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| ==Overview== | | ==Overview== |
| '''Low-density lipoprotein''' ('''LDL''') belongs to the [[lipoprotein]] particle family. Its size is approx. 22 nm but since LDL particles contain a changing number of fatty acids they actually have a mass and size distribution. Each native LDL particle contains a single [[apolipoprotein]] B-100 molecule (Apo B-100, a protein with 4536 [[amino acid]] residues) that circles the fatty acids keeping them soluble in the aqueous environment.<ref>{{cite journal|journal=Journal of Lipid Research|author=Segrest, J. P. ''et al''|date=September 2001|title=Structure of apolipoprotein B-100 in low density lipoproteins|volume=42|pages=1346-1367}}</ref> There is a direct association between cardiovascular death and duration of elevated plasma LDL-cholesterol (LDL-C) levels. In most cases, elevated LDL is a contribution of both polygenic factors and environmental influences.<ref name="pmid12813012">{{cite journal| author=Rader DJ, Cohen J, Hobbs HH| title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. | journal=J Clin Invest | year= 2003 | volume= 111 | issue= 12 | pages= 1795-803 | pmid=12813012 | doi=10.1172/JCI18925 | pmc=PMC161432 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813012 }} </ref> Not only does LDL transport cholesterol, but also this activity is key to control cholesterol homeostasis.<ref>Murtola T, Vuorela TA, Hyvonen MT et al. Low density lipoprotein: Structure, dynamics, and interactions of apoB-100 with lipids. Soft Matter. 2011;7:8136-8141</ref> Several factors contribute to the elevation of the LDL levels, such as primary hyperlipoproteinemia, [[diabetes mellitus]], [[hypothyroidism]], high fat diet and [[drugs]]. | | '''Low-density lipoprotein''' ('''LDL''') belongs to the [[lipoprotein]] particle family. Its size is approx. 22 nm but since LDL particles contain a changing number of fatty acids they actually have a mass and size distribution. Each native LDL particle contains a single [[apolipoprotein]] B-100 molecule (Apo B-100, a protein with 4536 [[amino acid]] residues) that circles the fatty acids keeping them soluble in the aqueous environment.<ref>{{cite journal|journal=Journal of Lipid Research|author=Segrest, J. P. ''et al''|date=September 2001|title=Structure of apolipoprotein B-100 in low density lipoproteins|volume=42|pages=1346-1367}}</ref> There is a direct association between cardiovascular death and duration of elevated plasma LDL-cholesterol (LDL-C) levels. In most cases, elevated LDL is a contribution of both polygenic factors and environmental influences.<ref name="pmid12813012">{{cite journal| author=Rader DJ, Cohen J, Hobbs HH| title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. | journal=J Clin Invest | year= 2003 | volume= 111 | issue= 12 | pages= 1795-803 | pmid=12813012 | doi=10.1172/JCI18925 | pmc=PMC161432 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813012 }} </ref> Not only does LDL transport cholesterol, but also this activity is key to control cholesterol homeostasis.<ref>Murtola T, Vuorela TA, Hyvonen MT et al. Low density lipoprotein: Structure, dynamics, and interactions of apoB-100 with lipids. Soft Matter. 2011;7:8136-8141</ref> Several factors contribute to the elevation of the LDL levels, such as primary hyperlipoproteinemia, [[diabetes mellitus]], [[hypothyroidism]], high fat diet and [[drugs]]. |
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| ==Clinical Significance==
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| ===Atherosclerosis===
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| * The term atherosclerosis was first introduced by Marchand to describe the association between fatty degeneration and medium to large-sized arterial sub-intimal thickening. Since the early 1980s, it has been emphasized that LDL oxidation is important for the development of atherosclerosis and coronary heart disease (CHD).<ref name="pmid6587396">{{cite journal| author=Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D| title=Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. | journal=Proc Natl Acad Sci U S A | year= 1984 | volume= 81 | issue= 12 | pages= 3883-7 | pmid=6587396 | doi= | pmc=PMC345326 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6587396 }} </ref> Atherosclerosis is considered the end-product and the most feared outcome of nearly all diseases that accompany an elevated LDL.
