Sophia Wong, MD, Ahmad Al-Sarraf, MD, FRCPC, Andrew Ignaszewski, MD, FRCPC, Jiri Frohlich, MD, FRCPC

Dr D.S. Fredrickson: Founding father of the field of

The quintessential physician-scientist, Dr Fredrickson contributed to medical breakthroughs that have shaped our understanding of and .

ABSTRACT: Dr D.S. Fredrickson is n the 21st century, physicians are Bos ton’s Peter Bent Brigham Hospi- considered by many to be the found- well versed in the association be- tal (now the Brigham and Women’s ing father of lipidology. An excep- Itween total (TC) and Hospital), Fredrickson completed a tional scientist, Fredrickson discov- coronary heart disease (CHD) risk. residency and fellowship in internal ered Tangier disease and cholesteryl The graded relationship of TC and medicine. He then spent a year in the ester storage disease, two genetic CHD has been meticulously docu- laboratory of Ivan Frantz, a choles- conditions caused by aberrant lipid mented in multiple epidemiological terol biochemist, at the Massachusetts metabolism. His identification of var- studies.1-3 In particular, the causal role General Hospital. ious components con- of low density cholesterol In 1953 Fredrickson moved to tributed to our current understand- (LDL-C) in is sup- Bethesda, Maryland, and the National ing of lipid transport and . ported by various clinical trials dem- Heart Institute (a division of the Na - His classification of lipoprotein ab - onstrating concurrent reductions in tional Institutes of Health, which was normalities, established on the basis LDL-C level and CHD morbidity and renamed the National Heart, Lung, of electrophoretic plasma lipopro- mortality.3,4 Lipid-lowering therapies, and Institute in 1976). There he tein patterns, was accepted by the especially , are known to be ef- began a tremendously fruitful career World Health Organization as a stan- fective in both primary5-8 and second- dard of clinical practice and pro- ary9-11 prevention of CHD. Certainly Dr Wong is a resident in medical biochem- voked global interest in dyslipidem- our present understanding of istry at the University of British Columbia. ic disorders. Fredrickson was part of exemplifies the leg acy of Dr Donald Dr Al-Sarraf is a clinical fellow in medical a remarkable trio of scientists who Sharp Fredrickson, whose pioneering at UBC and a diplomate of devised the formula for estimating work and inspiring endeavors have the American Board of Clinical Lipidology. low density lipoprotein cholesterol been fundamental in lipidology. Dr Ignaszewski is head of the Division of levels, a calculation that continues Cardiology at St. Paul’s Hospital and med- to be used in laboratories worldwide. Early years ical director of the Healthy Heart Program. He was also instrumental in the cre- Donald Sharp Fredrickson was born He is also a clinical professor in the division ation of the Lipid Research Clinics in Canon City, Colorado, in 1924 to an of Cardiology at UBC. Dr Frohlich is direc- Program, which sponsored the land- attorney father. He commenced under- tor of clinical trials at the Healthy Heart Pro- mark Coronary Primary Prevention graduate studies at the University of gram Prevention Clinic at St. Paul’s Hospi- Trial, the first major study to defini- Colorado, and subsequently trans- tal and a professor of and tively demonstrate that lowering ferred to the University of Michigan, laboratory medicine at UBC. He is also a cholesterol reduces coronary heart where he graduated with a bachelor member of the Health Canada Dyslipi- disease risk. of science degree in 1946 and an demia Working Group and the Canadian MD with distinction in 1949. Under Cardiovascular Risk Assessment Working This article has been peer reviewed. the mentorship of George Thorn at Group.

336 BC MEDICAL JOURNAL VOL. 54 NO. 7, SEPTEMBER 2012 www.bcmj.org Dr D.S. Fredrickson: Founding father of the field of lipidology

in lipidology. At the institute Fredrick- son furthered his research in lipids and with future Nobel laure- ate Christian B. Anfinsen; dabbled in cholesterol metabolism with Daniel Steinberg; and worked with collabo- rators to isolate and sequence the apo- lipoprotein components A-II, C-I, C-II, and C-III. Together with John Stanbury and James Wyngaarden, Fredrickson also edited The Metabolic Basis of Inherit- ed Disease, a compendium of infor- mation on hereditary disorders first published in 1960. The four-volume work, currently in its eighth edition, has since been renamed The Metabol- ic and Molecular Bases of Inherited Disease, and continues to be recogniz - ed as a classic in molecular medicine.

