Orthotopic Liver Transplantation Group Research Articles

Intraoperative and postoperative impact of pretransplantation transjugular intrahepatic portosystemic shunts in orthotopic liver transplantations: A systematic review and meta-analysis.

Orthotopic liver transplantation (OLT) remains the definitive treatment for patients afflicted with end-stage liver disease (ESLD). Transjugular intrahepatic portosystemic shunts (TIPS) have been adapted as a bridge to transplantation, allowing partial normalization of portal pressure and associated symptom improvement. Conflicting evidence exists on TIPS' impact on operative procedures. This study aimed to analyze available evidence on patients who underwent OLT with prior TIPS compared to OLT alone with the intent to determine TIPS' impact on surgical outcomes. Following PRISMA guidelines, a systematic review was conducted, identifying studies comparing TIPS + OLT versus OLT alone in patients with ESLD. Data were analyzed using Review Manager 5.3. Thirteen studies were included. Operative time, packed red blood cells transfusions, intensive care unit admission, length of stay, dialysis, serum creatinine levels, ascites, vascular complications, bleeding revisions, reintervention, and other complications rates were similar between both groups. Fresh frozen plasma transfusion -2.88 units (-5.42, -0.35; p= 0.03), was lower in the TIPS + OLT group. Our study found TIPS can be safely employed without having detrimental impacts on OLT outcomes, furthermore, these findings also suggest TIPS does not increase bleeding or complications.

Concomitant cardiac surgery and liver transplantation: an alternative approach in patients with end stage liver failure?

The results of cardiac surgery in patients with end-stage-liver-disease (ESLD) are poor. Concomitant cardiac surgery and orthotopic liver transplantation (OLT) may be an alternative treatment strategy in these patients. Between 2001 and 2018, eight patients underwent concomitant cardiac surgery and OLT (Conc_OLT) in our institution. We analyzed their preoperative, intraoperative and postoperative data and compared them to seven high risk patients with ESLD who underwent isolated cardiac surgery (Iso_Surg). The two groups were not significantly different in terms of gender and age (Conc_OLT: 5 males, 55 ± 15 years, Iso_Surg: 4 males, 60 ± 10 years). Causes for ESLD were primary biliary cirrhosis (Conc_OLT = 1, Iso_Surg = 1), alcoholism (Conc_OLT = 2, Iso_Surg = 2), viral hepatitis (Conc_OLT = 2, Iso_Surg = 2), cryptogenic (Conc_OLT = 2, Iso_Surg = 1), ischemic (Conc_OLT = 1) and hepatocellular carcinoma (Iso_Surg = 1). Model for End-stage-Liver-Disease (MELD) Score (Conc_OLT = 14, Iso_Surg = 13) and Child-Pugh Score (Conc_OLT = 9.5, Iso_Surg = 8) were not significantly different between the two groups. Median logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) was 9.5% (Conc_OLT) and 7.1% (Iso_Surg). Cardiac procedures undertaken were aortic valve replacement (Conc_OLT = 6, Iso_Surg = 3), coronary bypass grafting (Conc_OLT = 1,Iso_Surg = 2), tricuspid valve repair (Conc_OLT = 1), combined aortic and mitral valve replacement (Iso_Surg = 1) and excision of atrial myxoma (Iso_Surg = 1). Median length of in-hospital-stay was longer in the Conc_OLT group (73 vs. 42 days; p = 0.11). At 3 months, in-hospital mortality was 25% in the Conc_OLT group (n = 2) and lower compared to 71% observed in the Iso_Surg group (n = 5, p = 0.13). Concomitant cardiac surgery and OLT is a promising alternative compared to isolated cardiac surgery in high risk patients with ESLD. Given the high operative mortality of cardiac surgery in patients with ESLD, the complex peri-operative management of these patients should be performed in an interdisciplinary team with an expert team of liver specialists involved.

Inflammatory bowel disease course in liver transplant versus non-liver transplant patients for primary sclerosing cholangitis: LIVIBD, an IG-IBD study

BackgroundData regarding the effect of orthotopic liver transplantation (OLT) for primary sclerosing cholangitis (PSC) on inflammatory bowel disease (IBD) course are scarce and conflicting. AimsTo compare the incidence of refractory IBD in two groups (OLT and non-OLT) of patients affected by IBD and PSC. MethodsAn observational, multicentre, cohort retrospective study was conducted by the Italian Group for the study of IBD in Italy. The primary outcome was the need for biologic therapy or bowel resection for medically refractory IBD or hospitalization due to IBD relapse during the follow-up. Secondary outcomes were rate of colonic dysplasia, colorectal cancer, other solid tumours, lymphoma. ResultsEighty-four patients were included in the study. The primary outcome was not different between OLT and non-OLT groups (11/27, 40.7%, versus 20/57, 35.1%, respectively, p = 0.62). The lymphoma and other tumours (thyroid cancer, kidney cancer, ileal tumour, ovarian cancer, cervical cancer) rates were significantly higher in the OLT group (p = 0.04 and p = 0.005, respectively), at the limit of statistical significance for high-grade colonic dysplasia (p = 0.06). ConclusionOLT in patients affected by IBD and PSC is not a risk factor for a more severe IBD course, but it is associated with a higher occurrence of cancer.

