Bacterial translocation: cause or consequence of decompensation in cirrhosis?

Transcription

1 Journal of Hepatology 34 (2001) 150±155 Editorial Bacterial translocation: cause or consequence of decompensation in cirrhosis? Guadalupe GarcõÂa-Tsao* Gastroenterology Service, VA Connecticut Healthcare System; Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, P.O. Box , New Haven, CT 06520, USA See Article, pages 32± Introduction Intestinal bacterial translocation is de ned as the migration of viable microorganisms from the intestinal lumen to mesenteric lymph nodes and other extra-intestinal organs and sites. Bacterial translocation increases in conditions associated with a high risk of infections by gram-negative bacteria and multiple organ failure, such as hemorrhagic shock, intestinal obstruction, major burn injury and serious trauma [1]. Bacterial translocation has been postulated as the main mechanism in the pathogenesis of spontaneous bacterial peritonitis (SBP), a lethal complication of cirrhosis. The gut appears to be the main source of bacteria in SBP given the predominance of gram-negative enteric bacteria isolated from ascites [2] and the signi cant reduction in the incidence of SBP after the administration of oral nonabsorbable antibiotics [3,4]. The presence of bacteremia in half the cases of SBP and the occurrence of cases of isolated bacteremia in cirrhotic patients without an obvious primary focus of infection (spontaneous bacteremia), suggest that bacteria gain access to the systemic circulation prior to infecting the peritoneal uid. 2. Bacterial translocation in experimental animals The above observations have led to the performance of studies of bacterial translocation in experimental cirrhosis. In these studies the entire chain of mesenteric lymph nodes (MLN) is isolated, homogenized and cultured. A positive MLN culture is considered indicative of bacterial translocation. As shown in Table 1, bacterial translocation to MLN has been shown to be present in about 50% of cirrhotic rats (range of 37±83%), which is signi cantly greater than rates of 0±10% observed in normal rats. Rates of positive blood * Corresponding author. Tel.: ; fax: or ascites cultures are not as consistent among these studies, with bacteremia rates that range between 0 and 32% and rates of ascites culture positivity (i.e. SBP) ranging from 7 to 70%. The reason for these discrepancies is not entirely clear. However, most studies show that animals with positive ascites cultures have concurrent positive MLN or blood cultures, suggesting a causal relationship [5±10]. One study that performed DNA typing of microorganisms showed an identity rate of 80% in ve cases in which bacteria were isolated from both MLN and ascites [11]. As expected, bacteria isolated from MLN in these studies are mostly organisms from the Enterobacteriaceae family (enteric gram-negative rods), with Escherichia coli being the predominant organism (accounting for over half the organisms isolated). In one of the studies [6], cecal immunostaining showed E. coli antigens within neutrophils and macrophages in the super cial submucosa and in the muscularis propria of the cecum of cirrhotic rats with ascites. Such immunostaining was not present in the cecum of cirrhotic rats without ascites or in normal rat cecum. As has been suggested in other studies [12], it would appear that intestinal macrophages carry bacteria from the gut to MLN from where bacteria can enter the blood stream (and seed other sites, such as ascites) via the thoracic duct. 3. Bacterial translocation in humans Studies of bacterial translocation have been performed in humans subjected to elective or emergency laparotomy for a variety of reasons. In these studies, bacterial translocation has been de ned as the presence of positive bacteriological cultures of MLN and/or other extraintestinal sites. In contrast to animal studies, ethical constraints in human studies allow for the isolation and culture of a single or at the most of two MLN, generally from the mesentery of the terminal ileum. Table 2 summarizes the results of studies of /00/$20.00 q 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S (00)

