BCMEDICALJOURNALwwwbcmjorgABSTRACT Dr DS Fredrickson isconsidered - PDF document

BCMEDICALJOURNALwww.bcmj.orgABSTRACT: Dr D.S. Fredrickson isconsidered by many to be the found-ing father of lipidology. An excep-tional scientist, Fredrickson discov-ered Tangier disease and cholesterylester storage disease, two geneticconditions caused by aberrant lipidmetabolism. His identification of var-ious apolipoprotein components con-tributed to our current understand-ing of lipid transport and physiology.His classification of lipoprotein ab normalities, established on the basisof electrophoretic plasma lipopro-tein patterns, was accepted by theWorld Health Organization as a stan-dard of clinical practice and pro-voked global interest in dyslipidem-ic disorders. Fredrickson was part ofa remarkable trio of scientists whodevised the formula for estimatinglow density lipoprotein cholesterollevels, a calculation that continuesto be used in laboratories worldwide.He was also instrumental in the cre-ation of the Lipid Research ClinicsProgram, which sponsored the land-mark Coronary Primary PreventionTrial, the first major study to defini-tively demonstrate that loweringcholesterol reduces coronary heartn the 21st century, physicians arewell versed in the association be -The graded relationship of TC andIn particular, the causal roleported by various clinical trials dem -LDL-C level and mortality.especially statins, are known to be ef -9-11exemplifies the leg acy of Dr Donaldbeen fundamental in lipidology.in Canon City, Colorado, in 1924 to anattorney father. He commenced under-the mentorship of George Thorn at Bos tons Peter Bent Brigham Hospi-tal (now the Brigham and Womens Heart Institute (a division of the Na -and Blood Institute in 1976). There heto medical breakthroughs that have shaped our understanding ofSophia Wong, MD, Ahmad Al-Sarraf, MD, FRCPC, Andrew Ignaszewski, MD, FRCPC, Dr Wong is a resident in medical biochem-istry at the University of British Columbia.Dr Al-Sarraf is a clinical fellow in medicalbiochemistry at UBC and a diplomate ofthe American Board of Clinical Lipidology.Dr Ignaszewski is head of the Division ofCardiology at St. Paul’s Hospital and med-He is also a clinical professor in the divisionof Cardiology at UBC. Dr Frohlich is direc-tor of clinical trials at the Healthy Heart Pro-gram Prevention Clinic at St. Paul’s Hospi-tal and a professor of pathology andlaboratory medicine at UBC. He is also ademia Working Group and the CanadianCardiovascular Risk Assessment Working This article has been peer reviewed. www.bcmj.o

rgBCMEDICALJOURNALis an autosomal recessive condition at-tributed to mutation of the gene for en -Normally, when LDL binds to its re -ceptor and undergoes endocytosis, theenzyme LAL hydrolyzes and releasesLDL receptor and hydroxymethyl -reduc tase), thereby maintaining cho-Not surprising-ly, LAL deficiency leads to choles-in lipidology. At the institute Fredrick-ate Christian B. Anfinsen; dabbled inSteinberg; and worked with collabo-rators to isolate and sequence the apo -lipoprotein components A-II, C-I, C-II,Together with John Stanbury andJames Wyngaarden, Fredrickson alsoThe Metabolic Basis of Inherit-ed Disease, a compendium of infor-published in 1960. The four-volumework, currently in its eighth edition,, and continues to be recogniz -Tangier disease andlipid disorders. The first, Tangier dis-kindred was identified. TD manifest-ed clinically with hepatosplenomeg -aly, peripheral neuropathy, and tonsilsBiochemically, a significant decreaseterol (HDL-C) was evident. The here -and in Vancouver, Canada, 40 yearslater„mutation of the ATP-bindingcassette transporter A1 (ABCA1) gene,encoding for the cholesterol effluxImpaired cholesterol effluxpremature CHD frequently noted in TDDiminished efflux may alsolead to lipid-depleted nascent HDL par-of LDL receptor and HMG-CoA re duc tase, and further accumulation ofof LAL activity is seen in Wolman dis-ease, and affected patients rarely sur-trast, partial LAL deficiency accountsfor CESD, with a patient life expec -elevated transaminases to hepatom -egaly, jaundice, fibrosis, and liver erosclerosis are also features of this Dr Fredrickson, shown here in 1969, changed our understanding of lipid metabolism and pathologies. BCMEDICALJOURNALwww.bcmj.orgthat organizes lipoprotein abnormali-ogy and pathophysiology.The Lipid Research ClinicsCoronary PrimaryPrevention Triallishment of the nationwide Lipid Re -Primary Prevention Trial (CPPT),demonstrate the efficacy of choles-raised TC/LDL-C and increased CHD.However, no clinical trials had yetgenesis of CHD. The results of theseobservational studies, though encour-insufficient sample size, inadequatedouble-blind CPPT study followedfor a mean period of 7.4 years. The24 g of the bile acid sequestrant cho -lestyramine daily, while the controla 19% decrease (P )revealed that a 19% decline in CHDment of 8% in total cholesterol levelor 11% in LDL-C level (P )Equipped with CPPTs definitiveThrough its ed -recommendations, such as the AdultTreatment Panel III guidelines,NC

EP has taken a leading role in thediagnosis and management of hyper-Fredrickson classificationFredricksons best-known contribu-of lipoprotein disorders (), de -Lees. The five phenotypes were des -con ditions formerly referred to asIt is important to note that Fred -ricksons classification is based sim-primary or secondary. Furthermore, itadopted by the World Health Organi-orders. Amid the recent advances in Table Table. LDL: low density lipoprotein; VLDL: very low density lipoprotein; N: normal; abN: abnormalAdapted from Levy RI, Fredrickson DSIchylomicrons creamy Nmay be abNmarkedly abNIIa–LDL, IIb–LDL, VLDL IIa–NIIb– IIa–clearIIb–clear or turbidNusually NNN clear, cloudy, orNoften abNabNmildly abNIVVLDL clear, cloudy, orNusually AbNusually abNusually N or N often abNusually abNabN www.bcmj.orgBCMEDICALJOURNALFredrickson formulaRob ert Levy and William Friedewald,de vised an equation for estimatingcommon ly known as the Friedewaldcal culate a value for low density(in units of mg/dL)In this formula, where TG standsfor triglycerides, and TG/2.2 (or TG/5)to that of cholesterol in VLDL isassumed to be relatively constant. AnLDL-C value can therefore be ob -with routine analyses and rapid lipo -protein precipitation. This conse quent ly eliminates the need to measuretion„a cumbersome, costly, and notwidely available process. Although€Triglyceride concentration above4.52 mmol/L (400 mg/dL).€Presence of chylomicrons.€Type III hyperlipoproteinemia (dueto beta-VLDL particles).€Presence of other cholesterol-richparticles (e.g., lipoprotein(a), lipo -Executive engagementstook on prominent administrative po -of recombinant DNA technology ledFredricksons wisdom and foresightresponsibility.2002 Fredrickson was a scholar-in-Summary of achievementsdisorders. His discovery of the apo li -cholesterol diseases greatly en rich edtein physiology. His classification ofadoption of this system by the WorldHealth Organization helped shine aditions. His contribution to the Fried -in expensive method to monitor theath er ogenic LDL-C marker in ourFredricksons achievements werekey to the genesis of lipidology, an en -ago. As a dedicated mentor to the specialtys first disciples and a con-tributor to efforts that conclusivelydemonstrated the link between hyper- lipidemia and coronary heart disease, Competing interests References1.Stamler J, Wentworth D, Neaton JD. Isrelationship between serum cholesteroland risk of premature death from coronaryheart disease continuous an

