126 research outputs found
Well-differentiated hepatocellular neoplasm of uncertain malignant potential: proposal for a new diagnostic category
No full textTo the EditorPierre Bedossa, Alastair D. Burt, Elizabeth M. Brunt, Francesco Callea, Andrew D. Clouston, Hans-Peter Dienes, Zachary D. Goodman, Annette S.H. Gouw, Stefan G. Hubscher, Eve A. Roberts, Tania Roskams, Luigi Terracciano, Dina G. Tiniakos, Michael S. Torbenson, Ian R. Wanles
Peribiliary glands are key in regeneration of the human biliary epithelium after severe bile duct injury
No full textPeribiliary glands (PBG) are a source of stem/progenitor cells organized in a cellular network encircling large bile ducts. Severe cholangiopathy with loss of luminal biliary epithelium has been proposed to activate PBG, resulting in cell proliferation and differentiation to restore biliary epithelial integrity. However, formal evidence for this concept in human livers is lacking. We, therefore, developed a novel ex vivo model using precision-cut slices of extrahepatic human bile ducts obtained from discarded donor livers, providing an intact anatomical organization of cell structures, to study spatiotemporal differentiation and migration of PBG cells after severe biliary injury. Post-ischemic bile duct slices were incubated in oxygenated culture medium for up to a week. At baseline, severe tissue injury was evident with loss of luminal epithelial lining and mural stroma necrosis. In contrast, PBG remained relatively well preserved and different reactions of PBG were noted, including PBG dilatation, cell proliferation and maturation. Proliferation of PBG cells increased after 24 h of oxygenated incubation, reaching a peak after 72 h. Proliferation of PBG cells was paralleled by a reduction in PBG apoptosis and differentiation from a primitive and pluripotent (Nanog+/Sox9+) to a mature (CFTR+/secretin receptor+) and activated phenotype (increased expression of HIF-1α, Glut-1, and VEGF-A). Migration of proliferating PBG cells in our ex vivo model was unorganized, but resulted in generation of epithelial monolayers at stromal surfaces. CONCLUSION: Human PBG contain biliary progenitor cells and are able to respond to bile duct epithelial loss with proliferation, differentiation, and maturation to restore epithelial integrity. The ex vivo spatiotemporal behaviour of human PBG cells provides evidence for a pivotal role of PBG in biliary regeneration after severe injury. This article is protected by copyright. All rights reserved
Ductular reactions in human liver: Diversity at the interface
No full textInterest in hepatic ductular reactions (DRs) has risen in recent years because of a greater appreciation of their potential roles in regeneration, fibrogenesis, and carcinogenesis. However, confusion exists because there is significant, but often unappreciated diversity at the tissue, cellular, and subcellular levels in DRs of different diseases and stages of disease. DRs are encountered in virtually all liver disorders in which there is organ-wide liver damage and cell loss, but are also present in focal lesions such as focal nodular hyperplasia and adenoma. Moreover, diverse DR phenotypes can be present within any single disease entity, and are shaped by the etiology and evolution of the disease. Although much remains to be clarified, recent studies suggest that the diversity of appearances of the DRs are likely to reflect the differing signals at the anatomic, cellular, and molecular levels driving the proliferative response. These appear to determine the relative proportions of transit-amplifying cells, the degree of hepatocytic or cholangiocytic differentiation, and their relationships with stromal, vascular, and inflammatory components. The molecular signaling pathways governing these regenerative fate decisions closely replicate those found in human and other vertebrate embryos and more generally in stem cell niches throughout the body. Like the latter, complex interactions with matrix as well as mesenchymal and inflammatory cells, vessels, and innervation are likely to be of fundamental importance. Embracing systems/tissue biological approaches to exploring DRs, in addition to more traditional cellular and molecular biological techniques, will further enhance our understanding and, thereby, we believe potentiate new therapeutic possibilities
Persistent biliary hypoxia and lack of regeneration are key mechanisms in the pathogenesis of post-transplant non-anastomotic strictures
No full textNon-anastomotic biliary strictures (NAS) are a major cause of morbidity after orthotopic liver transplantation (OLT). Although ischemic injury of peribiliary glands (PBGs) and peribiliary vascular plexus (PVP) during OLT has been associated with the later development of NAS, the exact underlying mechanisms remain unclear. We hypothesized that bile ducts of patients with NAS suffer from ongoing biliary hypoxia and lack of regeneration from PBG stem/progenitor cells
