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Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia

Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia
Literature review current through: Jan 2024.
This topic last updated: Nov 08, 2023.

INTRODUCTION — Clinical dyslipidemia includes, but is not limited to, patients with abnormal levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, or lipoprotein(a). An abnormal level of each of these is the result of one or more genetic abnormalities or secondary to some underlying disease or environmental factors [1].

One definition of dyslipidemia is total cholesterol, LDL-C, triglyceride, or lipoprotein(a) levels above the 90th percentile or high-density lipoprotein cholesterol or apoA-1 levels below the 10th percentile for the general population (table 1).

Elevation of LDL-C is common in the general population. Most of these individuals have one or more genetic abnormalities rather than a secondary cause (such as liver or kidney disease) (see "Secondary causes of dyslipidemia"). For individuals with LDL-C above 190 mg/dL, the genetic defects that lead to familial hypercholesterolemia (FH) are the most common underlying cause (see "Familial hypercholesterolemia in adults: Overview"). This topic will discuss non-FH causes of elevated LDL-C.

General treatment guidelines for elevated LDL-C and possible indications for the therapy of other dyslipidemias, such as low serum high-density lipoprotein cholesterol, hypertriglyceridemia, and elevated serum lipoprotein(a), are discussed in other topic reviews. (See "HDL cholesterol: Clinical aspects of abnormal values" and "Lipoprotein(a)" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Hypertriglyceridemia in adults: Management".)

The approach to children with dyslipidemia is found elsewhere. (See "Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood" and "Overview of the management of the child or adolescent at risk for atherosclerosis".)

PREVALENCE OF LIPID ABNORMALITIES — The prevalence of one or more abnormal lipid fractions varies with the population being studied. It is highest in populations of patients with premature coronary heart disease (CHD), which can be defined as occurring before 55 to 60 years of age in men and before 65 years in women. In this setting, the prevalence of dyslipidemia is as high as 75 to 85 percent compared with approximately 40 to 48 percent in age-matched controls without CHD (figure 1) [2,3]. The lipid abnormality is often familial. In one study, for example, 54 percent of all patients with premature CHD (and 70 percent of those with a lipid abnormality) had a familial disorder [2]. In the great majority of patients, inheritance is polygenic and the expression of dyslipidemia is strongly influenced by factors such as obesity (particularly central obesity) and the saturated fat and cholesterol content of the diet.

In nations with low rates of obesity and where saturated fat intake is low, both the incidence of CHD and the prevalence of dyslipidemia are low compared with North America and Europe.

GENETICS OF ELEVATED LDL-C — The terminology surrounding the hereditary disorders of low-density lipoprotein cholesterol (LDL-C) metabolism can be confusing. Individual patients may have one (monogenic) or more (polygenic) genetic defects that lead to a particular phenotype. (See 'Polygenic hypercholesterolemia' below.)

The clinical syndrome of familial hypercholesterolemia (FH) is the leading clinical phenotype resulting from monogenic, usually dominantly inherited defects in LDL catabolism. As FH has been well studied and there is an extensive literature, it is discussed in detail elsewhere. (See "Familial hypercholesterolemia in adults: Overview".)

Familial combined hyperlipidemia and polygenic hypercholesterolemia are examples of syndromes with polygenic inheritance; there is overlap between these two types of hypercholesterolemia. In patients in with an isolated increase in LDL-C that is not high enough to carry out exhaustive cascade family screening for monogenic FH, these two are harder to distinguish. Therefore, most patients will be classified as having a mixed hyperlipidemia.

FAMILIAL COMBINED HYPERLIPIDEMIA — Familial combined hyperlipidemia (FCHL) is a common genetic lipid disorder (1 to 2 percent of the population). Patients present with elevated levels of plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and apolipoprotein (apo) B. Premature atherosclerotic cardiovascular disease (ASCVD) is not uncommon. There is overlap with metabolic syndrome (see "Metabolic syndrome (insulin resistance syndrome or syndrome X)") and diabetic dyslipidemia. When not initially present, there is an increased future likelihood of impaired glucose tolerance or type 2 diabetes.

