. Partial correlations, adjusting for steatosis, revealed cT1 correlated with inflammation and fibrosis, whereas PDFF did not, and both were still associated with the NAS, but correlation was weaker with PDFF than cT1. An estimated difference of 88 ms in cT1, or 21% relative difference in PDFF was related to a two-point difference in overall NAS.

Conclusion: The correlations between cT1 and PDFF with the histopathological hallmarks of NASH demonstrate the potential utility of both cT1 and PDFF as non-invasive biomarkers to detect a pharmacodynamic change in NASH, with cT1 showing superiority for detecting changes in inflammation and fibrosis, rather than liver fat alone.
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http://dx.doi.org/10.3389/fendo.2020.575843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877451PMC
June 2021

A relaxin-based nanotherapy for liver fibrosis.

Nat Nanotechnol 2021 04;16(4):365-366

Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1038/s41565-020-00832-wDOI Listing
April 2021

Quantitative magnetic resonance imaging predicts individual future liver performance after liver resection for cancer.

PLoS One 2020 2;15(12):e0238568. Epub 2020 Dec 2.

Hampshire Hospitals Foundation Trust, Basingstoke, United Kingdom.

The risk of poor post-operative outcome and the benefits of surgical resection as a curative therapy require careful assessment by the clinical care team for patients with primary and secondary liver cancer. Advances in surgical techniques have improved patient outcomes but identifying which individual patients are at greatest risk of poor post-operative liver performance remains a challenge. Here we report results from a multicentre observational clinical trial (ClinicalTrials.gov NCT03213314) which aimed to inform personalised pre-operative risk assessment in liver cancer surgery by evaluating liver health using quantitative multiparametric magnetic resonance imaging (MRI). We combined estimation of future liver remnant (FLR) volume with corrected T1 (cT1) of the liver parenchyma as a representation of liver health in 143 patients prior to treatment. Patients with an elevated preoperative liver cT1, indicative of fibroinflammation, had a longer post-operative hospital stay compared to those with a cT1 within the normal range (6.5 vs 5 days; p = 0.0053). A composite score combining FLR and cT1 predicted poor liver performance in the 5 days immediately following surgery (AUROC = 0.78). Furthermore, this composite score correlated with the regenerative performance of the liver in the 3 months following resection. This study highlights the utility of quantitative MRI for identifying patients at increased risk of poor post-operative liver performance and a longer stay in hospital. This approach has the potential to inform the assessment of individualised patient risk as part of the clinical decision-making process for liver cancer surgery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710097PMC
January 2021

The Eye as a Non-Invasive Window to the Microcirculation in Liver Cirrhosis: A Prospective Pilot Study.

J Clin Med 2020 Oct 17;9(10). Epub 2020 Oct 17.

Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4TJ, UK.

Microcirculatory dysfunction is associated with organ failure, poor response to vasoactive drugs and increased mortality in cirrhosis, but monitoring techniques are not established. We hypothesized that the chorioretinal structures of the eye could be visualized as a non-invasive proxy of the systemic microvasculature in cirrhosis and would correlate with renal dysfunction. Optical Coherence Tomography (OCT) was performed to image the retina in = 55 cirrhosis patients being assessed for liver transplantation. OCT parameters were compared with established cohorts of age- and sex-matched healthy volunteers (HV) and patients with chronic kidney disease (CKD). Retinal thickness, macular volume and choroidal thickness were significantly reduced relative to HV and comparable to CKD patients (macular volume: HV vs. cirrhosis mean difference 0.44 mm (95% CI 0.26-0.61), ≤ 0.0001). Reduced retinal thickness and macular volume correlated with renal dysfunction in cirrhosis (macular volume vs. MDRD-6 eGFR r = 0.40, = 0.006). Retinal changes had resolved substantially 6 weeks following transplantation. There was an inverse association between choroidal thickness and circulating markers of endothelial dysfunction (endothelin-1 r = -0.49, ≤ 0.001; von Willebrand factor r = -0.32, ≤ 0.05). Retinal OCT may represent a non-invasive window to the microcirculation in cirrhosis and a dynamic measure of renal and endothelial dysfunction. Validation in different cirrhosis populations is now required.
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http://dx.doi.org/10.3390/jcm9103332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603064PMC
October 2020

A composite biomarker using multiparametric magnetic resonance imaging and blood analytes accurately identifies patients with non-alcoholic steatohepatitis and significant fibrosis.

