Homozygous Familial Hypercholesterolemia and Its Management

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.

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
• 2 James R W, Martin B, Pometta D et al.. Apolipoprotein B metabolism in homozygous familial hypercholesterolemia.  J Lipid Res. 1989;  30 159-169
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 11 Keidar S, Ostlund Jr R E, Schonfeld G. Apolipoprotein E-rich HDL in patients with homozygous familial hypercholesterolemia.  Atherosclerosis. 1990;  84 155-163
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 20 Buja L M, Kovanen P T, Bilheimer D W. Cellular pathology of homozygous familial hypercholesterolemia.  Am J Pathol. 1979;  97 327-357
• 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
• 22 Stehbens W E, Martin M. The vascular pathology of familial hypercholesterolemia.  Pathology. 1991;  23 54-61
• 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
• 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
• 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
• 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
• 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
• 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
• 29 Moorjani S, Roy M, Gagne C et al.. Homozygous familial hypercholesterolemia among French Canadians in Quebec Province.  Arteriosclerosis. 1989;  9 211-216
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 42 Marais A D, Blom D J, Firth J C. Statins in homozygous familial hypercholesterolemia.  Curr Atheroscler Rep. 2002;  4 19-25
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 52 Thompson G R. LDL apheresis.  Atherosclerosis. 2003;  167 1-13
• 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
• 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
• 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
• 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
• 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
• 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
• 59 Starzl T E, Chase P, Ahrens E H et al.. Portocaval shunt in patients with familial hypercholesterolemia.  Ann Surg. 1983;  198 273-283
• 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
• 61 Revell S P, Noble-Jamieson G, Johnston P et al.. Liver transplantation for homozygous familial hypercholesterolaemia.  Arch Dis Child. 1995;  73 456-458
• 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
• 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
• 64 Rader D J, Tietge U J. Gene therapy for dyslipidemia: clinical prospects.  Curr Atheroscler Rep. 1999;  1 58-69