Acute on Chronic Liver Failure (ACLF)

Brief discussion on Acute on Chronic Liver Failure (ACLF)

1. Acute-on-chronic liver failure  (ACLF) Pratap Sagar Tiwari Total slides : 44 Pic src : EASL

2. Cirrhosis/ Fibrosis/ Chronic liver disease Cirrhosis is defined as the histological development of regenerative nodules surrounded by fibrous bands   in response to chronic liver injury , that leads to portal hypertension and its consequences and end stage liver disease. [1] Fibrosis describes replacement of injured tissue by a collagenous scar . Liver fibrosis results from the perpetuation of the normal wound healing response resulting in an abnormal continuation of fibrogenesis (connective tissue production and deposition). [1] Chronic liver disease refers to a condition of diffuse involvement of liver parenchyma that can be due to various etiologies like infections, metabolic, immunologic, toxic or genetic , lasting more than 6 months and has a propensity to inflammation followed by fibrosis and ultimately cirrhosis and its complications. Schuppan D and Afdhal NH. Liver Cirrhosis. Lancet. 2008 Mar 8; 371(9615): 838–851. 2

3. Schematic representation of the progression d'Amico , et al. Clinical states of cirrhosis and competing risks. Journal of hepatology 2018. Volume 68, Issue 3, Pages 563–576 3

4. The beginning.. In 2009, the APASL provided the first consensus on ACLF, defined as “ an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy ”.[1] The 2014 definition was further expanded to include ‘ high 28-day mortality ’.[2] Such initiative led the scientific community to identify new venues of research of a syndrome with extrahepatic OF a/with short-term mortality. Nevertheless, the key terms of the definition ‘ acute’, ‘chronic liver’ and ‘failure ’ have several variations. Three other major societies/ organisations have provided working definitions that, although not consistent, lay the groundwork for future research.[3-5] Sarin SK, Kumar A, Almeida JA, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2009;3:269–82. Sarin SK, Kedarisetty CK, Abbas Z, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014. Hepatol Int 2014;8:453–71. Bajaj JS, O’Leary JG, Reddy KR, et al. Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures. Hepatology 2014;60:250–6. Jalan R, Yurdaydin C, Bajaj JS, et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology 2014;147:4–10. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–37, 1437.e1–9.

5. Comparison of the existing ACLF definitions APASL EASL/CLIF NASCELD Definition Acute hepatic insult manifesting as jaundice (serum bilirubin ≥ 5 mg/dL and coagulopathy (INR ≥ 1.5 ) complicated within 4 weeks by clinical ascites and/or encephalopathy in a pt with previously DX or undiagnosed CLD/cirrhosis, and is a/with a high 28-day mortality. An acute deterioration of pre-existing CLD usually related to a precipitating event and a/with ↑ mortality at 3 months due to MOF A syndrome characterized
by acute deterioration in a pt of cirrhosis due to infection presenting with two or more extrahepatic OF. Study cohort First consensus was the expert opinion, subsequently prospectively evaluated in 1402 pt , subsequently in 3300 pts. Prospectively studied in 1343 pts Prospectively studied in 507 pts Inclusion Compensated Cirrhosis (DX or non-diagnosed) CLD but not cirrhosis Acute insult directed to liver Presentation with liver failure Cirrhosis only Compensated or decompensated Renal failure is mandatory (not liver failure for defining ACLF) Presentation not necessarily be liver failure Cirrhosis only Compensated or DLC Two extrahepatic OF Presentation not necessarily be liver failure

6. Comparison of the existing ACLF definitions APASL EASL/CLIF NASCELD Exclusion Criteria Prior decompensation HCC HCC Pts who had infections but did not require hospital admission. Cirrhosis without infection. Immune-compromised pts with HIV infection, prior organ transplant, and disseminated malignancies Homogeneity Yes. Index presentation, previously unknown or compensated, acute hepatic insult leading to liver failure as the driver No. Any presentation, with prior decompensation or recent worsening of ongoing decompensation, acute insult is not directed to liver, in particular (40% are of unknown acute insult), not liver but extrahepatic OF , i.e., renal failure is must, systemic inflammation but not the liver as driver. No. Any presentation, with prior decompensation or recent worsening of ongoing decompensation, acute insult is not directed to liver in particular Any extrahepatic OF Time frame 4 weeks 4–12 weeks (variable) Not defined 6

