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Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

In an aging population with cardiovascular comorbidities, anticoagulant (AC), antiplatelet (AP), and nonsteroidal anti-inflammatory drug (NSAID) use are increasing. It remains unclear whether these agents pose increased bleeding risk in cirrhosis. This study aimed to assess the association between these medications and bleeding and portal hypertension complications in cirrhosis.The IMS PharMetrics database was used to identify privately insured adults diagnosed with cirrhosis from 2007 to 2015, stratified as compensated or decompensated based on the presence of portal hypertensive complications 1 year before cirrhosis diagnosis. Bleeding or decompensation outcomes were assessed 6 to 18 months after cirrhosis diagnosis using a landmark analysis design. Multivariable Cox proportional hazards regression modeling assessed associations between AC, AP, and NSAID drug exposures and outcomes adjusting for covariates.A total of 18,070 cirrhosis patients were analyzed; 57% male; 74% ages 50 to 64 years; 34% with a prior decompensation. Overall, 377 (2%) had claims for ACs; 385 (2%) APs; and 1231 (7%) NSAIDs. APs were associated with increased bleeding [adjusted hazard ratio (aHR)=1.31; 95% confidence interval (CI): 1.00, 1.72] and decompensation events (aHR=1.44; 95% CI: 1.06, 1.95) in a 9-month landmark analysis. NSAIDs were significantly associated with bleeding events (aHR=1.29; 95% CI: 1.06, 1.57) on 3-month landmark analysis. No statistically significant associations were seen between ACs and bleeding or decompensation outcomes in adjusted analyses.AP use was associated with increased bleeding and decompensation events among privately insured patients with cirrhosis. NSAID use was associated with significant early bleeding, but not decompensations. Lastly ACs were not associated with bleeding or decompensation outcomes.

Background In an aging population with cardiovascular comorbidities, anticoagulant (AC), antiplatelet (AP), and nonsteroidal anti-inflammatory drug (NSAID) use are increasing. It remains unclear whether these agents pose increased bleeding risk in cirrhosis. This study aimed to assess the association between these medications and bleeding and portal hypertension complications in cirrhosis. Methods The IMS PharMetrics database was used to identify privately insured adults diagnosed with cirrhosis from 2007 to 2015, stratified as compensated or decompensated based on the presence of portal hypertensive complications 1 year before cirrhosis diagnosis. Bleeding or decompensation outcomes were assessed 6 to 18 months after cirrhosis diagnosis using a landmark analysis design. Multivariable Cox proportional hazards regression modeling assessed associations between AC, AP, and NSAID drug exposures and outcomes adjusting for covariates. Results A total of 18,070 cirrhosis patients were analyzed; 57% male; 74% ages 50 to 64 years; 34% with a prior decompensation. Overall, 377 (2%) had claims for ACs; 385 (2%) APs; and 1231 (7%) NSAIDs. APs were associated with increased bleeding [adjusted hazard ratio (aHR)=1.31; 95% confidence interval (CI): 1.00, 1.72] and decompensation events (aHR=1.44; 95% CI: 1.06, 1.95) in a 9-month landmark analysis. NSAIDs were significantly associated with bleeding events (aHR=1.29; 95% CI: 1.06, 1.57) on 3-month landmark analysis. No statistically significant associations were seen between ACs and bleeding or decompensation outcomes in adjusted analyses. Conclusions AP use was associated with increased bleeding and decompensation events among privately insured patients with cirrhosis. NSAID use was associated with significant early bleeding, but not decompensations. Lastly ACs were not associated with bleeding or decompensation outcomes.

