Familial Hypercholesterolemia - Pathophysiology

Pathophysiology

LDL cholesterol normally circulates in the body for 2.5 days, and subsequently binds to the LDL receptor on the liver cells, undergoes endocytosis, and is digested. LDL is removed, and synthesis of cholesterol by the liver is suppressed in the HMG-CoA reductase pathway. In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, resulting in significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins. In mutations of ApoB, reduced binding of LDL particles to the receptor causes the increased level of LDL cholesterol. It is not known how the mutation causes LDL receptor dysfunction in mutations of PCSK9 and ARH.

Although atherosclerosis occurs to a certain degree in all people, FH patients may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends of 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.

Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis. In addition to the classic risk factors such as smoking, high blood pressure, and diabetes, genetic studies have shown that a common abnormality in the prothrombin gene (G20210A) increases the risk of cardiovascular events in patients with FH. Several studies found that a high level of lipoprotein(a) was an additional risk factor for ischemic heart disease. The risk was also found to be higher in patients with a specific genotype of the angiotensin-converting enzyme (ACE).