Acute-on-chronic liver failure (ACLF) in 2022: have novel treatment paradigms already arrived?

Figures & data

Table 1. Definitions of acute on chronic liver failure (ACLF).

	APASL	EASL CLIF	NACSELD	CHINESE
Definition	Acute hepatic insult manifesting as jaundice (Bilirubin >5 mg/dL) and coagulopathy (INR>1.5) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed CLD including cirrhosis	An acute deterioration of preexisting chronic liver disease usually related to a precipitating event and associated with increased mortality at 3 months due to multi-organ failure	A syndrome characterized by acute deterioration in a patient with cirrhosis due to infection presenting with two or more extra-hepatic organ failures.	A complicated syndrome with a high short-term mortality rate that develops in patients with HBV-related chronic liver disease regardless of the presence of cirrhosis and is characterized by acute deterioration of liver function and hepatic and/or extrahepatic organ failure.
Study Cohort	First consensus was expert opinion	Prospectively studied in 1343 patients	Prospectively studied in 507 patients	Prospective study of 1322 hospitalized patients with acute decompensation of cirrhosis or severe liver injury due to chronic HBV.
Inclusion	Compensated Cirrhosis CLD but no cirrhosis Acute insult directed to liver Presentation with liver failure	Patients with AD or cirrhosis Patients with prior decompensation of cirrhosis	Patients with prior decompensation of cirrhosis Patients with infection at admission or during hospital stay	Patients with severe liver injury (TB≥5 mg/dL and INR≥1.5) from chronic hepatitis B or acute decompensation of cirrhosis (Ascites/HE/UGIB/bacterial infections)
Exclusions	Patients with bacterial infections Patients with cirrhosis and known prior decompensation who develop acute deterioration are considered to have acute decompensation but not ACLF	HCC outside Milan criteria Severe chronic extrahepatic diseases HIV infection and on-going immunosuppressive treatments	Outpatients with infection HIV infection Prior organ transplant Disseminated malignancies	Age <18 and >80 years Pregnant women Other liver malignancies Severe extra-hepatic disease Receiving immunosuppressive drugs for indications other than chronic liver disease
Priority criteria for severity	Experts consider the failing liver as predictor of severity	Pre-specified criteria for organ failure(s) according to the CLIF-SOFA score	Prespecified criteria for organ failure(s)	Chinese group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) criteria

Abbreviations: AD, Acute Decompensation; APASL, Asian Pacific Association for the Study of the Liver; CLD, Chronic liver disease; CLIF-SOFA, chronic liver failure-sequential organ failure assessment; EASL-CLIF, European Association for the Study of Liver-Chronic Liver failure; HBV, Hepatitis B; HCC, Hepatocellular carcinoma; HE, hepatic encephalopathy; HIV, Human immunodeficiency virus; INR, International normalized ratio; NACSELD, North American Consortium of End-stage Liver Disease; SOFA, Sequential Organ Failure Assessment; UGIB: Upper gastrointestinal bleed.

Figure 1. Pathophysiology of ACLF.

Intestinal dysbiosis, enhanced gut permeability, and ongoing liver damage contribute to a large circulating pool of immunogenic motifs including PAMPs (LPS, peptidoglycan, nucleic acids, unmethylated CPG motifs) and DAMPs (HMGB-1, histones, DNA) in decompensated cirrhosis. These drive uncontrolled myeloid cell activation via the toll-like receptors resulting in continual background inflammation typified by the SIRS: this is the hyperinflammatory stage of ACLF with high cytokine levels including IL6 and TNF-alpha. Perpetual immune cell activation results functional reprogramming of these cells which signifies immune exhaustion, this is the immunoparetic phase which portends to sepsis [21,22].Abbreviations: ACLF: acute-on-chronic liver failure, DAMPs: damage-associated molecular patterns, DNA: deoxyribonucleic acid, HMGB1: high mobility group box 1, HLA: human leukocyte antigens, IL: interleukin, LPS: lipopolysaccharide, PAMPs: pathogen-associated molecular pattern, SIRS: Systemic Inflammatory Response Syndrome); SLPI: secretory leukocyte peptidase inhibitor, TNF: tumor necrosis factor.

Figure 2. Novel interventions for ACLF.

FMT has the potential to alter the gut microbiome to alter the nature of bacterial translocation. ReCAP and TAK-242 reduce LPS-driven TLR activation. Emricasan and mitofusin modulate apoptosis products thus potentially reducing the immunogenic pool of DAMPS. G-CSF is hypothesized to reduce immunoparalysis by resetting immune exhaustion whilst ECLDs reduce the inflammatory cytokine burden driving the initial SIRS.

