Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells.

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.

Impact of the learning curve on the outcome of domino liver transplantation.

Domino liver transplantation (DLT) is a strategy used to increase the number of available grafts. In this procedure, the transplant recipient is a living donor of her own liver. It is mandatory that the graft should be fully functional and the genetic defect should recur with sufficient latency period in the new recipient. Corino-Andrade disease, or familial amyloidotic polyneuropathy (FAP), satisfies these conditions. We retrospectively reviewed our prospective database of DLT. From July 2004 to April 2013, we performed 12 DLTs. We assessed age, sex, real Model for End-Stage Liver Disease (MELD) score, waiting list time, cold and warm ischemia times, intraoperative transfusion requirements, hospital stay, early peritransplantation morbidity (post-reperfusion syndrome, intraoperative cardiac arrest, post-transplantation thrombotic events, and biliary morbidity), acute cellular rejection, retransplantation, mortality, patient and graft survivals. With the intention to study the effect of the learning curve in the global survival results (including both donors and recipients of livers with FAP), we divided our series into 2 periods: the early period (from 2004 to 2008) and the present period (from 2009 to 2013). The crude mortality was 40% vs 0% (P = .042) in the early and present periods, respectively. The cumulative patient survival was also significantly in favor of the present period (P = .049). The graft loss prevalence was 60% vs 7.1% (P = .019) in the early and present periods, respectively. The cumulative graft survival was also significantly in favor of the present period (P = .030; Fig 2). In conclusion, we consider DLT to be a complex procedure, whose initial results are conditioned by the learning curve.

Modigraf administration through jejunostomy in liver transplant recipient: case report.

We report our experience with a 61-year-old patient with alcoholic and hepatitis C cirrhosis who underwent liver transplantation. On the 3rd postoperative day he presented a mediastinitis secondary to esophageal perforation produced by a Linton tube. An esophagectomy with jejunostomy was performed. Tacrolimus granules for oral suspension (Modigraf) were administered through the jejunostomy. This case report highlights the use of Modigraf and the absence of secondary effects. We observed biochemical parameters during the jejunostomy period. We discuss the administration strategy applied and whether tacrolimus granules for oral suspension by jejunostomy affect the bioavailability and its side effects.

Liver transplantation due to fulminant hepatic failure.

OBJECTIVES: To analyze the epidemiology, causes, complications, and mortality of liver transplants following fulminant hepatic failure over the last 16 years. MATERIALS AND METHODS: We completed a descriptive analysis of 21 patients with fulminant hepatic failure and a liver transplant. In almost half of the cases, the origin of liver failure was unknown. RESULTS: The mean age was 36 years; the study group was 47.61% female (n = 10) and 52.39% male (n = 11). The most common early complication was transplant rejection, which occurred in 33.3% of all patients (n = 7) and was confirmed by liver biopsy; the most frequent long-term complication was autoimmune hepatitis. Two retransplantations were necessary. The total mortality rate was 38.1% (n = 8) with late mortality in three patients (14.3%). CONCLUSIONS: Orthotopic liver transplantation as a treatment for fulminant hepatitis has a higher mortality rate than orthotopic liver transplantation due to other causes. It does, however, enable the survival of 62% of the patients who otherwise would have died due to liver failure. The etiology of most of the cases was unknown. We should point out the high incidence rates for transplant rejection and late autoimmune hepatitis, in addition to the possibility of hemorrhagic colonic diseases that may be associated with the condition causing liver failure. Multidisciplinary control over the patient is useful for deciding at which time a liver transplant would become the only treatment option.

Intraoperative hepatic artery blood flow predicts early hepatic artery thrombosis after liver transplantation.

Hepatic artery complications after orthotopic liver transplantation are associated with a high rate of graft loss and mortality (23% to 35%) because they can lead to liver ischemia. The reported incidence of hepatic artery thrombosis (HAT) after adult liver transplantation is 2.5% to 6.8%. Typically, these patients are treated with urgent surgical revascularization or emergent liver retransplantation. Since January 2007, we have recorded the postanastomotic hepatic artery flow after revascularization. The aim of this study was to assess the relationship between hepatic blood flow on revascularization and early HAT. Retrospectively, we reviewed perioperative variables from 110 consecutive liver transplantation performed at the Virgen del Rocío University Hospital (Seville, Spain) between January 2007 and October 2010. We evaluated the following preoperative (donor and recipient) and intraoperative variables: donor and recipient age, cytomegalovirus serology, ABO-compatibility, anatomical variations of the donor hepatic artery, number of arterial anastomoses, portal and hepatic artery flow before closure, cold ischemia time, and blood transfusion. These variables were included in a univariate analysis. Of the 110 patients included in the study, 85 (77.7%) were male. The median age was 52 years. ABO blood groups were identical between donor and recipient in all the patients. The prevalence of early HAT was 6.36% (7 of 110). Crude mortality with/without HAT was 22% versus 2% (P = .001), respectively. Crude graft loss rate with/without HAT was 27% versus 4% (P = .003), respectively. Early HAT was shown to be primarily associated with intraoperative hepatic artery blood flow (93.3 mL/min recipients with HAT versus 187.7 mL/min recipients without HAT, P < .0001). No retransplantation showed early HAT. In our experience, intraoperative hepatic artery blood flow predicts early HAT after liver transplantation.

