Liver resection in obese patients: results of a case-control study.

OBJECTIVES: Obesity has been associated with worse postoperative outcomes. No data are available regarding short-term results after liver resection (LR). The aim of this study was to analyse outcomes in obese patients (body mass index [BMI] > 30 kg/m(2) ) undergoing LR. METHODS: 85 consecutive obese patients undergoing LR between 1998 and 2008 were matched on a ratio of 1:2 with 170 non-obese patients. Matching criteria were diagnosis, ASA score, METAVIR fibrosis score, extent of LR, and Child-Pugh score in patients with cirrhosis. RESULTS: Operative time, blood loss and blood transfusions were similar in the two groups. Mortality was 2.4% in both groups. Morbidity was significantly higher in the obese group (32.9% vs. 21.2%; P= 0.041). However, only grade II morbidity was increased in obese patients (14.1% vs. 1.8%; P < 0.001) and this was mainly related to abdominal wall complications (8.2% vs. 2.4%; P= 0.046). No differences were encountered in terms of grade III or IV morbidity. The same results were observed in major LR and cirrhotic patients. When patients were stratified by BMI (<20, 20-25, 25-30 and >30 kg/m(2) ), progressive increases in overall and infectious morbidity were observed (5.6%, 22.4%, 23.7%, 32.9%, and 5.6%, 11.8%, 14.5%, 18.8%, respectively). Rates of grade III and IV morbidity did not change. DISCUSSION: Obese patients have increased postoperative morbidity after LR in comparison with non-obese patients, but this is mainly related to minor abdominal wall complications. Severe morbidity rates and mortality are similar to those in non-obese patients, even in cirrhosis or after major LR.

Laparoscopic liver resection facilitates salvage liver transplantation for hepatocellular carcinoma.

BACKGROUND/PURPOSE: In patients with hepatocellular carcinoma (HCC), a previous liver resection (LR) may compromise subsequent liver transplantation (LT) by creating adhesions and increasing surgical difficulty. Initial laparoscopic LR (LLR) may reduce such technical consequences, but its effect on subsequent LT has not been reported. We report the operative results of LT after laparoscopic or open liver resection (OLR). METHODS: Twenty-four LT were performed, 12 following prior LLR and 12 following prior OLR. The LT was performed using preservation of the inferior vein cava. Indication for the LT was recurrent HCC in 19 cases (salvage LT), while five patients were listed for LT and underwent resection as a neoadjuvant procedure (bridge resection). RESULTS: In the LLR group, absence of adhesions was associated with straightforward access to the liver in all cases. In the OLR group, 11 patients required long and hemorrhagic dissection. Median durations of the hepatectomy phase and whole LT were 2.5 and 6.2 h, and 4.5 and 8.3 h in the LLR and OLR groups, respectively (P < 0.05). Median blood loss was 1200 ml and 2300 ml in the LLR and OLR groups, respectively (P < 0.05). Median transfusions of hepatectomy phase and whole LT were 0 and 3 U, and 2 and 6 U, respectively (P < 0.05). There were no postoperative deaths. CONCLUSIONS: In our study, LLR facilitated the LT procedure as compared with OLR in terms of reduced operative time, blood loss and transfusion requirements. We conclude that LLR should be preferred over OLR when feasible in potential transplant candidates.

Efficient hepatocyte engraftment in a nonhuman primate model after partial portal vein embolization.

BACKGROUND: Hepatocyte transplantation could be an alternative to whole liver transplantation for the treatment of metabolic liver diseases. However, the results of clinical investigations suggest that the number of engrafted hepatocytes was insufficient to correct metabolic disorders. This may partly result from a lack of proliferation of transplanted hepatocytes. In rodents, portal ligation enhances hepatocyte engraftment after transplantation. We investigated the effects of partial portal ligation and embolization on engraftment and proliferation of transplanted hepatocytes in primates. METHODS: Hepatocyte autotransplantation was performed in Macaca monkeys. The left lateral lobe was resected for hepatocyte isolation. The first group of monkeys underwent surgical ligation of the left and right anterior portal branches; in the second group, the same portal territories were obstructed by embolization with biological glue. To evaluate the proportion of cell engraftment hepatocytes were Hoechst-labeled and transplanted via the portal vein. Cell proliferation was measured by BrdU incorporation. RESULTS: Hepatocyte proliferation was induced by both procedures but it was significantly higher after partial portal embolization (23.5% and 11.2% of dividing hepatocytes on days 3 and 7) than after ligation (3% and 0.8%). Hepatocytes engrafted more efficiently after embolization than after ligation. They proliferated and participated to liver regeneration representing 10% of the liver mass on day seven and their number remained constant on day 15. CONCLUSIONS: These data suggest that partial portal embolization of the recipient liver improves engraftment of transplanted hepatocytes in a primate preclinical model providing a new strategy for hepatocyte transplantation.