Genetics — FCHL is a complex, polygenic disorder in which gene variants potentially causing elevations of VLDL and of LDL run in the same families. Screening of relatives reveals some with an increase in both cholesterol and triglycerides, some with increased cholesterol but normal triglycerides, some with principally hypertriglyceridemia (often mild, but occasionally type V), and others in whom there is little, if any, dyslipidemia.

The phenotype is usually determined by interaction of multiple susceptibility genes and the environment [4,5]. Coinheritance of two or more gene variants potentially affecting lipoprotein metabolism are generally required for the expression of FCHL.

In many cases, FCHL is caused by overproduction of hepatically-derived apoB-100 associated with very low-density lipoprotein (VLDL) [4]. In these cases, there is an autosomal dominant pattern of inheritance. ApoB levels are strongly correlated with LDL phenotype B in FCHL families [6,7]; LDL phenotype B levels are inherited as a Mendelian trait that is distinct from the apoB genotype [6]. LDL phenotype B is associated with increased serum concentrations of apoB and triglycerides, reduced serum high-density lipoprotein (HDL) (figure 2) [8], and a threefold increase in risk of CHD [9]. LDL phenotype A is associated with large buoyant LDL particles; in comparison, phenotype B is characterized by small, dense LDL particles. (See 'Small dense LDL (LDL phenotype B)' below.)

A study of 31 extended Finnish FCHL families suggested a novel locus on chromosome 1q21-q23 [10]. A follow-up study that included an additional 29 families found that FCHL was linked and associated with the gene-encoding upstream transcription factor 1 (USF1); USF1 encodes a transcription factor known to regulate several genes involved in glucose and lipoprotein metabolism [11].

The phenotypic heterogeneity derives from variations in LDL subclass pattern and an associated impairment in lipoprotein lipase (mass and activity) in one-third of cases [12]. Those patients with abnormal lipoprotein lipase (LPL) function have higher levels of triglycerides (due to decreased clearance) and lower levels of HDL-C (due to reduced production from triglyceride-depleted VLDL remnants) than those with normal LPL activity. In at least some patients, a mutation in the LPL gene is responsible [13]. (See "Hypertriglyceridemia in adults: Management".)

Clinical manifestations — The clinical manifestations include premature CHD (particularly in patients with concurrent hypertriglyceridemia), xanthelasma (in 10 percent of cases), and obesity [14]. Coexisting diabetes mellitus or impaired glucose tolerance is more common in patients who also have hypertriglyceridemia.

Obesity is common in FCHL, but some patients in whom the genetic components are particularly penetrant may be lean.

One study of 63 families with FCHL found that, after adjustment for baseline covariates, 20-year cardiovascular disease mortality was increased among siblings and offspring in FCHL compared with spouse control subjects (relative risk 1.7) [15]. Baseline triglyceride concentrations were not independently associated with an increased risk.

Pathophysiology — The pathophysiological mechanism underlying FCHL is believed to be hepatic overproduction of apoB-100-containing lipoprotein particles (ie, VLDL and LDL), resulting in increased plasma total cholesterol, triglycerides, and apoB levels [14,16,17]. In addition, lower levels of HDL-cholesterol and increased amounts of small dense LDL and remnant lipoprotein particles have been observed in patients with FCHL.

Diagnosis — FCHL is diagnosed in patients with a family history of premature CHD and whose apoB concentration is >120 mg/dL in combination with either elevations in both LDL-C and triglycerides or either elevated LDL-Col or triglycerides [16,17].

Because FCHL is phenotypically heterogeneous, and total cholesterol and triglyceride levels may vary within an affected individual over time [18], the diagnosis of this disorder or the possible variant hyperapobetalipoproteinemia requires family data. The presence of one of these two conditions is suggested by an LDL-to-apoB ratio of less than 1.2 (normal value >1.4).

Sometimes, familial dysbetalipoproteinemia (FDB; type III hyperlipoproteinemia) is the differential diagnosis (see "Lipoprotein classification, metabolism, and role in atherosclerosis", section on 'Clinical classification of dyslipidemias'). The simplest way to distinguish this from FCHL is to measure apoB, which is low in relation to triglycerides and cholesterol in FDB.

Treatment — The first-line treatment of FCHL is a statin, irrespective of whether or not triglyceride levels are elevated [19], which is effective therapy for lowering apoB levels [20]. The potency and dose of statin should be chosen with the aim of achieving LDL-C <100 mg/dL in primary prevention and <70 mg/dL in secondary prevention. High intensity statins (atorvastatin 80 mg daily and rosuvastatin 40 mg daily) lower triglycerides by 43 percent in patients with triglycerides as high as 800 to 850 mg/dL [21,22].

