Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intra- and/or extrahepatic biliary ducts. While its features ...and disease course can be variable, most patients with PSC have concurrent inflammatory bowel disease and will eventually develop liver cirrhosis and end-stage liver disease, with liver transplantation representing the only potentially curative option. Importantly, PSC is associated with a significantly increased risk of malignancy compared to the general population, mainly cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, and colorectal cancer, with nearly 50% of deaths in patients with PSC being due to cancer. Therefore, robust surveillance strategies are needed, though uncertainty remains regarding how to best do so. In this review, we discuss the epidemiology, prevention, and surveillance of cancers in patients with PSC. Where evidence is limited, we present pragmatic approaches based on currently available data and expert opinion.
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains ...obscure. We tested the hypothesis that germ‐free (GF) mutltidrug resistance 2 knockout (mdr2−/−) mice develop a distinct PSC phenotype, compared to conventionally housed (CV) mdr2−/− mice. Mdr2−/− mice (n = 12) were rederived as GF by embryo transfer, maintained in isolators, and sacrificed at 60 days in parallel with age‐matched CV mdr2−/− mice. Serum biochemistries, gallbladder bile acids, and liver sections were examined. Histological findings were validated morphometrically, biochemically, and by immunofluorescence microscopy (IFM). Cholangiocyte senescence was assessed by p16INK4a in situ hybridization in liver tissue and by senescence‐associated β‐galactosidase staining in a culture‐based model of insult‐induced senescence. Serum biochemistries, including alkaline phosphatase, aspartate aminotransferase, and bilirubin, were significantly higher in GF mdr2−/− (P < 0.01). Primary bile acids were similar, whereas secondary bile acids were absent, in GF mdr2−/− mice. Fibrosis, ductular reaction, and ductopenia were significantly more severe histopathologically in GF mdr2−/− mice (P < 0.01) and were confirmed by hepatic morphometry, hydroxyproline assay, and IFM. Cholangiocyte senescence was significantly increased in GF mdr2−/− mice and abrogated in vitro by ursodeoxycholic acid (UDCA) treatment. Conclusions: GF mdr2−/− mice exhibit exacerbated biochemical and histological features of PSC and increased cholangiocyte senescence, a characteristic and potential mediator of progressive biliary disease. UDCA, a commensal microbial metabolite, abrogates senescence in vitro. These findings demonstrate the importance of the commensal microbiota and its metabolites in protecting against biliary injury and suggest avenues for future studies of biomarkers and therapeutic interventions in PSC. (Hepatology 2016;63:185–196)
Cholangiocytes (biliary epithelial cells) actively participate in microbe-induced proinflammatory responses in the liver and contribute to inflammatory and infectious cholangiopathies. We previously ...demonstrated that cholangiocyte TLR-dependent NRas activation contributes to proinflammatory/ proliferative responses. We test the hypothesis that LPS-induced activation of NRas requires the EGFR. SV40-transformed human cholangiocytes (H69 cells), or low passage normal human cholangiocytes (NHC), were treated with LPS in the presence or absence of EGFR or ADAM metallopeptidase domain 17 (TACE) inhibitors. Ras activation assays, quantitative RT-PCR, and proliferation assays were performed in cells cultured with or without inhibitors or an siRNA to Grb2. Immunofluorescence for phospho-EGFR was performed on LPS-treated mouse samples and specimens from patients with primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis C, and normal livers. LPS-treatment induced an association between the TLR/MyD88 and EGFR/Grb2 signaling apparatus, NRas activation, and EGFR phosphorylation. NRas activation was sensitive to EGFR and TACE inhibitors and correlated with EGFR phosphorylation. The TACE inhibitor and Grb2 depletion prevented LPS-induced IL6 expression (p<0.05) and proliferation (p<0.01). Additionally, cholangiocytes from LPS-treated mouse livers and human primary sclerosing cholangitis (PSC) livers exhibited increased phospho-EGFR (p<0.01). Moreover, LPS-induced mouse cholangiocyte proliferation was inhibited by concurrent treatment with the EGFR inhibitor, Erlotinib. Our results suggest that EGFR is essential for LPS-induced, TLR4/MyD88-mediated NRas activation and induction of a robust proinflammatory cholangiocyte response. These findings have implications not only for revealing the signaling potential of TLRs, but also implicate EGFR as an integral component of cholangiocyte TLR-induced proinflammatory processes.
