SUMMARYThe ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

FGF21 is a critical metabolic regulator, pivotal for fasting adaptation and directly regulated by PPARalpha in rodents. However, the physiological role of FGF21 in man is not yet defined and was investigated in our study. Serum FGF21 varied 250-fold among 76 healthy individuals and did not relate to age, gender, body mass index (BMI), serum lipids, or plasma glucose. FGF21 levels had no diurnal variation and were unrelated to bile acid or cholesterol synthesis. Ketosis induced by a 2 day fast or feeding a ketogenic diet (KD) did not influence FGF21 levels, whereas a 74% increase occurred after 7 days of fasting. Hypertriglyceridemic nondiabetic patients had 2-fold elevated FGF21 levels, which were further increased by 28% during fenofibrate treatment. FGF21 circulates in human plasma and increases by extreme fasting and PPARalpha activation. The wide interindividual variation and the induction of ketogenesis independent of FGF21 levels indicate that the physiological role of FGF21 in humans may differ from that in mice.

Objective-To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes. Methods and Results-We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid-binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (Ͼ18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels. Conclusion-Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9. Key Words: circulating PCSK9 Ⅲ cholesterol synthesis Ⅲ LDL cholesterol Ⅲ diurnal rhythm Ⅲ growth hormone Ⅲ cholesterol-lowering drugs Ⅲ lipoproteins G enetic variants of proprotein convertase subtilisin kexin type 9 (PCSK9) influence plasma low-density lipoprotein (LDL) cholesterol in humans, accounting for both hypercholesterolemia and hypocholesterolemia and altered coronary risk. 1,2 PCSK9 modulates the number of LDL receptors (LDLRs) by triggering the degradation of LDLRs. 3 Gain-offunction mutations in the PCSK9 gene produce a phenotype of familial hypercholesterolemia, 1 whereas loss-of-function mutations reduce plasma LDL cholesterol levels. 2 Circulating PCSK9 is largely derived from the liver, 4,5 and plasma levels relate to the hepatic expression of PCSK9. 6 -9 It is still unclear to what extent PCSK9 is physiologically regulated and if such regulation may influence plasma LDL cholesterol levels in humans. Novel therapies aiming at lowering serum LDL cholesterol by interfering with PCSK9 activity are under development. 10 Fasting plasma levels of PCSK9 correlate positively with LDL cholesterol levels in healthy and diabetic patients 7,[11][12][13][14] ; however, in the most extensive study, 7 with Ͼ3000 subjects, PCSK9 levels only predicted 7% of the variation in LDL cholesterol. In animals, the hepatic gene expression of PCSK9 is partly under hormonal control: treatment with glucagon or high-dose estrogen reduces PCSK9 mRNA and increases the number of LDLRs, 15 whereas insulin 15,16 and growth hormone (GH) 17 both increase PCSK9 mRNA levels in rat liver.The gene expressions of PCSK9, the LDLR and 3-hydroxy-3-...