Familial Hypercholesterolemia: Symptoms, Types, Causes and Treatment

Familial Hypercholesterolemia (FH) is a common, yet often underdiagnosed, inherited disorder that dramatically raises cholesterol levels from birth and substantially increases the risk of early cardiovascular disease. Despite the seriousness of FH, timely diagnosis and tailored treatment can transform patient outcomes, often allowing individuals to lead longer, healthier lives. This article explores the symptoms, types, causes, and treatment approaches for FH, synthesizing the latest evidence to help patients, families, and clinicians understand and manage this condition effectively.

Symptoms of Familial Hypercholesterolemia

Familial Hypercholesterolemia often presents with subtle or even absent symptoms in its early stages, making awareness crucial for timely diagnosis. While elevated cholesterol is the hallmark, some people may develop visible signs or experience cardiovascular events earlier than expected. Understanding these symptoms is key to recognizing FH, especially in families with a history of premature heart disease.

Symptom	Description	Onset/Population	Source(s)
Elevated LDL-C	High "bad" cholesterol from birth	All ages	1,3,8
Xanthomas	Cholesterol-rich, yellowish skin/tendon bumps	Childhood/adulthood	2,6,16
Xanthelasmas	Yellowish cholesterol deposits around eyelids	Variable	2
Arcus corneae	Grayish-white ring around the cornea	Often in younger patients	2,16
Early CVD	Premature coronary artery/cardiovascular disease	Children to young adults	3,4,8

Table 1: Key Symptoms

Elevated LDL Cholesterol: The Silent Driver

• The defining feature of FH is markedly elevated low-density lipoprotein cholesterol (LDL-C) from birth, often exceeding 190 mg/dL in untreated adults and 160 mg/dL in children with heterozygous FH. In homozygous FH, levels can be much higher, sometimes double that of heterozygotes 1,4,8.
• Many individuals do not experience physical symptoms until cholesterol deposits or cardiovascular disease develops.

Skin and Tendon Manifestations

• Xanthomas are distinctive, painless, yellowish nodules or masses usually found on the Achilles tendons, elbows, knees, and hands. They are considered pathognomonic for FH, especially when seen in children or young adults 2,6,16.
• Xanthelasmas are yellow cholesterol deposits, typically around the eyelids, but are less specific, as they can also occur in non-FH hyperlipidemia 2.

Eye Findings

• Arcus corneae (or corneal arcus) appears as a grayish or white ring at the edge of the cornea. While it can occur with aging, its presence in younger individuals is suggestive of FH 2,16.

Early-Onset Cardiovascular Disease

• One of the most serious consequences of FH is the early development of atherosclerosis, which can lead to heart attacks, angina, or other cardiovascular events, sometimes even in childhood or early adulthood for the more severe forms 3,4,8.

Variability and Silent Progression

• The severity and presence of symptoms can vary widely, even among individuals with the same genetic mutation. Many people remain asymptomatic for years, underscoring the importance of family history and cholesterol screening 8,16.

Types of Familial Hypercholesterolemia

FH is not a single disease but a spectrum of related conditions with varying genetic backgrounds and clinical severities. Understanding the types of FH helps tailor management and anticipate risks.

Type	Genetic Basis	LDL-C Elevation	Clinical Severity	Source(s)
Heterozygous FH	1 mutation (dominant)	2–3x normal (190–400 mg/dL untreated)	High CVD risk (adult)	1,4,5
Homozygous FH	2 mutations (both)	4–6x normal (400–1000+ mg/dL untreated)	Severe, childhood CVD	1,2,4
Compound Heterozygous	2 different mutations	Similar to homozygous or intermediate	Variable	8
Oligogenic/Polygenic	Multiple gene variants	Varies, additive effects	Can be severe	7

Table 2: Types of Familial Hypercholesterolemia

Heterozygous Familial Hypercholesterolemia (HeFH)

• Caused by a single pathogenic mutation; inherited in an autosomal dominant fashion.
• Prevalence: 1 in 200 to 1 in 500 globally; higher in certain founder populations 1,4,5,8.
• LDL-C levels typically 2–3 times above normal.
• High risk of premature cardiovascular disease, usually manifesting in adulthood if untreated 4.

