Editor’s Note: Drug-induced liver injury (DILI) is a significant adverse reaction to medications, with severe cases leading to acute liver failure (ALF) and even death. DILI is the most common cause of ALF in Western countries, yet there is still a lack of simple, specific diagnostic indicators and effective treatment methods. The incidence of DILI in China is increasing year by year, related to the variety of clinical drugs, improper medication use, and insufficient awareness. During the recent closure of the 10th “Huaxia Shanghai Liver Disease Forum and Forum on the Diagnosis and Treatment of Liver Failure and its Complications,” Dr. Zhengsheng Zou from the Fifth Medical Center of the PLA General Hospital shared insights into the progress of the diagnosis and treatment of drug-induced liver failure, covering its importance, etiology, pathogenic mechanisms, clinical manifestations, treatment strategies, prognosis assessment, and large-scale studies in China.

  • Importance and Etiology of Drug-Induced Liver Failure Research

Dr. Zhengsheng Zou and his research team found that from 2002 to 2015, the proportion of drug-induced acute and subacute liver failure in the total cases of liver failure in the hospital increased year by year [1]. Epidemiological studies on ALF in different countries show that in Western countries, ALF is mainly caused by acetaminophen (APAP) [2]. In the etiology of acute liver failure in the United States, APAP accounts for 46%, and DILI accounts for 11% [3]. It is noteworthy that, comparing the incidence rates of herbal and dietary supplements (HDS/CAM) drug-induced liver failure between 2013-2020 and 1995-2003, the incidence rate during 2013-2020 has increased eightfold [4].

Table 1. Epidemiology of Drug-Induced Liver Failure in Different Countries

(Excerpt from Speaker’s Presentation)

  • Pathogenic Mechanism and Clinical Manifestations of Drug-Induced Liver Failure

When acetaminophen (APAP) is taken at the recommended or doctor-prescribed dose, its metabolic rate in the liver is approximately 10%. It undergoes metabolism by the CYP450 enzyme to generate a toxic substance, N-acetyl-p-benzoquinone imine (NAPQI). The generated NAPQI can be metabolized by the body’s glutathione (GSH), thereby reducing its hepatotoxicity. However, when the intake of APAP exceeds the recommended dose, i.e., when overused, the metabolic rate of the drug in the liver increases (beyond 15%), resulting in the excessive production of NAPQI. At this point, the body’s GSH is unable to metabolize all of the NAPQI, leading to the accumulation of NAPQI and causing hepatotoxicity, ultimately triggering liver damage and even liver failure (Figure 1) [5].

Figure 1. Pathogenic Mechanism of APAP-Related Drug-Induced Liver Failure (Excerpt from Speaker’s Presentation)

The occurrence of drug-induced liver injury (DILI) caused by non-APAP drugs is the result of the combined effects of drugs, hosts, and the environment [6]. Drug factors include the dosage and interactions of medications; host factors encompass age, metabolic conditions, etc.; and environmental factors involve various aspects such as diet, smoking history, alcohol consumption, and more. These factors interact, collectively influencing the metabolism and excretion processes of drugs within the body, as well as the extent of drug-induced damage to the liver. Therefore, in preventing and treating drug-induced liver injury, it is essential to comprehensively consider these factors and take corresponding measures to reduce the harm caused by drugs to the liver.

In comparison to non-APAP-induced liver failure, APAP-induced drug-induced liver failure is more likely to lead to hepatic encephalopathy, and its ALT levels are higher. Regarding bilirubin levels, non-APAP-induced liver failure exhibits higher bilirubin levels. Additionally, APAP-induced liver failure demonstrates higher rates of both transplant-free survival and overall survival (Table 2) [3].

Table 2. Comparison of APAP and Non-APAP-Related Drug-Induced Liver Failure in Demographics, Laboratory Tests, and Prognosis

(Excerpt from Speaker’s Presentation)

  • Treatment Strategies for Drug-Induced Liver Failure

Currently, the main clinical guidelines for the diagnosis and treatment of DILI include the 2014 ACG Drug-Induced Liver Injury Guidelines, the 2019 EASL Drug-Induced Liver Injury Guidelines, the updated 2021 ACG Drug-Induced Liver Injury Guidelines, the first AASLD Drug-Induced Liver Injury Guidelines in 2023, and the latest “Guidelines for the Diagnosis and Treatment of Drug-Induced Liver Injury (2023 Edition)” in China. In general, the most crucial measure for addressing the cause of liver injury is the timely discontinuation of suspected hepatotoxic drugs and avoiding the reuse of suspected or similar drugs. This is the fundamental treatment principle for DILI. In addition to providing necessary symptomatic supportive treatment, the choice of treatment drugs should be made based on current evidence from evidence-based medicine.

