Maxime Audet

Congenital Intrahepatic Bile Duct Dilatation is a Potentially Curable Disease: Long-Term Results of a Multi-institutional Study

Objective:To report clinical presentation, perioperative outcome, and long-term results of surgical management of congenital intrahepatic bile duct (IHBD) dilatations (including Caroli disease) in a multi-institutional setting. Summary Background Data:Congenital IHBD dilatations are a rare congenital disorder predisposing to intrahepatic stones, cholangitis, and cholangiocarcinoma. The management remains difficult and controversial for bilobar forms of the disease or when concurrent congenital hepatic fibrosis is associated. Methods:From 1976 to 2004, 33 patients (range 11 to 79 years) were retrospectively enrolled. Disease extent into the liver was unilobar in 26 patients and bilobar in 7 patients (21%). Cholangiocarcinoma, congenital hepatic fibrosis, and intrahepatic stones were present in 2, 10, and 20 patients, respectively. Transplantations or liver resections were performed in 5 and 27 patients, respectively, whereas 1 asymptomatic patient was managed conservatively. Results:Postoperative mortality was nil. Postoperative complications occurred in 16 of 32 operated patients (50%) and additional procedures for residual stones were required in 5 patients. During a median follow-up of 80 months (1 patient being lost for follow-up) no patient developed metachronous carcinoma. Six patients (30%) developed recurrent intrahepatic stones but satisfactory late outcome was achieved in 27 patients (87%). Conclusions:Partial or total liver resection achieves satisfactory late outcome in congenital IHBD dilatations, when the affection is treated at an early stage and when the extent of liver resection is tailored to intrahepatic disease extent and takes into consideration the presence and severity of underlying chronic liver and renal diseases.

Engraftment and albumin production of intrasplenically transplanted rat hepatocytes (Sprague-Dawley), freshly isolated versus cryopreserved, into Nagase analbuminemic rats (NAR).

Banking of cryopreserved hepatocytes is a prerequisite for large-scale hepatocyte transplantation in the clinic. We compared the efficacy of intrasplenic transplantation into Nagase analbuminemic rats (NAR) of freshly isolated (FIH) and cryopreserved (CH) hepatocytes. Hepatocytes were cryopreserved using a controlled rate freezing protocol. Albumin production of thawed CH and FIH was measured in vitro in culture by ELISA and by Western blot. After in vivo intrasplenic transplantation of NAR with either FIH or CH we assessed 1) albumin in the serum of recipients by ELISA and by Western blotting analysis at different time intervals, and 2) hepatocyte engraftment by albumin immunohistochemical staining into spleens and livers at euthanasia. In vitro, albumin was produced up to day 4 of culture in both CH and FIH. In vivo, no intrasplenic engraftment of hepatocytes occurred. Intrahepatic engraftment of CH (cell number/mm2) was significantly (twofold) lower than that of FIH and appeared only as isolated cells and small (<10 cells) clusters, while bigger clusters (>10 cells) were observed with FIH. In the FIH group, serum albumin production was observed up to 32 – 49 days posttransplantation while in the CH group no serum albumin production was detected. Our results emphasize the need to improve 1) hepatocyte transplantation procedures either by repeated hepatocytes injections and/or by transplantation under a regeneration response, and 2) the freeze/thaw protocols of hepatocytes.

Passenger lymphocyte syndrome and liver transplantation.

The authors reviewed the passenger lymphocyte syndrome (PLS) that has appeared after transplantation. The definition, mechanism, serological, clinical features, and treatment for PLS after solid organ transplantation, especially liver transplantation, are described. The PLS refers to the clinical phenomenon of alloimmune hemolysis resulting from the adoptive transfer of viable lymphocytes from donor during solid organ or hematopoietic stem cell transplant. Sometimes, it is very severe and may cause “unexplained” hemolysis during the postoperative period. The authors reviewed literature about the PLS in liver transplantation.

