Sarcoid Here, Sarcoid There, Sarcoid Everywhere.

Although usually more associated with the lungs, sarcoidosis can have multiple extrapulmonary manifestations. We present a case of a patient with previous biopsy-proven sarcoidosis who was admitted to the hospital secondary to worsening shortness of breath. The patient was found to be positive for Respiratory Syncytial Virus (RSV) which was believed to have exacerbated his pulmonary symptoms. He was treated with IV steroids, nebulizers, and antibiotics which ultimately helped relieve his symptoms. In terms of his sarcoidosis, he was previously treated in the past with steroids in regards to this pathology (which is the mainstay of treatment); while on the regimen, the patient noted his breathing was improved. Of note, he did also have a history of renal cell carcinoma (RCC) status post nephrectomy which was initially evaluated for possible sarcoidosis involvement. This medical therapy could also have been the reason his sarcoidosis did not progress to involve other organs.

Stratification Of LIver Disease (SOLID): protocol for a prospective observational cohort study to determine the optimum biomarker strategies for the detection of advanced liver disease at the primary-secondary care interface.

INTRODUCTION: Undiagnosed fatty liver disease is prevalent in the community, due to high rates of harmful alcohol consumption and/or obesity. Fatty liver disease can progress to cirrhosis and its complications. Early identification of liver disease and treatment may prevent progression to cirrhosis. Biomarkers including FIB-4, enhanced liver fibrosis (ELF), PRO-C3 and vibration controlled transient elastography (VCTE) can stage liver fibrosis, but it is not known how well they perform in a primary care population. Moreover, no assessment of long-term prognostic ability of these biomarkers has been conducted in primary care. We aim to evaluate the performance of fibrosis biomarkers in primary care to develop a pathway to detect advanced fibrosis. METHODS AND ANALYSIS: This prospective, observational cohort study will recruit 3000 individuals with fatty liver disease risk factors (obesity, type 2 diabetes or hazardous alcohol consumption) at their primary care 'annual chronic disease review'. Participants will have a 'liver health check'. Two pathways will be evaluated: (1) all have FIB-4, ELF and VCTE performed, and (2) patients have an initial assessment with FIB-4 and ELF, followed by VCTE in only those with increased FIB-4 and/or ELF. Individuals with suspected significant/advanced liver fibrosis (liver stiffness measurement>8 kPa), will be reviewed in secondary care to confirm their fibrosis stage and institute treatment. The performance of FIB-4, ELF, PRO-C3, VCTE and novel biomarkers alone or in combination for advanced fibrosis/cirrhosis will be evaluated. Participants will be followed longitudinally via their electronic health records to assess long-term clinical outcomes. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London-Chelsea Research Ethics Committee (22/PR/0535; 27 June 2022). Recruitment began on 31 October 2022. Outcomes of this study will be published in peer-reviewed journals and presented at scientific meetings. A lay summary of the results will be available for study participants and will be disseminated widely by LIVErNORTH.

Serum CC-Chemokine Ligand 2 Is Associated with Visceral Adiposity but Not Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver as a consequence of metabolic perturbations associated with obesity, type 2 diabetes, dyslipidemia, and insulin resistance. People with NAFLD may develop metabolic and cardiovascular complications and/or liver-related complications, especially fibrosis and hepatocellular carcinoma, associated with high morbidity and mortality. Due to the high and increasing prevalence of NAFLD, there is an urgent need to identify people at risk of developing liver fibrosis and complications. CC-chemokine ligand 2 (CCL2) is chemokine that attracts inflammatory monocytes to stressed or injured tissues. Infiltrating inflammatory monocytes and CCL2 are strongly implicated in the pathogenesis of liver disease in animal models; however, evidence in patient cohorts is conflicting. METHODS: We investigated associations between circulating CCL2 and clinical parameters, including fibrosis assessed by liver stiffness measurement, in a cohort of 250 NAFLD patients. We also measured fatty acid binding protein 2 (FABP2), a putative biomarker of intestinal permeability in patients with liver disease, since pro-inflammatory gut-derived microbial products may induce inflammatory chemokines such as CCL2. RESULTS: Serum CCL2 levels were weakly associated with liver stiffness, but the association was no longer significant after accounting for age, diabetes, and BMI in a multivariable model. Consistent with this, girth and BMI were the strongest predictors of elevated circulating CCL2. Serum FABP2 was weakly, but significantly, correlated with CCL2, and negatively correlated with estimated glomerular filtration rate. CONCLUSION: Circulating CCL2 and FABP2 are associated with NAFLD comorbidities but not liver disease progression in patients with NAFLD.

