Familial hypercholesterolemia in adults: Overview

INTRODUCTION — Familial hypercholesterolemia (FH) is a common genetic disease caused by mutation of one or more of the genes critical for low-density lipoprotein cholesterol (LDL-C) catabolism (see 'Genetic considerations' below). [1] The clinical syndrome (phenotype) is characterized by extremely elevated levels of LDL-C and a propensity to early onset atherosclerotic cardiovascular disease. Homozygotes generally manifest disease in childhood. (See "Familial hypercholesterolemia in children".)

This topic will focus on issues not related to the primary goal of therapy, which is to significantly lower LDL-C levels. Treatment details are presented separately. (See "Familial hypercholesterolemia in adults: Treatment".)

Other inherited lipid disorders are discussed separately. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

DEFINITION — An individual may be labeled as having FH in one of two ways:

●DNA-based evidence of mutation in the LDLR, PCSK9, or APOB gene. Each of these genes influence LDL-C levels.

●Clinical characteristics that usually include a high LDL-C.

The following are three recognized diagnostic criteria schemes [2]:

●Dutch Lipid Clinic (table 1).

●Simon Broome (table 2).

●American Heart Association criteria for the clinical diagnosis of FH: low-density lipoprotein cholesterol (LDL-C) >190 mg/dL (>4.9 mmol/L) and either a first degree relative with LDL-C>190 mg/dL or with known premature coronary heart disease (55 years men; <60 years women) [3].

When possible, we will attempt to specify which definition is being used.

GENETIC CONSIDERATIONS — FH is the most common autosomal dominant genetic disease. Patients with FH usually have a functional mutation of one of three genes: the low-density lipoprotein receptor gene (LDLR; sometimes called the apoB/E receptor); gain-of-function mutations of the proprotein convertase subtilisin kexin 9 gene (PCSK9), and the apolipoprotein B gene (principally APOB3500) (table 3). Each of these three mutations impairs LDL receptor-mediated catabolism of the LDL particle, leading to higher LDL-C in the blood [4,5]. Of these, LDLR mutations are by far the most common. Mutations in these genes exhibit additive gene dosing effects, such that individuals with two pathogenic mutations (homozygotes or compound heterozygotes) are more adversely affected than those with one pathogenic mutation (heterozygotes) (figure 1) [4].

The prevalence of pathogenic mutation in at least one of these three genes varies by the degree of certainty of FH definition, estimated at about 80 percent in patients with definite FH clinical syndrome and 20 to 30 percent of those with possible FH syndrome [6-9]. Among those with one of these three mutations, 85 to 90 percent have LDLR mutations, 2 to 4 percent gain-of function PCSK9 mutations, and 1 to 12 percent APOB mutations [10-14].

Those individuals who meet the phenotypic criteria for clinical FH (see 'Definition' above) and in whom no causative single gene mutation is identified (up to 20 percent in some series), are labeled as having severe polygenic hypercholesterolemia, whereby the combination of small effects of multiple individual variants jointly lead to a significantly elevated LDL-C [6,13,15-17]. Polygenic risk scores that estimate an individual's genetic risk by quantifying the burden of known susceptibility variants have been developed for hypercholesterolemia. The cumulative effect of multiple small effect loci can result in LDL-C levels within the same range as a single major gene associated with heterozygous FH [18]. In addition, some individuals with the highest polygenic risk scores (those above the 90th percentile of genetic risk) also carry additional deleterious monogenic variants [6,8,17,19]. Polygenic hypercholesterolemia is discussed in detail elsewhere. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Polygenic hypercholesterolemia'.)

It is likely that only a very small proportion of patients with FH have some as of yet undiscovered causative single gene mutation. For example, mutations in a signal transducing adaptor family member 1 (STAP1), occurring in <0.1 percent of cases, have been proposed as candidates to be the fourth cause of FH. 

Impact on clinical presentation — The development of atherosclerotic cardiovascular disease (ASCVD) attributable to elevated LDL is more related to the duration and degree of LDL-C elevation than it is to the specific genetic defect(s) present. Adults with heterozygous (and homozygous) FH have had high levels of LDL-C since birth, whereas adults with high LDL-C levels not due to FH have had high LDL-C for a shorter duration of time and thus are at somewhat lower risk of premature ASCVD.