Goal The goal of this study was to determine if bariatric surgeries are associated with de novo alcohol-related complications. Background Bariatric surgery is associated with an increased risk of alcohol use disorders. The effect of bariatric surgeries on other alcohol-related outcomes, including liver disease, is understudied. Materials and methods Using the IMS PharMetrics database, we performed a cohort study of adults undergoing bariatric surgery or cholecystectomy, excluding patients with an alcohol-related diagnosis within 1 year before surgery. The primary outcome was any alcohol-related diagnosis after surgery. We fit a multivariable Cox proportional hazards model to determine independent associations between bariatric surgeries [Roux-en-Y gastric bypass (RYGB); adjustable gastric band; sleeve gastrectomy] versus cholecystectomy and the development of de novo alcohol-related outcomes. We further fit complication-specific models for each alcohol-related diagnosis. Results RYGB was significantly associated with an increased hazard of any de novo alcohol-related diagnosis [adjusted hazard ratio (AHR)=1.51, 95% confidence interval (CI): 1.40-1.62], while adjustable gastric band (AHR=0.55, 95% CI: 0.48-0.63) and sleeve gastrectomy (AHR=0.77, 95% CI: 0.64-0.91) had decreased hazards. RYGB was associated with a 2- to 3-fold higher hazard for alcoholic hepatitis (AHR=1.98, 95% CI: 1.17-3.33), abuse (AHR=2.05, 95% CI: 1.88-2.24), and poisoning (3.14, 95% CI: 1.80-5.49). Conclusions RYGB was associated with higher hazards of developing de novo alcohol-related hepatitis, abuse, and poisoning compared with a control group. Patients without a history of alcohol use disorder should still be counseled on the increased risk of alcohol use and alcohol-related complications, including alcohol-related liver disease, following RYGB, and should be monitored long term for the development of alcohol-related complications.

Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity., This Review provides mechanistic and clinical insights into COVID-19 in the context of liver disease, discussing the potential underlying biology and clinical features of SARS-CoV-2 infection in patients with pre-existing liver conditions. The management of these patients is also discussed, including SARS-CoV-2 vaccination strategies., Key points Patients with cirrhosis have high rates of hepatic decompensation, acute-on-chronic liver failure and death from respiratory failure following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and should be prioritized for coronavirus disease 2019 (COVID-19) vaccination.The possible pathogenic mechanisms linking cirrhosis with severe COVID-19 lung disease include increased systemic inflammation, cirrhosis-associated immune dysfunction, coagulopathy and intestinal dysbiosis.Abnormal liver biochemistry values are common in patients with COVID-19; both the prognostic significance of these derangements and whether they are directly attributable to hepatic SARS-CoV-2 infection remain uncertain.Expression profiles of SARS-CoV-2 entry receptors vary across different in vitro and in vivo liver models; however, evidence of specific viral hepatotropism is limited.Liver transplant recipients do not appear to have an increased risk of mortality following SARS-CoV-2 infection compared with the matched general population.The pandemic has been associated with increased alcohol consumption, unhealthy eating habits, and interruptions to hepatology services, which might lead to an upward trend in liver disease incidence and severity.

Alcohol consumption has risen substantially in the United States in the past 2 decades.

Marijuana is legalized for either medical or recreational use in over half of the states in the United States and in Canada, but many transplant centers will not list patients who are using marijuana. However, the effect of marijuana on transplant outcomes remains unclear. Thus, we performed a retrospective analysis of all adult (≥18 years old) liver transplant patients treated at our center between 2007 and 2017. Patients were grouped according to their marijuana use and tobacco smoking status. We also evaluated tobacco smoking status for the comparative evaluation. Posttransplant morbidity, mortality, and graft survival were evaluated. In total, 316 patients were included: 171 (54%) patients were tobacco smokers (70 current; 101 former), 81 (26%) patients were marijuana smokers (13 current; 68 former), and 64 (20#x0025;) patients were both marijuana and tobacco smokers. A total of 136 (43%) reported never smoking marijuana or tobacco. After adjustment, current tobacco users were over 3 times as likely to die within 5 years compared with never users (hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.63-6.46; P 0.001), but no difference was seen between current/former and never marijuana users (HR, 0.52; 95% CI, 0.26-1.04; P = 0.06). No significant differences in inpatient respiratory complications, reintubation, or24-hour intubation was seen. Overall, pretransplant marijuana use, past or current, does not appear to impact liver transplant outcomes, though tobacco smoking remains detrimental.

