Are Hepatitis C Positive Female Liver Transplant Recipients Still at Increased Risk for Graft Failure? Reexamining the Disparity in the Modern Era of Direct-acting Antiviral Agents.

BACKGROUND: This study aimed to compare the outcomes of hepatitis C virus (HCV) positive (+) female liver transplant recipients to HCV negative (-) female and HCV+ male recipients before and after the direct-acting-antiviral (DAA) era. METHODS: The United Network for Organ Sharing liver transplant database was retrospectively reviewed from 2002 to 2017. The DAA era was defined as ≥2014. RESULTS: In the pre-DAA era, HCV+ female recipients had greater risk for graft failure compared with HCV+ male (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.01-1.11; P = 0.03) and HCV- female (HR, 1.51; 95% CI, 1.43-1.60; P < 0.001) recipients. In the post-DAA era, HCV+ female recipients had lower risk for graft failure compared with HCV+ male recipients (HR, 0.82; 95% CI, 0.70-0.97; P = 0.02) and equivalent outcomes to HCV- female recipients. HCV+ female recipients with graft failure had increased likelihood of graft failure due to disease recurrence compared with HCV+ male recipients in the pre-DAA era (odds ratio, 1.23; 95% CI, 1.08-1.39; P = 0.001) but not in the post-DAA era. CONCLUSIONS: Although historically HCV+ female recipients were at disproportionately increased risk for graft failure and disease recurrence, this disparity has been eliminated in the DAA era.

Fatigue, Pain, and Other Physical Symptoms of Living Liver Donors in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study.

Little is known about living liver donors' perceptions of their physical well-being following the procedure. We collected data on donor fatigue, pain, and other relevant physical outcomes as part of the prospective, multicenter Adult-to-Adult Living Donor Liver Transplantation Cohort Study consortium. A total of 271 (91%) of 297 eligible donors were interviewed at least once before donation and 3, 6, 12, and 24 months after donation using validated measures when available. Repeated measures regression models were used to identify potential predictors of worse physical outcomes. We found that donors reported more fatigue immediately after surgery that improved by 2 years after donation, but not to predonation levels. A similar pattern was seen across a number of other physical outcomes. Abdominal or back pain and interference from their pain were rated relatively low on average at all study points. However, 21% of donors did report clinically significant pain at some point during postdonation study follow-up. Across multiple outcomes, female donors, donors whose recipients died, donors with longer hospital stays after surgery, and those whose families discouraged donation were at risk for worse physical well-being outcomes. In conclusion, although not readily modifiable, we have identified risk factors that may help identify donors at risk for worse physical outcomes for targeted intervention. Liver Transplantation 00 000-000 2018 AASLD.

Prevalence and Predictors of Patient-Reported Long-term Mental and Physical Health After Donation in the Adult-to-Adult Living-Donor Liver Transplantation Cohort Study.

BACKGROUND: Prospective and longitudinal studies have examined liver donors' medical outcomes beyond the first 1 to 2 years postdonation. There is no analogous longitudinal evidence on long-term psychosocial outcomes, including patient-reported clinically significant mental health problems and perceptions of physical well-being. We examined prevalence, descriptive characteristics, and predictors of diagnosable mental health conditions and self-reported physical health problems, including fatigue and pain, in the long-term years after liver donation. METHODS: Donors from 9 centers who initially completed telephone interviews at 3 to 10 years postdonation (mean, 5.8 years; SD, 1.9) were reinterviewed annually for 2 years using validated measures. Outcomes were examined descriptively. Repeated-measures regression analyses evaluated potential predictors and correlates of outcomes. RESULTS: Of 517 donors initially interviewed (66% of those eligible), 424 (82%) were reassessed at least once. Prevalence rates of major depression and clinically significant pain were similar to general population norms; average fatigue levels were better than norms. All prevalence rates showed little temporal change. Anxiety and alcohol use disorder rates exceeded normative rates at 1 or more assessments. Longer postdonation hospitalization, female sex, higher body mass index, concerns about donation-related health effects, and burdensome donation-related financial costs were associated with increased risk for most outcomes (P's < 0.05). Men were at higher risk for alcohol use disorder (P < 0.001). CONCLUSIONS: Anxiety and alcohol use disorders were more common than would be expected; they may warrant increased research attention and clinical surveillance. Surveillance for long-term problems in the areas assessed may be optimized by targeting donors at higher risk based on identified predictors and correlates.

