Drug, Herbal and Dietary Supplement Induced Liver Injury
- Clinicians should be familiar with the three main types of hepatotoxicity when evaluating patients with suspected DILI.
- Direct hepatotoxins such as APAP can cause liver injury in nearly all exposed individuals once a threshold dose or duration of use is exceeded.
- Idiosyncratic DILI is largely independent of the dose and duration of medication use and characterized by a low incidence and variable drug latency and clinical and histological features.
- Idiosyncratic DILI is believed to arise from an aberrant adaptive host immune response to the drug and/or its metabolite(s).
- Indirect hepatotoxins are generally independent of the dose administered and have a variable latency and manifestations that arise from the biological action of the drug on the liver and/ or host immune system.
Proposed classification of DILI
|Mechanistic classification||Direct hepatotoxicity||Idiosyncratic hepatotoxicity||Indirect hepatotoxicity|
Epidemiology of idiosyncratic DILI
- The estimated annual incidence of idiosyncratic DILI in the general population is low (14–19/100,000) but higher in exposure-based studies using electronic medical record data (33–40/100,000).
- Antimicrobials, central nervous system agents, and anti-inflammatory agents are the most commonly implicated agents in the DILI series worldwide. However, HDS are most commonly implicated in some Asian countries and are increasingly implicated in Western countries as well.
- The daily dose of a medication, its lipophilicity, and extent of hepatic metabolism influence the risk of causing DILI when comparing medications.
- Insufficient data exist to confirm subject age, sex, and race and ethnicity as reliable risk factors for DILI susceptibility. However, some drugs are more likely to cause DILI in older individuals (e.g., amoxicillin-clavulanate, isoniazid), whereas others are more commonly implicated in children (valproate, minocycline).
- Medical comorbidities such as obesity and diabetes are associated with increased incidence and severity of DILI with specific drugs. However, the role of alcohol, tobacco, and diet in DILI susceptibility is not established.
- Patients with pre-existing liver disease are at increased risk of developing liver injury with selected drugs (e.g., methotrexate, anti-TB therapy). In addition, subjects with pre-existing liver disease are at increased risk of poor outcomes with a DILI episode.
- A polymorphism in PTPN22 is a genetic risk factor across multiple drugs and major ethnic groups. Various HLA alleles have also been associated with increased susceptibility to individual drugs, but the clinical utility of HLA testing in DILI diagnosis has yet to be determined.
Diagnostic approach to DILI
- Clinically significant DILI is typically defined as any one of the following: (1) serum AST or ALT > 5× ULN, or ALP > 2× ULN (or pretreatment baseline if baseline is abnormal) on two separate occasions; (2) total serum bilirubin > 2.5 mg/dl along with elevated AST, ALT, or ALP level; or (3) INR > 1.5 with elevated AST, ALT, or ALP.
- Most hepatotoxic drugs cause liver injury within the first 6 months of use but occasionally have longer latency intervals or may even present after drug discontinuation (e.g., amoxicillin-clavulanate). Therefore, evaluation of a patient with suspected DILI should include a detailed medication and HDS history within the 180 days before presentation.
- Idiosyncratic DILI cases should be categorized by the R value at presentation (R = (ALT/ULN)/(ALP/ULN)) into hepatocellular (R ≥ 5), mixed (2 < R < 5), and cholestatic (R ≤ 2) profiles, which can help guide the evaluation of alternative causes of liver injury.
- Excluding alternative causes of liver injury is required in all DILI cases, including testing for viral hepatitis, metabolic liver disease, AIH, and pancreaticobiliary disease.
- Certain drugs have been associated with specific laboratory and histologic phenotypes, termed signatures which may be useful in causality assessment.
- We recommend accessing the LiverTox website for a synopsis of the published literature on liver injury due to over 1000 prescription drugs and more than 60 HDS.
Liver biopsy in suspected DILI
- Liver biopsy is not required to make a diagnosis of idiosyncratic DILI but may be useful in DILI cases with a severe or protracted course and in those with diagnostic uncertainty. However, a biopsy is usually not required in mild or self-limited cases.
- A liver biopsy can help identify the hepatotoxic drugs based on specific histological patterns and can exclude concurrent liver diseases.
- A broad spectrum of histological patterns has been reported in patients with DILI, and a given drug may be associated with more than a single histopathological signature.
- The presence of eosinophils and granulomas on a liver biopsy in a patient with suspected DILI is associated with a more favorable outcome, whereas those who have necrosis or fibrosis have poorer outcomes.
- A liver biopsy from a patient with DILI may help determine the mechanism of injury, as was seen with the mitochondrial toxin fialuridine that led to microvesicular steatosis and necrosis.
- Currently there are three commonly used causality assessment methods, and each has its own strengths and limitations.
- Structured causality assessment instruments incorporate the dose, duration, and timing of suspect drug and other concomitant drug or HDS product use; an assessment of the laboratory, radiological, and histological features at presentation; and exclusion of competing causes of liver injury.
