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Familial Hypercholesterolemia

, MD and , MD, MPH.

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Last Update: June 22, 2016.

ABSTRACT

Familial hypercholesterolemia (FH) is a prevalent, autosomal dominant disorder of lipid metabolism that results in elevated low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerosis. Screening for and identifying heterozygous FH in childhood is critical, given its high prevalence and asymptomatic presentation. Furthermore, treatment of FH in childhood is effective at lowering LDL-C levels and has the potential to reduce atherosclerotic cardiovascular disease (ASCVD) events in adulthood. Selective screening based on family history criteria had previously been recommended to identify children and adolescents with FH or other lipid disorders. However, studies indicated that many heterozygous FH individuals were missed with this approach, and therefore in 2011, the National Heart, Lung, and Blood Institute Expert Panel recommended universal screening of children and adolescents between ages 9 and 11 years and again at ages 17 to 21 years, in addition to selective screening, in order to identify pediatric individuals with heterozygous FH. Once FH is diagnosed, prompt treatment with lifestyle modification should be initiated. When lifestyle interventions are not sufficient, pharmacotherapy using statins has been shown to be effective at lowering LDL-C, generally safe in short and medium term studies, and may be beneficial at reducing ASCVD events. Other medications may be useful at lowering LDL-C in conjunction with statin therapy, although generally statins are sufficient in young patients. Homozygous FH is a rare disorder manifesting as extremely high LDL-C and ASCVD in childhood, requiring aggressive multimodal management. Overall, studies are needed to determine the optimal timing and intensity of statin therapy, and to better understand long-term safety and ASCVD outcomes in adulthood for lipid-lowering pharmacotherapy initiated in pediatric patients with heterozygous FH. For complete coverage of all related aeas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Familial hypercholesterolemia (FH), as classically described, is the most common single gene disorder of lipoprotein metabolism, and causes severely elevated low-density lipoprotein cholesterol (LDL-C). The prevalence of FH is 1 in 200 to 1 in 300 individuals (1), and it is strongly associated with premature coronary artery disease (CAD) (2). Data from observational studies suggest that untreated FH is associated with ~90 fold increase in mortality due to atherosclerotic cardiovascular disease (ASCVD) in young adults (3). Since early treatment may significantly reduce CAD-related morbidity and mortality in individuals with heterozygous FH (4), early identification and intervention during childhood may greatly improve outcomes in adulthood.

EPIDEMIOLOGY

The prevalence of FH varies substantially, depending upon the criteria used to define the disorder and the ancestry of the population. Previously, the prevalence had been described as 1 in 500 individuals based on early work by Drs. Brown and Goldstein (5,6). However, such reported prevalence rates are often determined using data from white European populations (7,8), which tend to be less ethnically and racially diverse that the US. Recently, a published report using a modified version of the Dutch Lipid Clinic (DLC) criteria (9) applied to participants in the 1999 to 2012 National Health and Education National Surveys (NHANES), a nationally representative survey of the US population, suggest FH affects 1 in 250 US adults (1). However, the prevalence of FH in US children and adolescents is not well characterized.

PATHOPHYSIOLOGY

FH was initially defined by Brown and Goldstein as a disorder or defect in the LDL receptor (LDL-R) (2). However, more recently, the description of FH has been expanded and used to describe any defects in LDL-C processing and/or signaling that may lead to a phenotype characteristic of FH (10). Therefore, other etiologies for the FH phenotype include defects in apoB100 lipoprotein, the major atherogenic lipoprotein component of LDL-C, as well as gain of function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes the degradation of the LDLR, resulting in reduced LDL-C clearance (6). Gene mutations in LDL-R, the apolipoprotein B gene, or in PCSK9 occur in approximately 93, 5, and 2 percent of individuals with a phenotype consistent with FH, respectively (11). The associated impairment in function of these receptors or proteins results in overall reduced clearance of LDL particles from the circulation and elevation in plasma LDL-C. There is also increased uptake of modified LDL by macrophage scavenger receptors, resulting in lipid accumulation in macrophages and foam cell formation, a precursor to atherosclerotic plaque development (12). Thus, the typical lipid profile of FH is characterized by elevated LDL-C (as high as 300 mg/dL) with subsequently increased total cholesterol (TC) levels; in general, triglycerides are normal, and high-density lipoprotein (HDL-C) can be low or normal. FH has an autosomal dominant inheritance pattern which results in hypercholesterolemia and early ASCVD events.

GENETICS

In general, homozygotes for mutations in the LDL-R gene are usually more adversely affected than heterozygotes, reflecting a “gene dosing effect” of inheritance. Unless there is consanguinity in a family in which heterozygous FH is present, homozygous FH is rare, estimated to affect ~1 in 1,000,000 births. Additionally, the homozygous FH phenotype can be seen in compound heterozygotes which can occur in offspring of unrelated parents due to a different disease-causing mutation on each allele. The severity of the FH phenotype does not necessarily depend upon the presence of true homozygosity or compound heterozygosity inheritance; rather it is determined by the degree of disturbance in LDL metabolism.

FH PHENOTYPE

Clinical Symptoms

Due to the excessively high plasma LDL-C levels in homozygous FH, cholesterol deposits are common in the tendons (xanthomas) and eyelids (xanthelasmas), and generally appear by 1 year of age; in heterozygotes, xanthomas may only occur rarely or later in life (14). Tendon xanthomata are most common in the Achilles tendons and dorsum of the hands, but can occur at other sites. Tuberous xanthomata typically occur over extensor surfaces such as the knee and elbow. Planar xanthomas may occur on the palms of the hands and soles of the feet and are often painful. Xanthelasmas are cholesterol-filled, soft, yellow plaques that usually appear on the medial aspects of the eyelids. Corneal arcus is a white or grey ring around the cornea (14).

LDL-C Levels

Table 1 Acceptable, Borderline-High, and High Plasma Lipid Concentrations for Children and Adolescents*

LipidLow, mg/dLAcceptable, mg/dLBorderline-High, mg/dLHigh, mg/dL
TC-<170170-199≥200
LDL-C-<110110-129≥130
Non-HDL-<120120-144≥145
Triglycerides
0-9 yr
10-19 yr
-
-
<75
<90
75-99
90-129
≥100
≥130
HDL-C<40>120115-120-
*Adapted from the NCEP Expert Panel on Cholesterol Levels in Children(13)

In clinical practice, there is not a universal threshold for LDL-C levels to determine a diagnosis of FH. Generally, the level of LDL-C that warrants further evaluation depends upon the age of the patient and whether additional family members have known hypercholesterolemia and/or early ASCVD. As suggested by recent guidelines (6,15), children and adolescents with a negative or unknown family history, a persistent LDL-C level of ≥190 mg/dL (4.9 mmol/L) suggests FH; in patients with a positive family history of hypercholesterolemia and/or early CVD, an LDL-C level of ≥160 mg/dL (4.1 mmol/L) is consistent with FH.

Cardiovascular Disease

Cardiovascular risk in FH patients is determined by both the LDL-C concentration and by other traditional risk factors. Homozygotes have early-onset atherosclerosis, including myocardial infarction in the first decade of life (reported as early as age 2 years), and are at increased risk for CAD-related mortality in the first and second decades (14). Heterozygotes are also at increased risk for early-onset CAD between the ages of 30-60 years (16). Children with heterozygous FH have been shown to have thicker carotid intima-media thickness (cIMT), an anatomic measure of arterial thickness associated with atherosclerosis, compared to unaffected siblings and healthy controls (17,18) and one study showed those treated with statin medications (HMG-CoA reductase inhibitors) at younger ages had less carotid atherosclerosis compared to the placebo group (19).

SCREENING

Given the high prevalence of FH and the improved outcomes with early treatment, pediatric lipid screening has become very important for the detection of FH. However, the approach to lipid screening in childhood and adolescences has varied over the past decades and is somewhat controversial. Selective screening, specifically of only young individuals with a family history of hypercholesterolemia and/or early CV events or patients at risk for atherosclerosis for other medical conditions, was recommended for several decades (20,21,13). However, selectively screening individuals based only on family history may miss 30-50% of children with elevated LDL and fail to identify lipid disorders in children in the US (21,13,22). Thus, the Expert Panel Guidelines recommended universal lipid screening in 2011, which involved screening in childhood at two time points, once between ages 9 and 11 years, and then again between ages 17 and 21 years (23). Universal screening is recommended in addition to selective screening of children with a family history of hypercholesterolemia and/or early CVD events.

Selective screening involves obtaining a fasting lipid panel in individuals ages 2 to 21 years with:

  1. Family history of early atherosclerosis or high cholesterol
  2. Relatives of individuals with identified FH
  3. Presence of risk factors or medical diagnoses that increase risk for CVD (including hypertension, current cigarette smoking, body mass index ≥ 85th percentile, diabetes mellitus type I and II, chronic kidney disease/end-stage renal disease, chronic inflammatory diseases, human immunodeficiency virus infection, and nephrotic syndrome)(23)

Universal screening involves obtaining either a fasting lipid profile or a non-fasting non-HDL, (calculated by subtracting HDL from TC) in childhood at two time points:

