ABSTRACT
In the U.S., living donor liver transplant (LDLT), from both directed and non-directed living donors, has expanded over the past several years. LDLT is viewed as an important opportunity to expand the overall donor pool for liver transplantation, shorten waiting times for a life-prolonging liver transplant surgery, and reduce liver transplant waitlist mortality. The liver transplant community's focus on LDLT expansion in the U.S. is fostering discussions around future opportunities which include, safe expansion of donor and recipient candidate eligibility criteria, broadening indications for LDLT including applications in transplant oncology, developing national initiatives around liver paired exchange, and maintaining vigilance to living donor and recipient candidate risk/benefit equipoise. Potential opportunities for expanding living liver donor and recipient candidate criteria include utilizing donors with more than minimal hepatic steatosis, evaluating older donors, performing LDLT in older recipients to facilitate timely transplantation, and providing candidates who would benefit from liver transplant, but may otherwise have limited access (i.e., lower MELD scores), an avenue to receive a life-prolonging organ. Expansion opportunities for LDLT are particularly robust in the transplant oncology realm, including leveraging LDLT for patients with advanced hepatocellular carcinoma beyond Milan, intrahepatic cholangiocarcinoma, and nonresectable colorectal cancer liver metastases. With ongoing investment in the deliberate growth of LDLT surgical expertise, experience and technical advances in the U.S., the liver transplant community's future vision to increase transplant access to more patients with end-stage liver disease and selected oncology patients may be successfully realized.
ABSTRACT
Objective: There is an unmet need for optimizing hepatic allograft allocation from nondirected living liver donors (ND-LLD). Materials and method: Using OPTN living donor liver transplant (LDLT) data (1/1/2000-12/31/2019), we identified 6328 LDLTs (4621 right, 644 left, 1063 left-lateral grafts). Random forest survival models were constructed to predict 10-year graft survival for each of the 3 graft types. Results: Donor-to-recipient body surface area ratio was an important predictor in all 3 models. Other predictors in all 3 models were: malignant diagnosis, medical location at LDLT (inpatient/ICU), and moderate ascites. Biliary atresia was important in left and left-lateral graft models. Re-transplant was important in right graft models. C-index for 10-year graft survival predictions for the 3 models were: 0.70 (left-lateral); 0.63 (left); 0.61 (right). Similar C-indices were found for 1-, 3-, and 5-year graft survivals. Comparison of model predictions to actual 10-year graft survivals demonstrated that the predicted upper quartile survival group in each model had significantly better actual 10-year graft survival compared to the lower quartiles (p<0.005). Conclusion: When applied in clinical context, our models assist with the identification and stratification of potential recipients for hepatic grafts from ND-LLD based on predicted graft survivals, while accounting for complex donor-recipient interactions. These analyses highlight the unmet need for granular data collection and machine learning modeling to identify potential recipients who have the best predicted transplant outcomes with ND-LLD grafts.
Subject(s)
Liver Failure , Liver Transplantation , Humans , Liver Transplantation/adverse effects , Living Donors , Retrospective StudiesABSTRACT
Branched chain amino acids (BCAA) supplementation may reduce the incidence of liver failure and hepatocellular carcinoma in patients with cirrhosis. We aimed to determine whether long-term dietary intake of BCAA is associated with liver-related mortality in a well-characterized cohort of North American patients with advanced fibrosis or compensated cirrhosis. We performed a retrospective cohort study using extended follow-up data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. The analysis included 656 patients who completed two Food Frequency Questionnaires. The primary exposure was BCAA intake measured in grams (g) per 1000 kilocalories (kcal) of energy intake (range 3.0-34.8 g/1000 kcal). During a median follow-up of 5.0 years, the incidence of liver-related death or transplantation was not significantly different among the four quartiles of BCAA intake before and after adjustment of confounders (AHR 1.02, 95% CI 0.81-1.27, P-value for trend = 0.89). There remains no association when BCAA was modeled as a ratio of BCAA to total protein intake or as absolute BCAA intake. Finally, BCAA intake was not associated with the risk of hepatocellular carcinoma, encephalopathy or clinical hepatic decompensation. We concluded that dietary BCAA intake was not associated with liver-related outcomes in HCV-infected patients with advanced fibrosis or compensated cirrhosis. The precise effect of BCAA in patients with liver disease warrants further study.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis C , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Retrospective Studies , Amino Acids, Branched-Chain/therapeutic use , Liver Cirrhosis/pathology , Hepatitis C/drug therapy , Hepacivirus , Liver Neoplasms/drug therapy , North AmericaABSTRACT
