What Is Familial Hypercholesterolemia ?

Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc). Although moderate hypercholesterolemia is a common finding in industrialized countries, heterozygous FH occurs in approximately 1 per 500 persons worldwide.

Because FH is associated with a high risk for premature coronary artery disease (CAD), health professionals should be alert to the signs found during a physical examination and to the laboratory values suggestive of FH. Early detection and aggressive management to lower the LDLc level helps prevent or slows the progression of coronary atherosclerosis. Moreover, if the first-degree relatives of a patient with FH are screened, other gene carriers can be identified and treated.




FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors. The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. It is the primary determinant of hepatic LDL uptake, which normally processes approximately 70% of circulating LDL. Two ligands on LDL bind to the receptor, apolipoprotein B-100 (apoB-100) and apoE. The LDL receptor also binds another ligand, apoE, and is, therefore, more accurately termed the B,E receptor. ApoE is found on most lipoproteins other than LDL, including very low-density lipoprotein (VLDL) and chylomicrons and their remnants, intermediate-density lipoprotein (IDL), and a subclass of high-density lipoprotein (HDL). The LDL receptor binds apoE with higher affinity than apoB-100, and some mutations in the receptor may spare uptake of LDL by allowing binding to apoE.

Goldstein and Brown discovered the LDL receptor and determined that FH was caused by an autosomal dominant mutation. Since then, more than 700 mutations have been identified that have a meaningful impact on receptor function. LDL receptor function ranges from completely absent to approximately 25% of normal receptor activity.

Five classes of mutations have been defined as follows:

  • Class 1 includes null alleles that result in complete absence of the LDL receptor. 
  • Class 2 includes defective transport alleles, which disrupt normal folding of the receptor and cause either failure in transport to the cell surface or successful transport of truncated, mutated receptors.
    • Class 2a mutations completely block the transport of the receptor from the endoplasmic reticulum to the Golgi apparatus.
    • Class 2b mutations result in a partial blockade of transport of the receptor from the endoplasmic reticulum to the Golgi apparatus.
  • Class 3 includes defective binding alleles that affect binding of LDL and, in some cases, binding of VLDL as well.
  • Class 4 includes defective internalization alleles that affect the concentration of normal receptors in clathrin-coated pits for internalization by the hepatocyte. 
  • Class 5 includes defective recycling alleles that prevent dissociation of the receptor and the ligand and thereby interrupt recycling of the receptor.





United States


The prevalence of heterozygous FH is approximately 1 case per 500 persons. The prevalence of homozygous FH is 1 case per 1 million persons.



The prevalence of heterozygous FH in Europe approximates that of the United States, but certain regions, such as Iceland and Finland, or populations have a higher incidence. The prevalence of heterozygous FH among French Canadians is 1 case per 270 persons and is 1 case per 170 persons in Christian Lebanese. Due to the founder effect and relatively isolated populations, 3 distinct populations within South Africa have an extremely high prevalence of FH: 1 case per 67 in Ashkenazi Jews and 1 case per 100 persons in both Afrikaners and South African Indians.




  • Homozygous FH
    • Severe and widespread atherosclerosis affects all major arterial beds, including the carotid, coronary, femoral, and iliac.
    • Children are at risk for early coronary events, and sudden death or acute myocardial infarction may occur in patients as young as 1-2 years. Without heroic interventions to lower blood cholesterol levels, survival beyond young adulthood is unlikely.
    • Valve abnormalities are common, particularly aortic stenosis.
    • Accumulation of cholesterol in nonvascular tissue is of less clinical significance. Corneal arcus and planar, tendon, and tuberous xanthomas are present early in childhood and sometimes at birth. Recognition of the cutaneous manifestations of FH permits early diagnosis and treatment to prevent the otherwise severe and inevitable cardiovascular complications.
  • Heterozygous FH
    • Premature CAD is the most serious and preventable manifestation. Untreated men are likely to develop symptoms by the fourth decade of life. The onset of symptoms in women lags behind men by approximately 10-15 years. No accurate estimates of mortality rates are available.
    • Cholesterol deposition in nonvascular tissue is common, although heterozygous children do not usually have physical manifestations; adults do not invariably develop them. Corneal arcus is the most frequent finding, particularly in patients older than 30 years, but this finding is also common in older patients and African Americans without hypercholesterolemia. Similarly, xanthelasmas (palpebral xanthomas) can occur in older individuals with normal cholesterol levels. Neither xanthelasma nor corneal arcus is of clinical significance, except possibly cosmetically.
    • Xanthomas, most commonly of the Achilles tendon and extensor tendons of the hands, are rare in children and common in untreated adults. Tendon xanthomas may occur with other conditions such as familial defective apoB-100 and type III hyperlipoproteinemia. These deposits can cause Achilles tendonitis and articular symptoms, particularly of the hands, wrists, knees, and ankles.




