Liver

OPTN/SRTR 2017 Annual Data Report: Liver

Abstract

Data on adult liver transplants performed in the US in 2017 are notable for (1) continued growth in numbers of new waitlist registrants (11,514) and of transplants performed (8,082); (2) continued increase in the transplant rate (51.5 per 100 waitlist-years); (3) a precipitous decrease in waitlist registrations and transplants for hepatitis C-related indications; (4) reciprocal increases in waitlist registrants and recipients with alcoholic liver disease and with clinical profiles consistent with non-alcoholic fatty liver disease; and (5) continued improvement in graft survival despite changing recipient characteristics such as older age and higher rates of obesity. Variability in transplant rates remained by candidate race, presence of hepatocellular carcinoma, urgency status (status 1A versus model for end-stage liver disease (MELD) score >35), and geography. More than half of all children listed for liver transplant in 2017 were aged younger than 5 years in 2017, and the highest rate of pretransplant mortality persisted for children aged younger than 1 year. Children underwent transplant at higher acuity than the past, as evidenced by higher MELD/pediatric end-stage liver disease scores and listings at status 1A and 1B. Higher acuity at transplant is likely due to lack of access to suitable donor organs, which has been compensated for by persistent trends toward use of partial or split liver grafts and ABO-incompatible grafts. Despite higher illness severity scores at transplant, pediatric graft and patient survival posttransplant have improved over time.

Adult Transplant

Waiting List Registration

The number of candidates added to the liver transplant waiting list continued to increase in 2017 to 11,514, compared with 11,340 in 2016 and 10,636 in 2015 (Figure LI 1). In contrast, the number of candidates waiting at the end of the year continued a downward trend from its peak of 15,365 in 2011 to 13,239 in 2017 (Figure LI 2). Regarding actively listed candidates, 186 more were added to the list in 2017 than in 2016 (11,168 versus 10,982); 513 fewer were waiting at the end of 2017 than at the end of 2016 (10,628 versus 11,141). This is in part explained by more transplants performed (8082 in 2017 versus 7841 in 2016, net increase of 241, Figure LI 46).

The age distribution of adults waiting for liver transplant (Figure LI 3) showed that the proportion of older (aged ≥65 years) candidates continued to increase, to 22.9%, almost twice the proportion 10 years before. A reciprocal decrease occurred in the proportion of candidates aged 50-64 years over the past 5 years.

The proportion of candidates listed with a primary diagnosis of hepatitis C virus (HCV) decreased sharply (Figure LI 6), and proportions with alcoholic liver disease and other diagnosis increased. The latter category likely included many candidates with nonalcoholic fatty liver disease. As HCV patients tend to be over-represented among patients listed with hepatocellular carcinoma (HCC) as their primary diagnosis, the trend shown in Figure LI 6 should be interpreted accordingly. In 2017, 9.9% of candidates had a primary diagnosis of HCC.

Regarding medical urgency, candidates for liver transplant most commonly had model for end-stage liver disease (MELD) scores between 15 and 29 at their most severe during the year (45.6%), with approximately 20% of candidates listed with MELD score of ≥30 (Figure LI 7). Although not dramatically, the proportion of liver candidates with high body mass index (BMI) continued to increase (Figure LI 8). Nearly one in six (17%) liver candidates had a BMI above 35 kg/m², conventionally categorized as morbidly obese, although not all excess weight in these patients is adiposity.

Waiting List Outcome

Deceased donor liver transplant rates among active adult waitlist candidates continued to increase, a trend over the past 5 years (Figure LI 9). The overall deceased donor transplant rate was 51.4 per 100 waitlist-years, surpassing 50 for the first time in the past decade. The increase occurred regardless of age group, sex, or geography (e.g., metropolitan versus non-metropolitan areas) (Figure LI 9, Figure LI 11, Figure LI 12). The transplant rate was more than 20% lower for Hispanic and Asian candidates (41.5 and 40.1 per 100 waitlist-years, respectively) than for white (53.6 per 100 waitlist-years) and black (61.4 per 100 waitlist-years) candidates (Figure LI 10). Differences in underlying liver disease and listing MELD scores likely explain some of the differences, but further analysis of this trend may be warranted.

