Acute on chronic liver failure (ACLF) is a syndrome of systemic inflammation and multiple organ system failures that is associated with a significantly high 28-day mortality ranging from 15-89%,(1) and which is increasing in prevalence in the United States and globally.(2) Although several definitions for ACLF exist, it is generally agreed upon that this condition yields greater non-transplant mortality than mere decompensated cirrhosis. The EASL-CLIF definition of ACLF categorizes patients according to the number of organ failures present, specifically as 1 organ failure (ACLF-1), 2 organ failures (ACLF-2) and 3 or more organ failures (ACLF-3).(1) Liver transplantation (LT) remains the only life-saving intervention in this population, especially among those with ACLF-3

Jalan, R

Sundaram, V

English

UCL Discovery

 1 Waiting list priority for patients with acute-on-chronic liver failure: Not just horseplay  Vinay Sundaram, MD MSc1   Rajiv Jalan, MD, PhD2  (1) Karsh Division of Gastroenterology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA  (2) Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, London, UK  Article type: Editorial  Corresponding Author Contact Information:  Vinay Sundaram, MD MsC 8900 Beverly Blvd, Suite 250 Los Angeles, CA, 09948 Phone:  310-423-6000 Fax: 310-423-0849 Email: Vinay.Sundaram@cshs.org   List of Abbreviations: Acute on chronic liver failure (ACLF) Liver transplantation (LT) United Network for Organ Sharing (UNOS)  Financial Support: None  Disclosure: The authors have nothing to disclose regarding conflicts of interest relevant to this manuscript.  Writing Assistance: None  Author contributions: Drafting of manuscript: VS, RJ  Guarantors of the article: Vinay Sundaram, Rajiv Jalan  All authors approved the final version of the article, including the authorship list.  2 Acute on chronic liver failure (ACLF) is a syndrome of systemic inflammation and multiple organ system failures that is associated with a significantly high 28-day mortality ranging from 15-89%,(1) and which is increasing in prevalence in the United States and globally.(2) Although several definitions for ACLF exist, it is generally agreed upon that this condition yields greater non-transplant mortality than mere decompensated cirrhosis. The EASL-CLIF definition of ACLF categorizes patients according to the number of organ failures present, specifically as 1 organ failure (ACLF-1), 2 organ failures (ACLF-2) and 3 or more organ failures (ACLF-3).(1) Liver transplantation (LT) remains the only life-saving intervention in this population, especially among those with ACLF-3.  Previously, studies exploring the role of LT in the setting of ACLF were limited to a small sample size, even if performed at the multi-center level. Since 2018, however, several papers have been published utilizing the United Network for Organ Sharing (UNOS) database, allowing for the study of thousands of patients listed or transplanted with ACLF, including ACLF-3. The editorial by Goldberg and Bajaj in this issue of Liver Transplantation provide only one perspective about what has been learned from UNOS database in relation to the role of liver transplantation in ACLF patients. In this editorial, we discuss the important observations that were made from the studies analyzing the UNOS database, subsequent validation of these findings, limitations of the information provided by these investigations, and how the preliminary data generated by analysis of the UNOS database has contributed to the design of the prospective CHANCE study, that aims to address unanswered questions in the field of transplantation for ACLF. Important observations from the UNOS database and subsequent corroboration Current organ allocation policy in the United States and Europe is based on the Model for End-Stage Liver Disease (MELD) score and Model for End-Stage Liver  3 Disease-Sodium (MELD-Na) score, which prioritizes patients with decompensated cirrhosis according to expected 90-day mortality. There are no specific exception points for ACLF patients, partially due to the lack of consensus regarding how to define it. Subsequently, patients with ACLF are ranked on the waiting list based on their MELD or MELD-sodium score, regardless of the number of organ failures which have developed.  In the seminal study from the UNOS database addressing the role of LT in patients with ACLF, mortality on the waiting list was assessed in approximately 79,000 patients, including more than 5,000 patients with ACLF-3. Two important findings were demonstrated from this investigation.(3) First, using competing risks regression analysis, with LT as the competing event, the 1-year cumulative incidence of death or waitlist removal due to being too sick for LT increased with worsening grade of ACLF, with a significant rise in mortality among candidates listed with ACLF-3, approaching 20% at 6 months and 30% at 1 year.