Homozygous Familial Hypercholesterolemia (HoFH) is a rare inherited condition that causes dangerously high levels of LDL cholesterol from birth, leading to severe cardiovascular complications and early mortality. Despite affecting approximately 1 in 300,000 people worldwide, fewer than 5% of individuals with HoFH receive an accurate and timely diagnosis. Without intervention, children with HoFH often show signs of advanced heart disease before they even turn 20.
To better understand this life-threatening condition and highlight the urgent need for early detection and treatment, we spoke with two leading experts: Dr Sam Giddings, pediatric cardiologist, and Dr Raul Santos, President of the International Atherosclerosis Society. They emphasized the importance of assessing lifetime cholesterol exposure, expanding screening programmes—especially for children—and advocating for stronger policies to protect those living with HoFH from preventable heart disease.
QUESTIONS
What is HoFH, and why is it so dangerous if left undiagnosed?
Dr Raul Santos: HoFH is a rare but devastating disease! People born with HoFH usually have extremely high levels of LDL-cholesterol (typically > 400 mg/dL or 9.5 mmol/L). As a result, they may develop coronary heart disease, aortic valve disease, and xanthomas in the first and second decades of life if left untreated.
Dr Sam Gidding: HoFH is caused by the presence of two genetic variants that impact LDL receptor function. This leads to severe elevations of LDL cholesterol, typically over 400 mg/dl (10 mmol/L) and typically over 500 mg/dl. This leads to premature heart attacks which can occur as early as childhood, and in some cases aortic stenosis.
How can early screening in children help prevent heart disease caused by HoFH?
Dr Raul Santos: The only way to diagnose HoFH, and also the most common heterozygous form, is by testing blood cholesterol. This is something easy to do and inexpensive. Currently, we not only recommend cholesterol screening within families where FH has already been diagnosed, known as cascade screening, but also universal cholesterol screening to detect FH. Early diagnosis leads to early therapy with cholesterol-lowering medications and a healthy lifestyle.
Dr Sam Gidding: The morbidity of HoFH is related to lifelong exposure to severely elevated LDL cholesterol. The earlier HoFH is identified the earlier treatment can begin. Many longitudinal studies confirm that cholesterol control improves outcomes. New medications allow safe treatment very early in life.
What signs should families and doctors look for to detect HoFH early?
Dr Raul Santos: The development of early xanthomas (before the age of 10) in the skin and tendons, parental consanguinity, and a family history of high cholesterol and early coronary heart disease (usually < 50 years in men and 60 in women relatives) should prompt a suspected diagnosis of FH, and more specifically, HOFH. Cholesterol testing and genetic diagnosis should follow.
Dr Sam Gidding: Physical findings related to cholesterol deposition such as xanthoma and corneal arcus. Severely elevated cholesterol. A family history of elevated cholesterol and early heart attacks on both sides of the family.
Can starting treatment later in life fix the damage caused by years of high cholesterol?
Dr Raul Santos: Late onset of treatment can help, but it will not reverse the damage caused by years of extremely high blood cholesterol. Pharmacological therapy should begin at diagnosis. In addition to statins and ezetimibe, novel therapies such as evinacumab, lomitapide, and lipid apheresis can normalize LDL-C in individuals with HoFH. Therefore, we must diagnose and treat this severe disease as soon as possible. Are there other tests, like genetic testing or checking Lp(a), that can help find people at higher risk earlier?
Dr Sam Gidding: Starting cholesterol lowering treatment at the time of diagnosis is the only way to improve outcomes. However, achieving treatment goals is very difficult in HoFH as the genetic variants often limit efficacy of treatments, particularly those dependent on LDL receptor function. The later in life treatment is started, the more advanced atherosclerosis is present and this typically cannot be completely regressed.]
Are there other tests, like genetic testing or checking Lp(a), that can help find people at higher risk earlier?
Dr Raul Santos: Genetic testing is essential for individuals suspected of having HoFH. It helps distinguish HoFH from its phenocopies, i.e., diseases with the same clinical manifestations but requiring different treatments, such as sitosterolemia. Additionally, it can guide pharmacological therapy and assist in screening affected relatives. Testing for elevated Lp(a), another type of cholesterol-carrying lipoprotein, is relevant since an individual may have two genetic conditions associated with a higher risk of cardiovascular disease. Furthermore, given that HoFH leads to early atherosclerosis and valve disease, testing for asymptomatic plaques in the coronary arteries using computed tomography angiography, Doppler ultrasound to detect plaques in the carotids, and echocardiography is advisable to check for aortic valve disease.
Dr Sam Gidding: HoFH can be diagnosed based on phenotypic characteristics. Genetic testing, however, adds vital information, confirming a HoFH diagnosis and to provide insight into medication choice. Genetic testing becomes the basis for cascade testing of family members. Measurement of Lp(a) is important for risk stratification.