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Familial Hypercholesterolemia

Editor: Afshin Amini Updated: 9/26/2022 6:00:39 PM


Familial hypercholesterolemia (FH) is a group of inherited genetic defects that lead to the severe elevation of serum cholesterol concentrations. Clinically familial hypercholesterolemia is diagnosed by a high serum level of low-density lipoprotein (LDL) cholesterol and genetically is characterized into two subgroups: (1) autosomal dominant (AD), (2) codominant transmission with 90% or higher penetrance.[1] A dominant trait transmission is the most common type of familial hypercholesterolemia. In the Fredrickson classification, patients with familial hypercholesterolemia have been seen in type 2a, 2b, and 3 hyperlipidemias; however, type 2a is the most common familial hypercholesterolemia type.[2] Elevation of serum LDL cholesterol in patients with familial hypercholesterolemia leads to an increase in the risk of atherosclerotic disease and, subsequently, premature death.[3] Early detection of familial hypercholesterolemia and aggressive management to lower the LDL cholesterol level helps in preventing or slowing the progression of coronary atherosclerosis. First-degree relatives of a patient with FH should be screened, so that other gene carriers can be identified and treated.[4]


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The three main known genetic mutations in familial hypercholesterolemia are classified as defects in the LDL receptor (most common), apolipoprotein B  (ApoB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Each of these three mutations leads to impairment of LDL receptors and a reduction in uptake of LDL cholesterol and subsequently causes high LDL cholesterol concentration.[5][6] Patients can have a homozygous or a heterozygous defect, which will determine the severity of the disease and the age of onset of cardiovascular (CV )disease manifestations. Children who carry both defect genes from two heterozygote parents almost do not have LDLR to uptake LDL and subsequently present with extremely high LDL cholesterol levels and early-onset CV disease.[7] Over 1600 gene mutations in LDLR are detected in 85 to 90% of patients with familial hypercholesterolemia. APOB mutations accounting for about 10% of patients with familial hypercholesterolemia, and from this amount, the Arg3500Gln gene mutation is the most common cause. PCSK9 gene mutation causes less than 5% of patients with familial hypercholesterolemia. Moreover, only severe mutations in PCSK9 can lead to familial hypercholesterolemia.[8] However, a less common mutation in signal-transducing adaptor family member 1 (STAP1) was also reported to cause familial hypercholesterolemia.[9]


The study by De Ferranti et al. has estimated that familial hypercholesterolemia occurs in about 1 in 250 individuals older than 20-year-old in the United States. The most common age prevalence was from 60 to 69 years old, while the least common age prevalence was 20 to 29 years old. Also, familial hypercholesterolemia had a similar prevalence between men and women but was more common in the obese or black race.[10] Other studies have also estimated the prevalence of familial hypercholesterolemia in other countries. Results revealed 1 in 217 individuals in Denmark, 1 in 150 among French Canadians in Quebec, and 1 in 70 among Afrikaners in South Africa.[11][12][13] Heterozygous familial hypercholesterolemia is estimated at 1 in 300 to 500 people, from which it can be concluded that approximately 10 million people have familial hypercholesterolemia worldwide.[14]


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


The inheritance pattern is the same for males and females because the gene for FH is on chromosome 19.


A defective LDL receptor is present at birth, but the longer patients live with extremely elevated LDLc levels, the higher their risk of CAD.


Low-density lipoprotein (LDL) transports the majority of plasma cholesterol and binding to the low-density lipoprotein receptor (LDLR) cell membrane through two ligands on LDL, apolipoprotein B-100 (apoB-100) and apoE. The complex of LDL and LDLR enters the cells, then LDL is released, and LDLR recycles to the cell membrane.[15]

The liver secretes the proprotein PCSK9 that extracellularly binds to LDLR and inhibits the recycling of LDLR to the cell membrane. Therefore, PCSK9 leads to a decrease in LDLR and increases serum LDL.[8] The end-result in all three main gene mutations is the binding dysfunction of LDL receptors to the LDL cholesterol, thereby decreasing the uptake and destruction of LDL cholesterol in the liver and the resultant rise in serum LDL levels.[5] Clinically, it can not determine the causal gene mutation in familial hypercholesterolemia.[16]

LDL Receptor Genetic Defects

The impairment of LDLR results in decreased LDL clearance from the plasma and an elevation of low-density lipoprotein cholesterol (LDL-C ), which causes increased uptake of oxidase LDL or other modifications by macrophages and resulting in foam cell formation.[17] Gene mutation of LDLR can be categorized into 5 classes based on protein mutation.