Homozygous Familial Hypercholesterolemia (HoFH)

• Results from inheriting pathogenic mutations from both parents.
• Much rarer: around 1 in 160,000 to 1 in 1,000,000 1,2,4.
• LDL-C levels can be 4 to 6 times the normal, often exceeding 400 mg/dL even in children.
• Severe skin and tendon xanthomas often appear in childhood, and untreated individuals may develop heart disease before the age of 20 2,4.

Compound Heterozygous FH

• Occurs when a person inherits two different mutations affecting cholesterol metabolism.
• Clinical severity varies—can resemble the homozygous form or be intermediate 8.

Oligogenic and Polygenic FH

• Multiple gene variants (beyond the classic FH genes) may interact to cause high LDL-C and increased cardiovascular risk.
• Oligogenic FH (with mutations in more than one gene) is associated with higher LDL-C and possibly higher risk than single-gene (monogenic) FH 7.
• Polygenic FH refers to the cumulative effect of several common genetic variants, each contributing a small effect 7.

Causes of Familial Hypercholesterolemia

FH is fundamentally a genetic disorder, most often inherited in an autosomal dominant fashion. The genetic underpinnings determine the severity, response to treatment, and risk of complications.

Cause / Gene	Role in Cholesterol Metabolism	Inheritance Pattern	Source(s)
LDLR mutations	Defective LDL receptor	Autosomal dominant	1,4,8,9
APOB mutations	Defective binding to LDL receptor	Autosomal dominant	1,9,10
PCSK9 mutations	Enhanced LDL receptor degradation	Autosomal dominant	1,9
LDLRAP1 mutations	Impaired LDL receptor internalization	Autosomal recessive	1,9
Polygenic factors	Multiple variants with additive effect	Polygenic	7

Table 3: Genetic Causes of FH

Mutations in LDLR Gene

• The most frequent cause, accounting for up to 80–90% of FH cases 1,8,9.
• LDLR encodes the low-density lipoprotein receptor—a key protein responsible for clearing LDL cholesterol from the bloodstream.
• Mutations reduce the number or function of LDL receptors, leading to accumulation of LDL-C.

Mutations in APOB Gene

• APOB encodes apolipoprotein B, which is essential for LDL particles to bind to their receptor.
• Mutations disrupt this binding process, so LDL particles cannot be effectively cleared 1,9,10.

Mutations in PCSK9 Gene

• PCSK9 regulates the degradation of LDL receptors.
• Gain-of-function mutations cause excessive breakdown of LDL receptors, reducing their numbers and increasing LDL-C 1,9.

Mutations in LDLRAP1 and Other Rare Genes

• Mutations in LDLRAP1 (LDL receptor adaptor protein 1) cause a rare, autosomal recessive form of FH 1,9.
• Other rare or accessory genes (e.g., APOE, LIPA, ABCG5/8) can mimic FH or contribute to oligogenic forms 7,11.

Inheritance Patterns

• Autosomal Dominant: Most cases, with a 50% chance of passing the mutation to offspring 1,9.
• Autosomal Recessive: Rare, requiring two copies of the faulty gene—much less common 1,9.
• Polygenic Inheritance: Multiple small-effect variants aggregate to cause a similar phenotype 7.

Environmental and Modifier Factors

• Diet, additional health conditions (e.g., diabetes), and the type of mutation can influence disease severity and response to treatment 5,15.

Treatment of Familial Hypercholesterolemia

Effective management of FH requires a lifelong, multi-faceted approach. The goal is to reduce LDL-C levels as much as possible to mitigate the risk of early heart disease. Recent advances in therapy have expanded options for even the most severe cases.

