Mortality, Hepatic Decompensation, and Cardiovascular- and Renal-Related Outcomes in Lean Versus Non-lean Patients Hospitalized With Metabolic Dysfunction-Associated Steatohepatitis (MASH).

INTRODUCTION: Metabolic dysfunction-associated steatohepatitis (MASH) is an important cause of cirrhosis and end-stage liver disease. In addition, there have been reports of worse extrahepatic outcomes, especially cardiovascular events, in patients with lean patients' fatty liver disease compared to the non-lean group. There is limited data on hepatic, cardiac, and renal outcomes in lean compared to non-lean patients with MASH. This study aims to evaluate the cardiovascular, renal, and hepatic outcomes in hospitalized US adults with MASH, focusing on a comprehensive comparison between lean and non-lean patients. METHODS: The National Inpatient Sample (NIS) database was queried from 2016 to 2020 to identify hospitalizations with MASH. Hospitalizations with a history of overweight and obesity (lean body mass index (BMI) <25 vs. lean BMI >25) were also identified. The primary outcome was in-hospital mortality. Secondary outcomes were major adverse cardiovascular outcomes (MACE: a composite of acute myocardial infarction, cardiac arrest, stroke, heart failure, and atrial fibrillation); major adverse kidney outcome (MAKE: a composite outcome of acute kidney injury (AKI), renal replacement therapy, and renal cancer), and hepatic decompensation (esophageal varices with bleeding, ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy, and hepatorenal syndrome) Multivariate logistic regression analysis was used to derive risk ratios for clinical outcomes. RESULTS: We included 539,275 MASH patients in our sample; 324,330 (60%) were lean. The included patients were mostly female (61%), the mean age was 64 years, and 76% were White. At baseline, non-lean patients had a higher prevalence of heart failure, hypertension, and hyperlipidemia. There was no difference in the prevalence of smoking among both groups. In a multivariate analysis, with adjustment for age, sex, race, sarcopenia, cardiometabolic risk factors, hospital characteristics, admission type, socioeconomic factors, and all comorbidities (including 31 Elixhauser comorbidities), lean status was associated with a 40% increased risk of mortality (adjusted odds ratio (aOR) 1.40, confidence interval (CI) 1.29-1.53), 19% increased risk of MACE (aOR 1.19; 95% CI 1.14-1.24), 20% increased risk of renal decompensation (aOR 1.25; 95% CI 1.20-1.30), and 33% increased risk of hepatic decompensation (aOR 1.33 CI 1.28-1.38). CONCLUSION: Lean patients with MASH are at higher risk of cardiovascular and renal outcomes and may benefit from enhanced screening for early identification and treatment to improve outcomes.

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data.

Importance: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure. Objective: To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports. Design, Setting, and Participants: This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023. Exposures: Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity. Main Outcomes and Measures: Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports. Results: The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports. Conclusions and Relevance: In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.

Role of ammonia and glutamine in the pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease: A systematic review.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the global population, with a significant risk of advancing to liver cirrhosis and hepatocellular carcinoma. The roles of ammonia and glutamine in MASLD's pathogenesis are increasingly recognized, prompting this systematic review. This systematic review was conducted through a meticulous search of literature on December 21, 2023, across five major databases, focusing on studies that addressed the relationship between ammonia or glutamine and MASLD. The quality of the included studies was evaluated using CASP checklists. This study is officially registered in the PROSPERO database (CRD42023495619) and was conducted without external funding or sponsorship. Following PRISMA guidelines, 13 studies were included in this review. The studies were conducted globally, with varying sample sizes and study designs. The appraisal indicated a mainly low bias, confirming the reliability of the evidence. Glutamine's involvement in MASLD emerged as multifaceted, with its metabolic role being critical for liver function and disease progression. Variable expressions of glutamine synthetase and glutaminase enzymes highlight metabolic complexity whereas ammonia's impact through urea cycle dysfunction suggests avenues for therapeutic intervention. However, human clinical trials are lacking. This review emphasizes the necessity of glutamine and ammonia in understanding MASLD and identifies potential therapeutic targets. The current evidence, while robust, points to the need for human studies to corroborate preclinical findings. A personalized approach to treatment, informed by metabolic differences in MASLD patients, is advocated, alongside future large-scale clinical trials for a deeper exploration into these metabolic pathways.

