Environmental Factors in Primary Biliary Cirrhosis

Juran, Brian D.; Lazaridis, Konstantinos N.

doi:10.1055/s-0034-1383726

Cited by 67 publications

(62 citation statements)

References 110 publications

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“…14 Established environmental triggers include smoking, urinary tract infection, microorganisms such as the ubiquitous bacteria Novosphingobium aromaticivorans, and xenobiotics such as 2-octynoic acid, commonly used in artificial flavoring. 15 More than 90% of patients with primary biliary cirrhosis are women, and the mean age at diagnosis is 55 years. Diagnostic criteria are persistent (>6 months) biochemical evidence of cholestasis (ie, increased serum alkaline phosphatase levels more than twice the upper limit of normal), positive serum antimitochondrial antibodies (the disease hallmark), and a diagnostic liver biopsy.…”

Section: Primary Biliary Cirrhosismentioning

confidence: 99%

The Cholangiopathies

Lazaridis

LaRusso

2015

Mayo Clinic Proceedings

171

170

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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.

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Section: Primary Biliary Cirrhosismentioning

confidence: 99%

The Cholangiopathies

Lazaridis

LaRusso

2015

Mayo Clinic Proceedings

171

170

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“…Some bacteria such as Escherichia coli have been proposed to cross-react with mitochondrial proteins, and this may explain why recurrent urinary infections are more commonly seen in PBC patients than in healthy controls [17] . Furthermore, the role of xenobiotics in PBC is thought to be important; the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) can be replaced by a chemical xenobiotic mimic, which experimentally can be shown to be sufficient to break immunological self-tolerance [18] .…”

Section: Environmentmentioning

confidence: 99%

The Pathogenesis of Autoimmune Liver Disease

Arndtz

Hirschfield

2016

Dig Dis

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Background: Autoimmune liver disease (AILD) encompasses 3 main distinct clinical diseases: autoimmune hepatitis, primary biliary cholangitis (formally known as cirrhosis, PBC) and primary sclerosing cholangitis (PSC). These conditions are an important, yet under-appreciated cause of patient morbidity and mortality with ongoing unmet needs for further research and clinical advances. Key Messages: There is observational evidence for genetic predisposition, with all 3 conditions being more common in first degree relatives. AILD is associated with the presence of auto-antibodies and higher risks of other non-hepatic auto-immune conditions. Genetic risk association studies have identified HLA and non-HLA risk loci for the development of disease, with some HLA loci providing prognostic information. This re-enforces the concept that genetic predisposition to autoimmunity is important, likely in the context of environmental exposures. Such environmental triggers are unclear but relevant risks include smoking, drug and xenobiotic exposure as well as the complexities of the microbiome. There is evidence for a loss of immune tolerance to self-antigens playing a part in the development of these conditions. In particular the IL-2 and IL-12 regulatory pathways have been implicated in pre-disposing to an unopposed inflammatory response within the liver. Main immunological themes revolve around loss of immune tolerance leading to T-cell mediated injury, imbalance in the regulation of immune cells and defective immune response to foreign antigens. For PBC and PSC, there is then the added complexity of the consequences of cholestasis on hepato-biliary injury, immune regulation and liver fibrosis. Conclusions: Whilst specific disease causes and triggers are still lacking, AILD arises on the background of collective genetic and environmental risk, leading to chronic and abnormal hepato-biliary immune responses. Effective and more rational therapy will ultimately be developed when the multiple pathways to liver injury are better understood.

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“…Treatment with ursodeoxycholic acid (UDCA) is standard for PBC, and can improve liver functional tests and slow the progression of disease 4. PBC is thought to be triggered by environmental factors in genetically susceptible individuals 5. Genome-wide association and murine model studies have expanded our knowledge of PBC, but the pathogenesis of disease remains obscure 6–9…”

Section: Introductionmentioning

confidence: 99%