Drug-Induced Liver Injury Associated With the Angiotensin II Receptor Blocker Losartan in a 59-Year-Old Woman With Hypertension: A Case Report

Introduction

Drug-induced liver injury (DILI) is a leading cause of acute liver failure in developed countries and remains challenging to diagnose because of its diverse clinical presentations, ranging from asymptomatic elevations of liver enzymes to fulminant hepatic failure [1]. Epidemiological data show that although DILI is relatively uncommon, it constitutes a significant and increasingly recognized cause of liver-related morbidity worldwide [2]. DILI accounts for a substantial proportion of acute hepatitis and acute liver failure cases, with its incidence influenced by widespread medication use and global variations in prescribing patterns. Antibiotics, non-steroidal anti-inflammatory drugs, and antiepileptic medications are among the most frequently implicated drug classes [3].

DILI is broadly categorized as intrinsic (dose-dependent and predictable) or idiosyncratic (dose-independent and unpredictable), with the latter constituting the majority of clinically significant cases [4]. The pathogenesis of idiosyncratic DILI is multifactorial and can involve immune-mediated mechanisms, metabolic activation, mitochondrial dysfunction, oxidative stress, and inter-individual susceptibility [5,6]. Mitochondrial injury can impair oxidative phosphorylation and adenosine triphosphate (ATP) synthesis, whereas increased reactive oxygen species generation contributes to lipid peroxidation and hepatocellular damage [6,7]. Additional insights into DILI pathophysiology have emerged from drug responses observed during the COVID-19 era, highlighting the complex interactions between drug metabolism, host factors, and systemic inflammation [8]. The severity of DILI varies widely; Hy’s law criteria are applied clinically to identify patients at high risk for acute liver failure [9]. Hospital-based studies further emphasize that DILI accounts for a notable proportion of hepatology-related admissions [10].

Angiotensin II receptor blockers (ARBs) are widely used for the management of hypertension, heart failure, and diabetic nephropathy and generally possess an excellent safety profile [11]. However, hepatotoxicity, while rare, has been documented with ARBs, including losartan and olmesartan [12]. Registry data confirm that ARBs are recognized, although infrequent, causes of idiosyncratic DILI [13].

Losartan remains one of the most commonly prescribed ARBs worldwide. Despite its overall favorable safety characteristics, a growing body of literature reports cases of losartan-induced hepatotoxicity, with clinical presentations ranging from mild enzyme elevations to severe mixed or hepatocellular injury. We present the case of a 59-year-old woman who developed significant liver enzyme elevation after initiating losartan therapy, with complete biochemical normalization following drug withdrawal, supporting a diagnosis of losartan-induced DILI.

Case Report

MANAGEMENT AND OUTCOME:

Losartan was discontinued and replaced with amlodipine 5 mg daily. No specific hepatoprotective drugs were used. The patient improved clinically and biochemically within 1 month, with complete normalization of liver enzymes. Six-month follow-up confirmed sustained normalization of liver function and complete recovery (Figure 1, Table 2).

Discussion

This case highlights that losartan, although widely regarded as a safe antihypertensive agent, can rarely cause clinically significant DILI. It also shows that the pattern of injury can be mixed hepatocellular–cholestatic, and that early recognition and withdrawal of the drug can lead to complete recovery.

ARB-related hepatotoxicity, although uncommon, has been reported in association with several agents. Losartan is the most frequently implicated ARB in published case reports, with injuries ranging from asymptomatic enzyme elevation to severe hepatitis [2].

The exact pathophysiological mechanisms underlying ARB-induced liver injury are not fully clear, but several hypotheses have been proposed. Oxidative stress is considered a major contributor: ARBs can increase reactive oxygen species formation, leading to lipid peroxidation, mitochondrial injury, and hepatocellular damage. Mitochondrial dysfunction can occur through impaired oxidative phosphorylation, reduced ATP synthesis, and destabilization of mitochondrial membranes [5]. Losartan undergoes cytochrome P450-mediated bioactivation primarily via CYP2C9 and CYP3A4 to form its active metabolite EXP3174; this process can generate reactive intermediates capable of forming protein adducts and triggering cellular injury [5]. Immune-mediated mechanisms have also been implicated, with drug-protein adducts potentially activating innate and adaptive immune pathways and promoting hepatocellular inflammation. Cytokine-mediated injury involving tumor necrosis factor α and interleukin 6, as well as genetic polymorphisms affecting drug metabolism and detoxification pathways, can modulate individual susceptibility; reduced glutathione stores and impaired antioxidant defenses further potentiate reactive oxygen species–mediated hepatotoxicity [6]. Together, these mechanisms illustrate how losartan may induce idiosyncratic liver injury in predisposed individuals.

Tarantino and Finelli reported a losartan-induced hepatocellular liver injury that resolved completely after drug withdrawal [14]. Al-Halawani et al described a patient who developed significant enzyme elevation months after treatment initiation, with full recovery after discontinuation [15]. Midtvedt et al documented severe hepatocellular injury occurring within weeks of losartan initiation, resolving rapidly after withdrawal [16]. Nygaard and Strandgaard reported marked aminotransferase elevations that normalized after ceasing therapy [17].

Rechallenge has been shown to precipitate rapid and more severe recurrence of hepatotoxicity. Patti et al described a case of massive hepatocellular injury following re-exposure, underscoring the importance of avoiding rechallenge once DILI is suspected [18]. Diogo et al similarly reported a rechallenge case with severe recurrent hepatotoxicity and gradual recovery following definitive discontinuation [19]. Zahedi et al detailed a case involving severe hepatocellular injury with jaundice and altered sensorium shortly after losartan initiation, with improvement following withdrawal [20]. A biopsy-confirmed Tunisian case progressed to sub-fulminant hepatitis and hepatic encephalopathy despite drug discontinuation, demonstrating that losartan-induced DILI can be fatal [21] (Table 3).

Across the literature, the latency period between losartan initiation and onset of DILI ranges from days to months. The hepatocellular pattern is most common, although cholestatic and mixed patterns are also observed. In nearly all non-fatal cases, early drug withdrawal is associated with complete biochemical recovery.

In our patient, the R-ratio (3.9) indicated a mixed hepatocellular–cholestatic pattern, which is less commonly reported than the predominantly hepatocellular pattern described in earlier literature. The clear temporal relationship between drug initiation and biochemical injury, exclusion of alternative etiologies, and prompt improvement after cessation support losartan as the causative agent. This case reinforces the need for vigilance when evaluating new-onset liver enzyme abnormalities in patients receiving losartan.

Conclusions

Losartan-induced DILI is rare but clinically important. This case adds to the growing body of evidence that losartan can cause idiosyncratic liver injury with variable biochemical patterns, including mixed hepatocellular–cholestatic injury. Careful review of the medication history is essential in any patient presenting with new-onset liver enzyme elevation. Prompt recognition and withdrawal of the offending agent usually result in complete recovery, whereas rechallenge can lead to more severe injury. In patients with suspected losartan-induced DILI, alternative antihypertensive therapies should be selected and re-exposure to losartan avoided.