Journal of Hepatology
Volume 30, Issue 6 , Pages 1160-1162, June 1999

Endotoxemia: an unnecessary but aggravating condition in portal hypertension?

  • Philippe Sogni

      Affiliations

    • Corresponding Author InformationPhilippe Sogni, Service d'Hépato-gastroentérologie, Hôpital Cochin, 27 rue du Faubourg St Jacques, 75014 Paris, France. Fax: 33 1 42 34 55 09.
    • Service d'Hépato-gastroenterologie, Hôpital Cochin and UPRES-A (Laboratoire de Recherche Chirurgicale et de Biologie Hépatiques), Université Paris V, Paris France
    • ,
  • Richard Moreau

      Affiliations

    • Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM, Hôpital Beaujon, Clichy, France
    • ,
  • Didier Lebrec

      Affiliations

    • Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM, Hôpital Beaujon, Clichy, France

Article Outline

 

Endotoxin corresponds to the lipopolysaccharide component of gram-negative bacteria cell walls. A certain degree of normal portal endotoxemia has been described as a result of enteric flora (1). However, under normal conditions endotoxin is rapidly cleared from the splanchnic circulation by both Kupffer cells and hepatocytes 2., 3.. In cirrhosis, however, systemic endotoxemia can occur more easily. Favorable local intestinal conditions have frequently been reported associated with cirrhosis, such as intestinal bacterial overgrowth, intestinal barrier dysfunction and bacterial translocation to mesenteric nodes 4., 5., 6., 7.. Bacteremia and spontaneous infections of ascites and the urinary tract are particularly frequent in these patients. The presence of portosystemic shunts associated with damage to hepatocytes and Kupffer cell function could also play a role in the more frequent occurrence of systemic endotoxemia 2., 3., 8.. Finally, general dysfunction of the host-defense system with abnormal cytokine response of polymorphonuclear cells to endotoxemia and infections have been also described in cirrhosis 9., 10., 11..

Since local and general conditions are favorable to systemic endotoxemia in cirrhosis, the question of the relationship between endotoxemia and abnormal systemic hemodynamics in portal hypertension has been raised. Portal hypertension with or without liver disease is associated with a hyperdynamic syndrome which maintains high portal pressure 12., 13.. This hyperdynamic syndrome corresponds to the association of systemic and splanchnic vasodilation, an increase in cardiac output and splanchnic blood flow, and an increase in plasma volume. The pathophysiology of this syndrome is still controversial, although the initiating event seems to be the vasodilation (14) in response to an overproduction of nitric oxide (NO) 15., 16., 17.. In 1991, Vallance & Moncada hypothesized that in cirrhosis, systemic and splanchnic vasodilation could be associated with endotoxemia and with the hyperproduction of proinflammatory cytokines, which in turn induce the expression of the inducible isoform of NO synthase (iNOS or NOS2) (18). Experimental results do not seem entirely to confirm this theory in portal hypertension without liver disease or in compensated cirrhosis. Under these conditions, endotoxemia is absent 5., 19., 20. or rare 4., 21., 22.. In this issue of the Journal of Hepatology, Chu et al. (23) report that acute or chronic administration of polymyxin B failed to improve the hyperdynamic syndrome in a model of portal hypertension without liver disease. This is important since polymyxin B acts as an antimicrobial agent by direct binding of the active moiety of lipopolysaccharide (24). In this study (23), shortterm (7-day) as well as long-term (16-day) treatment with polymyxin B did not improve systemic and splanchnic hemodynamics in portal hypertensive rats. With this protocol, the authors demonstrated that polymyxin B prevented the hypotensive effects of endotoxin which was administered in association with dactinomycin (23). These findings confirm the results of the previous study with oral neomycin treatment which failed to improve portal hypertension in portal hypertensive rats (19). In this latter study, neomycin was prescribed to modify enteric flora without directly affecting lipopolysaccharide (19). When we also look at the systemic and splanchnic arterial wall, the experimental results are similar. In fact, numerous experiments have now demonstrated that in steady-state conditions, there is either no induction of NOS2 in the aorta or superior mesenteric artery of portal hypertensive rats or induction is too limited to cause local NO overproduction and arterial hyporeactivity 25., 26., 27.. Furthermore, under these conditions, increased activity and/or expression of endothelial NOS3 have usually been described 25., 26., 28.. Among several factors, local variations in shear stress in relation to blood flow are the major physiological factor controlling short-term and long-term regulation of this NOS isoform (29).

High levels of tumor necrosis factor-alpha (TNFα) have been found in vivo in portal hypertension with or without liver disease 22., 30., 31., 32., 33.. These results differ from endotoxemia in similar conditions. Moreover, substances with an anti-TNFα activity such as thalidomide (34) or pentoxifylline (35) as well as anti-TNFα antibodies (32), have beneficial hemodynamic effects in portal hypertensive rats, even if the selectivity of substances such as pentoxifylline has not been confirmed (35), and a good correlation between TNFα activity and hemodynamic results has not been found 32., 35.. It has also been demonstrated that specific inhibition of protein tyrosine kinase which blocks TNFα effects and production has beneficial effects in cirrhotic rats with ascites (36). However, pro-inflammatory cytokines such as TNFα are responsible for the induction of NOS2, which is not observed in portal hypertensive rat arteries in steady-state conditions 25., 26., 27.. This discrepancy has not been fully clarified. The level of circulating TNFα and the site of production of this cytokine could be in question. It has been suggested that TNFα may play a role in the regulation of NOS3 expression without affecting NOS2 expression (37). Another important point to be evaluated is the degree of portal hypertension development in different models or during the evolution of liver failure. When portal hypertension was created in animal models, we could hypothesize that endotoxemia, high TNFα production and NOS2 induction occurred at the beginning and at the end of development. For example, in the first days after portal vein stenosis, high rates of bacterial translocation and circulating TNFα associated with arterial hyporeactivity to vasoconstrictors and aortic NOS2 induction have been described 5., 34., 35., 38.. On the other hand, when portal hypertension was associated with decompensated liver disease, we could expect endotoxemia to be more frequent, the immune system to be more defective, high levels of pro-inflammatory cytokines to be detected and NOS2 induction to occur 5., 22., 34., 38., 39., 40.. This is mainly expected during the clinically stressful conditions which occur in sepsis and hemorrhage 4., 41.. Under these conditions the role of endotoxemia and cytokines in the aggravation of the liver failure and the occurrence of complications such as ascites, renal failure or multiple organ dysfunction can be suspected 39., 41..

In conclusion, endotoxemia does not seem to be necessary for the maintenance of the hyperdynamic circulation in fully developed portal hypertension. However, endotoxemia and pro-inflammatory cytokines may play a pathophysiological role during certain clinically stressful conditions associated with liver failure. Under these conditions, endotoxemia and cytokines are important targets for the development of new specific treatments.

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PII: S0168-8278(99)80275-X

Journal of Hepatology
Volume 30, Issue 6 , Pages 1160-1162, June 1999

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