Vatche G. Agopian

Liver transplantation for nonalcoholic steatohepatitis: the new epidemic.

Objective:To analyze incidence, outcomes, and utilization of health care resources in liver transplantation (LT) for nonalcoholic steatohepatitis (NASH). Summary of Background Data:With the epidemic of obesity and metabolic syndrome in nearly 33% of the US population, NASH is projected to become the leading indication for LT in the next several years. Data on predictors of outcome and utilization of health care resources after LT in NASH is limited. Methods:We conducted an analysis from our prospective database of 144 adult NASH patients who underwent LT between December 1993 and August 2011. Outcomes and resource utilization were compared with other common indications for LT. Independent predictors of graft and patient survival were identified. Results:The average Model for End-Stage Liver Disease score was 33. The frequency of NASH as the primary indication for LT increased from 3% in 2002 to 19% in 2011 to become the second most common indication for LT at our center behind hepatitis C. NASH patients had significantly longer operative times (402 vs 322 minutes; P < 0.001), operative blood loss (18 vs 14 packed red blood cell units; P = 0.001), and posttransplant length of stay (35 vs 29 days; P = 0.032), but 1-, 3-, and 5-year graft (81%, 71%, 63%) and patient (84%, 75%, 70%) survival were comparable with other diagnoses. Age greater than 55 years, pretransplant intubation, dialysis, hospitalization, presence of hepatocellular carcinoma on explant, donor age greater than 55 years, and cold ischemia time greater than 550 minutes were significant independent predictors of survival for all patients, whereas body mass index greater than 35 was a predictor in NASH patients only. Conclusions:We report the largest single institution experience of LT for NASH. Over a 10-year period, the frequency of LT for NASH has increased 5-fold. Although outcomes are comparable with LT for other indications, health care resources are stressed significantly by this new and increasing group of transplant candidates.

Survival Benefit of Solid-Organ Transplant in the United States

IMPORTANCE The field of transplantation has made tremendous progress since the first successful kidney transplant in 1954. OBJECTIVE To determine the survival benefit of solid-organ transplant as recorded during a 25-year study period in the United Network for Organ Sharing (UNOS) database and the Social Security Administration Death Master File. DESIGN, SETTING, AND PARTICIPANTS In this retrospective analysis of UNOS data for solid-organ transplant during a 25-year period (September 1, 1987, through December 31, 2012), we reviewed the records of 1,112,835 patients: 533,329 recipients who underwent a transplant and 579 506 patients who were placed on the waiting list but did not undergo a transplant. MAIN OUTCOMES AND MEASURES The primary outcome was patient death while on the waiting list or after transplant. Kaplan-Meier survival functions were used for time-to-event analysis. RESULTS We found that 2,270,859 life-years (2,150,200 life-years from the matched analysis) were saved to date during the 25 years of solid-organ transplant. A mean of 4.3 life-years were saved (observed to date) per solid-organ transplant recipient. Kidney transplant saved 1,372,969 life-years; liver transplant, 465,296 life-years; heart transplant, 269,715 life-years; lung transplant, 64,575 life-years; pancreas-kidney transplant, 79,198 life-years; pancreas transplant, 14,903 life-years; and intestine transplant, 4402 life-years. CONCLUSIONS AND RELEVANCE Our analysis demonstrated that more than 2 million life-years were saved to date by solid-organ transplants during a 25-year study period. Transplants should be supported and organ donation encouraged.

The evolution of liver transplantation during 3 decades: analysis of 5347 consecutive liver transplants at a single center.