Sci Rep 2020 09 17;10(1):15308. Epub 2020 Sep 17.

Perspectum, Gemini One, 5520 John Smith Drive, Oxford, OX4 2LL, UK.

Non-alcoholic steatohepatitis (NASH) is major health burden lacking effective pharmacological therapies. Clinical trials enrol patients with histologically-defined NAFLD (non-alcoholic fatty liver disease) activity score (NAS) ≥ 4 and Kleiner-Brunt fibrosis stage (F) ≥ 2; however, screen failure rates are often high following biopsy. This study evaluated a non-invasive MRI biomarker, iron-corrected T1 mapping (cT1), as a diagnostic pre-screening biomarker for NASH. In a retrospective analysis of 86 biopsy confirmed NAFLD patients we explored the potential of blood and imaging biomarkers, both in isolation and in combination, to discriminate those who have NAS ≥ 4 and F ≥ 2 from those without. Stepwise logistic regression was performed to select the optimal combination of biomarkers, diagnostic accuracy was determined using area under the receiver operator curve and model validated confirmed with and fivefold cross-validation. Results showed that levels of cT1, AST, GGT and fasting glucose were all good predictors of NAS ≥ 4 and F ≥ 2, and the model identified the combination of cT1-AST-fasting glucose (cTAG) as far superior to any individual biomarker (AUC 0.90 [0.84-0.97]). This highlights the potential utility of the composite cTAG score for screening patients prior to biopsy to identify those suitable for NASH clinical trial enrolment.
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http://dx.doi.org/10.1038/s41598-020-71995-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499258PMC
September 2020

Volatomic analysis identifies compounds that can stratify non-alcoholic fatty liver disease.

JHEP Rep 2020 Oct 15;2(5):100137. Epub 2020 Jun 15.

Hepatology Laboratory and Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh and The University of Edinburgh, Edinburgh, UK.

Background & Aims: Analysis of volatile organic compounds (VOCs) in exhaled breath, 'volatomics', provides opportunities for non-invasive biomarker discovery and novel mechanistic insights into a variety of diseases. The purpose of this pilot study was to compare breath VOCs in an initial cohort of patients with non-alcoholic fatty liver disease (NAFLD) and healthy controls.

Methods: Breath samples were collected from 15 participants with Child-Pugh class A NAFLD cirrhosis, 14 with non-cirrhotic NAFLD, and 14 healthy volunteers. Exhaled breath samples were collected using an established methodology and VOC profiles were analysed by gas chromatography-mass spectrometry. The levels of 19 VOCs previously associated with cirrhosis were assessed. Peaks of the VOCs were confirmed and integrated using Xcalibur® software, normalised to an internal standard. Receiver-operating characteristic (ROC) curves were used to determine the diagnostic accuracy of the candidate VOCs.

Results: Terpinene, dimethyl sulfide, and D-limonene provided the highest predictive accuracy to discriminate between study groups. Combining dimethyl sulfide with D-limonene led to even better discrimination of patients with NAFLD cirrhosis from healthy volunteers (AUROC 0.98; 95% CI 0.93-1.00; <0.001) and patients with NAFLD cirrhosis from those with non-cirrhotic NAFLD (AUROC 0.91; 95% CI 0.82-1.00; <0.001). Breath terpinene concentrations discriminated between patients with non-cirrhotic NAFLD and healthy volunteers (AUROC 0.84; 95% CI 0.68-0.99;  = 0.002).

Conclusion: Breath terpinene, dimethyl sulfide, and D-limonene are potentially useful volatomic markers for stratifying NAFLD; in addition, a 2-stage approach enables the differentiation of patients with cirrhosis from those without. However, these observations require validation in a larger NAFLD population. (ClinicalTrials.gov Identifier: NCT02950610).

