I wish that I had some conflicts to declare

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1 I wish that I had some conflicts to declare reubena@musc.edu

2 Trump s Shavuot I ve got my own commandments, Little Elohim

3

4 Acute Liver Failure (ALF) [Fulminant Hepatic Failure (FHF)] 1. Hepatic Encephalopathy (HE) : Altered mental status - Behavior, thinking and/or conscious level 2. Coagulopathy (INR > 1.5); not necessarily jaundice 3. Acute illness: < 26 wks: Speed = Days from Jaundice to HE a) Hyperacute 7 days; Acute 8-28 days ; Subacute 29 days-26 weeks b) FHF < 2 weeks, Subfulminant Hepatic failure (SFHF) ; 2-26 weeks 4. No pre-existing liver disease i.e. no cirrhosis - implicit but not always known or easily knowable e.g. hepatitis B, autoimmune hepatitis, Wilson disease 5. Definition is independent of etiology -- many causes Acute Liver Injury (ALI): Elevated ALT and INR, no HE

5 APAP Drug Hep B Hep A Autoimm Ischemic Wilson's dd-chiari regnancy Other Indeter Etiology of Acute Liver Failure in the USA Adult Registry (n = 2,344) % ALF Study Group, Jan % 12%

6 APAP Drug Hep B Hep A Autoimm Ischemic Wilson's dd-chiari regnancy Other Indeter Etiology of Acute Liver Failure in the USA Adult Registry (n = 2,344) % 11% APAP ALF Study Group, Jan 2016 = N- acetyl-para-aminophenol Tylenol = para-acetylaminophenol Paracetmol = para-acetylaminophenol Acamol = para-acetylaminophenol 12%

7 Differences in Etiologies Worldwide OTHER IND DILI HEV HBV APAP London Copenhagen Hannover Karachi Hong Kong Melbourne

8 Comparison of Different ALF Etiology Groups N = 2345 APAP Drug Indeterminate HepA/HepB All Others N=108 0 n=252 n=282 n=37/166 N=528 Age (median) / Gender (% F) /45 70 Jaundice to HE (Days) /8 7 HE 3 (%) /50 39 ALT (median IU) / Bili (median) / Tx (%) /39 30 Transplant-free Survival (%) Overall Survival (%) / /54 55

9 Etiology of Acute Liver Failure in the USA Adult Registry (n = 2,224) APAP Drug Hep B Hep A Autoimm Ischemic Wilson's Budd-Chiari Pregnancy Other Indeter # ALF Study Group (ALFSG), Jan %

10 Acetaminophen Cases as % of ALF per Year: ALFSG

11 ALF/ALI Admissions to Kings College Hospital Liver Intensive Therapy Unit (ICU) : Paracetamol* vs Non-Paracetamol Cases 1998 introduction of Paracetamol Sales Restriction in UK *Para-acetyl-aminophenol Bernal W et al. J Hepatology 2013; 59: 74 80

12 Suicidal or Intentional vs. Accidental or Staggered APAP cases N=606 Intentional Unintentional p-value (56=unknown) (n=251) (n=296) Female (%) NS Age < APAP (g) total/perday 38/38 47/7.5 NS Opioid containing (%) < More > 1 preparation (%) 5 38 < Coma (% HE grade >3) < ALT (IU/L) < Alcohol use/abuse (%) 50/18 50/17 NS Antidepressant (%) NS History of depression < Spontaneous survival (%) NS (Transplant-free)

13 Metabolism of acetaminophen by Cytochrome P450 leads to an unstable compound O C HN CH3 HN O C CH3 N O C CH3 SG Cytochrome p450 2E1 (phase I) OH Mercapturic Acid (nontoxic) OH (phase II) Nontoxic Metabolites O NAPQI N-acetyl-p-benzoquinoneimine (highly reactive intermediate) CYP2E1 is induced by alcohol Hepatocyte Damage Covalent binding to cell proteins, including enzymes ADDUCTS with cysteine residues Derangement of apoptosis?

