A Literature Review on Drugs Associated with Liver Enzyme Abnormalities: Mechanisms, Clinical Patterns, and Diagnostic Approaches

Abstract

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.

Keywords

Introduction

Fig.1: Metabolism of drug

Fig 2: Mechanism of Liver Injury

Fig 3: Pathway of Hepatic Damage

Drugs Associated with Liver Enzyme Abnormalities

Anti-Tubercular Drugs

Liver toxicity is a major complication of first-line anti-tubercular drugs—isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA)—and a significant contributor to treatment interruption and multidrug-resistant tuberculosis (MDR-TB) development (16). The prolonged use of multiple drugs exacerbates the risk, contributing to mortality rates of 6–12% among TB patients due to hepatotoxicity (16,17). Among these, PZA is the most hepatotoxic (18). Isoniazid toxicity is primarily linked to hepatic metabolism. The enzyme N-acetyltransferase 2 (NAT2) acetylates INH to form acetylhydrazine, a hepatotoxic intermediate. Slow acetylators (due to NAT2 polymorphisms) accumulate more acetylhydrazine, increasing the risk of liver injury up to fourfold. CYP2E1, another key enzyme, further oxidizes acetylhydrazine into reactive oxygen species (ROS), causing oxidative stress, mitochondrial dysfunction, and hepatocellular damage (15-18). INH also inhibits CYP450 activity, compounding oxidative stress and hepatocyte injury (20). Genetic variations in NAT2 and CYP2E1 are strong predictors of INH-induced liver damage (20–22). Rifampicin often causes cholestatic liver injury, particularly when used with INH. It disrupts bilirubin and bile acid transport by inhibiting bile salt export pumps (BSEP), leading to intrahepatic accumulation and clinical jaundice. Histological findings include canalicular cholestasis and bile plugs (23). RIF is also a potent inducer of CYP enzymes, especially CYP3A4 and CYP2E1, enhancing INH metabolism and promoting hepatotoxic intermediate formation (22,23). This synergistic interaction makes the INH-RIF combination more hepatotoxic than either alone. RIF-induced hepatotoxicity is often dose-dependent, with enzyme abnormalities emerging typically within 10–14 days of treatment initiation. While often transient and asymptomatic, the risk increases in patients with pre-existing liver conditions, older age, or alcohol use. Therefore, early and routine liver function monitoring is essential during RIF-based therapy (18–23). Pyrazinamide is the most hepatotoxic among first-line agents. Its metabolite, pyrazinoic acid, disrupts hepatocyte mitochondrial function, leading to oxidative stress, energy deficiency, and liver cell death. Histologically, centrilobular (zone 3) necrosis is common in PZA-induced injury (18). Unlike INH or RIF, PZA toxicity is primarily dose-dependent, with liver enzyme elevations and clinical hepatitis observed even at standard doses (20–25?mg/kg/day). Prolonged use or higher dosages significantly raise the risk, which is why PZA is typically limited to the initial two months (intensive phase) of TB treatment (20–24). When used with INH and RIF, its potent hepatotoxicity necessitates close LFT monitoring.