First-line treatment for nonalcoholic fatty liver disease (NAFLD) focuses on weight loss through lifestyle modifications.1,2 Weight loss ≥5% results in reduction of steatosis and weight loss ≥10% has been associated with improvement in hepatic inflammation and fibrosis.3 The incidence and sustainability of weight loss among patients with NAFLD were estimated and associating factors identified.

BACKGROUND AND AIMS Anesthesia services for endoscopic procedures have proliferated with the promise of increased comfort and safety. Cirrhosis patients are higher risk for sedation, yet limited data are available describing anesthesia complications in this population. APPROACH AND RESULTS This cross-sectional study utilized the National Anesthesia Clinical Outcomes Registry, a multicenter quality-improvement database from 2010 to 2015. Patients with cirrhosis undergoing an endoscopy were identified by International Classification of Diseases, Ninth Revision (ICD-9)/Current Procedures Terminology (CPT) codes. The outcome of interest was serious anesthesia-related complication defined as cardiovascular, respiratory, neurological, drug related, patient injury, death, or unexpected admission. A mixed-effects multivariate logistic regression model determined odds ratios (ORs) between variables and serious complications, adjusting for potential confounders. In total, 9,007 endoscopic procedures were performed among patients with cirrhosis; 92% were esophagogastroduodenoscopies. The majority (81%) were American Society of Anesthesiologists (ASA) class ≥3, and 72% had a history of hepatic encephalopathy, ascites, varices, hepatorenal syndrome, or spontaneous bacterial peritonitis identified by ICD-9/CPT codes. In total, 87 complications were reported, 33 of which were serious. Frequency of serious complications was 0.4% or 378.6 per 100,000 procedures (95% confidence interval [CI], 260.8, 531.3). The majority of serious complications were cardiovascular (21 of 33), including 15 cardiac arrests. Serious complications were significantly associated with ASA 4/5 (OR, 3.84; 95% CI, 1.09, 13.57) and general anesthesia (OR, 4.71; 95% CI, 1.20, 18.50), adjusting for age, sex, ASA class, anesthesia type, inpatient status, portal hypertension history, and variable complication reporting practices. CONCLUSIONS Anesthesia complications among endoscopic procedures in cirrhosis are rare overall. Serious complications were predominantly cardiac and associated with sicker patients undergoing general anesthesia. The complexity of end-stage liver disease may warrant more intensive care during endoscopic procedures, including anesthesia monitoring.

Background & Aims: Chronic liver disease (CLD) and cirrhosis are associated with immune dysregulation, leading to concerns that affected patients may be at risk of adverse outcomes following SARS-CoV-2 infection. We aimed to determine the impact of COVID-19 on patients with pre-existing liver disease, which currently remains ill-defined. Methods: Between 25th March and 8th July 2020, data on 745 patients with CLD and SARS-CoV-2 (including 386 with and 359 without cirrhosis) were collected by 2 international registries and compared to data on non-CLD patients with SARS-CoV-2 from a UK hospital network. Results: Mortality was 32% in patients with cirrhosis compared to 8% in those without (p, The COVID-Hep.net registry is supported by the European Association for the Study of the Liver (EASL) (2020RG03). This work was also supported by the National Institutes of Health grant T32 DK007634 (AMM and EJB), and North Carolina Translational and Clinical Sciences Institute (CTSA grant number UL1TR002489). We acknowledge the support of the National Institutes of Health, through Grant Award Number UL1TR002489. TC was funded as an academic clinical fellow by NIHR and by WT training fellowship for clinicians (grant number 211042/Z/18/Z). EB is supported by the Oxford NIHR Biomedical Research Centre and is an NIHR Senior Investigator. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Background Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients. Methods In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death. Findings Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47–66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44–84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p Interpretation Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic. Funding European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.

