LIVER

Tumour necrosis factor is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis

R P Mookerjee, S Sen, N A Davies, S J Hodges, R Williams, R Jalan

Liver Failure Group, Institute of Hepatology, London, UK

Correspondence to:
Correspondence to:
Dr R Jalan, Liver Failure Group, Institute of Hepatology, 69–75 Chenies Mews, London WC1E 6HX, UK;
r.jalan{at}ucl.ac.uk

Background: The role of proinflammatory cytokines in the pathogenesis of portal hypertension is unclear.

Aims and methods: This study tests the hypothesis that tumour necrosis factor (TNF-) 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- 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/m²; 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.

Conclusion: The results of this study illustrate that anti-TNF- 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- in mediating the circulatory disturbances in AH.

Keywords: tumour necrosis factor; inflammation; alcoholic hepatitis; haemodynamics; portal pressure

Abbreviations: AH, alcoholic hepatitis; ALT, alanine transaminase; CO, cardiac output; DF, discriminant function; FHVP, free hepatic venous pressure; HBF, hepatic blood flow; HSC, hepatic stellate cell; HVPG, hepatic venous pressure gradient; ICG, indocyanine green; IL, interleukin; MAP, mean arterial pressure; NO, nitric oxide; NOS, nitric oxide synthase; NOx, nitrate/nitrite; PAH, para-aminohippuric acid; RBF, renal blood flow; SIRS, systemic inflammatory response syndrome; SVR, systemic vascular resistance; TNF-, tumour necrosis factor ; WHVP, wedged hepatic venous pressure

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