Jennifer C. Lai

Frailty Predicts Waitlist Mortality in Liver Transplant Candidates

We aimed to determine whether frailty, a validated geriatric construct of increased vulnerability to physiologic stressors, predicts mortality in liver transplant candidates. Consecutive adult outpatients listed for liver transplant with laboratory Model for End‐Stage Liver Disease (MELD) ≥ 12 at a single center (97% recruitment rate) underwent four frailty assessments: Fried Frailty, Short Physical Performance Battery (SPPB), Activities of Daily Living (ADL) and Instrumental ADL (IADL) scales. Competing risks models associated frailty with waitlist mortality (death/delisting for being too sick for liver transplant). Two hundred ninety‐four listed liver transplant patients with MELD ≥ 12, median age 60 years and MELD 15 were followed for 12 months. By Fried Frailty score ≥3, 17% were frail; 11/51 (22%) of the frail versus 25/243 (10%) of the not frail died/were delisted (p = 0.03). Each 1‐unit increase in the Fried Frailty score was associated with a 45% (95% confidence interval, 4–202) increased risk of waitlist mortality adjusted for MELD. Similarly, the adjusted risk of waitlist mortality associated with each 1‐unit decrease (i.e. increasing frailty) in the Short Physical Performance Battery (hazard ratio 1.19, 95% confidence interval 1.07–1.32). Frailty is prevalent in liver transplant candidates. It strongly predicts waitlist mortality, even after adjustment for liver disease severity demonstrating the applicability and importance of the frailty construct in this population.

A Comparison of Measured and Calculated Free 25(OH) Vitamin D Levels in Clinical Populations

OBJECTIVE Our goal was to compare direct quantitation of circulating free 25-hydroxyvitamin D (25(OH)D)levels to calculated free 25(OH)D levels and their relationships to intact PTH (iPTH), a biomarker of 25(OH)D effect, in humans with a range of clinical conditions. PATIENTS AND METHODS Serum samples and clinical data were collected from 155 people: 111 without cirrhosis or pregnancy (comparison group), 24 cirrhotic patients with albumin <2.9 g/dL, and 20 pregnant women (second and third trimester). Total 25(OH)D (LC/MS/MS), free 25(OH)D (immunoassay), vitamin D binding protein (DBP) (immunoassay), albumin, and iPTH (immunoassay) were measured. RESULTS Total 25(OH)D, DBP, and albumin were lowest in patients with cirrhosis, but measured free 25(OH)D was highest in this group (P < .001). DBP was highest in pregnant women (P < .001), but measured free 25(OH)D did not differ from the comparison group. Calculated free 25(OH)D was positively correlated with measured free 25(OH)D (P < .0001) but explained only 13% of the variability with calculated values higher than measured. African Americans had lower DBP than other ethnic populations within all clinical groups (P < .03), and differences between measured and calculated free 25(OH)D were greatest in African Americans (P < .001). Measured free 25(OH)D was correlated with total 25(OH)D (P < .0001; r(2) = 0.51), but calculated free 25(OH)D was not. Similarly, both measured free 25(OH)D (P < .02) and total 25(OH)D (P < .05) were correlated with iPTH, but calculated free 25(OH)D was not. CONCLUSIONS Calculated free 25(OH)D levels varied considerably from direct measurements of free 25(OH)D with discrepancies greatest in the data for African Americans. Differences in DBP binding affinity likely contributed to estimation errors between the races. Directly measured free 25(OH)D concentrations were related to iPTH, but calculated estimates were not. Current algorithms to calculate free 25(OH)D may not be accurate. Further evaluation of directly measured free 25(OH)D levels to determine its role in research and clinical management of patients is needed.

Hepatitis C virus-infected women have a higher risk of advanced fibrosis and graft loss after liver transplantation than men.

