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Familial hypercholesterolemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
FH is heterogeneous genetically. It is caused by mutations in at least three different genes. The most common variant, accounting for approximately 93 percent of patients, is caused by mutations in the low-density lipoprotein receptor (LDLR); the resultant disease is currently known as familial hypercholesterolemia (FH). Mutations in apolipoprotein B-100 (APOB) account for approximately 5.5 percent of patients, and this disease is referred to as familial defective APOB (FDB). In approximately 2 percent of patients, the mutation is in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) [3]. Some 1741 mutations have been identified in the gene LDLR. Of these, 108 variants were found in Chinese patients [4].
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
In contrast to other plasma lipoprotein particles the plasma level of Lp(a) is genetically determined and cannot be influenced by life style or by nutrition and also not by the traditional lipid lowering agents with the exception of niacin that is, however, only poorly tolerated. Due to its pronounced similarity to LDL cholesterol with respect to its composition elevated Lp(a) concentrations (>30 mg/dL) mean an increased genetic risk for cardiovascular disease/coronary heart disease. To the LDL-like Lp(a) particle the glycoprotein apolipoprotein (a) is covalently attached which itself is linked to one apolipoprotein B100 via a single disulfide bond. As apolipoprotein (a) resembles plasminogen it can also induce thromboses and embolism (Nordestgaard et al., 2010; Libby, 2016). A treatment option is lipoprotein apheresis, a procedure resembling dialysis; it works with columns containing beads that are coated with antibodies to apolipoprotein B present in LDL and Lp(a) particles (Vogt, 2017).
Identification and Management of Children with Dyslipidemia
Published in James M. Rippe, Lifestyle Medicine, 2019
Julie A. Brothers, Stephen R. Daniels
Heterozygous familial hypercholesterolemia (HeFH) is an autosomal codominant disorder that occurs in the general population in approximately 1 in 250 people. It is also referred to as type IIa hyperlipoproteinemia by the Fredrickson classification system (Table 79.5).24 HeFH is one of the most common genetic lipid disorders seen in the pediatric population. It is caused by one or more of at least 500 LDL receptor gene defects that lead to either a defective or a diminished number of LDL receptors. This results in decreased LDL clearance from the circulation by the liver, which leads to a greater accumulation of LDL particles in the blood. Children and adolescents with HeFH may develop subclinical atherosclerosis with evidence of greater carotid intima media thickness (CIMT) and abnormal brachial artery reactivity, indicating endothelial dysfunction. While youth with HeFH generally do not manifest clinically apparent coronary artery disease until adulthood, if left untreated, they have a high risk of developing premature atherosclerosis. Familial defective apolipoprotein B100 is a rarer condition (approximately 1:1000 people) that presents with a similar phenotype but is treated in the same manner as HeFH.
Colesevelam – a bile acid sequestrant for treating hypercholesterolemia and improving hyperglycemia
Published in Expert Opinion on Pharmacotherapy, 2022
Oluwayemisi Esan, Adie Viljoen, Anthony S. Wierzbicki
Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality. A substantial component is caused by lipids with associations shown with total cholesterol and its easily measured subfractions low-density lipoprotein-cholesterol (LDL-C) [1] and high-density lipoprotein-cholesterol (HDL-C) [2]. Non-high density lipoprotein cholesterol (nHDL-C [2]; which adds the contribution of triglyceride (TG)-rich lipoproteins; (TGRLs) [3,4] to LDL-C is a better predictor of CVD than LDL-C alone. Studies also find a strong association of CVD with apolipoprotein B100 levels. As there is one molecule of apoB per very low density lipoprotein (VLDL) or LDL particle this translates to an association with the cholesterol content of nHDL-C particles . Statins and other LDL-C reducing drugs reduce the 5 year incidence of major coronary events, coronary revascularisation and stroke by about 21% per 1 mmol/L reduction in LDL-C [5]. Treatment options beyond statins are only considered as add-on treatment, when these drugs are not tolerated or when hypertriglyceridemia is present. Bile acid sequestrants (BAS) are one of the classes of traditional lipid-lowering therapies now viewed as third line agents for reducing LDL-C. This article reviews the mechanism of action, pharmacokinetics, pharmacodynamics, safety and efficacy of the BAS colesevelam in CVD and patients with type 2 diabetes (T2DM) focusing on their effects on glycemic control. Other reviews have addressed the role of colesevelam in reducing LDL-C [6,7]
Elevated lipoprotein A in acute on chronic CTEPH with cardiogenic shock: a case report
Published in Journal of Community Hospital Internal Medicine Perspectives, 2021
Kyaw Kyaw, Shakya Sabnam, Melanie Cheing, Fidencio Davalos, Michael Gramuglia
Our patient had remarkably elevated lipoprotein A and elevated homocysteine. Whether hyperhomocysteinemia or elevated lipoprotein A is associated with venous thromboembolism is controversial based on the current literature [9,10]. Lipoprotein A has been shown to have reduced thrombolysis [11,12]. Lipoprotein A is a complex plasma protein in which apolipoprotein B-100 is covalently linked by a disulfide bridge to a unique apolipoprotein (a). Lipoprotein A is structurally similar to plasminogen, and it competes the binding site of plasminogen on fibrin and diminishes its fibrinolytic activity [11]. Our patient most likely had undiagnosed single or multiple pulmonary emboli in the past because his initial echocardiogram reported pulmonary arterial pressure of 50–55 mmHg (normal ≤20 mmHg) and mild right-ventricular hypertrophy. On top of that, he probably suffered another acute pulmonary embolism or broken pulmonary emboli to distal pulmonary given that the repeat echocardiogram reported pulmonary arterial pressure 73 mmHg 6 days later. We hypothesis that the elevated lipoprotein A could have lessened the autoresorption of the emboli in his lungs and ultimately led to CTEPH. Morris et al. demonstrated that fibrin is resistant to lysis in patients with CTEPH [3].
Beyond the Usual Suspects: Expanding on Mutations and Detection for Familial Hypercholesterolemia
Published in Expert Review of Molecular Diagnostics, 2021
Shirin Ibrahim, Joep C. Defesche, John J.P. Kastelein
In families where a clear dominant inheritance pattern for FH is seen in the absence of an LDLR mutation, mutations can be found in additional causative loci [38] (Table 1). Genetic mapping and NGS studies have revealed mutations in the region of APOB, encoding the receptor-binding domain of APOB, which is an essential ligand for LDLR-mediated endocytosis. Mutations in APOB account for 5–10% of the patients with FH and occur more often in Northern Europe than in other regions [39]. Regarding the large size of the APOB gene, there is only a limited number of variants in APOB that cause familial defective apolipoprotein B100. Gain-of-function mutations in PCSK9 are more rare and account for approximately 1% of the genetic defects identified in patients with FH [12]. The geographical distribution of different types of PCSK9 mutations is largely unknown since the gene encoding PCSK9 is not systematically sequenced in many regions. However, mutations in exon 1 have been shown to predominate in Japan, whereas mutations in exon 5 and 7 are most commonly identified in Europe [21].