Orthotopic Liver Transplantation (orthotopic + liver_transplantation)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

Development of a Severe von Willebrand Factor/ADAMTS13 Dysbalance During Orthotopic Liver Transplantation

I. T. A. Pereboom
Patients with liver disease show profound changes in their hemostatic system, which may further change during liver transplantation. We previously demonstrated that highly elevated levels of the platelet adhesive protein von Willebrand factor (VWF) in patients with cirrhosis lead to an increased VWF-dependent platelet deposition under flow as compared to healthy controls. In this study we examined VWF parameters during the course of liver transplantation. We collected serial plasma samples from 20 patients undergoing liver transplantation in which we determined plasma levels of VWF and the VWF-cleaving protease ADAMTS13. Furthermore, we performed functional tests of VWF-dependent platelet adhesion. We found persistently elevated levels of VWF during and after liver transplantation. The capacity of VWF to interact with platelets normalized during the course of transplantation, and flow-mediated VWF-dependent platelet adhesion remained at levels far exceeding those observed in healthy individuals during and after transplantation. Plasma levels of ADAMTS13 dropped during transplantation, and in four patients levels below 10% of normal were observed after reperfusion. We observed the development of a hyperreactive primary hemostatic system, as evidenced by high levels of fully functional VWF and a temporary ADAMTS13 deficiency, during liver transplantation, and speculate that these changes contribute to postoperative thrombotic complications. [source]

Review article: the current management of acute liver failure

Aliment Pharmacol Ther,31, 345,358 Summary Background, Acute liver failure is a devastating clinical syndrome with a persistently high mortality rate despite critical care advances. Orthotopic liver transplantation (OLT) is a life-saving treatment in selected cases, but effective use of this limited resource requires accurate prognostication because of surgical risks and the requirement for subsequent life-long immunosuppression. Aim, To review the aetiology of acute liver failure, discuss the evidence behind critical care management strategies and examine potential treatment alternatives to OLT. Methods, Literature review using Ovid, PubMed and recent conference abstracts. Results, Paracetamol remains the most common aetiology of acute liver failure in developed countries, whereas acute viral aetiologies predominate elsewhere. Cerebral oedema is a major cause of death, and its prevention and prompt recognition are vital components of critical care support, which strives to provide multiorgan support and ,buy time' to permit either organ regeneration or psychological and physical assessment prior to acquisition of a donor organ. Artificial liver support systems do not improve mortality in acute liver failure, whilst most other interventions have limited evidence bases to support their use. Conclusion, Acute liver failure remains a truly challenging condition to manage, and requires early recognition and transfer of patients to specialist centres providing intensive, multidisciplinary input and, in some cases, OLT. [source]

Immunohistochemical and electron microscopic study of extrinsic hepatic reinnervation following orthotopic liver transplantation in rats

Tsuyoshi Takahashi
Abstract:Background/Aims: Because little has been known about the morphological and functional consequences of liver transplantation on hepatic autonomic nerves, we examined the time-course of extrinsic hepatic innervation at the level of the porta hepatis of liver allografts. Methods: Orthotopic liver transplantation was performed using male Lewis rats. Crosscut tissue specimens were obtained postoperatively for up to 6 months from the porta hepatis of transplanted livers, and processed for immunohistochemical staining for protein gene product 9.5 (PGP 9.5) and growth-associated protein 43 (GAP-43), and for transmission electron microscopy (TEM). Results: Extrinsic nerve fibers at the porta hepatis stained positively for PGP 9.5 throughout the entire study period. In contrast, the immunoreactivity of GAP-43 was negative at postoperative day (POD) 1 and 2. GAP-43-positive nerves were first observed to appear in the porta hepatis at POD 3. The immunoreactivity of GAP-43 remained positive thereafter until 3 months post-OLT, and became negative in all the specimens at 4 months post-OLT. Transmission electron microscopy demonstrated a small number of regenerating axons existing among many degenerating axons at POD 3. At 3 months post-OLT, most regenerating axons had been fully ensheathed by the cytoplasm of Schwann cells, although their density remained at a lower level compared with normal. Conclusion: The results of this study suggest that liver allografts become extrinsically reinnervated, with the regenerating axons reaching the hepatic hilus 3 days after transplantation. The process of extrinsic hepatic reinnervation is considered to almost terminate 4 months after transplantation in rats. [source]

Liver transplantation for non,hepatocellular carcinoma malignancy: Indications, limitations, and analysis of the current literature

