Familial hypercholesterolemia

Familial hypercholesterolemia (abbreviated FH, also spelled familial hypercholesterolaemia) is a genetic disorder characterized by high cholesterol levels, specifically very high low-density lipoprotein (LDL, "bad cholesterol") levels, in the blood and early cardiovascular disease. Many patients have mutations in the LDLR gene that encodes the LDL receptor protein, which normally removes LDL from the circulation, or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are heterozygous) of the LDLR gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being homozygous) may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.

Treatment of heterozygous FH is normally with statins, bile acid sequestrants or other drugs that lower cholesterol levels (hypolipidemic agents). New cases are generally offered genetic counseling. Homozygous FH often does not respond to medical therapy and may require other treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and occasionally liver transplantation.

Signs and symptoms

Physical signs

High cholesterol levels normally do not cause any symptoms. Cholesterol may be deposited in various places in the body that are visible from the outside, such as in yellowish patches around the eyelids (xanthelasma palpebrarum), the outer margin of the iris (arcus senilis corneae) and in the form of lumps in the tendons of the hands, elbows, knees and feet, particularly the Achilles tendon (tendon xanthoma).

Cardiovascular disease

Accelerated deposition of cholesterol in the walls of arteries leads to atherosclerosis, the underlying cause of cardiovascular disease. The most common problem in FH is the development of coronary artery disease (atherosclerosis of the coronary arteries that supply the heart) at a much younger age than would be expected in the general population. This may lead to angina pectoris (chest tightness on exertion) or heart attacks. Less commonly, arteries of the brain are affected; this may lead to transient ischemic attacks (brief episodes of weakness on one side of the body or inability to talk) or occasionally stroke. Peripheral artery occlusive disease (obstruction of the arteries of the legs) occurs mainly in people with FH who smoke; this can cause pain in the calf muscles during walking that resolves with rest (intermittent claudication) and problems due to a decreased blood supply to the feet (such as gangrene).

If lipids start infiltrating the aortic valve (the heart valve between the left ventricle and the aorta) or the aortic root (just above the valve), thickening of these structures may result in a narrow passage called aortic stenosis. Supravalvular aortic stenosis (tightening of the aorta above the level of the aortic valve) can occur in up to half of homozygous patients, whereas heterozygotes are less frequently affected. Aortic stenosis is characterized by shortness of breath, chest pain and episodes of dizziness or collapse.

Atherosclerosis risk is increased further with age and in those who smoke, have diabetes, high blood pressure and a family history of cardiovascular disease.


Lipid measurements

Cholesterol levels may be determined as part of health screening (e.g. for health insurance or in an occupational health setting), when the external physical signs (xanthelasma, xanthoma, arcus) are noticed, when symptoms of cardiovascular disease develop, or when a family member has been found to have FH. A pattern compatible with hyperlipoproteinemia type IIa (on the Fredrickson classification) is typically found: raised total cholesterol, markedly raised low-density lipoprotein (LDL), normal high-density lipoprotein (HDL) and normal triglycerides. The LDL is typically above the 95th percentile (i.e. 95% of the healthy population would have a lower LDL cholesterol), although patients with ApoB mutations have LDLs below this level in 25% of cases. Cholesterol levels can be drastically higher in FH patients who are also obese.

Mutation analysis

On the basis of the isolated high LDL and clinical criteria (which differ by country), genetic testing for LDL receptor mutations and ApoB mutations can be performed. Mutations are detected in between 50 and 80% of cases; those without a mutation often have higher triglyceride levels and may in fact have other causes for their high cholesterol, such as combined hyperlipidemia due to metabolic syndrome.

Differential diagnosis

FH needs to be distinguished from familial combined hyperlipidemia and polygenic hypercholesterolemia. Lipid levels and the presence of xanthomata can confirm the diagnosis. Sitosterolemia and cerebrotendineous xanthomatosis are two rare conditions that can also present with premature atherosclerosis and xanthomas. The latter condition can also involve neurological or psychiatric manifestations, cataracts, diarrhea and skeletal abnormalities.