Oncological Outcomes of Hepatic Resection vs Transplantation for Localized Hepatocellular Carcinoma

BackgroundScarce data are available comparing outcomes of hepatic resection vs orthotopic liver transplantation (OLT) for localized hepatocellular carcinoma (HCC) patients both meeting and exceeding the Milan criteria. This study compared the clinical and oncological outcomes of patients undergoing hepatic resection vs transplantation localized HCC. MethodBetween January 2005 and February 2017, clinical and oncological outcomes of patients who underwent liver resection (n = 38) vs OLT (n = 28) for localized HCC were compared using a prospectively maintained database. ResultsA total of 66 patients (with a median age of 62) who met the study criteria were analyzed. Comparable postoperative complications (13.2% vs 28.6%, P = .45) and perioperative mortality rates (7.9% vs 10.7%, P = .2) were noted for the resection vs OLT groups. While Child-Pugh Class A patients were more prevalent in the resection group (78.9% vs 7.1%, P = .0001), the rate of patients who met the Milan criteria was higher in the OLT group (89.3% vs 34.25, P = .0001). Recurrence rates were 36.8% in the resection group and 3.6% in the OLT group at the end of the median follow-up period (32 vs 39 months, respectively). The HCC-related mortality rate was significantly higher in the resection group (39.5% vs 10.7%, P = .034).However, a subgroup analysis of patients who met the Milan criteria revealed similar rates of recurrence and HCC-related mortality (15.4% vs 8%, P = .63). Based on logistic regression analysis, number of tumors (P = .034, odds ratio: 2.1) and “resection”-type surgery (P = .008, odds ratio: 20.2) were independently associated with recurrence. ConclusionCompared to liver transplantation, hepatic resection for localized hepatocellular carcinoma is associated with a higher rate of recurrence and disease-related mortality.

Mitofusin-2 mediated mitochondrial Ca2+ uptake 1/2 induced liver injury in rat remote ischemic perconditioning liver transplantation and alpha mouse liver-12 hypoxia cell line models.

AIMTo investigate the protective mechanism of mitofusin-2 (Mfn2) in rat remote ischemic perconditioning (RIC) models and revalidate it in alpha mouse liver-12 (AML-12) hypoxia cell lines.METHODSSprague-Dawley rats were divided into three groups (n = 6 each): sham, orthotopic liver transplantation and RIC. After operation, blood samples were collected to test alanine aminotransferase and aspartate aminotransferase. The liver lobes were harvested for histopathological examination, western blotting (WB) and quantitative real-time (qRT)-PCR. AML-12 cell lines were then subjected to normal culture, anoxic incubator tank culture (hypoxia) and anoxic incubator tank culture with Mfn2 knockdown (hypoxia + Si), and data of qRT-PCR, WB, mitochondrial membrane potential (ΔΨm), apoptosis, endoplasmic reticulum Ca2+ concentrations and mitochondrial Ca2+ concentrations were collected.RESULTSBoth sham and normal culture groups showed no injury during the experiment. The RIC group showed amelioration of liver function compared with the orthotopic liver transplantation group (P < 0.05). qRT-PCR and WB confirmed that Mfn2-mitochondrial Ca2+ uptake 1/2 (MICUs) axis was changed (P < 0.005). In AML-12 cell lines, compared with the hypoxia group, the hypoxia + Si group attenuated the collapse of ΔΨm and apoptosis (P < 0.005). The endoplasmic reticulum Ca2+ decrease and mitochondrial Ca2+ overloading observed in the hypoxia group were also attenuated in the hypoxia + Si group (P < 0.005). Finally, qRT-PCR and WB confirmed the Mfn2-MICUs axis change in all the groups (P < 0.005).CONCLUSIONMfn2 participates in liver injury in rat RIC models and AML-12 hypoxia cell lines by regulating the MICUs pathway.

The Impact of Bridging LRT on Survival in Patients Listed for Liver Transplantation.

Locoregional therapy (LRT) is recommended for certain groups of patients with hepatocellular carcinoma (HCC) listed for orthotopic liver transplantation (OLT) with expected wait times greater than 6months. A retrospective single-center study was performed to evaluate the effect of LRT on the outcomes of patients with HCC listed for OLT. Institutional database was reviewed to identify the patients listed for OLT with HCC (March 1998-December 2010). Patient and tumor characteristics were recorded with a follow-up period of 6.5years from diagnosis. Out of 359 listed patients, 72 patients were delisted (delisted group) and 287 underwent orthotopic liver transplantation (OLT group). One hundred fifty-five and 45 patients from the OLT and delisted groups underwent locoregional therapy (LRT), respectively. Median wait time and sum of largest tumor diameter were significantly higher for patients receiving LRT. LRT was associated with significantly better survival among delisted patients at the end of follow-up (1249.6±137.4 vs. 742.1±155.4days, p=0.028). In the OLT group, survival was similar between LRT and no LRT group, but survival was significantly better in patients with largest tumor diameter ≥30mm (1949.4±95.1 vs. 1694.8±135.5, p=0.02). Patients with HCC and the largest tumor greater than 30mm treated with LRT prior to OLT have improved survival compared to patients not receiving LRT. Additionally, for patients who did not undergo transplant survival is significantly longer for those receiving LRT.