Artificial intelligence in endoscopic imaging for detection of malignant biliary strictures and cholangiocarcinoma: a systematic review.

Background: Artificial intelligence (AI), when applied to computer vision using a convolutional neural network (CNN), is a promising tool in "difficult-to-diagnose" conditions such as malignant biliary strictures and cholangiocarcinoma (CCA). The aim of this systematic review is to summarize and review the available data on the diagnostic utility of endoscopic AI-based imaging for malignant biliary strictures and CCA. Methods: In this systematic review, PubMed, Scopus and Web of Science databases were reviewed for studies published from January 2000 to June 2022. Extracted data included type of endoscopic imaging modality, AI classifiers, and performance measures. Results: The search yielded 5 studies involving 1465 patients. Of the 5 included studies, 4 (n=934; 3,775,819 images) used CNN in combination with cholangioscopy, while one study (n=531; 13,210 images) used CNN with endoscopic ultrasound (EUS). The average image processing speed of CNN with cholangioscopy was 7-15 msec per frame while that of CNN with EUS was 200-300 msec per frame. The highest performance metrics were observed with CNN-cholangioscopy (accuracy 94.9%, sensitivity 94.7%, and specificity 92.1%). CNN-EUS was associated with the greatest clinical performance application, providing station recognition and bile duct segmentation; thus reducing procedure length and providing real-time feedback to the endoscopist. Conclusions: Our results suggest that there is increasing evidence to support a role for AI in the diagnosis of malignant biliary strictures and CCA. CNN-based machine leaning of cholangioscopy images appears to be the most promising, while CNN-EUS has the best clinical performance application.

Artificial intelligence in medical imaging for cholangiocarcinoma diagnosis: A systematic review with scientometric analysis.

INTRODUCTION: Artificial intelligence (AI), by means of computer vision in machine learning, is a promising tool for cholangiocarcinoma (CCA) diagnosis. The aim of this study was to provide a comprehensive overview of AI in medical imaging for CCA diagnosis. METHODS: A systematic review with scientometric analysis was conducted to analyze and visualize the state-of-the-art of medical imaging to diagnosis CCA. RESULTS: Fifty relevant articles, published by 232 authors and affiliated with 68 organizations and 10 countries, were reviewed in depth. The country with the highest number of publications was China, followed by the United States. Collaboration was noted for 51 (22.0%) of the 232 authors forming five clusters. Deep learning algorithms with convolutional neural networks (CNN) were the most frequently used classifiers. The highest performance metrics were observed with CNN-cholangioscopy for diagnosis of extrahepatic CCA (accuracy 94.9%; sensitivity 94.7%; and specificity 92.1%). However, some of the values for CNN in CT imaging for diagnosis of intrahepatic CCA were low (AUC 0.72 and sensitivity 44%). CONCLUSION: Our results suggest that there is increasing evidence to support the role of AI in the diagnosis of CCA. CNN-based computer vision of cholangioscopy images appears to be the most promising modality for extrahepatic CCA diagnosis. Our social network analysis highlighted an Asian and American predominance in the research relational network of AI in CCA diagnosis. This discrepancy presents an opportunity for coordination and increased collaboration, especially with institutions located in high CCA burdened countries.

