Vincent G. Bain

Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma.

An increasing number of patients with hepatocellular carcinoma (HCC) are undergoing evaluation for listing for liver transplantation. Criteria for selection require ongoing review for suitability. A consecutive series of 40 patients with HCC within the standard Milan criteria (single tumors n = 19 <5 cm, or up to 3 tumors <3 cm) and beyond (Extended Criteria; single tumors n = 21 <7.5 cm, multiple tumors <5 cm) underwent liver transplant with a sirolimus‐based immunosuppressive protocol designed to minimize exposure to calcineurin inhibitors and steroids. At 44.3 ± 19.3 months (mean ± standard deviation) follow‐up, 1‐ and 4‐year survivals (Kaplan‐Meier) are 94.1 ± 5.7% and 87.4 ± 9.3%, in the Milan group, respectively, and 90.5 ± 6.4% and 82.9 ± 9.3% in the Extended Criteria group, respectively. Five patients died during follow‐up, only 1 from recurrent HCC. Five tumor recurrences have occurred at median 17 (mean 22 ± 17) months posttransplant, 1 in the Milan group and 4 in the Extended Criteria group. Median survival in the patients with recurrent tumor is 42 months (mean 45 ± 25), and the median postrecurrence survival is 15.5 months (mean 23 ± 16). The rate of patients who were alive and free of tumor at 1 and 4 years is 94.1 ± 5.7% and 81.1 ± 9.9%, respectively, in the Milan group and is 90.5 ± 6.4% and 76.8 ± 10.5%, respectively, in the Extended Criteria group. Five patients had sirolimus discontinued for toxicity, while 24 of 35 surviving patients have sirolimus monotherapy immunosuppression. In conclusion, the Milan criteria for liver transplantation in the presence of HCC can be carefully extended without compromising outcomes. This sirolimus based immunosuppression protocol appears to have beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity. (Liver Transpl 2004;10:1301–1311.)

Severe muscle depletion in patients on the liver transplant wait list: Its prevalence and independent prognostic value

As detected by cross‐sectional imaging, severe muscle depletion, which is termed sarcopenia, holds promise for prognostication in patients with cirrhosis. Our aims were to describe the prevalence and predictors of sarcopenia in patients with cirrhosis listed for liver transplantation (LT) and to determine its independent prognostic significance for the prediction of waiting‐list mortality. Adults listed for LT who underwent abdominal computed tomography/magnetic resonance imaging within 6 weeks of activation were retrospectively identified. The exclusions were hepatocellular carcinoma, acute liver failure, prior LT, and listing for multivisceral transplantation or living related LT. Sixty percent of the 142 eligible patients were male, the median age was 53 years, and the median Model for End‐Stage Liver Disease (MELD) score at listing was 15. Forty‐one percent were sarcopenic; sarcopenia was more prevalent in males versus females (54% versus 21%, P < 0.001) and increased with the Child‐Pugh class (10% for class A, 34% for class B, and 54% for class C, P = 0.007). Male sex, the dry‐weight body mass index (BMI), and Child‐Pugh class C cirrhosis (but not the MELD score) were independent predictors of sarcopenia. Sarcopenia was an independent predictor of mortality (hazard ratio = 2.36, 95% confidence interval = 1.23‐4.53) after adjustments for age and MELD scores. In conclusion, sarcopenia is associated with increased waiting‐list mortality and is poorly predicted by subjective nutritional assessment tools such as BMI and subjective global assessment. If this is validated in larger studies, the objective assessment of sarcopenia holds promise for prognostication in this patient population. Liver Transpl 18:1209–1216, 2012.

De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: Long-term outcomes and side effects

Background. We report long-term outcomes and side effects after transplantation for hepatocellular carcinoma (HCC) using de novo, sirolimus-based immunosuppression (IS). Methods. A total of 70 patients with HCC (mean age: 54.4±7 years, female/male: 12/58) were transplanted and included in the study. Immunosuppression included de novo sirolimus, low-dose calcineurin inhibitor for 6 to 12 months, with short-course (3 months) or no steroids. Results. After 49 months-median follow-up, eight patients have experienced an HCC recurrence, 2 of 34 when Milan criteria were respected (6%) and 6 of 36 when beyond Milan criteria (17%). One- and 4-year tumor-free survivals were 85 and 73%, when Milan criteria were respected and 82% and 75% when they were not, respectively. (P=0.9). After recurrence, mean survival was 23±28 months. Half (35 of 70) of the patients experienced a rejection. Incisional hernia (24 of 70, 34%), wound infection (12 of 70, 17%), anemia (39 of 70, 56%), leucopenia (39 of 70, 56%), high triglyceride (43 of 70, 61%), and cholesterol (28 of 70, 40%) levels and mouth ulcers (20 of 70, 29%) were among the most frequent complications. No hepatic artery thrombosis was observed. Conclusions. These data suggest that de novo sirolimus-based immunosuppression is associated with satisfactory outcomes after transplantation, even in selected patients beyond Milan criteria. The protocol has proven safe, with an acceptable side-effect profile. This study supports the conduct of larger randomized trials investigating sirolimus after transplantation for HCC.

