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