Evidence-Based, Mechanistic Approach to the Management of Homozygous Familial Hypercholesterolemia
Year: 2022
Type: editorial
Abstract: omozygous familial hypercholesterolemia (HoFH) is a rare autosomal dominant disorder that results from 2 allelic variation in genes encoding the low-density lipoprotein receptor (LDLR) and, less commonly, the LDLR ligand binding site on apolipoprotein B100, the major structural protein of LDL, or gain-of-function mutations in the LDLR-degrading protein proprotein convertase subtilisin kinexin type 9 (PCSK9). 1 Less common causes of HoFH include homozygosity for LDLR adaptor protein 1 (LDLRAP1).Disruption in LDL clearance from the circulation yields marked elevations in LDL cholesterol in the bloodstream that facilitates cholesterol deposition in the skin, tendons, and arteries throughout the body.Depending on the severity of the impaired LDLR function, atherosclerotic cardiovascular disease events have been reported in young children and encompass the spectrum of supravalvular aortic valve stenosis, myocardial infarction, stroke, and peripheral arterial disease.Early screening for severe hypercholesterolemia in the offspring of patients with heterozygous familial hypercholesterolemia (HeFH), a common disorder affecting 1 gene encoding LDLR or LDLRregulating mutations, is essential to detect HoFH to forestall the malignant atherosclerosis that causes disability and early death in most of these individuals.2 Accepted criteria for the diagnosis of HoFH include 1 of the following: 1) confirmed mutations in 2 of the same LDLR regulating pathway genes (true homozygotes); 2) a combination of 2 different mutations in 1 of the disease-causing genes (compound heterozygotes); and 3) untreated total cholesterol of >500 mg/dL in childhood and with both parents having total cholesterol levels of $250 mg/dL or cutaneous xanthoma before the age of 10 years.Lifestyle modification achieved through a lowsaturated fat diet, caloric restriction in overweight individuals, and exercise that does not elicit ischemic symptoms in the patient is the cornerstone of treatment.1 However, pharmacologic and nonpharmacologic approaches are needed to aggressively lower LDL cholesterol in efforts to delay the onset of cardiovascular events that occur early in life and repeatedly throughout the lives of patients with HoFH.Successful treatment strategies require careful evaluation of pharmacologic agents that may be effective in patients with HeFH but ineffective in patients with HoFH because of the severity of the impairment in LDLR activity.Conventional cholesterol-lowering therapies with proven efficacy in the prevention of atherosclerotic cardiovascular events (statins, PCSK9 inhibitors) as well as an approved therapy that is undergoing a phase 3 trial (bempedoic acid) lower LDL cholesterol primarily by up-regulating LDLR activity.In patients with HoFH, the LDL cholesterol-lowering efficacy of statins and PCSK9 inhibitors is about 50% less than that observed in patients with HeFH and may be 0% in patients with null/null mutations in LDLR. 1 In the ODYSSEY (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment
Source: JACC Case Reports
Author: Robert S. Rosenson
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $700
OpenAlex ID: W4306827122