The gap in transplant rates between HCC and non-HCC candidates persisted, although it has been steadily narrowing since 2006 (Figure LI 11). The transplant rate was much higher for HCC than for non-HCC candidates. The gap was larger among women, with a transplant rate 2.1-fold higher for HCC than for non-HCC candidates (97.0 versus 45.4 per 100 waitlist-years). Among men, the transplant rate was 72% higher for HCC than for non-HCC candidates (89.4 versus 52.1 per 100 waitlist-years).

Figure LI 14 shows 3-year outcomes for adults listed for liver transplant in 2014: 55.2% underwent liver transplant (including 2.2% with living donor livers), 13.1% died, and 20.3% were removed from the list without undergoing transplant. These statistics were virtually identical to those reported in the 2016 ADR. Similarly, waiting time for urgency categories remained unchanged (Figure LI 15); waiting time was shortest for patients at status 1A (median 0.16 months, 4.9 days) followed by those with MELD >35 (median 0.23 months, 7.0 days).

Consistent with the trend in transplant rates (Figure LI 9), the proportion of patients undergoing deceased donor liver transplant within a given time period after listing trended upward (Figure LI 16). Geographic differences in deceased donor transplant rates persisted, regardless of geographic unit (donation service area [DSA], Figure LI 17 or state, Figure LI 18). In the DSA with the lowest proportion, 31.9% of candidates listed in 2014 underwent deceased donor liver transplant within 3 years, compared with 85.5% in the DSA with the highest proportion.

Pretransplant mortality rates for adults continued a downward trend in 2017 for all subgroups, including age, race/ethnicity, diagnosis, urgency category, and geography (Figure LI 19, Figure LI 20, Figure LI 21, Figure LI 22, Figure LI 23, Figure LI 24, Figure LI 25). As expected, mortality rates were lower for younger candidates, Asians, and candidates with lower MELD scores. The mortality rate for candidates with MELD >35 was 260.1 per 100 waitlist-years in 2017, higher than 188.0 per 100 waitlist-years in status 1A candidates (Figure LI 22). Mortality in candidates with MELD >35 continued to decrease since the implementation of the regional share 35 policy; however, as suggested in Figure LI 15, waiting time remained longer than for status 1A candidates. Furthermore, Figure LI 27 illustrates that 6-month mortality after waitlist removal was 69.0% among candidates with MELD >35, compared with 30.8% among status 1A candidates. Reducing mortality further remains a challenge for policy makers in their effort to improve the organ distribution and allocation system.

As previously recognized, waitlist mortality rates varied geographically (Figure LI 26), and did not necessarily mirror transplant rates, suggesting that waitlist outcomes were not determined simply by organ availability. Other potential factors may include access to healthcare in general and to high-quality specialty care for liver disease, referral and waitlist registration practices, and pre-transplant patient management.

Donation

There were a total of 7631 deceased donors in 2017, an increase of 220 over 2016. The proportion of donors aged 18-34 years increased noticeably in the past 4 years (Figure LI 29). This trend has been concomitant with dramatic increases in anoxic brain deaths, likely from drug overdose (Figure LI 38).

The organ discard rate (percentage of organs recovered for transplant and not transplanted) was 8.9%, continuing a downward trend since 2012. The trend was most noticeable for donors aged 65 years or older, although, in general, discard rates were higher for older donors (Figure LI 32). Discard rates were lowest for black donors (5.9%) and highest for donors of other/unknown race (11.0%) (Figure LI 34).

The most striking trend in organ utilization is related to HCV-positive donors (Figure LI 35). The liver discard rate was numerically lower for HCV-positive (8.5%) than for HCV-negative (8.9%) donors. This trend is driven by donation after brain death organs, with a discard rate of 7%, the lowest in the past decade (Figure LI 37). This is not surprising because many HCV-positive livers are from younger donors and are otherwise considered high quality, and because HCV therapy is highly successful even in patients receiving immunosuppression following liver transplant. Figure LI 36 depicts a similar trend of fewer discards of US Public Health Service high-risk organs compared with non-high-risk organs.

Compared with 2016, there were 23 more living donors in 2017, a 6.8% increase. The demographic characteristics of living donors did not change substantially over time (Figure LI 39, Figure LI 40, Figure LI 41, Figure LI 42).

