Isoniazid Hepatotoxicity Requiring Liver Transplantation

Abstract

A 65-year-old female Peruvian immigrant was initially evaluated for potential initiation of anti-tumor necrosis factor (TNF)-a therapy for her poorly controlled rheumatoid arthritis. The patient had a history of thyroid cancer that had required thyroidectomy and replacement levothyroxine. The patient’s quantiferon test was positive, and she also had a history of aspartate transaminase (AST) and alanine transaminase (ALT) values between 40 and 60 IU/ L for at least the previous 4 years. Previous laboratory evaluation had revealed a positive anti-nuclear antibody (ANA) titer at dilution of 1:640 with homogeneous pattern, positive anti-smooth muscle antibody, and elevated immunoglobulin G (IgG) levels at 2,310 mg/dL. The patient, however, denied any prior history of chronic liver disease; consequently, no further evaluation was pursued. Isoniazid (INH) prophylaxis for latent tuberculosis infection (LTBI), was instituted for an expected nine-month course. The patient did not take any dietary or herbal supplements and did not drink alcohol. One month after initiating INH, the patient sought evaluation for jaundice, nausea, and fatigue. Her total bilirubin level was 11.3 mg/ dL, direct bilirubin level 8.6 mg/dL, AST 1,642 IU/L, ALT 1,576 IU/L, alkaline phosphatase 246 IU/L, albumin 3.0 g/ dL, and international normalized ratio 1.2. Serologic testing for acute viral hepatitis was negative. Because of presumed INH hepatotoxicity, INH was discontinued. Two weeks later, the patient complained of worsening nausea as well as new-onset ascites and lower extremity edema. Her total bilirubin was 27.8 mg/dL, direct bilirubin 21.6 mg/ dL, AST 726 IU/L, ALT 588 IU/L, alkaline phosphatase 254 IU/L, albumin 2.4 g/dL, and international normalized ratio 1.8. Triphasic contrast CT imaging demonstrated a shrunken and nodular liver and moderate-volume ascites. The patient was treated with spironolactone, furosemide, and subcutaneous vitamin K, but continued to feel poorly. Two weeks later, she developed encephalopathy with worsening renal insufficiency and international normalized ratio rising to 2.3. She was transferred to Stanford Hospital for urgent liver transplant evaluation. Upon transfer, WBC was 14.2 K/lL, platelet count 112 K/lL, sodium level 126 mmol/L, potassium level 5.4 mmol/L, CO2 18 mmol/L, BUN 57 mg/dL, creatinine 2.9 mg/dL, AST 229 IU/L, ALT 251 IU/L, total bilirubin 26.1 mg/dL, alkaline phosphatase 502 IU/L, albumin 1.4 g/dL, and international normalized ratio 2.6. The patient’s model for end-stage liver disease (MELD) score was 40. Expedited transplant evaluation was initiated, and supportive care was provided with lactulose, rifaximin, and intravenous albumin. The patient also received intravenous vitamin K as well as fresh frozen plasma transfusions. Despite these measures, the patient experienced worsening encephalopathy, azotemia, and hepatic synthetic dysfunction. On E. Sheen (&) M. H. Nguyen Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, Stanford University, Alway Building, Room M-211, 300 Pasteur Drive, Stanford, CA 94305, USA e-mail: esheen@stanford.edu