152 N. Lampon & J. C. Tutor systemic inﬂammation (35,36). Signiﬁcant increases of serum ChE (37,38) and CRP (39,40) have been reported in epileptic patients treated with different anticonvulsant drugs. In our patients having CRP concentrations lower than 10 mg/L (subclinical chronic inﬂammation), a signiﬁcant positive corre- lation between serum ChE and CRP was found (r = 0.410;P < 0.001); however, in the cases with CRP greater than 10 mg/L (acute inﬂammation conditions) the correlation coefﬁcient between these two variables was negative, although due to the low number of patients considered, statistical signiﬁ- cance was not achieved (r = –0.405;P = 0.084). Similarly, in the group of patients with CRP levels lower than 10 mg/L the ChE activity was signiﬁ- cantly higher (P < 0.005) than in the patients with CRP greater than 10 mg/L (7,400.9 ± 189.7 U/L (7,309.0 U/L) versus 5,846.5 ± 681.2 U/L (6,004.0 U/L)), possibly due to a greater liver injury in these last patients. This is an interesting subject that should be studied in a greater detail. Non-alcoholic fatty liver disease ranges from simple steatosis, with a benign course, to non-alcoholic steatohepatitis with necroinﬂammation and ﬁbrosis, which can progress to cryptogenic cirrhosis and end- stage liver disease. As shown in Figure 1, most control subjects (98%) and VPA-treated patients (93%) have low scores for the APRI (<0.5) and FIB-4 (<1.45) indices, suggesting the absence of liver ﬁbrosis in these cases. Likewise, in the remaining patients the values obtained for both indices suggest a low likeli- hood of signiﬁcant hepatic ﬁbrosis. Only a 95-year- old male patient with platelet count of 107 109/L, AST 16 U/L, and ALT 11 U/L (AST/ALT ratio = 1.45), and presenting low serum levels of GGT 12 U/L, ChE 4,621 U/L, and albumin 31 g/L, had a FIB-4 score of 4.3 indicative of severe liver ﬁbrosis, although the APRI index was 0.60. The variables AST activity and platelet count are used for the calculation of the APRI (24) and FIB-4 (25) liver ﬁbrosis indices. With the progression of liver ﬁbrosis, serum AST activity increases due to its release from mitochondria and its diminished clearance; likewise, the platelet count decreases due to a hypo-production of thrombopoietin by the hepa- tocytes and an increased circulating platelet destruc- tion in spleen, as portal hypertension develops. In the VPA-treated patients studied, the coefﬁcient of deter- mination (estimated from the correspondent ﬁrst partial correlation coefﬁcients indicated above) shows that the APRI score is slightly more dependent on the platelet count (r2 = 0.806) than AST activity (r2 = 0.721). The dependence of FIB-4 score on the platelet count (r2 = 0.368) was also higher than with AST activity (r2 = 0.122). A 2 1.5 e r o 1 c s I R P A 0.5 0 B 5.0 4.0 re 3.0 o c s 4 - IFB 2.0 1.0 0.0 Controls VPA (M) VPA (P) Controls VPA (M) VPA (P) Figure 1. Distribution of the APRI score (A) and FIB-4 score (B) in males (.) and females (*) controls and patients treated with valproic acid in monotherapy (VPAM) and polytherapy (VPAP). The dashed lines correspond to the cut-off values for absence (APRI <0.5; FIB-4 <1.45) or presence of signiﬁcant liver ﬁbrosis (APRI>1.5; FIB-4 >3.25). Considering the MPV and PDW platelet indices of our 11 patients with thrombocytopenia, this fact may be due to a hyper-destruction of the circulating platelets as was indicated above. Thrombocytopenia is the most common hematologic adverse effect of VPA, although the exact mechanism has not yet been elucidated (41). Our study did not reveal any signif- icant correlation between serum VPA concentration and platelet count, or signiﬁcant higher VPA levels in the 11 patients with platelet count lower than 150 109/L with respect to the remaining patients (55.4 ± 7.7 mg/L (48.1 mg/L) versus