Introduction

Hyperlipidemia, sometimes referred to as dyslipidemia, occurs when blood lipid or lipoprotein levels are unusually high. Triglycerides and cholesterol are the main components of these lipids and they are very important to maintain regular physiological processes. They can cause life-threatening conditions when their concentrations exceed normal limits. In certain people, the genetic profile plays a major role in hyperlipidemia; in addition, lifestyle variables like diet, inactivity, and certain health conditions frequently contribute to the development of this condition. One of the most well-known and clinically relevant hereditary lipid disorders among the genetic causes is familial hypercholesterolaemia (FH).

Mutations in genes related to lipid metabolism are usually the root cause of genetic types of hyperlipidemia, also known as primary hyperlipidemias. In particular, atherosclerosis and coronary artery disease are at a much higher risk of developing in patients if these problems are not identified and treated early.

One well-known example of a monogenic condition that results in hyperlipidemia is familial hypercholesterolaemia. The hallmark of this condition is a significant rise in low-density lipoprotein cholesterol (LDL-C), also known as "bad cholesterol", as a result of its impaired clearance from the blood. There are two genetic forms of this condition: heterozygous and homozygous. The latter is far more severe. Although heterozygous FH is rather common, affecting around 1 in 250 persons worldwide, it is frequently misdiagnosed and receives inadequate treatment.¹

Overview of genetic disorders causing hyperlipidaemia

Genetic hyperlipidemias, or primary hyperlipidemias, cause abnormalities in the body's normal lipid metabolism, leading to high levels of triglycerides and/or cholesterol. Secondary hyperlipidemias are usually brought on by lifestyle choices or other medical conditions, including diabetes, obesity, or hypothyroidism.

Genetic lipid disorders can be classified into two major types: monogenic and polygenic hyperlipidaemias.

Monogenic hyperlipidaemia

A mutation in a single gene causes monogenic hyperlipidemia, which often has a distinct inheritance pattern (either autosomal dominant or recessive). These conditions can result in noticeably higher lipid levels and are frequently shown early in life. A well-known example is familial hypercholesterolemia.

Polygenic hyperlipidaemia

Polygenic hyperlipidemia results from the interaction of several genetic variants, each of which has a little impact. These variants, along with environmental and lifestyle factors, influence the overall lipid levels. While less severe than monogenic diseases, this variety is more prevalent.²

Common genetic lipid disorders

Familial hypercholesterolaemia (FH)

• Caused by mutations that alter the metabolism of LDL
• Raises LDL cholesterol and causes cardiovascular disease at an early age
• Both homozygous (severe) and heterozygous (mild to moderate) are possible

Familial combined hyperlipidaemia (FCHL)

• Characterised by high levels of triglycerides and/or LDL
• Frequently occurs when there’s a family history of early heart disease
• Multiple genes may be involved in this complex inheritance pattern

Familial dysbetalipoproteinaemia

• Caused by the APOE gene's abnormalities. This gene provides instructions for building apolipoprotein E, one of the main components of lipoproteins
• Causes the buildup of intermediate-density lipoproteins (IDL)
• Results in elevated triglyceride and cholesterol levels and may lead to tuberous xanthomas

Type I hyperlipoproteinaemia (familial chylomicronaemia syndrome)

• Resulting from changes in the LPL gene, which is involved in the breakdown of triglycerides in the bloodstream, or related cofactors
• Results in a risk of pancreatitis and abnormally elevated triglycerides
• Usually occurs in childhood and is uncommon

Type III hyperlipoproteinaemia

• Often brought on by homozygosity for APOE2
• Palmar xanthomas and elevated triglyceride and cholesterol levels are linked to it

Clinical characteristics, inheritance patterns, and health consequences vary across these illnesses. Nonetheless, the most common and thoroughly researched of them is familial hypercholesterolaemia, particularly with regard to its effects on cardiovascular health.²

Familial hypercholesterolaemia (FH)