Validation of the new 2021 EASL algorithm for the noninvasive diagnosis of advanced fibrosis in NAFLD.

BACKGROUND AND AIMS: The European Association for the Study of the Liver (EASL) has recently proposed an algorithm for the diagnosis of advanced liver fibrosis. We aimed to evaluate the diagnostic accuracy of this algorithm in nonalcoholic fatty liver disease (NAFLD). APPROACH AND RESULTS: One thousand fifty-one patients with NAFLD, liver biopsy, and four noninvasive tests (NITs; Fibrosis-4 [FIB4], vibration controlled transient elastography [VCTE], FibroMeter, Fibrotest) were included. The enhanced liver fibrosis (ELF) score was available in 396 patients. A cohort of 230 patients from primary care/diabetes clinics had FIB4, VCTE, and ELF. Compared with the performance of single NITs, agreement between two NITs (FIB4 and VCTE, VCTE and patented serum tests) increased specificity and positive predictive value by 20%, thus justifying the sequential use proposed in the EASL algorithm. The FIB4/VCTE/FibroMeter and FIB4/VCTE/Fibrotest algorithms performed similarly, providing 85% diagnostic accuracy and a liver biopsy requirement rate of only 10%. The FIB4/VCTE/ELF algorithm performed similarly in the subgroup where ELF was available. Simulations of algorithm accuracies at different prevalence showed that positive predictive values rapidly increased, reaching a plateau above 75% starting at 15% prevalence. Negative predictive values remained higher than 90% up to 25% prevalence. The rate of liver biopsy requirement remained stable, increasing by only 5% between low and high prevalence settings. When the EASL algorithm was applied in the primary care/diabetes clinic cohort, liver biopsy requirement was only 3%, and the agreement among the three steps provided 75% positive predictive value. CONCLUSIONS: Our study validates the algorithm proposed by the EASL in its latest 2021 guidelines for the diagnosis of advanced fibrosis in the setting of NAFLD.

Achieving tolerance modifies cancer susceptibility profiles in liver transplant recipients.

Long-term survival of transplant recipients is significantly impacted by malignancy. We aimed to determine whether calcineurin inhibitor (CNI)-treated recipients converted to and weaned off molecular target of rapamycin inhibitor (mTOR-I) therapy have favorable changes in their molecular profiles in regard to malignancy risk. We performed gene expression profiling from liver biopsy and blood (PBMC) specimens followed by network analysis of key dysregulated genes, associated diseases and disorders, molecular and cellular functions using IPA software. Twenty non-immune, non-viremic patients were included, and 8 of them achieved tolerance. Two comparisons were performed: (1) tolerance time point vs tacrolimus monotherapy and (2) tolerance time point vs sirolimus monotherapy. Upon achieving tolerance, IPA predicted significant activation of DNA damage response (p = 5.40e-04) and inhibition of DNA replication (p = 7.56e-03). Conversion from sirolimus to tolerance showed decrease in HCC (p = 1.30e-02), hepatic steatosis (p = 5.60e-02) and liver fibrosis (p = 2.91e-02) associated genes. In conclusion, this longitudinal study of patients eventually achieving tolerance reveals an evolving molecular profile associated with decreased cancer risk and improved hepatic steatosis and liver fibrosis. This provides a biological rationale for attempting conversion to mTOR-I therapy and tolerance following liver transplantation particularly in patients at higher risk of cancer incidence and progression post-transplant.

Aberrant MAPK Signaling Offers Therapeutic Potential for Treatment of Ovarian Carcinoma.

