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Medication DILI- emma : The Masquerade of Drug Induced Liver Injury

Medication DILI- emma : The Masquerade of Drug Induced Liver Injury. Jeffrey Eickhoff, MD PGY3 Navy ACP 2014. Disclaimer.

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Medication DILI- emma : The Masquerade of Drug Induced Liver Injury

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  1. Medication DILI-emma: The Masquerade of Drug Induced Liver Injury Jeffrey Eickhoff, MD PGY3 Navy ACP 2014

  2. Disclaimer The views expressed in this presentation are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Army, Department of Defense, nor the U.S. Government. We certify that all individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the writing of the document, and the approval of the submission of this version; that the document represents valid work; that if we used information derived from another source, we obtained all necessary approvals to use it and made appropriate acknowledgements in the document; and that each takes public responsibility for it. Nothing in the presentation implies any Federal/DOD/DON endorsement.

  3. Objectives • Case presentation • Drug-induced liver injury (DILI) • Illustrate the wide variety of presentations of DILI • Diagnosis of exclusion - importance of investigation for other possible causes of abnormal liver associated enzymes (LAE) • Methotrexate (MTX) use as a risk factor for drug-related hepatotoxicity • Final diagnosis • Epidemiology, presentation, diagnosis, treatment

  4. Case Initial referral: • A 66 year old female with rheumatoid arthritis (RA), referred for elevated AST (431 U/L) and ALT (364 U/L) Case background: • Started MTX 4 years prior - seropositive RA • One year ago noted elevations in her transaminases • (AST 79 U/L, ALT 114 U/L) • MTX was discontinued, enzymes normalized • (AST 23 U/L, ALT 27 U/L) • MTX re-initiated, similar increase in liver enzymes • (AST 291 U/L, ALT 271 U/L); persisted despite MTX cessation

  5. Case • Past Medical Hx: RA, obesity, hypothyroidism, HTN • Past Surgical Hx: Cholecystectomy several years prior for gallstones • Allergies: Lisinopril (urticaria) • Medications: Levothyroxine, HCTZ, ASA, hydroxychloroquine, folic acid and MTX (15mg once weekly); denies acetaminophen intake • Social History: No alcohol or drug use • Family History: No family history of liver disease • Physical Exam: Unremarkable; no findings of liver disease

  6. LAE trends: Stopped MTX

  7. LAE trends:

  8. The work-up: • Negative: • Viral hepatitis: (-) Hep B SAg, Hep B core Ab, Hep C Ab • Iron overload: normal ferritin, iron, TIBC, iron saturation • α-1 antitrypsin deficiency: normal • Wilson’s disease: ceruloplasmin normal • Right Upper Quadrant Ultrasound: Unremarkable post cholecystectomy right upper quadrant ultrasound. • Positive: • Positive anti-nuclear antibody (ANA 1:80) • Anti-smooth muscle antibody (ASMA 1:80) • Elevated immunoglobulins (IgG 2216 mg/dL, nl 700-1600)

  9. Liver Biopsy Low power (10x) - portal, parenchymal, and interface inflammation

  10. Liver Biopsy High power (40x) - portal area, mixed inflammatory infiltrate

  11. Drug-Induced Liver Injury (DILI) • Approximately 10 percent of all cases of acute hepatitis1; most common cause of acute liver failure in the USA2 • Over 1000 medications / herbals implicated3 • Clinical presentation: • Variable, asx failure; intrinsic vs idiosyncratic • Cholestatic, hepatocellular, mixed7 • R-value: ALT/ULN ÷ AP/ULN • R>5 = hepatocellular • R=2-5 = mixed • R<2 = cholestatic 1. ClinLiver Dis. 2000;4(1):73. 2. Ann Intern Med. 2002;137(12):947. 3. Swiss Med Wkly. 2010;140:w13080. 7. Am J Gastroenterol 2014; 109:950–966.

  12. Drug-Induced Liver Injury (DILI) • Diagnosis of exclusion, must establish causality • RUMAC Causal Assessment method7 • Diagnostic algorithm, scoring system • Methotrexate-induced liver injury4: • Abnormal LAEs generally resolve within 1 month of drug discontinuation; requires frequent monitoring (≤12weeks) 4. Arthritis Rheum. 2008;59(6):762. 7. Am J Gastroenterol 2014; 109:950–966.

  13. Autoimmune Hepatitis (AIH)5,8 • Epidemiology: Age 40s-50s, F:M 3.6 to 1, Prevalence 11-25/100,000 • Clinical Manifestations: Asymptomatic  Acute liver failure • Diagnosis: • Serology (auto-antibodies, Immunoglobulins, LAE) • Histology (interface hepatitis) • Exclude other chronic liver disease • Treatment: steroids +/- azathioprine / 6-MP 5. GastroenterolHepatol. 2010 Oct;25(10):1681-6. 8. ClinGastroenterolHepatol. 2004;2(7):625.

  14. Autoimmune Hepatitis (AIH)6 Concurrent autoimmune diseases common – clue to diagnosis 6. J ClinGastroenterol. 2010;44(3).

  15. Case update: LFTs normalized (AST 16 U/L, ALT 31 U/L) with corticosteroid treatment

  16. Take home points: DILI is common, has broad range of presentations DILI is diagnosis of exclusion In patients with other autoimmune conditions, elevated LAEs should prompt a workup for autoimmune hepatitis

  17. References 1. Zimmerman HJ. Drug-induced liver disease. ClinLiver Dis. 2000;4(1):73. 2. Ostapowicz et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States., U.S. Acute Liver Failure Study Group. Ann Intern Med. 2002;137(12):947. 3.Stirnimann G, Kessebohm K, Lauterburg B. Liver injury caused by drugs: an update. Swiss Med Wkly. 2010;140:w13080. 4. Saag et al, American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762. 5. Ngu JH, Bechly K, Chapman BA, Burt MJ, Barclay ML, Gearry RB, Stedman CA. Population-based epidemiology study of autoimmune hepatitis: a disease of older women? GastroenterolHepatol. 2010 Oct;25(10):1681-6. 6. Teufel et al. Concurrent AutoimmuneDiseases in Patients With Autoimmune Hepatitis. J ClinGastroenterol. 2010;44(3). 7. Chalasani et al. ACG Clinical Guideline: The Diagnosis and anagement of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol 2014; 109:950–966. 8. Kessler WR, Cummings OW, Eckert G, Chalasani N, Lumeng L, KwoPY. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis.ClinGastroenterolHepatol. 2004;2(7):625.

  18. Special thanks: • LCDR Manish B. Singla, MD, Member ACP, Gastroenterology, WRNMMC • COL (ret) Maria Sjogren, MD, Fellow ACP, Gastroenterology and Hepatology, WRNMMC • LCDR Jean Kemp, MD, Anatomic & Clinical Pathology, WRNMMC

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