7. Comparison of the existing ACLF definitions APASL EASL/CLIF NASCELD Acute insult Hepatic Hepatic or Systemic (extrahepatic) Infection, i.e., systemic (extrahepatic) Sepsis Consequence/complication Cause/precipitant Cause/precipitant Organ failure Liver is primary to start with. Others subsequently Systemic inflammation leading to kidney failure as the primary with or without other OF Systemic inflammation leading to extrahepatic OF Disease severity score AARC Score-prospective as well as validated CLIF-C SOFA MELD CLIF-C SOFA 7

8. Comparison of the existing ACLF definitions APASL EASL/CLIF NASCELD Golden window Well defined for therapy, i.e., by 7 days SIRS or sepsis as well as for decision regarding LT No such No such Pediatric cohort Yes None None Therapy Regenerative and bridging therapy with good result No such No such Reversibility of ACLF syndrome Yes Not described Not described 8

9. Sequence of events in DX Criteria of ACLF: East vs. West The figure describes the sequence of OF and its mechanism. An acute hepatic insult leading to hepatic decompensation is the driver and subsequent extrahepatic OF is due to failure of recovery/regeneration and development of sepsis after a Golden Window. With consideration of sepsis as the intiating factor and development of extrahepatic organ involvement as a part of definition leads to late identification of the ACLF pts where the therapeutic windos is lost. ‘Golden window ’ is a short period of about 1 week before the onset of sepsis and development of extrahepatic OF in a pt with ACLF . Therapeutic interventions during this period are likely to prevent OF and provide a potential opportunity for ameliorating or reversing the hepatic injury and failure [1]. Katoonizadeh A, Laleman W, Verslype C, Wilmer A, Maleux G, Roskams T, Nevens F. Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study. Gut 2010;59(11):1561–1569

10. Reversibility of the ACLF syndrome This is a feature of the ACLF defined by the AARC criteria , as nearly all the pts included are after the index presentation. With mitigation of acute insult and over time, the hepatic reserve improves, fibrosis regresses and the PP decreases. Reversibility is defined as reversal of key components that were used for defining the syndrome of liver failure, i.e., decrease of bilirubin < 5 mg/dL and reversal of coagulopathy to INR < 1.5 and no HE with or without resolution of ascites. It was interesting to find in the large AARC database, of the 1844 pts, about 70% of the survivors beyond day 90, showed reversibility and they maintained this status for a period of at least 1 year. Further, unlike pts with DLC and similar to pts with ALF, the reversal of coagulopathy preceded the reversal of jaundice , i.e., median time to reversal of coagulopathy was 7 (4–30) days versus 19 (7–60) days for jaundice, respectively. The median time to reversal of syndrome, i.e., jaundice and coagulopathy, was 30 days.

11. Liver failure grading system The basic premise for defining a syndrome is to identify a group of patients, who have a distinct presentation, course and outcome . A prospective study using AARC database with 1402 pts from several centers across Asia included a large derivation cohort of 480 pts from which a dynamic prognostic model was derived, which was validated in subsequently enrolled 922 pts to predict outcomes including mortality [1]. A simple ‘ liver failure grading system ’ was developed based on variables, namely serum bilirubin, INR, grade of HE, serum lactate and serum creatinine [2-5]. Serum lactate levels are elevated in relation to degree of hepatocellular injury, inflammation and degree of tissue perfusion. Choudhury A, A Jindal SK, Sarin, for the APASL ACLF Working Party, et al. Liver failure determines the outcome in patients of Acute-on-Chronic Liver Failure (ACLF)-comparison of APASL-ACLF Research Consortium (AARC) and CLIF-SOFA model. Hepatol Int 2017;11(5):461–71 Shi Y, Yang Y, Hu Y, et al. Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults. Hepatology 2015;62:232–242 Jeppesen JB, Mortensen C, Bendtsen F, Møller S. Lactate metabolism in chronic liver disease. Scand J Clin Lab Invest 2013;73(4):293–299 Cardoso NM, Silva T, Basile-Filho A, Mente ED, Castro-e-Silva O. A new formula as a predictive score of post-liver transplan - tation outcome: postoperative MELD-lactate. Transpl Proc 2014;46(5):1407–1412 Cordoba J, Ventura-Cots M, Simón- Talero M, Amorós A, Pavesi M, Vilstrup H, Angeli P, Domenicali M, Ginés P, Bernardi M, Arroyo V, CANONIC Study Investigators of EASL-CLIF Consortium. Char- acteristics , risk factors, and mortality of cirrhotic patients hospital- ized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF). J Hepatol 2014;60(2):275–281

12. APASL ACLF research consortium (AARC)  Grade I, Grade II and Grade III had 28-day mortality of 12.7, 44.5 and 85.9%, respectively. The grades of liver failure showed a potentially recoverable group (Gr. I), a group that needs special monitoring (Gr. II) and a group that demands immediate interventions for improved outcome (Gr. III).

