The Journal of Pediatrics
Volume 156, Issue 2 , Pages 176-177, February 2010

Familial Hypercholesterolemia: A Decade of Progress

  • Samuel S. Gidding, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Samuel S. Gidding, MD, Nemours Cardiac Center, 1600 Rockland Rd, Wilmington, DE 19803.

Cardiology Division Head, Nemours Cardiac Center, A.I. duPont Hospital for Children, Professor of Pediatrics, Thomas Jefferson University, Wilmington, Delaware

Article Outline

FH, Familial hypercholesterolemia, HDL, High-density lipoprotein, LDL, Low-density lipoprotein

 

See related article, p 231

Natural history studies of familial hypercholesterolemia (FH), a genetic disorder associated with elevated cholesterol level and premature coronary artery disease and with a frequency of about 1 of 500 in the general population, were first conducted in the 1970s.1 Homozygotes, with cholesterol levels >500mg/dL, experience coronary events as early as adolescence, and heterozygotes (with 1 normal and 1 abnormal gene) are affected prematurely in middle age. The first major breakthrough in understanding the disease came with the discovery of the low-density lipoprotein (LDL) receptor by Brown and Goldstein, in work that won the Nobel prize.2

In the last approximately 20 years, several hundred separate defects have been identified as causes of elevated LDL cholesterol level via alteration of function of the LDL receptor. These defects fall in several groups. Most common are defects of receptor function ranging from the absence of receptor expression (the most severe) to abnormalities in receptor function. The second most common group is defects in the formation of apolipoprotein B, the major protein on LDL, so that binding of the protein to the receptor is impaired.3 Finally, genes related to the regulation of LDL receptor function have recently been uncovered, PCSK9 is important in this process, and defects that impair receptor function increase LDL levels and risk for heart disease and those that enhance LDL receptor function lower the risk for heart disease.4 In Europe, genotyping of patients suspected of having FH is common, and a genetic defect is identified at least 80% of the time.5

Although cholesterol-lowering treatment has been well established in coronary disease prevention in adults, it has taken until this decade for work establishing evidence for the importance of early recognition and treatment of FH in childhood. Premature atherosclerosis in adolescents has been demonstrated with radiologic assessment of subclinical atherosclerosis. Approximately 25% to 30% of adolescents have measurable coronary calcium.6 Carotid intima media thickness is increased in affected individuals and increases faster in affected individuals than in unaffected siblings.7 The Pathobiological Determinants of Atherosclerosis in Youth Study has demonstrated that for every 30mg/dL increase in non-high-density lipoprotein (HDL) cholesterol level, the coronary vasculature develops the equivalent of 2 to 3 years of accumulation of atherosclerosis; because the average LDL cholesterol level in FH is 100 to 200mg/dl greater than the population median, the development of premature coronary disease with this genetic disorder is easily explained.8

Effective treatment for elevated cholesterol level, particularly for children, did not exist until the development of the statins, a class of drugs that inhibit cholesterol synthesis in hepatic cells (and elsewhere) and, in consequence, increase LDL receptor expression and thus lower serum cholesterol levels.9 Clinical trials of 1 to 2 years duration have now been conducted in children for all the important statins, leading to US Food and Drug Administration approval for lovastatin, pravastatin, simvastatin, and atorvastatin use in childhood; all these medications lowered cholesterol safely for the duration of the trials. Trials of rosuvastatin, the most potent statin on a milligram for milligram basis, are nearing completion. This experience has recently been reviewed in an American Heart Association scientific statement that provides guidelines for statin use in patients with elevated cholesterol levels.9

Medications that inhibit bile acid or cholesterol absorption have also been used to lower LDL cholesterol levels. Because they work via a different mechanism of action, they are synergistic with statins and can significantly increase LDL cholesterol level reduction when used in combination. Cholestyramine, a resin that inhibits bile re-absorption, has been used for decades, although gastrointestinal adverse effects are common. Ezetimibe, a cholesterol absorption inhibitor, has been studied with simvastatin and adds to the LDL level lowering achieved by that medication.10 In this issue of The Journal, Stein et al report the use of colesevelam, an inhibitor of bile acid reabsorption, to safely and effectively lower cholesterol in a dose-dependent fashion in children.11 All these drugs lower LDL cholesterol level in the range of 10% to 15%, in comparison with the 20% to 50% lowering achieved with statins, depending on the potency of the individual statin. The current role for these medications has not been firmly established, but it is likely they will be important in 2 settings: primary treatment for patients who are statin intolerant or preferred treatment for patients who have genetic defects that are particularly suited to the mechanism of action of these drugs (eg, sitosterolemia). A third role in children, use as adjuncts to statins to help achieve LDL level targets, is not yet firmly established, but may emerge as important if future primary prevention trials both in young and older adults can show increments of prevention of events related to achieving target LDL cholesterol goals, as opposed to settling for significant percent reduction but not achieving LDL levels <130mg/dL.

