Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury

Patient Guideline Summary

Publication Date: April 30, 2021
Last Updated: March 3, 2023

Objective

Objective

This patient summary means to summarize key recommendations from the American College of Gastroenterology (ACG) for diagnosis and management of idiosyncratic drug-induced liver injury.

Overview

Overview

  • We will use the abbreviation (DILI) throughout this summary to refer to drug-induced liver injury.
  • If you have DILI, you will probably be seen by gastroenterologists (doctors who specialize in the digestive tract).
  • DILI has intrinsic or idiosyncratic types. “Intrinsic” DILI refers to drugs that can cause liver injury predictably in humans or in animal models when given in sufficiently high doses. Acetaminophen (APAP) is perhaps the best-known and widely used drug to cause intrinsic DILI. “Idiosyncratic” DILI is less common, affects only susceptible individuals, has less consistent relationship to dose, and is more varied in its presentation.
  • Certain variables such as age, sex, and alcohol drinking may increase risk of DILI in a drug-specific fashion.
  • Diagnostic and therapeutic guidelines for APAP hepatotoxicity (ability to poison the liver) are well established. Therefore, this summary is limited to idiosyncratic DILI because it is more difficult to diagnose and treat.

Diagnosis of DILI

Diagnosis of DILI

  • Your doctor will take a detailed history related to medication and other chemical exposures when DILI is suspected.
  • DILI is a diagnosis of exclusion, which requires eliminating other causes in a systematic pattern.
  • Based on the R-value (used to define the pattern of liver injury) at presentation, DILI can be categorized into hepatocellular (related to the liver itself), cholestatic (related to the biliary system that flows through the liver), or mixed types:
    • R > 5 is labeled as hepatocellular DILI,
    • R < 2 is labeled as cholestatic DILI, and
    • 2 < R < 5 (R between 2 and 5) is labeled as mixed DILI.
  • Liver biopsy can support a clinical suspicion of DILI, provide important information regarding disease severity, and help exclude competing causes of liver injury.
  • If you have suspected hepatocellular or mixed DILI:
    • Your doctor will probably try to exclude acute viral hepatitis (A, B, and C) and autoimmune hepatitis (AIH) with standard serologies and hepatitis C virus (HCV) RNA testing.
    • Your doctor may order anti–hepatitis E virus (HEV) immunoglobulin (Ig)M testing if there is heightened clinical suspicion (e.g., recent travel to an endemic area, DILI phenotype is atypical, or there is no readily identifiable culprit agent).
    • Your doctor will probably order testing for acute cytomegalovirus, acute Epstein-Barr virus, or acute herpes simplex virus infection if classical viral hepatitis has been excluded or clinical features such as atypical lymphocytosis (an increase in white blood cells called lymphocytes) and lymphadenopathy (disease affecting the lymph nodes) suggest these causes.
    • ACG recommends evaluation for Wilson disease (a disease where copper accumulates in the liver and other organs) and Budd-Chiari syndrome (a disease with blocked liver veins) and possibly other conditions when clinically appropriate.
  • If you have suspected cholestatic DILI:
    • Your doctor will probably order abdominal imaging (ultrasound, computed tomography scan, and magnetic resonance imaging (MRI) in all instances to exclude biliary tract pathology and infiltrative processes.
  • When does your doctor considers a liver biopsy?
    • if AIH remains a possible cause of your problem and if immunosuppressive therapy is considered.
    • if there is a constant rise in liver biochemistries (tests) or signs of worsening liver function despite stopping the suspected offending agent.
    • if peak alanine aminotransferase (ALT) (a liver enzyme) test level has not fallen by >50% at 30–60 days after onset in cases of hepatocellular DILI, or if peak alkaline phosphatase (ALP) (a liver enzyme) has not fallen by >50% at 180 days in cases of cholestatic DILI despite stopping the suspected offending agent.
    • in cases of DILI where continued use or re-exposure to the suspected agent is considered.
    • if liver biochemistry test abnormalities persist beyond 180 days, especially if associated with symptoms (e.g., itching) or signs (e.g., jaundice (yellow coloring of skin and eyes) and hepatomegaly (enlarged liver)), to evaluate for the presence of chronic liver diseases (CLDs) and chronic DILI.