14 Determining Etiology of ALF: Degree of Certainty Acetaminophen History of ingestion of > 4 gm: Probable Acetaminophen level detected: Probable ALT 1,000 or 3,000 IU/L: Probable/Highly likely Any two of the above: Highly likely Acetaminophen adducts detected: Definite

15 Acetaminophen (APAP) adducts assay APAP is metabolized to toxic reactive N-acetyl-pbenzoqinoneimine (NAPQI), which binds to cellular proteins via cysteine residues to form 3-(cystein-S-yl)-APAP adducts Highly sensitive and specific HPLC-EC detects APAP-cysteine adducts (>1nM positive) Excellent correlation with AST Remains positive up to 9 days after ingestion Present in ~20% of indeterminate cases, pediatric and adult Soon to be available as point-of-care dipstick assay Davern TJ, et al. Gastroenterology 2006;130: James LP, et al. Pediatrics 2006;118:e Khandelwal N, et al Hepatology 2011; 53:

16 nmol APAP-CYS / mg protein Acetaminophen-CYS (umol/l)/mg protein Known APAP Indeterminate with adducts N= Other ALF APAP No tox Indeterminate N=29 A B C D E Patient Group Davern TJ, et al. Gastroenterology 2006; James LP et al Drug Metab Dispos 2009

17 Comparison of clinical features of patients with indeterminate ALF according to presence of APAP-Adducts Known APAP Indeterminate Etiology Adducts (+) Adducts (-) P N=188 N=20 N=90 Age (Y) NS Gender (%) < ALT (IU/L) 4,025 5, < Adducts (nm) < Bilirubin (mg/dl) < Spontaneous (%) < survival Adduct positive Indeterminate APAP Toxicity Khandelwal, et al. Hepatology. 2011; 53: 567.

18 Viral Hepatitis in ALF Overall incidence decreasing? Currently, Hepatitis A 0.8% vs 2.8% and Hepatitis B stable at 6.7% No Hepatitis A superimposed on Hepatitis C No occult Hepatitis B No clear-cut Hepatitis C-related ALF - nor B 19 or SEN viruses - 3 cases of Hepatitis E }see later Possible association with acetaminophen in some cases: AVOID acetaminophen for acute hepatitis

19 Hepatitis A Determining Etiologies: Degrees of Certainty Compatible history of acute illness: Possible Positive anti-hav IgM: Definite Hepatitis B History of acute exposure and no evidence of chronic infection/cirrhosis: Probable Anti-HBc IgM positive: Highly likely HBsAg positive: Probable HBV DNA positive: Probable Treat with nucleo(s)tide analog, although evidence is weak Consider Acute-on-Chronic Hepatitis B if: Known HBV, older patient, high viral load, Asian, and anti-hbc IgM neg

20 Drug-induced liver injury causing ALF Features of idiosyncratic DILI (idili) include: Slow evolution Failure to resolve after stopping drug Frequent autoimmune features Herbs and slimming aids often implicated may require repeated questioning Predictors of outcome: bilirubin, INR, HE grade and MELD Reuben A et al. Hepatology 2010; 52 :

21 Most Frequent DILI Agents in Adults Antibiotics INH (w/wo rif/pyraz) 25 (19) 28 (6) Sulfa (TMP/SMX, sulfasalazine) 12 (9) 8 (2) Nitrofurantoin 11 (8) 23 (4) Azoles 6 (5) 12 (2) Amox/Clavulanate 0 (0) 37 (7) Others 13 (10) 115 (22) Anti-convulsants ALFSG* N=133 (%) DILIN** N=519 (%) Total 67 (50) 223 (43) Phenytoin 8 (6) 7 (1) Others, including psychotropics 10 (8) 43 (8) NSAIDS 7 (5) 21 (4) Herbs & Complementary/Alternative Medicines 14 (11) 59 (11) *Reuben et al Hepatology 2010 **Chalasani et al Gastroenterology 2008

22 Therapeutic classes implicated worldwide in non-acetaminophen DILI Class/Country Sweden Spain USA Korea Japan Australia China Iceland India Antibiotics (%) amox-clav 58 Anti-TB 4 nitrofurantoin CNS (%) Hypolipidemic (%) Other drugs (%) diclofenac 5 dapsone 4 infliximab 4 azathioprine Herbals/DS/CAM (%) /6.5 Fontana, et al. Hepatology 2010; 52: ; Lucena et al. Hepatology. 2009;49: ; Suk et al Am J Gastroenterol 2012;107:1380-7; Sistanizad et al J Clin Pharm Ther 2013;38:115-20; Zhou et al Eur J Gastro Hepatol 2013;25:825-9; Bjornnson et al Gastroenterology 2013;144: ; Devarbhavi et al. Am J Gastroenterol 2010;105: ; Chalasani et al. Gastroenterology 2015; 148:

23 Herbal and Dietary Supplements (HDS) DILI % Enrolled in DILIN Clinical Liver Disease 2015; 5: Fatal DILI or LT (n = 62) Anti-microbial 27 HDS 10 Cardiovascular 5 CNS 6 Antineoplastic 7 Analgesic 1 Immuno 1 Endocrine 1 Rheumatologic 2 Other 2 Clinical Features and Outcomes of Complementary and Alternative Medicine Induced Acute Liver Failure and Injury. Hillman L, Gottfried M, Whitsett M, MD, Rakela J, Schilsky M, Lee WM, Ganger D. Am J Gastroenterol 2016 (in press)

24 APAP Drug Hep B Hep A Autoimm Ischemic Wilson's Budd-Chiari Pregnancy Other Indeter Etiology of Acute Liver Failure in the USA Adult Registry (n = 2,344) ALF Study Group, Jan %

25 Indeterminate cases - then 12% of cases 18% are probably due to acetaminophen NOT due to: occult HBV 1 Parvovirus B19 2 SEN-V virus 3 unrecognized HSV 4 1 Wai CT, et al. J Viral Hep 2005;12: Lee WM, et al. Dig Dis Sci 2006;51: Umemura T, et al. J Inf Dis 2003;188: Levitsky J, et al. Liver Transplant 2008;14:1498. Hepatitis E 2 (3 cases only ALFSG ) Other viruses or toxins are most likely Missed AIH maybe 58% Missed diagnoses? Need causality adjudication

26 Indeterminate cases - now Solving Indeterminate Etiology in Acute Liver Failure: The Contribution of Expert Opinion to the Process of Causality Adjudication (Abstract submitted to AASLD 2016) Ganger D, Rule JA, Bass NM, Rakela J, Stravitz RT, Sussman NL, Larson AL, Gottfried M, Reuben A, Lee WM Methods: APAP adducts, occult viral sequences by microarray analysis and deep sequencing, liver histology reviewed, CRFs analyzed for missing data. Causality algorithms, adjudicator review, expert committee, consensus diagnosis Results: 294/314 Indeterminate cases analyzed (11.6% of 2,718 cases) APAP 43 (15%) Autoimmune Hepatitis 33 (11%) Viral 7 (2%): Parvo-B19, HBV, EBV, VZV, HSV(3) Indeterminable 58, Indeterminate 91 (149, not 294) True Indeterminates: %

27 Prognosis in ALF: Speed is a Main Determinant Transplant-free survival rates differ greatly Hyperacute: APAP 70% Ischemia 72% Pregnancy 74% Hepatitis A 54% N=2,070 Subacute: DILI 33% Indeterminate 28% Autoimmune 24% Hepatitis B 28% Chronic: Wilson Disease 0%

28 Prognosis in ALF: Etiology is a Main Determinant Transplant-Free survival rates differ greatly Favorable etiology: APAP 76% Ischemia 74% Pregnancy 83% Hepatitis A 56% Unfavorable etiology: Drug toxicity 41% Indeterminate 33% Autoimmune 25% Hepatitis B 26% Wilson Disease 0% Obesity (BMI>30) and older age (>65yrs) have lower TFS rates

29 Prognosis in ALF: Is Mechanism the Determinant? Immune-based ALF does not subside Innate Immunity: APAP 70% Ischemia 72% Pregnancy 74% Hepatitis A 54% Etiology and mechanism probably determine speed of evolution Adaptive Immunity: DILI 33% Indeterminate 28% Autoimmune 24% Hepatitis B 28% Unique: Wilson Disease 0% N=2,070

30 Transplant-free survival by etiology and coma (HE) grade. (Data from Placebo Subjects in N-Acetylcysteine (NAC) Trial) 65% 68% 55% 56% 26% 26% 27% 25% Encephalopathy grade III-IV patients ~50% worse survival < I-II

31 Kings College Hospital Criteria For Non-APAP ALF: HE irrespective of grade INR > 6.5 OR HE (irrespective of grade) and Three of the following 5 criteria Age <10 or >40 years Serum bilirubin >300 μmol/l (17.5 mg/dl) Jaundice > 7days before onset of HE INR > 3.5 Etiology: non-hepatitis A/B or DILI

32 Comparison of Two ALFSG Models to the Kings College Criteria and MELD Scores, in Predicting Survival Rutherford A et al. Gastroenterology 2012;143: Development of an Accurate Index for Predicting Outcomes of Patients with Acute Liver Failure. Predicting transplant or death Variables: HE grade, INR, Bilirubin, PO 4, M subjects Koch DG, Tillman H, Durkalski V, Lee WM, Reuben A. - CGH in press Predicting spontaneous survival in patients with Acute Liver Failure. Variables: HE grade, INR, Bilirubin, Vasopressor use, Etiology favorability 1974 subjects