  • Class 1 – Null, due to defect in the synthesis of LDLR
  • Class 2 – Transport defective, in which impairment in the transport of LDLR from the endoplasmic reticulum to Golgi in the cells.
  • Class 3 – Binding defect, in which ability dysfunction of LDLR to bind with LDL.
  • Class 4 – Internalization defect, in which the LDL receptors do not cluster in the clathrin-coated pits, so minimizing LDL internalization by the hepatocyte.[18]
  • Class 5 - Recycling defect, in which LDLR is not recycling to the cell membrane.[19]

Familial Defective Apolipoprotein B-100

This disorder is related to a defect in the apoB-100 ligand on the LDL. Therefore, it reduces the LDL clearance from plasma and subsequently causes a high level of serum LDL.[20]

Mutations in the PCSK9 Gene

Mutations that cause increased activity of PCSK9 lead to increased degradation of the LDL receptor and subsequently elevation of plasma LDL. However, mutations that inactivate PCSK9 cause lower plasma LDL levels and reduce coronary heart disease (CHD).[21]

History and Physical

Homozygous Familial Hypercholesterolemia

These patients have symptoms of ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis. Patients may have tendonitis or arthralgia and a history of unusual skin lesions. Survival beyond 30 years of age is difficult unless treated with unusual methods.

Heterozygous Familial Hypercholesterolemia

These patients have severe hypercholesterolemia since childhood. Symptoms of ischemic heart disease are common, especially if other cardiovascular risk factors are present. Symptoms of recurrent Achilles tendonitis or arthritic complaints may be present.

Family History

Careful family history is essential for the assessment and diagnosis of familial hypercholesterolemia. Family history of premature coronary artery disease or high cholesterol in first-degree relatives (younger than 60 years in women and 55 years in men among first-degree relatives) are red flags.[22] It should also raise the suspicion for familial hypercholesterolemia with young patients showing early coronary events in second-degree relatives.[16]

Physical Examination

Usually, abnormal physical examinations are related to depositions of cholesterol in the eye or skin. It can happen at an early age with homozygous familial hypercholesterolemia.[22] Tendon xanthomas are pathognomonic for familial hypercholesterolemia and manifest as thickening of the tendons due to cholesterol deposited within macrophages in connective tissue (lipid-laden histiocytes). The Achilles tendon and finger extensor tendons are the most common sites, however patellar and triceps tendons are not unusual. Tendon xanthomas occur in less than half of patients with FH.[14] Corneal arcus senilis are depositions of cholesterol around the corneal rim. It is more specific in a patient younger than 45 years of age. Cholesterol deposition can also manifest as yellow-orange tuberous xanthomas (on hands, elbows, or knees) or xanthelasma (in the eyelids), which are more specific for FH in patients aged 20 to 25 years.[23]


Screening for Familial Hypercholesterolemia

Screening for familial hypercholesterolemia should occur in people age 2 years and older if the patient has a family history of hypercholesterolemia or premature CHD.[14] Universal screening, including measurement of a non-fasting non-high-density lipoprotein (HDL) cholesterol or fasting lipid profile, is recommended to diagnose children with familial hypercholesterolemia at ages 9 to 11 years.[24] Children with a non-fasting non-HDL cholesterol result 145 mg/dL and higher need to be evaluated by fasting lipid profile.[14]