Spontaneous clearance of HCV in HIV-hepatitis C virus coinfected liver transplant patients: prospective study.

BACKGROUND: Hepatitis C virus (HCV) clearance is an independent predictive factor for long-term survival in HIV-HCV liver transplantation patients. After 46 months of antiviral therapy it is achieved in up to 80% of cases. Little is known, however, about spontaneous viral clearance. We performed prospective study of HIV-HCV coinfected liver transplant patients. METHODS: Between January 1, 2001, and December 31, 2011, we analyzed the parameters from among HIV-HCV coinfected liver transplant patients of donor and recipient ages, transplant cause, Model for End-Stage Liver Disease (MELD) score, donor and recipient serology, transplant date, viral load before and after transplantation, immunosuppressive therapy, HCV recurrence, HCV viral clearance (spontaneous and duration), retransplant cause, and viral load before and after retransplant, as well as survival. RESULTS: The seven transplanted HIV-HCV coinfected patients had most commonly HCV-related hepatocarcinoma (n = 5, 71.42%). Three subjects (42.85%) developed HCV recurrences. Two patients (28.57%) were retransplanted, both due to HCV recurrence with one of them developing a spontaneous clearance of HCV (14.28%). This patient showed a preoperative HIV viral load < 50 copies IU/mL, CD4+ count 486/µL, HCV-RNA 2564 IU copies/mL, Anti-HBc+, and MELD 30. The donor was an 81-year-old female who was Anti-HBc+. Immunosuppressive therapy consisted of cyclosporine, mycophenolate, and prednisone. One month after transplantation, the patient developed an acute cellular rejection episode with progression of liver disease secondary to the HCV recurrence (56.5 × 105 copies IU/mL). He started antiviral treatment (α-interferon and ribavirin), but due to side effects and interactions with the antiretrovirals, they were stopped after four doses. The viral load decreased spontaneously and progressively until it became negative at 146 days after transplantation; he was retransplanted and HCV-RNA has continued to be negative after 772 days. CONCLUSION: Spontaneous clearance of HCV among HIV-HCV coinfected liver transplant patients is possible. Despite no treatment, one patient still has no detectable HCV viral load after retransplantation.

Use of fully covered self-expandable stent in biliary complications after liver transplantation: a case series.

AIMS: To present our case series of fully covered self-expandable metallic stents (FCSESs) placed to treat biliary stenosis after liver transplantation and leakage after failure of plastic stenting. MATERIALS AND METHODS: We retrospectively reviewed the courses of patients who had undergone liver transplantation with a biliary complication that was treated by an FCSES installed by endoscopic retrograde cholangiopancreatography. We evaluated the following variables: gender, age, indication for transplantation, time between transplant and diagnosis of the complication, number of plastic stents placed before the FCSES, and procedure-related complications. RESULTS: From April 2008 to March 2010, 11 patients who had undergone a duct-to-duct anastomosis suffered posttransplant biliary stenosis or leakage with failure of endoscopic treatment using a plastic biliary stent: Namely, eight cases of stenosis and three of biliary leaks. Three patients underwent a papillotomy to place the FCSES, with no significant morbidity. No severe complications were observed after the endoscopic treatments; two patients developed mild pancreatitis; two, hyperamylasemia; and one, mild biliary sepsis. We removed the FCSES after a mean of 280 (range=173-310) days. Five patients lost the FCSES spontaneously. One patient underwent a choledocojejunostomy and two are waiting biliary surgery. CONCLUSION: We avoided cholangiojejunostomy in 6/9 cases (not including the two deaths). Papillotomy did not engender a greater morbidity. The spontaneous loss of the stent is a problem that need to be resolved.

Posttransplantation portal thrombosis secondary to splenorenal shunt persistence.

