NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

Cover of Endotext

Endotext [Internet].

Show details

Hypertriglyceridemia: Pathophysiology, Role of Genetics, Consequences, and Treatment

, MD and , MD.

Author Information

Last Update: April 23, 2019.

ABSTRACT

Hypertriglyceridemia (HTG) can result from a variety of causes. Mild to moderate HTG occurs commonly as part of the metabolic syndrome, can be the result of multiple genetic mutations in an individual or family, and can be secondary to several diseases and drugs. Severe HTG with plasma triglyceride (TG) levels >1000-1500 mg/dL can result from 3 groups of conditions: (1) rare mutations in the lipoprotein lipase (LPL) complex, where it is termed the familial chylomicronemia syndrome (FCS), (2) the co-existence of genetic and secondary forms of HTG, termed the multifactorial chylomicronemia syndrome (MFCS), which is a much more common cause of severe HTG, and (3) familial partial lipodystrophy (FPLD). Mild to moderate HTG is associated with an increased risk of premature cardiovascular disease (CVD), while severe HTG can lead to pancreatitis and other features of the chylomicronemia syndrome, as well as an increased risk of premature CVD. Appropriate management of the patient with HTG requires knowledge of the likely cause of the HTG, in order to prevent its complications. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

PHYSIOLOGY

A detailed overview of lipoprotein physiology is provided in the chapter on Lipoprotein Metabolism (1). Here we will briefly review some aspects the metabolism of the triglyceride (TG)-rich lipoproteins (VLDL and chylomicrons) of particular relevance to this chapter.

Secretion of TG-rich Lipoproteins Into Plasma

TGs are transported through plasma as very low-density lipoproteins (VLDL), which transport TGs primarily made in the liver, and as chylomicrons, which transport dietary (exogenous) fat. VLDL secretion by the liver is regulated in several ways. Each VLDL particle has one apoB100 molecule, making apoB100 availability a key determinant of the number of VLDL particles, and hence, TG secretion by the liver. In addition to one molecule of apoB-100, each VLDL particle contains multiple copies of other apolipoproteins, together with varied amounts of TGs, cholesteryl esters and phospholipids. The extent of TG synthesis is in part determined by the flux of free fatty acids (FFA) to the liver. The addition of TG to the developing VLDL particle in the endoplasmic reticulum is mediated by the enzyme microsomal triglyceride transfer protein (MTP). The pool of apoB100 in the liver is not typically regulated by its level of synthesis, which is relatively constant, but by its level of degradation, which can occur in several proteolytic pathways (2). Insulin also plays a role in the regulation of VLDL secretion - it decreases hepatic VLDL production by limiting fatty acid influx into the liver, decreases the stability of, and promotes the posttranslational degradation of apoB100 (3). Recent studies have shown that apoC-III, an apolipoprotein thought to primarily play a role in inhibiting TG removal (see below), also is involved in the assembly and secretion of VLDL (4). VLDL particles (containing apoB100) also increase in plasma in the postprandial state as well as chylomicrons that contain apoB48 (5).

Consumption of dietary fat results in the formation of chylomicrons by enterocytes. Fatty acids and monoacylglycerols that result from digestion of dietary TGs by acid and pancreatic lipases are transported into enterocytes by mechanisms that are not completely understood. In the enterocyte, monoacylglycerol and fatty acids are resynthesized into TGs by the action of the enzymes acyl-coenzyme A: monoacylglycerol acyltransferase and acyl-coenzyme A: diacylglycerol acyltransferase 1 and 2. The resulting TGs are packaged with apoB48 to form chylomicrons, a process also mediated by MTP (6). Chylomicrons then pass into the thoracic duct from where they enter plasma and acquire additional apolipoproteins. Of particular relevance to their clearance from plasma is the acquisition of apoC-II and apoC-III.

Catabolism of the TG-rich Lipoproteins

TGs in both VLDL and chylomicrons are hydrolyzed by the lipoprotein lipase (LPL) complex. LPL is synthesized by several tissues, including adipose tissue, skeletal muscle and cardiac myocytes. After secretion by adipocytes, the enzyme is transported by glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1 (GPIHBP1) to the luminal side of the capillary endothelium, where it becomes tethered to glycosaminoglycans (GAGs). This pool of LPL is referred to as “functional LPL”, since it is available to hydrolyze TGs in both VLDL and chylomicrons. LPL can be liberated from these GAG binding sites by heparin injection. Several other proteins, reviewed in (7), regulate LPL activity. These include apoC-II, which activates LPL, and apoC-III, which inhibits LPL in addition to its effect on VLDL secretion alluded to earlier. Both are produced by the liver and are present on TG-rich lipoproteins. ApoC-III also inhibits the turnover of TG-rich lipoproteins through a hepatic clearance mechanism involving the LDL receptor/LDL receptor-related protein 1 (LDLR/LRP1) axis (8). ApoE also is present on the TG-rich lipoproteins and plays an important role in the uptake and clearance of the remnants of the TG-rich lipoproteins that result from hydrolysis of TGs in these lipoproteins. Other activators of LPL include apoA-IV (9), apoA-V (10-12) and lipase maturation factor 1 (LMF1) (13,14). In addition, several members of the angiopoeitin-like (ANGPTL) protein family play a role in regulating LPL activity. ANGPTL3 is produced by the liver and is an endocrine regulator by inhibiting LPL in peripheral tissues (7,15,16). ANGPTL4 is produced in several tissues (7), where it inhibits LPL in a paracrine fashion (7,17). Both ANPGTL3 and ANGPTL4 retard the clearance of the TG-rich lipoproteins (7).

The core TGs in VLDL and chylomicrons are hydrolyzed by apoC-II activated LPL; FFA thus formed are taken up by adipocytes and reincorporated into TGs for storage, or in skeletal and cardiac muscle, utilized for energy. Hydrolysis of chylomicron- and VLDL-TG results in TG-poor, cholesteryl ester and apoE-enriched particles called chylomicron and VLDL remnants, respectively, which under physiological conditions are removed by the liver by binding to LDL receptors, LDL receptor related protein, and cell surface proteoglycans (12,18). Hepatic TG lipase and apoA-V also are involved in the remnant clearance process (10-12,19,20).

It is important to appreciate that the clearance of TGs from plasma is saturable when plasma TGs exceed ~500-700 mg/dL (21). Once removal mechanisms are saturated, additional chylomicrons and VLDL entering plasma cannot readily be removed and hence accumulate. As a result, plasma TGs can increase dramatically, resulting in very high levels and the accumulation of chylomicrons in plasma obtained after an overnight fast.

Normal range for plasma triglycerides and definition of hypertriglyceridemia

Statistical Determination of a Normal Range

Normal ranges often are defined by statistical upper limits (e.g., >95th percentile or >2SD from the mean) for a normal local population. However, it is important to appreciate that TGs increase with age (22), differ between males and females (23), and that their distribution within populations is heavily skewed to the right (24,25). Because of this skewed distribution, logarithmic transformation is required to establish statistical normal ranges. A more rational approach might be to define normal as a level below which complications do not occur.

Normal Range Based on Risk of Complications of HTG

Use of such an approach to the establishment of a normal range for plasma TG concentrations requires a detailed knowledge of the morbidities associated with elevated TG levels. The major complications of hypertriglyceridemia (HTG) are (1) increased risk of cardiovascular disease (CVD) and (2) acute pancreatitis. These consequences of HTG are discussed in detail later in this chapter. As will become evident, these two complications occur at different levels of TGs, the risk of pancreatitis occurring at much higher TG levels than the risk of premature CVD. Moreover, the cause of the HTG can be an important determinant of risk. Equivalent TG levels may not confer equal risk of CVD in different genetic and secondary forms of HTG. Rather, the specific form of the HTG, associated lipid and lipoprotein abnormalities, and other CVD risk factors may be more important determinants of CVD risk than the TG level per se. Thus, establishing a normal range is actually more complicated than simply applying statistical approaches.

Normal Range According to Guidelines

Despite these concerns regarding establishment of an upper limit of normal for TGs, most guidelines define values for HTG, often without a strong biological rationale. Definitions for the diagnosis of HTG provided in several guidelines are shown in Table 1.

Cut points for HTG were first defined by the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP). The term moderate HTG has been used more recently by the Endocrine Society (26) for TG levels between 200 to 999 mg/dL, severe HTG for 1000 to 1999 mg/dL and very severe HTG for values >2000 mg/dL. Hegele et al have proposed a simplified classification of HTG(27). Based on genetic data, they divide HTG into two states: severe (TG concentration >10 mmol/L or 885 mg/dL), which is more likely to have a monogenic component; and mild-to-moderate (TG concentration 2-10 mmol/L, or 175-885 mg/dL). Rare autosomal recessive monogenic HTG usually results from large-effect mutations in six different genes. Mild-to-moderate HTG is typically multigenic and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. All genetic forms can be exacerbated by non-genetic factors.

Table 1.

Definition of Hypertriglyceridemia According to Various Clinical Guidelines

GuidelineClassificationTriglyceride Levels
NCEP/ ATP III (28)
American Heart Association (29)
National Lipid Association (30)
Normal
Borderline-high TGs
High TGs
Very high TGs
<150 mg/dL (< 1.7 mmol/L)
150-199 mg/dL (1.7-2.3 mmol/L)
200-499 mg/dL (2.3-5.6 mmol/L)
≥500 mg/dL (≥5.6 mmol/L)
The Endocrine Society (31)Normal
Mild HTG
Moderate HTG
Severe HTG
Very severe HTG
<150 mg/dL (< 1.7 mmol/L)
150-199 mg/dL (1.7-2.3 mmol/L)
200-999 mg/dL (2.3-11.2 mmol/L)
1000-1999 mg/dL (11.2-22.4 mmol/L)
≥2000 mg/dL (≥22.4 mmol/L)
European Society of Cardiology/European Atherosclerosis Society (32)Normal
Mild-moderate HTG
Severe HTG
<1.7 mmol/L (<150mg/dL)
1.7<10mmol/L (150-880 mg/dL)
> 10 mmol/L (> 880mg/dL)
Hegele (27)Normal
Mild to moderate
Severe
<2.0 mmol/L (<175 mg/dL)
2.0-10 mmol/L (175- 885 mg/dL)
>10 mmol/dL (>885 mg/dL)

In summary, establishing a precise definition of what constitutes abnormal TG values is fraught with difficulty. Evaluation of plasma TG values in the individual patient should be interpreted in the light of these considerations. For example, an acceptable level for the prevention of pancreatitis is likely to be quite different from that at which CVD risk might be increased. The impact of HTG on CVD risk needs to be evaluated in the context of the family history of premature CVD, associated abnormalities of lipids and lipoproteins, and other CVD risk factors, particularly those associated with the metabolic syndrome (see later).

Causes of hypertriglyceridemia

In general, HTG has been classified as primary, when a genetic or familial basis is suspected, or secondary, where other conditions that raise TG levels can be identified. However, this classification may be overly simplistic. It has become clear in the past decade that the spectrum of plasma TG levels, ranging from mild elevation to very severe HTG, is modulated by a multitude of genes working in concert with non-genetic secondary and environmental contributors Thus, in the vast majority of individuals, mutations in multiple genes with interaction from non-genetic factors result in altered TG-rich lipoprotein synthesis and catabolism and subsequent HTG.

Historical perspective

Phenotypic heterogeneity among patients with HTG has been historically defined by qualitative and quantitative differences in plasma lipoproteins. In the pre-genomic era, the Fredrickson classification of hyperlipoproteinemia was based on electrophoretic patterns of lipoprotein fractions (33). This classification included 6 phenotypes, five of which included HTG in their definition. The phenotypes are distinguished based on the specific class or classes of accumulated TG-rich lipoprotein particles, including chylomicrons, VLDL and VLDL-remnants. However, this classification system is dated, has neither improved clinical or scientific insight, and therefore does not find wide use at this time (27).

In 1973, Goldstein and colleagues characterized a variable pattern of lipid abnormalities in families of survivors of myocardial infarction that they termed familial combined hyperlipidemia (FCHL) (34). At the same time, this phenotype of mixed or combined hyperlipidemia was observed in another cohort, where it was called multiple-type familial hyperlipoproteinemia (35). Affected family members can present with hypercholesterolemia alone, HTG alone, or with elevations in both TGs and LDL. This pattern was estimated to have a population prevalence of 1-2% (36), making it the most common inherited form of dyslipidemia.

In the aforementioned study, a pattern of isolated HTG, historically called familial HTG (FHTG) also was described (34). This condition was characterized by increased TG synthesis, with secretion of normal numbers of large TG-enriched VLDL particles (37), elevated VLDL levels, but normal levels of LDL and HDL cholesterol (38). FHTG did not appear to be associated with an increased risk of premature CVD in an early study (39), but baseline TG levels predicted subsequent CVD mortality after 20 years of follow up among relatives in families classified as having FHTG (40), (41).

FCHL and FHTG were initially thought to be monogenic disorders (34). However, more recent genetic characterization of individuals with familial forms of HTG indicates that these are not disorders associated with variation within a single gene, but rather polymorphisms in multiple genes associated with HTG, as detailed below. Therefore, classification of FCHL and FHTG is potentially misleading. Nevertheless, it is important to note that FCHL as originally described is associated with a very high prevalence of premature CVD (39,40,42). Thus, identifying clinical “FCHL” or combined hyperlipidemia, albeit not a monogenic disorder, is useful for CVD prevention in individuals and their affected family members (43).

Current Concepts: Genetic Forms of Hypertriglyceridemia

Hypertriglyceridemia alone or with associated lipid or lipoprotein abnormities such as elevated levels of low density lipoproteins (LDL) or reduced levels of high density lipoprotein cholesterol (HDL-C), tends to cluster in families (27). It is now evident that clinically relevant abnormalities of plasma TG levels appear to require a polygenic foundation of common or rare genetic variants (27). Common small-effect gene variants confer a background predisposition that interact with rare large-effect heterozygous variants in genes that govern synthesis or catabolism of TG-rich lipoproteins, or nongenetic secondary factors, leading to the expression of a more severe TG phenotype (44). Recently, the most prevalent genetic feature underlying severe HTG was shown to be the polygenic accumulation of common (rather than rare) variants—more specifically, the accumulation of TG-raising alleles across multiple SNP loci (45).

Genetic characterization of individuals originally classified as FCHL and FHTG indicates that these are not simple disorders associated with variation within a single gene (46). Common variants in TG loci associate not only with TG but also with HDL-C and LDL-C levels. What was historically termed FHTG appears to be the foundation of all hypertriglyceridemic states; it results from presence of common and rare genetic variants that increase susceptibility to development of HTG. An excess of polygenic common LDL-C-raising alleles in the genomes of individuals who already carry a burden of polygenic HTG susceptibility can produce a combined hyperlipidemia phenotype with increased LDL-C and TG (historically referred to as “FCHL”).

Genome wide association studies (GWAS) have identified SNPs in at least 45 loci associated with plasma TG levels, affecting TGs alone or in combination with other lipoproteins (47,48). Certain common variants in several genes are strongly associated with susceptibility to HTG. One chromosomal locus that has been consistently linked to HTG is 1q21–23 (49). Linkage to several FCHL traits has been observed, including apoB, plasma TG and cholesterol levels (50). The apoA1/C3/A4/A5 gene cluster, which associates with TG levels and LDL particle size, is an important modifier gene present at the 1q21–23 locus that has been linked with FCHL and its related traits in several but not all studies (51). Another commonly linked gene is the ubiquitous transcription factor upstream stimulatory factor 1 (USF1), which has numerous target genes, including several related to lipid and glucose metabolism (52). Determining how genetic variance in USF1 contributes to the cause and phenotype of combined hyperlipidemia has thus far remained elusive.

Some of the currently known gene associations in combined hyperlipidemia are listed in Table 2 and a detailed review of gene associations is available (49). In general, implicated genes are primarily those involved in VLDL production, catabolism and adipose tissue function. These include hormone sensitive lipase (LIPC), which enables lipolysis of TG-rich lipoproteins, although its association with FCHL has been inconsistent (53-55), dysfunctional variants of LPL (56-61), adipose TG lipase (PNPLA2) (62) and the Pro446Leu variant of the glucokinase regulator gene (GCKR) that results in increased hepatic gluconeogenesis and reduced beta-oxidation (63).

In summary, lipid disorders historically classified as FCHL and FHTG on clinical grounds are complex, genetically heterogeneous disorders. Because they are a consequence of interaction between multiple susceptibility genes and lifestyle factors, it has been suggested by some that individuals with moderate HTG should be considered as a single group without distinction, irrespective of concomitant lipoprotein disturbances (27). Because of the complexity of these disorders, routine genetic testing is not recommended.

Table 2.

Selected Genes with Roles in Familial Combined Hyperlipidemia (FCHL)

LocusGeneGene nameProtein function
Genes linked to VLDL overproduction
2p23GCKRGlucokinase (hexokinase 4) regulatorInhibitor of glucokinase in liver
1q22-q23USF1Upstream transcription factor 1Transcription factor that regulates many genes involved in lipid metabolism
Genes with involvement in TG metabolism and clearance
11q23-24APOA-I, APOC-III, APOA-IV, APOA-VApo A-I,
apoC-III,
apoA-IV,
apoA-V
ApoA-1- cholesterol efflux;
ApoC-III- inhibitor of LPL and HL;
apoA-V- lipoprotein catabolism?
8p22LPLLipoprotein lipaseTG hydrolysis in heart, muscle, adipose
15q21-23HLHepatic lipaseTG hydrolysis in liver
7SLC25A40Solute carrier family 25 member 40Mitochondrial membrane transport
Genes involved in adipose dysfunction
1q22-q23USF1Upstream transcription factor 1Transcription factor that regulates many genes involved in lipid metabolism
19q13LIPEHormone sensitive lipaseIn WAT, hydrolyzes TG to FFA

Adapted from reference (49).

Pathogenesis of Genetic Forms of HTG

Genetic forms of HTG without other lipoprotein disturbances (i.e., pure HTG) are characterized by increased TG synthesis, where normal numbers of large TG-enriched VLDL particles are secreted (37,64-66). Reduced TG clearance also has been observed in some individuals (65-67). Affected people have elevated VLDL levels, but normal levels of LDL, and are generally asymptomatic unless clinical CVD or severe HTG develops.

