Search Article Keyword:  

PubMed Submission Abstarct PDF   Click Count: 5423 DownLoad Count: 2334 

ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2006 March 14;12(10):1493-1502

Gut flora and bacterial translocation in chronic liver disease

John Almeida, Sumedha Galhenage, Jennifer Yu, Jelica Kurtovic, Stephen M Riordan

John Almeida, Sumedha Galhenage, Jennifer Yu, Jelica Kurtovic, Stephen M Riordan, Gastrointestinal and Liver Unit, The Prince of Wales Hospital and University of New South Wales, Sydney, Australia

Correspondence to: Associate Professor Stephen M Riordan, Gastrointestinal and Liver Unit, The Prince of Wales Hospital, Barker Street, Randwick 2031, New South Wales, Australia.

Telephone: +61-2-93822753  Fax: +61-2-96633328

Received: 2005-06-09           Accepted: 2005-07-01



Increasing evidence suggests that derangement of gut flora is of substantial clinical relevance to patients with cirrhosis. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen, in particular, predispose to an increased potential for bacterial infection in this group. Recent studies suggest that, in addition to their role in the pathogenesis of overt infective episodes and the clinical consequences of sepsis, gut flora contributes to the pro-inflammatory state of cirrhosis even in the absence of overt infection. Furthermore, manipulation of gut flora to augment the intestinal content of lactic acid-type bacteria at the expense of other gut flora species with more pathogenic potential may favourably influence liver function in cirrhotic patients. Here we review current concepts of the various inter-relationships between gut flora, bacterial translocation, bacterial infection, pro-inflammatory cytokine production and liver function in this group.


© 2006 The WJG Press. All rights reserved.


Key words: Gut flora; Bacterial translocation; Cirrhosis


Almeida J, Galhenage S, Yu J, Kurtovic J, Riordan SM. Gut flora and bacterial translocation in chronic liver disease. World J Gastroenterol 2006; 12(10): 1493-1502



Disturbances of the microecology of the indigenous gut flora are prevalent in patients with chronic liver disease. Significantly increased viable counts of both Gram-positive and negative bacterial species have been recovered from faeces of cirrhotic patients[1]. A high prevalence of small intestinal bacterial overgrowth, in particular, has been demonstrated in this group[2-5]. This has been attributed, at least in part, to a decrease in small intestinal motility associated with increased adrenergic activity and portal hypertension[4-8]. Studies performed in experimental animals demonstrating important effects of gut flora on intestinal motility[9,10] suggest that the development of small intestinal bacterial overgrowth in the setting of intestinal stasis may further impair intestinal motility, thereby creating a self-perpetuating vicious cycle.

In addition to the range of symptoms and consequences of bacterial overgrowth per se[11], increasing evidences suggest that derangement of gut flora is of substantial clinical relevance to patients with cirrhosis. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen, in combination with failure of immune defence mechanisms to efficiently remove these translocating microorganisms, predispose to an increased potential for bacterial infection in this group[12]. Impaired immune defences include reduced opsonic activity due to low hepatic synthesis of complement, deranged function of macrophage Fc gamma receptors and reduced phagocytic and killing capacity of neutrophils[13-16]. Impairment of mucosal immunity may also be important. The high prevalence of associated malnutrition in cirrhotic patients[17] exacerbates the potential for infection to occur.

Recent studies suggest that, in addition to their role in the pathogenesis of overt infective episodes and the clinical consequences of sepsis, gut flora contributes to the pro-inflammatory state of cirrhosis even in the absence of overt infection[18]. Furthermore, manipulation of gut-flora using either a Gram-positive synbiotic (probiotic and fermentable fibre) regimen or fermentable fibre alone to augment the intestinal content of lactic acid-type bacteria at the expense of other gut flora species with more pathogenic potential may favourably influence liver function in cirrhotic patients[19]. Here we review current concepts of the various inter-relationships between gut flora, bacterial translocation, bacterial infection, pro-inflammatory cytokine production and liver function in this group.



Bacterial translocation is defined as the migration of bacteria from the intestinal lumen to mesenteric lymph nodes or other extra-intestinal sites[20]. Gram-negative members of the Enterobactereaceae family (such as Escherichia coli and Klebsiella spp), enterococci and other streptococci species are the most effective at bacterial translocation to mesenteric lymph nodes[21]. These bacterial flora, the organisms most commonly implicated in community-acquired infective episodes in patients with cirrhosis[22], can translocate across even histologically normal intestinal mucosa[21,23]. Certain strains of Escherichia coli are especially efficient at translocation, possibly as a result of a greater ability to adhere to the intestinal mucosal surface[24]. While obligate anaerobic bacterial flora outnumber aerobic species by more than 100-fold, these flora only rarely translocate from the intestinal lumen[21]. Conversely, anaerobic strains limit the growth of other species with higher translocation potential and their selective elimination has been shown to promote translocation of such aerobic flora[25].

Most data in support of the occurrence of increased bacterial translocation in cirrhosis come from studies performed in experimental animals, in which bacterial translocation was defined by the presence of positive bacteriological cultures for gut flora in surgically-removed mesenteric lymph nodes[26]. These studies demonstrate that the prevalence of bacterial translocation to mesenteric lymph nodes is around 40% in cirrhotic rats with ascites and around 80% in such animals with spontaneous bacterial peritonitis (SBP)[27-31]. The concept of bacterial translocation predisposing to infection in experimental cirrhosis is further supported by data showing that bacteria isolated from mesenteric lymph nodes are genetically identical to strains causing SBP in the same animal[32].

Clinical studies of bacterial translocation in cirrhosis have been limited by the lack of non-invasive methods to detect its presence. Nonetheless, available evidence suggests that increased translocation of gut flora does occur in cirrhotic patients. A high rate of positive mesenteric lymph node cultures for enteric bacteria (30.8%) has been reported in patients with Child-Pugh class C cirrhosis undergoing liver transplantation or hepatic resection, with the incidence in the order of five times higher in this group than in Child-Pugh class A or B patients[33]. In another study, almost 20% of cirrhotic patients were found to have positive mesenteric lymph node cultures following partial hepatectomy, with bacteria responsible for instances of post-operative infection the same as those recovered from mesenteric lymph nodes in most cases[34].

The presence of bacterial DNA in serum and ascitic fluid has recently been proposed as a relatively non-invasive surrogate marker of bacterial translocation in the clinical setting[35]. Using such molecular techniques, bacterial translocation may be present in as many as one third of cirrhotic patients with portal hypertension and culture-negative ascites, with Escherichia coli the most frequently identified bacterial species[35]. The clinical relevance of the presence of bacterial DNA in culture-negative ascites has been suggested by the finding of increased local levels of pro-inflammatory cytokines[36], although the validity of this approach and the full clinical relevance of a positive result remain to be firmly established. Increased serum levels of lipopolysaccharide-binding protein, a phenomenon attributed to translocation of bacteria from the gut to the circulation, have been documented in a proportion of cirrhotic patients without overt infection and to predict the later development of severe bacterial infection in this group[37].