Role of autophagy in hydrogen-induced inhibition of apoptosis in hippocampal neurons in a rat model of orthotopic liver transplantation

Objective To evaluate the role of autophagy in hydrogen-induced inhibition of apoptosis in hippocampal neurons in a rat model of orthotopic liver transplantation (OLT). Methods Fifty-six pathogen-free healthy adult male Sprague-Dawley rats, aged 8-10 weeks, weighing 220-250 g, were used in the study.Thirty-two rats were selected and assigned into 4 groups (n=8 each)using a random number table: sham operation group (group S), OLT group, hydrogen-rich saline group (group HS) and chloroquine group (group CQ). The other 24 rats severed as the donors.In group S, laparotomy was performed, and the related blood vessels were isolated.The model of OLT was established in OLT, HS and CQ groups.In group OLT, normal saline 6 ml/kg was slowly injected via the inferior vena cava at 5 min before anhepatic phase.In group HS, hydrogen-rich saline 6 ml/kg was slowly injected via the inferior vena cava at 5 min before anhepatic phase.In group CQ, autophagy inhibitor chloroquine 60 mg/kg was injected intraperitoneally at 1 h before establishment of the model, and the other treatments were similar to those previously described in group HS.At 6 h of reperfusion, the rats were sacrificed and hippocampi were isolated for determination of malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, for pathological examination (with light microscope), and for detection of cell apoptosis (by TUNEL staining) and expression of autophagy- and apoptosis-related proteins caspase-3, cytochrome c (Cyt c), microtubule-associated protein 1 light chain 3 Ⅱ (LC3 Ⅱ), Beclin-1 and p53 in hippocampal tissues (by Western blot analysis). Apoptosis index (AI) was calculated. Results Compared with group S, the MDA content and AI were significantly increased, the SOD activity was decreased, and the expression of caspase-3, Cyt c, LC3Ⅱ, Beclin-1 and p53 was up-regulated in OLT, HS and CQ groups (P<0.05). Compared with group OLT, the MDA content and AI were significantly decreased, the SOD activity was increased, the expression of caspase-3 and Cyt c was down-regulated, and the expression of LC3Ⅱ, Beclin-1 and p53 was up-regulated in group HS (P<0.05). Compared with group HS, the MDA content and AI were significantly increased, the SOD activity was decreased, and the expression of caspase-3 and Cyt c was up-regulated, and the expression of LC3Ⅱ, Beclin-1 and p53 was down-regulated in group CQ (P<0.05). Conclusion The mechanism by which hydrogen inhibits apoptosis in hippocampal neurons is related to promotion of autophagy in a rat model of OLT. Key words: Autophagy; Hydrogen; Liver transplantation; Brain injury; Apoptosis

Berberine protects against ischemia/reperfusion injury after orthotopic liver transplantation via activating Sirt1/FoxO3α induced autophagy

The effects and mechanism of berberine (BBR) on hepatic injury after orthotopic liver transplantation (OLT) have not been well characterized. We examined the role of Sirt1/FoxO3α axis in the protective effect of BBR on ischemia/reperfusion injury after OLT. Adult male Wistar rats were randomly allocated into four groups: Sham, OLT, OLT with BBR pretreatment (BBR), OLT with BBR and Sirt1 inhibitor (EX527) pretreatment group (EX527). The liver function and oxidative stress level were measured by biochemical and histopathologic examinations. The formation of autophagosome was observed by transmission electron microscopy. The apoptotic rate was determined by TUNEL analysis and the apoptotic mRNA expression. The expression of Sirt1, FoxO3α, Beclin-1, LC3-II/LC3-I, p62 and the acetylation of FoxO3α were assayed by western blot assay and immunoprecipitation. Compared with the OLT group, BBR dramatically attenuated the histopathologic damage, restored the liver function, and decreased the oxidative stress level. Simultaneously, BBR significantly ameliorated apoptosis by decreasing the apoptotic rate and the expression of apoptotic mRNA in rats subjected to OLT. The level of Beclin-1 and LC3-II/LC3-I were upregulated with the inhibition of p62. The deacetylation of FoxO3α by Sirt1 was enhanced in the nuclear of liver after pretreated with BBR. However, the inhibition of Sirt1 by EX527 counteracted the protective effects of BBR. Thus, BBR preconditioning promotes liver transplant ischemia/reperfusion injury partly via activating Sirt1/FoxO3α mediated autophagy.

Remote ischemic perconditioning prevents liver transplantation-induced ischemia/reperfusion injury in rats: Role of ROS/RNS and eNOS.