Efficacy of lamivudine in chronic hepatitis B patients with active viral replication and decompensated cirrhosis undergoing liver transplantation.

Liver transplantation for endstage hepatitis B virus (HBV) infection has been associated with survival inferior to that of liver transplantation in other chronic liver diseases due to HBV reinfection of the graft. Lamivudine is a new nucleoside analog with potent antiviral effects against hepatitis B. Our aim was to test its efficacy when used pre- and posttransplantation in HBV-DNA positive patients with endstage liver disease. Patients received oral lamivudine 100 mg daily both pretransplant and posttransplant. Viral serology, serum and tissue HBV-DNA and liver histology were assessed sequentially. Five consecutive patients with endstage hepatitis B were entered into the trial. Serum HBV-DNA was cleared pretransplant in all patients. Three of four transplanted patients cleared HBeAg and HBsAg postoperatively, whereas all four became negative for serum HBV-DNA (dot-blot and PCR). Liver biopsies were negative for HBV-DNA by PCR in 3 of 4 cases. Lymphocytes were negative for HBV-DNA by PCR in all cases. With follow-up of 3, 14, 16, and 26 months, two patients have normal liver enzymes and normal liver histology and two have developed recurrent hepatitis B. No significant side effects were seen. This pilot study shows that lamivudine can effectively inhibit hepatitis B virus in cirrhotic patients pretransplant and posttransplant. A lamivudine resistant mutant developed in two patients. Transplant recipients with actively replicating HBV related cirrhosis may achieve a good outcome after liver transplantation using lamivudine, but viral resistance is likely to be a significant problem.

Prediction of cardiac complications after liver transplantation.

Background. Orthotopic liver transplantation (OLT) stresses the cardiovascular system, and cardiac complications after OLT are common. Methods. Hundred ninety-seven patients (≥40 years) who had OLT from 2002 to 2007 were reviewed to identify predictors of cardiac complications within 6 months after transplantation. Results. Median age was 56 years (40–75 years); 69% men. Reasons for OLT were hepatitis C virus (HCV) 45.5%, alcohol 22%, hepatocellular carcinoma (HCC) 8%, primary biliary cirrhosis 10%, and others 14.5%. Eighty-two patients suffered one or more cardiac complications within 6 months after OLT (pulmonary edema=61 [overt heart failure=7], arrhythmia=13, pulmonary hypertension=7, pericardial effusion=2, and right atrial thrombus=1). Cardiac causes were the leading cause of death (n=5; 23.8% of all mortality). By multivariate analysis, after adjusting for age and sex, independent predictors were adverse intraoperative cardiovascular events (adjusted odds ratio; 95% confidence interval: 5.89, 1.82–19.14), history of cardiac disease (2.42, 0.89–6.6), and i-MELD (integrated model for end-stage liver disease) score (1.08, 1.02–1.14), whereas adverse intraoperative cardiovascular events (5.73, 1.96–16.78) and i-MELD (1.07, 1.01–1.13) predicted pulmonary edema. None of the following variables predicted complications: age, sex, OLT indication, body mass index, blood pressure, alcohol and smoking history, pre-OLT investigations (chest X-ray, electrocardiogram, echocardiography, coronary angiography, pulmonary arterial pressure, and 2-methoxy isobutyl isonitrile scan), immunosuppressive treatment, or intraoperative variables (transfusion amount, cadaveric vs. living graft or cold ischemia and rewarming times). Conclusions. Cardiac complications after OLT are common and were the leading cause of death after surgery. Adverse intraoperative cardiovascular events, previous cardiac disease, and advanced liver disease as quantified by i-MELD score predicted postoperative cardiac complications.

Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: A multicenter randomized clinical trial

Posttransplant chronic renal failure, secondary to calcineurin inhibitor agents, is emerging as a major problem in liver transplantation. We report a randomized clinical trial comparing daclizumab, delayed low‐dose tacrolimus (target trough level 4‐8 ng/mL, starting day 4‐6), Investigational Arm (n = 72), to standard tacrolimus induction/maintenance dosing, Standard Arm (n = 76), with mycophenolate mofetil and tapering corticosteroids in both study arms. The end‐points were renal function indicated by the Modification of Diet in Renal Disease (MDRD). There was no significant difference in patient survival (86.6% Investigational Arm vs. 92.9% Standard Arm; P = 0.21) or acute rejection (23.2% vs. 27.7%, respectively; P = 0.68). Statistically significant differences in median glomerular filtration rate (GFR) were found in favor of the Investigational Arm. With the CG equation, the GFR at the end of the first week was 110.7 vs. 89.6 mL/min (P = 0.019) without significant differences thereafter. With the MDRD, statistically significant differences extended to the first posttransplant month (86.8 vs. 70.1 mL/min/1.73 m2; P < 0.001) with and was seen at month 6 (75.4 vs. 69.5 mL/min/1.73 m2; P = 0.038). In conclusion, delayed low‐dose tacrolimus, in combination with daclizumab and mycophenolate mofetil, preserves early renal function post–liver transplantation without the cost of increased acute rejection. (Liver Transpl 2005;11:1064–1072.)