Nonalcoholic fatty liver disease (NAFLD), including its severe form known as steatohepatitis or NASH, are increasingly common in patients with type 2 diabetes mellitus (T2DM) and can progress to cirrhosis. However, there is limited information on their comorbid medical conditions in “real world” practice. Thus, the disease characteristics of patients with NASH or NASH-cirrhosis (cirrhosis), with or without T2DM, was evaluated in TARGET-NASH, an ongoing longitudinal observational study of patients with NAFLD, who are managed according to local standards at 60 community and academic hepatology and endocrinology practices in the United States. Among 3085 patients enrolled with NASH or cirrhosis, 1645 had NASH (47% T2DM) and 1440 had cirrhosis (72% T2DM). Patients with T2DM were older (median 61 vs. 56 years) and had a higher median BMI (34.0 vs. 32.0 kg/m2, p In conclusion, patients with type 2 diabetes and NASH or cirrhosis had more advanced liver disease compared to those without type 2 diabetes. Patients with type 2 diabetes had more than twice the risk of cirrhosis compared to those without type 2 diabetes. These results support a strong link of type 2 diabetes and metabolic risk factors with advanced NASH. Disclosure K. Cusi: Consultant; Self; Allergan plc., AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., Gilead Sciences, Inc., Merck & Co., Inc. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Poxel SA, Zydus Pharmaceuticals, Inc. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. A.S. Barritt: Consultant; Self; GENFIT, Intercept Pharmaceuticals, Inc., TARGET PharmaSolutions. R.J. Firpi: None. V. Clark: Research Support; Self; GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk Inc. S. Klein: Advisory Panel; Self; Danone Nutricia, Merck & Co., Inc. Research Support; Self; Johnson & Johnson, Pfizer Inc. Stock/Shareholder; Self; Aspire Bariatrics. A. Lok: None. P. Newsome: Research Support; Self; Novo Nordisk A/S. K. Corbin: None. M.B. Vos: Advisory Panel; Self; TARGET PharmaSolutions. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Immuron, Intercept Pharmaceuticals, Inc., Mallinckrodt Pharmaceuticals, Novo Nordisk A/S. Research Support; Self; Bristol Myers Squibb. R. Reddy: Advisory Panel; Self; Ambys, Epigenomics AG, Mallinckrodt Pharmaceuticals, Merck & Co., Inc. Research Support; Self; Conatus Pharmaceuticals, Exact Sciences, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Mallinckrodt Pharmaceuticals, Merck & Co., Inc. C. Schoen: None. A.R. Mospan: Employee; Self; TARGET PharmaSolutions. J.L. Taunk: None. K. Wyne: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Sanofi. B. Neuschwander-Tetri: Advisory Panel; Self; 89Bio, Allysta, ARTham, Blade, Bristol-Myers Squibb, Gelesis, GENFIT, Histoindex, Madrigal Pharmaceuticals, Inc., Medpace, Merck & Co., Inc., Sagimet, Siemens Corporation. Consultant; Self; Arrowhead Pharmaceuticals, Inc., Axcella, DURECT Corporation, Enanta Pharmaceuticals, Inc., Fortress, Indalo, Innovo, Lipocine, Mundipharma International, pH-Pharma, TARGET PharmaSolutions. A. Sanyal: Consultant; Self; Intercept Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc. Stock/Shareholder; Self; DURECT Corporation, GENFIT, HemoShear, Sanyal Bio, Tiziana Life Sciences plc. Funding TARGET-NASH