Ovarian cancer remains the most lethal gynecological malignancy worldwide due to lack of effective screening, vague early symptoms, poor description of biomarkers, and absence of effective treatment regimes. Epithelial ovarian carcinoma (EOC) is categorized into five distinct disease subtypes which collectively account for ~90% of ovarian carcinomas. Most women present at advanced stages contributing to a poor overall 5-year survival rate. Standard treatment for EOC is cytoreductive surgery and platinum-based chemotherapy; however, most patients suffer from recurrence and platinum-resistant disease, which highlights an urgent need for targeted therapy. The high frequency of molecular alterations affecting gain-of-function signaling through the RAS mitogen-activated protein kinase (MAPK) pathway in EOC has prompted pre-clinical and clinical efforts toward research into the effectiveness of MAPK pathway inhibition as a second-line treatment. The RAS/MAPK pathway is a highly conserved signal transduction cascade, often disrupted in cancer, that regulates tumorigenic phenotypes including cellular proliferation, survival, migration, apoptosis, and differentiation. Herein, the role of the MAPK pathway in EOC with emphasis on targetability of the pathway is described. Pre-clinical and clinical efforts to target MAPK signaling in EOC have identified several MAPK pathway inhibitors that offer efficacious potential for monotherapy and in combination with other compounds. Thus, inhibition of the RAS/MAPK pathway is emerging as a tractable strategy for treatment of ovarian cancer that may permit development of personalized therapy and improved prognosis for women challenged by this disease.

Interstitial lung disease incidence and mortality in the UK and the European Union: an observational study, 2001-2017.

Objective: To compare the trends in age-standardised incidence and mortality from interstitial lung diseases (ILD) in the UK and the European Union (EU). Methods: This was an observational study using data obtained from the Global Burden of Disease Study on residents of the UK and of the 27 EU countries. The main outcome measures were ILD age-standardised incidence rates per 100 000 (ASIR), age-standardised death rates per 100 000 (ASDR) and mortality-to-incidence ratios (MIRs), which are presented for men and women separately for each country for the years 2001-2017. Trends were analysed using joinpoint regression analysis. Results: In 2017, the median incidence of ILD was 7.22 (IQR 5.57-8.96) per 100 000 population for men and 4.34 (IQR 3.36-6.29) per 100 000 population for women. In 2017, the median ASDR attributed to ILD was 2.04 (IQR 1.13-2.71) per 100 000 population for men and 1.02 (0.68-1.37) per 100 000 population for women. There was an overall increase in ASDR during the observation period, with a median increase of +20.42% (IQR 5.44-31.40) for men and +15.44% (IQR -1.01-31.52) for women. Despite increases in mortality over the entire observation period, there were decreasing mortality trends in the majority of countries at the end of the observation period (75% for men and 86% for women). Conclusion: Over the past two decades, there have been increases in the incidence and mortality of ILD in Europe. The most recent trends, however, demonstrate decreases in mortality from ILD in the majority of European countries for both men and women. These data support the ongoing improvements in the diagnosis and management of ILD.

COVID-19 and liver cancer: lost patients and larger tumours.

BACKGROUND: Northern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region. OBJECTIVE: To assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region. DESIGN: We prospectively audited our service for the first year of the pandemic (March 2020-February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019-February 2020). RESULTS: We observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection. CONCLUSION: The pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage.

Underrepresentation of Black participants and adverse events in clinical trials of lenalidomide for myeloma.

Adverse events affecting Black patients, including skin hyperpigmentation, may be overlooked using existing clinical trial data on lenalidomide. The objective of this systematic review is to characterize the representation of Black participants and rate of skin hyperpigmentation in clinical trials. In this systematic review and pooled analysis of 21 clinical trials comprising 4539 participants, the proportion of Black participants in trials (6.9%, n = 315) was significantly less than the multiple myeloma population (p < 0.001). The rate of skin hyperpigmentation (0.066%, n = 3) and all skin changes (6.4%, n = 291) was significantly less compared to a 40.8% incidence in a recent retrospective study (p. <0.001). Among participants undergoing treatment with lenalidomide for multiple myeloma, Black patients were underrepresented and the adverse event of skin hyperpigmentation was underreported. Fair representation of Black patients in clinical trials is needed to better describe this adverse event and other events that may be underreported.

