Abstract
Primary biliary cirrhosis (PBC) is a cholestatic liver disease characterised by the autoimmune destruction of the small intrahepatic bile ducts. The disease has an unpredictable clinical course, but may progress to fibrosis and cirrhosis. Although medical treatment with urseodeoxycholic acid is largely successful, some patients may progress to liver failure requiring liver transplantation. PBC is characterised by the presence of disease specific anti-mitochondrial (AMA) antibodies, which are pathognomonic for PBC development. The disease demonstrates an overwhelming female preponderance and virtually all women with PBC present in middle age. The reasons for this are unknown; however several environmental and immunological factors may be involved. As the immune systems ages, it become less self tolerant, and mounts a weaker response to pathogens, possibly leading to cross reactivity or molecular mimicry. Some individuals display immunological changes which encourage the development of autoimmune disease. Risk factors implicated in PBC include recurrent urinary tract infection in females, as well as an increased prevalence of reproductive complications. These risk factors may work in concert with and possibly even accelerate, immune system ageing, contributing to PBC development. This review will examine the changes that occur in the immune system with ageing, paying particular attention to those changes which contribute to the development of autoimmune disease with increasing age. The review also discusses risk factors which may account for the increased female predominance of PBC, such as recurrent UTI and oestrogens.
Highlights
Primary Biliary Cirrhosis: a disease of Women Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of autoimmune origin, characterised by inflammatory destruction of the small intrahepatic bile ducts, and fibrosis which can progress to cirrhosis and subsequent liver failure [1,2,3]
-CD8+CD28- cells fail to display a regulatory response when incubated with IL-10 -Quantitative fluorescence in situ hybridisation has shown decreased telomere length in biliary epithelial cells (BEC) of primary biliary cirrhosis (PBC) patients - gammaH2AX-DNA-damage-foci detected in BEC -Apoptotic marker Bcl-2 in BEC -Increased apoptotic marker CD95 (Fas) on BEC -Unmodified pyruvate dehydrogenase complex (PDC)-E2 found in apoptotic blebs in BEC -Increased expression of senescence markers p16 and p21 in BEC -Decreased Ki67 expression in BEC, indicating decreased cellular proliferation -Decreased Bmi-1 expression in BEC -Increased LC3 expression in BEC, which correlated with increased autophagy
Concluding Remarks Primary biliary cirrhosis is an autoimmune disease with a striking predominance in middle-aged females
Summary
Primary Biliary Cirrhosis: a disease of Women Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of autoimmune origin, characterised by inflammatory destruction of the small intrahepatic bile ducts, and fibrosis which can progress to cirrhosis and subsequent liver failure [1,2,3]. PBC: A disease of the old PBC is overwhelmingly a disease of middle-aged and older females, and is virtually absent in the paediatric or adolescent population, several case reports indicate the development of PBC in children [23,36,37,38,39,40,41] On closer analysis, these cases rarely represent true (or confirmed) PBC, with several of these cases representing AMA positivity in the absence of clinical evidence of disease [41], or AMA positivity in the presence of liver disease other than PBC [23,38]. Histology in that case was not characteristic of PBC and the child was eventually diagnosed with IL-2-receptor- alpha deficiency, which resulted in defects of T regulatory cells [36] This is similar to another case report by Tsuda and colleagues, who noted AMA positivity in an 11 year old with IPEX syndrome, a congenital disorder of immune regulation [40]. Though the total T cell number does not appear to be significantly decreased with age, there is an alteration of T-cell receptor (TCR) signalling, as well as TCR reexpression, namely due to decreased CD28 expression
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