Jeffrey H. Fair

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure

Objective:The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure. Summary Background Data:In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. Methods:A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. Results:For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048). Conclusions:This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.

Donor Morbidity After Living Donation for Liver Transplantation

BACKGROUND & AIMS Reports of complications among adult right hepatic lobe donors have been limited to single centers. The rate and severity of complications in living donors were investigated in the 9-center Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). METHODS A retrospective observational study design was used. Participants included all potential living donors evaluated between 1998 and 2003. Complication severity was graded using the Clavien scoring system. RESULTS Of 405 donors accepted for donation, 393 underwent donation, and 12 procedures were aborted. There were 245 donors (62%) who did not experience complications; 82 (21%) had 1 complication, and 66 (17%) had 2 or more. Complications were scored as grade 1 (minor; n = 106, 27%), grade 2 (potentially life threatening; n = 103, 26%), grade 3 (life threatening; n = 8, 2%), and grade 4 (leading to death; n = 3, 0.8%). Common complications included biliary leaks beyond postoperative day 7 (n = 36, 9%), bacterial infections (n = 49, 12%), incisional hernia (n = 22, 6%), pleural effusion requiring intervention (n = 21, 5%), neuropraxia (n = 16, 4%), reexploration (n = 12, 3%), wound infections (n = 12, 3%), and intraabdominal abscess (n = 9, 2%). Two donors developed portal vein thrombosis, and 1 had inferior vena caval thrombosis. Fifty-one (13%) donors required hospital readmission, and 14 (4%) required 2 to 5 readmissions. CONCLUSIONS Adult living liver donation was associated with significant donor complications. Although most complications were of low-grade severity, a significant proportion were severe or life threatening. Quantification of complication risk may improve the informed consent process, perioperative planning, and donor care.

OUTCOMES OF 385 ADULT-TO-ADULT LIVING DONOR LIVER TRANSPLANT RECIPIENTS: A REPORT FROM THE A2ALL CONSORTIUM

Objective:The objective of this study was to characterize the patient population with respect to patient selection, assess surgical morbidity and graft failures, and analyze the contribution of perioperative clinical factors to recipient outcome in adult living donor liver transplantation (ALDLT). Summary Background Data:Previous reports have been center-specific or from large databases lacking detailed variables. The Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) represents the first detailed North American multicenter report of recipient risk and outcome aiming to characterize variables predictive of graft failure. Methods:Three hundred eighty-five ALDLT recipients transplanted at 9 centers were studied with analysis of over 35 donor, recipient, intraoperative, and postoperative variables. Cox regression models were used to examine the relationship of variables to the risk of graft failure. Results:Ninety-day and 1-year graft survival were 87% and 81%, respectively. Fifty-one (13.2%) grafts failed in the first 90 days. The most common causes of graft failure were vascular thrombosis, primary nonfunction, and sepsis. Biliary complications were common (30% early, 11% late). Older recipient age and length of cold ischemia were significant predictors of graft failure. Center experience greater than 20 ALDLT was associated with a significantly lower risk of graft failure. Recipient Model for End-stage Liver Disease score and graft size were not significant predictors. Conclusions:This multicenter A2ALL experience provides evidence that ALDLT is a viable option for liver replacement. Older recipient age and prolonged cold ischemia time increase the risk of graft failure. Outcomes improve with increasing center experience.

Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation

We examined mortality and recurrence of hepatocellular carcinoma (HCC) among 106 transplant candidates with cirrhosis and HCC who had a potential living donor evaluated between January 1998 and February 2003 at the nine centers participating in the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Cox regression models were fitted to compare time from donor evaluation and time from transplant to death or HCC recurrence between 58 living donor liver transplant (LDLT) and 34 deceased donor liver transplant (DDLT) recipients. Mean age and calculated Model for End‐Stage Liver Disease (MELD) scores at transplant were similar between LDLT and DDLT recipients (age: 55 vs. 52 years, p = 0.21; MELD: 13 vs. 15, p = 0.08). Relative to DDLT recipients, LDLT recipients had a shorter time from listing to transplant (mean 160 vs. 469 days, p < 0.0001) and a higher rate of HCC recurrence within 3 years than DDLT recipients (29% vs. 0%, p = 0.002), but there was no difference in mortality or the combined outcome of mortality or recurrence. LDLT recipients had lower relative mortality risk than patients who did not undergo LDLT after the center had more experience (p = 0.03). Enthusiasm for LDLT as HCC treatment is dampened by higher HCC recurrence compared to DDLT.

Recipient morbidity after living and deceased donor liver transplantation: Findings from the A2ALL retrospective cohort study

Patients considering living donor liver transplantation (LDLT) need to know the risk and severity of complications compared to deceased donor liver transplantation (DDLT). One aim of the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study (A2ALL) was to examine recipient complications following these procedures. Medical records of DDLT or LDLT recipients who had a living donor evaluated at the nine A2ALL centers between 1998 and 2003 were reviewed. Among 384 LDLT and 216 DDLT, at least one complication occurred after 82.8% of LDLT and 78.2% of DDLT (p = 0.17). There was a median of two complications after DDLT and three after LDLT. Complications that occurred at a higher rate (p < 0.05) after LDLT included biliary leak (31.8% vs. 10.2%), unplanned reexploration (26.2% vs. 17.1%), hepatic artery thrombosis (6.5% vs. 2.3%) and portal vein thrombosis (2.9% vs. 0.0%). There were more complications leading to retransplantation or death (Clavien grade 4) after LDLT versus DDLT (15.9% vs. 9.3%, p = 0.023). Many complications occurred more commonly during early center experience; the odds of grade 4 complications were more than two‐fold higher when centers had performed ≤20 LDLT (vs. >40). In summary, complication rates were higher after LDLT versus DDLT, but declined with center experience to levels comparable to DDLT.

