Altered intestinal tight junctions' expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability.
BACKGROUND
Increased intestinal permeability in cirrhosis exerts a pivotal role in the pathogenesis of spontaneous bacterial peritonitis and other complications of cirrhosis through promotion of systemic endotoxemia. This study was designed to investigate whether the expression of tight junction (TJ) proteins, which regulate gut paracellular permeability, is altered in the intestinal mucosa of patients with liver cirrhosis and study its potential association with the stage of liver disease and the development of systemic endotoxemia.


METHODS
Twenty-four patients with cirrhosis at a decompensated (n = 12, group A) or compensated condition (n = 12, group B) and 12 healthy controls (group C) were subjected to duodenal biopsy. The expression of the TJ proteins occludin and claudin-1 in the intestinal epithelium was evaluated by immunohistochemistry. Plasma endotoxin concentrations were also determined.


RESULTS
Patients with cirrhosis presented significantly higher serum endotoxin concentrations as compared to healthy controls (P < 0·001), whilst endotoxemia was higher in decompensated disease (P < 0·05 vs. compensated cirrhosis). Patients with decompensated and compensated cirrhosis presented significantly reduced expression of occludin and claudin-1 as compared to controls (P < 0·01, respectively). These alterations were significantly more pronounced in decompensated patients as compared to compensated (P < 0·05). Regarding occludin, in patients with cirrhosis, a specific pattern of expression in the intestinal epithelium was observed, with a gradually increasing loss of expression from crypt to tip of the villi. Occludin and claudin-1 expression were inversely correlated with Child-Pugh score (P < 0·001), the grade of oesophageal varices (P < 0·01) and endotoxin concentrations (P < 0·001).


CONCLUSIONS
This study demonstrates for the first time that human liver cirrhosis induces significant alterations in enterocytes' TJs. These changes might represent an important cellular mechanism for intestinal barrier dysfunction and hyperpermeability in patients with liver cirrhosis.
Department of Internal Medicine, University Hospital of Patras, Patras, Greece. sassim@upatras.gr
Stelios F
SF
Assimakopoulos
Athanassios C
AC
Tsamandas
Georgios I
GI
Tsiaoussis
Elli
E
Karatza
Christos
C
Triantos
Constantine E
CE
Vagianos
Iris
I
Spiliopoulou
Valeria
V
Kaltezioti
Aristidis
A
Charonis
Vassiliki N
VN
Nikolopoulou
Chrisoula D
CD
Scopa
Konstantinos C
KC
Thomopoulos
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D062445:Claudin-1; D020895:Enterocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D062793:Occludin; D010539:Permeability; D012720:Severity of Illness Index; D019108:Tight Junctions / Q000378:metabolism*
C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin