Acute Liver Failure in the USA 2011 Evaluation of diagnostic criteria to approach DILI causality

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1 Acute Liver Failure in the USA 2011 Evaluation of diagnostic criteria to approach DILI causality William M. Lee, MD Professor of Internal Medicine Meredith Mosle Chair in Liver Diseases UT Southwestern Medical Center at Dallas

2 Acute Liver Failure Study Group Rationale: Network to study a rare disease Began in 1998, once 23, now 13 adult sites 1,700 cases in adult ALFSG Developed ALI category, now 162 patients Three directions: Prospective clinical data, sera, plasma, DNA, tissue Numerous ancillary studies in progress Therapy trials: NAC trial done, others on the way Funding: NIDDK U-01 through 2015

3 Acute Liver Failure Study Group 14 face to face meetings 40 original manuscripts, 6 in ancillary studies requests 60,000 biosamples New insights in: Hep A, Hep B, Ischemia, AIH, Acetaminophen, DILI, Practice Guidelines Papers to come: Budd Chiari, Pregnancy, Coagulation, LTFU, Prognosis, Transplantation, ICU Management New trials: OPA, MBT (?), Nrf-2 activator

4 CAUSE Hep B Autoimmune Indeterminate HSV DILI Budd-Chiari Hep A HELLP Acetaminophen Wilson Disease Acute Liver Failure Coma Coagulopathy EFFECT Shock Bleeding Infection Renal failure

5 Comparison of Different ALF Etiology Groups N = 1,696 APAP n=787 Drug n=202 Indeterminate n=219 HepA/HepB n=37/123 All Others N=328 Age (median) /43 45 Sex (% F) /45 73 Jaundice (Days) (median) /5 4 Coma 3 (%) /55 43 ALT (median) / Bili (median) / Tx (%) /41 30 Spontaneous Survival (%) Overall Survival (%) / /61 65

6 1,696 Patients enrolled 660 (39%) listed Spontaneous survivors N=826 (49%) Transplanted N=409 (24%) Died (Not Transplanted) N=461 (27%) Alive N=371 (91%) Died N=38 (9%) Overall survival: N=1,197 (71%)

7 Prognosis in ALF: Etiology is a Main Determinant Transplant free survival rates differ greatly Good prognosis: APAP 67% Ischemia 67% Pregnancy 69% Hepatitis A 54% Bad prognosis: Drugs 31% Indeterminate 27% Autoimmune 26% Hepatitis B 24% N=1,696 Wilson Disease 5%

8 Prognosis in ALF: Etiology is a Main Determinant Transplant free survival rates differ greatly Hyperacute: APAP 67% Hypoxia 67% Pregnancy 69% Hepatitis A 54% Subacute: Drugs 31% Indeterminate 27% Autoimmune 26% Acute Hep B 24% Chronic: Wilson Disease 5% Chronic Hep B 13%

9 Prognosis for SS in ALF: Determined by mechanism Immune based ALF does not subside Innate immunity: APAP 67% Ischemia 67% Pregnancy 69% Hepatitis A 56% Adaptive Immunity: Drugs 31% Indeterminate 27% Autoimmune 26% Hepatitis B 24% Length of illness is relevant to pathogenesis

10 Most frequent DILI agents in adults Antibiotics ALFSG DILIN N=137 N=519 INH (w/wo rif/pyraz) Sulfa (TMP/SMX, sulfasalazine) 12 8 Nitrofurantoin Azoles 6 12 Amox/Clavulanate 0 37 Others Anti-convulsants Phenytoin 8 7 Others including psychotropics NSAIDS 7 21 Herbs 14 59

11 Determining Causality: What is the degree of certainty in ALF etiologies? Applying DILIN scale to different etiologies of ALF Definite: > 95% Highly likely: 75-95% Probable: 51-74% Possible: 26-50% Unlikely: 25% Goal: Try to apply a standard systematic approach to excluding other diagnoses which might help in approaching DILI causality.