Transplants

In 2017, 8082 liver transplants were performed in the US (Figure LI 46), higher than in any previous year. This represented a 3% increase over 2016 (7841) and a 24% increase over a decade before (6494 in 2007). Almost all (95%) were deceased donor transplants (7715, Figure LI 46).

Characteristics of adult transplant recipients in 2017 were similar to those of waitlist registrants (Figure LI 47, Figure LI 48, Figure LI 49). Liver recipients were most commonly aged 50-64 years, male, and white. The increase in numbers of transplants occurred in all age groups and both sexes. Between 2016 and 2017, the number of white recipients increased the most (5406 to 5678, a 5.0% increase); the increase was negligible for black recipients (750 to 752, 0.3% increase) and numbers actually decreased for Hispanic (1204 to 1182, 1.8% decrease) and Asian (369 to 342, 7.3% decrease) recipients. These trends likely reflect disease epidemiology and severity, although further analysis is necessary.

Numbers of adult liver transplant recipients with HCV further declined in 2017 (Figure LI 50). Of all adult recipients, 1005 recipients (12.4%) had HCV as their primary diagnosis, while in 2014 HCV accounted for 23.9% (1610). If this trend continues, fewer liver transplants may be performed for HCV than for cholestatic liver disease in 2018, although a proportion of patients whose primary diagnosis is HCC also have HCV.

In 2017, more than a third (35.9%) of adult recipients in 2017 had a BMI consistent with obesity (>30 kg/m²), and 14.0% were morbidly obese (BMI ≥35 kg/m², Figure LI 51). The number of recipients with alcoholic liver disease (1881), cholestatic disease (930) and other/unknown etiology (2628) is also increasing (Figure LI 50).

The majority (65.9%) of recipients did not receive an induction agent, although the proportion has been decreasing gradually (Figure LI 52). The predominant immunosuppressive regimen (Figure LI 53) in adult liver recipients remained the combination of tacrolimus, mycophenolate, and steroids (59.7%), followed by tacrolimus and mycophenolate (21.6%).

Geographic variability in access to liver transplant has been most commonly measured by the median MELD at transplant of the geographic unit. The median MELD ranged from 19 to 36 (Figure LI 54) by recipient DSA. The highest was reported in Los Angeles, California (CAOP), and the lowest in Puerto Rico (PRLL). The DSA with the lowest median MELD at transplant in the contiguous 48 states was in Connecticut (CTOP, median MELD 22.5). The median of all DSA’s median MELD scores remained at 28.0, unchanged from 2016 (Figure LI 55). However, the width of the interquartile ranges of the medians decreased (from 5.0 to 1.8), indicating reduction in geographic variability in recipient MELD scores. MELD exception score has been another focus of policy debate, with large variability in proportions of patients with exception scores (Figure LI 56). The DSA with the lowest proportion (7.9%) of recipients with exception scores was in Indiana (INOP) and the highest (59.3%) in Oregon (ORUO).

Between 2016 and 2017, a small but consistent decrease in cold ischemia time occurred, ordered in the expected direction (higher MELD strata with longer cold time). The median cold ischemia time for all MELD strata was less than 6 hours (Figure LI 57). Figure LI 58 shows the distribution of total numbers of HLA, B, and DR mismatches among liver-kidney recipients. Most commonly, recipients had five mismatches (33.6%), which has not changed in the recent past.

As the total number of transplants grew nationwide, distribution of the additional organs affected transplant program volume, which appears to have grown mostly in medium to large centers (Figure LI 59). Between 2016 and 2017, programs at the seventy-fifth percentile increased from 94 to 102 transplants per year and those at the fiftieth percentile from 52 to 56. Consequently, medium-large programs with an annual volume of 95-149 transplants performed the largest proportion of transplants (42.3%) (Figure LI 60).

Outcomes

Short- and long-term graft outcomes continued to improve in 2017. Graft failure occurred in 7.3% at 6 months and in 9.6% at 1 year among deceased donor liver transplants performed in 2016, in 16.3% at 3 years for transplants performed in 2014, in 24.1% at 5 years for transplants performed in 2012, and in 43.0% at 10 years for transplants performed in 2007 (Figure LI 61). Graft failure occurred in 6.7% of recipients at 6 months and in 9.9% at 1 year posttransplant among living donor transplants performed in 2016, in 20.3% at 3 years for transplants performed in 2014, in 19.4% at 5 years for transplants performed in 2012, and in 40.1% at 10 years for transplants performed in 2007 (Figure LI 62).