Due to the above described additive effects of pathogenic variation on LDL-C levels, patients with two pathogenic variants or one pathogenic variant and high polygenic cholesterol risk score can present with ASCVD early in life. Also, at similar levels of LDL-C as adults, the presence of monogenic FH increases the risk of premature CVD by about two- to fourfold relative to individuals without an FH-causing variant. This is consistent with observations that heterozygous FH patients typically have high LDL-C levels from birth and a higher risk of premature coronary heart disease. Genetic variations other than the three major ones described above (see 'Genetic considerations' above) cause more minor LDL-C raising and may also affect the LDL-C in FH patients and contribute to age at onset and severity of cardiovascular risk [6,20]. In general, heterozygous FH patients have high LDL-C levels from birth and a higher risk of premature coronary heart disease compared to polygenic individuals who usually do not have very high LDL-C levels in early life.

In adults, LDL-C concentrations should be treated similarly regardless of whether a definite diagnosis of FH has been made or whether the polygenic score is high [5,19,21]. However, the presence of a high polygenic risk score in a patient with monogenic FH is a very high risk.

LDL receptor genetic defects — In its most common form, FH is a monogenic disorder caused by defects in the gene that encodes for the apo B/E (LDL) receptor [11,22-24]. The associated impairment in function of these receptors results in reduced clearance of LDL particles from the circulation and an elevation in plasma LDL-C. In general, plasma levels of LDL-C are inversely related to the level of residual LDLR activity. There is also increased uptake of modified LDL (oxidized or other modifications) by the macrophage scavenger receptors, resulting in macrophage lipid accumulation and foam cell formation [25]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Lipoproteins and atherosclerosis'.)

Over 1600 different mutations in the LDLR gene have been identified [26]. The mutations at the LDLR locus have been categorized into four classes of alleles based on the phenotypic behavior of the mutant protein [22]:

●Class I – Null, in which synthesis is defective.

●Class II – Transport defective, in which intracellular transport from the endoplasmic reticulum to Golgi is impaired.

●Class III – Binding defective, in which proteins are synthesized and transported to the cell surface normally, but binding of LDL is defective.

●Class IV – Internalization defective, in which proteins reach the cell surface and bind LDL normally but the receptors do not cluster in the coated pits, thereby minimizing LDL internalization.

Patients with FH may be classified into one of two major groups based on the amount of LDLR activity: patients with less than 2 percent (receptor-negative) and patients with 2 to 25 percent of normal LDLR activity (receptor-defective) [27].

Mutations in the PCSK9 gene — Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease that is secreted by the liver. Extracellularly, it binds the LDLR expressed principally on liver cells. Once the PCSK9-LDLR complex is internalized into the hepatocyte physiologically through the coated pit region of its outer membrane, LDL receptors bound to PCSK9 are prevented from recycling to the cell surface and undergo destruction inside liver cells [28]. Fewer LDL receptors lead to less clearance of LDL-C and higher serum levels. Gain-of-function mutations in PCSK9 are rare, but lead to decreased LDLR expression, decreased LDL catabolism, higher levels of LDL-C, the heterozygous FH clinical syndrome, and increased risk of ischemic heart disease; loss-of-function mutations are more common and are associated with reductions of both LDL-C and risk of ischemic heart disease.

The following observations summarize the clinical importance of PCSK9:

●Elevated PCSK9 levels are associated with reduced expression of the hepatic LDLR and increased serum LDL-C [29,30]. There are polymorphisms in the PCSK9 gene that are associated with increased severity of coronary atherosclerosis in patients with polygenic hypercholesterolemia [31]. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Polygenic hypercholesterolemia'.)

●In multiple population studies, carriers of the loss-of-function 46L allele of PCSK9 have lower levels (9 to 16 percent) of LDL-C as well as a lower risk (6 to 47 percent) of ischemic heart disease compared with noncarriers [32,33]. In a meta-analysis of three large population studies, 46L allele carriers had a 12 percent reduction in LDL-C and a 28 percent reduction in the risk of ischemic heart disease [33]. The observed reduction in LDL-C predicted only 5 percent of the reduction in the risk of ischemic heart disease. Explanations include a greater effect with lifelong exposure or other non-LDL-C-lowering effects.

