scholarly journals NR0B2 regulation during Primary Sclerosing Cholangitis defines a metabolic and pre-malignant reprogramming of Cholangiocyte

2021 ◽  
Author(s):  
Christophe Desterke ◽  
Cyrille Feray
Keyword(s):  
Text Mining ◽  
Single Cell ◽  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Farnesoid X Receptor ◽  
Cholestatic Liver Disease ◽  
System Physiology ◽  
Cell Transcriptome ◽  
Cell Trajectory ◽  
Mining Work

SUMMARYPrimary Sclerosing Cholangitis (PSC) is an idiopathic, cholestatic liver disease that is characterized by persistent, progressive, biliary inflammation leading to cirrhosis. These patients present higher risk for developing bile duct cancers.Biomedical text-mining related to PSC symptoms like: biliary inflammation, biliary fibrosis, biliary cholestasis was initiated to collect gene associations with this pathophysiology. The text mining work was integrated in distinct omics data such as human transcriptome of PSC liver, Farnesoid X receptor (FXR) functional liver transcriptome and liver single cell transcriptome of the Abcb4-/- model of PSC. A molecular network implicated in abnormal hepatobiliary system physiology was built and confirming a major implication of Nr0b2 and its associated nuclear receptors like FXR in a metabolic cascade that could influence immune response. TNFRSF12A/TWEAK receptor, was found up regulated in PSC liver independently of FXR regulation and TWEAK signaling is known for its implication in pre-conditioning niche of cholangiocarcinoma. NR0B2 deregulation in PSC liver was found independent of gender, age and body mass index surrogates. At single cell level, Nr0b2 up regulation was found in cholangiocytes but not in hepatocytes. In affected cholangiocytes, the cell trajectory built on Nr0b2 expression, revealed implication of several metabolic pathways for detoxification like sulfur, glutathione derivative and monocarboxylic acid metabolisms. On this cell trajectory it was discovered some molecules potentially implicated in carcinogenesis like: GSTA3, ID2 and mainly TMEM45A a transmembrane molecule from golgi apparatus considered as oncogene in several cancers. All together, these observations found in humanPSC liver and in its murine models allowed to highlight an independent deregulation of NR0B2 with a metabolic and premalignant reprogramming of cholangiocytes.

Cholestatic Liver Injury: Care of Patients With Primary Biliary Cholangitis or Primary Sclerosing Cholangitis

2016 ◽  
Vol 27 (4) ◽  
pp. 441-452 ◽  
Author(s):  
Laurie Larson ◽  
Michelle James ◽  
Andrea Gossard
Keyword(s):  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Disease Recurrence ◽  
Outpatient Setting ◽  
Primary Biliary Cholangitis ◽  
Malignant Neoplasms ◽  
Cholestatic Liver Disease ◽  
Gallbladder Polyps ◽  
Increased Risk ◽  
Common Causes

The most common causes of chronic cholestatic liver disease are primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Both disease processes are characterized by a destruction of intrahepatic and/or extrahepatic biliary ducts. The etiology is not entirely clear; however, there is an underlying autoimmune component contributing to both disease processes. Although PBC and PSC are often diagnosed and managed in the outpatient setting, in some instances, a patient may have jaundice, fatigue, and pruritus requiring evaluation and determination of the cholestatic cause. Patients with PSC should be monitored for evidence of cholangiocarcinoma, colon cancer, and gallbladder polyps as they are at an increased risk of malignant neoplasms. Liver transplant has the potential for improving quality of life, although disease recurrence is a risk.

scholarly journals Primary sclerosing cholangitis

2008 ◽  
Vol 22 (8) ◽  
pp. 689-698 ◽  
Author(s):  
Marina G Silveira ◽  
Keith D Lindor
Keyword(s):  
Liver Disease ◽  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Serum Alkaline Phosphatase ◽  
Cholestatic Liver Disease ◽  
Biliary Strictures ◽  
Vitamin Deficiencies ◽  
Metabolic Bone ◽  
High Doses ◽  
End Stage

