Materiały źródłowe

• #1 Familial Hypercholesterolemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556009/

  Familial hypercholesterolemia is a group of inherited genetic defects that lead to the severe elevation of serum cholesterol concentrations. Clinically familial hypercholesterolemia is diagnosed by a high serum level of low-density lipoprotein (LDL) cholesterol and genetically is characterized into two subgroups: (1) autosomal dominant (AD), (2) codominant transmission with 90% or higher penetrance. […] The three main known genetic mutations in familial hypercholesterolemia are classified as defects in the LDL receptor (most common), apolipoprotein B (ApoB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Each of these three mutations leads to impairment of LDL receptors and a reduction in uptake of LDL cholesterol and subsequently causes high LDL cholesterol concentration. […] The end-result in all three main gene mutations is the binding dysfunction of LDL receptors to the LDL cholesterol, thereby decreasing the uptake and destruction of LDL cholesterol in the liver and the resultant rise in serum LDL levels.

• #2 Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease

  https://www.mdpi.com/1422-0067/19/11/3426

  Familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder primarily characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C), due to its reduced catabolism. […] If untreated, exposure to high LDL-C levels during lifetime increases atherosclerotic plaque development and premature cardiovascular disease risk. […] The major determinants in that system are LDLR, accounting for 80–85% of FH cases, apoB100, causing 5–10% of the cases, PCSK9 2% of the cases and LDL receptor adaptor protein 1 (LDLRAP1) accounting for less than 1% of the cases. […] Mutations that alter LDL metabolism are the most frequent defects leading to a cholesterol metabolism derived disease denominated familial hypercholesterolemia. […] Cholesterol metabolism is a complex mechanism with many factors involved that requires a high level of coordination. […] Hence, deregulation of these processes or mutation affecting proteins involved in these pathways can be disease causing.

• #3 Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease

  https://www.mdpi.com/1422-0067/19/11/3426

  Familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder primarily characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C), due to its reduced catabolism. […] If untreated, exposure to high LDL-C levels during lifetime increases atherosclerotic plaque development and premature cardiovascular disease risk. […] The major determinants in that system are LDLR, accounting for 80–85% of FH cases, apoB100, causing 5–10% of the cases, PCSK9 2% of the cases and LDL receptor adaptor protein 1 (LDLRAP1) accounting for less than 1% of the cases. […] Mutations that alter LDL metabolism are the most frequent defects leading to a cholesterol metabolism derived disease denominated familial hypercholesterolemia. […] Cholesterol metabolism is a complex mechanism with many factors involved that requires a high level of coordination. […] Hence, deregulation of these processes or mutation affecting proteins involved in these pathways can be disease causing.

• #4 Familial hypercholesterolemia – Wikipedia

  https://en.wikipedia.org/wiki/Familial_hypercholesterolemia

  The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. […] In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, resulting in a significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins. […] Although atherosclerosis occurs to a certain degree in all people, people with FH may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends on the number of LDL receptors still expressed and the functionality of these receptors. In many heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all.

• #5 Familial hypercholesterolemia – Wikipedia

  https://en.wikipedia.org/wiki/Familial_hypercholesterolemia

  The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. […] In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, resulting in a significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins. […] Although atherosclerosis occurs to a certain degree in all people, people with FH may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends on the number of LDL receptors still expressed and the functionality of these receptors. In many heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all.

• #6 Familial Hypercholesterolemia: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/121298-overview

  Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc). […] FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors. The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. It is the primary determinant of hepatic LDL uptake, which normally processes approximately 70% of circulating LDL. […] Goldstein and Brown discovered the LDL receptor and determined that FH was caused by an autosomal dominant mutation. […] Since then, more than 1700 mutations have been identified, with 79% of them probably expressed as a hypercholesterolemic phenotype. Defects in the genes encoding apoB and proprotein convertase subtilisin/kexin type 9 (PCSK9) are responsible for approximately 5% and less than 1% of FH cases, respectively.

• #7 Familial Hypercholesterolemia: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/121298-overview

  Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc). […] FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors. The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. It is the primary determinant of hepatic LDL uptake, which normally processes approximately 70% of circulating LDL. […] Goldstein and Brown discovered the LDL receptor and determined that FH was caused by an autosomal dominant mutation. […] Since then, more than 1700 mutations have been identified, with 79% of them probably expressed as a hypercholesterolemic phenotype. Defects in the genes encoding apoB and proprotein convertase subtilisin/kexin type 9 (PCSK9) are responsible for approximately 5% and less than 1% of FH cases, respectively.

• #8

  https://www.omim.org/entry/143890

  By studies of cultured fibroblasts from homozygotes, Goldstein and Brown (1973) and Brown and Goldstein (1974) showed that the basic defect concerns the cell membrane receptor for LDL. Normalnie, LDL is bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. In familial hypercholesterolemia, there is a binding defect due to a dysfunctional receptor. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Harders-Spengel et al. (1982) presented evidence that the receptor defect is present on liver membranes. […] To determine the influences of intrauterine and genetic factors on atherogenic lipid profiles in later life, Ijzerman et al. (2001) investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. They found an association between low birth weight and high levels of total cholesterol, LDL cholesterol, and apolipoprotein B that persisted in the intrapair analysis in dizygotic twin pairs but was reversed within monozygotic twin pairs. Furthermore, they found that the association between low birth weight and low levels of HDL cholesterol tended to persist in the intrapair analysis in both dizygotic and monozygotic twins. These data suggested that genetic factors may account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association of low birth weight with low levels of HDL cholesterol.

• #9

  https://www.omim.org/entry/143890

  By studies of cultured fibroblasts from homozygotes, Goldstein and Brown (1973) and Brown and Goldstein (1974) showed that the basic defect concerns the cell membrane receptor for LDL. Normalnie, LDL is bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. In familial hypercholesterolemia, there is a binding defect due to a dysfunctional receptor. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Harders-Spengel et al. (1982) presented evidence that the receptor defect is present on liver membranes. […] To determine the influences of intrauterine and genetic factors on atherogenic lipid profiles in later life, Ijzerman et al. (2001) investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. They found an association between low birth weight and high levels of total cholesterol, LDL cholesterol, and apolipoprotein B that persisted in the intrapair analysis in dizygotic twin pairs but was reversed within monozygotic twin pairs. Furthermore, they found that the association between low birth weight and low levels of HDL cholesterol tended to persist in the intrapair analysis in both dizygotic and monozygotic twins. These data suggested that genetic factors may account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association of low birth weight with low levels of HDL cholesterol.

