Open access peer-reviewed chapter - ONLINE FIRST
Abstract
Drug-induced liver injury (DILI) refers to a type of liver dysfunction induced by various drugs or their metabolites, which can be life-threatening. Its incidence is increasing gradually, and it has become a non-negligible global health burden. In daily life, many common medications can lead to DILI. However, there is still no single indicator which is specific for the diagnosis of DILI, and the medications for the treatment of DILI are clinically diverse. In addition, pharmacological therapy also faces additional challenges in some special populations with DILI, such as elderly people, children, and pregnant women. This chapter aims to summarize the current overview of various drugs to treat DILI in clinical practice.
Keywords
- drug-induced liver injury (DILI)
- pharmacotherapy
- hepatoprotective drug
- acetaminophen (APAP)
- N-acetylcysteine (NAC)
- glycyrrhetinic acid preparation (GAP)
- antioxidants
- silymarin
- ursodeoxycholic acid (UDCA)
- L-carnitine (LC)
- tiopronin (TP)
- polyene phosphatidylcholine (PPC)
- S-adenosyl-methionine (SAMe)
- glucocorticoids (GCs)
1. Introduction
Drug-induced liver injury (DILI) refers to a type of liver injury induced by various drugs or their metabolites [1], which will prolong the duration of hospitalization, increase the cost, and decrease the quality of life for patients [2]. In Western countries, DILI has become the most common cause of acute liver failure (ALF) [3]. In Asian countries, its incidence is also gradually increasing, accounting for up to 4–10% of hospitalized patients [4, 5]. Currently, DILI has become a global burden of diseases that cannot be ignored [6]. Risk factors for DILI include advanced age, female gender, drug interactions, and drug hepatotoxicity [7, 8, 9]. Anticancer drugs, antibiotics, and nonsteroidal anti-inflammatory drugs are the leading causes of DILI [10, 11, 12]. In addition, traditional Chinese medicine and dietary supplements are major causes of DILI, but it is difficult to determine their potential toxicity due to their complex composition [13]. The proportion of traditional Chinese medicine-induced liver injury among all DILI cases is estimated as 25.71%, and it is gradually increased year by year [14]. Unfortunately, there is still no single indicator specific for DILI, which increases its diagnostic difficulty and uncertainty [15].
Nowadays, there are diverse drug treatment regimens [16]. In clinical practice, commonly used first-line medications for DILI include N-acetylcysteine (NAC), glycyrrhetinic acid preparation (GAP), ursodeoxycholic acid (UDCA), glucocorticoids (GCs), and glutathione (GSH). Specifically, GAP can effectively inhibit the release of inflammatory factors and reduce the inflammatory response of the liver; UDCA can improve the condition of cholestasis, promote the excretion of bile, and alleviate the toxicity of bile acids on hepatocytes; and GSH can maintain the intracellular redox balance and counteract the drug-induced oxidative stress damage [17, 18, 19]. Some other potentially effective drugs, such as cholestyramine (CSM) and clausenamide (CLA), are emerging.
At present, there are still many challenges in the pharmacological therapy for DILI. First, long-term follow-up and large-scale clinical studies regarding pharmacological therapy for DILI are scarce, so it may be risky. Second, there are differences in individual responses to medications, and some patients have poor efficacy and may experience adverse effects. In addition, drug-drug interactions add to the complexity of treatment. Thus, how to accurately select drugs, avoid adverse effects, and develop personalized treatment plans are still the current challenges to be overcome in the treatment of DILI. This chapter aims to summarize the current overview of various drugs to treat DILI in clinical practice.
2. Pathophysiology of DILI
The pathophysiology of DILI is multifaceted and complex. First, drugs or their metabolites can directly damage hepatocytes. For example, excessive acetaminophen (APAP) produces toxic N-acetyl-p-benzoquinone imine (NAPQI) [20]. Second, drugs may inhibit bile duct transporters, causing the accumulation of bile acids in the liver, which can lead to hepatocellular damage, liver fibrosis, and even cirrhosis [21]. Third, drugs activate the immune system by binding to hepatocyte proteins to form antigens, triggering the immune system to attack the hepatocytes, causing hepatocyte damage or necrosis [22]. Fourth, drugs disrupt mitochondrial function, causing metabolic disorders and oxidative stress, ultimately leading to hepatocyte swelling, degeneration, necrosis, and other lesions [23]. In addition, genetic polymorphisms (e.g., cytochrome P450 enzyme lineage) can affect drug metabolism and increase the risk of DILI [24]. Collectively, multiple factors are working together to cause DILI.