Prognosis for DILI

Prognosis for DILI

  • Your doctor has available reliable information to calculate your risk of each of these diseases.

Treatment of DILI

Treatment of DILI

  • Your doctor will probably stop the suspected agent(s) immediately if you have suspected DILI, especially when liver tests are rising rapidly or there is evidence of liver dysfunction.
  • Although no definitive therapies are available either for idiosyncratic DILI with or without acute liver failure (ALF), ACG suggests consideration of N-acetylcysteine (NAC) treatment if you have early-stage ALF, given its good safety profile and some evidence for efficacy in early coma stage patients.
  • ACG suggest against using NAC for children with severe DILI leading to ALF.
  • Although there are no good studies to either recommend or refute corticosteroid therapy (cortisone) if you have DILI, they may be considered if you have DILI exhibiting AIH-like features.

Hepatotoxicity of some herbal and dietary supplements (HDS)

Hepatotoxicity of some herbal and dietary supplements (HDS)

Management:
  • Please report use of HDS to your health care providers and be reminded that supplements are not subjected to the same rigorous testing for safety and efficacy as are prescription medications.
  • Your doctor will probably apply the same diagnostic approach for DILI to suspected HDS-hepatotoxicity and exclude other forms of liver injury.
  • Your doctor will probably stop all HDS if you have suspected HDS hepatotoxicity and will continue monitoring for resolution of liver injury.
  • You doctor will probably consider evaluating you for liver transplantation if you develop ALF and severe cholestatic injury from HDS-DILI.

DILI in patients with chronic liver disease (CLD)

DILI in patients with chronic liver disease (CLD)

  • Since the diagnosis of DILI in patients with CLD requires a high index of suspicion, ACG recommends exclusion of other more common causes of acute liver injury including a flare-up of the underlying liver disease.
  • Your doctor decision to use potentially hepatotoxic drugs if you have CLD will be based on the risk vs. benefit of the proposed therapy on a case-by-case basis.
  • Please promptly report any new symptoms such as scleral icterus (yellow coloring of the white part of your eyes), abdominal pain/discomfort, nausea/vomiting, itching, or dark urine. In addition, your doctor may monitor serum liver tests at 4–6 weekly intervals, especially during the initial 6 months of treatment with a potentially hepatotoxic agent.

DILI in children

DILI in children

  • Children may rarely develop DILI. Antibiotics such as minocycline (often used for facial acne) and anti-epileptic agents (drugs to treat seizures) are the most common agents for DILI in children in the United States.
  • Pediatric DILI is a life-threatening condition that may require a liver transplantation.
  • Minocycline DILI may stay in your body for over a year and can look like AIH. Adolescents who appear to have AIH will be carefully questioned about their minocycline use for facial acne.

Abbreviations

  • ACG: American College Of Gastroenterology
  • AIH: Autoimmune Hepatitis
  • ALF: Acute Liver Failure
  • ALP: Alkaline Phosphatase
  • ALT: Alanine Aminotransferase
  • APAP: Acetaminophen
  • CLD: Chronic Liver Disease
  • DILI: Drug Induced Liver Injury
  • HCV: Hepatitis C Virus
  • HDS: Herbal And Dietary Supplements
  • HEV: Hepatitis E Virus
  • Ig: Immunoglobulin
  • MRI: Magnetic Resonance Imaging
  • NAC: N-acetylcysteine

Source Citation

Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol. 2021 May 1;116(5):878-898. doi: 10.14309/ajg.0000000000001259. PMID: 33929376.

Disclaimer

The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.