Abbreviations: DAMPS: damage-associated molecular pattern, ECLD: extracorporeal liver support devices, FMT: fecal microbiota transplantation, G-CSF: granulocyte-colony stimulating factor, LPS: lipopolysaccharides, PAMPS: pathogen-associated molecular pattern, ReCAP: recombinant alkaline phosphatase, SIRS: systemic inflammatory response syndrome, TLR: toll-like receptor.

Table 2. Artificial extracorporeal liver support devices used in ACLF*.

	Mechanism of action	Study	Biochemical improvement	Survival advantage	Comments
MARS	Albumin dialysis	Retrospective analysis (n = 101) [120]	Yes	No (reduced short-term mortality but effect deteriorated over time after discontinuation of therapy)	Adverse events include thrombocytopenia
		Case-control study (n = 73) [121]	Yes	No	Long follow up period of 6.5 yearsIn a cohort of patients with ALF and graft dysfunction
		Retrospective analysis (n = 69) [122]	Decreased ammonia -Worsening coagulopathy -Decreased phosphate and magnesium.	No	Both pediatric and adult patients. Median treatment time – 27 hours
		Prospective, observational study (n = 64)	Yes (RR in bilirubin – 25%) -No improvement in cytokine levels	No	Patients clinical characteristics on starting MARS predicted outcomes
		Prospective analysis (n = 53) [123]	Yes		Reduction in HE grades from grade 3 to 1 (n = 6, p < 0.001)
ELAD	Hepatoblastoma-derived C3A cells expressing growth factor and anti-inflammatory properties	Prospective, RCT (n = 203) [124]	No	No survival benefit in severe AH population with MELD scores ranging from 18–35.	In a subgroup of patients with MELD<28, ELAD was associated with non-significant trend of higher overall survival at 3 months (P = 0.08). Elevated INR and creatinine were predictors of a negative response to therapy.
Single pass albumin dialysis	Albumin dialysis	Retrospective analysis (n = 14) [125]	Weak correlation of decrease in total bilirubin induced by SPAD and amount of extracted total bilirubin -Strong correlation between SPAD and bile acid changes	No	Patients received n-acetylcysteine, antioxidant vitamins, terlipressin or norepinephrine.
		Retrospective analysis (n = 101) [126]	Yes (decrease in bilirubin and ammonia levels)	Reduced 30-day mortality in SMT+ECLS subgroup (p = 0.0238) but no difference in 3-month mortality.	High mortality (73.74%) but lower in comparison to SMT group (83.02%)
		Retrospective case control study (n = 13) [127]	Patients with paracetamol overdose but no improvement in clinical, physiological and biochemical parameters.	No	No anticoagulation was used. Observation period of 3 years
Plasma exchange		Randomized, controlled trial (Single-center study) (n = 34) of HBV-associated ACLF [135]		Reduced 90-day (60% v 47%; p = 0.016) and 5-year (43% v 31%; p = 0.013) mortality compared to SMT	Definition of ACLF according to the Chinese guidelines; cirrhosis and multiorgan failure were not taken as mandatory criteria.
SEPET^TM	Selective plasma filtration therapy	Case report [128]	Bilirubin reduction from 23.5 ± 3.7 to 16.4 ± 2.5 mg/DL and reduction of creatinine.		Only case control study in a 74-year-old man with hepatorenal syndrome. Lack of data for SEPET in literature.
Hemodiafiltration	Form of renal replacement therapy utilizing convective in combination with diffusive clearance.	Prospective study (n = 19) [129]	Improvement in bilirubin and ALT levels (p < 0.05)		Hemodiafiltration used only in combination with other plasma clearance techniques such as plasma exchange and hemoperfusion.
		Retrospective analysis (n = 110) [130]	Not analyzed and discussed.	Not mentioned	Analysis of recovery of consciousness receiving hemodiafiltration compared to plasma exchange.
Prometheus	Plasma separation, adsorption, resin and anion adsorbent	Randomized controlled trial (n = 145) [131]	Decreased serum bilirubin levels	No
		Retrospective analysis (n = 114) [132]	Yes	Mortality in FPSA+OLT −33% vs 68% for FPSA without OLT.>90% mortality without FPSA and OLT	Improvement in GCS scale.
		Retrospective analysis (n = 23) [133]	Yes (reduction of median bilirubin levels 23.7 mg/dL to 15 mg/dL; P < 0.001)		ALF patients had better survival compared to AoCLF patients (44% vs 22%; p = 0.022)
		Prospective observational cohort (n = 12) [134]	Biochemical improvement in total bilirubin, cholic acid, ammonia, bile acid concentration, IL2 and IL6.		Broad inclusion criteria for AoCLF.

