Download PDF
Semin Vasc Med 2004; 4(1): 51-57
DOI: 10.1055/s-2004-822986
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Diagnostic, Clinical, and Therapeutic Aspects of Familial Hypercholesterolemia in Children

Leiv Ose1
  • 1Lipid Clinic, Department of Medicine, Rikshospitalet, Oslo, Norway
Further Information

Publication History

Publication Date:
22 March 2004 (online)

    Permissions and Reprints

The clinical diagnosis of familial hypercholesterolemia (FH) in children is based on family history and laboratory findings. The best available value of low-density lipoprotein cholesterol (LDL-C) for the diagnosis of FH in children is >3.50 mmol/L (>135 mg/dL) when FH runs in the family. Levels below this concentration were only found in 4.3% of children that had a mutation in the LDL-receptor gene. In contrast, children with LDL-C equal to or above 3.50 mmol/L had 0.98 posttest probability of FH. Untreated FH carries a substantial burden of morbidity and mortality if left untreated or if inadequately treated. The guidelines of the American National Cholesterol Education Program suggested that drug treatment should be considered from the age of 10 years if LDL-C levels are greater than or equal to 4.9 mmol/L (190 mg/dL) or greater than or equal to 4.1 mmol/L (158 mg/dL) in the presence of other cardiovascular risk factors, including a positive family history of premature cardiovascular disease. Impaired flow mediated dilatation was more pronounced in FH children with a positive family history of premature cardiovascular disease. The currently prescribed diet is sometimes considered to be monotonous and can lead to problems with compliance. A reduction of the total intake fat and saturated fatty acids is important. Plant sterolesters should be evaluated in young FH children and can supplement drug and diet therapy, with an additional reduction of 10 to 15% of LDL-C. The use of resins leads to poor compliance, and statins are recommended for FH children and adolescents when drug treatment is indicated. Pravastatin, simvastatin, and atorvastatin decrease LDL-C 30 to 40% without serious adverse events and have a high degree of compliance.