13. Liver failure grading system: The AARC model The AARC model was found to be better than existing models for ACLF with an excellent predictability, i.e., in AUROC of 0.80 . The AARC-ACLF score is dynamic in nature . It could predict day 7 (score of 9 or below) and day 28 survival at presentation (score of 9 or below). For a baseline score of ≥ 10, with each one unit ↑, the day 7 mortality ↑ sharply compared to the pts who presented with a score of < 10 (20% vs. 4%). Thus, the AARC score provides a window to decide early and explore definitive therapies including LT.

14. Inclusion of organ failure in definition ?? The Western definitions of ACLF have included OF in the definition. In the APASL consensus, It was reiterated that OF other than liver should not be part of the definition . Diagnosis of liver failure along with kidney, circulatory and respiratory failure is generally a late event and is often a result of the primary organ, i.e., liver failure (jaundice, deranged coagulation and/or HE). The experts felt that organ dysfunction rather than organ failure should be the time for raising suspicion and making DX of ALCF rather than when organ failure(s) has already developed. This approach would help in prioritizing organ-specific interventions.

15. Triggers of decompensation in ACLF The prevalence of potential triggers also varies by the area of the world. For example, in the CANONIC study, bacterial infections and alcoholism are the two major identifiable factors, compared with China, where relapse of hepatitis B was predominant followed by bacterial infections. [1,2] The type of injury also seems to influence ACLF outcomes as recently published by Shi et al.[2] 405 Chinese pts who met CANONIC criteria were divided in hepatic-ACLF trigger, that is, driven by primarily liver toxins (alcohol, hepatitis) vs extrahepatic-ACLF ( eg , infections). Both groups had high 28-day mortality (48.3% vs 50.7%), but this difference changed after 90 days (58.9% vs 68.3%) and 1-year mortality (63.9% vs 74.6%). Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–37, 1437.e1–9. Shi Y, Yang Y, Hu Y, et al. Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults. Hepatology 2015;62:232–42.

16. Changing trends for the etiology of acute insult and chronic injury HBV infection–reactivation of hepatitis B-induced ACLF as well as acute HAV/HEV-induced ACLF shows a ↓ trend over time in certain regions, whereas alcohol and herbs, drugs and supplements (HDS)-induced ACLF show an ↑trend. Alcohol is now the commonest etiology for acute hepatic insult as well as for the underlying CLD in the Asian continent. The unknown causes for acute insult and chronic injury constitute only 5–15% cases of ACLF in the East in contrast to the West , where these are seen in about 40% of ACLF pts . In the AARC database, 329 (10%) of the 3132 pts of ACLF had an inciting event due to drugs. 

17. Acute variceal bleeding ; is this acute insult ? VH has been included as one of the events to define acute decompensation in the natural history of cirrhosis. VH has also been taken as an acute insult for ACLF in some western trials of ACLF. A scenario may exist that a pt who has already fulfilled the criteria of ACLF and has been DX ACLF, develops a VH. In such a pt , variceal bleed would be considered as a complication in the natural history of ACLF . It was discussed that for a pt with PHTN and LC who present for the first time with VH without any previous or present signs or symptoms of CLD, it would not constitute an acute insult. This is especially relevant if such a pt does not develop any jaundice. It was unanimously agreed that AVH is not an acute hepatic insult unless in the pts where it produces jaundice and coagulopathy fulfilling the criteria of ACLF(<5 %).

18. Other acute insults Bacterial infections ( Non-hepatotropic infections) , if they primarily precipitate hepatic failure, and present as ACLF, may be considered as a precipitant of ACLF , but data at present are inadequate to demonstrate that infection  per se  could lead to jaundice and liver failure. In pts with cirrhosis or BCS , development of acute hepatic vein thrombosis or PVT may precipitate ACLF. Pts with BCS may infrequently present with or develop ACLF. There is no evidence currently to suggest that NCPF or EHPVO may present as ACLF. 18

