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Barada K, 2009, J CLIN GASTROENTEROL, V43, P5, DOI 10.1097-MCG.0b013e31811edd13; Chiu PWY, 2009, CLIN GASTROENTEROL H, V7, P311, DOI 10.1016-j.cgh.2008.08.044; CHOUDARI CP, 1994, GUT, V35, P464, DOI 10.1136-gut.35.4.464; Cooper GS, 1997, J GEN INTERN MED, V12, P485, DOI 10.1046-j.1525-1497.1997.00087.x; Hallas J, 2006, BRIT MED J, V333, P726, DOI 10.1136-bmj.38947.697558.AE; Hearnshaw SA, 2011, GUT, V60, P1327, DOI 10.1136-gut.2010.228437; hsberg K, 2010, ALIMENT PHARM THER, V32, P801; Lanas A, 2011, ALIMENT PHARM THER, V33, P1225, DOI 10.1111-j.1365-2036.2011.04651.x; Marmo R, 2010, AM J GASTROENTEROL, V105, P1284, DOI 10.1038-ajg.2009.687; Marmo R, 2012, GASTROINTEST ENDOSC, V75, P263, DOI 10.1016-j.gie.2011.07.066; Marmo R, 2008, AM J GASTROENTEROL, V103, P1639, DOI 10.1111-j.1572-0241.2008.01865.x; Mose Hanne, 2006, Am J Geriatr Pharmacother, V4, P244, DOI 10.1016-j.amjopharm.2006.09.006; Ortiz V, 2009, DIGESTION, V80, P89, DOI 10.1159-000219345; Pirmohamed M, 2004, BRIT MED J, V329, P15, DOI 10.1136-bmj.329.7456.15; Rodriguez LAG, 2011, CIRCULATION, V123, P1108, DOI 10.1161-CIRCULATIONAHA.110.973008; Rubin TA, 2003, GASTROINTEST ENDOSC, V58, P369; Sostres C, 2011, DRUGS, V71, P1, DOI 10.2165-11585320-000000000-00000; Sung JJY, 2010, AM J GASTROENTEROL, V105, P84, DOI 10.1038-ajg.2009.507; Sung JJY, 2010, ANN INTERN MED, V152, P1, DOI 10.7326-0003-4819-152-1-201001050-00179; Taha AS, 2006, ALIMENT PHARM THERAP, V24, P633, DOI 10.1111-j.1365-2036.2006.03017.x; Theocharis GJ, 2008, J CLIN GASTROENTEROL, V42, P128, DOI 10.1097-01.mcg.0000248004.73075.ad; Thomopoulos KC, 2005, WORLD J GASTROENTERO, V11, P1365; van Leerdam ME, 2003, AM J GASTROENTEROL, V98, P1494, DOI 10.1016-S0002-9270(03)00299-5; Wang YR, 2010, ANN SURG, V251, P51, DOI 10.1097-SLA.0b013e3181b975b8; Wolf AT, 2007, AM J GASTROENTEROL, V102, P290, DOI 10.1111-j.1572-0241.2006.00969.x; Wong GLH, 2009, GASTROENTEROLOGY, V137, P525, DOI 10.1053-j.gastro.2009.05.006

Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P = 0.02), time to first event (hazard ratio [HR] = 0.56; P

Liver fibrosis, a model wound healing system, is characterized by excessive deposition of extracellular matrix (ECM) in the liver. Although many fibrogenic cell types may express ECM, the hepatic stellate cell (HSC) is currently considered to be the major effector. HSCs transform into myofibroblast-like cells, also known as hepatic myofibroblasts in a process known as activation; this process is characterized in particular by de novo expression of smooth muscle alpha actin (SM α-actin) and type 1 collagen. The family of actins, which form the cell's cytoskeleton, are essential in many cellular processes. β-actin and cytoplasmic γ-actin (γ-actin) are ubiquitously expressed, whereas SM α-actin defines smooth muscle cell and myofibroblast phenotypes. Thus, SM α-actin is tightly associated with multiple functional properties. However, the regulatory mechanisms by which actin isoforms might regulate type 1 collagen remain unclear. In primary HSCs from normal and fibrotic rat liver, we demonstrate that myocardin, a canonical SRF cofactor, is upregulated in hepatic myofibroblasts and differentially regulates SM α-actin, γ-actin, and β-actins through activation of an ATTA box in the SM α-actin and a CCAAT box in γ-actin and β-actin promoters, respectively; moreover, myocardin differentially activated serum response factor (SRF) in CArG boxes of actin promoters. In addition, myocardin-stimulated Smad2 phosphorylation and RhoA expression, leading to increased expression of type 1 collagen in an actin cytoskeleton-dependent manner. Myocardin also directly enhanced SRF expression and stimulated collagen 1α1 and 1α2 promoter activities. In addition, overexpression of myocardin in vivo during carbon tetrachloride-induced liver injury led to increased HSC activation and fibrogenesis. In summary, our data suggest that myocardin plays a critical role in actin cytoskeletal dynamics during HSC activation, in turn, specifically regulating type I collagen expression in hepatic myofibroblasts.

Kratom ( Mitragyna speciosa) is a prevalent medicinal plant used mainly for the stimulant and analgesic properties provided through multiple alkaloid compounds. Over the past decade, use of kratom has increased despite the limited knowledge of toxicities and adverse side effects. With the current opioid epidemic, both patients and providers are seeking alternative methods to treat both addiction and pain control, and kratom as an alternative means of treatment has increasingly entered the mainstream. In this article, we present the clinical course of a 47-year-old male who developed fatigue, pruritus, and abnormal liver tests (with a mixed hepatocellular/cholestatic pattern) approximately 21 days after beginning kratom. After extensive evaluation including a negligible alcohol history, negative hepatitis serologies, and inconclusive imaging, the patient was diagnosed with drug-induced liver injury (DILI) caused by kratom. Nine months after his liver tests returned to normal, he took kratom again, and after a latency of 2 days, he developed fatigue, pruritus, and loss of appetite along with abnormal liver tests (with the same biochemical profile as previously), consistent with a positive rechallenge. We believe, through the use of the Roussel-Uclaf Causality Assessment Method and expert opinion, that this is a highly likely or definite example of kratom-induced DILI. With the gaining popularity of this drug, it appears that DILI may be an important complication of kratom for providers to recognize.