Importance: Small waitlist candidates are significantly less likely than larger candidates to receive a liver transplant. Objective: To investigate the magnitude of the size disparity and test potential policy solutions. Design, Setting, and Participants: A decision analytical model was generated to match liver transplant donors to waitlist candidates based on predefined body surface area (BSA) ratio limits (donor BSA divided by recipient BSA). Participants included adult deceased liver transplant donors and waitlist candidates in the Organ Procurement and Transplantation Network database from June 18, 2013, to March 20, 2020. Data were analyzed from January 2021 to September 2021. Exposures: Candidates were categorized into 6 groups according to BSA from smallest (group 1) to largest (group 6). Waitlist outcomes were examined. A match run was created for each donor under the current acuity circle liver allocation policy, and the proportion of candidates eligible for a liver based on BSA ratio was calculated. Novel allocation models were then tested. Main Outcomes and Measures: Time on the waitlist, assigned Model for End-Stage Liver Disease (MELD) score, and proportion of patients undergoing a transplant were compared by BSA group. Modeling under the current allocation policies was used to determine baseline access to transplant by group. Simulation of novel allocation policies was performed to examine change in access. Results: There were 41â¯341 donors (24â¯842 [60.1%] male and 16â¯499 [39.9%] female) and 84â¯201 waitlist candidates (53â¯724 [63.8%] male and 30â¯477 [36.2%] female) in the study. The median age of the donors was 42 years (IQR, 28-55) and waitlist candidates, 57 years (IQR, 50-63). Females were overrepresented in the 2 smallest BSA groups (7100 [84.0%] and 7922 [61.1%] in groups 1 and 2, respectively). For each increase in group number, waitlist time decreased (234 days [IQR, 48-700] for group 1 vs 179 days [IQR, 26-503] for group 6; P < .001) and the proportion of the group undergoing transplant likewise improved (3890 [46%] in group 1 vs 4932 [57%] in group 6; P < .001). The smallest 2 groups of candidates were disadvantaged under the current acuity circle allocation model, with 37% and 7.4% fewer livers allocated relative to their proportional representation on the waitlist. Allocation of the smallest 10% of donors (by BSA) to the smallest 15% of candidates overcame this disparity, as did performing split liver transplants. Conclusions and Relevance: In this study, liver waitlist candidates with the smallest BSAs had a disadvantage due to size. Prioritizing allocation of smaller liver donors to smaller candidates may help overcome this disparity.
Subject(s)
End Stage Liver Disease , Liver Transplantation , Tissue and Organ Procurement , Adult , Humans , Male , Female , Middle Aged , End Stage Liver Disease/surgery , Body Surface Area , Severity of Illness Index , Living Donors , Tissue Donors , Waiting ListsABSTRACT
OBJECTIVES: We investigated whether the Liver Disease Health-Related Quality of Life Short Form or the Area Deprivation Index could be used to help identify liver transplant candidates at risk of delisting due to nonadherence. MATERIALS AND METHODS: We conducted a retrospective study of 358 adults (≥18 years old) listed for liver transplant at the University of Washington Medical Center from September 1, 2012, to August 30, 2017, who completed the Liver Disease Health-Related Quality of Life Short Form prior to listing. Wait list removal because of substance use or lack of attendance to clinical appointments was prospectively determined by a multidisciplinary transplant committee. A competing risk analysis was used to estimate risk of delisting for nonadherence. RESULTS: Among 358 liver transplant candidates, delisting occurred in 23 patients (6.4%) for nonadherence, 205 (57.3%) for transplant, 79 (22.1%) because of death or too sick, and 51 (14.2%) for other reasons. In the multivariable competing risk analysis, Liver Disease Health-Related Quality of Life Short Form responses indicating "poor memory" (subdistribution hazard ratio: 3.53; 95% CI, 1.49-8.36; P = .004) and "poor future outlook" (subdistribution hazard ratio: 2.94; 95% CI, 1.07-8.07; P = .03) were associated with higher risk of delisting for nonadherence. Female sex (subdistribution hazard ratio: 0.31; 95% CI, 0.10-0.93; P = .04) and previous abdominal surgery (subdistribution hazard ratio: 0.36; 95% CI, 0.14-0.92; P = .03) were associated with lower risk of delisting for nonadherence. The Area Deprivation Index was not associated with wait list removal. CONCLUSIONS: Liver Disease Health-Related Quality of Life Short Form responses indicating "poor memory" and "poor future outlook" were associated with increased risk of wait list removal due to nonadherence. Proactively identifying patients at high risk of nonadherence may help transplant programs better direct resources toward helping patients improve adherence and avoid delisting.