• #10

  https://www.omim.org/entry/143890

  By studies of cultured fibroblasts from homozygotes, Goldstein and Brown (1973) and Brown and Goldstein (1974) showed that the basic defect concerns the cell membrane receptor for LDL. Normalnie, LDL is bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. In familial hypercholesterolemia, there is a binding defect due to a dysfunctional receptor. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Harders-Spengel et al. (1982) presented evidence that the receptor defect is present on liver membranes. […] To determine the influences of intrauterine and genetic factors on atherogenic lipid profiles in later life, Ijzerman et al. (2001) investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. They found an association between low birth weight and high levels of total cholesterol, LDL cholesterol, and apolipoprotein B that persisted in the intrapair analysis in dizygotic twin pairs but was reversed within monozygotic twin pairs. Furthermore, they found that the association between low birth weight and low levels of HDL cholesterol tended to persist in the intrapair analysis in both dizygotic and monozygotic twins. These data suggested that genetic factors may account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association of low birth weight with low levels of HDL cholesterol.

• #11 Familial Hypercholesterolemia: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/121298-overview

  Five classes of mutations have been defined as follows: Class 1 includes null alleles that result in complete absence of the LDL receptor. Class 2 includes defective transport alleles, which disrupt normal folding of the receptor and cause either failure in transport to the cell surface or successful transport of truncated, mutated receptors. […] Class 3 includes defective binding alleles that affect binding of LDL and, in some cases, binding of VLDL as well. Class 4 includes defective internalization alleles that affect the concentration of normal receptors in clathrin-coated pits for internalization by the hepatocyte. Class 5 includes defective recycling alleles that prevent dissociation of the receptor and the ligand and thereby interrupt recycling of the receptor.

• #12 Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease

  https://www.mdpi.com/1422-0067/19/11/3426

  Familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder primarily characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C), due to its reduced catabolism. […] If untreated, exposure to high LDL-C levels during lifetime increases atherosclerotic plaque development and premature cardiovascular disease risk. […] The major determinants in that system are LDLR, accounting for 80–85% of FH cases, apoB100, causing 5–10% of the cases, PCSK9 2% of the cases and LDL receptor adaptor protein 1 (LDLRAP1) accounting for less than 1% of the cases. […] Mutations that alter LDL metabolism are the most frequent defects leading to a cholesterol metabolism derived disease denominated familial hypercholesterolemia. […] Cholesterol metabolism is a complex mechanism with many factors involved that requires a high level of coordination. […] Hence, deregulation of these processes or mutation affecting proteins involved in these pathways can be disease causing.

• #13 Familial Hypercholesterolemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556009/

  The impairment of LDLR results in decreased LDL clearance from the plasma and an elevation of low-density lipoprotein cholesterol (LDL-C), which causes increased uptake of oxidase LDL or other modifications by macrophages and resulting in foam cell formation. […] This disorder is related to a defect in the apoB-100 ligand on the LDL. Therefore, it reduces the LDL clearance from plasma and subsequently causes a high level of serum LDL. […] Mutations that cause increased activity of PCSK9 lead to increased degradation of the LDL receptor and subsequently elevation of plasma LDL. However, mutations that inactivate PCSK9 cause lower plasma LDL levels and reduce coronary heart disease (CHD).

• #14

  https://link.springer.com/article/10.1007/s11886-022-01783-5

  Monogenic FH is caused by mutations mainly in the LDLR, APOB, and PCSK9 genes. These mutations are autosomal dominant (one inherited mutated allele can cause FH). Most monogenic FHs (approximately 1:250-500 in prevalence) are heterozygous (mutations affect only one allele). The LDLR gene mutations account for about 80% of total monogenic FH cases, while Apo-B and PCSK9 mutations account for 5% and 1%, respectively. […] LDLR mutations leading to monogenic FH are loss-of-function mutations. These mutations can cover a broad spectrum of LDLC level based on the functionality of LDLR. […] APOB gene mutations that lead to FH are also loss-of-function mutations, resulting in defective LDLC binding to LDLR. […] Inversely, homozygous FH phenotypes are usually independent of the other risk factors.

• #15 Familial Hypercholesterolemia Panel, Sequencing | Test Fact Sheet

  https://arupconsult.com/ati/familial-hypercholesterolemia-panel-sequencing

  Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease. It is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) in the absence of an apparent secondary cause and premature atherosclerotic cardiovascular disease (ASCVD). […] Mechanisms of pathogenesis by gene: LDLR variants cause impaired LDL receptor function or absence of LDL receptor. […] APOB gain-of-function variants affect binding of LDL particle to LDL receptor resulting in elevated LDL-C. This condition is also referred to as familial defective apoB and is clinically indistinguishable from FH. […] PCSK9 gain-of-function variants may enhance affinity of PCSK9 protein binding with the LDL receptor, interfere with disassociation of LDL receptor/LDL complex, prevent recycling of receptor, or increase degradation of the LDL receptor. […] LDLRAP1 loss-of-function variants lead to absence of or nonfunctional LDL receptor adaptor protein 1, which prevents LDL receptor/LDL complex to be transported into the cell. This prevents the LDL receptor from effectively removing circulating LDL.