Pathogenesis of bacterial translocation in cirrhosis

Intestinal bacterial overgrowth Intestinal bacterial overgrowth is a major factor promoting bacterial translocation[38-41] and available evidence suggests that factors that promote intestinal bacterial overgrowth in particular, such as impaired intestinal motility, are important in facilitating bacterial translocation in cirrhosis. In experimental animals with cirrhosis, strategies to increase the intestinal transit rate, such as treatment with propranolol or cisapride, have been shown to reduce bacterial overgrowth and bacterial translocation[38,40,41]. In the clinical setting, cisapride has been shown to increase small intestinal motility and reduce bacterial overgrowth in patients with cirrhosis, with a trend towards a lower incidence of infection in treated patients[3,42]

Structural changes in intestinal mucosa Most clinical studies performed to investigate structural changes of intestinal mucosa in patients with cirrhosis have focussed on the small intestine. Shorter and thicker microvilli have been described. Morphologically intact tight junctions, which join together the apical poles of enterocytes and represent the first line of mucosal defence against paracellular absorption, have been reported in a small cohort of clinically stable cirrhotic patients with no prior history of infection with gut-derived bacteria[43]. Whether tight junctions are also intact in cirrhotic patients with a history of such infection and those with elevated nitric oxide levels may be more relevant, since nitric oxide, which is discussed in more detail below in relation to the clinical course of SBP, has been shown to reversibly dilate tight junctions in cultured intestinal epithelial cells[44]. Notably, dilatation of the intercellular space below tight junctions, the second line of defence against paracellular absorption, has been documented in patients with cirrhosis[43]. Mucosal alterations attributed to oxidative stress, including disturbed enterocyte mitochondrial function and increased lipid peroxidation of brush border membranes, have been reported in experimental animal models of cirrhosis[45], although the relevance of these changes to the pathogenesis of bacterial translocation is uncertain. 

Thick-walled, dilated capillaries along with oedema of the lamina propria, fibromuscular proliferation, a reduced villus/crypt ratio and thickened muscularis mucosa in the small bowel have been found in cirrhotic patients with portal hypertension[46] and it has been proposed that an increased potential for bacterial translocation may exist in this setting[47]. However, in a study of cirrhotic patients with an elevated mean portal venous pressure in the order of 25 mm Hg undergoing liver transplantation, portal venous pressure was not significantly different in 8 cirrhotic patients with bacterial translocation and 71 with negative mesenteric lymph node culture results, implying that additional factors are required for bacterial translocation to occur in this group[33].

Luminal factors contributing to intestinal barrier function Other factors that contribute to the normal intestinal barrier against bacterial translocation (BT), including luminal factors, such as levels of bile acids, secretory immunoglobulin A, mucins, defensins, lysozyme and phopholipase A2, have been little studied in cirrhotic patients. Bile acids exert a trophic effect on intestinal mucosa[48] and inhibit intestinal bacterial overgrowth, especially of Gram-positive species[49]. An increased incidence of bacterial translocation in patients with obstructive jaundice has been reported[50]. However, whether the reduced intestinal luminal levels of bile acids that may be found in cirrhotic patients, as a consequence of reduced hepatic secretion and luminal deconjugation by overgrowth bacteria[12], contribute importantly to the potential for increased bacterial translocation in this group has not been established.

Intestinal immunity Little is known concerning the functional capacity of intestinal immunity in patients with cirrhosis and whether any disturbance of intestinal immune mechanisms contributes importantly to bacterial translocation, especially in the clinical setting. An increased number of intraepithelial lymphocytes with markedly impaired proliferative activity and capacity for production of interferon-γ have been reported in a murine model, with these changes correlating with increased bacterial translocation[51]. Whether this mechanism is important in the clinical situation is unknown. Notably, modest increases in small intestinal intraepithelial lymphocyte counts are found in patients with small intestinal bacterial overgrowth[52], raising the possibility that the increased levels found in cirrhotic animals may be explained on this basis. Whether the number or function of dendritic cells and other mononuclear cells in intestinal mucosa are deranged and contribute to the pathogenesis of bacterial translocation in patients with cirrhosis remains to be defined.


Anatomical site of bacterial translocation in cirrhosis

The anatomical site(s) from which bacterial translocation in cirrhosis occurs remains to be determined. Data in the non-cirrhotic setting suggest that the small intestine rather than the colon may be the major site of bacterial translocation. In particular, experimental studies involving inoculation of various regions of the gastrointestinal tract with equal quantities of Escherichia coli suggest that translocation occurs preferentially from the small bowel rather than the colon[53]. Similarly, in experimental animals with impaired intestinal motility, treatment with the pro-kinetic agent, cisapride, is associated with a reduced rate of bacterial translocation that parallels a reduction in jejunal but not caecal bacterial counts[3].


Intestinal permeability and its relation to bacterial translocation in cirrhosis

Functional studies have demonstrated that increased intestinal permeability, as reflected by dual sugar absorption tests or absorption of other test substances, occurs in patients with cirrhosis, especially in those with advanced liver disease[54-58]. Factors predisposing to this increased permeability in cirrhosis remain to be defined. In particular, any relationships with the structural changes of intestinal mucosa described above are uncertain. Enhanced intestinal permeability, likely via the paracellular route, has been reported in association with small intestinal bacterial overgrowth with Gram-negative gut flora in the non-cirrhotic setting[52], raising the possibility that this entity may at least contribute to the increased intestinal permeability in patients with cirrhosis. The relationship between intestinal permeability and the potential for bacterial translocation is uncertain, as increased permeability results have been found to correlate with a history of septic complications in some, but not all, reports.



Bacterial infection, especially with intestinal-type flora, is a common complication in patients with cirrhosis[59-62]. Spontaneous bacterial peritonitis (SBP), urinary tract infection, respiratory tract sepsis (pneumonia and spontaneous bacterial empyema) and bacteraemia are the most frequent infective complications occurring in this group. The incidence of infection with Gram-positive cocci, in particular, has increased in recent years, with such flora now the most frequent isolates in hospitalised cirrhotic patients with nosocomial infection, especially those admitted to intensive care units, presumably due to the high rate of invasive procedures, including placement of indwelling vascular and bladder catheters, performed in this group[62]. Recent data suggest that between 15% and 35% of cirrhotic patients admitted to hospital develop nosocomial bacterial infection, substantially higher than the rate of hospital-acquired infection in the order of 5% to 7% in the general hospital setting[63].

Complicating infection may have severe adverse clinical consequences in cirrhotic patients. The associated pro-inflammatory response exacerbates hepatic dysfunction, encephalopathy and the haemodynamic disturbances that underlie the development of portal hypertension and hepatorenal syndrome[60,64,65]. Increasing evidence suggests that bacterial infection is a trigger for variceal haemorrhage in patients with cirrhosis[66,67], possibly as a consequence of both activation of hepatic stellate cells, leading to increased intrahepatic vascular resistance, and prostacyclin-related inhibition of platelet aggregation[66]. Conversely, variceal haemorrhage predisposes cirrhotic patients to bacterial infection with gut-derived flora[68-73], setting up a vicious cycle between gastrointestinal bleeding and infection in this group. This is a phenomenon of substantial clinical importance, as complicating infection is independently associated with early mortality in bleeding cirrhotic patients[69,70,72]. Worsening coagulopathy, due to the consumption of clotting factors by the extrinsic coagulation pathway[74] and the production of endogenous heparinoids[75], occurs in patients with cirrhosis and complicating bacterial infection. Sepsis is a common cause of death in cirrhotic patients[60,61,76-78]. The mortality rate associated with bacterial infection in this group is more than twenty times higher than in the general population[79].