19. The term ACLD was first used in 1995 as reported by Rajiv Jalan and much work has been done in this field in the past 5 years, but still the debate continues. The debate over several issues regarding ACLF clearly indicates that the exact mechanism how ACLF develops is not completely understood. Either sepsis is a cause or a sequalae of liver injury ,whether caused by hepatic insults or extra-hepatic insults ; the hallmark event that leads to organ failure which is directly related to outcome of patients with ACLF is intense systemic inflammation with cytokine burst. Systemic inflammation is a hallmark of ACLF; white cell count and plasma levels of CRP and pro-inflammatory molecules such as interleukin (IL)-6, IL-1β, IL-8 are higher in pts with ACLF than in those without. The inflammatory response develops as mediated by several inducers of inflammation. Inducers of inflammation are either exogenous or endogenous. Among exogenous inducers, only microbial inducers are important. PATHOGENESIS/PATHOPHYSIOLOGY IN ACLF

20. Endogenous inducers : Microbial: Bacterial inducers Virulence factor Structural feature recognition Functional feature recognition At the site of infection, the detection of the presence of the bacteria via the recognition of structural and functional bacterial features is thought to induce complementary responses aiming to eliminate the invading microbe. Text in the next slide

21. Text for the previous slide Bacteria trigger inflammation by using two distinct classes of molecules: pathogen-associated molecular patterns (PAMPs) and virulence factors. PAMPs are unique molecular signatures that are recognised via dedicated receptors called pattern-recognition receptors (PRRs), a process called structural feature recognition. PRRs are expressed in innate immune cells and epithelial cells. PRRs include toll-like receptors (TLRs), nucleotide-binding oligomerisation domain-like receptors (NLRs), retinoic acid-inducible gene (RIG)-I (a member of the RIG-I-like receptor (RLR) family), cytosolic DNA sensors, inflammatory caspase-4/5. PRR engagement by PAMPs stimulates intracellular signalling cascades that activate transcription factors, for example, nuclear factor-κB. PRR-activated transcription factors induce a broad variety of genes encoding molecules involved in inflammation such as cytokines, chemokines, among others. Virulence factors represent the second class of bacterial inducers of inflammation.These factors are generally not recognised by dedicated receptors but detected through the effects of their activity (a process called functional feature recognition ). At the site of infection, the detection of the presence of the bacteria via the recognition of structural and functional bacterial features is thought to induce complementary responses aiming to eliminate the invading microbe. Viruses or fungi are recognised by different PRRs. For example, viral nucleic acids can be recognised by endosomal TLRs, cytosolic receptors (RLRs or DNA sensors). Fungi express PAMPs that are detected by C-type lectin receptors . Like detection of bacterial PAMPs, that of viral or fungal PAMPs can trigger inflammation. 21

22. Endogenous inducers Endogenous inducers are released by necrotic cells or as a result of extracellular matrix breakdown.[1,2] These endogenous inducers are called danger-associated molecular patterns (DAMPs)[2] because they alert the host’s immune system about the presence of a serious tissue injury. DAMPs are recognised by receptors of the host and this recognition induces sterile inflammation. Medzhitov R. Origin and physiological roles of inflammation. Nature 2008;454:428–35. Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol 2008;8:279–89. 22

23. Severe alcoholic hepatitis However, systemic inflammation is also observed in pts with SAH without clinically detectable bacterial infection .[1,2] In this context, systemic inflammation may originate in the diseased livers from pts with SAH . Several pro-inflammatory molecules are overexpressed in livers with SAH relative to livers without SAH,[3] suggesting that these molecules may spill-over the liver and reach systemic circulation. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–37, 1437.e1–9. Michelena J, Altamirano J, Abraldes JG, et al. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology 2015;62:762–72. Dominguez M, Miquel R, Colmenero J, et al. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology 2009;136:1639–50.

24. Remaining questions: related to immune supression It has recently been shown that pts with ACLF had both marked systemic inflammation ( ie , ↑ plasma cytokines levels) and some features of immune suppression .[1] ACLF pts had ↑ frequency of circulating CD14-positive monocytes that overexpressed the protein MER and exhibited a decreased ex vivo response to LPS.[1] MER receptors are known to inhibit TLR4 signalling .[2] Another study, pts with ACLF had ↑ levels of prostaglandin E2 (PGE2), which may inhibit macrophage cytokine production in response to LPS . In addition, PGE2 was found to ↓ the macrophage ability to kill bacteria .[3] Bernsmeier C, Pop OT, Singanayagam A, et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology 2015;148: 603–615.e14. Zagórska A, Través PG, Lew ED, et al. Diversification of TAM receptor tyrosine kinase function. Nat Immunol 2014;15:920–8. O’Brien AJ, Fullerton JN, Massey KA, et al. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med 2014;20:518–23. Proto-oncogene tyrosine-protein kinase MER

