Treatment of Homozygous Familial Hypercholesterolemia

Michael France; Jonathan Schofield; See Kwok; Handrean Soran


Clin Lipidology. 2014;9(1):101-118. 

In This Article

Abstract and Introduction


Familial hypercholesterolemia results from gene mutations approximately halving the number of functional LDL receptors in heterozygotes and a greater lack in homozygotes. Reduced receptor-mediated catabolism of LDL causes high plasma LDL cholesterol (LDL-C) and premature coronary artery disease. Statins lower plasma cholesterol by upregulating LDL receptor gene expression and are consequently relatively ineffective in homozygous familial hypercholesterolemia (HoFH). The standard treatment for HoFH is LDL apheresis combined with maximum tolerated potent statins, ezetimibe and bile acid sequestrants. In untreated HoFH, coronary heart disease usually develops in the first and second decade of life and often involves the aortic root and aortic valve. Peripheral vascular disease is common. Besides reduced receptor-mediated catabolism, there are other abnormalities in lipid metabolism in HoFH due to lack of LDL receptors. These include increased apoB turnover, raised lipoprotein(a) levels, reduced HDL cholesterol and possibly decreased transintestinal cholesterol excretion. PCSK9, which mediates post-translational destruction of LDL receptors, is raised in HoFH and is further raised by statins. LDL-C, following apheresis, quickly rebounds due to increased synthesis and reduced LDL receptor-mediated clearance. Inhibitors of LDL synthesis, lomitapide and mipomersen, are new therapeutic options. PCSK9 inhibitors are being evaluated in HoFH and seem to be effective if there is residual receptor activity. E3-ubiquitin ligase inducible degrader of the LDL receptor has a similar function to PCSK9 and is a potential therapeutic target. A desirable treatment target for HoFH patients is LDL-C ≤1.8 mmol/l. Stabilization of atheroma and raising HDL cholesterol are important therapeutic objectives


Familial hypercholesterolemia (FH) is a genetic disease due to lack of functional LDL receptors. Receptor activity is approximately half of normal in heterozygous FH (HeFH). Homozygous FH (HoFH) may be classified as receptor negative with 0–2% receptor activity or receptor defective with 2–25% receptor function.[1] In a series of 200 HoFH patients in South Africa approximately 75% had between 2 and 25% residual receptor function and 15% were receptor negative (<2%) with the rest being unknown.[1–3] In series of patients in Greece and Italy 71 and 55% were receptor negative.[5] The Italian survey found up to 30% residual activity in the receptor-positive group.[6] This suggests that increasing residual receptor function may be an effective strategy in many HoFH patients. LDL receptors mediate 70% of hepatic LDL uptake.

HoFH has dominant and recessive forms. Autonomic dominant familial hypercholesterolemia is caused by mutations in genes for the LDL receptor, apoB or a chaperone protein promoting LDL receptor catabolism called PCSK9.[7] Familial defective apoB causes a phenotype similar to receptor mediated FH and is due to the presence of a variant of apoB with reduced affinity for the LDL receptor.[8,9] HoFH caused by a mutation affecting an LDL receptor adaptor protein (LDLRAP1)[10] necessary for receptor function is called autosomal recessive FH.[11,12] The major defect in all forms of FH is reduced apoB or apoE mediated hepatic LDL uptake. Serum LDL cholesterol (LDL-C) is characteristically >13.0 mmol/l (500 mg/dl) compared with approximately 5.2–10.4 mmol/l (200–400 mg/dl) in HeFH.[13] In HoFH, very high cholesterol from birth usually causes development of atheroma and cardiovascular disease (CVD) by the age of 20 years and often in childhood.[14,15] With current treatment the mean age of death is still only 33 years.[2] The degree and time of exposure to hypercholesterolemia determines atheroma development. A particular feature in HoFH is the development of supravalvular aortic stenosis due to atheromatous disease, which may be associated with aortic valve fibrosis.[16] Supravalvular disease may impinge on the ostia of both the main coronary arteries with increased risk of fatal myocardial infarction. The prevalence of HoFH[13] is approximately one in a million[17] but is much higher in some populations such as in South Africa, Quebec and Lebanon owing to founder effects,[18] which increases its importance as a cause of heart disease.[19] Autosomal recessive FH affects one in 20,000[20] in Sardinia. So far, there are approximately 1600 mutations described worldwide with 95% affecting the LDL receptor directly.