AIM To investigate the relationship between post-liver transplantation (LT) glycemic control and LT outcomes. METHODS A qualitative systematic review on relevant prospective interventions designed to control glucose levels including insulin protocols. Studies investigating an association between glycemic control and post-LT outcomes such as mortality, graft rejection, and infection rate were reviewed. PubMed, EMBASE, and other databases were searched through October 2016. RESULTS Three thousands, six hundreds and ninety-two patients from 14 studies were included. Higher mortality rate was seen when blood glucose (BG) ≥ 150 mg/dL (P = 0.05). BG ≥ 150 mg/dL also led to higher rates of infection. Higher rates of graft rejection were seen at BG > 200 mg/dL (P < 0.001). Mean BG ≥ 200 mg/dL was associated with more infections (P = 0.002). Nurse-initiated protocols and early screening strategies have shown a reduction in negative post-LT outcomes. CONCLUSION Hyperglycemia in the perioperative period is associated with poor post-LT outcomes. Only a few prospective studies have designed interventions aimed at managing post-LT hyperglycemia, post-transplant diabetes mellitus (PTDM) and their impact on post-LT outcomes.

Patients with polycystic liver disease are described in the literature as both recipient and donor for liver transplant. Due to well-preserved liver function, it is often difficult for these patients to receive an organ. Livers of these patients are often large and heavier than a normal organ. We describe two cases who had exceedingly large livers, weighing 14 and 19 kg. To the best of our knowledge and search, these are some of the heaviest explanted livers, and one of the patients incidentally received a liver from a donor with ADPKD. The aim of this report is to discuss the challenges and pitfalls of evaluating and listing, technical aspect of the transplant, possibility of transplanting a liver from a donor with a genetic cystic disease to a cystic disease recipient, and the related literature with some highlights on the facts from UNOS/OPTN data.

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. NAFLD comprises the spectrum from simple steatosis (nonalcoholic fatty liver, NAFL), to steatosis with inflammation (nonalcoholic steatohepatitis, NASH). Current primary therapy recommended for NAFLD is weight loss induced by lifestyle modification. The difficulty in achieving this has led to robust pharmacological therapy development. While new drugs may show efficacy in selected phase II/III clinical trial populations, their real-world effectiveness is unknown. TARGET-NASH is a 5-year, longitudinal, observational study of patients with NAFLD designed to evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. A biological specimen repository is included in TARGET-NASH for translational studies of genomics and biomarkers of disease activity. Patients are enrolling at adult and pediatric sites representing multiple specialties. All patients being managed for NAFLD are eligible, whereas those in other NASH registries or clinical trials will be excluded. Enrolled patients range in age from 6 and up and will have 3years of clinical data reviewed. Patient comorbidities, concomitant medications, disease progression and off-label interventions will be assessed, and adverse outcomes, monitored. Confirming the use, safety and effectiveness of NAFLD interventions in children and adults and establishing pragmatic methods of assessing disease progression under real-world conditions are key study outcomes. Ultimately, TARGET-NASH will establish a large, diverse registry of NAFLD patients at academic and community practices to be leveraged to improve health and reduce development of cirrhosis and hepatocellular carcinoma.

An association between periodontitis and nonalcoholic fatty liver disease (NAFLD) has been reported by experimental animal and epidemiologic studies. This study investigated whether circulating levels of serum C-reactive protein (CRP) and a weighted genetic CRP score representing markers of inflammatory burden modify the association between periodontitis and NAFLD. Data came from 2,481 participants of the Study of Health in Pomerania who attended baseline examination that occurred between 1997 and 2001. Periodontitis was defined as the percentage of sites (0%, 3 mg/L. Periodontitis was positively associated with higher prevalence odds of NAFLD, and this relationship was modified by serum CRP levels.

