Homozygous Familial Hypercholesterolemia: New Insights and Guidance to Improve Detection and Management
Editor's Note: Commentary based on Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57.
Homozygous familial hypercholesterolemia (HoFH) is a rare condition characterized by severely elevated plasma low-density lipoprotein cholesterol (LDL-C) concentrations since birth.1 As a consequence, if left untreated, HoFH patients may develop coronary artery disease within the first and second decades of life. In addition, HoFH can cause left ventricular outflow obstruction due to aortic and supra-aortic stenosis, as well as atherosclerosis in other vascular territories. In countries where a founder effect is not present, HoFH usually affects about one in a million individuals.1 However, at least in certain regions of the world such as the Netherlands, recent evidence suggests that HoFH is three times more frequent than thought in the past, affecting one in every 300,000 individuals.2
Recently, two new medications were approved for the treatment of HoFH: mipomersen (an antisense oligonucleotide for apolipoprotein B [apoB]) and lomitapide (a microsomal triglyceride transfer protein inhibitor).3 Also, there is evidence suggesting that proprotein convertase/subtilisin kexin 9 (PCSK9) inhibitors are also effective in reducing LDL-C in HoFH patients.4,5
The European Atherosclerosis Society invited experts in HoFH management from all over the world to review the literature and develop a guideline for diagnosis, risk stratification, and treatment of HoFH patients.6
Diagnosis: HoFH should be suspected when the following characteristics are present: 1) an untreated LDL-C >500 mg/dL (13 mmol/L) or treated LDL-C ≥300 mg/dL (8 mmol/L) [These LDL-C levels, however, are only indicative, and lower levels, especially in children or in treated patients, do not exclude HoFH.] together with either: cutaneous or tendon xanthoma before age 10 years or untreated elevated LDL-C levels consistent with heterozygous FH in both parents; 2) genetic confirmation of two mutant alleles at the LDL receptor (LDLR), apoB, PCSK9, or LDL RAP1 (adaptor protein) gene locus.
Clinical course: HoFH is characterized by greatly accelerated atherosclerosis, typically affecting the aortic root, although other vascular territories may also be affected. The first major cardiovascular events often occur during adolescence, possibly younger when patients are LDLR-negative and/or untreated. In young children, early symptoms and signs are often linked to aortic stenosis and regurgitation, due to massive accumulation of cholesterol at the valvular level.
- Subclinical disease detection: As aortic and supra-valvular aortic valve diseases may progress even when cholesterol levels are reduced, regular screening for subclinical aortic, carotid, and coronary heart disease is indicated. Patients should undergo comprehensive cardiovascular evaluation at diagnosis, with subsequent Doppler echocardiographic evaluation of the heart and aorta annually, stress testing, and, if available, computed tomography coronary angiography every five years, or more frequently if needed.
- Dyslipidemia treatment: A combination of lifestyle and statin treatment is indicated with or without ezetimibe, lipoprotein apheresis (if available), and novel drug therapy.
- Lipid-lowering therapy should be started as early as possible.
- Lipoprotein apheresis should be considered in all patients with HoFH, and started as soon as possible, ideally by age five and not later than eight years.
- Lomitapide and mipomersen should be considered as adjunctive treatments to further lower plasma LDL-C levels in patients with HoFH.
Albeit rare, HoFH is a severe condition associated with early onset of cardiovascular and aortic/supra-aortic valve disease. It needs to be detected early and treated effectively.
Early diagnosis, family cascade screening due to the autosomal co-dominant trait, and genetic counseling of affected families are of utmost importance.6,8 The advent of next generation molecular sequencing could facilitate, at a lower cost, the molecular diagnosis of HoFH.7 The recent approval of newer therapies for HoFH like mipomersen and lomitapide as well as the future possibility of the use of PCSK9 monoclonal antibodies, that have been shown to be efficacious in HoFH patients bearing LDLR defective mutations, are of great importance.4,5 Those therapies can lead to tremendous, never before achieved, reductions in LDL-C levels. This might change the natural history of this disease and prevent early death and reduce suffering.
- Santos RD, Raal FJ. Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment. Atherosclerosis 2012;223:262-8.
- Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J 2014 Feb 28. [Epub ahead of print]
- Santos RD. What are we able to achieve today for our patients with homozygous familial hypercholesterolaemia, and what are the unmet needs? Atheroscler Suppl 2014;15:19-25.
- Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2014 Oct 1. [Epub ahead of print].
- Santos RD, Watts GF. Familial hypercholesterolaemia: PCSK9 inhibitors are coming. Lancet 2014 Oct 1. [Epub ahead of print].
- Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57.
- Santos RD, Maranhao RC. What is new in familial hypercholesterolemia? Curr Opin Lipidol 2014;25:183-8.
- Feldman DI, Blaha MJ, Santos RD, et al. Recommendations for the management of patients with familial hypercholesterolemia. Curr Atheroscler Rep 2015;17:473.
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