Iron-related markers are associated with infection after liver transplantation.

Though serum iron has been known to be associated with an increased risk of infection, hepcidin, the major regulator of iron metabolism, has never been systematically explored in this setting. Finding early biomarkers of infection, such as hepcidin, could help identify patients in whom early empiric antimicrobial therapy would be beneficial. We prospectively enrolled consecutive patients (n = 128) undergoing first-time, single-organ orthotopic liver transplantation (OLT) without known iron overload disorders at 2 academic hospitals in Boston from August 2009 to November 2012. Cox regression compared the associations between different iron markers and the development of first infection at least 1 week after OLT; 47 (37%) patients developed a primary outcome of infection at least 1 week after OLT and 1 patient died. After adjusting for perioperative bleeding complications, number of hospital days, and hepatic artery thrombosis, changes in iron markers were associated with the development of infection post-OLT including increasing ferritin (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.12-2.05), rising ferritin slope (HR, 1.10; 95% CI, 1.03-1.17), and increasing hepcidin (HR, 1.43; 95% CI, 1.05-1.93). A decreasing iron (HR, 1.76; 95% CI, 1.20-2.57) and a decreasing iron slope (HR, 4.21; 95% CI, 2.51-7.06) were also associated with subsequent infections. In conclusion, hepcidin and other serum iron markers and their slope patterns or their combination are associated with infection in vulnerable patient populations. Liver Transplantation 23 1541-1552 2017 AASLD.

Early Postoperative Pain and its Predictors in the Adult to Adult Living Donor Liver Transplantation Cohort Study.

BACKGROUND: Little is known about how well postoperative pain is managed in living liver donors, despite pain severity being the strongest predictor of persistent pain with long-lasting disability. METHODS: We conducted a prospective multicenter study of 172 living liver donors. Self-reported outcomes for pain severity, activity interference, affective (emotional) reactions, adverse effects to treatment, and perceptions of care were collected using the American Pain Society Patient Outcomes Questionnaire-Revised. Mixed-effects linear regression was used to identify demographic and psychosocial predictors of subscale scores. RESULTS: Donors were young (36.8 ± 10.6) and healthy. Of 12 expert society analgesic recommendations for postoperative pain management, 49% received care conforming to 3 guidelines, and only 9% to 4 or 5. More than half reported adverse effects to analgesic treatment for moderate to severe pain that interfered with functional activity; however, emotional distress to pain was unexpectedly minimal. Female donors had higher affective (ß = 0.88, P = 0.005) and adverse effects scores (ß = 1.33, P < 0.001). Donors with 2 or more medical concerns before surgery averaged 1 unit higher pain severity, functional interference, adverse effects, and affective reaction subscale scores (ß range 1.06-1.55, all P < 0.05). Receiving information about pain treatment options increased perception of care subscale scores (ß = 1.24, P = 0.001), whereas depressive symptoms before donation were associated with lower scores (ß = -1.58, P = 0.01). CONCLUSIONS: Donors have a distinct profile of pain reporting that is highly influenced by psychological characteristics. Interventions to improve pain control should consider modifying donor behavioral characteristics in addition to optimizing pain care protocols.

Defining Benchmarks for Major Liver Surgery: A multicenter Analysis of 5202 Living Liver Donors.

OBJECTIVE: To measure and define the best achievable outcome after major hepatectomy. BACKGROUND: No reference values are available on outcomes after major hepatectomies. Analysis in living liver donors, with safety as the highest priority, offers the opportunity to define outcome benchmarks as the best possible results. METHODS: Outcome analyses of 5202 hemi-hepatectomies from living donors (LDs) from 12 high-volume centers worldwide were performed for a 10-year period. Endpoints, calculated at discharge, 3 and 6 months postoperatively, included postoperative morbidity measured by the Clavien-Dindo classification, the Comprehensive Complication Index (CCI), and liver failure according to different definitions. Benchmark values were defined as the 75th percentile of median morbidity values to represent the best achievable results at 3 month postoperatively. RESULTS: Patients were young (34 ± [9] years), predominantly male (65%) and healthy. Surgery lasted 7 ± [2] hours; 2% needed blood transfusions. Mean hospital stay was 11.7± [5] days. 12% of patients developed at least 1 complication, of which 3.8% were major events (≥grade III, including 1 death), mostly related to biliary/bleeding events, and were twice higher after right hepatectomy. The incidence of postoperative liver failure was low. Within 3-month follow-up, benchmark values for overall complication were ≤31 %, for minor/major complications ≤23% and ≤9%, respectively, and a CCI ≤33 in LDs with complications. Centers having performed ≥100 hepatectomies had significantly lower rates for overall (10.2% vs 35.9%, P < 0.001) and major (3% vs 12.1%, P < 0.001) complications and overall CCI (2.1 vs 8.5, P < 0.001). CONCLUSIONS: The thorough outcome analysis of healthy LDs may serve as a reference for evaluating surgical performance in patients undergoing major liver resection across centers and different patient populations. Further benchmark studies are needed to develop risk-adjusted comparisons of surgical outcomes.

