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Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia

Robert S Rosenson, MD
Paul Durrington, MD
Section Editors
Mason W Freeman, MD
Francesco Cosentino, MD, PhD
Deputy Editor
Gordon M Saperia, MD, FACC


Clinical dyslipidemia includes, but is not limited to, patients with abnormal levels of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol, triglycerides, or lipoprotein(a). An abnormal level of each of these is the result of one or more genetic abnormalities or secondary to some underlying disease or environmental factors [1].

One definition of dyslipidemia is total cholesterol, LDL-C, triglyceride, or lipoprotein(a) levels above the 90th percentile or high density lipoprotein cholesterol or apoA-1 levels below the 10th percentile for the general population (table 1).

Elevation of LDL-C is common in the general population. Most of these individuals have one or more genetic abnormalities rather than a secondary cause (such as liver or kidney disease) (see "Secondary causes of dyslipidemia"). For individuals with LDL-C above 190 mg/dL, the genetic defects that lead to familial hypercholesterolemia (FH) are the most common underlying cause (see "Familial hypercholesterolemia in adults: Overview"). This topic will discuss non-FH causes of elevated LDL-C.

General treatment guidelines for elevated LDL-C and possible indications for the therapy of other dyslipidemias, such as low serum high density lipoprotein cholesterol, hypertriglyceridemia, and elevated serum lipoprotein(a), are discussed in other topic reviews. (See "HDL cholesterol: Clinical aspects of abnormal values" and "Lipoprotein(a) and cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in secondary prevention of cardiovascular disease" and "Hypertriglyceridemia".)

The approach to children with dyslipidemia is found elsewhere. (See "Risk factors and development of atherosclerosis in childhood" and "Diseases associated with atherosclerosis in childhood" and "Overview of the management of the child at risk for atherosclerosis".)

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Literature review current through: Sep 2017. | This topic last updated: Sep 20, 2017.
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  1. Durrington P. Dyslipidaemia. Lancet 2003; 362:717.
  2. Genest JJ Jr, Martin-Munley SS, McNamara JR, et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992; 85:2025.
  3. Roncaglioni MC, Santoro L, D'Avanzo B, et al. Role of family history in patients with myocardial infarction. An Italian case-control study. GISSI-EFRIM Investigators. Circulation 1992; 85:2065.
  4. Williams RR, Hopkins PN, Hunt SC, et al. Population-based frequency of dyslipidemia syndromes in coronary-prone families in Utah. Arch Intern Med 1990; 150:582.
  5. Goldstein JL, Schrott HG, Hazzard WR, et al. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 1973; 52:1544.
  6. Kwiterovich PO Jr, Coresh J, Bachorik PS. Prevalence of hyperapobetalipoproteinemia and other lipoprotein phenotypes in men (aged < or = 50 years) and women (< or = 60 years) with coronary artery disease. Am J Cardiol 1993; 71:631.
  7. Austin MA, McKnight B, Edwards KL, et al. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: A 20-year prospective study. Circulation 2000; 101:2777.
  8. Venkatesan S, Cullen P, Pacy P, et al. Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia. Arterioscler Thromb 1993; 13:1110.
  9. Brouwers MC, van Greevenbroek MM, Troutt JS, et al. Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia. Clin Sci (Lond) 2011; 121:397.
  10. Jarvik GP, Brunzell JD, Austin MA, et al. Genetic predictors of FCHL in four large pedigrees. Influence of ApoB level major locus predicted genotype and LDL subclass phenotype. Arterioscler Thromb 1994; 14:1687.
  11. Dejager S, Bruckert E, Chapman MJ. Dense low density lipoprotein subspecies with diminished oxidative resistance predominate in combined hyperlipidemia. J Lipid Res 1993; 34:295.
  12. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990; 82:495.
  13. Austin MA, Breslow JL, Hennekens CH, et al. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988; 260:1917.
  14. Pajukanta P, Nuotio I, Terwilliger JD, et al. Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23. Nat Genet 1998; 18:369.
  15. Pajukanta P, Lilja HE, Sinsheimer JS, et al. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet 2004; 36:371.
  16. Babirak SP, Brown BG, Brunzell JD. Familial combined hyperlipidemia and abnormal lipoprotein lipase. Arterioscler Thromb 1992; 12:1176.
  17. Yang WS, Nevin DN, Peng R, et al. A mutation in the promoter of the lipoprotein lipase (LPL) gene in a patient with familial combined hyperlipidemia and low LPL activity. Proc Natl Acad Sci U S A 1995; 92:4462.
  18. Veerkamp MJ, de Graaf J, Hendriks JC, et al. Nomogram to diagnose familial combined hyperlipidemia on the basis of results of a 5-year follow-up study. Circulation 2004; 109:2980.
  19. Schonfeld G, Aguilar-Salina C, Elias N. Role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") in familial combined hyperlipidemia. Am J Cardiol 1998; 81:43B.
  20. Myerson M, Ngai C, Jones J, et al. Treatment with high-dose simvastatin reduces secretion of apolipoprotein B-lipoproteins in patients with diabetic dyslipidemia. J Lipid Res 2005; 46:2735.
  21. Hunninghake DB, Stein EA, Bays HE, et al. Rosuvastatin improves the atherogenic and atheroprotective lipid profiles in patients with hypertriglyceridemia. Coron Artery Dis 2004; 15:115.
  22. Bakker-Arkema RG, Davidson MH, Goldstein RJ, et al. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996; 275:128.
  23. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670.
  24. Rosenson RS, Abby SL, Jones MR. Colesevelam HCl effects on atherogenic lipoprotein subclasses in subjects with type 2 diabetes. Atherosclerosis 2009; 204:342.
  25. Hokanson JE, Austin MA, Zambon A, Brunzell JD. Plasma triglyceride and LDL heterogeneity in familial combined hyperlipidemia. Arterioscler Thromb 1993; 13:427.
  26. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 1995; 333:541.
  27. Wang J, Dron JS, Ban MR, et al. Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically. Arterioscler Thromb Vasc Biol 2016; 36:2439.
  28. Grundy SM. George Lyman Duff Memorial Lecture. Multifactorial etiology of hypercholesterolemia. Implications for prevention of coronary heart disease. Arterioscler Thromb 1991; 11:1619.
  29. Talmud PJ, Shah S, Whittall R, 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; 381:1293.
  30. Khera AV, Won HH, Peloso GM, et al. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. J Am Coll Cardiol 2016; 67:2578.
  31. Walden CC, Hegele RA. Apolipoprotein E in hyperlipidemia. Ann Intern Med 1994; 120:1026.
  32. Wilson PW, Myers RH, Larson MG, et al. Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. The Framingham Offspring Study. JAMA 1994; 272:1666.
  33. Frikke-Schmidt R, Tybjaerg-Hansen A, Steffensen R, et al. Apolipoprotein E genotype: epsilon32 women are protected while epsilon43 and epsilon44 men are susceptible to ischemic heart disease: the Copenhagen City Heart Study. J Am Coll Cardiol 2000; 35:1192.
  34. Bennet AM, Di Angelantonio E, Ye Z, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA 2007; 298:1300.
  35. Illingworth DR, Stein EA, Mitchel YB, et al. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Arch Intern Med 1994; 154:1586.
  36. Gerdes LU, Gerdes C, Kervinen K, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction : a substudy of the Scandinavian simvastatin survival study. Circulation 2000; 101:1366.
  37. Otvos JD, Jeyarajah EJ, Bennett DW, Krauss RM. Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement. Clin Chem 1992; 38:1632.
  38. Mora S, Otvos JD, Rifai N, et al. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 2009; 119:931.
  39. Austin MA, Newman B, Selby JV, et al. Genetics of LDL subclass phenotypes in women twins. Concordance, heritability, and commingling analysis. Arterioscler Thromb 1993; 13:687.
  40. Talmud PJ, Edwards KL, Turner CM, et al. Linkage of the cholesteryl ester transfer protein (CETP) gene to LDL particle size: use of a novel tetranucleotide repeat within the CETP promoter. Circulation 2000; 101:2461.
  41. Selby JV, Austin MA, Newman B, et al. LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation 1993; 88:381.
  42. Siegel RD, Cupples A, Schaefer EJ, Wilson PW. Lipoproteins, apolipoproteins, and low-density lipoprotein size among diabetics in the Framingham offspring study. Metabolism 1996; 45:1267.
  43. Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. Circulation 1999; 99:1959.
  44. Zambon A, Deeb SS, Hokanson JE, et al. Common variants in the promoter of the hepatic lipase gene are associated with lower levels of hepatic lipase activity, buoyant LDL, and higher HDL2 cholesterol. Arterioscler Thromb Vasc Biol 1998; 18:1723.
  45. Miller BD, Alderman EL, Haskell WL, et al. Predominance of dense low-density lipoprotein particles predicts angiographic benefit of therapy in the Stanford Coronary Risk Intervention Project. Circulation 1996; 94:2146.
  46. Zambon A, Deeb SS, Brown BG, et al. Common hepatic lipase gene promoter variant determines clinical response to intensive lipid-lowering treatment. Circulation 2001; 103:792.
  47. Griffin BA, Freeman DJ, Tait GW, et al. Role of plasma triglyceride in the regulation of plasma low density lipoprotein (LDL) subfractions: relative contribution of small, dense LDL to coronary heart disease risk. Atherosclerosis 1994; 106:241.
  48. Tornvall P, Karpe F, Carlson LA, Hamsten A. Relationships of low density lipoprotein subfractions to angiographically defined coronary artery disease in young survivors of myocardial infarction. Atherosclerosis 1991; 90:67.
  49. Lamarche B, Tchernof A, Mauriège P, et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 1998; 279:1955.
  50. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA 1996; 276:875.
  51. Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996; 276:882.
  52. St-Pierre AC, Ruel IL, Cantin B, et al. Comparison of various electrophoretic characteristics of LDL particles and their relationship to the risk of ischemic heart disease. Circulation 2001; 104:2295.
  53. Rosenson RS, Davidson MH, Pourfarzib R. Underappreciated opportunities for low-density lipoprotein management in patients with cardiometabolic residual risk. Atherosclerosis 2010; 213:1.
  54. Kathiresan S, Otvos JD, Sullivan LM, et al. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation 2006; 113:20.
  55. Gotto AM Jr, Whitney E, Stein EA, et al. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000; 101:477.
  56. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 2008; 31:811.
  57. de Graaf J, Hak-Lemmers HL, Hectors MP, et al. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arterioscler Thromb 1991; 11:298.
  58. Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med 1993; 94:350.
  59. Galeano NF, Al-Haideri M, Keyserman F, et al. Small dense low density lipoprotein has increased affinity for LDL receptor-independent cell surface binding sites: a potential mechanism for increased atherogenicity. J Lipid Res 1998; 39:1263.
  60. Nigon F, Lesnik P, Rouis M, Chapman MJ. Discrete subspecies of human low density lipoproteins are heterogeneous in their interaction with the cellular LDL receptor. J Lipid Res 1991; 32:1741.
  61. Vakkilainen J, Mäkimattila S, Seppälä-Lindroos A, et al. Endothelial dysfunction in men with small LDL particles. Circulation 2000; 102:716.
  62. Slyper AH. Low-density lipoprotein density and atherosclerosis. Unraveling the connection. JAMA 1994; 272:305.