In natural history studies of hepatitis C virus (HCV) infection, women have a lower risk of disease progression to cirrhosis. Whether female sex influences outcomes of HCV in the posttransplantation setting is unknown. All patients transplanted for HCV‐related liver disease from 2002‐2007 at five United States transplantation centers were included. The primary outcome was development of advanced disease, defined as biopsy‐proven bridging fibrosis or cirrhosis. Secondary outcomes included death, graft loss, and graft loss with advanced recurrent disease. A total of 1,264 patients were followed for a median of 3 years (interquartile range, 1.8‐4.7), 304 (24%) of whom were women. The cumulative rate of advanced disease at 3 years was 38% for women and 33% for men (P = 0.31), but after adjustment for recipient age, donor age, donor anti‐HCV positivity, posttransplantation HCV treatment, cytomegalovirus infection and center, female sex was an independent predictor of advanced recurrent disease (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.02‐1.70; P = 0.04). Among women, older donor age and treated acute rejection were the primary predictors of advanced disease. The unadjusted cumulative 3‐year rates of patient and graft survival were numerically lower in women (75% and 74%, respectively) than men (80% and 78%, respectively), and in multivariable analyses, female sex was an independent predictor for death (HR, 1.30; 95% CI, 1.01‐1.67; P = 0.04) and graft loss (HR, 1.31; 95% CI, 1.02‐1.67; P = 0.03). Conclusion: Female sex represents an underrecognized risk factor for advanced recurrent HCV disease and graft loss. Further studies are needed to determine whether modification of donor factors, immunosuppression, and posttransplantation therapeutics can equalize HCV‐specific outcomes in women and men. (HEPATOLOGY 2011;)

Functional decline in patients with cirrhosis awaiting liver transplantation: Results from the functional assessment in liver transplantation (FrAILT) study.

Cirrhosis is characterized by sarcopenia and malnutrition, leading to progressive functional decline. We aimed to objectively measure functional decline in patients with cirrhosis awaiting liver transplantation and its association with waiting list mortality. Consecutive adults listed for liver transplantation with laboratory Model for End‐Stage Liver Disease (MELD) ≥12 at a single center underwent functional status assessments at every outpatient visit using the Short Physical Performance Battery (0 = impaired to 12 = robust), consisting of gait, chair stands, and balance tests. Joint linear time‐to‐event analyses modeled the simultaneous impact of the longitudinal trajectory of physical function on waiting list mortality (=death or delisted for being too sick for liver transplantation). Included were 309 liver transplantation candidates. Median laboratory MELD was 15, serum albumin was 3.0 g/dL, 28% had ascites, 18% had hepatic encephalopathy, and 83% were Child class B or C. At a median follow‐up of 14 months, 15% died or were delisted and 28% underwent liver transplantation. Average physical function worsened per 3 months on the waiting list: −0.38 kg in grip strength, −0.05 meters/second in gait, 0.03 seconds in chair stands, and −0.16 Short Physical Performance Battery points. In joint models of longitudinal trajectories of physical function and waiting list mortality adjusted for MELD‐Na, albumin, hepatocellular carcinoma, and baseline physical function, the longitudinal trajectories of each physical function measure were significantly associated with waiting list mortality: grip (hazard ratio = 0.89, 95% confidence interval 0.83‐0.95), gait (hazard ratio = 0.72, 95% confidence interval 0.62‐0.84), chair stands (hazard ratio = 1.17, 95% confidence interval 1.09‐1.25), and Short Physical Performance Battery <10 (hazard ratio = 1.45, 95% confidence interval 1.15‐2.20). Conclusion: Liver transplantation candidates experience significant functional decline on the waiting list, despite modest wait time and low baseline MELD; decline in physical function is associated with an increased risk of death or delisting, independent of liver disease severity. (Hepatology 2016;63:574–580)

Center competition and outcomes following liver transplantation

In the United States, livers for transplantation are distributed within donation service areas (DSAs). In DSAs with multiple transplant centers, competition among centers for organs and recipients may affect recipient selection and outcomes in comparison with DSAs with only 1 center. The objective of this study was to determine whether competition within a DSA is associated with posttransplant outcomes and variations in patients wait‐listed within the DSA. United Network for Organ Sharing data for 38,385 adult cadaveric liver transplant recipients undergoing transplantation between January 1, 2003 and December 31, 2009 were analyzed to assess differences in liver recipients and donors and in posttransplant survival by competition among centers. The main outcome measures that were studied were patient characteristics, actual and risk‐adjusted graft and patient survival rates after transplantation, organ quality as quantified by the donor risk index (DRI), wait‐listed patients per million population by DSA, and competition as quantified by the Hirschman‐Herfindahl index (HHI). Centers were stratified by HHI levels as no competition or as low, medium (or mid), or high competition. In comparison with DSAs without competition, the low‐, mid‐, and high‐competition DSAs (1) performed transplantation for patients with a higher risk of graft failure [hazard ratio (HR) = 1.24, HR = 1.26, and HR = 1.34 (P < 0.001 for each)] and a higher risk of death [HR = 1.21, HR = 1.23, and HR = 1.34 (P < 0.001 for each)] and for a higher proportion of sicker patients as quantified by the Model for End‐Stage Liver Disease (MELD) score [10.0% versus 14.8%, 20.1%, and 28.2% with a match MELD score of 31‐40 (P < 0.001 for each comparison)], (2) were more likely to use organs in the highest risk quartile as quantified by the DRI [18.3% versus 27.6%, 20.4%, and 31.7% (P ≤ 0.001 for each)], and (3) listed more patients per million population [18 (median) versus 34 (P = not significant), 37 (P = 0.005), and 45 (P = 0.0075)]. Significant variability in patient selection for transplantation is associated with market variables characterizing competition among centers. These findings suggest both positive and negative effects of competition among health care providers. Liver Transpl 19:96–104, 2013.