An important limitation of the conduct of the colesevelam trial relates to the lack of tight control of statin use during the course of the study.11 Concomitant statin treatment was allowed, but not monitored for compliance, and doses of statins were adjusted during the study. Paradoxically, patients receiving both a statin and low-dose colesevelam actually had a slight rise in LDL cholesterol level. This result points out a common problem in pediatric lipid-lowering treatment: poor compliance with recommendations. The most likely explanation for the paradoxical finding is discontinuation of statins in preference for study drug (or placebo) during the trial. The benefits of cholesterol-lowering therapy cannot be achieved without regular use of the medication.

Because of the substantial progress in understanding the early natural history of FH in the last decade, what progress can be anticipated in the next decade? In Europe, where natural history studies of statin treatment have been underway for many years, it is highly likely that the benefits of LDL lowering for coronary artery disease prevention in this disease will be conclusively established. A second advance will likely be the incorporation of genetic testing into standard clinical practice to diagnose FH and risk stratify on the basis of the particular genetic defect. Future research should also be directed toward understanding whether clinicians should be satisfied with substantial cholesterol lowering from low to moderate statin dosing or whether it will be necessary to achieve specific LDL target levels to achieve prevention of events. Safety evaluations will be critical in these trials.

Research to date has allowed the United Kingdom to develop cholesterol-lowering guidelines specific for FH, the NICE guidelines.12 This approach is different than the approach in the United States, which is linked specifically to LDL cholesterol levels and not to the diagnosis of FH. Cost-benefit analysis has shown that the combination of genotype screening of potentially affected individuals and subsequent lipid-lowering therapy of affected individuals is justified. Perhaps the time has come in the United States to separate out individuals with known high-risk for premature coronary artery disease from more general population-based guidelines. This may allow for the development of clinical trials specifically directed toward these high-risk patients, those with FH, diabetes mellitus, and multiple risk states created by interactions of genetics with obesity, tobacco use, or both.

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References 

  1. Kwiterovich PO. Primary and secondary disorders of lipid metabolism in pediatrics. Pediatr Endocrinol Rev. 2008;2(5 Suppl):727–738
  2. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–438
  3. Varret M, Abifadel M, Rabes JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clinical Genet. 2008;73:1–13
  4. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50(Suppl):S172–S177
  5. Humphries SEYN, Talmud PJ. Cardiovascular disease risk prediction using genetic information (gene scores): is it really informative?. Curr Opin Lipidol. 2008;19:128–132
  6. Gidding SS, Bookstein LC, Chomka EV. Usefulness of electron beam tomography in adolescents and young adults with heterozygous familial hypercholesterolemia. Circulation. 1998;98:2580–2583
  7. Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 2004;363:369–370
  8. McMahan CA, Gidding SS, Malcom GT, Tracy RE, Strong JP, McGill HC. Pathobiological determinants of atherosclerosis in youth risk scores are associated with early and advanced atherosclerosis. Pediatrics. 2006;118:1447–1455
  9. McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, et al. Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. Circulation. 2007;115:1948–1967
  10. van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagne C, Shi G, et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia. J Am Coll Cardiol. 2008;52:1421–1429
  11. Stein E. Colesevelam HCl: Efficacy and Safety in Pediatric Subjects With Heterozygous Familial Hypercholesterolemia. J Pediatr. 2010;156:231–236
  12. Wierzbicki AS, Humphries SE, Minhas R. Familial hypercholesterolaemia: summary of NICE guidance. BMJ. 2008;337:a1095

PII: S0022-3476(09)01021-X

doi:10.1016/j.jpeds.2009.10.007

Refers to article:

  • Colesevelam Hydrochloride: Efficacy and Safety in Pediatric Subjects with Heterozygous Familial Hypercholesterolemia , 02 November 2009

    Evan A. Stein, A. David Marais, Tamas Szamosi, Frederick J. Raal, Daniel Schurr, Elaine M. Urbina, Paul N. Hopkins, Sulekha Karki, Jianbo Xu, Soamnauth Misir, Michael Melino
    The Journal of Pediatrics February 2010 (Vol. 156, Issue 2, Pages 231-236.e3)

The Journal of Pediatrics
Volume 156, Issue 2 , Pages 176-177, February 2010

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