Eric J. Grossman
Orthotopic liver transplantation (OLT) is currently incorporated into the treatment regimens for specific nonhepatocellular malignancies. For patients suffering from early-stage, unresectable hilar cholangiocarcinoma (CCA), OLT preceded by neoadjuvant radiotherapy has the potential to readily achieve a tumor-free margin, accomplish a radical resection, and treat underlying primary sclerosing cholangitis when present. In highly selected stage I and II patients with CCA, the 5-year survival rate is 80%. As additional data are accrued, OLT with neoadjuvant chemoradiation may become a viable alternative to resection for patients with localized, node-negative hilar CCA. Hepatic involvement from neuroendocrine tumors can be treated with OLT when metastases are unresectable or for palliation of medically uncontrollable symptoms. Five-year survival rates as high as 90% have been reported, and the Ki67 labeling index can be used to predict outcomes after OLT. Hepatic epithelioid hemangioendothelioma is a rare tumor of vascular origin. The data from single-institution series are limited, but compiled reviews have reported 1- and 10-year survival rates of 96% and 72%, respectively. Hepatoblastoma is the most common primary hepatic malignancy in children. There exist subtle differences in the timing of chemotherapy between US and European centers; however, the long-term survival rate after transplantation ranges from 66% to 77%. Fibrolamellar hepatocellular carcinoma is a distinct liver malignancy best treated by surgical resection. However, there is an increasing amount of data supporting OLT when resection is contraindicated. In the treatment of either primary or metastatic hepatic sarcomas, unacceptable survival and recurrence rates currently prohibit the use of OLT. Liver Transpl 16:930-942, 2010. © 2010 AASLD. [source]

Expanded criteria for liver transplantation in patients with cirrhosis and hepatocellular carcinoma

Mauricio Silva
Orthotopic liver transplantation (OLT) selection for patients with hepatocellular carcinoma (HCC) is a matter of debate. The Milan criteria (MC) have been largely adopted by the international community. The main aim of this study was to evaluate the survival rates and recurrence probabilities of a new proposal for criteria (up to 3 tumors, each no larger than 5 cm, and a cumulative tumor burden , 10 cm). Patients with cirrhosis and HCC included on the waiting list (WL) from 1991 to 2006 were retrospectively analyzed. Outcomes in patients who had tumors within and beyond the MC were compared. The survival analysis was done (1) with the intention-to-treat principle and (2) among transplanted patients. A total of 281 patients were included in WL. Twenty-four cases did not undergo OLT (a dropout rate of 8.5%); all but 1 case had tumors within the MC. Of the 257 transplanted patients, 26 had tumors beyond the MC in the pre-OLT evaluation. Based on the intention-to-treat analysis, the 5-year survival was 56% versus 66% in patients who had tumors within and beyond the MC, respectively (P = 0.487). Among transplanted patients, the 5-year survival was 62% versus 69%, respectively (P = 0.734). Through multivariate analysis, microvascular invasion was an independent prognostic factor of poor survival (P = 0.004). The recurrence probabilities at 1 and 5 years were 7% versus 12% and 14% versus 28% in patients with tumors within and beyond the MC, respectively (P = 0.063). The multivariate analysis demonstrated that both poorly differentiated tumors (P < 0.001) and microvascular invasion (P < 0.001) increased the risk of recurrence. The expansion to up to 3 nodules, each up to 5 cm, and a cumulative tumor burden , 10 cm did not result in a reduction of survival in comparison with patients who had tumors within the MC. Liver Transpl 14:1449,1460, 2008. © 2008 AASLD. [source]

Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease,

Raymond M. Planinsic
Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose-finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double-blind trial, patients with end-stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 ,g/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty-three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required. (Liver Transpl 2005;11:895,900.) [source]

Liver transplantation and health-related quality of life: Scoring differences between men and women

Terianne Cowling
Orthotopic liver transplantation (OLT) is the treatment of choice for end-stage liver disease of various etiologies. Its use, however, remains limited due to the scarcity of donor organs. Measures to assess health-related quality of life (HRQOL) are increasingly being implemented to examine the efficacy of medical therapies involving scarce resources. HRQOL was assessed and compared between 88 male and 61 female patients before and after liver transplantation. Data were gathered from subjects having completed a questionnaire pre-OLT, and again at 1 year and 2 years post-OLT. This questionnaire, developed specifically for OLT patients, contains at its core questions derived from several well-established instruments measuring health status and HRQOL. Male OLT recipients reported a higher degree of overall HRQOL than that reported by female OLT recipients, both before and after OLT. When controlling for disparity in education between the sexes, findings revealed that among the lesser educated (,12 years), men and women scored similarly, while among the more educated (>12 years), men scored higher than women. Employment findings revealed a higher percentage of men working before transplant and at 1-year post-OLT when compared with women. At 2 years post-OLT, men and women exhibited similar employment rates. Male OLT recipients report a higher level of overall HRQOL than that reported by female OLT recipients, both before and after liver transplantation. Education appears to significantly affect HRQOL and may account for, at least in part, differences in reported HRQOL between male and female OLT recipients. (Liver Transpl 2004;10:88,96.) [source]