d graded?Findings in 356,222 primary screeof the Multiple Risk Factor In Trial (MRFIT). JAMA 1986;256:2823-2828.2.Prospective Studies Collaboration, Lew-ington S, Whitlock G, et al. Blood choles-terol and vascular mortality by age, sex,Fredrickson’s achievementswere key to the genesis oflipidology, an en tirely unheard BCMEDICALJOURNALwww.bcmj.orgindividual data from 61 prospective stud-ies with 55,000 vascular deaths. Lancet3.LaRosa JC, Hunninghake D, Bush D, etal. The cholesterol facts. A summary ofthe evidence relating dietary fats, serumcholesterol, and coronary heart disease.A joint statement by the American HeartLung, and Blood Institute. The Task Forceon Cholesterol Issues, American Heart4.Expert Panel on Detection, Evaluation,and Treatment of High Blood Cholesterolin Adults. Executive Summary of theon Detection, Evaluation, and Treatmentof High Blood Cholesterol in Adults (AdultTreatment Panel III). JAMA 2001;285:5.Shepherd J, Cobbe SM, Ford I, et al. Pre-vention of coronary heart disease withpravastatin in men with hypercholes-terolemia. West of Scotland CoronaryPrevention Study Group. N Engl J Med6.Downs JR, Clearfield M, Weis S, et al.events with lovastatin in men and wo men with average cholesterol levels:Results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Preven-tion Study. JAMA 1998;279:1615-1622.7.Sever PS, Dahlöf B, Poulter NR, et al. Pre-vention of coronary and stroke eventswith atorvastatin in hypertensive pa tients who have average or lower-than-average cholesterol concentrations, in theAnglo-Scandinavian Cardiac OutcomesTrial—Lipid Lowering Arm (ASCOT-LLA):trial. Lancet 2003;361(9364):1149-1158.8.Montori VM, Devereaux PJ, Adhikari NK,et al. Randomized trials stopped early forbenefit: A systematic review. JAMA9.Randomised trial of cholesterol loweringin 4444 patients with coronary heart dis-ease: The Scandinavian Simvastatin Sur-vival Study (4S). Lancet 1994;344(8934):10.Sacks FM, Pfeffer MA, Moye LA, et al.The effect of pravastatin on coronaryevents after myocardial infarction inpatients with average cholesterol levels.Cholesterol and Recurrent Events Trialinvestigators. N Engl J Med 1996;335:11.Heart Protection Study CollaborativeGroup. MRC/BHF Heart Protection Studyof cholesterol lowering with simvastatinin 20,536 high-risk individuals: A ran-domised placebo-controlled trial. Lancet12.Fredrickson DS. The inheritance of highdensity lipoprotein deficiency (Tangierdisease). J Clin Invest 1964;43:228-236.13.Brooks-

Wilson A, Marcil M, Clee SM, etal. Mutations in ABC1 in Tangier diseaseciency. Nat Genet 1999;22:336-345.14.Bodzioch M, Orsó E, Klucken J, et al. Thegene encoding ATP-binding cassettetransporter 1 is mutated in Tangier dis-ease. Nat Genet 1999;22:347-351.15.Rust S, Rosier M, Funke H, et al. Tangierdisease is caused by mutations in thegene encoding ATP-binding cassettetransporter 1. Nat Genet 1999;22:352-16.Rader DJ, Daugherty A. Translatingmolecular discoveries into new therapiesfor atherosclerosis. Nature 2008;451:17.Fredrickson DS, Sloan HR, Ferrans VJ, etal. Cholesteryl ester storage disease: Amost unusual manifestation of deficien-cy of two lysosomal enzyme activities.Trans Assoc Am Physicians 1972;85:18.Hooper AJ, Tran HA, Formby MR, et al. Anovel missense LIPA gene mutation,storage disease. Clin Chim Acta 2008;19.Bowden KL, Bilbey NJ, Bilawchuk LM, etal. Lysosomal acid lipase deficiencyimpairs regulation of ABCA1 gene andformation of high density lipoproteins inChem 2011;286:30624-30635.20.Muntoni S, Wiebusch H, Jansen-Rust M,et al. Prevalence of cholesteryl ester stor-age disease. Arterioscler Thromb Vasc21.Fredrickson DS, Lees RS. A system forFredrickson DS, Lees RS. A system fortorial]. Circulation 1965;31:321-327.22.Levy RI, Fredrickson DS. Diagnosis andmanagement of hyperlipoproteinemia.Am J Cardiol 1968;22:576-583.23.Levy RI, Lees RS, Fredrickson DS. Theforms of familial hyperbetalipoproteine-mia. J Clin Invest 1967;46:1086.24.Beaumont JL, Carlson LA, Cooper GR, et al. Classification of hyperlipidaemias and hyperlipoproteinaemias. Bull World25.Fredrickson DS. An international classifi-proteinemias. Ann Intern Med 1971;26.Wyngaarden JB. Donald Sharp Fredrick-son. In: Biographical Memoirs. Vol. 87.Washington, DC: National AcademiesPress; 2005. p. 165-180.27.The Lipid Research Clinics Coronary Pri-mary Prevention Trial results. I. Reduc-tion in incidence of coronary heart dis-28.The Lipid Research Clinics Coronary Primary Prevention Trial results. II. Therelationship of reduction in incidence ofcoronary heart disease to cholesterol29.Gotto AM. In memoriam Donald S. Fred rickson, MD: 1924-2002. ArteriosclerThromb Vasc Biol 2002;22:1506-1508.30.Brown WV. Review of clinical trials: Prov-ing the lipid hypothesis. Eur Heart J31.Friedewald WT, Levy RI, Fredrickson DS.density lipoprotein cholesterol in plasma,without use of the preparative ultracen-trifuge. Clin Chem 1972;18:499-502. Dr D.S. Fredrickson: Founding father of the field of lipidology