A variety of metabolic defects that differ among families are associated with the combined hyperlipidemia phenotype. The characteristic lipoprotein abnormalities are increased apoB levels and increased number of small dense LDL particles (38), a phenotype similar to that seen in the metabolic syndrome and type 2 diabetes (68). These primary defects occur due to 1) hepatic overproduction of VLDL particles (37) due to increased apoB synthesis in the setting of disordered adipose metabolism (69,70), insulin resistance (37,71-73) and liver fat accumulation, and, 2) impaired clearance of apoB containing particles (74,75). Increased VLDL secretion results in an elevated plasma apoB and HTG (71). Long residence time of VLDL particles favors the formation of small dense LDL (74). An abundance of small dense LDL particles traditionally is associated with the presence of HTG; however, these LDL characteristics remain even after correction of the HTG by treatment with fibrates (76,77).

In addition to apo B abnormalities, other lipoprotein disturbances include abnormal expression of apoA-II, apoC-III, and PCSK9. VLDL-TG levels in combined hyperlipidemia are modulated by apoA-II and apoC-III (78). Plasma PCSK9 levels are higher in these patients, and levels correlate with TG and apo B levels (79).

Visceral adiposity appears to be an important determinant of insulin resistance, which occurs commonly in subjects with both isolated HTG (80) and combined hyperlipidemia (80-84). Other abnormalities that have been reported in clinical FCHL include impaired lipolysis due to decreased cyclic AMP dependent signaling (69,84), abnormal adipocyte TG turnover (85), fatty liver (86), increased arterial stiffness (87) and increased carotid intimal-medial thickness (88).

In all of the phenotypes described above, severe HTG can occur when secondary causes of HTG such as untreated diabetes, marked weight gain or use of TG-raising drugs are present concurrently, leading to the Multifactorial Chylomicronemia Syndrome (MFCS), described later (89).

Diagnosis

Because of the heterogeneity of genetic forms of HTG, it has been suggested that individuals with moderate HTG be considered as a single group, irrespective of concomitant lipoprotein disturbances. However, there is utility in making a clinical diagnosis of “FCHL”, since it identifies individuals and families at markedly increased risk for developing premature CVD, who likely would benefit from lipid-lowering therapy (90). Variation in the phenotype both within and between individuals can makes diagnosis challenging (91,92). The most consistent lipoprotein abnormality is an elevated apoB level in combination with elevated TGs (91). ApoB levels > 90th percentile and small, dense LDL particles (93) can occur independent of central obesity (94), although assessment of LDL particle size and/or density is not routinely done in clinical practice. Individuals with combined hyperlipidemia frequently have other CVD risk factors such as visceral adiposity, insulin resistance, impaired glucose tolerance and hypertension, i.e., features of the metabolic syndrome (see later). Premature CVD in a male family member under age 55 and female family member under age 65 (28) is often present in families. CVD occurs in 11–14% of individuals with a combined hyperlipidemia phenotype and increases CVD risk in first- and second-degree relatives of affected individuals by up to 5-fold (95,96). Conventional CVD risk assessment algorithms can underestimate absolute CVD risk in these because they do not account for family history of premature CVD. Obtaining a detailed family history is critical and assessment of plasma lipids from family members may be helpful in CV risk stratification in patients with elevated TGs, with or without a personal or family history of clinical CAD. The presence of normal apoB levels may help distinguish other genetic forms of HTG from FCHL, where apoB levels tend to be higher (38,91) . The presence of features of the metabolic syndrome also is useful in risk stratification. In the population-based Family Heart Study, a large part of the CVD risk was accounted for by features of the metabolic syndrome, which was highly prevalent in subjects with HTG (80). These observations suggest that identification of the metabolic syndrome may add benefit in risk stratifying patients with HTG. Moreover, appropriate identification of individuals with genetic forms of HTG is important, since they are prone to development of marked HTG and resultant TG-induced pancreatitis if they develop concomitant secondary forms of HTG, including from alcohol and several drugs (see later).

Hypertriglyceridemia as a Component of the Metabolic Syndrome

HTG may also be present as part of the metabolic syndrome independent of a genetic form of HTG. The metabolic syndrome defines a cluster of risk factors that is associated with an increased risk of developing premature CVD (97,98). One of the most widely used definitions for the diagnosis of the metabolic syndrome is from the NCEP ATP-III panel, which requires the presence of 3 of more of the following (28): central or abdominal obesity (measured by waist circumference ≥ 35 inches in women and ≥40 inches in men); TGs ≥ 150 mg/dL; HDL cholesterol <40 mg/dL in men and <50 mg/dL in women; blood pressure ≥130/85 mm Hg; and fasting glucose ≥100 mg/dL 2. Several other features of the metabolic syndrome not included in this definition are insulin resistance, hypercoagulability, and the presence of inflammatory markers such as elevated levels of C-reactive protein (99). It is estimated that up to one quarter to one third of the US population could have the metabolic syndrome (100), which constitutes a major risk for CVD in this country. Després and colleagues have coined the term “hypertriglyceridemic waist” to describe patients with HTG and central obesity who are at increased risk of developing CVD (101). There is likely to be considerable overlap between these individuals and those classified as having the metabolic syndrome, although HTG is a requirement for being classified as having a “hypertriglyceridemic waist”.

The mechanism by which plasma TG levels are increased as part of the metabolic syndrome may relate to insulin resistance, since the presence of hepatic insulin resistance is believed to prevent the physiological effect of insulin in lowering VLDL secretion (102-104). Overproduction of TG by the insulin resistant liver also is likely to be playing a major role in the pathogenesis of the HTG associated with type 2 diabetes (103). However, diabetes also leads to a defect in adipose tissue LPL that may take as long as 3 months to correct (105). The relationship between obesity and HTG also is complex. Obesity can generally be divided into two major categories - metabolically unhealthy and metabolically healthy (or less unhealthy) obesity (106,107). The former category occurs as part of the metabolic syndrome, the latter not so (108). An important feature of the HTG that occurs as part of the metabolic syndrome, including that seen in diabetes, is that it is accompanied by the accumulation of a preponderance of small, dense LDL particles, LDL-C levels that are usually high normal or normal, and abnormalities in HDL-C and HDL composition. The latter is characterized by low levels of HDL2 and a reduction in the ratio of apoA-I/A-II (38). This constellation of lipid and lipoprotein abnormalities has been termed diabetic dyslipidemia (109), but a similar lipoprotein pattern is characteristic of the metabolic syndrome (110).

Remnant Removal Disease (Dysbetalipoproteinemia)

Remnant removal disease, dysbetalipoproteinemia or type III hyperlipoproteinemia, is a rare autosomal recessive disorder that can present with elevated TG levels. This disorder is characterized by the accumulation of remnant lipoproteins.

PATHOGENESIS AND GENETICS

Remnant removal disease requires homozygosity for the apoE2 genotype or a rare heterozygosity for a dysfunctional mutation in the apoE gene, which results in impaired hepatic uptake of apoE-containing lipoproteins (46). Three common isoforms of apoE occur in humans, apoE2, apoE3, and apoE4 (111). Each differs in isoelectric point by one charge unit, apoE4 being the most basic isoform and apoE2 the most acidic. ApoE3 (Cys112→Arg158) is the commonest isoform. ApoE2 (Arg158→Cys) and apoE4 (Cys112→Arg) differ from apoE3 by single amino acid substitutions at positions 158 and 112, respectively (112). In the majority of cases, remnant removal disease is associated with the E2/E2 genotype and therefore an autosomal recessive disorder. The prevalence of apoE2 homozygosity in Caucasian populations is estimated to be about 1% (113). While the apoE2 genotype is inherited in a recessive manner, rarer apoE variants such as apoE3-Leiden (114) and apoE2 (Lys1463Gln) that also can cause remnant accumulation are dominantly inherited (115).

In the absence of additional genetic, hormonal, or environmental factors, remnants do not accumulate to a degree sufficient to cause hyperlipidemia in apoE2 homozygotes; in fact, hypolipidemia is commonly seen in this situation. Remnant accumulation results when the E2/2 genotype is accompanied by a second genetic or acquired defect that causes overproduction of VLDL such as obesity or diabetes (116) (117,118) , a decrease in remnant clearance, or a reduction in LDL receptor activity (e.g., hypothyroidism (119)). Thus, full phenotypic expression requires the presence of other environmental or genetic factors (120). In these circumstances, the reduced uptake of remnant lipoproteins by the liver results in reduced conversion of VLDL and intermediate density lipoproteins to LDL, with subsequent accumulation of remnant lipoproteins (121,122), hence the term remnant removal disease.

DIAGNOSIS

Patients with remnant removal disease have roughly equivalent elevations in plasma cholesterol and TGs. The disease rarely manifests before adulthood, and in some individuals never manifests clinically. It is more common in men than in women, where expression seldom occurs before menopause, since estrogen has a protective effect in women who are apoE2 homozygotes (113). Palmar xanthomas (Figure 1), orange lipid deposits in the palmar or plantar creases, are pathognomonic of remnant removal disease but are not always present (123). Tuberoeruptive xanthomas can be found at pressure sites on the elbows, knees and buttocks. The presence of remnant removal disease should be suspected when total cholesterol and TG levels range from 300 to 1000 mg/dL and are roughly equal in magnitude. VLDL particles are cholesterol- enriched, which can be determined by isolation of VLDL by ultracentrifugation and by the demonstration of beta migrating VLDL on electrophoresis. A VLDL-cholesterol/plasma TG ratio of <0.30 is usually observed (124). A low apoB/total cholesterol ratio of <0.33 also can be helpful in making the diagnosis (125). The diagnosis of remnant removal disease should be confirmed by demonstrating the presence of the E2/E2 genotype. If the genotype result is not E2/E2, an autosomal dominant variant of APOE should be suspected. There is a high prevalence of premature coronary artery disease (126-128) and peripheral arterial disease (129,130). Occasionally severe HTG and an increased risk of pancreatitis can develop in the presence of a concomitant secondary form of HTG or TG-raising drugs.

Figure 1. . Palmar Xanthomas: Note the orange-yellow discoloration confined to the palmar creases.

Figure 1.

Palmar Xanthomas: Note the orange-yellow discoloration confined to the palmar creases.

Secondary Forms of HTG

These are described in greater detail in the chapters on Secondary Disorders of Lipid and Lipoprotein Metabolism (131-134). However, in the section where we describe MFCS we will briefly touch on some aspects of secondary forms of HTG, since they assume importance in the pathogenesis of the severe HTG seen in the MFCS, where they often co-exist in individuals with genetic forms of HTG. In our experience, the commonest secondary forms of HTG that interact with genetic forms of HTG are type 2 diabetes (usually as part of the metabolic syndrome), alcohol, the use of TG-raising drugs, and chronic kidney disease (CKD)(89,135,136).

Severe Hypertriglyceridemia and the Chylomicronemia Syndrome

In the late 1960s Fredrickson, Levy and Lees (33) classified HTG into types dependent on the pattern of lipoproteins on paper electrophoresis and the presence or absence of chylomicrons in fasting plasma. They recognized that acute pancreatitis and eruptive xanthomata occurred in the presence of chylomicronemia that accumulate in what they termed Type I and Type V hyperlipoproteinemia. Chylomicrons are present in the post-prandial state, and usually are present in fasting plasma when TG levels exceed 1000 mg/dL, but absent in fasting plasma below that value (137). The term chylomicronemia syndrome was first used to describe a constellation of clinical findings such as abdominal pain, acute pancreatitis, eruptive xanthoma and lipemia retinalis that occurred in association with very high TG levels (138). Three groups of conditions can lead to severe HTG and clinical manifestations of the chylomicronemia syndrome; (1) familial chylomicronemia syndrome (FCS) due to mutations in the LPL complex, (2) multifactorial chylomicronemia syndrome (MFCS), in which genetic and secondary forms of HTG nearly always co-exist, and (3) familial partial lipodystrophy (FPLD).

FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS)

FCS resulting from a monogenic disorder is very rare, with an estimated prevalence of about 1 in 1,000,000 (139). It usually is due to mutations in one or more genes of the LPL complex that affect chylomicron catabolism. The most common gene affected in FCS is LPL itself, in which patients are homozygous or compound heterozygous for two defective LPL alleles. Over 180 mutations that result in LPL deficiency have been described with some clustered mutations due to founder effects (140-143). Loss of function mutations account for over 90% of cases (139). Many are missense mutations, some in catalytically important sites and some in regions that predispose to instability of the homodimeric structure of LPL required for enzyme activity (144). However, many common LPL gene variants have been described that have no clinical phenotype (145). Mutations in the APOC2 gene, which encodes apoC-II, an activator of LPL, is another cause of FCS. Mutations have been described in several families (146,147).

FCS can be due to homozygous mutations in other components of the LPL complex such as GPIHBP1, apoA-V, and LMF1 (Table 3), each of which plays an important role in determining LPL function (148). The lipoprotein phenotype in these mimics that seen that in classical LPL deficiency. Loss of function mutations in GPIHBP1, which directs transendothelial LPL transport and helps anchor chylomicrons to the endothelial surface near LPL, thereby providing a platform for lipolysis, has been described in several families (139). Autoantibodies to GPIHBP1 also can lead to chylomicronemia (149). A small number of individuals with homozygous mutations in apo A-V, which stabilizes the lipoprotein–enzyme complex thereby enhancing lipolysis (10), have been described (150). Mutations in LMF1, an endoplasmic reticulum chaperone protein required for post-translational activation of LPL, have been identified in 2 patients (151).

These disorders usually present in childhood or early adolescence with very high TG levels and features of the chylomicronemia syndrome, although it can present in adulthood (143). Clinical findings include eruptive xanthomas, lipemia retinalis and hepatosplenomegaly, and a predisposition to acute pancreatitis, a serious condition that can result in the systemic inflammatory response syndrome, multi-organ failure, and death.

Table 3.

Rare Genetic Disorders Affecting the LPL Complex

DisorderInheritanceIncidenceLipid PhenotypeUnderlying DefectClinical Features
LPL deficiencyAutosomal Recessive1 in 1,000,000Marked HTG/ chylomicronemia in infancy or childhoodVery low or absent LPL activity; circulating inhibitor of LPLHepato-splenomegaly; severe chylomicronemia
Apo C-II deficiencyAutosomal RecessiveRareMarked HTG/ chylomicronemia in infancy or childhoodAbsent Apo C-IIHepato-splenomegaly; severe chylomicronemia
Apo A-V mutationUnknownRareMarked HTG/ chylomicronemia later in adulthoodDefective or absent Apo A-VChylomicronemia
GPIHBP1 mutationUnknownRareMarked HTG/ chylomicronemia in adulthoodDefective or absent GPIHBP1Chylomicronemia
LFM1 mutationUnknownRareMarked HTG/ chylomicronemia in adulthoodDefective of absent LFM1Chylomicronemia

Adapted from Ref (139)

MULTIFACTORIAL CHYLOMICRONEMIA SYNDROME (MFCS)

The prevalence of MFCS is much higher than FCS (140). Most, if not all, patients with MFCS have a genetic form of moderate HTG co-existing with one or more secondary forms of HTG (152,153). The most common secondary cause of HTG in the past was undiagnosed or untreated diabetes (89), although earlier detection of diabetes may be making the association of marked hyperglycemia of untreated diabetes with very severe HTG less common. More recently, MFCS commonly results from the addition of specific drugs in patients with an underlying genetic form of HTG (26). These include beta-adrenergic blocking agents (selective and non-selective) and/or diuretics (thiazides and loop-diuretics such as furosemide) used for hypertension, retinoid therapy for acne, oral estrogen therapy for menopause or birth control, selective estrogen receptor modulators (particularly raloxifene) for osteoporosis or breast cancer, protease inhibitors for HIV/AIDS, atypical anti-psychotic drugs, alcohol, and possibly sertraline (140). Rarer causes of very severe HTG include autoimmune disease (sometimes with LPL- or GPIHBP1- specific antibodies), asparaginase therapy for acute lymphoblastic leukemia (154), (155) and bexarotene, a RXR agonist used in the treatment of cutaneous T cell lymphoma (156). In addition, weight regain following successful weight loss has been associated with increasing TG levels (26,140). These patients almost always have relatives with genetic forms of HTG, whose TG levels are considerably lower than the index patient with severe HTG, in whom secondary forms of HTG also are present (89).

Table 4.

Secondary Causes that Can Contribute to Severe HTG

Conditions
Hypothyroidism
Uncontrolled diabetes
Pregnancy
Nephrotic syndrome
Chronic Renal Failure
Acute hepatitis
Weight regain after weight loss
Sepsis
Autoimmune chylomicronemia
Systemic lupus erythematosis
Anti-LPL antibodies
Rare Genetic Causes
Glycogen storage disorders
Lipodystrophies
Congenital- generalized or partial
Acquired- HIV, autoimmune
Drugs
Alcohol
Beta blockers
Diuretics
Oral estrogens
Selective estrogen reuptake modulators - tamoxifen, raloxifene
Androgens
Glucocorticoids
Atypical anti-psychotics
Sertraline
Bile acid resins
Sirolimus, tacrolimus
Cyclosporine
RXR agonists -bexarotene, isotretinoin
HIV Protease inhibitors
L- asparaginase
Alpha-interferon
Propofol
Lipid emulsions

Following correction of treatable secondary forms of HTG in the MFCS, TG levels usually decrease to the moderately elevated levels seen in their affected relatives (152,153). Johansen and Hegele have reported several single nucleotide polymorphisms that account for about 20% of the TG elevation in individuals with very severe HTG. How the many common genetic variants that have small effects in patients with severe HTG (157) (see earlier) relate to the co-existence of familial and secondary forms of HTG, which in our experience is the usual cause of MFCS, is unknown. Perhaps an additional single nucleotide variant is required in addition to the genetic and secondary forms of HTG in order to develop TG levels above 2000 mg/dL (158).

FAMILIAL PARTIAL LIPODYSTROPHY (FPLD)

The lipodystrophies are a group of heterogeneous inherited or acquired disorders that are characterized by selective loss of body fat and HTG (159) and are reviewed elsewhere in the chapter on Lipodystrophies (160). Loss of fat can be either localized to small discrete areas, in some cases partial with loss from extremities, or generalized with fat loss from nearly the entire body. Inherited lipodystrophies, while rare, can be autosomal dominant or recessive. Some forms manifest at birth, while others become evident later in life.

Partial or generalized lipodystrophic disorders frequently are associated with significant metabolic derangements associated with severe insulin resistance, including HTG. The extent of fat loss sometimes determines the severity of metabolic complications (161). HTG is a common accompaniment of many lipodystrophies, often in conjunction with low HDL-C levels. Potential mechanisms for the development of HTG relate to decreased storage capacity of fat in adipose tissue, with increased hepatic VLDL synthesis and delayed clearance (161).

Genetics

Several genes have been implicated in the manifestation of various forms including LMNA, PPARG, LIPE, CIDEC (162). In the Dunnigan form, the most commonly identified genetic variant of FPLD, the commonest mutations are in the LMNA gene (159). No specific genetic defect has been identified in Köbberling’s FPLD, although recent evidence suggests a heavy polygenic burden in these individuals (163,164).

Diagnosis

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder in which near total absence of subcutaneous adipose tissue is evident from birth. HTG and hepatic steatosis are evident at a young age and are often difficult to control. Severe HTG, often associated with eruptive xanthoma and recurrent pancreatitis, can occur in patients with CGL. The prevalence of HTG in case series of CGL patients is over 70% (161,165). Plasma TGs are normal or slightly increased during early childhood, with severe HTG manifesting at puberty along with onset of diabetes mellitus.

Familial partial lipodystrophies (FPLD) are complex metabolic disorders that are often not recognized clinically (166). Partial lipodystrophies are characterized by partial loss of adipose tissue and significant metabolic derangements. The Dunnigan variety of FPLD (FPLD type 2) is a rare autosomal dominant disorder in which fat loss mostly involves the extremities and the trunk. Onset of fat loss in the buttocks and extremities occurs at puberty or late adolescence, with gain of fat to the face and neck. Acanthosis nigricans, muscle hypertrophy, phlebomegaly (prominent veins), and eruptive xanthomata can be observed. Metabolic dysfunction including diabetes, which is often very insulin resistant, and HTG often severe and difficult to treat, can occur. Myopathy, cardiomyopathy, and/or conduction system abnormalities can occur (167). CVD risk also is increased (168,169).

The Köbberling variety is believed to be less frequent (159,168), likely because common mutations leading to this phenotype have not yet been elucidated. In our experience, the diagnosis of the Köbberling form of partial lipodystrophy is frequently missed, since individuals with this disorder have many clinical features in common with the metabolic syndrome, including central obesity, diabetes, hypertension and HTG, which tends to be worse than in the Dunnigan form of FPLD (164). However, unlike the metabolic syndrome, they have very little subcutaneous adipose tissues in their extremities. A prominent ledge of fat above the gluteal area, and upper arm over the deltoid and upper triceps can be observed by careful examination of the legs, arms and buttocks (170), below which adipose tissue disappears (Figure 2).

Figure 2. . Diagnostic buttock shelf below which subcutaneous fat is absent in Köbberling lipodystrophy.

Figure 2.

Diagnostic buttock shelf below which subcutaneous fat is absent in Köbberling lipodystrophy.

A subscapular/calf skinfold ratio >3.5 was found to be a good diagnostic index for this condition (164) Since examination of the buttocks is not routinely performed during outpatient visits, this disorder is frequently missed and underdiagnosed. Extremities can be very lean and muscular with phlebomegaly and absent subcutaneous fat. Because patients with the Köbberling variety FPLD selectively lose subcutaneous fat on their limbs, but not on their abdomen or face, they can present with a Cushingoid appearance. In the absence of genetic markers, the diagnosis of Köbberling’s lipodystrophy can only be made on clinical grounds.

Some lipodystrophies, where fat loss appears to be proportionate to loss of total and lean body mass, do not result in dyslipidemia. Elevated TG levels have been reported in patients with atypical progeroid syndrome due to LMNA mutations (171,172). Of the acquired lipodystrophies, the HIV-associated form usually is characterized by more moderate HTG. HIV-associated lipodystrophy occurs in patients receiving protease inhibitor containing highly active anti-retroviral therapy regimens (173). Fat loss occurs in the face, buttocks and extremities.

Consequences of Hypertriglyceridemia

Increased Risk of Cardiovascular Disease

EPIDEMIOLOGY

HTG has long been known to be a risk factor for CVD (29,174-177), which has been reconfirmed in meta-analyses (41). However, HTG also is frequently associated with low levels of HDL-cholesterol and an accumulation of remnants of the TG-rich lipoproteins, both known risk factors for CVD. When adjusted for both HDL-C and non-HDL-C, which contains both remnants of the TG-rich lipoproteins and LDL, the association of TGs with CVD risk remained significant, although somewhat attenuated (23). Postprandial TGs are elevated throughout the day in subjects with HTG, and postprandial TG-rich lipoproteins and their remnants also have been hypothesized to be important in the pathogenesis of atherosclerosis (177). It is therefore of interest that non-fasting TGs also has been associated with CVD risk (177-179), despite non-fasting TGs being quite variable. However, unlike the situation with elevated LDL levels, the magnitude of the TG elevation does not appear to correlate with the extent of CVD risk. In particular, very severe HTG per se does not always appear to confer increased CVD risk, possibly because the chylomicrons that accumulate are too large to enter the arterial intima (180,181).

TRIGLYCERIDES IN THE PATHOGENESIS OF CVD

Although chylomicrons may be too large to enter the arterial intima, apoE-and cholesterol-enriched remnants of the TG-rich lipoproteins can enter with ease (179) where they can bind to vascular proteoglycans, similar to LDL (182,183). Modification of these retained lipoproteins by either oxidative damage or enzyme digestion of some of the lipid components can liberate toxic by-products, which have been hypothesized to play a role in atherogenesis by facilitating local injury, generation of adhesion molecule, and cytokine expression and inflammation (183). Remnants of the TG-rich lipoproteins also can be taken up by macrophages leading to the formation of foam cells, an important component of atherosclerotic plaques. HTG also is associated with a preponderance of small, dense LDL, particles, reduced levels of HDL-C, and in the metabolic syndrome, with abnormalities of HDL composition (see earlier). Small, dense LDL can traverse the endothelial barrier more easily than large, buoyant LDL particles (184), are retained more avidly than large, buoyant LDL (185), and also are more readily oxidized (186,187), all of which may facilitate atherogenesis. HDL particles in some hypertriglyceridemic states, e.g., in association with the metabolic syndrome, might be dysfunctional with respect to their cholesterol efflux, anti-inflammatory and anti-oxidant properties. Moreover, a hypercoagulable state has been reported in association with both HTG and the metabolic syndrome (110). Thus, HTG might accelerate atherosclerosis by several mechanisms, all of which could increase CVD risk.

GENETICS OF TRIGLYCERIDES AND CARDIOVASCULAR DISEASE

Recent human genetic studies have provided important insight into the contribution of TGs to CVD. Several genetic approaches, including candidate gene sequencing, GWAS of common DNA sequence variants, and genetic analysis of TG phenotypes have unraveled new proteins and gene variants involved in plasma TG regulation (188). Some genetic variants that influence TG levels appear to be associated with increased CVD risk even after adjusting for their effects on other lipid traits (189). GWAS have identified common noncoding variants of the LPL gene locus associated with TG and CVD risk (190,191). A common gain-of-function mutation in the LPL gene, S447X (10% allele frequency), is associated with reduced TG levels and reduced risk of CVD (192) and an LPL variant associated with reduced TG and apoB levels was associated with reduced CVD similar to LDL-C lowering variants, suggesting that the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in apoB (193). Conversely, several loss-of-function LPL variants linked with elevated TG levels are associated with increased CVD risk (194). Variants in the TRIB1 locus have been associated with LDL, HDL-C and TG levels (191), hepatic steatosis (195) and coronary artery disease (196). Mutations that disrupt APOC3 gene function and reduce plasma apoC-III concentration are associated with lower TG levels and decreased risk of clinical CVD (197,198). In contrast, carriers of rare mutations in APOA5, encoding apoA-V, an activator of LPL, are associated with elevated TGs and with increased risk of myocardial infarction (199,200). Loss of function variants in ANGPTL4 that had lower TG levels also were associated with reduced CVD risk (201,202). Thus, exciting new human genetics findings have causally implicated TG and TG-rich lipoproteins in the development of CVD risk. In particular, the LPL pathway and its reciprocal regulators apoC-III and apoA-V appear to have an important influence on atherosclerotic CVD risk.

Pancreatitis and Other Features of the Chylomicronemia Syndrome

The chylomicronemia syndrome describes a constellation of findings that occur with severe elevations of plasma TG levels. Although there is some lack of consensus as to what constitutes severe HTG, values >1000-1500 mg/dL are generally classified as severe, while values in the 500-1000 mg/dL range are classified as moderate (203). The most serious consequences of the chylomicronemia syndrome is acute pancreatitis, which often is recurrent. Atherosclerotic CVD also can occur as part of the chylomicronemia syndrome in individuals with MFCS and FPLD.

PANCREATITIS IN THE CHYLOMICRONEMIA SYNDROME

Individuals with both FCS and MFCS often present with acute pancreatitis, which can be recurrent. Pancreatitis due to very severe HTG also may occur during infusion of lipid emulsions for parenteral feeding (204) or with use of the anesthetic agent propofol, which is infused in a 10% fat emulsion (205). Severe HTG also can result in pancreatitis in a subset of women with HTG during pregnancy, particularly the third trimester (206).

The pancreatitis that occurs with severe HTG often is recurrent. With long term multiple episodes of acute, recurrent pancreatitis, exocrine pancreatic insufficiency or insulin deficient secondary diabetes may occur. Abdominal pain also may be the result of rapid expansion of the liver by fat, since fatty liver occurs commonly in all forms of severe HTG (207). In a prospective study of patients admitted with acute pancreatitis, the distribution of plasma TGs was bimodal when measured at the peak of the pain (152,153). TG levels less than 880 mg/dL were associated with gall bladder disease and chronic alcoholism, while those above 2000 mg/dL were associated with the simultaneous presence of familial and secondary forms of HTG. It has been suggested that individuals become prone to the development of TG-induced pancreatitis at TG values between 1500-2000 mg/dL (208). TG-induced pancreatitis has been reported with TG levels lower than 2000 mg/dL(209,210), although in our experience this usually occurs when patients with severe HTG stopped eating some time prior to the blood draw. The frequency of severe HTG leading to acute pancreatitis varies widely form about 6-20% of subjects, possibly related to the type of patient presenting to different type of medical centers (211,212). Moreover, the pancreatitis often is recurrent if HTG is not appreciated to be the cause and if TG levels are not adequately controlled (143). The effect of TG level on the cumulative incidence of acute pancreatitis in >3000 HTG subjects followed for >10 years, showed a stepwise increase in the cumulative incidence of pancreatitis as levels rose from 1000-1999 mg/dL through 2000-2999 to >3000 mg/dL, with diabetes and obesity being major contributing factors in the magnitude of TG elevation (213). A meta-analysis of observational studies suggests that TG-induced pancreatitis has worse outcomes that pancreatitis from other causes, with an approximate doubling of renal and respiratory failure, a nearly 4-fold increase of shock and a near doubling of mortality (214).

MECHANISM OF CHYLOMICRON-INDUCED PANCREATITIS

The mechanism by which very severe HTG leads to pancreatitis remains speculative. Suggested mechanisms include the local liberation of FFA from TGs and lysophosphatidylcholine from phosphatidycholine when pancreatic lipase encounters very high levels of TG-rich lipoproteins in the pancreatic capillaries (215). High local concentrations of FFA overwhelm the binding capacity of albumin with resultant aggregation into micellar structures with detergent properties. Both FFA and lysophosphatidylcholine have been shown to cause chemical pancreatitis when infused into pancreatic arteries in animal models (216-218). This leads to local liberation of more lipase, resulting in a vicious cycle (216,219). It also has been hypothesized that increased plasma viscosity due to the presence of increased numbers of chylomicrons in the pancreatic microcirculation contributes to the development of pancreatitis (220). There also is recent evidence of gene associations in TG-induced pancreatitis; in a Chinese cohort with HTG, a CFTR variant and TNF alpha promoter polymorphism were found to be independent risk factors for developing pancreatitis (221), while another study found an increased frequency of apoE4 (222).

DIAGNOSIS OF CHYLOMICRON-INDUCED PANCREATITIS

The diagnosis of HTG-associated pancreatitis can be made by the presence of severely elevated TG levels in a patient with acute pancreatitis. Falsely low serum amylase levels can be encountered due to assay interference by the TG-rich lipoproteins (223). Pseudohyponatremia due to the presence of large numbers of TG-rich lipoproteins in plasma can be seen with very high TG levels. Interference with liver transaminase assays may also occur, giving spuriously high values making it difficult to exclude alcoholic liver disease (223).

OTHER CLINICAL FEATURES SEEN IN INDIVIDUALS WITH CHYLOMICRONEMIA

With chronic chylomicronemia, patients may also develop eruptive xanthomata (Figure 3). Xanthomas represent an inflammatory response to the deposition of chylomicron-associated lipids in tissues and are yellow-red papules that usually appear on the buttocks, back and extensor surfaces of the upper limbs. Histologically, these lesions contain lipid laden foamy macrophages (224).

Figure 3. . Eruptive Xanthomas.

Figure 3.

Eruptive Xanthomas. The commonest site is on the buttocks. The lesions are popular with an erythematous base. They often are itchy.

Lipemia retinalis, where the retinal vessels take on a whitish hue with pallor of the optic fundus and retina can be observed with very high TG levels (Figure 4). There is no associated visual impairment.

Figure 4. . Lipemia retinalis.

Figure 4.

Lipemia retinalis. Note the pale color of the retinal vessels.

Acute recent memory loss and mental fogginess (138) can also occasionally be seen, but has not been extensively studied. Symptoms such as fatigue, blurred vision, dysesthesias, and transient ischemic attacks have been suggested to be related to hyperviscosity resulting from high TG levels (225,226). Hepatosplenomegaly is frequently present in FCS due to macrophage infiltration in response to the chylomicron accumulation. Fatty liver is a common finding on imaging in both FCS and MFCS.

CARDIOVASCULAR DISEASE IN THE CHYLOMIRONEMIA SYNDROME

As described earlier, chylomicrons have been considered to be too large to penetrate the vascular endothelium and play a role in atherogenesis (178), although remnants of the TG-rich lipoproteins may be atherogenic (178,227-230). The incidence of CVD is low in individuals with FCS (231), although premature atherosclerosis has been documented in well characterized subjects with this disorder (232). However, CVD risk clearly is increased in many patients with MFCS, although the exact frequency remains unclear. The frequency of CVD outcomes does not appear to relate to the magnitude of the TG elevations (213). It is not surprising that CVD is increased in MFCS considering the association between TGs and CVD that has been documented in many studies (reviewed in (177,233,234)). Many subjects develop severe HTG due to the co-existence of polygenic mutations that result in mild to moderate HTG (27) with secondary causes of HTG. Residual HTG due to these genetic disorders persists even after severely elevated TG levels have been reduced by treatment of the secondary forms of HTG and treatment of the HTG per se. Moreover, many patients with the MFCS have other CVD risk factors such as diabetes, reduced levels of HDL-C, and hypertension, the latter resulting in use of diuretics and beta-blockers, which play a role in raising their TGs to levels at which chylomicrons accumulate due to saturation of clearance mechanisms. Therefore, strategies to prevent CVD need to be undertaken once the TGs have been lowered to a level where pancreatitis is unlikely to recur. This is particularly true in cases where a presumptive clinical diagnosis of FCHL can be made by the presence of premature CVD in multiple family members. In such cases, statin therapy and lifestyle changes aimed at reducing the risk of CVD should be undertaken in addition to strategies to maintain reduced TG levels.

MANAGEMENT OF HYPERTRIGLYCERIDEMIA

Management of HTG by lifestyle and pharmacological means is discussed in detail in the chapters on Lifestyle Changes and Triglyceride Lowering and HDL Increasing Drugs (235,236). However, in this section we will make a few points specifically relevant to this chapter.

Cardiovascular Disease Prevention

CVD risk in HTG is modulated by the presence of several other factors, including other lipoprotein abnormalities, other CVD risk factors, and family history, with some families with HTG appearing to have a greater risk of CVD than others (40). Factors that might favor more aggressive therapy to reduce CVD risk (either for primary or secondary prevention) include the presence of a strongly positive family history of premature CVD (assuming sufficient family members are available to evaluate), elevated apoB and decreased apoA-I levels, and the presence of features of the metabolic syndrome and other CVD risk factors. Many of these individuals would be those carrying a clinical diagnosis of FCHL, as described earlier.

The best clinical trial data currently available for the prevention of CVD in patients with HTG demonstrate that statins are likely to confer the most benefit, even though their primary mode of action is not to reduce plasma TGs, nor are they very effective in so doing (237). Based on the results of the IMPROVE-IT trial (238), the addition of ezetimibe may be of additional benefit.

The role of TG lowering by pharmacological means remains somewhat controversial, but there is consensus that the presence of HTG imparts residual risk after LDL has been adequately lowered with statins. Fibrates, which are PPAR-α agonists, are effective in lowering plasma TG levels. Several studies have failed to demonstrate a benefit of fibrates on CVD events, either alone or in combination with statins. However, participants in these studies were not confined to individuals with HTG. Nonetheless, post-hoc analysis showed that subgroups of subjects who had HTG had a significant reduction of CVD events (239-242). In addition, the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-LIPID trial, which was confined to subjects with diabetes, showed a similar outcome in the subgroups with HTG, although the trial was negative for all subjects (240). Unfortunately, no fibrate studies to date have focused solely on subjects with HTG, although a clinical trial, Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes (PROMINENT - ClinicalTrials.gov Identifier: NCT03071692), using a novel selective peroxisome proliferator-activated receptor α modulator, pemafibrate, that possesses unique PPARα activity and selectivity (243), is currently being performed in individuals with HTG and diabetes.

