Familial Hypercholesterolemia (FH)

How FH affects cholesterol

LDL cholesterol is normally removed from the blood by LDL receptors on liver cells. In FH, a change in one of the genes that controls this process, most often the LDLR gene, and less often APOB or PCSK9, means fewer working receptors. LDL builds up in the blood from birth and is deposited in artery walls, causing atherosclerosis much earlier than usual.

Types

FH is inherited in an autosomal dominant way: each child of a parent with heterozygous FH has a 1 in 2 chance of inheriting it.

Signs and symptoms

Most people with FH feel well and have no visible signs. Clues include:

• very high LDL cholesterol on a blood test
• family history of very high cholesterol or early heart attacks
• tendon xanthomas: firm, yellowish lumps on the Achilles tendons, knuckles or elbows
• xanthelasma: yellow, flat patches on the eyelids
• corneal arcus: a white or gray ring around the iris before age 45
• early chest pain on exertion (angina) or heart attack

Diagnosis

FH is diagnosed using cholesterol levels, family history and physical signs, with genetic testing to confirm:

• Blood test: a lipid panel showing high LDL, with normal triglycerides in most cases.
• Clinical criteria: such as the Dutch Lipid Clinic Network or Simon Broome criteria, which score cholesterol levels, family history and signs.
• Genetic testing: finds a disease-causing variant in many people with clinical FH. A negative test does not rule FH out.

Secondary causes of high cholesterol, such as hypothyroidism, kidney disease, liver disease and some medicines, are checked and excluded.

Screening children and relatives

• Universal screening: the American Academy of Pediatrics recommends a cholesterol test for all children between ages 9 and 11, and again between 17 and 21.
• Earlier testing from age 2 is recommended if a parent has FH or there is a family history of early heart disease.
• Cascade screening: when one person is diagnosed, all first-degree relatives (parents, siblings, children) should be tested, then their relatives in turn.

Treatment

The goal is to lower LDL as much as possible, as early as possible. Typical targets are an LDL reduction of at least 50 percent, and LDL below 100 mg/dL (2.6 mmol/L), or below 70 mg/dL (1.8 mmol/L) or lower for people who already have heart disease.

Lifestyle

Lifestyle helps but is never enough on its own in FH:

• a heart-healthy diet low in saturated fat, rich in vegetables, whole grains, legumes, nuts and fish
• regular physical activity
• no smoking
• managing blood pressure, weight and diabetes

Medicines

• Statins: the first treatment. High-intensity statins for adults. In children with FH, statins are usually started around age 8 to 10.
• Ezetimibe: reduces cholesterol absorption from the gut. Added when statins alone are not enough.
• PCSK9 inhibitors: injectable antibodies (evolocumab, alirocumab) that greatly increase LDL clearance, or inclisiran, an injection given twice a year.
• Bempedoic acid: an oral option, especially for people who cannot tolerate statins.
• Bile acid sequestrants: an older option.

Homozygous FH

Needs specialist care with combinations of medicines, plus treatments such as evinacumab, lomitapide and LDL apheresis, a blood-filtering procedure every 1 to 2 weeks. Liver transplantation is used rarely.

Pregnancy

Statins are usually stopped before conception and during pregnancy and breastfeeding. Plan pregnancy with your doctor.

Outlook

With early diagnosis and treatment, people with FH can have a near-normal life expectancy. Studies show that children with FH who start statins have a dramatically lower risk of coronary artery disease in adulthood than their untreated parents had. The earlier treatment starts, the greater the benefit.

Frequently asked questions

What are the symptoms of familial hypercholesterolemia?

Most people have no symptoms until they develop heart disease. Possible signs include very high LDL cholesterol, yellowish lumps on tendons (xanthomas), yellow patches on the eyelids, a gray ring around the iris before 45, and a family history of early heart attacks.

How is familial hypercholesterolemia different from regular high cholesterol?

Regular high cholesterol usually develops in adulthood due to diet, weight and other factors. FH is genetic, causes much higher LDL from birth, and leads to heart disease decades earlier. It needs medicine, not just lifestyle changes.

Can FH be cured?

No, but it can be very effectively treated. Statins and other cholesterol-lowering medicines, started early and taken lifelong, bring LDL down and greatly reduce the risk of heart attack and stroke.

Should my children be tested for FH?

Yes. If you have FH, each of your children has a 1 in 2 chance of inheriting it. Children can be tested from about age 2. Early diagnosis allows lifestyle changes and, if needed, statin treatment from around age 8 to 10.

What LDL level suggests familial hypercholesterolemia?

An untreated LDL of 190 mg/dL (4.9 mmol/L) or higher in an adult, or 160 mg/dL (4.1 mmol/L) or higher in a child, should raise suspicion of FH, especially with a family history of high cholesterol or early heart disease.