Letter to the Editor: Fimasartan-Induced Liver Injury and Update on Hepatotoxicity Risks

To the Editor:

We read with great interest the retrospective cohort study by Choi et al.,1 which examined the incidence and biochemical patterns of aminotransferase elevation associated with four angiotensin II receptor blockers (ARBs), including fimasartan. Fimasartan was more strongly associated with alanine aminotransferase (ALT) elevation and probable drug-induced liver injury (DILI) than other ARBs (candesartan, valsartan, and losartan). However, published clinical reports of fimasartan-induced liver injury remain scarce—only a single case has been reported to date.2 Therefore, we wish to present a severe, biopsy-proven cholestatic DILI caused by fimasartan that needed systemic corticosteroids, which adds to Choi et al.’s findings.1

A 45-year-old man, treated for eight months with fimasartan 60 mg and amlodipine 5 mg, was referred to our hospital with intermittent fevers > 39°C for 3 weeks, truncal rash, myalgia, and 8-kg weight loss over 3 months. Laboratory testing revealed aspartate aminotransferase (AST) 1,273 IU/L, ALT 1,180 IU/L, alkaline phosphatase (ALP) 568 IU/L, total bilirubin 2.08 mg/dL, and markedly elevated ferritin > 15,000 ng/mL. Viral and autoimmune markers were negative, and imaging showed only reactive lymphadenopathy. Percutaneous liver biopsy revealed acute cholestatic hepatitis with centrilobular necrosis and sinusoidal lymphocyte infiltration. The modified RUCAM scale score was 6, categorizing the case as probable DILI. Fimasartan was discontinued immediately, and methylprednisolone 40 mg daily was initiated due to persistent clinical symptoms and hyperbilirubinemia (total bilirubin 8.27 mg/dL). The patient showed gradual improvement and was discharged on day 13 with complete recovery during outpatient follow-up.

Since Choi et al.’s study1 was published, some investigations have added new data on the potential liver risks associated with ARB use (Table 1). Kim et al.3 recently analyzed 229,881 patients across nine ARBs and found that azilsartan monotherapy carried the highest DILI risk compared to valsartan, while olmesartan showed protective effects. Regarding fimasartan specifically, comparable risk was found at standard doses, but significantly increased risk when doses exceeded twice the daily defined amount. Another analysis comparing 12,751 patients taking either fimasartan or losartan over 28 days confirmed that mild AST/ALT elevations (> 40 IU/L) were more common with fimasartan, though severe liver injury rates were comparable between the two agents.4

Table 1. Literature review of liver toxicity of fimasartan.

Case report
Author/Year	Age/Sex	Onset	Clinical manifestation	AST (IU/L)	ALT (IU/L)	Total Bilirubin (mg/dl)	Previously taken ARBs before Fimasartan	Treatment
Current case	45/M	7 months	Fever, myalgia, unintentional weight loss, skin rash	1,273	1,180	2.08	Telmisartan	Discontinuation of Fimasartan, Methylprednisolone administration
Park et al. (2017)2	73/M	10 months	Elevated liver enzyme	233	424	1.22	Candesartan, Irbesartan, Telmisartan	Discontinuation of Fimasartan, Supportive care via hepatotonics
Singapore HSA5	65/F	132 days	Two of them has AST exceeding more than 1,000 U/L and jaundice.				Olmesartan	Discontinuation of Fimasartan
	85/F	151 days					NR
	70/M	51 days					Olmesartan
	57/F	52 days					NR
Retrospective studies
Author/Year	Study design	Sample size (Total (Fimasartan))	Comparator drugs		Primary outcome	Study Findings
Choi et al. (2022)1	Retrospective	27,115 (5,543)	Valsartan, Losartan, Candesartan		ALT elevation pattern	- Elevation of ALT (≥ 120 IU/L) and DILI (maximum ALT ≥ 200 and RUCAM score ≥ 6) were more commonly associated with fimasartan than the other ARBs.
Kim et al. (2024)3	Retrospective	229,881 (26,863)	Valsartan, Telmisartan, Olmesartan, Losartan, Candesartan, Irbesartan, Azilsartan, Eprosartan		DILI	- Risk of DILI is comparable to Valsartan.
						- Higher DILI risk if dose ≥ 2 DDD.
Yoon et al. (2024)4	Retrospective	12,751 (3,063)	Losartan		AST, ALT elevation, DILI	- Mild elevation of AST or ALT (40–80 IU/L) was more common in fimasartan than losartan (3.17% vs 1.86%).
						- Moderate to high elevation of AST or ALT and incidence of liver injury is comparable with losartan.

