Treatment of homozygous familial hypercholesterolemia

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