AUXILIARY PARTIAL ORTHOTOPIC LIVER TRANSPLANTATION (APOLT) IN THE TREATMENT OF ACUTE LIVER FAILURE

Background. Auxiliary partial orthotopic liver transplantation (APOLT) has been developed in order to benefit from the efficacy of orthotopic liver transplantation (OLT) in the treatment of fulminant hepatic failure (FHF), but to avoid the negative counterpart of OLT which is to eliminate the possibility of native liver (NL) regeneration and which consequently implies a life-long immunosuppression.Methods. In our institution we performed 16 consecutive APOLTs in 15 patients between October 1992 and December 1999. Patients’ mean age was 30 years (range 0.5–65 years). The causes of FHF were viral (HAV = 3; HBV = 3), drugs (n = 4), or others (n = 5). None of the patients had a history of chronic liver disease. The decision to transplant was taken when the patients met well-defined criteria. All but one of the patients were in a coma.Results. Five patients died, 10 patients are alive (66.7%). Regeneration of the NL occurred in 11 of the 15 patients (73.3%) and in 8 of the 10 survivors. Six of these 8 patients have permanently stopped immunosuppressive therapy. These results can be favorably compared with those of OLT for FHF. In the European Transplant Registry, the survival rate is 57% at 5 years (2612 patients receiving OLT for FHF between 1988 and 1998). In our experience the survival rate is 59% at 5 years (42 patients receiving OLT for FHF between 1987 and 1999).Conclusions. APOLT is feasible in both adults and children; it rapidly restored liver function and reversed encephalopathy. Right APOLT seems more advisable since the right liver provides more functional hepatocytes; however, left APOLT harvested in an adult appears sufficient for a child. APOLT should be proposed only to patients with high chances of liver regeneration: age of recipient, etiology of liver failure, interval between onset of jaundice and occurrence of encephalopathy, and quality of liver graft are early prognostic indicators. Better results have been observed with younger patients (less than 40 years old) presenting with FHF (rather than subfulminant hepatic failure (SHF)) and due to HAV, HBV, or paracetamol.

Comparative evaluation of celsior solution versus viaspan in a pig liver transplantation model

BACKGROUND In a pig liver transplantation model, we compared the effects of Celsior solution (CS), an extracellular preservation solution, with Viaspan (University of Wisconsin solution, UW) on graft function and animal survival. METHODS Pig livers were flushed with either CS or UW solution and cold-stored for 12 hr (group 1) or for 8 to 10 hr (group 2). Grafts were transplanted orthotopically. Intrahepatic reduced and oxidized glutathione and adenine nucleotides were evaluated 1 hr after reperfusion. Liver function of transplanted animals was monitored for up to 6 days by serum transaminases, total bilirubin, purine nucleoside phosphorylase, and prothrombin levels. RESULTS In group 1, all animals died within 24 hr after reperfusion regardless of the preservation solution used. In group 2, no significant difference was seen in survival between the CS (72%) and the UW (67%) groups 6 days after transplantation, and there were no statistically significant differences in the biochemical data. There were no differences in histological evaluation of the livers at the time of death or killing of the animals between the CS and UW groups. CONCLUSION Within the limits of this pilot study, CS is equivalent to UW in terms of graft function and animal survival.

Robotic liver resection as a bridge to liver transplantation.

The da Vinci robotic system allowed for technical refinement of laparoscopic liver resection due to 3-dimensional visualization of the operative field and use of instruments with wrist-type end-effectors.

Four hundred and twenty-three consecutive adults piggy-back liver transplantations with the three suprahepatic veins: was the portal systemic shunt required?

Background and Aims:  The aim of this study is to analyze a single‐center experience in orthotopic liver transplantation with the piggy‐back technique (PB) realized with a cuff of three veins without temporary portacaval shunt. Outcome parameters were graft and patient survival and the surgical complications.

Are the Hangzhou Criteria Adaptable to Hepatocellular Carcinoma Patients for Liver Transplantation in Western Countries

We read with great interest the article by Silva et al. entitled “Expanded Criteria for Liver Transplantation in Patients with Cirrhosis and Hepatocellular Carcinoma,” which appeared in a previous issue of Liver Transplantation. 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). Outcomes in patients who had tumors within and beyond the Milan criteria (MC) were compared. Among transplanted patients, the 5-year survival and recurrence rates were not different between the 2 groups. The authors are to be congratulated on finding that these expanded criteria did not result in a reduction of survival in comparison with patients who had tumors within the MC. However, the low tumor recurrence rate reported at 5 years is the main concern of this article. Hepatocellular carcinoma (HCC) patients are known to have recurrence after liver transplantation (LT), especially when the disease is advanced. Therefore, in the last decade, there was a worldwide trend of selecting only early-stage HCC patients for LT. In fact, the 1996 cornerstone study by Mazzaferro et al., from which the MC were derived, albeit based on a relatively small number of patients, showed that the 4-year overall survival rate was 85% if the pretransplant tumor stage was early. However, with such criteria, only a few HCC patients are eligible for LT. In recent years, many transplant centers have explored the feasibility of expanding those criteria. Increasingly, there have been reports showing that the long-term outcome of patients following LT is the same regardless of whether the MC are followed or not. Recently, expandable Hangzhou criteria (HC) were established in China. Without macrovascular invasion, the criteria contain either a total tumor diameter 8 cm or a total tumor diameter 8 cm (histopathological grade I or II) along with a preoperative alpha-fetoprotein level 400 ng/mL. The outcome of the patients (all with hepatitis B virus infection) meeting such criteria is not different from those meeting the MC. Moreover, 37.5% of the HCC patients may benefit from LT. The purpose of this retrospective study was to investigate whether the Chinese expanded criteria could be used to select HCC patients for LT in Western countries. From 1997 to 2007, 196 patients with a preoperative diagnosis of HCC underwent LT in Strasbourg. Survival and recurrence rates were compared between MC and HC. Preoperatively, 68 of 196 (34.6%) patients were outside the MC. No difference was observed between the 2 groups in age, gender, etiology, Child-Pugh and Model for End-Stage Liver Disease scores, type of preoperative management (transarterial chemoembolization, radio frequency ablation, and surgical resection), waiting time between diagnosis and transplantation, type of graft and transplantation, immunosuppression regimen, or comorbidities. The 1-, 3-, and 5-year survival rates of the transplanted HCC patients within the MC versus those outside the MC but within the HC were 90% versus 88%, 85% versus 81%, and 77% versus 74%, respectively. Explant pathology showed 106 patients within the MC, 30 patients beyond the MC but within the HC, 32 patients across the HC, and 28 false-positive patients. Tumor recurrence rates at 5 years were 5/106 (5%), 6/30 (20%), and 17/32 (53%) in each of these groups. The tumor recurrence difference rate between the MC and the HC reached a statistical difference (P 0.04). The recurrence was treated with a multimodal approach in all patients (transarterial chemoembolization, radio frequency ablation, surgery, and chemotherapy). As shown here, whatever criteria are adopted, a significant proportion of patients will still develop HCC recurrence after LT. The likely cause is circulating cancer cells depositing in a favorable microenvironment. Therefore, the prediction of recurrence and the subsequent selection of patients should be based on the de-