SBP, an infection of ascitic fluid typically with a single bacterial species in the absence of any other primary intra-abdominal source, is the most characteristic and serious infection occurring in patients with cirrhosis. Prospective studies suggest that SBP, including culture-negative and non-neutrocytic cases, is present in up to 23% of all cirrhotic patients with ascites admitted to hospital[80]. Gram-negative gut flora, especially Escherichia coli and Klebsiella species, are isolated in approximately 70% of culture-positive cases of community-acquired SBP. Aerobic Gram-positive bacteria belonging to Streptococcus and Staphylococcus spp constitute most of the remaining isolates. Pathogens belonging to Aeromonas, Plesimonas, Listeria, Salmonella and Neisseria spp are occasionally responsible. In keeping with their reduced potential for translocation from the intestine discussed above, obligate anaerobes are isolated in fewer than 5% of cases[81]. In hospitalised cirrhotic patients with nosocomial SBP, Gram-positive pathogens are predominant, accounting for over 70% of isolates, with methicillin-resistant Staphylococcus aureus accounting for nearly 25% of cases in one recent series[82].

The overall likelihood of a cirrhotic patient with ascites developing SBP at one year is in the order of 10%[80]. Clinical studies have identified several sub-groups of patients with cirrhotic ascites at particularly high risk for SBP. Over 70% of cases occur in those classified as Child-Pugh C[83]. An increased prevalence of SBP has been reported in patients with small intestinal bacterial overgrowth compared to their non-overgrowth counterparts, presumably due to the increased propensity for bacterial translocation[84]. Gastrointestinal haemorrhage is another important precipitant of SBP in this group. Bacteraemia and/or SBP, typically with Gram-negative enteric-type flora, develop within 48 hours of gastrointestinal haemorrhage in nearly 50% of Child-Pugh C patients with ascites[85]. The likelihood of SBP is related to the functional activity of Kupffer cells, which is impaired in patients with advanced liver disease[86]. However, the most powerful predictive factor identified in several series is an ascitic fluid total protein level 10 g/L, which reflects a low complement protein C3 concentration and, hence, opsonisation capacity. Patients with such low levels are at a six- to ten-fold increased risk of a first episode of SBP compared to cirrhotic counterparts with ascitic fluid total protein levels > 10 g/L[87,88].



Despite a trend towards earlier diagnosis and commencement of antibiotic treatment, along with overall improvements in the general medical care of cirrhotic patients, the in-hospital mortality rate associated with SBP remains 30-50%[80]. This is largely related to underlying hepatic decompensation and a high prevalence of complicating hepatorenal syndrome. The latter occurs in approximately 30% of patients with SBP, predominantly in those with pre-existing renal impairment, and is progressive despite cure of infection in half of these cases[89]. Ascitic levels of nitric oxide, which are significantly increased in cirrhotic patients with SBP and persist for over two weeks despite appropriate antibiotic treatment[90,91], independently predict renal impairment in this setting[92]. Use of nephrotoxic antibiotics adds to the risk of renal failure in this setting[93]. The development of renal failure is the most important predictor of in-hospital mortality associated with SBP. This is in the order of 50% in those with complicating renal failure compared to only 6% in those without[89]. Albumin infusion improves systemic haemodynamics, prevents renal failure and improves survival compared to antibiotic treatment alone in patients with SBP. Beneficial effects are related to reduction in arterial vasodilatation and improved cardiac function[94]. Other correlates of poor outcome include increased ascitic levels of the pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor-α (TNF-α)[95]. A recent report suggests a higher mortality rate in patients with nosocomial infection with staphylococcal species compared to that in patients with community-acquired SBP[82]. A trend towards a higher mortality rate when infection is with encapsulated strains of Escherichia coli associated with tissue invasiveness has also been reported[96].

The medium term prognosis for cirrhotic patients who have recovered from an episode of SBP is similarly poor, with a mortality rate at one year in the order of 30-80%[80]. Approximately 20% of patients who die within one year of an episode of SBP succumb to a further episode of spontaneous peritoneal infection, the remainder dying of causes, such as variceal haemorrhage, hepatorenal syndrome or hepatocellular carcinoma[97-99]. The risk of SBP recurrence within one year ranges from 40-70% and, as for an initial episode, is influenced mainly by the degree of underlying liver dysfunction and the ascitic fluid total protein level[83,98,99]. Survivors of an episode of SBP should be evaluated for liver transplantation in view of the high risk of recurrence and poor overall prognosis.



Antibiotic prophylaxis against SBP may be beneficial in three high risk groups of cirrhotic patients, namely those who have survived a previous episode, those with low ascitic fluid total protein levels and those presenting with gastrointestinal haemorrhage[67-71,73,100-103]. Most prophylaxis studies have aimed to reduce or eradicate aerobic Gram-negative bacilli from the intestine using norfloxacin, a poorly absorbed quinolone with activity against these flora. The importance of antibiotic prophylaxis in patients with cirrhosis presenting with variceal haemorrhage is increasingly recognised. Treatment with norfloxacin, 400 mg twice daily either orally or via a nasogastric tube for seven days commencing immediately after emergency endoscopy, was associated with a significantly reduced in-hospital incidence of bacteraemia and/or SBP, especially with aerobic Gram-negative flora, compared to patients receiving no prophylactic antibiotics (3% vs 17%)[68]. Ciprofloxacin, 500 mg twice daily either orally or via nasogastric tube for 7 d immediately following endoscopy, has similarly been shown to significantly reduce the incidences of bacteraemia, SBP and urinary tract infection compared to placebo (0% vs 23%, 3% vs 13% and 5% vs 18%, respectively)[103]. Implementation of treatment protocols that incorporate antibiotic prophylaxis led to a fall in post-variceal bacterial infection rates from 38% to 14% over the past two decades in a large French centre[69]. Antibiotic prophylaxis has been shown to reduce the incidence of not only bacterial infection, but also early re-bleeding following variceal haemorrhage, especially in Child-Pugh class C patients, those requiring ventilatory support and those initially treated with balloon tamponade[67,70,71,73].

Several cost analysis studies have shown that prophylactic treatment with norfloxacin in each of these high risk groups is cost effective, as a consequence of the reduced incidence of SBP and its associated resource utilisation[104-106]. Short-term prophylaxis with trimethoprim-sulphamethoxazole is also cost-effective, especially in those at high risk for SBP[106]. Most studies report a reduction in overall mortality associated with prophylactic antibiotic treatment, although a statistically significant survival benefit has been more difficult to demonstrate. This is not surprising, as the likelihood of dying as a result of progressive liver failure, variceal haemorrhage, hepatocellular carcinoma or other causes is unaffected by the use of prophylactic antibiotics. More recently, a meta-analysis of 13 randomized controlled trials has suggested that antibiotic prophylaxis of hospitalized cirrhotic in-patients is efficacious in reducing the relative risk of in-hospital death (relative risk of dying 0.70), irrespective of underlying risk factors[107]. In addition, a meta-analysis of 534 cirrhotic patients with gastrointestinal bleeding has shown that short-term antibiotic prophylaxis significantly increases short-term survival rates by a mean 9% in this setting[108].

