Molecular Physiology of Bile Acid Signaling in Health, Disease, and Aging.

Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.

Peribiliary glands: development, dysfunction, related conditions and imaging findings.

Peribiliary glands are minute structures that are distributed along the intrahepatic large bile ducts, extrahepatic bile duct, and cystic duct. These glands regulate many physiological functions, such as enzyme secretion. Pancreatic exocrine tissues and enzymes are often observed in peribiliary glands; thus, peribiliary glands are involved in enzyme secretion. As such, these glands can be affected by conditions such as IgG4-related sclerosing cholangitis based on commonalities with their pancreatic counterparts. Cystic changes in peribiliary glands can occur de novo, as part of a congenital syndrome, or secondary to insults such as alcoholic cirrhosis. Biliary tree stem/progenitor cells have recently been identified in peribiliary glands. These cells are involved in turnover and regeneration of biliary epithelia as well as in sclerosing reactions in some pathological conditions, such as primary sclerosing cholangitis and hepatolithiasis. Notably, hepatolithiasis is involved in mucin secretion by the peribiliary glands. Additionally, these cells are associated with the manifestation of several neoplasms, including intraductal papillary neoplasm, cystic micropapillary neoplasm, and cholangiocarcinoma. Normal peribiliary glands themselves are particularly small structures that cannot be recognized using any available imaging modalities; however, these glands are closely associated with several diseases, as mentioned above, which have typical imaging features. Therefore, knowledge of the basic pathophysiology of peribiliary glands is helpful for understanding biliary diseases associated with the peribiliary glands.

Nivolumab-induced large-duct cholangiopathy treated with ursodeoxycholic acid and tocilizumab.

Immune checkpoint inhibitor therapy has become a cornerstone in the management of many oncologic diseases. Although it is well tolerated in most patients, a wide spectrum of adverse events has been described as a result of immune system alteration. We present a case of a woman with metastatic bronchogenic adenocarcinoma who was initially thought to have immune-mediated hepatitis, but eventually discovered to have a rarely described immune-mediated cholangiopathy. Her cholangiopathy appeared to stabilize following ursodeoxycholic acid and tocilizumab after several lines of guideline-directed therapy. Awareness of this unique toxicity following immune checkpoint inhibitor, and potential treatment options may help clinicians manage this rare but serious complication.

Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases.

Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases ß-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1ß and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.

Cholangiocyte pathobiology.

Cholangiocytes, the epithelial cells lining the intrahepatic and extrahepatic bile ducts, are highly specialized cells residing in a complex anatomic niche where they participate in bile production and homeostasis. Cholangiocytes are damaged in a variety of human diseases termed cholangiopathies, often causing advanced liver failure. The regulation of cholangiocyte transport properties is increasingly understood, as is their anatomical and functional heterogeneity along the biliary tract. Furthermore, cholangiocytes are pivotal in liver regeneration, especially when hepatocyte regeneration is compromised. The role of cholangiocytes in innate and adaptive immune responses, a critical subject relevant to immune-mediated cholangiopathies, is also emerging. Finally, reactive ductular cells are present in many cholestatic and other liver diseases. In chronic disease states, this repair response contributes to liver inflammation, fibrosis and carcinogenesis and is a subject of intense investigation. This Review highlights advances in cholangiocyte research, especially their role in development and liver regeneration, their functional and biochemical heterogeneity, their activation and involvement in inflammation and fibrosis and their engagement with the immune system. We aim to focus further attention on cholangiocyte pathobiology and the search for new disease-modifying therapies targeting the cholangiopathies.

Inflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies.

Cholangiocytes, the epithelial cells lining the bile ducts, represent the unique target of a group of progressive diseases known as cholangiopathies whose pathogenesis remain largely unknown. In normal conditions, cholangiocytes are quiescent and participate to the final bile volume and composition. Following exogenous or endogenous stimuli, cholangiocytes undergo extensive modifications of their phenotype. Reactive cholangiocytes actively proliferate and release a set of proinflammatory molecules, which act in autocrine/paracrine manner mediating the cross-talk with other liver cell types and innate and adaptive immune cells. Cholangiocytes themselves activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Gut microbiota has been implicated in the development and progression of the two most common cholangiopathies, i.e., primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), which have distinctive microbiota composition compared to healthy individuals. The impairment of intestinal barrier functions or gut dysbiosis expose cholangiocytes to an increasing amount of microorganisms and may exacerbate inflammatory responses thus leading to fibrotic remodeling of the organ. The present review focuses on the complex interactions between the activation of innate immune responses in reactive cholangiocytes, dysbiosis, and gut permeability to bacterial products in the pathogenesis of PSC and PBC.

Pathobiology of biliary epithelia.

