Drug-Induced Liver Injury: Mechanisms, Diagnosis, and Management: A Review

ABSTRACT

Drug-induced liver injury (DILI) stands as the worldwide medical problem that causes substantial portions of both acute liver failure incidents and necessary liver transplants and fatalities. The liver functions as the main detoxifying organ of the body therefore, it becomes easily susceptible to destructive effects from the medicine components as well as other substances such as herbal supplements. DILI produces diverse liver damage that extends from unnoticed enzyme level elevations through the acute liver failure detection points. The purpose of this review assessment is to deliver an extensive breakdown of DILI pathogenic elements alongside diagnostic hurdles and present rule-of-the-art clinical practices. Researchers analyze three major pathophysiological mechanisms—oxidative stress, along with mitochondrial dysfunction and immune-mediated damage—for liver damage formation. The article explains diagnostic tools for DILI alongside establishing biomarkers and employment of liver biopsy for diagnosis. This discussion explores detailed information about the three management options that consist of drug withdrawal and supportive care together with liver transplantation. The discovery of genetic DILI susceptibilities combined with pharmacogenomic applications in clinical care leads to promising patient-specific treatments for better clinical achievements.

INTRODUCTION

Drug-induced liver injury (DILI) stands as one of the principal perpetrators of liver-related illnesses which cause death throughout the world today. The liver as the body’s detoxification center remains exposed to harm from numerous pharmacological substances which include medicinal prescriptions and over-the-counter products and herbal supplements and recreational drugs. Acute liver failure in the United States develops from DILI at a rate between 10%–15% and this and other hepatic complications result in prescription drug market removal.[1] The knowledge of DILI pathways alongside the methods for detecting liver damage and available treatments for managing affected patients brings essential value in improving patient results. The diagnosis of DILI, includes mild asymptomatic elevation in liver enzymes through severe cases leading to acute liver failure that shows symptoms such as jaundice, coagulopathy, and encephalopathy. The occurrence of intrinsic DILI depends on drug dosage reaching a critical threshold which subsequently causes liver damage in a systematic manner. Drugs that lead to an idiosyncratic form of DILI create unpredictable liver damage in genetically predisposed individuals who come across specific environmental triggers even, while receiving their prescribed doses.[2]

MECHANISMS OF DRUG-INDUCED LIVER INJURY

Various mechanisms regulate DILI development including drug metabolism and oxidative stress and mitochondrial dysfunctions and immune system-mediated liver tissue damage. The pathways leading to DILI differ between drugs, while being influenced by genetic factors of individuals and their environmental surroundings.

Metabolic activation and reactive metabolites

Drugs submit to liver-based biotransformation through metabolism that primarily uses cytochrome P450 (CYP) enzymes as biological catalysts. The drug elimination process through detoxification requires enzymatic reactions that generate potentially toxic reactive metabolites which harm hepatocytes. The reactive metabolites damage cells through covalent binding with proteins and lipids as well as DNA thus, starting an inflammatory response.[3] Acetaminophen (paracetamol) represents one of several drugs which CYP enzymes metabolize through bioactivation. Intake of large amounts of acetaminophen leads to the production of toxic N-acetyl-p-benzoquinone imine (NAPQI) that removes glutathione from the liver. The lack of sufficient glutathione to detoxify NAPQI leads to toxic metabolite binding with liver proteins so that hepatocyte necrosis and inflammation develop together with oxidative stress.[4] Isoniazid and phenytoin along with halothane are among the drugs that produce reactive metabolites which exert hepatotoxic effects through this identical mechanism.[5]