Prenatal exposure to teratogenic medications in the era of Risk Evaluation and Mitigation Strategies.

BACKGROUND: Prevention of prenatal exposures to teratogenic drugs is a significant clinical and public health concern. With the enactment of the US Food and Drug Administration Amendments Act in 2007, the US Food and Drug Administration has begun to require manufacturers to implement Risk Evaluation and Mitigation Strategies to prevent prenatal exposures. Among 12 risk evaluation and mitigation strategy drugs, several had predecessor risk mitigation plans (eg, isotretinoin) and some were newly required (eg, mycophenolate). Only a small proportion of teratogenic drugs are currently subject to Risk Evaluation and Mitigation Strategies, and the extent of prenatal exposure to the universe of teratogenic drugs compared with drugs subject to Risk Evaluation and Mitigation Strategies is unknown. Moreover, the effectiveness of such advanced risk mitigation programs in preventing prenatal exposure is not clear. OBJECTIVE: This study aimed to characterize the epidemiology of prenatal exposures to definite and potential teratogens during the risk evaluation and mitigation strategy era. STUDY DESIGN: We constructed a time-series of pregnancies identified from a national private insurance claims database (IBM MarketScan) to estimate prenatal exposures to teratogenic drugs (2006-2017). Pregnancy outcomes, gestational age, and the onset of pregnancy were determined with previously validated algorithms. The Teratology Information Service and Clinical Pharmacology databases were used to identify drugs with definite (n=141) or potential (n=65) teratogenic effects, and drugs with debatable risks such as benzodiazepines, statins, tetracyclines, sex hormones, infertility treatments, and gonadotropin-releasing hormone analogs were excluded. We defined prenatal exposure as ≥1 prescription fill or medical encounter involving administration of drugs with a definite teratogenic risk (including 12 for which there is a "current or discontinued" risk evaluation and mitigation strategy) or a potential teratogenic risk. We evaluated secular trends and modeled the effects of age, preconception exposure, and state healthcare quality rankings on prenatal exposure, adjusting for demographic factors and clinical conditions. RESULTS: The cohort included 3,445,612 pregnancies (2,532,444 live deliveries). Prenatal exposures to definite teratogens decreased slightly during the study years from 1.86 to 1.24 per 100 pregnancies between 2006 and 2017, whereas exposure increased for potential teratogens from 3.40% to 5.33%. Prenatal exposure prevalences were higher during the first trimester and for pregnancies that ended in nonlive outcomes. Drugs subject to Risk Evaluation and Mitigation Strategies had low background utilization and contributed to a small proportion of prenatal exposures (15.1 per 100,000 pregnancies). We also observed fewer prenatal exposures to risk evaluation and mitigation strategy drugs among women of childbearing age who used these treatments (0.14% vs 0.36% for any definite teratogen). Age extremes and low state-level healthcare quality rankings were independent predictors of prenatal exposure. CONCLUSION: Fetuses in more than 1 in 16 pregnancies continued to be exposed to teratogenic drugs during the past decade. Drugs with Risk Evaluation and Mitigation Strategies imposed a small burden of prenatal exposure because of the low background utilization rates and lower pregnancy prevalence among women of childbearing age who used these drugs. Although the declining exposure rates to teratogenic drugs with definite risk are encouraging, the rising prenatal exposure to drugs with potential risk calls for more assessments. Future research is needed to elucidate the health outcomes of fetuses exposed to potential risk drugs, understand the effectiveness of risk evaluation and mitigation strategy programs, and prioritize teratogenic drugs for advanced risk mitigation.

Depressive symptoms in non-alcoholic fatty liver disease are identified by perturbed lipid and lipoprotein metabolism.