Liver transplantation in neonates

Shikha S. Sundaram
Orthotopic liver transplantation (OLT) has evolved over the past two decades to become the standard of care for end-stage liver disease in infants and children. Technical advances, particularly the use of technical variant allografts, have permitted extension of OLT into a much younger and smaller population than previously possible. Major centers around the world now routinely perform OLT in infants with survival success equivalent to that in older children and adults. We are beginning to see a small population of school-aged children who were infant OLT recipients. The further extension of OLT into neonates is more recent, with only a few pediatric centers reporting survival success. Very little is known about this frontier of transplantation. Our intent is to provide an overview of neonatal OLT using all available data and our experience in the field [source]

Presence of methylated arginine derivatives in orthotopic human liver transplantation: Relevance for liver function

Paloma Martín-Sanz
Orthotopic liver transplantation (OLT) is a frequent option in the treatment of liver diseases. During the cold ischemia period of the donor liver, there is an accumulation of metabolites that are potent inhibitors of the cytokine-inducible and endothelial nitric oxide synthase isoenzymes. We identified the presence of L - N -monomethylarginine and asymmetric dimethylarginine (ADMA) as the main inhibitors by means of analytic high-pressure liquid chromatography and mass spectrometry techniques. An average ADMA concentration of 450 ,mol/L was measured in the preservation medium of donor livers with poor outcomes after OLT. A statistically significant relationship was observed between the concentration of methylated arginine derivatives in the graft and liver function after OLT. These data suggest that measurement of methylated arginine, released after liver protein catabolism, might provide an indication of functional status of the liver that can help the development of strategies intended to improve graft viability. [source]

Recurrence of primary sclerosing cholangitis after liver transplantation

Ivo W. Graziadei MD
Orthotopic liver transplantation (OLT) has become the only effective therapeutic option for patients with end-stage liver disease caused by primary sclerosing cholangitis (PSC). Excellent long-term outcome has been reported, with 5-year patient survival rates of approximately 80%. In the last few years, increasing evidence has emerged that PSC recurs after OLT. The diagnosis of PSC is based on well-defined cholangiographic features combined with biochemical and histological findings. However, none of these features is specific for PSC, particularly after OLT, because biliary strictures in the liver allograft can occur from a variety of causes other than recurrence. Therefore, PSC recurrence remains a controversial issue, especially because of a lack of a gold standard for diagnosis and well-established diagnostic criteria. Some reports provided cholangiographic evidence that post-OLT biliary strictures occurred more frequently in patients with PSC than in those who underwent OLT for other liver diseases (including patients with a Roux-en-Y biliary reconstruction). Because no other possible cause of biliary strictures could be invoked to explain the greater prevalence of these strictures, recurrent disease has been implicated. There also is histological evidence suggesting that PSC recurs after OLT. Histological findings suggestive of PSC were found more often in PSC allografts compared with a control group. Furthermore, histological features typical for PSC (fibro-obliterative lesions) were seen exclusively in liver biopsy specimens from patients with PSC. Recurrence of PSC was defined in a recent study from the Mayo Clinic by means of strict cholangiographic and histological criteria in a large cohort of patients with PSC in whom other causes of biliary strictures were excluded. PSC recurrence was found in 20% of patients. No risk factor for PSC recurrence could be found, and recurrent disease did not influence patient or graft survival after a mean follow-up of 4.5 years. In conclusion, several studies provided convincing evidence that PSC recurs after OLT, with an incidence of 5% to 20% and an interval to diagnosis of at least 1 year after OLT. To date, patient and graft survival do not appear to be negatively affected by disease recurrence in the intermediate term of follow-up. (Liver Transpl 2002;8:575-581.) [source]

Orthotopic liver transplantation using low-dose tacrolimus and sirolimus

Vivian C. McAlister MB
Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r2 = 0.82 and r2 = 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial. [source]

Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma

Ilja De Vreede
Orthotopic liver transplantation (OLT) alone for unresectable cholangiocarcinoma is often associated with early disease relapse and limited survival. Because of these discouraging results, most programs have abandoned OLT for cholangiocarcinoma. However, a small percentage of patients have achieved prolonged survival after OLT, suggesting that adjuvant approaches could perhaps improve the survival outcome. Based on these concepts, a protocol was developed at the Mayo Clinic using preoperative irradiation and chemotherapy for patients with cholangiocarcinoma. We report our initial results with this pilot experience. Patients with unresectable cholangiocarcinoma above the cystic duct without intrahepatic or extrahepatic metastases were eligible. Patients initially received external-beam irradiation plus bolus fluorouracil (5-FU), followed by brachytherapy with iridium and concomitant protracted venous infusion of 5-FU. 5-FU was then administered continuously through an ambulatory infusion pump until OLT. After irradiation, patients underwent an exploratory laparotomy to exclude metastatic disease. To date, 19 patients have been enrolled onto the study and have been treated with irradiation. Eight patients did not go on to OLT because of the presence of metastasis at the time of exploratory laparotomy (n = 6), subsequent development of malignant ascites (n = 1), or death from intrahepatic biliary sepsis (n = 1). Eleven patients completed the protocol with successful OLT. Except for 1 patient, all had early-stage disease (stages I and II) in the explanted liver. All patients who underwent OLT are alive, 3 patients are at risk at 12 months or less, and the remaining 8 patients have a median follow-up of 44 months (range, 17 to 83 months; 7 of 9 patients > 36 months). Only 1 patient developed tumor relapse. OLT in combination with preoperative irradiation and chemotherapy is associated with prolonged disease-free and overall survival in highly selected patients with early-stage cholangiocarcinoma. [source]

Evaluation of catch-up growth after liver transplantation in children with biliary atresia

G. Alonso
Abstract:, Orthotopic liver transplantation (Tx) has improved survival in infants with extrahepatic biliary atresia (BA) when portoenteroanastomosis fails. Symptoms leading to Tx include liver failure, poor quality of life and growth failure. The objective of the study was to determine catch-up growth in children with BA. Medical records and growth data of 36 patients (24 girls) who received a Tx due to BA were analyzed. Thirty-two patients completed 3 yr and 15 patients 7 yr of follow-up after Tx. At Tx, the median age was 2.7 yr (range 0.7,12.6) and mean height Z score (±s.d.) was ,1.56 (±1.3). Patients were divided in two groups according to age at Tx: group I (n = 10), younger than 1.0 yr, and group II (n = 26) older than 1.0 yr. Median age (range) at Tx in group I was 0.8 yr (0.7,1.0) and in group II it was 3.35 yr (1.25,12.6). Thirteen patients (nine in group I) were receptors of living related donors. We evaluated linear growth, liver and renal function, immunosuppressive regimen and allograft rejection episodes. We did not find any significant differences in allograft or renal function, immunosuppressive therapy and number of acute rejection episodes or height Z score at Tx, second and third year post-Tx between both groups. The mean height Z score at Tx in group I was ,1.61 and in group II ,1.54; at the second year, group I ,0.66 and group II ,1.08; at the third year, group I ,0.17 and group II ,0.85; and at the seventh year (total group) ,0.3. However, the height gain at the third year was better in group I than in group II (p < 0.01, t-test). Height Z score at the third year improved more than 1 SDS in seven out of eight patients in group I and in only nine out of 24 in group II (odds ratio 11.6). We also found a correlation between height gain at the third year and age at Tx (r,0.65) and between height gain at the third year and height Z score at Tx (r,0.54) (Pearson, p < 0.05). Children with BA who are transplanted before 12 months of age presented better catch-up growth without change survival and morbidity. Orthotopic liver Tx improves survival and also enables height gain in these children. [source]

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

B. Ekser
A lack of deceased human donor livers leads to a significant mortality in patients with acute-on-chronic or acute (fulminant) liver failure or with primary nonfunction of an allograft. Genetically engineered pigs could provide livers that might bridge the patient to allotransplantation. Orthotopic liver transplantation in baboons using livers from ,1,3-galactosyltransferase gene-knockout (GTKO) pigs (n = 2) or from GTKO pigs transgenic for CD46 (n = 8) were carried out with a clinically acceptable immunosuppressive regimen. Six of 10 baboons survived for 4,7 days. In all cases, liver function was adequate, as evidenced by tests of detoxification, protein synthesis, complement activity and coagulation parameters. The major problem that prevented more prolonged survival beyond 7 days was a profound thrombocytopenia that developed within 1 h after reperfusion, ultimately resulting in spontaneous hemorrhage at various sites. We postulate that this is associated with the expression of tissue factor on platelets after contact with pig endothelium, resulting in platelet and platelet-peripheral blood mononuclear cell(s) aggregation and deposition of aggregates in the liver graft, though we were unable to confirm this conclusively. If this problem can be resolved, we would anticipate that a pig liver could provide a period during which a patient in liver failure could be successfully bridged to allotransplantation. [source]

Correlation of neurological manifestations and MR images in a patient with Wilson's disease after liver transplantation

J-C. Wu
Orthotopic liver transplantation (OLT) has been applied to patients with Wilson's disease (WD) for correction of irreversible liver cirrhosis. However, the neurological outcome and the correlation between clinical manifestations and neuroimage findings after OLT remain uncertain. We present a WD patient who showed an improvement in both liver functions and neurological manifestations after OLT. Serum levels of ceruloplasmin and copper returned to normal rapidly after the operation. His ataxic gait was improved 5 months later and dysmetria and tremor disappeared 11 months later. The high signal intensities on T2-weighted brain magnetic resonance images regressed at bilateral thalami 5 months later and disappeared in bilateral thalami and red nuclei 16 months after OLT. We conclude that the neurological improvement could be expected in WD patients after OLT. The improvement was correlated with the MRI changes in red nuclei and bilateral thalami. [source]

Is veno-venous bypass still needed during liver transplantation?

