Hypercholesterolemia: Types, Causes and Treatment

What hypercholesterolemia means

Cholesterol is a fat-like substance that the body needs for cell walls and hormones. It travels in the blood in particles called lipoproteins:

• LDL (low-density lipoprotein): carries cholesterol into artery walls; high levels drive plaque. This is what "hypercholesterolemia" mainly refers to.
• HDL (high-density lipoprotein): carries cholesterol away; higher is generally better.
• Non-HDL cholesterol and apolipoprotein B (apoB): measure all the particles that can cause plaque.
• Lipoprotein(a): a mostly inherited particle that adds extra risk.

Doctors sometimes use pure hypercholesterolemia when LDL is high but triglycerides are normal, and mixed hyperlipidemia when both are raised. For the wider picture including triglycerides, see hyperlipidemia. For everyday information on numbers and lifestyle, see high cholesterol.

LDL cholesterol levels

The number that matters for treatment also depends on your other risks: age, blood pressure, diabetes, smoking, kidney disease and family history.

Primary hypercholesterolemia

Polygenic (common) hypercholesterolemia

Most people with high LDL have many small genetic variants that each nudge LDL up, combined with diet (saturated and trans fats), excess weight and inactivity. It usually appears in adulthood.

Familial hypercholesterolemia

Familial hypercholesterolemia (FH) is caused by a single gene change, most often in the LDL receptor gene, that stops the liver clearing LDL. It affects about 1 in 250 people. LDL is high from birth, often above 190 mg/dL in adults, and heart attacks can occur in the 30s to 50s without treatment. Tendon xanthomas (lumps on the Achilles tendon or knuckles) are a strong clue.

Other inherited types

Familial combined hyperlipidemia raises both LDL and triglycerides and runs in families with early heart disease. High lipoprotein(a) is inherited separately and is measured once in adulthood in many guidelines.

Secondary hypercholesterolemia

Before labeling high cholesterol as primary, doctors look for treatable causes:

Treating the cause, for example thyroid hormone replacement, can bring LDL down substantially.

Symptoms and signs

Hypercholesterolemia causes no symptoms. It is found on a blood test, or after a complication such as coronary artery disease, heart attack, stroke or peripheral artery disease. Very high, long-standing levels can cause:

• xanthomas: yellowish lumps on tendons, elbows or knuckles
• xanthelasma: soft yellow patches on the eyelids (also seen with normal cholesterol)
• corneal arcus: a white or gray ring around the iris before about age 45

How it is diagnosed

1. Lipid panel: total cholesterol, LDL, HDL and triglycerides. Fasting is not usually needed unless triglycerides are high.
2. Repeat test to confirm an abnormal result.
3. Secondary-cause screen: TSH, glucose or HbA1c, kidney and liver function, urine protein.
4. Risk assessment: the 10-year risk of heart attack or stroke is estimated with a calculator (such as the AHA PREVENT equations in the US).
5. Additional tests if risk is unclear: lipoprotein(a), apoB, and a coronary artery calcium (CAC) CT scan.
6. Genetic testing and family screening if FH is suspected.

Treatment

Lifestyle

• Replace saturated fats (fatty meat, butter, full-fat dairy, coconut and palm oil) with unsaturated fats (olive and canola oil, nuts, oily fish).
• Eat more soluble fiber (oats, beans, lentils, barley, fruit); plant sterols can add a modest reduction.
• Exercise about 150 minutes a week, lose weight if needed, stop smoking, limit alcohol.

Lifestyle changes typically lower LDL by about 10% to 20%; genetic types usually need medicine as well.

Medicines

• Statins: first-line; lower LDL by about 30% to 50% or more and reduce heart attacks and strokes. Muscle aches are the most common complaint; true statin muscle damage is rare.
• Ezetimibe: blocks cholesterol absorption; added when LDL stays above target.
• PCSK9 inhibitors (injections every 2 to 4 weeks) and inclisiran (an injection twice a year): lower LDL by about 50% to 60%.
• Bempedoic acid: an oral option for people who cannot take statins.
• Specialist treatments such as LDL apheresis for severe homozygous FH.

Who is treated, and to what target

The ACC/AHA guideline recommends statins for adults with LDL of 190 mg/dL or more, people with established cardiovascular disease, people aged 40 to 75 with diabetes, and others based on their 10-year risk. People with existing heart disease are often aimed at an LDL below 70 mg/dL (1.8 mmol/L), and European guidelines set lower targets (below 55 mg/dL, 1.4 mmol/L) for very high risk.

Frequently asked questions

What is the difference between hypercholesterolemia and hyperlipidemia?

Hypercholesterolemia means high cholesterol, usually high LDL. Hyperlipidemia is a broader term for high blood fats of any type, including cholesterol, triglycerides or both. All hypercholesterolemia is a form of hyperlipidemia, but not all hyperlipidemia involves high cholesterol.

What is pure hypercholesterolemia?

Pure hypercholesterolemia is a raised LDL cholesterol with normal triglycerides. It is the coding term doctors often use for common high cholesterol and for familial hypercholesterolemia. Mixed hyperlipidemia means both LDL and triglycerides are high.

What causes secondary hypercholesterolemia?

The most common causes are an underactive thyroid, nephrotic syndrome and other kidney disease, cholestatic liver disease, poorly controlled diabetes, pregnancy and certain medicines such as steroids, some diuretics and retinoids. Treating the cause can lower cholesterol without extra medicine.

Is LDL of 190 dangerous?

An LDL of 190 mg/dL (4.9 mmol/L) or more is considered severe and often reflects a genetic cause such as familial hypercholesterolemia. It significantly raises lifetime heart risk, and guidelines recommend a high-intensity statin for most adults at this level, plus testing of close relatives.

Can hypercholesterolemia be cured?

Secondary hypercholesterolemia can resolve if the cause is treated. Primary hypercholesterolemia is usually lifelong, but it can be controlled. Lowering LDL with lifestyle changes and medicines reduces plaque build-up, and very low LDL levels can even help stabilize existing plaque.