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|
|Reproduced in animal models||Yes||No||Not usually|
|Latency||Rapid (days)||Variable (days to years)||Delayed (months)|
|Phenotypes of injury||Serum AST, ALT, or ALP elevations, hepatic necrosis, acute fatty liver, nodular regeneration||Mixed or cholestatic hepatitis, bland cholestasis, chronic hepatitis||Immune-mediated hepatitis, fatty liver, chronic hepatitis|
|Examples||Acetaminophen, niacin, intravenous methotrexate||Amoxicillin-clavulanate, cephalosporins, isoniazid, nitrofurantoin||Immune checkpoint inhibitors, anti-CD20 monoclonal Ab, protein kinase inhibitors|
|Touted mechanism of injury||Intrinsic hepatotoxicity that is dose-dependent||Idiosyncratic host metabolic or immune reaction||Indirect effect on liver or host immunity|
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|
|1. Definite beyond any reasonable doubt||> 95|
|2 Highly likely||75–95||Clear and convincing data, but not definite|
|3. Probable||50–74||Most data support causal relationship|
|4. Possible||25–49||Most data suggest no causal relationship, but possibility remains|
|5. Unlikely||< 25||Causal relationship very unlikely, with alternative etiology more likely|
|6. Insufficient data||Determinable||Missing key data|
- 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
|APAP analgesics||Mild to moderate pain||2 g maximum per day in divided doses||Consider short acting opiates if moderate to severe pain|
|Antiemetics||Moderate nausea/vomiting||Per package insert|
|Ursodeoxycholic acid||Severe pruritus||10–15 mg/kg in divided doses||Prospective efficacy data lacking; likely safe|
|Hospitalization||Dehydrated, coagulopathic, encephalopathic patients||NA||Transfer to transplant center if ALF|
|N-acetylcysteine||Hospitalized with ALF||See Table 10 for dosing; 72-h duration in studies||Requires cardiac monitoring (i.v.); greatest benefit in early-stage ALF|
|Corticosteroids||Severe hypersensitivity reactions; DRESS; checkpoint inhibitor with ALT > 5× ULN; histology showing AIH-like features||1 mg/kg per day of methylprednisolone equivalents for ICI cases; 40–60 mg of prednisone for others||Optimal dose and duration not established but frequently can be tapered in 1–3 months|
|l-carnitine||Valproate with hyperammonemia (hospitalized children)||100 mg/kg load followed by 50 mg/kg every 8 h||Short-term use|
|Cholestyramine||Leflunomide cases with persistent cholestasis||1 packet every 6–8 h for 14 days||Taper once cholestasis/pruritus resolves; give separately from other medications|
|Penicillin (i.v.)/silymarin and dialysis||Amanita mushroom toxicity||Hospitalized patients or ALF||Short-term use to remove enterohepatic toxin|
|Defibrotide (i.v.)||Hematopoietic cell transplant recipients with severe sinusoidal obstruction syndrome||6.25 mg/kg every 6 h for > 21 days up to a maximum of 60 days||Shown to improve survival in children and adults compared with historical controls|
Diagnosis and management of APAP hepatotoxicity
|Recommendation||Intentional overdose||Unintentional overdose|
|Time of ingestion||Single time point||Several days of repeated use|
|Dose||Supratherapeutic (typically > 4 g over 24 h)||Repeated therapeutic (up to 4 g per day) or supratherapeutic dosing|
|Presence of coingestants||Diphenhydramine and other sedatives can lead to central nervous system depression||Opioids often used in combination|
|Liver injury parameters||From time of ingestion: 24–72 h: rapid rise in ALT to > 1000 IU/L associated with variable rise in INR; total bilirubin is typically < 10 mg/dl. 72–96 h: Biochemical elevations peak, and can progress to acute liver failure or rapid and full recovery||Presentation is often delayed, but still see rapid rise in ALT to > 1000 IU/L, associated with rise in INR. Comorbid conditions, such as alcohol use, can affect total bilirubin levels. Eventually, liver injury can progress to acute liver failure or recovery|
|Serum APAP level||Use modified Rumack-Matthew nomogram to estimate risk of hepatotoxicity||Often undetectable at initial presentation. APAP-protein adducts useful but assay not commercially available|
|Excluding other causes of acute liver injury||Review clinical history to exclude risk factors for hepatic ischemia and perform tests for acute viral hepatitis|
|GI decontamination||Activated charcoal (1 g/kg, max dose 50 g) if within 4 h of ingestion. Gastric lavage also used in some cases||Usually not helpful nor recommended|
|N-acetylcysteine||Oral dosing: 140 mg/kg load followed by 70 mg/kg every 4 h; antiemetics as needed. Intravenous dosing: preferred if intolerant of oral intake/ileus or pregnant; telemetry monitoring recommended 150 mg/kg load over 15–60 min, followed by 50 mg/kg (12.5 mg/kg/h) over the next 4 h then 100 mg/kg (6.25 mg/kg/h) over 16 h thereafter (total 300 mg/kg over 24 h). For those with evidence of liver injury, treatment is extended at 6.25 mg/kg/h until ALT is decreasing and INR is < 2|
|Evidence of acute liver failure (coagulopathy and encephalopathy)||Close monitoring in intensive care unit and consider prompt referral to a liver transplant center|
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
American Association for the Study of Liver Diseases
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.