Background Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) — rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. Methods The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. Results Only 0.2% (11) of 4683 samples exceeded 500 μg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio > 2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels > 500 μg/ml. Conclusions The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Pharmacologic therapy (PT) for patients with esophageal variceal hemorrhage (EVH) may improve outcomes. The aim of this article is to assess the current and potential future use of PT in cirrhotic patients with EVH.We validated a 13-question survey about PT and physician preferences for specific therapies in cirrhotics with EVH; 2349 randomly selected Gastroenterology and Hepatology physicians worldwide were surveyed. The survey addressed institutional location, octreotide or terlipressin use and preference, PT prior to endoscopy, and future plans for terlipressin use, if not already instituted.Of those surveyed, 337 (14%) email addresses were nonfunctioning. Of the remaining 2012 surveyed, 371 (18%) responses were collected. Nearly two-thirds of physicians preferred to use PT prior to endoscopic intervention (p0.001). Nearly 70% of respondents only had octreotide available, while 6% had only terlipressin. Of the 24% having both octreotide and terlipressin available, 55% preferred terlipressin compared to 38% who preferred octreotide (p0.001). Of those physicians currently not using terlipressin because of its unavailability, 93% would be willing to use it if it were readily available.Of physicians with both terlipressin and octreotide available for treatment of EVH in cirrhotics, most prefer terlipressin, even if currently unavailable.

Background and aims Idiosyncratic drug-induced liver injury (DILI) can be caused by intravenous (IV) medications, but the characteristics of DILI caused by these agents are not known. The aim of this study is to characterize the clinical features of subjects with suspected DILI associated with IV agents enrolled into the Drug Induced Liver Injury Network Prospective Study. Methods Subjects with suspected DILI due to IV medications with probable, highly likely, or definite casuality scores were eligible. Results Between 2004 and October 2010, 542 cases of DILI were adjudicated for causality, of which 32 were eligible for inclusion in this study. DILI was ascribed to a single IV agent in 27 subjects, and to multiple IV agents in 5 subjects. Antimicrobial agents (62%), antineoplastic agents (16%), and phenytoin (9%) were most commonly implicated. The pattern of liver injury was hepatocellular in 30%, mixed in 33%, and cholestatic in 37%. The peak alanine aminotransferase (ALT), alkaline phosphatase (AlkP), and total bilirubin were 686 ± 915 U/L, 623 ± 563 U/L, and 8.7 ± 10.3 mg/dL, respectively. The duration for ≥ 50% improvement from peak ALT, AlkP, and total bilirubin were 25 ± 37, 59 ± 69, and 20 ± 28 days, respectively. DILI severity was mild in 37%, moderate in 47%, severe in 13%, and fatal in 3%, with no liver transplantation. Their causality was adjudicated as definite in 5, very likely in 17, and probable in 10 subjects. The frequency of chronic DILI was 13%. Conclusions Antimicrobial and antineoplastic agents are the most common IV agents to cause DILI. DILI ascribed to IV agents is relatively infrequent, but its outcomes are similar to those of the overall Drug Induced Liver Injury Network cohort.

Hemorrhagic ascites can pose diagnostic and therapeutic dilemmas in patients with cirrhosis. We aimed at exploring the characteristics and outcomes of patients with cirrhosis and hemorrhagic ascites.The records of all patients with cirrhosis and ascites, who underwent paracentesis between 2003 and 2010 at Parkland Memorial Hospital, were retrospectively reviewed. Hemorrhagic ascites was defined as an ascitic fluid red blood cell (RBC) count ≥ 10,000/μl. We compared each patient with 3 age- and gender-matched controls (cirrhotic patients with ascites and an ascitic RBC count10,000/μl). Survival curves were generated using Kaplan-Meier plots and compared using the log rank test.1113 cirrhotic patients underwent paracentesis; 214 (19%) had hemorrhagic ascites. Patients with hemorrhagic ascites had higher rates of spontaneous bacterial peritonitis (p0.001), acute kidney injury (AKI, p0.001), and were more likely to require intensive care unit (ICU)-level care (p=0.01) compared to patients without hemorrhagic ascites. Patients with hemorrhagic ascites had a higher mortality than controls at one month (87% vs. 72%), 1 year (72% vs. 50%) and 3 years (61% vs. 41%). Using multivariate regression analysis, hemorrhagic ascites was also an independent predictor of mortality (HR 1.34, 95% CI 1.07-1.68) after adjusting for the model for end-stage liver disease score (HR 1.04, 1.03-1.05), ICU-level care (HR 2.02, 1.63-2.51) and presence of hepatocellular carcinoma (HR 2.27, 1.61-3.19).Patients with hemorrhagic ascites had a significantly higher rate of ICU care, AKI, and mortality than patients with portal hypertension and ascites but without hemorrhagic ascites. We conclude that hemorrhagic ascites is a marker of advanced liver disease and poor outcome.

Background & Aims The liver's response to injury is fibrosis, and when chronic, cirrhosis. Age is a critical factor impacting many immune-mediated processes, potentially including the liver's wounding response to injury. Methods The effects of age on acute and chronic liver injury were evaluated using a carbon tetrachloride model in mice. Lymphocyte and macrophage populations were assessed by flow cytometry and immunohistochemical analysis. Results Acute liver injury was greater in 18-month-old (old) mice than in 9-month-old (middle-aged) mice as judged by changes in aminotransferases. Similarly, livers of 18-month-old mice had a significantly greater fibrogenic response to injury than did livers of 9-month-old mice after chronic injury (assessed by col1α1 mRNA expression, morphometric analysis and hydroxyproline measurement). Interestingly, livers from young mice (6 weeks old) also exhibited an increase in fibrogenesis compared to 9-month-old mice, albeit not to the same degree as in old mice. Consistent with a role for macrophages in fibrogenesis, the number of liver macrophages in young and 9-month-old mice increased, while in chronically injured livers of 18-month-old mice, the number of macrophages was reduced, and was less than in the livers of young and 9-month-old injured livers. Conclusions Our data indicate that the fibrogenic response to injury varies substantially with age, and moreover that macrophage recruitment and dynamics may be an important component in differential age-associated fibrotic disease.