Lay Summary: Breath malodour has been associated with a failing liver since the ancient Greeks. Analytical chemistry has provided us an insight into ubiquitous volatile organic compounds associated with liver (and other) diseases. This has vastly improved our understanding of the mechanistic processes of liver damage. Our study aims to identify volatile organic compounds which are specific to non-alcoholic fatty liver disease and that can be exploited for rapid diagnostics.
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http://dx.doi.org/10.1016/j.jhepr.2020.100137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397704PMC
October 2020

Non-invasive risk scores do not reliably identify future cirrhosis or hepatocellular carcinoma in Type 2 diabetes: The Edinburgh type 2 diabetes study.

Liver Int 2020 09 22;40(9):2252-2262. Epub 2020 Jul 22.

Western General Hospital, Edinburgh, UK.

Background: The incidence of cirrhosis and hepatocellular carcinoma (HCC) is increased in Type 2 diabetes, primarily secondary to non-alcoholic fatty liver disease (NAFLD). European guidelines recommend screening for NAFLD in Type 2 diabetes. American guidelines, while not advocating a screening protocol, suggest using non-invasive markers of fibrosis for risk-stratification and guiding onward referral.

Aims: To test the ability of individual fibrosis scores and the European screening algorithm to predict 11-year incident cirrhosis/HCC in an asymptomatic community cohort of older people with Type 2 diabetes.

Methods: The Edinburgh Type 2 Diabetes Study investigated men and women with Type 2 diabetes (n = 1066, aged 60-75 at baseline). Liver markers were measured at baseline and year 1; steatosis and fibrosis markers were calculated according to independently published calculations. During 11 years of follow-up, cases of cirrhosis and HCC were identified.

Results: Forty-three out of 1059 participants with no baseline cirrhosis/HCC developed incident disease. All scores were significantly associated with incident liver disease by odds ratio (P < .05). The ability of the risk-stratification tools to accurately identify those who developed incident cirrhosis/HCC was poor with low-positive predictive values (5-46%) and high false-negative and -positive rates (up to 60% and 77%) respectively. When fibrosis risk scores were used in conjunction with the European algorithm, they performed modestly better than when applied in isolation.

Conclusions: In a cohort with a moderately low incidence of cirrhosis/HCC, existing risk scores did not reliably identify participants at high risk. Better prediction models for cirrhosis/HCC in people with Type 2 diabetes are required.
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http://dx.doi.org/10.1111/liv.14590DOI Listing
September 2020

A phase 2 randomised controlled trial of serelaxin to lower portal pressure in cirrhosis (STOPP).

Trials 2020 Mar 12;21(1):260. Epub 2020 Mar 12.

Centre for Inflammation Research, University of Edinburgh, BioQuarter, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.

Background: In preclinical models, recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure.

Methods: In a phase 2, double-blind, randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically significant PH (CSPH; hepatic venous pressure gradient (HVPG) > 10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo was matched to serelaxin on appearance and administration protocol to create and maintain blinding. The primary endpoint was the change from baseline in fasting HVPG after 2 h of peripheral i.v. serelaxin infusion (80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin were assessed.

Results: A total of 17 participants were screened, 15 were randomised and 11 completed the study (n = 9 serelaxin, n = 2 placebo). Reasons for withdrawal were baseline HVPG < 10 mmHg (n = 2) and technical failure (n = 2). The trial ended early due to manufacturer discontinuation of the study drug. The median age was 56 (range 43-69) years and 73% of participants were male. Alcohol was the commonest cirrhosis aetiology (n = 10). Participants had a median Model for End-Stage Liver Disease score of 10 (range 6-14). The mean baseline HVPG was 16.3 (range 10.3-21.7) mmHg. Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h of i.v. serelaxin (arithmetic mean of difference ± SD was 0.4 ± 3.5 mmHg (95% CI -2.3, 3.1; p = 0.76)). There were also no substantial changes from baseline in hepatic or systemic haemodynamics. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events.

