Biliary tract complications after orthotopic liver transplantation. Endoscopic approach to diagnosis and therapy.

This study was undertaken to further define the role of endoscopic methods in the evaluation and treatment of biliary tract complications after liver transplantation and to determine the efficacy and safety of this approach. Fifty liver transplant patients were referred for endoscopic evaluation of a suspected biliary tract complication. Two patient groups were identified based on the indication for the endoscopic retrograde cholangiopancreatography (ERCP): Group 1 was suspected of having biliary fistula and group 2 was suspected of having bile duct obstruction. Group 1 consisted of 35 patients who developed bile peritonitis after inadvertent migration of the T-tube or intentional T-tube removal. Group 2 consisted of 15 patients who developed cholestatic hepatic chemistries in the absence of allograft rejection on liver biopsy. ERCP identified a biliary fistula at the T-tube insertion site into the bile duct in 32 (91%) group 1 patients. Twenty-six of 26 treated with a nasobiliary tube had fistula closure at a mean 5.2 days. Five of 6 treated with a stent, with or without sphincterotomy, had no leak at the time of stent removal (mean, 45 days). ERCP identified a cause for the cholestatic hepatic chemistries in 11 (73.5%) group 2 patients, including bile duct stones (n = 4), anastomotic (n = 3) or intrahepatic (n = 2) strictures, bile duct necrosis (n = 1), and hemobilia (n = 1). Five of the 5 patients undergoing endoscopic therapy were treated successfully. The endoscopic complication rate was 4% and the 30-day mortality rate was 2%. During a mean follow-up of 15 months, 94% of the patients who were treated successfully had no recurrent biliary tract disease. The results of this study suggest that ERCP is an effective modality in the evaluation of patients with suspected biliary tract complications after liver transplantation. In selected patients, endoscopic therapy obviates the need for additional surgical or percutaneous intervention.

A randomized prospective trial of steroid withdrawal after liver transplantation.

The safety of steroid withdrawal in orthotopic liver transplant (OLT) recipients has been studied in a prospective trial with a comparison control group. Sixty-four recipients of ABO-compatible grafts (42 adults, 22 children) were randomized into a steroid withdrawal (SW) group and a control group. Inclusion criteria included survival > one year post-OLT and no rejection > six months after OLT. Exclusion criteria included previous graft loss secondary to rejection, > two episodes of documented rejection, patients transplanted for autoimmune hepatitis, and patients unable to receive azathioprine. Target HPLC cyclosporine levels in both groups were 100-200 ng/ml. Thirty-three patients entered the SW group and 31 the control group at a mean of 3.5 years after OLT; follow-ups were 592 and 527 days, respectively. Two patients in each group developed biopsy-proven rejection. In the SW group one patient rejected at three months, the other at nine months. Both rejection episodes resolved with only reinstitution of oral prednisone. Of the two patients who rejected in the control group (one at 7 months, one at 11 months) one required conversion to tacrolimus and the other intravenous steroids. There were no significant differences between the two groups for prednisone, azathioprine, cyclosporine doses, cyclosporine levels, liver function tests, and white blood cell counts at base line compared with 12 months. Fasting serum cholesterol in the SW group decreased from 194 +/- 44 mg/dl at baseline to 175 +/- 37 mg/dl at one year, whereas in the control group cholesterol rose from 180 +/- 48 mg/dl to 193 +/- 44 mg/dl. In pediatric patients no significant difference in age-adjusted height velocities over one year was seen between the two groups. We concluded that dual therapy with cyclosporine and azathioprine in stable long-term liver allograft recipients is not associated with an increase in rejection incidence. Prednisone withdrawal may be associated with an improvement in lipid profiles.

Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation.