The role of omega-3 (n-3) fatty acids in CVD prevention in HTG also is controversial. A meta-analysis of 10 randomized trials involving ~78,000 patients did not show a beneficial effect on CVD events in subjects that received n–3 fatty acids supplements (244). ASCEND (A Study of Cardiovascular Events in Diabetes), also failed to demonstrate a beneficial effect of low dose n–3 fatty acids in patients with type 2 diabetes (245). Moreover, the Vitamin D and Omega-3 Trial (VITAL) primary-prevention trial in a large number of participants also failed to show a lower incidence of the CVD outcomes in the n-3 fatty acid limb of the trial (246). However, the recent Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), confined to high-risk patients with elevated TG levels who had been receiving effective statin therapy, demonstrated a surprising 25% lower risk in subjects who received a high dose of icosapent ethyl, a highly purified form of eicosapentaenoic (EPA) acid than in those receiving placebo (247). Interestingly, the reduction in CVD events was greater than the reduction in TG levels and did not correlate with either baseline or on trial TGs, raising the question of whether the benefit in CVD protection resulted from some effects of the agent other than on plasma TG. Nonetheless, the results of REDUCE-IT are similar to those seen in the earlier Japan EPA Lipid Intervention Study (JELIS), an open-label trial that reported a lower dose of EPA led a similar reduction in major adverse CVD in high risk subjects on therapy (248). Many of the negative trials used a low dose of n-3-fatty acid (e.g., 1 g/day), in contrast the positive trials that used higher doses JELIS (1.8 EPA g/day) and REDUCE-IT (4 icosapent ethyl g/day) It may be that the dose of omega-3-fatty acid makes a difference. It also is possible that EPA has effects that are not shared by the other main n-3 fatty acid, docosahexaenoic acid. Hopefully the ongoing STRENGTH (Statin Residual Risk Reduction With Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia) trial of another n–3 fatty acid will help shed light on the role of n-3 fatty acids on CVD prevention in patients with residual hypertriglyceridemia.

Treatment of Severe HTG that Accompanies the Chylomicronemia Syndrome

Therapeutic approaches to the three major causes of the chylomicronemia syndrome (MFCS, FCS and FPLD) differ considerably. Therefore, each will be considered separately.

FAMILIAL CHYLOMICRONEMIA SYNDROME (FCS)

Consumption of even small amounts of fat can lead to severe HTG in FCS due to the absence of functional LPL. Infants with FCS presenting with abdominal pain or failure to thrive require discontinuation of breast feeding with replacement by very low-fat formula feeding to decrease TG levels and symptoms. In children and adults with FCS, dietary fat calories should be severely restricted to control the severe HTG and abdominal pain. This translates to about 5% to 10% of total daily calories, which is a major burden for these patients (249). Medium-chain TGs, which are taken up directly by the liver after absorption and do not enter plasma as chylomicrons via the thoracic duct, are a potential alternate fat source for these patients. While n-3 fatty acids lower plasma TGs in MFCS, they can aggravate the severe HTG of FCS and therefore are contraindicated in FCS (250,251). Fibrates also do not appear to be beneficial in FCS (207). There are limited studies showing that orlistat might be beneficial in patients with FCS (252,253). Alcohol, oral contraceptives, and other TG-elevating drugs (see Table 4) can exacerbate severe HTG and precipitate acute pancreatitis in FCS. Successful pregnancies in patients with FCS have become more common of late (254,255).

Alipogene tiparvovec, an adeno-associated virus LPL gene therapy, is no longer available. It resulted in a significant improvement of postprandial chylomicron metabolism in patients with FCS (256), although fasting TG levels only fell by about 40% and subsequently returned towards baseline (257). Retrospective long-term follow up suggests that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, although the numbers were small (258). More recently, weekly subcutaneous injection of an antisense oligonucleotide inhibitor of apoC-III transcription resulted in substantial reductions in plasma TGs in three well characterized FCS patients who had no functional LPL (259), an approach that holds promise for the future treatment of FCS patients.

MULTIFACTORIAL CHYLOMICRONEMIA SYNDROME (MFCS)

To prevent pancreatitis in MFCS, the goal is to maintain TG levels below the threshold for pancreatitis, preferably <500 mg/dL. This requires reversal of secondary cause of HTG, such as treatment of poorly-controlled or undiagnosed diabetes, substitution of lipid neutral antihypertensive agents such as ACE inhibitors, ARBs, calcium channel inhibitors, or alpha blockers for beta-adrenergic blockers and diuretics for the treatment of hypertension, and discontinuation of other TG-raising drugs (table 4) where possible. Alcohol intake should be limited or eliminated, since even small amounts of alcohol can substantially raise TG levels in individuals with baseline HTG. Attention should be paid to avoid rebound weight gain that commonly occurs after successful weight loss. Oral estrogens should be substituted by transdermal or vaginal preparations, which raise plasma TGs to a lesser extent than oral estrogens (260,261). Residual HTG should be treated with fibrates (262), which together with management of the secondary disorder or disorders, usually reduces TG levels to below the threshold for developing pancreatitis. Other agents that can be used to lower TGs alone or in combination with fibrates, include n-3 fatty acids, high-dose statins and niacin. Although lifestyle measures and weight loss might be of value, caution needs to be exerted, since in our experience rapid weight regain after successful weight loss can be associated with rebound severe HTG. Bariatric surgery also has been used to reduce severe HTG in refractory patients (263). Antisense oligonucleotides against apoC-III, which have been shown to lower TGs in patients with severe HTG not due to FCS (264), may have a role to play in the future the management of severe HTG in patients with MFCS.

FAMILIAL PARTIAL LIPODYSTROPHY (FPLD)

The severe HTG that accompanies FPLD can be very resistant to treatment and can lead to recurrent episodes of acute pancreatitis (170). Fibrates and n-3 fatty acids sometimes but not always lower TGs sufficiently to reduce the risk of pancreatitis. Treatment of diabetes, which often is very insulin resistant, may help. If TG levels remain very elevated, addition of n-3 fatty acids, thiazolidinediones or cautious, selective use of GLP-1 receptor analogs may improve both TG levels and glycemic control in some patients, although these strategies are based on anecdotal rather than being evidence based. Leptin administration appears to be helpful in congenital total lipodystrophy and in some FPLD patients with low leptin levels (265). Because serum leptin levels are normal or high in the Köbberling variety of FPLD (164,170); there is little rationale for its use in this form of lipodystrophy. In the future, use of antisense oligonucleotides to apoC-III or ANGPTL 3 inhibition (266) might prove to be of value. Since ANGPTL3 inhibition also lowers LDL cholesterol and HDL cholesterol, and loss of function mutations of ANGPTL3 have been associated with a reduced risk of atherosclerosis (267), ANPTL3 inhibition might prove to be of value in the prevention of CVD in addition to prevention of TG-induced pancreatitis.

Prevention of and Treatment TG-induced Pancreatitis

Because of the low frequency of FCS, MFCS and FPLD, and because only some patients with these disorders develop pancreatitis, large random controlled clinical trials are difficult to perform and unlikely to be undertaken in the foreseeable future. Therefore, therapeutic decisions need to be based on less stringent criteria than might otherwise be desirable. However, keeping TG levels <500 mg/dL should prevent the onset of TG-induced pancreatitis (203,262,268).

The clinical presentation of HTG-induced pancreatitis is similar to that from other causes of acute pancreatitis and can be preceded by episodic nausea, epigastric pain radiating through to the back and increasing heart-burn. Individuals may present without severe elevation in pancreatic enzymes (269). Its management is similar to the management of non-TG induced pancreatitis, which includes cessation of all oral intake, fluid resuscitation, and management of metabolic abnormalities. Lipid emulsions for parenteral feeding should be avoided since their use will further delay clearance and exacerbate the HTG. TGs fall rapidly with discontinuation of oral intake. The use of plasmapheresis to acutely lower TGs is controversial. Although recommended by some (270,271), the current evidence for the benefit of use of plasmapheresis is limited to small uncontrolled anecdotal series (272) from which no firm conclusion can be made regarding its use in acute TG-induced pancreatitis (273). TG levels fall rapidly with cessation of oral intake and use of non-lipid-containing intravenous fluids. Additionally, plasmapheresis requires a specialized center and only temporarily improves TG levels without addressing the underlying cause (139). Therefore, we do not recommend its routine use in this situation unless clinical circumstances necessitate plasmapheresis such as severe acute necrotizing pancreatitis (274) or possibly pregnancy (275). Heparin will liberate LPL into plasma from its endothelial binding sites and hence rapidly lowers TGs (276). However, it also can cause rebound HTG due to rapid degradation of released LPL (277) and increase the risk of hemorrhagic pancreatitis. Therefore, the use of heparin is not recommended (278). The rationale for the use of an IV insulin infusion of regular insulin (in conjunction with IV glucose administration as needed) is that it can activate LPL and enhance clearance of TG-rich lipoproteins (279). Its use in TG--induced pancreatitis without diabetes has been reported in several case reports (280-284), but it is unclear whether similar changes would have occurred simply by restricting oral intake without the use of insulin. In a study of chylomicronemia with uncontrolled diabetes, insulin infusion lowered TGs more rapidly than plasmapheresis (285).

After TG lowering in the setting of acute pancreatitis, it is essential to determine both the primary and secondary causes of the severe HTG that precipitated the acute pancreatitis. Continued management of any secondary form of HTG, as well as lifestyle and drug therapy to maintain low TG levels is required to prevent recurrent pancreatitis. If fasting plasma TG levels remain above 1000 mg/dL after treating or removing the precipitating causes of the severe HTG, life-long therapy with fibrates or n-3 fatty acids, as described earlier, might be considered for patients with both MCFS and FPDL. Limited evidence suggests that orlistat, a gastrointestinal lipase inhibitor that decreases absorption of ingested fat, thereby reducing intestinal chylomicron synthesis, may be of benefit in reducing TG levels when used in conjunction with fibrate therapy (286,287). TG and glucose control can be particularly challenging in individuals with some forms of FPLD.

