FH Through the Retrospectoscope

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2020 Jul 12

PMID 32651185

Citations 1

Authors

Gilbert R Thompson

Affiliations

Soon will be listed here.

Abstract

After training as a gastroenterologist in the UK, the author became interested in lipidology while he was a research fellow in the USA and switched careers after returning home. Together with Nick Myant, he introduced the use of plasma exchange to treat familial hypercholesterolemia (FH) homozygotes and undertook non-steady state studies of LDL kinetics, which showed that the fractional catabolic rate of LDL remained constant irrespective of pool size. Subsequent steady-state turnover studies showed that FH homozygotes had an almost complete lack of receptor-mediated LDL catabolism, providing in vivo confirmation of the Nobel Prize-winning discovery by Goldstein and Brown that LDL receptor dysfunction was the cause of FH. Further investigation of metabolic defects in FH revealed that a significant proportion of LDL in homozygotes and heterozygotes was produced directly via a VLDL-independent pathway. Management of heterozygous FH has been greatly facilitated by statins and proprotein convertase subtilisin/kexin type 9 inhibitors but remains dependent upon lipoprotein apheresis in homozygotes. In a recent analysis of a large cohort treated with a combination of lipid-lowering measures, survival was markedly enhanced in homozygotes in the lowest quartile of on-treatment serum cholesterol. Emerging therapies could further improve the prognosis of homozygous FH; whereas in heterozygotes, the current need is better detection.

Citing Articles

Familial Hypercholesterolaemia as a Predisposing Factor for Atherosclerosis.

Poznyak A, Litvinova L, Poggio P, Orekhov A, Melnichenko A Biomedicines. 2022; 10(10).

PMID: 36289901 PMC: 9599590. DOI: 10.3390/biomedicines10102639.

References

Gibbons G, Soutar A, Thompson G . In Memoriam: Nick Myant (1917-2015). J Lipid Res. 2015; 56(6):1081-4. PMC: 4442866. View

Brown M, Goldstein J . Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc Natl Acad Sci U S A. 1979; 76(7):3330-7. PMC: 383819. DOI: 10.1073/pnas.76.7.3330. View

Shepherd J, Bicker S, LORIMER A, Packard C . Receptor-mediated low density lipoprotein catabolism in man. J Lipid Res. 1979; 20(8):999-1006. View

Luirink I, Wiegman A, Kusters D, Hof M, Groothoff J, de Groot E . 20-Year Follow-up of Statins in Children with Familial Hypercholesterolemia. N Engl J Med. 2019; 381(16):1547-1556. DOI: 10.1056/NEJMoa1816454. View

Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson G, Boerwinkle E . Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med. 1990; 322(21):1494-9. DOI: 10.1056/NEJM199005243222104. View

ODonoghue M, Fazio S, Giugliano R, Stroes E, Kanevsky E, Gouni-Berthold I . Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2018; 139(12):1483-1492. DOI: 10.1161/CIRCULATIONAHA.118.037184. View

Crosland P, Maconachie R, Buckner S, McGuire H, Humphries S, Qureshi N . Cost-utility analysis of searching electronic health records and cascade testing to identify and diagnose familial hypercholesterolaemia in England and Wales. Atherosclerosis. 2018; 275:80-87. PMC: 6116897. DOI: 10.1016/j.atherosclerosis.2018.05.021. View

Yamamoto A, Sudo H, Endo A . Therapeutic effects of ML-236B in primary hypercholesterolemia. Atherosclerosis. 1980; 35(3):259-66. DOI: 10.1016/0021-9150(80)90124-0. View

Thompson G, MYANT N, Kilpatrick D, Oakley C, Raphael M, STEINER R . Assessment of long-term plasma exchange for familial hypercholesterolaemia. Br Heart J. 1980; 43(6):680-8. PMC: 482769. DOI: 10.1136/hrt.43.6.680. View

10.

Lambert G . Unravelling the functional significance of PCSK9. Curr Opin Lipidol. 2007; 18(3):304-9. DOI: 10.1097/MOL.0b013e3281338531. View

11.

. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group. Atherosclerosis. 1999; 142(1):105-12. View

12.

Thompson G, Spinks T, Ranicar A, MYANT N . Non-stedy-state studies of low-density-liproprotein turnover in familial hypercholesterolaemia. Clin Sci Mol Med. 1977; 52(4):361-9. DOI: 10.1042/cs0520361. View

13.

Stefanutti C, Julius U, Watts G, Harada-Shiba M, Cossu M, Schettler V . Toward an international consensus-Integrating lipoprotein apheresis and new lipid-lowering drugs. J Clin Lipidol. 2017; 11(4):858-871.e3. DOI: 10.1016/j.jacl.2017.04.114. View

14.

Sabatine M, Giugliano R, Wiviott S, Raal F, Blom D, Robinson J . Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372(16):1500-9. DOI: 10.1056/NEJMoa1500858. View

15.

Garg A, Fazio S, Duell P, Baass A, Udata C, Joh T . Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort. J Endocr Soc. 2020; 4(1):bvz015. PMC: 6977948. DOI: 10.1210/jendso/bvz015. View

16.

Raal F, Stein E, Dufour R, Turner T, Civeira F, Burgess L . PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2014; 385(9965):331-40. DOI: 10.1016/S0140-6736(14)61399-4. View

17.

Wilemon K, Patel J, Aguilar-Salinas C, Ahmed C, Alkhnifsawi M, Almahmeed W . Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia: A Global Call to Action. JAMA Cardiol. 2020; 5(2):217-229. DOI: 10.1001/jamacardio.2019.5173. View

18.

Cuchel M, Bruckert E, Ginsberg H, Raal F, Santos R, Hegele R . Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014; 35(32):2146-57. PMC: 4139706. DOI: 10.1093/eurheartj/ehu274. View

19.

Umans-Eckenhausen M, Sijbrands E, Kastelein J, Defesche J . Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population. Circulation. 2002; 106(24):3031-6. DOI: 10.1161/01.cir.0000041253.61683.08. View

20.

Thompson G, Seed M, Naoumova R, Neuwirth C, Walji S, Aitman T . Improved cardiovascular outcomes following temporal advances in lipid-lowering therapy in a genetically-characterised cohort of familial hypercholesterolaemia homozygotes. Atherosclerosis. 2015; 243(1):328-33. DOI: 10.1016/j.atherosclerosis.2015.09.029. View