Oxidative stress and mitochondrial dysfunction

The development of DILI depends heavily on oxidative stress. During drug detoxification the liver functions as the primary detoxification organ yet becomes vulnerable through exposure to reactive oxygen species which reach extremely high levels in drug metabolism. Reactive oxygen species (ROS) damaging effects occur within cells when it degrades lipids as well as proteins and deoxyribonucleic acid (DNA) and produces cellular injuries followed by dysfunction. Oxidative stress damages mitochondria severely because it harms mitochondrial proteins along with DNA that impedes cellular adenosine triphosphate (ATP) production and causes mitochondrial malfunctions.[6] The functional breakdown of mitochondria develops into liver damage when pro-apoptotic factors like cytochrome c escape to activate apoptosis through its intrinsic pathway. Hepatocyte death occurs because of this sequence that worsens liver inflammation.[7] The buildup of toxic metabolites in mitochondria causes dysfunction that harms hepatocytes, while accelerating the development of fibrosis. Valproic acid stands as an example drug which causes mitochondrial dysfunction to produce DILI symptoms.[8]

Immune-mediated mechanisms

The development of immune-mediated reactions plays an essential role in idiosyncratic cases of DILI. Drugs in addition to their metabolites achieve hapten-like structures through their interaction with liver proteins which leads to an immune response that results in liver tissue damage. After proteins undergo modification in the drug reaction the immune system detects altered proteins as foreign substances which results in hepatocyte attacks leading to liver damage with ensuing inflammation. The immune response causes patients to develop either autoimmune hepatitis or drug-induced lupus-like syndromes.[9] The medications isoniazid, methyldopa, and nitrofurantoin trigger immune-mediated damage to the liver as one of their reported side effects. When the immune system targets liver antigens it creates persistent liver inflammation as well as fibrosis of the liver.[10] The drug phenytoin and carbamazepine, along with other medications demonstrate their ability to elicit T-cell-mediated reactions that cause immune-mediated DILI.[11] Science has not fully explained these immune reactions although it is believed they start with genetic tendencies and drug processing along with environmental elements, which produce abnormal immune reactions.[12]

Genetic and environmental factors

The way our bodies process drugs is greatly affected by hereditary differences that make us susceptible to DILI. Genetic variations in enzymes and transporters and immune system proteins which breakdown drugs as well as their responses to them lead to different drug processing rates. From example CYP2E1 genetic variants result in excessive toxic metabolites that raise the possibility of liver damage.[13] The risk for DILI gets worse because of environmental conditions which include what a person eats and how they drink alcohol and the state of their liver health. Drugs become more toxic to hepatocytes when patients consume alcohol chronically since alcohol degrades liver metabolic functions. When patients have pre-existing liver conditions such as chronic hepatitis or cirrhosis their liver becomes less able to process drugs and becomes more susceptible to damages.[14]

DIAGNOSIS OF DRUG-INDUCED LIVER INJURY

The diagnostic process for DILI proves difficult because patients exhibit common liver disease symptoms that fail to distinguish between conditions. It is essential to identify liver damage early to stop its development. Medical practitioners start DILI diagnostics through a comprehensive patient interview that reviews all medications and herbal supplements and toxin exposures [Table 1].[15]

Table 1.

Shows the different diagnostic methods to diagnose DILI with advantages and limitations

Diagnostic Method	Description	Advantages	Limitations	References
Clinical and Biochemical Assessment	Tests (ALT, AST, alkaline phosphatase) to assess liver injury.	Non-invasive; widely available.	Not specific for DILI.	[15,16]
RUCAM	Scoring system for DILI causality.	Objective and structured.	Needs accurate history.	[17]
Liver Biopsy	Examining liver tissue for damage.	Definitive diagnosis.	Invasive procedure.	[18,19]
Histopathological Features	Identifying DILI-specific damage patterns.	Distinguishes DILI types.	Complex interpretation.	[19,20]
Advanced Techniques	Biomarkers (e.g., microRNAs) for early detection.	Potential for early detection.	Not standardized yet.	[6]

