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

Modeling and Simulation of Microdialysis in the Deep Brain Structures

Microdialysis is a method for monitoring of the local biochemical environment in a region of interest. The method uses a catheter, mimicking the function of a blood capillary, to sample substances from the surrounding medium through diffusion. A recent application for microdialysis is the sampling of neuroactive substances in the deep brain, or basal ganglia, during deep brain stimulation (DBS) for patients with Parkinson’s disease. The basal ganglia consist of nuclei interconnected by chemical synapses, and it is hypothesized that the levels of neurotransmitter substances around the synapses are affected by DBS treatment. In order to relate the microdialysis data to their anatomical origin and to the effects of DBS, it is suitable to estimate the tissue volume which is sampled during a microdialysis experiment. In this thesis, the maximum tissue volume of influence (TVImax) for a microdialysis catheter was simulated and evaluated using the finite element method (FEM), to allow interpretation of biochemical data in relation to anatomical structures. A FEM model for simulation of the TVImax for a microdialysis catheter placed in grey brain matter was set up, using Fick’s law of diffusion. The model was used to investigate the impact of the analyte diffusion coefficient (D), the tissue tortuosity (λ) and the loss rate constant (k) on the size of the TVImax by regression analysis. Using relevant parameter intervals, the radius of the TVImax of a neurotransmitter was estimated to 0.85 ± 0.25 mm. A microdialysis experiment on calf brain tissue showed agreement with the regression model. A heterogeneous anisotropic FEM model based on diffusion tensor imaging (DTI) showed that the radius of the TVImax may vary by up to 0.5 mm as a consequence of local tissue properties, which was reasonable in relation to the 95% confidence interval from the regression estimation. The TVImax was simulated and patient-specifically visualized in relation to MRI images for four patients undergoing microdialysis in parallel to DBS. The size of the TVImax showed to be relevant in relation to the basal ganglia nuclei, and the obtained microdialysis data indicated that the biochemical response to DBS depends on the catheter position. The simulations of the TVImax were combined with patient-specific DBS electric field simulations, for further interpretation of the results in relation to the effects of DBS. In conclusion, simulations and visualizations of the TVImax allowed relating microdialysis data to its anatomical origin. Detailed knowledge about the parameters affecting the microdialysis sampling volume is valuable for the current application as well as other applications related to the migration of analytes in tissue.Mikrodialys är en metod som används för studera lokala nivåer av biokemiska substanser i ett specifict organ eller struktur. Metoden använder sig av en kateter med ett semipermeabelt membran, över vilket utbyte av substanser sker genom diffusion. Mikrodialys har nyligen använts för att studera nivåer av neurotransmittorer i de djupa hjärnstrukturerna, ävan kallade basala ganglierna, under djup hjärnstimulering (DBS) för patienter med Parkinsons sjukdom. De basala ganglierna består av ett antal millimeterstora hjärnstrukturer, sammankopplade via biokemiska synapser, och nivåerna av signalsubstanser runt dessa synapser tros påverkas av DBS. För att relatera mikrodialysmätningarna till dess anatomiska ursprung, och till effekterna av DBS, är det önskvärt att få en uppskattning av den vävnadsvolym som påverkar mätningen från en mikrodialyskateter. Målet med denna licentiatavhandling har varit att simulera och utvärdera den maximala påverkansvolymen (TVImax) för en mikrodialyskateter med hjälp av finita element-metoden (FEM), för att underlätta tolkningen av de biokemiska data som samlats in. En FEM-modell sattes upp för att simulera TVImax för en kateter placerad i grå hjärnvävnad, baserat på Ficks diffusionslag och lämpliga rand- och initialvillkor. Modellen användes för att göra en regressionsanalys av hur TVImax påverkades av analytens diffusionskoefficient (D), hjärnvävnadens tortuositet (λ) och analytens nedbrytningshastighet (k), och radien för TVImax för en neurotransmitter uppskattades till 0.85 ± 0.25 mm då fysiologiskt relevanta parameterintervall användes. En experimentell studie av mikrodialys på hjärnvävnad från kalv gav god överensstämmelse med simuleringsresultaten. En heterogen och anisotrop FEM-modell sattes upp med hjälp av diffusionstensordata (DTI), vilket visade att lokala vävnadsegenskaper påverkar diffusionen av analyter i de basala ganglierna med upp till 0.5 mm i enighet med den regressionsmodell som tagits fram. TVImax simulerades och visualiserades sedan i relation till MRI-bilder för fyra patienter som genomgått mikrodialys parallellt med DBS. Målområdena för mikrodialysmätningarna visade sig skilja mellan patienterna, och den insamlade mikrodialysdatan indikerade att den biokemiska responsen på DBS berodde på kateterns position. För att ytterligare underlätta tolkningen av resultatet i relation till effekterna av DBS, kombinerades TVImax-simuleringarna med simuleringar av det elektriska fältet runt DBS-elektroderna. Sammanfattningsvis kan simuleringar av TVImax vara en hjälp vid den fysiologiska tolkningen av insamlad mikrodialysdata, vilket underlättar jämförelser mellan patienter. Detaljerad kunskap om de parametrar som påverkar samplingsvolymen för en mikrodialyskateter är värdefulla både för den aktuella applikationen, och övriga applikationer relaterade till diffusion av substanser i vävnad