Role of Prophylactic Cholecystectomy After Endoscopic Sphincterotomy for Biliary Stone Disease: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to perform a structured systematic review and meta-analysis to evaluate the effectiveness and complication rate of cholecystectomy deferral versus prophylactic cholecystectomy among patients post-endoscopic biliary sphincterotomy for common bile duct stones. BACKGROUND: Although previous reports suggest a decreased risk of biliary complications with prophylactic cholecystectomy, biliary endoscopic cholangiopancreatography (ERCP) with sphincterotomy may provide a role for deferring cholecystectomy with the gallbladder left in situ. METHODS: Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed through August 2019 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Measured outcomes included: mortality, recurrent biliary pain or cholecystitis, pancreatitis, cholangitis, and eventual need for cholecystectomy. Random effects models were used to determine pooled effect size and corresponding 95% confidence intervals (CIs). RESULTS: Nine studies (n = 1605) were included. A total of 53.8% (n = 864) patients had deferred cholecystectomy post-sphincterotomy. Deferral cholecystectomy as compared to prophylactic cholecystectomy resulted in a significant increased risk of mortality [odds raio (OR) 2.56 (95% confidence interval, CI 1.54-4.23); P < 0.0001; I2 = 18.49]. Patients who did not undergo prophylactic cholecystectomy developed more recurrent biliary pain or cholecystitis [OR 5.10 (95% CI 3.39-7.67); P < 0.0001; I2 = 0.00]. Rate of pancreatitis [OR 3.11 (95% CI 0.99-9.83); P = 0.053; I2 = 0.00] and cholangitis [OR 1.49 (95% CI 0.74-2.98); P = 0.264; I2 = 0.00] was unaffected. Overall, 26.00% (95% CI 14.00-40.00) of patients with deferred prophylactic cholecystectomy required eventual cholecystectomy. CONCLUSIONS: Prophylactic cholecystectomy remains the preferred strategy compared to a deferral approach with gallbladder in situ post-sphincterotomy for patients with bile duct stones. Future studies may highlight a subset of patients (ie, those with large balloon biliary dilation) that may not require cholecystectomy.

Endoscopic Ultrasound-Guided, Percutaneous, and Transjugular Liver Biopsy: A Comparative Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Percutaneous liver biopsy (PCLB) or transjugular liver biopsy (TJLB) have traditionally been performed to obtain a sample of hepatic tissue; however, endoscopic ultrasound-guided liver biopsy (EUSLB) has become an attractive alternative. The aim of this study was to compare the efficacy and safety of EUSLB, PCLB, and TJLB. METHODS: Search strategies were developed in accordance with PRISMA and MOOSE guidelines. Major outcomes included the following: adequacy of biopsy specimens (i.e., complete portal triads [CPT], total specimen length [TSL] in mm, and length of longest piece [LLP]) in mm), and rate of adverse events. Only studies comparing all biopsy approaches (i.e., EUSLB, PCLB, and TJLB) were included. RESULTS: Five studies (EUSLB [n=301]; PCLB [n=176]; and TJLB [n=179]) were included. Biopsy cumulative adequacy rates for EUSLB, PCLB, and TJLB were 93.51%, 98.27%, and 97.61%, respectively. Based on the subgroup analysis limited to EUS biopsy needles in current clinical practice, there was no difference in biopsy adequacy or adverse events for EUSLB compared to PCLB and TJLB (all p>0.050). A comparison of EUSLB and PCLB revealed no difference between specimens regarding both CPT (p=0.079) and LLP (p=0.085); however, a longer TSL (p<0.001) was observed. Compared to TJLB, EUSLB showed no difference in LLP (p=0.351), fewer CPT (p=0.042), and longer TSL (p=0.005). CONCLUSION: EUSLB appears to be a safe, minimally invasive procedure that is comparable to PCLB and TJLB regarding biopsy specimens obtained and rate of adverse events associated with each method.

Safety of Bariatric Surgery in Morbidly Obese Patients with Human Immunodeficiency Virus: A Nationwide Inpatient Sample Analysis, 2004-2014.

Background: Despite rising rates of obesity among human immunodeficiency virus (HIV)-positive individuals, the safety and tolerability of surgery in this population have not been established. The primary aim of this study was to examine the safety of bariatric surgery and rate of in-hospital postoperative complications in morbidly obese patients with HIV. Materials and Methods: The U.S. Nationwide Inpatient Sample database was queried between 2004 and 2014 for discharges with codiagnoses of morbid obesity and bariatric surgery. The primary outcome was in-hospital mortality. Secondary outcomes included length of stay, hospitalization costs, and multiple categories of complications, including systemic complications, surgical complications, and nutritional and behavioral complications. Results: Among 267,082 patients with discharge diagnoses of morbid obesity and bariatric surgery, 346 (0.13%) were diagnosed with HIV. On multivariable analysis, HIV did not influence in-hospital mortality (p = 0.530). HIV was not associated with increased risk of renal failure (p = 0.274), thromboembolism (p = 0.713), myocardial infarction (p = 0.635), sepsis (p = 0.757), hemorrhage (p = 0.303), or wound infection (p = 0.229). Other measured surgical complications were not significantly different (p > 0.05). Notably, HIV-positive patients had an increased risk for postoperative pneumonia (p = 0.002), pancreatitis (p = 0.049), and thiamine deficiency (p = 0.016). Conclusion: Bariatric surgery among HIV-positive patients appears to be acceptably safe with the risk of postoperative complications comparable with non-HIV patients.