The main reason for introducing statins before fibrates in hypertriglyceridemic dyslipidemias is not that they are better at lowering triglycerides, but because of the randomized clinical trial evidence that they are safe and that they decrease cardiovascular disease risk and mortality [23]. Similar evidence does not exist for fibrates.

It should be kept in mind that when triglyceride concentrations are high (≥400 mg/dL), the laboratory may be unable to provide accurate LDL-C measurements; non-HDL cholesterol targets should be used. (See "Measurement of blood lipids and lipoproteins", section on 'Non-HDL cholesterol'.)

If the LDL-C or non-HDL-C therapeutic goals are not reached, addition of ezetimibe can be considered. Generally, bile acid sequestrants are avoided in hypertriglyceridemia, which they may exacerbate. The exception is colesevelam, which, if administered to achieve greater lowering of LDL or non-HDL-C, has a lesser adverse effect on triglycerides in studies that included an upper triglyceride limit of 300 mg/dL, while reducing the total atherogenic burden of apoB-containing lipoproteins, and it improves glucose intolerance [24].

Often, triglycerides will remain elevated after statin treatment (with or without ezetimibe). The decision to add a drug to lower triglycerides is a difficult one. For many years, fibrate drugs and niacin were employed for this purpose, but randomized clinical trial evidence does not support any effect of these drugs in reducing cardiovascular disease events or improving overall survival [25]. Subgroup analysis does suggest that fibrate monotherapy can decrease the likelihood of CHD events in hypertriglyceridemia. However, it is uncertain that this is the case in patients also receiving statin treatment. As the benefit is uncertain, we suggest referring statin-treated patients with significant residual hypertriglyceridemia to a lipid specialist for consideration of additional therapy. An alternative is to consider adding a highly purified omega-3 fatty acid preparation to the statin treatment to decrease triglycerides further. Evidence, although conflicted, does suggest improved survival from taking highly purified omega-3s in people with CHD. Furthermore, the risk of myopathy is not increased when omega-fatty acid is used in combination with statin treatment as it is with fibrates and niacin.

Glucose intolerance is common in hypertriglyceridemia and when type 2 diabetes is discovered in hypertriglyceridemia, metformin should be considered as initial treatment, because of its action in mitigating weight gain and improving lipid levels [26].

POLYGENIC HYPERCHOLESTEROLEMIA — Familial hypercholesterolemia (FH), which is a monogenic disorder, is the most common inherited disorder of LDL catabolism. It is discussed in detail elsewhere. (See "Familial hypercholesterolemia in adults: Overview".)

Many patients with the FH clinical phenotype, but without a single mutation of sufficient pathogenicity to produce it, will have multiple (polygenic) gene variants, each of which makes a small independent contribution to a significantly elevated LDL-C [27]. These patients are said to have polygenic hypercholesterolemia. Some of these individuals express marked hypercholesterolemia when only two or three penetrant gene variants combine, whereas others may require the combination of greater numbers of less penetrant ones. The former type of polygenic hypercholesterolemia mimicking monogenic FH is termed "oligogenic FH." It is possible to devise a "gene score" based on the number and likelihood of these variants to contribute to high LDL-C. (See 'Testing' below.)

Generally, polygenic hypercholesterolemia has less marked elevations in LDL-C (particularly in childhood and adolescence) than monogenic FH and does not carry the high risk of cardiovascular disease (CVD) in people aged less than 40 years [28]. Stated another way, a higher proportion of those with high LDL-C at a young age will have it as a result of FH rather than polygenic hypercholesterolemia [29].

