Javier Bustamante

Prognostic significance of hepatic encephalopathy in patients with cirrhosis

BACKGROUND There are numerous studies concerning the natural history and prognostic factors in cirrhosis, the results of which are useful in selecting liver transplant candidates. However, little attention has been paid to the prognostic significance of hepatic encephalopathy despite the high frequency of this complication. METHODS We reviewed the charts of 111 cirrhotic patients who developed a first episode of acute hepatic encephalopathy to determine their survival probability and to identify prognostic factors. RESULTS During follow-up (12+/-17 months), 82 (74%) patients died. The survival probability was 42% at 1 year of follow-up and 23% at 3 years. With univariate analyses followed by a multivariate analysis, 7 out of 30 clinical and standard laboratory variables were significantly associated with poor prognosis: male sex, increased serum bilirubin, alkaline phosphatase, potassium and blood urea nitrogen, and decreased serum albumin and prothrombin activity. Patients were classified into two groups according to a prognostic index calculated from these 7 variables. Survival probability at 1 and 3 years was 73% and 38%, respectively, in patients with a low prognostic index, and 10% and 3% in patients with a high prognostic index. CONCLUSION Hepatic encephalopathy is associated with short survival in cirrhotic patients. Although these patients can be classified into several groups with a different prognosis, the survival probability in every group is lower than that currently expected after liver transplantation. Therefore, cirrhotic patients developing a first episode of acute hepatic encephalopathy should be considered as potential candidates for this therapeutic procedure.

Diabetes mellitus after liver transplantation: prevalence and predictive factors.

AIMS/METHODS To investigate the prevalence and risk factors for the development of diabetes mellitus after orthotopic liver transplantation, we reviewed 27 variables (including previous history of diabetes mellitus, data related to pre-transplant liver disease, and postoperative events) in 102 patients who survived longer than 1 year after orthotopic liver transplantation. RESULTS Fourteen patients had diabetes mellitus prior to liver transplantation and all but one were alive 2 and 3 years after transplantation, with all survivors continuing to have diabetes mellitus 1, 2 and 3 years after transplantation. Among the 88 patients without pre-transplant diabetes mellitus, the prevalence of post-transplant diabetes mellitus was 27% at 1 year, 9% at 2 years and 7% at 3 years, probably related to a significant reduction in the daily prednisone dose (13 +/- 4 mg at 1 year, 7 +/- 6 mg at 2 years and 2 +/- 4 mg at 3 years, p < 0.001). Patients with post-transplant diabetes mellitus 1 year after transplantation had a higher number of rejection episodes during the first postoperative year than those without post-transplant diabetes mellitus (1.5 +/- 1.1 vs 1.1 +/- 0.7, p < 0.05) and also had higher, but not statistically significant, cumulative steroid dose and blood cyclosporine levels. Mortality of patients with post-transplant diabetes mellitus was significantly higher during the second postoperative year in comparison with patients without post-transplant diabetes mellitus: 4/24 vs 2/64 (17% vs 3%; p < 0.05). CONCLUSIONS Liver transplantation does not significantly modify pre-transplant diabetes mellitus. Diabetes mellitus frequently develops de novo after liver transplantation, although this complication is usually transient and probably related to immunosuppressive drug administration. The prognosis of patients with post-transplant diabetes mellitus is worse than that of those without this complication.

Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation

There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression‐free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4–25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3–11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post–liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option. Liver Transpl 18:45–52, 2012.