BACKGROUND Administrative data are used in clinical research, but the validity of ICD-9 codes to identify cirrhotic patients has not been well established. GOALS To determine the diagnostic accuracy of ICD-9 codes for cirrhosis in clinical practice. STUDY We conducted a retrospective cohort study of patients from a safety-net hospital between 2008 and 2011. Patients were initially identified using ICD-9 codes for cirrhosis or a resultant complication. The gold-standard for diagnosis of cirrhosis was histology and/or imaging based on medical record review. Sensitivity, specificity, positive predictive values, and negative predictive values for each ICD-9 code were calculated. Diagnostic accuracy was assessed by the c-statistic using receiver operator characteristic curve analysis. RESULTS We identified 2893 patients with an ICD-9 code for cirrhosis, of whom 50.2% had 1 ICD-9 code, 20.3% had 2 different codes, and 29.5% had 3 or more codes. Cirrhosis was confirmed in 44.0% of patients with 1 ICD-9 code, 82.6% with 2 codes, and 95.7% of those with at least 3 codes. Ascites had a significantly lower positive predictive values for cirrhosis than other ICD-9 codes (P

Background Cirrhotic patients admitted with altered mental status (AMS) represent a clinical challenge, as many potentially life-threatening diseases must be considered. Although many patients with AMS have hepatic encephalopathy (HE), other causes of AMS occur, and we hypothesized that these may have different outcomes. Aim We aimed to understand the causes of AMS in cirrhotic patients admitted to the hospital and investigate their associated outcomes. Methods We performed a retrospective cohort study in 1218 inpatients with cirrhosis. Altered mental status was defined a priori (HE, sepsis/infectious, metabolic, exogenous drugs/toxins, structural lesions, or psychiatric abnormalities). Results Patients with AMS had higher levels of serum bilirubin, international normalized ratio, blood urea nitrogen, creatinine, and lower levels of albumin and platelets than those with normal mental status (NMS) ( P = < 0.001). The most common cause of AMS was HE, accounting for nearly half of all patients. Other causes of AMS included the following: sepsis/infection (23%), metabolic disorders (8%), drugs/toxins (7%), structural lesions (5%), psychiatric disorders (1%), or multiple causes (8%). Mortality in patients with AMS was 35% compared to 16% in those with NMS ( P < 0.0001). Patients with sepsis/infection, structural lesions, or multiple disorders causing AMS had the highest mortality (61%, 68%, and 79%, respectively). Conclusions Nearly one third of admissions in cirrhotic patients were due to AMS, most commonly caused by HE. The overall mortality of patients admitted with AMS was greater than with NMS, particularly for those with infection or structural lesions, emphasizing the importance of a search for these causes of AMS in all patients with cirrhosis.

Great strides have been made in hepatitis B virus (HBV)-related fibrosis and cirrhosis. Available evidence indicates that HBV viral suppression causes regression of advanced fibrosis and even cirrhosis, and therefore should be attempted in all patients with advanced fibrosis and cirrhosis. The preferred agents in patients with cirrhosis are entecavir and tenofovir, primarily because the risk of breakthrough is low. HBV viral suppression leads to improved clinical outcomes even in patients with cirrhosis and complications. The risk of hepatocellular carcinoma is reduced, but not eliminated. Thus, patients with HBV cirrhosis should continue to have routine screening for hepatocellular carcinoma, even after viral suppression.

Acute lymphoblastic leukemia (ALL) in adults is a relatively rare malignancy. The typical presentation includes signs and symptoms associated with bone marrow failure, including fevers, infections, fatigue, and excessive bruising. In this article, we report an unusual systemic presentation of ALL in a previously healthy 18-year-old man. He initially presented with several-day history of nausea and vomiting, 10-pound weight loss, and right upper quadrant abdominal pain with evidence of acute hepatocellular liver injury (elevations in aspartate aminotransferase/alanine aminotransferase) and elevation in serum creatinine. Further history revealed that he just joined the Marine Corp; in preparation, he had been lifting weights and taking protein and creatine supplements. A complete serological evaluation for liver disease was negative and creatine phosphokinase was normal. His aspartate aminotransferase and alanine aminotransferase declined, and he was discharged with expected improvement. However, he returned one week later with continued symptoms and greater elevation of aminotransferases. Liver biopsy was nondiagnostic, revealing scattered portal and lobular inflammatory cells (primarily lymphocytes) felt to be consistent with drug-induced liver injury or viral hepatitis. Given his elevated creatinine, unresponsive to aggressive volume expansion, a kidney biopsy was performed, revealing normal histology. He subsequently developed an extensive left lower extremity deep venous thrombosis. Given his deep venous thrombosis, his peripheral blood was sent for flow cytometry, which revealed lymphoblasts. Bone marrow biopsy revealed 78% blasts with markers consistent with acute B-cell lymphoblastic leukemia. This report emphasizes that right upper quadrant abdominal pain with liver test abnormalities may be the initial presentation of a systemic illness such as ALL.

Moesin is a member of the ezrin-radixin-moesin (ERM) family of proteins that are important for organizing membrane domains and receptor signaling and regulating the migration of effector T cells. Whether moesin plays any role during the generation of TGF-β-induced Tregs (iTregs) is unknown. Here, we have discovered that moesin is translationally regulated by TGF-β and is also required for optimal TGF-β signaling that promotes efficient development of iTregs. Loss of moesin impaired the development and function of both peripherally derived iTregs and in vitro-induced Tregs. Mechanistically, we identified an interaction between moesin and TGF-β receptor II (TβRII) that allows moesin to control the surface abundance and stability of TβRI and TβRII. We also found that moesin is required for iTreg conversion in the tumor microenvironment, and the deletion of moesin from recipient mice supported the rapid expansion of adoptively transferred CD8+ T cells against melanoma. Our study establishes moesin as an important regulator of the surface abundance and stability of TβRII and identifies moesin's role in facilitating the efficient generation of iTregs. It also provides an advancement to our understanding about the role of the ERM proteins in regulating signal transduction pathways and suggests that modulation of moesin is a potential therapeutic target for Treg-related immune disorders.

In order to provide high quality, cost-efficient care, it is critical to understand drivers of the cost of care. Therefore, we sought to identify clinical variables associated with high utilization (cost) in patients admitted to medical services and to develop a robust model to identify high utilization patients. In this case–control analysis, cases were identified as the 200 most costly patients admitted to internal medicine/internal medicine subspecialty services using our institution's computerized clinical data warehouse over a 7-month time period (November 1, 2012–May 31, 2013). 400 patients admitted in the same time period were randomly selected to serve as controls. The mean cost for the highest utilization patients was $126,343, while that for randomly matched patients was $15,575. In a multivariable regression model, the following variables were associated with high utilization of resources: African American race, age 35–44, admission through the emergency department, primary service of hematology–oncology, a history of heart failure or paralysis, a diagnosis of HIV, cancer, collagen vascular diseases and/or coagulopathy, a reduced albumin, and/or an elevated creatinine. The in hospital mortality rate for high utilization patients was 19%, compared to 8% for controls (p=0.0002). A predictive model using 14 different readily available clinical variables predicted high utilization with an area under the curve of 0.85. The data suggest that high utilization patients share similar demographic and clinical features. We speculate that a predictive model using commonly known patient characteristics should be able to predict high utilization patients.