Conclusion: In a small randomised, phase 2, proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG.

Trial Registration: ClinicalTrials.gov, NCT02669875. Registered on 1 February 2016.
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http://dx.doi.org/10.1186/s13063-020-4203-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066808PMC
March 2020

Coffee Consumption and Kidney Function: A Mendelian Randomization Study.

Am J Kidney Dis 2020 05 11;75(5):753-761. Epub 2019 Dec 11.

Primary Care & Population Sciences Faculty of Medicine, University of Southampton, Southampton, United Kingdom.

Rationale & Objective: Chronic kidney disease (CKD) is a leading cause of morbidity and mortality worldwide, with limited strategies for prevention and treatment. Coffee is a complex mixture of chemicals, and consumption has been associated with mostly beneficial health outcomes. This work aimed to determine the impact of coffee consumption on kidney function.

Study Design: Genome-wide association study (GWAS) and Mendelian randomization.

Setting & Participants: UK Biobank baseline data were used for a coffee consumption GWAS and included 227,666 participants. CKDGen Consortium data were used for kidney outcomes and included 133,814 participants (12,385 cases of CKD) of mostly European ancestry across various countries.

Exposure: Coffee consumption.

Outcomes: Estimated glomerular filtration rate (eGFR), CKD GFR categories 3 to 5 (G3-G5; eGFR<60mL/min/1.73m), and albuminuria.

Analytical Approach: GWAS to identify single-nucleotide polymorphisms (SNPs) associated with coffee consumption in UK Biobank and use of those SNPs in Mendelian randomization analyses of coffee consumption and kidney outcomes in CKDGen.

Results: 2,126 SNPs were associated with coffee consumption (P<5×10), 25 of which were independent and available in CKDGen. Drinking an extra cup of coffee per day conferred a protective effect against CKD G3-G5 (OR, 0.84; 95% CI, 0.72-0.98; P=0.03) and albuminuria (OR, 0.81; 95% CI, 0.67-0.97; P=0.02). An extra cup was also associated with higher eGFR (β=0.022; P=1.6×10) after removal of 3 SNPs responsible for significant heterogeneity (Cochran Q P = 3.5×10).

Limitations: Assays used to measure creatinine and albumin varied between studies that contributed data and a sex-specific definition was used for albuminuria rather than KDIGO guideline recommendations.

Conclusions: This study provides evidence of a beneficial effect of coffee on kidney function. Given widespread coffee consumption and limited interventions to prevent CKD incidence and progression, this could have significant implications for global public health in view of the increasing burden of CKD worldwide.
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http://dx.doi.org/10.1053/j.ajkd.2019.08.025DOI Listing
May 2020

Safety profile of autologous macrophage therapy for liver cirrhosis.

Nat Med 2019 10 7;25(10):1560-1565. Epub 2019 Oct 7.

MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.

Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 10, 10 or up to 10 cells. Leukapheresis and macrophage infusion were well tolerated with no transfusion reactions, dose-limiting toxicities or macrophage activation syndrome. All participants were alive and transplant-free at one year, with only one clinical event recorded, the occurrence of minimal ascites. The primary outcomes of safety and feasibility were met. This study informs and provides a rationale for efficacy studies in cirrhosis and other fibrotic diseases.
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http://dx.doi.org/10.1038/s41591-019-0599-8DOI Listing
October 2019

Misclassification of coffee consumption data and the development of a standardised coffee unit measure.

BMJ Nutr Prev Health 2019 2;2(1):11-19. Epub 2019 May 2.

Primary Care and Population Sciences Academic Unit, University of Southampton Faculty of Medicine, Southampton, UK.

Background: Associations 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.

Methods: A 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.

Results: The 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.

Conclusion: Cup 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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http://dx.doi.org/10.1136/bmjnph-2018-000013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678482PMC
May 2019

Study protocol: HepaT1ca - an observational clinical cohort study to quantify liver health in surgical candidates for liver malignancies.

BMC Cancer 2018 Sep 12;18(1):890. Epub 2018 Sep 12.

