Departnment of pharmacy practice, JKKMMRF ANNAI JKK Samporani Ammal College of Pharmacy, Komarapalayam, Namakkal, Tamilnadu 638183
Drug-induced liver damage (DILI) presents a substantial problem in pharmacological and clinical settings. Decreases in liver enzymes including bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are frequently early markers of hepatic dysfunction, so identifying them early is essential for prompt diagnosis and treatment. With an emphasis on their hepatotoxic mechanisms, clinical presentation patterns, and implications for patient management and monitoring, this literature review looks at the variety of medications that are frequently linked to abnormalities in liver enzymes. DILI can be broadly divided into two types: idiosyncratic, which is unpredictable and influenced by a host's genetic predisposition, as seen with medications like isoniazid and amoxicillin-clavulanate, and intrinsic, which is predictable and dose-dependent, as exemplified by agents like acetaminophen. Numerous pharmacological types, such as statins, antifungals, antiepileptics, antitubercular medicines, antibiotics, and herbal supplements, have been shown to elevate liver enzymes to differing degrees of severity, from biochemical alterations that are asymptomatic to potentially fatal liver failure. Reactive metabolite production, immune-mediated damage, and mitochondrial dysfunction are some of the pathophysiological pathways that are examined in this review. Additionally, it highlights how important it is to diagnose the pattern of elevated liver enzymes, whether hepatocellular, cholestatic, or mixed, as this aids in therapeutic therapy. The review concludes by liver enzyme abnormality due drugs, mechanism, diagnosis approaches and the incorporation of liver safety education into clinical practice in order to prevent and lessen DILI.
Drug-induced liver damage (DILI) is a broad category of reactions that can follow exposure to any chemical molecule, whether it synthetic or natural. There isn't even a general consensus on what liver dysfunction is Typically, liver failure is separated into two main categories based on whether or not there is underlying liver disease. Rare, occurring without prior liver damage, acute liver failure (ALF) has a well-defined etiology and is divided into acute, subacute, and hyperacute processes based on the time between the beginning of hepatic encephalopathy and the emergence of jaundice (1, 2). Given that many cases of DILI are asymptomatic and that there are numerous unknowns around the direct relationship between a medicine and liver damage, it is challenging to estimate the absolute incidence of DILI (3). The term "drug-induced liver injury" (DILI) refers to liver damage brought on by different drugs, herbs, or other xenobiotics that results in abnormalities in liver tests or liver dysfunction after other causes have been reasonably ruled out.One Drug development and safety are severely hampered by DILI, which accounts for 13% of instances of acute liver failure in the US and is one of the main causes of the condition (4, 6). The most frequent causes of DILI are antimicrobials and central nervous system drugs, while dietary supplements or health foods are responsible for 7% of DILI cases in the United States. The projected yearly incidence of hospitalized cases at the university hospital in Korea was found to be 12/100,000 persons annually (6). Acetaminophen overdose is the most common cause of abrupt liver failure in the majority of Western nations. In Korea, acetaminophen was the cause of a small number of instances (2%).8. Fortunately, patients treated with N-acetylcysteine for acetaminophen-induced liver failure had a generally better prognosis than those treated for other types of DILI (60 to 80% versus 20 to 40%). A small percentage of people might get chronic liver disease. Chronic DILI was found to be 5.7% common in a prospective assessment of DILI patients included in the Spanish Hepatotoxicity (5).
Biochemical Markers of Drug Induced Liver Injury:
According to biochemical pattern of drug -induced liver injury, which is defined by the ratio (R value) of the elevation of serum levels of ALT to serum alkaline phosphatase (ALP), drug-induced liver injury has been categorized as hepatocellular, cholestatic, or mixed (6). A collection of biomarkers for an early DILI diagnosis in contrast to the current diagnostic guidelines. CK-18 (Cytokeratin-18), microRNA-122 (microarray RNA-122), total HMGB-1 (High Mobility Group Box protein-1), GLDH (Glutamate dehydrogenase), SDH (Sorbitol dehydrogenase) was suggested as a marker for hepatocyte necrosis, ccCK-18 (caspase-cleaved CytoKeratin-18) as a marker for apoptosis, hyperacetylated HMGB-1, and MCSFR-1 (Macrophage colony-stimulating factor receptor-1cholestatic pattern) (7). Additional suggestions included microRNA-192 (unspecified liver damage), M-30 (apoptosis), and M-65 (apoptosis/necrosis) (7,8). Liver function test such as total bilirubin (TBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) have long been used to diagnose DILI in clinical studies and with commercially available products. To assure subject safety in studies, however, a more rigorous diagnostic method is appropriate to identify early DILI that conventional LTs could miss. To close this gap, a number of novel biomarkers are being investigated, with the goal that they will surpass and eventually replace conventional LTs due to their high specificity and sensitivity (8,9).