A group of 52 liver transplant patients was prospectively randomized to receive prophylactic immunosuppressive therapy consisting of either Orthoclone OKT3 for 14 days, azathioprine, and steroids (25 patients); or cyclosporine, azathioprine, and steroids (27 patients). The groups were similarly matched for age, diagnosis, and Child's classification. The patients were studied to determine the effect of these two regimens on the incidence of rejection, infection, renal dysfunction, and mortality. Seven rejection episodes, as determined by clinical and histological criteria, occurred in seven of 25 patients (28%) receiving OKT3 compared with 18 episodes in 27 patients (67%) receiving cyclosporine during the first 14 days after transplantation (P less than 0.02). In 20% of the OKT3 patients, CD3+ levels of greater than 10% developed during therapy, and 16% of the patients developed anti-OKT3 antibodies during OKT3 treatment. Five patients were retreated with OKT3 for steroid-resistant acute rejection episodes; all had resolution of the rejection episode. Infectious complications were similar in each group. Renal function, as measured by serum creatinine, was significantly better with OKT3 than with cyclosporine (P less than 0.003) at 14 days. We conclude that prophylactic OKT3 is effective in reducing the number of early rejection episodes after liver transplantation; after 14 days the incidence of rejection is similar; reuse of OKT3 has been successful in liver transplant patients; infectious complications are similar between OKT3 and cyclosporine; and OKT3 preserves renal function better than cyclosporine and is thus indicated in patients with compromised preoperative renal function.

Liver transplantation for decompensated cirrhosis after jejunoileal bypass: a strategy for management.

BACKGROUND: Although jejunoileal bypass results in end-stage liver disease in up to 100% of patients, little is known about outcome after liver transplantation. METHODS: The clinical courses of six patients who underwent liver transplantation at UCLA for decompensated cirrhosis owing to a jejunoileal bypass were reviewed. Liver function, allograft pathology, renal function, and nutritional status were assessed. RESULTS: Of the four patients with an intact jejunoileal bypass, two of the three who were biopsied had recurrent steatotic liver disease. The two patients whose jejunoileal bypass was reversed at the time of liver transplantation had lower alkaline phosphatase, lower creatinine, higher albumin, and higher cholesterol, and were more obese than their counterparts with intact bypasses. CONCLUSIONS: Patients undergoing liver transplantation for jejunoileal bypass-associated liver disease should, if possible, have their bypass reversed at the time of transplantation; otherwise, they must be followed closely and be biopsied routinely. Recurrent liver disease should prompt reversal of the jejunoileal bypass.

Hyperlipidemia after liver transplantation: natural history and treatment with the hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin.

This study was designed to determine the frequency of hyperlipidemia after orthotopic liver transplantation and whether treatment with a hydroxy-methylglutaryl coenzyme A reductase inhibitor was safe and efficacious. Cholesterol levels were assessed in 45 consecutive adult liver transplants (mean +/- SE). Four of 22 patients on cyclosporine (CsA) (18%) and three of 23 patients on FK506 (13%) had levels >225 mg/dl at 12 months (cholesterol levels for patients on CsA [total n=22]: pre-Tx = 140+/-11, 1 month = 183+/-36,3 months = 221+/-12, 6 months = 211+/-11, 12 months = 202+/-14 [P<0.01 vs. pre-Tx]; FK506 [total n=23]: Pre-Tx = 151+/-13, 1 month = 187+/-22, 3 months = 188+/-10, 6 months = 184+/-13, 12 months = 164+/-9 [P=0.02 vs. CsA]). A separate cohort of patients with stable graft function, cholesterol >225 mg/dl, and two additional risk factors for coronary artery disease were started on pravastatin. Ninety-eight patients were enrolled. Sixteen patients (16%) discontinued the drug because of subjective complaints. No episodes of rhabdomyolysis or hepatotoxicity occurred (cholesterol levels for patients on CsA [total n=65]: pretreatment = 251+/-7, 6 months = 220+/-7 [P=0.01 vs. pretreatment], 12 months = 224+/-8 [P=0.01 vs. pretreatment]; FK506 [total n=17]: pretreatment = 251+/-17, 6 months = 219+/-17, 12 months = 208+/-17 [P=0.08 vs. pretreatment]). Natural killer cells isolated from normal volunteers (n=14) exhibited 27+/-9% specific lysis. Patients on FK506 or cyclosporine-based immunosuppression alone (n=11) exhibited 20+/-4% specific lysis. Standard immunosuppression plus pravastatin (n=10) decreased lysis to 0.2+/-10% (P<0.02 vs. controls and standard immunosuppression). We conclude: (1) posttransplant hyperlipidemia occurs less frequently in liver transplant patients than in renal or cardiac transplants; (2) pravastatin is safe and efficacious for cholesterol reduction in liver transplant patients; and (3) pravastatin coadministered with standard immunosuppression reduces natural killer cell-specific lysis in these recipients.

