Acute on chronic liver failure guidlines.pptx

acute on chronic liver failure, ACLF, DEFINATION as per different group , difference between various defination, pathophysiology , diagnosis, severity, management , novel thrapeutics on trials

1. ACUTE ON CHRONIC LIVER FAILURE(ACLF) Presented by : Dr. Sambit kumar patel

2. What is ACLF? Acute on chronic liver failure is is an acute deterioration in the function of liver ,with significant systemic inflammation and high short term mortality . Sarin S.K. et al hepatology int 2019;13:353-90

3. Distinct Features of ACLF Usually associated with a precipitating factor Occurs on an underlying chronic hepatitis or cirrhosis patient Acute failure has a reversible component Significant higher short term mortality rate Mortality depends not on the underlying liver disease but on the end organ failure Tae Yeob Kim et al. Acute on chronic liver failure. Clinical and molecular hepatology 2013:19:349-359

4. DEFINITIONS Though well recognised , poorly defined Defined as 2 insults operating simultaneously ; one is on-going chronic and other being acute Ohnishi et al .Acute on chronic liver failure. Ryoikibetsa Shokogun Shirizu 1995:217-219

5. APASL Vs EASL-CLIF Proposed by Definition Asia -Pacific Association for the Study of Liver Disease(APASL) 2014 Acute hepatic insult manifesting as jaundice and coagulopathy complicated within 4 weeks by ascites and/or encephalopathy in a patient with previous diagnosed or undiagnosed chronic liver disease a/w high 28 day mortality American Association for the Study of Liver Disease-European Association for the Study of Liver(EASL-CLIF) 2011 Acute deterioration of a pre-existing chronic liver disease, usually related to a precipitating event and associated with an increased mortality at 3 months due to multisystem organ failure

6. DIFFERNCES BETWEEN THE DEFINITIONS APASL EASL-CLIF Qualification of the p recipitating event Hepatic insults only (Sepsis/ variceal not included) Sepsis and variceal bleed also included along with hepatic insults Qualification of the underlying chronic liver disease Compensated cirrhosis +chronic liver diseases Only cirrhosis, both compensated and decompensated Duration between insult and ACLF 4 weeks Not defined Duration of high mortality 28 days 3 months Organ Failure Not Defined Defined Diagnosis Early, reversibility possible Too late ,reversibility unlikely

7. DIFFERNCES BETWEEN THE DEFINITIONS APASL EASL-CLIF Exclusion criteria Prior decompensation , HCC HCC Acute insult Hepatic Hepatic and extra hepatic Sepsis Consequence /cx Cause/precipitant Disease severity score AARC score CLIF C ACLF Golden window Well defined Not defined Therapy Regenerative and bridging therapy :good result Poor result

8. NACSELD –ACLF A cute deterioration of cirrhosis with failure in two or more extrahepatic organs . NACSELD Definition of extrahepatic organ failure Circulatory-=shock Brain=grade 3,4 HE Renal=dialysis Respiratory=mechanical ventilation

9. Definition of organ failure ( CLIF-SOFA) and GRADES OF ACLF in EASL-CLIF study

10. PATHOPHYSIOLOGY OF ACLF

11. PATHOPHYSIOLOGY OF ACLF Exact mechanism of development of ACLF still unknown Pathognomonic feature is the altered host response to injury and unregulated inflammation. The PIRO concept( P redisposition  I njury  R esponse  O rgan failure) CMH-Volume 19 Number 4 December 2013

12. UNDELYING LIVER DISEASE AND PRECIPITATING EVENT ALCOHOL has now emerged as the most common etiology for acute insult (49 %) as well as for underlying chronic liver disease both in WEST &EAST ( previuos data of HBV predominance in asian continent) DILI and autoimmune etiologies have shown increasing trend. HBV infectioninduced ACLF as well as HAV/HEV-induced ACLF is now showing a decreasing trend over time. The unknown causes for acute insult and chronic injury constitute only 5–15% in the East and 40 % in the West, Sarin SK et al (APASL): an update. Hepatol Int. 2019 Jul;13(4):353-390. Hepatol Int. 2019 Nov;13(6):826-828.