Purpose of review Acute on chronic liver failure (ACLF) causes significant morbidity and mortality in patients with cirrhosis and/or chronic liver disease (CLD). The purpose of this review is to highlight recent studies that have better defined ACLF, and to highlight current outcomes and treatment strategies. Recent findings Currently, there are no clear definitions for ACLF; however, ACLF requires a precipitating event that occurs in the setting of cirrhosis and/or CLD, and progresses rapidly to multiorgan failure with high mortality. Most precipitants of ACLF are due to infections, leading to inflammatory cascades, hence early treatment with antibiotics in these cases might show benefit. Prognosis in ACLF typically depends on the number of extrahepatic organs affected. Potential biomarkers in ACLF may result in early detection and risk stratification; however, further research is needed. ACLF portends a poor prognosis; however, rescue therapy with liver transplantation has been considered in selected cases. Summary ACLF is a common and devastating complication of cirrhosis or CLD. ACLF usually requires a precipitating event and rapid progression to multiorgan failure with high mortality. Although signs and symptoms might overlap in patients with ACLF and those with decompensated cirrhosis, the two entities should be distinguished separately (although it is challenging to differentiate these in certain cases). Furthermore, diagnosing each entity should be based on a variety of clinical indicators, laboratory data and precipitating factors, in order to determine the best possible targeted treatment strategies. Refinement in the clinical definitions for ACLF may lead to better management and possibly better outcomes if recognized early.

Oxidative stress plays an essential role in liver fibrosis. This study investigated whether MitoQ, an orally active mitochondrial antioxidant, decreases liver fibrosis. Mice were injected with corn oil or carbon tetrachloride (CCl4, 1:3 dilution in corn oil; 1 µl/g, ip) once every 3 days for up to 6 weeks. 4-Hydroxynonenal adducts increased markedly after CCl4 treatment, indicating oxidative stress. MitoQ attenuated oxidative stress after CCl4. Collagen 1α1 mRNA and hydroxyproline increased markedly after CCl4 treatment, indicating increased collagen formation and deposition. CCl4 caused overt pericentral fibrosis as revealed by both the sirius red staining and second harmonic generation microscopy. MitoQ blunted fibrosis after CCl4. Profibrotic transforming growth factor-β1 (TGF-β1) mRNA and expression of smooth muscle α-actin, an indicator of hepatic stellate cell (HSC) activation, increased markedly after CCl4 treatment. Smad 2/3, the major mediator of TGF-β fibrogenic effects, was also activated after CCl4 treatment. MitoQ blunted HSC activation, TGF-β expression, and Smad2/3 activation after CCl4 treatment. MitoQ also decreased necrosis, apoptosis and inflammation after CCl4 treatment. In cultured HSCs, MitoQ decreased oxidative stress, inhibited HSC activation, TGF-β1 expression, Smad2/3 activation, and extracellular signal-regulated protein kinase activation. Taken together, these data indicate that mitochondrial reactive oxygen species play an important role in liver fibrosis and that mitochondria-targeted antioxidants are promising potential therapies for prevention and treatment of liver fibrosis.

Given the controversy surrounding the use of 99m Tc-RBC scintigraphy (TRBCS) in lower gastrointestinal hemorrhage (LGIH), we examined how often it was performed and whether it led to specific therapy. We performed a retrospective cohort study of 565 admissions with a primary diagnosis of LGIH. We obtained detailed clinical data on all subjects, focusing in particular on outcomes after TRBCS. 199 TRBCS studies were performed during 166 patient admissions (a patient admission was defined as an incident LGIH episode in a single patient). Of the 166 patient admissions in which TRBCS was performed, the scan was positive in approximately half (84/166; 51%); if TRBCS themselves were considered, they were positive 42% (84/199) of the time. Of the 84 admissions with a positive TRBCS, angiography was performed 54 times. Among this group, angiography revealed bleeding in only 20 patients (11 patients underwent embolization and 9 had hemostatic therapy). Out of 64 patients with a positive TRBCS who underwent colonoscopy, only 3 patients underwent endoscopic hemostatic therapy. Surgery was performed in 20 patients after a positive TRBCS (including in 17/54 patients after angiogram) and hemostasis was achieved in 16. Angiography, surgery and therapeutic colonoscopy were more commonly performed after positive than after a negative TRBCS. Patients who underwent angiography within 4 h of a positive TRBCS were neither more likely to have active bleeding found nor to undergo successful embolization. Not all patients with a positive TRBCS underwent angiography, and an abnormal TRBCS did not appear to predict successful angiographic therapy; further, a positive TRBCS was not predictive of subsequent definitive therapy. Because TRBCS appears to be followed up inconsistently, the data bring into question its routine use in clinical practice, and specifically raise the possibility that it is overused in patients with LGIH.

Hepatic encephalopathy (HE) is a major complication in patients with decompensated cirrhosis, leading to higher readmission rates causing a profound burden of disease and considerable health care costs. Because ammonia is thought to play a crucial role in the pathogenesis of HE, therapies directed at reducing ammonia levels are now being aggressively developed. Ammonia scavengers such as AST-120 (spherical carbon adsorbent), glycerol phenylbutyrate, sodium phenylacetate or sodium benzoate, and ornithine phenylacetate have been used to improve HE symptoms. A new approach, bowel cleansing with polyethylene glycol 3350, appears to be a promising therapy, with a recent study demonstrating a more rapid improvement in overt HE (at 24 hours after treatment) than lactulose. Extracorporeal devices, although now used primarily in research settings, have also been utilized in patients with refractory HE, but are not approved for clinical management.

In patients with upper gastrointestinal bleeding (UGIB), identifying those with esophageal variceal hemorrhage prior to endoscopy would be clinically useful. This retrospective study of a large cohort of patients with UGIB used logistic regression analyses to evaluate the platelet count, aspartate aminotransferase (AST) to platelet ratio index (APRI), AST to alanine aminotransferase (ALT) ratio (AAR) and Lok index (all non-invasive blood markers) as predictors of variceal bleeding in (1) all patients with UGIB and (2) patients with cirrhosis and UGIB. 2233 patients admitted for UGIB were identified; 1034 patients had cirrhosis (46%) and of these, 555 patients (54%) had acute UGIB due to esophageal varices. In all patients with UGIB, the platelet count (cut-off 122,000/mm3), APRI (cut-off 5.1), AAR (cut-off 2.8) and Lok index (cut-off 0.9) had area under the curve (AUC)s of 0.80 0.82, 0.64, and 0.80, respectively, for predicting the presence of varices prior to endoscopy. To predict varices as the culprit of bleeding, the platelet count (cut-off 69,000), APRI (cut-off 2.6), AAR (cut-off 2.5) and Lok Index (0.90) had AUCs of 0.76, 0.77, 0.57 and 0.73, respectively. Finally, in patients with cirrhosis and UGIB, logistic regression was unable to identify optimal cut-off values useful for predicting varices as the culprit bleeding lesion for any of the non-invasive markers studied. For all patients with UGIB, non-invasive markers appear to differentiate patients with varices from those without varices and to identify those with a variceal culprit lesion. However, these markers could not distinguish between a variceal culprit and other lesions in patients with cirrhosis.