AIMTo investigate the underlying mechanisms of the protective role of remote ischemic perconditioning (RIPerC) in rat liver transplantation.METHODSSprague-Dawley rats were subjected to sham, orthotopic liver transplantation (OLT), ischemic postconditioning (IPostC) or RIPerC. After 3 h reperfusion, blood samples were taken for measurement of alanine aminotransferase, aspartate aminotransferase, creatinine (Cr) and creatinine kinase-myocardial band (CK-MB). The liver lobes were harvested for the following measurements: reactive oxygen species (ROS), H2O2, mitochondrial membrane potential (ΔΨm) and total nitric oxide (NO). These measurements were determined using an ROS/H2O2, JC1 and Total NOx Assay Kit, respectively. Endothelial NO synthase (eNOS) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, and peroxynitrite was semi-quantified by western blotting of 3-nitrotyrosine.RESULTSCompared with the OLT group, the grafts subjected to RIPerC showed significantly improved liver and remote organ functions (P < 0.05). ROS (P < 0.001) including H2O2 (P < 0.05) were largely elevated in the OLT group as compared with the sham group, and RIPerC (P < 0.05) reversed this trend. The collapse of ΔΨm induced by OLT ischemia/reperfusion (I/R) injury was significantly attenuated in the RIPerC group (P < 0.001). A marked increase of NO content and phosphoserine eNOS, both in protein and mRNA levels, was observed in liver graft of the RIPerC group as compared with the OLT group (P < 0.05). I/R-induced 3-nitrotyrosine content was significantly reduced in the RIPerC group as compared with the OLT group (P < 0.05). There were no significant differences between the RIPerC and IPostC groups for all the results except Cr. The Cr level was lower in the RIPerC group than in the IPostC group (P < 0.01).CONCLUSIONLiver graft protection by RIPerC is similar to or better than that of IPostC, and involves inhibition of oxidative stress and up-regulation of the PI3K/Akt/eNOS/NO pathway.

Role of Nrf2/HO-1 signaling pathway in reduction of acute kidney injury following orthotopic liver transplantation by hydrogen-rich saline in rats

Objective To investigate the role of nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathway in reduction of acute kidney injury following orthotopic liver transplantation(OLT)by hydrogen-rich saline in rats. Methods Thirty-two healthy adult male Sprague-Dawley rats, weighing 220-250 g, were randomly assigned into 4 groups(n=8 each)using a random number table: sham operation group(S group), OLT group, hydrogen-rich saline group(HS group), and all-trans retinoic acid(ATRA)group.Laparotomy was performed, and the related blood vessels were isolated in group S. The model of orthotopic autologous liver transplantation was established in OLT, HS and ATRA groups.Normal saline and hydrogen-rich saline 6 ml/kg were injected through the inferior vena cava at 5 min before the portal vein was clamped in OLT and HS groups, respectively.In group ATRA, Nrf2 inhibitor ATRA 7 mg/kg was injected intraperitoneally once a day for 2 consecutive days, the model of orthotopic autologous liver transplantation was established at 16 h after the last injection of ATRA, and the other treatments were similar to those previously described in group HS.At 6 h of reperfusion, blood samples were collected for determination of serum blood urea nitrogen(BUN), creatinine(Cr), interleukin-10(IL-10)and tumor necrosis factor-alpha(TNF-α)concentrations.After blood sampling, the lungs were removed for determination of malondialdehyde(MDA)content, superoxide dismutase(SOD)activity, expression of HO-1, Bcl-2 and Bax mRNA(by using real-time reverse transcriptase polymerase chain reaction), and HO-1 protein expression in lung tissues(by Western blot)and for microscopic examination.The damage to the renal tubules was scored. Results Compared with group S, the serum BUN, Cr and TNF-α concentrations were significantly increased, the serum IL-10 concentrations were decreased, the MDA content and renal tubular damage score were increased, the SOD activity was decreased, and the expression of HO-1 protein and mRNA, and Bcl-2 and Bax mRNA was up-regulated in group OLT(P<0.05). Compared with group OLT, the serum BUN, Cr and TNF-α concentrations were significantly decreased, the serum IL-10 concentrations were increased, the MDA content and renal tubular damage score were decreased, the SOD activity was increased, the expression of HO-1 protein and mRNA and Bcl-2 mRNA was up-regulated, and the expression of Bax mRNA was down-regulated in group HS(P<0.05). Compared with group HS, the serum BUN, Cr and TNF-α concentrations were significantly increased, the serum IL-10 concentrations were decreased, the MDA content and renal tubular damage score were increased, the SOD activity was decreased, the expression of HO-1 protein and mRNA and Bcl-2 mRNA was down-regulated, and the expression of Bax mRNA was up-regulated in group ATRA(P<0.05). Conclusion The mechanism by which hydrogen-rich saline reduces acute kidney injury following OLT is probably associated with activation of Nrf2/HO-1 signaling pathway in rats. Key words: Hydrogen; NF-E2-related factor 2; Heme oxygenase-1; Liver transplantation; Kidney injury

Effect of propofol on JAK2/STAT3 signaling pathway in hippocampus of rats undergoing orthotopic liver transplantation

