Anne Andert

Biliary complications in liver transplantation: Impact of anastomotic technique and ischemic time on short- and long-term outcome

AIM To elucidate the impact of various donor recipient and transplant factors on the development of biliary complications after liver transplantation. METHODS We retrospectively reviewed 200 patients of our newly established liver transplantation (LT) program, who received full size liver graft. Biliary reconstruction was performed by side-to-side (SS), end-to-end (EE) anastomosis or hepeaticojejunostomy (HJ). Biliary complications (BC), anastomotic stenosis, bile leak, papillary stenosis, biliary drain complication, ischemic type biliary lesion (ITBL) were evaluated by studying patient records, corresponding radiologic imaging and reports of interventional procedures [e.g., endoscopic retrograde cholangiopancreatography (ERCP)]. Laboratory results included alanine aminotransferase (ALT), gammaglutamyltransferase and direct/indirect bilirubin with focus on the first and fifth postoperative day, six weeks after LT. The routinely employed external bile drain was examined by a routine cholangiography on the fifth postoperative day and six weeks after transplantation as a standard procedure, but also whenever clinically indicated. If necessary, interventional (e.g., ERCP) or surgical therapy was performed. In case of biliary complication, patients were selected, assigned to different complication-groups and subsequently reviewed in detail. To evaluate the patients outcome, we focussed on appearance of postoperative/post-interventional cholangitis, need for rehospitalisation, retransplantation, ITBL or death caused by BC. RESULTS A total of 200 patients [age: 56 (19-72), alcoholic cirrhosis: n = 64 (32%), hepatocellular carcinoma: n = 40 (20%), acute liver failure: n = 23 (11.5%), cryptogenic cirrhosis: n = 22 (11%), hepatitis B virus /hepatitis C virus cirrhosis: n = 13 (6.5%), primary sclerosing cholangitis: n = 13 (6.5%), others: n = 25 (12.5%) were included. The median follow-up was 27 mo until June 2015. The overall biliary complication rate was 37.5% (n = 75) with anastomotic strictures (AS): n = 38 (19%), bile leak (BL): n = 12 (6%), biliary drain complication: n = 12 (6%); papillary stenosis (PS): n = 7 (3.5%), ITBL: n = 6 (3%). Clinically relevant were only 19% (n = 38). We established a comprehensive classification for AS with four grades according to clinical relevance. The reconstruction techniques [SS: n = 164, EE: n = 18, HJ: n = 18] showed no significant impact on the development of BCs in general (all n < 0.05), whereas in the HJ group significantly less AS were found (P = 0.031). The length of donor intensive care unit stay over 6 d had a significant influence on BC development (P = 0.007, HR = 2.85; 95%CI: 1.33-6.08) in the binary logistic regression model, whereas other reviewed variables had not [warm ischemic time > 45 min (P = 0.543), cold ischemic time > 10 h (P = 0.114), ALT init > 1500 U/L (P = 0.631), bilirubin init > 5 mg/dL (P = 0.595), donor age > 65 (P = 0.244), donor sex (P = 0.068), rescue organ (P = 0.971)]. 13% (n = 10) of BCs had no therapeutic consequences, 36% (n = 27) resulted in repeated lab control, 40% (n = 30) received ERCP and 11% (n = 8) surgical therapy. Fifteen (7.5%) patients developed cholangitis [AS (n = 6), ITBL (n = 5), PS (n = 3), biliary lesion BL (n = 1)]. One patient developed ITBL twelve months after LT and subsequently needed retransplantation. Rehospitalisation rate was 10.5 % (n= 21) [AS (n = 11), ITBL (n = 5), PS (n = 3), BL (n = 1)] with intervention or reinterventional therapy as main reasons. Retransplantation was performed in 5 (2.5%) patients [ITBL (n = 1), acute liver injury (ALI) by organ rejection (n = 3), ALI by occlusion of hepatic artery (n = 1)]. In total 21 (10.5%) patients died within the follow-up period. Out of these, one patient with AS developed severe fatal chologenic sepsis after ERCP. CONCLUSION In our data biliary reconstruction technique and ischemic times seem to have little impact on the development of BCs.

Expression of VEGFR-2 during Liver Regeneration after Partial Hepatectomy in a Bioluminescence Mouse Model.

