Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement

Abstract

Intestinal bacterial overgrowth and translocation, both common in cirrhosis with ascites, may lead to the activation of monocytes and lymphocytes, increased levels of proinflammatory cytokines, and enhanced synthesis of nitric oxide present in cirrhosis. Bacterial endotoxin promotes the synthesis of lipopolysaccharide (LPS)-binding protein (LBP), and forms a LPS-LBP complex that binds to CD14. This study was designed to evaluate LBP levels and their correlation to the immune response and the hemodynamic status in cirrhotic patients. Plasma LBP, endotoxin, soluble CD14 (sCD14), cytokines, renin, nitrites, and systemic vascular resistance were determined before and 4 weeks after norfloxacin or placebo in 102 cirrhotic patients and 30 controls. LBP was elevated in 42% of ascitic cirrhotic patients (15.7 ؎ 0.7 versus 6.06 ؎ 0.5 g/mL, P < .01). In 60% of high LBP patients, endotoxin was within normal range. Among ascitic patients, those with high LBP showed greater (P < .05) levels of sCD14, tumor necrosis factor ␣ (TNF-␣), interleukin 6 (IL-6), nitrites ؉ nitrates (NOx)/creatinine, and renin, and lower vascular resistance. In the cirrhotic patients with high LBP, norfloxacin normalized (P < .01) LBP (from 16.6 ؎ 0.5 to 5.82 ؎ 0.8 g/mL) and sCD14; reduced the level of cytokines, NOx/creatinine, and renin; and increased vascular resistance; but lacked effect in patients with normal LBP. Portal pressure was unchanged after norfloxacin in another group of 18 cirrhotic patients with high and 19 with normal LBP. In conclusion, the subset of ascitic cirrhotic patients with marked immune and hemodynamic derangement is identified by increased LBP levels. Amelioration of these abnormalities by norfloxacin suggests the involvement of enteric bacteria or their products in the triggering of the process. (HEPATOLOGY 2003;37:208-217.)

Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis

“…The finding of a marked increase in the number and activation of blood monocytes in these patients has been demonstrated previously in patients with alcoholic cirrhosis [6,12]. Furthermore, monocytes of cirrhotic patients exhibited a markedly increased capacity for spontaneous and LPS-stimulated proinflammatory cytokine expression [15,29].…”

“…Putative signals implicated in the monocyte and lymphocyte activation are the following: (i) first, bacterial translocation and endotoxaemia are known causes of monocyte activation [12,14,43]. In fact, this was our original hypothesis.…”

“…In fact, this was our original hypothesis. Patients with increased LBP, a validated marker of endotoxaemia [11][12][13][14], present elevated serum levels of monocyte-derived cytokines or a higher percentage of regulatory T cells. It could be speculated that intestinal decontamination, for example with quinolones, could modify these altered factors.…”

“…LPS increases the plasma levels of LPS binding protein (LBP), the principal plasma protein responsible for transporting LPS to immune effector cells [11]. It has been proposed that high serum LBP identifies a subset of cirrhotic patients with ascites characterized by the immune cells being activated to produce tumour necrosis factor (TNF)-a and other proinflammatory cytokines [12][13][14][15]. Moreover, raised levels of circulating LBP or proinflammatory cytokines have been implicated in the endothelial activation and haemodynamic derangement observed in cirrhosis [12,16].…”

“…It has been proposed that high serum LBP identifies a subset of cirrhotic patients with ascites characterized by the immune cells being activated to produce tumour necrosis factor (TNF)-a and other proinflammatory cytokines [12][13][14][15]. Moreover, raised levels of circulating LBP or proinflammatory cytokines have been implicated in the endothelial activation and haemodynamic derangement observed in cirrhosis [12,16]. To our knowledge, the plasma antigenic load and increased bacterial translocation have not been related previously to those immune abnormalities characteristic of an immunodepressed state in patients with liver cirrhosis.…”