●Statins increase serum levels of PCSK9 in a dose-dependent manner, potentially lessening their LDL-C-lowering effect, particularly with dose escalation [34]. In a case-control substudy of the TNT trial of high- versus low-dose statin therapy in patients with stable coronary heart disease, circulating PCSK9 levels measured at randomization were predictive of major cardiovascular events at five years in the group assigned to 10 mg of atorvastatin but not in the group assigned to 80 mg [35]. At one year, there was no difference in PCSK9 levels between the two treatment groups nor was there any difference between randomization or one-year levels in either treatment arm.

Infusion of a monoclonal antibody to PCSK9 reduces LDL-C levels [36]. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use", section on 'Clinical use'.)

Familial defective apolipoprotein B-100 — Familial defective apo B-100 is an autosomal dominant disorder that is associated with impaired binding of LDL particles to the apo B/E (LDL) receptor [37]. The defect is localized to the apo B-100 ligand on the LDL particle (mutation at residue 3500), not the apo B/E (LDL) receptor. The net effect is that the clearance of LDL is reduced and plasma levels increase by two- to threefold. The frequency of the apo B 3500 mutation among patients classified as FH heterozygotes is as high as 3 percent [38,39].

Only a minority of people inheriting of APOB3500 express raised LDL-C to the same extent as those inheriting loss of function LDLR mutations. One study evaluated the frequency and clinical significance of the apolipoprotein B 3500 mutation in 9255 subjects from the general population, 948 patients with coronary heart disease, and 36 patients with FH [40]. The mutation was present in 0.08 percent of subjects in the general population in whom the mean serum cholesterol concentration was 100 mg/dL (2.6 mmol/L) higher than in those without the mutation. The increment in serum cholesterol above the general population was more pronounced in the patients with coronary heart disease (154 mg/dL [4.0 mmol/L]) and those with FH (172 mg/dL [4.5 mmol/L]). Heterozygotes for the mutation were more common in patients with CHD (odds ratio 7.0) and FH (odds ratio 78) compared with the general population.

VARIATION IN LDL-C — While the low-density lipoprotein cholesterol (LDL-C) level is heavily dependent on one of the three genes discussed above (see 'Genetic considerations' above), other genes may further alter the LDL-C level (figure 2). (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

The likelihood of a monogenic or an oligogenic cause for heterozygous FH becomes increasingly likely the higher the LDL-C [19]. (See 'Genetic considerations' above.)

In addition, other factors such as diet, comorbid diseases (eg, hypothyroidism, liver disease), or genetic abnormalities not related to the LDL receptor, PCSK9, or apolipoprotein B genes may alter LDL-C levels. In addition, acute viral illness or inflammatory state or the post-surgical state can have a transient suppression of lipid synthesis that typically lowers LDL-C. (See "Secondary causes of dyslipidemia".)

GENETIC TESTING — Several companies and academic medical centers offer panels of tests (LDL-R) that capture major pathogenic low-density lipoprotein receptor mutations, ApoB3500 mutations, and PCSK9 gain of function mutations. In most cases, we order a gene-sequencing test. There is no population screening for FH in the United States; however, an investigation suggested it may be cost effective to perform in United States adults younger than 40 years if the testing cost is relatively low and probands have access to preventive interventions [41].

Indications — There is no widespread agreement as to when genetic testing is indicated in the process of evaluating a very elevated LDL-C. In general, we order such tests only when the results might alter clinical decision making.

There are two possible reasons for genetic testing:

●When the diagnosis is unclear from the LDL-C concentration, usually this is around puberty when its habitual level decreases due to the growth spurt or when some other illness lowers LDL. This is not absolute; the cholesterol can be repeated at a later stage when it has returned to its more typical level.

●The presence of tendon xanthomata in the proband is a good reason to begin cascade screening. The point of cascade is to identify affected relatives, usually younger ones who have yet to develop ASCVD. (See "Genetic counseling: Family history interpretation and risk assessment".)