• #16 Familial Hypercholesterolemia: The Most Frequent Cholesterol Metabolism Disorder Caused Disease

  https://www.mdpi.com/1422-0067/19/11/3426

  Familial hypercholesterolemia (FH) is a common inherited autosomal co-dominant disorder primarily characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C), due to its reduced catabolism. […] If untreated, exposure to high LDL-C levels during lifetime increases atherosclerotic plaque development and premature cardiovascular disease risk. […] The major determinants in that system are LDLR, accounting for 80–85% of FH cases, apoB100, causing 5–10% of the cases, PCSK9 2% of the cases and LDL receptor adaptor protein 1 (LDLRAP1) accounting for less than 1% of the cases. […] Mutations that alter LDL metabolism are the most frequent defects leading to a cholesterol metabolism derived disease denominated familial hypercholesterolemia. […] Cholesterol metabolism is a complex mechanism with many factors involved that requires a high level of coordination. […] Hence, deregulation of these processes or mutation affecting proteins involved in these pathways can be disease causing.

• #17 Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments

  https://www.imrpress.com/journal/RCM/24/11/10.31083/j.rcm2411311/htm

  Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase. It lowers LDL-C through a mechanism similar to statins by interfering with intrahepatic cholesterol biosynthesis, resulting in the upregulation of LDLR on the hepatocyte surface. […] PCSK9 is primarily produced in the liver and is secreted as a low-abundance plasma protein. It binds LDLR on the surface of hepatocytes, leading to its lysosomal degradation and decreased quantity of LDLR on the hepatic surface. Treatments targeting PCSK9 include monoclonal antibodies (evolocumab and alirocumab) that bind PCSK9, promoting its degradation, or a small interfering ribonucleic acid molecule (inclisiran) that inhibits translation of PCSK9 mRNA, blocking its synthesis. […] In summary, FH is the most common monogenic disorder in humans that results in elevated LDL-C levels from birth, leading to early-onset ASCVD. Although lipid-lowering therapies are effective in treating FH, the timely initiation of aggressive LDL-C-lowering treatment is crucial to reducing the morbidity and mortality associated with ASCVD. Regrettably, FH often goes undetected until after a cardiac event, and many individuals remain undiagnosed and undertreated. Therefore, raising awareness of FH among healthcare providers, patients, and the general public is critical to reducing morbidity and mortality associated with this condition.

• #18 Familial Hypercholesterolemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556009/

  The impairment of LDLR results in decreased LDL clearance from the plasma and an elevation of low-density lipoprotein cholesterol (LDL-C), which causes increased uptake of oxidase LDL or other modifications by macrophages and resulting in foam cell formation. […] This disorder is related to a defect in the apoB-100 ligand on the LDL. Therefore, it reduces the LDL clearance from plasma and subsequently causes a high level of serum LDL. […] Mutations that cause increased activity of PCSK9 lead to increased degradation of the LDL receptor and subsequently elevation of plasma LDL. However, mutations that inactivate PCSK9 cause lower plasma LDL levels and reduce coronary heart disease (CHD).

• #19 Mechanisms of Disease: Genetic Causes of Familial Hypercholesterolemia

  https://www.medscape.org/viewarticle/553656_3

  The mechanism by which mutations in PCSK9 cause hypercholesterolemia is not yet fully understood, but PCSK9 is a sterol-regulated gene, indicating involvement in cholesterol metabolism. […] Adenoviral-mediated overexpression of normal (or mutant) PCSK9 has been shown to reduce LDL-receptor protein levels in the liver of mice. […] This finding led to the interesting discovery that two loss-of-function truncating mutations in PCSK9, which occur in the US black population at a frequency of about 1/50, are associated with both markedly lower than normal plasma LDL levels and strong protection against early CHD. […] Under normal circumstances, therefore, the PCSK9 protein reduces hepatic LDL-receptor activity; loss-of-function mutations impede this reduction. […] The underlying mechanism of the gain-of-function mutations, however, remains unclear.

• #20 Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

  https://www.mdpi.com/1422-0067/24/4/3224

  The PCSK9 gene is the latest discovered gene, but probably the most relevant one for FH management because its discovery allowed the identification of the molecular mechanism that is mostly targeted by innovative therapies based on its inhibition by monoclonal antibodies or small interfering RNAs. […] The encoded protein is able to decrease the number of LDLRs on the plasma membrane through different mechanisms taking place either in the extracellular region or inside the cell. […] The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. […] The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. […] Extreme phenotypic variability can be observed among FH patients with the same genetic status, which was partially explained by the different impact of the mutated gene or by the different variant types, in both adult and pediatric patients.

• #21 Mechanisms of Disease: Genetic Causes of Familial Hypercholesterolemia

  https://www.medscape.org/viewarticle/553656_3

  This disorder was referred to as autosomal recessive hypercholesterolemia (ARH) to distinguish it from FH caused by LDLR mutations. […] When our research group identified its first 'clinically homozygous’ FH patient with a recessive mode of inheritance and no detectable LDLR defect, however, we chose to study immortalized lymphocytes from the patient rather than skin fibroblasts, and found that although the LDL-receptor protein was produced normally, it failed to be internalized and thus LDL could not be taken up. […] Subsequently, recessive null mutations in a novel gene called LDL receptor adaptor protein 1 (LDLRAP1; also known as ARH) were observed to cosegregate with hypercholesterolemia in members of these rare 'clinically homozygous’ families. […] We confirmed that these mutations were the cause of the FH phenotype by demonstrating that LDL-receptor function was restored in our patients’ lymphocytes by expression of the normal LDL-receptor protein.

• #22 Mechanisms of Disease: Genetic Causes of Familial Hypercholesterolemia

  https://www.medscape.org/viewarticle/553656_3

  The LDLRAP1 (also known as ARH) protein contains a conserved phosphotyrosine-binding domain, and seems to function as an accessory adaptor protein that interacts with the LDL receptor via its cytoplasmic domain, enabling the receptor to engage with the clathrin-coated pit machinery for endocytosis. […] The phenotype in ARH is similar to that of patients with homozygous FH due to mutations in LDLR, but it is somewhat milder in terms of serum total cholesterol and LDL cholesterol levels, and shows better response to treatment with lipid-lowering drugs with or without LDL apheresis. […] Mutations in PCSK9 […] First found in French families, mutations in PCSK9, a gene that encodes a putative protease named proprotein convertase subtilisin/kexin type 9 (PCSK9), have since been shown to cosegregate with severe hypercholesterolemia in a number of families in several countries, but remain a rare cause of FH.

