Liver & intrahepatic bile ducts

Drug / toxin induced hepatitis

Drug / toxin induced hepatitis (DILI)-general


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Deputy Editor-in-Chief: Catherine E. Hagen, M.D.
Anthony W.H. Chan, M.B.Ch.B.

Last author update: 21 July 2022
Last staff update: 21 July 2022

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PubMed Search: Drug / toxin induced hepatitis

Anthony W.H. Chan, M.B.Ch.B.
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Cite this page: Chan AWH. Drug / toxin induced hepatitis (DILI)-general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/liverdrugtoxingeneral.html. Accessed August 17th, 2022.
Definition / general
  • Liver injury associated with exposure to certain drugs or toxins
  • Drug / toxin reactions can be intrinsic or predictable when they are dose dependent (e.g., acetaminophen) or idiosyncratic and unpredictable when they are dose independent (e.g., isoniazid)
Essential features
  • Diagnosis is based on the likelihood of DILI: time to onset, time to recovery, clinicopathological phenotype, exclusion of other causes, potentially offensive drug / toxin being a known cause of liver injury, and response to re-exposure
  • Very wide range of clinical and pathological presentations
ICD coding
  • ICD-10: K71.6 - toxic liver disease with hepatitis, not elsewhere classified
Epidemiology
Pathophysiology
  • Underlying mechanisms include direct / indirect toxicity, aberrant metabolism producing toxic metabolites and immune mediated hypersensitivity
Etiology
  • Drug dependent risk factors (J Hepatol 2019;70:1222):
    • Dose
    • Hepatic drug metabolism
    • Lipophilicity
    • Special moieties: toxic metabolite, oxidative stress, mitochondrial liability, hepatobiliary transport inhibition
    • Concomitant drug / toxin
  • Host dependent risk factors (J Hepatol 2019;70:1222):
    • Age
    • Gender
    • Ethnicity
    • Alcohol consumption
    • Pregnancy
    • Underlying liver disease or comorbidity
Clinical features
  • Very wide range of clinical and pathological presentations can result; the time of onset after drug exposure varies from hours to months
  • Clinical manifestations range from asymptomatic deranged liver function to fulminant hepatic failure and death
  • Mimics all forms of acute, chronic, vascular or neoplastic liver diseases caused by other etiologies
  • Reference: J Hepatol 2019;70:1222
Diagnosis
  • Diagnosis is based on likelihood of DILI
    • Time to onset
    • Time to recovery
    • Clinicopathological phenotype
    • Exclusion of other causes
    • Potentially offensive drug / toxin being a known cause of liver injury
    • Response to re-exposure
  • LiverTox, which is produced by NLM (National Library of Medicine) and NIDDK (National Institute of Diabetes and Digestive and Kidney Disease), provides up to date, accurate and easily accessed information on drug induced liver injury
Laboratory
  • R value = [serum alanine aminotransferase (ALT) / upper limit of normal (ULN)] / [serum alkaline phosphatase (ALP) / ULN]
    • Hepatocellular injury: R value ≥ 5 or ALT elevation ≥ 5 fold above ULN
    • Cholestatic injury: R value ≤ 2 or ALP elevation ≥ 2 fold above ULN
    • Mixed injury: R value between 2 and 5
  • Liver biopsy may be considered in suspected DILI if:
    • Elevated serum autoimmune markers
    • Disease progresses or fails to resolve on withdrawal of suspected agent
  • Reference: J Hepatol 2019;70:1222
Prognostic factors
  • 5 - 20% may develop chronic DILI (Hepatology 2006;44:1581, Gastroenterology 2014;147:96, Gastroenterology 2019;156:2230)
  • DILI severity grading (U.S. Drug Induced Liver Injury Network) (Hepatology 2010;52:730)
    • Score 1 (mild): elevated ALT or ALP but total bilirubin < 2.5 mg/dL and international normalized ratio (INR) < 1.5
    • Score 2 (moderate): elevated ALT or ALP and total bilirubin ≥ 2.5 mg/dL or INR ≥ 1.5
    • Score 3 (moderate - severe): elevated ALT, ALP, total bilirubin or INR and hospitalization or ongoing hospitalization is prolonged because of a DILI episode
    • Score 4 (severe): elevated ALT or ALP and total bilirubin ≥ 2.5 mg/dL and at least 1 of the following:
      • Liver failure (INR > 1.5, ascites or encephalopathy)
      • Other organ failure due to DILI
    • Score 5 (fatal): death or liver transplantation due to DILI
Case reports
Treatment
  • Most patients recover spontaneously after withdrawal of offensive agent
  • Specific therapy targeted for specific forms of DILI:
    • Steroid for drug induced autoimmune hepatitis or those with marked hypersensitivity features
    • Ursodeoxycholic acid for drug induced chronic cholestasis
    • N-acetylcysteine for acetaminophen hepatoxicity
    • Carnitine for valproate hepatotoxicity
  • Reference: J Hepatol 2019;70:1222
Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Anthony W.H. Chan, M.B.Ch.B.
Hathothane associated hepatocellular necrosis

Hathothane associated hepatocellular necrosis

Methotrexate associated steatohepatitis

Methotrexate associated steatohepatitis

Herb associated acute cholestatic hepatitis

Herb associated acute cholestatic hepatitis

Virtual slides

Images hosted on other servers:
Acetaminophen induced acute hepatic necrosis

Acetaminophen induced acute hepatic necrosis

Electron microscopy description
Sample pathology report
  • Liver, biopsy:
    • Intrahepatic cholestasis without any significant necroinflammatory activity or fibrosis (see comment)
    • Comment: The histological features are those of bland cholestasis. Differential diagnoses include drug induced liver injury, sepsis, shock, paraneoplastic syndrome, intrahepatic cholestasis of pregnancy and familial disorders of bile acid transporter. According to the case note, the patient has used oral contraceptive pills for a few months. Oral contraceptive pills are one of the most common medications associated with drug induced bland cholestasis. Recommend correlation with clinical impression, drug history and disease progress after withdrawal of the oral contraceptive pill.
Board review style question #1
Which medication is associated with microvesicular steatosis?

  1. Corticosteroid
  2. Didanosine
  3. Methotrexate
  4. Tamoxifen
Board review style answer #1
B. Didanosine. Didanosine is associated with microvesicular steatosis, whereas the other 3 drugs are associated with macrovesicular steatosis.

Comment Here

Reference: Drug / toxin induced hepatitis (DILI) - general
Board review style question #2

A patient was found to have an incidental liver tumor during routine checkup. You received the wedge excision of the liver tumor. Microscopic examination revealed a well differentiated hepatocellular neoplasm. The hepatocytes were bland and arranged in trabeculae of up to 2 cells with intact reticulin framework. Unpaired arterioles were noted. Which medication is associated with this hepatic mass lesion?

  1. Azathioprine
  2. Ethanol
  3. Oral contraceptive pill
  4. Thorotrast
Board review style answer #2
C. Oral contraceptive pill. The description of the tumor is typical for hepatocellular adenoma. Oral contraceptive pills are a risk factor associated with hepatocellular adenoma.

Comment Here

Reference: Drug / toxin induced hepatitis (DILI) - general
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