Calculators, Algorithms, Drug Interaction CheckersTools
Back To Search Results

Familial Hypercholesterolemia

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

Introduction

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]

Etiology

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Etiology

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]

Epidemiology

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]

Race

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

Sex

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

Age

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

Pathophysiology

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]

Evaluation

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]

Radiology

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.

Biopsy

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)

Prognosis

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]

Complications

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

Consultations

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]

References

[1]

Goldstein JL, Brown MS. The LDL receptor locus and the genetics of familial hypercholesterolemia. Annual review of genetics. 1979:13():259-89     [PubMed PMID: 231932]

[2]

Carmena R, Roy M, Roederer G, Minnich A, Davignon J. Coexisting dysbetalipoproteinemia and familial hypercholesterolemia. Clinical and laboratory observations. Atherosclerosis. 2000 Jan:148(1):113-24     [PubMed PMID: 10580177]

[3]

Civeira F, Jarauta E, Cenarro A, García-Otín AL, Tejedor D, Zambón D, Mallen M, Ros E, Pocoví M. Frequency of low-density lipoprotein receptor gene mutations in patients with a clinical diagnosis of familial combined hyperlipidemia in a clinical setting. Journal of the American College of Cardiology. 2008 Nov 4:52(19):1546-53. doi: 10.1016/j.jacc.2008.06.050. Epub     [PubMed PMID: 19007590]

Level 2 (mid-level) evidence

[4]

Sibley C, Stone NJ. Familial hypercholesterolemia: a challenge of diagnosis and therapy. Cleveland Clinic journal of medicine. 2006 Jan:73(1):57-64     [PubMed PMID: 16444917]

[5]

Khera AV, Won HH, Peloso GM, Lawson KS, Bartz TM, Deng X, van Leeuwen EM, Natarajan P, Emdin CA, Bick AG, Morrison AC, Brody JA, Gupta N, Nomura A, Kessler T, Duga S, Bis JC, van Duijn CM, Cupples LA, Psaty B, Rader DJ, Danesh J, Schunkert H, McPherson R, Farrall M, Watkins H, Lander E, Wilson JG, Correa A, Boerwinkle E, Merlini PA, Ardissino D, Saleheen D, Gabriel S, Kathiresan S. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. Journal of the American College of Cardiology. 2016 Jun 7:67(22):2578-89. doi: 10.1016/j.jacc.2016.03.520. Epub 2016 Apr 3     [PubMed PMID: 27050191]

[6]

Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, Sijbrands EJ, Roeters van Lennep JE, Stalenhoef AF, Wiegman A, de Graaf J, Fouchier SW, Kastelein JJ, Hovingh GK. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. European heart journal. 2015 Mar 1:36(9):560-5. doi: 10.1093/eurheartj/ehu058. Epub 2014 Feb 28     [PubMed PMID: 24585268]

Level 2 (mid-level) evidence

[7]

Khachadurian AK, Uthman SM. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutrition and metabolism. 1973:15(1):132-40     [PubMed PMID: 4351242]

Level 3 (low-level) evidence

[8]

Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. Journal of lipid research. 2009 Apr:50 Suppl(Suppl):S172-7. doi: 10.1194/jlr.R800091-JLR200. Epub 2008 Nov 19     [PubMed PMID: 19020338]

Level 3 (low-level) evidence

[9]

Fouchier SW, Dallinga-Thie GM, Meijers JC, Zelcer N, Kastelein JJ, Defesche JC, Hovingh GK. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circulation research. 2014 Aug 29:115(6):552-5. doi: 10.1161/CIRCRESAHA.115.304660. Epub 2014 Jul 17     [PubMed PMID: 25035151]

Level 3 (low-level) evidence

[10]

de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation. 2016 Mar 15:133(11):1067-72. doi: 10.1161/CIRCULATIONAHA.115.018791. Epub     [PubMed PMID: 26976914]

Level 3 (low-level) evidence

[11]

Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. European heart journal. 2016 May 1:37(17):1384-94. doi: 10.1093/eurheartj/ehw028. Epub 2016 Feb 22     [PubMed PMID: 26908947]