2 Table 1 Experimental studies of bacterial translocation in cirrhosis a G. GarcõÂa-Tsao / Journal of Hepatology 34 (2001) 150± First author n Experimental model Positive bacteriologic cultures Enterobacteriaceae (E. coli) MLN Peripheral blood Ascites Runyon [5] 32 Cirrhosis (CCl 4 ) 78% 19% 50% 90% (45%) 23 Normal rats 4% 0 Llovet [23] 22 Cirrhosis (CCl 4 ) 1 ascites 45% 32% 50% 80% (80%) 10 Normal rats 0 Garcia-Tsao [6] 9 Cirrhosis (CCl 4 b ) 1 ascites 56% 0 11% 100% (100%) 9 Cirrhosis without ascites Normal rats 0 0 Runyon [24] 20 Cirrhosis (no treatment) 50% NE 70% 83% (75%) 25 Cirrhosis (nor oxacin) 28% NE 28% 28%(0) Llovet [25] 12 Cirrhosis 1 ascites 42% NE NE 33% (33%) 10 Normal rats 0 NE NE Guarner [7] 35 Cirrhosis 1 ascites 83% NE 60% 81% (58%) 10 Normal rats 0 NE 0 Casafont [8] 33 Cirrhosis 69% c NE 13/27 (48%) 85% (77%) Llovet [11] 27 Cirrhosis 1 ascites 37% 15% 40% 50% (50%) 10 Normal rats 10% 0 Guarner [9] 14 Cirrhosis (no treatment) 78% NE 50% 71% (43%) 17 Cirrhosis (TMP/SMX) 47% NE 29% 30% (0) Perez-Paramo [10] 29 Cirrhosis 1 ascites 48% 14% 34% 82% (76%) 20 Normal rats 0 12 Cirrhosis 1 ascites (no treatment) 58% 90% (60%) 13 Cirrhosis 1 ascites (propranolol) 15% 100% (100%) Pardo [26] 15 Cirrhosis 1 ascites (placebo) 40% 7% 7% 83% (50%) 15 Cirrhosis 1 ascites (cisapride) Normal rats 0 a b c NE, not evaluable; MLN, mesenteric lymph nodes; TMP/SMX, trimethoprim/sulfamethoxazole. CCl 4 administered by inhalation, in all other studies CCl 4 administered by gavage. Includes malnourished animals. In non-malnourished rats, MLN cultures were negative in animals without ascites and positive in 50% of rats with ascites. bacterial translocation in humans, excluding those performed in trauma patients. The prevalence of bacterial translocation to MLN ranges between 4 and 59% with highest rates observed in patients with intestinal obstruction, Crohn's disease and organ donors. The translocation rate in patients in whom bowel obstruction and in ammatory bowel disease are absent is approximately 5% that may represent the `normal ` rate of translocation in humans. Except for one [13], all studies in Table 2 include noncirrhotic patients. In the study by Ferri et al. [13], which only included ten cirrhotic patients subjected to liver resection, bacteriological cultures of MLN isolated prior to liver resection were negative. In this issue of the Journal of Hepatology, Cirera et al. [14] report the results of a large study of 101 cirrhotic patients examined for evidence of gut bacterial translocation at the time of surgery (liver transplantation or hepatic resection). Thirty- ve non-cirrhotic general surgical patients were used as controls. Bacterial analysis of a single MLN obtained from the mesentery of the terminal ileum was performed in all patients. Contrary to other human studies, bacterial translocation was de ned as the isolation of enteric organisms from MLN. Enteric organisms were in turn de ned as organisms regularly recovered from feces or ileal aspirates of normal subjects and included not only Enterobacteriaceae but also Streptococcus, enterococci, Neisseria, Bacteroides, Clostridium and Candida. Using this de nition, the overall translocation rate in the 101 cirrhotic patients was 9%, not signi cantly different from non-cirrhotic controls (Table 2). Twenty-two of the patients had a history of SBP and

3 152 G. GarcõÂa-Tsao / Journal of Hepatology 34 (2001) 150±155 had been on prophylactic oral nor oxacin prior to surgery. Bacterial translocation was present in 4% (1/22) of these patients, which was lower but not signi cantly so, compared to a 10% rate (8/79) in patients who were not on nor oxacin. In the latter patients, bacterial translocation to MLN was signi cantly increased only in Child C patients in whom the rate was 31% (4/13), compared to 8% (3/37) in Child B patients and 3% (1/29) in Child A cirrhotics. In fact, the only factor independently associated with the presence of translocation was the Child-Pugh class. It is notable that a signi cant number of non-enteric organisms were cultured from MLN and were considered contaminants. If any positive culture is considered indicative of bacterial translocation the calculated translocation rates to MLN are 21% Child A, 16% Child B, and 38% Child C patients. When analyzed in this manner, results lose their statistical signi cance although a tendency for higher translocation rates in Child C patients clearly remains. 