(3) (figure 1a) This finding has been subsequently validated in a retrospective, multi-center European study of over 300 patients who developed ACLF either at listing or afterwards,(4) with a total of 131 patients studied with ACLF-3 prior to LT. The cumulative incidence function, as based on competing risks regression, similarly revealed greater probability of death on the waiting list with worsening grade of ACLF. Patients with ACLF-3 also had a more than 30% likelihood of waitlist mortality within 6 months of listing.(4) (Figure 1b) Another substantial observation from this study was that the MELD and MELD-Na scores underestimated waitlist mortality with increasing grades of ACLF. Figure 2a displays 90-day mortality from listing as obtained from the UNOS database, categorized by different grades of ACLF and subcategorized according to MELD-Na category at waitlist registration. The analysis of waiting list mortality according to ACLF grade at listing indicated that highest risk of death or removal from the waiting list belonged to  4 patients with ACLF-3 and MELD-Na scores <25, followed by candidates with ACLF-2 and MELD-Na scores <25 at listing.(3) (Figure 1c) These findings not only suggest that the MELD-Na score underestimates mortality among patients with ACLF-2 or ACLF-3, but also implies that the presence of organ failures not captured by the MELD-Na score contributes significantly to death on the waiting list. A separate study to validate these results was performed by Hernaez et al through analysis of over 70,000 patients from 127 Veterans Administration hospitals.(5) Findings from this study similarly demonstrated the underestimation of patient mortality by the MELD-Na score in the setting of ACLF. (Figure 1d) Furthermore, the discrepancy between expected mortality according to the MELD-Na score and actual mortality widens with increasing grade of ACLF, thereby providing convergent validity to those of the UNOS database study. The relevant observations from additional studies regarding LT for patients with ACLF, along with corroborating data, are displayed in Table 1. Limitations of the UNOS database  Though several conclusions based on investigation of the UNOS database have been subsequently verified, there are important limitations which should be discussed. The initial purpose of the UNOS registry studies was to generate hypotheses based on longitudinal observations of a large patient sample, which require subsequent testing. The primary limitation, though, is due to the potential for misclassification of ACLF grade. The registry contains information to identify liver, coagulation and renal failure based on laboratory parameters. In addition, data are available regarding the presence grade 3-4 hepatic encephalopathy at listing and transplantation, which allows the identification of brain failure per the EASL-CLIF criteria. Circulatory and respiratory failure, though, are identified based on surrogates of vasopressor support and mechanical ventilation, and the indication for these interventions is not definitive. It is  5 therefore possible that certain patients who do not have circulatory or respiratory failure are incorrectly classified as having them, such as those who are intubated for airway protection. However, it is of paramount importance to discuss whether these limitations affect the conclusions of the studies. For the purpose of studying waitlist mortality, we believe that although misclassification is feasible, it would actually lead to underestimation of the probability of death on the waiting list, as determined by UNOS analyses. Specifically, the conclusions of the studies regarding waitlist mortality were centered around patients with ACLF-3, a group which has consistently been demonstrated to have the highest mortality risk in multiple prospective trials. Incorrectly categorizing certain patients as having ACLF-3, therefore, may lead to inclusion of patients with lower ACLF grades into the analysis and subsequently reducing the estimated mortality. We believe it is unlikely that misclassification would overestimate the observed mortality from the UNOS database, as the phenotype of a “high-mortality non-ACLF” patient does not exist.(6)   The global CHANCE study to address the unanswered questions Although the studies from the UNOS database have revealed important observations in relation to transplantation for ACLF, prospective validation of these findings is necessary to advance the field. In this context, the EASL-CLIF Consortium in collaboration with the International Liver Transplantation Society (ILTS) and the European Liver and Intestine Transplant Association (ELITA) have designed prospective non-interventional observational global study (CHANCE, liver transplantation in patients with CirrHosis and severe ACLF: iNdications and outcome, ClinicalTrials.gov: NCT04613921). The international nature of the CHANCE study will allow assessments of the different regional/national allocation systems on waitlist mortality and post-transplant outcomes.   