Incidental finding — Some patients will have genetic testing performed for reasons other than the two discussed directly above. Occasionally, a variant for FH is detected. In these patients, we evaluate the individual’s cardiovascular risk and consider intensive LDL-C lowering if a high lifetime risk is present.

PREVALENCE — FH is the most common monogenic, autosomal dominant disorder in humans. The reported prevalence of FH will vary by the definition used (see 'Definition' above) and the population (impact of the gene pool) studied. The evidence suggests that the prevalence of heterozygous FH in the general (or nonconsanguineous) population worldwide is about 1 in 300 individuals [2,4,20,42-46]. Homozygous patients are rare and have an estimated prevalence of approximately 1:300,000 to 1:400,000 [4]. Prevalence in consanguineous populations is higher.

Two large meta-analyses were published in 2020 to establish the worldwide prevalence of heterozygous FH [47,48]. In one, more than seven million people [47] were involved, and in the other, nearly 11 million [48]. Typically, using the Dutch Lipid Clinic Network Criteria for the diagnosis (table 1), the prevalence of heterozygous FH was similar in both reports: 1 in 311 and 1 in 31 of the general population, respectively. The prevalence among patients with atherosclerotic cardiovascular disease (ASCVD) [47] was 18 times higher, and in patients with premature IHD (as defined by the individual investigators), 21 times higher [48]. The findings in these two meta-analyses were consistent with earlier studies [43,49-51]. (See 'Definition' above and 'Genetic considerations' above.)

It should be kept in mind that the great majority of the estimated 7 percent of Americans with LDL-C exceeding 190 mg/dL do not fulfill the clinical criteria for a definite diagnosis of heterozygous FH and nor do they have any identifiable DNA mutation likely to cause heterozygous FH [5]. However, the combination of raised LDL-C and an identifiable FH-causing mutation significantly increases the risk for coronary artery disease above that of people with similar LDL-C but no FH-causing mutation.

CLINICAL PRESENTATION — Patients with undiagnosed homozygous familial hypercholesterolemia (FH) develop severe, premature, atherosclerotic cardiovascular disease and die before age 20 in many cases. (See "Familial hypercholesterolemia in children".)

In previously undiagnosed heterozygous FH, patients present with symptoms or signs of atherosclerotic cardiovascular disease (eg, angina, corneal arcus, xanthelasma, tendon xanthoma, or periosteal xanthoma) or adverse atherosclerotic cardiovascular disease events (eg, myocardial infarction, sudden cardiac death) in early middle age. In addition, many patients will be identified by the finding of a low-density lipoprotein cholesterol greater than the 90 percentile for age and sex when the test was performed for cardiovascular risk screening (figure 2).

Coronary artery calcification, a marker of coronary artery disease, can be identified at 11 to 23 years of age in heterozygotes [52]. (See "Coronary artery calcium scoring (CAC): Overview and clinical utilization".)

Patients demonstrate tendon xanthomata if untreated, and frequently have a family history of hypercholesterolemia (table 1). Some of the excess LDL-C is deposited in the arteries as atheroma and in the tendons and skin as xanthomata (picture 1A-D) and xanthelasma (picture 2). The prevalence of xanthomata increases with age, eventually occurring in 75 percent of FH heterozygotes.

CLINICAL SUSPICION — A diagnosis of familial hypercholesterolemia (FH) should be suspected in adults with any of the following [43,53,54]:

●Elevated plasma low-density lipoprotein cholesterol (LDL-C) – The level of LDL-C that warrants further evaluation depends upon whether additional family members have known hypercholesterolemia and/or early cardiovascular disease. In patients with a negative or unknown family history, an untreated LDL-C level of ≥190 mg/dL (4.9 mmol/L) suggests FH. This value is greater than the 90^th percentile for age and sex.

●Family member with known FH or elevated cholesterol (total cholesterol >240 mg/dL [6.2 mmol/L] in either parent).

●Cholesterol deposits (called xanthomas, which often occur in tendons, around the cornea, or perioral) in the patient or family members.

