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Homozygous Familial Hypercholesterolaemia (HoFH)

Homozygous familial hypercholesterolaemia (HoFH) is a rare, inherited metabolic disorder characterised by extremely high LDL cholesterol levels and a very high risk of early cardiovascular disease.

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Homozygous familial hypercholesterolaemia (HoFH) is a rare, inherited metabolic disorder characterised by extremely high LDL cholesterol levels and a very high risk of early cardiovascular disease.

What is homozygous familial hypercholesterolaemia?

Homozygous familial hypercholesterolaemia (HoFH) is a rare, genetically inherited metabolic disorder in which the body is unable to adequately clear LDL cholesterol (so-called “bad” cholesterol) from the bloodstream. Affected individuals inherit a defective gene copy from both parents, resulting in a particularly severe form of the condition. HoFH occurs in approximately 1 in 300,000 to 1 in 1,000,000 individuals and represents a medical emergency if left untreated.

Causes

HoFH is caused by mutations in genes encoding the LDL receptor or closely related proteins. The following genes may be affected:

LDLR (LDL receptor gene): the most common cause
APOB (apolipoprotein B): impaired binding of LDL to the receptor
PCSK9: increased degradation of LDL receptors
LDLRAP1 (LDL receptor adaptor protein 1): disruption of receptor function

Since both copies of the affected gene are defective (homozygous), the clearance of LDL from the blood is severely impaired or completely absent.

Symptoms

The clinical signs of HoFH result from years of excess cholesterol depositing in tissues and blood vessel walls:

Xanthomas: cholesterol deposits in tendons (e.g., Achilles tendon) and under the skin, often appearing in childhood
Xanthelasmas: yellowish deposits on the eyelids
Arcus lipoides corneae: a whitish ring around the cornea of the eye
Premature atherosclerosis: narrowing of blood vessels, often beginning in childhood or adolescence
Coronary artery disease (CAD): heart attacks can occur as early as 10–20 years of age
Aortic stenosis: narrowing of the aortic valve due to cholesterol deposits

Diagnosis

The diagnosis of HoFH is based on a combination of clinical findings, laboratory values, and genetic testing:

Lipid profile: LDL cholesterol levels typically > 400 mg/dL (10 mmol/L), often between 500 and 1,000 mg/dL
Family history: both parents usually have heterozygous familial hypercholesterolaemia (HeFH)
Genetic testing: identification of biallelic mutations in LDLR, APOB, PCSK9, or LDLRAP1
Clinical scoring systems: e.g., the Dutch Lipid Clinic Network Score or Simon Broome criteria
Imaging: echocardiography, carotid ultrasound, and CT angiography to assess vascular and cardiac damage

Treatment

Treatment of HoFH is complex and often requires a combination of several therapeutic strategies, as standard statin therapy alone is less effective in this form of the disease:

Pharmacological therapy

Statins (high-dose): reduce hepatic cholesterol synthesis; often insufficient as monotherapy in HoFH
Ezetimibe: inhibits intestinal cholesterol absorption and is frequently combined with statins
PCSK9 inhibitors (e.g., evolocumab, alirocumab): monoclonal antibodies that slow LDL receptor degradation; effective when residual receptor activity is present
Lomitapide: inhibits microsomal triglyceride transfer protein (MTP), reducing the production of LDL precursors in the liver
Evinacumab: antibody targeting angiopoietin-like protein 3 (ANGPTL3); effective even in the absence of LDL receptor function
Inclisiran: siRNA-based therapy for PCSK9 inhibition

LDL apheresis

LDL apheresis is an extracorporeal blood purification procedure in which LDL cholesterol is directly removed from the blood. It is a key pillar of treatment for HoFH patients and is typically performed every 1–2 weeks. In many countries, this procedure is covered by public health insurance.

Liver transplantation

In severe cases that do not respond adequately to other therapies, liver transplantation may be considered, as the liver is the primary site of LDL receptor-mediated cholesterol clearance. Transplantation normalises LDL receptor function and leads to a significant reduction in LDL levels.

Lifestyle modifications

A diet low in cholesterol and saturated fats combined with regular physical activity are supportive measures, but cannot compensate for the underlying genetic defect on their own.

Prognosis

Without treatment, individuals with HoFH face an extremely high risk of life-threatening cardiovascular events even during childhood and adolescence. However, early diagnosis and consistent treatment can significantly improve the prognosis. Lifelong regular cardiological monitoring is essential.

References

Cuchel M et al. - Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. European Heart Journal, 2014; 35(32): 2146–2157.
European Atherosclerosis Society Consensus Panel - Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population. European Heart Journal, 2013; 34(45): 3478–3490.
Watts GF et al. - Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. International Journal of Cardiology, 2014; 171(3): 309–325.

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