<a href="#content" class="sr-only">Skip to content</a> <header id="masthead" x-data="{ open: false }"> <div class="relative w-full bg-white px-6 text-body"> <div class="mx-auto flex max-w-4xl items-end justify-between pt-5 pb-3"> <div class="flex items-end"> <p> <a href="/hcp/" rel="home"> <img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/logos/dark/hfho.png" width="229" height="37" alt="Homozygous Familial Hypercholesterolemia" class="h-auto w-[14.3125rem]" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/logos/dark/hfho.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/logos/dark/hfho@2x.png 2x" /> </a> </p> <p class="ml-4 mb-[-0.03125rem] text-11px font-bold italic leading-12px text-magenta"> </p> </div> <nav id="site-navigation" aria-label="Main Navigation" class="hidden md:block"> <ul class="flex gap-x-2 text-13px leading-none [&_li]:after:float-right [&_li]:after:ml-2 [&_li]:after:block [&_li]:after:h-full [&_li]:after:w-px [&_li]:after:bg-grey-warm-15 [&_li]:after:content-[''] [&_li:last-child]:after:hidden"> </ul> </nav><!-- #site-navigation --> <span x-on:click="open = true" class="absolute right-0 top-0 flex aspect-square h-full items-center md:hidden"> <button type="button" class="mx-auto w-1/2"> <svg xmlns="http://www.w3.org/2000/svg" fill="none" viewBox="0 0 24 24" stroke-width="1.5" stroke="currentColor" class="h-full w-full"> <path stroke-linecap="round" stroke-linejoin="round" d="M3.75 6.75h16.5M3.75 12h16.5m-16.5 5.25h16.5" /> </svg> </button> </span> </div> </div> <div class="hidden w-full bg-magenta-15 px-6 md:block"> <nav id="home-navigation" class="mx-auto flex max-w-4xl items-end justify-between text-13px font-bold leading-4 tracking-[-0.25px] [&_a]:relative [&_a]:block [&_a]:py-3 [&_span]:inline-block [&_span]:border-r [&_span]:border-grey-warm [&_span]:px-3" aria-label="Home Navigation"> <ul class="-ml-3 flex text-body"> <li> <a href="/hcp/"><span >Sobre HFHo</span></a> </li> <li> <a 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class="h-auto w-[14.3125rem]" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/logos/dark/hfho.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/logos/dark/hfho@2x.png 2x" /> </a> </p> <span x-on:click="$dialog.close()" class="absolute right-0 top-0 flex aspect-square h-full items-center md:hidden"> <button type="button" class="mx-auto w-1/2"> <svg xmlns="http://www.w3.org/2000/svg" fill="none" viewBox="0 0 24 24" stroke-width="1.5" stroke="currentColor" class="h-full w-full"> <path stroke-linecap="round" stroke-linejoin="round" d="M6 18L18 6M6 6l12 12" /> </svg> </button> </span> </div> </div> <nav class="border-t border-grey-warm-15 bg-white p-6 text-body"> <ul class="text-14px [&_li]:mt-3 [&_li:first-child]:mt-0"> </ul> </nav><!-- #site-navigation --> <div class="w-full bg-magenta-15 p-6"> <nav class="text-14px font-bold tracking-[-0.25px] [&_li]:mt-4"> <ul class="text-body [&_li:first-child]:mt-0"> <li> <a href="/hcp/"><span>Sobre HFHo</span></a> </li> <li> <a href="/hcp/mecanismo/"><span>Mecanismo</span></a> </li> <li> <a href="/hcp/diagnostico/"><span>Diagnóstico</span></a> </li> <li> <a href="/hcp/impacto/"><span>Impacto</span></a> </li> <li> <a href="/hcp/acompanhamento/"><span>Acompanhamento</span></a> </li> <!-- <li> <a href="/hcp/resources/"><span>Resources</span></a> </li> --> </ul> <!-- <ul class="text-magenta"> <li> <a href="/hcp/stay-up-to-date/"><span>Stay up-to-date</span></a> </li> </ul> --> </nav><!-- #home-navigation --> </div> </div> </div> </header><!