Objective To evaluate the effect of propofol on Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in the hippocampus of rats undergoing orthotopic liver transplantation. Methods Twenty-four healthy male Sprague-Dawley rats, aged 8-10 weeks, weighing 220-250 g, were randomly divided into 3 groups (n=8 each) using a random number table: sham operation group (group S); orthotopic liver transplantation group (group O); propofol group(group P). After the rats were anesthetized with chloral hydrate, the model of orthotopic liver transplantation was established according to the method described by Nozato et al. in O and P groups.In group P, 30 min infusion of propofol was started at a rate of 20 mg·kg-1·h-1 via the right femoral vein immediately after onset of reperfusion.At 6 h of reperfusion, blood samples were collected from the infrahepatic vena cava, and then the rats were sacrificed.The hippocampi were harvested for determination of malondialdehyde (MDA) and nitric oxide (NO) contents and superoxide dismutase (SOD) activity.The serum levels of S100β protein and neuron-specific enolase (NSE) were determined by enzyme-linked immunosorbent assay.The expression of JAK2, STAT3 and inducible nitric oxide synthase (iNOS) mRNA was detected by quantitative real-time polymerase chain reaction.The pathological changes of hippocampal tissues were examined under the light microscope, and the cell apoptosis was measured using TUNEL.The apoptotic index was calculated. Results Compared with group S, the serum levels of S100β protein and NSE were significantly increased, the contents of MDA and NO were significantly increased, the activity of SOD was significantly decreased, the expression of JAK2, STAT3 and iNOS mRNA was significantly up-regulated, the apoptotic index was significantly increased (P<0.05), and the pathological changes of hippocampal tissues were significantly aggravated in the other groups.Compared with group O, the serum levels of S100β protein and NSE were significantly decreased, the contents of MDA and NO were significantly decreased, the activity of SOD was significantly increased, the expression of JAK2, STAT3 and iNOS mRNA was significantly down-regulated, the apoptotic index was significantly decreased (P<0.05), and the pathological changes of hippocampal tissues were significantly reduced in P group. Conclusion Propofol reduces injury to the hippocampus through blocking JAK2/STAT3 signaling pathway in the rats undergoing orthotopic liver transplantation. Key words: Janus kinase 2; STAT3 transcription factor; Signal transduction; Propofol; Liver transplantation; Reperfusion injury; Hippocampus

Health-related quality of life and affective status in liver transplant recipients and patients on the waiting list with low MELD scores

BackgroundThis study seeks to examine the impact of orthotopic liver transplantation (OLT) on Health-Related Quality of Life (HRQoL) and mental health in patients with different MELD scores. MethodsPatients who has undergone orthotopic liver transplant (OLT) or were on the waiting list for OLT were submitted to HRQoL and depression/anxiety assessment by questionnaire: Short-Form 36 (SF-36), Questions on Life Satisfaction (FLZ-M), Patient Health Questionnaire-4 (PHQ-4). Data were analysed following division of patients into three groups: pretransplant patients with a MELD score <10, ≥10, and OLT recipients. ResultsThe surveys were sent to 940 consecutive patients within one week in June 2013. Of these 940 patients, 869 (92.4%) met the inclusion criteria. In total, 291 (33.5%) eligible questionnaires (OLT group: 235, MELD <10: 25; MELD _10: 31) were suitable for analysis. General health (GH), vitality (VIT), and mental health (MH) were lower in both pretransplant groups compared to the OLT group (all p < 0.05). Anxiety and depression were higher in the MELD <10 group than in the OLT group (anxiety: p < 0.05; depression: p < 0.01). DiscussionPatients with low MELD scores seem to benefit from OLT with regards to HRQoL and mental health.

Percutaneous Management of Benign Biliary Strictures with Large-Bore Catheters: Comparison between Patients with and without Orthotopic Liver Transplantation

PurposeTo prospectively evaluate stricture resolution and patency rates of benign biliary strictures treated with percutaneous large-bore catheter “stenting” in patients with and without previous orthotopic liver transplantation (OLT) and to compare treatment outcomes between these two groups. Materials and MethodsForty-six consecutive patients (25 with OLT) underwent percutaneous catheter placement in extrahepatic and single-site biliary stricture for 6–8 months, with progressive catheter upsizing to 18–20 F. Primary patency rate was defined as the proportion of patients without recurrent bile duct stricture during the follow-up period after successful stricture resolution. Secondary patency rate was defined as the proportion of patients with a patent bile duct at the end of follow-up after stricture resolution, including patients with stricture recurrence and successful repeat percutaneous biliary catheter treatment. ResultsEleven patients terminated the protocol early, 6 as a result of treatment-related reasons in the orthotopic liver transplantation (OLT) group. Sixty-four percent of the OLT group and 86.4% of control patients successfully completed the protocol, with resolved biliary strictures (P = .1) after a median treatment time of 7 months for both groups (P = .96). During mean follow-up times of 20.3 months ± 11.8 (standard deviation) and 13.1 months ± 11.73 for OLT and non-OLT patients (P = .08), respectively, the primary/secondary patency rates were comparable between groups, at 81.25%/87.5% for OLT patients and 89.5%/100% for non-OLT patients (P = .64/P = .2). The mean time to recurrent stricture was 11.2 months ± 11.88. ConclusionsPercutaneous large-bore catheter treatment of benign, single-site biliary strictures showed a promising rate of stricture resolution, with comparable high primary and secondary patency rates in patients with and without previous OLT.

