Acute Necrotizing Cholangiohepatitis With Clostridium perfringens: A Rare Cause of Post-Transplantation Mortality.

Clostridial infections frequently have rapidly fatal results. Bradly and colleagues presented the case of a liver transplant recipient who died from Clostridium perfringens infection 32 days after liver transplantation.1 The patient had been re-admitted to the hospital only 6 hours earlier for vomiting, jaundice, right upper quadrant pain, and fever. Postmortem examination of the liver showed extensive necrosis, and C. perfringens was cultured from an antemortem blood culture. Transplant physicians and surgeons are familiar with Clostridium infection, as C. difficile can be found in many hospitalized patients and is frequently responsible for diarrhea. Necrotizing infections of the transplanted liver are thankfully rare. There have been 21 cases of gas gangrene or necrotizing infections of the liver reported in the literature.1-15 Thirteen (62%) of these 21 infections were caused by clostridial species. C. perfringens accounted for 10 infections, C. sordellii accounted for 1 infection, and C. clostridiiforme was responsible for 1 infection. Gram-positive rods were identified by histologic examination of the liver in the thirteenth case, but no culture was obtained.15 A variety of other bacteria were cultured from the other patients who had necrotizing infections of the liver, including Enterobacter cloacae, Streptococcus, Escherichia coli, Klebsiella, Enterobacter, Bacteroides, and Enterococcus faecium. Multiple organisms, 1 of which was Candida, were cultured from 3 patients. In 1 case, the cause of the necrotizing hepatic infection was not known. Ten (77%) of the 13 patients infected with Clostridium died, frequently within hours of becoming ill. The 3 patients who survived underwent prompt retransplantation. However, all 3 patients had less fulminant infections and survived long enough for the transplant team to find a liver. Furthermore, the infection had not resulted in shock or other systemic changes that significantly decreased the likelihood of successful retransplantation. Of the 8 patients with necrotizing hepatic infections due to non-clostridial bacteria, 2 died soon after the diagnosis. Six patients underwent retransplantation; 5 of these patients survived, and 1 died after retransplantation. Thus, of the total 9 patients who underwent retransplantation, 8 survived in the long term and 1 died. Although gangrene due to Clostridia can occur in other organs of apparently healthy individuals as well, it has not yet been reported in recipients of kidney, heart, or lung transplants. However, 1 unfortunate living liver donor died of gastric necrosis due to C. perfringens 3 days after donating the right lobe of his liver.16 Clostridium species are gram-positive spore-forming anaerobic bacteria (though, technically, they are not absolute anaerobes, as they can tolerate up to 3% of O2 ). They are normal inhabitants of the gastrointestinal tract. Transplant physicians most commonly encounter C. difficile, which can cause diarrhea, typically in hospitalized patients receiving antibiotics. The antibiotics cause a decrease in the normal colonic flora, allowing for an overgrowth of C. difficile. Some species of Clostridium (C. botulinum, C. tetani) cause disease through their ability to elaborate neurotoxins in vitro and do not cause actual invasive infections. These toxins, along with diphteria toxin, are the most potent known toxins. Surgeons are most familiar with Clostridium species that cause necrotizing soft tissue infections such as C. perfringens, C. novyi, C. welchii, C. histolyticum, C. septicum, C. tertium, and C. sordellii. Infections of internal organs are distinctly less common. Exotoxins elaborated by Clostridium species are thought to be important in the pathogenesis of these infections. C. perfringens has 5 subtypes: A, B, C, D, and E.17 This species elaborates at least 12 exotoxins designated by Greek letters and acts as an active enzyme against cell membrane constituents. The alpha and theta toxins contribute to progressive vascular injury, and the alpha toxin also inhibits myocardial contractility. Many of these and other clostridial species also elaborate an enterotoxin that can cause severe diarrhea. If these bacteria enter the blood, their toxins can cause hemolysis. If hemolysis occurs during the course of a clostridial infection, survival is unlikely. Although Clostridium is commonly found in the gastrointestinal tract and the outside environment, infection with these bacteria is rare, most likely in large part due to the anaerobic conditions required for growth. Furthermore, not all Clostridia produce toxin to the same degree. Isolates of C. perfringens can vary in their toxigenicity. It is not surprising that Clostridium may infect the liver. Because the liver has contact with the gastrointestinal tract via the portal venous system, intestinal tract bacteria may enter the liver via translocation across the intestinal mucosa into the portal venous system. This may occur in healthy individuals regularly, but infection does not result because the bacteria are phagocytosed by the normal functioning Kupffer cells. Occasionally in healthy individuals and perhaps more commonly in liver transplant recipients, the Kupffer cells do not function normally and the bacteria can establish infections in the liver. This mechanism may explain some of the cases of liver abscess. If this was the entire explanation, however, one would expect that clostridial infections would be recognized more commonly in healthy individuals and in those with liver disease. Clostridial species can also be found in the bile of healthy individuals undergoing cholecystectomy. Clostridium species have been cultured from between 4% and 22% of bile specimens obtained from patients undergoing cholecystectomy.18,19 The patient reported by Bradly and colleagues underwent a Roux-en-Y choledochojejunostomy, which meant that the normal valve mechanism of the sphincter of Oddi was not present and bacteria could have easily entered the biliary tract.1 The donor liver can also be the source of bacteria. Donors may have conditions that favor the growth of bacteria in bile or the translocation of bacteria into the portal venous blood. These conditions include trauma to the gastrointestinal tract, prolonged intensive care unit admissions, periods of hypotension, use of inotropic agents, and other conditions that increase the risk of potential infection. Because necrotizing infection of liver transplant due to Clostridium and other organisms is usually recognized late in the course of the disease, the only patients who survive are those who undergo urgent retransplantation. In these patients, the infection is confined to the liver; thus, removing the transplanted liver (together with antibiotics) during retransplantation can cure the infection. The possibility of retransplantation depends upon whether the patient has such a fulminant course of infection that there is no time to obtain a second transplant. In addition, the patient cannot have such profound systemic findings that retransplantation would be futile and possibly waste a liver. I take exception with Bradly and associates for characterizing retransplantation as the gold standard. Usually, the term gold standard refers to a treatment that has evidence demonstrating its superiority over alternative treatment methods. As there are so few cases of necrotizing infections of the liver in transplant recipients and because there is really no other current treatment, the term gold standard does not apply.