Polygenic Hypercholesterolemia Clinical Presentation
- Author: Catherine Anastasopoulou, MD, PhD, FACE; Chief Editor: George T Griffing, MD more...
Hypercholesterolemia is usually discovered during routine screening and does not produce symptoms. Hypercholesterolemia is more common in individuals with a family history of the condition, but lifestyle factors (eg, a diet high in saturated fat) clearly play a major role.
It is important to elicit history about cigarette smoking, diabetes mellitus, and sedentary lifestyle that may contribute to development of hypercholesterolemia and increased cardiovascular risk.
Tendon xanthomas are not present in persons with polygenic hypercholesterolemia. If tendon xanthomas are present, familial hypercholesterolemia or familial defective apoprotein B-100 is the correct diagnosis. Eruptive xanthomas signify extreme hypertriglyceridemia. Xanthelasmas may be present but do not necessarily indicate hypercholesterolemia. Secondary hypercholesterolemia is suggested by stigmata of liver disease, hypothyroidism, hypopituitarism, nephrotic syndrome, and chronic renal disease.
Several drugs and disease states are associated with hypercholesterolemia; however, for the overwhelming majority of patients, the Western lifestyle of a high-fat diet superimposed on a susceptible genotype appears to cause hypercholesterolemia. Nonetheless, ensuring that the patient does not have untreated hypothyroidism, renal disease, or liver disease is important. Furthermore, progestins, anabolic steroids, and glucocorticoids may adversely affect low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) values.
The risk factors for coronary heart disease (CHD), other than LDL-C, in the US National Cholesterol Education Program (NCEP) screening and treatment algorithm are as follows:
- Age and sex
- Men aged 45 years or older
- Women aged 55 years or older
- Family history of premature CHD (male first-degree relative < 55 y, female first-degree relative < 65 y)
- Current cigarette smoking
- Hypertension - Blood pressure greater than or equal to 140/90 mm Hg or current antihypertensive drug therapy
- Low HDL-C concentration - Less than 40 mg/dL, but one risk factor subtracted if HDL-C concentration is more than 60 mg/dL (This level has been increased from < 35 mg/dL compared with the value from the NCEP Adult Treatment Panel II [NCEP ATP II].)
National Cholesterol Education Program. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001. 285:2486-97. [Medline].
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004 Aug 4. 44(3):720-32. [Medline].
Griffin BP. Statins in aortic stenosis: new data from a prospective clinical trial. J Am Coll Cardiol. 2007 Feb 6. 49(5):562-4. [Medline].
Weghuber D, Widhalm K. Effect of 3-month treatment of children and adolescents with familial and polygenic hypercholesterolaemia with a soya-substituted diet. Br J Nutr. 2008 Feb. 99(2):281-6. [Medline].
Ruiu G, Pinach S, Veglia F, Gambino R, Marena S, Uberti B, et al. Phytosterol-enriched yogurt increases LDL affinity and reduces CD36 expression in polygenic hypercholesterolemia. Lipids. 2009 Feb. 44(2):153-60. [Medline].
De Castro-Oros I, Perez-Lopez J, Mateo-Gallego R, Rebollar S, Ledesma M, Leon M, et al. A genetic variant in the LDLR promoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia. BMC Med Genomics. 2014 Apr 7. 7:17. [Medline]. [Full Text].
Stein EA, Raal FJ. Polygenic familial hypercholesterolaemia: does it matter?. Lancet. 2013 Apr 13. 381(9874):1255-7. [Medline].
Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007 Apr. 4(4):214-25. [Medline].
Taylor A, Wang D, Patel K, Whittall R, Wood G, Farrer M, et al. Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. Clin Genet. 2010 Jun. 77(6):572-80. [Medline].
Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013 Apr 13. 381(9874):1293-301. [Medline].
National Health and Nutrition Examination Survey. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/nchs/nhanes.htm. Accessed: 5/19/15.
Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007 Dec 1. 370(9602):1829-39. [Medline].
Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 10. 355(6):549-59. [Medline]. [Full Text].
Sniderman AD, Tsimikas S, Fazio S. The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies. J Am Coll Cardiol. 2014 May 20. 63(19):1935-47. [Medline].
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24. 129(25 Suppl 2):S1-45. [Medline].
[Guideline] Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011 Jul. 217(1):3-46. [Medline].
Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16. 333(20):1301-7. [Medline].
Scandinavian Simvastatin Survival Study. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19. 344(8934):1383-9. [Medline].
Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997 Apr. 20(4):614-20. [Medline].
Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998 May 27. 279(20):1615-22. [Medline].
Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. The Post Coronary Artery Bypass Graft Trial Investigators. N Engl J Med. 1997 Jan 16. 336(3):153-62. [Medline].
Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med. 1999 Jul 8. 341(2):70-6. [Medline].
Bulbulia R, Bowman L, Wallendszus K, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011 Dec 10. 378(9808):2013-20. [Medline]. [Full Text].
Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007 May 15. 99 (10):1409-12. [Medline].
Bargossi AM, Grossi G, Fiorella PL, Gaddi A, Di Giulio R, Battino M. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors. Mol Aspects Med. 1994. 15 Suppl:s187-93. [Medline].
Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J Am Coll Cardiol. 2007 Jun 12. 49 (23):2231-7. [Medline].
Becker DJ, Gordon RY, Halbert SC, et al. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009 Jun 16. 150(12):830-9, W147-9. [Medline].
Halbert SC, French B, Gordon RY, Farrar JT, Schmitz K, Morris PB, et al. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol. 2010 Jan 15. 105 (2):198-204. [Medline].
National Institutes of Health. Red yeast rice: An introduction. National Center for Complementary and Integrative Health Web site. Available at http://nccam.nih.gov/health/redyeastrice. Accessed: July 13, 2015.
Jenkins DJ, Jones PJ, Lamarche B, et al. Effect of a dietary portfolio of cholesterol-lowering foods given at 2 levels of intensity of dietary advice on serum lipids in hyperlipidemia: a randomized controlled trial. JAMA. 2011 Aug 24. 306(8):831-9. [Medline].
Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006 Aug 10. 355(6):549-59. [Medline].
Bays HE, McKenney J, Maki KC, et al. Effects of prescription omega-3-acid ethyl esters on non--high-density lipoprotein cholesterol when coadministered with escalating doses of atorvastatin. Mayo Clin Proc. 2010 Feb. 85(2):122-8. [Medline]. [Full Text].
Blumenthal RS, Michos ED. The HALTS trial -- halting atherosclerosis or halted too early?. N Engl J Med. 2009 Nov 15. [Medline].
Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001 Nov 29. 345(22):1583-92. [Medline].
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8. 350(15):1495-504. [Medline].
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004 Aug 21-27. 364(9435):685-96. [Medline].
Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003 Jun 14. 361(9374):2005-16. [Medline].
de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004. 292(11):1307-16. [Medline].
Drazen JM, D'Agostino RB, Ware JH, Morrissey S, Curfman GD. Ezetimibe and cancer--an uncertain association. N Engl J Med. 2008 Sep 25. 359(13):1398-9. [Medline].
Garg A. Statins for all patients with type 2 diabetes: not so soon. Lancet. 2004 Aug 21-27. 364(9435):641-2. [Medline].
Grundy SM. Can statins cause chronic low-grade myopathy?. Ann Intern Med. 2002 Oct 1. 137(7):617-8. [Medline].
Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation. 1998 Apr 21. 97(15):1436-9. [Medline].
Guyton JR, Slee AE, Anderson T, Fleg JL, Goldberg RB, Kashyap ML, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013 Oct 22. 62(17):1580-4. [Medline]. [Full Text].
Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med. 1999 Dec 13-27. 159(22):2661-7. [Medline].
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6. 360(9326):7-22. [Medline].
Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 Apr 3. 358(14):1431-43. [Medline].
Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 Apr 3. 358(14):1431-43. [Medline].
Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, Tomson J, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014 Jul 17. 371(3):203-12. [Medline].
LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005. 352(14):1425-35. [Medline].
Long-Term Intervention with Pravastatin in Ischaemic Disease Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998 Nov 5. 339(19):1349-57. [Medline].
Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004 Mar 3. 291(9):1071-80. [Medline].
Ornish D, Brown SE, Scherwitz LW, et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet. 1990 Jul 21. 336(8708):129-33. [Medline].
Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002 Oct 1. 137(7):581-5. [Medline].
Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011 Jun 22. 305(24):2556-64. [Medline].
Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008 Sep 25. 359(13):1343-56. [Medline].
Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999 Aug 5. 341(6):410-8. [Medline].
Sempos CT, Cleeman JI, Carroll MD, et al. Prevalence of high blood cholesterol among US adults. An update based on guidelines from the second report of the National Cholesterol Education Program Adult Treatment Panel. JAMA. 1993 Jun 16. 269(23):3009-14. [Medline].
Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomi. Lancet. 2003 Apr 5. 361(9364):1149-58. [Medline].
Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002 Nov 23. 360(9346):1623-30. [Medline].
Stamler J, Daviglus ML, Garside DB, et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA. 2000 Jul 19. 284(3):311-8. [Medline].
Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26. 361(22):2113-22. [Medline]. [Full Text].
White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and the risk of stroke. N Engl J Med. 2000 Aug 3. 343(5):317-26. [Medline].
Zieve F, Wenger NK, Ben-Yehuda O, et al. Safety and efficacy of ezetimibe added to atorvastatin versus up titration of atorvastatin to 40 mg in patients > or = 65 years of age (from the ZETia in the ELDerly [ZETELD] study). Am J Cardiol. 2010 Mar 1. 105(5):656-63. [Medline].
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18. 372 (25):2387-97. [Medline].