• #23 Familial Hypercholesterolemia Panel, Sequencing | Test Fact Sheet

  https://arupconsult.com/ati/familial-hypercholesterolemia-panel-sequencing

  Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease. It is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) in the absence of an apparent secondary cause and premature atherosclerotic cardiovascular disease (ASCVD). […] Mechanisms of pathogenesis by gene: LDLR variants cause impaired LDL receptor function or absence of LDL receptor. […] APOB gain-of-function variants affect binding of LDL particle to LDL receptor resulting in elevated LDL-C. This condition is also referred to as familial defective apoB and is clinically indistinguishable from FH. […] PCSK9 gain-of-function variants may enhance affinity of PCSK9 protein binding with the LDL receptor, interfere with disassociation of LDL receptor/LDL complex, prevent recycling of receptor, or increase degradation of the LDL receptor. […] LDLRAP1 loss-of-function variants lead to absence of or nonfunctional LDL receptor adaptor protein 1, which prevents LDL receptor/LDL complex to be transported into the cell. This prevents the LDL receptor from effectively removing circulating LDL.

• #24 Mechanisms of Disease: Genetic Causes of Familial Hypercholesterolemia

  https://www.medscape.org/viewarticle/553656_3

  The LDLRAP1 (also known as ARH) protein contains a conserved phosphotyrosine-binding domain, and seems to function as an accessory adaptor protein that interacts with the LDL receptor via its cytoplasmic domain, enabling the receptor to engage with the clathrin-coated pit machinery for endocytosis. […] The phenotype in ARH is similar to that of patients with homozygous FH due to mutations in LDLR, but it is somewhat milder in terms of serum total cholesterol and LDL cholesterol levels, and shows better response to treatment with lipid-lowering drugs with or without LDL apheresis. […] Mutations in PCSK9 […] First found in French families, mutations in PCSK9, a gene that encodes a putative protease named proprotein convertase subtilisin/kexin type 9 (PCSK9), have since been shown to cosegregate with severe hypercholesterolemia in a number of families in several countries, but remain a rare cause of FH.

• #25 Familial Hypercholesterolemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556009/

  Familial hypercholesterolemia is a group of inherited genetic defects that lead to the severe elevation of serum cholesterol concentrations. Clinically familial hypercholesterolemia is diagnosed by a high serum level of low-density lipoprotein (LDL) cholesterol and genetically is characterized into two subgroups: (1) autosomal dominant (AD), (2) codominant transmission with 90% or higher penetrance. […] The three main known genetic mutations in familial hypercholesterolemia are classified as defects in the LDL receptor (most common), apolipoprotein B (ApoB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Each of these three mutations leads to impairment of LDL receptors and a reduction in uptake of LDL cholesterol and subsequently causes high LDL cholesterol concentration. […] The end-result in all three main gene mutations is the binding dysfunction of LDL receptors to the LDL cholesterol, thereby decreasing the uptake and destruction of LDL cholesterol in the liver and the resultant rise in serum LDL levels.

• #26 Familial Hypercholesterolemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556009/

  The impairment of LDLR results in decreased LDL clearance from the plasma and an elevation of low-density lipoprotein cholesterol (LDL-C), which causes increased uptake of oxidase LDL or other modifications by macrophages and resulting in foam cell formation. […] This disorder is related to a defect in the apoB-100 ligand on the LDL. Therefore, it reduces the LDL clearance from plasma and subsequently causes a high level of serum LDL. […] Mutations that cause increased activity of PCSK9 lead to increased degradation of the LDL receptor and subsequently elevation of plasma LDL. However, mutations that inactivate PCSK9 cause lower plasma LDL levels and reduce coronary heart disease (CHD).

• #27

  https://www.omim.org/entry/143890

  By studies of cultured fibroblasts from homozygotes, Goldstein and Brown (1973) and Brown and Goldstein (1974) showed that the basic defect concerns the cell membrane receptor for LDL. Normalnie, LDL is bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. In familial hypercholesterolemia, there is a binding defect due to a dysfunctional receptor. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Harders-Spengel et al. (1982) presented evidence that the receptor defect is present on liver membranes. […] To determine the influences of intrauterine and genetic factors on atherogenic lipid profiles in later life, Ijzerman et al. (2001) investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. They found an association between low birth weight and high levels of total cholesterol, LDL cholesterol, and apolipoprotein B that persisted in the intrapair analysis in dizygotic twin pairs but was reversed within monozygotic twin pairs. Furthermore, they found that the association between low birth weight and low levels of HDL cholesterol tended to persist in the intrapair analysis in both dizygotic and monozygotic twins. These data suggested that genetic factors may account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association of low birth weight with low levels of HDL cholesterol.

• #28

  https://www.jci.org/articles/view/18925

  LDL turnover studies documented the key role of hepatic LDLRs in LDL catabolism. […] More recent studies indicate that the LDLR may also regulate the rate of entrance of VLDL into the circulation. […] The importance of the LDLR in limiting VLDL secretion in vivo in humans remains controversial, because isotopic studies cannot readily determine the proportion of newly formed VLDL that enters the systemic circulation. […] The exact role of ARH in LDLR function is not known. […] ARH may be required to chaperone LDLRs to coated pits, or simply to anchor receptors in the pits during internalization. […] ARH appears to be a near perfect phenocopy of FH, which is consistent with the possibility that all clinical sequelae of ARH mutations result from defective LDLR activity. […] The increased LDLR expression induced by statins may compensate to some degree for the defective hepatic LDLR function in ARH.

• #29

  https://www.jci.org/articles/view/18925

  LDL turnover studies documented the key role of hepatic LDLRs in LDL catabolism. […] More recent studies indicate that the LDLR may also regulate the rate of entrance of VLDL into the circulation. […] The importance of the LDLR in limiting VLDL secretion in vivo in humans remains controversial, because isotopic studies cannot readily determine the proportion of newly formed VLDL that enters the systemic circulation. […] The exact role of ARH in LDLR function is not known. […] ARH may be required to chaperone LDLRs to coated pits, or simply to anchor receptors in the pits during internalization. […] ARH appears to be a near perfect phenocopy of FH, which is consistent with the possibility that all clinical sequelae of ARH mutations result from defective LDLR activity. […] The increased LDLR expression induced by statins may compensate to some degree for the defective hepatic LDLR function in ARH.

