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 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.

Treatment and prevention of viral hepatitis in pregnancy.

Viral hepatitis in pregnancy may be caused by many types of viruses that cause systemic infection or target hepatocytes in their pathogenesis. Because viral hepatitis during pregnancy may represent acute or chronic infection or the reactivation of a prior infection, a high clinical suspicion, medical history review, and awareness of risk factors for the acquisition of infection are important management principles. The route of infection varies widely and ranges from fecal-oral transmission for the hepatitis A and E viruses to vertical transmission for hepatitis B, blood-borne transmission for hepatitis C, and sexual transmission for the herpes simplex virus. For this reason, the exposure details about travel, food preferences, drug use, and sexual contacts are important to elicit. Although routine prenatal screening is recommended for chronic viral hepatitis caused by hepatitis B and C, most other causes of viral hepatitis in pregnancy are detected in the setting of compatible signs and symptoms (fatigue, abdominal discomfort, jaundice, scleral icterus) or incidentally noted transaminitis on routine labs. Serologic testing is helpful for diagnosis with molecular testing as indicated to guide the management of hepatitis B and C. Preventive vaccines for hepatitis A and B with established safety of use in pregnancy are recommended for women who are at risk of acquisition. Postexposure prophylaxis for hepatitis A is a single dose of immunoglobulin and vaccination can be used if immunoglobulin G is not available. Antiviral therapy with tenofovir disoproxil fumarate is recommended as prophylaxis in pregnant women with active hepatitis B and an elevated viral load (>200,000 IU/mL) during the third trimester to prevent vertical transmission. The neonate exposed to hepatitis B at birth should receive immunoglobulin G and a monovalent birth dose vaccine within 12 hours, followed by completion of the 3-dosage vaccine series. The prevalence of hepatitis C in women of reproductive age has increased in the United States, and the role of antiviral therapy during pregnancy is of great interest. Cesarean delivery is not currently recommended for the sole purpose of reducing vertical transmission risk in pregnant women with viral hepatitis. Breastfeeding is recommended in women with hepatitis A, B, and C. New and promising prevention and treatment options for hepatitis B and C are under investigation. Investigators and regulatory authorities should ensure that these clinical trials for promising antivirals and vaccines are designed to include pregnant and lactating women.

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.

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.

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.

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.

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.

Regional and Rural-Urban Differences in the Use of Direct-acting Antiviral Agents for Hepatitis C Virus: The Veteran Birth Cohort.

BACKGROUND: Veterans with hepatitis C virus (HCV) infection may face geographic obstacles to obtaining treatment. OBJECTIVE: We studied the influence of region and rural versus urban residence on receipt of direct-acting antiretroviral (DAA) medications for HCV. SUBJECTS: Veterans receiving care within Veterans Affairs Healthcare System born between 1945 and 1965. RESEARCH DESIGN: This is a observational study using national electronic health record data. MEASURES: Receipt of DAAs was defined as ≥1 filled prescription from January 1, 2014 to December 31, 2016. Region (South, Northeast, Midwest, and West) and residence (urban, rural-micropolitan, small rural towns, and isolated rural towns) variables were created using residential zone improvement plan codes and rural-urban commuting area (RUCA) codes. Multivariable models were adjusted for age, race, sex, severity of liver disease, comorbidities, and prior treatment experience. RESULTS: Among 166,353 eligible patients 64,854 received, DAAs. Variation by rural-urban residence depended on region. In unadjusted analyses, receipt varied by rural-urban designations within Midwest, and West regions (P<0.05) but did not vary within the South (P=0.12). Southern rural small town had the lowest incidence of DAA receipt (40.1%), whereas the incidence was 52.9% in Midwestern isolated rural towns. In adjusted logistic analyses, compared with southern urban residents (the largest single group), southern rural small town residents had the lowest odds ratio, 0.85 (95% confidence interval, 0.75-0.93), and Midwestern residents from isolated and small rural towns had the highest odds (odds ratio, both 1.27) to receive treatment. CONCLUSIONS: Substantial geographic variation exists in receipt of curative HCV treatment. Efforts are needed to provide more equitable access to DAAs.

