David Mayer

Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome

BACKGROUND Portal vein thrombosis (PVT) has been seen as an obstacle to liver transplantation (LTx). Recent data suggest that favorable results may be achieved in this group of patients but only limited information from small size series is available. The present study was conducted in an effort to review the surgical options in patients with PVT and to assess the impact of PVT on LTx outcome. Risk factors for PVT and the value of screening tools are also analyzed. METHODS Adult LTx performed from 1987 through 1996 were reviewed. PVT was retrospectively graded according to the operative findings: grade 1: <50% PVT +/- minimal obstruction of the superior mesenteric vein (SMV); grade 2: grade 1 but >50% PVT; grade 3: complete PV and proximal SMV thrombosis; grade 4: complete PV and entire SMV thrombosis. RESULTS Of 779 LTx, 63 had operatively confirmed PVT (8.1%): 24 had grade 1, 23 grade 2, 6 grade 3, and 10 grade 4 PVT. Being male, treatment for portal hypertension, Child-Pugh class C, and alcoholic liver disease were associated with PVT. Sensitivity of ultrasound (US) in detecting PVT increased with PVT grade and was 100% in grades 3-4. In patients with US-diagnosed PVT, an angiogram was performed and ruled out a false positive US diagnosis in 13%. In contrast with US, angiograms differentiated grade 1 from grade 2, and grade 3 from grade 4 PVT. Grade 1 and 2 PVT were managed by low dissection and/or a thrombectomy; in grade 3 the distal SMV was directly used as an inflow vessel, usually through an interposition donor iliac vein; in grade 4 a splanchnic tributary was used or a thrombectomy was attempted. Transfusion requirements in PVT patients (10 U) were higher than in non-PVT patients (5 U) (P<0.01). In-hospital mortality for PVT patients was 30% versus 12.4% in controls (P<0.01). Patients with PVT had more postoperative complications, renal failure, primary nonfunction, and PV rethrombosis. The overall actuarial 5-year patient survival rate in PVT patients (65.6%) was lower than in controls (76.3%; P=0.04). Patients with grade 1 PVT, however, had a 5-year survival rate (86%) identical to that of controls, whereas patients with grades 2, 3, and 4 PVT had reduced survival rates. The 5-year patient survival rate improved from the 1st to the 2nd era in non-PVT patients (from 72% to 83%; P<0.01), in grade 1 PVT (from 53% to 100%; P<0.01), and in grades 2 to 4 PVT (from 38% to 62%; P=0.11). CONCLUSIONS The value of US diagnosis in patients with PVT depends on the PVT grade, and false negative diagnoses occur only in incomplete forms of PVT (grades 1-2). The degree of PVT dictates the surgical strategy to be used, thrombectomy/low dissection in grade 1-2, mesoportal jump graft in grade 3, and a splanchnic tributary in grade 4. Taken altogether, PVT patients undergo more difficult surgery, have more postoperative complications, have higher in-hospital mortality rates, and have reduced 5-year survival rates. Analysis by PVT grade, however, reveals that grade 1 PVT patients do as well as controls; only grades 2 to 4 PVT patients have poorer outcomes. With increased experience, results of LTx in PVT patients have improved and, even in severe forms of PVT, a 5-year survival rate >60% can now be achieved.

Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial.

BACKGROUND The liver is the most frequent site for metastases of colorectal cancer, which is the second largest contributor to cancer deaths in Europe. We did a randomised trial to compare an intrahepatic arterial (IHA) fluorouracil and folinic acid regimen with the standard intravenous de Gramont fluorouracil and folinic acid regimen for patients with adenocarcinoma of the colon or rectum, with metastases confined to the liver. METHODS We randomly allocated 290 patients from 16 centres to receive either intravenous chemotherapy (folinic acid 200 mg/m2, fluorouracil bolus 400 mg2 and 22-h infusion 600 mg/m2, day 1 and 2, repeated every 14 days), or IHA chemotherapy designed to be equitoxic (folinic acid 200 mg/m2, fluorouracil 400 mg/m2 over 15 mins and 22-h infusion 1600 mg/m2, day 1 and 2, repeated every 14 days). The primary endpoint was overall survival, and analysis was by intention to treat. FINDINGS 50 (37%) patients allocated to IHA did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. The IHA group received a median of two cycles (0-6), compared with 8.5 (6-12) for the intravenous group. 45 (51%) IHA patients who did not start or did not receive six cycles switched to intravenous treatment. In both groups, grade 3 or 4 toxicity was uncommon. Median overall survival was 14.7 months for the IHA group and 14.8 months for the intravenous group (hazard ratio 1.04 [95% CI 0.80-1.33], log-rank test p=0.79). Similarly, there was no significant difference in progression-free survival. INTERPRETATION Our results showed no evidence of an advantage in progression-free survival or overall survival for the IHA group; thus continued use of this regimen cannot be recommended outside of a clinical trial.