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| * LDL undergoes oxidative modification in vivo by mechanisms that are still poorly understood. In-vitro studies have hypothesized the role of several enzymes in LDL oxidation, including 15-lipoxygenase, [[myeloperoxidase]], [[xanthine oxidase]], among several others.<ref name="pmid11518754">{{cite journal| author=Segrest JP, Jones MK, De Loof H, Dashti N| title=Structure of apolipoprotein B-100 in low density lipoproteins. | journal=J Lipid Res | year= 2001 | volume= 42 | issue= 9 | pages= 1346-67 | pmid=11518754 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11518754 }} </ref> It is believed that LDL oxidative modification accelerates accumulation of cholesterol within [[macrophage]]s ([[foam cells]]) and initiate atherosclerotic lesions, called [[fatty streak]]s. Fatty streaks predispose to vascular disease and perturbation in [[endothelial]] function.
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| * As a result, adhesive proteins such as ICAM-1 are overactivated allowing leukocytic and monocytic accumulation.<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref> The latter plays a central role in the activation of inflammatory cascade and proliferation of smooth muscle cell and [[monocyte]]s, further enhancing the inflammatory process and contributing to LDL oxidation and uptake by macrophages. Fatty streaks then evolve gradually into fibrous plaques, and subsequent lipid accumulation by LDL activity from the [[blood]] to the vessel wall leads to [[plaque]] instability and rupture resulting finally in thrombotic occlusion of the arterial bed. Oxidized LDL is considered significantly atherogenic and chemotactic for macrophages.
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| * Once LDL moves from the blood to the vessel media, one of three outcomes will occur:
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| # LDL returns to [[blood]] causing regression of the lesion.
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| # LDL undergoes [[oxidation]] due to [[leukocyte]]s and [[free radical]]s.
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| # LDL are taken up by scavenger receptors of macrophages that become foam cells. Scavenger receptors have particular recognition to LDL in oxidized form only.
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| ===Familial Hypercholersterolemia===
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| * Contrary to other polygenic etiologies of elevated LDL, familial hypercholesterolemia (FH), also known as hyperlipidemia type II-A according to Fredrickson's classification, is a monogenic hypercholesterolemia due to deficiency of [[LDL receptor]]s caused by a mutation of LDLR gene on chromosome 19. The disorder follows an autosomal co-dominant segregation pattern.<ref name="pmid12813012">{{cite journal| author=Rader DJ, Cohen J, Hobbs HH| title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. | journal=J Clin Invest | year= 2003 | volume= 111 | issue= 12 | pages= 1795-803 | pmid=12813012 | doi=10.1172/JCI18925 | pmc=PMC161432 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813012 }} </ref>
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| * Homozygous FH is a rare disorder; where individuals have extremely high levels of LDL, often > 1000 mg/dl in the presence of family history and cardiac or cutaneous symptoms, irrespective of other environmental factors, like diet, medications, or exercise.<ref name="pmid20846238">{{cite journal| author=Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M et al.| title=Preemptive liver transplantation in a child with familial hypercholesterolemia. | journal=Pediatr Transplant | year= 2011 | volume= 15 | issue= 2 | pages= E25-9 | pmid=20846238 | doi=10.1111/j.1399-3046.2010.01383.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20846238 }} </ref>
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| * Patients with homozygous FH are very susceptible to early-onset cardiovascular disease along with cutaneous manifestations of abnormal lipid metabolism, such as eruptive [[xanthoma]]s.