A simple model to estimate survival after retransplantation of the liver.

To formulate a model predicting survival after liver retransplantation, we analyzed in detail the last 150 cases of hepatic retransplantation at UCLA. Cox proportional hazards regression analysis identified five variables that demonstrated independent simultaneous prognostic value in estimating patient survival after retransplantation: (1) age group (pediatric or adult), (2) recipient requiring preoperative mechanical ventilation, (3) donor organ cold ischemia > or =12 hr, (4) preoperative serum creatinine, and (5) preoperative serum total bilirubin. The Cox regression equation that predicts survival based on these covariates was simplified by assigning individual patients a risk classification based on a 5-point scoring system. We demonstrate that this system can be employed to identify a subgroup of patients in which the expected outcome is too poor to justify retransplantation. These findings may assist in the rational selection of patients suitable for retransplantation.

The role of liver biopsy in evaluating acute allograft dysfunction following liver transplantation: a clinical histologic correlation of 34 liver transplants.

One hundred six liver biopsy specimens from 34 orthotopic liver transplant (OLT) patients were examined and the histologic findings correlated with the clinical course of the patients to determine if specific morphologic patterns were associated with specific causes of acute allograft dysfunction. The principle causes of allograft injury in these patients appeared to be acute rejection and ischemic injury, with rarer cases of viral infection and biliary obstruction. Graft rejection causing transient liver dysfunction was associated with a mixed inflammatory infiltrate in the portal tracts and involving the interlobular bile ducts. Rejection resulting in severe, persistent dysfunction was associated with destruction and loss of the interlobular bile ducts or portal inflammation, followed by acute centrilobular hepatocyte necrosis. Ischemic liver injury was characterized by hepatocyte ballooning and/or hepatocyte necrosis. Ischemic injury causing transient graft dysfunction demonstrated focal, limited areas of hepatocyte necrosis or transient centrilobular hepatocyte ballooning. Severe ischemic injury resulting in persistent dysfunction caused diffuse hepatocyte necrosis or centrilobular ballooning followed by centrilobular hepatocyte loss and severe cholestasis with evidence of bile duct epithelial injury. The histologic patterns observed were not pathognomonic; radiologic studies, bile cultures, and other laboratory tests were necessary to rule out biliary or vascular obstruction and bacterial cholangitis. However, liver biopsies, especially serial biopsies, were helpful in suggesting the probable cause of liver dysfunction and in predicting subsequent allograft recovery or failure.

Simultaneous retrohepatic inferior vena cavoplasty and side-to-side portacaval shunt for recurrent thrombosed mesoatrial shunt in the Budd-Chiari syndrome.

The Budd-Chiari syndrome is an unusual and often fatal form of portal hypertension caused by hepatic vein occlusion. It comprises less than 5% of surgically correctable causes of portal hypertension and can be one of the most difficult to treat. Recurrent Budd-Chiari syndrome associated with a thrombosed mesoatrial shunt can be an even more vexing problem because of the patient's debilitated condition, hypercoagulable state, and altered anatomy from the previous thoracic and abdominal operations. Although the literature describes numerous surgical methods of treating the Budd-Chiari syndrome, no report specifically addresses the reoperative management of a recurrent thrombosed mesoatrial shunt. We report a patient with a recurrent thrombosed mesoatrial shunt, tightly stenotic retrohepatic inferior vena cava, and occluded hepatic veins with severe portal hypertension. A simultaneous inferior vena cavoplasty and a side-to-side portacaval shunt have produced excellent results with 26-month follow-up. To the best of our knowledge, this method has not been previously described. Other reported surgical methods of treating the Budd-Chiari syndrome are discussed, with emphasis on their relative applicability to the reoperative management of this condition. We submit that this one-stage patch cavoplasty and side-to-side portacaval shunt are the best direct surgical methods to provide immediate and long-term benefit for patients with this most challenging problem.

A prospective study on the use of monoclonal anti-T3-cell antibody (OKT3) to treat steroid-resistant liver transplant rejection.