A particular concern, especially with long-term antibiotic prophylaxis, is the potential for the development of infection with antibiotic-resistant bacteria. Initial studies of norfloxacin prophylaxis against SBP reported a low incidence of infection with quinolone-resistant Gram-negative bacterial species. More recent studies, however, suggest an increased prevalence of infection with such microorganisms. Over 20% of cases of SBP due to Escherichia coli were with a norfloxacin-resistant strain in a recent series from Spain[109], while 50% of cases of culture-positive SBP in patients receiving long-term norfloxacin prophylaxis and 16% of instances in patients not treated with this drug were caused by norfloxacin-resistant Gram-negative bacteria in another Spanish report[62]. A high rate of SBP due to trimethoprim-sulphamethoxazole-resistant Gram-negative flora in excess of 40% was also documented in norfloxacin-treated patients. An increased proportion of infections with Gram-positive bacterial species has also been reported in this setting, including instances of severe hospital-acquired staphylococcal infections[110]. An increased incidence of carriage of methicillin-resistant Staphylococcus aureus has also been documented in cirrhotic patients treated with norfloxacin prophylaxis[111].

Such experiences highlight the need for non-antibiotic-based strategies to prevent intestinal bacterial overgrowth, bacterial translocation and SBP in patients with cirrhosis. As alluded to earlier, a six-month trial of the pro-motility agent, cisapride, was associated with improved small intestinal motility, reversal of bacterial overgrowth and a tendency towards a reduced incidence of infection with gut-derived flora in a cohort of cirrhotic patients[3,42]. Unfortunately, cisapride has been withdrawn from use in some countries because of potential for cardiac arrhythmia. Alternatively, treatment with either symbiotics (in the form of four species of lactic acid bacteria and fermentable fibre) or fermentable fibre alone has recently been shown to significantly reduce viable counts of potentially pathogenic Gram-positive and Gram-negative gut flora in patients with cirrhosis[19]. In another study, a lower rate of post-operative bacterial infection was documented in liver transplant recipients treated with an early enteral supply of a synbiotic regimen that included Lactobacillus plantarum and fermentable fibre than in patients receiving selective intestinal decontamination[112]. A follow-up randomised double-blind trial in liver transplant recipients showed that early enteral nutrition supplemented with a mixture of lactic acid bacteria and fermentable fibre significantly reduced the incidence of post-operative bacterial infection compared to supplementation with fermentable fibre alone[113]. Based on these reports, the possible use of synbiotics for prophylaxis against SBP in cirrhotic patients warrants investigation. Conversely, probiotic treatment with a lactobacillus strain without additional fermentable fibre was ineffective in preventing bacterial translocation and SBP in rats with experimental cirrhosis, despite successful intestinal colonisation[114].



Pro-inflammatory cytokines, such as TNF-α, have been shown to be critically involved in the development and/or exacerbation of liver injury in animal models[115,116]. Activation of macrophages by endotoxin, a cell wall component of Gram-negative bacteria, plays a key role in the over-production of TNF- α and liver injury in these settings[117,118]. Increased translocation from the gut lumen and reduced hepatic clearance have each been proposed to predispose to endotoxaemia in this situation[119,120]. In the clinical setting, increased circulating levels of both endotoxin and pro-inflammatory cytokines have been documented in patients with chronic liver disease, even in the absence of overt infection[121-126]. Based on experiences in experimental animals, it has, until recently, been assumed that endotoxaemia causes the raised pro-inflammatory cytokine levels in this group[122,127-129]. However, a significant correlation between circulating endotoxin and pro-inflammatory cytokine levels has generally not been shown[18,121,122,125,127], raising the possibility that, unlike in animal models, stimuli other than endotoxin may be important.

Recent analyses of the expression of Toll-like receptors (TLRs) in patients with cirrhosis have helped to clarify this issue. These receptors are the human homologues of the Drosophila Toll protein and comprise a family of at least ten transmembrane receptor proteins, the intracellular domains of which show distinct sequence homology with the interleukin-1 receptor. TLRs play a critical role in the induction of innate immunity to microbial pathogens via recognition of conserved molecular patterns. In particular, it is known that TLR4, in association with CD14 and MD-2, is responsible for signal transduction leading to TNF-α production in response to endotoxin. In contrast, TLR2 is required for signaling in response to a number of Gram-positive microbial stimuli, including whole bacteria and cell wall components, such as peptidoglycan and lipoteichoic acid[130-132]. Indeed, significantly increased expression on peripheral blood mononuclear cells (PBMCs) of TLR2 but not of TLR4 has recently been demonstrated in patients with cirrhosis but no overt infection[18]. Furthermore, PBMC expression of TLR2 but not that of TLR4 was shown to correlate significantly with circulating levels of both TNF-α and anti-inflammatory soluble TNF receptors[18]. These novel findings suggest that signaling via TLR2 but not TLR4 contributes to the increased circulating levels of TNF-α levels found in cirrhosis and imply, contrary to previous assumptions, an important role for Gram-positive microbial stimuli rather than endotoxin in this process. This contention is supported by in vitro PBMC stimulation data consistent with presensitisation by Gram-positive microbial stimuli but not endotoxin in vivo. In addition, supplementation of cirrhotic patients with a synbiotic regimen including four Gram-positive gut flora and fermentable fibre led to further increases in PBMC expression of TLR2 and circulating TNF-α levels in most cases, suggesting that Gram-positive stimuli derived from the gut, in particular, may be important in promoting the increased circulating levels of both pro-inflammatory and anti-inflammatory TNF-related molecules found in patients with cirrhosis[18].



Reversal of minimal hepatic encephalopathy has been reported in 50% of predominantly Child-Pugh class B or C cirrhotic patients treated with a lactic acid bacteria-based synbiotic regimen for 30 d, an efficacy comparable to that of treatment with lactulose[19]. In addition, the Child-Pugh class improves in nearly 50% of initially Child-Pugh class B or C synbiotic-treated patients, a proportion significantly higher than that in placebo-treated counterparts (8%). Treatment is associated with a significant increase in the faecal content of lactobacilli at the expense of potentially pathogenic Gram-positive and negative bacterial species. Bacterial overgrowth is also reversed and improvements in minimal hepatic encephalopathy and the Child-Pugh class occurs in 50% and 29%, respectively, of cirrhotic patients treated with fermentable fibre alone. Both in synbiotic- and fermentable fibre alone-treated patients, improvement in the Child-Pugh class occurs as a result of significant improvements in the serum bilirubin and albumin levels and in prothrombin activity. Significantly reduced hepatic necro-inflammatory activity, as reflected by serial ALT levels, is documented in both groups. Improvement in clearance of indocyanine green has also been reported in cirrhotic patients treated with synbiotics[133]. These findings are in keeping with reported experiences in experimental animals' suggesting that oral supplementation with Gram-positive probiotics can protect against hepatocellular damage. In particular, rats fed lactobacilli have been shown to be protected against alcohol-induced liver damage[134], while studies of probiotic use in a murine model of non-alcoholic fatty liver disease have found reductions in the intra-hepatic expression of various molecular markers of inflammation, including nuclear factor kappa-B and TNF-α[135,136].