Antiretrovirals

(Nevirapine, Efavirenz):  First-line antiretroviral treatment (ART) for HIV infection relies heavily on two commonly used non-nucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine and efavirenz. However, worries about hepatotoxicity, especially in populations with preexisting risk factors, have severely restricted their usage (15-20). These medications hepatotoxic potential has been well investigated and is now acknowledged as a crucial clinical factor in the management of ART. The cytochrome P450 (CYP450) enzyme system is involved in the extensive hepatic metabolism of both substances. While CYP2B6 metabolizes efavirenz largely, with small contributions from CYP3A4 and CYP2A6, CYP3A4 and CYP2B6 metabolize nevirapine primarily. Reactive intermediate metabolites produced by these metabolic pathways have the capacity to cause hepatic injury via immune-mediated processes as well as direct hepatocellular damage (25,26). Immunomediated hepatotoxicity, which usually appears within the first 6 to 12 weeks of therapy, is more closely linked to nevirapine. Rash, fever, eosinophilia, and a substantial increase in transaminase are common clinical manifestations; in extreme situations, fulminant hepatic failure may develop (27). Despite being typically well tolerated, efavirenz has also been linked to hepatocellular damage; evidence suggests that its metabolite, 8-hydroxy-Efavirenz, may be hazardous to mitochondria [28]. These agents usually produce idiosyncratic hepatotoxicity, which is mostly unexpected and not dose-dependent. Histologically, the damage pattern might range from mixed hepatocellular-cholestatic damage to hepatocellular necrosis. According to a major clinical research by Sulkowski et al., 1–2% of HIV patients using NNRTIs experienced serious hepatic events, and 14% of them had elevated liver enzymes [29]. Female sex, high baseline CD4 counts (particularly >250 cells/mm³ in women), co-infection with hepatitis B or C, concurrent use of other hepatotoxic drugs, and genetic polymorphisms, especially in the CYP2B6 enzyme, which affect Efavirenz metabolism, are some of the risk factors that have been found to increase the likelihood of hepatotoxicity [30,31]. For example, because of increased plasma concentrations and metabolite buildup, those with slow-metabolizing CYP2B6 alleles are more susceptible to Efavirenz-induced liver damage [32]. During the first few months of treatment, management techniques include a strong emphasis on routinely monitoring liver function tests (LFTs). If there are substantial transaminase increases, the offending medication is stopped. According to guidelines, baseline LFTs should be performed, followed by testing at 2, 4, and 8 weeks, and then on a quarterly basis after that [33]. Because of the increased risk of hypersensitivity-related hepatotoxicity, women with high CD4 counts should take nevirapine with great care [34].

Analgesics

(Paracetamol, NSAIDs): In the world, one of the most widely used over-the-counter analgesics and antipyretics is paracetamol. It is generally safe at therapeutic levels (≤4 g/day in humans), but in many industrialized countries, such as the US and the UK, it is the main cause of acute liver failure (ALF) (35). Phase II conjugation (glucuronidation and sulfation) occurs in the liver and excretes around 90% of an oral dosage in urine. NAPQI (N-acetyl-p-benzoquinone imine), a highly electrophilic metabolite, is produced when the cytochrome P450 enzyme system (mostly CYP2E1, but also CYP1A2 and CYP3A4) breaks down around 5–10% of it (36). Hepatotoxicity usually shows up as a hepatocellular pattern of elevated liver enzymes (ALT >3x ULN), which, if left untreated, frequently leads to fulminant hepatic failure (28,39). In severe instances, increased bilirubin, INR, and lactate are also present, along with a considerable rise in serum ALT and AST levels (typically >1000 IU/L) (37-39). Serum paracetamol concentration is used to determine the risk of hepatotoxicity after a single acute overdose using the Rumack-Matthew nomogram. N-acetylcysteine (NAC) is the particular antidote, specifically detoxifying NAPQI and restoring hepatic glutathione reserves [40].