Conventional treatment of acute liver allograft rejection has included high doses of corticosteroids and antithymocyte globulin. Urgent retransplantation was the only option for patients who failed to respond. We report our initial experience with the use of monoclonal anti-T3-cell antibody (OKT3) in 25 patients with acute hepatic allograft rejection that was resistant to steroid and/or antithymocyte globulin therapy. Twenty-four of 25 patients had a response to OKT3, which was complete in 14 and partial in ten. With a mean follow-up of 8.2 months, allograft salvage has been 80% and patient survival 88%; two patients underwent successful retransplantation. Side effects have been mild and well tolerated. Repeated rejection has occurred in 40% of patients, but these episodes have responded to steroid therapy. We conclude that OKT3 is well tolerated and highly effective in reversing severe episodes of acute hepatic allograft rejection that is resistant to high-dose steroid therapy.

Is liver transplantation justified for the treatment of hepatic malignancies?

Twenty-eight patients received orthotopic liver transplants for malignant disease between February 1, 1984, and December 31, 1989. Preoperative diagnoses included hepatocellular carcinoma (n = 16), cholangiocarcinoma (n = 3), other primary hepatic tumors (n = 6), and metastatic diseases to the liver (n = 3). Overall actuarial survivals at 6 months, 1 year, and 5 years were 67.3%, 51%, and 31%, respectively. Long-term survival longer than 5 years was achieved in 3 patients. The recurrence rate in patients surviving longer than 3 months is 48% (median, 7 months). Hepatocellular carcinoma and cholangiocarcinoma had the poorest survival and highest recurrence rates. Specific prognostic factors correlating with survival or recurrence could not be elucidated. These results indicate that orthotopic liver transplants can provide long-term cure and palliation for malignant disease; however, patient selection is extremely important in predicting outcome.

Infectious complications in liver transplantation.

Thirty-five patients received 42 liver homografts between February 1984 and August 1985. One or more infections developed in 23 patients (66%) some time after transplantation. An average of 2.5 infections per infected patient occurred. Of 37 bacterial infections, two thirds were either bacteremias or localized intra-abdominal infections. The median onset was 29 days after operation. Thirteen viral infections were identified, with a median onset of 18 days after operation. Nine fungal infections, six disseminated and three localized, were identified, with a median onset of nine days after operation. Infection was the primary cause of death in five (14%) of 35 patients. Fatal infections were evenly distributed among bacterial (two), fungal (three), and viral (two) pathogens. Despite advances in surgical techniques and the use of cyclosporine, infection after orthotopic liver transplantation is a serious problem. Certain patients can be identified as high risks for infection and require an aggressive diagnostic workup followed by early institution of antimicrobial therapy.

Prevalence and risk factors for diabetes mellitus in moderate term survivors of liver transplantation.

The prevalence and risk factors for diabetes mellitus after liver transplantation are not well understood. Thus, we sought to identify independent risk factors for the development of diabetes after liver transplantation using currently accepted medical criteria. We studied the prevalence and risk factors in 253 adult recipients transplanted at UCLA between January 1998 and December 2002. Analysis of the retrospective data was performed using demographic, immunosuppression and liver disease variables. Factors found to be significant on a univariate analysis were further studied in a multivariate analysis. There were 158 men and 95 women in our study. The mean age was 51.4 +/- 11.0 years. The mean [+/- standard deviation (SD) pretransplant body mass index was 26.7 (+/-5.1). Most patients were transplanted for hepatitis C (HCV). The prevalence of diabetes after transplantation was 17.8%. In a multivariate analysis only gender [odds ratio (OR) = 0.37; p = 0.02] was independently predictive of the development of diabetes. This study in a large liver transplant recipient population identifies male gender as an independent risk factor for the development of diabetes. Follow-up studies are needed to assess the impact of diabetes, and its intervention on post-transplant morbidity and mortality.

The symptoms of an amebic abscess of the liver simulating an acute surgical abdomen.

Amebic abscess of the liver has protean manifestations that often resemble causes of an acute surgical abdomen. Patients presenting at University of California, Los Angeles Hospital with acute abdominal injuries who underwent exploratory laparotomy and subsequently were found to have an amebic hepatic abscess were studied. There are various clinical symptoms of amebic hepatic abscess as well as problems of differentiating this pathologic entity from an acute surgical abdomen. Most patients with amebic hepatic abscess that mimics an acute abdomen present as acute cholecystitis or acute appendicitis. All patients recovered uneventfully once the diagnosis was made and appropriate therapy instituted. The salient features of the history, physical examination and laboratory data that can identify the amebic abscess were analyzed. The key to correct diagnosis is cognizance of the condition.