Homozygous Familial Hypercholesterolemia




Homozygous familial hypercholesterolemia, also known as Autosomal recessive hypercholesterolemia (ADH), is characterized by high levels of low-density lipoprotein (LDL) cholesterol, and associated with premature cardiovascular disease and myocardial infarction. Approximately 1:500 individuals worldwide are affected by ADH. Most ADH is caused by genetic variants leading to decreased intracellular uptake of cholesterol. The majority of these cases have familial hypercholesterolemia (FH), which is due to mutations in the LDLR gene, which encodes for the LDL receptor. Approximately 15% of ADH cases have familial defective apolipoprotein B-100 (FDB) due to mutations in the LDL receptor-binding domain of the APOB gene, which encodes for apolipoprotein B-100.


Signs and symptoms of homozygous FH in children include the following:

  • Symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis
  • Articular symptoms such as tendonitis or arthralgias
  • Unusual skin lesions, such as cutaneous xanthomas at birth or by early childhood (eg, planar xanthomas, tuberous xanthomas; later, tendon xanthomas)
  • Corneal arcus may be present and is sometimes circumferential
  • Murmur of aortic stenosis may be present


Familial hypercholesterolemia (FH) is usually inherited in an autosomal dominant manner (in which case it is referred to as heterozygous FH). Individuals inherit two copies of each gene (one from each parent). In an autosomal dominant condition, having only one abnormal (mutated) copy of the gene is sufficient to cause the condition. In most cases the mutated gene is inherited from an affected parent, but it is possible for the mutation to occur for the first time in the affected individual. An individual with an autosomal dominant condition has a 50% (1 in 2) chance to pass the mutation on to each of his/her children and a 50% chance to not pass on the mutation.

More rarely, familial FH may be inherited in an autosomal recessive manner. This occurs when an individual inherits a mutated copy of the gene from both parents (this is also called homozygous FH). This is a much more severe form of FH. An individual with this form of FH will always pass on a mutated copy of the gene, and therefore each of his/her children will have heterozygous FH.


Genetical counselling is advisable for parents that plan to have children.


A physical examination may reveal fatty skin growths called xanthomas and cholesterol deposits in the eye (corneal arcus).

The doctor will ask questions about your personal and family medical history. There may be:

  • A strong family history of familial hypercholesterolemia or early heart attacks
  • High levels of LDL in either or both parents

Individuals from families with a strong history of early heart attacks should have blood tests done to determine lipid levels.

Blood tests may show:
High levels of total cholesterol

  • Greater than 300 mg/dL in adults
  • Greater than 250 mg/dL in children

High LDL levels

  • Greater than 170-200 mg/dL in children
  • Greater than 220 mg/dL in adults
  • Normal triglyceride levels

Other tests that may be done include:

  • Studies of cells called fibroblasts to see how the body absorbs LDL cholesterol
  • Genetic test for the defect associated with this condition


Most patients with homozygous FH do not survive adulthood beyond age 30 years unless treated with unusual methods, such as liver transplantation, LDL apheresis, or ileal bypass surgery to dramatically lower their LDLc levels.


Beside change of diet, individuals with the more severe, homozygous form of FH need more aggressive therapies to treat their significantly elevated levels of cholesterol. Drug therapy is often not effective enough at lowering LDL cholesterol levels. Therefore, individuals with this form may need periodical LDL apheresis, a procedure that removes LDL from the blood. In some cases, major surgery such as a liver transplant is necessary

The following are procedures used in the treatment of homozygous FH:

  • Portacaval anastomosis (junction of two blond vessels)
  • Liver transplantation (rarely)

Approved therapies:

  • rosuvastatin (Crestor) - FDA approved indication: An adjunct to diet to reduce LDL-C, Total-C, nonHDL-C and ApoB in children and adolescents 7 to 17 years of age with homozygous familial hypercholesterolemia, either alone or with other lipid-lowering treatments (e.g., LDL apheresis). 
  • Evolocumab (Repatha) FDA-approved indication: As an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with HoFH who require additional lowering of LDL-C.