Certain populations with Finnish, Lebanese, Ashkenazi Jewish, Afrikaner, or French Canadian origins have a higher prevalence of FH.




  • The gene for FH is on chromosome 19; therefore, the inheritance pattern is the same for males and females.
  • In heterozygous FH, the consequences of severe hypercholesterolemia manifest earlier in men than in women because of the sex protection that benefits women until the postmenopausal years. Although a woman with no other major risk factors for CAD may not develop symptomatic CAD during her lifetime, men are rarely so fortunate.
  • Homozygous girls and boys have the same risk for a very early cardiovascular event.




  • The consequences of a defective LDL receptor and subsequent elevations of LDLc are present at birth, but age is relevant because the longer patients live with extremely elevated LDLc levels, the higher their risk of CAD.
  •  Early diagnosis and treatment to lower LDL levels and treat other coronary risk factors slows the progression of coronary atherosclerosis.




  • Children with homozygous FH
    • These patients may have symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis. Such symptoms may be confused with conditions that are more benign unless the diagnosis of homozygous FH is considered.
    • Patients may have articular symptoms such as tendonitis or arthralgias.
    • Patients have a history of unusual skin lesions.
    • Because they are obligate heterozygous hypercholesterolemics, both parents must have severe elevations in LDLc; although they are often too young to have developed symptomatic CAD. Because each must have a parent with heterozygous FH, a history of significant hypercholesterolemia and premature CHD can be traced to the patient’s second degree relatives. 
  • Children with heterozygous FH
    • Children with heterozygous FH do not have symptoms related to CHD.
    • One parent will have severe hypercholesterolemia and will probably have either a personal or family history for early CAD.
    • Statistically, because the gene for FH is dominant, 50% of the patient’s siblings will also have heterozygous FH.
  • Adults with homozygous FH
    • Most patients do not survive 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.
    • Their family history should be positive for severe hypercholesterolemia and premature CAD in both parental family lines.
  • Adults with heterozygous FH
    • These patients have a long-standing history of severe hypercholesterolemia dating back to childhood.
    • If an acute coronary event has not already occurred, symptoms consistent with ischemic heart disease are not uncommon, especially if other cardiovascular risk factors (especially smoking) are present.
    • Past or present symptoms of recurrent Achilles tendonitis or arthritic complaints may be present.
    • Premature CAD and severe hypercholesterolemia are present in one or more first-degree relatives.
  • If carefully questioned, patients with either homozygous or heterozygous FH may describe first-degree relatives who had visible tendon xanthomas on their hands.




The presence of tendon xanthomas is usually stated to be pathognomonic for FH, but that is not the case. As described in Causes, patients with familial ligand defective apoB-100 may have tendon xanthomas and elevated LDLc levels. 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) causes tendon xanthomas due to the accumulation of both cholesterol and cholestanol. However, this rare disease causes other abnormalities (eg, dementia, ataxia, cataracts) with reference range cholesterol levels and, therefore, cannot be confused with FH. Sitosterolemia (phytosterolemia), a rare autosomal recessive disease, is characterized by hyperabsorption of plant sterols. Tendon xanthomas are present at an early stage although cholesterol levels are within the reference range or only mildly elevated. Uncommonly, patients with dysbetahyperlipoproteinemia have tendon xanthomas.

Homozygous FH

  • These patients may have cutaneous xanthomas at birth or by early childhood.
  • Several types of xanthomas are usually obvious in the first decade of life, and they include (1) planar xanthomas (on hands, elbows, buttocks, or knees), which are diagnostic for the homozygous state and are distinct from other cutaneous xanthomas because of their yellow-to-orange coloration; (2) tuberous xanthomas (on hands, elbows, or knees); and (3) tendon xanthomas (especially on extensor tendons of hands or Achilles tendon) will occur somewhat later.
  • Children may have corneal arcus, which is sometimes circumferential. While occasionally present in older adults with normal cholesterol levels, corneal arcus is highly unusual in children, and this finding should prompt a workup for homozygous FH.
  • The murmur of aortic stenosis may be heard.