Objective:To analyze a 28-year single-center experience with orthotopic liver transplantation (OLT) for patients with irreversible liver failure. Background:The implementation of the model for end-stage liver disease (MELD) in 2002 represented a fundamental shift in liver donor allocation to recipients with the highest acuity, raising concerns about posttransplant outcome and morbidity. Methods:Outcomes and factors affecting survival were analyzed in 5347 consecutive OLTs performed in 3752 adults and 822 children between 1984 and 2012, including comparisons of recipient and donor characteristics, graft and patient outcomes, and postoperative morbidity before (n = 3218) and after (n = 2129) implementation of the MELD allocation system. Independent predictors of survival were identified. Results:Overall, 1-, 5-, 10-, and 20-year patient and graft survival estimates were 82%, 70%, 63%, 52%, and 73%, 61%, 54%, 43%, respectively. Recipient survival was best in children with biliary atresia and worst in adults with malignancy. Post-MELD era recipients were older (54 vs 49, P < 0.001), more likely to be hospitalized (50% vs 47%, P = 0.026) and receiving pretransplant renal replacement therapy (34% vs 12%, P < 0.001), and had significantly greater laboratory MELD scores (28 vs 19, P < 0.001), longer wait-list times (270 days vs 186 days, P < 0.001), and pretransplant hospital stays (10 days vs 8 days, P < 0.001). Despite increased acuity, post-MELD era recipients achieved superior 1-, 5-, and 10-year patient survival (82%, 70%, and 65% vs 77%, 66%, and 58%, P < 0.001) and graft survival (78%, 66%, and 61% vs 69%, 58%, and 51%, P < 0.001) compared with pre-MELD recipients. Of 17 recipient and donor variables, era of transplantation, etiology of liver disease, recipient and donor age, prior transplantation, MELD score, hospitalization at time of OLT, and cold and warm ischemia time were independent predictors of survival. Conclusions:We present the worlds largest reported single-institution experience with OLT. Despite increasing acuity in post-MELD era recipients, patient and graft survival continues to improve, justifying the “sickest first” allocation approach.

Liver transplantation in highest acuity recipients: identifying factors to avoid futility.

Objective:To identify medical predictors of futility in recipients with laboratory Model of End-Stage Liver Disease (MELD) scores of 40 or more at the time of orthotopic liver transplantation (OLT). Background:Although the survival benefit for transplant patients with the highest MELD scores is indisputable, the medical and economic effort to bring these highest acuity recipients through OLT presents a major challenge for every transplant center. Methods:This study was undertaken to analyze outcomes in patients with MELD scores of 40 or more undergoing OLT during the period February 2002 to December 2010. The analysis was focused on futile outcome (3-month or in-hospital mortality) and long-term posttransplant outcome. Independent predictors of futility and failure-free survival were identified and a futility risk model was created. Results:During the study period, 1522 adult cadaveric OLTs were performed, and 169 patients (13%) had a MELD score of 40 or more. The overall 1, 3, 5, and 8-year patient survivals were 72%, 64%, 60%, and 56%. Futile outcome occurred in 37 patients (22%). MELD score, pretransplant septic shock, cardiac risk, and comorbidities were independent predictors of futile outcome. Using all 4 factors, the futility risk model had a good discriminatory ability (c-statistic 0.75). Recipient age per year, life-threatening postoperative complications, hepatitis C, and metabolic syndrome were independent predictors for long-term survival in nonfutile patients (Harrels c-statistic 0.72). Conclusions:Short- and long-term outcomes of recipients with MELD scores of 40 or more are primarily determined by disease-specific factors. Cardiac risk, pretransplant septic shock, and comorbidities are the most important predictors and can be used for risk stratification in these highest acuity recipients.

A Novel Prognostic Nomogram Accurately Predicts Hepatocellular Carcinoma Recurrence after Liver Transplantation: Analysis of 865 Consecutive Liver Transplant Recipients

BACKGROUND Although radiologic size criteria (Milan/University of California, San Francisco [UCSF]) have led to improved outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC), recurrence remains a significant challenge. We analyzed our 30-year experience with LT for HCC to identify predictors of recurrence. STUDY DESIGN A novel clinicopathologic risk score and prognostic nomogram predicting post-transplant HCC recurrence was developed from a multivariate competing-risk Cox regression analysis of 865 LT recipients with HCC between 1984 and 2013. RESULTS Overall patient and recurrence-free survivals were 83%, 68%, 60% and 79%, 63%, and 56% at 1-, 3-, and 5-years, respectively. Hepatocellular carcinoma recurred in 117 recipients, with a median time to recurrence of 15 months, involving the lungs (59%), abdomen/pelvis (38%), liver (35%), bone (28%), pleura/mediastinum (12%), and brain (5%). Multivariate predictors of recurrence included tumor grade/differentiation (G4/poor diff hazard ratio [HR] 8.86; G2-3/mod-poor diff HR 2.56), macrovascular (HR 7.82) and microvascular (HR 2.42) invasion, nondownstaged tumors outside Milan criteria (HR 3.02), nonincidental tumors with radiographic maximum diameter ≥ 5 cm (HR 2.71) and <5 cm (HR 1.55), and pretransplant neutrophil-to-lymphocyte ratio (HR 1.77 per log unit), maximum alpha fetoprotein (HR 1.21 per log unit), and total cholesterol (HR 1.14 per SD). A pretransplantation model incorporating only known radiographic and laboratory parameters had improved accuracy in predicting HCC recurrence (C statistic 0.79) compared with both Milan (C statistic 0.64) and UCSF (C statistic 0.64) criteria alone. A novel clinicopathologic prognostic nomogram included explant pathology and had an excellent ability to predict post-transplant recurrence (C statistic 0.85). CONCLUSIONS In the largest single-institution experience with LT for HCC, excellent long-term survival was achieved. Incorporation of routine pretransplantation biomarkers to existing radiographic size criteria significantly improves the ability to predict post-transplant recurrence, and should be considered in recipient selection. A novel clinicopathologic prognostic nomogram accurately predicts HCC recurrence after LT and may guide frequency of post-transplantation surveillance and adjuvant therapy.