Tangier disease and cholesteryl ester storage disease During the 1960s and 1970s Fredrick- son and his colleagues were revered for their discovery of two familial Photo from the U.S. National Library of Medicine. lipid disorders. The first, Tangier dis- Dr Fredrickson, shown here in 1969, changed our understanding of and pathologies. ease (TD), was named after the island in Chesapeake Bay where the original kindred was identified. TD manifest- ticles, which are quickly catabolized.16 teryl ester aggregation, upregulation ed clinically with hepatosplenomeg - The second discovery made by of LDL receptor and HMG-CoA re - aly, peripheral neuropathy, and tonsils Fredrickson and his colleagues, cho- ductase, and further accumulation of “of unusual size and coloration.”12 lesteryl ester storage disease (CESD), lysosomal lipids. Complete absence Biochemically, a significant decrease is an autosomal recessive condition at- of LAL activity is seen in Wolman dis- in high-density-lipoprotein choles- tributed to of the gene for en - ease, and affected patients rarely sur- terol (HDL-C) was evident. The here- coding for lysosomal acid (LAL) vive beyond 6 months of age.19 In con- ditary defect responsible would be on chromosome 10q23.2-q23.3.17,18 trast, partial LAL deficiency accounts identified simultaneously in Europe Normally, when LDL binds to its re- for CESD, with a patient life expec - and in Vancouver, Canada, 40 years ceptor and undergoes , the tancy of less than 30 years.20 CESD later—mutation of the ATP-binding LAL hydrolyzes and releases can present in childhood or adulthood cassette transporter A1 (ABCA1) gene, cholesterol from the .18 The with abnormalities ranging from encoding for the cholesterol efflux subsequent rise in intracellular cho- elevated transaminases to hepatom - regulatory , on chromosome lesterol acts by way of negative feed- egaly, jaundice, fibrosis, and liver 9q31.13-15 Impaired cholesterol efflux back and reduces expression of both failure.18 (and from macrophages gives rise to foam LDL receptor and hydroxymethyl - oftentimes ), cells, and may potentially explain the glutaryl-CoA reductase (HMG-CoA decreased HDL-C, and premature ath- premature CHD frequently noted in TD reductase), thereby maintaining cho- erosclerosis are also features of this patients.15 Diminished efflux may also lesterol .18 Not surprising- disease.18 lead to lipid-depleted nascent HDL par- ly, LAL deficiency leads to choles-

www.bcmj.org VOL. 54 NO. 7, SEPTEMBER 2012 BC MEDICAL JOURNAL 337 Dr D.S. Fredrickson: Founding father of the field of lipidology

Fredrickson classification that organizes lipoprotein abnormali- 3806 asymptomatic middle-aged males of ties on the basis of their genetic etiol- with primary hypercholesterolemia Fredrickson’s best-known contribu- ogy and pathophysiology. for a mean period of 7.4 years. The tion to lipidology is his classification study subjects were divided into two of lipoprotein disorders (Table ), de- The Lipid Research Clinics groups: the treatment group received veloped with Robert Levy and Robert Coronary Primary 24 g of the acid sequestrant cho- Lees. The five phenotypes were des - Prevention Trial lestyramine daily, while the control cribed according to their clinical fea- Fredrickson was pivotal in the estab- group received a placebo. Subjects in tures and plasma lipoprotein patterns lishment of the nationwide Lipid Re - the cholestyramine arm demonstrated on paper electrophoresis.21 This clas- search Clinics Program at the Nation- a 19% decrease (P < .05) in the com- sification system was the first to rec- al Heart Institute.26 The group was bined primary endpoint of definite ognize phenotype III (now known as responsible for the landmark Coronary CHD death and/or definite nonfatal familial dysbetalipoproteinemia) as a Primary Prevention Trial (CPPT),27,28 myocardial infarction when compared unique clinical and biochemical enti- the first major study to conclusively with subjects in the control arm. Sep- ty distinct from the heterogeneous demonstrate the efficacy of choles- arate analysis of the resin-treated group conditions formerly referred to as terol lowering in reducing CHD.29,30 revealed that a 19% decline in CHD familial hypercholesterolemia.22-24 When study enrolment began in 1973, risk was associated with each decre- It is important to note that Fred - observational epidemiological studies ment of 8% in total cholesterol level rickson’s classification is based sim- had shown an association between or 11% in LDL-C level (P < .001). ply on biochemical parameters, and raised TC/LDL-C and increased CHD. Equipped with CPPT’s definitive does not represent actual diagnoses or However, no clinical trials had yet and long-sought-after evidence for address the source of as provided strong evidence for the CHD risk reduction by way of choles- primary or secondary. Furthermore, it causal role of these lipids in the patho- terol lowering, the National Institutes does not take into account plasma genesis of CHD. The results of these of Health launched the National Cho- HDL-C levels. Nevertheless, it was observational studies, though encour- lesterol Education Program (NCEP) in adopted by the World Health Organi- aging, were inconclusive because of November of 1985.29 Through its ed- zation as an international standard in insufficient sample size, inadequate ucational campaigns and expert panel 1972,25,26 and thus brought global cholesterol lowering, lack of a dou- recommendations, such as the Adult attention to lipoprotein and lipid dis- ble-blind design, inability to achieve Treatment Panel III guidelines,4 the orders. Amid the recent advances in identical study groups, and problem- NCEP has taken a leading role in the molecular medicine, the Fredrickson atic statistical analysis.27 diagnosis and management of hyper- classification is increasingly being The multicentre, randomized, cholesterolemia. replaced by a categorization scheme double-blind CPPT study followed

Table. Fredrickson classification of hyperlipidemias.

Postheparin Lipoprotein(s) Serum total Serum Plasma Glucose Phenotype lipolytic tolerance elevated cholesterol appearance tolerance inducibility activity

I N to creamy N may be abN markedly abN

IIa–LDL, IIa–N IIa–clear II N usually N N N IIb–LDL, VLDL IIb– IIb–clear or turbid

VLDL remnants, clear, cloudy, or III N often abN abN mildly abN chylomicrons milky clear, cloudy, or IV VLDL N to N usually AbN usually abN usually N milky chylomicrons, V creamy or N often abN usually abN abN VLDL

LDL: low density lipoprotein; VLDL: very low density lipoprotein; N: normal; abN: abnormal Adapted from Levy RI, Fredrickson DS22

338 BC MEDICAL JOURNAL VOL. 54 NO. 7, SEPTEMBER 2012 www.bcmj.org Dr D.S. Fredrickson: Founding father of the field of lipidology