  1. Between ages 9-11 years
  2. Between ages 17-21 years

Table 2 Approaches to screening for heterozygous FH during childhood

ApproachAge in YearsPopulationRecommended Method
Selective2-21-Family history of early atherosclerosis or high cholesterol
-Presence of risk factors or medical conditions that increased early CVD risk*
Fasting lipid profile
Universal9-11 and 17-21AllNon-fasting non-HDL

*Selective screening is indicated in individuals with hypertension, current cigarette smoking, body mass index ≥ 85th percentile, diabetes mellitus type I and II, chronic kidney disease/end-stage renal disease, chronic inflammatory diseases, human immunodeficiency virus infection, and nephrotic syndrome

DIAGNOSIS

The diagnosis of FH can be made clinically and through genetic testing; genotype needs to be interpreted in the context of phenotype. For heterozygous FH, the clinical diagnosis is made based on the presence of high levels of total and LDL cholesterol in combination with one or more of following (15):

  1. Family history of hypercholesterolemia (especially in children) or known FH
  2. History of premature CHD in the patient or in family members
  3. Physical examination findings of abnormal deposition of cholesterol in extravascular tissues (eg, tendon xanthoma), although these rarely occur in childhood

For the clinical diagnosis of homozygous FH, the diagnosis is generally made in individuals with the following criteria (24):

  1. Untreated LDL-C >500mg/dL (>13 mmol/L) or treated LDL-C ≥300 mg/dL (>8 mmol/L), AND
    1. Cutaneous or tendon xanthoma before age 10 years, OR
    2. Elevated LDL-C levels consistent with heterozygous FH in both parents

Genetic Testing

Identifiable gene defects in LDLR, apoB, or PCSK9 have been identified in 60 to 80% of individuals with a heterozygote FH phenotype. Genetic testing is not routinely performed in the clinical setting since it is expensive and is not likely to alter management, given that treatment decisions are usually based on LDL-C levels. The clinical significance of normal or moderately elevated LDL-C levels in the setting of a genetic defect in the LDLR or other possibly pathogenic defects is unknown.

TREATMENT

The guidelines for initiating treatment in patients with the FH phenotype are based on age, severity of LDL-C elevation, as well as family and medical histories. Lifestyle therapy is recommended for all children and adolescents with LDL-C levels ≥ 130 mg/dL. If lifestyle intervention is insufficient, medications can be considered in children beginning at age 10 years, or as early as age 8 in high risk patients and in the presence of a very high risk family history. For healthy, older children or adolescents ages 10-21 years, lifestyle therapy should be provided to those with an LDL-C ≥ 130 mg/dL, and medication should be initiated if LDL-C remains ≥ 190 mg/dL despite 6 or more months of lifestyle modification. If there is a family history of early atherosclerotic disease, then medication should be started in individuals with LDL-C levels ≥ 160 mg/dL who do not respond sufficiently to lifestyle modification. Additionally, if an individual has a high-risk medical condition as noted above, medication can be considered for those with a persistently elevated LDL-C ≥ 130 mg/dL. In general, the goal of treatment is to maintain an LDL-C level ≤ 130 mg/dL or ≥ 50% reduction in LDL concentration; lower cutpoints may be considered in high risk patients. Medications should be initiated in all patients with homozygous FH regardless of age, and additional treatments should also be considered.

Lifestyle Treatment

The mainstay of treatment for a pediatric lipid disorder is lifestyle modification or therapy. A low saturated fat diet, without trans-fat and high in fruits and vegetables, is the recommended diet for lowering LDL-C. This dietary approach has been shown to be both safe and beneficial in the general pediatric population (23,25,26). Additionally, nutritional and physical activity interventions have been shown to lower LDL-C and improve CVD risk factors in children with obesity in meta-analyses (27). Despite this, in adults with FH, lifestyle modifications have been shown to only lower LDL-C modestly (28). Furthermore, the effect of physical activity on LDL-C levels has not been well studied in children with FH.

Pharmacotherapy: Statins:

The majority of patients with FH are treated with medications, and statins are the recommended first line pharmacotherapy. In a Cochrane meta-analysis of pediatric patients with FH, statins were shown to lower LDL-C by 32% (29). Follow-up data from a statin trial in pediatric Dutch patients suggest efficacy and safety, as well as decreased atherosclerosis compared to the subjects’ parents (19). However, there have been no published reports of CVD outcomes of statins in children or adolescents with heterozygous FH, likely due to the long horizon for clinical events. Thus, the benefits of long-term statin use in childhood in preventing ASCVD compared to placebo, while suspected based on observational data, have not been proven.

