I. Introduction
Drug-induced liver injury (DILI) is one of the most common causes of hepatotoxicity, accounting for approximately 10% of all cases of acute hepatic failure1. Most patients with DILI recover completely after discontinuing the suspected drug. However, in 10-15% of cases, chronic histological manifestations may occur2. A 2-year prospective study conducted by the U.S. DILI Network involving 1,089 DILI cases reported 68 instances (6.2%) of death or liver transplantation. Of these, 80% involved acute liver failure, while 20% followed a non-acute progression3.
Acetaminophen (paracetamol) is the most well-known drug associated with DILI, accounting for half of all acute liver failure cases in the U.S. and many Western countries4. Other drugs, including troglitazone (an antidiabetic agent), anticonvulsants, analgesics, antibiotics, and anti-cancer medications, are also known to induce DILI5. Adverse drug reactions (ADRs) such as exanthematous rashes, urticaria, drowsiness, or nausea are typically dose-dependent and predictable. However, most DILI cases, except those caused by acetaminophen, are dose-independent and unpredictable, making early detection and prevention in clinical settings particularly challenging6. This underscores the need for constant vigilance regarding the hepatotoxic potential of any medication7.
Herbal medicine is frequently mentioned as a major cause of DILI in Asian countries, including China and Korea8,9. However, prospective and cohort studies suggest that the risk of herb-induced liver injury (HILI) is overestimated, with at least a 2-3 times lower risk compared to conventional drugs10,11. In addition, there is concern about the hepatotoxicity of conventional drugs when used concomitantly with herbal medicines12.
This study aims to present a case of drug-induced liver injury (DILI) associated with acne medication prior to the patient’s visit to a traditional Korean medicine (TKM) hospital, highlighting the importance of awareness among TKM physicians.
II. Report of the case
1. Medical history and examination
A 16-year-old female with a BMI of 20 had been healthy despite mild anemia. She began taking an herbal decoction (Guibi-tang supplemented with deer antler, Supplementary Table 1) for two days to address her anemia but subsequently developed symptoms including dyspepsia, nausea, fatigue, and dizziness. A TKM physician consulted me regarding her complaints. Blood tests revealed hepatic injury with elevated levels of aspartate transaminase (AST, 77 IU/L), alanine transaminase (ALT, 231 IU/L), alkaline phosphatase (ALP, 261 IU/L), and γ-glutamyl transferase (GGT, 381 IU/L). Serum tests for hepatitis A, B, and C viruses were negative (data not shown), and abdominal computed tomography (CT) showed no abnormalities (Fig. 1).
Fig. 1
Abdominal CT scanning image.
No specific finding observed in liver and surrounding organs including spleen and pancreas.
I diagnosed drug-associated hepatotoxicity based on the rapid onset of distressing subjective symptoms and abnormal hepatic enzyme levels, with no evidence of structural disorders. The R value was calculated as 2.6 ([231/40]/[261/117]), indicating a mixed type of drug-induced liver injury (DILI). During the initial interview, the patient reported not taking any medications other than herbal medicine, which she had used for only two days. However, given the low likelihood that two days of herbal medicine intake could cause liver injury, I conducted a detailed re-evaluation of her medical history. This revealed that she had been taking acne medication, including roxithromycin13-15, for one week until her first visit. Roxithromycin is known to have potential hepatotoxic effects (Table 1). The patient initially omitted mentioning the acne medication, as she considered her acne condition to be insignificant and thought the completed treatment was irrelevant to her current symptoms.
Table 1
Prescription of Antituberculosis Drugs
| Name of product (Dose per day) | Active ingredient | Main action | Warning for liver injury |
|---|---|---|---|
| Roxithrin Tab. (150 mg twice) | Roxithromycin | Semi-synthetic macrolide antibiotic | Heaptotoxicity13 |
| Loxoprofen Tab. (30 mg twice) | Loxoprofen Sodium | Anti-inflammatory : COX inhibitor | Intrahepatic cholestasis14 |
| Bronase enteric coated Tab. (100 mg twice) | Bromelain | Digestive enzyme | No report |
| Mosaren Tab. (5.3 mg twice) | Mosapride Citrate Hydrate | Prokinetics | Case reports of DILI15 |
| Dipalene Gel (1 mg/g, once) | Adapalene | Vitamin A derivative for skin | Topical |
| Acnin solution (10 mg/mL, once) | Clindamycin Phosphate | Antibiotics | Topical |
This case study had been approved by the Institutional Review Board for Human Research of Daejeon University Daejeon Hospital (#: DJDSKH-25-E-01-01)
2. Treatments and clinical outcome
Under the diagnosis of DILI, all medications, including acne treatments and anemia-related herbal remedies, were discontinued. Following this, the patient’s symptoms of epigastric fullness, nausea, and fatigue showed rapid improvement within 7 days, with the numeric rating scale (NRS) decreasing from 10 on the initial day to 2. Liver injury parameters, ALT (33 IU/L) and AST (18 IU/L), returned to normal levels. Although GGT (333 IU/L) and ALP (324 IU/L) remained abnormally elevated on the 7th day, they normalized within 5 weeks (Fig. 2, Supplementary Table 2).
