Homozygous Familial Hypercholesterolemia and Its Management

Abstract

Mutations in the low-density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia. In homozygous familial hypercholesterolemia, both genes for the LDL- receptor are mutated and LDL levels are markedly elevated. High-density lipoprotein cholesterol concentration is often reduced and lipoprotein(a) levels are high when corrected for apolipoprotein(a) isoforms. Cutaneous and tendinous xanthomata develop in childhood and are the most common reason for initial presentation. The diagnosis can be confirmed by analysis of LDL-receptor genes or studies of LDL receptor function in cultured cells. Severe aortic and coronary atherosclerosis usually occurs within the first or second decades of life. Left ventricular outflow tract obstruction may be at the level of the aortic valve or the supravalvar aorta. Treatment for the hyperlipidemia is with plasmapheresis, high-dose statins, and ezetimibe. Liver transplantation reverses the metabolic defect but requires chronic immunosupression, and rejection may still occur. Liver transplantation is indicated if cardiac transplantation becomes necessary. Portocaval shunt may still play a role in patients with coronary artery disease who do not have access to plasmapheresis. Gene therapy is currently not practicable but is being actively developed.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

“…Portacaval shunting can theoretically decrease the hepatic secretion of LDL in homozygous FH, but LDL-cholesterol reduction is variable and the procedure carries a high risk of encephalopathy; it could exceptionally be considered to treat severe homozygotes in countries where the above treatments are not available [171]. There may be a future role for gene therapy in treating severe FH [172,173].…”

Lomitapide and Mipomersen

“…8,9 The physiological importance of MTP in humans was demonstrated by the discovery that loss-of-function mutations in the gene encoding MTP (MTTP) are the proximate cause of the rare genetic condition abetalipoproteinemia. 5 Abetalipoproteinemia is characterized by marked hypocholesterolemia with the absence of apoB-containing lipoproteins in plasma. Patients with this condition were shown to lack MTP protein in the intestine 10 and subsequently to have loss-of-function mutations in both alleles of the MTTP gene.…”

“…Perhaps the single best example of a genetic condition in which patients frequently fail to achieve acceptable LDL-C levels despite aggressive therapy is familial hypercholesterolemia (FH). 3,4 This condition, classically caused by loss-of-function mutations in the LDL receptor, 5 is associated with substantially elevated LDL-C and premature atherosclerotic cardiovascular disease. Patients with heterozygous FH typically have untreated LDL-C levels in the range of 200 to 400 mg/dL, and many cannot achieve desirable LDL-C levels on available combination therapy.…”

“…Indeed, in controlled trials of patients with hoFH, high doses of potent statins reduced LDL-C by only 0% to 25%, bile acid sequestrants by 0% to 10%, and ezetimibe by 0% to 10%. 3,[5][6][7] The variability in response is likely due to variation in the amount of residual functional LDL receptor activity, with those patients with no receptor activity (receptor negative) having essentially no response to drugs that work through LDL receptor upregulation.…”

Off-pump coronary bypass in a child with familial hypercholesterolemia: premature atherosclerosis of the ascending aorta

“…Familial hypercholesterolemia is an autosomal-dominant disorder in which mutations in the low-density lipoprotein (LDL) receptor gene cause high levels of LDL and premature coronary artery disease in childhood (1). Extra coronary atherosclerotic lesions, including calcification of the aortic valve and root, are present in those patients.…”