Reversible cognitive impairment associated with a high free fraction but subtherapeutic total blood level of valproic acid due to hypoalbuminemia in a bipolar patient

Valproic acid (VPA) is widely used in the treatment of epilepsy and bipolar disorder. It is largely bound to serum proteins (80–95%) in particular albumin, with a saturable binding capacity. Under conditions of hypoalbuminemia, protein binding of VPA will decrease and its pharmacologically-active free fraction will rise, even to toxic levels while measuring subtherapeutic VPA total blood levels [1] . We present an elderly bipolar patient with (sub)clinical total levels of VPA and a high free fraction of VPA due to hypoalbuminemia (14–24 g/L) leading to severe reversible cognitive impairment. VPA and the free fraction in particular, was the most likely cause of the cognitive impairment [2] . There was a time-correlation with increasing blood levels of total VPA (68 mg/L, reference 80–120 mg/L [3] ), notably the free fraction (37.5 mg/L, reference 5–15 mg/L), and the intoxication. For therapeutic drug monitoring in laboratories, generally, total VPA concentrations (free + protein-bound) are measured instead of free fractions, due to technical difficulties, a lack of established reference ranges [4] and (inter)national guidelines [5] , [6] not requiring it. This presentation and literature points out that it is clinically relevant to measure the free fraction [7] , [8] , especially in patients with hypoalbuminemia [9] , [10] , [11] to prevent unnecessary side effects and toxicity. We recommend measuring albumin during VPA use; particularly in patients with nephrotic syndrome, liver disease [12] or older adults [13] , [14] , [15] . Hypoalbuminemia demands a free fraction measurement.