4. Pathogenic implications of bacterial translocation in cirrhosis The study's main nding is that bacterial translocation Table 2 Studies of bacterial translocation (BT) to mesenteric lymph nodes (MLN) in humans a Author n Clinical condition Positive MLN culture Relationship between BT and post-operative infections b Enterobacteriaceae (E. coli) Ambrose [21] 89 No Crohn's 2/41 (5%) Not signi cant (22 vs. 12%) 34% (27%) Crohn's disease 15/45 (33%) Deitch [27] 42 No intestinal obstruction 1/25 (4%) NE (none developed post-operative infection) 75% (50%) Intestinal obstruction 10/17 (59%) Sedman [28] 242 Various 21 (8%) Yes (28 vs. 12%) 72% (50%) Sagar [29] 254 Bowel obstruction 14/36 (39%) Yes (36 vs. 11%) 53% (42%) Other abdominal surgery 16/218 (7%) VanGoor [30] 21 Organ donors 11/21 (52%) NE 45% (NE) Kane [31] 39 Organ donors 18 (46%) NE 36% (21%) Prior hypotension 62% No hypotension 38% Ferri [13] 14 Pre-liver resection 0 No (0 vs. 12%) NE 14 Post-liver resection 6 (43%) O'Boyle [32] 448 Various 69 (15%) Yes (45 vs. 19%) 61% (55%) Age.70 21% Emergency surgery 21% Distal GI obst 41% O'Boyle [33] 43 GI cancer, IBD and other 9 (21%) Yes (33 vs. 15%) 56% (22%) Kale [22] 82 Elective laparotomy 6 (7%) Yes (33 vs. 12%) 56% (22%) Kuzu [34] 21 Obstructive jaundice 4 (19%) Yes (40 vs. 6%) 75% (25%) 30 Chronic cholecystitis 0 MacFie [35] 136 GI cancer, IBD and other 29 (21%) No (38 vs. 30%) 54% (42%) Woodcock [36] 51 AAA repair 5 (10%) Yes (80 vs. 20%) 57% (43%) Cirera [14] 101 All cirrhotics 9 (9%) No (0 vs. 21%) 25% c (12.5% c ) Child A 3% Child B 8% Child C 31% 35 Non-cirrhotics 3 (9%) a b NE, not evaluable; GI, gastrointestinal, IBD, in ammatory bowel disease; AAA, abdominal aortic aneurysm. Percentages in parentheses correspond to rates of postoperative infections, the rst percentage is the rate of postoperative infection in patients with bacterial translocation, the second percentage is the rate in patients without bacterial translocation. c Excluding `non-enteric' organisms.

4 G. GarcõÂa-Tsao / Journal of Hepatology 34 (2001) 150± occurs in cirrhotic patients with the most severe liver disease. This is consistent with experimental studies that demonstrate that translocation occurs only in cirrhotic animals with ascites, which have a lower serum albumin and higher bilirubin levels, i.e. a poorer liver function, compared to non-ascitic cirrhotic animals [6]. Cirrhotic animals with ascites are also more immunocompromised as demonstrated in a study in which a signi cantly higher rate of bacteremia occurred after the intratracheal instillation of Streptococcus pneumoniae in cirrhotic rats with ascites compared to cirrhotic animals without ascites or in normal controls [15]. In this study, cirrhotic rats with ascites were shown to have lower total hemolytic complement levels than cirrhotic animals without ascites. For translocation to become clinically signi cant, i.e. for it to lead to SBP, bacteremia or postoperative infection, a failure of local and systemic immune defenses should also be present. That is, in a healthy, non-immunocompromised host, translocated bacteria may reach MLN but these will usually be phagocytosed prior to multiplication and seeding of blood and other sites. In fact, although most human studies show that bacterial translocation correlates with postoperative infection, the majority of patients with evidence of bacterial translocation do not develop a related infection (Table 2). Furthermore, in patients that do develop an infection, the organisms cultured from MLN rarely correlate with those causing postoperative infection. This would indicate that bacterial translocation and postoperative infection are separate manifestations of an impaired immunity. In the study by Cirera et al. [14], bacterial translocation was not only unable to predict postoperative sepsis but was actually related to a lower rate of post-operative infection. However, this lack of association was probably related to the use of prophylactic antibiotics in the liver transplant group. Once bacterial translocation becomes clinically signi cant, e.g. once SBP develops, there is an increase in the mortality of the cirrhotic patient [16]. However, there is evidence suggesting that bacterial translocation per se, prior to the development of an overt infection, may lead to the deterioration of cirrhosis. A recent study performed in cirrhotic rats with ascites showed an association between the presence of bacterial translocation to MLN and a greater impairment in vascular contractility [17]. In this study, mean arterial pressure (in vivo) and perfusion pressure of the superior mesenteric arterial bed (in vitro) were signi cantly lower in ascitic cirrhotic rats with bacterial translocation to MLN compared to those without translocation. These hemodynamic changes were closely related to an increase in the production of tumor necrosis alpha