6 Conclusion In conclusion, transplantation for patients with ACLF, and particularly ACLF-3, is highly complicated, and relevant questions surrounding waiting list mortality are only beginning to be addressed. Investigation of the UNOS database has yielded important information that has been corroborated in subsequent studies and has provided the basis for changes in organ allocation policy in countries such as the UK and Spain, which have already made recommendations to allow prioritization of organ to transplantation patients with severe ACLF. Importantly, the UNOS database has provided has provided the foundation upon which future research, such as the CHANCE study, is being built.     7 References 1. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426-1437, 1437 e1421-1429. 2. Sundaram V, Jalan R, Shah P, Singal AK, Patel AA, Wu T, Noureddin M, et al. Acute on chronic liver failure from nonalcoholic fatty liver disease: a growing and aging cohort with rising mortality. Hepatology 2020. 3. Sundaram V, Jalan R, Wu T, Volk ML, Asrani SK, Klein AS, Wong RJ. Factors Associated with Survival of Patients With Severe Acute on Chronic Liver Failure Before and After Liver Transplantation. Gastroenterology 2018. 4. Belli LS, Duvoux C, Artzner T, Bernal W, Conti S, Cortesi PA, Sacleux SC, et al. Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: results of the ELITA/EF-CLIF collaborative study (ECLIS). J Hepatol 2021. 5. Hernaez R, Liu Y, Kramer JR, Rana A, El-Serag HB, Kanwal F. Model for end-stage liver disease-sodium underestimates 90-day mortality risk in patients with acute-on-chronic liver failure. J Hepatol 2020. 6. Trebicka J, Fernandez J, Papp M, Caraceni P, Laleman W, Gambino C, Giovo I, et al. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol 2020;73:842-854. 7. Artzner T, Michard B, Weiss E, Barbier L, Noorah Z, Merle JC, Paugam-Burtz C, et al. Liver transplantation for critically ill cirrhotic patients: Stratifying utility based on pretransplant factors. Am J Transplant 2020. 8. Sundaram V, Kogachi S, Wong RJ, Karvellas CJ, Fortune BE, Mahmud N, Levitsky J, et al. Effect of the clinical course of acute on chronic liver failure prior to liver transplantation on post-transplant survival. J Hepatol 2019. 9. Huebener P, Sterneck MR, Bangert K, Drolz A, Lohse AW, Kluge S, Fischer L, et al. Stabilisation of acute-on-chronic liver failure patients before liver transplantation predicts post-transplant survival. Aliment Pharmacol Ther 2018;47:1502-1510.     8 Figure Legends  Figure 1a. Cumulative incidence of waitlist mortality according to ACLF grade, per the UNOS database  Figure 1b. Cumulative incidence of waitlist mortality according to ACLF grader, per the ELITA study  Figure 1c. 90-day mortality or removal from the waiting list according to ACLF grade and MELD-Na score (UNOS database)  Figure 1d. 90-day mortality according to ACLF grade and MELD-Na score (Veterans Administration database)      9     01020304050No ACLF ACLF-1 ACLF-2 ACLF-3Mortality Rate (%)MELD-Na < 25 MELD-Na 25-29 MELD-Na 30-34 MELD-Na >= 351.9619.652.671.39.017.936.255.781.827.1 28.138.747.961.547.844.936.847.562.653.960.464.470.179.2≤9 10-19 20-29 30-39 40 +Expected non ACLF ACLF-1 ACLF-2 ACLF-3MELD-Na categories 10 Table 1. Summary of studies from the UNOS database regarding waitlist and post-transplant outcomes in patients with severe ACLF  Study (Year) Type of Study Total Patients with ACLF-3 Significance Corroborating Studies Sundaram (2019) (3) UNOS database years, 2005 to 2016 ,355 at listing  6,381 transplanted Identified > 80% 1-year survival after, including among patients with ACLF-3  Belli et al (4) Sundaram (2019) (3) UNOS database years, 2005 to 2016 5,355 at listing  6,381 transplanted Demonstrated waitlist mortality is highest among ACLF-3 patients regardless of MELD-Na  Identified presence of mechanical ventilation as strongest predictor of post-LT mortality Belli et al (4) Hernaez et al (5)      Artzner et al (7)  Sundaram (2019) (8) UNOS database, years 2004-2017 3,636 patients listed with ACLF-3 Improvement in ACLF grade increases survival after liver transplantation Heubener et al (9)  

Waitlist Priority for Patients with Acute-on-Chronic Liver Failure: Not Just Horseplay

https://discovery.ucl.ac.uk/id/eprint/10137942/3/Jalan_Waiting%20list%20priority%20for%20patients%20with%20acute-on-chronic%20liver%20failure%20Not%20just%20horseplay.pdf

Waitlist Priority for Patients with Acute-on-Chronic Liver Failure: Not Just Horseplay

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