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Familial Hypercholesterolemia


Familial Hypercholesterolemia

Article Author:
Zahra Vaezi
Article Editor:
Afshin Amini
Updated:
3/9/2020 7:14:07 PM
For CME on this topic:
Familial Hypercholesterolemia CME
PubMed Link:
Familial Hypercholesterolemia

Introduction

Familial hypercholesterolemia is known as a group of inherited genetic defects that lead to the severe elevation of serum cholesterol concentrations. Clinically FH is diagnosed by high serum level of low-density lipoprotein (LDL) cholesterol and genetically is characterized to 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 FH. In the Fredrickson classification, patients with FH have seen in type IIa, IIb, and III hyperlipidemias; however, type IIa is the most common type for FH.[2] Elevation of serum LDL cholesterol in patients with FH leads to an increase in the risk of atherosclerosis disease and, subsequently, premature death.[3]

Etiology

The three main known genetic mutations in familial hypercholesterolemia 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.[4][5] 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.[6] Over 1600, gene mutations in LDLR are detected in 85 to 90% of patients with FH.APOB mutations accounting for about 10% of patients with FH, and from this amount, Arg3500Gln gene mutation is the most common cause.PCSK9 gene mutation causes less than 5% of patients with FH. Moreover, only severe mutations in PCSK9 can lead to FH.[7] However, a less common mutation in signal-transducing adaptor family member 1 (STAP1) also reported as a cause of FH.[8]

Epidemiology

The Study by De Ferranti et al. is estimated familial hypercholesterolemia occurs in about 1 in 250 individuals with or 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 has belonged to 20 to 29 years old. Also, FH had a similar prevalence between men and women but was more common in the obese or black race.[9] Other studies also estimated the prevalence of FH in other countries. Results revealed 1 in 217 individuals in Denmark, 1 in 150 among French Canadians in Quebec, and 1 in 70 between Afrikaners in South Africa. [10][11][12] Heterozygous FH estimated about 1 in 300 to 500 people, which is concluded that approximately 10 million people have FH worldwide.[13]

Pathophysiology

Low-density lipoprotein (LDL) transport 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 enter the cells, then LDL is released, and LDLR recycles to the cell membrane.[14]

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.[7] 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.[4] Clinically, it can not determine the causal gene mutation in familial hypercholesterolemia.[15]

LDL Receptor Genetic Defects

The impairment of LDLR results in decreased clearance of LDL from the plasma and an elevation of low-density lipoprotein cholesterol (LDL-C ), which causes increased uptake of oxidase LDL or other modifications by macrophage and resulting foam cell formation. [16] Gene mutation of LDLR can be categorized into 5 classes based on protein mutation.

  • Class I – Null, due to defect in the synthesis of LDLR
  • Class II – Transport defective, in which impairment in the transport of LDLR from the endoplasmic reticulum to Golgi in the cells.
  • Class III – Binding defect, in which ability dysfunction of LDLR to bind with LDL.
  • Class IV – Internalization defective, in which the LDL receptors do not cluster in the clathrin-coated pits, so minimizing LDL internalization by the hepatocyte.[17]
  • Class V - Recycling defect, in which LDLR is not recycling to the cell membrane.[18]

Familial Defective Apolipoprotein B-100

This disorder is related to defect on APOB-100 ligand on the LDL. Therefore, it is reduced the LDL clearance from plasma and subsequently causes a high level of serum LDL.[19]

Mutations in the PCSK9 Gene

Mutations that cause increased activity of PCSK9 lead to increases degradation of the LDL receptor and subsequently elevation of plasma LDL. However, mutations that inactivate PCSK9 cause lowering plasma LDL levels and reducing coronary heart disease (CHD).[20]

History and Physical

Family History

Careful family history is essential for the assessment and diagnosis of familial hypercholesterolemia. Family history of premature history of CHD and/or high cholesterol in first-degree relatives (younger than 60 years in women and 55 years in men among first- degree relatives).[21] Also, it should raise the suspicion for FH in young patients with early coronary events in second-degree relatives.[15]

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 FH.[21] Tendon xanthomas are pathognomonic for FH and manifest as thickening of the tendons due to cholesterol deposited within macrophages in connective tissue (lipid-laden histiocytes). 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.[13] 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 is also can 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.[22]

Evaluation

Screening for Familial Hypercholesterolemia

Screening for FH should occur in people age 2 years and older if the patient has a family history of hypercholesterolemia or premature CHD.[13] Universal screening, including measurement of a non-fasting non-high-density lipoprotein (HDL) cholesterol or fasting lipid profile, is recommended to diagnose children with FH at ages 9 to 11 years.[23] Children with a non-fasting non-HDL cholesterol result 145 mg/dL and higher need to evaluate by fasting lipid profile.[13]

Suspicious for FH

1) In people with 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.[24]

3) FH in the family member or total cholesterol greater than 240 mg/dL in either parent.[15]

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.[13]

Genetic tests or clinical criteria can make diagnostic criteria for heterozygous FH and homozygous FH(HoFH).