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, resulting in end-stage liver disease and reduced life expectancy. PSC primarily affects young and middle-aged men, often in association with underlying inflammatory bowel disease. The etiology of PSC includes immune-mediated components and elements of undefined nature. A cholestatic picture of liver biochemistries with elevations in serum alkaline phosphatase, nonspecific autoantibodies such as perinuclear antineutrophilic antibody, antinuclear antibodies and smooth muscle antibodies, and diffuse multifocal biliary strictures, resulting in a ‘beaded’ appearance on radiographic studies, are the hallmarks of the disease. No effective medical therapy is currently available, although clinical studies are in progress. Ursodeoxycholic acid at high doses (28 mg/kg/day to 30 mg/kg/day) is the most promising agent but is unproven so far. Liver transplantation is currently the only life-extending therapy for patients with end-stage disease, although recurrent disease can be observed in the transplanted liver. The multiple complications of PSC include pruritus, fatigue, vitamin deficiencies, metabolic bone disease, peristomal varices, bacterial cholangitis, dominant biliary strictures, gallbladder stones and polyps, and malignancy, particularly cholangiocarcinoma, which is the most lethal complication of PSC.

scholarly journals Characteristic Findings of Primary Sclerosing Cholangitis on Endoscopic Retrograde Cholangiography: Which is the Most Common Finding?

2011 ◽  
Vol 5 ◽  
pp. CGast.S7850
Author(s):  
Amir Houshang Mohammad Alizadeh ◽  
Anahita Shahnazi ◽  
Aida Rasoulzadeh ◽  
Esmaeel Shams ◽  
Manijeh Mohammadi ◽  
...  
Keyword(s):  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Laboratory Data ◽  
Specific Pattern ◽  
Common Type ◽  
Endoscopic Retrograde Cholangiography ◽  
Common Finding ◽  
Cholestatic Liver Disease ◽  
Endoscopic Retrograde ◽  
Small Duct

Background Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease and one of the most common indications for liver transplantation in adults. There are conflicting data regarding characteristic findings of PSC disease on endoscopic retrograde cholangiography (ERCP). We undertook this study to clarify whether there is a specific pattern of involvement of the biliary tract in patients with PSC and to evaluate features of PSC disease on ERCP in order to be able to manage this disease better. Methods This retrospective study included 45 patients admitted to Taleghani Hospital in 2004-2010 and diagnosed to have PSC on the basis of typical cholangiographic findings in combination with clinical and laboratory data. Patients suspected to have secondary sclerosing cholangitis were excluded. Demographic and clinical data were recorded, along with cholangiographic findings and the frequency of large duct and small duct PSC. Results Forty-five patients of mean age 34.8 (range 15-66) years were included. Twenty-nine patients (64.4%) had inflammatory bowel disease, and the frequency of large duct PSC and small duct PSC was 93.4% and 6.6%, respectively. The intrahepatic ducts alone were involved in 11 (24.4%) patients and the extrahepatic ducts were involved in 14 (31.1%), with 17 (37.7%) patients having both intrahepatic and extrahepatic PSC. Three (6.6%) patients did not have bile duct involvement on ERCP, and their disease was diagnosed by liver biopsy as small duct PSC. The most common type of cholangiographic feature of intrahepatic duct involvement was type 2, found in 15 (33.3%) patients, with type 3 being the most common type of extrahepatic duct involvement and detected in 16 (35.5%) patients. Conclusion Our study demonstrates that the most common PSC finding on ERCP is involvement of both the extrahepatic and intrahepatic bile ducts, with small duct PSC being less common than large duct PSC.

scholarly journals Role of the Microbiota and Antibiotics in Primary Sclerosing Cholangitis

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
James H. Tabibian ◽  
Jayant A. Talwalkar ◽  
Keith D. Lindor
Keyword(s):  
Inflammatory Bowel Disease ◽  
Liver Disease ◽  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Clinical Evidence ◽  
Cholestatic Liver Disease ◽  
Concise Review ◽  
Inflammatory Bowel ◽  
Considerable Morbidity

