I . Introduction
Drug-induced liver injury (DILI) represents a significant concern as it stands as the leading cause of acute liver failure, accounting for approximately 10% of all cases of acute hepatitis1,2. The spectrum of DILI manifestations varies widely, ranging from asymptomatic mild elevation of biochemical parameters to severe hepatitis with jaundice that can ultimately result in mortality3. Typically, around 80% of DILI patients experience complete recovery upon discontinuation of the suspected drug. Nevertheless, it is important to note that approximately 10 to 15% of DILI cases exhibit persistently abnormal laboratory values for over a duration of six months4.
The commonly implicated agents in DILI encompass acetaminophen, troglitazone (an antidiabetic drug), anticonvulsants, analgesics, antibiotics, and anti-cancer drugs5. However, the hepatotoxicity can potentially arise from any type of medication, including over-the-counter drugs, herbal products, and dietary supplements, operating through various mechanisms6. In contrast to general adverse drug reactions (ADRs) that typically exhibit a dose-dependent and predictable nature, DILI mainly manifests as idiosyncratic metabolic responses that are independent of dosage and display an unpredictable pattern7. Consequently, the prevention and early detection of DILI pose significant challenges in clinical practice, representing complex and intricate issues8.
A nationwide multicenter study in Korea reported an incidence rate of approximately 0.6% for herb- induced liver injury (HILI), which is significantly lower, by at least 2-3 times, than that associated with conventional drugs9. However, the risk attributed to HILI has been overestimated thus far. Considering that patients visiting Korean Medicine (KM) clinics commonly receive treatment with Western drugs, it is crucial for KM physicians to be aware of the potential occurrence of DIL) caused by conventional drugs.
The objective of this study is to present a case of DILI induced by antipsychotic drugs in a woman, providing a typical example of DILI that highlights the necessity for awareness among practitioners in Korean medicine (KM) clinics. This study aims to report a woman case with a DILI by antipsychotics, which provides a typical DILI example for an awareness requirement in clinics of Korean medicine (KM).
II. Case presentation
1. Medical history and examination
A 56-year-old woman has been grappling with mixed connective tissue disease and major depressive disorder for the past 5 years. Despite receiving ongoing treatment with both immunosuppressants and antidepressants, her symptoms have exhibited frequent fluctuations. The patient previously admitted to my clinic, where her condition gradually improved, with no episodes of severe deterioration. The treatment primarily involved the utilization of acupuncture (mainly at both HT7, ST36, LI4, and LR3), and an indirect moxibustion (at Ki1) once a week, contributing to the gradual enhancement of her overall well-being.
One day, the patient’s psychological well-being deteriorated due to stress related to her family, which resulted in disrupted sleep and a decline in her overall condition. Consequently, her psychiatric doctor adjusted her medication regimen. However, after 7 days of the new prescription (Table 1), she began experiencing severe malaise, fatigue, and distressing sensations. In order to ascertain the absence of any objective disorders, I conducted laboratory tests including chemistry and complete blood count. The results unexpectedly revealed significantly elevated levels of serum alanine aminotransferase (ALT) at 103 IU/L and aspartate aminotransferase (AST) at 106 IU/L, while the levels of gamma glutamyl transpeptidase (GGT, 14 IU/L), alkaline phosphatase (ALP, 71 IU/L), and total bilirubin (0.38 mg/dl) fell within the normal range. The Institutional Review Board had approved this case study.
Table 1
Summary of Prescriptions
| Name of product (dose per day) | Active ingredient | Main action | Warning for liver injury |
|---|---|---|---|
| Quaichi Tab. (12.5 mg once) | Quetiapine | Atypical anti-psychotic for schizophrenia and bipolar | AST, ALT elevation19 |
| Depro Tab (10 mg once) | Escitalopram (SSRI) | Anti-depressant | A case report20 |
| Azolac Tab (0.4 mg twice) | Alprazolam | Anti-anxiety | A case report12 |
2. Treatments and clinical outcome
Based on the absence of any other potential causes, such as hepatitis B virus (HBV) infection, and the previous normal results of liver-related enzyme tests conducted at the author’s hospital, the elevations in both ALT and AST levels, exceeding 2.5 times the upper normal limit (UNL), were indicative of drug-induced liver injury (DILI). Consequently, I strongly advised the patient to discontinue the use of psychiatric medications. Subsequently, the patient experienced a rapid disappearance of subjective complaints (severe malaise, fatigue, and distressing sensations) within 5 days. Additionally, the follow-up test conducted at 14 days demonstrated a return of AST and AST serum levels to the normal range, measuring 36 IU/L and 31 IU/L, respectively (Fig. 1).
Fig. 1
Summary for changes of serum hepatic enzymes.
The upper normal limits are follows; 40 IU/L for AST and ALT, 64 IU/L for GGT, 120 IU/L for ALP. *For the readability, the total bilirubin (normal 0.1~1.2 mg/dL) value was 10-folded in this figure.