Subject(s)
Liver Diseases , Liver Transplantation , Adolescent , Adult , Female , Humans , Liver Diseases/etiology , Liver Transplantation/adverse effects , Quality of Life , Retrospective Studies , Risk Assessment , Treatment Outcome , Waiting ListsABSTRACT
US deceased donor solid organ transplantation (dd-SOT) depends upon an individual's/family's altruistic willingness to donate organs after death; however, there is a shortage of deceased organ donors in the United States. Informing individuals of their own lifetime risk of needing dd-SOT could reframe the decision-making around organ donation after death. Using United Network for Organ Sharing (UNOS) data (2007-2016), this cross-sectional study identified (1) deceased organ donors, (2) individuals waitlisted for dd-SOT (liver, kidney, pancreas, heart, lung, intestine), and (3) dd-SOT recipients. Using US population projections, life tables, and mortality estimates, we quantified probabilities (Pr) of (1) becoming deceased organ donors, (2) needing dd-SOT, and (3) receiving dd-SOT. Lifetime Pr (per 100 000 US population) for males and females of becoming deceased organ donors were 212 and 146, respectively, and of needing dd-SOT were 1323 and 803, respectively. Lifetime Pr of receiving dd-SOT was 50% for males, 48% for females. Over a lifetime, males were 6.2 and females 5.5 times more likely to need dd-SOT than to become deceased organ donors. Organ donation is traditionally contextualized in terms of charity toward others. Our analyses yield a new tool, in the form of quantifying an individual's own likelihood of needing dd-SOT, which may assist with reframing motivations toward deceased donor organ donation.
Subject(s)
Organ Transplantation , Tissue and Organ Procurement , Cross-Sectional Studies , Female , Humans , Kidney , Male , Tissue Donors , United StatesABSTRACT
BACKGROUND: Coagulopathy in cirrhosis represents complex coagulation derangements, and thromboelastography (TEG) measures these complex derangements. AIM: We sought to evaluate associations between TEG parameters and validated measures of cirrhosis severity, which have not been previously investigated. MATERIALS AND METHODS: Adults with cirrhosis undergoing liver transplant (LT) were identified. Patients had TEG drawn immediately prior to LT. TEG parameters included reaction time (R), kinetic time (K), alpha angle (α), and maximum amplitude (MA). The validated measures of cirrhosis severity were MELD-Na and clinical stage of cirrhosis (classified using history of varices, variceal bleeding, or ascites). Multivariable linear and logistic regression analyses were conducted to evaluate the associations between TEG and stage of cirrhosis and MELD-Na. RESULTS: Among 164 patients with cirrhosis, advancing stage of cirrhosis was associated with more hypocoagulable TEG parameters including longer K-time (p = 0.05) and lower MA (p < 0.001). Similarly, with increasing MELD-Na quartiles, K-time was longer (p < 0.001), and both MA and α-angle decreased (p < 0.001, for both). Variceal bleeding within 6 weeks prior to LT was associated with longer R-times (p = 0.02), longer K-times (p = 0.04), smaller α-angle (p = 0.03), and lower MA (p = 0.01). On multivariable analyses, decreasing MA remained statistically significantly associated with advancing stage of cirrhosis and increasing MELD-Na, after adjusting for multiple covariates including platelet count, (p = 0.02 and p < 0.0001, respectively). CONCLUSIONS: Hypocoagulable TEG measurements are associated with advancing stage of cirrhosis and increasing MELD-Na among patients with cirrhosis. These data indicate that TEG, as an informative measure of complex hemostatic function, may be a useful objective marker of liver disease severity in cirrhosis.