Purpose of review Chronic liver disease (CLD) causes significant morbidity and mortality, mainly due to complications [hepatic encephalopathy, ascites, hepatorenal syndrome (HRS), and esophageal variceal hemorrhage (EVH)]. Studies of the complications, management and outcomes in patients with CLD over the past 18 months are reviewed. Recent findings Percutaneous liver biopsy can be safely performed in patients with advanced liver disease with minimal complications. Predictors of response to lactulose, probiotics and L-ornithine-L-aspartate therapy in minimal hepatic encephalopathy have been reported. Rifaximin was found to lead to better maintenance of remission and decreased re-admission rates in patients with cirrhosis and hepatic encephalopathy, and may improve driving performance in those with minimal hepatic encephalopathy. In a controversial study, patients with refractory ascites taking propranolol were found to have poorer outcomes, perhaps related to beta-blockade associated paracentesis-induced circulatory dysfunction. Terlipressin and albumin therapy currently appears to be the best medical therapy available in patients with type 1 HRS, although pentoxifylline may be effective to treat HRS in patients with cirrhosis and ascites. In patients with gastric varices, primary prophylaxis with cyanoacrylate may decrease the probability of gastric variceal hemorrhage compared to nonselective beta-blockers. In patients with esophageal varices without bleeding, prophylaxis with variceal ligation or beta-blockers was similar in terms of bleeding, mortality, and adverse events. Erythromycin given 30 min prior to endoscopic evaluation in suspected EVH was associated with an overall benefit in visibility, duration of the procedure and length of hospital stay. Summary Refinement in clinical management strategies for patients with cirrhosis and its complications appears to continue to contribute to improved patient outcomes.

Safety-net hospital systems provide care to a large proportion of United States' under- and uninsured population. We have witnessed delayed colorectal cancer (CRC) care in this population and sought to identify demographic and systemic differences in these patients compared to those in an insured health-care system. DESIGN, PATIENTS, AND APPROACH/MEASUREMENTS: We collected demographic, socioeconomic, and clinical data from 2005-2007 on all patients with CRC seen at Parkland Health and Hospital System (PHHS), a safety-net health system and at Presbyterian Hospital Dallas System (Presbyterian), a community health system, and compared characteristics among the two health-care systems. Variables associated with advanced stage were identified with multivariate logistic regression analysis and odds ratios were calculated.Three hundred and eighteen patients at PHHS and 397 patients at Presbyterian with CRC were identified. An overwhelming majority (75 %) of patients seen at the safety-net were diagnosed after being seen in the emergency department or at an outside facility. These patients had a higher percentage of stage 4 disease compared to the community. Patients within the safety-net with Medicare/private insurance had lower rates of advanced disease than uninsured patients (25 % vs. 68 %, p 0.001). Insurance status and physician encounter resulting in diagnosis were independent predictors of disease stage at diagnosis.A large proportion of patients seen in the safety-net health system were transferred from outside systems after diagnosis, thus leading to delayed care. This delay in care drove advanced stage at diagnosis. The data point to a pervasive and systematic issue in patients with CRC and have fundamental health policy implications for population-based CRC screening.

Endothelial cell nitric-oxide (NO) synthase (eNOS), the enzyme responsible for synthesis of NO in the vasculature, undergoes extensive post-translational modifications that modulate its activity. Here we have identified a novel eNOS interactor, G-protein-coupled receptor (GPCR) kinase interactor-1 (GIT1), which plays an unexpected role in GPCR stimulated NO signaling. GIT1 interacted with eNOS in the endothelial cell cytoplasm, and this robust association was associated with stimulatory eNOS phosphorylation (Ser(1177)), enzyme activation, and NO synthesis. GIT1 knockdown had the opposite effect. Additionally, GIT1 expression was reduced in sinusoidal endothelial cells after liver injury, consistent with previously described endothelial dysfunction in this disease. Re-expression of GIT1 after liver injury rescued the endothelial phenotype. These data emphasize the role of GPCR signaling partners in eNOS function and have fundamental implications for vascular disorders involving dysregulated eNOS.

Integrin-linked kinase (ILK) is a multidomain focal adhesion protein implicated in signal transduction between integrins and growth factor/extracellular receptors. We have previously shown that ILK expression is increased in liver fibrosis and that ILK appears to be a key regulator of fibrogenesis in rat hepatic stellate cells, effectors of the fibrogenic response. Here we hypothesized that the mechanism by which ILK mediates the fibrogenic phenotype is by engaging the small GTPase, Rho in a signal transduction pathway linked to fibrogenesis. ILK function in quiescent (non-fibrogenic) and activated (fibrogenic) stellate cells was examined in cells isolated from rat livers. ILK, Rho, and Gα(12/13) signaling were manipulated using established chemical agents or specific adenoviral constructs. ILK activity was minimal in quiescent stellate cells, but prominent in activated stellate cells; inhibition of ILK activity had no effect in quiescent cells, but had prominent effects in activated cells. Overexpression of ILK in activated stellate cells increased Rho activity, but had no effect in quiescent cells. Further, endothelin-1 stimulated Rho activity in activated stellate cells, but not in quiescent cells. Rho, Rho guanine nucleotide exchange factors, and Gα(12/13) expression were increased after stellate cell activation. Inhibition of Gα(12/13) signaling, by expression of the RGS domain of the p115-Rho-specific GEF (p115-RGS) in activated stellate cells, significantly inhibited type I collagen and smooth muscle α-actin expression, both classically upregulated after stellate cell activation. The data suggest that ILK mediates Rho-dependent functional effects in activated stellate cells, and raise the possibility that ILK is important in cross-talk with the G-protein-coupled receptor system.