Background: Liver regeneration requires the formation of new blood vessels. Endothelial cell proliferation is stimulated by vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2. The aim of this study was to investigate VEGFR-2 expression in vivo during liver regeneration after partial hepatectomy (PHx). Methods: Transgenic VEGFR-2-luc mice were used in which the luciferase reporter gene was under control of the VEGFR-2 promoter. Following 2/3 PHx, the mice underwent in vivo bioluminescence imaging until the 14th postoperative day. Additionally, liver tissue was analyzed by immunohistochemistry, in vitro luminescence assays, and quantitative RT-PCR. Results: In vivo bioluminescence imaging showed a significant increase in VEGFR-2 promoter activity after PHx. Maximum signal was recorded on the 3rd day; 8 days postoperatively the signal intensity decreased significantly. On the 14th day, bioluminescence signal reached almost baseline levels. Immunohistochemistry, quantitative RT-PCR, and in vitro luminescence confirmed a significant increase on the 3rd day following resection. The mRNA expression of VEGFR-2 was significantly higher on day 3 than preoperatively as well as on day 8. Conclusion: In vivo bioluminescence imaging with transgenic VEGFR-2-luc mice is feasible and provides a convenient model for noninvasively studying VEGFR-2 expression during liver regeneration. This may facilitate further experiments with modulation of angiogenesis by different substances.

Liver Transplantation and Donor Body Mass Index >30: Use or Refuse?

BACKGROUND Organ shortage is a major problem in liver transplantation. The use of extended criteria donors has become the most important strategy for increasing the donor pool. However, the role of donor body mass index has not yet been thoroughly investigated. The aim of our study was to compare outcomes after liver transplantation in patients who received a liver from a donor with a BMI <30, 30-39, and ≥40, with special regard to the incidence of early allograft dysfunction (EAD) and primary non-function (PNF). MATERIAL AND METHODS One hundred and sixty-three patients who underwent liver transplantation at the University Hospital Aachen between June 2010 and January 2014 were included in this analysis. The outcome of liver transplantation was evaluated by the 30-day and 1-year patient and graft survival rates and the incidences of post-reperfusion syndrome (PRS), EAD, and PNF. RESULTS The BMI 30-39 group had a higher incidence of EAD than the BMI <30 and BMI ≥40 groups. We observed 5 cases of PNF in the BMI <30 group. The incidence of acute renal failure was significantly higher in the BMI 30-39 and BMI ≥40 groups than in the BMI <30 group. Patient and graft survival did not differ significantly among the 3 groups. CONCLUSIONS Based on the findings of this study, grafts from obese donors with a BMI >30 can be safely transplanted. Therefore, the donor pool can be enlarged to include such obese donors without a negative impact on the long-term patient outcome after liver transplantation.

Grade of donor liver microvesicular steatosis does not affect the postoperative outcome after liver transplantation

BACKGROUND The potential effect of graft steatosis on the postoperative liver function is discussed controversially. The present study aimed to evaluate the effect of the donor liver microvesicular steatosis on the postoperative outcome after liver transplantation. METHODS Ninety-four patients undergoing liver transplantation at the University Hospital Aachen were included in this study. The patient cohort was divided into three groups according to the grade of microvesicular steatosis (MiS): MiS <30% (n=27), MiS 30%-60% (n=41) and MiS >60% (n=26). The outcomes after liver transplantation were evaluated, including the 30-day and 1-year patient and graft survival rates and the incidences of early allograft dysfunction (EAD) and primary nonfunction (PNF). RESULTS The incidences of EAD and PNF did not differ significantly between the groups. We observed 5 cases of PNF, one occurred in the MiS <30% group and 4 in the MiS 30%-60% group. The 30-day and 1-year graft survivals did not differ significantly between groups. The 30-day patient survival rates were 100% in all groups. The 1-year patient survival rates were 94.4% in the MiS <30% group, 87.9% in the MiS 30%-60% group and 90.9% in the MiS >60% group. CONCLUSION Microvesicular steatosis of donor livers has no negative effect on the postoperative outcome after liver transplantation.