13. Precipitent of ACLF Infectious aetiology Hepatotropic - Reactivation of hepatitis B/C, superimposed viral hepatitis like hepatitis A/E Non hepatotropic - viruses like CMV, HSV Sepsis due to SBP, spontaneous bacterial empyema , UTI, cellulitis Non-infectious aetiology Alcohol intake within 4weeks Hepatotoxic drugs and toxins Autoimmune hepatitis flare Wilson disease Surgery Variceal bleed Ischemia Portal vein thrombosis

14. Outcomes of systemic inflammation Tissue hypoperfusion - PAMPs  inflammatory mediators  induce inducible nitric oxide (NO) synthase in splanchnic arteriolar walls  splanchnic vasodilation  effective arterial blood volume  triggering endogenous neurohumoral vasoconstrictor system  kidney hypoperfusion  AKI

15. 2. Immune mediated tissue damage PAMPS & DAMPS Inflamatory cytokines  activated immune cells that may migrate into tissues and cause immunopathology TNF -a and NF- k B -dependent signalling pathways  impaired left ventricular contractility NO-mediated pulmonary dysfunction and macrophage accumulation in lung microvasculature hepatocyte apoptosis . ACLF-associated AKI involve not only tissue hypoperfusion (see above) but also capillary leukocyte infiltration, vascular microthrombosis , and cell apoptosis  release of DAMPs further inflamation . Therefore , a vicious cycle of inflammatory responses organ failure

16. 3. Mitochondrial dysfunction in ACLF  marked decrease in mitochondrial fatty acid b-oxidation in peripheral organs  resulting in decreased oxidative phosphorylation and ATP production.  may lead to Ofs . Moreau R, Clària J, Aguilar F, Fenaille F, Lozano JJ, Junot C, et al. Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanismunderlying ACLF. J Hepatol 2020;72:688–701

17. ACLF is the state of acute inflammatory response with cytokine burst. It has 2 outcomes 1. resolution of inflammation and recovery 2. persistence of inflammation (leading to Compensatory Antiinflammatory Inflammatory Response Syndrome-CARS ) and sepsis Golden window’ is a short period of about 1 week before the onset of sepsis and development of organ failures in a patient with ACLF. SIRS needs consideration for organ support, antibiotics for occult sepsis and prioritization for definitive therapy, i.e., liver transplant

18. Organ Dysfunction in ACLF

19. Organ Dysfunction in ACLF Organ failure plays central role in the clinical course of ACLF Following the development of organ failure - ICU Mortality- 55% - Hospital mortality- 65 % Jalan et al.Acute on chronic liver failure.J Hepatology 2012;57:1336-1348

20. Changes In Liver in ACLF Hallmark is coagulopathy and hyperbilirubinemia Hyperbilirubinemia -failure detoxifying function Coagulopathy-failure of the synthetic function Both are independent predictors of mortality in ACLF Liver failure carries a lower risk of mortality if no other organ involved Jalan et al.Acute on chronic liver failure.J Hepatology 2012;57:1336-1348

21. Changes in Kidney in ACLF Kidney is almost universally affected in ACLF In the EASL-CLIF study ,kidney failure is associated with highest mortality rate Most common causes of renal involvement are prerenal azotemia, hepatorenal syndrome and acute tubular necrosis Prerenal and intrinsic renal failure in ACLF occurs as a consequence of the severe SIRS EASL-CLIF –European Association for the Study of Liver-Chronic Liver Failure

22. Hepatorenal Syndrome Development of functional renal failure in advanced liver disease Associated with a mortality rate of 80 % at 2 weeks Basic cause-portal hypertension Splanchnic vasodilatation Decreased effective vascular volume Activation of RAAS and SNS Intense renal vasoconstriction HRS RAAS-Renin Angiotensin Aldosterone System SNS-Sympathetic Nervous System HRS- Hepatorenal Syndrome

23. Cardiovascular Changes in ACLF ACLF patients-Peripheral Vasodilatation - Hyperdynamic circulation -High cardiac output -Low Mean Arterial Pressure These changes result in end organ hypoperfusion