Suspicious for Familial Hypercholesterolemia

  1. In people 20 years old or younger: if untreated fasting serum LDL cholesterol levels are 160 mg/dL and higher or non-HDL cholesterol levels are 190 mg/dL and higher
  2. In adults older than 20 years: if fasting LDL cholesterol levels are 190 mg/dL and higher or non-HDL cholesterol is 220 mg/dL and higher.[25]
  3. FH in the family member or total cholesterol greater than 240 mg/dL in either parent.[16]
  4. Tendon xanthomas at any age, corneal arcus senilis in a patient younger than 45 years of age, and yellow-orange xanthelasma tuberous or xanthomas in a patient aged 20 to 25 years.[14]

Genetic Tests or Clinical Criteria/Diagnostic Criteria for Heterozygous FH (HeFH) and Homozygous FH(HoFH)

  1. Heterozygous FH (HeFH): The two most commonly used criteria for evaluating and diagnosing FH are the Dutch lipid clinic criteria and the Simon Broome criteria.[26][27] Both incorporate LDL levels, presence of xanthomas, the presence of a genetic mutation or family history of FH, premature cardiovascular events, tendinous xanthomas, or corneal arcus senilis, and elevated LDL levels in young ages. The Dutch lipid clinic criteria categorize patients into definite, probable, possible, or unlikely FH, while Simon Broome classifies patients as definite or possible. Having only an LDL level of 330 mg/dl or more, or a mutation in the LDL receptor, ApoB-100, or the PCSK9 gene will earn a diagnosis of probable FH, based on the Dutch lipid clinic criteria. If a patient has any of the additional factors of the Dutch lipid clinic, on top of the gene mutation or the LDL level, as mentioned above, the diagnosis becomes definite FH. Based on the Simon Broom criteria, a diagnosis of definite FH requires an LDL level of at least 155 mg/dl and a gene mutation or tendinous xanthomas in the patient or first- or second-degree relatives. Generally, genetic screening for FH is not required for diagnosis, but it is helpful when the diagnosis is uncertain. However, approximately 20% of patients with FH are diagnosed with clinical criteria, and genetic tests are negative for mutations.[14]
  2. Homozygous FH (HoFH): Clinically, HoFH is diagnosed based on untreated LDL-C plasma level greater than 500 mg/dL (more than 13 mmol/L) or treated LDL-C plasma concentration equal to or greater than 300 mg/dL (more than 8 mmol/L), and the presence of tendon xanthoma or cutaneous manifestation before the age of 10 years or both parents has consistent criteria for HeFH based on the untreated elevation of LDL-C levels.[22]

Cascade Screening

Cascade screening is defined as evaluation and screening that involves family members of the patient with FH.[28] Cascade screening include lipid profile test in all first-degree family members of diagnosed patients with FH. The odds for detecting familial hypercholesterolemia in first, second, and third-degree relatives is 50%, 25%, and 12.5%, respectively. If genetic mutations are found in a patient, then the patient's family member also needs to receive genetic screening.[14]


Doppler echocardiographic evaluation of the heart and aorta is recommended annually in patients with homozygous FH. Radiographic imaging of the Achilles tendon helps accurately measure Achilles tendon xanthomas.


If a skin lesion or the diagnosis of heterozygous FH is unclear, a biopsy of the skin lesion can be performed. Both xanthelasmas and the xanthomas of FH contain accumulations of cholesterol.

Treatment / Management

Approach to Therapy

All patients with familial hypercholesterolemia and their families should receive education regarding lifestyle management. This includes a healthy diet, quitting smoking, and physical therapy/activity. Dietitians or nutritionists should advise patients and family members to reduce the amount of food with high cholesterol and encourage them to lose weight.[29] A holistic approach should be sought in the treatment of FH. Besides lowering LDL levels, controlling the patient’s lifestyle risk, and other modifiable risk factors of coronary heart disease is essential in reducing CV morbidity and mortality in these patients. Setting a suitable target LDL level is difficult, as patients with FH present with varying degrees of elevated LDL levels. Most guidelines recommend a reduction of 50% or more from the initial untreated LDL level in patients with FH.[30][31] Some guidelines consider patients with prior coronary heart disease or concomitant diabetes are considered high risk, and the recommendation is to have an LDL level below 70 mg/dL, while patients without prior coronary heart disease or diabetes are considered the low-moderate risk and have recommended target LDL level below 100 mg/dL. LDL levels should be checked every 2 to 3 months while on treatment to adjust drug therapies accordingly.[32](A1)

