Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

Abstract

Cholangitis requires bile duct obstruction and infection. Patients with cholangitis are often more affected than those with infections that reach the liver through the portal vein. We will attempt to study the influences of (i) route of entry and (ii) presence of bile duct obstruction on hepatic infection. C57BL/6 mice received injections of Escherichia coli or lipopolysaccharide into the obstructed bile duct or portal vein and were monitored for survival. Livers were assayed for bacteria, and cytokine mRNA was measured. In order to examine the effect of biliary obstruction on hepatic infection, animals were subjected to bile duct ligation 1 day prior to portal vein injection and were monitored for survival. The 50% lethal dose (LD 50 ) for E. coli injected into the bile duct was 50 CFU/animal; the LD 50 for E. coli injected into the portal vein was 5 ؋ 10 7 CFU/animal. Initial hepatic delivery of bacteria was equivalent 1 h after injection into the bile duct or portal vein. However, by 24 h, a significantly greater amount of bacteria was recovered from the livers of the bile duct-injected group. Interleukin 10 (IL-10) and IL-1RA mRNA was expressed at greater levels in the bile duct-injected group. Prior bile duct ligation followed by portal vein injection resulted in a higher incidence of death than when sham operation was performed prior to portal vein injection. Our data suggest that the increased mortality from cholangitis, compared with that from other hepatic infections, is related to the different route of delivery of pathogen and the maladaptive response (possibly involving IL-10 and IL-1RA) to biliary obstruction itself.Despite antibiotics and biliary drainage, either surgically or endoscopically, patients with ascending cholangitis have greater mortality and morbidity than patients with other appropriately treated intra-abdominal infections. In contrast to portal vein entry of bacteria into the liver, for example, after appendicitis or diverticulitis, entry via the biliary ducts has higher morbidity and mortality (4, 7). Indeed, small numbers of bacteria from the gastrointestinal tract may continually shower the liver via the portal vein without ill effect (11). This study reports a murine model that compares infection via the biliary and portal venous routes. This model reproduces the extraordinary mortality seen in patients after the former. Our model differs from others (9, 19). It focuses on early events within days of biliary infection, as opposed to late events after biliary obstruction has resulted in chronic liver injury.Our model suggests that the host response to infection via the bile duct is fundamentally different from the response to infection via the portal vein. We will show that one manifestation of this difference is the pattern of cytokines elicited by the infection. These cytokines affect the outcome in models of infection and injury and are supported by the literature. For example, levels of interleukin 6 (IL-6) in serum correlate with survival in critically ill patients; manipulat...

Late-presenting cholangitis and Roux loop obstruction after Kasai portoenterostomy for biliary atresia

“…Two recent experimental models have tended to favor Roux loop enteric organisms as the likeliest source. Thus, biliary inoculation of gram-negative organisms was associated with a more pronounced cytokine response and increased mortality compared with portal venous inoculation in 1 study [15] and was strain-specific in another [16]. This follows the clinical observation that cholangitis practically never occurs in post-Kasai infants who have failed to establish any postoperative bile flow.…”