Psychosocial Outcomes 3 to 10 Years After Donation in the Adult to Adult Living Donor Liver Transplantation Cohort Study.

BACKGROUND: Studies of liver donors' psychosocial outcomes focus on the short term and rely largely on quality-of-life measures not specific to donation. We sought to examine long-term donation effects on 3 psychosocial domains: perceived physical, emotional, and socioeconomic outcomes. METHODS: Individuals donating 3 to 10 years previously at 9 centers were eligible for telephone surveys. Survey responses were examined descriptively. Cluster analysis was used to identify distinct donor groups based on response profiles across psychosocial domains. Potential predictors of response profiles were evaluated with regression analysis. RESULTS: Five hundred seventeen donors (66%) participated (M = 5.8 years postdonation, SD = 1.9). Fifteen percent to 48% of donors endorsed current donation-related physical health problems and concerns, and 7%-60% reported socioeconomic concerns (eg, insurance difficulties, financial expenditures). However, on average, donors experienced high psychological growth, and 90% felt positively about donation. Cluster analysis revealed 5 donor groups. One group showed high psychological benefit, with little endorsement of physical or socioeconomic concerns (15% of donors). Four groups showed less favorable profiles, with varying combinations of difficulties. The largest such group showed high endorsement of physical concerns and financial expenditures, and only modest psychological benefit (31% of donors). Men and nonHispanic whites were most likely to have unfavorable response profiles (Ps < 0.01). Compared with donors aged 19 to 30 years, older donors were less likely to have unfavorable profiles; these differences were significant for donors in the >40 to 50 year age group (Ps < 0.008). CONCLUSIONS: Even many years postdonation, donors report adverse physical and socioeconomic effects, but positive emotional effects as well. Identification of response profiles and predictors may improve targeting of postdonation surveillance and care.

Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.

Patterns and predictors of sexual function after liver donation: The Adult-to-Adult Living Donor Liver Transplantation Cohort study.

Although sexual functioning is an important facet of a living donor's quality of life, it has not received an extensive evaluation in this population. Using data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, we examined donor sexual functioning across the donation process from the predonation evaluation to 3 months and 1 year after donation. Donors (n = 208) and a comparison group of nondonors (n = 155) completed self-reported surveys with specific questions on sexual desire, satisfaction, orgasm, and (for men) erectile function. Across the 3 time points, donor sexual functioning was lower at the evaluation phase and 3 months after donation versus 1 year after donation. In the early recovery period, abdominal pain was associated with difficulty reaching orgasm [odds ratio (OR), 3.98; 95% confidence interval (CI), 1.30-12.16], concerns over appearance were associated with lower sexual desire (OR, 4.14; 95% CI, 1.02-16.79), and not feeling back to normal was associated with dissatisfaction with sexual life (OR, 3.58; 95% CI, 1.43-8.99). Efforts to educate donors before the surgery and prepare them for the early recovery phase may improve recovery and reduce distress regarding sexual functioning.

Incidence of death and potentially life-threatening near-miss events in living donor hepatic lobectomy: a world-wide survey.