12 Determining Etiologies: Degree of Certainty in presence of ALF Acetaminophen History of ingestion of > 4 gm: Probable APAP level detected: Probable ALT 1,000 or 3,000 IU/L: Probable/Highly likely Any two of above: Highly likely APAP adducts detected: Definite Drug-induced liver injury Temporal course: Possible Recovery upon withdrawal: Possible Known history: Possible Compatible other drug: Unlikely/Possible Other conditions excluded: Possible

13 Hepatitis A Determining Etiologies: Degree of Certainty in presence of ALF 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

14 Determining Etiologies: Degree of Certainty in presence of ALF Autoimmune Hepatitis Positive serologies: ANA/ASMA: Possible Compatible biopsy: Possible Negative viral serologies: Possible Response to therapy: Possible Any combination of two or more: Probable to highly likely Acute liver failure of pregnancy Last trimester: Possible Hepatic failure with HELLP or AFLP signs: Highly likely Recovery following delivery: Probable Exclusion of viral hepatitis: Highly likely

15 Determining Etiologies: Degree of Certainty in presence of ALF Budd Chiari Syndrome RUQ pain, swelling, ascites, edema: Probable Xray/histologic evidence of hepatic congestion: Highly likely Evidence for hypercoagulablestate: Possible Bone marrow/clotting problems Ischemic Injury (shock liver) Documented history of hypotension: Probable Known cause of vascular collapse: Probable Hypovolemia/heart failure/drug causing vasodilation: Highly likely Course of recovery (rapid up/rapid down): Highly likely

16 Determining Causality in ALF: Has this helped? Most other etiologies have more robust criteria than DILI Is there value to looking at the list of exclusions separately: RUCAM lists A-C viruses, gallstones, EtOH, ischemia (Group 1) Group 2: underlying disease and HSV, EBV, CMV No mention made of: Acetaminophen Budd Chiari Autoimmune Cancer Pregnancy diseases

17 Acute Liver Failure Study Group Specific Aims Continue the registry ecrf, revamping of database, new Website, new committee structure Learn more about pathogenesis Ancillary studies continue Pathogenesis conference Oct th Trials of diagnostics: TEG, MBT Begin a new treatment trial (s) OPA Later, Nrf-2 activator

18 ALFSG Pathogenesis Forum October 16-18, 2011 Specific Aims Bring together basic scientists and clinicians to explore new ways to study: 1) basic mechanisms of liver injury including molecular targets and pathways 2) evolution to multi-organ failure and recovery This conference will be closed, and will provide a small group setting to discuss ways to better network between the basic science community and ALFSG.

19 Mechanism Apoptosis Loss of oval cells Innate immunity Necrosis Cytokines Local factors DIC Acute Liver Failure Cerebral edema Toxic cellular debris Poor synthetic fxn Result Poor toxin clearance No regeneration Increased infection risk

20 ALFSG Pathogenesis Forum October 16-18, 2011 Tentative Agenda 1. Cell stress/cell death/cytokines Speakers : Kaplowitz, Szabo, Vodovotz, Stravitz 2. Cell injury/inflammation/role of bacteria Speakers: Vollmar, Mehal, Diehl, Balko, Lee 3. Genomics approaches Speakers: Omary, Daly, Watkins, Fontana 4. Liver regeneration: mechanisms and markers Speakers: Apte, Gosling, Nyberg, Schiodt 5. Therapies: Beyond NAC: Speakers: Menger, Rakela, Brechot, Parekkadan, Wigley, Reddy

21 Study Sites (Adult) in the ALFSG 2011 UT Southwestern Lee/Larson/Sanders DCC/MUSC Durkalski/Zhao/Battenhouse//Dillon/Goddard U Washington Liou/Strom UCSF Fix/Semmel Northwestern Univ Ganger/Gottstein UCLA McClune/Peacock/Melgoza Michigan Fontana/Welch/Trivedi/Kochhar Univ Alabama Birmingham McGuire/Hogue Mass General Chung/Gustafson/Barlow VCU Stravitz/White/Genther MUSC Charleston Reuben/Crolley Pennsylvania Reddy/Wirjosemito Yale University Schilsky//Caldwell/Engle/Snyder

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