33 Initial Management Must have high index of suspicion at time of admission: ALI ALF/LT/death - 7% APAP, 40% non-apap Condition progresses rapidly Changes in consciousness occur hour-by-hour Admission or early transfer to ICU

34 Disease-Specific Treatments N-acetylcysteine (NAC) Acetaminophen overdose Non-acetaminophen ALF HE grade I-II,?III-IV Nucleos(t)ide analogues Acute hepatitis B Acyclovir Acute HSV Steroids AIH Plasmapheresis/ exchange transfusion Wilson disease Penicillin G and silymarin (milk thistle) Mushroom poisoning (Amanita phalloides) Outcome benefit not established, data scarce

35 Treatment for APAP Overdose N-acetylcysteine (NAC) is an effective antidote IV NAC will totally prevent toxicity if given < 12 hrs Uncertain benefit after 30 hours Supportive care in ICU: but may still develop fatal complications, e.g., brain edema, even if liver recovers Is it ALF? If yes, is patient a transplant candidate? If so, early transfer to Transplant Center

36 Primary/secondary outcomes in the NAC trial p< 0.28 *p< 0.04 *p< 0.01 p< 0.09 *p< p< 0.09 The most impressive result was in transplant-free survival in HE grades I-II Lee WM et al Gastroenterology 2009; 137: * = statistically significant

37 NAC Use in During Follow-Up of 2070 ALF Subjects NAC Usage Over Time NAC Use in APAP Overdose Percent Overall NAC Use NAC Use in Non-APAP Overdose Completion of NAC trial Study Enrollment Year Overall NAC Usage NAC Usage - APAP Subjects NAC Usage - Non-APAP Subjects

38 Outcomes in Adults with Acute Liver Failure from : An Observational Cohort Study Overview of ALF: What has changed over 16 years? Have changes in management/outcomes occurred? 2070 patients, all with 21 day outcomes known No differences in etiologies, demographics, disease severity, referral patterns, or time to referral Results: decline in: Listing, deaths, transplantation Use of vasopressors, ventilation, blood products Overall and transplant-free survival improved. Reuben A et al Ann Intern Med. 2016; 164:

39 Overall and transplant-free survival over time: Reuben A et al. Ann Intern Med. 2016; 164:

40 Treatment modalities over time Reuben A et al. Ann Intern Med. 2016; 164:

41 Determinants of Outcome Among Patients with Acute Liver Failure Listed for Liver Transplantation in the US Reddy KR, Ellerbe C, Schilsky M, Stravitz RT, Fontana RJ, Durkalski V, Lee WM; Acute Liver Failure Study Group. Liver Transpl. 2016; 22:

42 Reddy et al. Liver Transplant 2016; 22;

43 Reddy et al. Liver Transplant 2016 Reddy et al. Liver Transplant 2016; 22;

44 What are the outcomes for ALF patients listed for LT? APAP cases die very soon after listing, therefore decisions need to be made extremely rapidly. Those with slower disease evolution are more likely to receive a graft. Those receiving a liver, resemble those who recovered more than they resemble those who died. It is not clear that everyone who received a liver needed it. Reddy KR, Ellerbe C, Schilsky M, Stravitz RT, Fontana RJ, Durkalski V, Lee WM; Acute Liver Failure Study Group. Liver Transpl. 2016; 22:

45 Ornithine Phenyl-Acetate (OPA): STOP-ALF Trial Aim: To lower ammonia to manage cerebral edema Ammonia is the putative cause of cerebral edema OPA traps ammonia and allows renal excretion Could be used prophylactically or as treatment IV, few side effects, might work in cirrhosis also ALFSG has been studying the APAP ALF/ALI group since July 2012 to be completed 2015.

46 Ornithine-Phenylacetate (OCR-002) Uses Physiological Pathways to Eliminate Nitrogen ornithine OCR-002 Phenylacetate PhenylacetateCoenzyme A Phenacetyl-CoA : Gln acyltransferase + Glutamine Phenylacetylglutamine (PAGN) is excreted in the urine and cannot be recycled by glutaminase

47 January 20 th 2017? and I will, to the best of my ability - which is terrific ability, by the way. Everyone agrees, I have a fantastic ability. So there's no problem with my ability, believe me