Familial Hypercholesterolemia

Characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoproteins (LDL) cholesterol.

Heterozygous familial hypercholesterolemia is the most frequent monogenic disorder and major heritable cause of atherosclerotic cardiovascular disease worldwide.

Caused by mutations in genes encoding key proteins involved in LDL receptor endocytic and recycling pathways that lead to decreased cellular uptake of LDL cholesterol.

Mutations in the LDL receptor gene result in decreased were absent hepatic clearance of LDL cholesterol from the circulation and an elevated plasma LDL cholesterol level.

In the general population the estimated prevalence of heterozygous familiar hypercholesterolemia is 0.32% suggesting that one in 313 people are affected.

LDLreceptor is responsible for removing LDL from the blood.

Overactivity of PCSK9 which promotes LDL receptor degradation is the cause of familial hypercholesterolemia.

FH is it established independent risk factor for premature atherosclerotic cardiovascular disease, including acute myocardial infarction.

Patients with FH who present with  myocardial infarction have higher atheromatous burden and diffuse multi-vessel coronary artery disease.

Patients with FH who develop acute myocardial infarction have a higher risk for long-term recurrent myocardial infarction, stroke, and poor survival compared to those without familial hypercholesterolemia.

Patients with FH have similar survival with acute myocardial infarction compared to those without FH.

Statins, cholesterol absorption inhibitors, and PCSK9 inhibitors lower the plasma cholesterol level by increasing the expression of the LDL receptor on liver cells, stimulating the removal of LDL cholesterol from the blood.

PCSK9 Inhibitors added to statin therapy can lower the LDL cholesterol by 60% and reduce cardiovascular risk.

Associated with genetic variants that result in virtually absent or impaired LDL-receptor activity.

A relatively common Mendelian genetic disorder associated with markedly elevated low density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease.

Patients with heterozygous familial hypercholesterolemia, have plasma cholesterol levels 2-3 times the levels in individuals without disease, but because they have one functional copy of the LDL receptor, they still have some degree of response to standard cholesterol lowering medications.

Associated with severely elevated plasma levels of LDL cholesterol from birth onward and these patients are at very high risk of premature cardiovascular disease.

Coronary heart disease in FH potentiated by risk factors such as smoking, hypertension, obesity, and diabetes.

There is an association of raised lipoprotein(a) plasma concentrations with coronary heart disease in patients with FH.

Lipoprotein(a) is an LDL-like particle with additional apolipoprotein, apolipoprotein(a), attached to apolipoprotein B.

Caused by a loss of function mutations in both alleles of low density lipoprotein receptor gene.

Caused by transmission of defects on the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB), or the proprotein convertase subtilisn/kexin type 9 gene (PCSK9) all of which cause reduced LDL plasma clearance.

Pathogenic variants in one of three genes-LDLR, APOB, or PCSK9 account for most cases.

Familial hypercholesterolemia Is caused by variants in genes encoding proteins involved in the clearance of LDL particles.

More than 90% of patients with genetically confirmed familial hypercholesterolemia have mutations in the gene encoding the LDL receptor.

Childhood hypercholesterolemia leads to atherosclerosis: randomized controls have shown that reducing low density lipoprotein cholesterol levels with statins in children benefits subclinical vascular measures, delays or even regresses carotid intima-media thickness, and shows fewer events of atherosclerotic cardiovascular disease in treated children than in their affected parents, who started taking  statin as adults.

Familial hypercholesterolemia is also caused by mutations in genes encoding apoliporotein B, proprotein convertase subtilisin-kexin or LDL receptor adaptor protein 1.

Associated with a cell surface deficient receptor for LDL, which is the molecular basis of the disease.Most circulating LDL-C is removed from the blood by hepatic LDL receptor-mediated endocytosis.

Pathologic variants in LDLR lead to impaired LDL receptor function in elevated LDL-C levels.

Impaired hepatic cholesterol uptake characterized by high plasma levels of low-density lipoprotein cholesterol.

Increased risk for premature cardiovascular disease.

Unteated FH associated with a significantly shortened life expectancy, with sudden death and myocardial infarction as the principal causes of death.

Homozygous persons have severe coronary atherosclerosis and usually die in childhood from myocardial infarction.

Increased rate of progression of intimal-media thickness in childhood.

Patients have plasma cholesterol levels of more than 500 mg per deciliter and patients do not generally survive past 30 years of age.

Patients have poor response to conventional drugs which lower LDL cholesterol via up-regulation of hepatic LDL receptor.

Patients may be at lower risk to develop type 2 diabetes.

Statins are the preferred drug therapy in treatment should start at a young age.

The optimum age of initiation of statins is from as young as 8-10 years of age.

The initiation of statin therapy during childhood in patients with familial hypercholesterolemia slow the progression of carotid into a-media thickness and reduced the risk of cardiovascular disease in adults (Luirink LK).

Present care consists of LDL apheresis which can transiently reduce LDL cholesterol levels by more than 50% and may delay the onset of vascular disease.

Lipid-lowering treatment improves life expectancy.

Most patients do not achieve LDL-C levels less than 100 mg/dL.

Apheresis must be repeated every 1-2 weeks.

In patients with homozygous familial hypercholesterolemia evinacumab substantially lower LDL cholesterol levels.

In pediatric patients with familial hypercholesterolemia evolocumab reduced LDL cholesterol levels and other lipids.

Treatments that decrease LDL cholesterol levels in childhood is neededit if we are to prevent atherosclerotic cardiovascular disease in young people with heterozygous familial hypercholesterolemia.