Management of Hepatocellular Carcinoma Recurrence After Liver Transplantation

UNLABELLED Management of patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (OLT) is not well established. We conducted a retrospective analysis of our results in the treatment of HCC recurrence after OLT Patients. The 23 HCC recurrences developed after 182 OLT performed for HCC within Milan criteria, had an average follow-up of 60 months. RESULTS The median time to recurrence was 23.4 months. Surgical resection of the recurrence was possible in 11 patients, but an R-0 resection was obtained in 8 patients. Four of these 8 patients developed another recurrence, with 3 succumbing due to tumor recurrence and 1 alive at 12 months with recurrence. The other 4 patients without recurrences, include 3 who are alive at 19, 31, and 86 months and 1 who died at 32.6 months due to hepatitis C recurrence. The 3 patients with palliative resections developed recurrences. Twelve patients were rejected for surgery: 8 were treated symptomatically, 2 with systemic chemotherapy, and 2 with everolimus and sorafenib. This last treatment was also prescribed for 2 patients after R-0 surgery who are alive at 19 and 31 months and for 1 patient after R-1 surgery who is alive at 19 months. Of 15 patients who died, 13 succumbed to HCC recurrence. The average survival from transplantation was 61.7 +/- 37.5 and 48 +/- 34.3 months for patients without and with recurrence, respectively (P < .001). The survival from the recurrence was significantly higher among patients with R-0 surgery: 32.3 +/- 21.5 versus 11.9 +/- 6.9 months (P = .006). CONCLUSIONS HCC recurrence after OLT of patients within Milan criteria was low but had a great impact on survival. Few cases are amenable to R-0 resection, but when possible it was associated with a significantly increased survival, although with an high incidence of a new recurrence. There is a rationale for the use of sorafenib and mammalian target of rapamycin based immunosuppression, which warrants randomized studies.

Liver transplantation for hepatocellular carcinoma in cirrhotic patients

A consecutive series of 88 patients underwent transplantation for hepatocellular carcinoma with cirrhosis over a 7-year period. Liver transplantation was indicated because of the tumor in 75 cases (85.2%); tumor was an incidental finding in 13 cases (14.8%). One patient was retransplanted due to primary nonfunction. The perioperative mortality was 4.5%. Tumor recurrence was observed in seven patients (7.95%) with incidental tumor recurrence in one case. As in patients with known primary liver tumors pretransplant, a thorough follow-up is advisable to establish an early diagnosis of recurrence. The actuarial survival for nonincidental hepatocellular carcinoma at 1, 3, and 5 year was 92%, 77%, and 75%, respectively. The differences in actuarial survival between hepatitis C negative and positive hepatocellular carcinoma were not significant (log-rank test P=.27), though there was a clear improvement in results (94%, 85%, and 78% vs 90%, 71%, and 71%), at 1, 3, and 5 years meaning that HCV infection is an important prognostic factor. Although transplantation for HCC has the advantages of removing the tumor and the cirrhotic liver, it remains a controversial topic. In our experience patients showing lesions less than 5 cm or three or fewer lesions experience an equivalent survival to transplanted patients who do not have cancer.

Renal function improvement in liver transplant recipients after early everolimus conversion: A clinical practice cohort study in Spain: Everolimus in Liver Transplantation

A national, multicenter, retrospective study was conducted to assess the results obtained for liver transplant recipients with conversion to everolimus in daily practice. The study included 477 recipients (481 transplantations). Indications for conversion to everolimus were renal dysfunction (32.6% of cases), hepatocellular carcinoma (HCC; 30.2%; prophylactic treatment for 68.9%), and de novo malignancy (29.7%). The median time from transplantation to conversion to everolimus was 68.7 months for de novo malignancy, 23.8 months for renal dysfunction, and 7.1 months for HCC and other indications. During the first year of treatment, mean everolimus trough levels were 5.4 (standard deviation [SD], 2.7) ng/mL and doses remained stable (1.5 mg/day) from the first month after conversion. An everolimus monotherapy regimen was followed by 28.5% of patients at 12 months. Patients with renal dysfunction showed a glomerular filtration rate (4‐variable Modification of Diet in Renal Disease) increase of 10.9 mL (baseline mean, 45.8 [SD, 25.3] versus 57.6 [SD, 27.6] mL/minute/1.73 m2) at 3 months after everolimus initiation (P < 0.001), and 6.8 mL at 12 months. Improvement in renal function was higher in patients with early conversion (<1 year). Adverse events were the primary reason for discontinuation in 11.2% of cases. The probability of survival at 3 years after conversion to everolimus was 83.0%, 71.1%, and 59.5% for the renal dysfunction, de novo malignancy, and HCC groups, respectively. Everolimus is a viable option for the treatment of renal dysfunction, and earlier conversion is associated with better recovery of renal function. Prospective studies are needed to confirm advantages in patients with malignancy. Liver Transpl 21:1056‐1065, 2015.

