Successful living donor liver transplantation in a patient with hemophilia A and factor VIII inhibitor: A case report with perioperative recommendations.

Liver transplantation in patients with end-stage liver disease and coexisting hemophilia A has been described. Controversy exists over perioperative management of patients with factor VIII inhibitor predisposing patients to hemorrhage. We describe the case of a 58-year-old man with a history of hemophilia A and factor VIII inhibitor, eradicated with rituximab prior to living donor liver transplantation without recurrence of inhibitor. We also provide perioperative management recommendations from our successful multidisciplinary approach.

Positron emission tomography myocardial perfusion imaging (PET MPI) findings predictive of post-liver transplant major adverse cardiac events.

Positron emission tomography myocardial perfusion imaging (PET MPI) is a noninvasive diagnostic test capable of detecting coronary artery disease, structural heart disease, and myocardial flow reserve (MFR). We aimed to determine the prognostic utility of PET MPI to predict post-liver transplant (LT) major adverse cardiac events (MACE). Among the 215 LT candidates that completed PET MPI between 2015 and 2020, 84 underwent LT and had 4 biomarker variables of clinical interest on pre-LT PET MPI (summed stress and difference scores, resting left ventricular ejection fraction, global MFR). Post-LT MACE were defined as acute coronary syndrome, heart failure, sustained arrhythmia, or cardiac arrest within the first 12 months post-LT. Cox regression models were constructed to determine associations between PET MPI variable/s and post-LT MACE. The median LT recipient age was 58 years, 71% were male, 49% had NAFLD, 63% reported prior smoking, 51% had hypertension, and 38% had diabetes mellitus. A total of 20 MACE occurred in 16 patients (19%) at a median of 61.5 days post-LT. One-year survival of MACE patients was significantly lower than those without MACE (54% vs. 98%, p =0.001). On multivariate analysis, reduced global MFR ≤1.38 was associated with a higher risk of MACE [HR=3.42 (1.23-9.47), p =0.019], and every % reduction in left ventricular ejection fraction was associated with an 8.6% higher risk of MACE [HR=0.92 (0.86-0.98), p =0.012]. Nearly 20% of LT recipients experienced MACE within the first 12 months of LT. Reduced global MFR and reduced resting left ventricular ejection fraction on PET MPI among LT candidates were associated with increased risk of post-LT MACE. Awareness of these PET-MPI parameters may help improve cardiac risk stratification of LT candidates if confirmed in future studies.

Graft Survival and Segment Discards Among Split-Liver and Reduced-Size Transplantations in the United States From 2008 to 2018.

Split-liver transplantation has allocation advantages over reduced-size transplantation because of its ability to benefit 2 recipients. However, prioritization of split-liver transplantation relies on the following 3 major assumptions that have never been tested in the United States: similar long-term transplant recipient outcomes, lower incidence of segment discard among split-liver procurements, and discard of segments among reduced-size procurements that would be otherwise "transplantable." We used United Network for Organ Sharing Standard Transplant Analysis and Research data to identify all split-liver (n = 1831) and reduced-size (n = 578) transplantation episodes in the United States between 2008 and 2018. Multivariable Cox proportional hazards modeling was used to compare 7-year all-cause graft loss between cohorts. Secondary analyses included etiology of 30-day all-cause graft loss events as well as the incidence and anatomy of discarded segments. We found no difference in 7-year all-cause graft loss (adjusted hazard ratio [aHR], 1.1; 95% confidence interval [CI], 0.8-1.5) or 30-day all-cause graft loss (aHR, 1.1; 95% CI, 0.7-1.8) between split-liver and reduced-size cohorts. Vascular thrombosis was the most common etiology of 30-day all-cause graft loss for both cohorts (56.4% versus 61.8% of 30-day graft losses; P = 0.85). Finally, reduced-size transplantation was associated with a significantly higher incidence of segment discard (50.0% versus 8.7%) that were overwhelmingly right-sided liver segments (93.6% versus 30.3%). Our results support the prioritization of split-liver over reduced-size transplantation whenever technically feasible.

Intraoperative risk factors of acute kidney injury after liver transplantation.