Primary sclerosing cholangitis (PSC) is an idiopathic, progressive, cholestatic liver disease with considerable morbidity and mortality and no established pharmacotherapy. In addition to the long-recognized association between PSC and inflammatory bowel disease, several lines of preclinical and clinical evidence implicate the microbiota in the etiopathogenesis of PSC. Here we provide a concise review of these data which, taken together, support further investigation of the role of the microbiota and antibiotics in PSC as potential avenues toward elucidating safe and effective pharmacotherapy for patients afflicted by this illness.

scholarly journals Problem Diagnostik dan Tata Laksana Primary Sclerosing Cholangitis

2017 ◽  
Vol 3 (3) ◽  
pp. 158
Author(s):  
Rezky Aulia Nurleili ◽  
Intan Airlina ◽  
Anna Mira Lubis
Keyword(s):  
Liver Disease ◽  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Cholestatic Liver Disease ◽  
Best Management ◽  
High Incidence ◽  
Male Patients

Primary sclerosing cholangitis (PSC) merupakan penyakit hati kolestasis kronik dengan insiden yang cukup tinggi di Amerika yaitu sebesar 1/100.000 penduduk namun angka kejadiannya di Indonesia belum pernah dipublikasikan. Belum didapatkan tatalaksana yang terbaik pada penyakit ini. Pada artikel ini akan dibahas mengenai kasus PSC pada pasien laki-laki berusia 49 tahun di Rumah Sakit dr. Cipto Mangunkusumo (RSCM) Jakarta dan tatalaksana yang dilakukan.Kata Kunci: PSC, tata laksana Diagnostic and Treatment Problems of Primary Sclerosing CholangitisPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with high incidence reported in America (1/100.000 population), but there is still no data available in Indonesia. The best management of this disease is still not found. Thus, in this article author will discuss about the case of PSC in 49-years male patients hospitalized in Cipto Mangunkusumo hospital Jakarta and its treatment. Keywords: PSC, treatment

scholarly journals Expression Analysis of ATP-Binding Cassette Transporters ABCB11 and ABCB4 in Primary Sclerosing Cholangitis and Variety of Pediatric and Adult Cholestatic and Noncholestatic Liver Diseases

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Cornelia Thoeni ◽  
Ruediger Waldherr ◽  
Jutta Scheuerer ◽  
Stefanie Schmitteckert ◽  
Ralph Roeth ◽  
...  
Keyword(s):  
Disease Progression ◽  
Primary Sclerosing Cholangitis ◽  
Liver Diseases ◽  
Sclerosing Cholangitis ◽  
Efflux Pump ◽  
Atp Binding ◽  
Cholestatic Liver Disease ◽  
Altered Expression ◽  
Outer Leaflet ◽  
Atp Binding Cassette

ATP-binding cassette (ABC) transporters are the members of the efflux pumps that are responsible for the removal of cytotoxic substances by active transport. ABCB11, the bile salt efflux pump of hepatocytes, coordinates cellular excretion of numerous conjugated bile salts into the bile canaliculi, whereas ABCB4 acts as an ATP-dependent floppase translocating phosphatidylcholine from the inner to the outer leaflet of the bile canalicular membrane. Loss of functional ABCB11 and ABCB4 proteins causes early-onset refractory cholestasis or cholangiopathy. In this study, we investigated the expression and localization pattern of ABCB11 and ABCB4 using immunohistochemistry and RNA profiling in liver samples from patients with different types and stages of chronic cholestatic liver disease, with emphasis on primary sclerosing cholangitis (PSC), compared to a variety of cholestatic and noncholestatic hepatopathies. Therefore, ABCB11 and ABCB4 expressions were investigated on formalin-fixed and paraffin-embedded (FFPE) material in a patient cohort of total 43 patients with or without cholestatic liver diseases, on protein level using immunohistochemistry and on RNA level using nanoString technology. Intriguingly, our results demonstrated increased expression of ABCB11 and ABCB4 on protein as well as RNA level in PSC, and the expression pattern correlated with disease progression. We concluded from our study that patients with PSC demonstrate altered expression levels and pattern of ABCB11 and ABCB4 which correlated with disease progression; thereby, ABCB11 and ABCB4 analysis may be a useful tool for assessment of disease stages in PSC.

