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10/7/2021EIGHT different award types; INCREASED Junior Faculty FUNDING;NEW Health Equity Research Award; Med Resident and Student Awardswww.gi.org/research‐awardsGrant System Opens: September 7, 2021Deadline: December 3, 2021Read the Grant Flyer, FAQs, or visit the webpage for the full RFAs.1Read the flyer at gi.org/research‐awards to learn more!2American College of Gastroenterology1
10/7/2021EIGHT different award types; NEW Health Equity Research Award; BridgeFunding; GIQuIC Research funding; Med Resident and Student Awardswww.gi.org/research‐awardsGrant System Opens: September 7, 2021Deadline: December 3, 2021Read the Grant Flyer, FAQs, or visit the webpage for the RFAs.3Participating in the WebinarAll attendees will be muted andwill remain in Listen Only Mode.Type your questions here sothat the moderator can seethem. Not all questions will beanswered but we will get toas many as possible.4American College of Gastroenterology2
10/7/2021How to Receive CME and MOC PointsLIVE VIRTUAL GRAND ROUNDS WEBINARACG will send a link to a CME & MOC evaluation to allattendees on the live webinar.ABIM Board Certified physicians need to complete their MOC activities by December 31,2021 in order for the MOC points to count toward any MOC requirements that are due bythe end of the year. No MOC credit may be awarded after March 1, 2022 for this activity.5MOC QUESTIONIf you plan to claim MOC Points for thisactivity, you will be asked to: Please listspecific changes you will make in yourpractice as a result of the information youreceived from this activity.Include specific strategies or changes that you plan to implement.THESE ANSWERS WILL BE REVIEWED.6American College of Gastroenterology3
10/7/2021ACG Virtual Grand RoundsJoin us for upcoming Virtual Grand Rounds!Week 40, 2021ACG Clinical Guideline: Management of Upper GI Bleeding andBleeding UlcersLoren A. Laine, MD, FACGOctober 14, 2021 at Noon EasternWeek 41, 2021Identifying and Eliminating Racism in Science and Healthcare: HistoricalPerspective and Current OpportunitiesDarrell M. Gray, II, MD, MPH, FACGNovember 4, 2021 at Noon EasternVisit gi.org/ACGVGR to Register7Disclosures:Speaker:Haripriya Maddur, MDDr. Maddur, faculty for this educational event, has no relevant financial relationship(s) with ineligible companies to disclose.Moderator:Naga P. Chalasani, MD, FACGConsultant: AbbVie, Altimmune, Foresite Labs, Galectin, Genentech, Madrigal, ObsEva, Siemens, Zydus; Grant Support:DSM, Exact Sciences, Intercept.*All of the relevant financial relationships listed for these individuals have been mitigated8American College of Gastroenterology4
10/7/2021ACG CLINICAL GUIDELINE:DIAGNOSIS AND MANAGEMENT OFIDIOSYNCRATIC DRUG-INDUCEDLIVER INJURYHARIPRIYA MADDUR, MD910American College of Gastroenterology5
10/7/2021BACKGROUND Drug induced liver injury (DILI) culprit for 3-10% of cases ofacute liver injury Common cause for a medication to be abandoned during drugdevelopment Herbal and dietary supplements often culprit May result in ALFSlide courtesy of Naga Chalasani MD11ACUTE LIVER FAILURE FROM DILI11% of adult ALF pts had DILI 47% due to antibiotics, esp. TB drugsTransplant-free survival: 27%Transplant: 42%Overall survival: 66%Bernal NEJM 2014, Reuben Hepatology 2010, Squires J Peds 2006Slide courtesy of Naga Chalasani MD12American College of Gastroenterology6
10/7/2021Etiology of Acute Liver Failure in the USAdult Registry (n 2,102)1000974900ALF Study Group, Jan therIschemicAutoimmHep AHep BDrugAPAP013TOP 10 THERAPEUTIC CLASSES ANDINDIVIDUAL AGENTS TO CAUSE DILI IN THEUSA (N 899)Therapeutic ClassnIndividual agentn911Antimicrobials4081Amox-Clavulanate2Herbal and dietary1452INH483CVS agent883Nitrofurantoin424CNS agents824TMP/SMX vofloxacin131210Diclofenac1210 GastrointestinalSlide courtesy of NagaChalasani MDChalasani N, et al for the US DILIN. Gastroenterology 201514American College of Gastroenterology7
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10/7/202117HERBAL AND DIETARY SUPPLEMENTS Increasingly used in the US Increasing implicated as causing liver injury Body building supplements and weight loss supplements Body building agents – Cholestatic patterns Weight loss supplements - hepatocellular injurySlide courtesy of Naga Chalasani MD18American College of Gastroenterology9
10/7/2021TEMPORAL TRENDS IN HDSHEPATOTOXICITY%20181614121086420Other HDSBodybuilding7%5.5%3.7%1.7%12%11%9%5%N 1152004-2005N 1912006-2007N 2192008-2009N 3032010-2012Slide courtesy of Naga Chalasani MD19HDS DILI OUTCOMESBody buildingagents (n 45)Non-bodybuilding agents(n 85)DILI due toconventionalagents (n 709)P-valueHospitalization(%)7168580.07OLT0133 0.001Death0470.095Severe/fatal DILINseverity score1335260.02Navarro V, for the US DILIN. Hepatology 2014Slide courtesy of Naga Chalasani MD20American College of Gastroenterology10