25. Remaining questions: related to tolerance Although excessive systemic inflammation is believed to be the driver for the development of OFs , other mechanisms may also contribute to this development like failed disease tolerance ( ie , endurance). [1-3] There may be differences in disease tolerance among pts with ACLF. Thus, for any given level of systemic inflammation, pts who had prior episodes of decompensation of liver disease were less severe than those who did not have prior episodes of decompensation .[4] Pts with a prior history of liver decompensation may have acquired an increased tolerance capacity that protected them when exposed to new noxious stimuli. Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science 2012;335:936–41. Jamieson AM, Pasman L, Yu S, et al. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science 2013;340:1230–4. Figueiredo N, Chora A, Raquel H, et al. Anthracyclines induce DNA damage response-mediated protection against severe sepsis. Immunity 2013;39: 874–84. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–37, 1437.e1–9.

26. Other factors may have a role ? The severity of infection can also be related to pathogens (Gram-negative infections being more severe than Gram-positive Figure infections) or to the site of infection (intra-abdominal sites having the highest risk of death and urinary the lowest).[1] Host genetic factor : There are also studies showing that single nucleotide polymorphism (SNP) is some selected genes involved in the innate immune response were a/with ↑risk of infection and mortality . Cohen J, Vincent JL, Adhikari NK, et al. Sepsis: a roadmap for future research. Lancet Infect Dis 2015;15:581–614.

27. Summary Suppressed immunity Excessive systemic inflammation A B C Organ failure in ACLF

28. Algorithm for MX of pts with acute decompensation: Western method 3 month mortality <2 % 2 – 30 % 2 – 30 %

29. EASL-CLIF definition Basis of the definition Absence of ACLF because 28-day mortality is <5% in pts with: No organ failure Single organ failure in pts with a serum creatinine level of <1.5 mg/dL and no HE Cerebral failure in pts with a serum creatinine level of <1.5 mg/dL ACLF grade 1 because 28-day mortality is 22% in pts with: Single kidney failure Single liver, coagulation, circulatory or lung failure that is a/with a serum creatinine level of 1.5–1.9 mg/dL and/or HE grade 1 or grade 2 Single brain failure with a serum creatinine level of 1.5–1.9 mg/dL ACLF grade 2 because 28-day mortality is 32% in pts with: Two organs failures ACLF grade 3 because 28-day mortality is 77% in pts with: Three organ failures or more CANONIC study showed overall 28-day mortality of 33% of all cases of ACLF, and specific 28-day mortality rates in pts with ACLF-1, 2 and 3 was 22%, 32% and 73%, respectively.[1] Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–37, 1437.e1–9.

30. CLIF-OF score: simplified version of CLIF-SOFA score

31. Algorithm for MX of pts with acute decompensation: Western method 3 month mortality <2 % 2 – 30 % 2 – 30 % 31

32. 32

33. Algorithm for MX of pts with acute decompensation: Western method 3 month mortality <2 % 2 – 30 % 2 – 30 % 33

34. Patients with ACLF and high CLIF-C ACLF score (≥ 70) after 48 hours of intensive care may reach a threshold of futility for further ongoing intensive support.

35. Algorithm for MX of ACLF The specific treatment initiated, but if the disease severity is more, i.e., AARC Score ≥ 11 the response is poor with SMT; hence, early consideration for LT should be done , whereas other group needs to be seen for 4–7 days with specific therapy and SMT. The presence of extrahepatic OF needs to be MX, and optimization and improvement need to be correlated with over all recovery, else poor prognoses to be considered.

36. APASL ACLF research consortium (AARC)  Grade I, Grade II and Grade III had 28-day mortality of 12.7, 44.5 and 85.9%, respectively. The grades of liver failure showed a potentially recoverable group (Gr. I), a group that needs special monitoring (Gr. II) and a group that demands immediate interventions for improved outcome (Gr. III).

37. MANAGEMENT OF ACLF General management Currently, there is no specific effective RX available , and therefore RX is based on organ support and RX of associated complications. Overall, pts should be admitted to the ICU and should be preferably managed in a transplant centre. Organ function should be monitored frequently and early RX provided according to each specific organ in order to avoid a stage of multiple OF. When ACLF is a/with a precipitating factor ( ie , BIs, GI bleeding, alcoholism, drug toxicity), early identification and RX of the precipitating factor are essential. However, this may not prevent the development or worsening of the syndrome. In addition, in up to 40% of pts a PF may not be identified .