3. Pharmacological treatment for DILI
It is necessary to first discontinue the suspected medication related to DILI, and then intervene with the appropriate drugs [16]. Due to the complex pathophysiology of DILI, the efficacy of existing drugs remains limited. Based on the current evidence, the therapeutic drugs for DILI can be divided into four major categories: specific antidotes, non-specific hepatoprotective drugs, immunosuppressants, and potential drugs.
3.1 Specific antidotes
Currently, there are some specific antidotes for the treatment of DILI caused by certain drugs.
3.1.1 N-acetylcysteine
NAC is a sulfhydryl-containing GSH precursor compound with detoxifying, anti-inflammatory, and antioxidant effects [25]. It is the only antidote approved by the Food and Drug Administration for the treatment of APAP-induced endogenous DILI [26]. If an excessive amount of APAP was taken, the immediate use of NAC would effectively relieve symptoms, and the earlier it is taken, the better the effect will be [27].
NAC also seems to be effective for non-APAP-induced DILI. An open-label study suggests that NAC prevents anti-tuberculosis (TB) drug-induced DILI [28]. Lee et al. included 173 ALF patients who received NAC (n = 81) or placebo (n = 92) and demonstrated that patients who received NAC had a significantly higher transplant-free survival rate than those who received placebo (40% vs. 27%, P = 0.043) [29]. But Squires et al. failed to demonstrate that NAC improves survival in children with non-APAP ALF [30]. In conclusion, NAC is an antidote to APAP overdose-induced DILI and non-APAP-induced DILI, but not for children.
3.1.2 L-carnitine (LC)
LC, a class of amino acid analogs with anti-inflammatory and antioxidant properties, can be synthesized in small amounts by the human body, but mainly from daily intake of foods, such as red meat [31]. LC is a specific antidote for DILI caused by valproic acid (VPA). LC infusion may directly alleviate the LC deficiency induced by VPA and reduce hepatotoxicity. Meanwhile, Perrott et al. considered the use of LC in patients with acute VPA overdose and decreased consciousness based on the available evidence. Moreover, they recommended bolus intravenous infusion of LC at a dosage of 100 mg/kg, followed by 50 mg/kg every 8 hours with the maximum dosage not exceeding 3 g, until the ammonia level decreases, if initially elevated, and clinical symptoms are improved [32].
In addition, LC has been shown to be beneficial for preventing DILI caused by other drugs. A meta-analysis of 14 randomized controlled trials (RCTs) evaluated the efficacy of LC for various chronic liver diseases, and found that LC supplementation significantly reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in patients with chronic liver diseases [33]. Besides, Hatamkhani et al. demonstrated that anti-TB drugs combined with oral LC solution at a dosage of 2000 mg daily for 4 weeks significantly reduced the incidence of anti-TB drug-induced hepatotoxicity (ATDH) [34]. Taken together, LC, an antidote for VPA-induced DILI, has potential prophylactic effects on non-VPA-induced DILI.
3.2 Non-specific hepatoprotective drugs
Hepatoprotective drugs refer to a kind of drugs that prevent or reduce liver injury, promote liver cell regeneration, and thus improve liver function. Thus, various hepatoprotective drugs play an important role in the treatment of DILI.
3.2.1 Glycyrrhizic acid preparation
GAP, such as magnesium isoglycyrrhizate (MgIG) and compound glycyrrhizic acid, which is an extract preparation of
3.2.2 Silymarin
Silymarin is a flavonoid extracted from the seeds of the milk thistle [40]. It is a potent antioxidant, which can protect the structural integrity of hepatocytes and ensure the normal metabolic function of the liver [41]. Therefore, silymarin is more applicable for the hepatocyte injury type DILI. However, an RCT in Iran showed that folic acid significantly reduced ALT (P = 0.04) and AST (P = 0.007) levels in children with epileptic drug-induced DILI compared to silymarin [42]. Another RCT by Marjani et al. showed that silymarin had poor therapeutic effects on anti-TB drug-induced DILI [43]. Additionally, a meta-analysis evaluated the efficacy of several hepatoprotective drugs in decreasing AST and total bilirubin (TBIL) levels, and found that silymarin had lower efficacy [44]. On the other hand, silymarin, a natural plant extract, is safe with almost no adverse reactions and good tolerance [45, 46]. In conclusion, silymarin offers a safe option for the treatment of DILI, but its therapeutic efficacy is controversial.