AST = aspartate aminotransferase, ALT = alanine aminotransferase, ARBs = angiotensin II receptor blockers, NR = not reported, DILI = drug-induced liver injury, RUCAM = Roussel Uclaf Causality Assessment Method, DDD = defined daily dose.

These discrepancies may reflect differences in liver injury definitions, comparator groups, study populations, and analytical approaches across studies. Additionally, the idiosyncratic nature of fimasartan-induced liver injury may contribute to its underdetection in large-scale cohort studies, as such unpredictable, rare events are inherently difficult to capture through population-based analyses. Regardless of these methodological limitations, pharmacovigilance data suggest that fimasartan-associated liver injury may be more common than cohort studies indicate. According to Singapore's Health Sciences Authority (HSA), four serious adverse events of suspected fimasartan-induced liver injury were reported within one year, including two patients with ALT levels exceeding 1,000 U/L and jaundice.5 Furthermore, 221 liver-related adverse drug reactions associated with fimasartan were reported in World Health Organization's global pharmacovigilance database between 2012 to 2020.5 Taken together, the pharmacovigilance data, the findings of Choi et al.,1 and our present case report indicate that although fimasartan’s hepatotoxic potential has not yet been fully established, clinicians should consider fimasartan-induced liver injury when liver enzyme elevations or other signs of hepatic injury occur in patients receiving fimasartan.

Ethics statement

The study was approved by the Institutional Review Board (IRB) of Soonchunhyang University Bucheon Hospital (IRB number: SCHBC 2024-12-013; approval date: February 12, 2025). Informed consent for publication of the case details was obtained from the patient.

Author’s Response to the Letter

We would like to thank Dr. Yoo and colleagues for their insightful letter and for reporting an important case of biopsy-confirmed, steroid-responsive cholestatic hepatitis associated with fimasartan use. Their contribution significantly enriches the clinical understanding of fimasartan’s hepatotoxic potential, adding to the evidence from our prior cohort study, and highlighting the need for sustained awareness when prescribing ARBs.

In our original study, we demonstrated that the incidence of significant ALT elevation, defined as > 120 IU/L, was notably higher among patients treated with fimasartan compared to those receiving other ARBs, including candesartan, valsartan, and losartan.1 Furthermore, probable DILI, defined as ALT > 200 IU/L in conjunction with a RUCAM score ≥ 6,6 was observed most frequently in the fimasartan cohort. The authors’ case report reinforces our findings that, although most cases of ALT elevation are self-limiting, a subset may progress to severe hepatotoxicity requiring intervention.

Notably, Table 3 of the index article in our publication presents details of fimasartan-related DILI cases with a broad spectrum of ALT elevations, including several patients whose ALT exceeded 1,000 IU/L. While no fatalities were recorded, these findings attest to the potential for significant hepatic injury during fimasartan therapy. Additionally, as reported in Supplementary Table 3 of the index article, the incidence of DILI appeared to increase with higher daily doses of fimasartan, suggesting that in certain circumstances, fimasartan may not be limited to a purely idiosyncratic DILI profile but could also demonstrate dose-dependent toxicity at higher exposures.

Along with a previous case report,2 post-marketing reports, including those from the Singapore Health Sciences Authority,5 have similarly documented episodes of marked transaminase elevations and jaundice, further corroborating both our findings and those described by Dr. Yoo and colleagues.

We recognize, as the correspondents have highlighted, the inherent limitations of large-scale observational studies, which may undercapture rare or atypical DILI phenotypes due to methodological constraints. In this context, detailed case reports such as theirs are invaluable for delineating the real-world toxicity spectrum of fimasartan. Both epidemiological and case-based evidence now converge to suggest that clinicians should maintain a high index of suspicion for DILI in any patient manifesting unexplained hepatic dysfunction during fimasartan use.

We hope that the letter provided by Dr. Yoo and colleagues will stimulate heightened clinical awareness, robust pharmacovigilance reporting, and cautious prescribing of fimasartan. Given that most cases are reversible with timely recognition and withdrawal of the causative agent, continuous awareness and careful monitoring by prescribing physicians are crucial to ensure patient safety.

Eun Sun Jang

Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

Address for Correspondence: Eun Sun Jang, MD, PhD. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro, 173 beon-gil, Bundang-gu, Seongnam 13620, Korea. janges@snubh.org