Five-year graft survival outcomes varied in the expected direction for recipient age (Figure LI 63), primary diagnosis (Figure LI 64, Figure LI 68, Figure LI 72), BMI (Figure LI 69), urgency category (Figure LI 65, Figure LI 73), and retransplant status (Figure LI 67) for deceased and living donor recipient characteristics. Without adjustment for other variables, graft survival was better for recipients in metropolitan areas and for those traveling to a distant (>250 miles) program (Figure LI 70, Figure LI 71) for deceased donor recipients only, as these advantages were absent for living donor recipients (Figure LI 74, Figure LI 75).

As of June 30, 2017, 83,925 liver transplant recipients were alive with a functioning graft, including 73,317 who underwent liver transplant as adults (Figure LI 76). At the end of the first year, 11.7% of recipients experienced at least one episode of acute rejection, which was more common in younger recipients (Figure LI 77) and in recipients not receiving a T-cell depleting agent (Figure LI 78). Approximately 1% of adult liver recipients developed posttransplant lymphoproliferative disorder over 5 years, and incidence doubled in recipients who lacked antibodies against Epstein-Barr virus (Figure LI 79).

Adult patient survival after deceased and living donor liver transplant (Figure LI 80, Figure LI 81, Figure LI 82, Figure LI 83, Figure LI 84, Figure LI 85, Figure LI 86, Figure LI 87, Figure LI 88, Figure LI 89) mirrored graft survival (Figure LI 63, Figure LI 64, Figure LI 65, Figure LI 66, Figure LI 67, Figure LI 68, Figure LI 69, Figure LI 70, Figure LI 71, Figure LI 72, Figure LI 73, Figure LI 74, Figure LI 75), except that the geographic differences in graft survival in deceased donor recipients were attenuated when patient survival was considered (Figure LI 84, Figure LI 85).

Pediatric Transplant

Summary

As has been true in the past, more than half of all children listed for liver transplant were aged 5 years or younger in 2017, and the highest rate of pretransplant mortality persisted for children aged younger than 1 year. Children are undergoing transplant at higher acuity than the past, as evidenced by higher MELD/PELD scores and listings at status 1A and 1B. Higher acuity at transplant is likely due to lack of access to suitable donor organs, which has been compensated for by persistent trends toward use of partial or split liver grafts and ABO-incompatible grafts. Despite higher illness severity scores at transplant, graft and patient survival posttransplant have improved over time.

Waiting List

In 2017, 696 new active candidates were added to the pediatric liver transplant waiting list (Figure LI 90); very few (21) were added as inactive. The number of prevalent candidates (on the list on December 31 of the given year) was stable, 373 active and 177 inactive (Figure LI 91). Children aged 1-5 years (33.5%) and 11 years or older (31.7%) made up the largest age groups, followed by ages younger than 1 year, 20.4%, and 6-10 years, 14.4% (Figure LI 92). White candidates continued to make up the largest racial/ethnic group on the waiting list in 2017 (50.9%), followed by Hispanic (23.5%), black (15.4%), and Asian candidates (6.8%) (Figure LI 93). Most (66.4%) candidates had been waiting for less than 1 year, 12.1% for 1 to less than 2 years, 9.31% for 2 to less than 4 years, and 12.3% for 4 or more years (Figure LI 95). In 2006, 27.3% of pediatric candidates had been waiting for 4 or more years. This decline in long waiting times coincided with a shift in severity of illness since 2006. Considerably more candidates were listed with MELD/pediatric end-stage liver disease (PELD) scores above 35 (19.8% in 2017 vs. 6.4% in 2006), many of whom received MELD/PELD exception scores. More candidates were at status 1A/1B as their most severe status during the year (26.9% in 2017 vs. 16.7% in 2006), and fewer had MELD/PELD scores below 15 (15.6% in 2017 vs. 24.4% in 2006) or as inactive (11.7% in 2017 vs. 23.5% in 2006) (Figure LI 96).