Survival and Hepatitis C Virus Recurrence After Liver Transplantation in HIV- and Hepatitis C Virus–Coinfected Patients: Experience in a Single Center

INTRODUCTION Posttransplant hepatitis C virus (HCV) recurrence has been shown to negatively impact graft and patient survivals. It has been suggested that HCV recurrence among HIV- and HCV-coinfected transplant recipients is even more aggressive. OBJECTIVE To compare the histological severity and survival of posttransplant HCV recurrence between HIV- and HCV-coinfected and HCV-monoinfected patients. PATIENTS AND METHODS Among 72 adult patients who underwent primary liver transplantation at our institution for HCV-related cirrhosis between October 2001 and April 2007. We excluded one coinfected patient who died on postoperative day 5 leaving 12 HIV- and HCV-coinfected patients for comparison with 59 monoinfected patients. When listed, all coinfected patients fulfilled the criteria of the Spanish Consensus Document for transplantation in HIV patients. Immunosuppression did not differ between the two groups: all were treated with tacrolimus + steroids (slow tapering). Aggressive HCV recurrence was defined as cholestatic hepatitis and/or a fibrosis grade > or =2 during the first posttransplant year. RESULTS Coinfected patients were younger than monoinfected patients: 45 +/- 6 years vs 55 +/- 9 years (P = .0008). There were no differences in Child score, Model for End-stage Liver Disease score, donor age, graft steatosis, ischemia time, HCV pretransplant viral load or genotype between the groups. Significant rejection episodes were also equally distributed (25% vs 14%; P = .38). Seven coinfected patients and 29 monoinfected patients developed aggressive HCV recurrences (58% vs 49%; P = .75). Median follow-up was 924 days. Global survival at 3 years was 80%. Survivals at 1, 2, and 3 years were 83%, 75%, 62% in the coinfected vs 98%, 89%, 84% in the monoinfected patients, respectively (log-rank test = 0.09). CONCLUSIONS The severity of histological recurrence was similar among HIV- and HCV-coinfected and monoinfected HCV liver recipients in the first posttransplant year. Mortality attributed to recurrent HCV was similar in the groups. There were no short-term (3-year) differences in survival between the two groups of patients.

Biliary Complications in Orthotopic Liver Transplantation Using Choledochocholedochostomy with a T-tube

Despite significant advances in orthotopic liver transplantation (OLT), biliary tract reconstruction is still a major source of complications. Choledochocholedochostomy with a T-tube used to be the standard procedure for biliary reconstruction after OLT. However, many centers currently avoid use of the T-tube because of the high incidence of complications. Our aim was to study the biliary complications occurring at our center when end-to-end choledochocholedochostomy (EE-CC) over a T-tube was used as the standard procedure for biliary reconstruction. A retrospective review was conducted of all patients who underwent liver transplantation from February 1, 1996, to April 30, 2010. Only patients requiring any therapy to treat biliary complications were considered, whereas those with concomitant hepatic artery complications were excluded. The study cohort consisted of 743 patients who had EE-CC with a T-tube. Of these, 73 patients (9.8%) experienced any biliary complication. Anastomotic strictures occurred in 17 patients (2.3%), and non-anastomotic strictures in 2 (0.3%). Fifteen patients with anastomotic strictures were successfully treated by dilatation and stenting. Bile leakage was diagnosed in 39 patients (5.2%). Leakage occurred at the anastomosis in 15 patients (2%), and at the exit site of the T-tube in 24 patients (3.2%). Tube opening was the only treatment used in 30 patients with bile leakage (76.9%). Seven patients experienced leaks after elective T-tube removal (1%). Overall, repeat surgery to manage biliary complications was needed in 9 patients (1.2%). The mortality rate from biliary complications was 0.13%. In conclusion, EE-CC with a T-tube was followed by a low incidence of biliary complications. The complication rate after elective T-tube removal and the repeat surgery rate were extremely low. These results might challenge the current trend to avoid T-tube stenting in OLT.

