Proportion Of Liver Transplantation Research Articles

NASH vs. Non-NASH HCC within and Beyond Milan Criteria in Liver Transplantation for Hepatocellular Carcinoma

Introduction: With mounting obesity, non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) is a rising indication for HCC-related liver transplantation (LT). This unique population, often with multiple comorbidities, has potential for worse outcomes post-LT. The study aims to compare post-transplantation overall survival (OS) of NASH HCC versus non-NASH HCC patients using a large, North American cohort. Methods: Adults who received primary LT for HCC between 2008-2018, from the United Network for Organ Sharing transplant registry (UNOS) and University Health Network (UHN) database, were included. Two populations were defined: NASH HCC and non-NASH HCC. Recipient characteristics, transplant-specific variables, post-transplant survival outcomes, and causes of death were compared. Sensitivity analyses were performed for populations within and beyond Milan criteria. Results: 20,709 patients were transplanted for HCC, with 2,075(10.0%) NASH HCC. The proportion of LT for NASH HCC increased annually (P=0.02 UHN, P<0.001 UNOS). NASH HCC patients were older, more often female, had higher body mass index, and higher pre-transplantation model for end-stage liver disease score. The 1-, 3-, and 5-year OS were 90.7%, 83.9%, and 76.3% NASH-HCC versus 91.9%, 82.1%, and 74.9% non-NASH HCC (P=0.89). No OS differences were observed within and beyond Milan. Cardiovascular causes contributed to a greater proportion of deaths in NASH HCC (P<0.001). There were no differences in malignancy- or HCC recurrence-related deaths. Conclusion: The global obesity epidemic will have significant future implications in LT and organ allocation. Despite demographic differences, no post-transplantation survival differences exist between NASH and non-NASH HCC. This justifies equivalent organ allocation, irrespective of NASH status.

Trends of rapamycin in survival benefits of liver transplantation for hepatocellular carcinoma.

The proportion of liver transplantation (LT) for hepatocellular carcinoma (HCC) has kept on increasing over the past years and account for 20%-40% of all LT. Post-transplant HCC recurrence is considered the most important factor affecting the long-term survival of patients. The use of different types of immunosuppressive agents after LT is closely associated with an increased risk for HCC recurrence. The most commonly used conventional immunosuppressive drugs include the calcineurin inhibitors tacrolimus (FK506) and mammalian target of rapamycin inhibitor rapamycin (RAPA). Compared with tacrolimus, RAPA may carry an advantage in survival benefit because of its anti-tumor effects. However, no sufficient evidence to date has proven that RAPA could increase long-term recurrence-free survival and its anti-tumor mechanism of combined therapy remains incompletely clear. In this review, we will focus on recent advances in clinical application experience and basic research results of RAPA in patients undergoing LT for HCC to further guide the clinical practice.

Activated CD4+ T Cells and Highly Differentiated Alloreactive CD4+ T Cells Distinguish Operationally Tolerant Liver Transplantation Recipients.

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplantation (LT) recipients weaned off immunosuppressive (IS) drugs. Several studies have investigated whether peripheral blood circulating T cells could play a role in the development or identify operational tolerance, but never characterized alloreactive T cells in detail due to the lack of a marker for these T cells. In this study, we comprehensively investigated phenotypic and functional characteristics of alloreactive circulating T cell subsets in tolerant LT recipients (n = 15) using multiparameter flow cytometry and compared these with LT recipients on IS drugs (n = 23) and healthy individuals (n = 16). Activation‐induced CD137 was used as a marker for alloreactive T cells upon allogenic stimulation. We found that central and effector memory CD4+ T cells were hyporesponsive against donor and third‐party splenocyte stimulation in tolerant LT recipients, whereas an overall hyperresponsiveness was observed in alloreactive terminally differentiated effector memory CD4+ T cells. In addition, elevated percentages of circulating activated T helper cells were observed in these recipients. Lastly, tolerant and control LT recipients did not differ in donor‐specific antibody formation. In conclusion, a combination of circulating hyperresponsive highly differentiated alloreactive CD4+ T cells and circulating activated T helper cells could discriminate tolerant recipients from a larger group of LT recipients.

