THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 156, No. 2

Familial Hypercholesterolemia: A Decade of Progress

Natural history studies of familial hypercholesterol-emia (FH), a genetic disorder associated with ele-vated cholesterol level and premature coronary

artery disease and with a frequency of about 1 of 500 inthe general population, were first conducted in the

See related article, p 231

1970s.1 Homozygotes, with cholesterollevels >500 mg/dL, experience coronary events as early as adolescence, and heterozygotes (with 1normal and 1 abnormal gene) are affected prematurely inmiddle age. The first major breakthrough in understandingthe disease came with the discovery of the low-density lipo-protein (LDL) receptor by Brown and Goldstein, in workthat won the Nobel prize.2

In the last approximately 20 years, several hundred sep-arate defects have been identified as causes of elevatedLDL cholesterol level via alteration of function of theLDL receptor. These defects fall in several groups. Mostcommon are defects of receptor function ranging fromthe absence of receptor expression (the most severe) toabnormalities in receptor function. The second most com-mon group is defects in the formation of apolipoproteinB, the major protein on LDL, so that binding of the pro-tein to the receptor is impaired.3 Finally, genes related tothe regulation of LDL receptor function have recentlybeen uncovered, PCSK9 is important in this process,and defects that impair receptor function increase LDLlevels and risk for heart disease and those that enhanceLDL receptor function lower the risk for heart disease.4

In Europe, genotyping of patients suspected of havingFH is common, and a genetic defect is identified at least80% of the time.5

Although cholesterol-lowering treatment has been well es-tablished in coronary disease prevention in adults, it hastaken until this decade for work establishing evidence forthe importance of early recognition and treatment of FH inchildhood. Premature atherosclerosis in adolescents hasbeen demonstrated with radiologic assessment of subclinicalatherosclerosis. Approximately 25% to 30% of adolescentshave measurable coronary calcium.6 Carotid intima mediathickness is increased in affected individuals and increasesfaster in affected individuals than in unaffected siblings.7

The Pathobiological Determinants of Atherosclerosis inYouth Study has demonstrated that for every 30 mg/dLincrease in non-high-density lipoprotein (HDL) cholesterollevel, the coronary vasculature develops the equivalent of 2to 3 years of accumulation of atherosclerosis; because the av-erage LDL cholesterol level in FH is 100 to 200 mg/dl greaterthan the population median, the development of premature

FH Familial hypercholesterolemia

HDL High-density lipoprotein

LDL Low-density lipoprotein

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coronary disease with this genetic disorder is easilyexplained.8

Effective treatment for elevated cholesterol level, partic-ularly for children, did not exist until the development ofthe statins, a class of drugs that inhibit cholesterol synthe-

0022-3476/$ - see fro

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sis in hepatic cells (and elsewhere) and, inconsequence, increase LDL receptor ex-

pression and thus lower serum cholesterol levels.9 Clinicaltrials of 1 to 2 years duration have now been conducted inchildren for all the important statins, leading to US Foodand Drug Administration approval for lovastatin, pravasta-tin, simvastatin, and atorvastatin use in childhood; allthese medications lowered cholesterol safely for the dura-tion of the trials. Trials of rosuvastatin, the most potentstatin on a milligram for milligram basis, are nearing com-pletion. This experience has recently been reviewed in anAmerican Heart Association scientific statement that pro-vides guidelines for statin use in patients with elevatedcholesterol levels.9

Medications that inhibit bile acid or cholesterol absorptionhave also been used to lower LDL cholesterol levels. Becausethey work via a different mechanism of action, they aresynergistic with statins and can significantly increase LDLcholesterol level reduction when used in combination. Cho-lestyramine, a resin that inhibits bile re-absorption, has beenused for decades, although gastrointestinal adverse effects arecommon. Ezetimibe, a cholesterol absorption inhibitor, hasbeen studied with simvastatin and adds to the LDL level low-ering achieved by that medication.10 In this issue of The Jour-nal, Stein et al report the use of colesevelam, an inhibitor ofbile acid reabsorption, to safely and effectively lower choles-terol in a dose-dependent fashion in children.11 All thesedrugs lower LDL cholesterol level in the range of 10% to15%, in comparison with the 20% to 50% lowering achievedwith statins, depending on the potency of the individual sta-tin. The current role for these medications has not beenfirmly established, but it is likely they will be important in2 settings: primary treatment for patients who are statin in-tolerant or preferred treatment for patients who have geneticdefects that are particularly suited to the mechanism of actionof 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 importantif future primary prevention trials both in young and olderadults can show increments of prevention of events relatedto achieving target LDL cholesterol goals, as opposed to set-tling for significant percent reduction but not achieving LDLlevels <130 mg/dL.

An important limitation of the conduct of the coleseve-lam trial relates to the lack of tight control of statin use

nt matter. Copyright ª 2010 Mosby Inc.

.1016/j.jpeds.2009.10.007

February 2010 EDITORIALS

during the course of the study.11 Concomitant statin treat-ment was allowed, but not monitored for compliance, anddoses of statins were adjusted during the study. Paradoxi-cally, patients receiving both a statin and low-dose coleseve-lam actually had a slight rise in LDL cholesterol level. Thisresult points out a common problem in pediatric lipid-low-ering treatment: poor compliance with recommendations.The most likely explanation for the paradoxical finding isdiscontinuation of statins in preference for study drug (orplacebo) during the trial. The benefits of cholesterol-lower-ing therapy cannot be achieved without regular use of themedication.

Because of the substantial progress in understanding theearly natural history of FH in the last decade, what progresscan be anticipated in the next decade? In Europe, wherenatural history studies of statin treatment have been under-way for many years, it is highly likely that the benefits ofLDL lowering for coronary artery disease prevention inthis disease will be conclusively established. A second ad-vance will likely be the incorporation of genetic testinginto standard clinical practice to diagnose FH and riskstratify on the basis of the particular genetic defect. Futureresearch should also be directed toward understandingwhether clinicians should be satisfied with substantial cho-lesterol lowering from low to moderate statin dosing orwhether it will be necessary to achieve specific LDL targetlevels to achieve prevention of events. Safety evaluationswill be critical in these trials.

Research to date has allowed the United Kingdom todevelop cholesterol-lowering guidelines specific for FH,the NICE guidelines.12 This approach is different than theapproach in the United States, which is linked specificallyto LDL cholesterol levels and not to the diagnosis of FH.Cost-benefit analysis has shown that the combination ofgenotype screening of potentially affected individuals andsubsequent lipid-lowering therapy of affected individualsis justified. Perhaps the time has come in the United Statesto separate out individuals with known high-risk for pre-mature coronary artery disease from more general popula-tion-based guidelines. This may allow for the developmentof clinical trials specifically directed toward these high-riskpatients, those with FH, diabetes mellitus, and multiple riskstates created by interactions of genetics with obesity,tobacco use, or both. n

Samuel S. Gidding, MDCardiology Division HeadNemours Cardiac Center

A.I. duPont Hospital for ChildrenProfessor of Pediatrics, Thomas Jefferson University

Wilmington, Delaware

Reprint requests: Samuel S. Gidding, MD, Nemours Cardiac Center, 1600

Rockland Rd, Wilmington, DE 19803. E-mail: sgidding@nemours.org.

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