Nonsteroidal Anti-Inflammatory Drugs

(NSAIDs) such as celecoxib, naproxen, ibuprofen, diclofenac, and indomethacin are frequently prescribed. In spite of their medicinal advantages, NSAIDs have been linked to idiosyncratic drug-induced liver injury (iDILI)(16-18). NSAID-induced liver damage is usually unpredictable, dose-independent, and can appear after a variable latency period, ranging from a few days to months after exposure, in contrast to the predictable, dose-dependent hepatotoxicity observed with paracetamol [41,42]. The most common NSAID linked to hepatotoxicity is diclofenac. It is metabolized in the liver to produce quinone imine and reactive acyl glucuronide metabolites, which can attach to cellular proteins covalently to form neoantigens. These proteins adducts may cause immune-mediated liver damage, which can result in autoimmune-like hepatitis in rare cases as well as histological patterns with mixed hepatocellular and cholestatic damage (43). Ibuprofen, has a better hepatic safety historical significance (35,36). Ibuprofen-induced liver injury is rare and usually mild, temporary, and resolves on its own when the medication is stopped. However, in vulnerable people, especially those with underlying liver dysfunction or concurrent use of other hepatotoxic agents, high doses exceeding 2400 mg/day or prolonged therapy may present a hepatotoxic risk (44). Depending on the substance used, NSAID-induced liver damage can present with different clinical patterns. Drugs such as diclofenac often cause a hepatocellular pattern, characterized by elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (10-15). With medications like sulindac, a cholestatic pattern is more frequently seen, which is defined by elevated levels of bilirubin, gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP). There have been reports of mixed patterns with naproxen and other medications that show both hepatocellular and cholestatic features (10-16). People are more susceptible to NSAID-induced hepatotoxicity due to a number of risk factors. Preexisting liver disease, female sex, advanced age, genetic polymorphisms affecting drug metabolism (like those in the CYP2C9 or UGT genes), and concurrent use of other hepatotoxic medications are some of these. Clinicians must be aware of these factors in order to reduce the risk of liver damage while using NSAIDs.

Antiepileptic Drugs

(AEDs): Valproate and phenytoin antiepileptic drugs (AEDs), but both carry risks of hepatotoxicity ranging from transient enzyme elevations to acute liver failure, especially in vulnerable populations. Valproate-induced liver injury involves both idiosyncratic hypersensitivity and dose-dependent mitochondrial toxicity (46). About 30–50% of patients may experience mild ALT/AST elevations early in treatment, typically resolving spontaneously. However, severe hepatotoxicity—though rare—can occur, particularly in children under two, patients on polytherapy, or those with mitochondrial disorders such as POLG mutations (Alpers-Huttenlocher syndrome) (46,47). Valproate is metabolized via three main hepatic pathways: β-oxidation (40–50%), CYP-mediated ω-oxidation, and glucuronidation via UGTs. Impaired β-oxidation, due to genetic or mitochondrial dysfunction, shifts metabolism toward ω-oxidation, leading to accumulation of toxic intermediates like 4-ene-valproic acid. These cause oxidative stress, mitochondrial disruption, and result in microvesicular steatosis and centrilobular necrosis (48,49). Clinical signs may include hyperammonemia, lactic acidosis, and coagulopathy, often without jaundice, necessitating early biochemical monitoring. Valproate may also inhibit histone deacetylases (HDACs), altering gene expression and hepatocyte stress responses. Its unpredictable hepatotoxicity underscores the importance of routine liver function monitoring, especially during the first six months of therapy. Phenytoin-induced hepatotoxicity is typically idiosyncratic and immune-mediated, often manifesting within 2–8 weeks of initiation. It may present as Anticonvulsant Hypersensitivity Syndrome (AHS) or part of DRESS syndrome, characterized by fever, rash, lymphadenopathy, eosinophilia, and varying degrees of liver involvement—from mild enzyme elevations to acute liver failure (50,51). Phenytoin is bioactivated by CYP2C9 and CYP2C19 to form arene oxide intermediates, which bind to liver proteins forming neoantigens. This elicits a cytotoxic T-cell response and cytokine release. Genetic predispositions, particularly HLA-B*1502 and HLA-A*3101, are strongly linked to severe reactions (52,53). Management requires immediate drug withdrawal and supportive care. Systemic corticosteroids may be used in severe or systemic DRESS, though clinical evidence is limited. Rechallenge with phenytoin is contraindicated due to high risk of recurrence. In summary, valproate toxicity involves mitochondrial disruption and oxidative stress, often presenting with steatosis and encephalopathy, while phenytoin toxicity is immune-driven, marked by inflammatory infiltrates, eosinophilia, and systemic symptoms. Genetic risk factors differ: POLG mutations for valproate, HLA alleles for phenytoin (54–56).