Hepatic artery thrombosis following orthotopic liver transplantation: a 10-year experience from a single centre in the United Kingdom.

Hepatic artery thrombosis (HAT) occurs in 3–9% of all liver transplants and acute graft loss is a possible sequelae. We present our experience in the management of HAT over a 10‐year period. Prospectively collected data from April 1994 to April 2004 were analyzed. There were 1,257 liver transplants, 669 males, median age 51 (16–73) years. There were 61 (4.9%) cases of HAT. Early HAT occurred in 21 (1.8%). Thirty six had graft dysfunction, 11 required a regraft, and 14 died. Positive CMV serology in the donor, cold ischemia time, duration of operation, transfusions of more than 6 units of blood, and 15 units of plasma, an aortic conduit for arterial reconstruction, Roux‐en‐Y biliary reconstructions, regrafts and relaparotomy were associated with HAT. At multivariate analysis, type of biliary anastomosis was the only significant factor associated with HAT. Split or reduced liver graft were not risk factors for HAT. Number of hepatic arteries requiring multiple arterial anastomosis was not a risk for HAT. HAT resulted in a reduction in overall survival post liver transplantation. The incidence of HAT was 4.9%; with 1.8% early HAT and HAT impacted on survival. Surgical technique was not an aetiological factor for HAT. In conclusion, while a Roux‐en‐Y biliary reconstruction was an independent risk factor for HAT, cold ischemia and operative times, the use of blood and plasma and the use of aortic conduits in arterial reconstruction were associated with HAT. Regrafts and reoperation were also identified risk factors. Liver Transpl 12:146–151, 2006.

Corticosteroid‐free immunosuppression with tacrolimus following induction with daclizumab: A large randomized clinical study

This open, randomized (1 : 1), multicenter, 3‐month study compared a dual tacrolimus plus steroids (Tac / steroids) regimen with a steroid‐free immunosuppressive regimen of tacrolimus following daclizumab induction therapy (Tac / Dac) in adult liver transplant recipients. The full analysis set comprised 347 patients in the Tac / steroids group and 351 in the Tac / Dac group. Mean tacrolimus dose during month 3 was 0.11 mg/kg/day in both groups; mean whole‐blood trough levels during month 3 were 10.9 ng/mL (Tac / steroids) and 10.6 ng/mL (Tac / Dac). The incidence of biopsy‐confirmed acute rejection that required treatment was similar in both groups: 26.5% in the Tac / steroids group and 25.4% in the Tac / Dac group (P = .727). However, the incidence of biopsy‐confirmed corticosteroid‐resistant acute rejection was higher in the Tac / steroids group than in the Tac / Dac group (6.3 vs. 2.8%; P = .027). Kaplan‐Meier estimates of graft survival (92.2 vs. 90.5%) and patient survival (94.5 vs. 93.7%) were similar in both groups. While also the overall adverse event profiles were similar, the incidences of diabetes mellitus (15.3 vs. 5.7%, respectively; P < .001) and cytomegalovirus infection (11.5 vs. 5.1%, respectively; P = .002) were higher in the Tac / steroids group compared with the Tac / Dac group. Mean cholesterol levels increased by 16% in the Tac / steroids group, but were unchanged in the Tac / Dac group during the study. In conclusion, tacrolimus monotherapy following daclizumab induction is an effective and safe regimen, with an advantage over concomitant steroid‐maintenance therapy in terms of a lower incidence of diabetes and viral infection, and a lower incidence of steroid‐resistant acute rejection. (Liver Transpl 2005;11:61–67.)

Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12‐ and 36‐month results

Everolimus is a macrolide immunosuppressive agent with known consistent absorption. In this double‐blind study, we examined the safety and tolerability of everolimus vs. placebo in de novo liver transplant recipients. One hundred and nineteen liver allograft recipients were randomized to 1 of 4 groups: everolimus 0.5 mg bid, everolimus 1.0 mg bid, everolimus 2 mg bid, or placebo. Patients received oral cyclosporine to achieve a target trough level of 150‐400 ng/mL in combination with prednisone. Primary and secondary endpoints of safety, tolerability, and efficacy were determined at 12 months, and patients were followed through 36 months. There was a trend toward fewer treated acute rejections in the everolimus group than in the placebo group: everolimus 0.5 mg: 39.3%; everolimus 1.0 mg: 30.0%; everolimus 2 mg: 29.0%; placebo: 40.0% (P = not significant). Adverse events were higher in everolimus‐treated patients especially at the 4‐mg/day dose, but there was no difference in the incidence of thrombocytopenia or leukopenia between all groups and renal function as determined by serum creatinine, and creatinine clearance remained stable to 36 months in everolimus‐treated patients. Mean cholesterol and triglycerides increased from baseline in all treatment groups, and maximum levels were seen at 6 months. In conclusion, this study demonstrates that everolimus in combination with oral cyclosporine had an acceptable safety and tolerability profile, paving the way for additional studies in this transplant indication. Liver Transpl, 2006.

