What are the differences between familial, pure, and mixed hyperlipidemia?

From the Guidelines

Familial, pure, and mixed hyperlipidemia differ primarily in their lipid profile patterns, genetic basis, and clinical manifestations, with familial hyperlipidemia being inherited disorders, pure hyperlipidemia involving elevation of a single lipid fraction, and mixed hyperlipidemia featuring simultaneous elevation of multiple lipid fractions. The main types of familial hyperlipidemia include familial hypercholesterolemia (elevated LDL cholesterol), familial hypertriglyceridemia (elevated triglycerides), and familial combined hyperlipidemia (elevated cholesterol and triglycerides) 1.

Key Differences

• Familial hypercholesterolemia is characterized by elevated LDL cholesterol levels, often requiring treatment with statins or other LDL-lowering therapies, such as ezetimibe (10mg daily) or PCSK9 inhibitors, as recommended by the American College of Cardiology 1.
• Familial hypertriglyceridemia involves elevated triglyceride levels, which may be managed with fibrates, such as fenofibrate (145mg daily), or omega-3 fatty acids (2-4g daily) 1.
• Familial combined hyperlipidemia features elevated levels of both cholesterol and triglycerides, often necessitating combination therapy, including a statin plus a fibrate or ezetimibe.

Clinical Implications

The distinction between these types of hyperlipidemia is crucial for determining cardiovascular risk, identifying potential genetic causes requiring family screening, and selecting appropriate treatment strategies. Lifestyle modifications, including diet changes, exercise, and weight management, are foundational treatments for all types of hyperlipidemia. According to the European Guidelines on cardiovascular disease prevention in clinical practice, familial combined hyperlipidemia is likely to be more polygenic/multifactorial than familial hypercholesterolemia, and its diagnosis may involve the use of a nomogram to calculate the probability of being affected by FCHL 1.

Treatment Approaches

Treatment approaches vary based on the specific type of hyperlipidemia. For example, pure hypercholesterolemia often responds well to statins, while hypertriglyceridemia may require fibrates or omega-3 fatty acids. Mixed hyperlipidemia frequently requires combination therapy, such as a statin plus ezetimibe or a statin with a fibrate. The American Heart Association recommends that children with familial hypercholesterolemia be treated with statins, and that the diagnosis of familial hypercholesterolemia can be made clinically by observation of extreme abnormalities of the fasting lipoprotein levels in family members, combined with a positive family history of premature atherosclerotic cardiovascular disease and events 1.

Genetic Basis

The genetic basis of familial hyperlipidemia is complex, with multiple genes contributing to the development of these disorders. For example, familial combined hyperlipidemia has been associated with genetic variants in the APOA1/C3/A4/A5 cluster and the upstream stimulatory factor 1 (USF1) gene 1. The diagnosis of familial hypercholesterolemia can be confirmed by genetic testing, which is the criterion standard, although it is not widely available 1.

In summary, the accurate diagnosis and treatment of familial, pure, and mixed hyperlipidemia are crucial for reducing cardiovascular risk and improving patient outcomes, and should be based on the latest evidence and guidelines, such as those recommended by the American College of Cardiology and the American Heart Association 1.

From the FDA Drug Label

EZETIMIBE Tablets is indicated (1): • In combination with a statin, or alone when additional low density lipoprotein cholesterol (LDL-C) lowering therapy is not possible, as an adjunct to diet to reduce elevated LDL-C in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) • In combination with fenofibrate as an adjunct to diet to reduce elevated LDL-C in adults with mixed hyperlipidemia • In combination with a statin, and other LDL-C lowering therapies, to reduce elevated LDL-C levels in adults and in pediatric patients 10 years of age and older with homozygous familial hypercholesterolemia (HoFH)

The differences between familial, pure, and mixed hyperlipidemia are:

• Familial hyperlipidemia refers to a genetic disorder characterized by high levels of LDL-C, specifically heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH).
• Mixed hyperlipidemia is characterized by elevated levels of LDL-C and is treated with ezetimibe in combination with fenofibrate.
• Pure hyperlipidemia is not explicitly defined in the provided drug labels, but it can be inferred that it refers to primary hyperlipidemia, which includes HeFH and is treated with ezetimibe alone or in combination with a statin 2, 2, 2.

From the Research

Hyperlipidemia Types

The main difference between familial, pure, and mixed hyperlipidemia lies in their underlying causes, characteristics, and effects on lipid profiles.

• Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein (LDL) cholesterol, increased risk of cardiovascular disease, and a family history of hypercholesterolemia or premature cardiovascular disease 3.
• Pure hyperlipidemia refers to elevated levels of a single lipid component, such as hypercholesterolemia (elevated LDL cholesterol) or hypertriglyceridemia (elevated triglycerides) 4.
• Mixed hyperlipidemia is characterized by a combination of elevated LDL cholesterol and triglycerides, often seen in patients with familial combined hyperlipidemia (FCHL) 4.

Clinical Characteristics

The clinical characteristics of these hyperlipidemias differ:

• Familial hypercholesterolemia is often asymptomatic for decades but can lead to premature cardiovascular disease if left untreated 3.
• Pure hyperlipidemia may present with specific symptoms related to the elevated lipid component, such as xanthomas (fatty deposits under the skin) in hypercholesterolemia 4.
• Mixed hyperlipidemia often presents with a combination of symptoms related to both elevated LDL cholesterol and triglycerides, such as pancreatitis and cardiovascular disease 4.

Treatment Approaches

Treatment approaches for these hyperlipidemias vary:

• Familial hypercholesterolemia is typically treated with high-intensity statin therapy, often combined with ezetimibe, PCSK9 inhibitors, or other lipid-lowering agents 5, 6, 3, 7.
• Pure hyperlipidemia is treated based on the specific lipid abnormality, with options including statins, fibrates, nicotinic acid, or omega-3 fatty acids 4.
• Mixed hyperlipidemia is often treated with a combination of lipid-lowering agents, such as statins and fibrates, to address both elevated LDL cholesterol and triglycerides 4.