Metabolic Diseases - Laboratory and Clinical Research: Severe Hypercholesterolemia Phenotype (PDF)

This book raises very important issues that concern the severe hypercholesterolemia phenotype. The severe hypercholesterolemia phenotype such as familial hypercholesterolemia (FH) is characterised by increased plasma low density lipoprotein (LDL) cholesterol concentration above 190 mg/dl, regardless of the cause. The majority of patients with FH present mutations in genes controlling LDL concentration, such as genes caused by abnormalities in the LDL receptor protein function and clearance of the LDL particle. The most frequent mutations causing FH are observed in LDLR, ApoB and PCSK9 genes. However, a polygenic origin is also probable in several of FH cases. The marked elevation of plasma LDL cholesterol concentration leads to premature and severe cardiovascular disease, including death, regardless of the gene mutation. Particularly, in individuals with a homozygous form of FH (two identical mutations or compound heterozygotes). Thus, early diagnosis and treatment of FH is vital, since the risk of premature coronary heart disease is estimated to be approximately 20-fold higher in untreated FH patients compared with control subjects. On the contrary, the aggressive lowering of plasma LDL cholesterol concentration decreased the cardiovascular events. A hypolipidemic diet and lipid lowering drugs are the first steps in the treatment of FH patients. The most severe and resistant FH cases are treated with LDL apheresis on top of combined drug therapy. Consequently, the combination of classical hypolipidemic drugs and newly introduced medications, such as PCSK9 inhibitors, antisense oligonucleotide against APOB-100 (mipomersen) and microsomal triglyceride transfer protein inhibitors (lomitapide) provide a way for most FH patients to achieve LDL cholesterol treatment goals.