A review of the literature
Abstract:, Orthotopic liver transplantation has been made feasible with intra-operative femoral-to-jugular veno-venous bypass (VVB) to redirect the blood from the lower extremities and the kidneys to the heart. This reduces hemodynamic instability and metabolic disturbances. However, complications such as thromboses with pulmonary thrombembolism or post-reperfusion syndrome were observed in up to 30% of the cases. The latter, recent developments of cava-sparing surgical techniques, shorter anhepatic times plus optimized anesthetic management have made the necessity for a routine use of VVB questionable. [source]

EFNS guidelines on management of neurological problems in liver transplantation

M. Guarino
Neurological impairment after orthotopic liver transplantation (OLT) is common and represents a major source of morbidity and mortality. The diagnosis and management of neurological problems occurring after OLT are difficult and evidence-based guidelines for this task are currently lacking. A Task Force was set up under the auspices of the European Federation of Neurological Societies to devise guidelines to prevent and manage neurological problems in OLT. We selected six major neurological problems and approached them combining an evidence-based scientific literature analysis with a search of consensus by means of a Delphi process. Search results were translated into a series of recommendations constituting a basis for better care of patients with neurological complications after OLT. [source]

Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: An intention-to-treat analysis,,

HEPATOLOGY, Issue 3 2008
Francis Y. Yao
We previously reported encouraging results of down-staging of hepatocellular carcinoma (HCC) to meet conventional T2 criteria (one lesion 2,5 cm or two to three lesions <3 cm) for orthotopic liver transplantation (OLT) in 30 patients as a test of concept. In this ongoing prospective study, we analyzed longer-term outcome data on HCC down-staging in a larger cohort of 61 patients with tumor stage exceeding T2 criteria who were enrolled between June 2002 and January 2007. Eligibility criteria for down-staging included: (1) one lesion >5 cm and up to 8 cm; (2) two to three lesions with at least one lesion >3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or (3) four to five lesions with none >3 cm, with total tumor diameter up to 8 cm. A minimum observation period of 3 months after down-staging was required before OLT. Tumor down-staging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) had received OLT, including two who had undergone live-donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent OLT, 13 had complete tumor necrosis, 17 met T2 criteria, and five exceeded T2 criteria. The Kaplan-Meier intention-to-treat survival at 1 and 4 years after down-staging were 87.5% and 69.3%, respectively. The 1-year and 4-year posttransplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median posttransplantation follow-up of 25 months. The only factor predicting treatment failure was pretreatment alpha-fetoprotein >1,000 ng/mL. Conclusion: Successful down-staging of HCC can be achieved in the majority of carefully selected patients and is associated with excellent posttransplantation outcome. (HEPATOLOGY 2008.) [source]

Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence,

HEPATOLOGY, Issue 2 2008
Ying-Hong Shi
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Despite significantly improved diagnosis and treatment in recent years, the long-term therapeutic effect is compromised by the frequent recurrence and metastasis, of which the molecular mechanisms are not fully understood. Our initial studies in established HCC cell lines with different metastatic capabilities indicated a correlation of metastasis with the resistance to apoptosis and therefore the ability to survive in stressed conditions. Subsequent investigation revealed that increased expression of X-linked inhibitor-of-apoptosis protein (XIAP) was correlated with the resistance to apoptosis and enhanced invasiveness in vitro, which could contribute to increased metastatic foci in vivo. Furthermore, we found that nearly 90% of clinical samples from advanced HCC patients expressed high levels of XIAP. Patients with XIAP-positive tumors had a significantly increased risk of relapse, which resulted from metastasis after total liver resection and orthotopic liver transplantation. Indeed, XIAP expression could be an independent prognostic factor for predicting disease-free survival rate and overall survival rate of these patients. XIAP expression was also highly correlated with advanced cases that exceeded the Milan criteria and could be a prognostic factor for disease-free survival in these patients as well. Conclusion: Our studies have shown an important molecule in controlling HCC metastasis, defined a biomarker that can be used to predict HCC recurrence and patient survival after treatment, and suggest that XIAP can be a molecular target subject to intervention to reduce metastasis and recurrence. (HEPATOLOGY 2008;48:497,507.) [source]

Fractures and avascular necrosis before and after orthotopic liver transplantation: Long-term follow-up and predictive factors,

