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

, MD and , MD.

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Last Update: April 23, 2019.


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.


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
American Heart Association (29)
National Lipid Association (30)
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
<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
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).


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.


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.


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).


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)


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

Uncontrolled diabetes
Nephrotic syndrome
Chronic Renal Failure
Acute hepatitis
Weight regain after weight loss
Autoimmune chylomicronemia
Systemic lupus erythematosis
Anti-LPL antibodies
Rare Genetic Causes
Glycogen storage disorders
Congenital- generalized or partial
Acquired- HIV, autoimmune
Beta blockers
Oral estrogens
Selective estrogen reuptake modulators - tamoxifen, raloxifene
Atypical anti-psychotics
Bile acid resins
Sirolimus, tacrolimus
RXR agonists -bexarotene, isotretinoin
HIV Protease inhibitors
L- asparaginase
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).


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).


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).


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


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).


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.


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.


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).


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).


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).


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.


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 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.


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.


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.


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.


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