title: Markers of atherosclerotic development in children with familial hypercholesterolemia: a literature review.
abstract: OBJECTIVE
  Atherosclerosis is a multi-step process, where lipids, inflammatory and hemostatic mediators orchestrate plaque formation and progression, which subsequently may lead to myocardial infarction and ischemic stroke. Familial hypercholesterolemia (FH) is associated with increased risk of premature atherosclerosis due to the genetically determined elevated low density lipoprotein (LDL)-cholesterol seen in these individuals. Children with FH are suitable to investigate the isolated effect of elevated LDL-cholesterol on early markers of atherosclerosis. The aim of the present paper was to review the literature to summarize the findings of atherosclerotic markers in children with FH to better understand how elevated LDL-cholesterol per se promotes atherogenesis.
  
  
  METHODS
  We conducted a systematic literature search from the years 1990-2013, resulting in identification of 903 articles. In order to investigate whether intima-media thickness (IMT) is different in children with and without FH, we conducted a meta-analysis of the studies comparing FH children with a control group.
  
  
  RESULTS
  37 original articles were included. Among these, 24 reported subclinical measurements, whereas other articles reported measurements of atherogenic lipids (n = 9), inflammatory markers (n = 10), hemostatic markers (n = 6) and other surrogate markers of atherosclerosis (n = 7). In the meta-analysis (n = 8), IMT was significantly thicker in children with FH than in control children (weighted mean difference 0.06, 95% confidence interval [0.01, 0.11]).
  
  
  CONCLUSIONS
  Elevated LDL-cholesterol distinguishes children with and without FH, but these groups of children also differ in several other ways. In particular, children with FH display a variety of changes reflecting both the lipid and the inflammatory arm of atherosclerosis. The IMT-meta-analysis result strengthens the evidence of early atherosclerotic development in children with FH. In a clinical perspective, early diagnosing and treatment of children with FH is of high importance to attenuate development of the potential ongoing early atherosclerotic process in these individuals.
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, Blindern, 0317 Oslo, Norway; Lipid Clinic, Oslo University Hospital Rikshospitalet, P.O. Box 4950, Nydalen, 0424 Oslo, Norway. Electronic address: ingunn.narverud@medisin.uio.no.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Narverud
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, Blindern, 0317 Oslo, Norway; Lipid Clinic, Oslo University Hospital Rikshospitalet, P.O. Box 4950, Nydalen, 0424 Oslo, Norway. Electronic address: kjetil.retterstol@medisin.uio.no.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Retterstøl
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, Blindern, 0317 Oslo, Norway; Department of Haematology, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424 Oslo, Norway. Electronic address: p.o.iversen@medisin.uio.no.
authors.forename: Per Ole
authors.initials: PO
authors.lastname: Iversen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, P.O. Box 4950, Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway. Electronic address: Bente.Halvorsen@rr-research.no.
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, P.O. Box 4950, Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway. Electronic address: Thor.Ueland@rr-research.no.
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.affiliation: Department of Health, Nutrition and Management, Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, P.O. Box 4, St. Olavs Plass, 0130 Oslo, Norway. Electronic address: stinemarie.ulven@hioa.no.
authors.forename: Stine M
authors.initials: SM
authors.lastname: Ulven
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, Blindern, 0317 Oslo, Norway; Lipid Clinic, Oslo University Hospital Rikshospitalet, P.O. Box 4950, Nydalen, 0424 Oslo, Norway. Electronic address: lose@ous-hf.no.
authors.forename: Leiv
authors.initials: L
authors.lastname: Ose
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, P.O. Box 4950, Nydalen, 0424 Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O. Box 1171, Blindern, 0318 Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, P.O. Box 4950, Nydalen, 0424 Oslo, Norway; K.G. Jebsen Inflammatory Research Center, P.O. Box 1171, Blindern, 0318 Oslo, Norway. Electronic address: paukrust@ous-hf.no.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, Blindern, 0317 Oslo, Norway; Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317 Oslo, Norway. Electronic address: m.b.veierod@medisin.uio.no.
authors.forename: Marit B
authors.initials: MB
authors.lastname: Veierød
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, Blindern, 0317 Oslo, Norway. Electronic address: Kirsten.holven@medisin.uio.no.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Holven
mesh_terms: D000293:Adolescent; D050197:Atherosclerosis / Q000209:etiology*; D002097:C-Reactive Protein / Q000378:metabolism; D059168:Carotid Intima-Media Thickness; D002648:Child; D002675:Child, Preschool; D008078:Cholesterol, LDL / Q000097:blood; D004730:Endothelium, Vascular / Q000503:physiopathology; D006801:Humans; D006940:Hyperemia / Q000150:complications; D006938:Hyperlipoproteinemia Type II / Q000150:complications*; D007223:Infant; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D017270:Lipoprotein(a) / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D012039:Regional Blood Flow; D014664:Vasodilation
chemical_list: D008078:Cholesterol, LDL; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D002097:C-Reactive Protein
keywords: Atherosclerosis; Children; Familial hypercholesterolemia; Literature review; Markers of atherosclerosis