Subject(s)
Blood Coagulation Disorders/physiopathology , Esophageal and Gastric Varices/physiopathology , Liver Cirrhosis/complications , Liver Cirrhosis/physiopathology , Thrombelastography , Adult , Aged , Blood Coagulation , Blood Coagulation Disorders/etiology , Cross-Sectional Studies , End Stage Liver Disease/etiology , End Stage Liver Disease/physiopathology , End Stage Liver Disease/surgery , Esophageal and Gastric Varices/etiology , Female , Humans , Liver Transplantation , Male , Middle Aged , Retrospective Studies , Severity of Illness IndexABSTRACT
Risk of recurrent hepatocellular carcinoma (rHCC) after liver transplantation (LT) depends on the pre-LT HCC burden, tumor behavior, and response to locoregional therapy (LRT). In December 2017, LT priority for HCC was expanded to select patients outside the Milan criteria who respond to LRT. Our aims were to develop a novel objective measure of pre-LT HCC burden (model of recurrent hepatocellular carcinoma-initial, maximum, last [RH-IML]), incorporating tumor behavior over time, and to apply RH-IML to model post-LT rHCC. Using United Network for Organ Sharing data from between 2002-2014 (development) and 2015-2017 (validation), we identified adult LT recipients with HCC and assessed pre-LT HCC tumor behavior and post-LT rHCC. For each patient, HCC burden was measured at 3 points on the waiting list: initial (I), maximum (M) total tumor diameter, and last (L) exception petition. HCC burden at these 3 points were classified as (A) Subject(s)
Carcinoma, Hepatocellular/surgery
, Liver Neoplasms/surgery
, Liver Transplantation/adverse effects
, Models, Biological
, Neoplasm Recurrence, Local/epidemiology
, Tumor Burden
, Carcinoma, Hepatocellular/blood
, Carcinoma, Hepatocellular/classification
, Carcinoma, Hepatocellular/pathology
, Female
, Follow-Up Studies
, Humans
, Liver Neoplasms/blood
, Liver Neoplasms/classification
, Liver Neoplasms/pathology
, Male
, Middle Aged
, Neoplasm Recurrence, Local/pathology
, Postoperative Period
, Preoperative Period
, Retrospective Studies
, Risk Assessment/methods
, Risk Factors
, Time Factors
, Treatment Outcome
, Waiting Lists
, alpha-Fetoproteins/analysis
ABSTRACT
BACKGROUND: With increasing US adiposity, nonalcoholic steatohepatitis (NASH) is now a leading liver transplant (LT) indication. Given its association with hepatocellular carcinoma (HCC), the burden of NASH is substantial. We analyzed birth cohort effects among NASH LT registrants, with and without HCC. METHODS: All new LT registrants in United Network for Organ Sharing (1995-2015) were identified. Birth cohorts were defined as: 1936-1940, 1941-1945, 1946-1950, 1951-1955, 1956-1960, 1961-1965, 1966-1970, 1971-2015. Poisson regression examined trends in LT registration, by disease etiology (NASH, hepatitis C virus [HCV], other liver disease etiologies [OTHER]), and HCC. RESULTS: We identified 182 368 LT registrants with median age of 52 years (range, 0-86 years). Nine percent (n = 16 160) had NASH, 38% (n= 69 004) HCV, 53% (n = 97 204) OTHER. HCC was present in: 13% (n = 2181), 27% (n = 18 295), and 11% (n = 10 902), of NASH, HCV, and OTHER, respectively. Liver transplant registration for HCC increased significantly from 2002 to 2015 across all etiologies (NASH, 6%-18%; HCV, 19%-51%; OTHER, 9%-16%; P < 0.0001 for all). NASH LT registrations, with and without HCC, increased sharply in patients born from 1945 to 2015. This upward NASH trend is in stark contrast to HCV LT registrations, which showed a general decline. Notably, a sharp rise in LT registrations is occurring among younger NASH patients (35-55 years), mirroring the increasing adiposity across all age groups in the US population. CONCLUSIONS: NASH LT registrants, with and without HCC, have increased over time, and are projected to increase unabated in the future, notably among younger birth cohorts ("Adipose Wave Effect"). HCC LT registration patterns demonstrate that, compared with HCV, NASH patients encompass younger birth cohorts. These data illustrate that the full impact of NASH on demand for LT is yet to be realized.