Acute kidney injury (AKI) is one of the most common complications of liver transplantation (LT). We examined the impact of intraoperative management on risk for AKI following LT. In this retrospective observational study, we linked data from the electronic health record with standardized transplant outcomes. Our primary outcome was stage 2 or 3 AKI as defined by Kidney Disease Improving Global Outcomes guidelines within the first 7 days of LT. We used logistic regression models to test the hypothesis that the addition of intraoperative variables, including inotropic/vasopressor administration, transfusion requirements, and hemodynamic markers improves our ability to predict AKI following LT. We also examined the impact of postoperative AKI on mortality. Of the 598 adult primary LT recipients included in our study, 43% (n = 255) were diagnosed with AKI within the first 7 postoperative days. Several preoperative and intraoperative variables including (1) electrolyte/acid-base balance disorder (International Classification of Diseases, Ninth Revision codes 253.6 or 276.x and International Classification of Diseases, Tenth Revision codes E22.2 or E87.x, where x is any digit; adjusted odds ratio [aOR], 1.917, 95% confidence interval [CI], 1.280-2.869; p = 0.002); (2) preoperative anemia (aOR, 2.612; 95% CI, 1.405-4.854; p = 0.002); (3) low serum albumin (aOR, 0.576; 95% CI, 0.410-0.808; p = 0.001), increased potassium value during reperfusion (aOR, 1.513; 95% CI, 1.103-2.077; p = 0.01), and lactate during reperfusion (aOR, 1.081; 95% CI, 1.003-1.166; p = 0.04) were associated with posttransplant AKI. New dialysis requirement within the first 7 days postoperatively predicted the posttransplant mortality. Our study identified significant association between several potentially modifiable variables with posttransplant AKI. The addition of intraoperative data did not improve overall model discrimination.

Extinguishing burnout: National analysis of predictors and effects of burnout in abdominal transplant surgery fellows.

Burnout among surgeons has been attributed to increased workload and decreased autonomy. Although prior studies have examined burnout among transplant surgeons, no studies have evaluated burnout in abdominal transplant surgery fellows. The objective of our study was to identify predictors of burnout and understand its impact on personal and patient care during fellowship. A survey was sent to all abdominal transplant surgery fellows in an American Society of Transplant Surgeons-accredited fellowship. The response rate was 59.2% (n = 77) and 22.7% (n = 17) of fellows met criteria for burnout. Fellows with lower grit scores were more likely to exhibit burnout compared with fellows with higher scores (3.6 vs 4.0, P = .026). Those with burnout were more likely to work >100 hours per week (58.8% vs 27.6%, P = .023), have severe work-related stress (58.8% vs 22.4%, P = .010), consider quitting fellowship (94.1% vs 20.7%, P < .001), or make a medical error (35.3% vs 5.2%, P = .003). This national analysis of abdominal transplant fellows found that burnout rates are relatively low, but few fellows engage in self-care. Personal and program-related factors attribute to burnout and it has unacceptable effects on patient care. Transplant societies and fellowship programs should develop interventions to give fellows tools to prevent and combat burnout.

Association of Adjuvant Radiotherapy With Survival After Margin-negative Resection of Pancreatic Ductal Adenocarcinoma: A Propensity-matched National Cancer Database (NCDB) Analysis.

INTRODUCTION: There is conflicting evidence for the benefit of adjuvant radiotherapy (RT) after resection of pancreatic ductal adenocarcinoma (PDAC), especially for margin-negative (R0) resections. We aimed to evaluate the association of adjuvant RT with survival after R0 resection of PDAC. METHODS: Using National Cancer Database (NCDB) data from 2004 to 2013, we identified patients with R0 resection of nonmetastatic PDAC. Patients with neoadjuvant radiotherapy and chemotherapy and survival <6 months were excluded. Propensity score matching was used to account for treatment selection bias. A multivariable Cox proportional hazards model was then used to analyze the association of RT with survival. RESULTS: Of 4547 (36%) RT and 7925 (64%) non-RT patients, 3860 RT and 3860 non-RT patients remained in the cohort after matching. Clinicopathologic and demographic variables were well balanced after matching. Lymph node metastases were present in 68% (44% N1, 24% N2). After matching, RT was associated with higher survival (median 25.8 vs 23.9 mo, 5-yr 27% vs 24%, P < 0.001). After multivariable adjustment, RT remained associated with a survival benefit (HR 0.89, 95% CI 0.84-0.94, P < 0.001). Stratified and multivariable interaction analyses showed that this benefit was restricted to patients with node-positive disease: N1 (HR: 0.68, CI95%: 0.62-0.76, P = 0.007) and N2 (HR: 0.59, CI95%: 0.54-0.64, P = 0.04). CONCLUSIONS: In this large retrospective cohort study, adjuvant RT after R0 PDAC resection was associated with a survival benefit in patients with node-positive disease. Adjuvant RT should be considered after R0 resection of PDAC with node-positive disease.