Cholangiocytes are epithelial cells that line the intra- and extrahepatic biliary tree. They serve predominantly to mediate the content of luminal biliary fluid, which is controlled via numerous signaling pathways influenced by endogenous (e.g., bile acids, nucleotides, hormones, neurotransmitters) and exogenous (e.g., microbes/microbial products, drugs etc.) molecules. When injured, cholangiocytes undergo apoptosis/lysis, repair and proliferation. They also become senescent, a form of cell cycle arrest, which may prevent propagation of injury and/or malignant transformation. Senescent cholangiocytes can undergo further transformation to a senescence-associated secretory phenotype (SASP), where they begin secreting pro-inflammatory and pro-fibrotic signals that may contribute to disease initiation and progression. These and other concepts related to cholangiocyte pathobiology will be reviewed herein. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Gallbladder Dysfunction: Cholecystitis, Choledocholithiasis, Cholangitis, and Biliary Dyskinesia.

The prevalence of gallstones is 10% to 15% in adults. Individuals with acute cholecystitis present with right upper quadrant pain, fever, and leukocytosis. Management includes supportive care and cholecystectomy. The prevalence of choledocholithiasis is 10% to 20%, and serious complications include cholangitis and gallstone pancreatitis. The goal of management in individuals with choledocholithiasis consists of clearing common bile duct stones. Acute ascending cholangitis is a life-threatening condition involving acute inflammation and infection of the common bile duct. Treatment includes intravenous fluids, analgesia, intravenous antibiotics, and biliary drainage and decompression. Biliary dyskinesia includes motility disorders resulting in biliary colic in the absence of gallstones.

Diagnosis and outcomes of collateral arterial formation after irreversible early hepatic artery thrombosis in pediatric liver recipients.

BACKGROUND: Early hepatic artery thrombosis (eHAT) has been recognized as an important cause of graft loss and mortality. However, the incidence, etiology and outcome are not clear, especially for children. The present study was to investigate the formation of collateral artery flow after irreversible eHAT and its impact on patient's prognosis. METHODS: We analyzed eHAT after liver transplantation in children from October 2006 to April 2015 in our center, illustrated the formation of collateral hepatic artery flow after irreversible eHAT and explored the diagnosis, complications, treatment and prognosis. The basic and follow-up ultrasonographic images were also compared. RESULTS: Of the 330 pediatric liver recipients, 22 (6.67%) developed eHAT within 1 month. Revascularization attempts including surgical thrombectomy, interventional radiology and conservational treatment (thrombolysis) were successful in 5 patients. Among the 17 patients who had irreversible eHAT, follow-up ultrasonography revealed that collateral artery flow was developed as early as 2 weeks after eHAT. Liver abscess and bile duct complication occurred secondary to eHAT in variable time. CONCLUSIONS: Collateral arterial formation is a compensatory adaptation to eHAT to supply blood to liver grafts. However, the severe bile duct damage secondary to eHAT is irreversible and retransplantation is unavoidable.

Liver and biliary damages following transarterial chemoembolization of hepatocellular carcinoma: comparison between drug-eluting beads and lipiodol emulsion.

OBJECTIVES: To compare transarterial chemoembolization (TACE)-related hepatic toxicities of conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE) in patients with intermediate-stage hepatocellular carcinoma. METHODS: In this retrospective study, 151 consecutive patients undergoing cTACE or DEB-TACE and MRI 3-6 weeks before and after therapy were included. Toxicity was assessed on imaging (global hepatic damages (GHD), overall biliary injuries, biliary cast, bile duct dilatation, intrahepatic biloma, portal thrombosis), and clinico-biological follow-ups. Tumour response, time to progression (TTP), and overall survival were assessed. Factors influencing complication rate were identified by generalized equation logistic regression model. RESULTS: Biliary injuries and intrahepatic biloma incidence were significantly higher following DEB-TACE (p < 0.001). DEB-TACE showed a significant increased risk of GHD (OR: 3.13 [1.74-5.63], p < 0.001) and biliary injuries (OR: 4.53 [2.37-8.67], p < 0.001). A significant relationship was found between baseline prothrombin value and GHD, biliary injuries and intrahepatic biloma (all p < 0.01), and between the dose of chemotherapy and intrahepatic biloma (p = 0.001). Only TTP was significantly shorter following DEB-TACE compared to cTACE (p = 0.025). CONCLUSIONS: DEB-TACE was associated with increased hepatic toxicities compared to cTACE. GHD, biliary injuries, and intrahepatic biloma were more frequently observed with high baseline prothrombin value, suggesting that cTACE might be more appropriate than DEB-TACE in patients with less advanced cirrhosis. KEY POINTS: • DEB-TACE demonstrated more therapy-related hepatic locoregional complications compared to cTACE. • TACE-related hepatic locoregional toxicities occurred more frequently with high baseline PT value. • cTACE may be more appropriate in patients with high baseline PT value.

