Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis

Toronto Western Hospital, Toronto, Ontario, Canada
Liver International 07/2002; 22(3):228-34. DOI: 10.1046/j.0106-9543.2002.01595.x
Source: PubMed


Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by inflammatory destruction of small bile ducts. Primary sclerosing cholangitis (PSC) is a different, presumed autoimmune cholestatic liver disease where the bile ducts are also destroyed. In this study, apoptosis and portal triad inflammation in liver tissue from patients with PBC is examined and compared to that from patients with PSC and patients with normal liver.
Explanted liver tissue from patients with PBC and PSC and normal liver from patients with metastases to liver were examined. The liver samples were stained for apoptosis using the terminal deoxynucleotidyl triphosphate (TdT)-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay. The biliary epithelial cells (BEC) were then scored on the basis of their TUNEL stain and the degree of periductal inflammation.
In PBC, apoptosis of BEC, as detected by the TUNEL assay, was significantly increased in the presence of inflammation. Regardless of the presence or absence of inflammation, the small bile ducts in PBC liver tissue exhibited greater evidence of apoptosis than did similar ducts from PSC or control livers.
These findings suggest that in PBC, unlike PSC, the apoptosis of BEC in PBC is secondary to the invasion of inflammatory cells.

1 Read
  • Source
    • "In the present study, we focus on PBC, a disease that progressively evolves toward ductopenia with disappearance of interlobular bile ducts (Desmet et al. 1995,1998a,b; Kuroki et al. 1996; Boyer 1997; Nakanuma et al. 2000; Harada et al. 2001, Tinmouth et al. 2002; Alvaro et al. 2004; Kaplan and Gershwin 2005). Most studies demonstrated that apoptosis is a major mechanism of cholangiocyte death during PBC (Kuroki et al. 1996; Nakanuma et al. 2000; Harada et al. 2001, Tinmouth et al. 2002; Alvaro et al. 2004), and this was also confirmed by the present findings . In a previous study we showed that the progression toward ductopenia is caused by a relative predominance of cholangiocyte apoptosis toward proliferation that specifically occurs in the ductopenic PBC stage III and IV (Alvaro et al. 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We evaluated the IGF1 system in cholangiocytes of primay biliary cirrhosis (PBC) patients and investigated the relationships with apoptosis. Biopsies of PBC patients (n=32) and normal subjects (n=5) were investigated by immunohistochemistry for expression in cholangiocytes of IGF1, IGF1-R, pAKT, terminal deoxynucleotide transferase end labeling (TUNEL), Bax (proapoptotic protein), and Bcl2 (antiapoptotic protein). Whereas normal cholangiocytes were almost negative, cholangiocytes of PBC patients showed strong IHC staining for IGF1, IGF1-R, and pAKT, which increases from stage I to stage IV, where >70% of cholangiocytes were positive. Bax/Bcl2 ratio reached the highest value (4.6) in PBC stage III when apoptosis is maximal (24% TUNEL positivity), whereas it declines in stage IV (1.4) when only 7.8% cholangiocytes were TUNEL positive. In PBC stages III and IV, expression of IGF1, IGF1-R, and pAKT in cholangiocytes was directly correlated with the antiapoptotic Bcl2 and inversely correlated with proapoptotic Bax, Bax/Bcl2 ratio, and TUNEL positivity. In conclusion, cholangiocytes of PBC patients showed a marked increase in IGF1, IGF1-R, and pAKT expression involving most cholangiocytes surviving in the terminal ductopenic stage. This was associated and correlated with a balance of pro- and antiapoptotic proteins favoring survival rather than apoptosis, suggesting a major role of IGF1 system in promoting cholangiocyte survival.
    Journal of Histochemistry and Cytochemistry 05/2007; 55(4):327-34. DOI:10.1369/jhc.6R7125.2006 · 1.96 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Results: The apoptosis index of bile duct epithelial cells in the 38 BA children (51.74%±19.93%) was significantly higher than that of the 16 normal controls (12.34%±19.32%, P0.05). Comparison of the apoptosis index with the proliferation index of hepatocytes showed no statistical differences between the BA and the control groups. Within the BA group, the apoptosis index was significantly higher than the proliferation index in bile duct epithelial cells (P0.05). Similarly no statistical differences were observed between the indexes of apoptosis and proliferation of the bile duct epithelial cells in the controls (P>0.05). Conclusions: The occurrence and progressive development of BA are closely related to the imbalance between apoptosis and proliferation of intrahepatic bile duct epithelial cells. World J Pediatr 2006;3:212-216
  • [Show abstract] [Hide abstract]
    ABSTRACT: Primary biliary cirrhosis (PBC) can be defined by the triad of positive PBC-specific autoantibodies (antimitochondrial antibodies (AMA) in >95%), cholestatic liver function tests and diagnostic or compatible liver histology. PBC is generally considered to be an autoimmune disease. To be accepted as an autoimmune disease, tissue damaging lesions must be the consequence of either an antibody orT cell orchestrated response to one or more host components. Tissue damaging autoreactivity is a rarity requiring a complex series of events to occur. This complex induction requires multiple factors. In humans, as well as in animal models, there is a strong genetic component that always involves multiple genes. Non-genetic factors must also be involved and are assumed to include environmental, possibly dietary components and infectious agents. It is not clear if this autoimmune condition should be regarded as a single disease with a unique aetiology or a syndrome with a range of aetiological factors initiating similar pathogenic processes and culminating in the clinical picture that we recognise as PBC. How these factors lead to the development of primary biliary cirrhosis is not understood (Fig. 1) but important insights into the underlying molecular mechanisms have been made and parts of the intriguing puzzle are noe clearer. Figure. 1 Putative natural history of primary biliary cirrhosis indicating that the development of disease specific antimitochondrial and/or antinuclear ant ibodies is an early event requiring complex interaction of environmental factors with multiple host genes. Progression ofthe diseasemay be regarded as a pyramid in which some patients with autoreactiviry develop tissue damage, some of whom progress with time to symptomatic disease and a minority of these require an orrhotopic liver transplant (OLT) or die of liver failure. The ongoing role ofenvironmental factors and host genes in disease progression is not understood.
Show more