Liver homeostasis is maintained by midlobular zone 2 hepatocytes.

The liver is organized into zones in which hepatocytes express different metabolic enzymes. The cells most responsible for liver repopulation and regeneration remain undefined, because fate mapping has only been performed on a few hepatocyte subsets. Here, 14 murine fate-mapping strains were used to systematically compare distinct subsets of hepatocytes. During homeostasis, cells from both periportal zone 1 and pericentral zone 3 contracted in number, whereas cells from midlobular zone 2 expanded in number. Cells within zone 2, which are sheltered from common injuries, also contributed to regeneration after pericentral and periportal injuries. Repopulation from zone 2 was driven by the insulin-like growth factor binding protein 2-mechanistic target of rapamycin-cyclin D1 (IGFBP2-mTOR-CCND1) axis. Therefore, different regions of the lobule exhibit differences in their contribution to hepatocyte turnover, and zone 2 is an important source of new hepatocytes during homeostasis and regeneration.

Aging and the Biological Response to Liver Injury.

Interest in understanding the aging process has recently risen in the scientific community. Aging, commonly defined as the functional decline in the function of organs and tissues, is indeed the major risk factor for the development of many chronic diseases, such as cardiovascular diseases, pathologies of nervous system, or cancer. To date, the influence of aging in the pathophysiology of liver and biliary diseases is not fully understood. Although liver cells have a high regenerative capacity, hepatocytes and cholangiocytes undergo extensive molecular changes in response to aging. Following time-dependent damage induced by aging, liver cells initially activate compensatory mechanisms that, if hyperstimulated, may lead to the decline of regenerative capacity and the development of pathologies. A deeper understanding of molecular aging has undoubtedly the potential to improve the clinical management of patients, possibly unveiling new pathways for selective drug treatment.

Too Much, Too Little, or Just Right? The Importance of Allograft Portal Flow in Deceased Donor Liver Transplantation.

BACKGROUND: While portal flow (PF) plays an important role in determining graft outcomes in living donor liver transplantation, its impact in deceased donor liver transplantation (DDLT) is unclear. The aim of this study was to investigate the correlations between graft PF and graft outcomes in DDLT. METHODS: We retrospectively investigated 1001 patients who underwent DDLT between January 2007 and June 2017 at our institution. The patients were divided into 3 groups according to hazard ratio for 1-year graft loss at each PF value, which was standardized with graft weight. Graft and recipient outcomes were compared between the groups. RESULTS: The low-PF group (PF < 65 mL/min/100 g, n = 210, P = 0.011) and the high-PF group (PF ≥ 155 mL/min/100 g, n = 159, P = 0.018) showed significantly poorer 1-year graft survival compared with the intermediate-PF group (PF ≥ 65 mL/min/100 g and < 155 mL/min/100 g, n = 632). The patients in the low-PF group had severe reperfusion injury and were more frequently complicated with primary nonfunction (P = 0.013) and early allograft dysfunction (P < 0.001) compared with the other groups. In contrast, the patients in the high-PF group had milder reperfusion injury, but had lower intraoperative hepatic artery flow with higher incidence of hepatic artery thrombosis (P = 0.043) and biliary complication (P = 0.041) compared with the other groups. CONCLUSIONS: These results suggest that intraoperative PF plays an important role in determining early graft outcomes after DDLT.

Imaging of Acute Hepatobiliary Dysfunction.

Abdominal pain is a common cause for emergency department visits in the United States, and biliary tract disease is the fifth most common cause of hospital admission. Common causes of acute hepatobiliary include gallstones and its associated complications and multiple other hepatobiliary etiologies, including infectious, inflammatory, vascular, and neoplastic causes. Postoperative complications of the biliary tract can result in an acute abdomen. Imaging of the hepatobiliary tree is integral in the diagnostic evaluation of acute hepatobiliary dysfunction, and imaging of the biliary tree requires a multimodality approach utilizing ultrasound, computed tomography, nuclear medicine, and MR imaging.

Ischemic Damage Represents the Main Risk Factor for Biliary Stricture After Liver Transplantation: A Follow-Up Study in a Danish Population.