38. Sepsis in ACLF: recommendations Bacterial infection is present in about 1/3rd of ALCF pts at presentation to a referral hospital. BI is an important factor to predict development of OF in ACLF. The most frequent infections are SBP, pneumonia, UTI, and Bacteremia. The APR, such as C- rP and procalcitonin , have been proven to be reliable biomarkers a/with infection and are recommended for screening for the presence of BIs. As soon as BI is suspected or DX, broad spectrum antimicrobial agents alone or in combination should be started and thereafter, the therapy should be adjusted according to the results of the antibiotic sensitivity test results. Empirical antibiotic therapy should be based on environment, local bacterial resistance profiles, severity and type of infection.

39. Sepsis in ACLF: recommendations Invasive fungal infection is not uncommon in ACLF pts. Biomarkers such as galactomanan or B-D glucan can be used for supporting the DX. Predictors of poor progression (risk factors) of fungal infections in ACLF are the presence of diabetes, AKI, ICU admission, and admission with bacterial infection, prolonged antibiotic (> 5 days pre-admission) and prior hospitalization. Biomarkers such as galactomanan or B–D Glucan can be used for supporting DX if there is invasive fungal infection in ACLF. Administration of albumin is recommended in pts with SBP for preventing from type-1 HRS and reducing mortality. Prophylaxis with fluconazole followed by echinocandins needs to be evaluated in ACLF pts.

40. AKI in ACLF AKIN criteria should be used for the DX and prognostication of AKI in ACLF pts. In the absence of baseline serum creatinine, AKI should be dx based on the cutoff value of serum creatinine. A cutoff value of 1.1 mg/dl is a reliable marker of significant renal dysfunction and 1.5 mg/dl of kidney failure in pts with ACLF. Combating systemic inflammation with anti-inflammatory strategies (for eg IV albumin,  N -Acetylcysteine ), bilirubin reduction, avoidance of nephrotoxic drugs, aggressive management of circulatory failure and maintaining a high MAP may prevent AKI development and progression in pts with ACLF. Terlipressin given as an infusion is superior to noradrenaline in the MX of HRS-AKI in pts with ACLF, but needs extra precaution and close monitoring for terlipressin -related AE[1]. Response to vasoconstrictors in AKI in ACLF pts is partial and seen in only in about a third of pts . There is, therefore, quite often a need for RRT. Development of new AKI as well as non-resolution or persistence of AKI was a/with almost 50% mortality at 1 month in pts with ACLF [2]. Wan ZH, Wang JJ, You SL, Liu HL, Zhu B, Zang H, et al. Cystatin C is a biomarker for predicting acute kidney injury in patients with acute-on-chronic liver failure. World J Gastroenterol 2013;19(48):9432–9438 Maiwall R, Sarin SK, Kumar S, for APASL ACLF Research Consortium (AARC) working party, et al. Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure. Liver Int 2017.

41. Managing organ dysfunction/failure & others 41 /56 LOREM IPSUM Empirical Antibiotics Albumin in SBP Fluconazole in high risk/suspected fungal infn Infections (33 %) Ascites (91 %) Avoid PICD with Albumin/ Terlipressin @LVP Terlipressin , Albumin, RRT AKI EVL and NSBB as standard protocol in LC Varices in ACLF Well correlation with Ammonia Lactulose, rifaximin, LOLA HE (40 %) ACLF: Hypocoagulation state Global viscoelastic tests (TEG/ Sonoclot /ROTEM) Coagulation profile

42. Liver transplantation A characteristic feature of ACLF is its rapid progression, the requirement for multiple organ support and a high incidence of short- and medium-term mortality of 50–90%. The 28-day mortality rate was 15X higher in pts with ACLF compared to other CLD [1-12]. The baseline MELD > 28, AARC Score > 10, advanced HE in the absence of overt sepsis or MOF can be considered for early LT [3]. In the absence of LT option, these pts can be offered early bridge therapies in the form of therapeutic plasma exchange and liver dialysis and the response could be evaluated by end of first week [3, 13]. Pts with HBV reactivation should be assessed for early transplant if cirrhosis, bilirubin > 10 mg/dL, PT < 40% and platelet < 100 × 10 9 /L. Steroid ineligible pts with SAH should be listed on priority for LT. Selective use of LT can be lifesaving for medically refractory AH. References are at the end of the slides 42