Subject(s)
Carcinoma, Hepatocellular/surgery , Health Services Needs and Demand/trends , Liver Neoplasms/surgery , Liver Transplantation/trends , Needs Assessment/trends , Non-alcoholic Fatty Liver Disease/surgery , Adiposity , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/epidemiology , Child , Child, Preschool , Databases, Factual , Female , Forecasting , Humans , Infant , Infant, Newborn , Liver Neoplasms/diagnosis , Liver Neoplasms/epidemiology , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/epidemiology , Obesity/epidemiology , Retrospective Studies , Risk Factors , Time Factors , United States/epidemiology , Young AdultABSTRACT
BACKGROUND: The utilization of living donor grafts resulted in an increased availability of liver for pediatric recipients, and accordingly, this was associated with a significantly decreased waiting time before liver transplantation as well as reduced pre-transplant mortality. We hypothesized that the use of living donors in pediatric LT may lead to improved graft and patient survival, when compared to LT using deceased donors. METHODS: Retrospective cohort analysis of pediatric recipients (aged <18 years) registered in the UNOS database who received a primary liver transplant between February 2002 and December 2016. Covariates predictive of survival by multivariable analyses were included in the Cox proportional hazards regression models to determine predictors of patient and graft survival. RESULTS: A total of 6312 children received a primary LT from a LD (n = 800) or a deceased donor (n = 5517; partial graft n = 1784 and whole graft n = 3733). Vascular and biliary complications were similar. Kaplan-Meier graft and patient survival rates were superior in LD recipients compared with recipients of deceased whole and reduced graft (Figures 1 and 2). In the multivariable analysis, LD were an independent predictor of improved patient and graft survival. CONCLUSION: The use of LD in children is associated with improved patient and graft survival. The option of LD should be introduced early on in the evaluation of every pediatric patient being evaluated for liver transplant.
Subject(s)
Graft Survival , Liver Transplantation/methods , Living Donors , Adolescent , Child , Child, Preschool , Databases, Factual , Female , Humans , Infant , Infant, Newborn , Liver Transplantation/mortality , Male , Outcome Assessment, Health Care , Retrospective Studies , Survival AnalysisABSTRACT
BACKGROUND & AIMS: The neutrophil to lymphocyte ratio (NLR) is a biomarker of immune dysregulation in patients with cirrhosis and is inexpensive to measure. We investigated the association between NLR and mortality in hospitalized patients with cirrhosis at 4 liver transplant centers, controlling for severity of acute-on-chronic liver failure (ACLF). METHODS: We performed a retrospective study using data from the North American Consortium for the Study of End-stage Liver Disease on patients with index hospitalizations for cirrhosis from December 2011 through December 2016. We collected data on patient demographics, NLR, model for end-stage liver disease (MELD) scores, serum levels of Na, cirrhosis stages, infections, hepatocellular carcinomas, and ACLF severity (based on number of organ failures). Competing risk regression analysis evaluated mortality within 1 year after hospital discharge, accounting for competing events (liver transplant). RESULTS: At admission, the patients' mean age was 57 years, mean MELD score was 21, and mean serum level of Na was 134 mmol/L. Sixty-eight patients had no organ failure, 21 patients had 1 organ failures, 7 patients had 2 organ failures, 4 patients had 3 organ failures, and 1 patient had 4 organ failures; 36% of the patients had confirmed or suspected infections. In univariate models, risk of death associated with increasing NLR, up to a value of 8 (hazard ratio [HR]= 1.14; 95% CI, 1.07-1.20; P < .001), and NLR quartile (for NLR range of 3-5, HR = 2.17; for NLR range of >5-9, HR=2.46; for NLR quartile >9, HR=2.84 vs the lowest quartile [NLR<3]) (P ≤ .001). The NLR remained statistically significant in multivariable models, adjusting for age, MELD score, hepatocellular carcinoma, and ACLF severity. Additionally, NLR was a statistically significant independent predictor of length of index hospital stay and mortality within 90 days after discharge. CONCLUSION: In a retrospective analysis of patients with cirrhosis, we found NLR to associate with death within 1 year after non-elective hospitalization. In these patients, the risk of death associated with acute immune dysregulation persists long after their initial hospitalization.