Optimal Timing of Administration of Direct-acting Antivirals for Patients With Hepatitis C-associated Hepatocellular Carcinoma Undergoing Liver Transplantation.

OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.

Applying Administrative Data-Based Coding Algorithms for Frailty in Patients With Cirrhosis.

Frailty is a powerful prognostic tool in cirrhosis. Claims-based frailty scores estimate the presence of frailty without the need for in-person evaluation. These algorithms have not been validated in cirrhosis. Whether they measure true frailty or perform as well as frailty in outcome prediction is unknown. We evaluated 2 claims-based frailty scores-Hospital Frailty Risk Score (HFRS) and Claims-Based Frailty Index (CFI)-in 3 prospective cohorts comprising 1100 patients with cirrhosis. We assessed differences in neuromuscular/neurocognitive capabilities in those classified as frail or nonfrail based on each score. We assessed the ability of the indexes to discriminate frailty based on the Fried Frailty Index (FFI), chair stands, activities of daily living (ADL), and falls. Finally, we compared the performance of claims-based frailty measures and physical frailty measures to predict transplant-free survival using competing risk regression and patient-reported outcomes. The CFI identified neuromuscular deficits (balance, chair stands, hip strength), whereas the HFRS only identified poor chair-stand performance. The CFI had areas under the receiver operating characteristic curve (AUROCs) for identifying frailty as measured by the FFI, ADL, and falls of 0.57, 0.60, and 0.68, respectively; similarly, the AUROCs were 0.66, 0.63, and 0.67, respectively, for the HFRS. Claims-based frailty scores were associated with poor quality of life and sleep but were outperformed by the FFI and chair stands. The HFRS, per 10-point increase (but not the CFI) predicted survival of patients in the liver transplantation (subdistribution hazard ratio [SHR], 1.08; 95% confidence interval [CI], 1.03-1.12) and non-liver transplantation cohorts (SHR, 1.13; 95% CI, 1.05-1.22). Claims-based frailty scores do not adequately associate with physical frailty but are associated with important cirrhosis-related outcomes.

Marijuana use among adult liver transplant candidates and recipients.

BACKGROUND: Data regarding marijuana (MJ) use among liver transplant (LT) candidates are limited. We set out to determine the incidence and pre- and post-LT outcomes of adult LT candidates with a self-reported history of MJ use. METHODS: Baseline clinical characteristics, waitlist, and post-LT outcomes of adult LT candidates from January 2010 to March 2017 were compared. RESULTS: Among 2690 LT candidates, 630(23%) and 298(11%) reported a history of MJ use and use within the past 12 months, respectively. Although the proportion of MJ users increased over time(ß = .76, p = .03), the proportion listed and transplanted did not change. Listing for LT increased with male (OR 1.24, 95% CI 11.01-1.52), MELD score (OR 1.08, 95% CI 1.01-1.15), HCC (OR 1.83, 95% CI 1.39-2.41) but decreased among MJ users (OR 0.67, 95% CI 0.50-0.91, p = .01). The median time to listing was longer among MJ users compared to non-users (115 vs. 87 days, p < .0005). Post-LT survival was similar in 83 MJ users and 306 non-users. CONCLUSION: The proportion of MJ users among LT candidates is increasing. MJ users have a greater burden of psychosocial issues which may contribute to longer evaluations and lower rate of LT listing. Post-LT survival was not impacted by self-reported MJ use history.

Intraoperative glycemic control in patients undergoing Orthotopic liver transplant: a single center prospective randomized study.

