Drug-Induced Liver Injury (DILI)

Mohamed Asir *

Clinical Pharmacist, Kauvery Hospital, Tirunelveli, Tamil Nadu

*Correspondence

Abstarct

Drug-induced liver injury (DILI) is a significant cause of acute and chronic liver disease and represents the leading cause of acute liver failure in many countries. It can result from prescription medications, over-the-counter drugs, herbal products, and dietary supplements. The pathogenesis of DILI involves direct hepatotoxicity, metabolic activation producing toxic metabolites, mitochondrial dysfunction, oxidative stress, and immune-mediated mechanisms. Several factors increase susceptibility, including age, sex, alcohol consumption, pre-existing liver disease, and genetic predisposition. Clinical manifestations range from asymptomatic elevations of liver enzymes to jaundice, acute liver failure, and death. Diagnosis is primarily based on a temporal relationship between drug exposure and liver injury while excluding other causes of liver disease. Immediate discontinuation of the offending agent remains the cornerstone of management. Acetaminophen, antibiotics, antituberculosis drugs, NSAIDs, antiretroviral agents, antifungals, statins, and herbal medicines are among the most common causes. Early recognition and prompt intervention are essential to prevent serious complications and improve patient outcomes.

Key words: Drug-induced liver injury (DILI); Acetaminophen; Hepatocellular injury

Introduction

Drug-induced liver injury (DILI) is a common cause of liver disease and the leading cause of acute liver failure in the United States.[1,2] Nearly all classes of medications, including prescription drugs, over-the-counter medications, and herbal products, can cause hepatotoxicity. Most cases improve after withdrawal of the offending agent, but severe cases may progress to chronic liver disease, acute liver failure, or require liver transplantation. Early recognition and prompt discontinuation of the causative drug are essential. Genetic susceptibility, pre-existing liver disease, and environmental factors may influence the risk of DILI.[3,4,5-7]

The liver plays a central role in drug metabolism and is therefore particularly vulnerable to toxic injury. Drug-induced hepatotoxicity accounts for a substantial proportion of adverse drug reactions and remains a major clinical challenge.[1,2] Acetaminophen is the most common cause of severe DILI, although antibiotics, antituberculosis drugs, antiretroviral agents, anesthetics, NSAIDs, antifungals, statins, and herbal supplements are also important causes.[8] DILI may present as hepatocellular, cholestatic, or mixed liver injury. Hepatocellular injury is generally associated with a poorer prognosis, whereas cholestatic forms are more likely to become chronic.[9-10]

Mechanisms of drug-induced liver injury

Most drugs undergo hepatic metabolism through phase I cytochrome P[45]0 reactions followed by phase II conjugation reactions.[13] Toxic metabolites generated during phase I metabolism can damage hepatocytes if detoxification pathways become overwhelmed.[8],Mitochondrial dysfunction plays an important role in DILI. Drug-induced inhibition of mitochondrial respiration results in reactive oxygen species (ROS) production, ATP depletion, and eventual cell death.[14] Certain drugs such as amiodarone may impair fatty acid oxidation and promote steatosis, while nucleoside analogs can interfere with mitochondrial DNA replication.[15,16] Immune-mediated liver injury represents another important mechanism. Drug metabolites may bind cellular proteins and trigger immune responses through antigen presentation pathways.[17] This process can result in antibody production, cytokine release, and hepatocyte destruction. Repeated exposure to a sensitizing drug often produces a more severe reaction.[18, 19]

Risk Factors

Risk factors for DILI include age, sex, alcohol consumption, pre-existing liver disease, and genetic susceptibility. Advanced age is associated with cholestatic injury, whereas women have a greater tendency to develop severe hepatocellular injury and acute liver failure.[3,4] Patients with chronic hepatitis B or C may experience increased toxicity from certain medications, especially antituberculosis therapy.[20] Chronic alcohol use increases susceptibility to hepatotoxicity, particularly during acetaminophen exposure.[21,22] non-alcoholic fatty liver disease may also increase vulnerability to DILI.[23]

Clinical Features and Diagnosis

The clinical manifestations of DILI are often similar to those of other liver diseases. Patients are commonly present with fatigue, nausea, malaise, pruritus, and jaundice. In immune-mediated cases, fever, rash, and eosinophilia may also occur.[24] Diagnosis relies primarily upon establishing a temporal association between drug exposure and liver injury while excluding competing causes such as viral, autoimmune, and metabolic liver disease. Improvement following drug withdrawal strongly supports the diagnosis. Rechallenge is generally not recommended because of safety concerns. [25]

