Case Presentation: A healthy 44-year-old woman with latent TB on isoniazid (INH) for 6 months was sent to the hospital by her primary care physician for elevated liver tests and right sided abdominal pain, anorexia, and jaundice for two weeks. She had normal liver tests prior to starting INH. She denied illicit drugs, alcohol or herbal supplement use and has no family history of liver or autoimmune diseases. On presentation, she was tachycardic, jaundice, with altered mental status and asterixis. Blood tests are summarized in Table 1. MELD-Na score was 24. Abdominal ultrasonogram with doppler showed mild subcapsular nodularity in the liver and a normal biliary tree. Workup for metabolic, viral, and immune mediated causes of liver injury was negative. She underwent transjugular liver biopsy due to clinical deterioration, which showed submassive necrosis, hepatocellular dropout, and lobular inflammation with no evidence of fibrosis, consistent with acute cholestatic injury. Diagnosis of INH-induced hepatocellular liver injury with liver failure was confirmed (Figure 1A-D). She was started on oral furosemide, ursodiol, and completed two rounds of intravenous n-acetyl cysteine (NAC) protocol for non-acetaminophen DILI.At discharge, her abdominal pain and encephalopathy resolved, and her liver enzymes and INR downtrended. At one month outpatient follow-up, the patient was asymptomatic, though her liver enzymes remained mildly elevated (Table 1).

Discussion: DILI is the most common cause of acute liver failure in the United States and is a diagnosis of exclusion. INH is considered an idiosyncratic cause of DILI and is not dose dependent. The mechanism is thought to be due to direct toxicity of free radicals generated by metabolites1 or secondary to an immune response2. INH also inhibits the production of several cytochrome p450 enzymes, increasing the hepatotoxicity of other drugs. Mild INH-hepatotoxicity is asymptomatic, with mildly elevated serum aminotransferases. Severe hepatitis occurs in up to 1% of patients3, is symptomatic and can be fatal. Most present within 2 to 3 months of starting therapy, though cases from 1 week to 14 months have been reported. Patient characteristics can increase susceptibility to INH hepatotoxicity such as alcoholism, viral hepatitis, advanced age, Asian background, slow acetylator status, and female sex4. The idiosyncratic nature INH hepatotoxicity makes the clinical course and prognosis difficult to predict. Our patient was treated medically without need for liver transplant, which was reported in some cases of acute liver failure5. Aside from stopping the offending agent, no definitive treatment exist for DILI. Guidelines suggest consideration of NAC therapy and few studies exist regarding the use of corticosteroid therapy6. Despite known INH hepatotoxicity, there are no standard guidelines for monitoring liver tests. The CDC does not recommend routine testing unless the patient has baseline abnormalities or is at increased risk of hepatotoxicity7. The American Thoracic Society suggests baseline and monthly follow-up tests be obtained in high-risk patients and individuals over the age of 354.

Conclusions: Our case highlights INH hepatotoxicity causing sub-acute fulminant hepatitis with liver failure. Health care providers should be more vigilant on risk stratification of hepatotoxicity when prescribing INH and raise the patient’s awareness regarding signs of potential liver injury to prevent significant INH hepatotoxicity and fatal outcomes.

IMAGE 1: Table 1: Patient Lab Values

IMAGE 2: Figure 1: Liver Biopsy. A. Bile ductular proliferation and hepatocellular collapse with ceroid laden macrophages (20x H&E). Arrow: ceroid laden macrophages. Arrowhead: bile ductules B.Ceroid laden macrophages highlighted by PAS stain after diastase (20x PAS/D). Arrow: ceroid laden macrophages. Arrowhead: bile ductules C. Reticulin stain demonstrating hepatocellular collapse and prominent bile ductular proliferation (20x reticulin). Arrowhead: bile ductules D. Trichrome stains demonstrating hepatocellular collapse (faint blue staining) and prominent bile ductular proliferation (20x trichrome). Arrowhead: bile ductules