Rhythmic Fluctuations in Levels of Liver Enzymes During Menstrual Cycles of Healthy Women and Effects of Body Weight.

BACKGROUND & AIMS: Female sex hormones affect several non-reproductive organs, but little is known about their effects on the liver during a normal menstrual cycle. We aimed to investigate the association between sex hormones and liver enzymes in healthy menstruating women. METHODS: We performed a post-hoc analysis of data from the BioCycle study, a longitudinal cohort study designed to determine the association of sex hormones with markers of oxidative stress during the menstrual cycle. We analyzed data collected from 259 menstruating women, over 1-2 menstrual cycles, who had as many as 16 separate office visits, timed by fertility monitors. Levels of liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase, and alkaline phosphatase (ALKP), bilirubin, and lipids were measured by laboratory assays. RESULTS: We found a natural cyclic pattern for liver enzymes, with transaminases and ALKP peaking in the mid-follicular phase and reaching a trough in the late luteal phase; the peak to trough differences were 4.0 ± 4.9 U/L for ALT and 8.8 ± 4.0 U/L for ALKP. Levels of ALT were significantly and negatively associated with levels of progesterone on the preceding visit (P = 5x10-4), whereas level of ALKP was negatively associated with level of estrogen (P = .007) and progesterone (P = 1x10-11). Food and alcohol intake did not modify the association. The amplitude of ALT fluctuation was greater in African Americans and decreased with age. Fluctuations in levels of ALT were smaller in women with body mass indices >30 kg/m2 (P = .03). During menstrual fluctuation, 49% of participants had ALT values both above and below the normal cut-off value (19 U/L). CONCLUSIONS: Levels of liver enzymes fluctuate during the normal menstrual cycle, possibly mediated by progesterone, and the fluctuation varies with age and body mass index. These findings indicate the importance of accounting for phase of menstrual cycle when interpreting liver enzyme measurements in menstruating women.

Expression of the type 3 InsP3 receptor is a final common event in the development of hepatocellular carcinoma.

BACKGROUND & OBJECTIVES: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca2+ release channels in HCC. DESIGN: Expression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice. RESULTS: ITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis. CONCLUSIONS: These results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.

Impact of Bariatric Surgery on Outcomes of Patients with Sickle Cell Disease: a Nationwide Inpatient Sample Analysis, 2004-2014.

BACKGROUND: With advances in disease-specific treatments and improved overall survival, obesity rates are rising among patients with sickle cell disease (SCD). The primary aim of this study was to evaluate the role of bariatric surgery on clinical outcomes among hospitalized obese patients with SCD. METHODS: The United States Nationwide Inpatient Sample database was queried between 2004 and 2014 for discharges with co-diagnoses of morbid obesity and SCD. The primary outcome was in-hospital mortality. Secondary outcomes included vaso-occlusive crisis, acute chest syndrome, biliary-pancreatic complications, renal failure, urinary tract infection, malnutrition, sepsis, pneumonia, respiratory failure, thromboembolic events, strictures, wound infection, length of stay, and hospitalization costs. Using Poisson regression, adjusted incidence risk ratios (IRR) were derived for clinical outcomes in patients with prior-bariatric surgery compared to those without bariatric surgery. RESULTS: Among 2549 patients with a discharge diagnosis of SCD and morbid obesity, only 42 patients (1.7%) had bariatric surgery. On multivariable analysis, bariatric surgery did not influence mortality (P = 0.98). Bariatric surgery was not associated with increased risk for acute chest syndrome, sepsis, multi-organ failure, biliary-pancreatic, or surgery-related complications (all P > 0.05). Interestingly, bariatric surgery decreased risk of vaso-occlusive crises (IRR 0.21; 95% CI, 0.07-0.69; P = 0.01) in these patients and was associated with a shorter length of stay (P < 0.001) but higher hospitalization costs (P < 0.001). CONCLUSIONS: Bariatric surgery may lower rates of vaso-occlusive crises in morbidly obese sickle cell patients without significantly affecting mortality and other adverse outcomes. In spite of this, these weight loss surgeries are underutilized in this select population.

