Familial Hypercholesterolemia: Causes and Care

What is familial hypercholesterolemia?

Familial hypercholesterolemia (FH) is an inherited condition that leaves the body unable to clear LDL cholesterol (LDL-C) from the blood efficiently, so LDL stays very high from birth. A change in the gene for the LDL receptor usually causes it, and it happens regardless of diet or exercise.

Because genes cause FH, it responds less to lifestyle changes than "normal" high cholesterol does. Someone with FH can eat well, exercise regularly, and still carry an LDL-C two to three times higher than average.

What is primary hypercholesterolemia, and how does it differ from secondary?

Primary hypercholesterolemia means high cholesterol that comes from your genes, and familial hypercholesterolemia is its best-known form. Secondary hypercholesterolemia comes from another condition or a medicine. StatPearls sorts the causes this way, and its last update was April 2023.

Primary causes include FH (changes in the LDL receptor, APOB, or PCSK9 genes, plus a rare recessive form) and polygenic hypercholesterolemia. StatPearls calls polygenic the most common form: many unidentified genetic factors combine with a sedentary lifestyle and a diet high in saturated and trans fats. Secondary causes include an underactive thyroid (hypothyroidism), nephrotic syndrome, cholestasis, pregnancy, and certain medicines such as cyclosporine, thiazides, and diuretics. History, a physical exam, and lab tests can usually sort these out.

Clinicians rule out secondary causes before they diagnose FH. A 2022 Korean consensus statement on FH lists the same checks, and it names two other inherited conditions to consider: sitosterolemia and familial combined hyperlipidemia. If your LDL runs high, ask your clinician to look for these first.

What causes familial hypercholesterolemia? The genes involved

FH is caused by a change in one of three genes that control how the liver clears LDL: most often LDLR (the LDL receptor), less often APOB (the protein on LDL particles that the receptor grabs), and rarely PCSK9 (a protein that breaks down LDL receptors). An expert panel convened by the Family Heart Foundation recommends that FH genetic testing cover all three genes, and become standard care for people with definite or probable FH and their at-risk relatives.

A gene change isn't always found. According to the CDC, about 60 to 80% of people with FH have an identifiable genetic change, so a negative test does not rule FH out.

How is FH inherited?

FH is autosomal dominant: one changed copy of the gene, from either parent, is enough to cause it. This usual form is called heterozygous FH (HeFH). That means each child of a parent with FH has a 50% chance of inheriting it, and brothers and sisters of someone with FH have the same 50% chance. Inheriting a changed copy from both parents causes homozygous FH, a much rarer and more severe form that needs specialized care from childhood.

Because of this predictable pattern, finding FH in one person matters for the whole family. Once a gene change is known, relatives can be tested for that exact change, a process called cascade screening.

How common is FH, and why do doctors miss it?

FH affects about 1 in 250 to 1 in 313 people, making it one of the most common genetic conditions in medicine, yet it remains underdiagnosed. A 2017 meta-analysis of about 2.5 million people put it at 1 in 250, and a 2020 analysis of nearly 11 million put it at 1 in 313 (the CDC uses 1 in 311).

FH is far more common in some groups than in the general population. In that same 2020 analysis, about 1 in 15 people with premature heart disease and about 1 in 14 people with an LDL-C of 190 mg/dL or higher had FH.

How do you know if you have genetic high cholesterol? Signs that point to FH

Several findings together should raise suspicion of FH, since one sign alone rarely confirms it:

• LDL-C of 190 mg/dL or higher in an adult, or 160 mg/dL or higher in a child, without an obvious secondary cause
• A parent, sibling, or child with a heart attack or stroke before age 55 (men) or 65 (women)
• A close relative already diagnosed with FH or known to have very high cholesterol
• Physical signs in some patients: tendon xanthomas (cholesterol deposits, often in the Achilles tendon or knuckles), or a corneal arcus (a pale ring around the iris) appearing before age 45

How is FH diagnosed?

FH is usually diagnosed from your LDL level, family history, and physical exam, with genetic testing to confirm it when available. Clinicians often use a scoring system like the Dutch Lipid Clinic Network criteria, which weighs all of these together, since not everyone with clinically obvious FH will have a gene change identified on a genetic panel. The first step is a lipid panel, ideally with ApoB and Lp(a), since Lp(a) is a separate inherited risk factor for early heart disease.

Genetic testing can confirm a diagnosis and is increasingly used to test at-risk family members once one person in a family is identified. Our guide on whether high cholesterol is genetic covers the other inherited patterns, including polygenic high cholesterol.

How is FH treated? What to do about genetic high cholesterol

FH usually needs more LDL lowering than a single standard statin dose provides, because the starting LDL is so high. A statin may produce the same percentage reduction it would in anyone else, but a 50% reduction from an LDL-C of 250 mg/dL still leaves someone at 125 mg/dL, well above target for a person who has effectively had decades of extra cholesterol exposure.

In a Dutch study that followed 2,146 people with FH for about 8.5 years, statin treatment lowered the risk of coronary heart disease by 76%, and heart attack risk in treated patients was no longer significantly different from the general population.

Effective treatment for FH often means combination therapy early on:

• High-intensity statin plus ezetimibe as a baseline when LDL starts very high
• PCSK9 inhibitors, the most effective add-on for reaching target LDL-C, and needed more often in FH than in the general population. Options include Repatha and Praluent (injections every 2 to 4 weeks), Lerochol (a once-monthly injection), and Lipfendra (a daily pill); Lerochol and Lipfendra are both FDA-approved for adults with high cholesterol, including FH (see our Lerochol and Lipfendra guides). See how a PCSK9 inhibitor prescription works.
• Bempedoic acid or inclisiran for some people, especially when statins aren't tolerated. See alternatives to statins.
• Earlier treatment overall: because cholesterol exposure in FH starts at birth, treatment often begins in childhood or early adulthood rather than waiting for standard risk-based thresholds

Summary

Familial hypercholesterolemia is common, often undiagnosed, and very treatable once it is recognized as genetic. If early heart disease runs in your family alongside a very high LDL-C, that combination deserves a direct conversation about FH and a treatment plan with a specific LDL target.

At Preval Health, a family history of early cardiovascular disease is one of the clearest reasons to build a combination treatment plan from the start. A board-certified preventive cardiologist wrote our protocols, and licensed clinicians through our partner telehealth network deliver the care. Optional longevity genetic testing, offered at the first visit, includes the FH genes.