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.

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

BACKGROUND Although 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). METHODS An 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. RESULTS Delayed 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. CONCLUSIONS Delayed 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.

A simple scoring system to evaluate the effects of cold ischemia on marginal liver donors

Background. Exactly what constitutes a marginal donor remains ill defined. The authors set out to create a scoring system that objectively classifies a donor as marginal or nonmarginal and to define what the maximum acceptable preservation period is for the marginal liver to minimize early graft dysfunction. Methods. The authors performed an analysis on data collected prospectively of 397 cadaveric liver transplants. Both univariate and multivariate analyses were performed on donor, recipient, and perioperative factors with relation to early allograft dysfunction. A score was developed that classified donors into marginal and nonmarginal populations, and the influence of cold ischemia was determined for each group. Results. Multivariate analysis-determined donor age and steatosis (moderate to severe) were independent predictors of deranged function. This enabled the authors to produce a scoring system to differentiate marginal donors with respect to risk of early allograft dysfunction as follows: Formula=(20.06×steatosis)+ (0.44×donor age), cutoff 23.1. In the marginal group, the cutoff value of cold ischemia time was 12.6 hr. Conclusions. The authors developed a scoring system that classified an organ as marginal or nonmarginal depending on the donor age and degree of steatosis. Marginal livers have a strong risk of developing early allograft dysfunction with increasing cold ischemia times and should be transplanted within 12 hr. Cold ischemia time was not found to be an important factor in the development of early allograft dysfunction in nonmarginal donors.

Liver retransplantation in adults: a single-centre, 25-year experience

BACKGROUND Retransplantation is the only form of treatment for patients with irreversible graft failure. The aim of this study was to analyse a single centres experience of the indications for and outcomes of retransplantation. METHODS A total of 196 patients who underwent liver retransplantation using 225 grafts, between January 1982 and July 2007, were included in the study. The following parameters were analysed: patient demographics; primary diagnosis; distribution of retransplantation over different time periods; indications for retransplantation; time interval to retransplantation, and overall patient and graft survival. RESULTS Of the 2437 primary orthotopic liver transplantations, 196 patients (8%) required a first regraft, 23 patients (1%) a second regraft and six patients (0.25%) a third regraft. Autoimmune hepatitis was the most common primary diagnosis for which retransplantation was required (12.7% of primary transplantations). The retransplantation rate declined from 12% at the beginning of our programme to 7.6% at the end of the study period. The most common indication for retransplantation was hepatic artery thrombosis (31.6%). Nearly two-thirds of the retransplantations were performed within 6 months of the primary transplantation. The 1-, 3-, 5- and 10-year patient survival rates following first retransplantation were 66%, 61%, 57% and 47%, respectively. Five-year survival after second retransplantation was 40%. None of the patients have yet survived 3 years after a third regraft. Donor age of < or =55 years and a MELD (Model for End-stage Liver Disease) score of < or =23 were associated with better outcome following retransplantation. CONCLUSIONS First retransplantation was associated with good longterm survival. There was no survival benefit following second and third retransplantations. A MELD score of < or =23 and donor age of < or =55 years correlated with better outcome following retransplantation.

Biliary complications after paediatric liver transplantation: Birmingham's experience

Abstract Between 1983 and 1992, 112 children underwent liver transplantation. Of 138 grafts, 60 (43.4%) were whole livers, 77 (55.6%) were reduced livers, and 1 (0.7%) was a split liver. Biliary complications (BC) were defined as any abnormality, even minor, related to the biliary tract. Results were analysed with a minimum follow‐up of 9 months. Some 36 grafts (26.1%) in 34 patients (30.4%) presented with BC: bile leaks (17 grafts), biliary obstructions or dilatations (16 grafts), and other complications (3 grafts). Management was mainly surgical with biliary reconstruction via a Roux‐en‐Y loop. Interventional radiology had an increasing role in recent years. BC were associated with a mortality of 1.8% (2/112), a graft loss rate of 4.3% (6/138), and significant morbidity. Among the various factors whose association with BC was studied, the date of transplantation, the use of reduced grafts and the use of gallbladder conduits appeared to be the main determining factors for BC. From multivariate analysis the use of reduced grafts emerged as the most important factor in reducing BC. We therefore conclude that BC are associated with significant morbidity, but general improvements in both surgical and medical management seem to account for better results in recent years.