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.

Cost utility of ERCP-based modalities for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis.

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a leading cause of morbidity and mortality in patients with primary sclerosing cholangitis (PSC). Although several ERCP-based diagnostic modalities are available for diagnosing CCA, it is unclear whether one modality is more cost-effective than the others. The primary aim of this study was to compare the cost-effectiveness of ERCP-based techniques for diagnosing CCA in patients with PSC-induced biliary strictures. METHODS: We performed a cost utility analysis to assess the net monetary benefit for accurately diagnosing CCA using 5 different diagnostic strategies: (1) ERCP with bile duct brushing for cytology, (2) ERCP with brushings for cytology and fluorescence in situ hybridization (FISH)-trisomy, (3) ERCP with brushings for cytology and FISH-polysomy, (4) ERCP with intraductal biopsy sampling, and (5) single-operator cholangioscopy (SOC) with targeted biopsy sampling. A Monte Carlo simulation assessed outcomes including quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were also performed. RESULTS: SOC with targeted biopsy sampling, as compared with ERCP with brushing for FISH-polysomy, produced an incremental QALY gain of .22 at an additional cost of $8562.44, resulting in a base case ICER of $39,277.25. Deterministic and probabilistic sensitivity analyses demonstrated that diagnosis with SOC was cost-effective at conventional willingness-to-pay thresholds of $50,000 and $100,000. SOC was the most cost-effective diagnostic strategy. CONCLUSIONS: SOC with biopsy sampling is the most cost-effective diagnostic modality for CCA in PSC strictures.

Use of Wireless Capsule Endoscopy for the Diagnosis and Grading of Esophageal Varices in Patients With Portal Hypertension: A Systematic Review and Meta-Analysis.

INTRODUCTION: Esophageal variceal bleeding is a severe complication of portal hypertension with significant morbidity and mortality. Although traditional screening and grading of esophageal varices has been performed by endogastroduodenoscopy (EGD), wireless video capsule endoscopy provides a minimally invasive alternative that may improve screening and surveillance compliance. AIM OF THE STUDY: The aim of the study was to perform a systematic review and structured meta-analysis of all eligible studies to evaluate the efficacy of wireless capsule endoscopy for screening and diagnosis of esophageal varices among patients with portal hypertension. METHODS: Searches of PubMed, EMBASE, Web of Science, and the Cochrane Library databases were performed through December 2015. Bivariate and hierarchical models were used to compute the pooled sensitivity and specificity, and to plot the summary receiver operating characteristics curve with summary point and corresponding 95% confidence region. Bias of included studies was assessed using the quality assessment of diagnostic accuracy studies-2. RESULTS: Seventeen studies from 2005 to 2015 were included in this meta-analysis (n=1328). The diagnostic accuracy of wireless capsule endoscopy in the diagnosis of esophageal varices was 90% [95% confidence interval (CI), 0.88-0.93]. The diagnostic pooled sensitivity and specificity were 83% (95% CI, 0.76-0.89) and 85% (95% CI, 0.75-0.91), respectively. The diagnostic accuracy of wireless capsule endoscopy for the grading of medium to large varices was 92% (95% CI, 0.90-0.94). The pooled sensitivity and specificity were 72% (95% CI, 0.54-0.85) and 91% (95% CI, 0.86-0.94), respectively, for the grading of medium to large varices. The use of capsule demonstrated only mild adverse events. A sensitivity analysis limited to only high quality studies revealed similar results. DISCUSSION: Wireless esophageal capsule endoscopy is well tolerated and safe in patients with liver cirrhosis and suspicion of portal hypertension. The sensitivity of capsule endoscopy is not currently sufficient to replace EGD as a first exploration in these patients, but given its high accuracy, it may have a role in cases of refusal or contraindication to EGD.

Early transjugular intrahepatic portosystemic shunt in US patients hospitalized with acute esophageal variceal bleeding.