Perspectum Diagnostics Ltd, 23-38 Hythe Bridge Street, Oxford, OX1 2ET, UK.

Background: Accurate assessment of liver health prior to undertaking resectional liver surgery or chemoembolisation for primary and secondary cancers is essential for patient safety and optimal outcomes. LiverMultiScan™, an MRI-based technology, non-invasively quantifies hepatic fibroinflammatory disease, steatosis and iron content. We hypothesise that LiverMultiScan™can quantify liver health prior to surgery and inform the risk assessment for patients considering liver surgery or chemoembolization and seek to evaluate this technology in an operational environment.

Methods/design: HepaT1ca is an observational cohort study in two tertiary-referral liver surgery centres in the United Kingdom. The primary outcome is correlation between the pre-operative liver health assessment score (Hepatica score - calculated by weighting future remnant liver volume by liver inflammation and fibrosis (LIF) score) and the post-operative liver function composite integer-based risk (Hyder-Pawlik) score. With ethical approval and fully-informed consent, individuals considering liver surgery for primary or secondary cancer will undergo clinical assessment, blood sampling, and LiverMultiScan™multiparametric MRI before and after surgical liver resection or TACE. In nested cohorts of individuals undergoing chemotherapy prior to surgery, or those undergoing portal vein embolization (PVE) as an adjunct to surgery, an additional testing session prior to commencement of treatment will occur. Tissue will be examined histologically and by immunohistochemistry. Pre-operative liver health assessment scores and the post-operative risk scores will be correlated to define the ability of LiverMultiScan™to predict the risk of post-operative morbidity and mortality. Because technology performance in this setting is unknown, a pragmatic sample size will be used. For the primary outcome, n = 200 for the main cohort will allow detection of a minimum correlation coefficient of 0.2 with 5% significance and power of 80%.

Discussion: This study will refine the technology and clinical application of multiparametric MRI (including LiverMultiScan™), to quantify pre-existing liver health and predict post-intervention outcomes following liver resection. If successful, this study will advance the technology and support the use of multiparametric MRI as part of an enhanced pre-operative assessment to improve patient safety and to personalise operative risk assessment of liver surgery/non-surgical intervention.

Trial Registration: This study is registered on ClinicalTrials.gov Identifier: NCT03213314 .
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http://dx.doi.org/10.1186/s12885-018-4737-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136162PMC
September 2018

Non-invasive assessment of liver disease in rats using multiparametric magnetic resonance imaging: a feasibility study.

Biol Open 2018 Jul 2;7(7). Epub 2018 Jul 2.

MRC/University of Edinburgh Centre for Inflammation Research, Edinburgh EH16 4TJ, UK

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.
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http://dx.doi.org/10.1242/bio.033910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078340PMC
July 2018

Multiparametric magnetic resonance imaging for quantitation of liver disease: a two-centre cross-sectional observational study.

Sci Rep 2018 06 15;8(1):9189. Epub 2018 Jun 15.

MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, UK.

LiverMultiScan is an emerging diagnostic tool using multiparametric MRI to quantify liver disease. In a two-centre prospective validation study, 161 consecutive adult patients who had clinically-indicated liver biopsies underwent contemporaneous non-contrast multiparametric MRI at 3.0 tesla (proton density fat fraction (PDFF), T1 and T2* mapping), transient elastography (TE) and Enhanced Liver Fibrosis (ELF) test. Non-invasive liver tests were correlated with gold standard histothological measures. Reproducibility of LiverMultiScan was investigated in 22 healthy volunteers. Iron-corrected T1 (cT1), TE, and ELF demonstrated a positive correlation with hepatic collagen proportionate area (all p < 0·001). TE was superior to ELF and cT1 for predicting fibrosis stage. cT1 maintained good predictive accuracy for diagnosing significant fibrosis in cases with indeterminate ELF, but not for cases with indeterminate TE values. PDFF had high predictive accuracy for individual steatosis grades, with AUROCs ranging from 0.90-0.94. T2* mapping diagnosed iron accumulation with AUROC of 0.79 (95% CI: 0.67-0.92) and negative predictive value of 96%. LiverMultiScan showed excellent test/re-test reliability (coefficients of variation ranging from 1.4% to 2.8% for cT1). Overall failure rates for LiverMultiScan, ELF and TE were 4.3%, 1.9% and 15%, respectively. LiverMultiScan is an emerging point-of-care diagnostic tool that is comparable with the established non-invasive tests for assessment of liver fibrosis, whilst at the same time offering a superior technical success rate and contemporaneous measurement of liver steatosis and iron accumulation.
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http://dx.doi.org/10.1038/s41598-018-27560-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003924PMC
June 2018

