title: Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis.
abstract: BACKGROUND
  The role of proinflammatory cytokines in the pathogenesis of portal hypertension is unclear.
  
  
  OBJECTIVE
  This study tests the hypothesis that tumour necrosis factor alpha (TNF-alpha) is an important mediator of the circulatory disturbances in alcoholic hepatitis (AH) and evaluates the acute and short term effect of a single infusion of the monoclonal chimeric anti-TNF-alpha antibody (Infliximab) on portal and systemic haemodynamics in 10 patients with severe biopsy proven AH. Cardiovascular haemodynamics, hepatic venous pressure gradient (HVPG), and hepatic and renal blood flow were measured before, 24 hours after Infliximab, and prior to hospital discharge.
  
  
  RESULTS
  Serum bilirubin (p<0.05), C reactive protein (p<0.001), and white cell count (p<0.01) were reduced significantly, as were plasma levels of interleukin (IL)-6 and IL-8 after treatment. Of the 10 patients, nine were alive at 28 days. Mean HVPG decreased significantly at 24 hours (23.4 (2.8) to 14.3 (1.9) mm Hg; p<0.001) with a sustained reduction prior to discharge (12.8 (1.9) mm Hg; p<0.001). Mean arterial pressure and systemic vascular resistance increased significantly (p<0.001and p<0.01, respectively), mirrored by a reduction in cardiac index (5.9 (0.5) to 4.7 (0.5) l/min/m(2); p<0.05) prior to discharge. Hepatic and renal blood flow also increased significantly (506.2 (42.9) to 646.3 (49.2) ml/min (p=0.001) and 424.3 (65.12) to 506.3 (85.7) ml/min (p=0.001), respectively) prior to discharge.
  
  
  CONCLUSIONS
  The results of this study illustrate that anti-TNF-alpha treatment in AH patients produces a highly significant, early, and sustained reduction in HVPG, possibly through a combination of a reduction in cardiac output and intrahepatic resistance. In addition, there was a reduction in hepatic inflammation and improved organ blood flow, suggesting an important role for TNF-alpha in mediating the circulatory disturbances in AH.
authors.affiliation: Liver Failure Group, Institute of Hepatology, London, UK.
authors.forename: R P
authors.initials: RP
authors.lastname: Mookerjee
authors.forename: S
authors.initials: S
authors.lastname: Sen
authors.forename: N A
authors.initials: NA
authors.lastname: Davies
authors.forename: S J
authors.initials: SJ
authors.lastname: Hodges
authors.forename: R
authors.initials: R
authors.lastname: Williams
authors.forename: R
authors.initials: R
authors.lastname: Jalan
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006519:Hepatitis, Alcoholic / Q000503:physiopathology*; D006801:Humans; D006975:Hypertension, Portal / Q000503:physiopathology; D000069285:Infliximab; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab