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Semin Vasc Med 2004; 4(1): 43-50
DOI: 10.1055/s-2004-822985
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Homozygous Familial Hypercholesterolemia and Its Management

Adrian David Marais1 , Jean Catherine Firth1 , Dirk Jacobus Blom1
  • 1Lipidology Division of Internal Medicine and MRC Cape Heart Group, University of Cape Town Health Science Faculty, Observatory, South Africa
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Publication History

Publication Date:
22 March 2004 (online)

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Mutations in the low-density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia. In homozygous familial hypercholesterolemia, both genes for the LDL- receptor are mutated and LDL levels are markedly elevated. High-density lipoprotein cholesterol concentration is often reduced and lipoprotein(a) levels are high when corrected for apolipoprotein(a) isoforms. Cutaneous and tendinous xanthomata develop in childhood and are the most common reason for initial presentation. The diagnosis can be confirmed by analysis of LDL-receptor genes or studies of LDL receptor function in cultured cells. Severe aortic and coronary atherosclerosis usually occurs within the first or second decades of life. Left ventricular outflow tract obstruction may be at the level of the aortic valve or the supravalvar aorta. Treatment for the hyperlipidemia is with plasmapheresis, high-dose statins, and ezetimibe. Liver transplantation reverses the metabolic defect but requires chronic immunosupression, and rejection may still occur. Liver transplantation is indicated if cardiac transplantation becomes necessary. Portocaval shunt may still play a role in patients with coronary artery disease who do not have access to plasmapheresis. Gene therapy is currently not practicable but is being actively developed.

KEYWORDS

Homozygous familial hypercholesterolemia - low-density lipoprotein - plasmapheresis - statins

REFERENCES

  • 1 Brown M S, Goldstein J L. A receptor-mediated pathway for cholesterol homeostasis.  Science. 1986;  232 34-47
    CrossrefPubMedGoogle Scholar
  • 2 James R W, Martin B, Pometta D et al.. Apolipoprotein B metabolism in homozygous familial hypercholesterolemia.  J Lipid Res. 1989;  30 159-169
    PubMedGoogle Scholar
  • 3 Rubinsztein D C, Cohen J C, Berger G M et al.. Chylomicron remnant clearance from the plasma is normal in familial hypercholesterolemic homozygotes with defined receptor defects.  J Clin Invest. 1990;  86 1306-1312
    PubMedGoogle Scholar
  • 4 Watts G F, Barrett P H, Marais A D et al.. Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test.  Atherosclerosis. 2001;  157 519-523
    CrossrefPubMedGoogle Scholar
  • 5 Mamo J C, Bowler A, Elsegood C L, Redgrave T G. Defective plasma clearance of chylomicron-like lipid emulsions in Watanabe heritable hyperlipidemic rabbits.  Biochim Biophys Acta. 1991;  1081 241-245
    PubMedGoogle Scholar
  • 6 Moorjani S, Roy M, Torres A et al.. Mutations of low-density-lipoprotein-receptor gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous familial hypercholesterolaemia.  Lancet. 1993;  341 1303-1306
    CrossrefPubMedGoogle Scholar
  • 7 Napoli C, Postiglione A, Triggiani M et al.. Oxidative structural modifications of low density lipoprotein in homozygous familial hypercholesterolemia.  Atherosclerosis. 1995;  118 259-273
    CrossrefPubMedGoogle Scholar
  • 8 Napoli C, Postiglione A, Scarpato N et al.. LDL oxidation in homozygous familial hypercholesterolemia: effects of selective LDL-apheresis treatment.  Cardiologia. 1996;  41 (5) 435-439
    PubMedGoogle Scholar
  • 9 Aviram M, Fuhrman B, Boulos M, Ginsburg H, Brook J G. Effect of plasma lipoproteins on cholesterol accumulation in macrophages: comparison of lipoproteins from normal and homozygous familial hypercholesterolemic subjects.  Atherosclerosis. 1987;  65 207-214
    PubMedGoogle Scholar
  • 10 Goldberg R B, Fless G M, Baker S G et al.. Abnormalities of high density lipoproteins in homozygous familial hypercholesterolemia.  Arteriosclerosis. 1984;  4 472-478
    PubMedGoogle Scholar
  • 11 Keidar S, Ostlund Jr R E, Schonfeld G. Apolipoprotein E-rich HDL in patients with homozygous familial hypercholesterolemia.  Atherosclerosis. 1990;  84 155-163
    PubMedGoogle Scholar
  • 12 Schaefer J R, Rader D J, Ikewaki K et al.. In vivo metabolism of apolipoprotein A-I in a patient with homozygous familial hypercholesterolemia.  Arterioscler Thromb. 1992;  12 843-848
    PubMedGoogle Scholar
  • 13 Rader D J, Mann W A, Cain W et al.. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans.  J Clin Invest. 1995;  95 1403-1408
    PubMedGoogle Scholar
  • 14 Guo H C, Chapman M J, Bruckert E, Farriaux J P, De Gennes J L. Lipoprotein Lp(a) in homozygous familial hypercholesterolemia: density profile, particle heterogeneity and apolipoprotein(a) phenotype.  Atherosclerosis. 1991;  86 69-83
    PubMedGoogle Scholar
  • 15 Kraft H G, Lingenhel A, Raal F J, Hohenegger M, Utermann G. Lipoprotein(a) in homozygous familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 2000;  20 522-528
    PubMedGoogle Scholar
  • 16 Krempler F, Kostner G M, Roscher A et al.. Studies on the role of specific cell surface receptors in the removal of lipoprotein (a) in man.  J Clin Invest. 1983;  71 1431-1441
    PubMedGoogle Scholar
  • 17 Atkinson J B, Stacpoole P W, Swift L L. Morphologic abnormalities of erythrocytes from patients with homozygous familial hypercholesterolemia.  Biochim Biophys Acta. 1982;  712 211-216
    PubMedGoogle Scholar
  • 18 Illingworth D R, Alam N A, Lindsey S. Adrenocortical response to adrenocorticotropin in heterozygous familial hypercholesterolemia.  J Clin Endocrinol Metab. 1984;  58 206-211
    PubMedGoogle Scholar
  • 19 Boizel R, de Peretti E, Cathiard A M et al.. Pattern of plasma levels of cortisol, dehydroepiandrosterone and pregnenolone sulphate in normal subjects and in patients with homozygous familial hypercholesterolaemia during ACTH infusion.  Clin Endocrinol. 1986;  25 363-371
    PubMedGoogle Scholar
  • 20 Buja L M, Kovanen P T, Bilheimer D W. Cellular pathology of homozygous familial hypercholesterolemia.  Am J Pathol. 1979;  97 327-357
    PubMedGoogle Scholar
  • 21 Marais A D, Firth J C, Rose A G, Berger G M. Fatal outcome of homozygous familial hypercholesterolaemia in a black patient. A case report.  S Afr Med J. 1990;  77 588-590
    PubMedGoogle Scholar
  • 22 Stehbens W E, Martin M. The vascular pathology of familial hypercholesterolemia.  Pathology. 1991;  23 54-61
    PubMedGoogle Scholar
  • 23 Summers R M, Andrasko-Bourgeois J, Feuerstein I M et al.. Evaluation of the aortic root by MRI: insights from patients with homozygous familial hypercholesterolemia.  Circulation. 1998;  98 509-518
    CrossrefPubMedGoogle Scholar
  • 24 Summers R M, Choyke P L, Patronas N J et al.. MR virtual angioscopy of thoracic aortic atherosclerosis in homozygous familial hypercholesterolemia.  J Comput Assist Tomogr. 2001;  25 371-377
    CrossrefPubMedGoogle Scholar
  • 25 Bertolini S, Cassanelli S, Garuti R et al.. Analysis of LDL receptor gene mutations in Italian patients with homozygous familial hypercholesterolemia.  Arterioscler Thromb Vasc Biol. 1999;  19 408-418
    PubMedGoogle Scholar
  • 26 Haitas B, Baker S G, Meyer T E, Joffe B I, Seftel H C. Natural history and cardiac manifestations of homozygous familial hypercholesterolaemia.  Q J Med. 1990;  76 731-740
    PubMedGoogle Scholar
  • 27 Kawaguchi A, Miyatake K, Yutani C et al.. Characteristic cardiovascular manifestation in homozygous and heterozygous familial hypercholesterolemia.  Am Heart J. 1999;  137 410-418
    CrossrefPubMedGoogle Scholar
  • 28 Khachadurian A K, Uthman S M. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients.  Nutr Metab. 1973;  15 132-140
    PubMedGoogle Scholar
  • 29 Moorjani S, Roy M, Gagne C et al.. Homozygous familial hypercholesterolemia among French Canadians in Quebec Province.  Arteriosclerosis. 1989;  9 211-216
    PubMedGoogle Scholar
  • 30 Sprecher D L, Schaefer E J, Kent K M et al.. Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients.  Am J Cardiol. 1984;  54 20-30
    PubMedGoogle Scholar
  • 31 Norman D, Sun X, Bourbon M et al.. Characterization of a novel cellular defect in patients with phenotypic homozygous hypercholesterolaemia.  J Clin Invest. 1999;  104 619-628
    PubMedGoogle Scholar
  • 32 Thompson G R, Miller J P, Breslow J L. Improved survival of patients with homozygous familial hypercholesterolaemia treated with plasma exchange.  BMJ. 1985;  291 1671-1673
    PubMedGoogle Scholar
  • 33 Yamashita S, Ueyama Y, Funahashi T et al.. A 31-year-old woman with homozygous familial hypercholesterolemia without significant lesions in the coronary arteries.  Atherosclerosis. 1986;  62 117-121
    PubMedGoogle Scholar
  • 34 Jaeger B R, Tsobanelis T, Bengel F, Schwaiger M, Seidel D. Long-term prevention of premature coronary atherosclerosis in homozygous familial hypercholesterolemia.  J Pediatr. 2002;  141 125-128
    CrossrefPubMedGoogle Scholar
  • 35 Yasuda T, Kawasuji M, Sakakibara N, Watanabe Y. Aortic valve replacement for the calcified ascending aorta in homozygous familial hypercholesterolemia.  Eur J Cardiothorac Surg. 2000;  18 249-250
    CrossrefPubMedGoogle Scholar
  • 36 Raal F J, Pilcher G J, Waisberg R et al.. Low-density lipoprotein cholesterol bulk is the pivotal determinant of atherosclerosis in familial hypercholesterolemia.  Am J Cardiol. 1999;  83 1330-1333
    CrossrefPubMedGoogle Scholar
  • 37 Schmidt H H, Hill S, Makariou E V et al.. Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia.  Am J Cardiol. 1996;  77 575-580
    CrossrefPubMedGoogle Scholar
  • 38 Vergotine J, Thiart R, Langenhoven E et al.. Prenatal diagnosis of familial hypercholesterolemia: importance of DNA analysis in the high-risk South African population.  Genet Couns. 2001;  12 121-127
    PubMedGoogle Scholar
  • 39 Beigel Y, Bar J, Cohen M, Hod M. Pregnancy outcome in familial homozygous hypercholesterolemic females treated with long-term plasma exchange.  Acta Obstet Gynecol Scand. 1998;  77 603-608
    CrossrefPubMedGoogle Scholar
  • 40 Teruel J L, Lasuncion M A, Navarro J F, Carrero P, Ortuno J. Pregnancy in a patient with homozygous familial hypercholesterolemia undergoing low-density lipoprotein apheresis by dextran sulfate adsorption.  Metabolism. 1995;  44 929-933
    CrossrefPubMedGoogle Scholar
  • 41 Kroon A A, Swinkels D W, van Dongen P W, Stalenhoef A F. Pregnancy in a patient with homozygous familial hypercholesterolemia treated with long-term low-density lipoprotein apheresis.  Metabolism. 1994;  43 1164-1170
    CrossrefPubMedGoogle Scholar
  • 42 Marais A D, Blom D J, Firth J C. Statins in homozygous familial hypercholesterolemia.  Curr Atheroscler Rep. 2002;  4 19-25
    PubMedGoogle Scholar
  • 43 Raal F J, Pilcher G J, Illingworth D R et al.. Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia.  Atherosclerosis. 1997;  135 249-256
    CrossrefPubMedGoogle Scholar
  • 44 Raal F J, Pappu A S, Illingworth D R et al.. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.  Atherosclerosis. 2000;  150 421-428
    CrossrefPubMedGoogle Scholar
  • 45 Marais A D, Wood L, Firth J C, Hall J M, Jacobs P. Plasma exchange for homozygous familial hypercholesterolaemia: the Cape Town experience.  Transfus Sci. 1993;  14 239-247
    CrossrefPubMedGoogle Scholar
  • 46 Marais A D, Naoumova R P, Firth J C et al.. Decreased production of low density lipoprotein by atorvastatin after apheresis in homozygous familial hypercholesterolemia.  J Lipid Res. 1997;  38 2071-2078
    PubMedGoogle Scholar
  • 47 Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia.  Circulation. 2002;  105 2469-2475
    CrossrefPubMedGoogle Scholar
  • 48 Baker S G, Joffe B I, Mendelsohn D, Seftel H C. Treatment of homozygous familial hypercholesterolaemia with probucol.  S Afr Med J. 1982;  62 7-11
    PubMedGoogle Scholar
  • 49 Yamamoto A, Matsuzawa Y, Kishino B, Hayashi R, Kikkawa T. Effects of Probucol on Homozygous Cases of Familial Hypercholesterolaemia.  Atherosclerosis. 1983;  48 157-166
    PubMedGoogle Scholar
  • 50 Wetterau J R, Gregg R E, Harrity T W et al.. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.  Science. 1998;  282 751-754
    CrossrefPubMedGoogle Scholar
  • 51 Amano Y, Nishimoto T, Tozawa R et al.. Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia.  Eur J Pharmacol. 2003;  466 155-161
    CrossrefPubMedGoogle Scholar
  • 52 Thompson G R. LDL apheresis.  Atherosclerosis. 2003;  167 1-13
    CrossrefPubMedGoogle Scholar
  • 53 Stefanutti C, Vivenzio A, Colombo C et al.. Treatment of homozygous and double heterozygous familial hypercholesterolemic children with LDL-apheresis.  Int J Artif Organs. 1995;  18 103-110
    PubMedGoogle Scholar
  • 54 Keller C, Schmitz H, Theisen K, Zollner N. Regression of valvular aortic stenosis due to homozygous familial hypercholesterolemia following plasmapheresis.  Klin Wochenschr. 1986;  64 338-341
    CrossrefPubMedGoogle Scholar
  • 55 Forman M B, Baker S G, Mieny C J et al.. Treatment of homozygous familial hypercholesterolaemia with portacaval shunt.  Atherosclerosis. 1982;  41 349-361
    PubMedGoogle Scholar
  • 56 Bilheimer D W, Goldstein J L, Grundy S M, Brown M S. Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia.  J Clin Invest. 1975;  56 1420-1430
    PubMedGoogle Scholar
  • 57 Hoeg J M, Demosky Jr S J, Schaefer E J et al.. The effect of portacaval shunt on hepatic lipoprotein metabolism in familial hypercholesterolemia.  J Surg Res. 1985;  39 369-377
    CrossrefPubMedGoogle Scholar
  • 58 McNamara D J, Ahrens Jr E H, Kolb R et al.. Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes.  Proc Natl Acad Sci USA. 1983;  80 564-568
    PubMedGoogle Scholar
  • 59 Starzl T E, Chase P, Ahrens E H et al.. Portocaval shunt in patients with familial hypercholesterolemia.  Ann Surg. 1983;  198 273-283
    PubMedGoogle Scholar
  • 60 Bilheimer D W, Goldstein J L, Grundy S M, Starzl T E, Brown M S. Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia.  N Engl J Med. 1984;  311 1658-1664
    CrossrefPubMedGoogle Scholar
  • 61 Revell S P, Noble-Jamieson G, Johnston P et al.. Liver transplantation for homozygous familial hypercholesterolaemia.  Arch Dis Child. 1995;  73 456-458
    PubMedGoogle Scholar
  • 62 Lopez-Santamaria M, Migliazza L, Gamez M et al.. Liver transplantation in patients with homozygotic familial hypercholesterolemia previously treated by end-to-side portocaval shunt and ileal bypass.  J Pediatr Surg. 2000;  35 (4) 630-633
    CrossrefPubMedGoogle Scholar
  • 63 Grossman M, Rader D J, Muller D W et al.. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia.  Nat Med. 1995;  1 1148-1154
    PubMedGoogle Scholar
  • 64 Rader D J, Tietge U J. Gene therapy for dyslipidemia: clinical prospects.  Curr Atheroscler Rep. 1999;  1 58-69
    PubMedGoogle Scholar

A. D MaraisM.B.Ch.B. F.C.P.(SA) 

Lipid Laboratory, University of Cape Town Health Science Faculty

Anzio Road, 7925 Observatory, South Africa

Email: dmarais@capeheart.uct.ac.za

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