Hepatic elastin content is predictive of adverse outcome in advanced fibrotic liver disease.

Histopathology 2018 Jul 16;73(1):90-100. Epub 2018 Apr 16.

NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.

Aims: The aim of this study was to determine if elastin content in needle core native liver biopsies was predictive of clinical outcome in patients with chronic hepatitis C virus-related chronic liver disease.

Methods And Results: Elastin contents in liver biopsies were determined by image analysis, technically validated in an independent centre, and correlated with outcome in patients with advanced (Ishak stage ≥5) chronic hepatitis C virus-related chronic liver disease. Elastin was robustly quantified in an operator-independent and laboratory-independent manner, with very strong correlation of elastin staining measured with two methods of image classification (r = 0.873, P < 0.00001). Elastin content (but not absolute scar content or Ishak stage) was predictive for future clinical outcomes. In a cohort of patients without sustained virological response, the median hepatic elastin content was 3.4%, and 17 patients (57%) progressed to a liver-related clinical outcome; 11 of the 15 patients (73%) with a hepatic elastin content of >3.4% progressed to a clinical outcome, as compared with only six of 15 (40%) with an elastin content of <3.4%. The difference in time to outcome was significant.

Conclusions: We describe a simple and reproducible method for elastin quantification in liver biopsies that provides potentially valuable prognostic information to inform clinical management.
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http://dx.doi.org/10.1111/his.13499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033111PMC
July 2018

Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes.

BMJ 2017 11 22;359:j5024. Epub 2017 Nov 22.

Academic Unit of Primary Care and Population Sciences, Faculty of Medicine, University of Southampton, South Academic Block, Southampton General Hospital, Southampton, Hampshire SO16 6YD, UK.

 To evaluate the existing evidence for associations between coffee consumption and multiple health outcomes. Umbrella review of the evidence across meta-analyses of observational and interventional studies of coffee consumption and any health outcome. PubMed, Embase, CINAHL, Cochrane Database of Systematic Reviews, and screening of references. Meta-analyses of both observational and interventional studies that examined the associations between coffee consumption and any health outcome in any adult population in all countries and all settings. Studies of genetic polymorphisms for coffee metabolism were excluded. The umbrella review identified 201 meta-analyses of observational research with 67 unique health outcomes and 17 meta-analyses of interventional research with nine unique outcomes. Coffee consumption was more often associated with benefit than harm for a range of health outcomes across exposures including high versus low, any versus none, and one extra cup a day. There was evidence of a non-linear association between consumption and some outcomes, with summary estimates indicating largest relative risk reduction at intakes of three to four cups a day versus none, including all cause mortality (relative risk 0.83 (95% confidence interval 0.79 to 0.88), cardiovascular mortality (0.81, 0.72 to 0.90), and cardiovascular disease (0.85, 0.80 to 0.90). High versus low consumption was associated with an 18% lower risk of incident cancer (0.82, 0.74 to 0.89). Consumption was also associated with a lower risk of several specific cancers and neurological, metabolic, and liver conditions. Harmful associations were largely nullified by adequate adjustment for smoking, except in pregnancy, where high versus low/no consumption was associated with low birth weight (odds ratio 1.31, 95% confidence interval 1.03 to 1.67), preterm birth in the first (1.22, 1.00 to 1.49) and second (1.12, 1.02 to 1.22) trimester, and pregnancy loss (1.46, 1.06 to 1.99). There was also an association between coffee drinking and risk of fracture in women but not in men. Coffee consumption seems generally safe within usual levels of intake, with summary estimates indicating largest risk reduction for various health outcomes at three to four cups a day, and more likely to benefit health than harm. Robust randomised controlled trials are needed to understand whether the observed associations are causal. Importantly, outside of pregnancy, existing evidence suggests that coffee could be tested as an intervention without significant risk of causing harm. Women at increased risk of fracture should possibly be excluded.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696634PMC
http://dx.doi.org/10.1136/bmj.j5024DOI Listing
November 2017