●Premature coronary heart disease in the patient or family member(s). Among young patients with premature acute coronary syndromes in Switzerland (mean age about 50 years), 1.6 percent had probable/definite FH (Dutch Lipid Clinic definition) [55].

●Sudden premature cardiac death in a family member.

EVALUATION — In patients suspected of familial hypercholesterolemia (FH) (see 'Clinical suspicion' above), the evaluation includes a complete history and physical examination and some laboratory tests. An evaluation for secondary causes of hypercholesterolemia (table 4) should be performed. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Secondary causes of hypercholesterolemia'.)

●Personal history – The personal history should pay attention to symptoms or signs of ASCVD such as angina, transient ischemic attack, claudication or prior myocardial infarction, stroke, or arterial revascularization. The patient should be evaluated for the presence of other major risk factors for ASCVD. (See "Overview of established risk factors for cardiovascular disease", section on 'Established risk factors for atherosclerotic CVD'.)

●Family history – A detailed family history is essential in establishing the diagnosis of FH. Identifying family members with premature coronary heart disease, tendon xanthomas, and elevated cholesterol levels (particularly if present during childhood) help support the diagnosis of FH. Caregivers should also obtain a history of thyroid, renal, hepatic, or biliary disease in order to exclude secondary causes.

●Physical examination – The physical examination is directed at identifying evidence of abnormal deposits of cholesterol in the skin and eyes, which are rarely seen in children except in those with homozygous FH and sitosterolemia:

•Tendon xanthomata (picture 1A-C) are most common in the Achilles tendons and dorsum of the hands, but can occur at other sites.

•Planar xanthomas (picture 1D) may occur on the palms of the hands and soles of the feet and are often painful.

•Xanthelasmas (picture 2) 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 (picture 3 and picture 4).

•The pulses of the major arteries should be checked looking for evidence of vascular obstruction

•Signs of aortic stenosis should be sought. (See "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Physical examination'.)

●Fasting lipid profile – The characteristic fasting lipid profile in patients with FH consists of elevated total and low-density lipoprotein cholesterol with normal or low high-density lipoprotein cholesterol and normal triglyceride (TG) levels (unless the patient is obese, has diabetes, or other mutations in triglyceride-regulating genes, in which case TG levels may also be elevated). Elevated TG levels do not exclude the diagnosis of FH; however, other potential causes of hypertriglyceridemia should be considered.

●Genetic testing – Testing for mutations in the LDLR, APOB, and PCSK9 genes can be performed in individuals with a clinical diagnosis of homozygous FH based on the criteria discussed below [43] (see 'Diagnosis' below and 'Indications' above). However, in most cases, it does not alter the clinical approach. Genetic testing should be performed in consultation with a lipid specialist and/or geneticist. Genetic testing that does not find a major pathogenic LDL receptor mutation, an ApoB3500 mutation, or a PCSK9 gain-of-function mutations may not necessarily mean that there is no genetic defect.

Genetic testing in adults with a clinical picture consistent with heterozygous FH does not contribute substantially to clinical decision-making, and its role is not established.

The cost for genetic testing may not be reimbursable and some companies test for only a small number of mutations.

●Testing for lipoprotein(a) – Patients with FH and an elevated level of lipoprotein(a) have a significantly higher risk of cardiovascular disease events than those with normal lipoprotein(a) levels [56]. Thus, we test for lipoprotein(a) in all patients with FH. The finding of high Lp(a) in someone with elevated LDL-C makes that individual a case of suspected FH and militate in favor of genetic testing [57]. (See "Lipoprotein(a)", section on 'Genetics'.)

●Testing for apo E variants – Recently, rare apo E variants have been described that on their own cause FH syndrome. In FH due to LDLR, PCSK9, and APOB3500 mutation, the presence of the more common apo E variant (apoE4) leads to an even higher LDL-C [58].

DIAGNOSIS — The diagnosis of heterozygous familial hypercholesterolemia (FH) can be made with genetic testing or clinical criteria. A causative mutation in the LDLR, APOB, or PCSK9 gene(s) secures this diagnosis. (See 'Genetic considerations' above.)