Non-alcoholic fatty liver disease (NAFLD) and depression are common disorders and have bidirectional contributing relationships to metabolic syndrome. We aimed to determine whether a fasting serum signature of recent, self-reported depressive symptoms could be identified in a heterogeneous NAFLD cohort using nuclear magnetic resonance (NMR)-based metabolomics integrated with clinical chemistry. Serum nuclear magnetic resonance (NMR) metabolite profiles and corresponding clinical chemistry were compared between patients with depressive symptoms in the last 12-months (n = 81) and patients without recent depressive symptoms (n = 137 controls) using multivariate statistics. Orthogonal partial least squares discriminant analysis (OPLS-DA) of the biochemical and metabolomic data identified NAFLD patients with recent depression with a cross-validated accuracy of 61.5%, independent of age, sex, medication, and other comorbidities. This led to the development of a diagnostic algorithm with AUC 0.83 for future testing in larger clinical cohorts. Serum triglycerides, VLDL cholesterol, and the inflammatory biomarker GlycA were key metabolites increased in patients with recent depressive symptoms, while serum glutamine level was reduced. Here, serum NMR metabolite analysis provides a link between disturbed lipid metabolism, inflammation, and active mental health issues in NAFLD, irrespective of disease severity.

Predicting Liver-Related Outcomes in People With Nonalcoholic Fatty Liver Disease: The Prognostic Value of Noninvasive Fibrosis Tests.

It remains unclear whether screening for advanced fibrosis in the community can identify the subgroup of people with nonalcoholic fatty liver disease (NAFLD) at higher risk for development of liver-related complications. We aimed to determine the prognostic value of baseline noninvasive fibrosis tests for predicting liver-related outcomes and mortality in patients with NAFLD from type 2 diabetes (T2D) clinics or primary care. Patients (n = 243) who were screened for NAFLD with advanced fibrosis by using NAFLD fibrosis score (NFS), fibrosis 4 score (FIB-4), enhanced liver fibrosis (ELF) test, and liver stiffness measurements (LSMs) were followed up for clinical outcomes by review of electronic medical records. During a median follow-up of 50 months, decompensated liver disease or primary liver cancer occurred in 6 of 35 (17.1%) patients with baseline LSM > 13 kPa, 1 of 17 (5.9%) patients with LSM 9.5-13 kPa, and in no patients with LSM < 9.5 kPa. No patient with low-risk NFS developed liver decompensation or liver-related mortality. Following repeat NFSs at the end of follow-up, all patients with a liver-related complication were in the high-risk NFS category. Patients who developed liver-related complications were also more likely to have baseline high-risk FIB-4 scores or ELF test ≥9.8 compared to patients who did not develop liver outcomes. Conclusion: Liver fibrosis risk stratification in non-hepatology settings can identify the subset of patients at risk of liver-related complications. Although the rate of development of a decompensation event or hepatocellular carcinoma was low (2.1% per year) in our patients with compensated cirrhosis (LSM > 13 kPa), these events are projected to lead to a substantial increase in NAFLD-related disease burden over the next decade due to the high prevalence of NAFLD in people with obesity and T2D.

Combinatorial model of amyloid ß and tau reveals synergy between amyloid deposits and tangle formation.

AIMS: To illuminate the pathological synergy between Aß and tau leading to emergence of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), here, we have performed a comparative neuropathological study utilising three distinctive variants of human tau (WT tau, P301L mutant tau and S320F mutant tau). Previously, in non-transgenic mice, we showed that WT tau or P301L tau does not form NFT while S320F tau can spontaneously aggregate into NFT, allowing us to test the selective vulnerability of these different tau conformations to the presence of Aß plaques. METHODS: We injected recombinant AAV-tau constructs into neonatal APP transgenic TgCRND8 mice or into 3-month-old TgCRND8 mice; both cohorts were aged 3 months post injection. This allowed us to test how different tau variants synergise with soluble forms of Aß (pre-deposit cohort) or with frank Aß deposits (post-deposit cohort). RESULTS: Expression of WT tau did not produce NFT or altered Aß in either cohort. In the pre-deposit cohort, S320F tau induced Aß plaque deposition, neuroinflammation and synaptic abnormalities, suggesting that early tau tangles affect the amyloid cascade. In the post-deposit cohort, contemporaneous expression of S320F tau did not exacerbate amyloid pathology, showing a dichotomy in Aß-tau synergy based on the nature of Aß. P301L tau produced NFT-type inclusions in the post-deposit cohort, but not in the pre-deposit cohort, indicating pathological synergy with pre-existing Aß deposits. CONCLUSIONS: Our data show that different tau mutations representing specific folding variants of tau synergise with Aß to different extents, depending on the presence of cerebral deposits.