Whole genome sequencing has been used to develop polygenic scores that quantify DNA variants that contribute to a risk factor. The contribution of polygenic cholesterol scores to early-onset myocardial infarction (<55 years of age) was investigated in an analysis of 2081 patients hospitalized with a myocardial infarction from four racial subgroups and 3761 population-based controls. Among patients with early-onset myocardial infarction, 17.3 percent carried a high polygenic cholesterol score, defined as the upper fifth percentile, versus 5 percent of the control population [30]. The mean LDL-C in patients with versus without a high polygenic risk score was 132 versus 122 mg/dL. A high polygenic score was more common among patients with early-onset myocardial infarction. The multivariate adjusted risk of early-onset myocardial infarction varied among racial groups with odds ratios of 5.09 in White Americans, 3.38 in Hispanic Americans, 3.33 in Asian Americans, and 2.02 in Black Americans. The 0.2 percent of patients with a high polygenic risk score and confirmed monogenic mutation related to familial hypercholesterolemia had higher mean LDL-C levels than those with only a familial hypercholesterolemia monogenic mutation (LDL-C 235 versus 202 mg/dL). Thus, polygenes may contribute to variability in LDL-C levels seen in patients with the same monogenic mutation.

Genetics — The genetics of polygenic hypercholesterolemia are poorly understood but multiple abnormalities in LDL metabolism are involved [31].

These abnormalities in LDL metabolism include mild defects in the LDL receptor, defective apoB-100, increased synthesis of apoB, and the presence of the apoE4 phenotype. ApoE is required for receptor-mediated clearance of chylomicron and very low-density lipoprotein remnants from the circulation. ApoE4 has a higher affinity for the LDL receptor than the other apoE isoforms. The enhanced lipid binding leads, via negative feedback, to downregulation of LDL receptor synthesis and consequently a secondary rise in LDL-C levels.

A genetic study of over 600 patients with clinical FH and 3020 controls attempted to distinguish patients with polygenic and monogenic FH by genotyping for the three known genetic causes of FH (see 'Genetics of elevated LDL-C' above) and 12 common LDL-C raising single-nucleotide polymorphisms [32]. In this study, only about 50 percent of patients with clinical FH had monogenic FH; of these, many had multiple minor cholesterol-elevating alleles. Multiple genetic mutations were often found in those labeled as having a polygenic cause (none of the three known genetic causes found).

In a study of over 20,000 coronary artery disease-free individuals, the prevalence of LDL-C ≥190 mg/dL was 6.7 percent [33]. Using whole exam sequencing, 1.7 percent of these had an FH mutation. In patients with very high LDL-C levels (≥190 mg/dL) and no FH mutation compared with controls (LDL-C <130 mg/dL), the risk of coronary artery disease was sixfold higher (odds ratio: 6.0, 95% CI 5.2-6.9). However, in patients with LDL-C ≥190 mg/dL and an FH mutation, the risk was 22-fold higher (odds ratio 22.3; 95% CI 10.7-53.2).

Multiple studies and reviews have evaluated the relationship between apoE genotypes (particularly the apoE4 allele) and both LDL-C and the incidence of CHD [34-36]. However, these reports may have been underpowered to detect the true relationship and also subject to publication bias [37].

The largest meta-analysis of the impact of the presence of the apoE allele on LDL-C levels and CHD risk came to the following conclusions using the E3/E3 genotype as the reference [37]:

There was an approximately linear relationship of apoE genotypes (when ordered E2/E2, E2/E3, E3/E3, E3/E4, and E4/E4) with LDL-C. There was a weakly inverse relationship of these genotypes with high-density lipoprotein cholesterol (HDL-C) level and a non-linear relationship with triglycerides, with the E3/E3 genotype having the lowest triglyceride levels

There was an approximately linear relationship of apoE genotypes (when ordered E2/E2, E2/E3, E3/E3, E3/E4, and E4/E4) with CHD risk. Compared with the apoE3/E3 individual, the odds ratio for CHD was 0.8 (95% CI, 0.70-0.90) in E2 carriers and 1.06 (95% CI, 0.99-1.13) in E4 carriers.

Testing — In polygenic hypercholesterolemia, it may be important to screen relatives for elevated cholesterol even though an FH mutation is not present. Genes in combinations leading to severe hypercholesterolemia often occur in other family members and the proband should be advised to ask all his/her first-degree relatives to get a cholesterol check.

Until genetic testing has been shown to improve clinical outcomes in individuals with one (eg, FH) or more (eg, polygenic hypercholesterolemia) genetic mutations that might lead to a significantly elevated LDL-C, we do not perform routine testing, even after an adverse event such as myocardial infarction.

