Upsala Journal of Medical Sciences. 2011; 116: 148–154 ORIGINAL ARTICLE A preliminary investigation on the possible association between diminished copper availability and non-alcoholic fatty liver disease in epileptic patients treated with valproic acid NATALIA LAMPON & J. CARLOS TUTOR Unidad Monitorización Fármacos, Laboratorio Central, Hospital Clínico Universitario, Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain Abstract Background. Patients treated with valproic acid (VPA) present a high incidence of non-alcoholic fatty liver disease (NAFLD) (around 61%). Several recent studies suggest that low copper stores could be associated with NAFLD, and a signiﬁcant decrease of copper availability in VPA-treated patients has been described. Design and methods. In 101 adult epileptic patients treated with valproic acid in monotherapy (n = 75) and polytherapy (n = 26) the copper availability was evaluated using the speciﬁc oxidase activity of ceruloplasmin (activity per unit mass of enzyme protein) and the copper/ceruloplasmin ratio. Copper deﬁciency was supposed in the cases in which this biochemical variable was smaller than the lower reference limit (333 U/g). Results. The differences between the groups of patients with ceruloplasmin oxidase activity smaller or greater than 333 U/g for the serum levels of aminotransferases, gamma-glutamyltransferase, butyrylcholinesterase, cholesterol, triglycerides, and C-reactive protein, and the APRI and FIB-4 liver ﬁbrosis scores were not statistically signiﬁcant. Most patients (93%) had low APRI and FIB-4 scores, suggesting absence of signiﬁcant liver ﬁbrosis. Conclusions. The results obtained do not conﬁrm the hypothesis of an association between diminished copper availability and NAFLD in patients treated with valproic acid. Key words: APRI, butyrylcholinesterase, copper deﬁciency, FIB-4, non-alcoholic fatty liver disease, valproic acid Introduction Valproic acid (VPA) has been widely used since the late 1960s for the treatment of generalized and partial seizures, and it is still the antiepileptic drug with the broadest spectrum (1). New roles for this old drug were later conﬁrmed, due to its beneﬁcial effects in bipolar disorders, schizophrenia, depression, neuro- logical pain, migraine headaches, and a number of neurodegenerative diseases (2,3). It has been highlighted that on rare occasions serious complications may occur in some VPA- treated patients, including pancreatitis, coagulopa- thies, induced hepatotoxicity, and encephalopathy, although there is still a lack of knowledge about the incidence of these special side effects (1). Type I VPA-associated hepatotoxicity consists of a dose-dependent elevation of serum liver enzymes, which normalize after drug discontinuation, and type II consists of a rare idiosyncratic VPA-associated hepatotoxicity that is normally lethal (1). VPA has a signiﬁcant steatogenic effect in HpG2 cell cultures (4), and development of fatty liver is one of the clinical ﬁndings during treatment with this drug (5). Using abdominal ultrasound, Luef et al. demon- strated that non-alcoholic fatty liver disease was present in 61% of VPA-treated patients (6), with this high prevalence being conﬁrmed in a more recent study (7). Impaired hepatic fatty acid oxida- tion directly inhibiting mitochondrial b-oxidation Correspondence: J. Carlos Tutor, PharmD, PhD, Unidad Monitorización Fármacos, Laboratorio Central, Hospital Clínico Universitario, 15706 Santiago de Compostela, Spain. E-mail: jocatuva@hotmail.com; josecarlostutor@redfarma.org (Received 26 November 2010; accepted 2 December 2010) ISSN 0300-9734 print/ISSN 2000-1967 online 2011 Informa Healthcare DOI: 10.3109/03009734.2010.545898