Outcome of hepatitis C-related liver transplantation in direct-acting antiviral era.

Hepatitis C virus (HCV) has become an easily treatable disease after the introduction of sofosbuvir-based direct-acting antiviral (DAA) regimens. This is a large single center experience of changing severity and outcome profile of HCV-related liver disease after availability of DAAs. A retrospective analysis of prospectively collected liver transplantation (LT) database of adults (age > 18years at the time of LT) was performed from June 2010 to July 2018. A total of 410 patients (including 26 co-infection with hepatitis B) underwent LT for hepatitis C-related decompensated cirrhosis and/or hepatocellular carcinoma (HCC) out of 1754 adult transplantation in the defined period. The study group comprised of 296 males and 114 females aged 52.1 ± 7.9years. HCV-related decompensated cirrhosis and/or HCC as indication of LT was present in 289/1016 (28.4%) during 2010-2014, which was reduced to 121/738 (16.3%) during2015-2018 (p = 0.000). The LT recipients for HCV-related cirrhosis had significantly lower Child's and model for end-stage liver disease (MELD) score during 2015-2018 as compared to that during2010-2014; Child's score was 7.9 ± 2.2 vs. 8.6 ± 2.1, p = 0.003; MELD scorewas 13.9 ± 5.3 vs. 17.1 ± 5.8, p = 0.000, respectively. There was a trend towards better survival in HCV patients during 2015-2018 as compared to that during 2010-2014. Significantly more patients had HCV RNA negative status before LT during 2015-2018 (38.8% vs. 13%, p = 0.000); moreover, the proportion of LT for decompensated cirrhosis (without HCC) decreased significantly in the latter period, 64.0% vs. 42.1% (p = 0.000). In the DAA era, HCV as an indication for LT has decreased and patients have less severe disease at transplantation. There is a trend towards better patient survival.

P1668SIMULTANEOUS LIVER-KIDNEY TRANSPLANTATION IN PEOPLE LIVING WITH HIV: A CASE-SERIES WITH LONG TERM FOLLOW-UP

Abstract Background and Aims The number of simultaneous liver-kidney transplants (SLKT) has been constantly increasing in the past two decades. In the US, the relative proportion of liver transplants performed as part of SLKT augmented from 2.7% in 2000 to 9.3% in 2016. In this rapidly evolving scenario, people living with HIV (PLWH) have been substantially excluded from SLKT. The poor prognosis of SLKT in people living with HIV (PLWH) has refrained transplant centers to perform this procedure. Method We retrospectively describe indications, clinical characteristics and survival of HIV-infected patients who underwent SLKT at the Transplant Centre of Modena, Italy. Results Since 2001 five SLKTs were performed in HIV-affected subjects. With regards to medical eligibility criteria for SLKT all the patients were on hemodialysis and had liver end-stage disease or HCC at time of transplantation (Table 1A). Mean age at transplantation was 47.8± 5.93 years and all patients were Caucasian males. Mean duration of HIV was 25 years and all patients had undetectable HIV-viral load at SLKT. The causes of end-stage renal disease were different in all recipients and only one had biopsy-proven kidney disease. Dialysis vintage was 15.8±10.2 months. Four patients had HCV-related cirrhosis and one had hepato-carcinoma (HCC). Mean HCV-RNA at SOT was 464,327 copies/ml; in three HCV patients, the sustained virologic response to HCV therapy was obtained after transplant with peg-INF in one case (pre-direct antiviral agent era) and with a combination of sofosbuvir, daclatasvir and rifampicin in the other two. Only one patient had HBV-HDV-related cirrhosis and did not experience HBV or HDV relapse during the follow-up. At the end of a mean follow up of 7.6±4.71 years, four out of five patients are still alive One patient died on post-transplant day 41 for disseminated candidiasis with cerebral involvement (Table1 b). During the follow-up period, HIV-VL remained undetectable over nearly 10 years. Clinical outcome was characterized by the reverse of frailty in all the patients. All of them are conducting an independent living with quality of life exceeding 90% using the EUQoL 5D-5L questionnaire. The liver function was normal and remained stable during theobservation period. Bile duct stricture and bile duct calculi were the main surgical complications. Regarding renal function, mean serum creatinine was 1.7±0.4mg/dl corresponding to a mean estimated GFR of 47.7±5.9 ml/min. Only one patient had proteinuria (0.8 gr/daily) after 10 years of transplantation. Contrary to our expectations, no cases of graft rejections occurred during this long-term follow-up despite mean HLA mismatches of 5.75 and underexposure to the immunosuppressive agents. Withdrawn of steroids occurred after 1.8±2.5 years from SLKT. Thereafter, immunosuppressive therapy continued with monotherapy: calcineurin inhibitor in three recipients and inhibitors of the mammalian target of rapamycin in the other one. Conclusion Contrary to the previously published data, this case series describes a favorable clinical outcome in PLWH who received SLKT. The absence of graft rejection despite the reduced immunosuppressive therapy highlights the concept that the liver is able to induce tolerance in kidney transplantation. These results could lead other transplant programs to consider SLKT as a reliable clinical option in PLWH with liver and kidney failure.