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| * Goldstein and Brown described three cardinal features of FH:<ref name="pmid4355366">{{cite journal| author=Goldstein JL, Brown MS| title=Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. | journal=Proc Natl Acad Sci U S A | year= 1973 | volume= 70 | issue= 10 | pages= 2804-8 | pmid=4355366 | doi= | pmc=PMC427113 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4355366 }} </ref>
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| ** Selective elevation of LDL
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| ** Selective deposition of LDL-derived [[cholesterol]] into [[macrophages]] throughout the body but not in parenchyma
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| ** Inheritance as autosomal dominant trait with gene dosage effect
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| * On the other hand, heterozygous FH, where only one mutated allele is present, has an incidence of 1 out of 500.<ref name="pmid21191428">{{cite journal| author=Nemati MH, Astaneh B| title=Optimal management of familial hypercholesterolemia: treatment and management strategies. | journal=Vasc Health Risk Manag | year= 2010 | volume= 6 | issue= | pages= 1079-88 | pmid=21191428 | doi=10.2147/VHRM.S8283 | pmc=PMC3004511 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21191428 }} </ref> It is defined as any of the following:
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| ** LDL-C levels > 200 mg/dL + coronary heart disease/risk equivalents
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| ** LDL-C levels > 300 mg/dL regardless of disease or risk equivalents
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| * Heterogeneous FH responds better to anti-lipidemics than the homogeneous counterpart.<ref name="pmid12813012">{{cite journal| author=Rader DJ, Cohen J, Hobbs HH| title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. | journal=J Clin Invest | year= 2003 | volume= 111 | issue= 12 | pages= 1795-803 | pmid=12813012 | doi=10.1172/JCI18925 | pmc=PMC161432 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813012 }} </ref>
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| ===Diabetes Mellitus===
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| * Although plasma LDL concentration may be normal in patients with [[diabetes mellitus|type II diabetes mellitus]], several qualitative modifications aid in promoting [[atherosclerosis]] in this particular population.<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref> The quantity of small dense triglyceride-rich LDL particles seem to be more abundant in patients with type II diabetes.<ref name="pmid1450181">{{cite journal| author=Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM| title=LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. | journal=Arterioscler Thromb | year= 1992 | volume= 12 | issue= 12 | pages= 1496-502 | pmid=1450181 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1450181 }} </ref>
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| * Furthermore, patients with [[diabetes]] have increased LDL plasma residence time that contributes to increased arterial deposition of [[cholesterol]] and [[atherosclerosis]].<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref> Altered residence time is attributed to reduced LDL catabolism and decreased turnover,<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref> probably due to decreased expression of LDL receptors.<ref name="pmid12716819">{{cite journal| author=Duvillard L, Florentin E, Lizard G, Petit JM, Galland F, Monier S et al.| title=Cell surface expression of LDL receptor is decreased in type 2 diabetic patients and is normalized by insulin therapy. | journal=Diabetes Care | year= 2003 | volume= 26 | issue= 5 | pages= 1540-4 | pmid=12716819 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12716819 }} </ref> The modification in LDL receptor have been attributed to diabetes that causes increased glycation of Apo-B within LDL altering adequate LDL receptor affinity and even worsening LDL oxidation.<ref name="pmid1526339">{{cite journal| author=Lyons TJ| title=Lipoprotein glycation and its metabolic consequences. | journal=Diabetes | year= 1992 | volume= 41 Suppl 2 | issue= | pages= 67-73 | pmid=1526339 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1526339 }} </ref>
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| * However, it is notable that [[insulin]] therapy targeting diabetes and anti-lipidemic treatment with statins have profound beneficial effects on the unfavorable LDL modifications present in diabetics. By inhibiting HMG-CoA reductase, [[statin]] therapy indirectly increases the expression of LDL receptors thus improving the abnormal affinity.<ref name="pmid16357786">{{cite journal| author=Vergès B| title=New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. | journal=Diabetes Metab | year= 2005 | volume= 31 | issue= 5 | pages= 429-39 | pmid=16357786 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16357786 }} </ref>
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| ===Renal Disease===
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| * [[Renal disease]] causes a specific form of secondary dyslipidemia only when heavy [[proteinuria]] is present. Heavy proteinuria is required to exhibit decreased LDL receptor gene expression in hepatocytes, and alter gene expression of 2 key enzymes for LDL and [[cholesterol]] homeostasis: Increased activity of HMG-CoA reductase, the rate limiting enzyme for cholesterol synthesis, and reduced activity of 7α-hydroxylase, the rate limiting enzyme for cholesterol metabolism and [[bile acid]] synthesis.<ref name="pmid9249773">{{cite journal| author=Liang K, Vaziri ND| title=Gene expression of LDL receptor, HMG-CoA reductase, and cholesterol-7 alpha-hydroxylase in chronic renal failure. | journal=Nephrol Dial Transplant | year= 1997 | volume= 12 | issue= 7 | pages= 1381-6 | pmid=9249773 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9249773 }} </ref>
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| * Similar to the pathogenesis observed in diabetic patients, nephrotic dyslipidemia also demonstrates changes in Apo-B that reduce LDL affinity to its receptor. The proportion of atherogenic small dense LDL particles is also increased.