BACKGROUND: Biliary complications (BC) are frequently observed following liver transplantation. The aim of the present retrospective study, conducted at an outpatients' tertiary care hospital, was to determine the incidence of biliary complications and risk factors associated with their development in liver transplantation (lT) patients. MATERIALS AND METHODS: The medical records were reviewed for all patients who underwent liver transplantation at the Rigshospitalet, Copenhagen, Denmark, from 2000 to 2011 and were referred to the Aarhus University Hospital for follow-up. Patients who died within 3 months of surgery or had incomplete clinical information were excluded. All data for demographic characteristics and possible risk factors for development of biliary stricture were collected. Fifty-one patients were included. RESULTS: The median age at transplantation was 40 (range=7-64) years, and 53% of patients were males. Biliary complications occurred in 18 patients (35%), the majority of whom developed strictures (12 patients, 24%). Univariate and multivariate analyses revealed that cytomegalovirus infection (p=0.008), hepatic artery obstruction (p=0.03) and hepatic artery graft abnormalities (p=0.03) were independent risk factors for the development of biliary strictures. CONCLUSION: One-third of patients presented biliary complications after liver transplantation, among which biliary strictures were the most common. Cytomegalovirus infection, hepatic artery stenosis and anatomical abnormality of the graft's hepatic artery are independent risk factors for the development of biliary stricture.

Gallbladder and bile duct disease in Cystic Fibrosis.

Cystic fibrosis (CF) is a multi-organ, clinically diverse disorder caused by mutations in the cystic fibrosis transmembrane conductance receptor (CFTR). Awareness of extra-pulmonary manifestations, including gastrointestinal and hepatobiliary disturbances, is an increasingly important part of providing high-quality care to patients with CF. Furthermore, biliary disorders, including gallbladder and bile duct disease, are common complications of CF. Therefore, a thorough understanding and efficient clinical evaluation of the gallbladder and biliary tree is an important aspect of integrated care for the patient with CF in order to prevent progression of undetected pathology. This best practice article summarizes the basis for gallbladder and bile duct pathology, describes the context and clinical presentation of biliary disease, and provides recommended approaches to delivery of high-quality care for patients with CF.

The emerging role of endoscopic ultrasound for pancreaticobiliary diseases in the pediatric population.

BACKGROUND: Endoscopic ultrasound (EUS) is a useful diagnostic and therapeutic tool in the pediatric population. Given the high accuracy and sensitivity of EUS, it is particularly effective in evaluating pancreaticobiliary disease. Published literature in the use of pediatric EUS is limited. Therefore we aimed to review the current literature for EUS indications, safety, and effectiveness for the pediatric population. DATA SOURCES: English language articles on the use of pediatric endoscopic ultrasound in evaluating pancreaticobiliary diseases were retrieved from PubMed/ MEDLINE. RESULTS: We analyzed various retrospective studies and case series publications. Data were extrapolated for pediatric patients with pancreaticobiliary diseases. CONCLUSIONS: EUS offers superior imaging. It is comparible to magnetic resonance imaging and/or pancreatic-protocol computed tomography. In the current literature, there are a variety of pancreaticobiliary conditions where EUS was utilized to make a diagnosis. These include recurrent pancreatitis, congenital anomalies, microlithiasis, pancreatic pseudocysts, and pancreatic mass lesions. EUS was shown to be a safe and cost-effective modality with both diagnostic and therapeutic capabilities in the pediatric population. EUS is now increasingly being recognized as a standard of care when evaluating pancreaticobiliary conditions in children.

Regenerative Medicine and the Biliary Tree.

Despite decades of basic research, biliary diseases remain prevalent, highly morbid, and notoriously difficult to treat. We have, however, dramatically increased our understanding of biliary developmental biology, cholangiocyte pathophysiology, and the endogenous mechanisms of biliary regeneration and repair. All of this complex and rapidly evolving knowledge coincides with an explosion of new technological advances in the area of regenerative medicine. New breakthroughs such as induced pluripotent stem cells and organoid culture are increasingly being applied to the biliary system; it is only a matter of time until new regenerative therapeutics for the cholangiopathies are unveiled. In this review, the authors integrate what is known about biliary development, regeneration, and repair, and link these conceptual advances to the technological breakthroughs that are collectively driving the emergence of a new global field in biliary regenerative medicine.

Bile duct ligation-induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell-deficient KitW-sh mice.

Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL), increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC-deficient (KitW-sh ) mice. Wild-type (WT) and KitW-sh mice were subjected to sham or BDL for up to 7 days and KitW-sh mice were injected with cultured mast cells or 1× phosphate-buffered saline (PBS) before collecting serum, liver, and cholangiocytes. Liver damage was assessed by hematoxylin and eosin and alanine aminotransferase levels. IBDM was detected by cytokeratin-19 expression and proliferation by Ki-67 immunohistochemistry (IHC). Fibrosis was detected by IHC, hydroxyproline content, and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and transforming growth factor-beta 1 (TGF-ß1) expression/secretion were evaluated. Histidine decarboxylase (HDC) and histamine receptor (HR) expression were detected by qPCR and HA secretion by enzymatic immunoassay. To evaluate vascular cells, von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF)-C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and alpha-smooth muscle actin levels were measured. BDL-induced liver damage was reduced in BDL KitW-sh mice, whereas injection of MCs did not mimic BDL-induced damage. In BDL KitW-sh mice, IBDM, proliferation, HSC activation/fibrosis, and TGF-ß1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL KitW-sh mice. vWF and VEGF-C expression decreased in BDL KitW-sh mice. In KitW-sh mice injected with MCs, IBDM, proliferation, fibrosis, and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or KitW-sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL KitW-sh mice. CONCLUSION: MCs promote hyperplasia, fibrosis, and vascular cell activation. Knockout of MCs decreases BDL-induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies. (Hepatology 2017;65:1991-2004).

Prognostic significance of hepatic arterial collaterals in liver transplant recipients with biliary strictures.

BACKGROUND: The aim of this study was to determine the prevalence of hepatic artery stenosis (HAS) and the prognostic implications of hepatic arterial collaterals in liver transplant (LT) recipients with biliary strictures. METHODS: The 105 LT recipients transplanted between 2004 and 2015 at our center had documented biliary strictures. HAS and collaterals were assessed in high-quality imaging of the hepatic artery available from 66 recipients. Clinical, demographic, and biochemical recipient and donor data were retrospectively analyzed and tested for their association with biliary or arterial complications after LT. RESULTS: The prevalence of HAS was 68% (45 of 66) in LT recipients with biliary strictures. Seventy-six percent (37 of 49) of patients with nonanastomotic biliary strictures had HAS. This was significantly higher than in patients with anastomotic stricture, where 47% (8 of 17) of patients had a pathological hepatic arteriogram (P=.039). The location of bile duct strictures was not predictive for outcome. In contrast, arterial collaterals were associated with significantly better patient and graft survival. CONCLUSION: Impaired hepatic arterial perfusion is frequently associated with nonanastomotic strictures, but less closely correlated with anastomotic strictures. On survival analysis, hepatic arterial collaterals have a protective effect.

Gastrointestinal disorders associated with migraine: A comprehensive review.

Migraine is a recurrent and commonly disabling primary headache disorder that affects over 17% of women and 5%-8% of men. Migraine susceptibility is multifactorial with genetic, hormonal and environmental factors all playing an important role. The physiopathology of migraine is complex and still not fully understood. Many different neuropeptides, neurotransmitters and brain pathways have been implicated. In connection with the myriad mechanisms and pathways implicated in migraine, a variety of multisystemic comorbidities (e.g., cardiovascular, psychiatric and other neurological conditions) have been found to be closely associated with migraine. Recent reports demonstrate an increased frequency of gastrointestinal (GI) disorders in patients with migraine compared with the general population. Helicobacter pylori infection, irritable bowel syndrome, gastroparesis, hepatobiliary disorders, celiac disease and alterations in the microbiota have been linked to the occurrence of migraine. Several mechanisms involving the gut-brain axis, such as a chronic inflammatory response with inflammatory and vasoactive mediators passing to the circulatory system, intestinal microbiota modulation of the enteric immunological milieu and dysfunction of the autonomic and enteric nervous system, have been postulated to explain these associations. However, the precise mechanisms and pathways related to the gut-brain axis in migraine need to be fully elucidated. In this review, we survey the available literature linking migraine with GI disorders. We discuss the possible physiopathological mechanisms, and clinical implications as well as several future areas of interest for research.

