Familial Hypercholesterolemia: a Review of the Natural History, Diagnosis, and Management

Abstract

Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism characterized by premature cardiovascular disease. It is one of the most common metabolic disorders affecting humans. There are two clinical manifestations: the milder heterozygous form and more severe homozygous form. Despite posing a significant health risk, FH is inadequately diagnosed and managed. As the clinical outcome is related to the degree and duration of exposure to elevated low-density lipoprotein cholesterol (LDL-C) levels, early treatment is vital. Diagnosis can usually be made using a combination of clinical characteristics such as family history, lipid levels, and genetic testing. Mutations in the gene encoding the LDL receptor (LDLR), apolipoprotein B, the pro-protein convertase subtilisin/kexin 9 (PCSK9), and LDLR adaptor protein are the commonest abnormalities. Early identification and treatment of patients, as well as screening of relatives, helps significantly reduce the risk of premature disease. Although statins remain the first-line therapy in most cases, monotherapy is usually inadequate to control elevated LDL-C levels. Additional therapy with ezetimibe and bile acid sequestrants may be required. Newer classes of pharmacotherapy currently under investigation include lomitapide, mipomersen, and monoclonal antibodies to PCSK9. Lipoprotein apheresis may be required when multiple pharmacotherapies are inadequate, especially in the homozygous form. Effective early detection and treatment of the index individual and initiation of cascade screening will help reduce the complications associated with FH. In this article, we review the disease of FH, complexity of diagnosis and management, and the challenges faced in preventing the significant morbidity and mortality associated with it.Electronic supplementary materialThe online version of this article (doi:10.1007/s40119-015-0037-z) contains supplementary material, which is available to authorized users.

Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications

“…This finding essentially represents a transgenic model, consistent with previous evidence suggesting that most LDL cholesterol uptake in the body occurs in the liver and is mediated by LDL receptors. Since heterozygous FH is not extremely rare (prevalence 1/200 to 1/500 [59] ), our report raises concern of LT recipients acquiring unidentified FH from LT donors, especially since FH manifestations are extrahepatic and thus easily overseen during donor evaluation [60] .…”

Sitosterolemia Presenting as Pseudohomozygous Familial Hypercholesterolemia

“…The most common of these conditions, familial hypercholesterolemia, is a heritable condition arising from functional mutations of genes whose products are associated with lipid processing. 12,13 The most commonly reported mutations impact the LDL receptor gene (LDLR), resulting in receptors with reduced capacity to process LDL. 12,13 Less frequently observed mutations associated with familial hypercholesterolemia have also been defined and occur at the level of APOB, and gain-of-function mutations in PCSK9, whose gene products support normal functioning of the LDL receptor.…”

Šeiminė Hipercholesterolemija

“…visų atvejų [11]. Skiriamos dvi ligos formos: sunkios eigos homozigotinė ir sąlyginai lengvesnė heterozigotinė [12]. Tyrimų duomenimis, homozigotinės ŠH (Ho-ŠH) dažnis populiacijoje svyruoja nuo 1:160 000 iki 1:300 000 [13], tuo tarpu heterozigotinės ŠH (He-ŠH) dažnis populiacijoje siekia nuo 1:200 iki 1:500 [7].…”

“…Neįprastai didelė MTL-C koncentracija kraujyje daž-niausiai yra susijusi su MTL receptoriaus genetinėmis mutacijomis [12]. MTL receptorius yra glikoproteinas, aptinkamas hepatocitų paviršiuje, prie kurio jungiasi MTL ApoB-100 baltymas.…”

“…"pro-protein convertase subtilisin/kexin 9") mutacijos. ApoB mutacijos sumažina MTL afinitetą MTL receptoriams, todėl atitinkamai sumažėja MTL klirensas [12]. PCSK9 -fermentas, atsakingas už MTL receptorių degradaciją.…”