Experimental models of acute and chronic liver failure in nude mice to study hepatocyte transplantation.

Although hepatocyte transplantation is a promising therapy for acute liver failure in human, there is still a lack of animal models suffering from hepatic injury in which the benefits of hepatocyte transplantation could be evaluated solely, without the bias caused by immunosuppression. As a consequence, the aim of the study was first to develop reproducible models of partial hepatectomy and of thioacetamide (TA)- or Jo2-induced acute liver failure in nude mice. Chronic liver disease was also investigated by repeated injections of sublethal doses of thioacetamide. Survival rates, routine histologic observations, alanin aminotransferase sera content, Ki67, and caspase 3 immunodetection were investigated both after 40% partial hepatectomy and after toxic-induced damages. Liver injuries were more severe and/or precocious in nude mice than in Balb/c mice for a given treatment with a maximum of acute injury obtained 24 h after single toxic injection, and were found to be transitory and reversible within 10 days. Toxics induced apoptosis followed by necrosis, confirming recent published data. Onset of fibrosis leading to reproducible chronic cirrhosis in nude mice correlated with increasing number of Ki67-positive cells, indicating that high levels of cell proliferation occurred. Chronic cirrhosis progressively reversed to fibrosis when the treatment ceased. Preliminary results demonstrated that engrafted xenogeneic hepatocytes could be detected in the host liver by anti-MHC class I immunohistochemistry. Fractions enriched in 2n or 4n hepatocytes by cell sorting using a flow cytometer were equivalent to the unpurified fraction in terms of engraftment in control nude mice or in nude mice subjected to PH. However, in mice suffering from liver injury 24 h after Jo2 or TA treatment, the engraftment of 2n hepatocytes was about twice that of an unpurified hepatocyte population or of a population enriched in 4n hepatocytes.

Successful liver transplantation for Rendu–Weber–Osler disease, a single centre experience

Backrounds/purposeHereditary hemorrhagic telangiectasia or Rendu–Weber–Osler is an autosomal dominant inherited disorder characterized by arteriovenous malformations and telangiectasia that may affect the nose, skin, lungs, brain and gastrointestinal tract. Liver involvement of the disease has been described to be responsible of biliary tract necrosis, high cardiac output and portal hypertension, due to intra-hepatic vascular shunts. We aimed to present four cases of successful orthotopic liver transplantations in this indication performing our modified Piggy-back technique.Patients and methodsBetween 2002 and 2008, four patients have been diagnosed for Rendu–Weber–Osler disease and underwent liver transplantation. Three of them suffered from high cardiac output with heart failure, two presented HBV infection and one patient suffered from renal failure requiring a liver–kidney transplantation. We performed our modified Piggy-back technique for liver implantation, which consists to clamp selectively the hepatic veins during the hepatectomy, without venous bypass, the retro-hepatic vena cava is preserved.ResultsNo hemodynamic concerns disturbed the surgery and no massive transfusions were needed. The liver replacement corrected the cardiac insufficiency due to high cardiac output for the three patients. At present, the four patients are getting well.ConclusionsDespite new advances in immunotherapy for the medical treatment of Rendu–Weber–Osler disease, liver transplantation remains the curative option for hepatic based-hereditary hemorrhagic telangiectasia.