Neoadjuvant chemoradiation followed by orthotopic liver transplantation in cholangiocarcinomas: the emory experience.

Cholangiocarcinoma (CCA) is a bile duct tumor with a grim prognosis. The median survival after radiotherapy of unresectable disease is 9-12 months. The following is a review of our experience with neoadjuvant (NEO) chemoradiation followed by orthotopic liver transplantation (OLT) for CCA. Ten patients with CCAs were selected as candidates for NEO-OLT between 2008-2011. Patients with unresectable CCA above the cystic duct without intra or extrahepatic metastases were eligible. Primary sclerosing cholangitis (PSC) patients were included due to their poor resection response. Patients initially received external-beam radiation [via conventional fields or volumetric-modulated arc therapy (VMAT)] plus capecitabine (XEL) or 5-fluorouracil (5-FU), followed by either Iridium(192) (Ir(192)) brachytherapy high dose rate (HDR) or external boost. 5-FU or XEL was administered until OLT. Patients underwent periodic surveillance computed tomography (CT)/MRIs after OLT. Primary endpoints included actuarial rates (AR)/crude rates (CR) of overall survival (OS), and local control (LC) at 6, 12, and 24 months. Five males and five females were identified. Mean age was 58.3 years (range, 38-71 years). Mean composite radiation dose delivered was 59.0 Gy (range, 54-71.4 Gy). Forty percent of patients had an HDR boost. Fifty percent of patients received XEL during NEO. Two patients were excluded from the analysis as they did not go on to OLT due to metastases (n=1) and death due to GI bleed (n=1). Thirty-eight percent of the OLT patients had a pathological complete response (pCR) after NEO, while 25% required a Whipple due to positive margins. Median follow-up for the OLT group was 23 months (range, 6.5-37 months). Six, twelve, and twenty-four months LC AR was 100%. LC CR was 100% at longest interval (30 months). Six, twelve, and twenty-four months OS AR was 100%, 87.5%, and 87.5%, respectively. Mean OS AR was 30.2 months (95% CI: 22.8-37.7). OS CR was 75% at longest interval (37 months). Post OLT mortality resulted from (I) unknown causes (0.5 months), (II) allograft rejection (27.25 months). Other toxicities included: necrotic myelitis 12/10 months after NEO/OLT (n=1), post NEO biliary stricture requiring new stent (n=1); post Whipple bile leak repair (n=1), and post OLT fistula (n=1), cholangitis (n=1), and wound revision (n=2). Our outcomes using NEO-OLT for CCA are promising and comparable to other series. These results further justify (I) use of NEO and (II) prioritization of available transplant livers for CCA management.

Effect of hydrogen-rich saline on acute kidney injury after orthotopic liver transplantation and the role of autophagy

Objective To investigate the effects of hydrogen-rich saline on acute kidney injury after orthotopic liver transplantation(OLT)in rats and the role of autophagy. Methods Fifty-six healthy adult male Sprague-Dawley rats, weighing 220–250 g, served as donors and recipients.Thirty-two recipient rats were randomly assigned into 4 groups using a random number table: sham operation group(group S), OLT group, hydrogen-rich saline group(group HS), and autophagy inhibitor chloroquine group(group CQ). In group S, laparotomy was performed, and the related blood vessels were isolated.The model of OLT was established in OLT, HS and CQ groups.In OLT and HS groups, normal saline and hydrogen-rich saline 6 ml/kg were injected, respectively, through the inferior vena cava at 5 min before anhepatic phase.In group CQ, chloroquine 60 mg/kg was injected intraperitoneally at 1 h before establishment of the model, and the other treatments were similar to those previously described in group HS.Blood samples were obtained at 6 h of neohepatic phase for determination of serum blood urea nitrogen(BUN)and creatinine(Cr)concentrations.After the end of blood sampling, the left kidneys were removed for determination of malondialdehyde(MDA)content(using thiobarbituric acid method), superoxide dismutase(SOD)activity(xanthine oxidase method), and cell apoptosis(using TUNEL), and for examination of the pathological changes of renal tissues.The damage to the renal tubules was scored.Apoptosis index(AI)was calculated.The expression of phosphorylated p53(p-p53), activated caspase-3, cytochrome c(Cyt c), microtubule-associated protein light chain 3Ⅱ(LC3Ⅱ), and Beclin-1 was detected by Western blot analysis. Results Compared with group S, the levels of BUN, Cr, and MDA, AI, and renal tubular damage score were significantly increased, the SOD activity was decreased, and the expression of activated caspase-3, Cyt c and LC3Ⅱ was up-regulated(P 0.05). Compared with group OLT, the levels of BUN, Cr, and MDA, AI, and renal tubular damage score were significantly decreased, the SOD activity was increased, the expression of activated caspase-3, Cyt c was down-regulated, and the expression of LC3Ⅱ, Beclin-1 and p-p53 was up-regulated in group HS(P 0.05). Conclusion Hydrogen-rich saline can attenuate acute kidney injury after OLT, and the mechanism is associated with activation of p53, enhancement of autophagy and inhibition of cell apoptosis in rats. Key words: Hydrogen; Liver transplantation; Kidney injury; Autophagy; Apoptosis