Medication Discrepancies and Regimen Complexity in Decompensated Cirrhosis: Implications for Medication Safety.

Discrepancies between the medicines consumed by patients and those documented in the medical record can affect medication safety. We aimed to characterize medication discrepancies and medication regimen complexity over time in a cohort of outpatients with decompensated cirrhosis, and evaluate the impact of pharmacist-led intervention on discrepancies and patient outcomes. In a randomized-controlled trial (n = 57 intervention and n = 57 usual care participants), medication reconciliation and patient-oriented education delivered over a six-month period was associated with a 45% reduction in the incidence rate of 'high' risk discrepancies (IRR = 0.55, 95%CI = 0.31-0.96) compared to usual care. For each additional 'high' risk discrepancy at baseline, the odds of having ≥ 1 unplanned medication-related admission during a 12-month follow-up period increased by 25% (adj-OR = 1.25, 95%CI = 0.97-1.63) independently of the Child-Pugh score and a history of variceal bleeding. Among participants with complete follow-up, intervention patients were 3-fold less likely to have an unplanned medication-related admission (adj-OR = 0.27, 95%CI = 0.07-0.97) compared to usual care. There was no association between medication discrepancies and mortality. Medication regimen complexity, frequent changes to the regimen and hepatic encephalopathy were associated with discrepancies. Medication reconciliation may improve medication safety by facilitating communication between patients and clinicians about 'current' therapies and identifying potentially inappropriate medicines that may lead to harm.

Bilateral Cranial Nerve VI Palsies in Cryptococcal Meningitis, HIV, and Syphilis: A Case Report.

INTRODUCTION: Cranial nerve (CN) VI palsy is a common complaint seen in the emergency department (ED) and has a wide range of causes. Bilateral CN VI palsies are uncommon and appear to be associated with more severe complications. CASE REPORT: A 29-year-old male presented to the ED from an ophthalmology office for diplopia, headache, and strabismus. He was found to have bilateral CN VI palsies and new-onset seizure in the ED. A lumbar puncture revealed cryptococcal meningitis. Additional tests revealed a new diagnosis of human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), and syphilis. CONCLUSION: Cryptococcal meningitis remains a life-threatening complication of HIV/AIDS. Coinfections with HIV, particularly syphilis, further complicate a patient's prognosis as both can lead to devastating neurological sequelae. In cryptococcal meningitis, elevated intracranial pressure is a complication that can manifest as seizures, altered mental status, and cranial nerve palsies.

Is there scope to improve the selection of patients with alcohol-related liver disease for referral to secondary care? A retrospective analysis of primary care referrals to a UK liver centre, incorporating simple blood tests.

OBJECTIVES: Twenty per cent of people with alcohol use disorders develop advanced fibrosis and warrant referral to secondary care. Improving outcomes in alcohol-related liver disease (ArLD) relies on its earlier detection in primary care with non-invasive tests (NIT). We aimed to determine the proportion of alcohol-related referrals who were diagnosed with advanced fibrosis in secondary care, the prevalence of both alcohol and fatty liver disease ('BAFLD') and the potential impact of NIT on referral stratification. DESIGN/SETTING: Retrospective analysis of all general practitioner-referrals with suspected ArLD/non-alcoholic fatty liver disease (NAFLD) to a UK hepatology-centre between January 2015 and January 2018. PARTICIPANTS: Of 2944 new referrals, 762 (mean age 55.5±13.53 years) met inclusion criteria: 531 NAFLD and 231 ArLD, of which 147 (64%) could be reclassified as 'BAFLD'. PRIMARY OUTCOME MEASURE: Proportion of referrals with suspected ArLD/NAFLD with advanced fibrosis as assessed by tertiary centre hepatologists using combinations of FibroScan, imaging, examination and blood tests and liver histology, where indicated. SECONDARY OUTCOME MEASURES: Included impact of body mass index/alcohol consumption on the odds of a diagnosis of advanced fibrosis, and performance of NIT in predicting advanced fibrosis in planned post-hoc analysis of referrals. RESULTS: Among ArLD referrals 147/229 (64.2%) had no evidence of advanced fibrosis and were judged 'unnecessary'. Advanced fibrosis was observed in men drinking ≥50 units per week (U/w) (OR 2.74, 95% CI 1.51 to 5, p=0.001) and ≥35 U/w in women (OR 5.11, 95% CI 1.31 to 20.03, p=0.019). Drinking >14 U/w doubled the likelihood of advanced fibrosis in overweight/obesity (OR 2.11; 95% CI 1.44 to 3.09; p<0.001). Use of fibrosis 4 score could halve unnecessary referrals (OR 0.50; 95% CI 0.32 to 0.79, p=0.003) with false-negative rate of 22%, but was rarely used. CONCLUSIONS: The majority of referrals with suspected ArLD were deemed unnecessary. NIT could improve identification of liver damage in ArLD, BAFLD and NAFLD in primary care. Anecdotal thresholds for harmful drinking (35 U/w in women and 50 U/w in men) were validated. The impact of alcohol on NAFLD highlights the importance of multi-causality in chronic liver disease.

