Drug-Induced Liver Injury and Hepatic Encephalopathy William M. Lee, MD Division of Digestive and Liver Diseases UT Southwestern Medical Center at Dallas Division of Gastroenterology, Hepatology and Nutrition The Ohio State University DILI Pharma/FDA/Academy Meeting No. 12 March 20-21, 2013
Disclosures: William M. Lee, MD Research Grants to UTSW Anadys, Boehringer-Ingelheim, BMS, Cumberland, Gilead, Merck, Roche, Vertex, Consulting Lilly, Novartis
AIMS Review current thinking about hepatic encephalopathy (HE) and liver failure Compare acetaminophen toxicity with DILI as causes of acute liver failure Discuss current therapies for HE Review current treatment trials in HE
DILI Causes Acute Liver Failure Defining Feature is Encephalopathy Most severe form of liver injury but rare, 2000/yr Devastating: survival <10% in earlier era Definition: INR 1.5, any grade enceph, acute illness UNOS Status 1a Fascinating Frustrating Hard to treat Difficult to study
Etiology of Acute Liver Failure in the USA Adult Registry (n = 2,000) 46% ALF Study Group, Jan 2013 11% 12%
Comparison of Different ALF Etiology Groups N = 2000 APAP Drug Indeterminate HepA/HepB All Others N=916 n=220 n=245 n=36/142 N=441 Age (median) 37 46 39 49/43 45 Sex (% F) 76 69 59 44/44 71 Jaundice (Days) 1 11.5 11 4/8 7 Coma 3 (%) 53 35 48 56/52 38 ALT 3773 639.5 865 2275/1649 681 Bili (median) 4.3 19.8 21.1 12.3/18.4 13.9 Tx (%) 9 40 42 33/39 32 Spontaneous Surv (%) Overall Survival (%) 63 24 22 50/21 31 70 58 60 72/55 58
Two forms of encephalopathy: hyperacute and subacute Hyperacute Acetaminophen Cerebral edema Rapid onset/recovery Early presentation High ALT/low Bili No ascites/some KI Subacute/Chronic idili/aih/hep B/Indeter No cerebral edema Slow onset/poor recovery Late presentation Low ALT/High Bili Frequent ascites/hrs Edema likely indicates that rapid onset yields osmotic changes that cannot be compensated
Current Treatment for HE/Cerebral Edema Hyperacute Quiet room No sedation Maintain MAP Mannitol Hypertonic saline Hypothermia Anti-convulsants Subacute/Chronic Low protein diet Lactulose (?) Antibiotics: rifaximin Liver support devices (??) No therapy directed at the cause. Is it really NH 3?
32 Year-old male with ALF of indeterminate etiology Admission head CT 48 h after admission
Effects of Mannitol or Induced Hypernatremia on Intracranial Hypertension in Patients with ALF 120 90 ICP (mmhg) 60 N=10 30 10 Before After Hanid, et al. Gut 1980;21:866. Murphy, et al. Hepatology. 2004; 39: 464.
Effects of Hypothermia in Patients with ALF and Uncontrolled Intracranial Hypertension Precooling 4 h 10-24 h ICP (mmhg) 36.5 16.3 16.8 33 CBF (ml/100 g/min) MAP (mmhg) 78.2 46.5 44.0 76.6 82.8 84.9 Jalan, et al. Gastroenterology. 2004; 127:1338. N=14; 13 bridged to liver transplantation
The STOP-ALF Trial Why Target Ammonia? Associated with hepatic encephalopathy Highly associated with brain edema: Levels of NH3 above 150-200 mmol/l associated with increased intra-cranial pressure Lowering ammonia should prevent both Might prove of value in patients with cirrhosis
Several studies highlight role of NH 3 in raising ICP
Ornithine Phenyl Acetate: STOP-ALF Trial Lower ammonia to manage cerebral edema Ammonia is the putative cause for 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 begun to study in APAP patient group
OCR-002 Uses Physiological Pathways to Eliminate Nitrogen ornithine OCR-002 phenylacetate Phenacetyl-CoA : Gln acyltransferase PAGN
STOP-ALF Trial: Study Features Phase IIa, ALFSG holds the IND Ornithine phenylacetate will effectively lower ammonia levels and improve encephalopathy and prevent/control cerebral edema in ALF. First cohort Cr < 1.0 and NH3 > 75 Initial Pilot Study: PK and Safety, 24 patients, ascending dose Six high enrolling sites: UCSF, Penn, VCU, Michigan, MUSC, UTSW Drug and all PK monitoring and NH3 labs supplied by Ocera
STOP-ALF Trial: Early Results 29 APAP pts screened at the 6 sites/57 pts overall 27 screen failures/2 patients enrolled! Reasons for screen failures: High Cr (Acute Kidney Injury) 13 (45%) Low Ammonia (< 75 µmol/l) 11 (41%) Administrative glitches 2 (7%)
Ammonia and creatinine levels for 355 acetaminophen pts.
STOP-ALF Trial: Other Scenarios
STOP-ALF Trial: Lessons Learned Initial criteria were too stringent, excluded many patients! Acetaminophen toxicity is very commonly associated with kidney injury, ~ 70% of the time. High ammonia levels are associated with kidney injury. Also, broadening criteria to include presumed acetaminophen, since many patients cannot give a history at the time of presentation. Meeting with FDA is resulting in protocol revisions.
Summary Hepatic encephalopathy = acute liver failure Seen in both APAP and DILI Cerebral edema mostly in APAP and high NH 3 Agents are not directed at lowering NH 3 New agents will determine whether this strategy is effective.
Study Sites (Adult) in the ALFSG 2009-13 UT Southwestern Lee/Larson/Sanders U Washington Liou UCSF Fix Mt. Sinai NYC Liu/Zuniga Univ Nebraska Omaha McCashland/Teten Baylor Dallas Murray/Coultrup Univ Pittsburgh Shakil/Gooch Northwestern University Ganger/Gottstein OHSU, Portland Zaman/Ingram/Wilson UCLA McClune/Peacock/Melgoza Michigan Fontana/Welch Univ Alabama Birmingham McGuire/Hogue Mass General Chung/Rutherford/Lundmark/Gustafson Columbia/Cornell NYC Brown/Odeh-Ramadan VCU Stravitz/White/Topaz Mayo Clinic: Rochester, Jax Hay, Raj,Kramer: Groettum/Kontras UC Davis Rossaro/Dhaliwal Einstein Philadelphia Munoz/Riera/Carmody MUSC Charleston Reuben/Minshall Pennsylvania Reddy/Wirjosemito Yale University Schilsky/Emre/Engle/Snyder CPMC Davern, Fajardo