Paul McMaster

Colorectal cancer in patients with inflammatory Bowel disease after liver transplantation for primary sclerosing cholangitis

Background. Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) may have an increased risk of developing colorectal cancer (CRC) after liver transplantation (LT). We evaluated our patients with PSC after LT to identify risk factors for CRC and its impact on survival. Patients and Methods. A total of 152 patients (108 men, 100 with IBD) with PSC who underwent 173 LTs between 1986 and May 2000 were analyzed in three groups: (1) PSC without IBD (n=52); (2) PSC with colectomy (pre-LT and at LT) (n=17, colectomy pre-LT in 13 and simultaneous colectomy at LT in four); and (3) PSC with IBD and an intact colon (n=83). The following factors were studied: age, gender, liver, and renal biochemistry, international normalized ratio, Child-Pugh stage, operative time, blood use, hospital stay, immunosuppression, risk of CRC, retransplantation rate, and mortality. Results. The incidence of CRC after LT was 5.3% (8/152) compared with 0.6% (7/1,184) in non-PSC cases (P <0.001). All CRCs in the PSC group were in patients with IBD and an intact colon. The cumulative risk of developing CRC in the 83 patients with an intact colon and IBD was 14% and 17% after 5 and 10 years, respectively (PSC non-IBD group 0% risk after 10 years, P <0.06). The multivariate analysis showed three significant variables related to the risk of developing CRC: colonic dysplasia after LT (P <0.0003), duration of colitis more than 10 years (P <0.002), and pancolitis (P <0.004). The cause of death in patients with CRC was cancer related in 75% of cases with a reduced 5-year survival of 55% versus 75% without CRC (not significant). Conclusion. Patients with PSC undergoing LT with a long history of ulcerative colitis and pancolitis have an increased risk of developing CRC with reduced survival. We advocate long-term aggressive colonic surveillance and colectomy in selected high-risk patients with longstanding severe colitis.

High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation

BACKGROUND/AIMSnOrthotopic liver transplantation has an established role for the treatment of patients with chronic liver failure secondary to hepatitis B virus (HBV) infection. Unfortunately, recurrent infection of the graft can be associated with aggressive disease, and with diminished graft and patient survival. Currently, the role of nucleoside analogues for prevention of graft re-infection is being evaluated. Preliminary results are encouraging, but treatment failure has been associated with emergence of drug-resistant virus.nnnMETHODSnWe have studied ten consecutive patients who received lamivudine prophylaxis for prevention of HBV graft reinfection. Sequential sera, collected prelamivudine then during treatment before and after liver transplantation, were examined. Conventional serological markers were measured, as were serum viral DNA levels with a sensitive quantitative polymerase chain reaction assay.nnnRESULTSnLamivudine treatment effected a reduction in serum HBV levels, but six patients still had measurable viral DNA at the time of transplantation. Five patients developed graft re-infection with lamivudine-resistant virus. Resistant virus emerged 8 to 15 months post-transplant. The likelihood of emergence of resistant virus was related to the pre-treatment serum HBV titre. Persistent serum viral DNA positivity and evidence of graft re-infection during the early post-transplant period did not predict the subsequent emergence of resistant virus.nnnCONCLUSIONSnOur observations suggest that the resistant species may be present in the viral quasispecies in the serum and liver of patients with high-level replication prior to lamivudine exposure. The resistant species can persist during lamivudine treatment prior to transplantation, and emerge following transplantation. These observations suggest strategies which might prevent the emergence of drug-resistant species, and imply that graft re-infection may be a preventable phenomenon.

Bile duct injury following laparoscopic cholecystectomy: Referral pattern and management

