Copper availability and NAFLD in epileptic patients treated with valproic acid 151 Table II. Results obtained in the patients treated with valproic acid in polytherapy according to its ceruloplasmin-speciﬁc oxidase activity. Speciﬁc oxidase activity<333(U/g) Speciﬁc oxidase activity ‡333(U/g) n (males/females) VPA Css (mg/L) VPA dose (mg/24h) Speciﬁc oxidase activity (U/g) Copper/ceruloplasmin ratio (mg/mg) Glucose (mg/dL) Cholesterol (mg/dL) Triglycerides (mg/dL) GGT (U/L) ALP (U/L) ChE (U/L) AST(U/L) ALT(U/L) AST/ALT ratio CRP (mg/L) APRI score FIB-4 score aSigniﬁcance: P < 0.05. bSigniﬁcance: P < 0.001. 10 (7/3) 49.4 ± 4.1 (48.1) 1900.0 ± 362.5 (1500.0) 256.0 ± 19.5 (279.8)b 3.3 ± 0.2 (3.2)a 85.4 ± 1.7 (86.0) 215.4 ± 19.6 (194.0) 126.8 ± 17.6 (130.5) 65.0 ± 19.3 (50.5) 145.2 ± 21.1 (147.0) 7198.6 ± 845.9 (7308.0) 17.6 ± 4.4 (14.5) 27.4 ± 9.2 (19.0) 0.8 ± 0.1 (0.7) 38.7 ± 26.0 (8.9) 0.33 ± 0.07(0.30) 0.69 ± 0.12(0.70) 16 (10/6) 49.1 ± 6.3 (41.5) 1733.3 ± 244.5 (1500.0) 454.3 ± 18.0 (439.3) 3.9 ± 0.2 (3.9) 98.9 ± 7.8(87.5) 222.8 ± 23.5 (209.0) 130.2 ± 25.0 (102.0) 70.6 ± 18.2 (44.0) 201.2 ± 34.1 (164.5) 7638.0 ± 798.0 (7147.0) 15.9 ± 1.7 (15.0) 21.1 ± 3.1 (16.0) 0.9 ± 0.1 (0.8) 27.0 ± 14.7 (4.9) 0.25 ± 0.04 (0.20) 0.63 ± 0.15 (0.50) treated with VPA (6,7), and around 38% of these patients may have a diminished copper availability (11), a particular condition that would be involved in the development of liver steatosis (12–14). A relevant proportion of non-alcoholic fatty liver disease patients had low copper stores (12,13), which is associated with more pronounced insulin resistance and other clinical features of the metabolic syndrome, and might be a typical feature of pathophysiological relevance to its hepatic manifestation as non-alcoholic fatty liver disease (12,13). Patients with serum copper levels in the currently applied ‘normal’ range may include a signiﬁcant proportion of cases with copper stores that can be considered depleted (12). The speciﬁc oxidase activity of circulating cerulo- plasmin, which in adults is not inﬂuenced by non- dietary factors such as age, gender, or hormone use, is a more sensitive indicator of copper status than either serum copper, ceruloplasmin, or erythrocyte super- oxide dismutase (29,30). In the VPA-treated patients with ceruloplasmin-speciﬁc oxidase activity below the lower limit of reference (333 U/L) a reduced copper content of the circulating ceruloplasmin due to the diminished liver copper availability should be supposed (11). Recently, it has been reported that the severity of non-alcoholic fatty liver disease correlates with high-sensitivity CRP values (31). In our patients, a signiﬁcant relationship of the speciﬁc oxidase activity of ceruloplasmin with CRP levels was not attained, indicating that the speciﬁc oxidase activity is not inﬂuenced by the inﬂammatory status. Signiﬁcant increases of the serum AST, ALT, GGT, and ChE activities in groups of patients with non-alcoholic fatty liver disease are well documented (15–22), as well as its correlation with the grade of steatosis and ﬁbrosis assessed by liver ultrasound (17,19,20). In particular, increased serum ChE is considered a useful marker of liver steatosis (21,32), associated with adiposity, insu- lin resistance, lipid proﬁle (22,33), and fatty liver inﬁltration degree (34). The serum levels of AST, ALT, GGT, and ChE, and AST/ALT ratio, APRI and FIB-4 indices were analogous and without sig- niﬁcant differences between the groups of VPA- treated patients with ceruloplasmin-speciﬁc oxidase activities lower or greater than 333 U/L (Tables I and II). These results do not conﬁrm the hypothesis of a signiﬁcant association between copper deﬁciency and fatty liver disease in the patients treated with VPA. It has been hypothesized that elevated ChE activities could lead to a decrease of acetyl- choline which has anti-inﬂammatory actions and consequently could trigger the onset of low-grade