• #30 Familial hypercholesterolemia: Detect, treat, and ask about family | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/2/109

  The type of mutation also affects treatment response. For instance, LDLR mutations can result in either a defective but somewhat functional LDL receptor or one with no functionality (null LDLR). Thus, cases of null LDLR mutations are more likely to be medically refractory, as lipid-lowering therapy often relies on somewhat functional LDL receptors. […] Genetic testing is the gold standard for diagnosing familial hypercholesterolemia. Most of the known mutations are in LDLR, but APOB, PCSK9, and potentially other genes involved in LDL-C catabolism can also have mutations. Several mutations remain unknown, and not finding a genetic mutation does not exclude the diagnosis, especially if there is strong phenotypic evidence. Finding a mutation also has prognostic value. At any LDL-C level, a gene-positive individual carries a higher risk of atherosclerotic cardiovascular disease than does a gene-negative one. The type of LDLR mutation also carries its own risk.

• #31 Mechanisms of Disease: Genetic Causes of Familial Hypercholesterolemia

  https://www.medscape.org/viewarticle/553656_3

  The mechanism by which mutations in PCSK9 cause hypercholesterolemia is not yet fully understood, but PCSK9 is a sterol-regulated gene, indicating involvement in cholesterol metabolism. […] Adenoviral-mediated overexpression of normal (or mutant) PCSK9 has been shown to reduce LDL-receptor protein levels in the liver of mice. […] This finding led to the interesting discovery that two loss-of-function truncating mutations in PCSK9, which occur in the US black population at a frequency of about 1/50, are associated with both markedly lower than normal plasma LDL levels and strong protection against early CHD. […] Under normal circumstances, therefore, the PCSK9 protein reduces hepatic LDL-receptor activity; loss-of-function mutations impede this reduction. […] The underlying mechanism of the gain-of-function mutations, however, remains unclear.

• #32 Mechanisms of Disease: Genetic Causes of Familial Hypercholesterolemia

  https://www.medscape.org/viewarticle/553656_3

  Some evidence indicates that apoB secretion might be increased in addition to a reduction in LDL-receptor activity, and LDL with an abnormal composition has been observed in patients heterozygous for mutant PCSK9. […] Despite all the improvements in mutation detection technology, when groups of clinically diagnosed FH patients are screened for LDLR mutations there are always some in whom no mutation can be found. […] The presence of mutations in other candidate genes has been postulated, but these are very rare.

• #33 Investigation of the underlying genes and mechanism of familial hypercholesterolemia through bioinformatics analysis | BMC Cardiovascular Disorders | Full Text

  https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-020-01701-z

  Up-regulated ITGAL, TLN1, POLR2A, VASP, HNRNPUL1, SF1, SRRM2, and down-regulated CD69, GZMA and ITGAV performed important promotional effects for the formation of atherosclerotic plaques those suffering from FH. […] These findings provide a theoretical basis for us to understand the potential etiology of the occurrence and development of AS in FH patients and we may be able to find potential diagnostic and therapeutic targets. […] The KEGG pathway analysis revealed that DEGs were significantly enriched in focal adhesion and glucagon signal pathway. […] These significant DEGs and their functions were theorized to contribute to atherosclerosis development in FH patients. […] The main risk of FH patients is the early onset of atherosclerosis and cardiovascular disease. Atherosclerosis is characterized by blood vessel wall hyperplasia, lipid accumulation in blood vessel wall, cytokine-activated macrophage invasion of blood vessel wall and formation of macrophage foam cells.

• #34 Familial hypercholesterolemia – Wikipedia

  https://en.wikipedia.org/wiki/Familial_hypercholesterolemia

  The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. […] In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, resulting in a significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins. […] Although atherosclerosis occurs to a certain degree in all people, people with FH may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends on the number of LDL receptors still expressed and the functionality of these receptors. In many heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all.

• #35 Investigation of the underlying genes and mechanism of familial hypercholesterolemia through bioinformatics analysis | BMC Cardiovascular Disorders | Full Text

  https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-020-01701-z

  Up-regulated ITGAL, TLN1, POLR2A, VASP, HNRNPUL1, SF1, SRRM2, and down-regulated CD69, GZMA and ITGAV performed important promotional effects for the formation of atherosclerotic plaques those suffering from FH. […] These findings provide a theoretical basis for us to understand the potential etiology of the occurrence and development of AS in FH patients and we may be able to find potential diagnostic and therapeutic targets. […] The KEGG pathway analysis revealed that DEGs were significantly enriched in focal adhesion and glucagon signal pathway. […] These significant DEGs and their functions were theorized to contribute to atherosclerosis development in FH patients. […] The main risk of FH patients is the early onset of atherosclerosis and cardiovascular disease. Atherosclerosis is characterized by blood vessel wall hyperplasia, lipid accumulation in blood vessel wall, cytokine-activated macrophage invasion of blood vessel wall and formation of macrophage foam cells.

• #36 Mechanism of the Molecular Pathophysiology for Familial Hypercholesterolemia · 研飞ivySCI

  https://www.ivysci.com/en/articles/9217189__Mechanism_of_the_Molecular_Pathophysiology_for_Familial_Hypercholesterolemia

  Familial hypercholesterolemia (FH) is characterized by high serum low-density lipoprotein cholesterol (LDL-C) levels from birth, tendon/skin xanthomas, and premature coronary artery disease. […] FH is caused by a pathogenic (rare) variant in the LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. […] Those without pathogenic variants in the LDLR or PCSK9 genes account for approximately 36% of patients with FH. […] We examined all the APOB variants and showed that the low-frequency APOB p.(Pro955Ser) variant has a moderate effect size in FH patients via functional analysis of hepatocytes. […] We also reported that low-frequency PCSK9 variants contribute to the severity of the FH phenotype in patients with FH harboring an LDLR pathogenic variant. […] Thus, the combination of low-frequency variants and age, environmental factors such as diet, or other genetic factors contribute to the severity of or variability in the FH phenotype.