The Enhanced Liver Fibrosis test maintains its diagnostic and prognostic performance in alcohol-related liver disease: a cohort study.

BACKGROUND: Alcohol is the main cause of chronic liver disease. The Enhanced Liver Fibrosis (ELF) test is a serological biomarker for fibrosis staging in chronic liver disease, however its utility in alcohol-related liver disease warrants further validation. We assessed the diagnostic and prognostic performance of ELF in alcohol-related liver disease. METHODS: Observational cohort study assessing paired ELF and histology from 786 tertiary care patients with chronic liver disease due to alcohol (n = 81) and non-alcohol aetiologies (n = 705). Prognostic data were available for 64 alcohol patients for a median of 6.4 years. Multiple ELF cut-offs were assessed to determine diagnostic utility in moderate fibrosis and cirrhosis. Survival data were assessed to determine the ability of ELF to predict liver related events and all-cause mortality. RESULTS: ELF identified cirrhosis and moderate fibrosis in alcohol-related liver disease independently of aminotransferase levels with areas under receiver operating characteristic curves of 0.895 (95% CI 0.823-0.968) and 0.923 (95% CI 0.866-0.981) respectively, which were non-inferior to non-alcohol aetiologies. The overall performance of ELF was assessed using the Obuchowski method: in alcohol = 0.934 (95% CI 0.908-0.960); non-alcohol = 0.907 (95% CI 0.895-0.919). Using ELF < 9.8 to exclude and ≧ 10.5 to diagnose cirrhosis, 87.7% of alcohol cases could have avoided biopsy, with sensitivity of 91% and specificity of 85%. A one-unit increase in ELF was associated with a 2.6 (95% CI 1.55-4.31, p < 0.001) fold greater odds of cirrhosis at baseline and 2.0-fold greater risk of a liver related event within 6 years (95% CI 1.39-2.99, p < 0.001). CONCLUSIONS: ELF accurately stages liver fibrosis independently of transaminase elevations as a marker of inflammation and has superior prognostic performance to biopsy in alcohol-related liver disease.

Association of exercise participation levels with cardiometabolic health and quality of life in individuals with hepatitis C.