1     Floch MH, Katz J, Conn HO. Qualitative and quantitative relationships of the fecal flora in cirrhotic patients with portal systemic encephalopathy and following portacaval anastomosis. Gastroenterology 1970; 59: 70-75   PubMed

2     Bauer TM, Schwacha H, Steinbruckner B, Brinkmann FE, Ditzen AK, Aponte JJ, Pelz K, Berger D, Kist M, Blum HE. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxaemia. Am J Gastroenterol 2002; 97: 2364-2370   PubMed

3    Pardo A, Bartoli R, Lorenzo-Zuniga V, Planas R, Vinado B, Riba J, Cabre E, Santos J, Luque T, Ausina V, Gassull MA. Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis. Hepatology 2000; 31: 858-863   PubMed

4    Bauer TM, Steinbruckner B, Brinkmann FE, Ditzen AK, Schwacha H, Aponte JJ, Pelz K, Kist M, Blum HE. Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol 2001; 96: 2962-2967   PubMed

5    Chang CS, Chen GH, Lien HC, Yeh HZ. Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1998; 28: 1187-1190   PubMed

6    Chesta J, Defilippi C, Defilippi C. Abnormalities in proximal small bowel motility in patients with cirrhosis. Hepatology 1993; 17: 828-832   PubMed

7    Stewart JJ, Battarbee HD, Farrar GE, Betzing KW. Intestinal myoelectrical activity and transit time in chronic portal hypertension. Am J Physiol 1992; 263: G474-G479   PubMed

8    Sadik R, Abrahamsson H, Bjornsson E, Gunnarsdottir A, Stotzer PO. Etiology of portal hypertension may influence gastrointestinal transit. Scand J Gastroenterol 2003; 38: 1039-1044   PubMed

9    Husebye E, Hellstrom PM, Sundler F, Chen J, Midtvedt T. Influence of microbial species on small intestinal myoelectric activity and transit in germ-free rats. Am J Physiol Gastrointest Liver Physiol 2001; 280: G368-G380   PubMed

10   Liu MT, Rothstein JD, Gershon MD, Kirchgessner AL. Glutamatergic enteric neurons. J Neurosci 1997; 17: 4764-4784   PubMed

11   Riordan SM. A critical appraisal of diagnostic tests for small intestinal bacterial overgrowth. Gastroenterology International 1996; 9: 110-118   PubMed

12   Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005; 41: 422-433   PubMed

13   Gomez F, Ruiz P, Schreiber AD. Impaired function of macrophage Fc gamma receptors and bacterial infection in alcoholic cirrhosis. N Engl J Med 1994; 331: 1122-1128   PubMed

14   Hassner A, Kletter Y, Jedvab M, Aronson M, Shibolet S. Impaired monocyte function in liver cirrhosis. Lancet 1979; 1: 329-330   PubMed

15   Ono Y, Watanabe T, Matsumoto K, Ito T, Kunii O, Goldstein E. Opsonophagocytic dysfunction in patients with liver cirrhosis and low responses to tumor necrosis factor-alpha and lipopolysaccharide in patients’ blood. J Infect Chemother 2004; 10: 200-207   PubMed

16   Rajkovic IA, Williams R. Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Hepatology 1986; 6: 252-262   PubMed

17   Riordan SM, Williams R. Nutrition and liver transplantation. J Hepatol 1999; 31; 955-962   PubMed

18   Riordan SM, Skinner N, Nagree A, McCallum H, McIver CJ, Kurtovic J, Hamilton JA, Bengmark S, Williams R, Visvanathan K. Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. Hepatology 2003; 37: 1154-1164   PubMed

19   Liu Q, Duan ZP, Ha da K, Bengmark S, Kurtovic J, Riordan SM. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004; 39: 1441-1449   PubMed

20   Berg RD, Garlington AW. Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun 1979; 23: 403-411   PubMed

21   Steffen EK, Berg RD, Deitch EA. Comparison of translocation rates of various indigenous bacteria from the gastrointestinal tract to the mesenteric lymph node. J Infect Dis 1988; 157: 1032-1038   PubMed

22   Garcia-Tsao G. Spontaneous bacterial peritonitis. Gastroenterol Clin North Am 1992; 21: 257-275   PubMed

23   Wells CL. Colonization and translocation of intestinal bacterial flora. Transplant Proc 1996; 28: 2653-2656   PubMed

24   Ljungdahl M, Lundholm M, Katouli M, Rasmussen I, Engstrand L, Haglund U. Bacterial translocation in experimental shock is dependent on the strains in the intestinal flora. Scand J Gastroenterol 2000; 35: 389-397   PubMed

25   Wells CL, Maddaus MA, Reynolds CM, Jechorek RP, Simmons RL. Role of anaerobic flora in the translocation of aerobic and facultatively anaerobic intestinal bacteria. Infect Immun 1987; 55: 2689-2694   PubMed

26   Garcia-Tsao G, Wiest R. Gut microflora in the pathogenesis of the complications of cirrhosis. Best Pract Res Clin Gastroenterol 2004; 18: 353-372   PubMed

27   Llovet JM, Bartoli R, Planas R, Cabre E, Jimenez M, Urban A, Ojanguren I, Arnal J, Gassull MA. Bacterial translocation in cirrhotic rats. Its role in the development of spontaneous bacterial peritonitis. Gut 1994; 35: 1648-1652   PubMed

28   Runyon BA, Squier S, Borzio M. Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis. J Hepatol 1994; 21: 792-796   PubMed

29   Guarner C, Runyon BA, Young S, Heck M, Sheikh MY. Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J Hepatol 1997; 26: 1372-1378   PubMed

30   Garcia-Tsao G, Lee FY, Barden GE, Cartun R, West AB. Bacterial translocation to mesenteric lymph nodes is increased in cirrhotic rats with ascites. Gastroenterology 1995; 108: 1835-1841   PubMed

31   Runyon BA, Borzio M, Young S, Squier SU, Guarner C, Runyon MA. Effect of selective bowel decontamination with norfloxacin on spontaneous bacterial peritonitis, translocation, and survival in an animal model of cirrhosis. Hepatology 1995; 21: 1719-1724   PubMed

32   Llovet JM, Bartoli R, March F, Planas R, Vinado B, Cabre E, Arnal J, Coll P, Ausina V, Gassull MA. Translocated intestinal bacteria cause spontaneous bacterial peritonitis in cirrhotic rats: molecular epidemiologic evidence. J Hepatol 1998; 28: 307-313   PubMed

33   Cirera I, Bauer TM, Navasa M, Vila J, Grande L, Taura P, Fuster J, Garcia-Valdecasas JC, Lacy A, Suarez MJ, Rimola A, Rodes J. Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol 2001; 34: 32-37   PubMed

34   Yeh DC, Wu CC, Ho WM, Cheng SB, Lu IY, Liu TJ, Peng FK. Bacterial translocation after cirrhotic liver resection: a clinical investigation of 181 patients. J Surg Res 2003; 111: 209-214   PubMed

35   Such J, Frances R, Munoz C, Zapater P, Casellas JA, Cifuentes A, Rodriguez-Valera F, Pascual S, Sola-Vera J, Carnicer F, Uceda F, Palazon JM, Perez-Mateo M. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology 2002; 36: 135-141   PubMed

36   Frances R, Munoz C, Zapater P, Uceda F, Gascon I, Pascual S, Perez-Mateo M, Such J. Bacterial DNA activates cell mediated immune response and nitric oxide overproduction in peritoneal macrophages from patients with cirrhosis and ascites. Gut 2004; 53: 860-864   PubMed

37   Albillos A, de-la-Hera A, Alvarez-Mon M. Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites. Lancet 2004; 363: 1608-1610   PubMed