3.2.3 Ursodeoxycholic acid
UDCA was originally extracted from bear bile, and can be artificially synthesized now [47]. UDCA can promote the secretion of bile acids and excretion of toxic metabolites, thus reducing the burden on the liver [18]. Accordingly, UDCA has long been used clinically for cholestatic DILI. Lang et al. showed that oral UDCA reversed the hepatotoxicity of ATDH [48]. Another study found that UDCA was effective and well-tolerated in children with anticonvulsant-induced hypertransaminasemia (n = 22) [49]. Moreover, UDCA also shows some preventive effects. A retrospective study by Kojima et al. suggested the prophylactic effect of UDCA against flutamide-induced hepatopathy in patients with prostate cancer [50]. A prospective study showed that UDCA prevents the hepatotoxicity of chemotherapy drugs in pediatric patients with B-cell acute lymphoblastic leukemia [51]. Based on the available evidence, UDCA should be beneficial for both the prevention and treatment of DILI, and is particularly indicated for cholestatic DILI.
3.2.4 Bicyclol
In 2004, bicyclol was approved in China as an anti-inflammatory and hepatoprotective drug for the treatment of various forms of liver injury [52]. Bicyclol can alleviate liver inflammation, enhance antioxidant capacity of hepatocytes, and promote hepatocyte repair and regeneration [53]. It can play an important role in the treatment of DILI presenting with a significantly elevated ALT, because it can rapidly reduce ALT levels and be favorable for hepatic recovery. In 2014, Wu et al. randomized patients with statin-induced liver injury into a treatment group (bicyclol 25 mg three times per day, n = 79) and a control group (polyene phosphatidylcholine [PPC] 456 mg three times per day, n = 78). After 4 weeks, the rate of ALT normalization was significantly higher in the treatment group than the control group (74.68% vs. 46.15%). Therefore, bisacodyl is safe and effective in the treatment of statin-induced DILI [54]. Meanwhile, Li et al. showed that oral administration of bicyclol at a dosage of 75 mg daily significantly reduced the incidence and extent of chemotherapeutic agent-induced liver damage in elderly patients with cancer [55]. In addition, a phase II trial in 2022 showed that bicyclol had better efficacy for the treatment of idiopathic acute DILI when it was taken three times a day at a dosage of 50 mg [56]. On the other hand, Chen et al. evaluated the pharmacoeconomics of bicyclol, diammonium glycyrrhizinate, and silibinin for the treatment of ATDH, and concluded that bicyclol was the most cost-effective therapy and the first choice for the treatment of ATDH [57]. In brief, bicyclol has excellent efficacy, safety, and affordability, making it one of the preferred drugs for the treatment of DILI.
3.2.5 Polyene phosphatidylcholine
PPC is purified from phospholipids extracted from soybeans, which can bind with the liver cell membrane to protect and repair hepatocytes [58]. Currently, PPC is widely used globally for the treatment of various liver diseases and is mainly used in China for the treatment of DILI. A retrospective study from China showed that both PPC and MgIG had positive efficacy in the treatment of DILI, resulting in a significant reduction in ALT levels, and that the safety and efficacy of these two drugs in treating DILI were comparable [59]. Notably, it should be used with caution in patients with bean allergies, primarily considering the ingredient of PPC. In conclusion, PPC is mainly used in China for the treatment of DILI, especially for DILI presenting with a significantly elevated ALT.
3.2.6 Tiopronin
TP, a sulfhydryl-containing glycine, can be detoxified by formulating non-toxic mixtures with toxic substances [60]. Li et al. included 150 patients with advanced colorectal cancer to assess the efficacy of TP infusion on chemotherapy-induced hepatotoxicity. Compared to the control group, the TP group had significantly lower proportions of abnormal mean ALT, AST, TBIL, and albumin levels. Therefore, TP reduced the incidence of chemotherapy-induced hepatotoxicity and enhanced the patients’ tolerance to chemotherapy [61]. Wang et al. investigated the efficacy of MgIG on DILI, and showed a positive effect of TP [37]. In addition, a case report suggests that TP is effective for liver injury caused by long-term use of antiepileptic drugs, but more clinical studies are needed to determine the exact mechanism of action [62]. Collectively, TP is beneficial for the treatment of DILI, especially in patients who received chemotherapy.