HEPATOLOGY, Issue 4 2007
Maureen M. J. Guichelaar
With early posttransplant bone loss, orthotopic liver transplantation (OLT) recipients experience a high rate of fracturing and some avascular necrosis (AVN), but little is known about the incidence of and predictive factors for these skeletal complications. We studied 360 consecutive patients who underwent transplantation for primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and assessed both vertebral and nonvertebral (rib, pelvic, and femur) fractures in a protocolized fashion. Before OLT, 20% of the patients had experienced fracturing, and 1.4% of the patients had experienced AVN. Following OLT, there was a sharp increase in fracturing, with a 30% cumulative incidence of fractures at 1 year and 46% at 8 years after transplantation. In contrast to previous studies, there was a similar incidence of posttransplant vertebral and nonvertebral fractures. The greatest risk factors for posttransplant fracturing were pretransplant fracturing and the severity of osteopenia and posttransplant glucocorticoids. Nine percent of the liver recipients experienced AVN after OLT, and this correlated with pretransplant and posttransplant lipid metabolism, bone disease (bone mineral density and fracturing), and posttransplant glucocorticoids. A novel association between cholestasis and AVN was also identified, the mechanism for which is not known. Conclusion: Fortunately, recent years have seen an increase in the bone mass of liver recipients and, along with this, less fracturing and less AVN. Nonetheless, 25% of patients undergoing OLT for chronic cholestatic liver disease still develop de novo fractures after OLT; this situation demands an ongoing search for effective therapeutic agents for these patients. (HEPATOLOGY 2007.) [source]

Biliverdin therapy protects rat livers from ischemia and reperfusion injury

HEPATOLOGY, Issue 6 2004
Constantino Fondevila
Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV). The role of BV and its potential use in preventing ischemia/reperfusion injury (IRI) had never been studied. This study was designed to explore putative cytoprotective functions of BV during hepatic IRI in rat liver models of ex vivo perfusion and orthotopic liver transplantation (OLT) after prolonged periods of cold ischemia. In an ex vivo hepatic IRI model, adjunctive BV improved portal venous blood flow, increased bile production, and decreased hepatocellular damage. These findings were correlated with amelioration of histological features of IRI, as assessed by Suzuki's criteria. Following cold ischemia and syngeneic OLT, BV therapy extended animal survival from 50% in untreated controls to 90% to 100%. This effect correlated with improved liver function and preserved hepatic architecture. Additionally, BV adjuvant after OLT decreased endothelial expression of cellular adhesion molecules (P-selectin and intracellular adhesion molecule 1), and decreased the extent of infiltration by neutrophils and inflammatory macrophages. BV also inhibited expression of inducible nitric oxide synthase and proinflammatory cytokines (interleukin 1,, tumor necrosis factor ,, and interleukin 6) in OLTs. Finally, BV therapy promoted an increased expression of antiapoptotic molecules independently of HO-1 expression, consistent with BV being an important mediator through which HO-1 prevents cell death. In conclusion, this study documents and dissects potent cytoprotective effects of BV in well-established rat models of hepatic IRI. Our results provide the rationale for a novel therapeutic approach using BV to maximize the function and thus the availability of donor organs. (HEPATOLOGY 2004;40:1333,1341.) [source]

Biliary reconstruction using non-penetrating, tissue everting clips versus conventional sewn biliary anastomosis in liver transplantation

HPB, Issue 2 2006
K. Tyson Thomas
Background. Biliary complications occur following approximately 25% of liver transplantations. Efforts to decrease biliary complications include methods designed to diminish tissue ischemia. Previously, we reported excellent short-term results and decreased biliary anastomosis time in a porcine liver transplant model using non-penetrating, tissue everting clips (NTEC), specifically VCS® clips. Methods. We examined the incidence of biliary anastomotic complications in a group of patients in whom orthotopic liver transplantation was performed with biliary reconstruction using NTEC and compared that group to a matched group treated with biliary reconstruction via conventional end-to-end sewn choledochocholedochostomy. Patients were matched in a 1:2 fashion by age at transplantation, disease etiology, Child-Turcot-Pugh scores, MELD score or UNOS status (prior to 1998), cold and warm ischemia times, organ donor age, and date of transplantation. Results. Seventeen patients had clipped anastomosis and 34 comparison patients had conventional sewn anastomosis. There were no differences between groups in terms of baseline clinical or demographic data. The median time from completion of the hepatic artery anastomosis to completion of clipped versus conventional sewn biliary anastomosis was 45 (interquartile range = 20 min) versus 47 min (interquartile range = 23 min), respectively (p=0.12). Patients were followed for a mean of 29 months. Biliary anastomotic complications, including leak or anastomotic stricture, were observed in 18% of the clipped group and 24% of the conventional sewn group. Conclusions. Biliary reconstruction can be performed clinically using NTEC as an alternative to conventional sewn biliary anastomoses with good results. [source]