Keywords

Familial hypercholesterolemia - diet - drug treatment - children - adolescents

REFERENCES

  • 1 Kwiterovich P O. Identification and treatment of heterozygous familial Hypercholesterolemia in children and adolescents.  Am J Cardiol. 1993;  72 30D-37D
    CrossrefPubMedGoogle Scholar
  • 2 Kwiterovich P O. Biochemical, clinical, epidemiological, genetic, and pathological data in the pediatric age group relevant to the cholesterol hypothesis.  Pediatrics. 1992;  89 525-584
    PubMedGoogle Scholar
  • 3 Academy of Pediatrics . National Cholesterol Education Program: report of the expert panel on blood cholesterol levels in children and adolescents.  Pediatrics. 1992;  89 525-584
    PubMedGoogle Scholar
  • 4 Wiegman A, Rodenburg J, De Jongh S et al.. Family history and cardiovascular risk in Familial Hypercholesterolemia: data in more than 1000 children.  Circulation. 2003;  107 1473-1478
    CrossrefPubMedGoogle Scholar
  • 5 Tonstad S. Stratification of risk in children with familial hypercholesterolemia with focus on psychological issues.  Nutr Metab Cardiovasc Dis. 2001;  11(Suppl 5) 64-67
    PubMedGoogle Scholar
  • 6 Tonstad S, Refsum H, Sivertsen M, Christophersen B, Ose L, Ueland P M. Relation of homocysteine and lipid levels in children to premature cardiovascular death in male relatives.  Pediatr Res. 1996;  40 47-52
    PubMedGoogle Scholar
  • 7 Tonstad S, Joakimsen O, Stensland-Bugge E et al.. Risk factors related to carotid intima-media thickness and plaque in children with familial hypercholesterolemia and controls.  Arterioscler Thromb Vasc Biol. 1996;  16 984-991
    PubMedGoogle Scholar
  • 8 Tonstad S, Refsum H, Ose L, Ueland P M. The C677T mutation in the methylene-tetrahydrofolate reductase gene predisposes to hyperhomocysteinemia in children with familial hypercholesterolemia treated with cholestyramine.  J Pediatr. 1998;  132 365-368
    PubMedGoogle Scholar
  • 9 Umans-Eckenhausen M AW, Sijbrands E JG, Kastelein J JP, Defesche J C. Low-Density Lipoprotein-receptor gene mutations and cardiovascular risk in a large genetic cascade screening population.  Circulation. 2002;  106 3031-3036
    CrossrefPubMedGoogle Scholar
  • 10 Couture C, Brun L D, Szots F et al.. Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 1998;  18 1007-1012
    PubMedGoogle Scholar
  • 11 Tell G S, Mittelmark M B, Vellar O D. Cholesterol, high density lipoprotein cholesterol and triglycerides during puberty: the Oslo Youth study.  Am J Epidemiol. 1985;  122 750-761
    PubMedGoogle Scholar
  • 12 Setälä-Alto K, Viikarari J, Åkerblom H K, Kuusela V, Kontula K. DNA polymorphisms of the apolipoprotein B and A-I/C-III genes are associated with variations of serum low density lipoprotein cholesterol level in childhood.  J Lipid Res. 1991;  32 1477-1487
    PubMedGoogle Scholar
  • 13 De Jongh S, Lilien M R, Bakker H D, Hutten B A, Kastelein J JP, Stroes E S. Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia.  Atherosclerosis. 2002;  163 193-197
    CrossrefPubMedGoogle Scholar
  • 14 Tuzco E M, Kapadia S R, Tutar E et al.. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound.  Circulation. 2001;  103 2705-2710
    PubMedGoogle Scholar
  • 15 Pathological Determinants of Atherosclerosis in Youth Research Group . Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. A preliminary report from Pathological Determinants of Atherosclerosis in Youth (PDAY) Research Group.  JAMA. 1990;  264 3018-3024
    CrossrefPubMedGoogle Scholar
  • 16 Davis P H, Dawson J D, Riley W A, Lauer R M. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: the Muscatine Study.  Circulation. 2001;  104 2815-2819
    PubMedGoogle Scholar
  • 17 Jarvisalo M S, Jartti L, Nanto-Salonen K et al.. Increased aortic intima-media thickens: a marker of preclinical atherosclerosis in high risk children.  Circulation. 2001;  104 2943-2947
    PubMedGoogle Scholar
  • 18 Wiegman A, Rodenburg J, Gort J et al.. B-mode ultrasound material wall thickness measurements in children proven heterozygous for familial hypercholesterolemia.  Atherosclerosis. 2002;  3S 236
    PubMedGoogle Scholar
  • 19 Poustie V J, Rutherford P. Dietary treatment for familial hypercholesterolemia.  Cochrane Database Syst Rev. 2001;  (2) , CD001918. Review
    PubMedGoogle Scholar
  • 20 Mabuchi H, Yagi K, Haraki T, Matsushita H, Inazu A, Kajinami K, Koizumi J. Molecular genetics of cholesterol transport and cholesterol reverse transport disorders (familial hypercholesterolemia and CETP deficiency.  Ann N Y Acad Sci. 1995;  748 333-341
    PubMedGoogle Scholar
  • 21 Grundy S M, Denke M A. Dietary influences on serum lipids and lipoproteins.  J Lipid Res. 1990;  31 1149-1172