-- #masthead --> <div id="content" class="bg-white text-body"> <section id="primary"> <main id="main" class="overflow-hidden"> <div class="hcp-header"> <div class="mx-auto flex max-w-4xl items-end justify-between md:items-start"> <h1 class="mb-8 max-w-[26.5rem] self-center text-24px font-bold text-white xs:text-28px sm:text-36px md:mb-0 md:mt-[3.625rem] md:ml-[4.75rem] md:self-auto"> 85-90% dos pacientes com HFHo apresentam variantes patogênicas no gene LDLR<sup>1,2</sup> </h1> <img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/people/header-mecanismo.png" width="227" height="308" class="w-[14.1875rem] h-auto mt-[0.3125rem] md:mr-[6.3125rem] max-w-[50%] sm:max-w-none" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/people/header-mecanismo.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/people/header-mecanismo@2x.png 2x" /> </div> </div> <div class="px-6" x-data="{ open: false }"> <!-- <div class="mx-auto my-9 flex max-w-4xl items-start gap-x-5 text-16px sm:my-[4.5rem]"> <div x-on:click="open = true" class="aspect-video w-[56.818181818%] cursor-pointer"> <img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/thumbnails/video-pathogenesis.png" width="500" height="291" class="w-full h-auto" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/thumbnails/video-pathogenesis.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/thumbnails/video-pathogenesis@2x.png 2x" /> </div> <h2 class="w-[40.909090909%] text-28px font-bold">Watch this 2-minute video on the HoFH mechanism of disease.</h2> </div> --> <div class="mx-auto my-9 max-w-4xl text-16px sm:my-[4.5rem]"> <h2 class="text-28px font-bold">A HFHo está associada a variantes patogênicas de vários genes que afetam a atividade do receptor de LDL (LDLR)<sup>2,3</sup></h2> <p class="mt-3"> A maior parte do LDL é removida do plasma pelos receptores de LDL (LDLRs) localizados nas membranas celulares dos hepatócitos<sup>3</sup> </p> <div class="mt-6 md:flex md:gap-x-8"> <div class="md:w-[42.840909091%]"> <p> Essas variantes patogênicas afetam diferentes aspectos da função do LDLR e podem ser amplamente classificadas em seis categorias:<sup>3</sup> </p> <ul class="mt-3 text-12px [&_li]:mt-2.5 [&_li]:flex [&_li]:items-center [&_li]:gap-x-[0.5625rem]"> <li><img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/1.png" width="22" height="24" class="h-6 w-auto" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/1.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/1@2x.png 2x" />Ausência de síntese do LDLR ou da proteína precursora.</li> <li><img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/2.png" width="22" height="24" class="h-6 w-auto" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/2.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/2@2x.png 2x" />Transporte defeituoso do LDLR do retículo endoplasmático.</li> <li><img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/3.png" width="22" height="24" class="h-6 w-auto" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/3.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/3@2x.png 2x" />Ligação prejudicada ao LDL.</li> <li><img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/4.png" width="22" height="24" class="h-6 w-auto" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/4.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/4@2x.png 2x" />Falha na internalização do LDLR/LDL devido a defeitos no agrupamento em vesículas revestidas por clatrina.</li> <li><img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/5.png" width="22" height="24" class="h-6 w-auto" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/5.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/5@2x.png 2x" />Reciclagem do LDLR ausente.</li> <li><img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/6.png" width="22" height="24" class="h-6 w-auto" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/6.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/bullets/6@2x.png 2x" />Transporte falho do LDLR para a superfície da membrana celular.