When genetic testing is not available or not felt to be necessary, we use the Dutch Lipid Clinic Network criteria (table 1), which assigns points based on low-density lipoprotein cholesterol (LDL-C) levels, personal history of early atherosclerotic cardiovascular disease (ASCVD), family history of early ASCVD, or high cholesterol in a first-degree relative, and physical examination findings [43].

An alternative definition is that of the Simon Broome Register Group, which is used predominately in the United Kingdom [59]. This system classifies patients as having definite or probable heterozygous FH.

Criteria for the clinical diagnosis of homozygous FH include [60]:

●Untreated LDL-C >500 mg/dL (>13 mmol/L) or treated LDL-C ≥300 mg/dL (>8 mmol/L), AND

•Cutaneous or tendon xanthoma before age 10 years, OR

•Elevated LDL-C levels consistent with heterozygous FH in both parents

It is important to note, however, that untreated LDL-C levels <500 do not exclude homozygous FH, particularly in young children.

Differential diagnosis — It is important to distinguish FH from other causes of hypercholesterolemia, xanthomata, and/or premature ASCVD:

●Hypercholesterolemia and premature ASCVD – Other common causes of hypercholesterolemia and premature ASCVD include (table 5):

•Familial combined hyperlipidemia (see "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Familial combined hyperlipidemia')

•Hyperapobetalipoproteinemia (see "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Familial combined hyperlipidemia')

•Polygenic hypercholesterolemia (see "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Polygenic hypercholesterolemia')

•Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) (see "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Moderate or moderate to severe hypertriglyceridemia')

The clinical history and evaluation of the lipid profile are helpful in distinguishing these disorders.

●Xanthomata – Xanthomata, particularly in children, are highly suggestive of FH, but they can be seen on other rare genetic disorders (eg, sitosterolemia and cerebrotendinous xanthomatosis, described below). In addition, juvenile xanthogranulomas (JXG) and other non-Langerhans cell histiocytoses have a similar appearance and may be mistaken for xanthomata. The distribution of the lesions helps to differentiate xanthomata in FH from the lesions in JXG (in FH, xanthomata commonly occur on Achilles tendons, dorsum of the hands, and extensor surfaces of the knees and elbows; whereas lesions in JXG typically occur on the head, neck, and upper trunk). A definitive distinction is made on the basis of the lipid profile, which is normal in JXG. (See "Juvenile xanthogranuloma (JXG)".)

●Tendon xanthomata and premature atherosclerosis – Tendon xanthomata and premature atherosclerosis can also occur in two rare genetic disorders:

•Sitosterolemia – Sitosterolemia (alternatively termed "phytosterolemia") is an autosomal recessive disorder associated with hyperabsorption of cholesterol and plant sterols from the intestine [61]. It is characterized by tendinous and/or tuberous xanthomas in childhood associated with very high plasma cholesterol and atherosclerotic complications. Sitosterolemia can be differentiated from FH based upon markedly (>30-fold) increased plasma concentrations of plant sterols. In addition, patients with sitosterolemia typically respond well to diet, ezetimibe, and/or bile acid sequestrants, which generally is not the case in patients with homozygous FH. Diagnosis of sitosterolemia can be confirmed by genetic analysis, with detection of mutations in two ATP-binding cassette transporter (ABC transporters) genes, ABCG5, and/or ABCG8 [60].

•Cerebrotendinous xanthomatosis – Cerebrotendinous xanthomatosis is caused by a block in bile acid synthesis due to the absence of hepatic mitochondrial 27-hydroxylase (CYP27). It can be distinguished from FH by the presence of neurological, cognitive, and ophthalmic symptoms and usually normal serum cholesterol concentrations. (See "Cerebrotendinous xanthomatosis".)

INDICATIONS FOR REFERRAL — We suggest referring the following groups of patients to a specialist in the care of lipid disorders:

●All those with homozygous familial hypercholesterolemia (FH).

●All those with heterozygous FH or other primary disorders of low-density lipoprotein cholesterol (LDL-C) metabolism who remain above their LDL-C target on maximum tolerated dose of a statin. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Goal of therapy'.)

