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Drug / toxin induced hepatitis

Drug / toxin induced hepatitis (DILI)-general

Author: Anthony W.H. Chan, M.B.Ch.B.

Editorial Board Member: Aaron R. Huber, D.O.

Deputy Editor-in-Chief: Catherine E. Hagen, M.D.

Last author update: 21 July 2022

Last staff update: 21 July 2022

Copyright: 2002-2022, PathologyOutlines.com, Inc.

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Table of Contents

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

10 - 20/100,000 based on prospective population based studies (Hepatology 2002;36:451, Am J Gastroenterol 2012;107:1380, Gastroenterology 2013;144:1419)
Leading cause of acute liver failure and one of the major reasons for liver transplantation in the U.S. and Europe (Hepatology 2010;52:2065)
Conventional medications are the most common cause of idiosyncratic DILI in the U.S. and Europe, whereas herbal medicine and dietary supplements are the major cause in Asia (Liver Int 2007;27:465)

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

34 year old woman with acute cholestatic hepatitis after Moderna vaccination (J Hepatol 2022 Apr 18 [Epub ahead of print])
39 year old woman with acute cholestatic hepatitis after herbal supplement containing ashwagandha root extract (J R Coll Physicians Edinb 2021;51:363)
51 year old man with vanishing bile duct syndrome after infliximab for malignant melanoma (Cureus 2022;14:e21940)
61 year old woman with secondary sclerosing cholangitis after apatinib and vinorelbine for metastasis breast cancer (Thorac Cancer 2021;12:1912)
80 year old woman with amiodarone induced submassive necrosis in background of cirrhosis (ACG Case Rep J 2015;2:116)

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

Morphological patterns can be categorized into the following:
- Necroinflammatory injury:
  - Acute hepatic necrosis: acetaminophen, carbon tetrachloride
  - Drug induced autoimmune hepatitis: diclofenac, halothane, indomethacin, infliximab, methyldopa, minocycline, nitrofurantoin, statins (J Hepatol 2019;70:1222)
  - Granulomatous hepatitis: allopurinol, carbamazepine, methyldopa, phenytoin, quinidine, sulphonamides (J Hepatol 2019;70:1222)
- Cholestatic injury:
  - Bland cholestasis: oral contraceptives
  - Acute cholestatic hepatitis: amoxicillin / clavulanate, phenothiazines (Gut 1992;33:368)
  - Chronic cholestatic injury: chlorpromazine, azathioprine, androgens, amoxicillin clavulanate, carbamazepine, chlorpromazine, erythromycin, estradiol, flucloxacillin, phenytoin, terbinafine, cotrimoxazole (Hepatology 1994;20:1437, J Hepatol 2019;70:1222)
- Steatosis and steatohepatitis:
  - Microvesicular steatosis: amiodarone, didanosine, stavudine, valproate, zalcitabine, aspirin (Reye syndrome) (J Hepatol 2019;70:1222)
  - Macrovesicular steatosis and steatohepatitis: corticosteroids, 5-fluorouracil, irinotecan, methotrexate, tamoxifen (J Hepatol 2019;70:1222)
- Vascular lesion:
  - Sinusoidal obstruction syndrome: antineoplastic cytotoxic agents (Paediatr Drugs 2010;12:277)
  - Budd-Chiari syndrome: oral contraceptives, dacarbazine (Postgrad Med J 2015;91:692)
  - Nodular regenerative hyperplasia: azathioprine, busulphan, bleomycin, cyclophosphamide, chlorambucil, cysteine arabinoside, carmustine, doxorubicin, 6-thioguanine, oxaliplatin (J Hepatol 2019;70:1222)
  - Sinusoidal dilatation and peliosis: oral contraceptives (Dig Liver Dis 2015;47:e10)
- Neoplasm and neoplasm-like lesion:
  - Focal nodular hyperplasia (FNH): oral contraceptives (not associated with FNH pathogenesis; associated with larger and more symptomatic FNH)
  - Hepatocellular adenoma: oral contraceptives, anabolic steroids (J Gastroenterol 2000;35:557)
  - Angiosarcoma and cholangiocarcinoma: thorotrast (Hepatology 1995;22:1674, Cancer 1982;49:2161)
- Adaptive change:
  - Pseudo ground glass inclusion: barbiturates, diazepam, cyanamide, transplant patients on multiple immunosuppressive drugs (steroids, tacrolimus and mycophenolate mofetil) (J Clin Pathol 2009;62:481)

Microscopic (histologic) images

Contributed by Anthony W.H. Chan, M.B.Ch.B.

Hathothane associated hepatocellular necrosis

Methotrexate associated steatohepatitis

Herb associated acute cholestatic hepatitis

Virtual slides

Images hosted on other servers:

Acetaminophen induced acute hepatic necrosis

Electron microscopy description

Amiodarone: lamellar lysosomal inclusion bodies representing phospholipidosis (Hum Pathol 1990;21:59)

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?

Corticosteroid
Didanosine
Methotrexate
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?

Azathioprine
Ethanol
Oral contraceptive pill
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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