For pediatric liver waitlist candidates from 2007 to 2017, sex, race, diagnosis, and geography changed little (Table LI 13, Table LI 14). The proportion of candidates aged 1-5 years increased slightly, and the proportion aged 11-17 years decreased. Medical urgency has changed over time, with an increase in the proportions listed as status 1A and 1B. The proportion of candidates on the waiting list with exception status has increased notably, at 30.0% in 2017 compared with 8.8% a decade earlier (Table LI 14). Waiting time shifted such that 52.9% of candidates waited less than 1 year in 2017, compared with 37.6% in 2007 (Table LI 15). Proportions of candidates listed for multi-organ transplants including liver have increased over time. Liver-kidney transplant candidates accounted for only 1.6% of pediatric liver transplant candidates in 2007 and for 3.5% in 2017. The proportion of liver-pancreas-intestine transplant candidates increased from 8.5% in 2007 to 13.6% in 2017 (Table LI 15). Among candidates removed from the waiting list in 2017, 72.1% underwent deceased donor transplant, 10.1% underwent living donor transplant, 5.0% died, 7.9% were removed from the list because their condition improved, and 1.3% were considered too sick to undergo transplant (Table LI 17). Just over 73% of candidates newly listed in 2014 underwent deceased donor transplant within 3 years, 8.2% underwent living donor transplant, 4.8% died, 8.2% were removed from the list, and 5.4% were still waiting (Figure LI 97). In 2017, the rate of deceased donor transplant among active pediatric candidates continued to increase, reaching 96.1 per 100 active waitlist-years compared with 61.2 in 2007 (Figure LI 98). Rates were highest for candidates aged younger than 1 year, 213.8 per 100 active waitlist-years. The lowest rates were for candidates aged 11 years or older (62.5 per 100 active waitlist-years). Regarding medical urgency status, as expected, transplant rates were highest for status 1A (531.4 per 100 active waitlist-years) and status 1B candidates (422.9 per 100 active waitlist-years) (Figure LI 100). Among candidates listed with MELD/PELD scores, rates ranged from 173.2 for those with MELD/PELD 30-34 to 73.3 for those with MELD/PELD below 15 (Figure LI 99). Pretransplant mortality decreased for all age groups, to 4.6 deaths per 100 waitlist-years in 2016-2017 (Figure LI 103). The pretransplant mortality rate was highest for candidates aged younger than 1 year, at 19.6 deaths per 100 waitlist-years in 2016-2017, compared with 2.6 in the 6-10 and 11-17 year age groups.

Transplant

The number of pediatric liver transplants peaked at 613 in 2008 and was 599 in 2017 (Figure LI 107). The number of pediatric living donor liver transplants remained steady at 72 in 2017, with most (53%) from donors closely related to the recipients (Figure LI 108). Recipients aged younger than 6 years underwent the highest proportion of transplant from living donors, 14.9% (Figure LI 109). In 2017, 21 programs were performing pediatric-only liver transplants, compared with 90 performing adult-only transplants and 29 performing transplants in both adults and children (Figure LI 110). In 2017, 5.3% of transplants in candidates aged 0-10 years, 7.7% in those aged younger than 15 years, and 9.3% in those aged younger than 18 years were performed at programs with volumes of five or fewer pediatric transplants in that year (Figure LI 111). In 2017, 18.0% of liver transplants in pediatric recipients were split liver transplants, compared with 14.4% a decade ago (Figure LI 112). Among adults, the proportion of split liver transplants has remained stable at approximately 1%. Among pediatric transplant recipients 2015-2017, the percentage with exception points by donation service area ranged from 9.1% to 100% in 6 DSAs, with a mean of 68.7% (Figure LI 114). In 2017, median cold ischemia time was similar by allocation MELD/PELD at approximately 6 hours (Figure LI 115). Over the past decade, recipient age, sex, and racial distributions have changed little, although fewer recipients were aged younger than 1 year (23.3% in 2015-2017 compared with 30.0% in 2005-2007) and more were aged 1-5 years (41.3% and 36.2%, respectively, Table LI 18). Cholestatic biliary atresia remained the leading cause of liver failure (32.5%) (Table LI 19). Most pediatric liver transplant recipients were not hospitalized before transplant (62.3%) and fewer were in the intensive care unit, 18.6% in 2015-2017 vs. 26.7% in 2005-2007. Regarding medical urgency status, over the past decade, proportions of recipients undergoing transplant at status 1A decreased markedly, and proportions at status 1B increased. The proportion of patients undergoing transplant with a MELD/PELD 30 or higher increased from 26.8% to 37.6% over the past 10 years. MELD/PELD exception use increased from 24.8% in 2005-2007 to 41.9% in 2015-2017. Types of liver transplant procedures in pediatric recipients changed little over the past decade; 62.8% of patients received a whole liver in 2015-2017, 21.2% received a partial liver (i.e., less than a whole liver was transplanted, possibly from a living donor, and the remainder of the liver was discarded), and 16.0% received a split liver (i.e., two recipients, usually an adult and a child, received one deceased donor liver) (Table LI 20). ABO-incompatible liver transplants occurred in 5.1% of recipients in 2015-2017, increased from 2.3% in the earlier era. In 2015-2017, 8.0% of pediatric liver transplant recipients had undergone previous transplant, a decrease from 10.2% a decade earlier.