PROGNOSIS — Prior to the widespread use of statin therapy for patients with heterozygous familial hypercholesterolemia (FH), the risk of premature coronary heart disease (CHD) was very high [62]. In a 1974 study of over 1000 first and second degree relatives of 116 index patients, the risk of fatal or nonfatal CHD by age 60 was 52 percent for male and 32 percent for female relatives [63]. In relatives without FH, the comparable rates were 13 and 9 percent, respectively. Treatment leads to a marked improvement in prognosis. (See "Familial hypercholesterolemia in adults: Treatment", section on 'Rationale for intense LDL-C lowering'.)

At any level of untreated low-density lipoprotein cholesterol (LDL-C), the prognosis for patients with heterozygous FH is worse than those without. Gene (LDLR, APOB, and PCSK9) sequencing (see 'Genetic considerations' above) was performed in a study of 1386 patients with LDL-C ≥190 mg/dL [5]. Compared with a reference group with LDL-C <130 mg/dL, those with LDL-C ≥190 mg/dL and an FH mutation had a 22-fold increased risk (odd ratio 22.3, 95% CI 10.7-53.2) for coronary artery disease.

Some of the heterogeneity in the time course for the development of clinical CHD is likely explained by the presence or absence of other risk factors.

In heterozygous FH patients who have sustained an acute coronary syndrome and have been treated with high-dose statins, the risk of death and nonfatal myocardial infarction within one year is approximately three times higher than matched individuals without FH [49].

For homozygous patients, the extent of reduction of serum cholesterol, achieved by any therapeutic intervention, is a major determinant of survival [64].

SCREENING — Once we identify familial hypercholesterolemia (FH) in a patient, we strongly recommend screening of all first degree relatives, including children beginning at age two years. This is due to the particularly high risk of premature cardiovascular disease. Screening for and the diagnostic evaluation of FH in children are discussed separately. (See "Familial hypercholesterolemia in children", section on 'Screening'.)

TREATMENT — The primary goal of treatment in patients with familial hypercholesterolemia is reduced the risk adverse cardiovascular disease events by lowering LDL-C. This issue is discussed in detail separately. (See "Familial hypercholesterolemia in adults: Treatment".)

Patients in whom the diagnosis of FH has been considered based on a LDL-C ≥190 mg/dL [5], but in whom a monogenic cause has not been established by genetic testing, should not be dismissed as being at lower ASCVD risk, both because certainly in the presence of additional ASCVD risk factors their risk may reach that of monogenic FH and because people with higher LDL-C levels can derive greater benefit from cholesterol-lowering treatment than many with lower levels even in the absence of a monogenic cause.’

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary prevention of cardiovascular disease" and "Society guideline links: Lipid disorders in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Familial hypercholesterolemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease caused by functional mutations at one of three genetic loci. In the absence of genetic testing, which confirms one of these mutations, FH is defined based on clinical criteria. (See 'Definition' above and 'Diagnosis' above.)

●Prevalence – Homozygous patients are rare and have an estimated prevalence of approximately 1:300,000 to 1:400,000. Heterozygous FH is estimated to occur in about 1 in 300 individuals in Europe and 1 in 200 to 250 individuals in the United States. (See 'Prevalence' above.)

●Clinical presentation – Previously undiagnosed heterozygous FH patients present with symptoms or signs of cardiovascular disease or adverse cardiovascular disease events in early middle age. Many patients will be identified by the finding of a low-density lipoprotein cholesterol (LDL-C) greater than the 90^th percentile for age and sex when the test was performed for cardiovascular risk screening. (See 'Clinical presentation' above.)

●Screening – Health care providers should recommend lipid profiles for all first-degree relatives of patients with FH in order to identify other individuals at risk. (See 'Screening' above.)

●Prognosis – In the absence of aggressive lipid lowering therapy, life span is significantly shortened. In addition, for a given level of LDL-C, the prognosis is worse for FH patients than those without FH. (See 'Prognosis' above.)

●Indications for referral – We suggest referring patients with homozygous FH or those with heterozygous FH who do not meet their target LDL-C with statin therapy to a specialist in the care of lipid disorders. (See 'Indications for referral' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Sarah D. de Ferranti for her past contributions as an author to prior versions of this topic review.