What Is Homozygous Familial Hypercholesterolemia?

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Homozygous familial hypercholesterolemia (HoFH) is a very rare genetic condition, affecting about one in 250,000 people.

This condition leads to extremely high LDL cholesterol levels, even in childhood and early adulthood. If left untreated, it can increase the risk of having an early cardiovascular event, such as a heart attack or stroke.

This article will review the symptoms, risk factors, and treatment protocol for HoFH.

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Homozygous Familial Hypercholesterolemia Symptoms

LDL cholesterol levels in someone with HoFH are sky-high, usually above 400 mg/dl. At these levels, cholesterol is seeping out of the skin, and the risk of having a cardiovascular event is high, even at a young age, without aggressive treatment.

In addition to elevated LDL cholesterol, symptoms of HoFH often include:

  • Xanthomas, or fatty yellow deposits under the skin: These may develop by early childhood and can be found on the skin of the hands, elbows, buttocks, and knees in a young child. They are diagnostic for this condition.
  • Corneal arcus, or deposits of cholesterol and triglycerides in the eye: These common deposits usually occur in an arc on either the top or bottom side of the iris (the colored part of the eye), inside the cornea.
  • Xanthelasmas, or cholesterol deposits in the eyelids
  • Chest pain: If left untreated, a person with HoFH may experience symptoms of coronary artery disease such as chest pain in their 20s. Very aggressive therapy is needed to reduce the likelihood of vascular events
  • Cramping of one or both calves when walking: Narrowing of blood vessels can lead to reduced blood flow in the extremities.
  • Poor wound healing and sores on the toes or heels
  • Sudden cardiac or cardiovascular events such as heart attack or stroke

Causes

HoFH is a rare disorder resulting from inheriting one gene mutation from each biological parent.

The most common cause of HoFH is genetic mutations of the LDL receptor (LDL‐R) gene—these make up 85% to 90% of cases.

The remaining 5% to 15% of cases are due to pathogenic variants of the APOB gene, resulting in decreased binding of LDL to the LDL‐R, or mutations in the gene for PCSK9, resulting in increased destruction of LDL receptors.

Of note, PCSK9 mutations are unique in that they do not result in loss of function. PCSK9, the enzyme that normally breaks down the cholesterol receptors after they have done their job, is actually turned on indefinitely.

Over time, the PCSKP mutation leads to overuse and excess degradation of LDL receptors. This creates a lack of LDL receptors, which means that “bad” cholesterol cannot be appropriately recycled. As a result, LDL-C levels increase, leading to the development of atherosclerosis (plaque buildup of the arteries).

Diagnosis

Although HoFH is caused by genetic mutations responsible for the normal function of LDL receptors, it is usually diagnosed clinically, based on a combination of physical findings, personal or family history of hypercholesterolemia, early onset cardiovascular disease risk score, and LDL-C levels measured by a lipid panel blood test.

Diagnosis of FH may be confirmed with genetic testing that involves testing for pathogenic variants in the genes for LDL‐R, APOB, and PCSK9 or whole‐gene sequencing, but a diagnosis of HoFH cannot be excluded in the absence of a causative mutation.

Treatment

Dietary and lifestyle modifications, like eating a very low-sodium, low-fat diet, and exercise (if possible), are the starting points for lowering LDL‐C in people with hypercholesterolemia, but multi-drug treatment is always required to achieve adequate LDL‐C levels in people with HoFH.

Statins, the mainstay of treatment for other forms of familial hypercholesterolemia, like heterozygous FH, are usually not sufficient to treat HoFH alone. This is because statins trigger the liver to express additional LDL receptors, but in the most severe cases of HoFH, the LDL receptors are rendered inactive.

High-dose statins, such as Crestor (rosuvastatin) and Lipitor (atorvastatin), have been shown to be effective for some individuals with HoFH.

Other cholesterol-lowering medicines include:

  • Ezetimibe: Studies have shown that the use of ezetimibe results in an additional 15% to 20% reduction in LDL-C regardless of the therapeutic approach used.
  • PCSK9 inhibitors: This newer class of medications has provided some hope for the treatment of HoFH. Some commonly used drugs are Praluent (alirocumab) and Repatha (evolocumab).
  • Microsomal triglyceride transfer protein inhibitors (MTP-I): MTP-I, like lomitapide, is an oral pill that blocks the enzyme that is responsible for the synthesis of very low-density lipoproteins (VLDL) in the liver and chylomicrons in the intestine. This effect has been shown to lower cholesterol levels by 40%, but the drug is very expensive, as much as $350,000 a year. Mipomersen is a cheaper alternative, but it is administered via injection and has been found to cause some adverse reactions at the injection site.

Apheresis is used in most people with HoFH. Apheresis is a special process, similar to kidney dialysis, that uses a filter to remove extra LDL cholesterol from the blood plasma. The blood plasma is then returned to the body.

Historically, liver transplantation has been used as a first option for treatment, however it is currently considered a last resort.

Prognosis 

HoFH is a serious and life-threatening medical condition that can lead to early cardiovascular disease and death in men, women, and children if left untreated. The average age of death is 18 years, although children have died as early as 5 years of age. Timely and aggressive treatment can increase life expectancy.

Summary

HoFH is a rare genetic condition that must be inherited from both parents. It causes extremely elevated LDL cholesterol levels, which can increase the risk of heart disease, even in early childhood and young adults.

If you have a family history of FH or early onset heart disease, it is important to consult your healthcare provider and have regular blood tests and screenings for high LDL cholesterol to manage and treat this condition effectively.

A Word From Verywell

Having HoFH can be jarring for many who find that they need to make sweeping lifestyle changes before they are ready to. Fortunately, advances in modern medicine are providing hope. Children and adults with HoFH can now use a combination of lifestyle changes, procedures, and drugs to get their cholesterol levels under control.

Mainstay treatments like LDL-C apheresis, ezetimibe, and PCSK9 inhibitors are often covered by insurance, making them cost-effective solutions. MTP inhibitors are also becoming increasingly more popular, but the high cost of these drugs needs to come down so that they can become more widely used and available.

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7 Sources
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