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| * Individuals undergoing [[dialysis]] also have abnormal LDL profiles. Patients on hemodialysis generally have normal LDL cholesterol but more concentrated small dense particules.<ref name="pmid12694323">{{cite journal| author=Kronenberg F, Lingenhel A, Neyer U, Lhotta K, König P, Auinger M et al.| title=Prevalence of dyslipidemic risk factors in hemodialysis and CAPD patients. | journal=Kidney Int Suppl | year= 2003 | volume= | issue= 84 | pages= S113-6 | pmid=12694323 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12694323 }} </ref> Specifically, patients on [[peritoneal dialysis]] generally have higher [[LDL]] and total [[cholesterol]] due to the considerable protein loss into the peritoneal dialysate that stimulates hepatic protein synthesis, including LDL and other [[lipoproteins]].<ref name="pmid8914053">{{cite journal| author=Wheeler DC| title=Abnormalities of lipoprotein metabolism in CAPD patients. | journal=Kidney Int Suppl | year= 1996 | volume= 56 | issue= | pages= S41-6 | pmid=8914053 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8914053 }} </ref>
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| ===Liver Disease===
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| * [[Non-alcoholic fatty liver disease]] (NAFLD) eventually contributes to the overproduction of LDL, among other [[lipoproteins]]. A two-hit hypothesis has been proposed by Day and James in 1998.<ref name="pmid9547102">{{cite journal| author=Day CP, James OF| title=Steatohepatitis: a tale of two "hits"? | journal=Gastroenterology | year= 1998 | volume= 114 | issue= 4 | pages= 842-5 | pmid=9547102 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9547102 }} </ref> Initially, lipid accumulates in [[hepatocytes]] following insulin resistance. Second, [[oxidative stress]] leads to [[NASH|non-alcoholic steatohepatitis]] (NASH). Irregular metabolism of [[fatty acid]]s causes hypertriglyceridemia due to overproduction of [[VLDL]] that is eventually metabolized into LDL through CETP-mediated exchange of cholesteryl esters and triglycerides between the two lipoproteins.
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| * Similar to other disease entities, [[hepatocellular damage]] yields small dense triglyceride-rich lipoproteins that have low LDL receptor affinity, carry more residence time, and are more susceptible to [[oxidation]] and [[atherosclerosis]].<ref name="pmid21773052">{{cite journal| author=Fon Tacer K, Rozman D| title=Nonalcoholic Fatty liver disease: focus on lipoprotein and lipid deregulation. | journal=J Lipids | year= 2011 | volume= 2011 | issue= | pages= 783976 | pmid=21773052 | doi=10.1155/2011/783976 | pmc=PMC3136146 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21773052 }} </ref>
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| * Cholestatic liver disease is associated with marked hyperlipidemia and elevated LDL. It is hypothesized that because [[HDL]] is also elevated in these patients and is believed to play a protective role, cardiovascular disease does not seem to be increased in patients with cholestatic liver disease. Such outcomes, however, remain controversial.<ref name="pmid11469968">{{cite journal| author=Longo M, Crosignani A, Podda M| title=Hyperlipidemia in Chronic Cholestatic Liver Disease. | journal=Curr Treat Options Gastroenterol | year= 2001 | volume= 4 | issue= 2 | pages= 111-114 | pmid=11469968 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11469968 }} </ref>
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| ===Thyroid Disease===
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| * [[Hypothyroidism]] is associated with marked elevations of LDL due to reduced LDL receptors that decrease LDL clearance. Since [[hypothyroidism]] also reduces oxygen consumption of cardiac [[myocytes]], cardiac contractility is reduced and vascular resistance is increased.
