A B S T R A C TPrimary sclerosing cholangitis (PSC) is characterized by increased mast cell (MC) infiltration, biliary damage and hepatic fibrosis. Cholangiocytes secrete stem cell factor (SCF), which is a chemoattractant for c-kit expressed on MCs. We aimed to determine if blocking SCF inhibits MC migration, biliary damage and hepatic fibrosis. Methods: FVB/NJ and Mdr2 −/− mice were treated with Mismatch or SCF Vivo-Morpholinos. We measured (i) SCF expression and secretion; (ii) hepatic damage; (iii) MC migration/activation and histamine signaling; (iv) ductular reaction and biliary senescence; and (v) hepatic fibrosis. In human PSC patients, SCF expression and secretion were measured. In vitro, cholangiocytes were evaluated for SCF expression and secretion. Biliary proliferation/senescence was measured in cholangiocytes pretreated with 0.1% BSA or the SCF inhibitor, ISK03. Cultured HSCs were stimulated with cholangiocyte supernatant and activation measured. MC migration was determined with cholangiocytes pretreated with BSA or ISK03 loaded into the bottom of Boyden chambers and MCs into top chamber. Results: Biliary SCF expression and SCF serum levels increase in human PSC. Cholangiocytes, but not hepatocytes, from SCF Mismatch Mdr2 −/− mice have increased SCF expression and secretion. Inhibition of SCF in Mdr2 −/− mice reduced (i) hepatic damage; (ii) MC migration; (iii) histamine and SCF serum levels; and (iv) ductular reaction/biliary senescence/hepatic fibrosis. In vitro, cholangiocytes express and secrete SCF. Blocking stellate cell; hHSC, human hepatic stellate cell; IBDM, intrahepatic bile duct mass; Ki-67, marker of proliferation; MC, mast cell; Mdr2 −/− , multidrug resistance transporter 2/ABC transporter B family member 2 knock out; mMCP-1, mouse mast cell protease 1; p16, cyclin-dependent kinase inhibitor 2A; p18, Cyclin-dependent kinase 4 inhibitor C; PCNA, proliferating cell nuclear antigen; PSC, primary sclerosing cholangitis; qPCR, quantitative PCR; SASP, senescence-associate secretory phenotype; SCF, stem cell factor; SYP-9, synaptophysin 9; WT, wild type ☆ 0925-4439/ Published by Elsevier B.V.T biliary SCF decreased MC migration, biliary proliferation/senescence, and HSC activation. Conclusion: Cholangiocytes secrete increased levels of SCF inducing MC migration, contributing to biliary damage/hepatic fibrosis. Targeting MC infiltration may be an option to ameliorate PSC progression.

Galanin (Gal) is a peptide with a role in neuroendocrine regulation of the liver. In this study, we assessed the role of Gal and its receptors, Gal receptor 1 (GalR1) and Gal receptor 2 (GalR2), in cholangiocyte proliferation and liver fibrosis in multidrug resistance protein 2 knockout (Mdr2KO) mice as a model of chronic hepatic cholestasis. The distribution of Gal, GalR1, and GalR2 in specific liver cell types was assessed by laser-capture microdissection and confocal microscopy. Galanin immunoreactivity was detected in cholangiocytes, hepatic stellate cells (HSCs), and hepatocytes. Cholangiocytes expressed GalR1, whereas HSCs and hepatocytes expressed GalR2. Strategies were used to either stimulate or block GalR1 and GalR2 in FVB/N (wild-type) and Mdr2KO mice and measure biliary hyperplasia and hepatic fibrosis by quantitative PCR and immunostaining of specific markers. Galanin treatment increased cholangiocyte proliferation and fibrogenesis in both FVB/N and Mdr2KO mice. Suppression of GalR1, GalR2, or both receptors in Mdr2KO mice resulted in reduced bile duct mass and hepatic fibrosis. In vitro knockdown of GalR1 in cholangiocytes reduced a-smooth muscle actin expression in LX-2 cells treated with cholangiocyte-conditioned media. A GalR2 antagonist inhibited HSC activation when Gal was administered directly to LX-2 cells, but not via cholangiocyte-conditioned media. These data demonstrate that Gal contributes not only to cholangiocyte proliferation but also to liver fibrogenesis via the coordinate activation of GalR1 in cholangiocytes and GalR2 in HSCs.

The orexigenic peptide ghrelin (Ghr) stimulates hunger signals in the hypothalamus via growth hormone secretagogue receptor (GHS-R1a). Gastric Ghr is synthetized as a preprohormone which is proteolytically cleaved, and acylated by a membrane-bound acyl transferase (MBOAT). Circulating Ghr is reduced in cholestatic injuries, however Ghr’s role in cholestasis is poorly understood. We investigated Ghr’s effects on biliary hyperplasia and hepatic fibrosis in Mdr2-knockout (Mdr2KO) mice, a recognized model of cholestasis. Serum, stomach and liver were collected from Mdr2KO and FVBN control mice treated with Ghr, des-octanoyl-ghrelin (DG) or vehicle. Mdr2KO mice had lower expression of Ghr and MBOAT in the stomach, and lower levels of circulating Ghr compared to WT-controls. Treatment of Mdr2KO mice with Ghr improved plasma transaminases, reduced biliary and fibrosis markers. In the liver, GHS-R1a mRNA was expressed predominantly in cholangiocytes. Ghr but not DG, decreased cell proliferation via AMPK activation in cholangiocytes in vitro. AMPK inhibitors prevented Ghr-induced FOXO1 nuclear translocation and negative regulation of cell proliferation. Ghr treatment reduced ductular reaction and hepatic fibrosis in Mdr2KO mice, regulating cholangiocyte proliferation via GHS-R1a, a G-protein coupled receptor which causes increased intracellular Ca2+ and activation of AMPK and FOXO1, maintaining a low rate of cholangiocyte proliferation.

Gastroduodenal artery (GDA) pseudoaneurysms are rare clinical entities that typically develop in the setting of chronic inflammation of the pancreas, although idiopathic pseudoaneurysms can occur. Although GDA pseudoaneurysms carry the risk of rupture with resultant hemorrhage, they seldom are reported to cause biliary obstruction. We report a unique case of biliary obstruction secondary to extrinsic compression of the bile duct by a GDA pseudoaneurysm successfully managed by nonoperative means.

Physician burnout has increasingly been recognized as a multifactorial issue leading to detrimental outcomes for both the physician and patients being treated. Burnout is defined as “a pathological syndrome in which emotional depletion and maladaptive detachment develop in response to prolonged occupational stress”.  It has been proven that poor work-life balance (WBL), a state in which personal and professional life are in a state of imbalance, is  connected to burnout. Upwards of 61% of all U.S. physicians are dissatisfied with their WBL. Burnout rates among physicians are correlated with frequency of work-home conflicts leading to greater dissatisfaction of their WLB. With the prevalence of burnout among US physicians ranging between 34-76%, addressing modifiable causes such as optimizing WLB should be a priority for administrators. In this systematic review, we explore the importance of creating schedules that prioritize protecting physicians’ WLB as a means to decrease burnout and the associated sequelae including medical errors, alcohol abuse, and depression. After identifying 202 studies through PubMed; data from 21 articles published between 2011-2017 were analyzed. We found that schedules that emphasize the following were protective of physician WBL: <70-hour work week goals, a maximum of one on-call night per five consecutive days, providing physicians with schedule information one month in advance, limiting the consecutive work days to five and providing vacation time. As the importance of mental health, and wellness within the health care setting are being regarded as a cause of concern, it is apparent that positive changes need to be made.