The Cholangiopathies

Abstract

Cholangiocytes (ie, the epithelial cells that line the bile ducts) are an important subset of liver cells. They are actively involved in the modification of bile volume and composition, are activated by interactions with endogenous and exogenous stimuli (eg, microorganisms, drugs), and participate in liver injury and repair. The term cholangiopathies refers to a category of chronic liver diseases that share a central target: the cholangiocyte. The cholangiopathies account for substantial morbidity and mortality given their progressive nature, the challenges associated with clinical management, and the lack of effective medical therapies. Thus, cholangiopathies usually result in end-stage liver disease requiring liver transplant to extend survival. Approximately 16% of all liver transplants performed in the United States between 1988 and 2014 were for cholangiopathies. For all these reasons, cholangiopathies are an economic burden on patients, their families, and society. This review offers a concise summary of the biology of cholangiocytes and describes a conceptual framework for development of the cholangiopathies. We also present the recent progress made in understanding the pathogenesis of and how this knowledge has influenced therapies for the 6 common cholangiopathies—primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis involving the liver, biliary atresia, polycystic liver disease, and cholangiocarcinoma—because the latest scientific progress in the field concerns these conditions. We performed a search of the literature in PubMed for published papers using the following terms: cholangiocytes, biliary epithelia, cholestasis, cholangiopathy, and biliary disease. Studies had to be published in the past 5 years (from June 1, 2009, through May 31, 2014), and non-English studies were excluded.

Current strategies to generate mature human induced pluripotent stem cells derived cholangiocytes and future applications

“…45 Such an effect is achieved clinically in the polycystic liver disease (PLD) cholangiopathy, characterized by cystic lesions due to benign cholangiocyte hyperproliferation, but with octreotide, a synthetic somatostatin analog. 3 Of worth noting, both disease models have shown valid applications of this iPSCs not only in the proving of pathophysiological interactions, but in biliary-specific pharmacological screening as well. In the close future, functional grafts all from iPSCs are also expected, potentially serving as treatment for diseases with no other cure available.…”

“…3 Their significance resides in the fact that they are the leading cause in up to a third of all liver transplants done on adults, with primary biliary cholangitis and primary sclerosing cholangitis being the principal leading cholangiopathies. In children, biliary atresia represents the main reason for liver transplant.…”

“…Primary biliary cholangitis and primary sclerosing cholangitis are similar cholangiopathies in the sense that both are characterized by chronic immune-mediated inflammation and destruction of the bile ducts, although their differences are evident including a female preponderance and distinctive antimitochondrial antibodies in the former, and male preponderance and probable HLA antigen-B locus related susceptibility in the latter. 3,76 As with the other cholangiopathies discussed, their etiology is still not clearly elucidated, in part because of the complex interaction between environment and genes. Current animal models have recurred mainly to genetic alterations, xenobiotic immunization, infectious agents, and chemical induction, though neither one can fully show all disease-specific characteristics.…”

“…Cholangitic diseases not only are responsible for significant morbidity and mortality, but also account for the majority of pediatric liver transplants and a significant percentage of young adult liver transplants; unfortunately, at present there are few models to accurately replicate them and seek new therapeutic goals. 3 With the rise of stem cell research, the new ideal cell source to generate cholangiocytes in vitro is being generated both for disease modeling and for potential curative alternatives as well, which involves pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) whose continuous proliferation and ability to differentiate into any of the three germ-layers is ideal for this purpose. Due to the lack of limitations that ESCs have shown, including immune rejection after transplantation and ethical concerns, iPSCs have appeared as an alternate and reproducible source of differentiated cells with therapeutic interest, making it even feasible to create patient-matched pluripotent stem cells.…”

Guest editor’s introduction: cholangiopathies: review and update

“…In its broadest and most generic sense, cholangiopathy is defined as any disease of the bile ducts. In contrast, cholangiopathy may be defined in more specific terms such as a category of chronic, progressive liver diseases that share a central target, the cholangiocyte, and lead to end-stage liver disease [1]. To further complicate matters, cholangiopathies include both neoplastic entities such as cholangiocarcinoma and nonneoplastic entities that range from the relatively common to the obscure.…”