REFERENCES

1.
Feingold KR, Grunfeld C. Introduction to Lipids and Lipoproteins. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, eds. Endotext. South Dartmouth (MA)2018.
2.
Fisher EA. The degradation of apolipoprotein B100: multiple opportunities to regulate VLDL triglyceride production by different proteolytic pathways. Biochim Biophys Acta. 2012;1821:778–781. [PMC free article: PMC3593638] [PubMed: 22342675]
3.
Sundaram M, Yao Z. Recent progress in understanding protein and lipid factors affecting hepatic VLDL assembly and secretion. Nutrition & metabolism. 2010;7:35. [PMC free article: PMC2873297] [PubMed: 20423497]
4.
Yao Z. Human apolipoprotein C-III - a new intrahepatic protein factor promoting assembly and secretion of very low density lipoproteins. Cardiovascular & hematological disorders drug targets. 2012;12:133–140. [PubMed: 23030451]
5.
Schneeman BO, Kotite L, Todd KM, Havel RJ. Relationships between the responses of triglyceride-rich lipoproteins in blood plasma containing apolipoproteins B-48 and B-100 to a fat-containing meal in normolipidemic humans. Proc Natl Acad Sci U S A. 1993;90:2069–2073. [PMC free article: PMC46022] [PubMed: 8446630]
6.
Kindel T, Lee DM, Tso P. The mechanism of the formation and secretion of chylomicrons. Atheroscler Suppl. 2010;11:11–16. [PubMed: 20493784]
7.
Kersten S. Physiological regulation of lipoprotein lipase. Biochim Biophys Acta. 2014;1841:919–933. [PubMed: 24721265]
8.
Gordts PL, Nock R, Son NH, Ramms B, Lew I, Gonzales JC, Thacker BE, Basu D, Lee RG, Mullick AE, Graham MJ, Goldberg IJ, Crooke RM, Witztum JL, Esko JD. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest. 2016;126:2855–2866. [PMC free article: PMC4966320] [PubMed: 27400128]
9.
Goldberg IJ, Scheraldi CA, Yacoub LK, Saxena U, Bisgaier CL. Lipoprotein ApoC-II activation of lipoprotein lipase. Modulation by apolipoprotein A-IV. J Biol Chem. 1990;265:4266–4272. [PubMed: 2307668]
10.
Nilsson SK, Heeren J, Olivecrona G, Merkel M. Apolipoprotein A-V; a potent triglyceride reducer. Atherosclerosis. 2011;219:15–21. [PubMed: 21831376]
11.
Priore Oliva C, Pisciotta L, Li Volti G, Sambataro MP, Cantafora A, Bellocchio A, Catapano A, Tarugi P, Bertolini S, Calandra S. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411–417. [PubMed: 15591215]
12.
Gonzales JC, Gordts PL, Foley EM, Esko JD. Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans. J Clin Invest. 2013;123:2742–2751. [PMC free article: PMC3668842] [PubMed: 23676495]
13.
Kroupa O, Vorrsjo E, Stienstra R, Mattijssen F, Nilsson SK, Sukonina V, Kersten S, Olivecrona G, Olivecrona T. Linking nutritional regulation of Angptl4, Gpihbp1, and Lmf1 to lipoprotein lipase activity in rodent adipose tissue. BMC Physiol. 2012;12:13. [PMC free article: PMC3562520] [PubMed: 23176178]
14.
Lamiquiz-Moneo I, Bea AM, Mateo-Gallego R, Baila-Rueda L, Cenarro A, Pocovi M, Civeira F, de Castro-Oros I. Clin Investig Arterioscler. 2015 [Identification of variants in LMF1 gene associated with primary hypertriglyceridemia]
15.
Inukai K, Nakashima Y, Watanabe M, Kurihara S, Awata T, Katagiri H, Oka Y, Katayama S. ANGPTL3 is increased in both insulin-deficient and -resistant diabetic states. Biochem Biophys Res Commun. 2004;317:1075–1079. [PubMed: 15094378]
16.
Shimamura M, Matsuda M, Ando Y, Koishi R, Yasumo H, Furukawa H, Shimomura I. Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor. Biochem Biophys Res Commun. 2004;322:1080–1085. [PubMed: 15336575]
17.
Koster A, Chao YB, Mosior M, Ford A, Gonzalez-DeWhitt PA, Hale JE, Li D, Qiu Y, Fraser CC, Yang DD, Heuer JG, Jaskunas SR, Eacho P. Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology. 2005;146:4943–4950. [PubMed: 16081640]
18.
Foley EM, Gordts PL, Stanford KI, Gonzales JC, Lawrence R, Stoddard N, Esko JD. Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice. Arterioscler Thromb Vasc Biol. 2013;33:2065–2074. [PMC free article: PMC3821931] [PubMed: 23846497]
19.
Crawford SE, Borensztajn J. Plasma clearance and liver uptake of chylomicron remnants generated by hepatic lipase lipolysis: evidence for a lactoferrin-sensitive and apolipoprotein E-independent pathway. J Lipid Res. 1999;40:797–805. [PubMed: 10224148]
20.
Dichek HL, Johnson SM, Akeefe H, Lo GT, Sage E, Yap CE, Mahley RW. Hepatic lipase overexpression lowers remnant and LDL levels by a noncatalytic mechanism in LDL receptor-deficient mice. J Lipid Res. 2001;42:201–210. [PubMed: 11181749]
21.
Brunzell JD, Hazzard WR, Porte D Jr, Bierman EL. Evidence for a common saturable triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. J Clin Invest. 1973;52:1578–1585. [PMC free article: PMC302428] [PubMed: 4352459]
22.
Greenfield MS, Kraemer F, Tobey T, Reaven G. Effect of age on plasma triglyceride concentrations in man. Metabolism. 1980;29:1095–1099. [PubMed: 7001176]
23.
Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213–219. [PubMed: 8836866]
24.
Asplund-Carlson A, Carlson LA. Studies in hypertriglyceridaemia. 1. Serum triglyceride distribution and its correlates in randomly selected Swedish middle-aged men. J Intern Med. 1994;236:57–64. [PubMed: 8021574]
25.
Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. J Lipid Res. 2011;52:189–206. [PMC free article: PMC3023540] [PubMed: 21041806]
26.
Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, Stalenhoef AF. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97:2969–2989. [PMC free article: PMC3431581] [PubMed: 22962670]
27.
Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, Boren J, Bruckert E, Catapano AL, Descamps OS, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A, Watts GF, Wiklund O. European Atherosclerosis Society Consensus P. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2:655–666. [PMC free article: PMC4201123] [PubMed: 24731657]
28.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497. [PubMed: 11368702]
29.
Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S. American Heart Association Clinical Lipidology T, Prevention Committee of the Council on Nutrition PA, Metabolism, Council on Arteriosclerosis T, Vascular B, Council on Cardiovascular N, Council on the Kidney in Cardiovascular D. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292–2333. [PubMed: 21502576]
30.
Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, Wilson DP, Brown WV. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol. 2015;9:129–169. [PubMed: 25911072]
31.
Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, Stalenhoef AF. Endocrine s. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97:2969–2989. [PMC free article: PMC3431581] [PubMed: 22962670]
32.
Authors/Task Force Members. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Z, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WM, Vlachopoulos C, Wood DA, Zamorano JL. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016;253:281–344. [PubMed: 27594540]
33.
Fredrickson D, Levy R, Lees R. Fat transport and lipoproteins - an integrated approach to mechanisms and disorders. N Engl J Med. 1967;276:32–94,148,215,273. [PubMed: 5334042]
34.
Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973;52:1544–1568. [PMC free article: PMC302426] [PubMed: 4718953]
35.
Nikkila EA, Aro A. Family study of serum lipids and lipoproteins in coronary heart-disease. Lancet. 1973;1:954–959. [PubMed: 4121585]
36.
Brunzell JD. Clinical practice. Hypertriglyceridemia. N Engl J Med. 2007;357:1009–1017. [PubMed: 17804845]
37.
Chait A, Albers JJ, Brunzell JD. Very low density lipoprotein overproduction in genetic forms of hypertriglyceridemia. Eur J Clin Invest. 1980;10:17–22. [PubMed: 6768562]
38.
Brunzell JD, Albers JJ, Chait A, Grundy SM, Groszek E, McDonald GB. Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. J Lipid Res. 1983;24:147–155. [PubMed: 6403642]
39.
Brunzell JD, Schrott HG, Motulsky AG, Bierman EL. Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism. 1976;25:313–320. [PubMed: 1250165]
40.
Austin MA, McKnight B, Edwards KL, Bradley CM, McNeely MJ, Psaty BM, Brunzell JD, Motulsky AG. Cardiovascular disease mortality in familial forms of hypertriglyceridemia: A 20-year prospective study. Circulation. 2000;101:2777–2782. [PubMed: 10859281]
41.
Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta- analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213–219. [PubMed: 8836866]
42.
McNeely M, Edwards K, Marcovina S, Brunzell J, Motulsky A, Austin M. Lipoprotein and apolipoprotein abnormalities in familial combined hyperlipidemia: a 20-year prospective study. Atherosclerosis. 2001;159:417–481. [PubMed: 11730829]
43.
van Greevenbroek MM, Stalenhoef AF, de Graaf J, Brouwers MC. Familial combined hyperlipidemia: from molecular insights to tailored therapy. Curr Opin Lipidol. 2014;25:176–182. [PubMed: 24811296]
44.
Lewis GF, Xiao C, Hegele RA. Hypertriglyceridemia in the genomic era: a new paradigm. Endocr Rev. 2015;36:131–147. [PubMed: 25554923]
45.
Dron JS, Wang J, Cao H, McIntyre AD, Iacocca MA, Menard JR, Movsesyan I, Malloy MJ, Pullinger CR, Kane JP, Hegele RA. Severe hypertriglyceridemia is primarily polygenic. J Clin Lipidol. 2019;13:80–88. [PubMed: 30466821]
46.
Johansen CT, Wang J, Lanktree MB, McIntyre AD, Ban MR, Martins RA, Kennedy BA, Hassell RG, Visser ME, Schwartz SM, Voight BF, Elosua R, Salomaa V, O'Donnell CJ, Dallinga-Thie GM, Anand SS, Yusuf S, Huff MW, Kathiresan S, Cao H, Hegele RA. An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2011;31:1916–1926. [PMC free article: PMC3562702] [PubMed: 21597005]
47.
Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM, Do R, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkila K, Hypponen E, Isaacs A, Jackson AU, Johansson A, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J, Lyytikainen LP, Magnusson PKE, Mangino M, Mihailov E, Montasser ME, Muller-Nurasyid M, Nolte IM, O'Connell JR, Palmer CD, Perola M, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney ASF, Doring A, Elliott P, Epstein SE, Ingi Eyjolfsson G, Gigante B, Goodarzi MO, Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen AL, Hayward C, Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P, Kastelein JJP, Khaw KT, Kim E, Klopp N, Komulainen P, Kumari M, Langenberg C, Lehtimaki T, Lin SY, Lindstrom J, Loos RJF, Mach F, McArdle WL, Meisinger C, Mitchell BD, Muller G, Nagaraja R, Narisu N, Nieminen TVM, Nsubuga RN, Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ, Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K, Stancakova A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH, Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M, Boehm BO, Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Campbell H, Chakravarti A, Chambers JC, Chen YI, Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire U, Feranil AB, Ferrieres J, Ferrucci L, Freimer NB, Gieger C, Groop LC, Gudnason V, Gyllensten U, Hamsten A, Harris TB, Hingorani A, Hirschhorn JN, Hofman A, Hovingh GK, Hsiung CA, Humphries SE, Hunt SC, Hveem K, Iribarren C, Jarvelin MR, Jula A, Kahonen M, Kaprio J, Kesaniemi A, Kivimaki M, Kooner JS, Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO, Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG, Marz W, McCarthy MI, McKenzie CA, Meneton P, Metspalu A, Moilanen L, Morris AD, Munroe PB, Njolstad I, Pedersen NL, Power C, Pramstaller PP, Price JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D, Salomaa V, Sanghera DK, Saramies J, Schwarz PEH, Sheu WH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J, Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L, Wareham NJ, Whitfield JB, Wolffenbuttel BHR, Ordovas JM, Boerwinkle E, Palmer CNA, Thorsteinsdottir U, Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA, Sandhu MS, Rich SS, Boehnke M, Deloukas P, Kathiresan S, Mohlke KL, Ingelsson E, Abecasis GR, Global Lipids Genetics C. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–1283. [PMC free article: PMC3838666] [PubMed: 24097068]
48.
Ripatti P, Ramo JT, Soderlund S, Surakka I, Matikainen N, Pirinen M, Pajukanta P, Sarin AP, Service SK, Laurila PP, Ehnholm C, Salomaa V, Wilson RK, Palotie A, Freimer NB, Taskinen MR, Ripatti S. The Contribution of GWAS Loci in Familial Dyslipidemias. PLoS Genet. 2016;12:e1006078. [PMC free article: PMC4882070] [PubMed: 27227539]
49.
Brouwers MC, van Greevenbroek MM, Stehouwer CD, de Graaf J, Stalenhoef AF. The genetics of familial combined hyperlipidaemia. Nat Rev Endocrinol. 2012;8:352–362. [PubMed: 22330738]
50.
Pajukanta P, Nuotio I, Terwilliger JD, Porkka KV, Ylitalo K, Pihlajamaki J, Suomalainen AJ, Syvanen AC, Lehtimaki T, Viikari JS, Laakso M, Taskinen MR, Ehnholm C, Peltonen L. Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23. Nat Genet. 1998;18:369–373. [PubMed: 9537421]
51.
Mar R, Pajukanta P, Allayee H, Groenendijk M, Dallinga-Thie G, Krauss RM, Sinsheimer JS, Cantor RM, de Bruin TW, Lusis AJ. Association of the APOLIPOPROTEIN A1/C3/A4/A5 gene cluster with triglyceride levels and LDL particle size in familial combined hyperlipidemia. Circ Res. 2004;94:993–999. [PubMed: 15001527]
52.
Suviolahti E, Lilja HE, Pajukanta P. Unraveling the complex genetics of familial combined hyperlipidemia. Ann Med. 2006;38:337–351. [PubMed: 16938803]
53.
Pihlajamaki J, Valve R, Karjalainen L, Karhapaa P, Vauhkonen I, Laakso M. The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance. Eur J Clin Invest. 2001;31:302–308. [PubMed: 11298776]
54.
Pajukanta P, Porkka KV, Antikainen M, Taskinen MR, Perola M, Murtomaki-Repo S, Ehnholm S, Nuotio I, Suurinkeroinen L, Lahdenkari AT, Syvanen AC, Viikari JS, Ehnholm C, Peltonen L. No evidence of linkage between familial combined hyperlipidemia and genes encoding lipolytic enzymes in Finnish families. Arterioscler Thromb Vasc Biol. 1997;17:841–850. [PubMed: 9157946]
55.
Hoffer MJ, Snieder H, Bredie SJ, Demacker PN, Kastelein JJ, Frants RR, Stalenhoef AF. The V73M mutation in the hepatic lipase gene is associated with elevated cholesterol levels in four Dutch pedigrees with familial combined hyperlipidemia. Atherosclerosis. 2000;151:443–450. [PubMed: 10924721]
56.
Yang WS, Nevin DN, Peng R, Brunzell JD, Deeb SS. A mutation in the promoter of the lipoprotein lipase gene in a patient with familial combined hyperlipidemia and low LDL activity. Proc Natl Acad Sci USA. 1995;92:4462–4466. [PMC free article: PMC41964] [PubMed: 7753827]
57.
Yang WS, Nevin DN, Iwasaki L, Peng R, Brown BG, Brunzell JD, Deeb SS. Regulatory mutations in the human lipoprotein lipase gene in patients with familial combined hyperlipidemia and coronary artery disease. J Lipid Res. 1996;37:2627–2637. [PubMed: 9017514]
58.
Reymer PW, Groenemeyer BE, Gagne E, Miao L, Appelman EE, Seidel JC, Kromhout D, Bijvoet SM, van de Oever K, Bruin T, et al. A frequently occurring mutation in the lipoprotein lipase gene (Asn291Ser) contributes to the expression of familial combined hyperlipidemia. Hum Mol Genet. 1995;4:1543–1549. [PubMed: 8541837]
59.
Gagne E, Genest J Jr, Zhang H, Clark LA, Hayden MR. Analysis of DNA changes in the LPL gene in patients with familial combined hyperlipidemia. Arterioscler Thromb. 1994;14:1250–1257. [PubMed: 8049185]
60.
Hoffer MJV, Bredie SJH, Boomsma D, Reymer PWA, Kastelein JJP, deKnijff P, Demacker PNM, Stalenhoef AFH, Havekes LM, Frants RR. The lipoprotein lipase (Asn291Ser) mutation is associated with elevated lipid levels in families with familial combined hyperlipidemia. Atherosclerosis. 1995;119:159–167. [PubMed: 8808493]
61.
Nevin DN, Brunzell JD, Deeb SS. The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity. Arterioscler Thromb. 1994;14:869–873. [PubMed: 8199176]
62.
Nanni L, Quagliarini F, Megiorni F, Montali A, Minicocci I, Campagna F, Pizzuti A, Arca M. Genetic variants in adipose triglyceride lipase influence lipid levels in familial combined hyperlipidemia. Atherosclerosis. 2010;213:206–211. [PubMed: 20832801]
63.
Weissglas-Volkov D, Aguilar-Salinas CA, Sinsheimer JS, Riba L, Huertas-Vazquez A, Ordonez-Sanchez ML, Rodriguez-Guillen R, Cantor RM, Tusie-Luna T, Pajukanta P. Investigation of variants identified in caucasian genome-wide association studies for plasma high-density lipoprotein cholesterol and triglycerides levels in Mexican dyslipidemic study samples. Circ Cardiovasc Genet. 2010;3:31–38. [PMC free article: PMC2827864] [PubMed: 20160193]
64.
Eaton RP, Allen RC, Schade DS. Overproduction of a kinetic subclass of VLDL-apoB, and direct catabolism of VLDL-apoB in human endogenous hypertriglyceridemia: an analytical model solution of tracer data. J Lipid Res. 1983;24:1291–1303. [PubMed: 6644179]
65.
Grundy SM, Mok HYI, Zech L, Steinberg D, Berman M. Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia. J Clin Invest. 1979;63:1274–1283. [PMC free article: PMC372076] [PubMed: 221538]
66.
Beil U, Grundy SM, Crouse JR, Zech L. Triglyceride and cholesterol metabolism in primary hypertriglyceridemia. Arteriosclerosis. 1982;2:44–57. [PubMed: 7059323]
67.
Sigurdsson G, Nicoll A, Lewis B. Metabolism of very low density lipoproteins in hyperlipidaemia: studies of apolipoprotein B kinetics in man. Eur J Clin Invest. 1976;6:167–177. [PubMed: 177296]
68.
Ayyobi AF, Brunzell JD. Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. Am J Cardiol. 2003;92:27J–33J. [PubMed: 12957324]
69.
Reynisdottir S, Eriksson M, Angelin B, Arner P. Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia. J Clin Invest. 1995;95:2161–2169. [PMC free article: PMC295819] [PubMed: 7738184]
70.
Reynisdottir S, Angelin B, Langin D, Lithell H, Eriksson M, Holm C, Arner P. Adipose tissue lipoprotein lipase and hormone-sensitive lipase. Contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome. Arterioscler Thromb Vasc Biol. 1997;17:2287–2292. [PubMed: 9351402]
71.