BACKGROUND AND AIM: Early transjugular intrahepatic portosystemic shunt (TIPS) used as preventive therapy prior to recurrent bleeding has been recommended in patients presenting with acute esophageal variceal bleeding (EVB) who are at high risk of further bleeding and death. We investigated the impact of early TIPS on outcomes of US patients hospitalized with EVB from 2000 to 2010. METHODS: The Nationwide Inpatient Sample database was queried to identify patients with EVB and decompensated cirrhosis (because early TIPS is recommended only in high-risk patients). The primary outcome was in-hospital death, and secondary outcomes included rebleeding and hepatic encephalopathy. Early preventive TIPS was defined by placement within 3 days of hospitalization for acute EVB after one session of endoscopic therapy. Rescue TIPS was defined as TIPS after two interventions for EVB. RESULTS: The study included 142 539 patients. From 2000 to 2010, the age-adjusted in-hospital mortality rate decreased 37.2% from 656 per 100 000 to 412 per 100 000 (P <0.01), while early and rescue TIPS increased (0.22% to 0.70%; P < 0.01 and 1.1% to 6.1%; P < 0.01). On multivariate analysis, as compared with no TIPS, early TIPS was associated with decreased inpatient mortality (risk ratio [RR] = 0.87; 95% confidence interval [CI], 0.84-0.90) and rebleeding (RR = 0.56; 95% CI, 0.45-0.71) without an increase in hepatic encephalopathy (RR = 1.01; 95% CI, 0.93-1.11). CONCLUSION: Early preventive TIPS in patients with EVB and decompensated cirrhosis was associated with significant in-hospital reductions in rebleeding and mortality without a significant increase in encephalopathy in "real-world" US clinical practice.

Emerging trends in hepatocellular carcinoma incidence and mortality.

UNLABELLED: The rise in incidence of hepatocellular carcinoma (HCC) in the United States has been well documented. The purpose of this analysis was to examine temporal trends in HCC incidence, mortality, and survival within the U.S. population. The Surveillance, Epidemiology, and End Results data were used to examine incidence and incidence-based (IB) mortality in HCC from 1973 to 2011. Secular trends in age-adjusted incidence and IB mortality by sex and cancer stage were characterized using the Joinpoint Regression program. In 1973, HCC incidence was 1.51 cases per 100,000, whereas in 2011, HCC incidence was 6.20 cases per 100,000. Although HCC incidence continues to increase, a slowing of the rate of increase occurs around 2006. In a sensitivity analysis, there was no significant increase in incidence and IB mortality from 2009 to 2011. There was a significant increase in overall median survival from the 1970s to 2000s (2 vs. 8 months; P < 0.001). On multivariable Cox's regression analysis, age, sex, race, tumor grade, stage at diagnosis, lymph/vascular invasion, number of primary tumors, tumor size, and liver transplant were independently associated with mortality. CONCLUSION: Our results indicate a deceleration in the incidence of HCC around 2006. Since 2009 and for the first time in four decades, there is no increase in IB mortality and incidence rates for HCC in the U.S. population. The nonsignificant increase in incidence and IB mortality in recent years suggest that the peak of the HCC epidemic may be near. A significant survival improvement in HCC was also noted from 1973 to 2010, which seems to be driven by earlier detection of HCC at a curative stage and greater utilization of curative modalities (especially transplant).

Diagnosis of sessile serrated adenomas/polyps with image-enhanced endoscopy: a systematic review and meta-analysis.