Cholangiocytes derived from induced pluripotent stem cells for disease modeling.

PURPOSE OF REVIEW: Biliary diseases are a significant cause of morbidity and mortality. Challenges in establishing accurate in-vitro methods to model human bile duct diseases and evaluate therapies have contributed to a lack of effective medical treatments. The recent discovery of strategies to reprogram human somatic cells to a state of induced pluripotency has opened up new possibilities for studying both development and disease in a wide variety of human tissues. This review was undertaken to summarize the recent progress made in generating biliary tissue from induced pluripotent stem cells (iPSCs) and the application of this technology to biliary disease modeling. RECENT FINDINGS: Several groups have reported defined differentiation protocols that incorporate key signaling cues from normal biliary development to yield cholangiocyte-like cells from wild-type human iPSCs that demonstrate epithelial morphology in two and three-dimensional culture, cholangiocyte markers, biliary gene expression profiles, and functional attributes consistent with biliary epithelium. Key features of Alagille syndrome and polycystic liver disease can be modeled with iPSC-derived cholangiocytes, whereas the use of iPSCs from cystic fibrosis patients has facilitated not only modeling of cystic fibrosis biliary disease but also in-vitro correction of the disorder with pharmacological agents. SUMMARY: Mature, functional cholangiocytes can be derived from human iPSCs and utilized to model biliary diseases in vitro. These advances should facilitate further research to improve our understanding of the pathophysiology of cholangiopathies and evaluate novel treatments. In the future, this technology will likely form a key element of tissue replacement strategies.

[BILE DUCT PROBLEMS - ENDOSCOPIC SOLUTIONS].

Patients with symptomatic bile duct stones are at increased risk for complications, which can be life-threatening. In the last four decades, with the development of endoscopic retrograde cholangiopancreatography (ERCP) and biliary sphincterotomy, endoscopic treatment has almost totally replaced surgical treatment of bile duct stones. In addition, a variety of benign and malignant conditions such as iatrogenic strictures (post cholecystectomy/post liver transplant), PSC, papillary adenoma or malignant tumors of bile duct or pancreas, are now amenable to endoscopic treatment. In the early years, ERCP served as a diagnostic and therapeutic tool With the development of non-invasive imaging alternatives, ERCP became a purely therapeutic procedure. However, in recent years, advanced technologies have restored diagnostic abilities to FRCP.

Cholestasis induced antinociception and decreased gene expression of MOR1 in rat brain.

We examined antinociception and gene expression of mu-opioid receptor 1 (MOR1) in some brain areas of cholestatic rats, 21 days after common bile duct ligation (BDL). Cholestasis was induced in male Wistar rats during laparotomy and common BDL. Pain behavior was assessed on days 7, 14 or 21 of BDL using a hotplate test in control, sham and cholestatic groups. On day 21 of BDL, other groups of rats were sacrificed, whole brains were extracted, and the hypothalamus, prefrontal cortex (PFC), hippocampus and striatum in control, sham and cholestatic rats were dissected. We used a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method for evaluating MOR1 gene expression. The results revealed that cholestatic rats showed significant antinociception on days 14 and 21 of ligation with the most significant effect on day 21, which was prevented by naloxone (1 mg/kg). On the other hand, the expression of MOR1 gene compared to the sham group was decreased by 42% in the hypothalamus, 41% in the PFC, and 67% in the hippocampus after 21 days of BDL, while no significant change in its expression in the striatum was observed. It can be concluded that a change in endogenous opioid levels and its subsequent influence on the gene expression of MOR in some areas of the rat brain may underlie the altered nociception and other possible pathological changes such as pruritus after induction of cholestasis.

Biliary Pancreatitis. Liver Function Tests and Common Biliopancreatic Channel Kinetics--Biliopancreatic Reflux.

OBJECTIVE: To determine the prevalence of biliopancreatic reflux (BPR) in patients with biliary pancreatitis (BP) undergoing elective cholecystectomy with intraoperative cholangiography (IOC) in comparison with a control group of symptomatic cholelithiasis (CG). PATIENTS AND METHODS: Retrospective review of 107 consecutive BP cases. BPR was determined by IOC and liver function tests (LFT) were recorded at admission (A), 48hours, and preoperative examination (P). LFT analysis between A and P were analysed between groups with respect to BPR, time interval to cholecystectomy within the same group and by determination of observed value/maximum normal value ratio (OV/MNV). RESULTS: BPR incidence was 38.3% in BP in comparison with 5% in CG (p=0.0001) it was independent from interval time to cholecystectomy, in contrast with Odditis, suggesting an anatomical condition for CCBP and a functional one for Odditis. LFT analysis showed no differences in relation to BPR incidence. LFT excluding AP and GGT returned to normal values with significant differences in OV/MNV when BPR was present which points to an increased cholestasis in BPR group. US dilatation of CBD was noted in 10.3% and was associated to CCBP. CONCLUSIONS: BPR in BP increases cholestasis and contributes to confusion in the estimation of common bile duct stones increasing ERCP-EE rates. US and biochemical markers of CBDS show a low specificity due to BPR-CCBP which suggests that MRI-cholangiography is a mandatory exploration before ERCP-EE examination.