Clinical and biochemical assessment

Medical tests for DILI diagnosis mainly monitor liver function by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bilirubin levels. The evaluation of ALT and AST enables determination of hepatocellular damage and alkaline phosphatase increases point toward cholestasis.[16] The diagnostic tests do not establish DILI exclusively since they could show elevated results across different liver pathology conditions. Medical professionals commonly employ the Roussel Uclaf Causality Assessment Method (RUCAM) to evaluate whether a particular drug has provoked DILI. RUCAM incorporates drug-exposure timing against symptom appearance together with medical background analysis and confirmation of other hepatic problem rules with no alternate diagnosis.[17] Medicine experts typically use liver biopsy testing to establish DILI diagnosis particularly in situations where immune inflammatory reactions appear or when doctors need additional proof. The assessment of drug-induced liver damage requires liver biopsy to remain as the primary diagnostic procedure. Liver biopsy analysis in DILI reveals that hepatocellular necrosis together with inflammation and sporadic fibrosis help doctors identify DILI from alternative hepatic problems.[18]

Liver biopsy and histopathological features

Liver biopsy serves as a valuable tool during situations when DILI diagnosis remains uncertain and when doctors need to evaluate the extent of liver harm. The distinct features of DILI can be detected through liver tissue analysis during histopathological examination because they include hepatocellular apoptosis together with necrosis and cholestasis.[19] The presence of fibrosis observed through liver biopsy shows whether a patient may face persistent liver harm. Clinical need or test uncertainties lead healthcare professionals to conduct liver biopsies as this procedure demands surgical invasiveness. A mixed inflammatory pattern emerges during histopathological examination of immune-mediated DILI because it includes lymphocytic infiltrates and granulomas. The liver injury from acetaminophen and other non-immune-mediated drugs displays strong centrilobular necrosis and hepatocyte ballooning degeneration.[20] The obtained data enables physicians to differentiate various DILI types to make appropriate treatment decisions.

Advanced diagnostic techniques

The medical field shows increasing interest in establishing DILI diagnostic methods that do not require invasive procedures. Several biomarkers including serum microRNAs, cytokines and cell death biomarkers hold potential to detect liver injury at a stage that is earlier than what traditional liver function tests reach.[6] New biomarkers potentially enable doctors to use them jointly with liver biopsy for advanced DILI diagnosis.

MANAGEMENT OF DRUG-INDUCED LIVER INJURY

The primary treatment for DILI consists of discontinuing the responsible drug because it remains the most effective strategy to avoid additional liver harm. Promptly stopping drug exposure must happen immediately to stop the disease from turning into either acute liver failure or cirrhosis. Individuals with severe forms of DILI need admission to hospitals for supportive clinical treatment as well as pharmaceutical interventions to deal with symptoms and secondary effects. When someone experiences liver damage from acetaminophen intake the medical standard of care requires N-Acetylcysteine (NAC). The administration of NAC both restores glutathione levels and becomes effective in detoxification which minimizes liver cell injury.[5] Medical experts determine liver transplantation as the treatment for severe DILI when immediate liver failure risks exist. Corticosteroids with immunosuppressive properties represent the standard therapeutic approach for treating immune-mediated DILI by reducing inflammation during immune response suppression.[21] The use of immunosuppressive agents remains controversial because they might deteriorate liver damage but healthcare providers should use them with caution.

CONCLUSION

The condition of DILI leads to numerous worldwide liver failures and required liver transplantations.[1,2] The multiple factors causing DILI include metabolic activation combined with oxidative stress together with mitochondrial dysfunction as well as immune-mediated mechanisms.[3,4,5,6] According to medical research an early clinical diagnosis is essential to protect the liver from permanent damage and liver biopsy continues serving as a diagnostic technique to evaluate the damage extent.[18,19,20] The discontinuation of drugs that cause DILI along with supportive treatment leads to better results without specific treatments available.[5,17] Future research on biomarkers alongside genetic susceptibility will lead to improved methods of diagnosing and treating DILI patients.[6,13,14]

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.