Antibiotics:

Many medical professionals use amoxicillin-clavulanate, a combination of β-lactam and β-lactamase inhibitors, for respiratory and soft tissue infections. Even though it works well, it has been recognized as a major source of liver damage caused by antibiotics in Western nations. Cholestatic or mixed hepatocellular-cholestatic hepatitis is the most common kind of liver injury, however pure hepatocellular injury can also happen. The latency phase is generally between 1 and 6 weeks after the start of the disease. Symptoms may include jaundice, itching, tiredness, loss of appetite, and an enlarged liver. Tests in the lab frequently show that alkaline phosphatase (ALP) and conjugated bilirubin are too high, although alanine aminotransferase (ALT) may also be too high. A liver biopsy may indicate portal-based inflammatory infiltrates full of eosinophils, canalicular cholestasis, and bile duct damage, which are all signs of a hypersensitivity-mediated immunoallergic response. Genetic factors, especially HLA-A02:01 and HLA-DRB11501 alleles, have been linked to a higher risk, which suggests that adaptive immunity may play a role (58,59). Most cases go away after stopping the medication, but there have been reports of severe or long-lasting cholestasis and, in rare circumstances, acute liver failure, especially in older people or those who have been exposed to the drug several times (60,61). Nitrofurantoin, a synthetic nitrofuran derivative, is often used to treat urinary tract infections and keep them from coming back, especially in women. Hepatotoxicity isn't very frequent, but it can show itself in two ways: as an acute hepatitis-like sickness or as a chronic autoimmune-like hepatitis. Acute damage usually happens between days to weeks and looks like viral hepatitis, with very high levels of ALT and AST. It is commonly accompanied by fever, rash, and eosinophilia, which are signs of a hypersensitive reaction. Chronic hepatotoxicity can happen after months or years of using low doses of nitrofurantoin or using it as a preventive measure. It is more sneaky and can seem like autoimmune hepatitis, with positive antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and high levels of immunoglobulin G (IgG). In some cases, liver histology shows interface hepatitis, plasma cell infiltrates, piecemeal necrosis, and in more severe cases, bridging fibrosis or cirrhosis (62,63). Older women are more likely to get chronic DILI from nitrofurantoin, especially if they already have autoimmune tendencies or have been exposed to it for a long time. It's important to note that acute harm usually goes away when the treatment is stopped, but chronic instances may need immunosuppressive therapy and have a higher risk of long-term liver problems (60-62).

Herbal/Traditional Medications

Herbal and traditional medicines, integral to systems like Ayurveda, Traditional Chinese Medicine (TCM), Siddha, and Unani, are often perceived as natural and safe. However, increasing global use has raised concerns about hepatotoxicity. Studies from China show TCM accounts for over 25% of liver injury cases (64), while reports of liver damage linked to Ayurvedic and Siddha medicines are rising in India (66). Toxic mechanisms include direct hepatotoxicity, idiosyncratic immune responses, and mitochondrial dysfunction. For example, pyrrolizidine alkaloids in comfrey can cause veno-occlusive disease (65), while Tinospora cordifolia (Guduchi) has been linked to autoimmune hepatitis-like injury (66). Kava-kava and green tea extract impair mitochondrial function, especially at high doses (67), and Polygonum multiflorum may cause cholestatic and hepatocellular damage (68). Many herbal products are contaminated with heavy metals like mercury, lead, and arsenic, especially unregulated online or over-the-counter items (69). Additionally, herb-drug interactions may occur via cytochrome P450 modulation, enhancing conventional drug toxicity (70). Specific cases include Guduchi-related liver injury reported during the COVID-19 pandemic in India, with some requiring corticosteroids (66). Polygonum multiflorum, used for anti-aging in China, has shown histological evidence of interface hepatitis and bile duct injury (68). Kava-kava has been implicated in severe hepatic necrosis and liver failure (72), while black cohosh and high-dose green tea extract have been associated with hepatotoxicity (67,71,73). Clinical presentation ranges from asymptomatic enzyme elevation to fulminant liver failure. Common signs include fatigue, nausea, jaundice, pruritus, and abdominal pain. Laboratory findings show elevated ALT, AST, ALP, and bilirubin, with variable hepatocellular, cholestatic, or mixed patterns. Liver biopsy may reveal portal inflammation, interface hepatitis, bile duct damage, or granulomas. Diagnosis is challenging due to heterogeneous formulations; the RUCAM scale helps assess causality, though less reliable with polyherbal products (74). Lack of regulation remains a major concern. Over 20% of online Ayurvedic products have detectable heavy metals (75). Weak oversight leads to inconsistent quality, labeling, and dosage. The WHO advocates for improved pharmacovigilance of traditional medicine. Management includes immediate discontinuation, supportive care, and corticosteroids in immune-mediated cases. Severe damage may necessitate liver transplantation. Clinicians should always inquire about herbal use during patient evaluations.

