Homozygous Familial Hypercholesterolemia: Diagnosis and Emerging Therapies

Familial hypercholesterolemia (FH) is the most common autosomal-dominant genetic disorder, affecting approximately 30 million patients worldwide and characterized by lifelong elevations in low-density lipoprotein cholesterol (LDL-C).1 Loss-of-function mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein (b) (Apo[b]), as well as gain-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9), represent the most common causal mutations, accounting for the vast majority of FH cases.2,3 Whereas heterozygous familial hypercholesterolemia (HeFH) is more common, homozygous familial hypercholesterolemia (HoFH), due to mutations in two alleles, is much more lethal. Left untreated, children as young as 4 years of age have suffered sudden death due to myocardial infarction, highlighting the urgency needed to both identify and treat patients with this extremely high-risk condition.4

Detection and Diagnosis

Clinical features of HoFH generally appear early in life, either in the first or second decade.5 Common physical examination findings include cutaneous or tuberous xanthomas, tendon xanthomas (with interdigital xanthomas between the thumb and index finger being pathognomonic), xanthelasma, and arcus corneae. The diagnosis of HoFH can be made based on clinical and/or genetic criteria that endorsed by the European Atherosclerosis Society (EAS). The diagnosis includes meeting one of the following: 1) genetic confirmation of two mutant alleles of the LDLR, Apo(b), PCSK9, or LDLR adaptor protein 1 gene locus; or 2) an untreated LDL-C >500 mg/dL or treated LDL-C ≥300 mg/dL together with either cutaneous or tendon xanthoma before 10 years of age or untreated elevated LDL-C levels consistent with HeFH in both parents.6 However, this historical definition of HoFH has limitations. For example, a considerable number of patients meeting the clinical diagnosis may have negative genetic testing, leading to confusion with the diagnosis and limitations in therapy. To address the difficulties with diagnosis, a scientific statement from the American Heart Association (AHA) proposed a simpler classification for HoFH (Table 1).7 Screening for elevated levels of lipoprotein(a) (Lp[a]) is also strongly encouraged, given its high prevalence among patients with HoFH and significant association with atherosclerotic cardiovascular disease (ASCVD) independent of LDL-C.

Table 1

  Clinical Criteria With Genetic Testing Performed
HoFH LDL-C ≥400 mg/dL and one or both parents having clinically diagnosed FH, positive genetic testing for a known LDL-C–raising (LDLR, Apo[b], PCSK9) gene defect, or autosomal-recessive FH Presence of two identical (HoFH) or nonidentical (compound HeFH) abnormal LDL-C–raising gene defects, including the rare autosomal-recessive type
If LDL-C >560 mg/dL or LDL-C >400 mg/dL with aortic valve disease or xanthomata at <20 years of age Occasionally, HoFH will have LDL-C <400 mg/dL
Apo(b) = apolipoprotein (b); FH = familial hypercholesterolemia; HeFH = heterozygous familial hypercholesterolemia; HoFH = homozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9.

Adapted from Gidding SS, Champagne MA, de Ferranti SD, et al.; American Heart Association Atherosclerosis, Hypertension, and Obesity in Young Committee of Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, Council on Lifestyle and Cardiometabolic Health. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation 2015;132:2167-92.


Once a diagnosis is established, systematic cascade screening is essential to identify family members with FH given the autosomal-dominant inheritance pattern of the disease. A pedigree can be helpful in planning cascade screening, starting with first-degree relatives of the index patient, which can then be extended to second- and third-degree relatives. After consent is obtained, family members should be offered a standard lipid panel and genetic testing if a specific mutation is known. Traditional risk factors should be treated aggressively. Additionally, testing for Lp(a) should be offered. Genetic counseling also may help patients and their families better understand their diagnosis and future implications.

Challenges in Standard Pharmacotherapy

Lipid lowering remains a challenge for patients with HoFH. First, extreme elevations in LDL-C present at birth, which may be four to five times higher than in the general population,8 make it difficult to reach optimal LDL-C levels. Second, multiple lipid-lowering medications at maximally tolerated doses are usually necessary, many of which have not been adequately studied in the pediatric population, assuming the diagnosis is made at a young age. Most importantly, many of the typical therapies used for lipid lowering are contingent on a functional LDLR. Given that most HoFH cases are due to defects in genes related to LDLR function, these medications are often inadequate. Statins deliver modest reductions in LDL-C of 10-25%, even in individuals without significant LDLR activity, which may be mediated by inhibition of hepatic cholesterol synthesis.7,9,10 The addition of ezetimibe, which lowers LDL-C by inhibiting intestinal absorption, can lead to additional reductions in LDL-C of 10-15%.11 Other lipid-lowering therapies, including bile acid sequestrants, fibrates, and niacin, can be considered, although cost, tolerability, and efficacy often limit their use. Historically, a combination of lifestyle modification, statins, additional lipid-lowering therapies, and lipoprotein apheresis was needed to manage patients with HoFH. Liver transplant has also been considered in extreme cases.7

FDA-Approved Medications for HoFH

Lomitapide is an oral microsomal transport protein inhibitor responsible for trafficking triglycerides and phospholipids into chylomicron and very low-density lipoprotein (VLDL) particles during their assembly in the intestine and liver, respectively. HoFH trials have demonstrated dramatic reductions in LDL-C of approximately 50% with lomitapide when added to standard therapy,12 although adverse gastrointestinal effects and hepatotoxicity may be limiting. The manufacturer of this medication is required by the Food and Drug Administration (FDA) to submit a Risk Evaluation and Mitigation Strategy to educate prescribers on the significant risks and need for close monitoring, and to restrict access to patients with a clear diagnosis of HoFH. Mipomersen is an antisense oligonucleotide (ASO) targeted against Apo(b) messenger RNA (mRNA) that leads to reduced translation of Apo(b), LDL, and VLDL particles. Although this medication is FDA approved in patients with HoFH, it is no longer available in the United States.