Medicaid Policy and Liver Transplant for Alcohol-Associated Liver Disease.

In some states, liver transplantation (LT) for alcohol-associated liver disease (ALD) is covered by Medicaid only with documentation of abstinence and/or alcohol rehabilitation. Different Medicaid policies may affect the distribution of LT for ALD, particularly post-2011, as centers have adopted early (i.e., specific abstinence period not required) LT practices. We surveyed Medicaid policies in all states actively performing LT and linked state policies to prospectively collected national registry data on LT recipients from 2002 to 2017 with ALD as the primary listing diagnosis. We categorized Medicaid policies for states as "restrictive" (requiring documentation of a specific abstinence period and/or rehabilitation) versus "unrestrictive" (deferring to center eligibility policies). Difference-of-differences analysis, comparing 2002-2011 versus 2012-2017, evaluated whether restrictive policies were associated with decreased proportion of LTs paid by Medicaid among patients with ALD post-2011. We performed sensitivity analyses to account for any differences by diagnosis of hepatocellular carcinoma, hepatitis C virus, nonalcoholic steatohepatitis, or Medicare insurance. We also performed a sensitivity analysis to account for any difference by prevalence of ALD among restrictive versus unrestrictive states. Of 10,836 LT recipients in 2002-2017, 7,091 were from 24 states in the restrictive group and 3,745 from 14 states in the unrestrictive group. The adjusted proportion (95% confidence interval) of LTs paid by Medicaid among restrictive versus unrestrictive states between 2002 and 2011 was 17.6% (15.4%-19.8%) versus 18.9% (15.4%-22.3%) (P=0.54) and between 2012 and 2017, 17.2% (14.7%-19.7%) versus 23.2% (19.8%-26.6%) (P=0.005). In difference-of-differences analysis, restrictive (versus unrestrictive) policies were associated with a 4.7% (0.8%-8.6%) (P=0.02) absolute lower adjusted proportion of LTs for ALD paid by Medicaid post-2011. Restrictive Medicaid policies are present in most states with active LT centers and are associated with lower proportions of LTs for ALD paid by Medicaid post-2011 compared to states with unrestrictive Medicaid policies. Reevaluation of Medicaid alcohol use policies may be warranted, to align more closely with contemporary center-level practices.

Liver Transplantation in Unauthorized Immigrants in the United States.