Drug Therapies

Statins are the standard therapy for familial hypercholesterolemia. All guidelines recommend statins as first-line drugs for patients with FH, with a goal of reaching maximally tolerated doses.[33] The effect of statins has been well studied, and most randomized clinical trials observed a reduction of around 50 percent of the initial untreated LDL levels, as well as a reduction in cardiovascular events.[34][35][36] Unfortunately, a large number of patients with FH, even on maximally-tolerated statins alone, either do not show this level of reduction in LDL levels, or they do not reach their goal LDL levels, even with a 50 percent reduction, because their initial LDL levels are so high.[35] Second-line therapies include ezetimibe and PCSK9 inhibitors. Ezetimibe has been showing to add an extra 10 to 30 percent reduction in LDL levels for patients on maximally tolerated statins.[37][38] Currently, ezetimibe is the drug of choice as the second line in most guidelines.[39] PCSK9 inhibitors have shown a great reduction in LDL levels and cardiovascular outcomes in different randomized clinical trials.[22][40] In those trials, PCKS9 inhibitors lowered LDL levels by 50 to 60 percent. While exhibiting higher efficacy than ezetimibe, the use of PCSK9 inhibitors is limited by their high cost and the reluctance of insurance companies to approve their use.[41] Hence, PCSK9 inhibitors can be used as second or third-line drugs for patients with familial hypercholesterolemia. Fourth line therapies include mipomersen (mRNA inhibition of apolipoprotein B), lomitapide (microsomal triglyceride transfer protein inhibition), niacin, lipoprotein apheresis, ileal bypass surgery, and liver transplantation.[42][43][44][45] These are usually reserved if the LDL does not reach the target level using statins, ezetimibe, and PCSK9 inhibitors.[44](A1)

Treatment Guidelines for Homozygous FH

European Atherosclerosis Society (EAS) guidelines for the screening and treatment of homozygous FH are summarized as follows:[46][47]

  • Treatment of homozygous FH involves a combination of lifestyle changes, statin therapy (first approach), and lipoprotein apheresis for severe cases
  • LDL apheresis should begin as early as age 5 years
  • For homozygous FH patients, the LDL cholesterol targets are less than 100 mg/dL for adults, less than 70 mg/dL for adults with clinical cardiovascular disease (CVD), and less than 135 mg/dL for children
  • Other novel agents for LDL cholesterol lowering (eg, lomitapide with or without apheresis) can be considered as adjunctive treatments for patients who do not achieve the recommended LDL cholesterol targets and remain at high cardiovascular risk.

Treatment Guidelines for Heterozygous FH

In patients with heterozygous FH, lifestyle modification is unlikely to result in acceptable LDLc levels; therefore, cholesterol-lowering medication is necessary. EAS consensus statement for screening and treatment of heterozygous FH includes the following recommendations:[16](B3)

  • An LDL target of less than 135 mg/dL for children with FH
  • An LDL target of less than 100 mg/dL for adults with FH
  • An LDL target of less than 70 mg/dL for adults with known CHD or diabetes
  • Lifestyle modifications include a diet that severely limits saturated fats, trans fats, and cholesterol
  • Desirable weight should be attained
  • Significant weight loss should improve all lipid parameters (LDLc, HDLc, triglycerides)
  • Aerobic and toning exercises improve blood lipid levels if performed for longer than 30 minutes, 4 or more days per week

Familial Hypercholesterolemia and Pregnancy

Women with familial hypercholesterolemia planning to conceive should discontinue all lipid-lowering agents, including statins, ezetimibe, and PCSK9 inhibitors. Cardiovascular risk assessment is recommended before conception. Lipoprotein apheresis may be used if necessary.[48]