Blood transfusion requirement during liver transplantation is an important risk factor for mortality.

BACKGROUND Blood loss during liver transplantation is not incorporated into the dominant models for post-transplant survival. Our objective was to investigate blood transfusion requirement as a risk factor for mortality after liver transplantation, and to further analyze risk factors for intraoperative blood transfusion requirement and hepatectomy time. STUDY DESIGN We conducted a retrospective analysis of 233 consecutive liver transplant recipients over a span of 3 years by a single experienced surgeon. Mean follow-up was 2.5 years. Independent risk factors for patient survival after liver transplantation were identified using Cox proportion hazard regression. Independent risk factors for intraoperative blood transfusion requirement and hepatectomy time were identified using logistic regression. RESULTS Two factors were identified as significant predictors in multivariate analysis for survival after liver transplantation: hepatocellular carcinoma (hazard ratio [HR] 1.9, 95% CI 1.1 to 3.2) and intraoperative blood transfusion requirement per unit (HR 1.01, 95% CI 1.0 to 1.02). Threshold analysis revealed that intraoperative blood transfusion volume ≥28 units or 85(th) percentile (HR 2.5, 95% CI 1.3 to 4.7) was a significant risk factor for patient survival. Four covariates were identified as significant risk factors for intraoperative blood requirement: warm ischemia time (odds ratio [OR] 1.12, 95% CI 1.06 to 1.18), bilirubin (OR 1.04, 95% CI 1.02 to 1.08), previous surgery (OR 1.7, 95% CI 1.02 to 2.9), and hepatectomy time (OR 1.01, 95% CI 1.00 to 1.02). The only risk factor for prolonged hepatectomy time was previous major abdominal surgery (OR 4.0, 95% CI 1.7 to 9.5). CONCLUSIONS Intraoperative blood transfusion requirement is an important risk factor for mortality after liver transplantation. The strongest risk factors for intraoperative blood transfusion requirement are warm ischemia time and bilirubin levels. Intraoperative blood loss and its risk factors should be incorporated into models to predict survival after liver transplantation.

Complete pathologic response to pretransplant locoregional therapy for hepatocellular carcinoma defines cancer cure after liver transplantation: analysis of 501 consecutively treated patients.

OBJECTIVES To evaluate the rate, effect, and predictive factors of a complete pathologic response (cPR) in patients with hepatocellular carcinoma (HCC) undergoing locoregional therapy (LRT) before liver transplantation (LT). BACKGROUND Eligible patients with HCC receive equal model for end-stage liver disease prioritization, despite variable risks of tumor progression, waitlist dropout, and posttransplant recurrence. Pretransplant LRT mitigates these risks by inducing tumor necrosis. METHODS Comparisons were made among HCC recipients with cPR (n = 126) and without cPR (n = 375) receiving pre-LT LRT (1994-2013). Multivariable predictors of cPR were identified. RESULTS Of 501 patients, 272, 148, and 81 received 1, 2, and 3 or more LRT treatments. The overall, recurrence-free, and disease-specific survival at 1-, 3-, and 5 years was 86%, 71%, 63%; 84%, 67%, 60%; and 97%, 90%, 87%. Compared with recipients without cPR, cPR patients had significantly lower laboratory model for end-stage liver disease scores, pretransplant alpha fetoprotein, and cumulative tumor diameters; were more likely to have 1 lesion, tumors within Milan/University of California, San Francisco (UCSF) criteria, LRT that included ablation, and a favorable tumor response to LRT; and had superior 1-, 3-, and 5-year recurrence-free survival (92%, 79%, and 73% vs 81%, 63%, and 56%; P = 0.006) and disease-specific survival (100%, 100%, and 99% vs 96%, 89%, and 86%; P < 0.001) with only 1 cancer-specific death and fewer recurrences (2.4% vs 15.2%; P < 0.001). Multivariate predictors of cPR included a favorable post-LRT radiologic/alpha fetoprotein tumor response, longer time interval from LRT to LT, and lower model for end-stage liver disease score and maximum tumor diameter (C-statistic 0.75). CONCLUSIONS Achieving cPR in patients with HCC receiving LRT strongly predicts tumor-free survival. Factors predicting cPR are identified, allowing for differential prioritization of HCC recipients based on their variable risks of post-LT recurrence. Improving LRT strategies to maximize cPR would enhance posttransplant cancer outcomes.