scholarly journals Novel Insights of Primary Sclerosing Cholangitis and Primary Biliary Cholangitis

2020 ◽  
Vol 25 (2) ◽  
pp. 107-117
Author(s):  
Dong-Won Ahn
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Primary Sclerosing Cholangitis ◽  
Liver Diseases ◽  
Sclerosing Cholangitis ◽  
Acute Cholangitis ◽  
Magnetic Resonance Cholangiopancreatography ◽  
Primary Biliary Cholangitis ◽  
Cholestatic Liver Disease ◽  
Biliary Cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are immune-mediated chronic liver diseases. PSC is a rare disorder characterized by multi-focal bile duct strictures and progressive liver diseases, in which liver transplantation is required ultimately in most patients. Imaging studies such as magnetic resonance cholangiopancreatography have important role in diagnosis in most cases of PSC. PSC is usually accompanied by inflammatory bowel disease and there is a high risk of cholangiocarcinoma and colorectal cancer in PSC. No medical therapies have been proven to delay progression of PSC. Endoscopic intervention for tissue diagnosis or biliary drainage is frequently required in cases of PSC with dominant stricture, acute cholangitis, or clinically suspected cholangiocarcinoma. PBC is a chronic inflammatory autoimmune cholestatic liver disease, which when untreated will culminate in endstage biliary cirrhosis requiring liver transplantation. Diagnosis is usually based on the presence of serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse in PBC and risk stratification is important to ensure all patients receive a personalised approach to their care. Medical therapy using ursodeoxycholic acid (UDCA) or obeticholic acid (OCA) has an important role to reduce the progression to end-stage liver disease in PBC.

Therapy of Primary Sclerosing Cholangitis - Today and Tomorrow

2015 ◽  
Vol 33 (Suppl. 2) ◽  
pp. 149-163 ◽  
Author(s):  
Emina Halilbasic ◽  
Claudia Fuchs ◽  
Harald Hofer ◽  
Gustav Paumgartner ◽  
Michael Trauner
Keyword(s):  
Bile Acid ◽  
Primary Sclerosing Cholangitis ◽  
Sclerosing Cholangitis ◽  
Farnesoid X Receptor ◽  
Therapeutic Options ◽  
Current Status ◽  
Peroxisome Proliferator ◽  
Hepatocellular Injury ◽  
Close Link ◽  
Acid Receptor

Primary sclerosing cholangitis (PSC) represents a fibro-obliterative bile duct disease with unpredictable individual clinical course that may progress to liver cirrhosis and malignancy. Due to our incomplete understanding of the etiology and pathogenesis of this disease, the therapeutic options are still rather limited. Bile acids play a key role in mediating cholangiocellular and hepatocellular injury in cholangiopathies such as PSC. Therefore, strategies targeting bile composition and homeostasis are valid approaches in PSC. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and its role in medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid (norUDCA), a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid). Other nuclear receptors such as fatty acid-activated peroxisome proliferator-activated receptors, vitamin D receptor and vitamin A receptors (retinoic acid receptor, retinoid X receptor) are also of potential interest and can be targeted by already available drugs. Furthermore, drugs targeting the gut-liver axis (e.g. intregrin blockers such as vedolizumab, antibiotics) appear promising, based on the close link of PSC to inflammatory bowel disease and the emerging relevance of the gut microbiome for the development of PSC. Finally, fibrosis represents a valid therapeutic target for anti-fibrotic drugs (e.g. simtuzumab) in PSC as paradigm fibro-obliterative disease. This review summarizes the current status and recent progress in the development of targeted therapeutic approaches based on increasing knowledge about the pathogenesis of this disease.

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