Association of fungal infection and increased mortality in liver transplant recipients.

BACKGROUND: Invasive fungal infection is associated with increased morbidity and mortality following orthotopic liver transplantation (OLTx). Understanding the risk factors associated with fungal infection may facilitate identification of high-risk patients and guide appropriate initiation of antifungal therapy. OBJECTIVES: The aim of this study was to determine the incidence of fungal infections, identify the most common fungal pathogens, and determine the risk factors associated with fungal infections and mortality in OLTx recipients. METHODS: Medical records from 96 consecutive OLTx in 90 American veterans (88 males, 2 females; mean age 48 years, range 32 to 67) performed from January 1994 to December 1997 were retrospectively reviewed for fungal infection in the first 120 days after transplantation. Infection was defined by positive cultures from either blood, urine (<105 CFU/mL), cerebrospinal or peritoneal fluid, and/or deep tissue specimens. Superficial fungal infection and asymptomatic colonization were excluded from study. All patients received cyclosporine, azathioprine, and prednisone as maintenance immunosuppressive therapy. Fungal prophylaxis consisted of oral clotrimazole (10 mg) troches, five times per day during the study period. RESULTS: Thirty-five patients (38%) had documented infection with one or more fungal pathogens, including Candida albicans (25 of 35; 71%), C torulopsis (7 of 35; 20%), C tropicalis (2 of 35; 6%), non-C albicans (2 of 35; 6%), Aspergillus fumigatus (4 of 35; 11%), and Cryptococcus neoformans (1 of 35; 3%). The crude survival for cases with or without fungal infection was 68% and 87%, respectively (P <0.0001). The median intensive care unit stay and overall duration of hospitalization were significantly longer for patients with fungal infection (P <0.01). The mean time interval from transplantation to the development of fungal infection was 15 days (range 4 to 77) with a mean survival time from fungal infection to death of 21 days (range 3 to 64). Fungal infections occurred significantly more often in patients with renal insufficiency (serum creatinine >2.5 mg/dL), biliary/vascular complications, and retransplantation. CONCLUSIONS: Fungal infections were associated with increased morbidity and mortality following OLTx, with Candida albicans being the most common pathogen. Treatment strategies involving antifungal prophylaxis for high-risk patients and earlier initiation of antifungal therapy in cases of presumed infection are warranted.

Acute liver failure associated with prolonged use of bromfenac leading to liver transplantation. The Acute Liver Failure Study Group.

Bromfenac, a nonnarcotic analgesic nonsteroidal anti-inflammatory drug, was associated with reversible, minor elevations in serum aminotransferase levels during clinical trials. The aim of this study is to describe the clinical, laboratory, and histological features of 4 patients with severe bromfenac hepatotoxicity identified at 3 tertiary care centers participating in the US Acute Liver Failure Study Group. Bromfenac was administered for chronic musculoskeletal disorders to 4 women in therapeutic doses of 25 to 100 mg/d for a minimum of 90 days. All patients reported a prodrome of malaise and fatigue and presented with severe, symptomatic hepatocellular injury with associated hypoprothrombinemia. None of the subjects had underlying liver or kidney disease, and there was no evidence of a hypersensitivity reaction. Other identifiable causes of acute liver failure were uniformly excluded. Despite supportive measures, all the subjects developed progressive liver failure over 5 to 37 days, leading to emergency liver transplantation in 3 patients and death in 1 patient while awaiting transplantation. Extensive confluent parenchymal necrosis that appeared to begin in the central zones and was accompanied by a predominantly lymphocytic infiltrate was noted in all the livers examined. Nodular regeneration was seen in the 2 patients with a more protracted clinical course. Administration of therapeutic doses of bromfenac for greater than 90 days was associated with the development of acute liver failure leading to liver transplantation or death in 4 adult women. The poor outcomes observed in this series, coupled with the inability to identify individuals at risk for severe, idiosyncratic bromfenac hepatotoxicity, preclude further use of bromfenac in the medical community.

Vancomycin-resistant Enterococcus in liver transplant patients.