Outcomes in Hepatitis C Virus–Infected Recipients of Living Donor vs. Deceased Donor Liver Transplantation

In this retrospective study of hepatitis C virus (HCV)–infected transplant recipients in the 9‐center Adult to Adult Living Donor Liver Transplantation Cohort Study, graft and patient survival and the development of advanced fibrosis were compared among 181 living donor liver transplant (LDLT) recipients and 94 deceased donor liver transplant (DDLT) recipients. Overall 3‐year graft and patient survival were 68% and 74% in LDLT, and 80% and 82% in DDLT, respectively. Graft survival, but not patient survival, was significantly lower for LDLT compared to DDLT (P = 0.04 and P = 0.20, respectively). Further analyses demonstrated lower graft and patient survival among the first 20 LDLT cases at each center (LDLT ⩽20) compared to later cases (LDLT > 20; P = 0.002 and P = 0.002, respectively) and DDLT recipients (P < 0.001 and P = 0.008, respectively). Graft and patient survival in LDLT >20 and DDLT were not significantly different (P = 0.66 and P = 0.74, respectively). Overall, 3‐year graft survival for DDLT, LDLT >20, and LDLT ⩽20 were 80%, 79% and 55%, with similar results conditional on survival to 90 days (84%, 87% and 68%, respectively). Predictors of graft loss beyond 90 days included LDLT ⩽20 vs. DDLT (hazard ratio [HR] = 2.1, P = 0.04), pretransplant hepatocellular carcinoma (HCC) (HR = 2.21, P = 0.03) and model for end‐stage liver disease (MELD) at transplantation (HR = 1.24, P = 0.04). In conclusion, 3‐year graft and patient survival in HCV‐infected recipients of DDLT and LDLT >20 were not significantly different. Important predictors of graft loss in HCV‐infected patients were limited LDLT experience, pretransplant HCC, and higher MELD at transplantation. Liver Transpl 13:122–129, 2007.

Incidence and severity of acute cellular rejection in recipients undergoing adult living donor or deceased donor liver transplantation

Living donor liver transplantation (LDLT) may have better immunological outcomes compared to deceased donor liver transplantation (DDLT). The aim of this study was to analyze the incidence of acute cellular rejection (ACR) after LDLT and DDLT. Data from the adult‐to‐adult living donor liver transplantation (A2ALL) retrospective cohort study on 593 liver transplants done between May 1998 and March 2004 were studied (380 LDLT; 213 DDLT). Median LDLT and DDLT follow‐up was 778 and 713 days, respectively. Rates of clinically treated and biopsy‐proven ACR were compared. There were 174 (46%) LDLT and 80 (38%) DDLT recipients with ≥1 clinically treated episodes of ACR, whereas 103 (27%) LDLT and 58 (27%) DDLT recipients had ≥1 biopsy‐proven ACR episode. A higher proportion of LDLT recipients had clinically treated ACR (p = 0.052), but this difference was largely attributable to one center. There were similar proportions of biopsy‐proven rejection (p = 0.97) and graft loss due to rejection (p = 0.16). Longer cold ischemia time was associated with a higher rate of ACR in both groups despite much shorter median cold ischemia time in LDLT. These data do not show an immunological advantage for LDLT, and therefore do not support the application of unique posttransplant immunosuppression protocols for LDLT recipients.

Isolated Donor Specific Alloantibody-Mediated Rejection after ABO Compatible Liver Transplantation

Antibody‐mediated rejection (AMR) after liver transplantation is recognized in ABO incompatible and xeno‐transplantation, but its role after ABO compatible liver transplantation is controversial.

Outcomes of donor evaluation in adult-to-adult living donor liver transplantation

The purpose of donor evaluation for adult‐to‐adult living donor liver transplantation (LDLT) is to discover medical conditions that could increase the donor postoperative risk of complications and to determine whether the donor can yield a suitable graft for the recipient. We report the outcomes of LDLT donor candidates evaluated in a large multicenter study of LDLT. The records of all donor candidates and their respective recipients between 1998 and 2003 were reviewed as part of the Adult‐to‐Adult Living Donor Liver Transplantation Cohort Study (A2ALL). The outcomes of the evaluation were recorded along with demographic data on the donors and recipients. Of the 1011 donor candidates evaluated, 405 (40%) were accepted for donation. The donor characteristics associated with acceptance (P < 0.05) were younger age, lower body mass index, and biological or spousal relationship to the recipient. Recipient characteristics associated with donor acceptance were younger age, lower Model for End‐stage Liver Disease score, and shorter time from listing to first donor evaluation. Other predictors of donor acceptance included earlier year of evaluation and transplant center. Conclusion: Both donor and recipient features appear to affect acceptance for LDLT. These findings may aid the donor evaluation process and allow an objective assessment of the likelihood of donor candidate acceptance. (HEPATOLOGY 2007.)

Hepatic progenitors and strategies for liver cell therapies

Abstract: Liver cell therapies, including liver cell transplantation and bioartificial livers, are being developed as alternatives to whole liver transplantation for some patients with severe liver dysfunction. Hepatic progenitors are proposed as ideal cells for use in these liver cell therapies given their ability to expand extensively, differentiate into all mature liver cells, have minimal immunogenicity, be cryopreservable, and reconstitute liver tissue when transplanted. We summarize our ongoing efforts to develop clinical programs of hepatic progenitor cell therapies with a focus on hepatic stem cell biology and strategies that have emerged in analyzing that biology.