An Examination of Liver Offers to Candidates on the Liver Transplant Wait-List

BACKGROUND & AIMS We aimed to characterize offers of organs to candidates awaiting liver transplantation (LT). METHODS We analyzed data from the United Network for Organ Sharing registry on all US LT candidates with nonfulminant disease who were offered livers from February 1, 2005, to January 31, 2010, and ultimately received transplants. We excluded candidates with a final Model for End-stage Liver Disease score of less than 15. Livers were classified as high quality if they were from donors 18-50 years of age who were ≥ 170 cm tall, of non-black race, suffered brain death secondary to trauma, hepatitis C antibody-negative, not categorized as high risk by the Centers for Disease Control, and locally or regionally located. RESULTS Of 33,389 candidates for LT, 20% died or were removed from the list and 64% received LT; the median (interquartile range) number of liver offers for all candidates was 5 (range, 2-12). Of those who died or were removed from the list, 84% received 1 or more liver offers. Overall, 55% of those who died or were removed from the list, and 57% of those who received LT, received 1 or more offers of a high-quality liver when they had Model for End-stage Liver Disease scores of 15 or greater (P = .005). However, the proportion of last liver offers of high quality to patients who underwent LT was twice that of patients who died or were removed from the list (28% vs 14%; P < .001). Most liver offers (68%) were refused for reasons related to donor quality. CONCLUSIONS Most candidates for LT who died or were removed from the list received 1 or more offers of a liver beforehand, and 55% received 1 or more offers of a high-quality liver. These findings indicate that a substantial proportion of wait-list mortality results in part from declined livers, rather than lack of opportunity, for transplantation. Understanding the real-time factors involved in the complex decision to accept a liver offer is vital to reducing wait-list mortality for LT candidates.

A multicenter study to define sarcopenia in patients with end‐stage liver disease

Sarcopenia is associated with increased wait‐list mortality, but a standard definition is lacking. In this retrospective study, we sought to determine the optimal definition of sarcopenia in end‐stage liver disease (ESLD) patients awaiting liver transplantation (LT). Included were 396 patients newly listed for LT in 2012 at 5 North American transplant centers. All computed tomography scans were read by 2 individuals with interobserver correlation of 98%. Using image analysis software, the total cross‐sectional area (cm2) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI), which normalizes muscle area to patient height, was then calculated. The primary outcome was wait‐list mortality, defined as death on the waiting list or removal from the waiting list for reasons of clinical deterioration. Sex‐specific potential cutoff values to define sarcopenia were determined with a grid search guided by log‐rank test statistics. Optimal search methods identified potential cutoffs to detect survival differences between groups. The overall median SMI was 47.6 cm2/m2: 50.0 in men and 42.0 in women. At a median of 8.8 months follow‐up, mortality was 25% in men and 36% in women. Patients who died had lower SMI than those who survived (45.6 versus 48.5 cm2/m2; P < 0.001), and SMI was associated with wait‐list mortality (hazard ratio, 0.95; P < 0.001). Optimal search method yielded SMI cutoffs of 50 cm2/m2 for men and 39 cm2/m2 for women; these cutoff values best combined statistical significance with a sufficient number of events to detect survival differences between groups. In conclusion, we recommend that an SMI < 50 cm2/m2 for men and < 39 cm2/m2 for women be used to define sarcopenia in patients with ESLD awaiting LT. Liver Transplantation 23 625–633 2017 AASLD.