BACKGROUND: Vancomycin-resistant Enterococcus (VRE) infection is emerging in the transplant population, and there is no effective antibiotic therapy available. The aims of this retrospective review were to (1) investigate the outcome of and (2) identify common characteristics associated with VRE infection and colonization in orthotopic liver transplant (OLTx) candidates. METHODS: From October 1994 through September 1998, 126 isolates of VRE were identified in 42 of 234 OLTx recipients and 5 OLTx candidates who did not proceed to transplantation. Data were collected by patient chart review or from a computerized hospital database. RESULTS: The 1-year mortality rate with VRE infection was 82%, and with VRE colonization, 7%. This mortality rate contrasts with a 14% 1-year mortality for non-VRE transplant patients (P <0.01, infected patients and colonized patients). Characteristics of VRE colonized and infected patients included recent prior vancomycin (87%), coinfection by other microbial pathogens (74%), recent prior susceptible enterococcal infection (72%), concurrent fungal infection (62%), additional post-OLTx laparotomies (47%), and renal failure (Cr >2.5 mg/dL or need for dialysis; 43%). Biliary complications were seen in 52% of post-OLTx VRE-infected or VRE-colonized patients (versus 22% in non-VRE transplant patients, P <0.05). CONCLUSION: VRE infection is associated with a very high mortality rate after liver transplantation. The incidence of biliary complications prior to VRE isolation is very high in VRE-infected and VRE-colonized patients. The most common characteristics of VRE patients were recent prior vancomycin use, recent prior susceptible enterococcal infection, coinfection with other microbial pathogens, and concurrent fungal infection. With no proven effective antimicrobial therapy for VRE, stringent infection control measures, including strict and limited use of vancomycin, must be practiced.

Liver transplantation for disulfiram-induced hepatic failure.

Fulminant hepatitis is a rare but potentially fatal adverse reaction that may occur after the use of disulfiram. A patient without a known history of liver disease was transplanted for fulminant hepatic failure secondary to disulfiram. A high index of suspicion and aggressive therapeutic approaches are essential for the prompt diagnosis and treatment of disulfiram-induced hepatic failure. The clinical presentation, histopathology, treatment, and all cases of disulfiram-induced hepatic failure reported in the English literature are reviewed. The role of orthotopic liver transplantation in a case of disulfiram-induced hepatic failure is discussed.

Hepatic allograft abscess with hepatic arterial thrombosis.

BACKGROUND: Intrahepatic abscess (IA) is an uncommon complication after liver transplantation (OLTx) usually found in the setting of hepatic arterial thrombosis (HAT) often with associated biliary tree necrosis and/or stricture. Conventional treatment of IA in this setting has required retransplantation. METHODS: A retrospective review of 274 patients (287 OLTx) from September 1991 through September 1996 was performed. Median follow-up was 3.6 years. Diagnosis of HAT was confirmed by arteriography and IA was documented by computerized tomography. Percutaneous drainage of the abscess and stenting of biliary strictures, if present, was achieved using conventional interventional radiology techniques. RESULTS: The diagnosis of hepatic artery complication was made in 14 patients (5.1%), 2 of whom required retransplantation. Hepatic artery thrombosis associated with solitary IA was found in 3 patients (1%) who were transplanted in our center and in 1 additional patient followed up at our center but transplanted elsewhere. All 4 patients had complete resolution of IA using this approach. Three of the 4 patients are alive and well, with the fourth patient succumbing to recurrent hepatitis B infection resulting in allograft failure. CONCLUSIONS: Solitary hepatic allograft abscesses associated with HAT respond to percutaneous drainage and antibiotics, obviating the need for retransplantation in this setting.

Timing and severity of initial hepatitis C recurrence as predictors of long-term liver allograft injury.

BACKGROUND: The majority of patients infected with hepatitis C virus (HCV) undergoing liver transplantation develop evidence of histologic recurrence, and multiple mechanisms are likely poised to affect long-term allograft injury. The purpose of this analysis was to study the hypothesis that histologic and biochemical features at the onset of HCV recurrence predict the long-term evolution of allograft hepatitis. METHODS: We studied 34 consecutive liver transplant recipients with evidence of histologic HCV recurrence and with a minimal histologic follow-up of 1 year (up to 6.2 years; mean: 696+/-83.2 days). Two-hundred and seventy-eight serial allograft biopsies (mean: 6.85+/-0.62 per patient, range: 4-21) were analyzed. The hepatic activity index was utilized to quantitate piecemeal necrosis, intralobular degeneration, portal inflammation, and hepatic fibrosis. The presence of hepatocyte ballooning degeneration and cholestasis was also assessed. RESULTS: Although there was no significant difference with regard to initial hepatic activity index scores between patients who ultimately developed allograft cirrhosis (group 1; n=8) versus those with milder hepatitis (group 2; n=26), the finding of ballooning degeneration/cholestasis was more frequent in the former group (P=0.04). The distribution of HCV genotypes, the mean follow-up after orthotopic liver transplantation, the mean number of allograft biopsy specimens per patient, basal immunosuppression, and incidence of rejection were comparable in both groups. Patients who ultimately developed allograft cirrhosis had significantly higher initial total bilirubin at the onset of histologic recurrence and peak total bilirubin (pT. Bili, the highest value in the ensuing month). Actuarial rates of moderate-to-severe allograft hepatitis were significantly greater in patients with pT. Bili > or = 3.5 mg/dl (P=0.004). Multiple regression analysis identified pT. Bili as the only independent predictor of allograft cirrhosis. CONCLUSIONS: Features at the onset of histologic HCV recurrence predict the natural history of allograft injury; specifically, marked, transient hyperbilirubinemia is associated with the subsequent development of allograft cirrhosis.