Background: Computed tomographic (CT) and magnetic resonance (MR) colonography are new noninvasive techniques to examine the colon. Methods: A literature search was performed through 2/1/2012, and relevant studies included in the review. Results: MR colonography is evolving, and holds the promise that it may achieve high-level sensitivity for adenomas and cancers without exposure to radiation. CT colonography is much more mature at this point in time, and has received great attention in the last decade as a colon imaging tool, including potentially as a primary colon cancer screening method. Its accuracy for detection of polypoid lesions ≥1 cm is high, likely close to that of colonoscopy. New techniques focusing on minimally prepped CT colonography hold the potential of making the procedure more widely accepted. While radiation exposure with CT colonography is a concern, this risk is likely very modest, particularly if used in patients over the age of 50. CT colonography, while a viable colon cancer screening modality in the USA, could not be widely implemented, largely because of lack of standards for training and reading, and because the number of skilled readers is limited. Summary: MR and CT colonography are relatively novel and exciting modalities that can be used to identify colonic lesions. They promise a high level of sensitivity and pose essentially no (MR) or modest (CT) risks. Future investigation will likely lead to wider acceptance of both of these tests, including perhaps to their use in colon cancer screening programs.

Although multiple medical professional societies, governmental agencies, and third-party payers recommend colorectal cancer (CRC) screening for adults at average or increased risk for CRC, screening rates for these populations continue to lag behind those of other malignancies. There are multiple reasons why population-wide CRC screening compliance remains “low” (near 50%–55%), and chief among them is the inconvenient, invasive, and/or uncomfortable nature of commonly used screening tests such as fecal occult blood testing, flexible sigmoidoscopy, and colonoscopy. In response, CRC screening technologies are constantly being developed and evaluated. One of the newer tests, computed tomographic (CT) colonography, is an attractive option for CRC screening because of its ability to visualize the colon in a noninvasive way and because it is also relatively simple for patients to undergo. Over the past decade, experience and clinical information surrounding CRC screening and adenoma detection with CT colonography have increased dramatically. Although CT colonography was largely developed and typically performed by radiology professionals, it can also be used by gastroenterologists. As the technology surrounding CT colonography evolves, it is important that gastroenterologists not only understand the multiple issues surrounding CT colonography, but also that those who wish to perform it be able to interpret it accurately. To facilitate diffusion of knowledge pertaining to CT colonography, the American Gastroenterological Association (AGA) Institute’s Governing Board convened the CT Colonography Task Force to develop training standards for gastroenterologists for CT colonography. These standards, first published in 2007, were intended to outline the basic requirements that board-certified gastroenterologists should meet to be involved in and/or perform CT colonography.1 All statements were based on the literature available at that time. Since the publication of the original standards, additional literature and regulatory decisions regarding multiple aspects of CT colonography, with implications for the performance of this diagnostic modality by gastroenterologists, have been published. This document is an update based on that new information. Indications/Contraindications

Background Renal dysfunction is a common and potentially life-threatening complication in hospitalized patients with cirrhosis. Aims To determine the prevalence, cause, and outcome of patients with cirrhosis and acute kidney injury (AKI) and/or chronic kidney disease (CKD). Methods This retrospective analysis examined hospital records of 152 consecutive patients with cirrhosis and creatinine levels of 1.5 mg/dL or greater. Multiple clinical and laboratory variables were abstracted for each subject. Precise definitions were used to define cirrhosis and etiologies of renal dysfunction. Univariate and multivariable logistic regression analyses were performed to identify features with prognostic value for hospital mortality. Results The most common type of renal dysfunction was AKI, present in 107 patients (70%). Acute kidney injury plus CKD was found in 26 patients (17%), and CKD alone was present in 19 patients (13%). Prerenal azotemia was the most common cause of AKI (69%), often occurring secondary to gastrointestinal hemorrhage. The overall mortality for the cohort was 31%, with the highest mortality occurring in patients with type 1 hepatorenal syndrome (HRS) (11/14, 79%). We were unable to identify any patient meeting diagnostic criteria for type 2 HRS. The development of AKI on preexisting CKD did not infer worse prognosis than AKI alone. The presence of upper gastrointestinal bleeding, bacteremia, and HRS-1 predicted mortality. Conclusions Both AKI and CKD are common in hospitalized patients with cirrhosis, often occurring simultaneously. Type 2 HRS was not identified, suggesting that its diagnostic criteria may need reevaluation or that this syndrome may not represent a unique functional kidney disorder.

In patients with acute upper gastrointestinal hemorrhage, standard practice is to transfuse packed red blood cells, often to an arbitrary level of hemoglobin or hematocrit (typically 10 g/dL and 30%, respectively) before endoscopy. Therefore, we aimed to determine first whether performing endoscopy in patients with upper gastrointestinal hemorrhage and a low hematocrit is safe and whether it predicts outcomes.This cohort study included patients with carefully defined upper gastrointestinal hemorrhage captured in our gastrointestinal Healthcare Registry who underwent esophagogastroduodenoscopy. Patients were placed into 2 groups: low hematocrit (30%) or high hematocrit (30%). Clinical variables and outcomes, including cardiovascular events, intensive care unit transfer, and death, were measured.A total of 920 patients meeting entry criteria were identified. Baseline features among those with a low and high hematocrit were identical. Eight cardiovascular events occurred during or after esophagogastroduodenoscopy, including 5 of 587 (1%) in the less than 30% hematocrit group and 3 of 333 (1%) in the greater than 30% hematocrit group (P=.29). Blood transfusions were more common in the low hematocrit group (74% vs 24%, P.001). However, correlation between the amount of blood transfused and hematocrit level was poor, and the number units of blood transfused was highly variable. There was no significant mortality difference in the 2 hematocrit groups.Most patients with upper gastrointestinal hemorrhage presented with a hematocrit less than 30%. Performing endoscopy in patients with a low hematocrit was clearly safe; these data strongly imply that waiting for the hematocrit to reach a certain level before endoscopy is not necessary.

Transient hepatomegaly often accompanies acute bacterial infections. Reversible, dose-dependent hepatomegaly also occurs when animals are given intravenous infusions of bacterial lipopolysaccharide (LPS). We found that recovery from LPS-induced hepatomegaly requires a host enzyme, acyloxyacyl hydrolase (AOAH), that inactivates LPS. When we challenged Aoah−/− mice with low doses of LPS or Gram-negative bacteria, their livers remained enlarged (as much as 80% above normal) many weeks longer than did the livers of Aoah+/+ animals. When compared with livers from LPS-primed Aoah+/+ mice, LPS-primed Aoah−/− livers had (1) more numerous and larger Kupffer cells, (2) intrasinusoidal leukocyte aggregates and activated sinusoidal endothelial cells, and (3) sustained production of interleukin (IL)-10 and messenger RNAs (mRNAs) for tumor necrosis factor (TNF), IL-10, and IRAK-M. Depleting Kupffer cells decreased the liver enlargement by ≈40%, whereas depletion of neutrophils, dendritic cells, natural killer (NK) cells, NK-T cells, or B cells had no effect. Pretreatment with dexamethasone almost completely prevented prolonged hepatomegaly in Aoah−/− mice, whereas neutralizing TNF or interleukin-1β was only partially effective. In contrast, an antagonistic antibody to the IL-10 receptor increased LPS-induced hepatomegaly by as much as 50%. Conclusion: our findings suggest that persistently active LPS induces Kupffer cells to elaborate mediators that promote the accumulation of leukocytes within enlarged sinusoids. Large increases in IL-10 and several other modulatory molecules are unable to prevent prolonged hepatomegaly in mice that cannot inactivate LPS. The striking findings in this mouse model should encourage studies to find out how AOAH contributes to human liver physiology and disease. (HEPATOLOGY 2011;)