BACKGROUND & AIMS: Estimates of disease burden can inform national health priorities for research, clinical care, and policy. We aimed to estimate health care use and spending among gastrointestinal (GI) (including luminal, liver, and pancreatic) diseases in the United States. METHODS: We estimated health care use and spending based on the most currently available administrative claims from commercial and Medicare Supplemental plans, data from the GI Quality Improvement Consortium Registry, and national databases. RESULTS: In 2015, annual health care expenditures for gastrointestinal diseases totaled $135.9 billion. Hepatitis ($23.3 billion), esophageal disorders ($18.1 billion), biliary tract disease ($10.3 billion), abdominal pain ($10.2 billion), and inflammatory bowel disease ($7.2 billion) were the most expensive. Yearly, there were more than 54.4 million ambulatory visits with a primary diagnosis for a GI disease, 3.0 million hospital admissions, and 540,500 all-cause 30-day readmissions. There were 266,600 new cases of GI cancers diagnosed and 144,300 cancer deaths. Each year, there were 97,700 deaths from non-malignant GI diseases. An estimated 11.0 million colonoscopies, 6.1 million upper endoscopies, 313,000 flexible sigmoidoscopies, 178,400 upper endoscopic ultrasound examinations, and 169,500 endoscopic retrograde cholangiopancreatography procedures were performed annually. Among average-risk persons ages 50–75 years who underwent colonoscopy, 34.6% had 1 or more adenomatous polyps, 4.7% had 1 or more advanced adenomatous polyps, and 5.7% had 1 or more serrated polyps removed. CONCLUSIONS: GI diseases contribute substantially to health care use in the United States. Total expenditures for GI diseases are $135.9 billion dollars annually—greater than for other common diseases. Expenditures are likely to continue increasing.

Nonalcoholic Fatty Liver Disease (NAFLD), ranging from simple steatosis to its more severe form, steatohepatitis (NASH), is an increasingly common problem in patients with T2DM and is associated with progression to cirrhosis and extrahepatic complications (i.e., cardiovascular disease [CVD]). There is limited information on the clinical profile of T2DM patients with NASH in “real world” practice. Accordingly, we studied the clinical profile of participants (pts) with NASH, with or without T2DM (nonDM), enrolled in TARGET-NASH, a large longitudinal observational study of patients with NAFLD followed at 54 sites (39 academic/15 community) across the U.S. Data collected from medical records (including lab data, imaging, pathology, procedures, and outcomes) is sent to a central database utilizing novel data abstraction technology. Among 1743 pts studied to date in TARGET-NASH, 1261 had NASH diagnosed by biopsy or clinical criteria (699 T2DM and 562 nonDM). Pts with T2DM and NASH were older (median 61 vs. 56 years) and had a higher BMI than nonDM (34.0 vs. 32.0 kg/m2, both p Disclosure K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc. A.S. Barritt: Consultant; Self; Targetpharma solutions. Consultant; Spouse/Partner; Targetpharma solutions, Takeda Pharmaceuticals U.S.A., Inc., AbbVie Inc.. V. Clark: None. R.J. Firpi: None. S. Klein: Stock/Shareholder; Self; Aspire Bariatrics. Consultant; Self; Pfizer Inc.. Research Support; Self; Merck & Co., Inc., Johnson & Johnson Services, Inc., REMD Biotherapeutics. A. Lok: None. R. Loomba: Research Support; Self; Adheron, Arora, BMS, Daiichi-Sankyo Inc., Galectin, Galmed, GE, Genfit, Gilead, Immuron, Intercept, Kinemed, Madrigal, Merck, NGM, Promedior, Prometheus, Siemens, Sirius, Tobira. Advisory Panel; Self; Arrowhead Research, Conatus, Galmed, Gilead, Intercept, NGM, Nimbus, Octeta, Tobira. Consultant; Self; Alnylam, Bird Rock Bio, BMS, Boehringer Ingleheim, Celgene, Conatus, DeuteRx, Eli Lily, Enanta, Fibrogen, Genkyotex, Gilead, GRI Bio, ISIS, Janssen Inc.Kirin, Madrigal, Metacrine, NGM, Nitto Denko, Pf, Sanofi,Scholar Rock, Shire, Tasly, Viking, Yuhan Pharmaceuticals, Zafgen. L. Malahias: None. B. Neuschwander-Tetri: None. C. Schoen: None. K. Reddy: Advisory Panel; Self; Gilead Sciences, Inc., Merck & Co., Inc., AbbVie Inc.. Other Relationship; Self; Novartis AG, Gilead Sciences, Inc., Merck & Co., Inc., AbbVie Inc., Mallinckrodt Pharmaceuticals, Conatus Pharmaceuticals Inc., Intercept Pharmaceuticals, Inc.. J.L. Taunk: None. K. Wyne: Research Support; Self; Sanofi. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. A.J. Sanyal: Stock/Shareholder; Self; Sanyal Bio, Genfit, Durect, Indalo, Exhalenz. Consultant; Self; Gilead, Boehringer Ingelheim, Intercept. Advisory Panel; Self; Galectin, NGM. Consultant; Self; Pfizer.