[12]

Couture P, Morissette J, Gaudet D, Vohl MC, Gagné C, Bergeron J, Després JP, Simard J. Fine mapping of low-density lipoprotein receptor gene by genetic linkage on chromosome 19p13.1-p13.3 and study of the founder effect of four French Canadian low-density lipoprotein receptor gene mutations. Atherosclerosis. 1999 Mar:143(1):145-51     [PubMed PMID: 10208489]

[13]

Steyn K, Goldberg YP, Kotze MJ, Steyn M, Swanepoel AS, Fourie JM, Coetzee GA, Van der Westhuyzen DR. Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations. Human genetics. 1996 Oct:98(4):479-84     [PubMed PMID: 8792826]

[14]

Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Journal of clinical lipidology. 2011 Jun:5(3 Suppl):S9-17. doi: 10.1016/j.jacl.2011.03.452. Epub 2011 Apr 3     [PubMed PMID: 21600530]

[15]

Arias-Moreno X, Velazquez-Campoy A, Rodríguez JC, Pocoví M, Sancho J. Mechanism of low density lipoprotein (LDL) release in the endosome: implications of the stability and Ca2+ affinity of the fifth binding module of the LDL receptor. The Journal of biological chemistry. 2008 Aug 15:283(33):22670-9. doi: 10.1074/jbc.M802153200. Epub 2008 Jun 23     [PubMed PMID: 18574243]

[16]

Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Borén J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A, European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. European heart journal. 2013 Dec:34(45):3478-90a. doi: 10.1093/eurheartj/eht273. Epub 2013 Aug 15     [PubMed PMID: 23956253]

Level 3 (low-level) evidence

[17]

Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. The New England journal of medicine. 1989 Apr 6:320(14):915-24     [PubMed PMID: 2648148]

Level 3 (low-level) evidence

[18]

Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annual review of genetics. 1990:24():133-70     [PubMed PMID: 2088165]

Level 3 (low-level) evidence

[19]

Varret M, Abifadel M, Rabès JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clinical genetics. 2008 Jan:73(1):1-13     [PubMed PMID: 18028451]

[20]

Tybjaerg-Hansen A, Gallagher J, Vincent J, Houlston R, Talmud P, Dunning AM, Seed M, Hamsten A, Humphries SE, Myant NB. Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases. Atherosclerosis. 1990 Jan:80(3):235-42     [PubMed PMID: 2310429]

Level 3 (low-level) evidence

[21]

Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends in biochemical sciences. 2007 Feb:32(2):71-7     [PubMed PMID: 17215125]

[22]

Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjærg-Hansen A, Watts GF, Averna M, Boileau C, Borén J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ, European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. European heart journal. 2014 Aug 21:35(32):2146-57. doi: 10.1093/eurheartj/ehu274. Epub 2014 Jul 22     [PubMed PMID: 25053660]

Level 3 (low-level) evidence

[23]

Yuan G, Wang J, Hegele RA. Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2006 Apr 11:174(8):1124-9     [PubMed PMID: 16606962]

[24]

Wald DS, Bestwick JP, Wald NJ. Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis. BMJ (Clinical research ed.). 2007 Sep 22:335(7620):599     [PubMed PMID: 17855284]

Level 1 (high-level) evidence

[25]

Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, Ludwig EH, Hopkins PN. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. The American journal of cardiology. 1993 Jul 15:72(2):171-6     [PubMed PMID: 8328379]

[26]

Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJ. Advanced method for the identification of patients with inherited hypercholesterolemia. Seminars in vascular medicine. 2004 Feb:4(1):59-65     [PubMed PMID: 15199434]

[27]

Wierzbicki AS, Humphries SE, Minhas R, Guideline Development Group. Familial hypercholesterolaemia: summary of NICE guidance. BMJ (Clinical research ed.). 2008 Aug 27:337():a1095. doi: 10.1136/bmj.a1095. Epub 2008 Aug 27     [PubMed PMID: 18753174]

[28]