Immunosuppression and Outcomes

In 2017, 56.6% of pediatric liver transplant recipients received no induction therapy, 27.6% received interleukin-2 receptor antagonists, and 16.7% received a T-cell depleting agent (Figure LI 116). The most commonly used initial immunosuppression regimens were tacrolimus and steroids (50.6%) and tacrolimus, mycophenolate mofetil, and steroids (25.0%) (Figure LI 117).

Graft survival continued to improve over the past decade among pediatric recipients of deceased donor and living donor livers. Graft failure occurred in 9.4% at 6 months and in 11.0% at 1 year among deceased donor liver transplants performed in 2016, in 13.0% at 3 years for transplants performed in 2014, in 16.0% at 5 years for transplants performed in 2012, and in 26.6% at 10 years for transplants performed in 2007 (Figure LI 119). Graft failure occurred in 3.4% of recipients at 6 months and in 5.5% at 1 year posttransplant among living donor transplants performed in 2015-2016, in 8.4% at 3 years for transplants performed in 2013-2014, in 8.9% at 5 years for transplants performed in 2011-2012, and in 16.7% at 10 years for transplants performed in 2007-2008 (Figure LI 120). By age, 5-year graft survival was 78.4% for recipients aged younger than 1 year, 79.8% for ages 1-5 years, 88.7% for ages 6-10 years, and 81.9% for ages 11-17 years (Figure LI 121). Five-year graft survival was 84.1% for recipients who underwent transplant with a MELD/PELD of 15 or lower, compared with approximately 78% for recipients who underwent transplant as status 1A/1B (Figure LI 123). Five-year graft survival was 82.6% for recipients of a first liver transplant, compared with 68.0% for retransplant recipients (Figure LI 124). In 2015-2016, incidence of acute rejection by 1 year post transplant was 24.7% overall, varying from 26.2% in recipients aged 11-17 years to 21.3% in those aged 6-10 years (Figure LI 126). Regarding use of induction agents and acute rejection, rates ranged from 21.6% among recipients who received interleukin-2 receptor antagonists to 28.4% among those who received T-cell depleting agents (Figure LI 125). Incidence of posttransplant lymphoproliferative disorder was 4.5% at 5 years posttransplant for recipients who were negative for Epstein-Barr virus and 2.9% for those who were positive (Figure LI 127). Among pediatric liver transplants 2008-2012, overall 5-year patient survival was 87.5%, varying from 85.9% for recipients aged 1-5 years to 93.0% for those aged 6-10 years (Figure LI 128). By primary diagnosis, metabolic disease and cholestatic biliary atresia were associated with superior patient survival (Figure LI 129). Of deceased donor transplant recipients in 2011-2016, 6.1% died within 1 year of transplant with cardio/cerebrovascular complications as the leading cause of death (Figure LI 130). Of deceased donor transplant recipients in 2010-2012, 10.6% died within 5 years of transplant (Figure LI 131). The leading causes of death were graft failure (1.6%) and cardio/cerebrovascular complications (1.4%) (Figure LI 131).