The expression of hepatic transporters, including organic anion transporting polypeptides (OATPs) and multidrug resistance-associated proteins (MRPs), is altered in nonalcoholic steatohepatitis (NASH); however, functional data in humans are lacking. In this study, 99m Tc-mebrofenin (MEB) was used to evaluate OATP1B1/1B3 and MRP2 function in NASH patients. Healthy subjects (n = 14) and NASH patients (n = 7) were administered MEB (∼2.5 mCi). A population pharmacokinetic model was developed to describe systemic and hepatic MEB disposition. Study subjects were genotyped for SLCO1B1 variants. NASH increased systemic and hepatic exposure (median ± 2 SE, healthy vs. NASH) to MEB (AUC0-300,blood : 1,780 ± 242 vs. 2,440 ± 775 μCi*min/L, P = 0.006; AUC0-180,liver : 277 ± 36.9 vs. 433 ± 40.3 kcounts*min/sec, P < 0.0001) due to decreased biliary clearance (0.035 ± 0.008 vs. 0.017 ± 0.002 L/min, P = 0.0005) and decreased Vcentral (11.1 ± 0.57 vs. 6.32 ± 1.02 L, P < 0.0001). MEB hepatic CLuptake was reduced in NASH and also in healthy subjects with SLCO1B1 *15/*15 and *1A/*15 genotypes. The pharmacokinetics of drugs that are OATP1B1/1B3 and MRP2 substrates may be substantially altered in NASH.

BACKGROUND & AIMS Pretransplant renal failure is commonly reported to be a poor prognostic indicator affecting survival after liver transplantation (LT). However, whether the impact of renal failure on patient outcome varies according to the aetiology of the underlying liver disease is largely unknown. METHODS We investigated the association between renal failure at the time of LT and patient outcome in patients with alcoholic liver disease (ALD) (n = 6920), non-alcoholic steatohepatitis (NASH) (n = 2956) and hepatitis C (HCV) (n = 14 922) using the United Network for Organ Sharing (UNOS) database between February 2002 and December 2013. A total of 24 798 transplant recipients were included. RESULTS The presence of renal failure was more frequently seen in patients with ALD (23.95%) and NASH (23.27%) compared to patients with HCV (19.38%) (P < 0.001). In multivariate analysis, renal failure was an independent predictor of poor survival. Renal failure showed detrimental effect on patient survival in the overall series (HR = 1.466, P < 0.0001). Importantly, the impact of renal failure was less marked in patients with ALD (HR = 1.31, P < 0.0001) than in patients with NASH (HR = 1.73, P < 0.0001) or HCV (HR = 1.52, P < 0.0001). Despite a higher model for end-stage liver disease (MELD) score at the time of LT, ALD patients with renal failure had better long-term prognosis than non-ALD patients. CONCLUSIONS Renal failure at the time of LT conferred a lower patient and graft survival post-LT. However, renal failure has less impact on the outcome of patients with ALD than that of patients with non-alcoholic liver disease after LT.

