Itraconazole-induced lanosterol accumulation mimicking genetic sterol disorders

This is the authors' abstract. We don't add key points for this paper.

Elevated plasma lanosterol is associated with different metabolic genetic disorders. Here, we describe a 14-year-old girl with hematological abnormalities, hyperbilirubinemia, intellectual disability, peripheral neuropathy, and persistently elevated plasma lanosterol without underlying genetic cause. Because she received prophylactic itraconazole for severe neutropenia, drug-induced lanosterolosis was suspected. So far, the effect of itrazonazole on cholesterol biosynthesis, including lanosterol accumulation has not been extensively studied. Plasma sterol profiling by UPLC-MS/MS was performed in index patient (P1) before and after itraconazole withdrawal and in two other itraconazole-treated patients (P2, P3). We retrospectively analyzed sterol measurements from our center ( n = 607), measured blood sterols in a patient with CYP51A1 variants (Lanosterolosis), and reviewed literature on adverse effects of itraconazole and other azole antifungals. P1 showed markedly elevated plasma lanosterol (range 3.97–4.86 μmol/L; reference range 0.05–0.45) with low-normal cholesterol, which normalized after itraconazole withdrawal. Elevated lanosterol was also observed in two other itraconazole-treated patients (P2 4.21 μmol/L; P3 1.94 μmol/L), supporting the drug effect. Lanosterol was significantly increased compared to patients with CTX, Sitosterolemia, and cholestasis, and the CYP51A1 patient. The lanosterol/cholesterol ratio further discriminated the itraconazole effects from other patient groups. Literature review linked long-term itraconazole use to hematological, neurological, gastrointestinal, and hepatic side-effects. Our findings suggest that long-term itraconazole use is associated with lanosterol accumulation, biochemically mimicking an inherited sterol disorder. Further studies are needed to clarify the clinical significance of chronic lanosterol accumulation. These findings highlight the importance of reviewing medication history to avoid misdiagnosis and unnecessary testing.