• #37 Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

  https://www.mdpi.com/1422-0067/24/4/3224

  The PCSK9 gene is the latest discovered gene, but probably the most relevant one for FH management because its discovery allowed the identification of the molecular mechanism that is mostly targeted by innovative therapies based on its inhibition by monoclonal antibodies or small interfering RNAs. […] The encoded protein is able to decrease the number of LDLRs on the plasma membrane through different mechanisms taking place either in the extracellular region or inside the cell. […] The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. […] The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. […] Extreme phenotypic variability can be observed among FH patients with the same genetic status, which was partially explained by the different impact of the mutated gene or by the different variant types, in both adult and pediatric patients.

• #38

  https://www.jci.org/articles/view/18925

  The disease has an autosomal codominant pattern of inheritance and is caused by mutations in the LDLR gene; individuals with two mutated LDLR alleles (FH homozygotes) are much more severely affected than those with one mutant allele (FH heterozygotes). […] The severity of atherosclerosis is proportional to the extent and duration of elevated plasma LDL-C levels (calculated as the cholesterol-year score). […] Despite our detailed knowledge of the molecular biology of the LDLR, fundamental questions regarding how the receptor delivers its cargo in cells without being degraded itself have only recently been elucidated. […] The crystal structure of the extracellular domain of the protein has provided a compelling model of how the receptor binds LDL with high affinity at the cell membrane and then releases it in the appropriate intracellular compartment.

• #39 Update on Familial Hypercholesterolemia: Diagnosis, Cardiovascular Risk, and Novel Therapeutics

  https://www.e-enm.org/journal/view.php?number=1858

  In recent studies, the reported prevalence of heterozygous familial hypercholesterolemia (FH) has been higher than in previous reports. […] Cardiovascular risk is much higher in FH patients due to longstanding low density lipoprotein cholesterol (LDL-C) burden and is also influenced by other risk factors. […] Most monogenic causes of FH are mutations of low density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. All of these genes are involved in the pathway that clears circulating low-density lipoprotein. […] Pathogenic mutations are not identified in about 60% of clinically diagnosed FH patients, although the proportion differs according to the ethnicity or diagnostic criteria. […] The most critical complication in FH is life-time cardiovascular disease due to longstanding LDL-C burden.

• #40 Update on Familial Hypercholesterolemia: Diagnosis, Cardiovascular Risk, and Novel Therapeutics

  https://www.e-enm.org/journal/view.php?number=1858

  The risk of CAD is known to be 3.5- to 16-fold higher in heterozygous FH patients compared to non-FH individuals. […] Even with the same LDL-C levels, carriers of mutations for FH show higher risk for CAD. […] The main purpose of preventive measures in FH is the reduction of cardiovascular risk. […] As mentioned above, because vascular risk is very high and associated with cholesterol burden, lowering LDL-C is the mainstay of cardiovascular prevention in FH. […] Although, the majority of patients cannot reach a LDL-C goal by conventional pharmacotherapy, novel therapeutics such as PCSK9 inhibitors are expected to improve treatment results.

• #41

  https://link.springer.com/article/10.1007/s11886-022-01783-5

  Monogenic FH has a worse cardiovascular risk profile and responsiveness to lipid-lowering therapy compared to polygenic hypercholesterolemia. Therefore, whenever possible, genetic diagnosis should be performed to assist with clinical diagnosis. Identifying genetic background (monogenic or polygenic) can reinforce early diagnosis, determine drug of choice and intensity, disease prognosis, and optimize disease screening. […] Because monogenic FH has a higher cardiovascular risk independent of LDLC level and is less responsive to therapy than polygenic FH, distinguishing between the two is important for risk stratification and therapy.

• #42 Familial hypercholesterolemia: Detect, treat, and ask about family | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/2/109

  The type of mutation also affects treatment response. For instance, LDLR mutations can result in either a defective but somewhat functional LDL receptor or one with no functionality (null LDLR). Thus, cases of null LDLR mutations are more likely to be medically refractory, as lipid-lowering therapy often relies on somewhat functional LDL receptors. […] Genetic testing is the gold standard for diagnosing familial hypercholesterolemia. Most of the known mutations are in LDLR, but APOB, PCSK9, and potentially other genes involved in LDL-C catabolism can also have mutations. Several mutations remain unknown, and not finding a genetic mutation does not exclude the diagnosis, especially if there is strong phenotypic evidence. Finding a mutation also has prognostic value. At any LDL-C level, a gene-positive individual carries a higher risk of atherosclerotic cardiovascular disease than does a gene-negative one. The type of LDLR mutation also carries its own risk.

• #43

  https://link.springer.com/article/10.1007/s11886-022-01783-5

  Monogenic FH has a worse cardiovascular risk profile and responsiveness to lipid-lowering therapy compared to polygenic hypercholesterolemia. Therefore, whenever possible, genetic diagnosis should be performed to assist with clinical diagnosis. Identifying genetic background (monogenic or polygenic) can reinforce early diagnosis, determine drug of choice and intensity, disease prognosis, and optimize disease screening. […] Because monogenic FH has a higher cardiovascular risk independent of LDLC level and is less responsive to therapy than polygenic FH, distinguishing between the two is important for risk stratification and therapy.

• #44 Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis

  https://www.mdpi.com/1422-0067/24/4/3224

  The PCSK9 gene is the latest discovered gene, but probably the most relevant one for FH management because its discovery allowed the identification of the molecular mechanism that is mostly targeted by innovative therapies based on its inhibition by monoclonal antibodies or small interfering RNAs. […] The encoded protein is able to decrease the number of LDLRs on the plasma membrane through different mechanisms taking place either in the extracellular region or inside the cell. […] The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. […] The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. […] Extreme phenotypic variability can be observed among FH patients with the same genetic status, which was partially explained by the different impact of the mutated gene or by the different variant types, in both adult and pediatric patients.