BACKGROUNDnLaparoscopic cholecystectomy is associated with a higher incidence of bile duct injury than open cholecystectomy. This study reviews the management of bile duct injury in a tertiary hepatobiliary unit.nnnMETHODSnFrom 1991 to 1995, 27 patients (18 women) of median age 49 (range 25-67) years were referred to this unit with bile duct injury following elective laparoscopic cholecystectomy. Laparoscopic cholecystectomy was described as uneventful in 14 and difficult in 13 patients; six injuries were recognized at operation.nnnRESULTSnPatients were transferred a median of 26 (range 0-990) days after laparoscopic cholecystectomy, although initial symptoms were recorded a median of 3 (range 0-700) days after cholecystectomy. Fifteen patients underwent additional surgery before referral. Management before referral included surgical exploration (15 patients), endoscopic cholangiography (ERC) and stent insertion (three), external drainage of bile collections (five), and conservative management (five). Management after referral included surgical reconstruction (19 patients), laparotomy with drainage (one), percutaneous drainage (two), ERC and stent insertion (two), percutaneous cholangiography with dilatation and stent placement (three), and conservative management (two). One patient died and the median inpatient stay following referral was 14 (range 7-78) days. Ten of 15 patients who had surgery before referral required a further biliary reconstruction. After median follow-up of 30 (range 3-60) months, four of nine patients with complex high injuries continue to have episodes of cholangitis and one patient has developed secondary biliary cirrhosis.nnnCONCLUSIONnBile duct injury following laparoscopic cholecystectomy is a complex management problem and results in significant postoperative morbidity. Most patients referred after attempted repair require further reconstructive surgery, and patients with complex high injuries have a risk of long-term morbidity.

Steroid withdrawal from long-term immunosuppression in liver allograft recipients.

Corticosteroids were withdrawn from the immunosuppressive regimen of 168/197 (85%) of liver transplant patients who survived for more than three months. In 14, steroids were restarted for reasons other than rejection. The remaining 154 patients were evaluated for the occurrence of rejection and graft loss. Risk factors for the development of rejection after steroid withdrawal were assessed. There were 13 episodes of rejection in 12 (7.8%) grafts; 7 (4.5%) experienced acute cellular rejection, and 6 (3.9%) developed chronic ductopenic rejection. All cases of acute rejection resolved with high-dose steroids. Graft and patient loss due to chronic rejection was 3 (1.9%) and 2 (1.3%), respectively. Chronic rejection resolved in 1 patient, 1 was successfully retransplanted, and in the other 2 the principal cause of death was recurrent tumor. None of the risk factors examined (primary indication for transplant, severity of previous acute rejection, use of OKT3, retransplantation, ABO blood group donor/recipient match, CMV infection, and CsA mono versus CsA and AZA double therapy) were associated with the development of chronic rejection poststeroid withdrawal. The prevalence of side effects, after steroid withdrawal, was low; 66% of patients never required antihypertensive medication; 14% experienced a significant septic episode, and only 4 died with sepsis as the major factor. There were no fungal sepsis and no new cases of diabetes. Withdrawal of corticosteroids after 3 months can be successfully achieved in the majority of liver allograft recipients and is associated with a low rate of rejection, graft loss, and complications attributable to immunosuppressive medication.

Selective decontamination of the digestive tract reduces gram-negative pulmonary colonization but not systemic endotoxemia in patients undergoing elective liver transplantation.

Objective: To examine the effect of selective antibiotic decontamination of the digestive tract in patients undergoing elective orthotopic liver transplantation. Design: Prospective, randomized, concurrent allocation to either selective decontamination or standard antibiotic prophylaxis. Setting: Operating theater and intensive care unit at a tertiary referral, university teaching hospital. Patients: Fifty‐nine adult patients were recruited into the study and underwent liver transplantation. Interventions: Thirty‐two patients were randomized to standard treatment (control group) and 27 patients were randomized to receive selective decontamination. After early deaths and exclusions, 31 controls and 21 decontamination patients were available for analysis. Measurements and Main Results: Portal and systemic endotoxemia, colonization and infection rates, severity of illness (organ system failures, Acute Physiology and Chronic Health Evaluation II score, Therapeutic Intervention Scoring System score), antibiotic costs, and hospital survival rates were measured. Selective decontamination significantly reduced pulmonary infections and enteric, aerobic, and Gram‐negative bacillary colonization without facilitating the emergence of resistant organisms, but selective decontamination had no effect on endotoxemia or the development of organ system failures. The financial costs of the selective decontamination regimen outweighed the advantages gained from an associated reduction in antibiotic usage. Conclusion: The failure of selective decontamination to enhance survival rates in many studies of the regimen in critically ill patients may, in part, be related to the inability of selective decontamination to abolish endotoxemia. (Crit Care Med 1994; 22:40‐49)