In this study, we elucidated the mechanism by which adiponectin modulates hepatic stellate cell activation and fibrogenesis. Adiponectin-overexpressing transgenic mice receiving thioacetamide were resistant to fibrosis, compared with controls. In contrast, adiponectin-null animals developed severe fibrosis. Expression of collagen α1(I) and α-smooth muscle actin (α-SMA) mRNAs were significantly lower in adiponectin-overexpressing mice, compared with controls. In wild-type stellate cells exposed to a lentivirus encoding adiponectin, expression of peroxisome proliferator-activated receptor-γ (PPARγ), SREBP1c, and CEBPα mRNAs was significantly increased (3.2-, 4.1-, and 2.2-fold, respectively; n = 3; P < 0.05, adiponectin virus versus control), consistent with possible activation of an adipogenic transcriptional program. Troglitazone, a PPARγ agonist, strongly suppressed up-regulation of collagen α1(I) and α-SMA mRNA in stellate cells isolated from wild-type mice; however, stellate cells from adiponectin-null animals failed to respond to troglitazone. Furthermore, in isolated stellate cells in which PPARγ was depleted using an adenovirus-Cre-recombinase system and in which adiponectin was also overexpressed, collagen α1(I) and α-SMA were significantly inhibited. We conclude that the PPARγ effect on stellate cell activation and the fibrogenic cascade appears to be adiponectin-dependent; however, the inhibitory effect of adiponectin on stellate cell activation was not dependent on PPARγ, suggesting the presence of PPARγ-dependent as well as independent pathways in stellate cells.

Chronic liver disease (CLD) causes significant morbidity and mortality, mainly due to complications [hepatic encephalopathy, ascites, hepatorenal syndrome (HRS) and esophageal variceal hemorrhage (EVH)]. Studies of the complications, management and outcomes in patients with CLD over the last 18 months are reviewed.Predictors of response to lactulose therapy in hepatic encephalopathy have been reported, along with the effect of minimal hepatic encephalopathy on driving. Rifaximin was found to lead to better maintenance of remission and decreased readmission rates in patients with cirrhosis and hepatic encephalopathy. Satavaptan (a vasopressin receptor antagonist) was investigated for treatment of refractory ascites and appeared to be effective, but this compound is not currently approved by the US Food and Drug Administration (FDA). Patients with refractory ascites taking propranolol were found to have poorer outcomes than those not taking propranolol. Terlipressin currently appears to be the best medical therapy available for patients with type 1 HRS; the addition with albumin to terlipressin appeared to decrease mortality in patients with type 1 HRS. In primary prophylaxis of EVH, carvedilol was found to reduce the rate of initial bleeding compared with band ligation. Early transjugular intrahepatic portosystemic shunts placed in highly selected patients with acute EVH and a high risk of endoscopic failure decreased long-term mortality. In patients with gastric varices, primary prophylaxis with cyanoacrylate may decrease the probability of gastric variceal hemorrhage compared with nonselective beta-blockers.Refinement in clinical management strategies for patients with cirrhosis and its complications appear to continue to contribute to improved patient outcomes.

Endothelin-1 (ET-1), a potent vasoconstrictor peptide up-regulated during wound healing and fibrosis, induces myofibroblasts to contract tissue. Here we have used a liver injury model to test the hypothesis that TNFα may be an important stimulator of ET-1 production in hepatic wound healing. We examined primary rat hepatic stellate cells, isolated from either normal or injured livers and used standard methodology to measure preproET-1 mRNA and mature ET-1 peptide, specific kinases, and preproET-1 promoter activity. Chromatin immunoprecipitation analysis was used to determine basal binding of transcription factors to the preproET-1 promoter. TNFα induced preproET-1 expression in activated hepatic stellate cells in a c-Jun N-terminal kinase (JNK)/AP-1-dependent fashion. TNFα activated JNK through an IκB kinase (IKK) pathway, which activated the transcriptional factor, c-Jun, leading to preproET-1 promoter mediated ET-1 transcription. The TNFα mediated induction of ET-1 synthesis also had functional effects, specifically mediating autocrine induced stellate cell contraction. TNFα stimulated activated stellate cells to produce ET-1 via a novel IKK-JNK-dependent signaling pathway. The resulting autocrine functional effects of ET-1 are likely to be important in the wound-healing process.

