Vitamin K requirement in children .... beyond coagulation

Abstract

In past decades, novel treatment strategies of chronic diseases in childhood have lead to significant improvement in (functional) outcome and increased patient-survival. As a result, the treatment and prevention of long-term complications associated with chronic diseases have become of additional importance. These complications may give rise to considerable morbidity, extending into later (adult) life. For example, reduced bone mineral density and concurrent increased fracture risk are associated conditions in many pediatric chronic diseases. Furthermore, several chronic diseases in childhood may predispose patients to (subclinical) atherosclerosis resulting in early cardiovascular disease. The pathophysiological processes underlying osteoporosis and atherosclerosis are complex. In the adult population, the role of vitamin K and the vitamin K-dependent proteins osteocalcin and matrix Gla protein (MGP) in both conditions has been studied. However, this field of research in children has remained fairly unexplored up to now. This thesis contains several studies on the role of osteocalcin in childhood bone health and the role of MGP in relation to ectopic calcification in pediatric disease. In chapter 2, vitamin K status in healthy children is compared to that in adults, together with its relation with bone turnover markers. In chapter 3, vitamin K status in healthy children during puberty is studied together with its association with bone mass and changes in bone mass over 2 years. From these two studies, it appears that the majority of healthy children have a suboptimal vitamin K status which may be related to decreased bone health. Chapter 4 describes the findings of a randomized controlled trial in which the effect of vitamin K2 on osteocalcin carboxylation in healthy children was studied. Vitamin K supplementation had an effect on osteocalcin carboxylation, even in children with a high vitamin K status. In chapter 5, vitamin K status in children with juvenile idiopathic arthritis (JIA) was compared to that in healthy children and the association between vitamin K status of bone, bone markers and quantitative ultrasound properties of calcaneal bone were studied as well. In chapter 6, the circulating levels of the vascular calcification inhibitors MGP and fetuin-A in children after renal transplantation are compared to healthy children, together with possible associations with vascular properties of the carotid artery. In chapter 7, the localization of the different forms of MGP in muscle biopsies from juvenile dermatomyositis (JDM) patients with and without calcification are studied. The various forms of MGP were found to be present at the site of muscle damage in JDM patients in different staining intensities. In pediatric medicine, vitamin K and vitamin K-dependent proteins are best known for their role in blood coagulation. The works as presented in this thesis are a substantial addition to the body of evidence on different aspects of the vitamin K-dependent proteins. The findings from this thesis suggest that vitamin K may be of possible benefit in preventing ectopic calcification and osteoporosis in pediatric patients. Furthermore, also healthy children may benefit from elevated vitamin K intakes leading to increased osteocalcin carboxylation, which may result in improved bone health.