Techniques of orthotopic liver transplantation

HPB, Issue 2 2004
L Lladó
Background Throughout the history of liver transplantation many improvements have been made in the field of surgical technique. It is beyond the scope of this paper to review all aspects of surgical technique in liver transplantation; thus, in this review we focus on the description of our current technique in most cases, which is orthotopic liver transplantation with preservation of the inferior vena cava and temporary portocaval shunt. We advocate this technique because it has been demonstrated that it achieves better haemodynamic stability during the anhepatic phase, transfusion can be reduced and renal function is improved. The different options for vascular anastomoses are described, particularly the options for arterial anastomoses in case of finding a non-adequate recipient hepatic artery. Technical possibilities for patients with preoperative portal vein thrombosis and the procedure in case of domino or sequential liver transplantation are further explained. [source]

Malignant fibrous histiocytoma complicating nephrogenic systemic fibrosis post liver transplantation

K. So
Abstract A 46-year-old man with cirrhosis secondary to hepatitis C virus infection and alcohol underwent orthotopic liver transplantation, which required urgent re-grafting because of biliary sepsis from necrosis of the left liver lobe. Recovery was complicated by renal failure and nephrogenic systemic fibrosis (probably related to intravenous gadolinium exposure). He subsequently developed a malignant fibrous histiocytoma. We present this case highlighting the occurrence of two rare conditions in the same patient following liver transplantation. We believe this is the first case of its kind to be reported. [source]

Role of endoscopic retrograde cholangiopancreatography in late biliary tract complications after orthotopic liver transplantation

Hiroyuki Furukawa
No abstract is available for this article. [source]

Individualized population pharmacokinetic model with limited sampling for cyclosporine monitoring after liver transplantation in clinical practice

Summary Background, We recently developed and validated limited sampling models (LSMs) for cyclosporine monitoring after orthotopic liver transplantation based on individualized population pharmacokinetic models with Bayesian modelling. Aim, To evaluate LSM in practice, and to seek optimal balance between benefit and discomfort. Methods, In 30 stable patients, more than 6 months after orthotopic liver transplantation, previously switched from trough- to 2 h post-dose (C2)-monitoring, we switched to 3-monthly LSM 0,1,2,3 h-monitoring. During 18 months we evaluated dose, creatinine clearance, calculated area under the curve, intra-patient pharmacokinetic variability and ability to assess systemic exposure by several previously validated LSMs. Results, Within patients, there was variability of cyclosporine-area under the curve with the same dose (CV of 15%). Compared to C2-monitoring, there was no significant difference in dose (P = 0.237), creatinine clearance (P = 0.071) and number of rejections. Some models showed excellent correlation and precision with LSM 0,1,2,3 h comparing area under the curves (0,2 h: r2 = 0.88; 0,1,3 h: r2 = 0.91; 0,2,3 h: r2 = 0.92, all P < 0.001) with no difference in advised dose. Conclusions, The limited sampling model, with only trough- and 2-h sampling, yields excellent accuracy and assesses systemic exposure much better than C2 with less bias and greater precision. Considering the calculated intra-patient variability, more precision is redundant, so LSM 0,2 h seems the optimal way of cyclosporine-monitoring. [source]

Predictors of outcome in patients with unresectable hepatocellular carcinoma receiving transcatheter arterial chemoembolization

Summary Background, Transcatheter arterial chemoembolization (TACE) has been shown to improve survival in patients with unresectable hepatocellular carcinoma (HCC). Aim, To identify pretreatment factors that predicts increased mortality in HCC patients receiving TACE. Methods, Retrospective review of all patients who underwent TACE for HCC from January 1999 to November 2004. Patient demographics, aetiology of liver disease, laboratory and imaging data regarding tumour characteristics were obtained. Results, Eighty-eight patients (57 ± 1 years age) received 1,4 sessions of TACE (1.4 ± 0.1). Tumour size was 3.3 ± 0.2 cm (range 1,13 cm, median 3 cm) with mean number of lesions 1.9 ± 0.1 (range 1,7). Mean model for the end stage liver disease score: 11 ± 0.4; cancer of the liver Italian program score: 1.3 ± 0.1. Survival post-TACE (excluding those underwent orthotopic liver transplantation) was 12 ± 0.3 months. By multivariate analysis, tumour size (HR = 1.37, 95% CI: 1.11,1.68, P = 0.003), hypovascularity (HR = 12.62, 95% CI: 1.79,88.92, P = 0.01) and elevated international normalized ratio (HR = 1.46, 95% CI: 1.10,1.92 P = 0.008) are shown to be significant risk factors for increased mortality. Conclusion, TACE therapy leads to a mean survival of 12 months in patients not receiving orthotopic liver transplantation. Tumour size, hypovascularity on imaging, and elevated international normalized ratio are predictors of increased mortality after TACE therapy for HCC. [source]