Laboratory findings vary according to the pattern of injury. Hepatocellular injury is characterized by marked elevations of ALT and AST, whereas cholestatic injury is associated with elevated alkaline phosphatase. Severe acetaminophen toxicity may cause aminotransferase levels exceeding [20],000 IU/L.[26] Several causality assessment tools have been developed, including the RUCAM/CIOMS system and the Maria and Victorino scale.[27,28] The Drug-Induced Liver Injury Network (DILIN) has further improved the collection and analysis of hepatotoxicity data.[29]

Management

The cornerstone of management is immediate withdrawal of the offending agent. Drug discontinuation is generally recommended when significant elevations of liver enzymes or bilirubin occur, particularly when accompanied by symptoms.[25] Most patients recover completely after drug withdrawal; however, some progress to acute liver failure. N-acetylcysteine remains the only widely accepted specific antidote and is reserved primarily for acetaminophen toxicity.[25] Patients with severe acute liver failure may require liver transplantation. Prognostic systems such as the King’s College Criteria are widely used to identify candidates for transplantation.[30] The MELD score may also assist in predicting outcomes.[31]

 

Important Examples of DILI

Acetaminophen

Acetaminophen is the classic example of dose-dependent hepatotoxicity and remains the leading cause of acute liver failure.[2,8] Toxicity results from accumulation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) following depletion of glutathione stores. Alcohol consumption enhances toxicity through increased CYP[45]0 activation and reduced detoxification capacity.[[32],[33],[34]] Clinical progression occurs in stages, beginning with nonspecific gastrointestinal symptoms and potentially progressing to massive hepatocellular necrosis, coagulopathy, encephalopathy, and death. Serum acetaminophen levels and the Rumack-Matthew nomogram guide management. N-acetylcysteine is highly effective when administered early.[35]

Anesthetics

Halothane-induced hepatitis is primarily immune-mediated and usually follows repeated exposure. Autoantibodies directed against CYP2E1-associated antigens contribute to liver injury.[34] Clinical features include fever, jaundice, eosinophilia, and elevated transaminases. Severe cases may progress to acute liver failure.[36]

Non-Steroidal Anti-Inflammatory Drugs

NSAIDs are a significant cause of DILI because of their widespread use. Diclofenac is the best-studied example and can cause hepatocellular injury through both metabolic and immune mechanisms.[37-39] Nimesulide and sulindac have also been associated with severe liver injury and cholestatic hepatitis.[40-42]

Antimicrobial Agents

Antibiotics account for a large proportion of DILI cases.[[43]],[[[44]]] Among antituberculosis drugs, isoniazid is particularly important because its metabolites can induce severe hepatocellular injury.[45,46] Rifampin contributes to cholestatic liver injury and may increase isoniazid toxicity.[47,48] Amoxicillin-clavulanate is one of the most common causes of antibiotic-associated cholestatic hepatitis and may occasionally lead to severe outcomes.[49-51] Macrolides and sulfonamides are also recognized causes of cholestatic liver injury.[52,53]

Antifungal Agents

Azole antifungals, particularly ketoconazole, are associated with hepatocellular injury and occasionally severe liver failure.[54] Terbinafine-induced liver injury is rare but well documented, necessitating monitoring during prolonged therapy.[55]

Antiretroviral Therapy

DILI occurs in a significant proportion of patients receiving highly active antiretroviral therapy. HBV and HCV coinfection, alcohol consumption, older age, and female sex increase the risk.[56] Nevirapine is especially associated with hepatotoxicity through hypersensitivity and idiosyncratic mechanisms.[57] Abacavir toxicity is strongly associated with HLA-B*[57]01 positivity.[58]

Lipid-Lowering Agents

Statins commonly cause mild asymptomatic elevations in liver enzymes, but clinically significant hepatotoxicity is uncommon.[59] Ezetimibe has also been implicated in cholestatic and autoimmune-like liver injury.[60]

Herbal and Traditional Medicines

Herbal supplements are increasingly recognized causes of DILI. Limited regulation, variable composition, and contamination may contribute to toxicity.[61-63] Herbalife products, kava, chaparral, comfrey, ma huang, and several traditional Chinese herbal preparations have all been associated with significant liver injury, including acute liver failure.[64]