38   Zhang SC, Wang W, Ren WY, Zhou K, He BM, Zhu WN. Effects of cisapride on intestinal bacterial and endotoxin translocation in cirrhotic rats. Zhonghua Ganzangbing Zazhi 2003; 11: 539-541   PubMed

39   Zhang S, Wang W, Ren W, Dai Q, He B, Zhou K. Effects of lactulose on intestinal endotoxin and bacterial translocation in cirrhotic rats. Chin Med J (Engl) 2003; 116: 767-771   PubMed

40   Zhang SC, Wang W, Ren WY, He BM, Zhou K, Zhu WN. Effect of cisapride on intestinal bacterial and endotoxin translocation in cirrhosis. World J Gastroenterol 2003; 9: 534-538   PubMed

41   Perez-Paramo M, Munoz J, Albillos A, Freile I, Portero F, Santos M, Ortiz-Berrocal J. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 2000; 31: 43-48   PubMed

42   Madrid AM, Hurtado C, Venegas M, Cumsille F, Defilippi C. Long-Term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am J Gastroenterol 2001; 96: 1251-1255   PubMed

43   Such J, Guardiola JV, de Juan J, Casellas JA, Pascual S, Aparicio JR, Sola-Vera J, Perez-Mateo M. Ultrastructural characteristics of distal duodenum mucosa in patients with cirrhosis. Eur J Gastroenterol Hepatol 2002; 14: 371-376   PubMed

44   Salzman AL, Menconi MJ, Unno N, Ezzell RM, Casey DM, Gonzalez PK, Fink MP. Nitric oxide dilates tight junctions and depletes ATP in cultured Caco-2BBe intestinal epithelial monolayers. Am J Physiol 1995; 268: G361-G373   PubMed

45   Ramachandran A, Prabhu R, Thomas S, Reddy JB, Pulimood A, Balasubramanian KA. Intestinal mucosal alterations in experimental cirrhosis in the rat: role of oxygen free radicals. Hepatology 2002; 35: 622-629   PubMed

46   Misra V, Misra SP, Dwivedi M, Gupta SC. Histomorphometric study of portal hypertensive enteropathy. Am J Clin Pathol 1997; 108: 652-657   PubMed

47   Hashimoto N, Ohyanagi H. Effect of acute portal hypertension on gut mucosa. Hepatogastroenterology 2002; 49: 1567-1570   PubMed

48   Levi AC, Borghi F, Petrino R, Bargoni A, Fronticelli CM, Gentilli S. Modifications of the trophism of intestinal mucosa after intestinal and bilio-pancreatic diversion in the rat. Ital J Gastroenterol 1991; 23: 202-207   PubMed

49   Simon GL, Gorbach SL. Intestinal flora in health and disease. Gastroenterology 1984; 86: 174-193   PubMed

50   Sakrak O, Akpinar M, Bedirli A, Akyurek N, Aritas Y. Short and long-term effects of bacterial translocation due to obstructive jaundice on liver damage. Hepatogastroenterology 2003; 50: 1542-1546   PubMed

51   Inamura T, Miura S, Tsuzuki Y, Hara Y, Hokari R, Ogawa T, Teramoto K, Watanabe C, Kobayashi H, Nagata H. Ishii H. Alteration of intestinal intraepithelial lymphocytes and increased bacterial translocation in a murine model of cirrhosis. Immunol Lett 2003; 90: 3-11   PubMed

52   Riordan SM, McIver CJ, Thomas DH, Duncombe VM, Bolin TD, Thomas MC. Luminal bacteria and small-intestinal permeability. Scand J Gastroenterol 1997; 32: 556-563   PubMed

53   Koh IH, Guatelli R, Montero EF, Keller R, Silva MH, Goldenberg S, Silva RM. Where is the site of bacterial translocation--small or large bowel? Transplant Proc 1996; 28: 2661   PubMed

54   Zuckerman MJ, Menzies IS, Ho H, Gregory GG, Casner NA, Crane RS, Hernandez JA. Assessment of intestinal permeability and absorption in cirrhotic patients with ascites using combined sugar probes. Dig Dis Sci 2004; 49: 621-626   PubMed

55   Pascual S, Such J, Esteban A, Zapater P, Casellas JA, Aparicio JR, Girona E, Gutierrez A, Carnices F, Palazon JM, Sola-Vera J, Perez-Mateo M. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology 2003; 50: 1482-1486   PubMed

56   Di Leo V, Venturi C, Baragiotta A, Martines D, Floreani A. Gastroduodenal and intestinal permeability in primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2003; 15: 967-973   PubMed

57   Campillo B, Pernet P, Bories PN, Richardet JP, Devanlay M, Aussel C. Intestinal permeability in liver cirrhosis: relationship with severe septic complications. Eur J Gastroenterol Hepatol 1999; 11: 755-759   PubMed

58   Ersoz G, Aydin A, Erdem S, Yuksel D, Akarca U, Kumanlioglu K. Intestinal permeability in liver cirrhosis. Eur J Gastroenterol Hepatol 1999; 11: 409-412   PubMed

59   Planas R, Balleste B, Alvarez MA, Rivera M, Montoliu S, Galeras JA, Santos J, Coll S, Morillas RM, Sola R. Natural history of decompensated hepatitis C virus-related cirrhosis. A study of 200 patients. J Hepatol 2004; 40: 823-830   PubMed

60   Strauss E, Gomes de Sa Ribeiro Mde F. Bacterial infections associated with hepatic encephalopathy: prevalence and outcome. Ann Hepatol 2003; 2: 41-45   PubMed

61   Yoneyama K, Miyagishi K, Kiuchi Y, Shibata M, Mitamura K. Risk factors for infections in cirrhotic patients with and without hepatocellular carcinoma. J Gastroenterol 2002; 37: 1028-1034   PubMed

62   Fernandez J, Navasa M, Gomez J, Colmenero J, Vila J, Arroyo V, Rodes J. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002; 35: 140-148   PubMed

63   Navasa M, Fernandez J, Rodes J. Bacterial infections in liver cirrhosis. Ital J Gastroenterol Hepatol 1999; 31: 616-625   PubMed

64   Riordan SM, Williams R. Mechanisms of hepatocyte injury, multiorgan failure, and prognostic criteria in acute liver failure. Semin Liver Dis 2003; 23: 203-215   PubMed

65   Kantrow SP, Taylor DE, Carraway MS, Piantadosi CA. Oxidative metabolism in rat hepatocytes and mitochondria during sepsis. Arch Biochem Biophys 1997; 345: 278-288   PubMed

66   Goulis J, Patch D, Burroughs AK. Bacterial infection in the pathogenesis of variceal bleeding. Lancet 1999; 353: 139-142   PubMed

67   Soriano G, Guarner C, Tomas A, Villanueva C, Torras X, Gonzalez D, Sainz S, Anguera A, Cusso X, Balanzo J. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 1992; 103: 1267-1272   PubMed

68   Carbonell N, Pauwels A, Serfaty L, Fourdan O, Levy VG, Poupon R. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 2004; 40: 652-659   PubMed

69   Pohl J, Pollmann K, Sauer P, Ring A, Stremmel W, Schlenker T. Antibiotic prophylaxis after variceal hemorrhage reduces incidence of early rebleeding. Hepatogastroenterology 2004; 51: 541-546   PubMed