Effects of Hypercholesterolemia and Statin Exposure on Survival in a Large National Cohort of Patients With Cirrhosis.

BACKGROUND & AIMS: Concerns related to hepatotoxicity frequently lead to discontinuation or non-initiation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase therapy in patients with cirrhosis despite data supporting statin use. We investigated the independent effects of hyperlipidemia and statin exposure on mortality, hepatic decompensation, and hepatocellular carcinoma development in a large national cohort of patients with cirrhosis. METHODS: We performed a retrospective cohort study of patients with newly diagnosed cirrhosis from January 1, 2008 through June 30, 2016 in the Veterans Health Administration. Subjects were divided into 2 cohorts: 21,921 patients with prior statin exposure (existing users) and 51,023 statin-naïve individuals, of whom 8794 subsequently initiated statin therapy (new initiators) and 44,269 did not (non-initiators). Multivariable Cox proportional hazard models with inverse probability weighting were constructed to assess the effects of time-updating lipid profiles and cumulative exposure to statins on survival and hepatic decompensation. Statin-naïve new initiators were propensity matched with non-initiators to simulate a randomized controlled trial of statin use in cirrhosis. RESULTS: In statin-naïve subjects, every 10-mg/dL increase in baseline total cholesterol was associated with a 3.6% decrease in mortality. In existing users, each year of continued statin exposure was associated with a hazard ratio of 0.920 (95% confidence interval 0.0.897-0.943) for mortality. After risk-set matching, each year of statin exposure among new initiators was associated with a hazard ratio of 0.913 (95% confidence interval 0.890-0.937) for mortality. CONCLUSIONS: In a retrospective cohort study of veterans with a new diagnosis of cirrhosis, we associated hypercholesterolemia with well-preserved hepatic function and decreased mortality. Nonetheless, each cumulative year of statin exposure was associated with an independent 8.0%-8.7% decrease of mortality of patients with cirrhosis of Child-Turcotte-Pugh classes A and B.

Impact of bariatric surgery on outcomes of patients with celiac disease: a nationwide inpatient sample analysis, 2004-2014.

BACKGROUND: While patients with celiac disease have increasingly developed an atypical pattern of weight gain and obesity, the role of bariatric surgery remains unclear. The primary aim of this study was to evaluate the effect of bariatric surgery on clinical outcomes among hospitalized patients with celiac disease. METHODS: The United States Nationwide Inpatient Sample database was queried for discharges with co-diagnoses of morbid obesity and celiac disease between 2004 and 2014. The primary outcome was in-hospital mortality. Secondary outcomes included renal failure, urinary tract infection, malnutrition, sepsis, pneumonia, respiratory failure, thromboembolic events, strictures, micronutrient deficiency, length of stay, and hospitalization costs. Using Poisson regression, adjusted incidence risk ratios (IRR) were derived for clinical outcomes in patients with prior bariatric surgery compared to those without bariatric surgery. RESULTS: Among 1499 patients with a discharge diagnosis of celiac disease and morbid obesity, 126 patients (8.4%) underwent bariatric surgery. Despite an increase in morbid obesity over the study period, the proportion of morbidly obese patients with celiac disease who had bariatric surgery declined by 18.5% (Ptrend<0.05). On multivariable analysis, bariatric surgery did not influence mortality (P=0.98), but was associated with a lower risk of renal failure, pneumonia, sepsis, urinary tract infection and respiratory failure (all P<0.05). Bariatric surgery increased the risk of vitamin D deficiency (IRR 3.5; 95% confidence interval [CI] 1.6-7.7; P=0.002) and post-operative strictures (IRR 3.3; 95%CI 1.5-7.5; P=0.004). CONCLUSION: Despite the underutilization of bariatric surgery in morbidly obese celiac disease patients, the procedure is safe and appears to significantly reduce morbidity.