*Studies included have a minimum of 10 patients

Abbreviations: ACLF, acute-on-chronic liver failure; ALF, acute liver failure; ECLS, extracorporeal liver system; FPSA, fractionated plasma separation and absorption; GCS, Glasgow coma scale; HE, hepatic encephalopathy; IL, interleukin; MARS, molecular adsorbent recirculatory system; OLT, orthoptic liver transplantation; RR, relative risk; SMT, standard medical therapy; SPAD, single pass albumin dialysis

Nautiyal N, Maheshwari D, and Tripathi DM, et al., Establishment of a murine model of acute-on-chronic liver failure with multi-organ dysfunction. Hepatol Int. 15(6): 1389–1401. 2021.

 PubMed Web of Science ®Google Scholar

Cullaro G, Sharma R, Trebicka J, et al. Precipitants of acute-on-chronic liver failure: an opportunity for preventative measures to improve outcomes. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2020;26:283–293.

 Google Scholar

Gerth HU, Pohlen M, Thölking G, et al. Molecular adsorbent recirculating system can reduce short-term mortality among patients with acute-on-chronic liver failure-a retrospective analysis. Crit Care Med. 2017;45(10):1616–1624.

 PubMed Web of Science ®Google Scholar

Gerth HU, Pohlen M, Thölking G, et al. Molecular adsorbent recirculating system (Mars) in acute liver injury and graft dysfunction: results from a case-control study. PLOS ONE. 2017;12(4):e0175529.

 PubMed Web of Science ®Google Scholar

Olin P, Hausken J, Foss A, et al. Continuous molecular adsorbent recirculating system treatment in 69 patients listed for liver transplantation. Scand J Gastroenterol. 2015;50(9):1127–1134.

 PubMed Web of Science ®Google Scholar

Cisneros-Garza LE, Del R M-RM, Muñoz-Espinoza LE, et al. The molecular adsorbent recirculating system as a liver support system: summary of Mexican experience. Ann Hepatol. 2014;13(2):240–247.

 PubMed Web of Science ®Google Scholar

Thompson J, Jones N, Al‐Khafaji A, et al. Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: a multinational, prospective, controlled, randomized trial. Liver Transpl. 2018;24(3):380–393.

 PubMed Web of Science ®Google Scholar

Benyoub K, Muller M, Bonnet A, et al. Amounts of bile acids and bilirubin removed during single-pass albumin dialysis in patients with liver failure. Ther Apher Dial Off Peer-Rev J Int Soc Apher Jpn Soc Apher Jpn Soc Dial Ther. 2011;15. 504–506.

 Google Scholar

Piechota M, Piechota A, Misztal M, et al., An evaluation of the usefulness of extracorporeal liver support techniques in patients with severe liver dysfunction. Arch Med Sci AMS. 15(1): 99–112. 2019.

 PubMed Web of Science ®Google Scholar

Karvellas CJ, Bagshaw SM, McDermid RC, et al. A Case-Control Study of single-pass albumin dialysis for acetaminophen-induced acute liver failure. Blood Purif. 2009;28(3):151–158.

 PubMed Web of Science ®Google Scholar

Qin G, Shao J-G, Wang B, et al. Artificial liver support system improves short- and long-term outcomes of patients with HBV-associated acute-on-chronic liver failure: a single-center experience. Medicine (Baltimore). 2014;93(28):e338.

 PubMed Web of Science ®Google Scholar

Nakae H, Igarashi T, Tajimi K, et al. A case report of hepatorenal syndrome treated with plasma diafiltration (selective plasma filtration with dialysis). Ther Apher Dial Off Peer-Rev J Int Soc Apher Jpn Soc Apher Jpn Soc Dial Ther. 2007;11. 391–395.

 Google Scholar

Li M, Li J, Shi Z, et al. Efficacy of various combined blood purification techniques for treating patients with non-viral acute liver failure. Cell Biochem Biophys. 2014;68(3):571–575.

 PubMed Web of Science ®Google Scholar

Fujiwara K, Abe R, Yasui S, et al. High recovery rate of consciousness by high-volume filtrate hemodiafiltration for f ulminant hepatitis. Hepatol Res. 2019;49(2):224–231.

 PubMed Web of Science ®Google Scholar

Kribben A, Gerken G, Haag S, et al. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology. 2012;142(4):782–789.e3.

 PubMed Web of Science ®Google Scholar

Grodzicki M, Kotulski M, Leonowicz D, et al. Results of treatment of acute liver failure patients with use of the prometheus FPSA system. Transplant Proc. 2009;41(8):3079–3081.

 PubMed Web of Science ®Google Scholar

Oppert M, Rademacher S, Petrasch K, et al. Extracorporeal liver support therapy with prometheus in patients with liver failure in the intensive care unit. Ther Apher Dial Off Peer-Rev J Int Soc Apher Jpn Soc Apher Jpn Soc Dial Ther. 2009;13. 426–430.

 Google Scholar

Santoro A, Faenza S, Mancini E, et al. Prometheus system: a technological support in liver failure. Transplant Proc. 2006;38(4):1078–1082.

 PubMed Web of Science ®Google Scholar