Which are the causes of Familial Hypercholesterolemia?

Familial Hypercholesterolemia (FH) is a genetic disorder characterized by high levels of cholesterol in the blood. It is primarily caused by mutations in specific genes that are responsible for regulating cholesterol metabolism. These mutations affect the function of receptors on the surface of liver cells, leading to impaired removal of low-density lipoprotein (LDL) cholesterol from the bloodstream.

1. Genetic Mutations: FH is typically inherited in an autosomal dominant pattern, meaning that a person only needs to inherit one copy of the mutated gene from either parent to develop the condition. The most common genes associated with FH are the LDL receptor (LDLR) gene, apolipoprotein B (APOB) gene, and proprotein convertase subtilisin/kexin type 9 (PCSK9) gene. Mutations in these genes disrupt the normal function of LDL receptors, impairing their ability to remove LDL cholesterol.

2. LDL Receptor Dysfunction: The LDL receptor plays a crucial role in removing LDL cholesterol from the bloodstream by binding to LDL particles and facilitating their uptake into liver cells. In FH, the mutated LDL receptors are either absent or defective, resulting in reduced clearance of LDL cholesterol. As a result, LDL cholesterol levels remain elevated, leading to the development of atherosclerosis and an increased risk of cardiovascular diseases.

3. Inheritance: FH is an inherited disorder, meaning it is passed down from generation to generation within families. If one parent has FH, there is a 50% chance of passing the mutated gene to each child. This genetic predisposition significantly increases the likelihood of developing high cholesterol levels and related complications.

4. Heterozygous and Homozygous FH: FH can be classified into two types: heterozygous FH (HeFH) and homozygous FH (HoFH). HeFH occurs when a person inherits one mutated gene and one normal gene, resulting in moderately elevated cholesterol levels. HoFH, on the other hand, occurs when a person inherits two copies of the mutated gene, leading to extremely high cholesterol levels from birth. HoFH is rarer but more severe than HeFH.

5. Lifestyle Factors: While FH is primarily a genetic disorder, certain lifestyle factors can exacerbate the condition. Unhealthy dietary choices, lack of physical activity, obesity, and smoking can all contribute to higher cholesterol levels in individuals with FH. These factors can further increase the risk of developing cardiovascular diseases.

Early diagnosis and appropriate management of FH are crucial to prevent complications. Individuals with FH may require lifelong treatment, including a combination of cholesterol-lowering medications, lifestyle modifications, and regular monitoring of cholesterol levels. Genetic testing and family screening are essential to identify affected individuals and provide appropriate interventions.