- The semiquantitative expert opinion causality assessment scale developed by the DILIN is frequently used in clinical practice and in prospective research studies, but the need for specialized expertise limits its generalizability.
- The updated RUCAM has improved user instructions and more complete diagnostic evaluation compared with the original RUCAM but retains risk factors of age, alcohol, and pregnancy that are of unclear value.
- The RECAM is a newly developed, computerized causality assessment instrument that may prove more reproducible and reliable than RUCAM but further validation studies are needed.
- Intentional suspect drug rechallenge is rarely undertaken in clinical practice, but when available, may prove useful in causality assessment.
Drug-Induced Liver Injury Network expert opinion scoring categories
|Causality score||Likelihood, %||Description|
- HDS are commonly used worldwide, with permissive standards of safety in the United States and other countries leading to the possibility of inaccurate labeling, adulteration, and contamination.
- Supplements can cause severe hepatotoxicity that can have variable clinical, laboratory, and histological phenotypes.
- Genetic polymorphisms in the HLA region and the conditions under which a product is consumed may influence the likelihood of an individual patient developing HDS hepatotoxicity.
- HLA-B 35:01 has been associated with hepatotoxicity attributed to GTE in White populations and P. multiflorum hepatotoxicity in Asian populations.
Recommended interventions for patients with idiosyncratic DILI
Diagnosis and management of APAP hepatotoxicity
|Recommendation||Intentional overdose||Unintentional overdose|
Management of APAP overdose
- APAP is a dose-dependent hepatotoxin that leads to acute pericentral liver injury when doses exceeding 4 g are ingested within a 24-h period or excessive doses over several days.
- APAP overdose is the leading cause of ALF among adults in the United States.
- A diagnosis of APAP hepatotoxicity relies on a history of excessive APAP ingestion, detection of an elevated serum APAP level following single-time-point ingestion, and exclusion of competing causes of acute hepatocellular liver injury.
- Gastric lavage and activated charcoal should be given to all patients presenting within 4 h of a single-time-point APAP overdose.
- Intravenous or orally administered NAC can prevent liver injury nearly completely if given within 12 h of ingestion, but is also recommended for patients presenting later.
- The prognosis in APAP-related ALF is related to the degree of encephalopathy, coagulopathy, and acidosis.
- Currently available serum markers of liver injury such as serum AST, ALT, and ALP levels are not sensitive or specific enough to detect early DILI.
- DILI research continues to be hampered by the lack of an objective, reliable laboratory test to confirm a particular drug as the correct suspect agent.
- DILI biomarkers in development are currently being directed toward improved DILI diagnosis and prognosis as well as to provide mechanistic insight into DILI pathogenesis.
- DILI registries worldwide should use standardized methods and protocols for clinical and biological sample collection and causality assessment to facilitate studies of DILI epidemiology, outcomes, and treatment.
- AIH: Autoimmune Hepatitis
- ALF: Acute Liver Failure
- ALP: Alkaline Phosphatase
- ALT: Alanine Aminotransferase
- APAP: Acetaminophen
- AST: Aspartate Aminotransferase
- DI-AIH: Drug-induced AIH
- DILIN: Drug-Induced Liver Injury Network
- DRESS: Drug Reaction With Eosinophilia And Systemic Symptoms
- GTE: Green Tea Extract
- HDS: Herbal And Dietary Supplements
- HLA: Human Leukocyte Antigen
- IMH: Immune-mediated Hepatitis
- INR: International Normalized Ratio
- NAC: N-acetylcysteine
- NRH: Nodular Regenerative Hyperplasia
- OPV: Obliterative Portal Venopathy
- RECAM: Revised Electronic Causality Assessment Method
- RUCAM: Roussel-Uclaf Causality Assessment Method
- SOS: Sinusoidal Obstruction Syndrome
- ULN: Upper Limit Of Normal
- VBDS: Vanishing Bile Duct Syndrome
- irAE: Immune-related Adverse Event(s)
Drug, Herbal and Dietary Supplement Induced Liver Injury
July 26, 2022
Country of Publication
Male, Female, Adult, Older adult
Health Care Settings
Nurse, nurse practitioner, physician, physician assistant
Diagnosis, Assessment and screening, Treatment, Management
D019587 - Dietary Supplements, D056486 - Chemical and Drug Induced Liver Injury, D019509 - Herbal, D029001 - Herbal Medicine
supplements, Idiosyncratic drug-induced liver injury, liver injury, dietary supplement, herbal supplement
Fontana RJ, Liou I, Reuben A, Suzuki A, Fiel I, Lee W, Navarro V. AASLD Practice Guidance on Drug, Herbal and Dietary Supplement Induced Liver Injury. Hepatology. 2022 Jul 27. doi: 10.1002/hep.32689. Epub ahead of print. PMID: 35899384.