Venous outflow reconstruction with surgically reopened obliterated umbilical vein in domino liver transplantation
No full textDevelopment and prognostic relevance of a histologic grading and staging system for alcohol-related liver disease
No full textBackground & Aims: The SALVE Histopathology Group (SHG) developed and validated a grading and staging system for the clinical and full histological spectrum of alcohol-related liver disease (ALD) and evaluated its prognostic utility in a multinational cohort of 445 patients. Methods: SALVE grade was described by semiquantitative scores for steatosis, activity (hepatocellular injury and lobular neutrophils) and cholestasis. The histological diagnosis of steatohepatitis due to ALD (histological ASH, hASH) was based on the presence of hepatocellular ballooning and lobular neutrophils. Fibrosis staging was adapted from the Clinical Research Network staging system for non-alcoholic fatty liver disease and the Laennec staging system and reflects the pattern and extent of ALD fibrosis. There are 7 SALVE fibrosis stages (SFS) ranging from no fibrosis to severe cirrhosis. Results: Interobserver κ-value for each grading and staging parameter was >0.6. In the whole study cohort, long-term outcome was associated with activity grade and cholestasis, as well as cirrhosis with very broad septa (severe cirrhosis) (p <0.001 for all parameters). In decompensated ALD, adverse short-term outcome was associated with activity grade, hASH and cholestasis (p = 0.038, 0.012 and 0.001, respectively), whereas in compensated ALD, hASH and severe fibrosis/cirrhosis were associated with decompensation-free survival (p = 0.011 and 0.001, respectively). On multivariable analysis, severe cirrhosis emerged as an independent histological predictor of long-term survival in the whole study cohort. Severe cirrhosis and hASH were identified as independent predictors of short-term survival in decompensated ALD, and also as independent predictors of decompensation-free survival in compensated ALD. Conclusion: The SALVE grading and staging system is a reproducible and prognostically relevant method for the histological assessment of disease activity and fibrosis in ALD. Lay summary: Patients with alcohol-related liver disease (ALD) may undergo liver biopsy to assess disease severity. We developed a system to classify ALD under the microscope by grading ALD activity and staging the extent of liver scarring. We validated the prognostic performance of this system in 445 patients from 4 European centers.SCOPUS: ar.jinfo:eu-repo/semantics/publishe
Comparison of functional parameters of biliary epithelial cell function in DCD livers that were preserved by either 4 h of oxygenated HMP or 4 h of SCS and subsequently reperfused for 2 h by normothermic <i>ex vivo</i> sanguineous perfusion.
No full text<p>There were no significant differences in biliary pH (<i>Panel A</i>), biliary bicarbonate (<i>Panel B</i>) and glucose concentration (<i>Panel C</i>) at 2 h after reperfusion between the two groups. Relative mRNA expression of the main cholangiocyte transporter proteins involved in biliary bicarbonate secretion, CFTR (cystic fibrosis transmembrane conductance regulator; ABC35) (<i>Panel D</i>) and AE2 (anion exchanger 2; SLC4A2) (<i>Panel E</i>) after 2 h of <i>ex vivo</i> sanguineous reperfusion of DCD livers that were preserved by either 4 h of oxygenated HMP or SCS. There were no significant differences between the two groups.</p
Comparison of biochemical parameters of bile duct injury and oxidative stress in DCD livers that were preserved by either 4 h of oxygenated HMP or 4 h of SCS and subsequently reperfused for 2 h by normothermic <i>ex vivo</i> sanguineous perfusion.
No full text<p><i>Panel A–C</i>: Concentration of LDH, alkaline phosphatase, and gamma-GT in bile samples at 2 h after reperfusion. <i>Panel D</i>: Comparison of biliary concentration of TBARS, a marker for oxidative stress and lipid peroxidation in bile ducts, at 2 h after graft reperfusion. There were no significant differences between the SCS preserved and HMP preserved livers.</p
Representative examples of histology of liver parenchyma of DCD liver grafts preserved by either 4 h of SCS or 4 h of oxygenated HMP followed by 2 h by normothermic <i>ex vivo</i> sanguineous perfusion.
No full text<p><i>Panel A</i>: H&E staining of a central biopsy of the liver parenchyma. <i>Panel B</i>: Caspase-3 immunohistochemistry of liver parenchyma showing less intense caspase-3 staining of hepatocytes, sinusoidal endothelial cells, and Kupffer cells in the HMP group, compared to the SCS group. Brown color indicates immunopositivity. Original magnification 200x.</p
- …