BACKGROUND AND STUDY AIMS: Distinguishing sessile serrated adenomas/polyps (SSA/Ps) from non-neoplastic tissue may be challenging when white-light endoscopy (WLE) is used. Image-enhanced endoscopy (IEE) has shown accuracy in differentiating adenomas from hyperplastic polyps. The aim of this systematic review and meta-analysis was to evaluate the utility of IEE in diagnosis of SSA/Ps. METHODS: Studies were eligible if: they included patients undergoing colonoscopy with an endoscopy-based image-enhancement modality; endoscopic diagnoses, including SSA/P, were based on the appearance of polyps at IEE; and the corresponding histologic diagnoses of polyps were provided. The primary outcome was sensitivity of IEE for SSA/Ps differentiated from non-neoplastic lesions (primary convention) and differentiated from all non-SSA/P lesions, including adenomas (secondary convention). RESULTS: 13 studies met inclusion criteria. Sensitivity ranged from 38 % to 100 % but sensitivity ≥ 90 % was seen in 4 of 10 narrow band imaging (NBI) or magnification-NBI studies. Pooled sensitivities for discriminating SSA/Ps from non-neoplastic lesions were 80 % for magnification-NBI, 60 % for NBI, 49 % for autofluorescence, and 47 % for flexible spectral imaging color enhancement. In head-to-head comparisons with WLE, NBI (89 % vs. 75 %) and magnification-NBI (78 % vs. 63 %) demonstrated significantly greater sensitivity, while autofluorescence imaging (56 % vs. 66 %), flexible spectral imaging color enhancement (100 % vs. 100 %), and high-resolution endomicroscopy (88 % vs. 100 %) did not. CONCLUSION: IEE currently cannot be recommended as a diagnostic tool for SSA/P. While NBI studies showed promise, more IEE studies employing validated SSA/P criteria in well-defined polyp populations are needed. IEE studies assessing SSA/P detection rates at colonoscopy are also needed.

Comparative efficacy of antiviral therapy in preventing vertical transmission of hepatitis B: a network meta-analysis.

BACKGROUND & AIMS: Antiviral drugs are safe and effective in the third trimester to prevent intrauterine transmission of hepatitis B virus, and are recommended for hepatitis B virus (HBV) infected gravid mothers (between weeks 28 and 32) with high viral load, followed by postnatal hepatitis B immunization in the newborn. We estimated the comparative efficacy of antiviral drugs for prevention of vertical transmission of HBV, through a network meta-analysis of clinical trials. METHODS: We conducted a comprehensive search of MEDLINE, EMBASE and published proceedings from major liver meetings from January 1980 to November 2014. We conducted pair-wise meta-analyses and Bayesian framework using Markov chain Monte Carlo methods, combining direct and indirect evidence for any given pair of treatments. RESULTS: Seventeen clinical trials involving 2764 newborns of hepatitis B surface antigen seropositive mothers were eligible for analysis. There were no clinical trials involving tenofovir or entecavir. On pair-wise meta-analyses, telbivudine (hazard ratio, HR 0.12, 95% confidence interval (CI) 0.04-0.37; I(2)  = 0%), and Lamivudine (HR 0.40, 95% CI 0.24-0.65; I(2)  = 0%), were more effective than placebo in reducing vertical transmission of HBV in high viremic hepatitis B e antigen (HBeAg)-positive chronic Hepatitis B Chinese patients. Sensitivity analyses limited to studies with HBeAg seropositive mothers revealed similar results. CONCLUSIONS: Based on a Bayesian network meta-analysis of clinical trials, combining direct and indirect treatment comparisons, telbivudine appears to be more effective than Lamivudine for preventing vertical transmission of HBV infection. Trials assessing the efficacy of tenofovir or entecavir compared to placebo or other antiviral drugs are lacking.

Corticosteroids Versus Pentoxifylline for Severe Alcoholic Hepatitis: A Sequential Analysis of Randomized Controlled Trials.

INTRODUCTION: Despite the significant morbidity and mortality associated with alcoholic hepatitis, a consensus or generally accepted therapeutic strategy has not yet been reached. The purpose of this analysis was to evaluate the effects of corticosteroids and pentoxifylline on short-term mortality, incidence of hepatorenal syndrome, and sepsis in patients with severe alcoholic hepatitis. MATERIALS AND METHODS: We conducted a comprehensive search of the Cochrane library, PUBMED, Scopus, EMBASE, and published proceedings from major hepatology and gastrointestinal meetings from January 1970 to June 2015. All relevant articles irrespective of language, year of publication, type of publication, or publication status were included. Two independent reviewers extracted data and scored publications; a third investigator adjudicated discrepancies. The κ scores were measured to assess the agreement between the 2 initial reviewers. The review and meta-analyses were performed following the recommendations of The Cochrane Collaboration. Conventional meta-analysis and Trial sequential analysis were performed. GRADEpro version 3.6 was used to appraise the quality of epidemiologic evidence. RESULTS: A total of 14 studies satisfied inclusion criteria comparing corticosteroids, pentoxifylline, or placebo. Compared with placebo, corticosteroids reduced 28-day mortality (RR=0.53; 95% CI, 0.33-0.84; P=0.006). There was no statistically significant difference in short-term mortality between pentoxifylline and placebo (RR=0.74; 95% CI, 0.46-1.18; P=0.21). Neither corticosteroids nor pentoxifylline impacted the incidence of hepatorenal syndrome or sepsis. Trial sequential analysis confirmed the results of our conventional meta-analysis. CONCLUSIONS AND RELEVANCE: Corticosteroids demonstrated a decrease in 28-day mortality in patients with severe alcoholic hepatitis. The evidence from this study is insufficient to support any recommendations regarding the mortality benefit of pentoxifylline in severe alcoholic hepatitis.

