*6.5. Liver Transplantation*

Several studies showed that LT improved survival in patients with ACLF [52,53]. In a recent multi-center European investigation, one-year post-LT survival was >than 80% independently from ACLF grade [54]. Despite these findings, prioritization for LT of patients with ACLF remains complicated. Commonly used scores for listing patients with cirrhosis were demonstrated not to be accurate enough to predict survival in patients with OFs. Mortality of patients with ACLF of grade 3 and a MELD score < 25 was shown to

be higher than in patients with a MELD score > 35 but without ACLF [52]. MELD-Na score underestimates mortality at 90-days in patients with ACLF, especially in those with MELD-Na < 30 [55]. Moreover, patients with ACLF grade 3 had a greater waitlist 14-day mortality than patients listed as status 1a, independent of MELD-Na score [56]. These findings emphasize the importance of early discussion for LT and consideration of priority for patients with ACLF, irrespective of traditional listing scores. Recently, a novel score which incorporates MELD score and ACLF grade demonstrably performs better than traditional scores by giving a higher impact to ACLF grade at lower MELD listing [57].

The Spanish Society of Liver Transplantation (SETH) proposed a consensus statement in which expedited organ allocation is recommended to allow ACLF patients to be transplanted [58]. SETH recommends the use of CLIF-C ACLF score instead of MELD to assess prognosis and suggests prioritisation of these patients because of their poor short-term prognosis [58]. NHS Blood and Transplant recently set the ACLF Liver Transplantation Tier (ACLFLTT) which gives a priority below that of super-urgent listed patients to those with cirrhosis and liver failure (as manifested by jaundice and coagulopathy) who stay on ICU for organ support and have risk of 28-day mortality of >50%. These patients usually fulfill EASL-CLIF criteria for ACLF of grade 2 or 3 [59].

An optimal selection of candidates for LT is equally important to avoid futile LT. Factors independently associated with poor post-LT survival were found to be lactate levels > 4 mmol/L, need for RRT at LT, older age of recipient, use of marginal organs and infections with MDROs while on the waiting list [52,54,60].

#### *6.6. Extracorporeal Liver Support*

Two large randomized clinical trials demonstrated no improvement in short-term survival in ACLF patients treated with albumin dialysis versus standard medical therapy [61,62]. Other two randomized trials are currently assessing plasma exchange (APACHE trial; ClinicalTrials.gov number, NCT03702920) and albumin exchange with endotoxin removal (DIALIVE trial, NCT03065699).

#### *6.7. Granulocyte-Colony Stimulating Factor*

Two small single-center studies reported improved survival and reduced rate of bacterial infections in ACLF patients treated with Granulocyte-Colony Stimulating Factor (G-CSF) [63,64]. This result was not confirmed by the recent large multicenter randomized trial (GRAFT study), which failed to demonstrate the superiority of G-CSF over standard medical treatment and reported serious drug-related adverse events [65].

#### *6.8. Human Allogeneic Liver-Derived Progenitor Cells*

Low doses of human allogeneic liver-derived progenitor cells (HALPC) appeared to be safe in a clinical phase II study which involved 24 patients [66]. Further studies are needed to confirm safety and assess efficacy of this medicinal product.

#### **7. Conclusions**

ACLF is a distinct syndrome without a universally accepted definition and is characterized by high short-term mortality due to OFs. Patients with ACLF should access ICU without delay if necessary. LT has good outcomes and should be considered irrespective of traditionally used scores for waiting list allocation. Prioritization of ACLF for LT should be improved using proper scores for ACLF patients. Further studies are needed in order to better clarify the pathophysiology of the syndrome and to develop treatments other than supportive measures for OFs.

**Author Contributions:** Writing—original draft, C.G., S.P. and P.A.; Writing—review & editing, C.G., S.P. and P.A. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** C.G.: None; S.P.: Mallinckrodt advisory board; P.A.: None.