FH can be classified into two genetic forms:

• Heterozygous FH (HeFH): one copy of the defective gene is inherited, leading to a moderate increase in LDL cholesterol levels
• Homozygous FH (HoFH): both copies of the gene are mutated, leading to extremely high cholesterol levels and a much higher risk of early cardiovascular events³

Epidemiology

Despite being one of the most prevalent hereditary diseases in the world, familial hypercholesterolaemia is frequently underdiagnosed. The heterozygous type of FH afflicts around 1 in 250 people globally; the more severe homozygous variant is far less common, affecting around 1 in 160,000 to 300,000 people. People with one parent who has FH have a 50% risk of developing it since the illness is inherited in an autosomal dominant way.⁴

Genetic basis of FH

The primary cause of FH is mutations in genes involved in lipid metabolism. 

LDLR (Low-Density Lipoprotein Receptor) gene

• LDL receptors interact with LDL cholesterol and help liver cells absorb it, which is how LDL cholesterol is eliminated from the circulation
• FH is characterised by a decreased ability to remove LDL due to mutations in the LDLR gene that affect these receptors' functionality. Consequently, LDL cholesterol builds up in the blood

APOB (Apolipoprotein B) gene

• The LDL particle contains a protein called apolipoprotein B, which attaches to the LDL receptor for clearance
• Ineffective LDL clearance may result from mutations in the APOB gene that affect the binding of LDL particles to the receptors

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) gene

• The quantity of LDL receptors on liver cells is controlled by a protein that is produced by the PCSK9 gene
• This gene's mutation can result in increased LDL receptor degradation, which further impairs the body's capacity to eliminate LDL cholesterol⁵

Pathophysiology of FH

To understand the underlying mechanism of FH, it is essential to first grasp the normal process of cholesterol metabolism.

Normal LDL metabolism

The liver produces LDL cholesterol, which is then carried by the circulation to other tissues. By recognising and binding to LDL particles, liver cells' LDL receptors enable the particles to be internalised and processed, lowering the quantity of LDL cholesterol in the blood. The body's lipid profile remains balanced because the liver produces less cholesterol once LDL is eliminated.

In familial hypercholesterolemia

Functional LDL receptors on liver cells are reduced when the LDLR gene is mutated. LDL particles are thus removed from the circulation in smaller amounts. Because of the substantial buildup of LDL cholesterol in the blood caused by the decreased LDL clearance, atherosclerosis, a condition in which fatty deposits form in the walls of arteries, occurs, narrowing them and raising the risk of heart attacks and strokes.⁶

Clinical features

The main symptom of familial hypercholesterolaemia (FH) is high LDL cholesterol, which can cause a number of clinical symptoms. Individuals who have not gotten early therapy or management tend to exhibit these traits more often. The onset of symptoms can differ based on whether an individual has homozygous FH (HoFH) or heterozygous FH (HeFH), with the latter exhibiting more severe symptoms and arriving at a significantly earlier age.

Elevated LDL cholesterol

The main characteristic of FH is elevated LDL cholesterol. This happens when LDL receptors are lacking or malfunctioning, which reduces the amount of LDL particles removed from the circulation. In FH patients:

• Heterozygous FH manifests with LDL values ranging from 190 to 400 mg/dL
• Homozygous FH frequently causes LDL levels to surpass 500 mg/dL. The disease is considerably more severe

These high LDL cholesterol levels considerably raise the risk of cardiovascular illnesses, especially atherosclerosis.

Early onset of atherosclerosis and cardiovascular disease

The slow accumulation of fatty deposits (plaques) in the artery walls, known as early-onset atherosclerosis, is a major worry for people with FH. Because of the consistently elevated LDL cholesterol, patients with FH, particularly those who have homozygous FH, are significantly more likely to develop cardiovascular illnesses like:

• Coronary artery disease (CAD)
• Heart attacks (myocardial infarction)
• Stroke

Xanthomas

A hallmark indicator of FH is deposits of cholesterol-rich material called xanthomas, which can develop in the tendons or beneath the skin. Usually seen around the eyes, elbows, knees, hands, and Achilles tendons, these deposits appear as yellowish-orange nodules or plaques. Different kinds of xanthomas exist.