Eleven million unauthorized immigrants reside in the United States and may account for 3% of deceased organ donors. Recently introduced federal and state legislation propose to address access to organ transplantation among unauthorized immigrants. The national landscape of liver transplantation (LT) for unauthorized immigrants is unknown. We included all US LT recipients between March 2012 and December 2018 who were linked to Pew Center of Research data to estimate the population of unauthorized immigrants in each US state and by country of origin, based on US Census data. We categorized patients as unauthorized immigrants versus US citizens/residents. The main outcome measures were (1) the proportion of LTs performed for unauthorized immigrants compared with the proportion of unauthorized immigrants among total population in each US state and (2) graft failure and death post-LT. Of 43,192 LT recipients, 43,026 (99.6%) were US citizens/residents and 166 (0.4%) were unauthorized immigrants. Among unauthorized immigrants, most LTs were performed in California (47%) and New York (18%). The absolute difference in proportion of LTs performed for unauthorized immigrants compared with the proportion of unauthorized immigrants among the total population differed among states, ranging from +20% in California to -12% in Texas. The most common countries of birth among LT recipients who were unauthorized immigrants were Mexico (52%), Guatemala (7%), China (6%), El Salvador (5%), and India (5%). In competing risk analysis, unauthorized immigration status (vs. US citizens/residents) was associated with a similar risk of graft failure (subdistribution hazard ratio [sHR] 0.74; 95% confidence interval [CI], 0.40-1.34; P=0.38) and death (sHR 0.68; 95% CI, 0.36-1.29; P=0.23). LT for unauthorized immigrants is rare, and disparities in access to LT by state are present. Patient and graft survival among unauthorized immigrants is comparable with citizens/residents.

Challenges and future developments in liver transplantation.

Liver transplantation (LT) has become the treatment of choice for a wide range of liver diseases in both adult and pediatric patients. Until recently, the largest proportion of LT in adults, were performed in patients with hepatitis C (HCV) related cirrhosis. The recent availability of safe and effective direct antiviral agents to cure HCV infection in almost all patients whatever the HCV genotype and severity of liver disease, will reduce the need for LT in this category of recipients. Thus, it is presumed that in the next 1 to 2 decades HCV related liver disease will diminish substantially, whereas non-alcoholic steato-hepatitis (NASH) will correspondingly escalate as an indication for LT. The greatest challenges facing LT remain the limited supply of donor organs, and the need for chronic immunosuppression, which represent the true obstacles to the greater application and durable success of the LT procedure. This review aimed to highlight, in different sections, the main open issues and future developments in LT. These will be focused to explore current and future strategies to maximize the use of limited organs, to offer an update on potential new approaches to immunosuppression and to imagine new indications for LT when the number of patients awaiting transplants for HCV related liver disease is reduced.

Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review

ABSTRACT Backgrounds Traditional Chinese medicine (TCM) is becoming increasingly popular and related adverse events are often ignored or underestimated. Aims This systematic review aimed to evaluate the clinical characteristics and outcomes of TCM-induced liver injury (TCM-ILI) and to estimate the proportion of TCM-ILI in all drug-induced liver injuries (DILI). Methods China National Knowledge Infrastructure, Wanfang, VIP, PubMed, and Embase databases were searched. Demographic, clinical, and survival data were extracted and pooled. Factors associated with worse outcomes were calculated. For the proportion meta-analyses, the data were pooled by using a random-effects model. Results Overall, 21,027 articles were retrieved, of which 625 were finally included. There was a predominance of female and older patients. The proportion of liver transplantation was 2.18% (7/321). The mortality was 4.67% (15/321). Male, higher aspartate aminotransferase and direct bilirubin, and lower albumin were significantly associated with an increased risk of death/liver transplantation in TCM-ILI patients. The proportion of TCM-ILI in all DILI was 25.71%. The proportion was gradually increased with year. Conclusions Our work summarises current knowledge regarding clinical presentation, disease course, and prognosis of TCM-ILI. TCM can result in hepatotoxicity, even death or necessitate life-saving liver transplantation. Governmental regulation of TCM products should be strictly established.