Subject(s)
Decision Support Techniques , Diagnostic Tests, Routine/methods , End Stage Liver Disease/mortality , End Stage Liver Disease/pathology , Fibrosis/pathology , Leukocyte Count/methods , Aged , Female , Fibrosis/complications , Humans , Lymphocytes/immunology , Male , Middle Aged , Neutrophils/immunology , Prognosis , Retrospective Studies , Survival AnalysisABSTRACT
The Model for End-Stage Liver Disease (MELD) score has reduced accuracy for liver transplantation (LT) wait-list mortality when MELD ≤ 20. Neutrophil-to-lymphocyte ratio (NLR) is a biomarker associated with systemic inflammation and may predict cirrhotic decompensation and death. We aimed to evaluate the prognostic utility of high NLR (≥4) for liver-related death among low MELD patients listed for LT, controlling for stage of cirrhosis. In a nested case-control study of cirrhotic adults awaiting LT (February 2002 to May 2011), cases were LT candidates with a liver-related death and MELD ≤ 20 within 90 days of death. Controls were similar LT candidates who were alive for ≥90 days after LT listing. NLR and other covariates were assessed at the date of lowest MELD, within 90 days of death for cases and within 90 days after listing for controls. There were 41 cases and 66 controls; MELD scores were similar. NLR 25th, 50th, 75th percentile cutoffs were 1.9, 3.1, and 6.8. NLR was ≥ 4 in 25/41 (61%) cases and in 17/66 (26%) controls. In univariate analysis, NLR (continuous ≥ 1.9, ≥ 4, ≥ 6.8), increasing cirrhosis stage, jaundice, encephalopathy, serum sodium, and albumin and nonselective beta-blocker use were significantly (P < 0.01) associated with liver-related death. In multivariate analysis, NLR of ≥1.9, ≥ 4, ≥ 6.8 were each associated with liver-related death. Furthermore, we found that NLR correlated with the frequency of circulating low-density granulocytes, previously identified as displaying proinflammatory properties, as well as monocytes. In conclusion, elevated NLR is associated with liver-related death, independent of MELD and cirrhosis stage. High NLR may aid in determining risk for cirrhotic decompensation, need for increased monitoring, and urgency for expedited LT in candidates with low MELD. Liver Transplantation 23 155-165 2017 AASLD.
Subject(s)
End Stage Liver Disease/mortality , Liver Cirrhosis/mortality , Liver Transplantation , Lymphocytes , Neutrophils , Waiting Lists/mortality , Biomarkers/blood , Case-Control Studies , End Stage Liver Disease/blood , End Stage Liver Disease/etiology , Female , Humans , Liver Cirrhosis/blood , Liver Cirrhosis/complications , Lymphocyte Count , Male , Middle Aged , Multivariate Analysis , Prognosis , Risk Factors , Severity of Illness IndexABSTRACT
BACKGROUND AND AIM: Associations between pre-liver transplantation (pre-LT) BMI and post-LT survival are well described; however, there are few data assessing the associations between the commonly observed post-LT BMI changes and survival. We investigated the impact of early post-LT BMI change on post-LT patient and graft survival. METHODS: Using United Network for Organ Sharing data, we identified 2968 adult primary LT recipients who were not overweight pre-LT (BMI >16 to ≤25 kg/m), and who had BMI recorded at 2 years post-LT. Delta BMI was defined as the BMI difference between pre-LT and 2 years post LT. Recipients were grouped into three categories: BMI gain (increase by >1 BMI point), BMI loss (decrease by >1 BMI point), and BMI stable (maintained BMI within 1 point). Associations between delta BMI and patient and graft survival were evaluated using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: BMI gain was common (54%) and associated with significantly greater 5-year patient and graft survival (90 and 89%, respectively), compared with recipients who had either BMI loss (77 and 74%, respectively, P<0.0001 for both) or were BMI stable (83%, P=0.04 and 82%, P=0.007, respectively). In multivariable analyses, increasing delta BMI was found to be inversely associated with risk for death and graft loss [hazard ratio 0.89 (95% confidence interval 0.86-0.91), P<0.001; and hazard ratio 0.88 (95% confidence interval 0.86-0.91), P<0.001, respectively]. CONCLUSION: This study of a large national liver transplant database demonstrated that post-LT BMI gain was associated with better patient and graft survival, whereas BMI loss was associated with reduced patient and graft survival.