Effects of Endotoxin on Type 3 Inositol 1,4,5-Trisphosphate Receptor in Human Cholangiocytes.

Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca2+ release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor, Toll-like receptor 4 (TLR4), which links to activation of nuclear factor-κB (NF-κB). Analysis of the human ITPR3 promoter revealed five putative response elements to NF-κB, and promoter activity was inhibited by p65/p50. Nested 0.5- and 1.0-kilobase (kb) deletion fragments of the ITPR3 promoter were inhibited by NF-κB subunits. Chromatin immunoprecipitation (ChIP) assay showed that NF-κB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from those with severe AH. Conclusion: Stimulation of TLR4 by LPS activates NF-κB to down-regulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or AH.

Bariatric Surgery and Hepatocellular Carcinoma: a Propensity Score-Matched Analysis.

BACKGROUND: The association between obesity and rising incidence of hepatocellular carcinoma (HCC) in the USA has been documented; however, the role of bariatric surgery remains less clear. AIM: To evaluate the cross-sectional association of prior-bariatric surgery and HCC. METHODS: The United States Nationwide Inpatient Sample (NIS) database was queried from 2004 to 2014 for discharges with a diagnosis of morbid obesity. Primary outcomes of interest were HCC and in-hospital mortality rate. Secondary outcomes were length of stay and cost. Baseline characteristics were balanced using propensity score matching (PSM). Using Poisson and logistic regressions, adjusted HCC prevalence ratio (PR) and mortality odds ratio (OR) were derived in patients with prior-bariatric surgery compared to those without bariatric surgery. RESULTS: Of the 2,881,414 patients included in our study, 267,082 (9.3%) underwent bariatric surgery. From 2004 to 2014, there was a threefold increase in age-adjusted prevalence of HCC from 27 per 100,000 to 72 per 100,000 (PTrend < 0.001). After PSM, 230,956 patients with prior-bariatric surgery were matched with 230,956 patients without bariatric surgery. Prior-bariatric surgery was associated with lower prevalence of HCC (PR 0.11; 95% CI, 0.03-0.48; P < 0.001). In-hospital mortality was also lower for patients with surgery (OR 0.22; 95% CI, 0.20-0.26; P < 0.001). The occurrence of HCC added $18,840 extra cost, increased mean length of stay by 2 (95% CI; 1-3) days, and increased risk of death by 65% (aOR 1.65; 95% CI 1.18-2.29). CONCLUSION: In this nationwide study of morbidly obese patients, prior-bariatric surgery was associated with a lower prevalence of HCC and lower in-patient mortality.

Cannabis Use Is Associated With Increased Risk of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: Analysis of the US Nationwide Inpatient Sample Database, 2004-2014.

OBJECTIVE: The aim of this study was to investigate the impact of cannabis on post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). METHODS: The US Nationwide Inpatient Sample was queried to identify patients who underwent endoscopic retrograde cholangiopancreatography pancreatitis from 2004 to 2014. Cannabis use was identified by International Classification of Diseases, Ninth Edition codes, and patients in remission were excluded. Poisson regression models were used to derive adjusted incidence risk ratios (IRRs) for outcomes. RESULTS: Among 37,712 patients with PEP, 0.4% had documented cannabis use disorder. From 2004 to 2014, the rate of PEP and cannabis use increased (8.9%-11.0% [P < 0.01] and 0.20%-0.70% [P < 0.01], respectively). Univariate analysis demonstrated cannabis was associated with increased risk of PEP (IRR, 1.70; 95% confidence interval [CI], 1.50-1.90; P < 0.01). On multivariate analysis, cannabis use was an independent predictor of PEP (IRR, 1.2; 95% CI, 1.1-1.4; P = 0.004). Cannabis was not associated with in-hospital death (IRR, 0.15; 95% CI, 0.02-1.04; P = 0.06) but was associated with shorter hospital stay (IRR, 0.96; 95% CI, 0.94-0.98; P < 0.001) and lower costs (IRR, 0.91; 95% CI, 0.91-0.92; P < 0.001). CONCLUSIONS: Cannabis use was associated with an increase in PEP without significant increase in mortality.