Vaseghi G, Arabi S, Haghjooy-Javanmard S, Sabri M, Sadeghi M, Khosravi A, Zarfeshani S, Sarrafzadegan N. CASCADE screening and registry of familial hypercholesterolemia in Iran: Rationale and design. ARYA atherosclerosis. 2019 Mar:15(2):53-58. doi: 10.22122/arya.v15i2.1899. Epub     [PubMed PMID: 31440286]

[29]

Broekhuizen K, Jelsma JG, van Poppel MN, Koppes LL, Brug J, van Mechelen W. Is the process of delivery of an individually tailored lifestyle intervention associated with improvements in LDL cholesterol and multiple lifestyle behaviours in people with familial hypercholesterolemia? BMC public health. 2012 May 14:12():348. doi: 10.1186/1471-2458-12-348. Epub 2012 May 14     [PubMed PMID: 22583789]

Level 1 (high-level) evidence

[30]

Writing Committee, Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. Journal of the American College of Cardiology. 2016 Jul 5:68(1):92-125. doi: 10.1016/j.jacc.2016.03.519. Epub 2016 Apr 1     [PubMed PMID: 27046161]

Level 3 (low-level) evidence

[31]

Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Journal of clinical lipidology. 2011 May-Jun:5(3):133-140. doi: 10.1016/j.jacl.2011.03.001. Epub 2011 Mar 11     [PubMed PMID: 21600517]

[32]

American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2019. Diabetes care. 2019 Jan:42(Suppl 1):S103-S123. doi: 10.2337/dc19-S010. Epub     [PubMed PMID: 30559236]

[33]

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2014 Jul 1:63(25 Pt B):2889-934. doi: 10.1016/j.jacc.2013.11.002. Epub 2013 Nov 12     [PubMed PMID: 24239923]

Level 1 (high-level) evidence

[34]

Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). The American journal of cardiology. 1998 Mar 1:81(5):582-7     [PubMed PMID: 9514454]

Level 1 (high-level) evidence

[35]

Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet (London, England). 2001 Feb 24:357(9256):577-81     [PubMed PMID: 11558482]

Level 1 (high-level) evidence

[36]

deGoma EM, Ahmad ZS, O'Brien EC, Kindt I, Shrader P, Newman CB, Pokharel Y, Baum SJ, Hemphill LC, Hudgins LC, Ahmed CD, Gidding SS, Duffy D, Neal W, Wilemon K, Roe MT, Rader DJ, Ballantyne CM, Linton MF, Duell PB, Shapiro MD, Moriarty PM, Knowles JW. Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry. Circulation. Cardiovascular genetics. 2016 Jun:9(3):240-9. doi: 10.1161/CIRCGENETICS.116.001381. Epub 2016 Mar 24     [PubMed PMID: 27013694]

[37]

Murphy SA, Cannon CP, Blazing MA, Giugliano RP, White JA, Lokhnygina Y, Reist C, Im K, Bohula EA, Isaza D, Lopez-Sendon J, Dellborg M, Kher U, Tershakovec AM, Braunwald E. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome: The IMPROVE-IT Trial. Journal of the American College of Cardiology. 2016 Feb 2:67(4):353-361. doi: 10.1016/j.jacc.2015.10.077. Epub     [PubMed PMID: 26821621]

[38]

Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E, ENHANCE Investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. The New England journal of medicine. 2008 Apr 3:358(14):1431-43. doi: 10.1056/NEJMoa0800742. Epub 2008 Mar 30     [PubMed PMID: 18376000]

Level 1 (high-level) evidence

[39]

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2019 Jun 25:73(24):e285-e350. doi: 10.1016/j.jacc.2018.11.003. Epub 2018 Nov 10     [PubMed PMID: 30423393]

Level 1 (high-level) evidence

[40]

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England journal of medicine. 2017 May 4:376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17     [PubMed PMID: 28304224]

Level 2 (mid-level) evidence

[41]

Arrieta A, Hong JC, Khera R, Virani SS, Krumholz HM, Nasir K. Updated Cost-effectiveness Assessments of PCSK9 Inhibitors From the Perspectives of the Health System and Private Payers: Insights Derived From the FOURIER Trial. JAMA cardiology. 2017 Dec 1:2(12):1369-1374. doi: 10.1001/jamacardio.2017.3655. Epub     [PubMed PMID: 29049467]