Venkatesan S, Cullen P, Pacy P, Halliday D, Scott J. Stable isotopes show a direct relation between VLDL apoB overproduction and serum triglyceride levels and indicate a metabolically and biochemically coherent basis for familial combined hyperlipidemia. Arterioscler Thromb. 1993;13:1110–1118. [PubMed: 8318511]
72.
Aitman T, Godsland I, Farren B, Crook D, Wong H, Scott J. Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 1997;17:748–754. [PubMed: 9108790]
73.
Janus ED, Nicoll AM, Turner PR, Magill P, Lewis B. Kinetic bases of the primary hyperlipidemias: Studies of apolipoprotein B turnover in genetically defined subjects. Eur J Clin Invest. 1980;10:161–172. [PubMed: 6780364]
74.
Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res. 2002;43:1363–1379. [PubMed: 12235168]
75.
Cabezas MC, de Bruin TW, Jansen H, Kock LA, Kortlandt W, Erkelens DW. Impaired chylomicron remnant clearance in familial combined hyperlipidemia. Arterioscler Thromb. 1993;13:804–814. [PubMed: 8499400]
76.
Hokanson JE, Austin MA, Zambon A, Brunzell JD. Plasma triglyceride and LDL heterogeneity in familial combined hyperlipidemia. Arterioscler Thromb. 1993;13:427–434. [PubMed: 8443147]
77.
Hokanson JE, Krauss RM, Albers JJ, Austin MA, Brunzell JD. LDL physical and chemical properties in familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 1995;15:452–459. [PubMed: 7749856]
78.
Cruz-Bautista I, Mehta R, Cabiedes J, Garcia-Ulloa C, Guillen-Pineda LE, Almeda-Valdes P, Cuevas-Ramos D, Aguilar-Salinas CA. Determinants of VLDL composition and apo B-containing particles in familial combined hyperlipidemia. Clin Chim Acta. 2015;438:160–165. [PubMed: 25172037]
79.
Brouwers MC, van Greevenbroek MM. Lipid metabolism: the significance of plasma proprotein convertase subtilisin kexin type 9 in the elucidation of complex lipid disorders. Curr Opin Lipidol. 2011;22:317–318. [PubMed: 21743308]
80.
Hopkins PN, Heiss G, Ellison RC, Province MA, Pankow JS, Eckfeldt JH, Hunt SC. Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia: a case-control comparison from the National Heart, Lung, and Blood Institute Family Heart Study. Circulation. 2003;108:519–523. [PubMed: 12847072]
81.
Purnell JQ, Kahn SE, Schwartz RS, Brunzell JD. Relationship of insulin sensitivity and ApoB levels to intra-abdominal fat in subjects with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 2001;21:567–572. [PubMed: 11304474]
82.
Ascaso J, Lorente R, Merchante A, Real J, Priego A, Carmena R. Insulin resistance in patients wtih familial combined hyperlipidemia and coronary artery disease. Am J Cardiol. 1997;80:1481–1487. [PubMed: 9399729]
83.
Castro Cabezas M, de Bruin T, de Valk H, Shoulders C, Jansen H, Willem Erkelens D. Impaired fatty acid metabolism in familial combined hyperlipidemia: a mechanism associating hepatic apolipoprotein B overproduction and insulin resistance. J Clin Invest. 1993;92:160–168. [PMC free article: PMC293556] [PubMed: 8100834]
84.
van der Kallen C, Voors-Pette C, Bouwman F, Keizer H, Lu J, van de Hulst R, Bianchi R, Janssen M-J, Keulen E, Boeckx W, Rotter J, de Bruin T. Evidence of insulin resistant lipid metabolism in adipose tissue in familial combined hyperlipidemia, but not type 2 diabetes mellitus. Atherosclerosis. 2002;164:337–346. [PubMed: 12204806]
85.
Arner P, Bernard S, Salehpour M, Possnert G, Liebl J, Steier P, Buchholz BA, Eriksson M, Arner E, Hauner H, Skurk T, Ryden M, Frayn KN, Spalding KL. Dynamics of human adipose lipid turnover in health and metabolic disease. Nature. 2011;478:110–113. [PMC free article: PMC3773935] [PubMed: 21947005]
86.
Brouwers MC, Bilderbeek-Beckers MA, Georgieva AM, van der Kallen CJ, van Greevenbroek MM, de Bruin TW. Fatty liver is an integral feature of familial combined hyperlipidaemia: relationship with fat distribution and plasma lipids. Clin Sci (Lond). 2007;112:123–130. [PubMed: 16958621]
87.
Brouwers MC, Reesink KD, van Greevenbroek MM, Meinders JM, van der Kallen CJ, Schaper N, Hoeks AP, Stehouwer CD. Increased arterial stiffness in familial combined hyperlipidemia. J Hypertens. 2009;27:1009–1016. [PubMed: 19402225]
88.
Keulen ET, Kruijshoop M, Schaper NC, Hoeks AP, de Bruin TW. Increased intima-media thickness in familial combined hyperlipidemia associated with apolipoprotein B. Arterioscler Thromb Vasc Biol. 2002;22:283–288. [PubMed: 11834529]
89.
Chait A, Brunzell JD. Severe hypertriglyceridemia: Role of familial and acquired disorders. Metabolism. 1983;32:209–214. [PubMed: 6827992]
90.
Luijten J, van Greevenbroek MMJ, Schaper NC, Meex SJR, van der Steen C, Meijer LJ, de Boer D, de Graaf J, Stehouwer CDA, Brouwers M. Incidence of cardiovascular disease in familial combined hyperlipidemia: A 15-year follow-up study. Atherosclerosis. 2019;280:1–6. [PubMed: 30448567]
91.
Veerkamp MJ, de Graaf J, Hendriks JC, Demacker PN, Stalenhoef AF. Nomogram to diagnose familial combined hyperlipidemia on the basis of results of a 5-year follow-up study. Circulation. 2004;109:2980–2985. [PubMed: 15184285]
92.
Veerkamp MJ, de Graaf J, Bredie SJ, Hendriks JC, Demacker PN, Stalenhoef AF. Diagnosis of familial combined hyperlipidemia based on lipid phenotype expression in 32 families: results of a 5-year follow-up study. Arterioscler Thromb Vasc Biol. 2002;22:274–282. [PubMed: 11834528]
93.
Ayyobi AF, McGladdery SH, McNeely MJ, Austin MA, Motulsky AG, Brunzell JD. Small, dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 2003;23:1289–1294. [PubMed: 12750118]
94.
Purnell JQ. Kahn, Steven E., Schwartz, Robert S., Brunzell, John D. Relationship of insulin sensitivity and apoB levels to intra-abdominal fat in subjects with familial combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 2001;21:567–572. [PubMed: 11304474]
95.
Voors-Pette C, de Bruin TW. Excess coronary heart disease in Familial Combined Hyperlipidemia, in relation to genetic factors and central obesity. Atherosclerosis. 2001;157:481–489. [PubMed: 11472750]
96.
Genest JJ Jr, Martin-Munley SS, McNamara JR, Ordovas JM, Jenner J, Myers RH, Silberman SR, Wilson PW, Salem DN, Schaefer EJ. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992;85:2025–2033. [PubMed: 1534286]
97.
Eckel RH, Alberti KG, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2010;375:181–183. [PubMed: 20109902]
98.
Ninomiya JK, L'Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation. 2004;109:42–46. [PubMed: 14676144]
99.
Sutherland JP, McKinley B, Eckel RH. The metabolic syndrome and inflammation. Metab Syndr Relat Disord. 2004;2:82–104. [PubMed: 18370640]
100.
Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr. International Diabetes Federation Task Force on E, Prevention, Hational Heart L, Blood I, American Heart A, World Heart F, International Atherosclerosis S, International Association for the Study of O. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–1645. [PubMed: 19805654]
101.
Lemieux I, Pascot A, Couillard C, Lamarche B, Tchernof A, Almeras N, Bergeron J, Gaudet D, Tremblay G, Prud'homme D, Nadeau A, Despres JP. Hypertriglyceridemic waist: A marker of the atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men? Circulation. 2000;102:179–184. [PubMed: 10889128]
102.
Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab. 2011;22:353–363. [PMC free article: PMC3163828] [PubMed: 21616678]
103.
Ginsberg HN, Zhang YL, Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetes. Archives of medical research. 2005;36:232–240. [PubMed: 15925013]
104.
Adiels M, Westerbacka J, Soro-Paavonen A, Hakkinen AM, Vehkavaara S, Caslake MJ, Packard C, Olofsson SO, Yki-Jarvinen H, Taskinen MR, Boren J. Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance. Diabetologia. 2007;50:2356–2365. [PubMed: 17849096]
105.
Brunzell JD, Porte D Jr, Bierman EL. Abnormal lipoprotein lipase mediated plasma triglyceride removal in untreated diabetes mellitus associated with hypertriglyceridemia. Metabolism. 1979;28:897–903. [PubMed: 481215]
106.
Ruderman NB, Schneider SH, Berchtold P. The "metabolically-obese," normal-weight individual. Am J Clin Nutr. 1981;34:1617–1621. [PubMed: 7270486]
107.
Phillips CM. Metabolically healthy obesity: definitions, determinants and clinical implications. Rev Endocr Metab Disord. 2013;14:219–227. [PubMed: 23928851]
108.
Hamer M, Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab. 2012;97:2482–2488. [PMC free article: PMC3387408] [PubMed: 22508708]
109.
Chahil TJ, Ginsberg HN. Diabetic dyslipidemia. Endocrinol Metab Clin North Am. 2006;35:491–510. vii-viii. [PubMed: 16959582]
110.
Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H, Eckel RH. The metabolic syndrome. Endocr Rev. 2008;29:777–822. [PMC free article: PMC5393149] [PubMed: 18971485]
111.
Siest G, Pillot T, Regis-Bailly A, Leininger-Muller B, Steinmetz J, Galteau MM, Visvikis S. Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin Chem. 1995;41:1068–1086. [PubMed: 7628082]
112.
Weisgraber KH, Rall SC Jr, Mahley RW. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981;256:9077–9083. [PubMed: 7263700]
113.
Smelt AH, de Beer F. Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects. Semin Vasc Med. 2004;4:249–257. [PubMed: 15630634]
114.
Dong LM, Innerarity TL, Arnold KS, Newhouse YM, Weisgraber KH. The carboxyl terminus in apolipoprotein E2 and the seven amino acid repeat in apolipoprotein E-Leiden: role in receptor-binding activity. J Lipid Res. 1998;39:1173–1180. [PubMed: 9643348]
115.
Mahley RW, Huang Y, Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res. 1999;40:1933–1949. [PubMed: 10552997]
116.
Mahley RW, Rall SC, Jr. Type III hyperlipoproteinemia (dysbetalipoproteinemia): The role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill; 1989:1195.
117.
Brummer D, Evans D, Berg D, Greten H, Beisiegel U, Mann WA. Expression of type III hyperlipoproteinemia in patients homozygous for apolipoprotein E-2 is modulated by lipoprotein lipase and postprandial hyperinsulinemia. J Mol Med (Berl). 1998;76:355–364. [PubMed: 9587070]
118.
Koopal C, Marais AD, Visseren FL. Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder. Curr Opin Endocrinol Diabetes Obes. 2017;24:133–139. [PubMed: 28098593]
119.
Feussner G, Ziegler R. Expression of type III hyperlipoproteinaemia in a subject with secondary hypothyroidism bearing the apolipoprotein E2/2 phenotype. J Intern Med. 1991;230:183–186. [PubMed: 1865171]
120.
Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ. Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2. J Lipid Res. 1982;23:1224–1235. [PubMed: 7175379]
121.
Chait A, Brunzell JD, Albers JJ, Hazzard WR. Type-III Hyperlipoproteinaemia ("remnant removal disease"). Insight into the pathogenetic mechanism. Lancet. 1977;1:1176–1178. [PubMed: 68276]
122.
Chait A, Hazzard WR, Albers JJ, Kushwaha RP, Brunzell JD. Impaired very low density lipoprotein and triglyceride removal in broad beta disease: comparison with endogenous hypertriglyceridemia. Metabolism. 1978;27:1055–1066. [PubMed: 210351]
123.
Rothschild M, Duhon G, Riaz R, Jetty V, Goldenberg N, Glueck CJ, Wang P. Pathognomonic Palmar Crease Xanthomas of Apolipoprotein E2 Homozygosity-Familial Dysbetalipoproteinemia. JAMA Dermatol. 2016;152:1275–1276. [PubMed: 27603268]
124.
Albers JJ, Warnick GR, Hazzard WR. Type III hyperlipoproteinemia: a comparative study of current diagnostic techniques. Clin Chim Acta. 1977;75:193–204. [PubMed: 191218]
125.
Blom DJ, O'Neill FH, Marais AD. Screening for dysbetalipoproteinemia by plasma cholesterol and apolipoprotein B concentrations. Clin Chem. 2005;51:904–907. [PubMed: 15855667]
126.
Morganroth J, Levy RI, Fredrickson DS. The biochemical, clinical, and genetic features of type III hyperlipoproteinemia. Ann Intern Med. 1975;82:158–174. [PubMed: 163608]
127.
Havel RJ, Kane JP. Primary dysbetalipoproteinemia: Predominancy of a specific apoprotein species in triglyceride-rich lipoproteins. Proc Natl Acad Sci USA. 1973;70:2015. [PMC free article: PMC433655] [PubMed: 4352966]
128.
Koopal C, Retterstol K, Sjouke B, Hovingh GK, Ros E, de Graaf J, Dullaart RP, Bertolini S, Visseren FL. Vascular risk factors, vascular disease, lipids and lipid targets in patients with familial dysbetalipoproteinemia: a European cross-sectional study. Atherosclerosis. 2015;240:90–97. [PubMed: 25768710]
129.
Mahley R, Rall S. Type III Hyperlipoproteinemia (Dysbetalipoproteinemia): The Role of Apolipoprotein E in Normal and Abnormal Lipoprotein Metabolism. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic & Molecular Bases of Inherited Disease. Vol 119. 8th ed. New York: McGraw-Hill; 2001:2835-2862.
130.
Koopal C, Geerlings MI, Muller M, de Borst GJ, Algra A, van der Graaf Y, Visseren FL, Group SS. The relation between apolipoprotein E (APOE) genotype and peripheral artery disease in patients at high risk for cardiovascular disease. Atherosclerosis. 2016;246:187–192. [PubMed: 26800308]
131.
Herink M, Ito MK. Medication Induced Changes in Lipid and Lipoproteins. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, eds. Endotext. South Dartmouth (MA)2000.
132.
Feingold KR, Grunfeld C. The Effect of Inflammation and Infection on Lipids and Lipoproteins. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, eds. Endotext. South Dartmouth (MA)2018.
133.
Feingold KR, Grunfeld C. Obesity and Dyslipidemia. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, eds. Endotext. South Dartmouth (MA)2018.
134.
Feingold K, Brinton EA, Grunfeld C. The Effect of Endocrine Disorders on Lipids and Lipoproteins. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, eds. Endotext. South Dartmouth (MA)2017.
135.
Chait A. Secondary hyperlipidemia. J Clin Pathol. 1973;26:68–71. [PMC free article: PMC1436099] [PubMed: 4582172]
136.
Chait A, Brunzell JD. Acquired hyperlipidemia (secondary dyslipoproteinemia). Endocrinol Metab Clin North Am. 1990;19:259–278. [PubMed: 2192873]
137.
Brunzell JD, Bierman EL. Chylomicronemia syndrome. Interaction of genetic and acquired hypertriglyceridemia. Med Clin North Am. 1982;66:455–468. [PubMed: 7040847]
138.
Chait A, Robertson HT, Brunzell JD. Chylomicronemia syndrome in diabetes mellitus. Diabetes Care. 1981;4:343–348. [PubMed: 7344882]
139.
Brahm AJ, Hegele RA. Chylomicronaemia-current diagnosis and future therapies. Nat Rev Endocrinol. 2015 [PubMed: 25732519]
140.
Brunzell J, Deeb S. Familial lipoprotein lipase deficiency, apo CII deficiency, and hepatic lipase deficiency. In: Scriver C, Beaudet A, Sly W, Vale D, eds. The Metabolic and Molecular Basis of Inherited Disease. Vol II. 8th ed. New York: McGraw-Hill Book Co.; 2001:2789-2816.
141.
Rahalkar AR, Giffen F, Har B, Ho J, Morrison KM, Hill J, Wang J, Hegele RA, Joy T. Novel LPL mutations associated with lipoprotein lipase deficiency: two case reports and a literature review. Can J Physiol Pharmacol. 2009;87:151–160. [PubMed: 19295657]
142.
Martin-Campos JM, Julve J, Roig R, Martinez S, Errico TL, Martinez-Couselo S, Escola-Gil JC, Mendez-Gonzalez J, Blanco-Vaca F. Molecular analysis of chylomicronemia in a clinical laboratory setting: diagnosis of 13 cases of lipoprotein lipase deficiency. Clin Chim Acta. 2014;429:61–68. [PubMed: 24291057]
143.
Blom DJ, O'Dea L, Digenio A, Alexander VJ, Karwatowska-Prokopczuk E, Williams KR, Hemphill L, Muniz-Grijalvo O, Santos RD, Baum S, Witztum JL. Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study. J Clin Lipidol 2018; 12:1234-1243 e1235. [PubMed: 30318066]
144.
Peterson J, Ayyobi AF, Ma Y, Henderson H, Reina M, Deeb SS, Santamarina-Fojo S, Hayden MR, Brunzell JD. Structural and functional consequences of missense mutations in exon 5 of the lipoprotein lipase gene. J Lipid Res. 2002;43:398–406. [PubMed: 11893776]
145.
Nickerson DA, Taylor SL, Weiss KM, Clark AG, Hutchinson RG, Stengard J, Salomaa V, Vartiainen E, Boerwinkle E, Sing CF. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nat Genet. 1998;19:233–240. [PubMed: 9662394]
146.
Breckenridge WC, Little JA, Steiner G, Chow A, Poapst M. Hypertriglyceridemia associated with deficiency of apolipoprotein C-II. N Engl J Med. 1978;298:1265. [PubMed: 565877]
147.
Rabacchi C, Pisciotta L, Cefalu AB, Noto D, Fresa R, Tarugi P, Averna M, Bertolini S, Calandra S. Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia. Atherosclerosis. 2015;241:79–86. [PubMed: 25966443]
148.
Surendran RP, Visser ME, Heemelaar S, Wang J, Peter J, Defesche JC, Kuivenhoven JA, Hosseini M, Peterfy M, Kastelein JJ, Johansen CT, Hegele RA, Stroes ES, Dallinga-Thie GM. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med. 2012;272:185–196. [PMC free article: PMC3940136] [PubMed: 22239554]
149.
Kristensen KK, Midtgaard SR, Mysling S, Kovrov O, Hansen LB, Skar-Gislinge N, Beigneux AP, Kragelund BB, Olivecrona G, Young SG, Jorgensen TJD, Fong LG, Ploug M. A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase. Proc Natl Acad Sci U S A. 2018;115:E6020–E6029. [PMC free article: PMC6042107] [PubMed: 29899144]
150.
Calandra S, Priore Oliva C, Tarugi P, Bertolini S. APOA5 and triglyceride metabolism, lesson from human APOA5 deficiency. Curr Opin Lipidol. 2006;17:122–127. [PubMed: 16531747]
151.
Peterfy M. Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism. Biochim Biophys Acta. 2012;1821:790–794. [PMC free article: PMC3288453] [PubMed: 22063272]
152.
Brunzell JD, Schrott HG. The interaction of familial and secondary causes of hypertriglyceridemia: Role in pancreatitis. Trans Assoc Am Physicians. 1973;86:245–254. [PubMed: 4788799]
153.
Brunzell JD, Schrott HG. The interaction of familial and secondary causes of hypertriglyceridemia: role in pancreatitis. J Clin Lipidol. 2012;6:409–412. [PubMed: 23009776]
154.
Parsons SK, Skapek SX, Neufeld EJ, Kuhlman C, Young ML, Donnelly M, Brunzell JD, Otvos JD, Sallan SE, Rifai N. Asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia. Blood. 1997;89:1886–1895. [PubMed: 9058708]
155.
