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Department of Pediatrics Faculty PapersDepartment of Pediatrics
Familial Hypercholesterolemia: A Decade of
Samuel S. Gidding, MD
Thomas Jefferson University and A.I. duPont Hospital for Children, firstname.lastname@example.org
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Gidding, MD, Samuel S., "Familial Hypercholesterolemia: A Decade of Progress" (2010).
Department of Pediatrics Faculty Papers.Paper 21.
As submitted to:
Journal of Pediatrics
And later published as:
“Familial Hypercholesterolemia: A Decade of Progress”
Volume 156, Issue 2, February 2010, Pages 176-177
Samuel S. Gidding, MD
Cardiology Division Head
Nemours Cardiac Center
A.I. duPont Hospital for Children
Professor of Pediatrics, Thomas Jefferson University
Running Title: Progress in FH
Nemours Cardiac Center
1600 Rockland Road
Wilmington, DE 19803
302 651 6639 (5345, fax)
Natural history studies of familial hypercholesterolemia (FH), a genetic disorder
associated with elevated cholesterol and premature coronary artery disease, and with a
frequency of about 1:500 in the general population, were first conducted in the 1970s. 1
Homozygotes, with cholesterol levels in excess of 500 mg/dl experience coronary events
as early as adolescence and heterozygotes (with one normal and one 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, work that won the Nobel prize.2
Over the last 20 or so years, several hundred separate defects have been identified
as causes of elevated LDL cholesterol via alteration of function of the LDL receptor.
These defects fall into 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 are 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 while 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
Though 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 by radiologic assessment of
subclinical atherosclerosis. About 25-30% have measurable coronary calcium. 6 Carotid
intima media thickness is increased in affected individuals and increases faster in affected
individuals compared to unaffected siblings. 7 The Pathobiological Determinants of
Atherosclerosis in Youth Study has demonstrated that for every 30 mg/dl increase in non-
HDL cholesterol, the coronary vasculature develops the equivalent of 2-3 years of
accumulation of atherosclerosis; since the average LDL cholesterol in FH is 100-200
mg/dl above the population median, the development of premature coronary disease with
this genetic disorder is easily explained. 8
Effective treatment for elevated cholesterol, 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 FDA approval for
lovastatin, pravastatin, simvastatin, and atorvastatin use in childhood; all lower
cholesterol safely for the duration of the trials. Trials of rosuvastatin, the most potent
statin on a mg for mg basis, are nearing completion. This experience has recently been
reviewed in an American Heart Association scientific statement that provides guidelines
for their use in those with elevated cholesterol. 9
Medications that inhibit bile acid or cholesterol absorption have also been used to
lower LDL cholesterol; because they work by a different mechanism of action, they are
synergistic with statins and can significantly increase LDL cholesterol reduction when
used in combination. Cholestyramine, a resin that inhibits bile reabsorption, has been
used for decades though gastrointestinal side effects are common. Ezetimibe, a
cholesterol absorption inhibitor, has been studied in conjunction with simvastatin and
adds to LDL lowering achieved by that medication. 10 In this issue of the Journal of
Pediatrics, 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 FH children.
(ref) All of these drugs lower LDL cholesterol in the range of 10-15% in comparison to
the 20-50% lowering achieved by 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 two settings: primary treatment for patients who are
statin intolerant or preferred treatment for those who have genetic defects that are
particularly suited to the mechanism of action of these drugs (e.g. sitosterolemia). A
third pediatric role, use as adjuncts to statins to help achieve LDL 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 % reduction but not
achieving LDL levels below 130 mg/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. 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 regularly using the
Given the substantial progress in understanding the early natural history of FH in
the last decade or so, 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 based on the particular genetic defect. Future research should also be directed
towards understanding whether clinicians should be satisfied with substantial cholesterol
lowering from low to moderate statin dosing or if it will be necessary to achieve specific
LDL target levels to achieve prevention of events. Safety evaluations will be critical in
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 that 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 those 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 towards these high risk patients, those with FH,
diabetes mellitus, and multiple risk states created by interactions of genetics with obesity
and/or tobacco use.
Kwiterovich PO. Primary and secondary disorders of lipid metabolism in
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Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. Apr
Varret M, Abifadel M, Rabes JP, Boileau C. Genetic heterogeneity of autosomal
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Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL
catabolism. J Lipid Res. Apr 2009;50 Suppl:S172-177.
Humphries SE YN, Talmud PJ. Cardiovascular disease risk prediction using
genetic information (gene scores): is it really informative? Curr Opin Lipidol.
Gidding SS, Bookstein LC, Chomka EV. Usefulness of electron beam
tomography in adolescents and young adults with heterozygous familial
hypercholesterolemia. Circulation. Dec 8 1998;98(23):2580-2583.
Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, Sijbrands
EJ, Kastelein JJ. Arterial intima-media thickness in children heterozygous for
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McMahan CA, Gidding SS, Malcom GT, Tracy RE, Strong JP, McGill HC, Jr.
Pathobiological determinants of atherosclerosis in youth risk scores are associated
with early and advanced atherosclerosis. Pediatrics. Oct 2006;118(4):1447-1455.
McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini
AP, Hayman LL, Daniels SR. Drug therapy of high-risk lipid abnormalities in
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van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagne C, Shi G, Veltri
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Wierzbicki AS, Humphries SE, Minhas R. Familial hypercholesterolaemia:
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