70   Zhao C, Chen SB, Zhou JP, Xiao W, Fan HG, Wu XW, Feng GX, He WX. Prognosis of hepatic cirrhosis patients with esophageal or gastric variceal hemorrhage: multivariate analysis. Hepatobiliary Pancreat Dis Int 2002; 1: 416-419   PubMed

71   Deschenes M, Villeneuve JP. Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis. Am J Gastroenterol 1999; 94: 2193-2197   PubMed

72   Schachter M. Heredofamilial tremors and sporadic “essential” tremors in the child and adolescent. Pediatrie 1975; 30: 401-411   PubMed

73   Goulis J, Armonis A, Patch D, Sabin C, Greenslade L, Burroughs AK. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1998; 27: 1207-1212   PubMed

74   Plessier A, Denninger MH, Consigny Y, Pessione F, Francoz C, Durand F, Francque S, Bezeaud A, Chauvelot-Moachon L, Lebrec D, Valla DC, Moreau R. Coagulation disorders in patients with cirrhosis and severe sepsis. Liver Int 2003; 23: 440-448   PubMed

75   Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK. Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study. J Hepatol 2002; 37: 463-470   PubMed

76   Jarcuska P, Veseliny E, Orolin M, Takacova V, Hancova M. Infectious complications in patients with liver cirrhosis. Klin Mikrobiol Infekc Lek 2004; 10: 176-180   PubMed

77   Brann OS. Infectious complications of cirrhosis. Curr Gastroenterol Rep 2001; 3: 285-292   PubMed

78   Borzio M, Salerno F, Piantoni L, Cazzaniga M, Angeli P, Bissoli F, Boccia S, Colloredo-Mels G, Corigliano P, Fornaciari G, Marenco G, Pistara R, Salvagnini M, Sangiovanni A. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33: 41-48   PubMed

79   Vilstrup H. Cirrhosis and bacterial infections. Rom J Gastroenterol 2003; 12: 297-302   PubMed

80   Navasa M, Rodes J. Bacterial infections in cirrhosis. Liver Int 2004; 24: 277-280   PubMed

81   Hoefs JC, Canawati HN, Sapico FL, Hopkins RR, Weiner J, Montgomerie JZ. Spontaneous bacterial peritonitis. Hepatology 1982; 2: 399-407   PubMed

82   Campillo B, Richardet JP, Kheo T, Dupeyron C. Nosocomial spontaneous bacterial peritonitis and bacteremia in cirrhotic patients: impact of isolate type on prognosis and characteristics of infection. Clin Infect Dis 2002; 35: 1-10   PubMed

83   Andreu M, Sola R, Sitges-Serra A, Alia C, Gallen M, Vila MC, Coll S, Oliver MI. Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites. Gastroenterology 1993; 104: 1133-1138   PubMed

84   Morencos FC, de las Heras Castano G, Martin Ramos L, Lopez Arias MJ, Ledesma F, Pons Romero F. Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Dig Dis Sci 1995; 40: 1252-1256   PubMed

85   Bleichner G, Boulanger R, Squara P, Sollet JP, Parent A. Frequency of infections in cirrhotic patients presenting with acute gastrointestinal haemorrhage. Br J Surg 1986; 73: 724-726   PubMed

86   Bolognesi M, Merkel C, Bianco S, Angeli P, Sacerdoti D, Amodio P, Gatta A. Clinical significance of the evaluation of hepatic reticuloendothelial removal capacity in patients with cirrhosis. Hepatology 1994; 19: 628-634   PubMed

87   Runyon BA. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology 1986; 91: 1343-1346   PubMed

88   Llach J, Rimola A, Navasa M, Gines P, Salmeron JM, Gines A, Arroyo V, Rodes J. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration. Hepatology 1992; 16: 724-727   PubMed

89   Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, Rimola A, Gassull MA, Arroyo V, Rodes J. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994; 20: 1495-1501   PubMed

90   Jimenez W, Ros J, Morales-Ruiz M, Navasa M, Sole M, Colmenero J, Sort P, Rivera F, Arroyo V, Rodes J. Nitric oxide production and inducible nitric oxide synthase expression in peritoneal macrophages of cirrhotic patients. Hepatology 1999; 30: 670-676   PubMed

91   Bories PN, Campillo B, Azaou L, Scherman E. Long-lasting NO overproduction in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1997; 25: 1328-1333   PubMed

92  Such J, Hillebrand DJ, Guarner C, Berk L, Zapater P, Westengard J, Peralta C, Soriano G, Pappas J, Frances R, Munoz C, Runyon BA. Nitric oxide in ascitic fluid is an independent predictor of the development of renal impairment in patients with cirrhosis and spontaneous bacterial peritonitis. Eur J Gastroenterol Hepatol 2004; 16: 571-577   PubMed

93   Hampel H, Bynum GD, Zamora E, El-Serag HB. Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis. Am J Gastroenterol 2001; 96: 2206-2210   PubMed

94   Fernandez J, Navasa M, Garcia-Pagan JC, G-Abraldes J, Jimenez W, Bosch J, Arroyo V. Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis. J Hepatol 2004; 41: 384-390   PubMed

95   Propst T, Propst A, Herold M, Schauer G, Judmaier G, Braunsteiner H, Stoffler G, Vogel W. Spontaneous bacterial peritonitis is associated with high levels of interleukin-6 and its secondary mediators in ascitic fluid. Eur J Clin Invest 1993; 23: 832-836   PubMed

96   Soriano G, Coll P, Guarner C, Such J, Sanchez F, Prats G, Vilardell F. Escherichia coli capsular polysaccharide and spontaneous bacterial peritonitis in cirrhosis. Hepatology 1995; 21: 668-673   PubMed

97   Runyon BA, McHutchison JG, Antillon MR, Akriviadis EA, Montano AA. Short-course versus long-course antibiotic treatment of spontaneous bacterial peritonitis. A randomized controlled study of 100 patients. Gastroenterology 1991; 100: 1737-1742   PubMed

98   Kurtovic J, Riordan SM, Williams R. Liver transplantation for hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2005; 19: 147-160   PubMed

99   McHutchison JG, Runyon BA. Spontaneous bacterial peritonitis. In: Surawicz C, Owen CS (eds). Gastrointestinal and Hepatic Infections. Philadeplphia: WB Saunders Co; 1995; 455-475   PubMed

100  Gines P, Rimola A, Planas R, Vargas V, Marco F, Almela M, Forne M, Miranda ML, Llach J, Salmeron JM. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 1990; 12: 716-724   PubMed

101  Soriano G, Guarner C, Teixido M, Such J, Barrios J, Enriquez J, Vilardell F. Selective intestinal decontamination prevents spontaneous bacterial peritonitis. Gastroenterology 1991; 100: 477-481   PubMed

102  Novella M, Sola R, Soriano G, Andreu M, Gana J, Ortiz J, Coll S, Sabat M, Vila MC, Guarner C, Vilardell F. Continuous versus inpatient prophylaxis of the first episode of spontaneous bacterial peritonitis with norfloxacin. Hepatology 1997; 25: 532-536   PubMed

103  Hsieh WJ, Lin HC, Hwang SJ, Hou MC, Lee FY, Chang FY, Lee SD. The effect of ciprofloxacin in the prevention of bacterial infection in patients with cirrhosis after upper gastrointestinal bleeding. Am J Gastroenterol 1998; 93: 962-966   PubMed

