Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein (LDL) cholesterol in your blood. Doctors classify FH as either homozygous (HoFH) or heterozygous (HeFH), depending on whether you have one or two copies of the gene that causes FH.

While FH is relatively common, affecting at least 1 out of 250 people, the HoFH subtype is very rare. Fewer than 200,000 people in the United States are estimated to have HoFH. HeFH is much more common but also less serious.

This article will discuss the less common but more severe HoFH subtype and how it compares with HeFH.

A genetic mutation in the gene for LDL cholesterol (LDL-C) receptors causes FH. In some cases, mutations in other genes may be the cause. Examples include your PCSK9 or apolipoprotein B genes. It’s also possible to have multiple genetic mutations in HoFH.

Like other genetic mutations, you inherit FH from one or both of your parents. HeFH results when you inherit the mutated gene from one parent. You have HoFH if you inherited the mutated genes from both parents.

Having FH means your body can’t recycle LDL-C as it should. This leaves atypically high LDL-C levels in your bloodstream. LDL-C levels are higher in HoFH than they are in HeFH.

Risk factors for FH include a family history of this gene mutation, or a personal or family history of cholesterol problems or heart disease. You may be at a higher risk of developing HoFH if both of your parents carry a related gene mutation.

FH is also generally more prevalent in the following populations:

  • Afrikaners in South Africa
  • Ashkenazi Jews from Lithuania
  • French Canadians
  • Lebanese Christians

Below is a quick look at how HoFH compares with HeFH:

IncidenceRare, affecting fewer than 200,000 people in the United StatesMost cases of FH are HeFH
CausesMultiple mutations in LDL receptor genes that you inherit from both parentsSingle or multiple of the same mutations that you inherit from one parent only
LDL-C levelsAbove 400 mg/dLMore than 190 mg/dL
SymptomsVisible nodules called xanthomas

Cardiovascular-related symptoms, such as chest pain
Doesn’t usually cause symptoms until the development of heart disease

Possible chest pain and other symptoms in the case of related heart disease
TreatmentLDL apheresis

Certain lipid-lowering medications approved specifically for HoFH
Cholesterol-lowering medications and injections

Possible LDL apheresis

FH is underdiagnosed in most countries because those affected may not have any symptoms until they develop coronary artery disease (CAD).

When HeFH causes symptoms, these are usually due to the development of heart disease. Signs and symptoms may include:

People with HoFH may also experience the above symptoms with CAD caused by FH. The key difference is that these symptoms may appear earlier in life, with vascular diseases developing by your teenage years.

Children with HoFH are also more likely to develop cholesterol-containing skin nodules called xanthomas. While people with HeFH may develop xanthomas later in life, these raised, yellowish nodules may appear in early childhood in people with HoFH.

A child with HoFH may have xanthomas in the following areas:

  • hands
  • elbows
  • knees
  • buttocks

Children with HoFH may also develop corneal arcus at a young age. This is another condition where cholesterol deposits build up — in this case, around the inner edge of the cornea in your eye.

HoFH may first be identified early in life due to heart-related symptoms or the presence of xanthomas. The only way to know for sure that you have this genetic condition is to undergo testing.

A doctor may use the following diagnostic tools:

  • physical exam
  • personal and family medical history evaluation
  • blood testing for cholesterol, with a focus on LDL-C levels
  • other blood tests to help rule out other possible causes of high LDL-C, including kidney and thyroid diseases

It’s important to note that an ideal LDL-C level is less than 100 mg/dL. With HeFH, your level may be in the “very high” range of 190 mg/dL. But with HoFH, LDL-C levels can be 400 mg/dL or more.

Additionally, a doctor may use a scoring system, such as the Dutch Lipid Clinic Network Score, to help determine the likelihood that you have FH.

From there, the only way to definitively confirm that you have the homozygous subtype of FH is to undergo genetic testing.

Genetic testing

If you have a family history of FH, it’s important to undergo genetic testing to see if you’re carrying the genetic mutations that might increase your risk of this condition. All first degree relatives, such as parents, children, and siblings, also should get tested.

A doctor may also recommend genetic testing if you have a personal or family history of early heart disease, or if you’re currently showing possible signs of HoFH, such as xanthomas or chest pain.

HoFH requires aggressive treatment as soon as possible. This will help lower your risk of developing serious vascular disease at a young age.

First-line treatments for HeFH include cholesterol-lowering medications, such as statins. However, such treatments are rarely effective in HoFH due to the high level of LDL cholesterol in the bloodstream.

Instead, a doctor will likely recommend medications approved by the Food and Drug Administration (FDA) specifically for treating HoFH. These include:

  • PCSK9 inhibitors: These may induce your liver to remove LDL cholesterol. Doctors use these inhibitors specifically for people with PCSK9 genetic mutations confirmed by testing. They’re available in injectable form.
  • Lomitapide (Juxtapid): When used along with a low fat diet, this lipid-lowering medication may help treat HoFH, especially in cases where heart disease may be present. Your doctor may gradually increase your dose based on your tolerance level.
  • Mipomersen (Kynamro): Approved by the FDA for HoFH in 2013, this injectable treatment is for those who don’t experience results from other treatments.

Another treatment doctors use to treat HoFH is LDL apheresis, which removes LDL cholesterol from the blood through a system similar to kidney dialysis. For the best results, you may need to repeat this treatment every few weeks.

People with HeFH may sometimes undergo LDL apheresis, but only if their LDL-C levels are extremely high.

Generally, HeFH is manageable if it’s found and treated early.

However, HoFH is far more aggressive. Experts estimate that without appropriate treatment, children with HoFH may develop severe CAD by their mid-20s. Without aggressive treatment, HoFH has a high mortality rate before the age of 30.

A 25-year study of 133 people with HoFH showed that aggressive treatment to lower LDL-C levels significantly improved their outlook.

HoFH is a rare subtype of FH. Unlike the more common HeFH subtype, HoFH causes significant LDL cholesterol levels in the blood, usually above 400 mg/dL. Without early and aggressive treatment, HoFH may be deadly in early adulthood.

Despite the aggressive nature of HoFH, treatment options specific to this type of FH are available. You should also talk with a doctor about possible genetic testing if you or a family member has either a history of FH or early heart disease.