Biliary tract complications of side-to-side without T tube versus end-to-end with or without T tube choledochocholedochostomy in liver transplant recipients.

BACKGROUND: Biliary anastomotic complications remain a major cause of morbidity in liver transplant recipients, ranging between 10% and 50% in large clinical series. An end-to-end choledochocholedochostomy with or without T tube (CDCD EE with T tube and CDCD EE w/o T tube) and a Roux-en Y choledochojejunostomy have been standard methods for biliary drainage. METHODS: The objectives of this retrospective study were to: (1) evaluate the incidence of biliary tract complications using a new method of side-to-side choledochocholedochostomy without T tube (CDCD SS w/o T tube) and (2) compare the results of CDCD SS w/o T tube with those of CDCD EE with T tube and CDCD EE w/o T tube. From September 1991 through June 1996, 279 orthotopic liver transplants were performed in 268 patients and followed through December 1996 (minimum of 6 months' follow-up). A total of 227 CDCD anastomoses in 220 patients were studied (7 retransplants > 30 days): CDCD EE with T tube (n=124), CDCD EE w/o T tube (n=44), and CDCD SS w/o T tube (n=59). RESULTS: Sixty-nine biliary complications were observed in 220 patients (30%). Anastomotic and/or T-tube leaks were seen in 43 patients (19%), and anastomotic strictures were found in 26 patients (12%). Forty patients (18%) required percutaneous or endoscopic stent placement (6%) or surgical interventions (12%). CDCD EE with T tube had the highest incidence of biliary leak requiring rehospitalization but the lowest anastomotic stricture and intervention rate and the lowest 6-month mortality rate. CONCLUSIONS: CDCD EE with T tube was superior to CDCD EE or CDCD SS w/o T tube despite the increased number of rehospitalizations. CDCD SS w/o T tube did not offer significant advantages over conventional biliary anastomotic techniques.

Liver disease in cystic fibrosis.

CF is a common hereditary disorder of ion transport, with increasing numbers of patients surviving beyond childhood and developing manifestations of hepatobiliary involvement. Inspissated secretions within the biliary tree result in obstruction and periductular inflammation that eventually progresses to focal and then multilobular cirrhosis. Fatty infiltration of the liver and hepatomegaly is common. Variceal hemorrhage and other findings of portal hypertension may be the initial presentation. At present, therapy with high-dose ursodeoxycholic acid should be considered standard, as it has been shown repeatedly to reduce the injurious effects of the cholestasis. Liver transplantation has been successfully performed on those with advanced disease and adequate pulmonary function. Innovative therapies for CF, including gene transfer, appear promising in preliminary studies, offering hope that earlier intervention in the course of hepatobiliary CF may soon be possible.

Cytomegalovirus viremia: risk factor for allograft cirrhosis after liver transplantation for hepatitis C.

BACKGROUND: Despite recent advances in diagnosis and treatment, cytomegalovirus (CMV) infection continues to be a common cause of morbidity in liver transplant (LT) recipients. Because CMV infection suppresses cell-mediated immunity, which seems to be important in neutralizing hepatitis C virus (HCV) infection, we assessed the impact of CMV infection on histopathological HCV recurrence after LT. METHODS: The study group was comprised of 43 consecutive LT recipients with at least 6 months of histologic follow-up. Group 1 consisted of the 8 patients who developed CMV viremia after LT; group 2 comprised the 35 patients without CMV viremia. There was no significant difference with regard to age, initial immunosuppression, incidence of rejection, distribution of HCV genotypes, or mean follow-up between the groups. Semiquantitative histopathologic assessment of allograft hepatitis was performed using the Knodell's score. RESULTS: The mean total Knodell score of the final allograft biopsy was significantly greater in group 1 patients (P=0.016), with most of the difference due to periportal/bridging necrosis (P=0.009) and lobular activity subitem (P=0.01) scores. Half of the CMV viremic patients eventually developed allograft cirrhosis as compared with 11% of the CMV-negative patients (P=0.027). Accordingly, the cirrhosis-free actuarial survival by Kaplan-Meier estimates was significantly diminished in the CMV viremic patients. Glycoprotein B genotype analysis of CMV isolates revealed no significant differences between patients who did and those who did not develop allograft cirrhosis. CONCLUSIONS: After LT for chronic HCV, patients who develop CMV viremia incur a significantly greater risk of severe HCV recurrence.