3.2.7 S-adenosyl-methionine (SAMe)
SAMe is involved in numerous biochemical reactions in vivo as a methyl donor and precursor of physiological sulfhydryl compounds and has been referred to as a control switch for regulating liver function [63, 64]. Because the metabolism of exogenous SAMe is hardly affected by chronic liver diseases, it should be potentially more effective in the setting of chronic liver diseases [65]. Santini et al. administered SAMe supplementation orally to cancer patients (n = 50) who have anticancer chemotherapy-induced hepatotoxicity, and showed that SAMe could significantly reduce AST and ALT levels [66]. In addition, it has been shown to regulate the process of bile acid metabolism, relieve symptoms associated with cholestasis, and can be used during pregnancy [67, 68]. It has been confirmed that SAMe improves hepatic biochemical parameters and cholestatic symptoms [69]. It should be noted that SAMe is unstable in nature and requires attention to storage conditions and the time frame for use after configuration [70]. Collectively, SAMe can improve liver function in cholestatic DILI.
3.3 Immunosuppressants
Immunosuppressants play a key role in the treatment of DILI, especially immune-mediated injury. When certain drugs are administered to the human body, immune response is abnormally activated, triggering a series of inflammatory chain reactions [71]. Immunosuppressants inhibit the activation and proliferation of T-lymphocytes, thereby reducing the intensity of the attack on hepatocytes [72]. However, they are not omnipotent, and their use requires a rigorous assessment of the patient’s condition, immune status, and potential risks.
GCs are steroid hormones secreted by the adrenal cortex. In clinical practice, empirical administration of GCs can effectively improve liver function in severe DILI [73, 74]. Wang et al. demonstrated that GC plus glycyrrhizin for chronic DILI can achieve both biochemical response and histological improvements with good safety [75]. A retrospective study strongly recommended short-term use of GCs in severe DILI patients with hyperbilirubinemia, which may improve liver injury and patient survival [76]. But another study demonstrated that GCs do not improve the cure rate of severe DILI, but can rapidly reduce TBIL at early stage [77]. A study from Iceland noted that GCs were effective for the treatment of infliximab-induced DILI, with normalization of liver function indices and no recurrence after long-term follow-up period [78]. However, it has also been shown that GCs are not beneficial for the treatment of DILI, and even harmful at a daily dosage of >40 mg [37]. In conclusion, GCs are effective for the treatment of DILI, but may trigger adverse effects, such as Cushing’s syndrome. Therefore, clinicians need to accurately grasp the dosage and duration of GCs according to the patient’s specific condition, and weigh the pros and cons of GCs before their use.
3.4 Potential drugs
Development of new potential agents has opened new avenues to strengthen the treatment efficacy. Notably, clinical studies of these agents are limited. Their potential benefits for treating DILI have been demonstrated in animal studies or in some cases, providing new options for the treatment of DILI in the future.
3.4.1 Cholestyramine
CSM, an anion-exchange resin, is not absorbed by the gastrointestinal tract after oral administration, and is excreted in the feces by irreversibly binding to bile acids in the intestinal tract, forming an insoluble complex [79]. Thus, CSM reduces the hepatic-intestinal circulation of bile acids and lowers the concentration of bile acids in the bile, which in turn attenuates the toxic effects of bile acids on hepatocytes. According to the European Association for the Study of the Liver guidelines, the use of CSM is recommended for ALF induced by leflunomide to accelerate drug clearance [80]. In two cases of DILI where UDCA and GCs were ineffective, oral CSM immediately relieved jaundice and pruritus [81]. Besides, terbinafine has been reported to potentially cause cholestatic DILI [82]. The Asia Pacific Association for the Study of the Liver guidelines recommend oral CSM for terbinafine-induced DILI. In conclusion, CSM is indicated for cholestatic DILI and alleviation of itchy skin.