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| * Both vascular changes and LDL accumulation seen in [[hypothyroidism]] promote [[atherosclerosis]].<ref name="pmid12034052">{{cite journal| author=Duntas LH| title=Thyroid disease and lipids. | journal=Thyroid | year= 2002 | volume= 12 | issue= 4 | pages= 287-93 | pmid=12034052 | doi=10.1089/10507250252949405 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12034052 }} </ref>
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| ===Obstructive Sleep Apnea===
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| Oxidized LDL measured in patients with [[obstructive sleep apnea syndrome]] (OSAS) shows significant increase when compared to control groups.<ref name="pmid19574336">{{cite journal| author=Kizawa T, Nakamura Y, Takahashi S, Sakurai S, Yamauchi K, Inoue H| title=Pathogenic role of angiotensin II and oxidised LDL in obstructive sleep apnoea. | journal=Eur Respir J | year= 2009 | volume= 34 | issue= 6 | pages= 1390-8 | pmid=19574336 | doi=10.1183/09031936.00009709 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19574336 }} </ref> This was believed to be due to the [[hypoxemia]] experienced by these patients that cause lipid peroxidation and an imbalance between reactive oxygen species and counteracting antioxidant reserve.<ref name="pmid9595608">{{cite journal| author=Wali SO, Bahammam AS, Massaeli H, Pierce GN, Iliskovic N, Singal PK et al.| title=Susceptibility of LDL to oxidative stress in obstructive sleep apnea. | journal=Sleep | year= 1998 | volume= 21 | issue= 3 | pages= 290-6 | pmid=9595608 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9595608 }} </ref> However, newer research findings have not entirely supported this theory; thus the exact mechanism that associates [[OSAS]] and elevated LDL remains controversial. Elevated LDL normalizes following appropriate [[continuous positive airway pressure]] (CPAP) therapy for patients with [[OSAS]].
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| ==Measurement Methods== | | ==Measurement Methods== |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Rim Halaby, M.D. [3]
Synonyms and keywords: LDL-cholesterol, LDL-C
Overview
Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. Its size is approx. 22 nm but since LDL particles contain a changing number of fatty acids they actually have a mass and size distribution. Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues) that circles the fatty acids keeping them soluble in the aqueous environment.[1] There is a direct association between cardiovascular death and duration of elevated plasma LDL-cholesterol (LDL-C) levels. In most cases, elevated LDL is a contribution of both polygenic factors and environmental influences.[2] Not only does LDL transport cholesterol, but also this activity is key to control cholesterol homeostasis.[3] Several factors contribute to the elevation of the LDL levels, such as primary hyperlipoproteinemia, diabetes mellitus, hypothyroidism, high fat diet and drugs.
Measurement Methods
Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available. However, there is increasing evidence and recognition of the value of more sophisticated measurements. Specifically, LDL particle number (concentration), and to a lesser extent size, have shown much tighter correlation with atherosclerotic progression and cardiovascular events than is obtained using chemical measures of total LDL concentration contained within the particles. LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Alternatively, LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. If LDL particle concentration is tracked against event rates, many other statistical correlates of cardiovascular events, such as diabetes mellitus, obesity and smoking, lose much of their additive predictive power.
LDL Subtype Patterns
LDL particles actually vary in size and density, and studies have shown that a pattern that has more small dense LDL particles ("Pattern B") equates to a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less dense LDL particles ("Pattern A"). This is because the smaller particles are more easily able to penetrate the endothelium. "Pattern I", meaning "intermediate", indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).
The correspondence between Pattern B and CHD has been suggested by some in the medical community to be stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common lipid profile test has been used more commonly.
The lipid profile does not measure LDL level directly but instead estimates it via the Friedewald equation using levels of other cholesterol such as HDL:
In mg/dl: LDL cholesterol = total cholesterol – HDL cholesterol – (0.2 × triglycerides)
In mmol/l: LDL cholesterol = total cholesterol – HDL cholesterol – (0.45 × triglycerides)
There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at LDC-L levels 2.5 to 4.5 mmol/L, this formula is considered to be inaccurate. If both total cholesterol and triglyceride levels are elevated then a modified formulat may be used
LDL-C = Total-C HDL-C (0.16 x TAG)
This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer. (However, the concentration of LDL particles, and to a lesser extent their size, has far tighter correlation with clinical outcome than the content of cholesterol with the LDL particles, even if the LDL-C estimation is about correct.)
There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense LDL.
However, cholesterol and lipid assays, as outlined above were never promoted because they worked the best to identify those more likely to have problems, but simply because they used to be far less expensive, by about 50 fold, than measured lipoprotein particle concentrations and subclass analysis. With continued research, decreasing cost, greater availability and wider acceptance of other "lipoprotein subclass analysis" assay methods, including NMR spectroscopy, research studies have continued to show a stronger correlation between human clinically obvious cardiovascular event and quantitatively measured particle concentrations.
References
Template:WikiDoc Sources