Impact of bariatric surgery in patients with HIV infection: a nationwide inpatient sample analysis, 2004-2014.

OBJECTIVE: Despite rising rates of obesity among patients with HIV, the potential role for weight loss surgery in this population remains less clear. The primary aim of this study was to evaluate the role of bariatric surgery on relevant clinical outcomes among hospitalized obese patients with HIV. DESIGN: Retrospective analysis using the United States Nationwide Inpatient Sample database from 2004 to 2014. Using Poisson regression, adjusted incidence risk ratios (IRR) were derived for clinical outcomes in patients with prior-bariatric surgery compared with those without bariatric surgery. PATIENTS: Patients with discharge co-diagnoses of morbid obesity and HIV. INTERVENTION: Bariatric surgery. MAIN OUTCOME MEASURES: Primary outcome was in-hospital mortality. Secondary outcomes included renal failure, urinary tract infection, malnutrition, sepsis, pneumonia, respiratory failure, thromboembolic events, gastrointestinal strictures, micronutrient deficiency, length of stay, and hospitalization costs. RESULTS: Among 7803 patients with discharge diagnoses of HIV and morbid obesity, 346 patients (4.4%) had bariatric surgery. The proportion of bariatric surgery in obese patients with HIV initially declined by -0.10% per year from 2004 to 2009 (Ptrend < 0.05), then increased at an annual rate of +0.33% from 2012 to 2014 (Ptrend < 0.05). On multivariable analysis, bariatric surgery did not influence mortality (P = 0.98). Bariatric surgery was associated with decreased risk for renal failure, respiratory failure, and sepsis (all P < 0.001). However, bariatric surgery increased the risk for postoperative strictures (IRR 2.5; 95% CI 1.5-4.5; P = 0.001). CONCLUSION: Though initially underutilized, bariatric surgery in morbidly obese HIV patients is increasing and appears to be well tolerated and effective in significantly reducing life-threatening morbidity.

Efficacy of transoral incisionless fundoplication for refractory gastroesophageal reflux disease: a systematic review and meta-analysis.

BACKGROUND: Given poor symptomatic response rates and rising awareness of the adverse events associated with the long-term use of proton pump inhibitors (PPIs), endoscopic modalities for treatment of refractory gastroesophageal reflux disease (GERD) have become more prominent. The aim of this study was to perform a systematic review and meta-analysis to evaluate feasibility, efficacy, and tolerability of transoral incisionless fundoplication (TIF) for the treatment of refractory GERD. METHODS: Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed to March 2017. Measured outcomes included immediate technical success rate and serious adverse events. Symptomatic improvement was measured using GERD Health-related Quality of Life (HRQL), Gastroesophageal Reflux Symptom Score (GERSS), and Reflux Symptom Index (RSI). Objective success was determined by hiatal hernia reduction and pH monitoring. RESULTS: 32 studies (1475 patients; 48.2 % male) met inclusion criteria. TIF success rate was 99 % (95 % confidence interval [CI] 97 to 100; P < 0.001), with an adverse event rate of 2 % (95 %CI 1 to 3; P < 0.001). GERD HRQL, GERSS, and RSI improved significantly post-TIF (mean difference 17.72, 95 %CI 17.31 to 18.14; mean difference 23.78, 95 %CI 22.96 to 24.60; mean difference 14.28, 95 %CI 13.56 to 15.01; all P < 0.001, respectively). Hernia reduction occurred in 91 % of patients (95 %CI 83 to 98; P < 0.001). DeMeester scores improved significantly (mean difference 10.22, 95 %CI 8.38 to 12.12; P < 0.001). PPI therapy was discontinued post-procedure in 89 % of patients (95 %CI 82 to 95; P < 0.001). CONCLUSIONS: TIF appears to be a safe and effective endoscopic procedure for patients with refractory GERD. Future controlled trials are needed to directly compare efficacy, long-term durability, and safety between TIF and Nissen fundoplication.