Advagraf De Novo in Liver Transplantation: A Single-Center Experience

UNLABELLED Advagraf, a prolonged release formulation of tacrolimus, is administered once daily in the morning. The aim of this study was to show the results obtained in our center, analyzing the safety, efficacy, blood trough levels, and drug doses. METHODS We analyzed 50 consecutive recipients of a first liver transplantation with 6 months follow-up. Efficacy and safety variables were collected as the incidence of acute rejection episodes, patient and graft survivals, kidney function as well as incidences of diabetes mellitus and arterial hypertension de novo. RESULTS The incidence of biopsy proven acute rejection episodes was 10% (n = 5), none 7 of which were steroid resistant and all resolved favorably. The rate of diabetes mellitus de novo was 22% (n = 11), 7 of whom required insulin. Hypertension developed in 9 patients (18%), all of whom were treated with a single drug. The mean serum creatinine level was 1.08 ± 0.25 mg/dL, with 3 patients (6%) displaying a value ≥ 1.5 mg/dL. Patient and graft survivals were 100%. CONCLUSION Advagraf is an effective immunosuppressant in liver transplantation with a low incidence of biopsy-confirmed acute rejection episodes. The good results for patient and graft survival with few side effects make it a useful drug for de novo liver transplantation.

Infección después del trasplante hepático ortotópico: análisis de los 120 primeros casos consecutivos

Objetivo Describir las complicaciones infecciosas y tiempo de presentacion en los 120 primeros trasplantes hepaticos consecutivos realizados en nuestro centro. Metodos Estudio prospectivo de las complicaciones infecciosas que presentaron 120 pacientes adultos consecutivos que recibieron trasplante hepatico ortotopico en el Hospital de Cruces entre febrero de 1996 y noviembre de 1998. Dos pacientes recibieron simultaneamente trasplante renal. En todos los pacientes se realizaron los mismos controles de vigilancia y los criterios para definir las infecciones fueron los descritos por otros autores. Resultados. Del grupo total, 95 eran varones y 25 mujeres. La edad oscilo entre 20 y 66 anos (media: 54 ± 9 anos). Las indicaciones de trasplante fueron: cirrosis alcoholica (47%), cirrosis por virus de la hepatitis C (VHC) (20%), carcinoma hepatocelular (17,5%), hepatitis fulminante (6%), cirrosis biliar primaria (2,5%) y otras indicaciones (7%). Tres pacientes precisaron retrasplante. Se diagnostico histologicamente rechazo agudo en 38 pacientes (31%). Ninguno presento rechazo corticorresistente. Cincuenta y un pacientes (42,5%) desarrollaron 76 episodios de infeccion grave, que correspondian: infeccion bacteriana, 48 episodios en 33 pacientes (27,5%); tuberculosis, 7 pacientes (6%); infeccion fungica, 9 episodios en 8 pacientes (7%), y enfermedad por citomegalovirus (CMV) el 8,5% de los pacientes. Ningun paciente desarrollo infeccion por Pneumocystis carinii. Fallecieron 15 (12,5%): seis (40%) con infeccion activa y en cuatro de ellos la infeccion se considero causa mayor de la muerte. Conclusiones. La tasa de infecciones por bacterias y hongos es similar a la recogida en la literatura. Encontramos una tasa alta de tuberculosis, que se corresponde posiblemente con la alta incidencia de esta enfermedad en la poblacion general. La baja incidencia de enfermedad por CMV la asociamos con el tratamiento anticipado con ganciclovir. La profilaxis con trimetropin-sulfametoxazol es altamente eficaz frente a Pneumocystis carinii.