The incidence of morbidity and mortality after living donor liver transplantation (LDLT) is not well understood because reporting is not standardized and relies on single-center reports. Aborted hepatectomies (AHs) and potentially life-threatening near-miss events (during which a donor's life may be in danger but after which there are no long-term sequelae) are rarely reported. We conducted a worldwide survey of programs performing LDLT to determine the incidence of these events. A survey instrument was sent to 148 programs performing LDLT. The programs were asked to provide donor demographics, case volumes, and information about graft types, operative morbidity and mortality, near-miss events, and AHs. Seventy-one programs (48%), which performed donor hepatectomy 11,553 times and represented 21 countries, completed the survey. The average donor morbidity rate was 24%, with 5 donors (0.04%) requiring transplantation. The donor mortality rate was 0.2% (23/11,553), with the majority of deaths occurring within 60 days, and all but 4 deaths were related to the donation surgery. The incidences of near-miss events and AH were 1.1% and 1.2%, respectively. Program experience did not affect the incidence of donor morbidity or mortality, but near-miss events and AH were more likely in low-volume programs (≤50 LDLT procedures). In conclusion, it appears that independently of program experience, there is a consistent donor mortality rate of 0.2% associated with LDLT donor procedures, yet increased experience is associated with lower rates of AH and near-miss events. Potentially life-threatening near-miss events and AH are underappreciated complications that must be discussed as part of the informed consent process with any potential living liver donor.

Checking the harness: safety for living liver donors.

KEY POINTS: 1. Expertise in hepatobiliary surgery. 2. Donor selection criteria. 3. Selective liver biopsy in donors. 4. Accurate determination of hepatic volumes and anatomy. 5. Extent of donor hepatectomy. 6. Donor psychosocial evaluation. 7. Catastrophic events. 8. Long-term follow up.

Ambivalence in living liver donors.

All right hepatic lobe (RHL) donors in our program are asked to participate in a longitudinal quality-of-life study that begins at their evaluation and continues throughout the first postdonation year. Here we report the characteristics of donor candidates who completed the donation process despite ambivalence. In all, 183 RHL candidates consented, and 133 became donors. Ambivalent donors (ADs; n = 45) identified themselves through verbal statements or written comments, or they were identified by staff during the evaluation. ADs were predominantly male (73.3%), were older than unambivalent donors (UADs; >35 years: 76% of ADs versus 53% of UADs, P = 0.008), and were well educated (college graduate: 60% of ADs versus 17% of UADs, P = 0.01). Brother-to-brother and son-to-father combinations were most common among ADs. Alcohol (22% versus 11%, P = 0.04) and hepatitis C virus (51% versus 27%, P = 0.008) were more common as disease etiologies for recipients with ADs versus recipients with UADs. More ADs than UADs considered themselves to be religious (68.9% versus 43.2%, P = 0.007). Ambivalence about RHL donation was present in 33.8% of the candidates who completed the donation process. These results suggest that ambivalence should not be the sole reason for disqualifying a potential donor who otherwise satisfies program requirements.

Patterns of recurrent hepatitis C after liver transplantation in a recent cohort of patients.

Clinicopathologic trends of recurrent hepatitis C after liver transplantation (LT) in hepatitis C (HCV) patients seem to have changed in recent years. Our aims were to define the current post-LT patterns of HCV recurrence and identify features of diagnostic and/or prognostic significance. Detailed analysis was performed on 92 HCV patients who underwent LT from June 1999 to December 2003 and survived early post-LT period. The study patients were grouped, as follows: no histologic recurrence (n = 31), "typical" recurrent HCV (n = 52), and post-LT autoimmune-like hepatitis ("AIH-like") (n = 9). The typical and AIH-like groups had mostly common features with post-LT progressive fibrosis (stage > or =2) more frequent in the latter. Based on post-LT progressive fibrosis (stage > or =2), the 2 post-LT hepatitis categories were regrouped as progressive (n = 24) and nonprogressive (n = 37). High viral counts, HCV genotype 1, and native liver inflammation grade 2 or higher with plasmacytic periseptitis were more frequent in progressive cases than nonprogressive or nonrecurrent cases. Sex mismatch of male recipient and female donor was more common in nonrecurrent group. Overall, death rate was comparable in all groups; however, post-LT HCV-related deaths were more common in progressive cases. In conclusion (1) two thirds (66.2%) of HCV patients developed histologic hepatitis after LT with either typical or AIH-like features; (2) progressive fibrosis was seen in 39.3% of patients with post-LT hepatitis and 26% of the entire study group and was more frequent in AIH-like cases; (3) inflammation grade 2 or higher with plasmacytic periseptitis in native livers may be a predictor of post-LT progressive fibrosis; and (4) male recipient/female donor combination was more common in nonrecurrent cases.

