Correlation between Endosonographic and Doppler Ultrasound Features of Portal Hypertension in Patients with Cirrhosis

Purpose. Endoscopic ultrasound (EUS) permits the detailed visualization of clinically significant features of portal hypertension; however, it is an invasive procedure that is not widely available. The aim of this cross-sectional study was to determine whether a correlation exists between the features of portal hypertension detected using both Doppler ultrasound and EUS in subjects with liver cirrhosis. Materials and Methods. Analyzed cohort included 42 patients who underwent a detailed Doppler ultrasound focusing on the parameters of blood flow in the portal/splenic vein as well as an endoscopic/EUS procedure that included the assessment of the size and localization of “deep” varices. Results. The size of “deep” oesophageal varices detected with EUS exhibited no correlation with the parameters assessed by Doppler ultrasound. However, the size of the “deep” gastric varices detected using EUS correlated with the time averaged maximum velocity (Tmax as well as Vmin, Vmax) for the portal vein using Doppler ultrasound and exhibited a correlation with the Vmax and Tmax for the splenic vein. No significant correlation was determined between the diameter of the azygous vein and the thickness of the gastric wall when seen on EUS versus the parameters measured with Doppler ultrasound. Conclusion. EUS provides important information regarding the features of portal hypertension, and in the case of “deep” oesophageal varices exhibits a limited correlation with the parameters detected by Doppler ultrasound. Thus, despite its invasiveness, EUS is a method that provides a reliable and unique assessment of the features of portal hypertension in patients with liver cirrhosis

TRAF1-C5

Background. Previous studies reported associations between specific alleles of non-HLA immunoregulatory genes and higher fatigue scores in patients with primary biliary cirrhosis (PBC). Aim. To study the relationship between variables of health-related quality of life (HRQoL) and single nucleotide polymorphisms of TRAF1-C5, a member of the tumor necrosis factor receptor family. Patients and Methods. TRAF1-C5 gene polymorphisms, rs2900180 and rs3761847, were analysed in 120 Caucasian PBCs. The HRQoL was assessed with SF-36, PBC-40, and PBC-27 questionnaires. Results. We found a negative association between TT genotype of rs2900180 and SF-36’s domains vitality (P<0.05), mental health (P<0.05), and mental component summary score (P<0.05). GG homozygotes of rs3761847 had lower vitality (P<0.05), mental health (P<0.05), mental component summary score (P<0.05) and impairment of social functioning (P<0.01). Allelic analysis has shown that T allele of rs2900180 and G allele of rs3761847 related to SF-36’s vitality (P<0.05 and P<0.01), social functioning (P<0.05 and P<0.05), mental health (P<0.01 and P<0.05), and mental component summary score (P<0.01 and P<0.05), respectively. Genotyping and allelic analysis did not reveal correlation with PBC-40 and PBC-27 domains. Conclusion. The association between rs2900180 and rs3761847 polymorphisms and HRQoL variables indicates that TRAF1 is involved in the induction of impaired QoL in PBC

Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis

OBJECTIVE: Hepatic stellate cells (HSC) transdifferentiation into myofibroblasts is central to fibrogenesis. Epigenetic mechanisms, including histone and DNA methylation, play a key role in this process. Concerted action between histone and DNA-mehyltransferases like G9a and DNMT1 is a common theme in gene expression regulation. We aimed to study the efficacy of CM272, a first-in-class dual and reversible G9a/DNMT1 inhibitor, in halting fibrogenesis. DESIGN: G9a and DNMT1 were analysed in cirrhotic human livers, mouse models of liver fibrosis and cultured mouse HSC. G9a and DNMT1 expression was knocked down or inhibited with CM272 in human HSC (hHSC), and transcriptomic responses to transforming growth factor-β1 (TGFβ1) were examined. Glycolytic metabolism and mitochondrial function were analysed with Seahorse-XF technology. Gene expression regulation was analysed by chromatin immunoprecipitation and methylation-specific PCR. Antifibrogenic activity and safety of CM272 were studied in mouse chronic CCl4 administration and bile duct ligation (BDL), and in human precision-cut liver slices (PCLSs) in a new bioreactor technology. RESULTS: G9a and DNMT1 were detected in stromal cells in areas of active fibrosis in human and mouse livers. G9a and DNMT1 expression was induced during mouse HSC activation, and TGFβ1 triggered their chromatin recruitment in hHSC. G9a/DNMT1 knockdown and CM272 inhibited TGFβ1 fibrogenic responses in hHSC. TGFβ1-mediated profibrogenic metabolic reprogramming was abrogated by CM272, which restored gluconeogenic gene expression and mitochondrial function through on-target epigenetic effects. CM272 inhibited fibrogenesis in mice and PCLSs without toxicity. CONCLUSIONS: Dual G9a/DNMT1 inhibition by compounds like CM272 may be a novel therapeutic strategy for treating liver fibrosis

Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988-2008

Background: A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX require

Rozpoznawanie i leczenie raka wątrobowokomórkowego — rekomendacje Sekcji Hepatologicznej Polskiego Towarzystwa Gastroenterologii

Rak wątrobowokomórkowy (HCC) jest najczęstszym pierwotnym nowotworem złośliwym wątroby. W najbliższych latach przewiduje się dalszy wzrost częstości jego występowania. Większość przypadków HCC wiąże się z dobrze poznanymi czynnikami ryzyka, z których najważniejsze to marskość wątroby, przewlekłe zakażenia HBV i HCV oraz alkoholowa i niealkoholowa choroba stłuszczeniowa wątroby. Pomimo znacznego postępu diagnostycznego, nadal w wielu przypadkach HCC jest rozpoznawany w późnym stadium, co ogranicza możliwości terapeutyczne. W niniejszym opracowaniu zawarto przegląd wiedzy na temat diagnostyki, leczenia i opieki nad pacjentami z HCC. Przedstawiono zalecenia, które są oparte na rekomendacjach panelu ekspertów European Association for the Study of the Liver (EASL) i European Organization for Research and Treatment of Cancer (EORTC). Krajowi eksperci biorący udział w panelu przedstawili komentarze uwzględniające odrębności w podejściu do pacjenta z HCC w stosunku do zaleceń europejskich

In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice

We describe a two-photon microscopy-based method to evaluate the in vivo systemic transport of compounds. This method comprises imaging of the intact liver, kidney and intestine, the main organs responsible for uptake and elimination of xenobiotics and endogenous molecules. The image quality of the acquired movies was sufficient to distinguish subcellular structures like organelles and vesicles. Quantification of the movement of fluorescent dextran and fluorescent cholic acid derivatives in different organs and their sub-compartments over time revealed significant dynamic differences. Calculated half-lives were similar in the capillaries of all investigated organs but differed in the specific sub-compartments, such as parenchymal cells and bile canaliculi of the liver, glomeruli, proximal and distal tubules of the kidney and lymph vessels (lacteals) of the small intestine. Moreover, tools to image immune cells, which can influence transport processes in inflamed tissues, are described. This powerful approach provides new possibilities for the analysis of compound transport in multiple organs and can support physiologically based pharmacokinetic modeling, in order to obtain more precise predictions at the whole body scale

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; PPeer reviewe

Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities

Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). Approach and Results We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such asTP53(35.5%),KRAS(28.0%),CDKN2A(14.5%), andSMAD4(11.3%), as well as potentially druggable mutations (e.g.,HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.Peer reviewe

Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses

Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancerstrategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Herewe use genetic ablation of this enzyme to induce indolence in two cancer types, andshow this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha(HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inabilityto respond to hypoxia, concordantly with the persistence of human oncocytomas. Wedemonstrate that CI-deficient tumors survive and carry out angiogenesis, despite theirinability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated mac-rophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneouspharmacological inhibition of CI function through metformin and macrophage infiltrationthrough PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basisfor an efficient combinatorial adjuvant therapy in clinical trials