[CHANGES OF CAROTID AND VERTEBRAL ARTERIES IN PATENTS WITH ARTERIAL HYPERTENSION AND HEPATOBILIARY PATHOLOGY].

The study included 1172 patients (410 men and 762 women) at the mean age of 60.3 ± 10.4 years with grade I-II (stage I-II) arterial hypertension (AH) admitted to the clinic of Institute of Experimental Medicine. The patients were divided into 2 groups based on the results of clinical and laboratory diagnostics. Group 1 (n = 525) included patients with AH and hepatobiliary system (HBS) diseases, group 2 (n = 647) patients with AH without HBS diseases. The patients group 1 had a thicker intima-media complex of carotid arteries, higher peak systolic bloodflow rate in the internal and vertebral carotid arteries, more pronounced coiling of internal carotid arteries than patients of group 2. Patients with AH and HBS diseases exhibited correlation between bloodflow rate in external carotid arteries and atherogenicity coefficient. Duplex scanning of neck vessels of in patients with AH without HBS diseases revealed peculiar changes of the intima-media thickness and hemodynamically significant changes of the blood flow in the internal carotid arteries that may be of prognostic value in this nosological syntropy and require the personified approach to diagnostics, treatment, and prevention of these conditions.

Late Biliary Complications after Pancreaticoduodenectomy.

Since morbidity of pancreaticoduodenectomy (PD) has been improved, concerns about late complications have raised. We present a review of long-term biliary complications after PD attended at our institution. The data of 86 patients operated on from January 2001 to May 2014 were examined and incidence of late biliary complications was recorded. The preoperative features of the patients, timing of symptoms appearance, results of diagnostic imaging test, and the management strategies were analyzed. Late biliary complications occurred in 14 patients (16.3%). The median time to diagnosis was 9.50 months. The preoperative peak bilirubin level, need for preoperative drainage and intraoperative blood loss were not significantly different for patients with long-term biliary events. Eight patients (57.14%) developed true biliary strictures. Three of them (37.5%) had experienced a postoperative biliary leak (P < 0.0005) and resulted in benign strictures. The remaining five patients revealed tumor recurrence. Six patients had no biliary obstruction and cholangitis could only be explained through afferent-limb stasis. Late biliary strictures appear predominantly in the first postoperative year and develop more likely if a bile leak occurred in the postoperative period. However, biliary strictures are not always responsible for late biliary symptoms and afferent limb stasis may also be included in the differential diagnosis.

Bile acid signaling through farnesoid X and TGR5 receptors in hepatobiliary and intestinal diseases.

BACKGROUND: The well-known functions of bile acids (BAs) are the emulsification and absorption of lipophilic xenobiotics. However, the emerging evidences in the past decade showed that BAs act as signaling molecules that not only autoregulate their own metabolism and enterohepatic recirculation, but also as important regulators of integrative metabolism by activating nuclear and membrane-bound G protein-coupled receptors. The present review was to get insight into the role of maintenance of BA homeostasis and BA signaling pathways in development and management of hepatobiliary and intestinal diseases. DATA SOURCES: Detailed and comprehensive search of PubMed and Scopus databases was carried out for original and review articles. RESULTS: Disturbances in BA homeostasis contribute to the development of several hepatobiliary and intestinal disorders, such as non-alcoholic fatty liver disease, liver cirrhosis, cholesterol gallstone disease, intestinal diseases and both hepatocellular and colorectal carcinoma. CONCLUSION: Further efforts made in order to advance the understanding of sophisticated BA signaling network may be promising in developing novel therapeutic strategies related not only to hepatobiliary and gastrointestinal but also systemic diseases.

Animal models of gastrointestinal and liver diseases. Animal models of cystic fibrosis: gastrointestinal, pancreatic, and hepatobiliary disease and pathophysiology.

Multiple organ systems, including the gastrointestinal tract, pancreas, and hepatobiliary systems, are affected by cystic fibrosis (CF). Many of these changes begin early in life and are difficult to study in young CF patients. Recent development of novel CF animal models has expanded opportunities in the field to better understand CF pathogenesis and evaluate traditional and innovative therapeutics. In this review, we discuss manifestations of CF disease in gastrointestinal, pancreatic, and hepatobiliary systems of humans and animal models. We also compare the similarities and limitations of animal models and discuss future directions for modeling CF.