Therapy	Mechanism / Use	Typical LDL-C Reduction	Source(s)
Statins	Inhibit cholesterol synthesis	20–50%	8,14,16
Ezetimibe	Reduces intestinal cholesterol absorption	+15–20% (add-on)	8,15,17
PCSK9 inhibitors	Enhance LDL receptor recycling	50–60%	8,13,16,17
Bile acid sequestrants	Bind bile acids in gut, lower cholesterol	10–20%	2,8
LDL apheresis	Physically removes LDL from blood	Up to 60% (per session)	16,17
Lomitapide/MTP inhibitors	Inhibit lipoprotein assembly	30–50%	16,17
Inclisiran	siRNA to suppress PCSK9 production	~40% (biannual)	13
Lifestyle changes	Diet, exercise, weight management	Variable	8,17

Table 4: Treatment Options for Familial Hypercholesterolemia

Statins: The Foundation of Therapy

• Statins are the first-line therapy for nearly all patients with FH, shown to reduce LDL-C by 20–50% and dramatically lower the risk of cardiovascular events 8,14,16.
• Early initiation, even in children, can slow the progression of atherosclerosis and improve long-term outcomes 14.

Add-On and Advanced Therapies

• Ezetimibe: Often added to statins when LDL-C targets are not met, further lowering cholesterol by 15–20% 8,15,17.
• PCSK9 Inhibitors: Monoclonal antibodies (e.g., evolocumab, alirocumab) or siRNA (inclisiran) provide powerful LDL-C reduction (up to 60%), especially valuable for severe or resistant cases 8,13,16,17.
• Bile Acid Sequestrants: Used as adjuncts, though less potent and sometimes limited by gastrointestinal side effects 2,8.

Therapies for Severe FH and Drug-Resistant Cases

• LDL Apheresis: An extracorporeal process similar to dialysis, used primarily for homozygous FH or refractory heterozygous FH, removing LDL directly from the blood 16,17.
• Lomitapide (MTP inhibitors): Blocks the production of lipoproteins in the liver and intestine; reserved for severe FH, especially when other measures fail 16,17.

Lifestyle Modifications

• A heart-healthy diet, regular physical activity, and weight control are essential adjuncts to medical therapy, though rarely sufficient alone in FH 8,17.

Screening and Cascade Testing

• Early identification of affected family members through "cascade screening" is vital for timely intervention 1,8,16.

Treatment Targets

• LDL-C goals are stringent: <100 mg/dL for most adults with FH, <70 mg/dL if they have established heart disease or diabetes, and <135 mg/dL for children 17.
• Achieving these targets can be challenging; many require combination therapy 15,17.

Special Populations

• Children, pregnant women, and those with severe or drug-resistant FH should be managed in specialized lipid clinics 16.

Conclusion

Familial Hypercholesterolemia is a serious but manageable inherited cholesterol disorder. Early recognition, genetic insights, and evolving therapies have dramatically improved prognosis for those affected. By understanding the symptoms, types, genetic mechanisms, and treatment strategies, patients and clinicians can work together to prevent the devastating consequences of premature cardiovascular disease.

Key Takeaways:

• FH is a common inherited disorder with high LDL cholesterol from birth, often causing early heart disease if untreated 1,4,8.
• Symptoms may include skin/tendon xanthomas, xanthelasmas, arcus corneae, and most importantly, early-onset cardiovascular disease 2,3,4.
• There are several types, with heterozygous FH being the most common and homozygous FH being much more severe and rare 1,2,4,8.
• FH is usually caused by mutations in the LDL receptor gene, but other genes and combinations can contribute 1,9,10.
• Treatment requires aggressive LDL-C lowering, starting with statins, and often including ezetimibe, PCSK9 inhibitors, or advanced therapies for severe cases 8,13,16,17.
• Early diagnosis and family screening are crucial to prevent premature cardiovascular events and save lives 1,8,16.

By staying informed and proactive, individuals and families affected by FH can significantly reduce their risk and enjoy healthier, longer lives.