Liver transplantation for incidental cholangiocarcinoma: Analysis of the Canadian experience

Cholangiocarcinoma is a biliary tumor, which not infrequently complicates primary sclerosing cholangitis. It carries a poor prognosis and, with the exception of carefully selected individuals in research protocols, contraindicates orthotopic liver transplantation. There has been some suggestion that cholangiocarcinomas incidentally discovered at the time of transplantation carry a better prognosis. The goal of this retrospective study was to perform a national review of outcomes after liver transplantation in Canadian recipients found to have incidental cholangiocarcinoma in their explanted native liver. Six of the seven liver transplant centers in Canada provided clinical and follow‐up information on all liver transplant recipients found to have incidental cholangiocarcinoma in their explants. The diagnosis or suspicion of cholangiocarcinoma prior to transplantation were exclusion criteria for this study. Ten individuals with cholangiocarcinoma were transplanted between 1996 and 2003. The median duration of follow‐up was 28 months. Eight of the 10 had PSC. All of the tumors were stage I or II. The 3‐year survival for these patients was 30%. The median time to recurrence was 26 months (95% confidence interval 13uu‐uu37), and the median time to death was 30 months (95% confidence interval 28uu‐uu53). In conclusion, although early survival of patients transplanted for incidental cholangiocarcinoma appears good, intermediate‐ and long‐term survival rates are not better than for individuals historically transplanted with known cholangiocarcinoma. Aggressive investigation for cholangiocarcinoma is mandated. Incidentally found tumours remain a difficult treatment problem, and prospective adjuvant chemo‐, radio‐, and immunotherapies should be investigated. (Liver Transpl 2005;11:1412–1416.)

Evolution of autoimmune hepatitis to primary sclerosing cholangitis: A sequential syndrome☆

Recently, the autoimmune hepatitis (AIH)/primary sclerosing cholangitis (PSC) overlap syndrome has been reported increasingly. In this syndrome, patients present with features of both AIH and PSC. It has been suggested that the 2 diseases may be sequential in their occurrence, whereby patients have features of AIH and then after a number of years develop features of PSC, but clear confirmation of evolution has not been documented in adults. We describe 6 adult cases in which PSC was diagnosed many years after well‐established AIH. Six patients are described in whom AIH definitely was diagnosed at presentation. No evidence of biliary disease was noted on the initial liver biopsy or endoscopic retrograde cholangiography (ERCP). All patients responded well to immunosuppressive therapy. After an average duration of follow‐up of 4.6 years they became resistant to immunosuppression, and developed clear features of PSC, which was confirmed by ERCP in all patients. The average age of the patients at first presentation was 31.3 years, 2 were women and 4 were men, and 3 had ulcerative colitis. We found no specific features at presentation that could predict this evolutionary outcome. In conclusion, patients with well‐established AIH can, after variable duration of follow‐up, develop PSC. In patients with AIH who become resistant to immunosuppression of develop significant cholestasis, PSC should be ruled out by ERCP. (HEPATOLOGY2002;36:1393–1399).

Transplant immunosuppressive agents in non‐transplant chronic autoimmune hepatitis: the Canadian association for the study of liver (CASL) experience with mycophenolate mofetil and tacrolimus

Background: Conventional treatment of autoimmune hepatitis consists of either prednisone alone or in combination with azathioprine. Ten to 20% of patients do not respond to or are intolerant of this treatment. Novel drug treatments include immunosuppressive drugs such as tacrolimus (TAC), mycophenolate mofetil (MMF), methotrexate and cyclosporine. We describe a multi‐centre Canadian experience with MMF and TAC.

Rapid resolution of chylous ascites after liver transplantation using somatostatin analog and total parenteral nutrition

Chylous ascites is the accumulation of chylomicronrich lymphatic fluid within the peritoneal cavity. It is a rare complication of retroperitoneal surgery, and may occur spontaneously in 0.5% of patients with cirrhosis. Its management is controversial, and despite a variety of treatment options with limited efficacy, the course is usually indolent. In this article, we report a case of rapid resolution of chylous ascites after liver transplantation following 10 days of treatment using somatostatin analog (Octreotide, 100 micrograms sc. t.i.d.) and total parenteral nutrition (TPN). A 55-year-old man underwent liver transplantation for hepatitis C cirrhosis, and developed an infected chylous fistula on the 10th day. Treatment by fasting, TPN, and somatostatin analog resulted in a rapid falloff in fistula output, with complete resolution of ascites within 2 days. This is the first report, to our knowledge, of somatostatin analog and TPN used in combination for rapid and successful closure of a chylous fistula.