Trends in esophageal cancer survival in United States adults from 1973 to 2009: A SEER database analysis.

BACKGROUND AND AIM: The rise in incidence of esophageal cancer (EC) in the USA over the last four decades has been well documented; however, data on trends in long-term survival and impact on modern therapies associated with survival are lacking. METHODS: The Surveillance, Epidemiology, and End Results database was queried to identify patients with confirmed EC. Cox proportional hazard regression was used to determine independent mortality factors. RESULTS: Of 93 167 patients diagnosed with EC between 1973 and 2009, 49% had a histologic diagnosis of esophageal adenocarcinoma (EAC). There was an increase (almost double) in the proportion of patients with adenocarcinoma from the 1970s to 2000s (n = 2,350; 35% to n = 32,212; 61%, P < 0.001). Surgery was performed for localized disease in a majority of EC regardless of type (n = 46 683; 89%). Use of surgical treatment increased significantly over the study period (49% to 64%, P < 0.001). There was also an increase in overall median survival (6 months versus 10 months, P < 0.001) and 5-year survival rate (9% to 22%, P < 0.001). Median survival increased consistently for EAC and squamous cell carcinoma (SCC) until the 1990s. After this period, median survival of EAC continued to increase more rapidly while SCC remained relatively stable. CONCLUSION: A significant survival improvement in esophageal cancer was seen from 1973 to 2009, largely because of earlier detection at a curative stage and greater utilization of treatment modalities (especially surgery). Despite the rising prevalence, patients with EAC have better long-term survival outcomes than those SCC.

Use of transient elastography in patients with HIV-HCV coinfection: A systematic review and meta-analysis.

BACKGROUND AND AIM: Patients with HIV-hepatitis C virus (HCV) coinfection progress towards liver fibrosis and cirrhosis more rapidly compared with HCV mono-infected individuals. This necessitates an accurate assessment of liver stiffness with transient elastography to guide treatment. METHODS: Searches of PubMed, EMBASE, Web of Science, and the Cochrane Library databases were performed through January 2016 to assess the diagnostic accuracy of transient elastography for liver stiffness in the HIV-HCV population. Included studies were analyzed according to the Cochrane DTA Working Group methodology. Bivariate and hierarchical models were used to compute pooled sensitivity and specificity. Positive and negative likelihood ratios were also determined. A Fagan nomogram was constructed. Meta-regression analysis was performed with assessment of publication bias using Deeks' funnel plot asymmetry testing. RESULTS: A total of six studies (n = 756) met the inclusion criteria. The diagnostic accuracy of elastography for the diagnosis of moderate (≥F2) fibrosis was 88% (95% confidence interval [CI], 0.85-0.90). The pooled sensitivity and specificity of moderate fibrosis was 97% (95% CI, 0.82-0.91) and 64% (95% CI, 0.45-0.79), respectively. The diagnostic accuracy of elastography for the assessment of cirrhosis was 94% (95% CI, 0.91-0.95). The pooled sensitivity and specificity for cirrhosis was 90% (95% CI, 0.74-0.97) and 87% (95% CI, 0.80-0.92), respectively. Meta-regression analysis demonstrated that CD4 cell count did not impact diagnostic accuracy of elastography. CONCLUSIONS: Transient elastography is a noninvasive imaging modality with excellent ability to assess for cirrhosis in patients with HIV-HCV coinfection.