A preliminary investigation on the possible association between diminished copper availability and non-alcoholic fatty liver disease in epileptic patients treated with valproic acid

Abstract

BackgroundPatients 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 methodsIn 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).ResultsThe 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.ConclusionsThe results obtained do not confirm the hypothesis of an association between diminished copper availability and NAFLD in patients treated with valproic acid.

Apparent clearance of valproic acid in elderly epileptic patients: estimation of the confounding effect of albumin concentration

“…Although the principal pathways of VPA metabolism are glucuronidation and β-oxidation, and CYPs pathways account for less than 10% of the dose ( 33 ), functional polymorphisms of several cytochrome oxidase isoenzymes may explain part of the inter-individual variability in VPA pharmacokinetics ( 34 ). In accordance with previously published results ( 35 ), data indicated above for APRI suggest a low likelihood of significant liver fibrosis in epileptic patients treated with VPA in monotherapy, even in elderly subjects ( Table I ); however, significant negative correlations were obtained between the apparent CL N of VPA and the APRI score and AST/ALT ratio.…”

“…In our patients that were treated with VPA in monotherapy, significant positive correlations were also found between the apparent CL N of VPA and serum GGT and ALT. VPA is not an enzyme-inducing agent, and in these patients GGT and ALT activities may be associated with over-weight and fat accumulation in the liver ( 33,35 ). Although in simple steatosis the function of several liver CYPs isoenzymes may be impaired, the activity of phase II conjugation enzymes, such as UDP-glucuronyltransferase, would be enhanced ( 36 ), with the consequent increase of VPA biotransformation and elimination.…”

The Role of Copper as a Modifier of Lipid Metabolism

“…Significance of these observations is becoming more and more apparent given recent data that dietary influences (such as amount of fat in the diet) could be important modifiers of the course and severity of the disorders associated with copper misbalance (11). Reciprocally, copper deficiency has emerged as a factor in the development of Non-alcoholic Fatty-Liver Disease (NAFLD) (12,13), although current reports paint complex picture (14) and further studies are needed. Despite ample phenotypic evidence in support of copperlipid interactions, little mechanistic work has been done so far, and current understanding of this metabolic interaction at the molecular level is very limited.…”

Classification and differential diagnosis of Wilson’s disease

“…An increased zinc uptake [through dietary supplements, denture adhesive cream ( 79)] also decreases the serum copper level (80). Taking valproic acid leads to a copper deficiency via a not yet clarified mechanism (81). A cause for copper deficiency cannot be found in approx.…”