Background & Aims Gastrointestinal (GI), liver, and pancreatic diseases are a source of substantial morbidity, mortality, and cost in the United States. Quantification and statistical analyses of the burden of these diseases are important for researchers, clinicians, policy makers, and public health professionals. We gathered data from national databases to estimate the burden and cost of GI and liver disease in the United States. Methods We collected statistics on health care utilization in the ambulatory and inpatient setting along with data on cancers and mortality from 2007 through 2012. We included trends in utilization and charges. The most recent data were obtained from the Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, and the National Cancer Institute. Results There were 7 million diagnoses of gastroesophageal reflux and almost 4 million diagnoses of hemorrhoids in the ambulatory setting in a year. Functional and motility disorders resulted in nearly 1 million emergency department visits in 2012; most of these visits were for constipation. GI hemorrhage was the most common diagnosis leading to hospitalization, with >500,000 discharges in 2012, at a cost of nearly $5 billion dollars. Hospitalizations and associated charges for inflammatory bowel disease, Clostridium difficile infection, and chronic liver disease have increased during the last 20 years. In 2011, there were >1 million people in the United States living with colorectal cancer. The leading GI cause of death was colorectal cancer, followed by pancreatic and hepatobiliary neoplasms. Conclusions GI, liver and pancreatic diseases are a source of substantial burden and cost in the United States.

Background: The number of liver transplants performed in the US increased annually until 2006, but has since declined despite ongoing increases in demand. One possible reason for this decline is a reduction in donor organ utilization as a result of decreased organ quality. We aimed to (1) evaluate the association between various donor characteristics and organ discard and (2) examine trends over time in these characteristics that may explain any increased discard rate. Methods: We performed a retrospective cohort study using the United Network for Organ Sharing database comprising all donors ≥ 18 years old who successfully donated at least one organ between 1994 and 2010. Living donors, split livers, and donors with a body mass index (BMI) 50 kg/m2 were excluded. Multivariable logistic regression was used to evaluate the association between donor characteristics and the discard of donor livers. Population attributable risk proportions were determined to estimate the contribution of various donor factors to liver discard. Results: Of 93,232 organ donors, 69,833 (75%) livers were used, and 23,399 (25%) went unused. The number of discarded organs was stable until 2003, and then increased from 1,058 (19%) in 2003 to 1,828 (26%) in 2010. In bivariate analysis, discarded livers were more often from donors who were older (median 49 vs. 43 years). Rates of discard were higher in donors with obesity (35% vs. 22% of non-obese donors), diabetes (DM) (35% vs. 24% of non-diabetics), hypertension (HTN) (31% vs. 22% of normotensive donors), and donation after cardiac death (DCD) (65% vs. 22% of non-DCD). In the multivariable model, discarded livers were associated with donor age (OR 1.03 for each year increase, 95% CI 1.03-1.04), obesity (OR 1.92, 95% CI 1.82-2.03), DM (OR 1.42, 95% CI 1.32-1.53), HTN (OR 1.15, 95% CI 1.081.22), and DCD (OR 12.3, 95%CI 11.3-13.4). Between 1994 and 2010, there were significant increases in the median donor age (40 to 46) and the prevalence of obesity (13% to 31%), DM (3% to 13%), HTN (22% to 39%), and DCD (2% to 12%). In 2010, 44% of non-use was due to increased age, 9% to obesity, 5% to diabetes, and 5% to hypertension. These proportions were stable over time. In contrast, the proportion discarded due to DCD rose dramatically from 0.2% in 2000 to 26% in 2010. The OR for DCD liver discard also increased from 1.80 to 25.0 reflecting increasing reluctance to use these grafts. Conclusions: Organ donors are increasingly older, with more obesity, DM, and HTN, all of which may limit expansion of the donor pool. DCD is becoming more common, but its ability to expand the donor pool is significantly hindered by an increasing discard rate. Indeed, if the DCD option is taken merely as an alternative to donation after brain death, then more DCD will lead to a significant decline in usable grafts.