PURPOSE: The aim of this study was to analyze our experience with portal vein thrombosis after liver transplantation with a persistent splenorenal shunt. MATERIALS AND METHODS: The study population included 780 liver transplantations from 1990 to 2009. We analyzed the existence of portal vein thrombosis in the immediate posttransplant period, selecting cases with a persistent splenorenal shunt requiring surgery. RESULTS: The incidence of posttransplant portal vein thrombosis was 1.41% (n=11), of which 3 (27%) had a splenorenal shunt as a possible cause (0.38% of the total). Two cases required liver retransplantation due to portal vein thrombosis, and the third a thrombectomy. In all cases the shunt was also closed. During the early postoperative follow-up of these 3 patients, 2 needed repeat surgeries because of a new portal vein thrombosis (thrombectomy) in one and a bilioperitoneum in the other. After a median follow-up of 11 months, the patients showed a good evolution with no primary graft dysfunction. DISCUSSION: The portal steal phenomenon secondary to persistence of a splenorenal shunt promotes the occurrence of portal vein thrombosis. Although it is a rare cause of graft dysfunction, it must be treated early, because it can lead to a small-for-size syndrome.

Influence of donor age on survival in liver transplantation due to hepatitis C virus.

Cirrhosis secondary to hepatitis C virus (HCV) is one of the most frequent indications for liver transplantation. During recent years, the age of donors has increased, which has led to a worse prognosis for persons undergoing transplantations because of this virus. In this study, we analyzed the 93 transplantations performed during a 6-year period (2000-2005) due to HCV, dividing them into 2 groups according to donor age: <60 years (group A) and >/=60 years (group B). We examined graft and recipient survivals with a mean follow-up of 34 months. Recipient survival among group A was 61% compared with 57% among Group B, the difference being greater if we excluded the initial months after transplantation, since this eliminated the complications inherent to the intervention. Graft survival, according to the Knodell histological activity index, was summarized as: 55.7% histological recurrence, 16.7% fibrosis, and 21% cirrhosis among group A versus 65.6%, 25%, and 18.7%, respectively, among group B. In conclusion, there was improved survival and disease progression was slower among group A compared with group B, suggesting that donor age was an important factor; patient and graft survivals fell progressively with increased donor age.

Liver transplantation consequential to Caroli's syndrome: a case report.

Caroli's disease is a rare condition that includes fibrocystic malformations of the bile duct. It consists of multifocal congenital dilatations of the intrahepatic bile ducts, which may be diffuse or limited, presenting in sack form that produces cystic structures which communicate with the biliary tree. Herein we have presented the case of a 44-year-old woman with recurrent cholangitis consequential to Caroli's syndrome. The distinctive feature of this case was that it was the first and only liver transplantation performed to date for this cause at our center among 700 procedures that had been performed over 19 years. The hepatectomy sample from the liver transplantation showed large cystic dilatations at the level of segments VII and VIII. The pathological study reported congenital dilatation of the intrahepatic bile ducts, associated with congenital hepatic fibrosis (Caroli's syndrome). Caroli's syndrome is a complex association of conditions which usually presents together with polycystic kidney lesions. Orthotopic liver transplantation is still the only therapeutic option for diffuse, uncontrollable cases or those with significant portal hypertension, as well as being the final option in the other cases in the event of a lack of response to other therapeutic options or as an alternative to them.

Pharmacokinetic evaluation of mycophenolic acid profiles during the period immediately following an orthotopic liver transplant.

BACKGROUND: Area under the curve (AUC) limited sampling strategies have been proposed to improve the efficiency of mycophenolic acid (MPA), treatment of the transplanted patient. Our objective was to develop a model in the initial phase of the transplantation that explains the variability in the pharmacokinetic behavior of MPA in the immediate posttransplant period, following treatment with mycophenolate mofetil (MMF) in adult liver transplantation. METHODS: One hundred ten pharmacokinetic simplified sampling profiles were collected, including four samples over a 6-hour postdose interval, in over 60 patients treated with cyclosporine or tacrolimus, MMF, and steroids, combining Daclizumab in more than a third of the patients. For an enzyme-multiplied immunoassay technique method was established for MPA estimates. The correlation between the AUC and the plasma concentration points was established using a multiple linear regression with various equations for three different pharmacokinetic groups. RESULTS: The maximum mean values of MPA AUC and predose concentration (C0h) (20.8 +/- 11.8 and 2.3 +/- 1.8, respectively) were reached on the third day. The single sample showing the greatest correlation with the MPA AUC was the one collected after 3 hours (r(2) = 0.575); 59.1% of profiles displayed a single peak with more than half showing a tmax >/= 3 hours. CONCLUSIONS: This profile analysis during the first few weeks highlighted the problems in determining therapeutic targets. Profiles showing a double peak revealed the marked influence of the enterohepatic cycle on MPA concentrations during the initial phase.