Familial HypercholesterolemiaUnderstanding Inherited High Cholesterol

Familial hypercholesterolemia (FH) is a genetic condition that causes dangerously high LDL cholesterol from birth. Unlike typical high cholesterol that develops with age and lifestyle, people with FH are born with impaired cholesterol processing. Without treatment, they face dramatically elevated risk of early heart disease—many experience heart attacks in their 30s, 40s, or even younger.

FH affects approximately 1 in 250 people—making it one of the most common serious genetic disorders. Yet it remains vastly underdiagnosed. More than 90% of people with FH don't know they have it. This guide explains what FH is, how to recognize it, and why early diagnosis and treatment are crucial for preventing heart disease.

What Is Familial Hypercholesterolemia?

FH is caused by mutations in genes that control how your body removes LDL cholesterol from the bloodstream. The most common mutations affect:

• LDLR gene: Makes LDL receptors that pull LDL from blood into cells (most common)
• APOB gene: Makes the protein on LDL that binds to receptors
• PCSK9 gene: Regulates how many LDL receptors are on cell surfaces

When these genes don't work properly, LDL accumulates in the blood at levels 2-4 times higher than normal. This cholesterol deposits in artery walls from childhood onward, causing premature atherosclerosis.

Two Forms of FH

Type	Inheritance	Typical LDL	Prevalence	Risk
Heterozygous FH	One mutated gene	190-400 mg/dL	1 in 250	Heart disease 10-20 years early
Homozygous FH	Two mutated genes	400-1000+ mg/dL	1 in 250,000	Heart disease in childhood/teens

Heterozygous FH (one abnormal gene) is much more common. Homozygous FH (two abnormal genes) is rare but extremely severe, often causing heart attacks in childhood without aggressive treatment.

Signs and Symptoms

FH itself causes no symptoms until heart disease develops. However, very high cholesterol can produce visible physical signs:

Physical Signs of FH

• Tendon xanthomas: Cholesterol deposits in tendons, especially the Achilles tendon and tendons on the back of the hand. They feel like bumps or thickening.
• Xanthelasmas: Yellowish, flat cholesterol deposits around the eyelids
• Corneal arcus: A grayish-white ring around the colored part of the eye (iris); significant if appearing before age 45

Not everyone with FH develops these signs, and their absence doesn't rule out the condition. Many people with FH have no visible signs at all.

Warning Signs in Family History

FH should be suspected if you or family members have:

• Very high LDL cholesterol (over 190 mg/dL in adults, over 160 in children)
• Heart attack or coronary artery disease before age 55 in men or 65 in women
• Multiple generations with high cholesterol or early heart disease
• Cholesterol that doesn't respond well to typical treatments

Diagnosis

Clinical Criteria

Doctors use several scoring systems to diagnose FH. The most common considers:

• LDL cholesterol level: Higher levels score more points
• Physical signs: Tendon xanthomas, corneal arcus
• Family history: Early heart disease or high cholesterol in relatives
• Personal history: Early cardiovascular disease

A definite diagnosis can be made when LDL is very high and other criteria are met, even without genetic testing.

Genetic Testing

Genetic testing can confirm FH and identify the specific mutation. This is valuable because:

• It provides definitive diagnosis when clinical criteria are borderline
• It allows cascade screening—testing family members for the same mutation
• Finding a mutation in one person identifies a 50% risk in first-degree relatives
• Some insurance coverage and treatments depend on confirmed genetic diagnosis

Genetic testing finds a mutation in about 60-80% of clinically diagnosed FH cases. A negative test doesn't rule out FH—some mutations haven't been identified yet.

Cascade Screening

When someone is diagnosed with FH, all first-degree relatives should be tested. Parents, siblings, and children each have a 50% chance of having the same mutation. Identifying affected family members allows early treatment before heart disease develops.

Treatment

FH requires aggressive treatment because the cardiovascular risk is so high. Lifestyle changes alone are rarely sufficient—most people with FH need medication, often multiple medications.

Treatment Goals

• LDL reduction of at least 50% from untreated levels
• LDL under 100 mg/dL for most adults with FH
• LDL under 70 mg/dL for those with existing heart disease

Medications

Statins

High-intensity statins are the foundation of FH treatment. Most people with FH need maximum doses of potent statins (atorvastatin 40-80 mg or rosuvastatin 20-40 mg). Statins typically lower LDL by 50% or more.

Ezetimibe

Ezetimibe blocks cholesterol absorption in the intestine and is usually added to statin therapy. The combination provides an additional 15-20% LDL reduction beyond statins alone.

PCSK9 Inhibitors

PCSK9 inhibitors (evolocumab, alirocumab) are injectable medications that dramatically lower LDL—often by an additional 50-60% on top of statins. They're particularly valuable for FH patients who can't reach goals with oral medications. These drugs have revolutionized FH treatment.

Other Options

• Bile acid sequestrants: Older medications that can add modest LDL reduction
• Bempedoic acid: Newer option for those who can't tolerate statins
• Inclisiran: New injectable given only twice yearly

LDL Apheresis

For homozygous FH or severe heterozygous FH that doesn't respond adequately to medications, LDL apheresis is an option. This procedure, similar to dialysis, physically removes LDL from the blood every 1-2 weeks. It's time-consuming but can reduce LDL by 50-75% immediately after each treatment.

Lifestyle Measures

While lifestyle changes alone can't control FH, they still contribute to cardiovascular protection:

• Heart-healthy diet low in saturated fat
• Regular physical activity
• Not smoking (extremely important)
• Maintaining healthy weight
• Managing other risk factors (blood pressure, blood sugar)

FH in Children

Children with FH should be identified and treated early. Guidelines recommend:

• Screening by age 2 if a parent has FH or very high cholesterol
• Lifestyle changes starting immediately upon diagnosis
• Medication consideration starting at age 8-10

Studies show that starting statin treatment in childhood significantly reduces cardiovascular events in adulthood. Children on statins show slowed progression of arterial thickening and better outcomes than those who start treatment later.

Living with FH

Prognosis with Treatment

With modern treatment, people with FH can have near-normal life expectancy. The key is early diagnosis and consistent treatment. Untreated men with FH have a 50% chance of heart attack by age 50; treated individuals have dramatically better outcomes.

Monitoring

Regular follow-up is essential:

• Lipid panels every 3-12 months depending on treatment status
• Cardiovascular imaging to assess arterial health
• Monitoring for medication side effects
• Assessment of other cardiovascular risk factors

Family Planning Considerations

If you have FH, each child has a 50% chance of inheriting it. Genetic counseling can help you understand the implications and options. Women with FH need special planning around pregnancy, as statins must be stopped during pregnancy and breastfeeding.