Drug-induced liver injury (DILI) refers to liver damage caused by various prescription or over-the-counter chemical drugs, biological agents, herbal medicine, health supplements, dietary supplements, their metabolites, or even excipients. With the increasing variety of medications, the incidence of DILI has shown a rising trend, with an annual incidence rate of approximately 1–10 per 100,000. Clinically, DILI can present as acute or chronic liver injury, which may progress to cirrhosis and, in severe cases, result in acute liver failure or even death.
Pathogenesis
The mechanisms of DILI are generally divided into two categories: direct hepatotoxicity and idiosyncratic hepatotoxicity. Direct hepatotoxicity refers to the direct damage to the liver caused by the drug and/or its metabolites after ingestion. Idiosyncratic hepatotoxicity involves mechanisms such as metabolic abnormalities, mitochondrial damage, oxidative stress, immune injury, inflammatory responses, and genetic factors. Current research has identified a close relationship between genetic polymorphisms in the CYP450 enzyme family and HLA antigens and the occurrence of DILI.
Clinical Classifications
Mechanism-Based Classification
Intrinsic (Dose-Dependent) Type
This type is caused by the direct hepatotoxicity of the drug, often dose-dependent, predictable, with a short latency period, and shows little individual variability. It is relatively rare, as only drugs with a clear benefit-to-risk ratio are approved for market use.
Idiosyncratic Type
This type occurs only in a small subset of individuals exposed to the drug. It is generally not dose-dependent and cannot be predicted based on known pharmacological actions. Its occurrence is primarily associated with unique host characteristics, such as metabolic or immune idiosyncrasies.
Indirect Type
This type results from certain drugs exacerbating pre-existing liver diseases (e.g., chronic viral hepatitis or fatty liver) or altering the immune system, indirectly leading to liver injury. Examples include reactivation of viral hepatitis caused by high-dose corticosteroids or certain monoclonal antibodies, immune-mediated liver injury triggered by immune system activation (e.g., immune checkpoint inhibitor-induced liver injury), and drug-induced autoimmune-like hepatitis (DI-AIH).
Course-Based Classification
Acute DILI
This refers to liver damage caused by the drug itself or its metabolites, with a disease course generally less than 3 months and not exceeding 6 months.
Chronic DILI
This is defined as persistent abnormalities in serum ALT, AST, ALP, and TB levels 6 months after the onset of DILI, or evidence of portal hypertension or chronic liver injury on imaging or histology. Clinically, acute DILI accounts for the majority of cases, with 6%–20% progressing to chronic DILI. Cholestatic DILI is relatively more likely to progress to chronic disease.
Target Cell-Based Classification
Hepatocellular Injury Type
This type clinically resembles viral hepatitis, characterized by a significant elevation in serum ALT levels. Diagnostic criteria include ALT ≥3 times the upper limit of normal (ULN) and an R-value ≥5. The R-value is calculated as: R=[ALT (measured) / ALT ULN]/[ALP (measured) / ALP ULN].
ALT levels typically return to normal within 1–2 months after drug withdrawal. Histological findings include hepatocellular necrosis with eosinophil and lymphocyte infiltration in the portal area.
Cholestatic Type
This type primarily presents with jaundice and pruritus, with ALP ≥2 times ULN and an R-value ≤2. Histological features include bile canalicular cholestasis.
Mixed Type
This type exhibits clinical and pathological features of both hepatocellular injury and cholestasis, with ALT ≥3 times ULN, ALP ≥2 times ULN, and an R-value between 2 and 5.
Vascular Injury Type
This type is relatively rare, with unclear pathogenesis. Clinical subtypes include sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease, peliosis hepatis, Budd-Chiari syndrome, perisinusoidal fibrosis, and portal vein thrombosis.
Laboratory and Auxiliary Examinations
Laboratory Tests
Serum ALT levels are a sensitive marker for evaluating hepatocellular injury. Approximately 80% of AST is located in mitochondria, and its elevation indicates more severe hepatocellular damage. Drug-induced injury to hepatocytes or bile ducts can lead to elevated bilirubin, ALP, and γ-GT levels.
Imaging Studies
Ultrasound has diagnostic value for conditions such as liver cirrhosis, hepatic space-occupying lesions, fatty liver, and vascular liver diseases. CT provides greater diagnostic accuracy than ultrasound for liver cirrhosis and hepatic space-occupying lesions.
Liver Biopsy
In the diagnosis of DILI, liver biopsy is primarily used to exclude liver damage caused by other hepatobiliary diseases. The presence of eosinophilic infiltration, microvesicular fat droplets, or heavy metal deposits in liver tissue can support the diagnosis of DILI.
Diagnosis
Diagnosis is primarily based on the medication history, recovery after drug withdrawal, reactions upon re-administration, and laboratory evidence of hepatocellular injury or cholestasis. When clinical diagnosis is challenging, the internationally recognized RUCAM scoring system can be used to assist in diagnosis.
Differential Diagnosis
DILI must be differentiated from various conditions, including viral hepatitis, nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune liver disease, and metabolic/genetic disorders (such as Wilson's disease, hemochromatosis, and α1-antitrypsin deficiency).
Treatment
The first step is to discontinue and prevent the re-administration of drugs causing liver injury. Early removal and excretion of the drug should be prioritized, and drugs with similar pharmacological actions or chemical structures should be avoided as much as possible. Symptomatic and supportive treatment is required for patients with existing liver injury or liver failure.
Reduced glutathione (GSH), the primary antioxidant in the body, scavenges free radicals and inhibits lipid peroxidation of cell membranes, thereby mitigating liver damage. Glycyrrhizin-containing medications not only have anti-lipid peroxidation effects but also reduce serum transaminase levels. Polyene phosphatidylcholine binds to membranes, aiding in the repair, stabilization, and protection of biological membranes. S-adenosylmethionine enhances the synthesis of glutathione and cysteine through trans-sulfuration, countering free radical-induced liver damage. Taurine synthesized in the body combines with bile acids, increasing bile acid solubility, and has a preventive effect on intrahepatic cholestasis. For severe cases, N-acetylcysteine (NAC) may be used. NAC scavenges various free radicals, and its clinical efficacy is greater when administered early. Typical adult dosage is 50–150 mg/(kg·d), with a total treatment duration of no less than 3 days. The infusion rate should be carefully controlled during treatment to prevent adverse reactions. Ursodeoxycholic acid (UDCA), an endogenous hydrophilic bile acid, improves hepatocyte and bile duct cell secretion and has immunomodulatory effects.
The efficacy of glucocorticoids in DILI lacks robust evidence from randomized controlled trials. Their use should be carefully considered, particularly in patients with hypersensitivity or autoimmune features who do not show biochemical improvement or continue to deteriorate after discontinuing the offending drug. The potential benefits and risks of treatment must be weighed.
For severe cases of liver failure, treatment includes symptomatic and supportive care, removal of toxic drugs (e.g., artificial liver therapy), prevention and management of complications, and liver transplantation when necessary.
Prognosis
Most patients have a good prognosis if the offending drug is discontinued promptly. However, patients with severe liver damage have a poorer prognosis. Reports indicate that mortality rates vary among different types of DILI: approximately 12.7% for hepatocellular injury type, 7.8% for cholestatic type, and 2.4% for mixed type.
Prevention
Patients with a history of drug allergies, allergic constitutions, liver or kidney dysfunction, newborns, and those with nutritional deficiencies should be cautious in drug selection and dosage.
The use of potentially hepatotoxic drugs should be minimized.
Adverse reactions should be closely monitored during treatment with new drugs.