Repopulation of athymic mouse liver by cryopreserved early human fetal hepatoblasts.

Transplantation of hepatocytes is a promising alternative to liver transplantation for the treatment of severe liver diseases. However, this approach is hampered by the shortage of donor organs and intrinsic limitations of adult hepatocytes. To investigate whether most of the hurdles faced with adult hepatocytes could be surmounted by the use of human fetal hepatoblasts, we have developed a method to isolate, transduce, and cryopreserve hepatoblasts from human livers at an early stage of development (11-13 weeks of gestation). Cells were characterized in vitro for expression of specific markers, and in vivo for their proliferation and differentiation potential after transplantation into athymic mice. Most of the cells (80-90%) harbored a bipotent phenotype, expressing cytokeratins 8/18, albumin, and CK19. They proliferated spontaneously in culture and were efficiently transduced by a beta-galactosidase-expressing retrovirus (90%). After transplantation, cryopreserved cells engrafted into the liver of athymic mice and proliferated, resulting in up to 10% repopulation. Engrafted cells expressed markers of differentiated adult hepatocytes including albumin, alpha1-antitrypsin, cytochrome P450 3A4, and alpha-glutathione-S-transferase. When retrovirally transduced before transplantation they expressed the transgene in vivo. In summary, early human fetal hepatoblasts engraft, proliferate, and mature in athymic mouse liver, without conditioning the donor.

In utero allotransplantation of fetal hepatocytes in primates.

OBJECTIVE: Because intrauterine transplantation of fetal hepatocytes could become an effective approach for treating severe genetic disorders of the liver, the objective of this study was to demonstrate the feasibility of in utero allotransplantation of fetal hepatocytes in a nonhuman primate model using direct intraparenchymal administration of donor cells. METHODS: Fetal primary hepatocytes were isolated from 3 fetal primates (MACACA MULATTA) at 89-120 days of gestation, and cryopreserved. When a recipient was available, the cells were thawed and transduced by a beta-galactosidase-expressing retrovirus (3 cases) or labelled with a fluorescent dye (4 cases). Hepatocytes were infused directly into the fetal liver under surgical visual control. Engraftment was assessed by surgical liver biopsies taken 8-60 days following transplantation. RESULTS: Six recipients survived until liver biopsy, and 1 died during the surgical procedure. There was no evidence of engraftment in the 3 fetuses that received genetically marked hepatocytes. All 3 monkeys who received 20-25 x 10(6) hepatocytes from an 89-day-old donor labelled with fluorescent dye had positive liver biopsies 8-11 days following intrauterine transplantation. CONCLUSIONS: In utero allotransplantation of fetal hepatocytes is feasible in the nonhuman primate, and direct intraparenchymal administration enables short-term detection of persisting donor hepatocytes.

Immortalization of a primate bipotent epithelial liver stem cell.

Liver regeneration after partial hepatectomy results primarily from the simple division of mature hepatocytes. However, during embryonic and fetal development or in circumstances under which postnatal hepatocytes are injured, organ regeneration is believed to occur from a compartment of epithelial liver stem or progenitor cells with biliary and hepatocytic bipotentiality. The ability to identify, isolate, and transplant epithelial liver stem cells from fetal liver would greatly facilitate the treatment of hepatic diseases currently requiring orthotopic liver transplantation. Here we report the identification and immortalization by retrovirus-mediated transfer of the simian virus 40 large T antigen gene of primate fetal epithelial liver cells with a dual hepatocytic biliary phenotype. These cells grow indefinitely in vitro and express the liver epithelial cell markers cytokeratins 8/18, the hepatocyte-specific markers albumin and alpha-fetoprotein, and the biliary-specific markers cytokeratins 7 and 19. Bipotentiality of gene expression was confirmed by clonal analysis initiated from single cells. Endogenous telomerase also is expressed constitutively. After orthotopic transplantation via the portal vein, approximately 50% of the injected cells integrated into the liver parenchyma of athymic mice without tumorigenicity. Three weeks after transplantation, cells having seeded in the liver parenchyma expressed both albumin and alpha-fetoprotein but had lost expression of cytokeratin 19. These results provide strong evidence for the existence of a bipotent epithelial liver stem cell in nonhuman primates. This unlimited source of donor cells also should enable the establishment of a model of allogenic liver cell transplantation in a large animal closely related to humans and shed light on important questions related to liver organogenesis and differentiation.