Primary sclerosing cholangitis – a comprehensive review Karlsen, Tom H.; Folseraas, Trine; Thorburn, Douglas ...
Journal of hepatology,
December 2017, 2017-Dec, 2017-12-00, 20171201, Letnik:
67, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Primary sclerosing cholangitis (PSC) is a rare disorder characterised by multi-focal bile duct strictures and progressive liver disease. Inflammatory bowel disease is usually present and there is a ...high risk of cholangiocarcinoma and colorectal cancer. Most patients ultimately require liver transplantation, after which disease recurrence may occur. With limited therapeutic options and a lack of proven surveillance strategies, patients currently have significant unmet needs. In the present seminar, we provide a comprehensive review of the status of the field. We emphasise developments related to patient stratification and disease behaviour, and provide an overview of management options from a practical, patient-centered perspective. We survey advances made in the understanding of PSC pathogenesis and summarise the ongoing efforts to develop an effective therapy based on these insights.
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available ...herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
Primary sclerosing cholangitis Hirschfield, Gideon M, Dr; Karlsen, Tom H, Prof; Lindor, Keith D, Prof ...
The Lancet (British edition),
11/2013, Letnik:
382, Številka:
9904
Journal Article
Recenzirano
Summary Primary sclerosing cholangitis is the classic hepatobiliary manifestation of inflammatory bowel disease and is generally chronic and progressive. Patients frequently present with ...asymptomatic, anicteric cholestasis, but many develop progressive biliary strictures with time, leading to recurrent cholangitis, biliary cirrhosis, and end-stage liver disease. Medical treatment does not slow the progression of disease, and many patients need liver transplantation, after which recurrent disease is a risk. The increased incidence of hepatobiliary cancer, which is not related to the underlying severity of biliary fibrosis, is of particular concern. Risk of colorectal cancer is also increased in patients with coexistent inflammatory bowel disease. Mechanistic insights have arisen from studies of secondary sclerosing cholangitis, in which a similar clinical profile is associated with a specific cause, and genomic studies have elucidated potential disease-initiating pathways in the primary form. The close association between inflammatory bowel disease and primary sclerosing cholangitis underscores the need to further understand the role of environmental factors in generation of lymphocytes that are postulated to be retargeted, deleteriously, to the biliary tree. Treatment of primary sclerosing cholangitis is confined to supportive measures, but advances in pathobiology suggest that new stratified approaches will soon be available.
Primary sclerosing cholangitis (PSC) is a chronic disease leading to fibrotic scarring of the intrahepatic and extrahepatic bile ducts, causing considerable morbidity and mortality via the ...development of cholestatic liver cirrhosis, concurrent IBD and a high risk of bile duct cancer. Expectations have been high that genetic studies would determine key factors in PSC pathogenesis to support the development of effective medical therapies. Through the application of genome-wide association studies, a large number of disease susceptibility genes have been identified. The overall genetic architecture of PSC shares features with both autoimmune diseases and IBD. Strong human leukocyte antigen gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in disease pathogenesis, and position PSC as an autoimmune disease. In this Review, we survey the developments that have led to these gene discoveries. We also elaborate relevant interpretations of individual gene findings in the context of established disease models in PSC, and propose relevant translational research efforts to pursue novel insights.
Most patients with autoimmune hepatitis respond well to standard immunosuppressive therapy with steroids and azathioprine, and while untreated disease is usually fatal, patients who respond well to ...therapy have an excellent prognosis. However, insufficient response to standard therapy or intolerable side effects requiring dose adaptions or treatment changes occur in 10–20% of patients. While there is fairly good agreement on second-line treatment options, there is very wide variation in the indication and use of possible third-line therapies. Herein, the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the International Autoimmune Hepatitis Group (IAIHG) outline a treatment algorithm for both children and adults that should help to standardise treatment approaches, in order to improve patient care and to enable the comparison of treatment results between scientific publications.
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MAIN RECOMMENDATIONS
1
ESGE/EASL recommend that, as the primary diagnostic modality for PSC, magnetic resonance cholangiography (MRC) should be preferred over endoscopic retrograde ...cholangiopancreatography (ERCP).
Moderate quality evidence, strong recommendation.
2
ESGE/EASL suggest that ERCP can be considered if MRC plus liver biopsy is equivocal or contraindicated in patients with persisting clinical suspicion of PSC. The risks of ERCP have to be weighed against the potential benefit with regard to surveillance and treatment recommendations.
Low quality evidence, weak recommendation.
6
ESGE/EASL suggest that, in patients with an established diagnosis of PSC, MRC should be considered before therapeutic ERCP.
Weak recommendation, low quality evidence.
7
ESGE/EASL suggest performing endoscopic treatment with concomitant ductal sampling (brush cytology, endobiliary biopsies) of suspected significant strictures identified at MRC in PSC patients who present with symptoms likely to improve following endoscopic treatment.
Strong recommendation, low quality evidence.
9
ESGE/EASL recommend weighing the anticipated benefits of biliary papillotomy/sphincterotomy against its risks on a case-by-case basis.
Strong recommendation, moderate quality evidence.
Biliary papillotomy/sphincterotomy should be considered especially after difficult cannulation.
Strong recommendation, low quality evidence.
16
ESGE/EASL suggest routine administration of prophylactic antibiotics before ERCP in patients with PSC.
Strong recommendation, low quality evidence.
17
EASL/ESGE recommend that cholangiocarcinoma (CCA) should be suspected in any patient with worsening cholestasis, weight loss, raised serum CA19-9, and/or new or progressive dominant stricture, particularly with an associated enhancing mass lesion.
Strong recommendation, moderate quality evidence.
19
ESGE/EASL recommend ductal sampling (brush cytology, endobiliary biopsies) as part of the initial investigation for the diagnosis and staging of suspected CCA in patients with PSC.
Strong recommendation, high quality evidence.
The T-cell receptor (TCR), located on the surface of T cells, is responsible for the recognition of the antigen-major histocompatibility complex, leading to the initiation of an inflammatory ...response. Analysing the TCR repertoire may help to gain a better understanding of the immune system features and of the aetiology and progression of diseases, in particular those with unknown antigenic triggers. The extreme diversity of the TCR repertoire represents a major analytical challenge; this has led to the development of specialized methods which aim to characterize the TCR repertoire in-depth. Currently, next generation sequencing based technologies are most widely employed for the high-throughput analysis of the immune cell repertoire.
Here, we report on the latest methodological advancements in the field by describing and comparing the available tools; from the choice of the starting material and library preparation method, to the sequencing technologies and data analysis. Finally, we provide a practical example and our own experience by reporting some exemplary results from a small internal benchmark study, where current approaches from the literature and the market are employed and compared.
Several valid methods for clonotype identification and TCR repertoire analysis exist, however, a gold standard method for the field has not yet been identified. Depending on the purpose of the scientific study, some approaches may be more suitable than others. Finally, due to possible method specific biases, scientists must be careful when comparing results obtained using different methods.
BackgroundPatients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its ...interplay with bile acid metabolism in PSC.MethodsPatients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1–V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20).ResultsThe bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10−5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021).ConclusionPSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.
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