• #45 Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments

  https://www.imrpress.com/journal/RCM/24/11/10.31083/j.rcm2411311/htm

  The utility of the established clinical criteria for diagnosing FH has been challenged previously due to the phenotypic heterogeneity of these patients. For example, a study of the Dutch Lipid Clinic network database identified 2400 patients as having FH using established clinical diagnostic criteria, but showed significantly different clinical and laboratory profiles between those with versus without a known LDLR mutation. […] Considering the autosomal dominant pattern of FH, it is essential to identify other family members with FH. Cascade testing is a mandatory part of the approach in which LDL-C measurement, genetic testing, or both are performed on all first-degree relatives of FH patients. It has been demonstrated that cascade testing leads to earlier FH detection and is a cost-effective strategy for reducing CAD, myocardial infarction, and death.

• #46 Familial hypercholesterolemia: Detect, treat, and ask about family | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/2/109

  Starting lipid-lowering therapy early is as important as early detection of disease. In untreated heterozygous patients, the first coronary event occurs about 20 years earlier than in the general population. In untreated homozygous patients, the prognosis is even worse, with the first event often occurring in childhood. […] Statins inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, resulting in decreased cholesterol production and increased LDL receptor expression on the surface of hepatocytes, which further reduces plasma LDL-C. Statin therapy should be started as soon as possible to help prevent cardiovascular events. In homozygous familial hypercholesterolemia patients, statin therapy is often started in the first decade of life. […] PCSK9 inhibitors are monoclonal antibodies that target circulating PCSK9, which normally degrades LDL receptor. More LDL receptor is therefore recycled to the hepatocyte surface and is available to remove more LDL-C from circulation. These medications are recommended when traditional lipid-lowering therapy cannot effectively lower LDL-C.

• #47 Familial hypercholesterolemia: Detect, treat, and ask about family | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/2/109

  Starting lipid-lowering therapy early is as important as early detection of disease. In untreated heterozygous patients, the first coronary event occurs about 20 years earlier than in the general population. In untreated homozygous patients, the prognosis is even worse, with the first event often occurring in childhood. […] Statins inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, resulting in decreased cholesterol production and increased LDL receptor expression on the surface of hepatocytes, which further reduces plasma LDL-C. Statin therapy should be started as soon as possible to help prevent cardiovascular events. In homozygous familial hypercholesterolemia patients, statin therapy is often started in the first decade of life. […] PCSK9 inhibitors are monoclonal antibodies that target circulating PCSK9, which normally degrades LDL receptor. More LDL receptor is therefore recycled to the hepatocyte surface and is available to remove more LDL-C from circulation. These medications are recommended when traditional lipid-lowering therapy cannot effectively lower LDL-C.

• #48 Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments

  https://www.imrpress.com/journal/RCM/24/11/10.31083/j.rcm2411311/htm

  Lack of early detection remains the biggest challenge in FH care. Once diagnosed, the primary goal of therapy in FH is aggressive LDL-C lowering, which is shown to decrease the atheroma burden and prevent CV events. […] The treatment of FH begins with the maximally tolerated dose of a high-intensity statin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. These drugs interfere with the rate-limiting step in cholesterol biosynthesis by antagonizing HMG-CoA reductase, thus decreasing intrahepatic cholesterol and increasing LDLR expression, which lowers circulating LDL-C through increased hepatic uptake. […] Ezetimibe is the most commonly prescribed LDL-C-lowering drug after statins. It acts by inhibiting the Niemann-Pick C1-Like 1 transporter, which prevents intestinal uptake of dietary and biliary cholesterol and decreases cholesterol delivery to the liver, thus upregulating LDLR and increasing hepatic LDL-C uptake.

• #49 Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments

  https://www.imrpress.com/journal/RCM/24/11/10.31083/j.rcm2411311/htm

  Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase. It lowers LDL-C through a mechanism similar to statins by interfering with intrahepatic cholesterol biosynthesis, resulting in the upregulation of LDLR on the hepatocyte surface. […] PCSK9 is primarily produced in the liver and is secreted as a low-abundance plasma protein. It binds LDLR on the surface of hepatocytes, leading to its lysosomal degradation and decreased quantity of LDLR on the hepatic surface. Treatments targeting PCSK9 include monoclonal antibodies (evolocumab and alirocumab) that bind PCSK9, promoting its degradation, or a small interfering ribonucleic acid molecule (inclisiran) that inhibits translation of PCSK9 mRNA, blocking its synthesis. […] In summary, FH is the most common monogenic disorder in humans that results in elevated LDL-C levels from birth, leading to early-onset ASCVD. Although lipid-lowering therapies are effective in treating FH, the timely initiation of aggressive LDL-C-lowering treatment is crucial to reducing the morbidity and mortality associated with ASCVD. Regrettably, FH often goes undetected until after a cardiac event, and many individuals remain undiagnosed and undertreated. Therefore, raising awareness of FH among healthcare providers, patients, and the general public is critical to reducing morbidity and mortality associated with this condition.

• #50 Familial hypercholesterolemia: Detect, treat, and ask about family | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/87/2/109

  Starting lipid-lowering therapy early is as important as early detection of disease. In untreated heterozygous patients, the first coronary event occurs about 20 years earlier than in the general population. In untreated homozygous patients, the prognosis is even worse, with the first event often occurring in childhood. […] Statins inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, resulting in decreased cholesterol production and increased LDL receptor expression on the surface of hepatocytes, which further reduces plasma LDL-C. Statin therapy should be started as soon as possible to help prevent cardiovascular events. In homozygous familial hypercholesterolemia patients, statin therapy is often started in the first decade of life. […] PCSK9 inhibitors are monoclonal antibodies that target circulating PCSK9, which normally degrades LDL receptor. More LDL receptor is therefore recycled to the hepatocyte surface and is available to remove more LDL-C from circulation. These medications are recommended when traditional lipid-lowering therapy cannot effectively lower LDL-C.