43. ACLF Pt characteristics that were reported to be considered unfit for LT: (1) Sepsis with ≥2 OF or uncontrolled sepsis. [1] (2) Advanced azotemia, i.e., s creat  > 4 mg/dl or ↑ in creatinine by 300% from baseline or the need of RRT. [2] (3) Respiratory failure [severe ARDS defined by a  P /F ratio < 150] or HE requiring ventilator support > 72 h. [3] (4) 4 or more OF anytime. (5) Active GIB. (6) Hemodynamic instability requiring > 3 mg/h noradrenaline [4]. Chan AC, Fan ST, Lo CM, Liu CL, Chan SC, Ng KK, et al. Liver transplantation for acute-on-chronic liver failure. Hepatol Int 2009;3(4):571–581 Chok KSh , Chan SC, Fung JY, Cheung TT, Chan AC, Fan ST, Lo CM. Survival outcomes of right-lobe living donor transplantation for patients with high model for end stage Liver Disease scores. Hepatobiliary Pancreat Dis Int 2013;12(3):256–262 Choudhury AK, Sharma M, Mehtab M, Sarin SK, for APASL ACLF Working party, et al. The decision for liver transplant in acute-on-chronic liver failure (ACLF)—first week is the crucial period-analysis of the APASL ACLF Research Consortium (AARC) prospective data of 1021 patients. J Hepatol 2016;64:S1–S51 Gustot T, Fernandez J, Garcia E, for CANONIC Study Investigators of the EASL-CLIF Consortium, et al. Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 2015;62(1):243–252

44. Artificial liver support in ACLF Kjaergard LL, Liu J, Als -Nielsen B, Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review. JAMA 2003;289(2):217–222 Extracorporeal liver support therapies are used to bridge the liver until recovery or LT in pts with ALF and ACLF. Various RCTs in pts with ACLF have shown improvement in HE, HRS, circulatory dysfunction and immune dysfunction without improvement in TFS. However, contrary results were shown by systematic review by Kjaergard et al. where it was seen that ALS reduced mortality by 33% in pts with ACLF as compared to SMT [1].  44

45. Artificial liver support in ACLF Recently published two large European randomized multicentric controlled trials, i.e., HELIOS (for Prometheus) [2] and RELIEF trial (for MARS) [1] which failed to show any benefit with these modalities on short-term transplant-free survival which was the primary end point of these studies. 45 References are at the end of the slides

46. Regeneration therapy in ACLF Garg V, Garg H, Khan A, Trehanpati N, Kumar A, Sharma BC, et al. Granulocyte colony stimulating factor mobilizes CD 34 + cells and improves survival of patients with acute-on-chronic liver failure. Gastroenterology 2012;142(3):505–512 The foremost reason for no demonstrable survival benefit with the currently available ALS systems is the functional incompetence as most of these provide only the detoxification function of the entire armamentarium of liver functions and thus incorporation of synthetic function by living hepatocytes, i.e., the “ bioartificial liver ” or therapies to potentiate hepatic regeneration look more realistic. Garg et al. [1] have shown that GCSF can help in hepatic regeneration by mobilizing bone marrow-derived CD34 + cells. In addition, it significantly ↓ the development of sepsis and subsequent MOF. 46

47. Stem cells therapy in ACLF Shi et al. 2012 [1] 24 Vs 19 After 90 days, 79.2% on the UC-MSC survived vs 52.5% in the control group. MELD scores also decreased over time (in both groups) but more in the UC-MSC (10 vs 15, p=0.04). UC-MSC transfusions may serve as a novel therapeutic approach for HBV-associated ACLF pts. Singlecenter , open label, prospective , PI/II UC-MSCs Vs Placebo 47 Shi M, Zhang Z, Xu R, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med 2012;1:725–31. There is only one stem cells trial in humans. Shi et al [1] using an open-label controlled trial in HBV-ACLF to receive umbilical cord-derived mesenchymal stem cells (UC-MSC) . Overall, both therapies (G-CSF and stem cells) showed encouraging results , but the optimism is limited by the small number of participants. MSCs are multipotent cells that have self-renewing abilities and the potential to differentiate into various types of cells, including hepatocytes. More importantly, these cells can interact with immune cells, leading to immunomodulation & appear to be effective in regulating the immune response in settings such as tissue injury.

48. Future perspectives: pathophysiologial -based treatments Considering that currently there is no specific RX for the MX of ACLF, research should be based on potential new RXs addressed to pathophysiological mechanisms leading to the development of the syndrome. Large body of evidence from the last decades suggests that bacterial translocation (BT) and an excessive systemic inflammation are the key mechanisms leading to the progression of cirrhosis and the development of ACLF. Therapeutic interventions acting on BT ( ie , probiotics, norfloxacin, rifaximin ) would probably act in the prevention of the development of ACLF rather than in the MX of the syndrome itself once it has developed. In contrast, therapeutic interventions addressed to mitigate the excessive systemic inflammation and to restore the immunological response should be investigated as potential RX options.