Fig. 2
Summary for changes of serum hepatic enzymes and symptoms
The upper normal limits are as follows : 40 IU/L for AST and ALT, 40 IU/L for GGT, and 117 IU/L for ALP. The level of subjective symptoms was reported using the Numeric Rating Scale (NRS), with a score of 10 on the day of diagnosis (Day 1).
By the 20th day, when GGT (138 IU/L) and ALP (112 IU/L) had nearly normalized, the patient resumed taking the herbal medication for her anemia. Despite this, all hepatic enzyme levels remained within the normal range during follow-up blood tests (Fig. 2, Supplementary Table 2). No specific medications were prescribed for the patient’s DILI, apart from minimal acupuncture and moxibustion.
III. Discussion and Conclusion
The patient reported experiencing moderate dyspepsia, nausea, and fatigue after taking Guibi-tang supplemented with deer antler for two days. Biochemical tests revealed acute hepatic injury of a mixed type, consistent with the patient’s subjective symptoms. Although bilirubin level was normal (0.58 mg/dL, data not shown), there was a significant elevation of GGT (approximately 10 times the upper limit of normal [ULN]) and ALP (2 times the ULN). These findings sometimes warrant examination of the anatomical structure of the extrahepatic and intrahepatic biliary tree16. However, the abdominal CT scan showed no abnormalities (Fig. 1), and viral hepatitis was ruled out (data not shown), strongly suggesting DILI.
Although the adverse reaction could be attributed to Guibi-tang, I considered this possibility nearly low due to the well-documented safety of Guibi-tang in clinical practice17. The herbal compositions of Guibi-tang are believed to be non-toxic, and a preclinical studt showed no observed adverse effects even very high doses (up to 2000 mg/kg/day in rats)18. Additionally, only the two-day duration of herbal drug use seemed too short to induce hepatotoxicity, even though most cases of DILI including herb-induced liver injury (HILI) are idiosyncratic, dose-independent, and unpredictable6.
To investigate further, I conducted a thorough interview regarding any additional medications or supplements. It was subsequently revealed that the patient had used acne medication for one week until her hospital visit. The patient unconsciously forgot to state the medication because the acne and the medication used for it seemed insignificant, and she had already completed the course of treatment.
The patient’s blood test results, particularly the further elevation of GGT on the seventh day, prompted me to reassess other potential risk factors or diseases beyond DILI. However, an abdominal CT scan and further analysis ruled out any other causative conditions, confirming DILI as the most likely diagnosis. Acne medications were ultimately suspected as the primary cause of the DILI, particularly since the prescription included hepatotoxic drugs such as the antibiotic roxithromycin. One study well reported acute hepatotoxicity associated with roxithromycin13. Loxoprofen sodium, an anti-inflammatory agent in the prescription, also could be a causative drug of hepatic injury. This agent had been reported to induce intrahepatic cholestasis during 3 week-exposure14, which aligned with the observed GGT elevation (Table 1, Fig. 1). According to the Roussel Uclaf Causality Assessment Method (RUCAM)19, the score for this case was 8 (time to onset 2 points, course of ALP after cessation 2 points, exclude alternative causes 2 points, and previous hepatotoxicity 2 points), indicating a “probable” association with DILI. The case was classified as a mixed type of DILI, based on the calculated 2.6 of R ratio ([ALT value÷ALT ULN]÷[ALP value÷ALP ULN])20. Once the patient’s hepatic enzyme levels normalized, re-administration of Guibi-tang did not lead to any abnormal findings, ruling out HILI as a cause.
This report highlights a case of DILI due to the short-term use of acne medication. Given that most TKM clinics lack routine blood testing capabilities, this case underscores the importance of careful observation and differentiation of conventional drug-induced hepatotoxicity, particularly in patients presenting with abdominal complaints in the TKM setting.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation 
Print 