OBJECTIVE: Hepatitis C virus (HCV) infection is associated with an increased risk of cardiovascular disease (CVD) and reduced health-related quality of life (HRQoL). Although physical activity (PA)/exercise has been shown to reduce CVD risk and improve HRQoL in patients with liver disease, there is limited data in HCV. We aimed to explore the association between PA/exercise levels, CVD risk and HRQoL in patients with HCV and assess individuals' attitudes to PA/exercise. DESIGN: Cross-sectional observational study recruiting consecutive patients with HCV from viral hepatitis clinics. Data were collected on CVD risk factors, anthropometry, HRQoL and the Exercise Benefits and Barriers Scale (EBBS). RESULTS: 86 patients were recruited (71% men, 94% white, age 52±13 years); 49% of the cohort self-reported to be currently active. Although HRQoL was reduced across the cohort, patients that were regularly 'active' reported significantly higher HRQoL scores across Short-Form 36v2 domains compared with their inactive counterparts (p<0.05). Metabolic and cardiovascular characteristics were no different between groups stratified by PA/exercise status (p>0.05). EBBS scores were similar in the 'active' versus 'inactive' groups, however, patients categorised as 'active' scored significantly higher on the psychological outlook and social interaction subscales (p<0.05) than those that were 'inactive'. There were significant associations between EBBS scores and HRQoL (p<0.05). CONCLUSIONS: PA/exercise is associated with increased HRQoL in patients with HCV irrespective of clinical parameters. Addressing specific motivators/barriers to exercise for patients will be key to designing effective PA/exercise interventions in this patient population to ensure maximum uptake and adherence.

Serum matrix metalloproteinase 7 (MMP7) is a biomarker of fibrosis in patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population globally. Since liver fibrosis is the most important predictor of liver-related complications in patients with NAFLD, identification of patients with advanced fibrosis among at-risk individuals is an important issue in clinical practice. Transient elastography is the best evaluated non-invasive method used in referral centres to assess liver fibrosis, however serum-based tests, such as the Enhanced Liver Fibrosis (ELF) score, have a practical advantage as first-line tests due to their wider availability and lower cost. We previously identified matrix metalloproteinase 7 (MMP7) as a serum biomarker of histological advanced fibrosis in a mixed-etiology patient cohort. In this study we aimed to determine the association between MMP7 and fibrosis, assessed by transient elastography, in patients with NAFLD. Serum MMP7 levels were measured in a cohort of 228 patients with NAFLD. Associations between MMP7, liver stiffness measurement (LSM), ELF score and clinical parameters were determined using logistic regression modelling. Serum MMP7 was associated with clinically significant fibrosis (LSM ≥ 8.2), independent of age, gender, BMI and diabetes. The addition of MMP7 significantly improved the diagnostic performance of the ELF test, particularly in patients over the age of 60. Combinations of serum biomarkers have the potential to improve the sensitivity and specificity of detection of advanced fibrosis in at-risk patients with NAFLD. We have demonstrated that serum MMP7 is independently associated with clinically significant fibrosis and improves the diagnostic performance of currently available tests in older patients.

Normothermic Ex Situ Liver Perfusion Enhances Mitochondrial Function of DCD Grafts as Evidenced by High-throughput Metabolomics.

BACKGROUND: Normothermic ex situ liver perfusion (NEsLP) reduces reperfusion injury of donation after circulatory death (DCD) grafts and optimizes graft function. The goal of our study was to elucidate how NEsLP impacts global metabolism in DCD grafts using high-throughput metabolomics. METHODS: Pig livers were preserved by 2 different techniques: static cold storage and NEsLP. Grafts obtained from heart-beating donors were compared with donation after circulatory death (DCD) grafts with either 30 minutes (DCD30) or 60 minutes (DCD60) ischemia time. Liver tissues were collected at the end of preservation period (T0) with either cold storage or NEsLP (n = 5 per group). Grafts were transplanted into recipient pigs and a second liver biopsy was collected 2 hours following liver transplantation (T1). Snap-frozen tissue was processed and analyzed by Sciex 6600 Q-TOF high-resolution mass spectrometer. Data analysis was performed using MetaboAnalyst 4.0 software. RESULTS: Prolonged ischemia resulted in 38 out of 81 metabolites being differentially abundant over time. Mitochondrial metabolism was significantly affected, with disruption in oxidative phosphorylation capacity i.e the Warburg effect (P = 3.62E-03) and urea cycle (P = 7.95E-0.4). NEsLP resulted in improved mitochondrial metabolism and glycolysis (4.20E-02) oxidation of branched chain fatty acids (P = 4.07E-02). CONCLUSIONS: This unbiased, high-throughput metabolomics study reveals that mitochondrial function is globally rescued with NEsLP, associated with improvement in DCD graft function. NEsLP is able to rescue DCD grafts, improving their metabolic function to that of livers not exposed to DCD procurement.