PRO: Patients With Acute‐on‐Chronic Liver Failure Should Receive Priority on the Liver Transplant Waiting List

Acute‐on‐chronic liver failure (ACLF) is a clinically, prognostically, and pathophysiologically distinct syndrome that occurs in patients with cirrhosis.¹ It typically occurs in the context of acute decompensation (ascites, hepatic encephalopathy, variceal hemorrhage) usually precipitated by superimposed hepatic or extrahepatic insult and results in single or multiple organ failures. ACLF is associated with increased short‐term mortality and thus dictates the need for urgent and intensive intervention.² Timely liver transplantation (LT) is lifesaving for correctly selected patients with ACLF^3,4 (Fig. 1). In this review, we highlight why patients with ACLF should receive priority for transplantation, taking into account individualized patient benefit, the evidence in supporting priority transplantation, organ utility, and ethical considerations.

FIG 1: (A) Kaplan‐Meier’s 180‐day transplant‐free survival curves of patients based on their ACLF grade at days 3 to 7 (d3‐7 ACLF). (B) Probability of (180‐day) survival in patients with d3‐7 ACLF‐2 or ACLF‐3 without LT and in patients undergoing early (28‐day) LT. Reprinted with permission from Hepatology.⁵ Copyright 2015, American Association for the Study of Liver Diseases.

Benefit of LT in ACLF

• LT in ACLF significantly improves patient survival at 1 year, and there is a significant transplant benefit gained beyond that seen in cirrhosis and no ACLF.
• One‐year LT survival rates in ACLF grade 1 (ACLF‐1) to ACLF‐2 are similar to those seen in patients with no ACLF, and the survival rate is in excess of 80% in ACLF‐3.

The development of ACLF confers a substantially elevated short‐term mortality, which increases rapidly as organ failures and hence grade of ACLF increase. This is exemplified by the large multicenter CANONIC study where the overall 28‐day mortality in ACLF‐1 was 22%, increasing to 79% in ACLF‐3, compared with just 2% in patients with acute decompensation alone^3,5 (Fig. 1). This group further nuanced 28‐day mortality prediction in ACLF by developing the CLIF‐C ACLF score (Chronic Liver Failure Consortium Organ Failure Score; https://www.efclif.com/scientific‐activity/score‐calculators/clif‐c‐aclf), which incorporates liver‐specific parameters with organ failure data. This score, when calculated between days 3 and 7 after development of ACLF, allows confident, individualized, and dynamic evaluation of short‐term mortality that can be used to guide prognostic discussions and help define benefit of LT.^6,7

LT is a lifesaving treatment for patients with ACLF‐1 to ACLF‐3, with 1‐year survival rates of between 80% and 90%.^3,4 Specifically, in ACLF‐1 and ACLF‐2, LT has excellent outcomes comparable with that of patients transplanted from the chronic waiting list (Fig. 2). Moreover, given the elevated short‐term mortality the syndrome confers beyond patients with no ACLF, the transplant benefit in ACLF‐1 and ACLF‐2, incorporating both risk for death without LT and survival after LT, is significantly higher. It is thus rational and appropriate on medical, ethical, and organ utility grounds that such patients receive a priority for organs higher than patients with no ACLF.

FIG 2: One‐year survival of patients with LT according to ACLF grade. Reprinted with permission from Journal of Hepatology.⁴ Copyright 2017, Elsevier.

ACLF‐3 defines a population with three or more organ failures, and concerns regarding futility and patients being “too sick” for LT are frequent. Several studies have highlighted evidence to the contrary, demonstrating highly acceptable 1‐year survival rates and thus exceptional transplant benefit.^3,4 For example, a retrospective French study reported 1‐year survival rates of 83.9% in 73 patients with ACLF‐3 who underwent LT, compared with survival rates of just 7.9% in those without LT.⁴ Although retrospective studies carry the risk of residual confounding information and selection biases, which are likely to reflect positively on survival data, they still clearly demonstrate the significant transplant benefit in ACLF‐3.

Timing and Prioritization of Organs for LT in ACLF

• The timing of LT in ACLF is critical; a longer wait impacts negatively on both wait‐list mortality and post‐LT outcomes.
• One third of listed patients for ACLF have either died or been delisted because of clinical deterioration by day 21.
• Conventional organ allocation scores do not reflect the increased mortality seen in ACLF.
• The United Kingdom is currently piloting organ prioritization for patients with ACLF.

Early LT in ACLF is of paramount importance with regard to its role as a lifesaving treatment, post‐LT outcomes, and avoidance of futility. Timing is particularly pertinent in patients with ACLF‐3 given they have the shortest “transplant window” and highest mortality without LT. Providing priority organ allocation to such patients within current allocation systems will need to be facilitated to maximize successful outcomes of LT in ACLF.⁸

In the United Network for Organ Sharing registry, 33% of patients listed for ACLF‐3 had died or were removed from the waiting list by 21 days having not received a suitable organ offer.³ Moreover, a single‐center study by Umgelter et al.⁹ reported a 1‐year post‐LT survival rate in ACLF‐3 of only 46% with the caveat that those surviving had a significantly shorter intensive therapy unit stay prior to LT than those who died (8 versus 32 days). Subsequent studies have all reported excellent outcomes in ACLF‐3 but all with LT occurring within 14 days of listing the patient.^3‐5 These studies highlight that a successful outcome can only be achieved if patients are given priority to avail organs while the clinical status of the patient remains favorable for LT.

Given ACLF is a distinct clinical entity from no ACLF, it is not surprising that conventional scores used to guide priority and allocation of organs (Model for End‐Stage Liver Disease [MELD], MELD‐Na) significantly underpredict mortality in ACLF^3,7 (Fig. 3). Currently, neither the presence of ACLF nor ACLF‐specific scores are used to guide the allocation of organs for such patients on the LT waiting list. Allocating lifesaving organs based on inaccurate prognostic scores is neither rational nor ethically sound and highlights the need for a more robust priority allocation of organs in ACLF to ensure utility and equity. The first pilot service evaluation of prioritizing such patients is open in the United Kingdom, providing allocation of organs to patients with ACLF after those with acute liver failure and hepatoblastoma.

FIG 3: Death or removal from wait list within 90 days according to ACLF and MELD‐Na score. Reprinted with permission from Gastroenterology.³ Copyright 2019, American Gastroenterological Association Institute.

Futility of LT in Patients With ACLF

• Understanding futility of LT in ACLF is essential when accepting organs.
• Standard contraindications to LT must still apply to patients with ACLF.

Among the sickest patients with ACLF, we have an obligation to understand when LT would be futile and define what constitutes an acceptable post‐LT survival. Conventionally, acceptable post‐LT survival has been defined as an anticipated greater than 50% 5‐year survival rate. Data strongly support this in patients with ACLF‐1 to ACLF‐3 with the caveat that organs are offered with priority and within a short time frame.³ The CHANCE (Liver transplantation in patients with CirrHosis and severe Acute‐on‐Chronic Liver Failure: iNdications and outComEs) study, which is a large, prospective, global, multicentered, observational study evaluating LT in ACLF, has been launched to provide clarity and an evidence base to help inform such decisions.

Conclusion

These data provide compelling evidence for LT in ACLF and the need for this to occur within a short time window for it to be maximally effective. Conventional organ allocation scores do not capture the increased mortality conferred in ACLF. Priority outside of these scores is urgently needed to allocate organs on a basis that is patient centered, maximizes organ utility and transplant benefit, and is ethically sound.