Circulating FoxP3+ Regulatory T and Interleukin17-Producing Th17 Cells Actively Influence HBV Clearance in De Novo Hepatitis B Virus Infected Patients after Orthotopic Liver Transplantation

ObjectiveTo longitudinally investigate the role of FoxP3+ Regulatory T cells (Treg) and interleukin17-producing T helper 17 cells (Th17) in De Novo Hepatitis B Virus infection after orthotopic Liver Transplantation (DNHB-OLT), and analyze the possible correlation between these cells and HBV clearance of the disease.MethodsWe enrolled 12 control cases after orthotopic Liver Transplantation (OLT) and 24 patients, including 12 diagnosed with DNHB-OLT and 12 diagnosed with Acute Hepatitis B Virus infection (AHB), into the study from the liver transplantation and research center at Beijing 302 Hospital. Flow cytometry was used to detect the frequencies of Treg and Th17, and ELISA was applied to detect the concentration of IL6, IL22, TGF-β and IL2 in peripheral blood. We also measured the gene expression level by real time-quantitative PCR and protein expression using immunohistochemistry and western-blot. Furthermore, we divided DNHB-OLT patients into the clearance and non-clearance groups and examined longitudinally Th17, Treg cells at different times.ResultsThe percentage of Treg cells, expression of FoxP3 mRNA and related anti-inflammatory cytokines such as IL2 and TGF-β1 in the DNHB-OLT group were significantly higher than that in the AHB and OLT groups. The percentage of Th17 cells, expression of RORγt mRNA and related pro-inflammatory cytokines such as IL17 and IL22 in the DNHB-OLT group were significantly lower than that in the AHB group, but the levels of these cytokines are very similar to the OLT group. The ratios of Treg to Th17 in the DNHB-OLT group were significantly higher than that in the OLT and AHB groups. Treg frequencies significantly correlated with HBV DNA, whereas IL17 frequencies didn’t significantly correlate with ALT. In DNHB-OLT patients, the clearance group was accompanied by a rapid increase in the Th17 cells during the first 4th week and afterwards continuously decrease to the control group, together with a continuously decrease in Treg cells from the onset time point, which lead to a significant reduction in the ratios of Treg to Th17. The non-clearance group was accompanied by an increase in the Treg cells during the first 4th week and afterwards sharply decrease, together with a relatively stable and unchanged Th17 cells, which lead to a significant change in the ratios. In addition, compared to clearance group, the ratios of Treg to Th17 in non-clearance group were significantly higher at the onset point, 4th and 12th week, but no difference at 24th week.ConclusionDNHB-OLT patients possessed a favorable Treg differentiation environment, accompanied by a sustained higher preferentially Treg frequencies and up-regulation of related anti-inflammatory cytokines. The immune imbalance of the ratios between Treg and Th17 existed in DNHB-OLT patients. The changes of the ratios during the DNHB-OLT events were associated with HBV clearance, which suppressed immune inflammation reaction as well as inhibited ability of specific HBV clearance and led to immune escape and chronicity.

New-Onset Diabetes Mellitus and the Analysis of Dipeptidyl-Peptidase-4 After Liver Transplantation

BackgroundNew-onset diabetes mellitus after transplantation (NODAT) is a common complication after orthotopic liver transplantation (OLT). The diabetogenic effect of hepatitis C virus (HCV) infection is well known. The aim of this study was to analyze the glucose homeostasis before and after OLT. The oral glucose tolerance test (OGTT) was carried out, and dipeptidyl-peptidase-4 (DPP-4) activity was measured. MethodsThe study period was from 2012 to 2014. We enrolled 49 non-diabetic patients from the waiting list (group A) and 21 patients after OLT (group B). Seven patients were monitored continuously both before and after OLT. According to our preoperative OGTT results, 13 patients in group A had newly diagnosed diabetes mellitus (group A/DM) and 11 had impaired glucose tolerance (group A/IGT). In 25 cases, normal glucose tolerance was diagnosed (group A/NGT). The calculated homeostasis model assessment insulin resistance (HOMA2-IR) values were both in group A/DM and-IGT higher compared with group A/NGT (2.42 ± 0.81 vs 2 ± 0.98 vs 1.28 ± 0.67; P = .001). In the case of HCV infection (n = 14; 29%) DM and IGT were more frequent. ResultsSix patients in group B had NODAT. In 9 cases, IGT and in 6 cases NGT was detected. In the case of HCV infection (n = 9; 43%), DPP-4 levels were higher compared with that in patients with all other indications for OLT (15.5 ± 5.2 vs 8.7 ± 3.5; P = .008). We evaluated the same individuals before and after OLT (n = 7), and a decrease in β-cell function was noted. ConclusionsPreoperative OGTT is an important and easy investigation to rule out glucose imbalance before OLT. The HOMA2 calculation can also be useful both in preoperative and postoperative risk assessment. In our results, DPP-4 activity is not specific for the type of glucose homeostasis imbalance, but, in HCV infection, it is higher. DPP-4 inhibitors can be effective in the therapy of NODAT, especially in HCV-infected patients.