Without genetic testing, it can be difficult to differentiate polygenic hypercholesterolemia from FH. Studies have identified minor LDL-C-elevating alleles that contribute to the familial basis for this disorder [27]. Similar to patients with monogenic FH, these patients have familial aggregation of moderate hypercholesterolemia and the premature onset of coronary heart disease. The lipid profile shows an elevated LDL-C level, and (usually) a normal triglyceride level; tendon xanthoma are not seen (table 2). As age advances, cardiovascular disease risk in patients with severe polygenic hypercholesterolemia or possible FH with no single causal gene identified carries a similar risk to monogenic FH. (See "Familial hypercholesterolemia in adults: Overview", section on 'Genetic considerations'.)

When resources permit and heterozygous FH is suspected on clinical grounds we do, however, recommend cascade family screening, ideally establishing the DNA mutation in one family member and then seeking this in others. The aim is to identify affected family members at an early age when we believe treatment can improve clinical outcomes. (See "Familial hypercholesterolemia in adults: Overview", section on 'Indications' and "Familial hypercholesterolemia in children", section on 'Testing family members'.)

Treatment — Therapy in polygenic hypercholesterolemia usually begins with a statin; ezetimibe, a bile acid sequestrant, PCSK9 inhibitor, or nicotinic acid are alternatives in patients who cannot tolerate a statin [38]. The 4S trial, which followed 966 survivors of a myocardial infarction for 5.5 years, found that those with the apoE4 allele had a nearly twofold increased risk of dying compared with other patients; this excess mortality was abolished by treatment with simvastatin [39].

Further lowering of LDL-C may be accomplished by combining a statin with ezetimibe. Low doses of nicotinic acid (1 to 1.5 g/day) will also raise HDL-C, a desirable effect in patients with hypercholesterolemia and low HDL-C.

SMALL DENSE LDL (LDL PHENOTYPE B) — Low-density lipoprotein (LDL) particles are heterogeneous in size, density, and composition [40]. Individuals can be classified according to their predominant LDL size into one of three phenotypic patterns on gradient gel electrophoresis:

Phenotype pattern A – Large particle size, ≥26.3 nm in diameter

Phenotype pattern B – Small particle size, <25.8 nm in diameter

Phenotype pattern I – Intermediate particle size (mixed distribution), 25.8 to 26.3 nm in diameter

Small, dense LDL particles (phenotype B) are cholesterol-depleted LDL particles that are associated with increased serum concentrations of triglycerides, reduced serum high density-lipoprotein cholesterol (HDL-C) levels (figure 2), and an increased risk of coronary heart disease (CHD) that presumably derives from the excess total LDL particles. The risk of cardiovascular disease associated with small, dense LDL is increased only when the total LDL particle concentration is elevated [41].

Determinants — LDL phenotype B levels are in part genetically determined [6]. Studies of monozygotic and dizygotic women twin pairs suggest that one-third to one-half of the variation in LDL particle diameter can be attributed to genetic factors [42]. One gene that may contribute is the gene for cholesteryl ester transfer protein (CETP), which plays a central role in reverse cholesterol transport [43]. CETP moves cholesterol from peripheral tissues to the liver by transferring cholesteryl ester from HDL-C to apoB-containing lipoproteins with triglyceride transfer in the opposite direction. Increased CETP activity may be proatherogenic and is associated with LDL phenotype B [43].

LDL phenotype B levels are also influenced by acquired conditions. As an example, they are associated with obesity, type 2 diabetes, and the manifestations of the acquired insulin resistance syndrome such as hypertriglyceridemia, hyperinsulinemia, increased waist-to-hip ratio, low levels of large HDL particles, and systolic hypertension [44,45].