1) Heterozygous FH (HeFH): The two most commonly used criteria for evaluation and diagnosis of FH are the Dutch lipid clinic criteria and the Simon Broome criteria.[25][26] Both incorporate LDL levels, presence of xanthomas, presence of a genetic mutation or family history of FH, premature cardiovascular events, tendinous xanthomas, and/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 the 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 diagnosed with clinical criteria, and genetic tests are negative for mutations.[13]

2) Homozygous FH (HoFH): Clinically, HoFH diagnosed based on untreated LDL-C plasma level >500 mg/dL (>13 mmol/L) or treated LDL-C plasma concentration ≥300 mg/dL (>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.[21]

Cascade Screening

Cascade screening define as evaluation and screening that involve family members of the patient with FH.[27] Cascade screening include lipid profile test in all first-degree family members of diagnosed patients with FH. The chance for detection of FH in first, second, and third-degree relatives is 50%, 25%, and 12.5%, respectively. If genetic mutations found in a patient, then the patient's family member needs to screen for genetic tests as well.[13]

Treatment / Management

Approach to Therapy

All patients with familial hypercholesterolemia and their families should educate for lifestyle management. These are including a healthy diet, quit smoking, and physical therapy. Dietitians or nutritionists should advise patients and family members to reduce the amount of food with high cholesterol and encourage them to lose weight.[28] A holistic approach should be sought in the treatment of FH. Besides lowering LDL levels, control of the patient’s lifestyle risk, and other modifiable risk factors of coronary heart disease is essential in reducing CV morbidity and mortality in patients with FH. 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 of the initial untreated LDL level in patients with FH.[29][30] Some guidelines consider patients with prior coronary heart disease or concomitant diabetes are considered high risk and are recommended 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.[31]

Drug Therapies

Statins are the standard therapy for FH. All guidelines recommend statins as first-line drugs for patients with FH, with a goal of reaching maximally tolerated doses.[32]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.[33][34][35] 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.[34] 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.[36][37] Currently, ezetimibe is the drug of choice as the second line in most guidelines.[38] PCSK9 inhibitors have shown a great reduction in LDL levels and cardiovascular outcomes in different randomized clinical trials.[21][39] 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 costs and the reluctance of insurance companies to approve their use.[40] Hence, PCSK9 inhibitors can be used as second or third-line drugs for patients with FH. 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.[41][42][43][44] These are usually reserved if the LDL does not reach the target level with the use of statins, ezetimibe, and PCSK9 inhibitors.[43]

FH and Pregnancy

Women with FH 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 required.[45]

Differential Diagnosis

  • Sitosterolemia - an autosomal recessive disorder leading to hyperabsorption of plant sterols from the intestine and elevation of plant sterol concentrations in tissues[46]
  • Cerebrotendinous xanthomatosis - an autosomal recessive disorder caused by a defective in a block in bile acid synthesis enzyme leading to the deposition of cholestanol and cholesterol ocular, neurological, vascular, and musculoskeletal[47]
  • Polygenic hypercholesterolemia
  • Familial combined hyperlipidemia
  • Hyperapobetalipoproteinemia
  • Familial dysbetalipoproteinemia (type III hyperlipoproteinemia)

Prognosis

The risk of CHD before the use of statin in patients with heterozygous familial hypercholesterolemia was very high.[48] However, the risk of death in patients with heterozygous FH after acute coronary syndrome within the first year one year is almost more than two times higher than matched individuals without FH despite high-intensity statins therapy.[49] The risk of death or coronary artery disease in relatives of patients with FH was 52% and 32% in males and females, respectively.[50] Patients with homozygous FH have a poor prognosis. They usually die before the third decade of life from CV events.[21]

Complications

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

Consultations

Consultation to certified dietitians/nutritionists should support the realization of a healthy diet with the patient and the whole family. Refer to the lipid specialist or familial hypercholesterolemia clinics recommends whenever, despite maximally tolerated statins, LDL cholesterol is still above goal.[15]

Deterrence and Patient Education

Patients with familial hypercholesterolemia should be educated about a healthy lifestyle, quit smoking, and avoid overweight. A healthy lifestyle should include in the reduction of 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.[15]

Patients with FH should be educated about their risk of CV disease. Patients should educate about controlling of all modifiable risk factors of CV disease and treatment strategies of FH, once a diagnosis is made. All first degree relatives of patients with FH should be counseled about the importance of screening.[13]

Pearls and Other Issues

  • Familial hypercholesterolemia is a common cause of premature cardiovascular events in children and adults.
  • Various diagnostic criteria of FH are available online and can help direct further workup.
  • Heterozygous FH is underrecognized and commonly treated sub-optimally.
  • Cascade screening of first-degree relatives of patients with FH is essential in primary prevention of CV events.
  • Referral to a lipid specialist can help optimize the control of LDL hypercholesterolemia in patients with FH.[13]

Enhancing Healthcare Team Outcomes

Optimal screening and diagnosis of familial hypercholesterolemia are paramount in the prevention of premature cardiovascular events. Management of patients with FH requires an interprofessional approach, including primary care physicians, cardiologists, endocrinologists, lipid specialists, dietitians, 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 the optimization of care.[15] [Level 3] 


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