title: Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
abstract: OBJECTIVE
  We evaluated the gastrointestinal permeability and bacterial translocation in cirrhotic patients with portal hypertension (PHT) prior to and after non-selective betablocker (NSBB) treatment.
  
  
  METHODS
  Hepatic venous pressure gradient (HVPG) was measured prior to and under NSBB treatment. Gastroduodenal and intestinal permeability was assessed by the sucrose-lactulose-mannitol (SLM) test. Anti-gliadin and anti-endomysial antibodies were measured. Levels of LPS-binding protein (LBP) and interleukin-6 (IL-6) were quantified by ELISA, and NOD2 and toll-like receptor 2 (TLR2) polymorphisms were genotyped.
  
  
  RESULTS
  Fifty cirrhotics were included (72% male, 18% ascites, 60% alcoholic etiology). Abnormal gastroduodenal and intestinal permeability was found in 72% and 59% of patients, respectively. Patients with severe portal hypertension (HVPG ≥20 mm Hg; n=35) had increased markers of gastroduodenal/intestinal permeability (urine sucrose levels p=0.049; sucrose/mannitol ratios p=0.007; intestinal permeability indices p=0.002), and bacterial translocation (LBP p=0.002; IL-6 p=0.025) than patients with HVPG <20 mm Hg. A substantial portion of patients showed elevated levels of anti-gliadin antibodies (IgA: 60%, IgG: 34%) whereas no anti-endomysial antibodies were detected. A significant correlation of portal pressure (i.e., HVPG) with all markers of gastroduodenal/intestinal permeability and with LBP and IL-6 levels was observed. NOD2 and TLR2 risk variants were associated with abnormal intestinal permeability and elevated markers of bacterial translocation. At follow-up HVPG measurements under NSBB, we found an amelioration of gastroduodenal/intestinal permeability and a decrease of bacterial translocation (LBP - 16% p=0.018; IL-6 - 41% p<0.0001) levels, which was not limited to hemodynamic responders. Abnormal SLM test results and higher LBP/IL-6 levels were associated with a higher risk of variceal bleeding during follow-up but not with mortality.
  
  
  CONCLUSIONS
  Abnormal gastroduodenal/intestinal permeability, anti-gliadin antibodies, and bacterial translocation are common findings in cirrhotic patients and are correlated with the degree of portal hypertension. NSBB treatment ameliorates gastroduodenal/intestinal permeability and reduces bacterial translocation partially independent of their hemodynamic effects on portal pressure, which may contribute to a reduced risk of variceal bleeding.
authors.affiliation: Div. of Gastroenterology & Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Austria. thomas.reiberger@meduniwien.ac.at
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiberger
authors.forename: Arnulf
authors.initials: A
authors.lastname: Ferlitsch
authors.forename: Berit A
authors.initials: BA
authors.lastname: Payer
authors.forename: Mattias
authors.initials: M
authors.lastname: Mandorfer
authors.forename: Birgit B
authors.initials: BB
authors.lastname: Heinisch
authors.forename: Hubert
authors.initials: H
authors.lastname: Hayden
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.forename: Harald
authors.initials: H
authors.lastname: Vogelsang
mesh_terms: D000209:Acute-Phase Proteins; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D018988:Bacterial Translocation / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000097:blood*; D002463:Cell Membrane Permeability / Q000187:drug effects* / Q000502:physiology; D015897:Comorbidity; D005260:Female; D005500:Follow-Up Studies; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood*; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D053208:Kaplan-Meier Estimate; D007792:Lactulose / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism*; D008297:Male; D008353:Mannitol / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000097:blood*; D008875:Middle Aged; D013395:Sucrose / Q000378:metabolism; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D000319:Adrenergic beta-Antagonists; D002352:Carrier Proteins; D015850:Interleukin-6; D007792:Lactulose; D008353:Mannitol; D008562:Membrane Glycoproteins; D013395:Sucrose; D000099231:Lipopolysaccharide-Binding Protein