3.4.2 Glutathione
GSH is one of the most important antioxidants in cells, and intracellular GSH levels are crucial for maintaining redox homeostasis [19]. When NAC binds toxic NAPQI, it reduces the body’s natural storage of GSH, leading to hepatocyte necrosis. Many drugs used to treat DILI, such as NAC, SAMe, MgIG, and UDCA, work by increasing the GSH level in the body [83]. They are GSH precursors, and can promote GSH production. Similarly, DILI can be treated with direct GSH supplementation. If GSH is decreased in vivo, it indicates a greater susceptibility to oxidative stress, thus GSH has potential as a biochemical indicator of DILI [84]. Currently, experimental researches focus on the molecular signaling pathway of GSH action, and more clinical studies are needed to provide theoretical support for its role in the treatment of DILI.
3.4.3 Clausenamide
CLA is an amide compound isolated from the leaves of the plant
4. Pharmacological therapy for special populations with DILI (SP-DILI)
When DILI develop in SP-DILI groups, such as elderly people, children, and pregnant women, additional challenges are faced. Therefore, we need to pay great attention to the treatment of DILI in SP-DILI and deeply explore the efficacy and safety of medications.
4.1 Elderly people
Elderly people (65 years and over) have an increased incidence of various diseases, require multiple medications to maintain their health, and are more susceptible to DILI than the general population. Weersink et al. found increased rates of comorbidities and polypharmacy and more severe DILI with increasing age in all elderly groups [89]. When medications were administrated to elderly patients with DILI, there is a need for consideration regarding decreased ability to metabolize medications in the elderly. Moreover, there is a gradual shift in the pattern of liver injury toward cholestasis in the elderly, so the drugs indicated for cholestatic DILI are favored [7]. Collectively, elderly patients with DILI need a comprehensive selection of therapeutic agents according to the age, comorbidities, and type of liver injury. Future studies involving more elderly patients with DILI are needed.
4.2 Children
In children, the liver is still under development, and the drug metabolism enzyme system is incomplete [90]. In the United States, the leading causes of DILI in children are antimicrobials (51%) and antiepileptic drugs (21%), especially minocycline and valproate [91]. Physicians should be aware of their potential risk of liver damage in children. And the choice of medications must be made carefully in children with DILI. On the one hand, the choice of dosage form is crucial, and the preference should be given to oral liquid formulations that are easily accepted by children and also allow for more precise control of dosage [92]. On the other hand, given the sensitivity of children to drug reactions, the dosage should be calculated accurately according to the age and weight throughout the treatment. At the same time, we should be aware of the potential effects of drugs on the children’s growth and development and fully weigh whether they interfere with the absorption and metabolism of nutrients.
4.3 Pregnant women
In pregnant women, DILI is complex and can adversely affect both mother and fetus. When choosing medications for DILI, we must not only consider their efficacy, but also avoid the use of teratogenic drugs. Second, it is important to regularly examine the fetus and the mother’s liver function. In addition, multidisciplinary collaboration plays an integral role in the treatment of DILI. Obstetricians focus on the safety of mother and fetus, while hepatologists focus on the efficacy of pharmacological therapy for DILI. In the future, it is necessary to summarize adverse events during pregnancy and provide more evidence on the safety of medication for pregnant women with DILI.
5. Conclusion
Currently, DILI is a challenge in the global medical field. Specific antidotes (NAC and LC) are well-targeted but have limited application, hepatoprotective drugs (GAP, silymarin, and UDCA, etc.) are beneficial but lack high-quality clinical studies, immunosuppressants (GCs) are rapidly effective but potentially risky, and potential drugs (CSM, GSH, and CLA) require further assessment. Moreover, it is important to pay attention to the pharmacological treatment of DILI in SP-DILI.
Authors’ contributions
Qinke Wu reviewed and searched the literature and wrote the first draft.
Ting Wang, Qianqian Li, Fei Gao, and Chenghai Liu discussed the findings, revised the manuscript, and gave critical comments.
Xingshun Qi conceived and supervised the work, reviewed and searched the literature, and revised the manuscript.
All authors participated in the discussion of this study protocol, gave critical comments on this manuscript, and approved this submission.
Funding
Liaoning Provincial Science and Technology Plan Joint Plan (Technology Research and Attack Plan Project) 2024JH2/102600285.
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