The most common genetic defects in FH are LDLR mutations (prevalence 1 in 500, depending on the population), ApoB mutations (prevalence 1 in 1000), PCSK9 mutations (less than 1 in 2500) and LDLRAP1. The related disease sitosterolemia, which has many similarities with FH and also features cholesterol accumulation in tissues, is due to ABCG5 and ABCG8 mutations.

LDL receptor

The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. The plasma LDL levels are inversely related to the LDL receptor activity. Homozygotes have an LDL receptor activity of less than 2%, while heterozygotes have a defective LDL processing with receptor activity being 2–25%, depending on the nature of the mutation. Over 1000 different mutations are known.

There are five major classes of FH due to LDLR mutations:

  • Class I: LDL receptor (LDL-R) is not synthesized at all
  • Class II: LDL-R is not properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface
  • Class III: LDL-R does not properly bind LDL on the cell surface (this may be caused by a defect in either Apolipoprotein B100 (R3500Q) or in LDL-R)
  • Class IV: LDL-R bound to LDL does not properly cluster in clathrin-coated pits for receptor-mediated endocytosis
  • Class V: the LDL-R is not recycled back to the cell surface


ApoB, in its ApoB100 form, is the main apoprotein of LDL (protein part of the lipoprotein particle). Its gene is located on the second chromosome (2p24-p23) and is between 21.08 and 21.12 Mb long. The R3500Q mutation (replacement of arginine by glutamine at position 3500) is most commonly associated with FH. The mutation is located on a part of the protein that normally binds with the LDL receptor, and binding is reduced as a result of the mutation. Like LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia.


Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report. The gene is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid protein that is expressed in the liver. It is suspected to cause FH mainly by reducing the number of LDL receptors on liver cells.


Abnormalities in the ARH gene, also known as LDLRAP1, were first reported in a family in 1973. In contrast to the other causes, two abnormal copies of the gene are required for FH to develop (autosomal recessive). The mutations in the protein tend to cause the production of a shortened protein. Its real function is unclear, but it seems to play a role in the relation between the LDL receptor and clathrin-coated pits. Patients with autosomal recessive hypercholesterolemia tend to have more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes.


LDL cholesterol normally circulates in the body for 2.5 days, after which it binds to the LDL receptor on the liver cells, undergoes endocytosis, and is digested. Apart from removing LDL, this process also suppresses synthesis of cholesterol by the liver by a group of enzymes collectively referred to as the HMG-CoA reductase pathway. In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, leading to significantly increased levels of LDL cholesterol in the blood with normal levels of other lipoproteins. In LDL receptor mutations, this is the mechanism behind the receptor malfunctioning; in ApoB mutations, this is due to reduced binding of LDL particles to the receptor. In PCSK9 and ARH mutations, it is not known how the mutation causes LDL receptor dysfunction.

Although atherosclerosis occurs to a certain degree in all people, FH patients may develop accelerated atherosclerosis due to the excess LDL. The degree of atherosclerosis roughly depends of the number of LDL receptors still expressed and the functionality of these receptors. In many heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all.

Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis. Apart from the classic risk factors (smoking, high blood pressure, diabetes), genetic studies have shown that a common abnormality in the prothrombin gene (G20210A) increases the risk of cardiovascular events in patients with FH. Several studies found that a high level of apolipoprotein A was an additional risk factor for ischemic heart disease. The risk was also found to be higher in patients with a specific genotype of the angiotensin-converting enzyme (ACE).


Heterozygous FH

The mainstay of treatment of FH is medication from the class of the statins. They act by inhibiting the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA-reductase) in the liver. In response, the liver produces more LDL receptors, which remove circulating LDL from the blood. Statins effectively lower cholesterol and LDL levels, although sometimes add-on therapy with other drugs is required, such as bile acid sequestrants (cholestyramine or colestipol), nicotinic acid preparations or fibrates. Control of other risk factors for cardiovascular disease is required, as risk remains somewhat elevated even when cholesterol levels are controlled, as the high levels of cholesterol have been present since birth. Professional guidelines recommend that the decision to treat an FH patient with statins should not be based on the usual risk prediction tools (such as those derived from the Framingham Heart Study), as they are likely to underestimate the risk of cardiovascular disease. Prior to the introduction of the statins, clofibrate (an older fibrate that often caused gallstones), probucol (especially in large xanthomas) and thyroxine were used to reduce LDL cholesterol levels.

More controversial is the addition of ezetimibe, which inhibits cholesterol absorption in the gut. While it reduces LDL cholesterol, it does not appear to improve a marker of atherosclerosis called the intima-media thickness. Whether this means that ezetimibe is of no overall benefit in FH is unknown.

There are no interventional studies that directly show mortality benefit of cholesterol lowering in FH patients. Rather, evidence of benefit is derived from a number of trials conducted in people who have polygenic hypercholesterolemia (in which heredity plays a smaller role). Still, an observational study of a large British registry showed that mortality in FH patients had started to improve in the early 1990s, when statins were introduced.

Homozygous FH

Homozygous FH is harder to treat. The LDL receptors are minimally functional, if at all. Only high doses of statins, often in combination with other medications, are modestly effective in improving lipid levels. If medical therapy is not successful at reducing cholesterol levels, LDL apheresis may be used; this filters LDL from the bloodstream in a process reminiscent of dialysis. Very severe cases may be considered for a liver transplant; this provides a liver with normally functional LDL receptors, and leads to rapid improvement of the cholesterol levels, but at the risk of complications from any solid organ transplant (such as rejection, infections, or side-effects of the medication required to suppress rejection). Other surgical techniques include partial ileal bypass surgery, in which part of the small bowel is bypassed to decrease the absorption of nutrients and hence cholesterol, and portacaval shunt surgery, in which the portal vein is connected to the vena cava to allowing blood with nutrients from the intestine to bypass the liver. Inhibition of the microsomal triglyceride transfer protein and infusion of recombinant human apolipoprotein A1 are being explored as medical treatment options. Gene therapy is a possible future alternative.

Pediatric patients

Given that FH is present from birth and atherosclerotic changes may begin early in life, it is sometimes necessary to treat adolescents or even teenagers with agents that were originally developed for adults. Due to safety concerns, many doctors prefer to use bile acid sequestrants and fenofibrate as these are licensed in children. Nevertheless, statins seem safe and effective, and in older children may be used as in adults.

A multidisciplinary expert panel in 2006 advised on early combination therapy with LDL apheresis, statins and cholesterol absorption inhibitors in children with homozygous FH at the highest risk.


In most populations studied, heterozygous FH occurs in about 1:500 people, but not all develop symptoms. Homozygous FH occurs in about 1:1,000,000.

LDLR mutations are more common in certain populations, presumably because of a genetic phenomenon known as the founder effect—they were founded by a small group of individuals, one or several of whom was a carrier of the mutation. The Afrikaner, French Canadians, Lebanese Christians, and Finns have high rates of specific mutations that make FH particularly common in these groups. APOB mutations are more common in Central Europe.


Although case finding among family members of patients with known FH is a cost-effective approach, other strategies such as universal screening at the age of 16 have also been suggested. The latter approach may however be less cost-effective in the short term. Screening at an age lower than 16 would lead to an unacceptably high rate of false positives.


The Norwegian physician Dr C. Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938. In the early 1970s and 1980s, the genetic cause for FH was described by Dr Joseph L. Goldstein and Dr Michael S. Brown of Dallas, Texas. Initially, they found increased activity of HMG-CoA reductase, but studies showed that this did not explain the very abnormal cholesterol levels in FH patients. The focus shifted to the binding of LDL to its receptor, and effects of impaired binding on metabolism; this proved to be the underlying mechanism for FH. Subsequently numerous mutations in the protein were directly identified by sequencing. They later won the 1985 Nobel Prize in Medicine for their discovery of cholesterol and lipoprotein metabolism.


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