Acute Necrotizing Cholangiohepatitis With Clostridium perfringens

Mild infection is a common complication in liver transplantation patients. Most patients are managed successfully without significant sequelae. However, severe infection may lead to significant morbidity and mortality. Recently, we observed an unusual infectious cause of acute necrotizing cholangiohepatitis in a post-transplantation patient at our institution.

Case Report

Our patient was a 52-year-old white man with a history of hepatitis B cirrhosis and hepatocellular carcinoma who qualified for liver transplantation. The patient underwent a successful Roux-en-Y hepaticojejunostomy without significant complications. On postoperative day 32, he was admitted to the hospital for fever (101.5F), nausea, vomiting, jaundice, and severe right upper quadrant pain. Initial laboratory findings were significant for a slightly elevated white blood cell count of 11.62 X 10³/UL and an elevated hepatic function panel, including an aspartate aminotransferase level of 2,782 U/L, alanine aminotransferase of 1,649 U/L, alkaline phosphatase of 1,514 U/L, total bilirubin of 17.4 mg/dL, and direct bilirubin of 15.4 mg/dL. Laboratory evaluation was negative for alpha-fetoprotein, hepatitis B virus, hepatitis C virus, and cytomegalovirus. Blood and urine cultures were collected, with pending results. An abdominal ultrasound showed multiple, unusual, well-delineated spaces in the liver filled with faint speckled debris (Figure 1, arrows). During the work-up, the patient required intubation after developing signs of shock, including tachypnea, tachycardia, and hypotension. Several hours later, he developed asystole and was pronounced dead. The time elapsed from admission to death was 6 hours.

Figure 1.

Abdominal ultrasound showing liver with well-delineated echogenic spaces (arrows).

Examination of the liver at autopsy showed multiple foci of parenchymal holes (0.6 cm in the greatest dimension; Figure 2). No other organs were involved in this process. Histologic sections showed extensive necrosis with sinusoidal clusters of bacilli (Figure 3). There was little viable hepatic tissue remaining. The most striking feature was the lack of inflammatory cell infiltrate. The blood cultures obtained antemortem on admission grew flat white colonies with a slightly raised center with beta hemolysis. The species was further identified as Clostridium perfringens.

Figure 2.

Autopsy liver with multiple parenchymal holes.

Figure 3.

Necrotic liver parenchyma with sinusoidal clusters of bacilli (40x magnification).

Discussion

Necrotizing infection with C. perfringens (gas gangrene) is usually recognized as a soft tissue phenomenon that presents with myonecrosis, gas production, and sepsis. Gas gangrene has rarely been reported to involve solid organs, including the liver, gallbladder, pancreas, kidney, heart, brain, or uterus. In humans, C. perfringens is a component of normal intestinal flora and resides in the stomach, small intestine, and bile ducts.¹ It has been postulated that hepatic infection results from ascension of bacteria through the biliary tree and into the liver.^1-3 As liver transplant recipients are generally immunocompromised, immunosuppression is also thought to play a critical role, though the exact mechanism has not yet been elucidated.

C. perfringens secretes potent exotoxins, including alpha toxin (phospholipase C).^1,4-6 It is currently thought that bacterial release of these exotoxins causes aggregation of platelets, fibrin, and neutrophils. These heterotypic aggregates lodge within the hepatic artery and arterioles, almost completely obstructing local and regional blood flow.⁴ As the hepatic artery is the sole blood supply to the biliary tree, inadequate hepatic artery perfusion leads to decreased oxygen tension, allowing anaerobic bacteria to ascend further into the liver and multiply.⁴ Therefore, the presence of thrombosis in the arterial or venous vasculature should raise suspicion for concomitant clostridial infection. In addition, at high concentrations, these exotoxins have been shown to be cytotoxic for neutrophils, destroying any infiltrating phagocytes at the site of active bacterial proliferation and toxin elaboration.⁴ This phenomenon explains the marked reduction of inflammatory cells in these areas. Viable neutrophils are instead found in heterotypic aggregates in vasculature, halted at sites distal to where the alpha and theta toxins are at cytotoxic concentrations.

The incidence of mild infection after liver transplantation has been reported to be 60-80%.^7,8 Despite this high incidence rate, most patients are managed successfully without significant sequelae. The majority of infections are bacterial and occur within 1 month post-transplantation due to catheter-related infections and primary bacteremia.^7,9 The most common organism isolated in these circumstances is coagulase-negative Staphylococci.^7,9 Two months post-transplantation, biliary tract infections associated with Enterococcus spp. and Escherichia coli are the most prevalent infections.⁷ Patients are usually treated with organism-specific antibiotics without significant complications. However, severe infection can be a cause of morbidity and mortality. The incidence and prevalence of liver graft failure due to sepsis has not been definitively reported but is thought to be a rare phenomenon. C. perfringens is an even rarer cause of allograft failure, with only a few cases reported in the literature.^1-3,10-12

Once hepatic infection with C. perfringens is suspected, liver transplant recipients are treated with metronidazole and concomitant administration of penicillin G, aminoglycoside, and clindamycin.¹⁰ Currently, the gold standard for treatment is liver retransplantation. Rapid intervention with this procedure has been remarkably successful without frequent persistence or recurrence of infection and has a relatively good prognosis, which has been reported to be 50%.³ Active infection is usually a contraindication to transplantation, with the exception of hepatic gas gangrene, in which case urgent retransplantation is indicated and may be life-saving.³ Unfortunately, many patients deteriorate rapidly and die before transplantation can be performed, as seen in our case.