Assessment of a course of realistic surgical training during medical education as a tool for pre-residential surgical training

BackgroundIn recent years the focus on practical skills in the German curriculum of medical school has increased greatly. In this study we evaluate the value of a practical surgery course for medical students as a tool for surgical education, as a way of enhancing interest in surgical fields, and as a method of influencing medical students to subsequently choose a surgical career.MethodsThe “Feel like a surgeon”-course is an optional practical surgery course in which topographical anatomy and realistic surgical training using fresh human cadavers are combined for medical students of the RWTH Aachen University. Between 2010 and 2015 every student completed a survey before starting and after completing our course, and in 2015 a follow-up was performed. Using a standardized questionnaire, course quality, learning success and impact on post-instructional career and choice of profession was evaluated.ResultsIn total, 82 students attended our course between 2010 and 2015 and took part in the evaluation. Evaluation of the course was positive overall, with an average grade of 1.4° ± °0.50. Significant improvement of basic, as well as more complex surgical skills and theoretical knowledge was noted. Furthermore, self-confidence for patient related assignments improved as well. In the follow-up evaluation, a high level of recommendation for surgical residents was seen, as was a high influence of the course on our students’ career choice, although no significant change in career plans before and after taking the course was noted.ConclusionsOur results indicate that a practical surgical course can be a valuable tool to prepare students for a surgical residency and to improve their practical skills generally.

Influence of Telomere Length in Hepatocytes on Liver Regeneration after Partial Hepatectomy in Rats

Background: The aim of this study was to investigate telomere length in hepatocytes as a biomarker for liver regeneration after partial hepatectomy (PH) in rats. Materials and Methods: Sixty male Wistar rats underwent a 70% PH. One-month-old rats were assigned to group Y (n = 30) and 4-month-old rats were assigned to group O (n = 30). The rats were euthanized, and their livers were then harvested at postoperative day (POD) 1, 2, 3, 4, or 7. Telomere lengths and established parameters for liver regeneration (residual liver weight and levels of proliferating cell nuclear antigen [PCNA], Ki67, and interleukin [IL]-6) were measured. Results: We observed a significant increase in residual liver weight in group Y compared to that in group O (p = 0.001). The levels of Ki67 (p = 0.016), PCNA (p < 0.0001), and IL-6 (p < 0.001) were significantly higher in group Y. Furthermore, the rats in group Y had significantly earlier peak values of Ki67 and PCNA. Telomeres were significantly longer at the time of PH in group Y (p = 0.001). We showed a correlation between telomere length at the day of PH and liver regeneration. Animals with longer telomeres at the time of PH had better liver regeneration (p = 0.015). In group Y, animals with increased liver regeneration (median cut-off: > 122%) did not show any significant difference in telomere length (p = 0.587) compared to rats with regular regeneration (< 122%). However, in the older animals, rats with increased regeneration had significantly longer telomeres (p = 0.019) than rats with regular regeneration. Conclusion: Telomere length in rat hepatocytes depends on age, and animals with long telomeres had earlier and better regeneration of healthy liver tissue than rats with short telomeres. Our data confirms that telomere length in rat hepatocytes could be used as a possible predictive marker for liver regeneration, and could help to identify older individuals with a high capacity for hepatic regeneration.

Incisional Hernia Repair of Medium- and Large-Sized Defects: Laparoscopic IPOM Versus Open SUBLAY Technique

Abstract Background: Small incisional hernias can be repaired laparoscopically with low morbidity and reasonable recurrence rates. The aim of this study was to compare laparoscopic with open technique in medium- and large-sized defects regarding postoperative complications and recurrence rates. Methods: Between 2012 and 2016, 102 patients with medium- or large-sized defects according to EHS classification underwent incisional hernia repair. Patients’ characteristics, hernia size and postoperative complications were prospectively recorded. In October 2016, eligible patients were assessed for recurrence. Results: About 31 patients underwent laparoscopic IPOM and 71 patients open SUBLAY repair. Morbidity rate was significantly lower in IPOM group than in SUBLAY group (19% versus 41%; p = .028). Postoperative complications according to Clavien–Dindo classification were significantly lower in the IPOM group (p = .021). Duration of surgery (88 versus 114 min; p = .009) and length of hospital stay (five versus eight days; p < .001) were significantly shorter for IPOM than for SUBLAY. 71 patients were available for follow-up. Recurrence rates showed no significant difference between study groups (13% versus 7%, p = .508). Conclusions: Laparoscopic repair in medium- and large-sized defects is a feasible and safe approach. IPOM compared to SUBLAY significantly reduces postoperative complications and hospital stay; recurrence rates are comparable.