BACKGROUND: Perioperative hyperglycemia is associated with poor outcomes yet evidence to guide intraoperative goals and treatment modalities during non-cardiac surgery are lacking. End-stage liver disease is associated with altered glucose homeostasis; patients undergoing liver transplantation display huge fluctuations in blood glucose (BG) and represent a population of great interest. Here, we conduct a randomized trial to compare the effects of strict versus conventional glycemic control during orthotopic liver transplant (OLT). METHODS: Following approval by the Institutional Review Board of the University of Michigan Medical School and informed consent, 100 adult patients undergoing OLT were recruited. Patients were randomized to either strict (target BG 80-120 mg/dL) or conventional (target BG 180-200 mg/dL) BG control with block randomization for diabetic and nondiabetic patients. The primary outcomes measured were 1-year patient and graft survival assessed on an intention to treat basis. Graft survival is defined as death or needing re-transplant (www.unos.org). Three and 5-year patient and graft survival, infectious and biliary complications were measured as secondary outcomes. Data were examined using univariate methods and Kaplan-Meir survival analysis. A sensitivity analysis was performed to compare patients with a mean BG of ≤120 mg/dL and those > 120 mg/dL regardless of treatment group. RESULTS: There was no statistically significant difference in patient survival between conventional and strict control respectively;1 year, 88% vs 88% (p-0.99), 3 years, 86% vs 84% (p- 0.77), 5 years, 82% vs 78. % (p-0.36). Graft survival was not different between conventional and strict control groups at 1 year, 88% vs 84% (p-0.56), 3 years 82% vs 76% (p-0.46), 5 years 78% vs 70% (p-0.362). CONCLUSION: There was no difference in patient or graft survival between intraoperative strict and conventional glycemic control during OLT. TRIAL REGISTRATION: Clinical trial number and registry: www.clinicaltrials.gov NCT00780026. This trial was retrospectively registered on 10/22/2008.

Frailty in liver transplantation: An expert opinion statement from the American Society of Transplantation Liver and Intestinal Community of Practice.

Frailty has emerged as a powerful predictor of outcomes in patients with cirrhosis and has inevitably made its way into decision making within liver transplantation. In an effort to harmonize integration of the concept of frailty among transplant centers, the AST and ASTS supported the efforts of our working group to develop this statement from experts in the field. Frailty is a multidimensional construct that represents the end-manifestation of derangements of multiple physiologic systems leading to decreased physiologic reserve and increased vulnerability to health stressors. In hepatology/liver transplantation, investigation of frailty has largely focused on physical frailty, which subsumes the concepts of functional performance, functional capacity, and disability. There was consensus that every liver transplant candidate should be assessed at baseline and longitudinally using a standardized frailty tool, which should guide the intensity and type of nutritional and physical therapy in individual liver transplant candidates. The working group agreed that frailty should not be used as the sole criterion for delisting a patient for liver transplantation, but rather should be considered one of many criteria when evaluating transplant candidacy and suitability. A road map to advance frailty in the clinical and research settings of liver transplantation is presented here.

Impact of a Prohibitive Versus Restrictive Tobacco Policy on Liver Transplant Candidate Outcomes.

Tobacco use has been associated with poorer outcomes after liver transplantation (LT). Our study examined the effect on LT listing outcomes of a newly implemented policy prohibiting the use of all tobacco products compared with a prior restrictive policy. Medical records of consecutive adult patients evaluated for LT from January 2010 to July 2013 (era 1, n = 1344) and August 2013 to March 2017 (era 2, n = 1350) were reviewed. The proportion of LT candidates listed was the primary outcome. The mean age of the 2694 LT candidates was 54 ± 11 years, 60% were male, and the mean Model for End-Stage Liver Disease (MELD) score was 15 ± 7. Although the proportion of LT candidates who were smokers was significantly higher in era 2 (33% versus 23%; P < 0.005), the proportion of smokers listed for LT remained stable (13% versus 17%; P = 0.25). However, there were more smokers excluded for ongoing tobacco use in era 2 compared with era 1 (9.6% versus 4.4%; P = 0.001). Factors independently associated with LT listing included a diagnosis of hepatocellular carcinoma, being married, private insurance, absence of psychiatry comorbidity, and absence of tobacco, marijuana, or opiate use but evaluation during era 2 was not associated with LT listing. However, the median time to listing significantly increased over time, especially in smokers (from 65 to 122 days; P = 0.001), and this trend was independently associated with evaluation during era 2, a lower MELD score, not having children, and a lower level of education (P < 0.05). In conclusion, despite an increasing incidence of active smokers being referred for LT evaluation, the proportion of smoker candidates listed for LT was unchanged after instituting our prohibitive tobacco use policy. However, the time to get on the waiting list for smokers who were eventually listed was significantly longer due to the need to achieve complete tobacco cessation.

Hepatic encephalopathy impacts the predictive value of the Fried Frailty Index.