Upper gastrointestinal bleeding is caused by many different lesions and varies greatly in severity, ranging from clinically insignificant to life threatening. It is common, accounting for around 300,000 admissions per year in the United States (1, 2). The most common causes of upper gastrointestinal bleeding in the United States include peptic ulcer disease and esophagogastric varices (3). Outcomes in upper gastrointestinal bleeding, specifically caused by esophageal varices have improved, at least over the last 20 years – in parallel with the routine introduction of esophageal band ligation, use of pharmacologic agents, and prophylaxis against bacterial infections with antibiotics (4). Multiple variables in acute upper gastrointestinal bleeding appear to help predict outcome - including the presence of certain symptoms (bright red bleeding), signs (hypotension on presentation), and laboratory features (elevated Model for End Stage Liver Disease (MELD) score in cirrhotics). One of the more controversial variables in assessment of prognosis in gastrointestinal bleeding is that of the “red blood cell” volume or mass (i.e., hematocrit or hemoglobin). In some studies, initial hemoglobin or hematocrit levels have been shown to be associated with outcome (5), while in other studies the level of hematocrit or hemoglobin was not important in predicting outcome (3, 6). Specifically in patients with cirrhosis, a recent study of a large number of patients with upper gastrointestinal bleeding suggested that the combination of MELD score, need for use of pressors, and albumin, and not the hematocrit level, were the most meaningful predictors of outcome, regardless of the cause of bleeding (7). While volume resuscitation is clearly important in patients with volume depletion, by inference, these data have raised questions about the importance of aggressive transfusion in patients with acute upper gastrointestinal bleeding. Further, in patients with portal hypertension, transfusion of blood products may increase portal pressure or alter coagulation parameters and lead to rebleeding (8, 9). Once a patient with upper gastrointestinal bleeding presents to the hospital, current practice is to address that particular patient’s hemodynamic stability and administer intravenous colloids and transfuse blood (PRBCs) to correct hemodynamics and the hematocrit level. Unfortunately, little data exist about how to best transfuse blood, and practice in the United States has evolved into a scenario in which blood is often arbitrarily transfused to a “hematocrit of 30” or “hemoglobin of 10”, depending on ones preference for hematocrit or hemoglobin. For that matter, fresh frozen plasma is also often given to correct the INR (typically to 50K). However, meaningful endpoints are unfortunately often lacking. This becomes a problematic approach because it is clear that blood transfusion has risks, and a variety of studies in the setting of trauma, in the intensive care unit, and in other situations have demonstrated that blood transfusion may have deleterious effects (10–12). The study by Villaneuva et al (13) demonstrated that a “restrictive” hemoglobin threshold for transfusion of 7 g/dL hemoglobin per deciliter compared to a “liberal” a threshold of 9 g/dL per deciliter, was associated with a 45% relative-risk reduction in 45-day mortality. Mortality was significantly improved in patients with esophageal variceal hemorrhage, but not in patients with peptic ulcer bleeding. Some details of the study are noteworthy. First, in all patients with cirrhosis, rebleeding was lower in patients in the restrictive group than in the liberal transfusion group (16/139 [12%] vs. 31/138 [22%], p = 0.02), although this difference appeared to be limited to those with Child-Pugh A/B scores, and was not evident in patients with Child-Pugh C cirrhosis. Further, the decrease in mortality was accounted for primarily by fewer deaths from bleeding that could not be successfully controlled. Among the most compelling data from the study were those that demonstrated transfusion was associated with increases in hepatic venous pressure gradient (HVPG). Remarkably, an HVPG was obtained in 86 patients in the restrictive transfusion group and in 89 in the liberal transfusion group within the first 48 hours after presentation, and was repeated 2 to 3 days later in 74 and 77 patients, respectively. Patients in the liberal transfusion arm had a significant increase in the mean HVPG between the first and second measurements (from 20.5 ± 3.1 mm Hg to 21.4 ± 4.3 mm Hg, p = 0.03). There was no significant change in the mean HVPG in the restrictive transfusion arm. There are two important points concerning these data; the first is that it was not clearly reported as to how much blood was given between the HVPG measurement, and the second is that this is a very small increase in HVPG, and may not be clinically meaningful. Common sense suggests that the more blood given, particularly in the setting in which bleeding has stopped, the greater the change in HVPG. A further important detail in the study is that all the patients underwent emergency gastroscopy within the first 6 hours of presentation. The routine use of such “urgent” endoscopy would be generally considered to be highly aggressive, and the practice of performing emergency endoscopy has become highly controversial. For example, many practioners intentionally defer endoscopy until after the patient has been fully volume resuscitated and become hemodynamically stable. This practice has been justified on the basis that performing so called “early endoscopy” has failed to demonstrate improvement in mortality (14–17). However, it has been demonstrated that performing endoscopy even in patients with low hematocrits is safe (3). From a practical standpoint, urgent endoscopy and therapy would be expected to stop ongoing bleeding (at least in the majority of patients), and several studies suggest that early endoscopy improves outcomes (18, 19) or quality of care (17). This in turn would be expected to reduce transfusion demand. Thus, an important question has to do with the effect of early endoscopy in the context of a restrictive blood transfusion approach. One could argue that in the current study, while it would have been expected for there to be a reduction in the need for blood transfusion in both arms (since all patients underwent early endoscopy), it very well may be that aggressive early endoscopy played a role in definitively treating lesions so that blood transfusion was in fact not necessary - contributing to an improved outcome. A key question at this point is how to integrate the findings from this study into the management of patients with upper gastrointestinal bleeding, and in particular those with cirrhosis and portal hypertension. Whether the practice reported in this single center study is generalizable to a wider clinical audience remains unknown, particularly given the issues surrounding aggressive early endoscopy. Even though stopping bleeding early with mechanical endoscopic therapy makes good common sense, the results are not likely to be generalizable to most practices in the United States, primarily because truly early endoscopy and aggressive intervention is not often performed. Nonetheless, any decision to transfuse blood or blood products must take into account the risks and benefits associated with transfusion. Although the data from the Villaneuva study suggest that less aggressive blood transfusion is beneficial, experienced clinicians would all likely agree that the decision to transfuse is complex and should not be predicated solely on a specific hemoglobin/hematocrit value. Indeed, further studies on the issues surrounding blood transfusion as well as the role of early endoscopy in patients with upper gastrointestinal bleeding are clearly needed.

Introduction The peroxisome proliferator-activated receptors (PPARs) are well established to be important in modulating the fibrogenic response to liver injury. PPARγ plays a role in hepatic fibrosis, presumably by virtue of its expression in hepatic stellate cells, which are key effectors of fibrosis. In this study, we evaluated whether the potent nonthiozolidinedione PPARγ agonist, GW570, had effects on isolated stellate cells and hepatic fibrosis in vivo. Methods Liver fibrosis and stellate cell activation were induced in vivo by either bile duct ligation (BDL) or administration of carbon tetrachloride (CCl(4)). Primary cultures of stellate cells isolated from normal rats were exposed to GW570. The PPARγ agonist was also given to male Sprague-Dawley rats before or during injury to test its ability to ameliorate fibrosis. Fibrosis biomarkers including total collagen, hydroxyproline, collagen I α1 and smooth muscle α actin were measured. Results GW570 had potent effects on isolated stellate cells, both simulating PPARγ mediated gene transcription, as well as inhibiting collagen I α1 mRNA and protein expression and smooth muscle α actin protein abundance, consistent with suppression of stellate cell activation. In BDL liver injury, a daily dose of 10 mg/kg per day of GW570 inhibited collagen I α1 mRNA, while concentrations of 1 also inhibited fibrosis as measured by hydroxyproline and total collagen content. Lower doses of GW570 (0.1-1.0 mg/kg per day) did not significantly abrogate whole liver collagen or hydroxyproline content in this model. In a CCl(4) model, 0.1-1.0 mg/kg per day GW570 reduced expression of smooth muscle α actin, but did not affect whole liver collagen or hydroxyproline content. Finally, we found that GW570 had anti-inflammatory effects on Kupffer cells as well as in vivo during CCl(4) injury. Conclusion PPARγ receptor agonism with the nonthiozolidinedione, GW570, inhibited stellate cell activation in vitro and in vivo, and abrogated the fibrogenic response to injury in a dose responsive fashion.