Martina Sterneck

In situ splitting of cadaveric livers. The ultimate expansion of a limited donor pool.

OBJECTIVE The authors evaluate the safety, applicability, and effectiveness of a new technique for split-liver transplantation. SUMMARY BACKGROUND DATA Split-liver transplantation offers an attractive way to increase the donor pool for cadaveric liver transplantation. The application of this concept has been hampered by inferior patient and graft survivals and higher complication rates. Without supportive data, the concern about increasing biliary leakage and poor initial graft function persisted. The authors focused on the causes of these complications by presenting a new technique to eliminate these problems. METHODS Liver splitting was performed in the heart-beating cadaveric organ donor, using the technique described for procurement of the left lateral lobe of a live donor. A detailed description of the technique is presented. A retrospective review of the first 14 transplantations resulting from 7 in situ splitting procedures was collected. The results were compared with 19 conventional split-liver transplants performed during the same period. RESULTS Six-month patient and graft survivals after in situ split-liver transplantation were 92.8% and 85.7%, respectively. Biliary complications were absent. Postoperative courses were mostly uneventful and characterized by lower peak transaminase levels compared with standard techniques. Early graft function of extrahepatic organs procured simultaneously was excellent. CONCLUSIONS In situ split-liver transplantation provides superior results, related mainly to reduction of cold ischemic damage of the grafts and avoidance of biliary complications. In situ split-liver transplantation renders graft reduction alone obsolete and opens a donor pool for adults to receive right lobes safely. It allows for long-distance sharing between pediatric and adult liver transplant units because the procedure abolishes ex situ benching and prolonged ischemia time and provides two anatomically perfect grafts with hemostasis accomplished.

Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

BACKGROUND & AIMS We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. METHODS A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls). RESULTS The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 x 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 x 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes. CONCLUSIONS Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.

Naturally occurring variants of hepatitis B virus.

Publisher Summary Although most living biological systems have developed intricate mechanisms to keep the genetic information stable, many viruses, including hepatitis B virus (HBV) can undergo rapid and drastic sequence changes. This discusses the data from extensive research on the genetic variability of HBV done during the past decade and the implications for the life cycle of the virus, immune recognition, and pathogenesis. It also discusses currently available data on the epidemiology of mutants and their functional significance. It is still largely unknown whether mutants, particularly those with combinations of different mutations, have an impact on liver disease, virus persistence, and course and outcome, especially of chronic infection. Therefore, more long-term follow-up studies, analyses of complete genomes, and functional studies of variants in appropriate animal models are needed. Important questions to be answered in the future concern the driving forces for the selection of HBV variants and the influence of mutations on immune recognition. Answering these questions will deepen the understanding of the virus–host interplay and eventually help to develop new strategies for the successful therapy and eradication of HBV infection.

Using Transjugular Intrahepatic Portosystemic Shunts to Control Variceal Bleeding before Liver Transplantation

OBJECTIVE To determine the safety and efficacy of transjugular intrahepatic portosystemic shunts (TIPS) in controlling bleeding from esophageal varices in patients awaiting liver transplantation. DESIGN Prospective, uncontrolled trial. SETTING University medical center with an active liver transplant program. PATIENTS Thirteen patients referred for liver transplantation with either active variceal hemorrhage or recurrent variceal hemorrhage despite sclerotherapy; four patients had been previously treated with surgical portosystemic shunts. INTERVENTION An intrahepatic portosystemic shunt created via a transjugular approach to the hepatic veins using expandable, flexible metallic stents. MEASUREMENTS Portal pressures before and after the creation of the shunt, the direction of portal blood flow at differing diameters of the shunts, procedure-related complications, and outcome in terms of survival, liver transplantation, and recurrent variceal bleeding. MAIN RESULTS The transjugular intrahepatic portosystemic shunt was placed successfully in 13 patients, and bleeding was controlled acutely in all 13. After the procedure, the mean portal pressure decreased from 34 +/- 8.9 cm H2O to 22.4 +/- 5.4 cm H2O (P less than 0.001). No complications were associated with the procedure; however, two patients died of causes unrelated to the procedure. Seven patients subsequently underwent liver transplantation and are doing well, and three patients are being managed conservatively. Bleeding recurred in one patient 102 days after the procedure secondary to shunt occlusion caused by neointimal proliferation. CONCLUSION Placement of a transjugular intrahepatic portosystemic shunt is apparently safe and effective therapy for variceal hemorrhage in patients referred for liver transplantation.

Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.

Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4–7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively).

Evolution of Donor Morbidity in Living Related Liver Transplantation: A Single-Center Analysis of 165 Cases