Review article: medical management of the liver transplant recipient , a primer for non-transplant doctors

Summary Background Survival 10 years after orthotopic liver transplantation now approaches 65%. Consequently, community doctors must manage the metabolic and neoplastic complications of orthotopic liver transplantation in an ageing population. Aims To review common sources of morbidity and mortality in long-term orthotopic liver transplantation recipients, and to make evidence-based recommendations regarding their management. Methods Pertinent studies and reviews were identified by literature search through PubMed. Where evidence-based recommendations could not be gleaned from the literature, expert opinion was obtained from syllabi of national meetings. Results The two most common causes of morbidity and mortality in orthotopic liver transplantation recipients are atherosclerotic vascular disease and de novo malignancy. The pathogenesis of many complications begins before orthotopic liver transplantation, and many are potentially modifiable. Most complications, however, can be directly ascribed to immunosuppressive agents. Despite improvements in our understanding of the pathogenesis and epidemiology of the metabolic and neoplastic complications of orthotopic liver transplantation, remarkably few randomized-controlled studies exist to define their optimal management. Conclusions Orthotopic liver transplantation recipients experience and succumb to the same afflictions of old age as non-transplant patients, but with greater frequency and at an earlier age. Most recommendations regarding surveillance for, and treatment of, medical complications of orthotopic liver transplantation remain based upon expert opinion rather than evidence-based medicine. [source]

A comparison of sirolimus vs. calcineurin inhibitor-based immunosuppressive therapies in liver transplantation

Summary Background, Sirolimus is a potent immunosuppressive agent whose role in liver transplantation has not been well-described. Aim, To evaluate the efficacy and side-effects of sirolimus-based immunosuppression in liver transplant patients. Methods, Retrospective analysis of 185 patients who underwent orthotopic liver transplantation. Patients were divided into three groups: group SA, sirolimus alone (n = 28); group SC, sirolimus with calcineurin inhibitors (n =56) and group CNI, calcineurin inhibitors without sirolimus (n = 101). Results, One-year patient and graft survival rates were 86.5% and 82.1% in group SA, 94.6% and 92.9% in group SC, and 83.2% and 75.2% in group CNI (P = N.S.). The rates of acute cellular rejection at 12 months were comparable among the three groups. At the time of transplantation, serum creatinine levels were significantly higher in group SA, but mean creatinine among the three groups at 1 month was similar. More patients in group SA required dialysis before orthotopic liver transplantation (group SA, 25%; group SC, 9%; group CNI, 5%; P = 0.008), but at 1 year, post-orthotopic liver transplantation dialysis rates were similar. Conclusions, Sirolimus given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies to evaluate the efficacy and side-effect profile of sirolimus in liver transplant patients are warranted. [source]

Review article: hepatitis C virus infection and type-2 diabetes mellitus in renal diseases and transplantation

F. Fabrizi
Summary A link between hepatitis C virus infection and development of diabetes mellitus has been suggested by many investigators; however, this remains controversial. The mechanisms underlying the association between hepatitis C virus and diabetes mellitus are unclear but a great majority of clinical surveys have found a significant and independent relationship between hepatitis C virus and diabetes mellitus after renal transplantation and orthotopic liver transplantation. We have systematically reviewed the scientific literature to explore the association between hepatitis C virus and diabetes mellitus in end-stage renal disease; in addition, data on patients undergoing orthotopic liver transplantation were also analysed. The unadjusted odds ratio for developing post-transplant diabetes mellitus in hepatitis C virus-infected renal transplant recipients ranged between 1.58 and 16.5 across the published studies. The rate of anti-hepatitis C virus antibody in serum was higher among dialysis patients having diabetes mellitus (odds ratio 9.9; 95% confidence interval 2.663,32.924). Patients with type-2 diabetes-related glomerulonephritis had the highest anti-hepatitis C virus prevalence [19.5% (24/123) vs. 3.2% (73/2247); P < 0.001] in a large cohort of Japanese patients who underwent renal biopsy. The link between hepatitis C virus and diabetes mellitus may explain, in part, the detrimental role of hepatitis C virus on patient and graft survival after orthotopic liver transplantation and/or renal transplantation. Preliminary evidence suggests that anti-viral therapies prior to renal transplantation and novel immunosuppressive regimens may lower the occurrence of diabetes mellitus in hepatitis C virus-infected patients after renal transplantation. Clinical trials are under way to assess if the hepatitis C virus-linked predisposition to new onset diabetes mellitus after renal transplantation may be reduced by newer immunosuppressive medications. [source]