    PubMedGoogle Scholar
  • 22 Jacques H, Laurin D, Moorjani S et al.. Influence of diets containing cow's milk or soy protein beverages on plasma lipids in children with familial hypercholesterolemia.  J Am Coll Nutr. 1992;  11(Suppl) 69S-73S
    PubMedGoogle Scholar
  • 23 Gylling H, Siimes M A, Miettinen T A. Sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia.  J Lipid Res. 1995;  36 1807-1812
    PubMedGoogle Scholar
  • 24 Amundsen A L, Ose L, Nenseter M S, Ntanios F Y. Plant sterol ester-enriched spread lowers plasma total and LDL-cholesterol in children with familial hypercholesterolemia.  Am J Clin Nutr. 2002;  76 338-344
    PubMedGoogle Scholar
  • 25 de Jongh S, Vissers M N, Rol P, Bakker H D, Kastelein J JP, Stroes E SG. Plant sterols lower LDL cholesterol without improving endothelial function in pre-pubertal children with familial hypercholesterolemia.  J Inherit Metab Dis. 2003;  26 343-351
    CrossrefPubMedGoogle Scholar
  • 26 National Cholesterol Education Program . Report of the Expert Panel on blood cholesterol levels in children and adolescents.  Pediatrics. 1992;  89 525-584
    PubMedGoogle Scholar
  • 27 Tonstad S, Knudtzon J, Sivertsen M, Refsum H, Ose L. Efficacy and safety of cholestyramine in pubertal a prepubertal children with familial hypercholesterolemia.  J Pediatr. 1996;  129 42-39
    PubMedGoogle Scholar
  • 28 Writing Group for the Dros Inf ServC Collaborative Research Group . Efficacy and safety of lowering dietary intake of fat and cholesterol in children with elevated low-density lipoprotein cholesterol. The Dietary Intervention Study in Children (Dros Inf ServC).  JAMA. 1995;  273 1429-1435
    CrossrefPubMedGoogle Scholar
  • 29 Tonstad S, Sivertsen M, Aksnes L, Ose L. Low dose colestipol in adolescents with familial hypercholesterolemia.  Arch Dis Child. 1996;  74 157-160
    PubMedGoogle Scholar
  • 30 McCrindle B W, O'Neill M B, Cullen-Dean G, Helden E. Acceptability and compliance with two forms of cholestyramine in the treatment of hypercholesterolemia in children: a randomized, crossover trial.  J Pediatr. 1997;  130 266-273
    PubMedGoogle Scholar
  • 31 Knapp H H, Schrott H, Ma P et al.. Efficacy and safety of combination simvastatin and colesevalam in patients with primary hypercholesterolemia.  Am J Med. 2001;  110 352-360
    CrossrefPubMedGoogle Scholar
  • 32 De Jongh S, Stalenhoef A FH, Tuohy M B, Mercuri M, Bakker H D, Kastelein J JP. Efficacy and tolerability of simvastatin in children with familial hypercholesterolemia.  Clinical Drug Investigation. 2002;  22 533-540
    PubMedGoogle Scholar
  • 33 De Jongh S, Ose L, Szamosi T et al.. Efficacy and safety of statin therapy in children with familial Hypercholesterolemia.  Circulation. 2002;  106 2213-2237
    PubMedGoogle Scholar
  • 34 McCrindle B, Ose L, Marais D. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia and/or severe hyperlipidemia: multicenter, randomized, placebo-controlled trial.  J Pediatr. 2003;  143 74-80
    CrossrefPubMedGoogle Scholar
  • 35 Stein E A, Illingworth D R, Kwiterovich P O et al.. Efficacy and safety of lovastin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.  JAMA. 1999;  281 137-144
    CrossrefPubMedGoogle Scholar
  • 36 Ducobu J, Brasseur D, Chaudron J M et al.. Simvastatin in children.  Lancet. 1992;  339 1488
    PubMedGoogle Scholar
  • 37 Knipscheer H C, Boelen C C, Kastelein J JP et al.. Short term efficacy and safety of pravastatin in 72 children with familial Hypercholesterolemia.  Pediatr Res. 1996;  39 867-871
    PubMedGoogle Scholar
  • 38 Lambert M, Lupien P J, Cagne C et al.. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin.  Pediatrics. 1996;  97 619-628
    PubMedGoogle Scholar
  • 39 Stein E A, Illingworth D R, Kwiterovich P O et al.. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.  JAMA. 1999;  281 137-144
    CrossrefPubMedGoogle Scholar
  • 40 Newman T B, Browner W S, Hulley S B. The case against childhood cholesterol screening.  JAMA. 1990;  264 3039-3043
    CrossrefPubMedGoogle Scholar
  • 41 Holzman N A. The great god cholesterol.  Pediatrics. 1991;  87 943-945
    PubMedGoogle Scholar
  • 42 Tonstad S, Nøvik T C, Vandvik I H. Psychosocial function during treatment for familial hypercholesterolemia.  Pediatrics. 1996;  98 249-255
    PubMedGoogle Scholar
  • 43 de Jongh S, Kerckhoffs M C, Grootenhuis M A, Bakker H D, Heymans H S, Last B F. Quality of life, anxiety and concerns among statin-treated children with familial hypercholesterolaemia and their parents.  Acta Paediatr. 2003;  92 1096-1101
    CrossrefPubMedGoogle Scholar

Leiv OseM.D. Ph.D. 

Rikshospitalet

NO-0027 Oslo, Norway

Email: Leiv.ose@klinmed.uio.no

      >