JEFFREY E ICKHOFF, MD PGY3 NAVY ACP 2014
Medication DILI-emma: The Masquerade of Drug Induced Liver Injury
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Disclaimer
Objectives
Case presentationDrug-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 hepatotoxicityFinal diagnosis
Epidemiology, presentation, diagnosis, treatment
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
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
LAE trends:
9/11/2
013
10/2/2
013
10/23/2
013
11/13/2
013
12/4/2
013
12/25/2
013
1/15/2
014
2/5/2
014
2/26/2
014
3/19/2
014
4/9/2
014
4/30/2
014
5/21/2
014
6/11/2
0140
50
100
150
200
250
300
350
400
450
500
AST (U/L) (Ref 0-32)ALT (U/L) (Ref 0-33)Alk Phos (U/L) (Ref 35-104)
Stopped
MTX
Restarted MTXStopped MTX
LAE trends:
9/11/2
013
10/2/2
013
10/23/2
013
11/13/2
013
12/4/2
013
12/25/2
013
1/15/2
014
2/5/2
014
2/26/2
014
3/19/2
014
4/9/2
014
4/30/2
014
5/21/2
014
6/11/2
0140
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Total bili (mg/dL) (Ref 0-1.0)Albumin (g/dL) (Ref 3.5-5.2)
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)
Liver Biopsy
Low power (10x) - portal, parenchymal, and interface inflammation
Liver Biopsy
High power (40x) - portal area, mixed inflammatory infiltrate
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. Clin Liver 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.
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.
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. Gastroenterol Hepatol. 2010 Oct;25(10):1681-6. 8. Clin Gastroenterol Hepatol. 2004;2(7):625.
Autoimmune Hepatitis (AIH)6
Concurrent autoimmune diseases common – clue to diagnosis6. J Clin Gastroenterol. 2010;44(3).
Case update:LFTs normalized (AST 16 U/L, ALT 31 U/L) with corticosteroid
treatment
9/11/2
013
10/6/2
013
10/31/2
013
11/25/2
013
12/20/2
013
1/14/2
014
2/8/2
014
3/5/2
014
3/30/2
014
4/24/2
014
5/19/2
014
6/13/2
014
7/8/2
014
8/2/2
014
8/27/2
0140
50100150200250300350400450500
AST (U/L) (Ref 0-32)ALT (U/L) (Ref 0-33)Alk Phos (U/L) (Ref 35-104)
After
treatment
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
References 1. Zimmerman HJ. Drug-induced liver disease. Clin Liver 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? Gastroenterol Hepatol. 2010 Oct;25(10):1681-6.
6. Teufel et al. Concurrent Autoimmune Diseases in Patients With Autoimmune Hepatitis. J Clin Gastroenterol. 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, Kwo PY. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis.Clin Gastroenterol Hepatol. 2004;2(7):625.
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