• Tendinous xanthomas: typically appear as firm, yellowish lumps around tendons, especially the Achilles tendon or knuckles
• Eruptive xanthomas: small, red-yellow spots that appear on the skin, commonly on the buttocks or elbows
• Xanthelasma: soft yellow plaques around the eyelids

Corneal arcus

Arcus senilis, another name for corneal arcus, is a white or grey ring that develops around the eye's cornea. This illness is frequently linked to elevated cholesterol levels and is caused by cholesterol deposits. Even though corneal arcus can appear as people age, its occurrence in young people, particularly those under 40, is a symptom of FH.

Early-onset heart disease and other cardiovascular events

Cardiovascular problems, including angina, heart attacks, and heart failure, can happen extremely early in life in those with homozygous FH (typically before 20 years old). Due to their exceedingly high cholesterol, these people usually acquire atherosclerosis at a very young age, which can result in serious and sometimes fatal problems if aggressive treatment is not received.

Even in heterozygous FH, the risk for early cardiovascular disease is elevated, though it is less severe than in the homozygous form. Early identification and treatment are essential since untreated heterozygous FH patients may experience cardiovascular events in their 30s to 50s.

Family history of hyperlipidaemia and early heart disease

A familial history of high cholesterol and/or early heart disease is a crucial clinical characteristic of FH. FH should be suspected if there is a family history of early-onset atherosclerotic cardiovascular disease, such as heart attacks or strokes that happen before the age of 50.⁷

Diagnosis of FH

Clinical criteria

• Elevated LDL cholesterol and a family history of early heart disease are key signs
• Simon Broome and Dutch Lipid Clinic criteria help assess the likelihood of FH

Blood tests

• LDL cholesterol levels are typically >190 mg/dL in adults and >160 mg/dL in children
• Genetic testing confirms mutations in LDLR, APOB, or PCSK9 genes

Family screening

• Cascade screening is essential for identifying affected family members

Management of FH

Lifestyle modifications

• Diet: a heart-healthy diet low in saturated fats and cholesterol is crucial
• Exercise: regular physical activity can help manage cholesterol levels
• Weight management: maintaining a healthy weight is important for overall lipid control

Medications

• Statins: first-line treatment to lower LDL cholesterol by inhibiting cholesterol production in the liver
• Ezetimibe: often combined with statins to further reduce LDL cholesterol by blocking cholesterol absorption in the intestines
• PCSK9 inhibitors: used in more severe cases to lower LDL levels by preventing the degradation of LDL receptors
• Bile acid sequestrants: may be used in addition to statins to further reduce cholesterol levels

Advanced therapies

• LDL apheresis: a procedure to remove excess LDL cholesterol from the blood in severe cases of homozygous FH
• Liver transplant: a rare option for individuals with homozygous FH who do not respond to other treatments

Summary

The common and dangerous hereditary condition known as familial hypercholesterolemia (FH) raises LDL cholesterol levels and increases the risk of cardiovascular illnesses. The risk of heart disease and early mortality can be decreased with early identification and vigorous care, especially for those with the more severe homozygous FH.

The management of FH has greatly improved due to developments in genetic research, cholesterol-lowering drugs, and screening methods, which raise the prospect of better long-term results. To lessen the disorder's impact on people and families, however, broad awareness, early discovery through cascade screening, and prompt treatment are still essential.

The future of people with FH is bright due to ongoing research and developing of medications, as well as the continuous evolution of novel preventative measures and treatments. It is critical that the public and healthcare professionals understand the value of early FH management in order to enhance quality of life and avoid premature cardiovascular events.