Level 3 (low-level) evidence

[42]

Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJP. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. Journal of clinical lipidology. 2016 Jul-Aug:10(4):1011-1021. doi: 10.1016/j.jacl.2016.04.013. Epub 2016 May 9     [PubMed PMID: 27578134]

[43]

Cuchel M, Meagher EA, du Toit Theron H, Blom DJ, Marais AD, Hegele RA, Averna MR, Sirtori CR, Shah PK, Gaudet D, Stefanutti C, Vigna GB, Du Plessis AM, Propert KJ, Sasiela WJ, Bloedon LT, Rader DJ, Phase 3 HoFH Lomitapide Study investigators. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet (London, England). 2013 Jan 5:381(9860):40-6. doi: 10.1016/S0140-6736(12)61731-0. Epub 2012 Nov 2     [PubMed PMID: 23122768]

[44]

Buchwald H, Campos CT. Partial ileal bypass in the therapy of familial hypercholesterolemia. The POSCH Group. Beitrage zur Infusionstherapie = Contributions to infusion therapy. 1988:23():47-60     [PubMed PMID: 2484782]

[45]

Matsuzaki M, Hiramori K, Imaizumi T, Kitabatake A, Hishida H, Nomura M, Fujii T, Sakuma I, Fukami K, Honda T, Ogawa H, Yamagishi M. Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia: the Low Density Lipoprotein-Apheresis Coronary Morphology and Reserve Trial (LACMART). Journal of the American College of Cardiology. 2002 Jul 17:40(2):220-7     [PubMed PMID: 12106923]

Level 1 (high-level) evidence

[46]

Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European heart journal. 2020 Jan 1:41(1):111-188. doi: 10.1093/eurheartj/ehz455. Epub     [PubMed PMID: 31504418]

[47]

Raal FJ, Hovingh GK, Catapano AL. Familial hypercholesterolemia treatments: Guidelines and new therapies. Atherosclerosis. 2018 Oct:277():483-492. doi: 10.1016/j.atherosclerosis.2018.06.859. Epub     [PubMed PMID: 30270089]

[48]

Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, McCrindle B, Raal F, Rader D, Santos RD, Lopes-Virella M, Watts GF, Wierzbicki AS, American Heart Association Atherosclerosis, Hypertension, and Obesity in Young Committee of Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and Council on Lifestyle and Cardiometabolic Health. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. 2015 Dec 1:132(22):2167-92. doi: 10.1161/CIR.0000000000000297. Epub 2015 Oct 28     [PubMed PMID: 26510694]

[49]

Veit L, Allegri Machado G, Bürer C, Speer O, Häberle J. Sitosterolemia-10 years observation in two sisters. JIMD reports. 2019 Jul:48(1):4-10. doi: 10.1002/jmd2.12038. Epub 2019 May 28     [PubMed PMID: 31392106]

[50]

Parry AH, Wani AH, Bashir M, Gojwari TA. Cerebrotendinous xanthomatosis - A case report. The Indian journal of radiology & imaging. 2019 Jul-Sep:29(3):332-334. doi: 10.4103/ijri.IJRI_444_18. Epub 2019 Oct 30     [PubMed PMID: 31741606]

Level 3 (low-level) evidence

[51]

Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. American journal of epidemiology. 2004 Sep 1:160(5):421-9     [PubMed PMID: 15321838]

[52]

Nanchen D, Gencer B, Muller O, Auer R, Aghlmandi S, Heg D, Klingenberg R, Räber L, Carballo D, Carballo S, Matter CM, Lüscher TF, Windecker S, Mach F, Rodondi N. Prognosis of Patients With Familial Hypercholesterolemia After Acute Coronary Syndromes. Circulation. 2016 Sep 6:134(10):698-709. doi: 10.1161/CIRCULATIONAHA.116.023007. Epub 2016 Jul 26     [PubMed PMID: 27462068]

[53]

Stone NJ, Levy RI, Fredrickson DS, Verter J. Coronary artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation. 1974 Mar:49(3):476-88     [PubMed PMID: 4813182]