High hepatic lipase activity hydrolyzes triglyceride in triglyceride-enriched LDL and triglyceride-enriched HDL particles, which results in small, dense LDL particles and larger HDL particles (HDL-S [HDL3 cholesterol by ultracentrifugation]), and increased HDL particle size. Interventions that alter hepatic lipase activity can reduce the concentration of small, dense LDL particles. Among patients in the FATS trial with a personal and family history of CHD and apoB levels ≥125 mg/dL (3.3 mmol/L), intensive lipid-lowering therapy with lovastatin-colestipol or niacin-colestipol produced a significant reduction in hepatic lipase activity and an increase in large, buoyant LDL particles [46]. These changes were associated with a significant improvement in disease severity; in a multivariate analysis, an increase in LDL buoyancy was most strongly associated with regression of CHD, accounting for 37 percent of the variance of change in coronary stenosis. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Hepatic lipase deficiency should be suspected when the HDL-C is unexpectedly high. Hepatic lipase hydrolyses fatty acyl chains of phospholipids, monoacylglycerols, diacylglycerols, and triacyl‐glycerols are associated with HDL and other lipoproteins [47]. Rare, loss‐of‐function variants can cause of deficiency of hepatic lipase, resulting in a two- to threefold increased HDL‐C levels [48]. In some susceptible families, hepatic lipase deficiency can result in increased risk of ASCVD. This occurs from elevations in potentially proatherogenic apoB-containing lipoproteins [48]. 

The effect of hepatic lipase may be related to a polymorphism in the hepatic lipase gene promoter, the most common being a C to T substitution. The presence of a C allele is associated with higher hepatic lipase activity; smaller, denser, and more atherogenic LDL particles; and lower serum HDL-C [49].

The angiographic improvement with lipid lowering is most prominent in subjects with small, dense LDL and lower serum HDL-C, suggesting that hepatic lipase polymorphism might have predictive value [50]. This hypothesis was evaluated in a study of 49 men with established coronary disease and dyslipidemia; patients with the CC genotype had the greatest decrease in hepatic lipase activity, improvement in LDL density, and regression in coronary atherosclerosis (96 versus 60 and 0 percent for TC and TT genotypes) [51].

Increase in coronary risk — Based on the high residual cardiovascular risk in metabolic syndrome and type 2 diabetes patients who achieve current recommended LDL-C targets on statin therapy, we agree with the American Diabetes Association/American College of Cardiology Foundation-issued consensus statement recommending measurement of apoB (or LDL-P concentration) in patients at high cardiometabolic risk, as well as treatment of high levels of apoB or LDL-P concentration, after therapeutic interventions have been initiated for treatment of LDL-C and non-HDL-C [52]. Treatment targets for LDL-C/non-HDL-C/LDL-P/apoB are presented in the following table (table 3).

Small, dense LDL particles have been consistently associated with CHD in case-control studies [9,53-57]; however, these studies are limited because most studies did not control for the total LDL particle or apoB concentration. The Stanford Five-City Project evaluated the association between LDL particle diameter with incident fatal and nonfatal myocardial infarction (MI) in a nested case-control study [56]. The study included 124 case-control pairs (90 pairs of men and 34 pairs of women). The patients with MI had a smaller LDL size (mean 26.17 versus 26.68 nm, p<0.001) and there was a graded association across quintiles of LDL size. Small LDL size was a stronger independent predictor of CHD than all other parameters except for the total cholesterol-to-HDL-C ratio.

The Physicians' Health Study used a nested case-control study to evaluate whether small, dense LDL particles and nonfasting triglyceride levels were independent predictors for MI in men [57]. The study group included 266 cases and 308 controls that were matched for age and smoking status. The cases had a significantly lower average LDL diameter (25.6 versus 25.9 nm, p<0.001) and higher serum triglycerides. Small, dense LDL was associated with higher triglyceride and lower HDL-C levels, and LDL diameter was not an independent risk factor after adjustment for the high triglyceride levels. (See "Hypertriglyceridemia in adults: Management".)

It may be possible to refine the risk associated with small, dense LDL particle size. In a prospective study of over 2000 men, for example, the ability to predict CHD was improved by measuring the cholesterol concentration in the small LDL particles [58].

In addition to determining coronary risk, LDL particle size is also an important predictor of the response to risk-factor reduction. The Stanford Coronary Risk Intervention Project (SCRIP) was a four-year angiographic trial of multifactorial risk reduction versus usual care [50]. LDL particles were classified by density into a "buoyant" (density <1.0378 g/mL) or "dense" mode (density >1.0378 g/mL). Cholesterol-lowering therapy produced a significant treatment benefit only in the dense-mode subjects. As noted above, an improvement in LDL density and regression of atherosclerosis appears to be most prominent in patients with the CC genotype for the hepatic lipase gene promoter [51].

