Familial hypercholesterolemia (FH) is an inherited condition that causes dangerously high levels of LDL cholesterol from birth. Unlike typical high cholesterol caused by diet or lifestyle, FH is genetic: your body’s system for clearing LDL (“bad” cholesterol) from the bloodstream is fundamentally broken. Adults with FH typically have LDL levels above 190 mg/dL, and children above 160 mg/dL. Left untreated, this lifelong exposure to excess cholesterol leads to heart attacks and heart disease decades earlier than usual.
FH is also far more common than most people realize. The heterozygous form, where you inherit one faulty gene copy, affects roughly 1 in 250 to 300 people worldwide. That makes it one of the most common serious genetic conditions in humans, yet the majority of people who have it don’t know it.
How the Genetics Work
Your liver clears LDL cholesterol from your blood using receptors on the surface of liver cells. These receptors grab onto LDL particles, pull them inside the cell, and break them down. FH is caused by mutations that disrupt this process at one of three points.
The most common culprit is a mutation in the LDLR gene, which provides the blueprint for those LDL receptors. Some mutations prevent the receptor protein from reaching the cell surface at all. Others allow the receptor to form but change its shape so it can’t grab LDL particles effectively. Either way, LDL builds up in the bloodstream because the liver can’t pull it out fast enough.
The second most common cause involves the APOB gene. Every LDL particle has a protein on its surface called apoB-100, which acts like a docking connector that plugs into the liver’s LDL receptor. When APOB mutations alter that connector, LDL particles can’t latch on properly. These mutations tend to produce somewhat less severe cholesterol elevations than LDLR mutations.
A third gene, PCSK9, plays a regulatory role. Normally, it controls how many LDL receptors your liver keeps active. Certain gain-of-function mutations cause PCSK9 to destroy too many receptors, leaving fewer available to clear cholesterol.
Heterozygous vs. Homozygous FH
Since you inherit one copy of each gene from each parent, the severity of FH depends on how many faulty copies you receive. Most people with FH are heterozygous, meaning they have one working copy and one mutated copy. This form affects about 1 in 250 to 300 people. LDL levels are typically two to three times higher than normal, and without treatment, heart disease often develops in the 40s or 50s.
Homozygous FH is far rarer, occurring in roughly 1 in 250,000 to 360,000 people. These individuals inherited defective copies from both parents, leaving them with little to no ability to clear LDL. Their cholesterol levels can exceed 500 mg/dL, and without aggressive treatment, heart attacks can occur in childhood or the teenage years. Homozygous FH also causes severe physical changes, including cholesterol deposits throughout the body and damage to the aortic valve.
Physical Signs to Recognize
FH sometimes produces visible clues, especially when cholesterol has been severely elevated for years. Tendon xanthomas are firm, yellowish lumps that form where cholesterol accumulates in tendons. They appear most often on the hands (particularly over the knuckle joints), the Achilles tendons, and the elbows. Cutaneous xanthomas look like raised yellowish plaques on the skin, often painless and without itching. In severe cases, cholesterol deposits around finger joints can cause visible deformities that resemble rheumatoid arthritis.
Another sign is corneal arcus, a white or grayish ring around the edge of the iris. While this is common and harmless in older adults, corneal arcus appearing before age 45 is a red flag for FH. Not everyone with FH develops these physical signs, though. Many people have no visible symptoms at all, which is one reason the condition goes undiagnosed so often.
How FH Is Diagnosed
Doctors use a combination of cholesterol levels, physical findings, family history, and genetic testing to diagnose FH. The most widely used framework is the Dutch Lipid Clinic Network scoring system, which assigns points across several categories.
The highest-value indicators are an untreated LDL level above 325 mg/dL (8 points) and a confirmed mutation in one of the three FH genes (8 points). Tendon xanthomas score 6 points, and corneal arcus before age 45 scores 4 points. LDL between 251 and 325 mg/dL adds 5 points, while levels between 191 and 250 mg/dL add 3 points. Family history of early heart disease or very high cholesterol in a close relative adds 1 to 2 points depending on specifics.
- Definite FH: more than 8 points
- Probable FH: 6 to 8 points
- Possible FH: 3 to 5 points
Genetic testing can confirm the diagnosis definitively when a mutation is found, but not finding a mutation doesn’t rule FH out. Some mutations haven’t been identified yet, and the clinical diagnosis based on cholesterol levels and family history remains valid on its own.
Why Screening Families Matters
Because FH follows a simple inheritance pattern, each first-degree relative of someone with the heterozygous form has a 50% chance of also having it. This makes cascade screening, the practice of testing an affected person’s family members one by one, extremely effective at finding undiagnosed cases.
Once someone is diagnosed, screening starts with parents, siblings, and children. If one parent is found to carry the mutation, testing extends to that parent’s siblings and their children. Each newly diagnosed person then becomes the starting point for screening their own relatives, expanding the net outward through the family tree.
Screening can rely on cholesterol testing alone, but roughly 20% of people who carry FH mutations have only modestly elevated LDL levels, especially in adulthood. These individuals will be missed by cholesterol testing alone. When the specific mutation in a family is known, genetic testing of relatives gives an unambiguous yes-or-no answer.
For children, a National Heart, Lung and Blood Institute expert panel recommends universal lipid screening between ages 9 and 11, with a second round between 17 and 21. Some research suggests screening even earlier. A pilot study in Australia found that testing children aged 1 to 2 at routine immunization appointments was feasible and well-accepted by families, and combining this with cascade testing of parents identified cases faster than either approach alone.
Treatment Options
The cornerstone of FH treatment is statin therapy, which lowers cholesterol production in the liver and prompts it to pull more LDL from the blood. For many people with heterozygous FH, statins alone aren’t enough to reach safe LDL levels, so additional medications are layered on.
One common addition is ezetimibe, which blocks cholesterol absorption in the gut. Bempedoic acid works through a different step in the same cholesterol-production pathway that statins target, offering another oral option for people who need further lowering.
For patients whose LDL remains stubbornly high, injectable medications that block PCSK9 have been a significant advance. These drugs, given by injection every two to four weeks, reduce LDL by 50% to 60% in people with heterozygous FH. A newer option uses a different technology (small interfering RNA) to shut down PCSK9 production in the liver, requiring less frequent dosing.
Homozygous FH requires more aggressive intervention because the liver’s LDL receptors are absent or barely functional, making receptor-dependent treatments less effective. These patients often need a combination of multiple medications along with lipoprotein apheresis, a procedure similar to dialysis that mechanically filters LDL particles out of the blood. Lomitapide, an oral drug that prevents cholesterol-carrying particles from being assembled in the liver and intestines, is another option specifically for homozygous FH. A newer antibody treatment targeting a protein called ANGPTL3 works through a completely different pathway that doesn’t depend on functional LDL receptors, making it particularly relevant for the most severe cases.
Why Early Treatment Changes the Outcome
The damage from FH is cumulative. Every year of elevated LDL adds more cholesterol to artery walls, building up plaques that eventually restrict blood flow or rupture and cause a heart attack. The earlier treatment starts, the less total exposure your arteries endure over a lifetime. A person diagnosed and treated in childhood faces a dramatically different cardiovascular future than someone first treated in their 40s after a heart attack.
This is what makes FH different from ordinary high cholesterol. The cholesterol is elevated from birth, not from decades of dietary choices, so the clock starts ticking immediately. Identifying it early, whether through family screening or childhood lipid testing, is the single most impactful step in changing its course.