Liver transplantation for “very early” intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment

The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 [2.5‐4.4] versus 1.6 [1.5‐1.8]). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178‐1188)

Assessment of hepatic steatosis by transplant surgeon and expert pathologist: A prospective, double‐blind evaluation of 201 donor livers

An accurate clinical assessment of hepatic steatosis before transplantation is critical for successful outcomes after liver transplantation, especially if a pathologist is not available at the time of procurement. This prospective study investigated the surgeons accuracy in predicting hepatic steatosis and organ quality in 201 adult donor livers. A steatosis assessment by a blinded expert pathologist served as the reference gold standard. The surgeons steatosis estimate correlated more strongly with large‐droplet macrovesicular steatosis [ld‐MaS; nonparametric Spearman correlation coefficient (rS) = 0.504] versus small‐droplet macrovesicular steatosis (sd‐MaS; rS = 0.398). True microvesicular steatosis was present in only 2 donors (1%). Liver texture criteria (yellowness, absence of scratch marks, and round edges) were mainly associated with ld‐MaS (variance = 0.619) and were less associated with sd‐MaS (variance = 0.264). The prediction of ≥30% ld‐MaS versus <30% ld‐MaS was excellent when liver texture criteria were used (accuracy = 86.2%), but it was less accurate when the surgeons direct estimation of the steatosis percentage was used (accuracy = 75.5%). The surgeons quality grading correlated with the degree of ld‐MaS and the surgeons steatosis estimate as well as the incidence of poor initial function and primary nonfunction. In conclusion, the precise estimation of steatosis remains challenging even in experienced hands. Liver texture characteristics are more helpful in identifying macrosteatotic organs than the surgeons actual perception of steatosis. These findings are especially important when histological assessment is not available at the donors hospital. Liver Transpl 19:437–449, 2013.

TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-initiating Stem-like Cells in Livers of Mice.

BACKGROUND & AIMS Obesity and alcohol consumption contribute to steatohepatitis, which increases the risk for hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCCs). Mouse hepatocytes that express HCV-NS5A in liver up-regulate the expression of Toll-like receptor 4 (TLR4), and develop liver tumors containing tumor-initiating stem-like cells (TICs) that express NANOG. We investigated whether the TLR4 signals to NANOG to promote the development of TICs and tumorigenesis in mice placed on a Western diet high in cholesterol and saturated fat (HCFD). METHODS We expressed HCV-NS5A from a transgene (NS5A Tg) in Tlr4-/- (C57Bl6/10ScN), and wild-type control mice. Mice were fed a HCFD for 12 months. TICs were identified and isolated based on being CD133+, CD49f+, and CD45-. We obtained 142 paraffin-embedded sections of different stage HCCs and adjacent nontumor areas from the same patients, and performed gene expression, immunofluorescence, and immunohistochemical analyses. RESULTS A higher proportion of NS5A Tg mice developed liver tumors (39%) than mice that did not express HCV NS5A after the HCFD (6%); only 9% of Tlr4-/- NS5A Tg mice fed HCFD developed liver tumors. Livers from NS5A Tg mice fed the HCFD had increased levels of TLR4, NANOG, phosphorylated signal transducer and activator of transcription (pSTAT3), and TWIST1 proteins, and increases in Tlr4, Nanog, Stat3, and Twist1 messenger RNAs. In TICs from NS5A Tg mice, NANOG and pSTAT3 directly interact to activate expression of Twist1. Levels of TLR4, NANOG, pSTAT3, and TWIST were increased in HCC compared with nontumor tissues from patients. CONCLUSIONS HCFD and HCV-NS5A together stimulated TLR4-NANOG and the leptin receptor (OB-R)-pSTAT3 signaling pathways, resulting in liver tumorigenesis through an exaggerated mesenchymal phenotype with prominent Twist1-expressing TICs.