Impact of model for end-stage liver disease (MELD) scoring system on pathological findings at and after liver transplantation.

The Model for End-Stage Liver Disease (MELD) scoring system, a validated objective liver disease severity scale, was adopted in February 2002 to allocate cadaveric organs for liver transplantation (LT). To improve transplantability before succumbing to advanced disease, patients with low-stage hepatocellular carcinoma (HCC) are given extra points in this system commensurate with their predicted mortality. Our aims were to determine 1) any change in the pathological findings at LT following the implementation of this system and 2) the impact of scoring advantage given to early-stage HCC. Clinicopathologic findings were compared before (pre-MELD, n = 87) and after (MELD, n = 58) the introduction of the MELD system. The findings in the pre-MELD vs. MELD groups were as follows: HCC, 27.5% vs. 48.3% (P = 0.001); portal vein thrombosis (PVT), 13.7% vs. 25.9% (P = 0.08); cholestasis, 16.1% vs. 32.7% (P = 0.026); inflammation grade of 2 or more, 43.7% vs. 48.3% (P = not significant); hepatitis C (HCV), 45.9% vs. 51.7% (P = not significant); HCV with lymphoid aggregates, 25% vs. 60% (P = 0.003); HCV with hyperplastic hilar nodes, 15.0% vs. 36.6% (P = 0.001); and post-LT HCC recurrence, 4.1% vs. 3.4% (P = not significant). Non-HCC-related findings were further compared in the 2 subgroups of pre-MELD (n = 57) and MELD (n = 31) after exclusion of HCC and fulminant hepatic failure (FHF) cases, and only cholestasis was significantly increased in the subgroup MELD. In conclusion, increased incidence of native liver cholestasis in the MELD era may be the histologic correlate of clinically severe liver disease. The scoring advantage given to low-stage HCC did result in a significantly increased incidence of HCC in the MELD group, but it did not adversely affect the post-LT recurrence rate.

Living donor adult liver transplantation: a longitudinal study of the donor's quality of life.

We report the results of a prospective, longitudinal quality of life survey on our adult right lobe (RL) liver donors. A total of 47 donors were enrolled; a standard SF-36 form and 43 questions developed by our team were completed before donation, at 1 week, and 1, 3, 6 and 12 months after donation. There were no donor deaths. Twenty-nine complications occurred in 16 patients. Major complication rate was 12.8%. Employment status and personal finances were identified as major stressors. All donors who wished to return to work did so by 1 year (mean 3.4 months). Individuals reported between 0 dollars and 25,000 dollars in losses (wages, travel, lodging, etc.). Relationships with recipients and other family members were not altered significantly. Anticipated pain (predonation) was greater than actual pain reported. Donors indicated satisfaction with the donation process regardless of recipient outcome. Physical complaints were significant at 1 week and 1 month, but returned to baseline. Donor mental health remained stable. In conclusion, RL donors found the experience to be a positive one throughout the first postdonation year. The study identified areas (finances, employment and expected recipient outcomes) to be stressed as future donors are evaluated.

Excellent outcome following transplantation of a domino donor liver with high-grade macrosteatosis.

Severe macrosteatosis in the donor liver is considered a major predictive factor of primary graft non-function. Such livers are usually discarded despite an ever-growing need for donor livers. We report our recent experience in a patient (#1) who had an excellent outcome following liver transplantation (LT) of a 65-70% macrosteatotic graft and compare his findings with those of two other (#2 and #3) recipients of moderate to severe macrosteatotic grafts. Both patients (#2 and #3) had initial diminished function, with recovery in patient #2 but delayed graft non-function requiring re-LT (day 24) in patient #3. Patient #1 had no intra-operative complications, while patient #2 had mild complications due to prior adhesions and graft capsular laceration. In patient #3, extensive intra-abdominal adhesions resulting in excessive bleeding occurred during recipient hepatectomy. Total ischemic times: 2.48, 6.10, and 8.18 h; total blood product usage: 43, 81, and 223 units; post-LT hospital stay: 9, 21, and 69 days were seen in patients #1, #2 and #3, respectively. In conclusion, post-LT excellent graft function was seen in one recipient of 65-70% macrosteatotic graft. Transplantation of grafts with moderate/severe macrosteatosis may be inadvisable in patients with extensive intra-abdominal adhesions with expectant excessive bleeding and long ischemia times.