Frailty is increasingly recognized as a predictor of poor outcomes in solid organ transplantation. The most widely utilized frailty tool, the Fried Frailty Index (FFI), includes patient-reported exhaustion, weight loss, and physical activity as well as measured walk speed and handgrip. Although hepatic encephalopathy (HE) is common among liver transplant candidates, data are lacking regarding its impact on the interpretation of frailty. We prospectively enrolled 685 patients with cirrhosis during their transplant evaluation, following them until death or transplantation. Our cohort was aged 54.5 ± 10.3 years, 60% male, with an average MELD score of 14.7 ± 6.3. A history of HE was present in 39%. Frailty was present in 41%, associated with higher MELD, low albumin, ascites, and HE. HE was associated with frail performance on three components of the FFI-grip (odds ratio 1.41 95% CI, 1.03-1.92), walk speed (1.56 95% CI, 1.14-2.15), and decreased energy (1.44 95% CI, 1.05-1.99). These three components were associated with transplant free survival in the whole cohort: energy (hazard ratio 1.67 95% CI, 1.25-2.28), grip (1.63 95% CI, 1.24-2.16), and walk speed (1.56 95% CI, 1.19-2.04). However, among patients with HE, the FFI was not associated with survival. HE plays a critical role in the frailty phenotype and the implications of frailty among patients with cirrhosis evaluated for liver transplantation.

Bone mineral density predicts posttransplant survival among hepatocellular carcinoma liver transplant recipients.

Hepatocellular carcinoma (HCC) is a common indication for liver transplantation (LT). Recent data suggest that body composition features strongly affect post-LT mortality. We examined the impact of body composition on post-LT mortality in patients with HCC. Data on adult LT recipients who received Model for End-Stage Liver Disease exception for HCC between February 29, 2002, and December 31, 2013, and who had a computed tomography (CT) scan any time 6 months prior to LT were reviewed (n = 118). All available CT scan Digital Imaging and Communication in Medicine files were analyzed using a semiautomated high throughput methodology with algorithms programmed in MATLAB. Analytic morphomics measurements including dorsal muscle group (DMG) area, visceral and subcutaneous fat, and bone mineral density (BMD) were taken at the bottom of the eleventh thoracic vertebral level. Thirty-two (27%) patients died during the median follow-up of 4.4 years. The number of HCC lesions (hazard ratio [HR], 2.81; P < 0.001), BMD (HR = 0.90/Hounsfield units [HU]; P = 0.03), pre-LT locoregional therapy (HR = 0.14; P < 0.001), and donor age (HR = 1.05; P < 0.001) were the independent predictors of post-LT mortality. DMG area did not affect post-LT survival. In conclusion, in addition to number of HCC lesions and pre-LT locoregional therapy, low BMD, a surrogate for bone loss rather than DMG area, was independently associated with post-LT mortality in HCC patients. Bone loss may be an early marker of deconditioning that precedes sarcopenia and may affect transplant outcomes. Liver Transplantation 22 1092-1098 2016 AASLD.

Abdominal adiposity, body composition and survival after liver transplantation.

BACKGROUND: Current measures of obesity do not accurately describe body composition. Using cross-sectional imaging, objective measures of musculature and adiposity are possible and may inform efforts to optimize liver transplantation outcomes. METHODS: Abdominal visceral fat area and psoas muscle cross-sectional area were measured on CT scans for 348 liver transplant recipients. After controlling for donor and recipient characteristics, survival analysis was performed using Cox regression. RESULTS: Visceral fat area was significantly associated with post-transplant mortality (p < 0.001; HR = 1.06 per 10 cm(2) , 95% CI: 1.04-1.09), as were positive hepatitis C status (p = 0.004; HR = 1.78, 95% CI: 1.21-2.61) and total psoas area (TPA) (p < 0.001; HR = 0.91 per cm(2) , 95% CI: 0.88-0.94). Among patients with smaller TPA, the patients with high visceral fat area had 71.8% one-yr survival compared to 81.8% for those with low visceral fat area (p = 0.15). At five yr, the smaller muscle patients with high visceral fat area had 36.9% survival compared to 58.2% for those with low visceral fat area (p = 0.023). CONCLUSIONS: Abdominal adiposity is associated with survival after liver transplantation, especially in patients with small trunk muscle size. When coupled with trunk musculature, abdominal adiposity offers direct characterization of body composition that can aid preoperative risk evaluation and inform transplant decision-making.