Comparative study of the effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats

BACKGROUND Post-hepatectomy liver failure as a result of insufficient liver remnant is a feared complication in liver surgery. Efforts have been made to find new strategies to support liver regeneration. The aim of this study was to investigate the effects of terlipressin versus splenectomy on postoperative liver function and liver regeneration in rats undergoing 70% partial hepatectomy. METHODS Seventy-two male Wistar rats were randomly assigned into three groups (n=24 in each group): 70% partial hepatectomy as control (PHC), 70% partial hepatectomy with splenectomy (PHS) or 70% partial hepatectomy with a micropump for terlipressin administration (PHT). Eight rats in each group were sacrificed on postoperative day (POD) 1, 3 and 7. To assess liver regeneration, immunohistochemical analysis of liver tissue using bromodeoxyuridine (BrdU) and Ki-67 labeling was performed. Portal venous pressure, serum concentrations of creatinine, urea, albumin, bilirubin and prothrombin time as well as liver-, body-weight and their ratio were determined on POD 1, 3 and 7. RESULTS The liver-, body-weight and their ratio were not statistically different among the groups. On POD 1, 3 and 7 portal venous pressure in the intervention groups (PHT: 8.13±1.55, 10.38±1.30, 6.25±0.89 cmH2O and PHS: 7.50±0.93, 8.88±2.42, 5.75±1.04 cmH2O) was lower compared to the control group (PHC: 8.63±2.06, 10.50±2.45, 6.50±2.67 cmH2O). Hepatocyte proliferation in the intervention groups was delayed, especially after splenectomy on POD 1 (BrdU: PHS vs PHC, 20.85%±13.05% vs 28.11%±10.10%; Ki-67, 20.14%±14.10% vs 23.96%±11.69%). However, none of the differences were statistically significant. CONCLUSIONS Neither the administration of terlipressin nor splenectomy improved liver regeneration after 70% partial hepatectomy in rats. Further studies assessing the regulation of portal venous pressure as well as extended hepatectomy animal models and liver function tests will help to further investigate mechanisms of liver regeneration.

Argon Delays Initiation of Liver Regeneration after Partial Hepatectomy in Rats

Background: The liver can heal up to restitutio ad integrum following damage resulting from various causes. Different studies have demonstrated the protective effect of argon on various cells and organs. To the best of our knowledge, the organ-protective effects of the noble gas argon on the liver have not yet been investigated, although argon appears to influence signal paths that are well-known mediators of liver regeneration. We hypothesized that argon inhalation prior to partial hepatectomy (70%) has a positive effect on the initiation of liver regeneration in rats. Methods: Partial hepatectomy (70%) with or without inhaled argon (50 vol%) was performed for 1 h. Liver tissue was harvested after 3, 36, and 96 h to analyze the mRNA and protein expression of hepatocyte growth factor (HGF), interleukin-6 (IL-6), tumor necrosis factor-α, and extracellular signal-regulated kinase 1/2. Histological tissue samples were prepared for immunohistochemistry (bromodeoxyuridine [BrdU], Ki-67, and TUNEL) and blood was analyzed regarding the effects of argon on liver function. Statistical analyses were performed using 1-way ANOVA followed by the post hoc Tukey-Kramer test. Results: After 3 h, the primary outcome parameter of hepatocyte proliferation was significantly reduced with argon 50 vol% inhalation in comparison to nitrogen inhalation (BrdU: 15.7 ± 9.7 vs. 7.7 ± 3.1 positive cells/1,000 hepatocytes, p = 0.013; Ki-67: 17.6 ± 13.3 vs. 4.7 ± 5.4 positive cells/1,000 hepatocytes, p = 0.006). This was most likely mediated by significant downregulation of HGF (after 3 h: 5.2 ± 3.2 vs. 2.3 ± 1.0 fold, p = 0.032; after 96 h: 2.1 ± 0.5 vs. 1.3 ± 0.3 fold, p = 0.029) and IL-6 (after 3 h: 43.7 ± 39.6 vs. 8.5 ± 9.2 fold, p = 0.032). Nevertheless, we could detect no significant effect on the weight of the residual liver, liver-body weight ratio, or liver blood test results after argon inhalation. Conclusion: Impairment of liver regeneration was apparent after argon 50 vol% inhalation that was most probably mediated by downregulation of HGF and IL-6 in the initial phase. However, the present study was not adequately powered to prove that argon has detrimental effects on the liver. Further studies are needed to evaluate the effects of argon on livers with preexisting conditions as well as on ischemia-reperfusion models.