What clinical studies report ivermectin-induced liver enzyme elevations in humans?
Executive summary
Existing clinical evidence that ivermectin causes liver enzyme elevations in humans is limited but real: randomized/tolerability trials and pharmacovigilance databases document transient aminotransferase rises, and multiple case reports describe clinically apparent hepatic injury including one well‑documented severe hepatitis; conversely, preclinical studies and many clinical series find no consistent hepatotoxic signal, and causality is often uncertain [1] [2] [3] [4].
1. Clinical trials and controlled studies — small signals, rare events
Dose‑escalation tolerability work in healthy volunteers noted transient liver test abnormalities: Guzzo et al. reported that 2 of 30 subjects receiving 30 mg developed elevations >2× baseline in alanine aminotransferase (ALT) and gamma‑glutamyl transferase (GGT), though higher doses up to 60 mg did not clearly increase hepatotoxic risk in that program [2]; more broadly, LiverTox summarizes that single‑dose ivermectin therapy has been associated with a low rate of serum aminotransferase elevations and that many anthelmintic trials lacked routine liver monitoring, potentially underestimating incidence [1].
2. Pharmacovigilance and aggregate reports — clustering of hepatic adverse events during COVID repurposing
Analyses of VigiBase and other pharmacovigilance sources flagged reports of hepatitis, hepatocellular injury, cholestasis and isolated transaminase elevations temporally associated with ivermectin when used for SARS‑CoV‑2, prompting calls for closer study and enzyme monitoring, especially in patients with preexisting liver disease [2] [5]; these database signals document events but cannot by themselves prove causality because of reporting bias and confounding from COVID‑19 polypharmacy [2].
3. Case reports of clinically apparent liver injury — documented but rare
The literature includes several case reports linking ivermectin to clinically apparent hepatitis: the first published severe case described a 20‑year‑old woman developing jaundice, pruritus and mixed/cholestatic enzyme abnormalities about one month after a single dose, with biopsy showing confluent necrosis and inflammatory infiltrates that led authors to attribute causality to ivermectin (Veit et al., reported in the literature and summarized by LiverTox) [3] [1]. Subsequent case reports and clinical abstracts describe mixed‑pattern enzyme elevations and fulminant presentations after self‑administration or off‑label use during the COVID‑19 era, including a case managed with prednisone and another with progressive jaundice and marked enzyme elevation where RUCAM scoring supported a probable drug‑induced liver injury [6] [4] [7].
4. Mechanistic and animal data — conflicting signals that complicate interpretation
Preclinical work is mixed: some animal models show hepatotoxic changes in susceptible species, whereas other studies found ivermectin attenuated experimentally induced liver fibrosis in mice and reduced AST/ALT in that context, illustrating that mechanisms are not settled and animal data do not straightforwardly predict human risk [8] [9] [2]. Metabolism via CYP3A4 and potential interactions with CYP inhibitors or other drugs (eg, warfarin noted in a case) create plausible mechanistic routes for idiosyncratic or interaction‑mediated liver injury [10] [6].
5. How to weigh the evidence — rare true hepatotoxicity plausible but uncertain frequency
The best current synthesis is that ivermectin can cause transient, usually mild aminotransferase elevations in some people and that rare, idiosyncratic clinically apparent liver injury has been reported and documented in case reports and pharmacovigilance databases [1] [2] [3] [4]; however, randomized and controlled data do not show a large signal of routine hepatotoxicity, and confounding factors—COVID‑19 infection, co‑medications, dosing deviations (self‑injection, veterinary formulations), and reporting bias—limit certainty about incidence and direct causation [2] [7].
6. Practical conclusion and gaps — monitor and study more rigorously
Clinicians and regulators cited in these sources recommend vigilance: consider liver enzyme monitoring when ivermectin is used off‑label or repeatedly, especially in patients with preexisting liver disease or those on interacting drugs, while acknowledging that the published evidence base is dominated by small trials, signal reports and case studies rather than large prospective hepatotoxicity trials; major knowledge gaps remain because many anthelmintic studies did not perform routine LFT monitoring and pharmacovigilance cannot fully adjudicate causality [1] [2] [5].