Drug ClassRepresentative DrugsPharmacological MOA (Class)Mechanism / Pattern of DILI
Analgesics and AntipyreticsAcetaminophen (Paracetamol)Central inhibition of prostaglandin synthesisDose-dependent hepatocellular necrosis due to toxic metabolite NAPQI and glutathione depletion; leading cause of acute liver failure.
General AnestheticsHalothane, Enflurane, IsofluranePotentiate inhibitory neurotransmission producing general anesthesiaImmune-mediated hepatitis related to reactive metabolites and anti-CYP2E1 antibodies; may progress to liver failure.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)Diclofenac, Nimesulide, Sulindac, IbuprofenInhibition of cyclooxygenase (COX) enzymes reducing prostaglandin synthesisIdiosyncratic hepatocellular, cholestatic, or mixed injury through metabolic and immune-mediated mechanisms.
Antituberculosis DrugsIsoniazid, Rifampin, PyrazinamideInhibit mycobacterial cell wall synthesis or RNA synthesisHepatocellular injury from toxic metabolites (especially isoniazid); cholestatic injury with rifampin; combination therapy increases risk.
β-Lactam AntibioticsAmoxicillin-Clavulanate, FlucloxacillinInhibit bacterial cell wall synthesisCommon cause of idiosyncratic cholestatic hepatitis; immune-allergic mechanisms implicated.
Macrolide AntibioticsErythromycin, Clarithromycin, AzithromycinBind 50S ribosomal subunit and inhibit bacterial protein synthesisUsually cholestatic or mixed liver injury; often immune-mediated.
Sulfonamide AntibioticsSulfamethoxazole-TrimethoprimInhibit bacterial folate synthesisHypersensitivity-associated hepatocellular or cholestatic injury with fever, rash, and eosinophilia.
Azole AntifungalsKetoconazole, Itraconazole, Fluconazole, VoriconazoleInhibit fungal CYP450-dependent ergosterol synthesisHepatocellular injury ranging from mild enzyme elevation to severe liver failure.
Allylamine AntifungalsTerbinafineInhibits squalene epoxidase, blocking ergosterol synthesisRare idiosyncratic hepatocellular or cholestatic liver injury.
Antiretroviral Agents (NNRTIs/NRTIs)Nevirapine, Efavirenz, AbacavirInhibit HIV reverse transcriptase and viral replicationHypersensitivity reactions, mitochondrial toxicity, and idiosyncratic hepatotoxicity; risk increased in HBV/HCV coinfection.
Lipid-Lowering Agents (Statins)Atorvastatin, Simvastatin, RosuvastatinInhibit HMG-CoA reductase reducing cholesterol synthesisUsually asymptomatic aminotransferase elevation; clinically significant DILI is rare.
Cholesterol Absorption InhibitorsEzetimibeInhibits intestinal NPC1L1-mediated cholesterol absorptionRare cholestatic and autoimmune-like hepatitis.
Antiepileptic DrugsValproic Acid, Phenytoin, Carbamazepine, LamotrigineReduce neuronal excitability through sodium-channel blockade or GABA enhancementMitochondrial toxicity and hypersensitivity reactions causing hepatocellular injury.
Anticancer AgentsMethotrexate, Cyclophosphamide, Temozolomide, CisplatinInhibit DNA synthesis, replication, or cell divisionChronic fibrosis, steatohepatitis, sinusoidal injury, or acute hepatotoxicity depending on the agent.
Immunomodulatory/Biologic AgentsInfliximab, Adalimumab, TocilizumabSuppress cytokine-mediated immune responsesAutoimmune-like hepatitis and idiosyncratic hepatocellular injury.
Herbal and Dietary SupplementsHerbalife®, Kava, Comfrey, Chaparral, Ma HuangVariable mechanisms depending on constituent compoundsDirect toxicity, contamination, adulteration, immune-mediated injury, or sinusoidal obstruction syndrome.
Traditional Chinese and Ayurvedic MedicinesMulti-herbal formulationsMultiple bioactive phytochemicals with diverse actionsIdiosyncratic hepatocellular, cholestatic, or mixed liver injury; often related to unidentified compounds or contaminants.

Conclusion

Drug-induced liver injury remains an important cause of acute and chronic liver disease. Most cases resolve after withdrawal of the offending medication, but severe forms can progress to liver failure and require transplantation. Since DILI can mimic many other liver disorders, early recognition and accurate diagnosis are essential. Careful medication review and prompt discontinuation of suspected agents play a crucial role in improving patient outcomes and preventing serious complications.

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