Primary sclerosing cholangitis (PSC) is an incurable cholangiopathy of unknown etiopathogenesis. Here we tested the hypothesis that cholangiocyte senescence is a pathophysiologically important ...phenotype in PSC. We assessed markers of cellular senescence and senescence‐associated secretory phenotype (SASP) in livers of patients with PSC, primary biliary cirrhosis, hepatitis C, and in normals by fluorescent in situ hybridization (FISH) and immunofluorescence microscopy (IFM). We tested whether endogenous and exogenous biliary constituents affect senescence and SASP in cultured human cholangiocytes. We determined in coculture whether senescent cholangiocytes induce senescence in bystander cholangiocytes. Finally, we explored signaling mechanisms involved in cholangiocyte senescence and SASP. In vivo, PSC cholangiocytes expressed significantly more senescence‐associated p16INK4a and γH2A.x compared to the other three conditions; expression of profibroinflammatory SASP components (i.e., IL‐6, IL‐8, CCL2, PAI‐1) was also highest in PSC cholangiocytes. In vitro, several biologically relevant endogenous (e.g., cholestane 3,5,6 oxysterol) and exogenous (e.g., lipopolysaccharide) molecules normally present in bile induced cholangiocyte senescence and SASP. Furthermore, experimentally induced senescent human cholangiocytes caused senescence in bystander cholangiocytes. N‐Ras, a known inducer of senescence, was increased in PSC cholangiocytes and in experimentally induced senescent cultured cholangiocytes; inhibition of Ras abrogated experimentally induced senescence and SASP. Conclusion: Cholangiocyte senescence induced by biliary constituents by way of N‐Ras activation is an important pathogenic mechanism in PSC. Pharmacologic inhibition of N‐Ras with a resultant reduction in cholangiocyte senescence and SASP is a new therapeutic approach for PSC. (Hepatology 2014;59:2263–2275)
Hemobilia refers to macroscopic blood in the lumen of the biliary tree. It represents an uncommon, but important, cause of gastrointestinal bleeding and can have potentially lethal sequelae if not ...promptly recognized and treated. The earliest known reports of hemobilia date to the 17th century, but due to the relative rarity and challenges in diagnosis of hemobilia, it has historically not been well‐studied. Until recently, most cases of hemobilia were due to trauma, but the majority now occur as a sequela of invasive procedures involving the hepatopancreatobiliary system. A triad (Quincke's) of right upper quadrant pain, jaundice and overt gastrointestinal bleeding has been classically described in hemobilia, but it is present in only a minority of patients. Therefore, prompt diagnosis depends critically on a high index of suspicion based on a patient's clinical presentation and a history of recently undergoing hepatopancreatobiliary intervention or having other predisposing factors. Treatment of hemobilia depends on the suspected source and clinical severity and thus ranges from supportive medical care to urgent advanced endoscopic, interventional radiologic, or surgical intervention. In the present review, we provide a historical perspective, clinical update and overview of current trends and practices pertaining to hemobilia.
Cholestatic liver diseases (CLDs) encompass a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury and ultimately end‐stage liver disease. ...Many patients with CLD are diagnosed between the ages of 20‐50 years, a particularly productive period of life professionally, biologically and in other respects; it is not surprising, thus, that CLD is often associated with impaired health‐related quality of life (HRQOL) and uncertainty regarding implications for and outcomes of pregnancy. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most prominent CLDs, both having considerable morbidity and mortality and representing major indications for liver transplantation. These disorders, as a consequence of their complications (eg ascites, hepatic osteodystrophy), associated conditions (eg inflammatory bowel disease) and symptoms (eg pruritus and fatigue), can significantly impair an array of domains of HRQOL. Here we review these impactful clinical aspects of PSC and PBC as well as the topics of fertility and pregnancy.
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