Several different formulations of statin therapy are available. Lovastatin, simvastatin, pravastatin, rosuvastatin, and atorvastatin are approved by the US Food and Drug Administration (FDA) for use in children. Treatment is initiated at a low dose (generally 5-20mg depending on the statin potency), which is given once a day, often at night. If needed, the dose is increased to meet the goals of therapy. Side effects with statins are rare, but include myopathy, new-onset type 2 diabetes mellitus (reported in adult primary prevention statin trials), and hepatic enzyme elevation. In pediatric clinical trials, rates of side effects with statin therapy were low and adherence to statin therapy was generally good (30). Side effects of statins are more likely at higher doses and in patients taking other medications, particularly cyclosporine, azole antifungal agents, and other medications and foods (such as grapefruit) that impact the cytochrome P450 system. Adolescent females should be counseled about the possibility of drug teratogenicity and appropriate contraceptive methods while receiving statin therapy. Additionally, providers should be aware that oral contraceptive pills can increase lipid levels.

The NHLBI guidelines recommend the following baseline laboratory evaluation when initiating statin therapy (23):

  • Fasting lipid profile
  • Serum creatine kinase (CK)
  • Hepatic enzymes (ie, serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST])

Liver function tests and fasting lipid profiles are repeated four and eight weeks after the initiation of statin therapy to determine the efficacy of the treatment and to assess for adverse effects, and are repeated every six months in patients on stable therapy. Ongoing monitoring of growth and other measures of general and cardiovascular health, such as blood pressure, and review for the presence of additional ASCVD risk factors such as smoking exposure should also occur at each visit.

Bile Acid Binding Resins:

Although bile acid binding resins or bile acid sequestrants have been shown to lower LDL-C by ~10-20% in pediatric trials (31,32), they are often difficult to tolerate given their unpalatability and associated adverse effects (such as bloating and constipation) (33). For these reasons, bile acid binding resins are used relatively infrequently. However, they may be useful in combination with a statin for patients who fail to meet target LDL-C levels (34). The sequestrants are not absorbed systemically, remain in the intestines, and are excreted along with bile containing cholesterol. Therefore, they are considered to be very safe. They can be used in patients who prefer to avoid statins, although they may not lower LDL-C sufficiently to achieve goal levels. Bile acid binding resins can also be used during pregnancy and therefore can be used in women who are trying to conceive.

Cholesterol Absorption Inhibitors (Ezetimibe):

Ezetimibe is a lipid-lowering mediation that inhibits absorption of cholesterol and plant sterols in the intestines. This agent can be useful in pediatric patients with FH who are not able to reach LDL-C treatment goals on high-intensity statin therapy. Furthermore, ezetimibe further lowers serum LDL-C and improves cardiovascular outcomes without altering the side effect profile (35–37).

PCSK9 Inhibitors:

PCSK9 inhibitors (evolocumab and alirocumab) are human monoclonal antibodies that bind to PCSK9 and promote plasma LDL cholesterol clearance. In Europe, evolocumab is approved in adolescents (≥12 years old) with homozygous FH. In the US, alirocumab is approved only for use in adult patients and evolocumab is approved for use in adults with heterozygous FH and in homozygous FH, ages 13 and older, who have not responded to other LDL-C lowering therapies. Overall, PCSK9 inhibitors appear to have a good safety and side effect profile in adults (38). The main disadvantage of these medications is that they require injection for administration; cost is also a concern. Pediatric trials to determine efficacy, safety, and long-term outcomes in children and adolescents with FH are still needed.

Figure: Dyslipidemia algorithm

Image fam-hypercholest_LP-40-fig1.jpg

Dyslipidemia algorithm:

target LDL cholesterol. Values given are in mg/dL. To convert to SI units, divide results for TC, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol by 38.6; for triglycerides, divide by 88.6. TG indicates triglycerides; C, cholesterol; RF, risk factor; FHx, family history; a Obtain FLPs at least 2 weeks but no more than 3 months apart. b Per Table 9-9, use of drug therapy is limited to children aged 10 years and older with defined risk profiles. c In a child with an LDL cholesterol level of >190 mg/dL and other risk factors, a trial of the CHILD-2–LDL may be abbreviated. (23)

SUMMARY

FH is an autosomal dominant disorder of LDL metabolism that affects 1 in 200 to 300 individuals. Screening involving lipid measurements, family and medical history, and physical examination is needed to identify affected individuals. Lifestyle modification is the first-line therapy for hyperlipidemia in pediatrics, but is usually not sufficient to achieve goal LDL levels. Available evidence suggests that treatment with lipid-lowering pharmacotherapy, such as statins, is effective and generally safe in the short and medium term. However, further studies are needed to determine the long-term safety and the efficacy in preventing ASCVD of lipid lowering medication in pediatric patients with FH.

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