104  Soriano G, Guarner C, Tomas A, Villanueva C, Torras X, Gonzalez D, Sainz S, Anguera A, Cusso X, Balanzo J. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 1992; 103: 1267-1272   PubMed

105  Younossi ZM, McHutchison JG, Ganiats TG. An economic analysis of norfloxacin prophylaxis against spontaneous bacterial peritonitis. J Hepatol 1997; 27: 295-298   PubMed

106  Inadomi J, Sonnenberg A. Cost-analysis of prophylactic antibiotics in spontaneous bacterial peritonitis. Gastroenterology 1997; 113: 1289-1294   PubMed

107  Soares-Weiser K, Brezis M, Tur-Kaspa R, Paul M, Yahav J, Leibovici L. Antibiotic prophylaxis of bacterial infections in cirrhotic inpatients: a meta-analysis of randomized controlled trials. Scand J Gastroenterol 2003; 38: 193-200   PubMed

108  Bernard B, Grange JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology 1999; 29: 1655-1661   PubMed

109  Cereto F, Molina I, Gonzalez A, Del Valle O, Esteban R, Guardia J, Genesca J. Role of immunosuppression in the development of quinolone-resistant Escherichia coli spontaneous bacterial peritonitis and in the mortality of E. coli spontaneous bacterial peritonitis. Aliment Pharmacol Ther 2003; 17: 695-701   PubMed

110  Campillo B, Dupeyron C, Richardet JP, Mangeney N, Leluan G. Epidemiology of severe hospital-acquired infections in patients with liver cirrhosis: effect of long-term administration of norfloxacin. Clin Infect Dis 1998; 26: 1066-1070   PubMed

111  Campillo B, Dupeyron C, Richardet JP. Epidemiology of hospital-acquired infections in cirrhotic patients: effect of carriage of methicillin-resistant Staphylococcus aureus and influence of previous antibiotic therapy and norfloxacin prophylaxis. Epidemiol Infect 2001; 127: 443-450   PubMed

112  Rayes N, Seehofer D, Hansen S, Boucsein K, Muller AR, Serke S, Bengmark S, Neuhaus P. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation 2002; 74: 123-127   PubMed

113  Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S, Bengmark S, Neuhaus P. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation--a randomized, double-blind trial. Am J Transplant 2005; 5: 125-130   PubMed

114  Bauer TM, Fernandez J, Navasa M, Vila J, Rodes J. Failure of Lactobacillus spp. to prevent bacterial translocation in a rat model of experimental cirrhosis. J Hepatol 2002; 36: 501-506   PubMed

115  Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 1997; 26: 1530-1537   PubMed

116  Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 1999; 117: 942-952   PubMed

117  Enomoto N, Ikejima K, Bradford BU, Rivera CA, Kono H, Goto M, Yamashina S, Schemmer P, Kitamura T, Oide H, Takei Y, Hirose M, Shimizu H, Miyazaki A, Brenner DA, Sato N, Thurman RG. Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury. J Gastroenterol Hepatol 2000; 15 Suppl: D20-D25   PubMed

118  French SW. Intragastric ethanol infusion model for cellular and molecular studies of alcoholic liver disease. J Biomed Sci 2001; 8: 20-27   PubMed

119  Nanji AA, Khettry U, Sadrzadeh SM, Yamanaka T. Severity of liver injury in experimental alcoholic liver disease. Correlation with plasma endotoxin, prostaglandin E2, leukotriene B4, and thromboxane B2. Am J Pathol 1993; 142: 367-373   PubMed

120  Rivera CA, Bradford BU, Seabra V, Thurman RG. Role of endotoxin in the hypermetabolic state after acute ethanol exposure. Am J Physiol 1998; 275: G1252-G1258   PubMed

121  Khoruts A, Stahnke L, McClain CJ, Logan G, Allen JI. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. Hepatology 1991; 13: 267-276   PubMed

122  von Baehr V, Docke WD, Plauth M, Liebenthal C, Kupferling S, Lochs H, Baumgarten R, Volk H-D. Mechanisms of endotoxin tolerance in patients with alcoholic liver cirrhosis: role of interleukin 10, interleukin 1 receptor antagonist, and soluble tumour necrosis factor receptors as well as effector cell desensitisation. Gut 2000; 47: 281-287   PubMed

123  Fukui H, Brauner B, Bode JC, Bode C. Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J Hepatol 1991; 12: 162-169   PubMed

124  Lin RS, Lee FY, Lee SD, Tsai YT, Lin HC, Lu RH, Hsu WC, Huang CC, Wang SS, Lo KJ. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol 1995; 22: 165-172   PubMed

125  Chan CC, Hwang SJ, Lee FY, Wang SS, Chang FY, Li CP, Chu CJ, Lu RH, Lee SD. Prognostic value of plasma endotoxin levels in patients with cirrhosis. Scand J Gastroenterol 1997; 32: 942-946   PubMed

126  Hanck C, Manigold T, Bocker U, Kurimoto M, Kolbel CB, Singer MV, Rossol S. Gene expression of interleukin 18 in unstimulated peripheral blood mononuclear cells of patients with alcoholic cirrhosis. Gut 2001; 49: 106-111   PubMed

127  Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, Huber C. Serum levels of cytokines in chronic liver diseases. Gastroenterology 1992; 103: 264-274   PubMed

128  Schafer C, Schips I, Landig J, Bode JC, Bode C. Tumor-necrosis-factor and interleukin-6 response of peripheral blood monocytes to low concentrations of lipopolysaccharide in patients with alcoholic liver disease. Z Gastroenterol 1995; 33: 503-508   PubMed

129  Deviere J, Content J, Denys C, Vandenbussche P, Le Moine O, Schandene L, Vaerman JP, Dupont E. Immunoglobulin A and interleukin 6 form a positive secretory feedback loop: a study of normal subjects and alcoholic cirrhotics. Gastroenterology 1992; 103: 1296-1301   PubMed

130  Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med 2000; 343: 338-344   PubMed

131  Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R, Golenbock D. Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J Immunol 1999; 163: 1-5   PubMed

132  Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001; 2: 675-680   PubMed

133  Kurtovic J, Ruettimann U, Adamson H, Bihari D, Bengmark S, Williams R, Riordan SM. Improvement in indocyanine green clearance following synbiotic treatment in cirrhosis. Gut 2003; 52 Suppl 1: A3   PubMed

134  Nanji AA, Khettry U, Sadrzadeh SM. Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease). Proc Soc Exp Biol Med 1994; 205: 243-247   PubMed

135  Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, Desimone C, Song XY, Diehl AM. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 2003; 37: 343-350   PubMed

136  Solga SF. Probiotics can treat hepatic encephalopathy. Med Hypotheses 2003; 61: 307-313   PubMed


                                                                                               S- Editor Wang J    L- Editor Kumar M    E- Editor Liu WF



Reviews Add

Related Articles:
Etiology and management of hemmorrhage in spontaneous liver rupture: a report of 70 cases
Hepatoprotective role of ganoderma lucidum polysaccharide against BCG-induced immune liver injury in mice
Liver disease and Helicobacter
Carotid lesions in outpatients with nonalcoholic fatty liver disease
Characterization of focal liver lesions with SonoVue(R)-enhanced sonography: International multicenter-study in comparison to CT and MRI