In search of a small molecule agonist of the relaxin receptor RXFP1 for the treatment of liver fibrosis.

Sci Rep 2017 09 7;7(1):10806. Epub 2017 Sep 7.

MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.

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.
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http://dx.doi.org/10.1038/s41598-017-10521-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589886PMC
September 2017

Assessment of Haemodynamic Response to Nonselective Beta-Blockers in Portal Hypertension by Phase-Contrast Magnetic Resonance Angiography.

Biomed Res Int 2017 15;2017:9281450. Epub 2017 Jun 15.

MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

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, = 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).
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http://dx.doi.org/10.1155/2017/9281450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494094PMC
April 2018

Liver Fibrosis: Understanding the Dynamics of Bidirectional Wound Repair to Inform the Design of Markers and Therapies.

Dig Dis 2017 3;35(4):310-313. Epub 2017 May 3.

Pro Vice-Chancellor Health, University of Bristol, Senate House, Bristol, UK.

Background: Liver fibrosis is the final common pathway of iterative or chronic liver damage. When it reaches an advanced stage, cirrhosis develops and this indicates a loss of normal liver architecture, disruption of normal blood flow, the development of nodules of proliferative hepatocytes and consequent functional failure. Cirrhosis is also associated with life-threatening complications. Importantly, this dysregulation of blood flow involves changes resulting from both architectural disruption and a dynamic rise in portal pressure mediated in part by the contraction of myofibroblasts - the major cell mediator of the fibrogenic process - which are derived from hepatic stellate cells (HSC) and termed activated HSC (myofibroblast/activated HSC). Key Messages: There is now compelling data from both rodent and human models that liver fibrosis is bidirectional. By studying models of progressive and regressing liver fibrosis it has been possible to identify mediators that may be therapeutic targets. Arguably, by identifying the mediators of spontaneous resolution that result in a return of normal architecture, the attributes of a highly effective antifibrotic or pro resolution therapy can be defined. Among these key attributes, understanding the balance of matrix-degrading enzymes and their inhibitors (the metalloproteinases and Tissue inhibitors of metalloproteinases (TIMPs), respectively) led to the identification of both therapeutic targets and the value of TIMP-1 as a serum marker of fibrosis. Furthermore, the action of a potential therapeutic agent, relaxin (RLN) acting through its cognate G-protein coupled receptor (RXFP1) on the surface of activated HSC shows promise. Activation of the RLN-RXFP1-mediated pathway can be detected in vivo by measuring the dynamic contractility of activated HSC and the consequent changes in portal pressure and blood flow as a responsive physical biomarker.

Conclusion: By understanding progressive and resolving liver fibrosis, a series of therapeutic targets have been identified. At the same time, key mediators of fibrosis may have an integral role to play as soluble or physical biomarkers.
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http://dx.doi.org/10.1159/000456581DOI Listing
October 2017

Serelaxin as a potential treatment for renal dysfunction in cirrhosis: Preclinical evaluation and results of a randomized phase 2 trial.

PLoS Med 2017 Feb 28;14(2):e1002248. Epub 2017 Feb 28.

MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.

Background: Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension.

Methods And Findings: To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 μg/kg/d and then 60 min at 30 μg/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study's main limitations were the relatively small sample size and stable, well-compensated population.

Conclusions: Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required.

Trial Registration: ClinicalTrials.gov NCT01640964.
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http://dx.doi.org/10.1371/journal.pmed.1002248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330452PMC
February 2017
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