Novel Therapeutic Approaches to LDL-C Reduction in HoFH

Inhibition of PCSK9

The advent of monoclonal antibodies (mAbs) targeted against PCSK9 has ushered in a new era in lipid lowering among patients with hypercholesterolemia. Nevertheless, as with statins, the efficacy of these medications is contingent on a functional LDLR. Accordingly, trials assessing mAbs against PCSK9 inhibitors have demonstrated modest reduction in LDL-C in patients with HoFH on background lipid-lowering therapy, with evolocumab lowering LDL-C by approximately 20-30% and alirocumab lowering LDL-C by 36%.13,14 Notably, only evolocumab carries an FDA indication for LDL-C lowering in HoFH. Inclisiran is a small interfering RNA (siRNA) molecule specific for a unique sequence in the PCSK9 mRNA that prevents translation. Clinical trials with inclisiran demonstrated significant LDL-C lowering in multiple populations through the ORION trials. Patients with HoFH in the small (n = 4) ORION-2 (Sustained LDL Reduction With Inclisiran in Homozygous FH) pilot study experienced changes in LDL-C ranging from +3% to -37% over 180 days.3,15 The ongoing ORION-5 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) will examine the LDL-C–lowering efficacy of inclisiran among 56 patients with HoFH on a background of maximally tolerated lipid-lowering therapy.

Inhibition of Angiopoietin-like 3

Angiopoietin-like 3 (ANGPTL3) is a protein that inhibits lipoprotein and endothelial lipase. Given data showing significant reductions in LDL-C and triglycerides among patients with ANGPTL3 deficiency,16 several medications have been developed to target this protein. Importantly, reductions in lipid levels via inhibition of ANGPTL3 are independent of the LDLR, providing hope to patients with HoFH who cannot achieve adequate LDL-C lowering with standard therapy. Evinacumab is a mAb that inhibits ANGLPTL3 and represents the newest agent for lipid lowering in HoFH, gaining FDA approval in February 2021. Compared with placebo, monthly evinacumab resulted in a 47% LDL-C reduction from baseline, which is especially impressive given background therapy that consisted of a high-intensity statin (77%), ezetimibe (75%), mAb against PCSK9 (77%), lomitapide (25%), and lipid apheresis (34%).17 Additionally, a subgroup analysis of patients with HoFH who had <2% LDLR function achieved LDL-C reductions of 72% compared with placebo. Notably, evinacumab costs approximately $450,000 per year.3 ASO and siRNA molecules targeting ANGLPTL3 mRNA translation are also in development, although they have not been studied in HoFH.

Gene Therapy: A Possible Cure?

Clustered regularly interspaced short palindromic repeat (CRISPR) technology has also gained traction as a tool for genome editing in patients with monogenic diseases. Scientists from the University of Pennsylvania introduced loss-of-function mutations in ANGPTL3 mouse models using CRISPR technology.18 Another study from China used CRISPR technology to repair LDLR point mutations in a mouse model.19 Additional proof-of-concept work using CRISPR gene editing of PCSK9 targeted in the liver of cynomolgus monkeys resulted in reductions of LDL-C by approximately 60%.20


Patients with HoFH are at high risk of early, aggressive ASCVD and premature death due to extreme elevations in LDL-C present at birth. Survival is contingent on early identification and treatment with combination lipid-lowering therapies. Although defects in the LDLR have previously limited therapeutic options for patients with HoFH, several new and emerging LDLR-independent medications have made low LDL-C possible, potentially circumventing the need for invasive treatments, including lipoprotein apheresis and liver transplant. New and emerging therapies, including evinacumab, now provide hope that these extremely high-risk patients can live longer, healthier lives.

Educational grant support provided by: Regeneron
To visit the course page for the Familial Hypercholesterolemia: Improving Detection to Accelerate Treatment project, click here!


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Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Valvular Heart Disease, Genetic Arrhythmic Conditions, Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Hypertension

Keywords: Hyperlipoproteinemia Type III, Hypercholesterolemia, International Classification of Diseases, Antibodies, Monoclonal, RNA, Small Interfering, Cholesterol, LDL, PCSK9 protein, human, Proprotein Convertase 9, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Niacin, Cardiovascular Diseases, Maximum Tolerated Dose, American Heart Association, Arcus Senilis, Gain of Function Mutation, Genetic Counseling, Risk Evaluation and Mitigation, United States Food and Drug Administration, Ezetimibe, Blood Component Removal, Triglycerides, Risk Factors, Oligonucleotides, Antisense, Myocardial Infarction, Intestinal Absorption, Aortic Valve Disease, Inheritance Patterns, Genomics, Apolipoproteins, Atherosclerosis, Genetic Testing, Chemical and Drug Induced Liver Injury, Lipoprotein(a), RNA, Messenger, Phospholipids, Chylomicrons, Hypertension, Subtilisins, Life Style, Bile Acids and Salts, Xanthomatosis, Fibric Acids, Fibric Acids, Informed Consent, Obesity, Stroke, Apolipoproteins B

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