Heterozygous FH

Most children with heterozygous FH do not develop tendon xanthomas or corneal arcus. By the third decade of life, more than 60% of patients with untreated FH develop tendon xanthomas as in the image below. 


Xanthomas are noted commonly on the Achilles tendons and metacarpal phalangeal extensor tendons of the hands.

The figures in many textbooks suggest that tendon xanthomas in heterozygous patients are readily apparent upon gross inspection. Unfortunately, this often is not the case. Careful palpation rather than simple inspection may be necessary for detection of Achilles tendon xanthomas. A diffusely thickened tendon or one with discreet irregularities is suggestive of a xanthoma.

Tendon xanthomas of the metacarpophalangeal joints may be seen by careful inspection and palpation. Slowly flexing and extending the digits and watching for nodules that move with the motion of the tendon make these xanthomas more noticeable and distinguish them from cutaneous or subcutaneous nodules.

Xanthelasmas may occur in older patients with normal cholesterol levels and this finding is, therefore, not specific for FH.

The presence of tendon xanthomas is often stated to be pathognomonic for FH but that is not the case.

  • As described below, patients with familial ligand defective apoB-100 may have tendon xanthomas and equivalent laboratory values.
  • 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) causes tendon xanthomas due to the accumulation of both cholesterol and cholestanol. But this rare disease causes other abnormalities (dementia, ataxia, cataracts) with normal cholesterol levels and, therefore, cannot be confused with FH.
  • Sitosterolemia (phytosterolemia), a rare autosomal recessive disease, is characterized by hyperabsorption of plant sterols. Tendon xanthomas may be present though cholesterol levels are normal or only mildly elevated.
  • Uncommonly, patients with dysbetalipoproteinemia have tendon xanthomas.





A major change in the number or functional status of LDL receptors directly affects serum cholesterol levels. If the liver does not take up LDL particles, serum LDLc levels increase. Also, when LDL is not internalized by hepatocytes, hepatic synthesis of cholesterol is not suppressed. This leads to further cholesterol production despite high levels of circulating cholesterol. Therefore, circulating cholesterol levels are increased dramatically. The total and LDLc levels of infants and children with homozygous FH are higher than 600 mg/dL. In patients with heterozygous FH, half the LDL receptors are normal and half are rendered ineffective by the mutation. These patients' total cholesterol and LDLc levels are twice as high as the population average. LDLc levels of 200-400 mg/dL are common.

High levels of LDLc increase cholesterol uptake in nonhepatic cells that is independent of LDL receptors. These scavenger pathways allow cholesterol uptake by monocytes and macrophages, leading to foam cell formation, plaque deposition in the endothelium of coronary arteries, and premature CAD. Cholesterol also accumulates in other areas, particularly the skin, causing xanthelasmas and a variety of xanthomas. Early corneal arcus is frequent, and, in patients with the homozygous condition, valvular abnormalities, most frequently aortic stenosis, are common secondary to the deposition of cholesterol.

Several conditions other than FH cause severely elevated LDL levels, and each is caused by a single gene abnormality.

Familial ligand defective apoB-100

Familial ligand defective apoB-100 (FLDB), also called familial defective apoB-100, is responsible for a syndrome almost indistinguishable from heterozygous FH.  Instead of an abnormal or absent LDL receptor, this syndrome is caused by an abnormality at the binding site of apoB-100, which impedes its role as a ligand for the receptor. ApoB-100 is a single polypeptide chain composed of 4536 amino acids. The gene resides on the short arm of chromosome 2 and the first described mutation was a substitution of glycine for arginine at the codon for amino acid 3500.  Different mutations at the same and different codons have since been described.

 Although the LDL receptors are normal in both number and function, LDL is taken up inefficiently, leading to elevated LDLc levels that can be indistinguishable from those associated with heterozygous FH. These patients can present with cutaneous manifestations and an increased risk of premature CAD similar to patients with heterozygous FH. Because LDL receptors function normally with respect to the apoE ligand, uptake of very low-density lipoprotein, very low-density lipoprotein remnants, and intermediate-density lipoprotein is normal. The consequence may be that patients with defective apoB-100 may have a clinically more benign course than patients with heterozygous FH. The finding that patients homozygous for familial defective apoB-100 are clinically similar to those with the heterozygous condition supports this supposition.

Autosomal recessive hypercholesterolemia

Another recently identified molecular defect that also causes severely elevated LDL levels is autosomal recessive hypercholesterolemia. These patients have LDLc levels that are higher 400 mg/dL; however, heterozygous individuals have normal levels 

Author: Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael

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Jul 11, 2010