The role of canalicular ABC transporters in cholestasis

Item does not contain fulltextCholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases

Taurine-conjugation critically determines the therapeutic effectiveness of 24-nor-ursodeoxycholic acid (NORUDCA) in the treatment of sclerosing cholangitis in MDR2 (ABCB4) knockout mice

This article does not have an abstract

Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis.

BACKGROUND & AIMS: Cholestasis is a liver disorder characterized by impaired bile flow, reduction of bile acids (BAs) in the intestine, and retention of BAs in the liver. The farnesoid X receptor (FXR) is the transcriptional regulator of BA homeostasis. Activation of FXR by BAs reduces circulating BA levels in a feedback mechanism, repressing hepatic cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting enzyme for the conversion of cholesterol to BAs. This mechanism involves the hepatic nuclear receptor small heterodimer partner and the intestinal fibroblast growth factor (FGF) 19 and 15. We investigated the role of activation of intestine-specific FXR in reducing hepatic levels of BAs and protecting the liver from cholestasis in mice. METHODS: We generated transgenic mice that express a constitutively active FXR in the intestine. Using FXR gain- and loss-of-function models, we studied the roles of intestinal FXR in mice with intrahepatic and extrahepatic cholestasis. RESULTS: Selective activation of intestinal FXR induced FGF15 and repressed hepatic Cyp7a1, reducing the pool size of BAs and changing the BA pool composition. Activation of intestinal FXR protected mice from obstructive extrahepatic cholestasis after bile duct ligation or administration of α-naphthylisothiocyanate. In Mdr2(-/-) mice, transgenic expression of activated FXR in the intestine protected against liver damage, whereas absence of FXR promoted progression of liver disease. CONCLUSIONS: Activation of FXR transcription in the intestine protects the liver from cholestasis in mice by inducing FGF15 expression and reducing the hepatic pool of BA; this approach might be developed to reverse cholestasis in patient

Taurine-conjugation critically determines the therapeutic effectiveness of 24-nor-ursodeoxycholic acid (norUDCA) in the treatment of sclerosing cholangitis in Mdr2 (ABCB4) knockout mice

Background and Aims: We recently demonstrated that norUDCA reverses sclerosing cholangitis and biliary fibrosis in $Mdr2^{-/-}$ mice (Fickert et al., Gastroenterology 2006) and hypothesized that its therapeutic efficacy may be critically related to its relative resistance against taurine- and glycin-conj ugation resulting in cholehepatic shunting and bicarbonate-rich hypercholeresis (Hofmann et al., Hepatology, 2005). Therefore we aimed to compare the therapeutic mechanisms and effects of norUDCA and its taurine conjugate (TnorUDCA) in the $Mdr2^{-/-}$ model for sclerosing cholangitis