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We read with interest the study of Thalheimer et al (Gut 2005;54:556–63) in which they reviewed actual knowledge regarding the influence of infection on haemodynamics, variceal haemorrhage, heparinoid effects, liver damage, and other effects.
We agree with these assumptions and would like to add information not quoted in the paper that may help explain some of the immune abnormalities usually found in patients with advanced decompensated cirrhosis. As the authors detailed in their paper, our group has reported on the detection of bacterial DNA in a significant proportion of patients with cirrhosis and culture negative non-neutrocytic ascites,1 and has also shown that these fragments may last in blood for variable periods of time.2 In our opinion, the presence of bacterial DNA is not only representative in itself of the presence of bacteria (either viable or non-viable) in our patients, but induces similar immunological changes as endotoxin or viable bacteria. The question of whether bacterial DNA also induces haemodynamic disturbances is currently under investigation.
Bacterial DNA contains a series of CpG motifs that join toll-like receptor 9 and activates a series of intracellular mechanisms leading to the synthesis of proinflammatory cytokines.3 We therefore observed that peritoneal white cells obtained from ascitic fluid in patients with the presence of bacterial DNA showed a marked activation pattern when the intracellular presence of cytokines involved in a type 1 immune response by means of flow cytometry was analysed,4 and also an increased ability to secrete this type of cytokines when cultured.5 Importantly, white cells in culture also displayed a significantly higher ability to secrete nitric oxide than cells obtained from patients without the presence of bacterial DNA, and nitric oxide levels showed a direct and significant relationship with the inducible form of nitric oxide synthase,5 suggesting that in this setting, ascitic fluid nitric oxide synthesis is, at least in part, induced by this isoform.
Nitric oxide is a key agent in the pathogenesis of haemodynamic disturbances present in patients with advanced cirrhosis, and its levels are further increased in patients with hepatorenal syndrome.6 Ascitic fluid nitric oxide levels are independently related to the development of renal impairment in patients with spontaneous bacterial peritonitis.7
Thus the relation between the presence of bacterial DNA in blood and the ability to secrete proinflammatory cytokines and nitric oxide by cells of the immune system in patients with decompensated cirrhosis suggest that endotoxin and viable bacteria should not only be taken into account in the design of new research protocols, but also bacterial DNA, or similar molecules, as demonstration of the presence of bacteria in patients with advanced cirrhosis.
We are grateful to Such et al for their comments on our review. As we had outlined, the influence of bacterial infection on the pathophysiology of cirrhosis is indeed an important one and Such et al have contributed significantly to this topic.1–4 We were aware of their data, but unfortunately some of it could not be retained in the final version of our paper due to editorial restrictions. Nevertheless, we agree that the presence of bacterial DNA, in the absence of viable bacteria or endotoxaemia, might be an additional step in the sequence of events outlined in fig 2 of our review, maybe even preliminary to endotoxaemia.
Conflict of interest: None declared.
Conflict of interest: None declared.
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