Comparison of rat liver cold ischemia/reperfusion injury model with portosystemic shunt and liver transplantation model

Objective To establish a rat model of in situ cold ischemia/reperfusion (I/R) with portosystemin shunt and compare to liver transplantation model.Methods Wistar rats were divided into three groups:group A (n =10),control group; group B (n =140),orthotopic liver transplantation group; and group C (n =94),liver cold ischemia group with splenic transposition (LCI).The parameters measured included portal venous pressure (PVP),liver enzymes [(total bilirubin (TBIL),alanine aminotransferase (ALT),alkaline phosphatase (ALP) and GGT),and 14-day survival rate.Results Both groups showed characteristic I/R histologic changes at 24th h and 7th day.PVP at 1 min and 10 min after porta hepatis clamping in group B was significantly higher than that in group C [1 min:(29.93 ± 2.42) mm Hg vs.(22.91 ±4.01) mmHg,P＜0.01; 10 min:(57.12 ±4.44) mmHgvs.(18.32 ±4.42) mmHg,P ＜0.01].TBIL,GGT and ALP were higher in groups B and C than in group A on the postoperative day (POD) 0 (P＜0.05).TBIL,GGT,ALT and ALP were higher in groups B and C than in group A on POD 1 (P ＜ 0.05),and the index was higer in Group B than group C on POD 1 (P ＜ 0.05).GGT was still higher in group B than in groups C and A on POD 7 [groups B and A:(2.16 ±0.34) IU/L vs.(1.39 ± 0.36) IU/L; groups B and C:(2.16 ±0.34) IU/L vs.(1.75 ±0.32) IU/L; P＜0.05 for both].The 14-day survival rate in group C was higher than in group A (P ＞ 0.05).Conclusion LCI model is ideal for the study on cold I/R injury. Key words: Liver; Cold ischemia/reperfusion; Model, animal

Role of Integrin αvβ6 in the Pathogenesis of Ischemia-Related Biliary Fibrosis After Liver Transplantation

Biliary fibrosis has been referred to as the "final common pathway" of acute and chronic bile duct injury after orthotopic liver transplantation (OLT). We studied the role of integrin αvβ6 in the pathogenesis of ischemia-related biliary fibrosis after OLT. The mouse nonarterialized OLT model with prolonged cold ischemia time was used in this study. A total of 54 FVB/N mice were divided into three groups: sham-operated group (sham, n=18), OLT group that was given the blocking antibody to integrin αvβ6 (OLT+antibody, n=18), and OLT group that was given the isotype control immunoglobulin G (OLT+vehicle, n=18). The expression of αvβ6 and major fibrosis-related genes were studied by real-time polymerase chain reaction and immunohistochemistry. Serum and bile were collected and analyzed biochemically. The histopathologic evaluation was performed to determine the severity of biliary fibrosis and bile duct injury. Integrin αvβ6 was highly expressed on newly formed bile ducts because of cholangiocyte proliferation and was gradually upregulated with the progression of biliary fibrosis after liver transplantation. αvβ6 transcripts closely correlated with fibrosis stages but not bile duct injury severity. Inhibition of αvβ6 attenuated peribiliary collagen deposition remarkably, induced significant downregulation of fibrogenic genes, and improved hepatic function. Integrin αvβ6 is strongly induced de novo in newly formed bile ducts because of cholangiocyte proliferation during ischemia-related biliary fibrogenesis after liver transplantation. Inhibition of αvβ6 could retard the progression of biliary fibrosis of liver allograft significantly, suggesting that αvβ6 is a potential target for the treatment of ischemic biliary complications.

Transplantation for Hepatocellular Carcinoma in Younger Patients Has an Equivocal Survival Advantage as Compared With Resection

Whereas some investigators in the surgical field advocate liver resection for the treatment of hepatocellular carcinoma (HCC), orthotopic liver transplantation (OLT) shows a significant survival advantage. Age was used to stratify survival in these groups to analyze beneficence. The Surveillance, Epidemiology, and End Results database (1998–2008) was used to identify 2355 patients who underwent either a segmentectomy, lobectomy, or extended lobectomy (resection) and 1873 patients who underwent an OLT for HCC. These patients were further stratified according to age and their relative survival was calculated. As shown in previous studies, the survival advantage is maintained in patients 40 to 59 and 60 to 79 years of age with HCC treated with OLT. However, within the 20 to 39-year-old age group, this advantage is insignificant. In this younger age group, resection patients (n = 157) have a 5-year survival rate of 50.9% whereas the OLT group (n = 40) has a 5-year survival rate of 58.9% (P = .42). Moreover, when assessing patient with lesions within the Milan criteria ages 20 to 39 years, resection shows a slight, although insignificant 4-year survival advantage: 78.2% for resection (n = 56) and 64.4% for OLT (n = 21; P = .283). This data may temper the enthusiasm for OLT in younger patients given the possibility of equivalent treatment with surgical resection.