Objective:During the last 14 years, living donor liver transplantation (LDLT) has evolved to an indispensable surgical strategy to minimize mortality of adult and pediatric patients awaiting transplantation. The crucial prerequisite to performing this procedure is a minimal morbidity and mortality risk to the healthy living donor. Little is known about the learning curve involved with this type of surgery. Patients and Methods:From January 1991 to August 2003, a total of 165 LDLTs were performed in our center. Of these, 135 were donations of the left-lateral lobe (LL, segments II and III), 3 were of the left lobe (L, segments II–IV), 3 were full-left lobes (FL, segments I–IV), and 24 were of the full-right lobe (FR, segments V–VIII). We divided the procedures into 3 periods: period 1 included the years 1991 to 1995 (LL, n = 49; L, n = 2; FR, n = 1), period 2 covered 1996 to 2000 (LL, n = 47), and period 3 covered 2001 to August 2003 (LL, n = 39; FR, n = 23; FL, n = 3; L, n = 1). Perioperative mortality and morbidity were assessed using a standardized classification. Length of stay in intensive care unit, postoperative hospital stay, laboratory results (bilirubin, INR, and LFTs), morbidity, and the different types of grafts in the 3 different periods were compared. Results:One early donor death was observed in period 1 (03/07/93, case 30; total mortality, 0.61.%). Since 1991, the perioperative morbidity has continually declined (53.8% vs. 23.4% vs. 9.2%). In period 1, 28 patients had 40 complications. In period 2, 11 patients had 12 complications, and in period 3, 6 patients had 9 complications. Within the first period, 1 donor underwent relaparotomy because of bile leakage. Postoperative hospital stay was 10 days, 7 days, and 6 days, respectively. Donation of the full right lobe, in comparison with that of the left lateral lobe, resulted in a significantly diminished liver function (bilirubin and INR) during the first 5 days after donation but did not increase morbidity. One donor from period 1 experienced late death caused by amyotrophic lateral sclerosis. Conclusions:In a single center, morbidity after living liver donation strongly correlates to center experience. Despite the additional risks associated with temporary reduction of liver function, this experience enabled the team to bypass part of the learning curve when starting right lobe donation. Specific training of the surgical team and coaching by an experienced center should be implemented for centers offering this procedure to avoid the learning curve.

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci

BACKGROUND & AIMS A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). METHODS We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. RESULTS Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. CONCLUSIONS We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC.

Living donor for liver transplantation

Since living related liver transplantation was first performed in 1989, more than 150 cases have been performed worldwide, mostly in the United States and Japan. This paper reports the first series of living related liver transplantation in Europe. Twenty living related liver transplantation surgeries were performed over a 13‐mo period, with an overall patient survival of 85%. For patients who underwent elective transplantation (n=13), the survival rate was 100%. Technical complications included one arterial thrombosis necessitating retransplantation and five bile leaks requiring surgical revision. The technical improvements that permit avoidance of these complications are discussed. A detailed description of the living related liver procurement is given. All procurements yielded grafts of excellent quality. No intraoperative complications occurred, and no reoperations were necessary. No heterologous blood transfusion was needed. In two patients, incisional hernias developed after wound infection. Living related liver transplantation does not absolve the transplant community of efforts to promote cadaveric organ procurement. Nevertheless, living related liver transplantation does have the advantage of a readily available graft of excellent quality, permitting transplantation with optimal timing under elective conditions. Several centers are now preparing living related segmental liver transplants, following the model of our protocol, for three reasons: (a) to obtain superior results compared with cadaveric liver transplantation; (b) to overcome cadaveric organ shortage and further reduce pretransplantation mortality and (c) to provide viable organs in countries where cadaveric organ procurement is not established. When performed by a team experienced in pediatric liver transplantation and in adult liver resection, living related liver transplantation is an excellent modality for the treatment of end‐stage liver disease in children. (Hepatology 1994;20:49S‐55S.)

Intragraft cytokine profile during human liver allograft rejection.

Forty-three human liver allograft biopsies and normal liver were directly analyzed for inflammatory and immunoregulatory cytokine gene expression by polymerase chain reaction (PCR). IL-5 gene expression was predominantly present in biopsies from liver allografts with histopathological evidence of acute rejection. IL-2 gene expression was rarely observed in rejecting allografts or allografts without evidence of rejection. In contrast, IL-4 message was readily detectable in the majority of liver allografts regardless of clinical status. The inflammatory mediators IL-1 beta, TNF-alpha, and IL-6 were detected with similar frequency in rejecting allografts and allografts without evidence of rejection. These findings suggest that inflammatory and immunoregulatory cytokines are produced within the allograft. Moreover, IL-5 may play a role in the local mechanisms of liver allograft rejection.

Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: An international multicenter cohort study

BACKGROUND & AIMS Long-term viral suppression is a major goal to prevent disease progression in patients with HBV. Aim of this study was to investigate the efficacy and safety of entecavir plus tenofovir combination in 57 CHB partial responders or multidrug resistant patients. METHODS Investigator-initiated open-label cohort study. Quantitative HBV-DNA measurement and resistance testing (line-probe-assays and direct-sequencing) at baseline and every 3 months. RESULTS Fifty seven patients (37 HBeAg+), median age 45 years, previously treated with a median of three lines of antiviral therapy (range 1-6), 24/57 with advanced liver disease, were included. Median ALT at baseline was 1.0 ULN (range 0.3-22) and HBV-DNA 1.5 × 10(4)IU/ml (range 500-1 × 10(11)IU/ml). Median treatment duration of combination therapy was 21 months. HBV-DNA level dropped 3 logs (median, range 0-8 log; p<0.0001), 51/57 patients became HBV-DNA undetectable, median after 6 months (95% CI, 4.6-7). The probability for HBV DNA suppression was not reduced in patients with adefovir or entecavir resistance or in patients with advanced liver disease. Viral suppression led to decline in ALT (median 0.7 ULN; range 0.2-2.4; p=0.001). Five patients lost HBeAg (after 15, 18, 20, 21, and 27 months, respectively), one patient showed HBs-seroconversion. Patients with advanced disease did not show clinical decompensation, two patients with cirrhosis and undetectable HBV DNA developed HCCs. No death, newly induced renal impairment or lactic acidosis were reported. CONCLUSIONS Rescue therapy with entecavir and tenofovir in CHB patients harboring viral resistance patterns or showing only partial antiviral responses to preceding therapies was efficient, safe, and well tolerated in patients with and without advanced liver disease (249).