24. Hepatic Encephalopathy in ACLF HE in 75% of patients with ACLF Cause of HE-Brain edema Synergy between hyperammonemia and inflammation Ammonia will prime the microglial cells in brain to the deleterious effect of inflammation

25. Hepatic Encephalopathy Hyperammonemia in ACLF Combines with glutamate in brain to form glutamine Increased glutamine level result in astrocyte swelling HE SIRS Hyponatremia

26. Other effects of ACLF Adrenal insufficiency occurs in 2/3 rd of patients with ACLF Possible causes are - decreased adrenal blood flow - inhibition of secretion of cortisol Jalan R et al.Acute on chronic liver failure.J Hepatology 2012;57:1336-1348

27. NATURAL HISTORY AND PROGNOSIS ACLF is a dynamic syndrome that may improve or worsen during hospitalisation . Overall, ACLF resolved or improved in 49% of patients, had a steady or fluctuating course in 30% and worsened in the remaining 20%. While ACLF resolved in 55% of patients with ACLF grade 1, it only resolved in 15% of patients with ACLF grade 3.

28. The clinical course during hospitalisation is the most important determinant of short-term mortality rather than severity of presentation So, the assessment of ACLF grade at days 3–7 after diagnosis predicted prognosis more accurately than ACLF grade at diagnosis.

29. Mortality in ACLF

30. Number of organ failure and mortality in patients with ACLF (n=213) Number of Organ failure N (%), total n =213 Mortality n (%) 29 (13.6%) 3/29 (10.3%) 1 82 (38.5%) 18/82 (22%) 2 48 (22.5%) 24/48 (50%) 3 29 (13.6%) 24/29 (82.8%) 4 14 (6.6%) 12/14 (85.7%) 5 9 (4.2%) 9/9 (100%) 6 2 (1.0%) 2/2 (100%) Slide courtesy -Dr. Shalimar. Department of Gastroenterology ,AIIMS

31. Mortality(%) 22% 32% 77%

32. MANAGEMENT Currently, there is no specific effective treatment available for patients with ACLF, and treatment is based on organ support and treatment of complications . Early identification and treatment of the precipitating factor are essential. ( ie , bacterial infections, GI bleeding, alcoholism, drug toxicity ) In up to 40% of patients a precipitating factor may not be identified . Patients with ACLF should be considered to be admitted to the ICU and should be preferably managed in a transplant centre.

33. Management of ACLF Control of precipitating factor Prevention of further liver injury End organ support for HE and HRS Extracorporeal liver support Liver transplant

34. Management of Precipitating Factors Bacterial infection like SBP, UTI and pneumonia should be adequately treated Accurate distinction of alcoholic hepatitis; -treatment with steroids or anti TNF alpha therapies Diagnosis and treatment in ACLF due to Hepatitis B

35. SUPPORT OF END ORGAN FAILURE

36. Circulatory Support Correction of under filling by plasma volume expansion Treatment goals are similar to severe sepsis CVP of >8-12 cms water MAP of 65-90 mmHg Hematocrit of >30 % Oxygen saturation of >93% Central venous oxygen saturation of >70% Rivers et al. Early goal directed therapy in the treatment of severe sepsis and septic shock NEJM 2001:345;1368-1377

37. Management of Hepatorenal Syndrome

38. Hepatorenal Syndrome Hepatorenal syndrome is one of the most common presentation in ACLF Liver transplantation is the definitive treatment Medical management-Vasoconstrictors + and albumin -Effective in 40-70% of patients with HRS Narahara Y et al. The efficacy and safety of terlipressin and albumin in patients with type 1 hepatorenal syndrome: a multicenter , open-label, explorative study.  J Gastroenterol . Oct 25 2011:37;313-320

39. Treatment of HRS Narahara Y et al. The efficacy and safety of terlipressin and albumin in patients with type 1 hepatorenal syndrome: a multicenter , open-label, explorative study.  J Gastroenterol . Oct 25 2011:37;313-320 Initiate with low dose terlipressin (0.5-1mg /4hr ) with i.v albumin (1 gm/kg slowly i.v over 24 hour) If no positive response is seen after 48 hrs dose of terlipressin is increased to 2mg every 4 hour If there is adequate response ,treatment is continued until creatinine is <1.5mg/dl or till 14 days -Positive response indicated by decrease in level of creatinine of greater than or equal to 25% from baseline