Subject(s)
Body Mass Index , Graft Survival , Liver Transplantation/mortality , Obesity/epidemiology , Adult , Cause of Death , Female , Humans , Incidence , Kaplan-Meier Estimate , Liver Transplantation/adverse effects , Male , Middle Aged , Obesity/etiology , Proportional Hazards Models , Survival Rate , United States/epidemiology , Weight Gain , Weight Loss , Young AdultABSTRACT
With the high prevalence of obesity, diabetes, and other features of the metabolic syndrome in United States, nonalcoholic fatty liver disease (NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis (NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor (TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.
ABSTRACT
Donor age has become the dominant donor factor used to predict graft failure (GF) after liver transplantation (LT) in hepatitis C virus (HCV) recipients. The purpose of this study was to develop and validate a model of corrected donor age (CDA) for HCV LT recipients that transforms the risk of other donor factors into the scale of donor age. We analyzed all first LT recipients with HCV in the United Network for Organ Sharing (UNOS) registry from January 1998 to December 2007 (development cohort, n = 14,538) and January 2008 to December 2011 (validation cohort, n = 7502) using Cox regression, excluding early GF (<90 days from LT). Accuracy in predicting 1 year GF (death or repeat LT) was assessed with the net reclassification index (NRI). In the development cohort, after controlling for pre-LT recipient factors and geotemporal trends (UNOS region, LT year), the following donor factors were independent predictors of GF, all P < 0.05: donor age (hazard ratio [HR], 1.02/year), donation after cardiac death (DCD; HR, 1.31), diabetes (HR, 1.23), height < 160 cm (HR, 1.13), aspartate aminotransferase (AST) ≥ 120 U/L (HR, 1.10), female (HR, 0.94), cold ischemia time (CIT; HR, 1.02/hour), and non-African American (non-AA) donor-African American (AA) recipient (HR, 1.65). Transforming these risk factors into the donor age scale yielded the following: DCD = +16 years; diabetes = +12 years; height < 160 cm = +7 years; AST ≥ 120 U/L = +5 years; female = -4 years; and CIT = +1 year/hour > 8 hours and -1 year/hour < 8 hours. There was a large effect of donor-recipient race combinations: +29 years for non-AA donor and an AA recipient but only +5 years for an AA donor and an AA recipient, and -2 years for an AA donor and a non-AA recipient. In a validation cohort, CDA better classified risk of 1-year GF versus actual age (NRI, 4.9%; P = 0.009) and versus the donor risk index (9.0%, P < 0.001). The CDA, compared to actual donor age, provides an intuitive and superior estimation of graft quality for HCV-positive LT recipients because it incorporates additional factors that impact LT GF rates.