Classification of Drug-Induced Hepatotoxicity
Drug-induced liver injury (DILI) represents a significant clinical challenge and is a leading cause of acute liver failure. It can be broadly classified based on biochemical patterns of liver enzyme elevation and the underlying mechanisms of hepatotoxicity. Biochemically, three main patterns of liver injury are recognized: hepatocellular, cholestatic, and mixed. The hepatocellular pattern is characterized by a marked elevation in serum alanine aminotransferase (ALT) levels exceeding those of alkaline phosphatase (ALP), indicating primary injury to the liver parenchymal cells (9-11). This pattern is commonly associated with medications such as isoniazid and paracetamol. The cholestatic pattern, on the other hand, presents with a more prominent increase in ALP relative to ALT, suggesting injury to the bile ducts or impaired bile flow, and is typically seen with drugs like amoxicillin-clavulanate or anabolic steroids. A mixed pattern involves elevations in both ALT and ALP without a dominant enzyme, reflecting concurrent damage to hepatocytes and the biliary tract. Mechanistically, DILI is further divided into intrinsic and idiosyncratic types. Intrinsic liver injury is dose-dependent, predictable, and occurs in a consistent manner among individuals when toxic levels of a drug or its metabolites accumulate—acetaminophen overdose being a classic example. In contrast, idiosyncratic DILI is unpredictable, not dose-dependent, and varies greatly among individuals. It may involve complex interactions between drug metabolism, genetic predispositions, and immune-mediated responses. Unlike intrinsic injury, idiosyncratic reactions often have a variable latency period and can occur even with therapeutic doses, making early detection and diagnosis challenging. Recognizing the pattern and mechanism of liver injury is crucial for appropriate management, risk assessment, and the development of preventive strategies in clinical pharmacology.
Based on pattern of liver injury:
A drug can undergo both Phase?I and Phase?II metabolism. Phase?I, usually catalyzed by CYP450s, introduces polar groups (e.g., –OH, –NH?); Phase?II conjugates small molecules to increase hydrophilicity, directing biliary or renal excretion (10). Biotransformation can create reactive intermediates that precipitate oxidative or organelle stress or cholestatic injury by hampering bile?acid transport (10,?11). Although cellular defenses often limit damage, high drug doses or susceptible host factors can overwhelm these responses, triggering immune activation and cell death (12). The resulting hepatocellular stress produces distinctive biochemical and histological patterns. Clinically, liver?enzyme ratios define the R value: cholestatic when alkaline phosphatase (ALP)?≥?2?×?ULN or R?≤?2; mixed when R?>?2–<5; and hepatocellular when alanine aminotransferase (ALT)?≥?5?×?ULN or R?≥?5, where R?=?(ALT/ULN?ALT?)/(ALP/ULN?ALP?). Pathology most often shows acute or chronic hepatitis, cholestasis, or cholestatic hepatitis; less frequent findings include micro?/macro?vesicular steatosis, granulomas, steatohepatitis, and zonal necrosis (13). Drug?specific profiles exist: acetaminophen produces centrilobular necrosis with R?≥?5, erythromycin predominantly causes cholestasis with R?≤?2, and statins can evoke either pattern and even autoimmune?like features such as elevated IgG and anti?smooth?muscle or antinuclear antibodies (14). The heterogeneity of clinical and histologic manifestations complicates mechanistic attribution.
Fig.1: Metabolism of drug
Source: https://wjbphs.com/sites/default/files/WJBPHS-2024-0284
The most clinically relevant medication interactions usually involve metabolic pathways, according to recent studies on metabolism or biotransformation. The liver is a prime target for reactive metabolites of medicines since it is the primary organ for drug metabolism (15). Many medications are eliminated from the body by chemically changing into less lipid-soluble forms that are unable to pass through lipid membranes again. These changed products are subsequently eliminated in the bile or by the kidneys. Although drug metabolism can take place in a number of places, including the skin, lungs, intestines, and plasma, the hepatocyte's smooth endoplasmic reticulum is the main site (Fig 1).
Phase I Reactions – Functionalization
In the liver, lipophilic drugs (Drug-R), which are not water-soluble and hence difficult to excrete, first undergo Phase I reactions. These reactions are catalyzed mainly by enzymes such as cytochrome P450 monooxygenases. The purpose here is to introduce or expose a functional group like a hydroxyl (-OH), amino (-NH?), or sulfhydryl (-SH) group to the drug molecule. These modifications result in slightly more polar metabolites such as:
However, these Phase I products are not always ready for elimination and may still retain biological activity or even become more toxic in some cases. Hence, they often require further processing (12-14)
Phase II Reactions – Conjugation
To ensure safe and efficient elimination, these intermediate metabolites are subjected to Phase II reactions, also known as conjugation reactions. Here, the liver attaches endogenous hydrophilic molecules like:
This step transforms the drug into highly water-soluble compounds such as Drug-R-GSH, Drug-R-Ac, Drug-R-SO?H, and Drug-R-GL. These conjugates are pharmacologically inactive and are now ready for excretion from the body.Systemic Circulation and Excretion Pathways After metabolism, these drug metabolites enter the systemic circulation, from where they are distributed to various excretory organs (12-14). The body employs multiple routes to eliminate these substances:
BASED ON MECHANISM:
Drug-induced liver injury (DILI) involves both metabolic and immune-mediated pathways. Upon drug entry, hepatic enzymes like cytochrome P450 (CYPs) metabolize it, generating reactive metabolites (A) that cause hepatocellular stress, mitochondrial dysfunction, and cell damage (3-5). Simultaneously, drug-protein adducts (haptens) (B) may trigger adaptive immune responses via B- and T-cell activation, which can be reactivated upon re-exposure. Tyrosine kinase and TNF-α inhibitors are
Dony D.*, Balaji S., Silambarasan M., Jackson Selvin Y., A Literature Review on Drugs Associated with Liver Enzyme Abnormalities: Mechanisms, Clinical Patterns, and Diagnostic Approaches, Int. J. Sci. R. Tech., 2025, 2 (10), 198-210. https://doi.org/10.5281/zenodo.17335112
10.5281/zenodo.17335112