Tozuka M, Yamauchi K, Hidaka H, Nakabayashi T, Okumura N, Katsuyama T. Characterization of hypertriglyceridemia induced by L-asparaginase therapy for acute lymphoblastic leukemia and malignant lymphoma. Ann Clin Lab Sci. 1997;27:351–357. [PubMed: 9303174]
156.
Yadav D, Pitchumoni CS. Issues in hyperlipidemic pancreatitis. Journal of clinical gastroenterology. 2003;36:54–62. [PubMed: 12488710]
157.
Johansen CT, Hegele RA. Allelic and phenotypic spectrum of plasma triglycerides. Biochim Biophys Acta. 2012;1821:833–842. [PubMed: 22033228]
158.
Rosenthal E RJ, Cosslin DR, Burt A, Brunzell JD, Motulsky AG, Nickerson DA, Wijsman EM, Jarvik GP. Exome Sequencing Project NHLBI GO ESP. Joint linkage and association analysis with exome sequence data implicates SLC25A40 in hypertriglyceridemia. . Am J Hum Genet. 2014. In press. [PMC free article: PMC3852929] [PubMed: 24268658]
159.
Garg A. Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96:3313–3325. [PubMed: 21865368]
160.
Akinci B, Sahinoz M, Oral E. Lipodystrophy Syndromes: Presentation and Treatment. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, eds. Endotext. South Dartmouth (MA)2017.
161.
Simha V, Garg A. Inherited lipodystrophies and hypertriglyceridemia. Curr Opin Lipidol. 2009;20:300–308. [PubMed: 19494770]
162.
Lightbourne M, Brown RJ. Genetics of Lipodystrophy. Endocrinol Metab Clin North Am. 2017;46:539–554. [PMC free article: PMC5424609] [PubMed: 28476236]
163.
Lotta LA, Gulati P, Day FR, Payne F, Ongen H, van de Bunt M, Gaulton KJ, Eicher JD, Sharp SJ, Luan J, De Lucia Rolfe E, Stewart ID, Wheeler E, Willems SM, Adams C, Yaghootkar H. Consortium EP-I, Cambridge FC, Forouhi NG, Khaw KT, Johnson AD, Semple RK, Frayling T, Perry JR, Dermitzakis E, McCarthy MI, Barroso I, Wareham NJ, Savage DB, Langenberg C, O'Rahilly S, Scott RA. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet. 2017;49:17–26. [PMC free article: PMC5774584] [PubMed: 27841877]
164.
Guillin-Amarelle C, Sanchez-Iglesias S, Castro-Pais A, Rodriguez-Canete L, Ordonez-Mayan L, Pazos M, Gonzalez-Mendez B, Rodriguez-Garcia S, Casanueva FF, Fernandez-Marmiesse A, Araujo-Vilar D. Type 1 familial partial lipodystrophy: understanding the Kobberling syndrome. Endocrine. 2016;54:411–421. [PubMed: 27473102]
165.
Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002;87:408–411. [PubMed: 11788685]
166.
Ajluni N, Meral R, Neidert AH, Brady GF, Buras E, McKenna B, DiPaola F, Chenevert TL, Horowitz JF, Buggs-Saxton C, Rupani AR, Thomas PE, Tayeh MK, Innis JW, Omary MB, Conjeevaram H, Oral EA. Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort. Clin Endocrinol (Oxf). 2017;86:698–707. [PMC free article: PMC5395301] [PubMed: 28199729]
167.
Subramanyam L, Simha V, Garg A. Overlapping syndrome with familial partial lipodystrophy, Dunnigan variety and cardiomyopathy due to amino-terminal heterozygous missense lamin A/C mutations. Clin Genet. 2010;78:66–73. [PMC free article: PMC3150739] [PubMed: 20041886]
168.
Hussain I, Garg A. Lipodystrophy Syndromes. Endocrinol Metab Clin North Am. 2016;45:783–797. [PubMed: 27823605]
169.
Hussain I, Patni N, Garg A. Lipodystrophies, dyslipidaemias and atherosclerotic cardiovascular disease. Pathology. 2019;51:202–212. [PMC free article: PMC6402807] [PubMed: 30595509]
170.
Herbst KL, Tannock LR, Deeb SS, Purnell JQ, Brunzell JD, Chait A. Kobberling type of familial partial lipodystrophy: an underrecognized syndrome. Diabetes Care. 2003;26:1819–1824. [PubMed: 12766116]
171.
Jacob KN, Baptista F, dos Santos HG, Oshima J, Agarwal AK, Garg A. Phenotypic heterogeneity in body fat distribution in patients with atypical Werner's syndrome due to heterozygous Arg133Leu lamin A/C mutation. J Clin Endocrinol Metab. 2005;90:6699–6706. [PubMed: 16174718]
172.
Garg A, Subramanyam L, Agarwal AK, Simha V, Levine B, D'Apice MR, Novelli G, Crow Y. Atypical progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab. 2009;94:4971–4983. [PMC free article: PMC2795646] [PubMed: 19875478]
173.
Calvo M, Martinez E. Update on metabolic issues in HIV patients. Curr Opin HIV AIDS. 2014;9:332–339. [PubMed: 24824886]
174.
Castelli WP. The triglyceride issue: a view from Framingham. Am Heart J. 1986;112:432–437. [PubMed: 3739899]
175.
Harchaoui KE, Visser ME, Kastelein JJ, Stroes ES, Dallinga-Thie GM. Triglycerides and cardiovascular risk. Curr Cardiol Rev. 2009;5:216–222. [PMC free article: PMC2822144] [PubMed: 20676280]
176.
Langsted A, Freiberg JJ, Tybjaerg-Hansen A, Schnohr P, Jensen GB, Nordestgaard BG. Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med. 2011;270:65–75. [PubMed: 21198993]
177.
Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384:626–635. [PubMed: 25131982]
178.
Zilversmit DB. Atherogenesis: A postprandial phenomenon. Circulation. 1979;60:473–485. [PubMed: 222498]
179.
Zilversmit DB. Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins. Clin Chem. 1995;41:153–158. [PubMed: 7813071]
180.
Nordestgaard BG, Zilversmit DB. Large lipoproteins are excluded from the arterial wall in diabetic cholesterol-fed rabbits. J Lipid Res. 1988;29:1491–1500. [PubMed: 3241125]
181.
Nordestgaard BG, Stender S, Kjeldsen K. Reduced atherogenesis in cholesterol-fed diabetic rabbits. Giant lipoproteins do not enter the arterial wall. Arteriosclerosis. 1988;8:421–428. [PubMed: 3395278]
182.
Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995;15:551–561. [PMC free article: PMC2924812] [PubMed: 7749869]
183.
Williams KJ, Tabas I. The response-to-retention hypothesis of atherogenesis reinforced. Curr Opin Lipidol. 1998;9:471–474. [PubMed: 9812202]
184.
Krauss RM. Dense low density lipoproteins and coronary artery disease. Am J Cardiol. 1995;75:53B–57B. [PubMed: 7863975]
185.
Olin-Lewis K, Krauss RM, La Belle M, Blanche PJ, Barrett PH, Wight TN, Chait A. ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan. J Lipid Res. 2002;43:1969–1977. [PubMed: 12401896]
186.
Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of small, dense low density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B. Am J Med. 1993;94:350–356. [PubMed: 8475928]
187.
Tribble DL, van den Berg J, Motchnik PA, Ames BN, Lewis DM, Chait A, Krauss RM. Oxidative susceptibility of LDL density subfractions is related to their ubiquinol-10 and à-tocopherol content. Proc Natl Acad Sci USA. 1994;91:1183–1187. [PMC free article: PMC521478] [PubMed: 8302851]
188.
Rosenson RS, Davidson MH, Hirsh BJ, Kathiresan S, Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2014;64:2525–2540. [PubMed: 25500239]
189.
Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkila K, Hypponen E, Isaacs A, Jackson AU, Johansson A, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J, Lyytikainen LP, Magnusson PK, Mangino M, Mihailov E, Montasser ME, Muller-Nurasyid M, Nolte IM, O'Connell JR, Palmer CD, Perola M, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney AS, Doring A, Elliott P, Epstein SE, Eyjolfsson GI, Gigante B, Goodarzi MO, Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen AL, Hayward C, Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P, Kastelein JJ, Khaw KT, Kim E, Klopp N, Komulainen P, Kumari M, Langenberg C, Lehtimaki T, Lin SY, Lindstrom J, Loos RJ, Mach F, McArdle WL, Meisinger C, Mitchell BD, Muller G, Nagaraja R, Narisu N, Nieminen TV, Nsubuga RN, Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ, Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K, Stancakova A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH, Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M, Boehm BO, Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Campbell H, Chakravarti A, Chambers JC, Chen YD, Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire U, Feranil AB, Ferrieres J, Ferrucci L, Freimer NB, Gieger C, Groop LC, Gudnason V, Gyllensten U, Hamsten A, Harris TB, Hingorani A, Hirschhorn JN, Hofman A, Hovingh GK, Hsiung CA, Humphries SE, Hunt SC, Hveem K, Iribarren C, Jarvelin MR, Jula A, Kahonen M, Kaprio J, Kesaniemi A, Kivimaki M, Kooner JS, Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO, Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG, Marz W, McCarthy MI, McKenzie CA, Meneton P, Metspalu A, Moilanen L, Morris AD, Munroe PB, Njolstad I, Pedersen NL, Power C, Pramstaller PP, Price JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D, Salomaa V, Sanghera DK, Saramies J, Schwarz PE, Sheu WH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J, Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L, Wareham NJ, Whitfield JB, Wolffenbuttel BH, Altshuler D, Ordovas JM, Boerwinkle E, Palmer CN, Thorsteinsdottir U, Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA, Sandhu MS, Rich SS, Boehnke M, Deloukas P, Mohlke KL, Ingelsson E, Abecasis GR, Daly MJ, Neale BM, Kathiresan S. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345–1352. [PMC free article: PMC3904346] [PubMed: 24097064]
190.
Waterworth DM, Ricketts SL, Song K, Chen L, Zhao JH, Ripatti S, Aulchenko YS, Zhang W, Yuan X, Lim N, Luan J, Ashford S, Wheeler E, Young EH, Hadley D, Thompson JR, Braund PS, Johnson T, Struchalin M, Surakka I, Luben R, Khaw KT, Rodwell SA, Loos RJ, Boekholdt SM, Inouye M, Deloukas P, Elliott P, Schlessinger D, Sanna S, Scuteri A, Jackson A, Mohlke KL, Tuomilehto J, Roberts R, Stewart A, Kesaniemi YA, Mahley RW, Grundy SM, Wellcome Trust Case Control C, McArdle W, Cardon L, Waeber G, Vollenweider P, Chambers JC, Boehnke M, Abecasis GR, Salomaa V, Jarvelin MR, Ruokonen A, Barroso I, Epstein SE, Hakonarson HH, Rader DJ, Reilly MP, Witteman JC, Hall AS, Samani NJ, Strachan DP, Barter P, van Duijn CM, Kooner JS, Peltonen L, Wareham NJ, McPherson R, Mooser V, Sandhu MS. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol. 2010;30:2264–2276. [PMC free article: PMC3891568] [PubMed: 20864672]
191.
Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, Zee RY, Wright AF, Witteman JC, Wilson JF, Willemsen G, Wichmann HE, Whitfield JB, Waterworth DM, Wareham NJ, Waeber G, Vollenweider P, Voight BF, Vitart V, Uitterlinden AG, Uda M, Tuomilehto J, Thompson JR, Tanaka T, Surakka I, Stringham HM, Spector TD, Soranzo N, Smit JH, Sinisalo J, Silander K, Sijbrands EJ, Scuteri A, Scott J, Schlessinger D, Sanna S, Salomaa V, Saharinen J, Sabatti C, Ruokonen A, Rudan I, Rose LM, Roberts R, Rieder M, Psaty BM, Pramstaller PP, Pichler I, Perola M, Penninx BW, Pedersen NL, Pattaro C, Parker AN, Pare G, Oostra BA, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, Meitinger T, McPherson R, McCarthy MI, McArdle W, Masson D, Martin NG, Marroni F, Mangino M, Magnusson PK, Lucas G, Luben R, Loos RJ, Lokki ML, Lettre G, Langenberg C, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, Kronenberg F, Konig IR, Khaw KT, Kaprio J, Kaplan LM, Johansson A, Jarvelin MR, Janssens AC, Ingelsson E, Igl W, Kees Hovingh G, Hottenga JJ, Hofman A, Hicks AA, Hengstenberg C, Heid IM, Hayward C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Gyllensten U, Guiducci C, Groop LC, Gonzalez E, Gieger C, Freimer NB, Ferrucci L, Erdmann J, Elliott P, Ejebe KG, Doring A, Dominiczak AF, Demissie S, Deloukas P, de Geus EJ, de Faire U, Crawford G, Collins FS, Chen YD, Caulfield MJ, Campbell H, Burtt NP, Bonnycastle LL, Boomsma DI, Boekholdt SM, Bergman RN, Barroso I, Bandinelli S, Ballantyne CM, Assimes TL, Quertermous T, Altshuler D, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Adair LS, Taylor HA Jr, Borecki IB, Gabriel SB, Wilson JG, Holm H, Thorsteinsdottir U, Gudnason V, Krauss RM, Mohlke KL, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Rotter JI, Boerwinkle E, Strachan DP, Mooser V, Stefansson K, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, van Duijn CM, Peltonen L, Abecasis GR, Boehnke M, Kathiresan S. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–713. [PMC free article: PMC3039276] [PubMed: 20686565]
192.
Rip J, Nierman MC, Ross CJ, Jukema JW, Hayden MR, Kastelein JJ, Stroes ES, Kuivenhoven JA. Lipoprotein lipase S447X: a naturally occurring gain-of-function mutation. Arterioscler Thromb Vasc Biol. 2006;26:1236–1245. [PubMed: 16574898]
193.
Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Di Angelantonio E, Danesh J, Nicholls SJ, Bhatt DL, Sabatine MS, Catapano AL. Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019;321:364–373. [PMC free article: PMC6439767] [PubMed: 30694319]
194.
Pimstone SN, Gagne SE, Gagne C, Lupien PJ, Gaudet D, Williams RR, Kotze M, Reymer PW, Defesche JC, Kastelein JJ, et al. Mutations in the gene for lipoprotein lipase. A cause for low HDL cholesterol levels in individuals heterozygous for familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995;15:1704–1712. [PubMed: 7583547]
195.
Burkhardt R, Toh SA, Lagor WR, Birkeland A, Levin M, Li X, Robblee M, Fedorov VD, Yamamoto M, Satoh T, Akira S, Kathiresan S, Breslow JL, Rader DJ. Trib1 is a lipid- and myocardial infarction-associated gene that regulates hepatic lipogenesis and VLDL production in mice. J Clin Invest. 2010;120:4410–4414. [PMC free article: PMC2993600] [PubMed: 21084752]
196.
Douvris A, Soubeyrand S, Naing T, Martinuk A, Nikpay M, Williams A, Buick J, Yauk C, McPherson R. Functional analysis of the TRIB1 associated locus linked to plasma triglycerides and coronary artery disease. J Am Heart Assoc. 2014;3:e000884. [PMC free article: PMC4309087] [PubMed: 24895164]
197.
TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, Lu Y, Tang ZZ, Zhang H, Hindy G, Masca N, Stirrups K, Kanoni S, Do R, Jun G, Hu Y, Kang HM, Xue C, Goel A, Farrall M, Duga S, Merlini PA, Asselta R, Girelli D, Olivieri O, Martinelli N, Yin W, Reilly D, Speliotes E, Fox CS, Hveem K, Holmen OL, Nikpay M, Farlow DN, Assimes TL, Franceschini N, Robinson J, North KE, Martin LW, DePristo M, Gupta N, Escher SA, Jansson JH, Van Zuydam N, Palmer CN, Wareham N, Koch W, Meitinger T, Peters A, Lieb W, Erbel R, Konig IR, Kruppa J, Degenhardt F, Gottesman O, Bottinger EP, O'Donnell CJ, Psaty BM, Ballantyne CM, Abecasis G, Ordovas JM, Melander O, Watkins H, Orho-Melander M, Ardissino D, Loos RJ, McPherson R, Willer CJ, Erdmann J, Hall AS, Samani NJ, Deloukas P, Schunkert H, Wilson JG, Kooperberg C, Rich SS, Tracy RP, Lin DY, Altshuler D, Gabriel S, Nickerson DA, Jarvik GP, Cupples LA, Reiner AP, Boerwinkle E, Kathiresan S. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22–31. [PMC free article: PMC4180269] [PubMed: 24941081]
198.
Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41. [PubMed: 24941082]
199.
Soufi M, Sattler AM, Kurt B, Schaefer JR. Mutation screening of the APOA5 gene in subjects with coronary artery disease. J Investig Med. 2012;60:1015–1019. [PubMed: 22914599]
200.
Do R, Stitziel NO, Won HH, Jorgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O, Guella I, Asselta R, Lange LA, Peloso GM, Auer PL, Project NES, Girelli D, Martinelli N, Farlow DN, DePristo MA, Roberts R, Stewart AF, Saleheen D, Danesh J, Epstein SE, Sivapalaratnam S, Hovingh GK, Kastelein JJ, Samani NJ, Schunkert H, Erdmann J, Shah SH, Kraus WE, Davies R, Nikpay M, Johansen CT, Wang J, Hegele RA, Hechter E, Marz W, Kleber ME, Huang J, Johnson AD, Li M, Burke GL, Gross M, Liu Y, Assimes TL, Heiss G, Lange EM, Folsom AR, Taylor HA, Olivieri O, Hamsten A, Clarke R, Reilly DF, Yin W, Rivas MA, Donnelly P, Rossouw JE, Psaty BM, Herrington DM, Wilson JG, Rich SS, Bamshad MJ, Tracy RP, Cupples LA, Rader DJ, Reilly MP, Spertus JA, Cresci S, Hartiala J, Tang WH, Hazen SL, Allayee H, Reiner AP, Carlson CS, Kooperberg C, Jackson RD, Boerwinkle E, Lander ES, Schwartz SM, Siscovick DS, McPherson R, Tybjaerg-Hansen A, Abecasis GR, Watkins H, Nickerson DA, Ardissino D, Sunyaev SR, O'Donnell CJ, Altshuler D, Gabriel S, Kathiresan S. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015;518:102–106. [PMC free article: PMC4319990] [PubMed: 25487149]
201.
Dewey FE, Gusarova V, O'Dushlaine C, Gottesman O, Trejos J, Hunt C, Van Hout CV, Habegger L, Buckler D, Lai KM, Leader JB, Murray MF, Ritchie MD, Kirchner HL, Ledbetter DH, Penn J, Lopez A, Borecki IB, Overton JD, Reid JG, Carey DJ, Murphy AJ, Yancopoulos GD, Baras A, Gromada J, Shuldiner AR. Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease. N Engl J Med. 2016;374:1123–1133. [PMC free article: PMC4900689] [PubMed: 26933753]
202.
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Stitziel NO, Stirrups KE, Masca NG, Erdmann J, Ferrario PG, Konig IR, Weeke PE, Webb TR, Auer PL, Schick UM, Lu Y, Zhang H, Dube MP, Goel A, Farrall M, Peloso GM, Won HH, Do R, van Iperen E, Kanoni S, Kruppa J, Mahajan A, Scott RA, Willenberg C, Braund PS, van Capelleveen JC, Doney AS, Donnelly LA, Asselta R, Merlini PA, Duga S, Marziliano N, Denny JC, Shaffer CM, El-Mokhtari NE, Franke A, Gottesman O, Heilmann S, Hengstenberg C, Hoffman P, Holmen OL, Hveem K, Jansson JH, Jockel KH, Kessler T, Kriebel J, Laugwitz KL, Marouli E, Martinelli N, McCarthy MI, Van Zuydam NR, Meisinger C, Esko T, Mihailov E, Escher SA, Alver M, Moebus S, Morris AD, Muller-Nurasyid M, Nikpay M, Olivieri O, Lemieux Perreault LP, AlQarawi A, Robertson NR, Akinsanya KO, Reilly DF, Vogt TF, Yin W, Asselbergs FW, Kooperberg C, Jackson RD, Stahl E, Strauch K, Varga TV, Waldenberger M, Zeng L, Kraja AT, Liu C, Ehret GB, Newton-Cheh C, Chasman DI, Chowdhury R, Ferrario M, Ford I, Jukema JW, Kee F, Kuulasmaa K, Nordestgaard BG, Perola M, Saleheen D, Sattar N, Surendran P, Tregouet D, Young R, Howson JM, Butterworth AS, Danesh J, Ardissino D, Bottinger EP, Erbel R, Franks PW, Girelli D, Hall AS, Hovingh GK, Kastrati A, Lieb W, Meitinger T, Kraus WE, Shah SH, McPherson R, Orho-Melander M, Melander O, Metspalu A, Palmer CN, Peters A, Rader D, Reilly MP, Loos RJ, Reiner AP, Roden DM, Tardif JC, Thompson JR, Wareham NJ, Watkins H, Willer CJ, Kathiresan S, Deloukas P, Samani NJ, Schunkert H. Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. N Engl J Med. 2016;374:1134–1144. [PMC free article: PMC4850838] [PubMed: 26934567]
