Last updated:
7/22/2024
Years published: 2024
NORD gratefully acknowledges Joshua W. Knowles, MD, PhD, Attending Physician and Hannah Ison, MS, LCGC, Cardiovascular Genetic Counselor, Stanford Center for Inherited Cardiovascular Disease, for assistance in the preparation of this report.
Familial hypercholesterolemia (FH) is a diagnosis which refers to individuals with significantly elevated low-density lipoprotein (LDL) cholesterol (LDL-C) or “bad cholesterol” and an increased risk of early onset of coronary artery disease if not sufficiently treated. Most commonly, individuals have heterozygous familial hypercholesterolemia (HeFH), caused by a single gene variant for FH that they have inherited from a parent. HeFH is not rare occurring in about 1 in 250 individuals.
Homozygous familial hypercholesterolemia (HoFH) occurs when an individual inherits two FH gene variants, one from each parent. Molecular genetic testing on an individual with HoFH shows two disease-causing variants, usually in the LDLR gene though reports of individuals with variants in two other genes have also been reported (APOB, or PCSK9). HoFH is very rare, occurring in about 1 in 250,000 individuals.
Individuals with HoFH typically have LDL-C levels that are almost always >400 mg/dl. Severe vascular disease including coronary artery disease (CAD) and aortic stenosis are often seen by the teenage years. Without very aggressive treatment including LDL-C apheresis and HoFH specific medications, death can occur before age 30.
When an individual is diagnosed with HoFH, it is important to identify other family members with FH through “cascade screening” or “family screening.” Without proper family screening, some family members may have undetected very high cholesterol and are at risk of developing early onset CAD. It is common for individuals with FH to have a strong family history of premature CAD (men < 50 years, women <60 years) and sudden cardiac death. With improved detection and preventative treatment, the prevalence of premature CAD in families is declining.
Individuals with HoFH have extremely high LDL-C levels, usually above 400 mg/dL. They usually have firm nodules caused by cholesterol buildup (xanthomas) by early childhood. The most common sites are the Achilles tendon and the tendons on top of the hands. Planar xanthomas affecting the skin on the hands, elbows, buttocks and knees in a young child are diagnostic for this condition. Corneal arcus, a white, grey or blue opaque ring surrounding the entire inside edge of the cornea is often present. Most individuals with HoFH have severe CAD by their mid-20’s if not aggressively treated. Narrowing of the heart valve leading to the aorta (aortic stenosis) often occurs, which may make it necessary to replace the aortic valve. Very aggressive therapy is needed to reduce the likelihood of vascular events. Most affected people require filtering of their blood (LDL apheresis) and/or medications specifically approved by the U.S Food and Drug Administration (FDA) for HoFH (lomitapide, PCSK9 inhibitors or evinacumab).
Most individuals with HoFH have inherited one disease-causing gene variant for FH (LDLR) from each parent, such that each parent has HeFH. Very rarely individuals with HoFH have been reported to have APOB or PCSK9 gene variants. New, spontaneous variants appear to be very rare. When both parents have HeFH, they have a 25% risk in each pregnancy to have a child with HoFH, a 50% chance of having a child with HeFH, and a 25% chance that the child will inherit a normal gene from each parent and not have FH. The risk is the same for males and females.
When one parent has HeFH and the other has HoFH, there is a 50% chance with each pregnancy to have a child with HeFH and a 50% chance to have a child with HoFH.
When one parent has HoFH and the other has two normal genes, all children will have HeFH.
When both parents have HoFH, all children will have HoFH.
The frequency of HoFH across populations is estimated to be about 1 in 250,000. HoFH is more likely to occur in countries where the prevalence of HeFH is very high, especially where consanguinity (marriage between relatives) is common.
HoFH is easily identified in infants and young children by the presence of planar xanthomas, corneal arcus and exceedingly high total and LDL-C; LDL-C is usually greater than 400 mg/dL. The parents are “obligate heterozygotes” who are considered to have HeFH until proven otherwise. Genetic testing is available to determine the specific gene variants in an affected individual.
Once an individual is diagnosed with HoFH, it is recommended that other family members with FH are identified so early and intensive treatment can be initiated, and disease and death prevented. This “cascade screening” in families can identify people with FH who are not being appropriately treated.
Cascade screening has been shown in numerous studies to be cost-effective and has been recommended by the National Institute for Health and Clinical Excellence (NICE) in the UK. The Office of Public Health Genomics at the Centers for Disease Control and Prevention considers cascade screening of relatives of those with FH a “tier 1 application” which means that there is good evidence that implementation will prevent disease and save lives.
Clinical Testing and Workup
Evaluations following initial diagnosis
To establish the extent of disease and needs of an individual diagnosed with HoFH, the following evaluations are recommended in adults and children:
• Pre-treatment lipid values
• Lipoprotein(a) levels when possible as lipoprotein(a) is an additional risk factor for CAD
• Exclusion of concurrent illnesses (kidney disease, uncontrolled hypothyroidism, acute myocardial infarction, infection) that can affect lipid values
• Lipid panel including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides
• Consultation with a lipid specialist or clinician with expertise in FH
• Medical genetics or a genetic counseling consultation
In children, noninvasive imaging tools (e.g., measurement of carotid intima-media thickness) are recommended in some guidelines to help inform treatment decisions.
Individuals diagnosed with HoFH should be referred to a lipid specialist. Early initiation of therapy and monitoring using CT coronary angiography and other imaging are recommended; these patients often require additional treatment strategies, as drug treatment and lifestyle changes may not be sufficient. Statins are usually started as soon as the diagnosis is made (though may not be effective as explained below). Lomitapide is an FDA-approved treatment for adults with HoFH and should be considered for these patients, especially if LDL-C level cannot be controlled using other drugs. PCSK9 inhibitors such as evolocumab are approved by the FDA for HoFH. In 2021, the FDA approved evinacumab-dgnb (Evkeeza) injection as an add-on treatment for patients aged 12 and older with HoFH and in 2023 approval was expanded to children aged 5-11. Additional options include LDL apheresis or liver transplantation.
Often, medications that are the mainstay of treatment for HeFH (such as statins) are relatively ineffective in HoFH. This is because the mechanism of action of statins normally “triggers” the liver to express additional LDL receptors. In the most severe cases of HoFH, the LDL receptors are completely inactive which makes this response futile. Statins can be effective in individuals with HoFH if there is some residual LDL-R activity, or if they have variants in the APOB or PCSK9 genes.
LDL apheresis
Using a process similar to kidney dialysis, blood is withdrawn from a vein via a catheter and processed to remove LDL-C particles. Normal blood products are returned via another catheter. LDL-C levels will decrease approximately 50% but will rise between apheresis sessions, so they are necessary approximately weekly or every other week. The procedure is effective and well tolerated though time-consuming and only available in 50-60 sites in the US.
Liver transplantation
Liver transplants are extraordinarily rare and may become even less common with the new medications available. As the donor liver will have normal LDL receptors, the LDL-C quickly normalizes after the procedure, but the risks of any organ transplant are significant and include complications from major surgery and the effects of lifelong suppression of the immune system. Donor organs are often not available. Patients with familial disease-causing APOB or PCSK9 gene variants have normal LDL receptors, so liver transplantation is not an option for them.
Various imaging tools such as echocardiograms, CT angiograms and cardiac catheterization may be recommended to monitor individuals with HoFH.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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INTERNET
Ison HE, Clarke SL, Knowles JW. Familial Hypercholesterolemia. 2014 Jan 2 [Updated 2022 Jul 7]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK174884/ Accessed May 28, 2024.
How to Treat Homozygous Familial Hypercholesterolemia. Family Heart Foundation. HoFH Treatments | the Family Heart. Accessed May 28, 2024.
Myrie SB, Steiner RD, Mymin D. Sitosterolemia. 2013 Apr 4 [Updated 2020 Jul 16]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK131810/ Accessed May 28, 2024.
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