• #51 Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments

  https://www.imrpress.com/journal/RCM/24/11/10.31083/j.rcm2411311/htm

  Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase. It lowers LDL-C through a mechanism similar to statins by interfering with intrahepatic cholesterol biosynthesis, resulting in the upregulation of LDLR on the hepatocyte surface. […] PCSK9 is primarily produced in the liver and is secreted as a low-abundance plasma protein. It binds LDLR on the surface of hepatocytes, leading to its lysosomal degradation and decreased quantity of LDLR on the hepatic surface. Treatments targeting PCSK9 include monoclonal antibodies (evolocumab and alirocumab) that bind PCSK9, promoting its degradation, or a small interfering ribonucleic acid molecule (inclisiran) that inhibits translation of PCSK9 mRNA, blocking its synthesis. […] In summary, FH is the most common monogenic disorder in humans that results in elevated LDL-C levels from birth, leading to early-onset ASCVD. Although lipid-lowering therapies are effective in treating FH, the timely initiation of aggressive LDL-C-lowering treatment is crucial to reducing the morbidity and mortality associated with ASCVD. Regrettably, FH often goes undetected until after a cardiac event, and many individuals remain undiagnosed and undertreated. Therefore, raising awareness of FH among healthcare providers, patients, and the general public is critical to reducing morbidity and mortality associated with this condition.

• #52 PCSK9 Inhibitors

  https://www.hcplive.com/view/pcsk9-inhibitors

  PCSK9i are a class of monoclonal antibodies that effectively lower LDL-C levels and are particularly useful for patients with high cardiovascular risk, including those with acute coronary syndrome (ACS) or familial hypercholesterolemia. Currently, 2 PCSK9i have been approved for clinical use. […] Alirocumab is a fully human monoclonal antibody that targets PCSK9, preventing it from binding to LDL receptors on hepatocytes, which enhances the livers ability to clear LDL-C from the blood. […] It is approved for patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease (ASCVD) who need additional LDL-C level lowering, particularly in those not achieving sufficient reduction with statins or who are statin-intolerant. […] Evolocumab is approved for patients with heterozygous familial hypercholesterolemia, ASCVD, and those requiring additional LDL-C level lowering beyond what statins alone can provide. […] Both medications have demonstrated significant efficacy in lowering LDL-C levels and improving cardiovascular outcomes in high-risk patients, particularly those who do not achieve adequate LDL-C level reduction with statin therapy alone.

• #53 PCSK9 Inhibitors

  https://www.hcplive.com/view/pcsk9-inhibitors

  PCSK9i are a class of monoclonal antibodies that effectively lower LDL-C levels and are particularly useful for patients with high cardiovascular risk, including those with acute coronary syndrome (ACS) or familial hypercholesterolemia. Currently, 2 PCSK9i have been approved for clinical use. […] Alirocumab is a fully human monoclonal antibody that targets PCSK9, preventing it from binding to LDL receptors on hepatocytes, which enhances the livers ability to clear LDL-C from the blood. […] It is approved for patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease (ASCVD) who need additional LDL-C level lowering, particularly in those not achieving sufficient reduction with statins or who are statin-intolerant. […] Evolocumab is approved for patients with heterozygous familial hypercholesterolemia, ASCVD, and those requiring additional LDL-C level lowering beyond what statins alone can provide. […] Both medications have demonstrated significant efficacy in lowering LDL-C levels and improving cardiovascular outcomes in high-risk patients, particularly those who do not achieve adequate LDL-C level reduction with statin therapy alone.

• #54 Familial Hypercholesterolemia: Early Diagnosis and Treatment is Key for Cardiovascular Prevention

  https://www.acc.org/Latest-in-Cardiology/Articles/2020/04/16/09/58/Familial-Hypercholesterolemia

  Genetic testing is considered the gold standard for diagnosing FH. […] Patients with severe HeFH can have LDL-C levels that overlap with HoFH who often have completely null LDLR that make therapies like statins ineffective. […] Reducing the LDL-C level is one of the primary goals of treatments. Therefore, the first-line treatment is maximally tolerated statin therapy and should be started as early as possible, especially if LDL-C is 190 mg/dL (class I). […] In cases where LDL-C does not respond to medical therapy, often seen in HoFH, LDL apheresis can be considered. […] The US Centers for Disease Control and Prevention has designated FH as a tier 1 genomic application.38 This indicates that FH imposes a significant public health burden.

• #55 Familial hypercholestrolemia | PPT

  https://www.slideshare.net/slideshow/familial-hypercholestrolemia/35053340

  The PCSK9 protein appears to control the number of low-density lipoprotein receptors, which are proteins on the surface of cells. The PCSK9 protein helps control blood cholesterol levels by breaking down low-density lipoprotein receptors before they reach the cell surface. […] Heterozygous FH is normally treated with statins – drugs that lower cholesterol levels. Bile acid sequestrants (hypolipidemic agents), Ezetimibe, Fibrates (such as gemfibrozil or fenofibrate), and nicotinic acid are also other hypolipidemic agents that lower cholesterol levels. Homozygous FH often does not respond to regular medical therapy and may require LDL-apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

• #56 Familial Hypercholesterolemia: From Clinical Suspicion to Novel Treatments

  https://www.imrpress.com/journal/RCM/24/11/10.31083/j.rcm2411311/htm

  Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase. It lowers LDL-C through a mechanism similar to statins by interfering with intrahepatic cholesterol biosynthesis, resulting in the upregulation of LDLR on the hepatocyte surface. […] PCSK9 is primarily produced in the liver and is secreted as a low-abundance plasma protein. It binds LDLR on the surface of hepatocytes, leading to its lysosomal degradation and decreased quantity of LDLR on the hepatic surface. Treatments targeting PCSK9 include monoclonal antibodies (evolocumab and alirocumab) that bind PCSK9, promoting its degradation, or a small interfering ribonucleic acid molecule (inclisiran) that inhibits translation of PCSK9 mRNA, blocking its synthesis. […] In summary, FH is the most common monogenic disorder in humans that results in elevated LDL-C levels from birth, leading to early-onset ASCVD. Although lipid-lowering therapies are effective in treating FH, the timely initiation of aggressive LDL-C-lowering treatment is crucial to reducing the morbidity and mortality associated with ASCVD. Regrettably, FH often goes undetected until after a cardiac event, and many individuals remain undiagnosed and undertreated. Therefore, raising awareness of FH among healthcare providers, patients, and the general public is critical to reducing morbidity and mortality associated with this condition.

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