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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Familial Hypercholesterolaemia</title><author><name sortKey="Marais, A David" sort="Marais, A David" uniqKey="Marais A" first="A David" last="Marais">A David Marais</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">18516203</idno><idno type="pmc">1853359</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1853359</idno><idno type="RBID">PMC:1853359</idno><date when="2004">2004</date><idno type="wicri:Area/Pmc/Corpus">000334</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000334</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Familial Hypercholesterolaemia</title><author><name sortKey="Marais, A David" sort="Marais, A David" uniqKey="Marais A" first="A David" last="Marais">A David Marais</name></author></analytic><series><title level="j">The Clinical Biochemist Reviews</title><idno type="ISSN">0159-8090</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Familial hypercholesterolaemia (FH), defined as the heritable occurrence of severe hypercholesterolaemia with cholesterol deposits in tendons and premature heart disease, is caused by at least four genes in sterol and lipoprotein pathways and displays varying gene-dose effects. The genes are the low-density lipoprotein (LDL) receptor, apolipoprotein (apo) B, proprotein convertase subtilisin/kexin 9, and the autosomal recessive hypercholesterolaemia (ARH) adaptor protein. All of these disorders have in common defective clearance of LDL within a complex system of lipid and lipoprotein metabolism and regulation. Normal cellular cholesterol and lipoprotein metabolism is reviewed before describing the disorders, their metabolic derangements and their clinical effects. FH is classified as two simplified phenotypes of disease according to the severity of the metabolic derangement. The dominantly inherited heterozygous phenotype comprises defects in the LDL receptor, apoB100, and neural apoptosis regulatory cleavage protein. The homozygous phenotype is co-dominant in defects of the LDL receptor, and occurs also as the ARH of adapter protein mutations. Defective binding of apoB100 does not result in a significant gene dose effect, but enhances the severity of heterozygotes for LDL receptor mutations. The genetic diagnosis of FH has provided greater accuracy in definition and detection of disease and exposes information about migration of populations. All of these disorders pose a high risk of atherosclerosis, especially in the homozygous phenotype. Studies of influences on the phenotype and responses to treatment are also discussed in the context of the metabolic derangements.</p></div></front></TEI><pmc article-type="review-article" xml:lang="EN"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Biochem Rev</journal-id><journal-title>The Clinical Biochemist Reviews</journal-title><issn pub-type="ppub">0159-8090</issn><publisher><publisher-name>The Australian Association of Clinical Biochemists</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">18516203</article-id><article-id pub-id-type="pmc">1853359</article-id><article-id pub-id-type="publisher-id">cbr25_1p049</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review Articles</subject></subj-group></article-categories><title-group><article-title>Familial Hypercholesterolaemia</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Marais</surname><given-names>A David</given-names></name><xref ref-type="corresp" rid="c1-cbr25_1p049"></xref></contrib><aff id="af1-cbr25_1p049">Lipidology Division of Internal Medicine and MRC Cape Heart Group, 5th Floor, C Barnard Building, University of Cape Town Health Science Faculty, Anzio Rd, Observatory 7925, Republic of South Africa</aff></contrib-group><author-notes><corresp id="c1-cbr25_1p049">For correspondence: Prof A. David Marais e-mail:
<email>dmarais@capeheart.uct.ac.za</email></corresp></author-notes><pub-date pub-type="ppub"><month>2</month><year>2004</year></pub-date><volume>25</volume><issue>1</issue><fpage>49</fpage><lpage>68</lpage><copyright-statement>The contents of articles or advertisements in The Clinical Biochemist – Reviews are not to be construed as official statements, evaluations or endorsements by the AACB, its official bodies or its agents. Statements of opinion in AACB publications are those of the contributors. Print Post Approved - PP255003/01665. Copyright © 2005 The Australasian Association of Clinical Biochemists Inc. No literary matter in The Clinical Biochemist – Reviews is to be reproduced, stored in a retrieval system or transmitted in any form by electronic or mechanical means, photocopying or recording, without permission. Requests to do so should be addressed to the Editor. ISSN 0159 – 8090</copyright-statement><copyright-year>2004</copyright-year><abstract><p>Familial hypercholesterolaemia (FH), defined as the heritable occurrence of severe hypercholesterolaemia with cholesterol deposits in tendons and premature heart disease, is caused by at least four genes in sterol and lipoprotein pathways and displays varying gene-dose effects. The genes are the low-density lipoprotein (LDL) receptor, apolipoprotein (apo) B, proprotein convertase subtilisin/kexin 9, and the autosomal recessive hypercholesterolaemia (ARH) adaptor protein. All of these disorders have in common defective clearance of LDL within a complex system of lipid and lipoprotein metabolism and regulation. Normal cellular cholesterol and lipoprotein metabolism is reviewed before describing the disorders, their metabolic derangements and their clinical effects. FH is classified as two simplified phenotypes of disease according to the severity of the metabolic derangement. The dominantly inherited heterozygous phenotype comprises defects in the LDL receptor, apoB100, and neural apoptosis regulatory cleavage protein. The homozygous phenotype is co-dominant in defects of the LDL receptor, and occurs also as the ARH of adapter protein mutations. Defective binding of apoB100 does not result in a significant gene dose effect, but enhances the severity of heterozygotes for LDL receptor mutations. The genetic diagnosis of FH has provided greater accuracy in definition and detection of disease and exposes information about migration of populations. All of these disorders pose a high risk of atherosclerosis, especially in the homozygous phenotype. Studies of influences on the phenotype and responses to treatment are also discussed in the context of the metabolic derangements.</p></abstract></article-meta></front><floats-wrap><fig id="f1-cbr25_1p049" position="float"><label>Figure 1</label><caption><p>Cholesterol metabolism and pathways in the hepatocyte. The cholesterol pool receives cholesterol from the blood through the LDL receptor (LDLR), LRP and SRB1. Additional inputs to the cholesterol pool are from CE by NCEH and <italic>de novo</italic> synthesis from AcCoA involving HMG-CoA reductase. Outputs of cholesterol from the pool are to lipoproteins as free cholesterol (FC), and CE by the reaction of cholesterol with non-esterified fatty acid (NEFA) catalysed by ACAT2. ACAT1 catalyses esterification of cholesterol for intracellular storage and cytochrome P<sub>450</sub>7A (CYP7A) initiates bile acid synthesis. Lipoprotein assembly in the lumen of the ER involves (PL) and TG, apoB and MTP. The lipoproteins synthesised by the liver include VLDL<sub>1</sub> and VLDL<sub>2</sub>, IDL and LDL. The ligand for internalisation of IDL is apoE (E) and for internalisation of LDL is apoB100 (B).</p></caption><graphic xlink:href="cbr25_1p049f1"></graphic></fig><fig id="f2-cbr25_1p049" position="float"><label>Figure 2</label><caption><title>Lipoprotein metabolism in plasma and RCT</title><p>Predominantly TG-rich lipoproteins are secreted into the plasma: CMs containing apoB48 from the intestine and VLDL<sub>1</sub> and VLDL<sub>2</sub> from the liver, containing apoB100. The TG in these lipoproteins is hydrolysed by LPL on vascular endothelium to release non-esterified fatty acids (NEFA) and redundant phospholipid, free cholesterol and apoA-I bud off to form HDL. IDL constituting remnants of the TG-rich lipoproteins leaves the plasma by virtue of the ligand, apoE. HL acts on IDL to produce LDL. Large LDL (LDL<sub>A</sub>) becomes enriched with TG by exchange between the TG-rich lipoproteins and cholesterol-rich LDL by the action of CETP. HL converts the TG-rich LDL<sub>A</sub> to a smaller LDL species (LDL<sub>B</sub>). LDL enters the liver as a result of apoB100 being a ligand for the LDL receptor, but oxidatively modified LDL (oxLDL) as well as LDL complexed with antibody (LDL:Ab) can be internalised by macrophages depicted in the lower left hand corner. The macrophage cholesterol pool is regulated by esterification of cholesterol to CE by ACAT1 and export via the adenosine binding cassette transporter A1 (ABCA1) as free cholesterol (FC) to HDL. LCAT esterifies cholesterol and thus increases the size of smaller HDL into the density range of HDL<sub>3</sub> and subsequently into more buoyant HDL<sub>2</sub>. NCEH catalyses the production of cholesterol from CE.</p></caption><graphic xlink:href="cbr25_1p049f2"></graphic></fig><fig id="f3-cbr25_1p049" position="float"><label>Figure 3</label><caption><title>Clinical manifestations of FH</title><p>Top left panel: arcus cornealis is a thin white crescentic line due to cholesterol deposition, typically on the lower aspect of the cornea. Top right panel: thickening of the Achilles tendons above the heels due to xanthoma formation. Bottom left panel: the tendons of the middle and ring fingers of this hand have visible thickening due to xanthoma formation adjacent to the knuckles and there are two small xanthomas in the skin. Bottom right panel: skin xanthomata on the hands of a child with homozygous FH, the planar xanthomata on the webs between the fingers being highly specific for this condition. Tendon xanthomata appear later.</p></caption><graphic xlink:href="cbr25_1p049f3"></graphic></fig><table-wrap id="t1-cbr25_1p049" position="float"><label>Table 1</label><caption><p>FH phenotypes and their genetic causes.</p><p><graphic xlink:href="cbr25_1p049t1"></graphic></p></caption></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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