10/7/2021CLINICAL CHEMISTRY CRITERIA FOR DILI Any one of the following 5 ULN of ALT 2 ULN of Alk P (of liver origin) 3 ULN of ALT 2 ULN of Total bilirubin In the absence of a competing etiologyAithal GP, et al. Clin Pharmacol Therapeutics 201121DRUG INDUCED LIVER INJURYIntrinsicinjury is frequent(1-100%),dose-relatedreproducible inanimal models,“expected”not inherentlyhepatotoxicrare (1:10001:1,000,000)not dose relatednot reproducible inanimals,“unexpected”Idiosyncratic22American College of Gastroenterology11
10/7/2021INTRINSIC HEPATOTOXICITY Expected outcome, dose related Acetaminophen Aspirin Niacin Many antineoplastic agents Serum enzyme elevations Acute hepatic necrosis Sinusoidal obstruction syndrome Lactic acidosis, steatosis and hepatic dysfunction Nodular regenerative hyperplasia23IDIOSYNCRATIC HEPATOXICITY Unexpected outcome, rare, and generally not-dose related Isoniazid Troglitazone Amoxicillin/Clavulanic acid Minocycline Diclofenac Idiosyncrasy: immunologic or metabolic Phenotypes, acute hepatitis, cholestatic hepatitis, blandcholestasis, nonalcoholic fatty liver Etiology, generally unknown Challenge to clinical and basic research24American College of Gastroenterology12
10/7/2021INDIRECT HEPATOXICITY A third form of hepatotoxicity The medication induces a liver disease or alters a predicting condition. Reactivation of hepatitis B Worsening or flare of hepatitis C Triggering of autoimmune liver disease Exacerbation of NASH or ASH (weight gain) Phenotypes: acute hepatitis, acute liver failure, chronic hepatitis, cirrhosis,fatty liver Often can be predicted and prevented or avoided25PATTERNS OF INJURYR ratio: ALT/Alk P[expressed as x ULN]MixedHC 5, Cholestatic 2, Mixed 2-5Cholestatic similar to biliaryobstructionHepatocellular acute viral hepatitis like26American College of Gastroenterology13
10/7/2021CAUSALITY IN DRUG INDUCED LIVER INJURY DILI is a diagnosis of exclusion Compatible history; no specific tests to prove causality Negative tests for hepatitis A, B, C and E Absence of heavy alcohol use, shock, autoimmunity Imaging studies of liver and biliary tree Special attention to exacerbation of underlying liverdisease such as fatty liver, Hep C, Hep B, or Primary SclerosingCholangitis27FROM THE GUIDELINES.28American College of Gastroenterology14
10/7/202129THE ROLE OF LIVER BIOPSY?30American College of Gastroenterology15
10/7/2021ARE THERESPECIFICRISKFACTORS?31PROGNOSTICATION AND RECHALLENGE32American College of Gastroenterology16
10/7/2021TREATMENT?33AUTOIMMUNE LIKE DILI Clinical syndrome with high resemblance to autoimmune hepatitis Nitrofurantoin and minocycline are prototypes but many others can alsodo this (TNFα antagonists, statins, α-methyl dopa) Long latency and presence of autoantibodies Identification is critically important Steroid therapySlide Courtesy of Naga Chalasani MD34American College of Gastroenterology17
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10/7/2021IMMUNOTHERAPY INDUCED DILIRule out Hepatitis B reactivation37Peerphatdit, et al, Hepatotoxicity from Checkpoint Inhibitors,Hepatology,72, Nov, 202038American College of Gastroenterology19
10/7/2021Peerphatdit, et al, Hepatotoxicity from CheckpointInhibitors, Hepatology,72, Nov, 202039SPECIAL POPULATIONS40American College of Gastroenterology20
10/7/2021SPECIAL POPULATIONS (CHILDREN)41SUMMARY Drug induced liver injury is a diagnosis of exclusion Prompt recognition needed as drug cessation is mainstay of therapy Antimicrobial agents often culprit in addition to antimicrobial therapy No definitive role for steroid therapy Rechallenge should be avoided unless no viable alternatives Immunotherapy induced DILI more likely with multiple agents;management depended on severity42American College of Gastroenterology21
10/7/2021Special Thanks to Naga Chalasani MD43Questions?Speaker:Haripriya Maddur, MDModerator:Naga P. Chalasani, MD, FACG*All of the relevant financial relationships listed for these individuals have been mitigated44American College of Gastroenterology22
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Grant System Opens: September 7, 2021 . Consultant: AbbVie, Altimmune, ForesiteLabs, Galectin, Genentech, Madrigal, ObsEva,Siemens, . management depended on severity 41 42 American College of Gastroenterology. 10/7/2021 22 Special Thanks to Naga Chalasani MD Questions?