The Friedewald-Levy- Heart Institute from 1966 to 1968, global spotlight on dyslipidemic con- Fredrickson formula then as director of the National Insti- ditions. His contribution to the Fried - Fredrickson, in conjunction with tutes of Health from 1975 to 1981. ewald formula gave us a simple and Robert Levy and William Friedewald, During his tenure at the NIH, the rise in expensive method to monitor the devised an equation for estimating of recombinant DNA technology led ath er ogenic LDL-C marker in our LDL-C in 1972.31 This method, now to political and ethical controversies. patients. commonly known as the Friedewald formula, uses lipid levels to calculate a value for low density lipoprotein cholesterol: LDL-C = TC Ϫ HDL-C Ϫ TG/2.2 (in units of mmol/L) or Fredrickson’s achievements LDL-C = TC Ϫ HDL-C Ϫ TG/5 (in units of mg/dL) were key to the genesis of In this formula, where TG stands lipidology, an en tirely unheard for triglycerides, and TG/2.2 (or TG/5) serves as a proxy for very low density of specialty 50 years ago. lipoprotein cholesterol (VLDL-C), the ratio of the mass of to that of cholesterol in VLDL is assumed to be relatively constant. An LDL-C value can therefore be ob - tained indirectly using the total cho- lesterol, HDL-C, and triglyceride lev- Fredrickson’s wisdom and foresight Fredrickson’s achievements were els, all of which can be quantitated during this tumultuous period shaped key to the genesis of lipidology, an en - with routine analyses and rapid lipo- public policies that maintained a tirely unheard of specialty 50 years protein precipitation. This conse quent- delicate balance between the pursuit ago. As a dedicated mentor to the ly eliminates the need to measure of scientific knowledge and social specialty’s first disciples and a con- LDL-C directly using ultracentrifuga- responsibility. tributor to efforts that conclusively tion—a cumbersome, costly, and not From 1984 to 1987 Fredrickson demonstrated the link between hyper- widely available process. Although was president of the Howard Hughes lipidemia and coronary heart disease, convenient, the Friedewald formula Medical Institute, a leading private Fredrickson has left a lasting imprint has several well-established limita- medical research and funding estab- in the field of cardiovascular medicine. tions,31 and should not be used when lishment. From 1987 until his death in specimens indicate: 2002 Fredrickson was a scholar-in- Competing interests • Triglyceride concentration above residence at the National Library of None declared. 4.52 mmol/L (400 mg/dL). Medicine. • Presence of chylomicrons. References • Type III hyperlipoproteinemia (due Summary of achievements 1. Stamler J, Wentworth D, Neaton JD. Is to beta-VLDL particles). Fredrickson was an internationally relationship between serum cholesterol • Presence of other cholesterol-rich renowned expert on lipid metabolism and risk of premature death from coronary particles (e.g., lipoprotein(a), lipo - disorders. His discovery of the apoli - heart disease continuous and graded? protein-X). poprotein components and hereditary Findings in 356,222 primary screenees cholesterol diseases greatly enrich ed of the Multiple Risk Factor In ter vention Executive engagements our knowledge of lipid and lipopro- Trial (MRFIT). JAMA 1986;256:2823-2828. In addition to his research involve- tein physiology. His classification of 2. Prospective Studies Collaboration, Lew- ments and clinical duties, Fredrickson hyperlipidemias and the subsequent ington S, Whitlock G, et al. Blood choles- took on prominent administrative po- adoption of this system by the World terol and vascular mortality by age, sex, sitions as director of the National Health Organization helped shine a and blood pressure: A meta-analysis of