40. Treatment of HRS Terlipressin -vasoconstriction -Contraindicated in patients with CAD - Look for peripheral ischemia Noradrenaline(dose of 0.5-3 mg /hour)* -As effective and safe as Terlipressin -Low cost and easily available RRT may be needed depending on electrolyte and fluid status and acid base disorder in prerenal azotemia & ATN * Noradrenalin vs terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded , pilot study.J Hepatol.2007;47:499-505

41. Hepatic Encephalopathy 4 Pronged approach Care for patients with altered consciousness Alternative causes of altered mental status Precipitating factors and their correction Empirical Hepatic Encephalopathy treatment Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol (2014)

42. Hepatic Encephalopathy For acute encephalopathy, lactulose (ingested or via nasogastric tube), 25-30 ml Is followed by dosing every 12 th hourly until evacuation occurs. Target -2-3 soft bowel movements/ day Rifaximin can be used as a add on therapy Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol (2014)

43. Coagulopathy In ACLF Failure to produce clotting factors Hypersplenism + thrombocytopenia and DIC Reduction of both pro and anticoagulants Prophylactic correction of PT with FFP not indicated unless active bleeding 10 mg Vitamin K i.v per day for 3 days recommended Stravitz RT et al. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography . J Hepatol 2011;56: 129-136.

44. Liver Transplantation Only definitive treatment Scarcity of studies in ACLF-not systematically analysed Retrospective study in 332 patients* 157 with ACLF 175 with no ACLF 26% mortality 17%mortality Bahirwani et al; ACLF before liver transplantation :impact on post transplant outcome. Transplantation 2011 ;92:952-957

45. Liver Transplantation An Asian study* evaluating transplantation in ACLF due to Hep B reactivation reported survival rate of 80% at 5 years. Issues of transplantation in ACLF patients -Transplantation before MODS -No priority for ACLF patients -Better definitions and prognostic criteria required for prioritisation *Chen Z et al; A single institution experience of transplantation for acute on chronic Hepatits B liver failure; Hepatogastroenterology 2011

46. Novel therapy

47. Thank you

48. Therapeutic approaches include targeting gut bacterial translocation and the microbiome , liver inflammation, cell death and regeneration, circulating immune cells and extracorporeal liver support

49. Dysbiosis in ACLF results in increased translocation of bacterial components ( PAMPs ) Antibiotics , NSBBs, engineered bacteria, FMT and phage therapy aim to improve dysbiosis and reduce bacterial translocation

50. Hepatocytes are injured by PAMPs and DAMPs and the resulting local inflammatory response . IL-1 inhibitors and TLR4 inhibitors decrease this inflammation. RIPK1 inhibitors inhibit cell death and NKG2D, TRAIL, KCTD9 and CXCR2 inhibitors aim to reduce innate immune cell-mediated hepatocyte death IL-22 and G-CSF promote hepatic regeneration

51. G CSF IN ACLF Asian randomised trial with G-CSF, found that the probability of survival at day 60 was 66% when compared to SMT.(26 %) CTPS and SOFA scores also improved in patients with G-CSF administration One more randomised trial showed probability of survival at 90 days was 48% in the G-CSF group compared with 21.4% in the placebo group . Overall, the use of G-CSF in ACLF is still experimental as it has been used in small no.of patients but the results are encouraging .

52. STEM CELL TRIALS There is very few stem cells related trial in humans in ACLF in one studyEnrolled 43 hepatitis B patients with ACLF to receive umbilical cord-derived mesenchymal stem cells After 90 days, 79.2% on the UC-MSC survived vs 52.5% in the control group. But,further studies needed.