Outcome of 100 patients after transjugular intrahepatic portosystemic shunt for variceal hemorrhage.

OBJECTIVES: One hundred consecutive patients with recurrent or refractory acute variceal hemorrhage treated with a transjugular intrahepatic portosystemic shunt (TIPS) from June 1990 to June 1993 at Oregon Health Sciences University or the Portland Veterans Affairs Medical Center were evaluated to assess shunt patency and clinical outcome, including complications of TIPS, rebleeding, and survival. METHODS: Success of shunt placement, reduction in portal pressure, complications, survival, recurrent hemorrhage, severity of ascites, hepatic encephalopathy before and after TIPS, and shunt patency were assessed in each patient. RESULTS: The mean follow-up period was 17.7 months (range, 0.1-56.7 months). TIPS was successfully completed in all patients, with a mean reduction in portosystemic gradient from 24 to 11 mm Hg. Major complications occurred in 11 patients, including one death. Survival after TIPS was 85% at 30 days, 71% at 1 yr, and 56% at 2 yr. Variceal bleeding stopped within 24 hours after TIPS in all eight patients with active hemorrhage. Recurrent variceal hemorrhage occurred in 18 patients at a mean of 4.3 months (range, 1-713 days) after TIPS. The cumulative rate of recurrent variceal bleeding was 20% at 1 yr and 25% at 2 yr after TIPS. Recurrent variceal bleeding was associated with shunt stenosis or occlusion in all patients with endoscopically documented variceal hemorrhage, which was successfully managed by reopening obstructed shunts and performing variceal embolization. The prevalence of ascites was significantly reduced among surviving patients evaluated 3 months after TIPS (67 vs 25%, p < 0.005). Three months after TIPS, the incidence of new or worsening hepatic encephalopathy was 20%, but encephalopathy improved in an equal proportion of patients. Seventy-three of 77 (95%) shunts examined for patency were open at the last follow-up examination. However, most shunts required intervention to maintain patency, and only 48% (37 of 77) were primarily patent at a mean of 168 days (range, 2-538 days) of follow-up. Shunt stenosis or occlusion, as determined by venography, became increasingly frequent with longer follow-up (52% at 3-9 months and 70% at 9-15 months). CONCLUSIONS: TIPS is effective in lowering elevated portal pressures in patients with refractory variceal hemorrhage, has acceptable postprocedure complication and mortality rates, ameliorates ascites, and in, a minority of patients, worsens encephalopathy. Shunt stenosis occurs in the majority of patients but can be effectively treated by interventional techniques to maintain patency. The incidence of recurrent variceal hemorrhage is low and is associated with shunt stenosis or occlusion.

Stent-grafts for revision of TIPS stenoses and occlusions: a clinical pilot study.

PURPOSE: To assess the clinical and technical results of stent-graft placement for revision of transjugular intrahepatic portosystemic shunt (TIPS) stenoses and occlusions. MATERIALS AND METHODS: Six patients who developed recurrent TIPS stenosis or occlusion of the parenchymal tract underwent shunt revision with use of polytetrafluoroethylene (PTFE) stent-grafts anchored at both ends by Z stents and centrally supported by Wallstents. RESULTS: Before graft placement, mean primary patency was 50 days (range, 9-100 days). Patients underwent one to eight revisions with angioplasty or stent placement (mean, 3.2). Three patients had biliary-TIPS fistulas documented with use of a prototype double occlusion balloon catheter. Stent-grafts were successfully placed within the obstructed shunt, creating an excellent lumen in all cases. The portosystemic gradient was decreased from a mean of 24.3 mm Hg (range, 12-35 mm Hg) to a mean of 10.3 mm Hg (range, 7-16 mm Hg). Five of six patients were asymptomatic and no complications occurred (median clinical follow-up, 331 days). One patient died of pre-existing multi-organ system failure. The duration of primary patency after stent-grafting was improved (mean, 229 days; range, 27-324 days) and the difference approached statistical significance despite the small sample size (P = .056, paired t test). Three patients remained primarily patent at a mean venographic follow-up of 315 days. One shunt occluded at 1 month from residual thrombus in the portal vein, and one stenosis occurred that was secondary to misplacement of the original stent-graft. Patency was re-established in each of these patients. CONCLUSION: PTFE covered stent-grafts are effective for shunt revision in patients with tract stenosis or occlusion and appear to improve TIPS patency.

