4.2 Article Proceedings Paper

Pathogenesis of Primary Biliary Cirrhosis and Its Fatigue

期刊

DIGESTIVE DISEASES
卷 32, 期 5, 页码 615-625

出版社

KARGER
DOI: 10.1159/000360515

关键词

Primary biliary cirrhosis; Fatigue; Pathogenesis

资金

  1. Medical Research Council [G0500020, MC_PC_12039, MR/K501037/1, MR/L001489/1] Funding Source: Medline
  2. MRC [MC_PC_12039, MR/L001489/1, G0500020] Funding Source: UKRI
  3. National Institute for Health Research [NF-SI-0513-10091, IS-BRC-0211-10046] Funding Source: researchfish
  4. NIHR Newcastle Biomedical Research Centre [BH121729, BH134330, BH141402, BH137357] Funding Source: researchfish

向作者/读者索取更多资源

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterised by a breakdown of immune tolerance to mitochondrial and nuclear antigens, causing injury to the biliary epithelial cells (BEC) lining the small intrahepatic bile ducts. This leads to bile duct injury and the retention of hydrophobic bile acids which cause further BEC injury leading to a self-sustaining cycle of bile duct injury. Initially the BEC respond to injury via a homeostatic response including through proliferation. Ultimately they become senescent; an active process with accompanying release of inflammatory cytokines ('the senescent secretome') which contributes to the process of interface hepatitis which is a feature of high-risk and treatment-unresponsive disease. This model for pathogenesis of PBC has implications for potential therapy approaches in targeting both the 'upstream' immune injury and 'downstream' BEC response to the immune injury. Fatigue is the commonest reported symptom in PBC and has a negative impact on patients' perceived quality of life, often through social isolation. It is unrelated to the severity of liver disease and appears unresponsive to current therapies, including ursodeoxycholic acid and transplantation. Fatigue in PBC is complex, with numerous associated peripheral and CNS features. Initially, cholestasis causes degenerative CNS change affecting areas of the brain regulating autonomic dysfunction and sleep, and these changes lead directly to some manifestations of fatigue and the associated cognitive impairment. In addition to this, the anti-mitochondrial antibody has direct muscle level metabolic effects leading to over-utilisation of anaerobic metabolism. Autonomic dysfunction contributes to the impact of this metabolic change by limiting the capacity of the muscle to respond through increased proton/lactate efflux from cells and outflow from tissues. The model has a number of implications for potential therapy approaches. (C) 2014 S. Karger AG, Basel

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