49. Conclusions In summary, the field of ACLF has moved very rapidly in the past 5 years. The need for having a well-defined homogenous population of pts , with well characterized acute and chronic insult and which would reflect the term acute-on-chronic liver failure, is at the core. Attempts to ameliorate or reverse the ongoing injury would allow return of hepatic synthetic functions and reversal of the liver damage. Early predictors of mortality and non-reversibility of the condition would pave way to offer priority LT to such pts. An attempt to converge the thoughts from the East and West is possibly the only way forward to achieve more scientific and timely interventions for such patients.

50. Differentiating ACLF from acute decompensation Parameter(s) Acute-on-chronic liver failure (ACLF) Acute decompensation (AD) Presentation Hepatic insult Index Hepatic or non-hepatic Can be index or subsequent Identifiable precipitant In up-to 95% cases In up to 70% cases Time from insult to presentation Within 4 weeks Up to 12 weeks Underlying cirrhosis May or may not be present Always present Prior decompensation No With or without Prior Decompensation Mortality at 1 and 3 months 33–51% 23–29% Reversal or recovery In half of cases Uncommon

51. ACLF Vs DLC: diagrammatic representation of the clinical concept The red line describes the course of a pt with chronic decompensation of cirrhosis that during evolution of their liver disease will at some point develop OF. This is usually in a/with advanced liver disease where the only option for RX is LT and the chances of reversibility are very limited. Figure describes the clinical concept of ACLF to distinguish it from chronic decompensated cirrhosis. In pt with ACLF (blue line) who may often have a good liver reserve and can deteriorate acutely over a short period, usually in a/ with a precipitating illness that results in OF and high risk of death. By contrast, this pt has a potential for reversibility and recovery to the state the pt was in, prior to the acute event. Kamath PS, et al. Acute-on chronic liver failure. Journal of Hepatology 2012 vol. 57 j 1336–1348

52. Artificial liver support in ACLF Bañares , R., Nevens , F., Larsen, F. S., Jalan, R., Albillos , A., … Dollinger, M. (2013). Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: The RELIEF trial. Hepatology, 57(3), 1153–1162. Kribben , A., Gerken , G., Haag, S., Herget –Rosenthal, S., Treichel , U., Betz, C., … Rifai, K. (2012). Effects of Fractionated Plasma Separation and Adsorption on Survival in Patients With Acute-on-Chronic Liver Failure. Gastroenterology, 142(4), 782–789.e3.

53. Liver transplantation Sarin SK, Chandan K, Zaigham A, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2014;8:453–471 Sarin SK, Kumar A, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2009;3(269):282 Choudhury A, A Jindal SK, Sarin, for the APASL ACLF Working Party, et al. Liver failure determines the outcome in patients of Acute-on-Chronic Liver Failure (ACLF)-comparison of APASL-ACLF Research Consortium (AARC) and CLIF-SOFA model. Hepatol Int 2017;11(5):461–71 Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490 O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273–275 Jalan R, Pavesi M, Wendon J, CANONIC Study Investigators; EASLCLIF Consortium, et al. The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure. J Hepatol 2015;62(4):831–840 Sen S, William R, Jalan R. The pathophysiological basis of acute-on- chronic liver failure. Liver 2002;22(Suppl 2):5–13 Wlodzimirow KA, Eslami S, Abu-Hanna A, et al. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. Liver Int 2013;33(1):40–52 Bajaj JS, Moreau R, Kamath PS, Vargas HE, Arroyo V, Reddy KR, Szabo G, Tandon P, Olson J, Karvellas C, Gustot T, Lai JC, Wong F. Acute-on-chronic liver failure: getting ready for prime time? Hepatology 2018;68(4):1621–1632 PMID:29689120 Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy- definition, nomenclature, diagnosis and quantification: final report of the working party at the 11th World Congress of Gastroenterology, Vienna 1998. Hepatology 2002;25(3):716–721 Moreau R, Jalan R, Gines P, 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 Jindal A, Kumar M, Sarin SK. Management of acute hepatitis B and reactivation of hepatitis B. Liver Int 2013;33(Suppl 1):164–175 Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, Garcia-Tsao G, et al. Acute-on chronic liver failure. J Hepatol 2012;57(6):1336–1348