What is Familial Hyperlipidemia (Familial Hypercholesterolemia)?

From the Guidelines

Familial hyperlipidemia should be managed with a combination of lifestyle modifications and medications, prioritizing statin therapy as the first-line treatment, as recommended by the most recent guidance from the International Atherosclerosis Society in 2023 1. The primary goal of treatment is to reduce low-density lipoprotein (LDL) cholesterol levels, which are elevated in individuals with familial hyperlipidemia. According to the 2022 ACC expert consensus decision pathway, non-statin therapies such as ezetimibe, bile acid sequestrants, and PCSK9 inhibitors may be considered in addition to statins for patients who require further LDL cholesterol lowering 1. Key components of lifestyle modifications include:

• Following a heart-healthy diet low in saturated fats and cholesterol
• Exercising regularly
• Maintaining a healthy weight
• Avoiding smoking First-line medication therapy usually includes statins such as atorvastatin (20-80 mg daily) or rosuvastatin (10-40 mg daily), which reduce cholesterol production in the liver. For patients who cannot tolerate statins or need additional lipid lowering, ezetimibe (10 mg daily) may be added to reduce intestinal cholesterol absorption. In severe cases, PCSK9 inhibitors like evolocumab or alirocumab may be prescribed as injections every 2-4 weeks. Regular monitoring of lipid levels is essential, typically every 3-6 months after starting therapy, then annually once stable. Early diagnosis and treatment are crucial as familial hyperlipidemia significantly increases the risk of premature cardiovascular disease due to accelerated atherosclerosis from lifelong exposure to elevated lipid levels. The condition follows an autosomal dominant inheritance pattern, so family screening is recommended for first-degree relatives of affected individuals. It is also important to note that hyperlipidemias secondary to other diseases, such as hypothyroidism, kidney and liver diseases, and diabetes, should be excluded with an appropriate clinical assessment and tests before introducing drug therapy, as stated in the 2004 principles for national and regional guidelines on cardiovascular disease prevention 1.

From the Research

Definition and Epidemiology of Familial Hyperlipidemia

• Familial hypercholesterolemia (FH) is a genetic disorder of lipid metabolism characterized by significant elevation in levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary heart disease (CHD) 2.
• The average worldwide prevalence of heterozygous familial hypercholesterolemia is at least 1 in 500, although recent genetic epidemiological data suggest the frequency may be closer to 1 in 250 3.
• Familial combined hyperlipidemia (FCH) is a frequent disorder associated with premature coronary artery disease, transmitted in an autosomal dominant manner, and often associated with type 2 diabetes mellitus, arterial hypertension, and central obesity 4.

Risk Factors and Clinical Management

• Patients with FH are at very high risk for premature CHD, and early identification and aggressive treatment are necessary to minimize this risk 2.
• The therapeutic approach for FH must be complex and comprehensive, with high-intensity statin therapy usually combined with ezetimibe and possibly complemented with bile acid sequestrant 5.
• Patients with FCH require lipid-lowering treatment using potent statins and sometimes combined lipid-lowering treatment, as well as management of other cardiovascular risk factors such as type 2 diabetes and hypertension 4.

Treatment Options

• Statins are the mainstay treatment for hyperlipidemia, but patients with FH may require higher doses of statins, more potent statins, statin-based combination therapy, or adjunctive therapies such as niacin, bile acid sequestrants, fibric acids, and ezetimibe 6.
• New treatment approaches for FH include mipomersen, lomitapide, and proprotein convertase subtilisin/kexin type 9 inhibitors, which may be used in addition to high-dose statins or other agents 6, 2.
• Statin treatment is an effective lipid-lowering therapy in children with familial hypercholesterolemia, with few or no safety issues identified in short-term studies, but long-term safety remains unknown 3.

Diagnosis and Screening

• Diagnosis of familial hypercholesterolemia in children is based on elevated total cholesterol and low-density lipoprotein cholesterol levels or DNA-based analysis, or both 3.
• Early identification and screening of all first-degree relatives are recommended to minimize the risk for premature CHD in patients with FH 2.