Subject(s)
Decision Support Techniques , Donor Selection , End Stage Liver Disease/surgery , Graft Survival , Hepatitis C/complications , Liver Transplantation/methods , Tissue Donors , Adult , Age Factors , End Stage Liver Disease/diagnosis , End Stage Liver Disease/mortality , End Stage Liver Disease/virology , Female , Hepatitis C/diagnosis , Hepatitis C/mortality , Humans , Likelihood Functions , Liver Transplantation/adverse effects , Liver Transplantation/mortality , Male , Middle Aged , Multivariate Analysis , Predictive Value of Tests , Proportional Hazards Models , Reproducibility of Results , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , United StatesABSTRACT
With increasing attention being paid to optimizing patient outcomes, it has been proposed that liver transplantation (LT) for individuals with elevated body mass index (BMI) values and high Model for End-Stage Liver Disease (MELD) scores may adversely affect post-LT outcomes. We investigated the impact of BMI on post-LT outcomes in the context of MELD at LT. Using United Network for Organ Sharing data, we identified all adult (≥ 18 years) primary LT recipients from March 1, 2002 to September 30, 2011. BMI categories included the following: underweight, normal, overweight, class I obese, class II obese, and class III obese (<18.5; 18.5-24.9; 25-29.9; 30-34.9; 35-39.9; ≥ 40 kg/m(2), respectively). One-year post-LT death and graft loss were modeled using Cox regression, including interactions between BMI and MELD. A total of 45,551 adult recipients were identified: 68% male; median (interquartile range [IQR]) age 55 years (IQR, 49-60 years); MELD, 19 (IQR, 13-26); and donor risk index, 1.39 (IQR, 1.12-1.69). Representations in the BMI categories were underweight (n = 863, 2%), normal (n = 13,262, 29%), overweight (n = 16,329, 36%), class I obese (n = 9639, 21%), class II obese (n = 4062, 9%), and class III obese (n = 1396, 3%). In adjusted analyses, elevated BMI was not associated with increased risk for death or graft loss. Among the underweight, there were significant interactions between BMI and MELD with respect to death (P = 0.02) and graft loss (P = 0.01), with significantly increased risks for death (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.38-2.09; P = 0.006) and graft loss (HR, 1.45; 95% CI, 1.21-1.74; P = 0.02) among those with low MELD (≤ 26), compared to normal BMI recipients with low MELD. In conclusion, overweight and obese LT recipients do not have increased risk of death or graft loss regardless of MELD. Underweight patients are at increased risk for poor outcomes post-LT, specifically underweight recipients with low MELD have increased risk for death and graft loss. Mechanisms underlying this phenomenon warrant further investigation.
Subject(s)
Body Mass Index , Decision Support Techniques , Graft Survival , Liver Transplantation/adverse effects , Obesity/complications , Thinness/complications , Databases, Factual , Female , Humans , Kaplan-Meier Estimate , Liver Transplantation/mortality , Logistic Models , Male , Middle Aged , Multivariate Analysis , Obesity/diagnosis , Obesity/mortality , Obesity/physiopathology , Odds Ratio , Predictive Value of Tests , Proportional Hazards Models , Risk Assessment , Risk Factors , Thinness/diagnosis , Thinness/mortality , Thinness/physiopathology , Time Factors , Treatment Outcome , United StatesABSTRACT
Repeat liver transplantation (LT) is controversial because of inferior outcomes versus primary LT. A minimum 1-year expected post-re-LT survival of 50% has been proposed. We aimed to identify combinations of Model for End-Stage Liver Disease (MELD), donor risk index (DRI), and recipient characteristics achieving this graft survival threshold. We identified re-LT recipients listed in the United States from March 2002 to January 2010 with > 90 days between primary LT and listing for re-LT. Using Cox regression, we estimated the expected probability of 1-year graft survival and identified combinations of MELD, DRI, and recipient characteristics attaining >50% expected 1-year graft survival. Re-LT recipients (n = 1418) had a median MELD of 26 and median age of 52 years. Expected 1-year graft survival exceeded 50% regardless of MELD or DRI in Caucasian recipients who were not infected with hepatitis C virus (HCV) of all ages and Caucasian HCV-infected recipients <50 years old. As age increased in HCV-infected Caucasian and non-HCV-infected African American recipients, lower MELD scores or lower DRI grafts were needed to attain the graft survival threshold. As MELD scores increased in HCV-infected African American recipients, lower-DRI livers were required to achieve the graft survival threshold. Use of high-DRI livers (>1.44) in HCV-infected recipients with a MELD score > 26 at re-LT failed to achieve the graft survival threshold with recipient age ≥ 60 years (any race), as well as at age ≥ 50 years for Caucasians and at age < 50 years for African Americans. Strategic donor selection can achieve >50% expected 1-year graft survival even in high-risk re-LT recipients (HCV infected, older age, African American race, high MELD scores). Low-risk transplant recipients (age < 50 years, non-HCV-infected) can achieve the survival threshold with varying DRI and MELD scores.