Commonly used drugs in the treatment of acute liver failure (ALF) caused by DILI include the use of special detoxifying agents such as N-acetylcysteine (NAC) to prevent complications such as hepatic encephalopathy, cerebral edema, coagulation disorders, sepsis, metabolic disorders, acute kidney injury, or renal failure. For cases with poor prognosis, timely liver transplantation should be considered. Research has confirmed that in non-APAP-induced drug-induced liver failure, NAC can improve the transplant-free survival rate of patients and shorten their hospital stay [7]. Studies show that compared to the period between 1998-2008, the use of NAC increased significantly by 44.5% in the period between 2008-2018, and the transplant-free survival rate also increased by 15.2% [8].

  • Prognostic Assessment of Drug-Induced Liver Failure

Reliable prognosis assessment is crucial for determining whether immediate liver transplantation treatment should be given to patients with drug-induced liver failure. The U.S. ALFSG has developed a related prognosis scoring system that predicts the 21-day transplant-free survival rate by combining clinical variables such as the severity of hepatic encephalopathy, the cause of ALF, vasopressor use, serum bilirubin, and INR. The ALFSG model is significantly superior to KCC and MELD in predicting the prognosis of acute liver failure caused by various drugs [9]. Galectin-9 can also be used to predict the survival rate of patients with drug-induced liver failure and is applicable to various drugs. Research has shown that[10], whether caused by APAP or non-APAP, the levels of Galectin-9 in the liver and serum of patients are higher than those in the control group. Stratification of non-transplant survival rates can be achieved by using a serum Galectin-9 level threshold of 690.

Moreover, studies have indicated that[11] factors such as age, degree of hepatic encephalopathy, use of vasoactive drugs, maximum MELD score, King’s College Hospital criteria (KCC) score, and continuous renal replacement therapy (CRRT) are associated with the prognosis of APAP-induced drug-induced liver failure.

In recent years, Dr. Zhengsheng Zou’s research team has conducted a multicenter, non-APAP drug-induced liver failure cohort study, aiming to explore the clinical characteristics and prognosis of patients with non-APAP drug-induced liver failure, elucidate the high-risk factors of non-APAP drug-induced liver failure, and construct a new non-invasive nomogram model for evaluating the prognosis of patients with non-APAP drug-induced liver failure[12]. This study is a cross-sectional, multicenter, retrospective, real-world study, including the largest global cohort of drug-induced liver failure studies to date. By screening and analyzing 482 cases of non-APAP drug-induced liver failure patients, covering aspects such as drug types, clinical indicators, complications, etc.

Based on easily obtainable clinical data, this study established a new DIALF-5 prediction model, which is significantly superior to KCC and MELD scoring models in predicting non-APAP-induced drug-induced liver failure. Compared to the ALFSG model, the new DIALF-5 model has the same predictive efficacy, but the ALFSG model can only predict the 21-day transplant-free survival rate, while the new DIALF-5 model can predict the transplant-free survival rate at different time points, thus having higher predictive accuracy and broader applicability.

Figure 2. Predictive Ability of DIALF-5 Nomogram for Non-APAP-Induced Drug-Induced Liver Failure (Excerpt from Speaker’s Presentation)

Conclusion

Drug-induced liver injury is a complex interdisciplinary disease involving hepatology, gastroenterology, infectious diseases, oncology, and hematology, among others. Its diagnosis and management pose significant challenges. Drug-induced liver failure primarily affects the female population. Antibiotics and traditional Chinese medicine are the main categories of drugs leading to drug-induced liver failure, with secondary drugs including antitumor drugs, immunomodulatory drugs, antiepileptic drugs, non-steroidal anti-inflammatory drugs, and thiazolidinediones. In recent years, the proportion of TCM/HDS in non-APAP drug-induced liver failure has been continuously increasing, and its transplant-free survival rate is lower. Therefore, improving transplant-free survival has become the main goal of treating drug-induced liver failure. Many patients require emergency liver transplantation, and artificial liver support systems play a crucial role in this process. Through univariate and multivariate analysis, we have established a new DIALF-5 prognostic model and constructed a nomogram to assess the prognosis of patients with drug-induced liver failure. These models have demonstrated excellent performance and are superior to other existing models.

References:

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  12. Wang JB, Huang A, Wang Y, et al. Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomized open-label trial. Aliment Pharmacol Ther. 2022;55:1297–1310.

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Last updated on 2024.03.15