Risk of advanced fibrosis with grafts from hepatitis C antibody–positive donors: A multicenter cohort study†

Over the last decade, the use of liver grafts from hepatitis C virus antibody–positive donors [HCV(+)Ds] has tripled in the United States. Although previous studies have demonstrated no association between an HCV(+)D status and graft loss, the effects of an HCV(+)D on histological outcomes are not well known. Hepatitis C virus (HCV)–infected recipients at 5 US centers (2002‐2007) who survived more than 30 days with 1 or more posttransplant biopsy samples were included. Cox regression was used to examine the association between an HCV(+)D status and advanced fibrosis (stage 3/4 or higher). Ninety‐nine of the 1206 patients (8%) received an HCV(+)D graft. Recipients of HCV(+)D grafts were older than recipients of hepatitis C virus antibody–negative donor [HCV(−)D] grafts (P = 0.03), but they were otherwise similar. HCV(+)D grafts were significantly lower in quality according to the donor risk index (P < 0.001). Advanced fibrosis occurred in 32% of HCV(+)D graft recipients and in 28% of HCV(−)D graft recipients (P = 0.39). The unadjusted 1‐ and 3‐year rates of advanced fibrosis were significantly higher for HCV(+)D graft recipients (14% and 48%) versus HCV(−)D graft recipients (7% and 33%, P = 0.01). Transplantation with HCV(+)D grafts was associated with a 58% increased risk of advanced fibrosis [95% confidence interval (CI) = 1.05‐2.36, P = 0.03]. However, in an analysis stratified by the mean donor age of 45 years, an HCV(+)D status was associated with advanced fibrosis only with donors >45 years old [hazard ratio (HR) = 1.76, 95% CI = 1.06‐2.93, P = 0.03] and not with donors ≤45 years old (HR = 0.94, 95% CI = 0.47‐1.87, P = 0.85). In conclusion, a careful consideration of the risks and benefits is needed with HCV(+)D grafts. Recipients of HCV(+)D grafts (especially from older donors) should undergo close monitoring for more rapidly progressive fibrosis. Studies are needed to determine whether early HCV therapy modifies this risk. Liver Transpl, 2012.

Gender differences in liver donor quality are predictive of graft loss.

Some studies have found that donor–recipient gender mismatch predicts posttransplant outcomes but whether this is independent of donor quality is unknown. To evaluate the association between gender mismatch and graft loss, 11 508 females (F) and 16 714 males (M) who underwent liver transplant from March 1, 2002 to December 31, 2007 were studied. Of 11 donor characteristics, clinically relevant differences between F and M donors were median age (47 vs. 39 years), height (165 vs. 178 cm) and proportion dying of stroke (59 vs. 35%) (p < 0.001 for all). The donor risk index was significantly lower for F than M donors (1.3 vs. 1.6, p < 0.001). Recipients of gender‐mismatched grafts had an 11% higher risk of graft loss (p < 0.001). Compared to M→M donor–recipient‐matched transplants in univariable analysis, F→M mismatch was associated with a 17% increased risk of graft loss (95% CI = 1.11–1.24, p < 0.001), whereas M→F mismatch was not (HR = 1.02; 95% CI = 0.96–1.09; p = 0.46). However, adjustment for significant recipient and donor factors eliminated the association between F→M mismatch and graft loss (HR = 0.95; 95% CI = 0.89–1.02; p = 0.18). In conclusion, donor quality differs significantly between female and male donors—female donors are older, shorter and die more frequently of stroke—and gender differences in donor quality, rather than gender mismatch are predictive of graft loss.

Height contributes to the gender difference in wait-list mortality under the MELD-based liver allocation system.

This study examined factors associated with the gender disparity in wait‐list mortality in the MELD era. Adult patients listed for liver transplantation from 2002 to 2008 were included. Females [12 585(36%)] and males [22 126(64%)] differed clinically by age (54 vs. 52 years), height (1.6 vs. 1.8 m), listing estimated glomerular filtration rate [(eGFR); 70 vs. 83 mL/min] and cirrhosis etiology. Holding MELD constant, females were at 19% (95% CI, 1.13–1.25, p < 0.001) higher risk of wait‐list mortality than males under the current allocation system. The relative hazard increased with worsening renal function, whether measured by serum creatinine or eGFR. Adjustment for MELD, age, African‐American race, cirrhosis etiology, region and ABO group attenuated this relative hazard (HR 1.16; 95% CI, 1.10–1.22; p < 0.001) but additional adjustment for height completely explained this gender disparity in wait‐list mortality (HR 1.05; 95% CI, 0.98–1.12; p = 0.2). Transplantation rates, however, remained lower among females, even after adjustment for height (HR 0.88; 95% CI, 0.82–0.92; p < 0.001). In conclusion, under the current liver allocation system, women have a 19% increased risk of wait‐list mortality compared to men with the same MELD scores. Height contributes to this gender disparity, possibly reflecting differences in transplantation rates for shorter individuals.