</li> </ul> </div> <img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-01.png" width="471" height="299" class="h-auto w-full mt-6 md:mt-0 md:w-[53.522727273%]" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-01.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-01@2x.png 2x" /> </div> <div class="mt-11 bg-grey-warm-15 p-6"> <p> Variantes patogênicas em outros genes que comprometem a função do LDLR também foram identificadas em pacientes com HFHo:<sup>3,4</sup> </p> <ul class="yellow-bullets mt-3"> <li><em>APOB: Gene que codifica a apolipoproteína B.</em></li> <li><em>LDLR: Gene que codifica o receptor de lipoproteína de baixa densidade.</em></li> <li><em>LDLRAP1: Gene que codifica a proteína adaptadora do receptor de lipoproteína de baixa densidade 1.</em></li> <li><em>PCSK9: Gene que codifica a proteína proproteína convertase subtilisina/kexina tipo 9 (PCSK9).</em></li> </ul> </div> <div class="mx-auto my-9 max-w-4xl text-16px sm:my-[3.5rem]"> <h2 class="text-28px font-bold">Há uma considerável heterogeneidade fenotípica e genotípica entre os pacientes com HFHo<sup>2</sup></h2> <p class="mt-8"> Uma variante herdada de cada pai/mãe dos genes LDLR, APOB ou PCSK9 também pode contribuir para o fenótipo homozigoto de HF.<sup>2,11</sup> O fenótipo HFHo inclui variantes da proteína 1 (LDLRAP1) do adaptador de LDLR. Pode haver outras causas poligênicas de hipercolesterolemia.<sup>9,10</sup> </p> <div class = "pathogenesis_img02"> <img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-02.png" width="600" height="307" class="w-[37.1875rem] h-auto mt-[0.3125rem]" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-02.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-02@2x.png 2x" /> <p class="mt-8"> HFHo está associada a variantes em 4 genes: LDLR, APOB, PCSK9, LDLRAP126 </p> </div> </div> <div class="mt-11"> <p> As variantes patogênicas causam disfunção na via do LDL e reduzem a remoção do LDL-C do sangue, levando a aterosclerose precoce e complicações cardiovasculares<sup>1,3-5</sup> </p> <img src="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-03.png" width="880" height="349" class="h-auto w-full mt-3" srcset="https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-03.png, https://www.hfho.com.br/wp-content/themes/hofh/graphics/hcp/figures/pathogenesis-03@2x.png 2x" /> <p class="mt-3 text-10px"> Esta figura se aplica à hipercolesterolemia familiar em geral.<br> MI=infarto do miocárdio. CVD=doença cardiovascular. FH=hipercolesterolemia familiar. LDLR=receptor de lipoproteína de baixa densidade.<br>LDL-C=colesterol da lipoproteína de baixa densidade. </p> </div> <div class="mt-11 bg-grey-warm-15 p-6"> <h3 class="font-bold">Critérios Genéticos</h3> <p class="mt-3"> Confirmação genética de variantes patogênicas/possivelmente patogênicas bi-alélicas em diferentes cromossomos nos genes LDLR, APOB, PCSK9 ou LDLRAP1, ou mais de 2 variantes dessas em diferentes loci<sup>4</sup> </p> </div> <div class="mt-24 text-12px"> <h4 class="uppercase">REFERÊNCIAS</h4> <p class="mt-1.5"> 1. France M et al.<em>Atherosclerosis. </em> 2016;255:128-139. 2. Cuchel M et al.<em> Eur Heart J. </em> 2014;35:2146-2157. 3. Gidding SS et al.<em> Circulation.</em> 2015;132:2167-2192. 4. Cuchel M et al. <em> Eur Heart J.</em> 2023;44(25):2277-2291. 5. Nordestgaard BG et al.<em> Eur Heart J.</em> 2013;34:3478-3490. 6. Bruckert E.<em> Atheroscler Suppl. </em>2014;15:26-32. 7. Sjouke B et al.<em> Eur Heart J. </em> 2015;36:560-565. 8. Alonso R et al.<em> J Clin Lipidol. </em> 2016;10:953-961. 9. Cuchel M, Meagher EA, du Toit Theron H, et al.<em> Lancet.</em> 2013;381(9860):40-46. 10. Bajaj A, Cuchel M. J Atheroscler Thromb. 2022;29(8):1125-1135. 11.Kamar A, Khalil A, Nemer G. 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