Diagnostic Approach:

To diagnose drug-induced liver damage (DILI) and herbal and traditional medicine-induced liver injury (HILI/TILI) since there are no clear diagnostic indicators. It is important to use a systematic and objective method to figure out if a suspected agent is causing liver damage since liver damage might look like other illnesses including viral hepatitis, autoimmune liver disease, or damage from drinking too much alcohol. The Roussel Uclaf Causality evaluation Method (RUCAM) is the most commonly used and validated of the many causality evaluation techniques that have been created over the years. The RUCAM score is a structured, point-based methodology that was initially developed in 1993 and modified in 2016. It helps figure out how likely it is that a certain medicine or herb will cause liver damage. It includes important clinical areas like the time it takes for liver damage to happen after taking a drug, the levels of liver enzymes after stopping the drug (dechallenge), risk factors like alcohol use or age, the presence of other drugs, the exclusion of non-drug causes, the known hepatotoxicity profile of the agent, and the response to rechallenge, if available (76,77). A weighted score is given to each domain, and the overall score is read as follows: ≥9 = extremely likely, 6–8 = likely, 3–5 = plausible, 1–2 = improbable, and ≤0 = not likely (77). This grading method lets doctors carefully look at the clinical, biochemical, and time-based links between exposure and liver damage. The new RUCAM also has instructions for using it to treat liver damage caused by herbs. This is important since polyherbal formulations and unknown product compositions are widespread in traditional medicine systems like Ayurveda and Traditional Chinese Medicine (78). The RUCAM score is easy to reproduce, has a clear structure, and is only for liver-related events. It is very useful in clinical research, and large registries like the DILI Network (DILIN) and worldwide pharmacovigilance systems have started using it. But it does have certain problems. RUCAM is only as accurate as the clinical data it uses, and it may not be as trustworthy when there are several possible hepatotoxins or herbal items that haven't been tested. Also, rechallenge, which is one of the scoring criteria, is typically seen as inappropriate in clinical settings, especially when there has been substantial liver damage before (79,80). The Naranjo algorithm and the WHO-UMC causation categories are two other techniques that are utilized in larger adverse drug reaction (ADR) situations, but they don't have the level of detail needed to assess liver harm. In the United States, the DILIN expert opinion scale is used to give a systematic, consensus-based grade of causation, although it depends on specialist panels and isn't always possible in everyday clinical practice (81).

CONCLUSION:

Drug-induced liver injury (DILI) is frequently detected by changes in liver enzymes such bilirubin, ALT, AST, and ALP. Identifying the medication classes frequently involved and comprehending the mechanisms, whether intrinsic or idiosyncratic, are crucial for early detection and efficient treatment. Making decisions about diagnosis and therapy is aided by recognizing the pattern of elevated liver enzymes. In order to reduce the dangers associated with hepatotoxic medicines, it is imperative that healthcare personnel get targeted education, regular monitoring, and increased awareness. To maximize therapeutic results and enhance patient safety in medication therapy, ongoing research and pharmacovigilance initiatives are required.

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