Familial hypercholesterolemia (FH) is an inherited condition that causes dangerously high levels of LDL cholesterol from birth. It affects roughly 1 in 250 people worldwide, making it one of the most common genetic disorders, yet the vast majority of cases go undiagnosed. Without treatment, people with FH face a 20-fold increased lifetime risk of coronary heart disease compared to the general population.
How FH Works at the Genetic Level
Your liver clears LDL cholesterol (often called “bad cholesterol”) from the bloodstream using specialized receptors on its cell surface. These receptors grab onto LDL particles, pull them inside the cell for breakdown, and then cycle back to the surface to repeat the process. A single receptor does this roughly 100 to 150 times over its 24-hour lifespan. In FH, a genetic mutation disrupts this recycling system, leaving excess LDL circulating in the blood where it gradually damages artery walls.
The most common culprit is a mutation in the gene that builds these LDL receptors. Over 2,000 different mutations have been identified in this one gene alone, and they cause problems in different ways: some prevent the receptor from being made at all, others block it from reaching the cell surface, and still others stop it from grabbing onto LDL particles or pulling them inside.
Less commonly, FH results from mutations in other genes. One affects the protein on the surface of LDL particles that acts as the “key” fitting into the receptor “lock,” preventing the two from connecting. Another involves a protein called PCSK9, which normally helps retire old receptors. When a mutation makes PCSK9 overactive, it destroys receptors too quickly, leaving fewer available to clear cholesterol.
Heterozygous vs. Homozygous FH
Because you inherit two copies of every gene (one from each parent), the severity of FH depends on whether you received one defective copy or two. The heterozygous form, where one copy is affected, is by far the more common version at about 1 in 250 people. LDL cholesterol levels typically run two to three times higher than normal, often in the range of 190 to 400 mg/dL without treatment.
Homozygous FH, where both gene copies are affected, is extremely rare. These individuals can have LDL levels above 500 mg/dL from early childhood and may develop severe heart disease in their teens or twenties. Treatment is more complex and often requires multiple therapies working in combination.
What Untreated FH Does to the Body
The core danger of FH is that cholesterol accumulates in artery walls for decades, starting in childhood. Untreated men face a 50% chance of a fatal or nonfatal heart attack by age 50. Untreated women have a 30% risk of the same by age 60. Because LDL levels are elevated from birth rather than developing gradually in middle age, the total cholesterol exposure over a lifetime is enormous, even in people who otherwise seem healthy.
Cholesterol deposits can also appear in visible places outside the arteries. Tendon xanthomas, which are firm, yellowish lumps that form along tendons (especially the Achilles tendon and the tendons on the back of the hand), are highly characteristic of FH. Some people develop xanthelasmata, flat yellowish patches around the eyelids. A whitish ring around the edge of the iris, called corneal arcus, is another telltale sign when it appears before age 45. Not everyone with FH develops these signs, but when they’re present, they’re strong indicators.
How FH Is Diagnosed
Diagnosis relies on a combination of cholesterol levels, family history, physical signs, and sometimes genetic testing. One widely used framework, the Dutch Lipid Clinic Network criteria, assigns points across several categories. For cholesterol alone, untreated LDL above 325 mg/dL earns 8 points, 251 to 325 mg/dL earns 5, 191 to 250 mg/dL earns 3, and 155 to 190 mg/dL earns 1. Points from other categories (family history of early heart disease, physical signs like tendon xanthomas, or a confirmed genetic mutation) are added together. A total above 8 points indicates a definite diagnosis, 6 to 8 is probable, and 3 to 5 is possible.
Genetic testing can confirm the diagnosis and identify the specific mutation, which becomes valuable for screening relatives. But a negative genetic test doesn’t rule FH out entirely, since not all causative mutations have been identified.
Screening Children and Family Members
The American Academy of Pediatrics recommends cholesterol screening for all children between ages 9 and 11. For children with a parent or grandparent who had early heart disease or known high cholesterol, screening can begin as early as age 2. Early detection matters because treatment in childhood can prevent decades of arterial damage.
Once someone in a family is diagnosed, cascade screening is the standard approach. This starts with first-degree relatives: parents, siblings, and children of the diagnosed person. If the affected parent is identified, testing expands to as many relatives on that side of the family as possible, including the children of the affected parent’s siblings. Screening can involve a simple cholesterol blood test, genetic analysis, or both. Because FH follows a predictable inheritance pattern, each first-degree relative of someone with heterozygous FH has a 50% chance of carrying the same mutation.
Treatment: Medications That Lower LDL
Diet and lifestyle changes alone cannot bring LDL levels into a safe range for people with FH. Medication is the cornerstone of treatment, and most people need it for life.
Statins are the first-line therapy and have been used for decades. For many people with heterozygous FH, a high-intensity statin combined with ezetimibe (a drug that blocks cholesterol absorption in the gut) provides a significant reduction but still may not reach target levels. That’s where newer drug classes come in.
PCSK9 inhibitors, given as injections every two to four weeks, work by blocking the protein that destroys LDL receptors, effectively keeping more receptors active on liver cells. In people with heterozygous FH, these drugs lower LDL by 50% to 60% on top of existing therapy. For homozygous FH, the response is smaller and more variable, averaging 20% to 35%, because there are fewer functional receptors to preserve.
A newer option called inclisiran works on the same pathway but through a different mechanism, silencing the gene that produces PCSK9. It requires only two injections per year after the initial doses, reducing LDL by about 48% in people with heterozygous FH. Bempedoic acid, taken as a pill, offers an additional 18% to 20% LDL reduction when added to statins and can be combined with ezetimibe for a stronger effect.
For homozygous FH, which responds poorly to standard therapies, additional options exist. One drug that blocks a protein involved in assembling cholesterol-carrying particles in the liver reduced LDL by 49% in clinical trials of homozygous patients already on other medications. Another oral medication reduced LDL by a median of 33% overall in a long-term registry, though side effects involving fat accumulation in the liver require monitoring.
The Role of Diet
Dietary changes support medication but cannot replace it in FH. Standard recommendations focus on limiting saturated fat from animal sources, including full-fat dairy, fatty cuts of meat, butter, lard, and poultry skin. Tropical oils like coconut and palm oil are also advised against. The emphasis is on substituting these with non-tropical vegetable oils, lean proteins, and low-fat dairy.
It’s worth understanding the scale of the problem: diet modifications typically lower LDL by 10% to 15% in the general population, while someone with heterozygous FH may need their LDL cut by 50% or more. Diet is a useful addition, not a solution on its own. Regular physical activity and maintaining a healthy weight contribute to overall cardiovascular health and can improve how well medications work, but the genetic nature of FH means that even people with excellent lifestyles will have high LDL without pharmacological treatment.