Metabolic Effects of Cyclosporin A and FK 506 in Liver Transplant Recipients

Postoperative diabetes is a reported feature of the immunosuppressive agents cyclosporin A and FK 506. To date, however, no randomized comparative studies of the metabolic effects of these two drugs have been performed. In this study, extended (300 min) oral glucose tolerance tests (75 g) were performed a median of 8 mo (range 5–9 mo) postoperatively in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with either cyclosporin A (with or without azathioprine) or FK 506. None of the patients had clinically overt diabetes antedating transplantation. To avoid the confounding effects of corticosteroids, prednisolone was withdrawn at least 6 wk beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Overall blood glucose concentrations after the glucose challenge were significantly elevated in both groups of transplant recipients (P < 0.005 and P < 0.001 for cyclosporin A and FK 506 treatment groups, respectively) compared with the healthy control subjects. Venous whole-blood glucose concentration (mean ± SE) 120 min after the ingestion of oral glucose was significantly higher in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) treatment groups compared with the control subjects (6.6 ± 0.5 vs. 8.8 ± 0.9 vs. 5.2 ± 0.2 mM, respectively). According to 1985 WHO criteria, 4 of 10 cyclosporin A-treated patients had impaired glucose tolerance, whereas 3 of 10 FK 506–treated patients had diabetes with 4 others having impaired glucose tolerance. Overall plasma immunoreactive insulin concentrations were significantly elevated in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) groups, as were C-peptide concentrations (P < 0.02 and P < 0.01, respectively). By contrast, fasting lactate concentrations were significantly lower (P < 0.05) in the transplant patients compared with the control subjects. Total blood ketone body concentrations were slightly higher in both transplant groups with an increased ratio of 3-hydroxybutryate:acetoacetate in the cyclosporin A–treated (P < 0.01) and FK 506–treated (P < 0.02) patients. In conclusion, successful liver transplantation in humans is associated with significant postoperative glucose intolerance and hyperinsulinemia. These metabolic abnormalities are independent of corticosteroid therapy and are more pronounced in patients treated with FK 506 than in comparable patients receiving cyclosporin A with or without azathioprine. Alterations in the circulating ketone body ratio suggest a relatively more reduced hepatic intramitochondrial redox state in liver transplant recipients treated with these immunosuppressive agents.

HYPERKALAEMIA IN CYCLOSPORIN-TREATED RENAL ALLOGRAFT RECIPIENTS

Mean serum potassium levels were significantly higher for 9 months in renal allograft recipients receiving cyclosporin than in those receiving prednisolone and azathioprine. Sustained hyperkalaemia (serum potassium 6.0-7.1 mmol/l) inappropriate for their renal function (glomerular filtration rate 21-36 ml/min) developed in seven of forty-three cyclosporin-treated patients. All seven patients had hyperchloraemic acidosis; four were able to acidify their urine to pH less than or equal to 5.4. Six of the seven patients were hypertensive and receiving beta-blockers; one had had bilateral nephrectomy. Despite hyperkalaemia, plasma aldosterone levels were within the normal range in five patients and raised in two. During moderate sodium restriction, plasma renin activity was low or low-normal in five of the seven patients. In these patients a combination of hypoaldosteronism and renal tubular damage leading to a tubular defect of potassium and hydrogen ion secretion is the apparent cause of the hyperkalaemia and hyperchloraemic acidosis. Hyporeninaemia caused by beta-blockade probably blunts the aldosterone response to hyperkalaemia, thereby worsening it.

Delayed hepatic artery thrombosis in adult orthotopic liver transplantation-a 12-year experience.

