Cirrhotics have increased levels of endotoxin.14–16
Similarly, plasma TNF-α and IL-6 levels were higher in cirrhotic patients with early bacterial infection than non-cirrhotic patients,17
with enhanced proinflammatory cytokine responses following LPS challenge in cirrhotic rats.18,19
Furthermore, ex vivo, LPS induced proinflammatory cytokine production by monocytes was more marked in cirrhotics than in controls.20
There is evidence that LPS induced cytokine production is mediated via upregulation of endothelin productions, as the use of a non-specific endothelin receptor, tezosentan, was associated with reduced cytokine production and less hepatic inflammation.19
More interestingly, activation of TLR-4 by LPS is related to upregulation of IL-8 and monocyte chemoattractant protein 1 expression in hepatic stellate cells, a process regulated by NFκB,21
associated with enhanced stellate cell survival, and potentially increased hepatic fibrosis. However, in a recent study by Riordan et al
, the relationship between endotoxins, enterotoxins, their TLRs, and cytokine production was re-evaluated.16
While levels of endotoxins were elevated in patients with cirrhosis of all aetiologies, TLR-4 (receptors for products of Gram negative organisms) expression was not increased nor was there a correlation between endotoxin levels and TNF-α levels in these patients.16
On the contrary, peripheral blood mononuclear cell expression of TLR-2 (receptors for products of Gram positive organisms) was significantly upregulated and correlated significantly with serum TNF-α levels. These findings suggest that Gram positive microbial components, but not endotoxin, as previously assumed, mainly contribute to increased circulating levels of this cytokine in cirrhosis.
The liver synthesises precursors (zymogens) of coagulation factors, and cirrhosis is associated with decreased synthesis of the factors VII, X, V, and II. Cirrhotic patients with sepsis present greater coagulation abnormalities than their counterparts without sepsis, reflecting more severe underlying liver disease.22
The consumption of coagulation factors by sepsis induced activation of extrinsic coagulation pathway leads to a further worsening of coagulation abnormalities.
The protein C zymogen, which is also synthesised by the liver, is reduced in cirrhosis, and further decreases with severe sepsis.22
Thus failure to achieve adequate levels of activated protein C may be a mechanism contributing to the sepsis severity. To our knowledge, plasma concentrations of activated protein C have not yet been measured in cirrhotic patients. However, in patients with fulminant liver failure, protein C activity is reduced.23
This may be one of the mechanisms underlying the susceptibility of these patients to sepsis.
NO production is usually increased in cirrhosis, the highest levels being found in patients with the worse hepatic function. With bacterial infection, LPS induces NOS, especially in the liver, leading to increased production of TNF-α and nitrates.18
Plasma nitrate and nitrite concentrations, metabolites of NO, are correlated with those of endotoxins, which are also increased, suggesting a causal relationship between endotoxin levels and NO production in cirrhosis.24
The release of various cytokines and endotoxins in sepsis further enhances NO production, which mediates some of the damaging effects of infection by reacting with superoxides to form reactive oxygen species. These species bind irreversibly to multiple components of the mitochondrial respiratory chain, affecting cell respiration and precipitating cell necrosis.25
Indeed, in an animal model of cirrhosis, there was increased formation of S-nitrosothiols, the circulating form of NO during endotoxaemia.26
S-nitrosothiols are potent inhibitors of platelet aggregation, and this may be one of the explanations why infection is associated with an increased risk of variceal bleeds in cirrhosis.27