Ultrasound measurements of the bile ducts and gallbladder: normal ranges and effects of age, sex, cholecystectomy, and pathologic states.

OBJECTIVE: The objectives of this study were to determine the normal values and ranges for bile duct and gallbladder measurements, adjusted for demographic data, and to assess the effects of a variety of pathologic states on these values. METHODS: Four thousand one hundred nineteen abdominal ultrasounds were retrospectively analyzed. The values for the extrahepatic bile duct (EHD), left (LIHD) and right (RIHD) intrahepatic ducts, gallbladder wall thickness, and gallbladder volume in "normal" patients were evaluated with respect to age, sex, ethnicity, and cholecystectomy status. These values were compared using multivariate analysis to those in a variety of diseased states, including cirrhosis, fatty liver, gallstones, sludge, cholecystitis, and biliary obstruction. RESULTS: One thousand four hundred eighty-four of the 4119 examinations were classified as normal. The mean EHD, RIHD, LIHD, and gallbladder wall thickness and volume measurements in normal patients were 3.8 ± 1.6 mm, 1.9 ± 1.9 mm, 1.9 ± 1.1 mm, 2.6 ± 1.6 mm, and 242 ± 234 mL, respectively.There were small increases in EHD diameter with age (+0.02 ± 0.11 mm/y, P < 0.001), female sex (+0.3 ± 1.6 mm, P < 0.0001), and cholecystectomy (+1.0 ± 1.6 mm, P < 0.0001) and a small decrease with fatty liver (-0.4 ± 1.6 mm, P = 0.0003). The gallbladder wall was thicker in patients with gallstones (+0.4 ± 1.4 mm, P = 0.0049), sludge (+0.5 ± 1.4 mm, P = 0.0019), and acute cholecystitis (+3.1 ± 1.6 mm, P < 0.0001). With biliary obstruction, the mean EHD, RIHD, LIHD, and gallbladder volume measurements were 6.0 ± 2.1 mm, 4.2 ± 1.4 mm, 4.1 ± 1.4 mm, and 171 ± 207 mL, respectively (P < 0.0001 for all values). CONCLUSIONS: This study clarifies normal values and ranges for bile duct and gallbladder measurements, adjusted for demographic data, and evaluates these measurements in a variety of common pathologic states.

Assessment of physiologic bile flow in the extrahepatic bile duct with cine-dynamic MR cholangiopancreatography and a spatially selective inversion-recovery pulse.

PURPOSE: To determine the feasibility of directly and noninvasively visualizing physiologic bile flow in the extrahepatic bile duct by means of nonpharmacologic cine-dynamic magnetic resonance (MR) cholangiopancreatography with a spatially selective inversion-recovery (IR) pulse and assess the flow dynamic pattern of bile in the extrahepatic bile duct. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the need for informed consent. Thirty-five patients without known pancreatobiliary diseases and 11 patients with dilatation of the extrahepatic bile duct were included. Cine-dynamic MR cholangiopancreatography with a spatially selective IR pulse was performed by imaging every 15 seconds over a 5-minute interval (20 images acquired total). The images were evaluated for the visualization of bile flow, the frequency that bile flow was observed in the extrahepatic bile duct, and the distance the bile moved within the area of the IR pulse. Statistical analysis was performed by using Spearman rank correlation coefficient and Mann-Whitney U tests. RESULTS: Antegrade bile flow was observed in 29 of 35 patients (83%) in the nondilated group. Bile flow was observed much more frequently in the nondilated group than in the dilated group (4.4 times vs 1.8 times, P = .029). The distance that bile moved forward within the area of the IR pulse was significantly greater in the nondilated group than in the dilated group (mean grade, 0.44 vs 0.14; P = .033), suggesting stagnation or slowdown of antegrade bile flow in patients with biliary dilatation. Reversed bile flow was also observed in 26 of 35 patients (74%) in the nondilated group without biliary diseases. CONCLUSION: Nonpharmacologic cine-dynamic MR cholangiopancreatography with a spatially selective IR pulse allows direct and noninvasive visualization of bile flow in the extrahepatic bile duct, demonstrating that reversed bile flow is a physiologic phenomenon.