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individual data from 61 prospective stud- ease: The Scandinavian Simvastatin Sur- formation of high density lipoproteins in ies with 55,000 vascular deaths. Lancet vival Study (4S). Lancet 1994;344(8934): cholesteryl ester storage disease. J Biol 2007;370(9602):1829-1839. 1383-1389. Chem 2011;286:30624-30635. 3. LaRosa JC, Hunninghake D, Bush D, et 10. Sacks FM, Pfeffer MA, Moye LA, et al. 20. Muntoni S, Wiebusch H, Jansen-Rust M, al. The cholesterol facts. A summary of The effect of pravastatin on coronary et al. Prevalence of cholesteryl ester stor- the evidence relating dietary , serum events after myocardial infarction in age disease. Arterioscler Thromb Vasc cholesterol, and coronary heart disease. patients with average cholesterol levels. Biol 2007;27:1866-1868. A joint statement by the American Heart Cholesterol and Recurrent Events Trial 21. Fredrickson DS, Lees RS. A system for Association and the National Heart, investigators. N Engl J Med 1996;335: phenotyping hyperlipoproteinemia [edi- Lung, and Blood Institute. The Task Force 1001-1009. torial]. Circulation 1965;31:321-327. on Cholesterol Issues, American Heart 11. Heart Protection Study Collaborative 22. Levy RI, Fredrickson DS. Diagnosis and As sociation. Circulation 1990;81:1721- Group. MRC/BHF Heart Protection Study management of hyperlipoproteinemia. 1733. of cholesterol lowering with simvastatin Am J Cardiol 1968;22:576-583. 4. Expert Panel on Detection, Evaluation, in 20,536 high-risk individuals: A ran- 23. Levy RI, Lees RS, Fredrickson DS. The and Treatment of High Blood Cholesterol domised placebo-controlled trial. Lancet clinical and biochemical definition of two in Adults. Executive Summary of the 2002;360(9326):7-22. forms of familial hyperbetalipoproteine- Third Report of the National Cholesterol 12. Fredrickson DS. The inheritance of high mia. J Clin Invest 1967;46:1086. Education Program (NCEP) Expert Panel density lipoprotein deficiency (Tangier 24. Beaumont JL, Carlson LA, Cooper GR, on Detection, Evaluation, and Treatment disease). J Clin Invest 1964;43:228-236. et al. Classification of hyperlipidaemias of High Blood Cholesterol in Adults (Adult 13. Brooks-Wilson A, Marcil M, Clee SM, et and hyperlipoproteinaemias. Bull World Treatment Panel III). JAMA 2001;285: al. in ABC1 in Tangier disease Health 1970;43:891-915. 2486-2497. and familial high-density lipoprotein defi- 25. Fredrickson DS. An international classifi- 5. Shepherd J, Cobbe SM, Ford I, et al. Pre- ciency. Nat Genet 1999;22:336-345. cation of hyperlipidemias and hyperlipo- vention of coronary heart disease with 14. Bodzioch M, Orsó E, Klucken J, et al. The proteinemias. Ann Intern Med 1971; pravastatin in men with hypercholes- gene encoding ATP-binding cassette 75:471-472. terolemia. West of Scotland Coronary transporter 1 is mutated in Tangier dis- 26. Wyngaarden JB. Donald Sharp Fredrick- Prevention Study Group. N Engl J Med ease. Nat Genet 1999;22:347-351. son. In: Biographical Memoirs. Vol. 87. 1995;333:1301-1307. 15. Rust S, Rosier M, Funke H, et al. Tangier Washington, DC: National Academies 6. Downs JR, Clearfield M, Weis S, et al. disease is caused by mutations in the Press; 2005. p. 165-180. Primary prevention of acute coronary gene encoding ATP-binding cassette 27. The Lipid Research Clinics Coronary Pri- events with in men and wo - transporter 1. Nat Genet 1999;22:352- mary Prevention Trial results. I. Reduc- men with average cholesterol levels: 355. tion in incidence of coronary heart dis- Results of AFCAPS/TexCAPS. Air Force/ 16. Rader DJ, Daugherty A. Translating ease. JAMA 1984;251:351-364. Texas Coronary Atherosclerosis Preven- molecular discoveries into new therapies 28. The Lipid Research Clinics Coronary tion Study. JAMA 1998;279:1615-1622. for atherosclerosis. Nature 2008;451: Primary Prevention Trial results. II. The 7. Sever PS, Dahlöf B, Poulter NR, et al. Pre- 904-913. relationship of reduction in incidence of vention of coronary and stroke events 17. Fredrickson DS, Sloan HR, Ferrans VJ, et coronary heart disease to cholesterol with atorvastatin in hypertensive pa- al. Cholesteryl ester storage disease: A lowering. JAMA 1984;251:365-374. tients who have average or lower-than- most unusual manifestation of deficien- 29. Gotto AM. In memoriam Donald S. Fred - average cholesterol concentrations, in the cy of two lysosomal enzyme activities. rickson, MD: 1924-2002. Arterioscler Anglo-Scandinavian Cardiac Outcomes Trans Assoc Am Physicians 1972;85: Thromb Vasc Biol 2002;22:1506-1508. Trial—Lipid Lowering Arm (ASCOT-LLA): 109-119. 30. Brown WV. Review of clinical trials: Prov- A multicentre randomised controlled 18. Hooper AJ, Tran HA, Formby MR, et al. A ing the lipid hypothesis. Eur Heart J trial. Lancet 2003;361(9364):1149-1158. novel missense LIPA gene mutation, 1990;11(supplH):15-20. 8. Montori VM, Devereaux PJ, Adhikari NK, N98S, in a patient with cholesteryl ester 31. Friedewald WT, Levy RI, Fredrickson DS. et al. Randomized trials stopped early for storage disease. Clin Chim Acta 2008; Estimation of the concentration of low- benefit: A systematic review. JAMA 398:152-154. density lipoprotein cholesterol in plasma, 2005;294:2203-2209. 19. Bowden KL, Bilbey NJ, Bilawchuk LM, et without use of the preparative ultracen- 9. Randomised trial of cholesterol lowering al. Lysosomal acid lipase deficiency trifuge. Clin Chem 1972;18:499-502. in 4444 patients with coronary heart dis- impairs regulation of ABCA1 gene and

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