203.
Brown WV, Brunzell JD, Eckel RH, Stone NJ. Severe hypertriglyceridemia. J Clin Lipidol. 2012;6:397–408. [PubMed: 23009775]
204.
Mirtallo JM, Dasta JF, Kleinschmidt KC, Varon J. State of the art review: Intravenous fat emulsions: Current applications, safety profile, and clinical implications. The Annals of pharmacotherapy. 2010;44:688–700. [PubMed: 20332339]
205.
Devaud JC, Berger MM, Pannatier A, Marques-Vidal P, Tappy L, Rodondi N, Chiolero R, Voirol P. Hypertriglyceridemia: a potential side effect of propofol sedation in critical illness. Intensive Care Med. 2012;38:1990–1998. [PubMed: 23052949]
206.
Goldberg AS, Hegele RA. Severe hypertriglyceridemia in pregnancy. J Clin Endocrinol Metab. 2012;97:2589–2596. [PubMed: 22639290]
207.
Brunzell JD DS. Familial lipoprotein lipase deficiency, apo CII deficiency and hepatic lipase deficiency. The Metabolic and Molecular Basis of Inherited Disease, 8th edition New York: McGraw-Hill Book Co.; 2001:2789-2816.
208.
Brunzell JD. Lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In: Scriver CR, Beuadel AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. Vol 6th. New York: McGraw-Hill; 1989:1165-1180.
209.
Tremblay K, Methot J, Brisson D, Gaudet D. Etiology and risk of lactescent plasma and severe hypertriglyceridemia. J Clin Lipidol. 2011;5:37–44. [PubMed: 21262505]
210.
Lloret Linares C, Pelletier AL, Czernichow S, Vergnaud AC, Bonnefont-Rousselot D, Levy P, Ruszniewski P, Bruckert E. Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia. Pancreas. 2008;37:13–12. [PubMed: 18580438]
211.
Cameron JL, Capuzzi DM, Zuidema GD, Margolis S. Acute pancreatitis with hyperlipidemia: The incidence of lipid abnormalities in acute pancreatitis. Ann Surg. 1973;177:483–489. [PMC free article: PMC1355660] [PubMed: 4691868]
212.
Farmer RG, Winkelman EI, Brown HB, Lewis LA. Hyperlipoproteinemia and pancreatitis. Am J Med. 1973;54:161–165. [PubMed: 4685843]
213.
Zafrir B, Jubran A, Hijazi R, Shapira C. Clinical features and outcomes of severe, very severe, and extreme hypertriglyceridemia in a regional health service. J Clin Lipidol. 2018;12:928–936. [PubMed: 29685592]
214.
Wang Q, Wang G, Qiu Z, He X, Liu C. Elevated Serum Triglycerides in the Prognostic Assessment of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Observational Studies. Journal of clinical gastroenterology. 2017;51:586–593. [PubMed: 28682990]
215.
Havel RJ. Pathogenesis, differentiation and management of hypertriglyceridemia. Adv Intern Med. 1969;15:117–154. [PubMed: 4908616]
216.
Yang F, Wang Y, Sternfeld L, Rodriguez JA, Ross C, Hayden MR, Carriere F, Liu G, Schulz I. The role of free fatty acids, pancreatic lipase and Ca+ signalling in injury of isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice. Acta Physiol (Oxf). 2009;195:13–28. [PubMed: 18983441]
217.
Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud A. Hypertriglyceridemic pancreatitis: presentation and management. The American journal of gastroenterology. 2009;104:984–991. [PubMed: 19293788]
218.
Valdivielso P, Ramirez-Bueno A, Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med. 2014;25:689–694. [PubMed: 25269432]
219.
Saharia P, Margolis S, Zuidema GD, Cameron JL. Acute pancreatitis with hyperlipemia: studies with an isolated perfused canine pancreas. Surgery. 1977;82:60–67. [PubMed: 877857]
220.
Seplowitz AH, Chien S, Smith FR. Effects of lipoproteins on plasma viscosity. Atherosclerosis. 1981;38:89–95. [PubMed: 7470209]
221.
Chang YT, Chang MC, Su TC, Liang PC, Su YN, Kuo CH, Wei SC, Wong JM. Association of cystic fibrosis transmembrane conductance regulator (CFTR) mutation/variant/haplotype and tumor necrosis factor (TNF) promoter polymorphism in hyperlipidemic pancreatitis. Clin Chem. 2008;54:131–138. [PubMed: 17981921]
222.
Ivanova R, Puerta S, Garrido A, Cueto I, Ferro A, Ariza MJ, Cobos A, Gonzalez-Santos P, Valdivielso P. Triglyceride levels and apolipoprotein E polymorphism in patients with acute pancreatitis. Hepatobiliary Pancreat Dis Int. 2012;11:96–101. [PubMed: 22251476]
223.
Dyslipidaemia Durrington P. Lancet. 2003;362:717–731. [PubMed: 12957096]
224.
Parker F, Bagdade JD, Odland GF, Bierman EL. Evidence for the chylomicron origin of lipids accumulating in diabetic eruptive xanthomas: A correlative lipid biochemical, histochemical and electron microscopic study. J Clin Invest. 1970;49:2172–2187. [PMC free article: PMC322718] [PubMed: 5480845]
225.
Rosenson RS, Shott S, Lu L, Tangney CC. Hypertriglyceridemia and other factors associated with plasma viscosity. Am J Med. 2001;110:488–492. [PubMed: 11331062]
226.
Inokuchi R, Matsumoto A, Azihara R, Sato H, Kumada Y, Yokoyama H, Okada M, Ishida T, Nakamura K, Nakajima S, Yahagi N, Shinohara K. Hypertriglyceridemia as a possible cause of coma: a case report. J Med Case Rep. 2012;6:412. [PMC free article: PMC3520695] [PubMed: 23198781]
227.
Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995;15:534–542. [PubMed: 7749867]
228.
Norata GD, Grigore L, Raselli S, Redaelli L, Hamsten A, Maggi F, Eriksson P, Catapano AL. Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies. Atherosclerosis. 2007;193:321–327. [PubMed: 17055512]
229.
Malloy MJ, Kane JP. A risk factor for atherosclerosis: triglyceride-rich lipoproteins. Adv Intern Med. 2001;47:111–136. [PubMed: 11795072]
230.
Mamo JC, Proctor SD, Smith D. Retention of chylomicron remnants by arterial tissue; importance of an efficient clearance mechanism from plasma. Atherosclerosis. 1998;141 Suppl 1:S63–69. [PubMed: 9888645]
231.
Havel RJ, Gordon RS Jr. Idiopathic hyperlipemia: metabolic studies in an affected family. J Clin Invest. 1960;39:1777–1790. [PMC free article: PMC441903] [PubMed: 13712364]
232.
Benlian P, De Gennes JL, Foubert L, Zhang H, Gagne SE, Hayden M. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. N Engl J Med. 1996;335:848–854. [PubMed: 8778602]
233.
Austin MA, Hokanson JE. Epidemiology of triglycerides, small dense low-density lipoprotein, and lipoprotein(a) as risk factors for coronary heart disease. Med Clin North Am. 1994;78:99–115. [PubMed: 8283937]
234.
Goldberg IJ, Eckel RH, McPherson R. Triglycerides and heart disease: still a hypothesis? Arterioscler Thromb Vasc Biol. 2011;31:1716–1725. [PMC free article: PMC3141088] [PubMed: 21527746]
235.
Feingold KR, Grunfeld C. Triglyceride Lowering Drugs. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, eds. Endotext. South Dartmouth (MA)2018.
236.
Enkhmaa B, Surampudi P, Anuurad E, Berglund L. Lifestyle Changes: Effect of Diet, Exercise, Functional Food, and Obesity Treatment on Lipids and Lipoproteins. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP, eds. Endotext. South Dartmouth (MA)2018.
237.
Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389. [PubMed: 7968073]
238.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM. Investigators I-I. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 [PubMed: 26039521]
239.
Koskinen P, Mänttäri M, Manninen V, Huttunen J, Heinonon O. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diab Care. 1992;15:825–829. [PubMed: 1516498]
240.
ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC, Jr., Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574. [PMC free article: PMC2879499] [PubMed: 20228404]
241.
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M. investigators Fs. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–1861. [PubMed: 16310551]
242.
Bezafibrate Infarction Prevention Study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation. 2000;102:21–27. [PubMed: 10880410]
243.
Camejo G. Phase 2 clinical trials with K-877 (pemafibrate): A promising selective PPAR-alpha modulator for treatment of combined dyslipidemia. Atherosclerosis. 2017;261:163–164. [PubMed: 28434555]
244.
Aung T, Halsey J, Kromhout D, Gerstein HC, Marchioli R, Tavazzi L, Geleijnse JM, Rauch B, Ness A, Galan P, Chew EY, Bosch J, Collins R, Lewington S, Armitage J, Clarke R. Omega-3 Treatment Trialists C. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77917 Individuals. JAMA Cardiol. 2018;3:225–234. [PMC free article: PMC5885893] [PubMed: 29387889]
245.
ASCEND Study Collaborative Group. Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto R, Baigent C, Collins R, Parish S, Armitage J. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med. 2018;379:1540–1550. [PubMed: 30146932]
246.
Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Albert CM, Gordon D, Copeland T, D'Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE, Group VR. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. 2018 [PMC free article: PMC6392053] [PubMed: 30415637]
247.
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM. Investigators R-I. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2018 [PubMed: 30415628]
248.
Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K. Japan EPAlisI. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–1098. [PubMed: 17398308]
249.
Davidson M, Stevenson M, Hsieh A, Ahmad Z, Crowson C, Witztum JL. The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study. Expert Rev Cardiovasc Ther. 2017;15:415–423. [PubMed: 28338353]
250.
Rouis M, Dugi KA, Previato L, Patterson AP, Brunzell JD, Brewer HB, Santamarina-Fojo S. Therapeutic response to medium-chain triglycerides and omega-3 fatty acids in a patient with the familial chylomicronemia syndrome. Arterioscler Thromb Vasc Biol. 1997;17:1400–1406. [PubMed: 9261273]
251.
Brunzell JD. Familial Lipoprotein Lipase Deficiency. GeneReviews at GeneTests: Medical Genetics Information Resource. Seattle: University of Washington; 2011:1997-2010.
252.
Patni N, Quittner C, Garg A. Orlistat Therapy for Children With Type 1 Hyperlipoproteinemia: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2018;103:2403–2407. [PMC free article: PMC6456945] [PubMed: 29659879]
253.
Blackett P, Tryggestad J, Krishnan S, Li S, Xu W, Alaupovic P, Quiroga C, Copeland K. Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat. J Clin Lipidol. 2013;7:132–139. [PubMed: 23415432]
254.
Tsai EC, Brown JA, Veldee MY, Anderson GJ, Chait A, Brunzell JD. Potential of essential fatty acid deficiency with extremely low fat diet in lipoprotein lipase deficiency during pregnancy: A case report. BMC pregnancy and childbirth. 2004;4:27. [PMC free article: PMC544881] [PubMed: 15610556]
255.
Al-Shali K, Wang J, Fellows F, Huff MW, Wolfe BM, Hegele RA. Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase. Clin Biochem. 2002;35:125–130. [PubMed: 11983347]
256.
Carpentier AC, Frisch F, Labbe SM, Gagnon R, de Wal J, Greentree S, Petry H, Twisk J, Brisson D, Gaudet D. Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab. 2012;97:1635–1644. [PubMed: 22438229]
257.
Gaudet D, Methot J, Dery S, Brisson D, Essiembre C, Tremblay G, Tremblay K, de Wal J, Twisk J, van den Bulk N, Sier-Ferreira V, van Deventer S. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther. 2013;20:361–369. [PMC free article: PMC4956470] [PubMed: 22717743]
258.
Gaudet D, Stroes ES, Methot J, Brisson D, Tremblay K, Bernelot Moens SJ, Iotti G, Rastelletti I, Ardigo D, Corzo D, Meyer C, Andersen M, Ruszniewski P, Deakin M, Bruno MJ. Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis. Hum Gene Ther. 2016;27:916–925. [PubMed: 27412455]
259.
Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, Geary RS, Baker BF, Graham MJ, Crooke RM, Witztum JL. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200–2206. [PubMed: 25470695]
260.
Sanada M, Tsuda M, Kodama I, Sakashita T, Nakagawa H, Ohama K. Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: effects on hypertriglyceridemia. Menopause. 2004;11:331–336. [PubMed: 15167313]
261.
Hemelaar M, van der Mooren MJ, Mijatovic V, Bouman AA, Schijf CP, Kroeks MV, Franke HR, Kenemans P. Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study. Menopause. 2003;10:550–558. [PubMed: 14627865]
262.
Capell WH, Eckel RH. Treatment of hypertriglyceridemia. Curr Diab Rep. 2006;6:230–240. [PubMed: 16898578]
263.
Hsu SY, Lee WJ, Chong K, Ser KH, Tsou JJ. Laparoscopic bariatric surgery for the treatment of severe hypertriglyceridemia. Asian J Surg. 2015;38:96–101. [PubMed: 25161086]
264.
Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W, Geary RS, Hughes SG, Viney NJ, Graham MJ, Crooke RM, Witztum JL, Brunzell JD, Kastelein JJ. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med. 2015;373:438–447. [PubMed: 26222559]
265.
Diker-Cohen T, Cochran E, Gorden P, Brown RJ. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab. 2015;100:1802–1810. [PMC free article: PMC4422900] [PubMed: 25734254]
266.
Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, Yu R, Hurh E, Paz E, McEvoy BW, Baker BF, Pham NC, Digenio A, Hughes SG, Geary RS, Witztum JL, Crooke RM, Tsimikas S. Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017;377:222–232. [PubMed: 28538111]
267.
Stitziel NO, Khera AV, Wang X, Bierhals AJ, Vourakis AC, Sperry AE, Natarajan P, Klarin D, Emdin CA, Zekavat SM, Nomura A, Erdmann J, Schunkert H, Samani NJ, Kraus WE, Shah SH, Yu B, Boerwinkle E, Rader DJ, Gupta N, Frossard PM, Rasheed A, Danesh J, Lander ES, Gabriel S, Saleheen D, Musunuru K, Kathiresan S. Promis, Myocardial Infarction Genetics Consortium I. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol. 2017;69:2054–2063. [PMC free article: PMC5404817] [PubMed: 28385496]
268.
Chaudhry R, Viljoen A, Wierzbicki AS. Pharmacological treatment options for severe hypertriglyceridemia and familial chylomicronemia syndrome. Expert Rev Clin Pharmacol. 2018;11:589–598. [PubMed: 29842811]
269.
Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176:1113–1120. [PMC free article: PMC1839776] [PubMed: 17420495]
270.
Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, Sarode R, Schwartz J, Weinstein R, Shaz BH. Apheresis Applications Committee of the American Society for A. Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher. 2010;25:83–177. [PubMed: 20568098]
271.
Stefanutti C, Julius U. Treatment of primary hypertriglyceridemia states - General approach and the role of extracorporeal methods. Atheroscler Suppl. 2015;18:85–94. [PubMed: 25936310]
272.
Furuya T, Komatsu M, Takahashi K, Hashimoto N, Hashizume T, Wajima N, Kubota M, Itoh S, Soeno T, Suzuki K, Enzan K, Matsuo S. Plasma exchange for hypertriglyceridemic acute necrotizing pancreatitis: report of two cases. Ther Apher. 2002;6:454–458. [PubMed: 12460410]
273.
Click B, Ketchum AM, Turner R, Whitcomb DC, Papachristou GI, Yadav D. The role of apheresis in hypertriglyceridemia-induced acute pancreatitis: A systematic review. Pancreatology. 2015;15:313–320. [PMC free article: PMC6609092] [PubMed: 25800175]
274.
Koutroumpakis E, Slivka A, Furlan A, Dasyam AK, Dudekula A, Greer JB, Whitcomb DC, Yadav D, Papachristou GI. Management and outcomes of acute pancreatitis patients over the last decade: A US tertiary-center experience. Pancreatology. 2017;17:32–40. [PubMed: 28341116]
275.
Huang C, Liu J, Lu Y, Fan J, Wang X, Liu J, Zhang W, Zeng Y. Clinical features and treatment of hypertriglyceridemia-induced acute pancreatitis during pregnancy: A retrospective study. J Clin Apher. 2016;31:571–578. [PubMed: 26946248]
276.
Whayne TF Jr, Felts JM. Activation of lipoprotein lipase. Effects of rat serum lipoprotein fractions and heparin. Circ Res. 1970;27:941–951. [PubMed: 5487079]
277.
Weintraub M, Rassin T, Eisenberg S, Ringel Y, Grosskopf I, Iaina A, Charach G, Liron M, Rubinstein A. Continuous intravenous heparin administration in humans causes a decrease in serum lipolytic activity and accumulation of chylomicrons in circulation. J Lipid Res. 1994;35:229–238. [PubMed: 8169526]
278.
Whayne TF Jr. Concerns about heparin therapy for hypertriglyceridemia. Arch Intern Med. 2010;170:108–109. [PubMed: 20065209]
279.
Goldberg IJ. Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J Lipid Res. 1996;37:693–707. [PubMed: 8732771]
280.
Aryal MR, Mainali NR, Gupta S, Singla M. Acute pancreatitis owing to very high triglyceride levels treated with insulin and heparin infusion. BMJ Case Rep 2013; 2013. [PMC free article: PMC3645636] [PubMed: 23608843]
281.
Khan AS, Latif SU, Eloubeidi MA. Controversies in the etiologies of acute pancreatitis. JOP. 2010;11:545–552. [PubMed: 21068485]
282.
Coskun A, Erkan N, Yakan S, Yildirim M, Carti E, Ucar D, Oymaci E. Treatment of hypertriglyceridemia-induced acute pancreatitis with insulin. Prz Gastroenterol. 2015;10:18–22. [PMC free article: PMC4411402] [PubMed: 25960810]
283.
Mikhail N, Trivedi K, Page C, Wali S, Cope D. Treatment of severe hypertriglyceridemia in nondiabetic patients with insulin. Am J Emerg Med. 2005;23:415–417. [PubMed: 15915436]
284.
Jabbar MA, Zuhri-Yafi MI, Larrea J. Insulin therapy for a non-diabetic patient with severe hypertriglyceridemia. J Am Coll Nutr. 1998;17:458–461. [PubMed: 9791843]
285.
Thuzar M, Shenoy VV, Malabu UH, Schrale R, Sangla KS. Extreme hypertriglyceridemia managed with insulin. J Clin Lipidol. 2014;8:630–634. [PubMed: 25499946]
286.
Wierzbicki AS, Reynolds TM, Crook MA. Usefulness of Orlistat in the treatment of severe hypertriglyceridemia. Am J Cardiol. 2002;89:229–231. [PubMed: 11792350]
287.
Tolentino MC, Ferenczi A, Ronen L, Poretsky L. Combination of gemfibrozil and orlistat for treatment of combined hyperlipidemia with predominant hypertriglyceridemia. Endocr Pract. 2002;8:208–212. [PubMed: 12113634]
Copyright © 2000-2020, MDText.com, Inc.

This electronic version has been made freely available under a Creative Commons (CC-BY-NC-ND) license. A copy of the license can be viewed at http://creativecommons.org/licenses/by-nc-nd/2.0/.

Bookshelf ID: NBK326743PMID: 26561703

Views

  • PubReader
  • Print View
  • Cite this Page

Links to www.endotext.org

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...