and endothelial nitric oxide. According to this study, bacterial translocation leads to further derangement of the already altered circulatory state of cirrhosis. Maneuvers that produce more vasodilatation, such as the chronic use of nitrates [18] and total paracentesis without albumin replacement [19], are associated to an increased mortality in the cirrhotic patient. Therefore, patients with bacterial translocation could be expected to have a higher mortality. The hemodynamic changes observed in cirrhosis are not unlike those of multiple organ failure in which the phenomenon of bacterial translocation has also been implicated, although the association is still controversial [20]. As in multiple organ failure, it could be argued that bacterial translocation, rather than being the cause, is the result of the hemodynamic changes. The experimental ndings of a deteriorated hemodynamic status in animals with bacterial translocation are not supported by the study by Cirera et al. [14]. No differences were found in systemic or portal hemodynamics or in mortality rates between the eight patients with bacterial translocation and the 71 patients in whom MLN cultures were negative for enteric bacteria. There are several reasons that could account for this lack of signi cant ndings, including the presence of porto-systemic shunts ( ve patients had an intrahepatic portosystemic shunt and three had a surgical shunt), the possibility of arterio±venous shunting in patients with hepatocellular carcinoma, volume status at the time of surgery and possible use of propranolol or other vasoactive drugs. However, the most important reasons are a probable underestimation of the translocation rate and a low rate of isolation of aerobic gram-negative bacteria. While in experimental studies bacterial translocation occurs in about half of the animals with cirrhosis, in the study by Cirera et al. [14] only 20% (5/25) of the patients with ascites had bacterial translocation. As for all human studies, sampling of a single MLN almost certainly underestimated the prevalence of bacterial translocation in this study. More extensive MLN sampling might have shown a greater number of positive cultures as demonstrated in studies that have isolated two mesenteric lymph nodes [21,25]. Similar to ndings in experimental studies (Table 1), the most common organisms isolated from MLN in human studies are Enterobacteriaceae, mainly E. coli, which are also the most common organisms that produce spontaneous infections in cirrhosis. In humans, about 56% of bacteria isolated from MLN are Enterobacteriacea and around 42% of the organisms isolated are E. coli (Table 2). This is another discrepant nding in the study by Cirera et al. [14] in which only 25% of enteric organisms isolated from MLN were Enterobacteriacea and only half of these corresponded to E. coli. If all bacteria, enteric and nonenteric, had been considered these percentages would be even lower. This is relevant because gram-negative bacteria and endotoxins (that are constituents of their outer membrane) are more likely than other type of bacteria to stimulate tumor necrosis factor and cytokines that would lead to the production of nitric oxide and vasodilatation. The isolation of Clostridium, and Streptococcus spp. in more than half the cases is notable because these organisms have been found to translocate only rarely in animal studies and are the infecting organism in less than 25% of the cases

5 154 G. GarcõÂa-Tsao / Journal of Hepatology 34 (2001) 150±155 of SBP [2]. The reason for these discrepancies is unclear and cannot be explained by sampling error since most other studies in humans also isolated a single MLN. The authors explain it by suggesting that the development of ascites is a more ominous sign in cirrhotic animals than in cirrhotic patients and that probably Enterobacteriaceae translocate as the last step prior to the development of SBP. If this were true, isolation of Enterobacteriaceae would at least have been more prevalent in Child C patients. However, none of the MLN obtained from Child C patients were infected with these organisms. The observed discrepancies do not invalidate the main observation made in this important study, that is, that bacterial translocation occurs mostly in cirrhotics with the most severe disease. The study also re ects the methodological problems associated with investigating pathophysiological mechanisms in a clinical setting. 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