Surgical Care

  • Liver transplantation for homozygous FH because a new liver provides functional LDL receptors and causes dramatic decreases in LDLc levels
  • Portacaval anastomosis for homozygous FHT

Differential Diagnosis

The differential diagnoses of familial hypercholesterolemia include but are not limited to the following:

  • Sitosterolemia - an autosomal recessive disorder leading to hyperabsorption of plant sterols from the intestine and elevation of plant sterol concentrations in tissues[49]
  • Cerebrotendinous xanthomatosis - an autosomal recessive disorder caused by a defective block in bile acid synthesis enzyme leading to the deposition of cholestanol and cholesterol ocular, neurological, vascular, and musculoskeletal[50]
  • Polygenic hypercholesterolemia
  • Familial combined hyperlipidemia
  • Hyperapobetalipoproteinemia
  • Familial dysbetalipoproteinemia (type 3 hyperlipoproteinemia)


The risk of coronary heart disease before the use of statin in patients with heterozygous familial hypercholesterolemia was very high.[51] However, the risk of death in patients with heterozygous FH after acute coronary syndrome within the first year is almost more than two times higher than matched individuals without familial hypercholesterolemia despite high-intensity statins therapy.[52] The risk of death or coronary artery disease in relatives of patients with FH was 52% and 32% in males and females, respectively.[53] Patients with homozygous FH have a poor prognosis. They usually die before the third decade of life from cardiovascular events.[22]


Familial hypercholesterolemia can lead to serious complications. These include:

  • Stable coronary artery disease
  • Fatal and non-fatal myocardial infarctions
  • Congestive heart failure
  • Cerebrovascular accidents
  • Aortic stenosis
  • Peripheral arterial disease
  • Cardiovascular death


Consultation with certified dietitians/nutritionists should support implementing a healthy diet for the patient and their whole family. Refer to the lipid specialist or familial hypercholesterolemia clinic recommendations whenever, despite maximally tolerated statins, LDL cholesterol is still above goal.[16] Management of patients with familial hypercholesterolemia requires an interprofessional approach, including:

  • Primary care providers
  • Cardiologists
  • Endocrinologists
  • Lipid specialists
  • Dietitians
  • Pharmacists
  • Nurses

Deterrence and Patient Education

Patients with familial hypercholesterolemia should be educated about a healthy lifestyle, quitting smoking, and taking measures to avoid being overweight. A healthy lifestyle should include reducing food and beverages with high cholesterol, trans fat content, and saturated fat. Also, patients should consider foods resulting in a decrease in cholesterol, such as plant stanols and sterols.[16]

Patients with familial hypercholesterolemia should also receive education regarding their risk of CV disease. Patients should learn about controlling all modifiable risk factors for CV disease and treatment strategies for familial hypercholesterolemia once a diagnosis is made. All first-degree relatives of patients with FH should be counseled about the importance of screening.[14]

Pearls and Other Issues

  • Familial hypercholesterolemia is a common cause of premature cardiovascular events in children and adults.
  • Various diagnostic criteria of familial hypercholesterolemia are available online and can help direct further workup.
  • Heterozygous FH is underrecognized and commonly treated sub-optimally.
  • Screening of first-degree relatives of patients with FH is essential in the primary prevention of CV events.
  • Referral to a lipid specialist can help optimize the control of LDL hypercholesterolemia in patients with FH.[14]

Enhancing Healthcare Team Outcomes

Optimal screening and diagnosis of familial hypercholesterolemia are paramount in the prevention of premature cardiovascular events. Management of patients with familial hypercholesterolemia requires an interprofessional approach, including primary care providers, cardiologists, endocrinologists, lipid specialists, dietitians, pharmacists, and nursing care, to improve outcomes. An extensive discussion of treatment strategies should be done at diagnosis. A close follow-up to observe the response to treatment and development of side effects from lipid-lowering agents is essential in optimizing care.[16] [Level 3]



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