The Women's Health Study examined the associations of small, dense LDL versus large buoyant LDL in multivariate models that controlled for the total LDL particle concentration [41]. In this analysis, small, dense LDL was not as closely associated with a significantly higher risk of cardiovascular events as large, buoyant LDL after adjusting for the total LDL particle concentration.

At any level of LDL-C, individuals with an increased number of small LDL particles have higher LDL particle (LDL-P) concentrations. In multivariate models, LDL-P size is not related to increased cardiovascular risk after adjustment for LDL-P concentration or its surrogate measure apolipoprotein B (apoB) [41,59]. Thus, LDL size represents part of the pattern of atherogenic dyslipidemia, and it is not a specific therapeutic target. In individuals with disorders of insulin resistance (obesity, metabolic syndrome, type 2 diabetes), LDL-C under-represents cardiovascular risk due to the discordance between LDL-C and LDL-P [59,60]. Thus, LDL-P, or its surrogate measure apoB, has been considered a target of therapy, as this measure is associated with a twofold higher risk of cardiovascular disease events than LDL-C. Moreover, in statin-treated patients, apoB levels are more strongly associated with residual cardiovascular risk than LDL-C [61].

Mechanisms of increased atherogenicity — The atherogenic potential of small LDL particles has been related to both direct and indirect mechanisms. The direct mechanisms include:

Enhanced oxidative susceptibility [62,63]

Reduced clearance by LDL receptors in the liver with increased LDL receptor-independent binding in the arterial wall [64,65].

Endothelial dysfunction that is independent of the concentrations of other lipids [66]

These factors may interact. Less avid binding to the LDL receptor prolongs the half-life of small, dense LDL in the circulation, increasing the likelihood that they will undergo oxidative modification and subsequent uptake by the macrophage scavenger receptors [65].

Indirect associations between small, dense LDL and atherogenic risk include:

Inverse relationship with HDL-C (figure 2)

Marker for accumulation of atherogenic triglyceride remnant particles [67]

Insulin resistance [44]

LOW LDL-CHOLESTEROL LEVELS — Two genetic disorders causing extremely low levels of low-density lipoprotein-cholesterol have been identified. These two, "abetalipoproteinemia" and "hypobetalipoproteinemia," are referred to as "familial hypobetalipoproteinemia." These disorders are discussed elsewhere. (See "Low LDL-cholesterol: Etiologies and approach to evaluation".)

SCREENING — As a result of the frequency of familial disease and the associated risk, screening lipid analysis is recommended for first-degree relatives of patients with myocardial infarction (particularly if premature). Screening begins with a standard lipid profile; if this is normal, further testing should be considered depending on the abnormalities identified in the affected family member, such as the measurement of lipoprotein(a) and apolipoproteins B and A-I; approximately 25 percent of patients with premature coronary heart disease and a normal standard profile will have an abnormality in one of these factors. A larger discussion of screening for dyslipidemia is found elsewhere. (See "Screening for lipid disorders in adults".)

INDICATIONS FOR REFERRAL — Patients who have persistently elevated LDL-C or non HDL-C on maximum tolerated statins should be referred to a lipid specialist.

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: Lipid disorders and atherosclerosis in children" and "Society guideline links: Lipid disorders in adults".)

SUMMARY AND RECOMMENDATIONS

Introduction – Elevation of low-density lipoprotein cholesterol (LDL-C) is common in the general population. Most individuals with elevated LDL-C have one or more genetic abnormalities rather than a secondary cause (such as liver or kidney disease). (See 'Introduction' above.)

Genetics of elevated LDL-C – The clinical syndrome of familial hypercholesterolemia is the leading clinical phenotype resulting from inheritance of a monogenic abnormality in LDL metabolism. Familial combined hyperlipidemia and polygenic hypercholesterolemia are examples of syndromes with polygenic inheritance. (See 'Genetics of elevated LDL-C' above.)

Familial combined hyperlipidemia (FCHL) – This is a relatively common lipid disorder. Statins are generally the first drug added to treat FCHL. (See 'Familial combined hyperlipidemia' above.)

Polygenic hypercholesterolemia – The genetics of polygenic hypercholesterolemia are poorly understood but multiple abnormalities in LDL metabolism are likely involved. Statins are generally the first drug added to treat polygenic hypercholesterolemia. (See 'Polygenic hypercholesterolemia' 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.

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Topic 4567 Version 53.0

References

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