BACKGROUNDnAlthough the clinical features of early hepatic artery thrombosis (HAT) are well defined, the features of delayed (more than 4 weeks after transplantation) hepatic artery thrombosis are less clearly defined. The aim of our study was to identify risk factors, clinical presentation, and outcome of management of delayed hepatic artery thrombosis (HAT) after liver transplant (LTx).nnnMETHODSnAn analysis of prospectively collected data of all patients transplanted from 1986 to 1998 was performed. The importance of recipient (age, sex, primary indication for LTx, cytomegalovirus status, and intraabdominal sepsis) and donor factors (donor age, cold ischemia time, and donor cytomegalovirus status), modes of presentation, and outcome of treatment (biliary reconstruction/stenting, regraft, vascular reconstruction, observation) were analyzed.nnnRESULTSnDelayed HAT was seen in 31/1097 adult LTx recipients (incidence 2.8%). No recipient or donor factors were identified as risk factors. A total of 16 patients were symptomatic at presentation (HAT diagnosed on abdominal ultrasound). Six patients had recurrent episodes of cholangitis, four had cholangitis with a stricture, four had cholangitis and intrahepatic abscesses, and two had bile leaks. Biliary reconstruction was done in six patients (all of whom subsequently required a regraft), vascular reconstruction was performed in two patients (one regrafted and one died shortly after), four patients with cholangitis and stricture on presentation had a biliary stent (all four were later regrafted). A total of 16 patients were regrafted, 9 are alive, 5 died within 6 months (septic at time of LTx), 1 died after 1 year, and 1 died after 2 years. Fifteen patients were asymptomatic and detected on routine screening. 5 have remained asymptomatic and are still alive, 1 developed a biliary stricture that was stented and is alive 105 months later, 4 had recurrence of the original disease, 3 developed progressive graft failure and were listed for transplant but died before regraft due to overwhelming sepsis and hepatic encephalopathy. Two patients died due to nonbiliary sepsis.nnnCONCLUSIONSnDelayed HAT is a rare complication of LTx that may present with biliary sepsis, or remain asymptomatic. Biliary or vascular reconstructions do not increase graft survival. Of the patients who were clinically silent on presentation, 20% developed progressive graft failure requiring a second transplant. A total of 33% survived in the long-term without a second transplant. Ongoing severe sepsis at the time of regraft results in poor survival.

Transplantation of the liver in adults and children with fulminant hepatic failure

Fulminant hepatic failure has a high mortality rate despite intensive medical treatment. Urgent hepatic transplantation was considered over a 3 year period in 26 (36%) of 73 patients with the worst prognostic features of fulminant hepatic failure. The criteria for patient selection were based on the duration of advanced hepatic coma and the deterioration of liver function. Sixteen patients were transplanted, and 9 (56%) are currently alive. The median duration of follow-up is 16 months and actuarial 1 year survival 55%. Six patients died because of the absence of offers of organ donation. Twenty-two (85%) of the 26 patients considered were referred with advanced encephalopathy or hepatorenal syndrome. Of the 57 patients not transplanted, 18 (95%) of 19 patients with grade I/II encephalopathy survived compared to 13 (34%) of 38 patients with grade III/IV encephalopathy. Transplantation does improve the chance of survival in selected patients with fulminant hepatic failure, early referral and availability or organ donation being important factors.

Timing, significance, and prognosis of late acute liver allograft rejection.

Liver allograft rejection is usually divided into acute (cellular) rejection and chronic (ductopenic) rejection. Most cases of acute rejection occur within four weeks of transplantation. There is a paucity of published literature on late acute rejection (LAR) in liver allografts and little is known about factors affecting its occurrence and outcome. To study the predisposing factors, clinical presentation, and prognosis of LAR, data prospectively collected on consecutive adult patients who underwent liver transplantation between 1982 and 1994, were analyzed. LAR was defined as histologically confirmed acute cellular rejection occurring 30 or more days after liver transplantation. Of the 717 patients, 59 (7.5%) had 71 episodes of LAR. Fifty-seven episodes were seen during the first year after transplantation, the remaining occurring between 1 and 6 years. Age, sex, pretransplant diagnosis, donor match of HLA, and blood groups was not associated with risk of LAR. Twenty-seven (38%) episodes were preceded by subtherapeutic blood levels of cyclosporine/FK506 (< 100 ng/ml and < 5 ng/ml, respectively) while an additional 6 (8%) had marginally low blood levels (< 150 ng/ml and < 10 ng/ml, respectively). Treatment with high-dose prednisolone resulted in complete resolution of rejection in 36 (51%) episodes, partial response in 21, and no response in 14 patients. Sixteen patients (27%) developed chronic rejection and graft loss. Development of chronic rejection was not affected by age or sex of the patient, timing of LAR, or histological severity of AR. Delayed response to therapy during an earlier episode of AR, and histological findings of centrilobular necrosis or bile duct loss at the time of diagnosis of LAR were associated with high risk of progression to chronic rejection and graft loss.