Given the prompt recovery of AST and AST levels, there was no necessity for liver-focused radiologic examinations such as abdominal ultrasonography in this case. Apart from regular acupuncture and moxibustion, I refrained from prescribing any conventional or herbal medications for DILI of the patient.
III. Discussion and conclusion
In general, the majority of DILI cases is characterized by idiosyncratic metabolic responses, displaying patterns that are independent of dosage and unpredictable7. Among the commonly encountered drug groups, anti-tuberculosis (anti-TB) medications are well known to induce idiosyncratic DILI, accounting for an estimated 5% to 28% of hepatotoxicity cases among individuals undergoing anti-TB treatment10,11. Additionally, certain antibiotics such as amoxicillin- clavulanate and flucloxacillin have been frequently associated with cases of idiosyncratic DILI worldwide12.
The patient in this case had been prescribed three different antipsychotic drugs: quetiapine, escitalopram, and alprazolam. These medications are typically prescribed for individuals with conditions such as schizophrenia, bipolar disorder, depression, or anxiety. Shortly after initiating the administration of these newly prescribed drugs for 7 days, the patient experienced novel symptoms including severe malaise, fatigue, and distressing sensations. Based on the significant elevation of hepatic enzymes (ALT and AST) to over 2.5 times UNL, the absence of other liver disorders such as viral hepatitis, and the rapid normalization of enzyme levels after discontinuing the drugs, there was a strong suspicion of DILI. In addition, her subjective symptoms of malaise, fatigue, and distress rapidly disappeared after drug-cessation. In terms of withdrawal symptoms, I had provided a warning to the patient, but no withdrawal symptoms were observed. The Roussel Uclaf Causality Assessment Method (RUCAM)13 was employed to evaluate the causality, yielding a RUCAM score of 9 for this case, indicating a classification of “highly probable” for DILI.
DILI can be classified into three distinct patterns: hepatocellular, cholestatic, or mixed type. The specific pathological pattern observed in a DILI case is determined by calculating the R ratio, which is derived from the ratio of ALT value to the UNL, divided by the ratio of ALP value to the UNL14. A R ratio greater than 5 indicates a hepatocellular pattern, while a ratio below 2 suggests a cholestatic pattern, and values between 2 and 5 are indicative of a mixed pattern. Alternatively, an ALT value equal to or greater than 2 times the ULN with a normal range of ALP level is suggestive of a hepatocellular pattern, whereas an ALP value equal to or greater than 2 times the ULN with a normal range of ALT level points towards a cholestatic pattern15.
Although the prescription of antipsychotic drugs or antidepressants is generally considered safe16, the worldwide increase in the use of psychotropic drugs, along with long-term use, polypharmacy, and the presence of common comorbidities such as metabolic disorders, has led to an increased incidence of psychotropics-induced drug-induced liver injury (DILI) in psychiatric patients17. According to a systematic review, approximately 1.3% of patients taking antipsychotic medications exhibited clinically significant abnormal liver function tests (3-fold> UNL for ALT, AST and GGT, and 2-fold>ALP level)18. The current case patient had been receiving medication for her mixed connective tissues disease and major depressive disorder for over 5 years, with no abnormalities observed in her liver function tests. There is no information of the extent how the hepatotoxicity can raise by three drugs taken by the patient either in Korea or worldwide. However, there have been case reports associated with the those drugs: fulminant hepatic failure with quetiapine19, and liver injury with escitalopram and alprazolam20,21, respectively. These reports highlight the potential risk of hepatotoxicity related to these medications regardless the general belief of safety of antipsychotic drugs.
Early detection and prompt withdrawal of suspected drugs are essential principles in the management of DILI3. In the present case, the DILI was identified at an early stage due to the unusual manifestations reported by the patient and the author’s suspicion, facilitated by the availability of laboratory testing in the medical environment. It is worth mentioning that there is sometimes an excessive focus on the risk of herbal drug-associated DILI, which can lead to a distorted reputation for herbal medicine in Korea22. Furthermore, the author cautiously hypothesizes the possibility of pre-existing DILI or the development of DILI caused by chemical drugs during the treatment with herbal drugs. While it is unfortunate that not all Korean medicine (KM) clinicians have access to laboratory facilities for timely diagnosis, it is crucial for KM clinicians to remain aware of the potential occurrence of DILI caused by conventional drugs. By being mindful of this possibility, KM clinicians can take appropriate precautions and closely monitor patients for any signs of hepatotoxicity.
In summary, this case report highlights the importance of raising awareness among doctors in the KM field regarding conventional drug-induced hepatotoxicity. Through the example of DILI induced by antipsychotic drugs having the increase in the clinical use, it emphasizes the need for doctors in the KM field to be vigilant and informed about the potential risks associated with antipsychotic medications.
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