53. Emerging therapies Inhibition of toll like receptor 4 : uncontrolled TLR activation of innate immune system propagates inflammation . TAK-242- inhibits TLr4 activation and blocks LPS and DAMP triggered proinflammatory cytokine production. Recombinant ALP (Rec-ALP)- neutralizes key PAMP ,LPS in ACLF Emricasan – Caspase inhibitor, blocks apoptotic pathway and acts as hepatoprotective.Frenette et al . Mitofusin 2- mi tochondrial fusion protein 2 ,has antoapoptotic effect. Statins – Antioxidative,anti -inflammatory, anti proliferative .initial setback LIVER HOPE & SAFETY trials.

54. NAC - glutathione precursor,antioxidant scavenges free radical.Has been found useful in HBV associated ACLF FMT - Alleviates gut dysbiosis and immune dysfunction. Has been tried in severe AH, psc , NAFLD,HBV infection. ALBUMIN -Homeostatic effects,antioxidant ,immunomodulation, endothelial stabilisation,binding toxic metabolites including bile acids. LIVER TRANPLANTATION- controversial, superselective patients ARTIFICIAL LIVER DEVICES

55. POINTS TO REMEMBER ACLF is a sudden hepatic decompensation due to a known or unknown precipitating factor in a patient with chronic liver disease Altered host response to injury- SIRS plays an important role Bacterial infection on the background of varying degrees of immune paralysis Underlying liver disease and the precipitating factors are different in East and West

56. POINTS TO REMEMBER Systemic, cardiac and hepatic hemodynamics are important determinants of outcome Survival of patients is dependent upon the severity of organ failure rather than the underlying liver disease Treatment strategies are limited Early Liver transplantation needed

57. THANK YOU

58. algorithm for the management of patients with acute-on-chronic liver failure (ACLF) or decompensated cirrhosis. A proposed management strategy for patients with ACLF based on mortality rate data from the CANONIC study

59. molecular adsorbent recirculating system (MARS) is a modified dialysis method using an albumin-containing dialysate that is recirculated and perfused online through charcoal and anion-exchanger columns. MARS enables the selective removal of albumin-bound substances.

60. Systemic inflammation can be induced by PAMPs and DAMPs recognised by dedicated receptors called pattern-recognition receptors (PRRs ), drives intracellular signalling cascades, ultimately leading to the transcription and synthesis of inflammatory mediators High levels of circulating PAMPs, mostly related to translocation of bacterial products from the intestinal lumen, rather than ongoing bacterial infections Systemic inflammation can also occur in the absence of infection and is due to the release of DAMPs by dying or damaged host cells Several forms of liver injury are well-known causes of DAMP release . In alcoholic hepatitis, alcohol-induced hepatocyte apoptosis has been shown to be triggered by endoplasmic reticulum (ER) stress involving the ER-resident adaptor STING, a cytosolic PRR for cytosolic DNA. Ischemia-reperfusion liver injury is characterised by the release of high mobility group box 1 ( HMGB1) from hepatocytes exposed to hypoxia and oxidative stress. HMGB1 can induce cytokine production and promote chemotaxis by binding to several receptors .

61. ORGAN INVOLVED CRITERIA FOR FAILURE Liver failure serum bilirubin level of ≥12.0 mg/dL Kidney failure serum creatinine level of ≥2.0 mg/dL or the use of renal replacement therapy Cerebral failure grade III or IV hepatic encephalopathy Coagulation failure international normalized ratio >2.5 and/or a platelet count of 20x10 9 /L Circulatory failure use of dopamine, dobutamine, or terlipressin Respiratory failure PaO2/FiO2 ≤200 or an SpO2/FiO2 ≤ 214. Definition of organ failure ( CLIF-SOFA) and GRADES OF ACLF in EASL-CLIF study CLIF- SOFA: Chronic Liver Failure-Sequential Organ Failure Score

62. GRADES OF ACLF in EASL-CLIF study No ACLF Patients with no organ failure OR patients with a single “non-kidney” organ failure who had a serum creatinine level <1.5mg/dl ACLF grade 1A Patients with single kidney failure ACLF Grade 1 B Patients with single “non -kidney” organ failure who had a serum creatinine level of 1.5 to 1.9 mg/dl AND/OR HE I /II ACLF grade 2 P atients with 2 organ failures ACLF grade 3A Patients with 3 organ failures ACLF GRADE 3 B Patient with 4 or more organ failure