Psychological assessment of quality of life following liver transplantation.

Administered measures of functional status, psychological distress, and quality of life to a consecutive series of 48 liver transplant recipients in follow-up clinic. Results showed that nearly total functional recovery was the norm. Thirty-six patients (75%) had a Karnofsky Performance Status (KPS) score of 80-100. Twelve transplant recipients had KPS scores below 80; none were employed, and most had been transplanted within 1 year. In spite of their impaired financial status, eight of these 12 reported being mostly satisfied on the self-report Quality-of-Life Scale (QLS). For the posttransplant sample as a whole, 83% were mostly satisfied with their quality of life. Pre- and posttransplant patient samples were not significantly different in reporting mild emotional distress. Results for the small subgroup with significant objective or subjective problems in achieving acceptable quality of life following liver transplantation were reviewed. Higher than normal emotional distress on the Symptom Checklist (SCL-90-R) was consistently reported by these patients. Prospective studies are needed to identify predictor variables of quality-of-life problems and to develop prevention and rehabilitation interventions.

Increased hepatocyte expression of hepatitis B virus transcription in patients with features of fibrosing cholestatic hepatitis.

BACKGROUND: Recurrent hepatitis B after liver transplantation may be complicated by fibrosing cholestatic hepatitis. This syndrome is associated with rapid graft failure and is characterized by ballooning degeneration of hepatocytes and abundant viral antigen expression. METHODS: To study this disorder further, in situ hybridization studies were performed on 36 liver biopsy specimens from 14 transplanted patients with recurrent hepatitis B and 18 nontransplanted controls with chronic hepatitis B. Biopsy specimens were scored for histological features and intensity of riboprobe hybridization signal to hepatitis B virus (HBV) DNA and RNA. RESULTS: HBV DNA hybridization signals of 2+ to 3+ intensity were observed in 53% of the posttransplant biopsies but none of the nontransplanted samples (P < 0.001). HBV RNA signals of this intensity were found in 42% of the transplant biopsy specimens compared with 17% of the nontransplant specimens (P < 0.07). Features of fibrosing cholestatic hepatitis were noted in 12 biopsies; 11 of these displayed RNA signals of 2+ to 3+ intensity (92%) compared with 4 of 24 (17%) biopsy specimens without this diagnosis (P < 0.001). The level of hepatocyte RNA correlated with the extent of hepatocellular ballooning (P < 0.007). CONCLUSIONS: These data suggest that fibrosing cholestatic hepatitis is associated with enhanced hepatitis B virus transcription and support a cytopathic role for the virus in the development of this syndrome.

Fibrosing cytolytic liver failure secondary to recurrent hepatitis B after liver transplantation.

Four patients who underwent transplantation for hepatitis B virus-related liver disease developed rapidly progressive liver failure attributable to recurrent hepatitis B disease typified by hyperbilirubinemia and distinctive hepatocyte ballooning and progressive fibrosis consistent with recently reported fibrosing cholestatic hepatitis. Among these four patients, the mean interval from transplantation to redocumentation of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) was 5 months, to development of malaise and jaundice 6 months, to histological diagnosis 7 months, and to graft failure 8 months. The only patient who underwent retransplantation had accelerated recurrence of the same syndrome with biopsy documentation 1 month later and graft failure 2 months later. Distinctive histological features included confluent hepatocellular ballooning and progressive periportal fibrosis followed by lobular collapse over 4-6 weeks without significant inflammation. Immunohistochemical staining showed marked HBsAg and hepatitis B core antigen (HBcAg) immunoreactivity. The rapid development of cytolytic hepatocellular necrosis and lobular collapse with prominent HBcAg immunoreactivity without significant inflammation suggests a cytolytic rather than immune pathogenesis for this unique and devastating form of recurrent hepatitis B that might better be termed "fibrosing cytolytic hepatitis."