Introduction
Background
Hypertriglyceridemia (hTG), a condition in which triglyceride levels are elevated, is a common disorder in the United States. It is often caused or exacerbated by uncontrolled diabetes mellitus, obesity, and sedentary habits, all of which are more prevalent in industrialized societies than in developing nations. In epidemiologic and interventional studies, hypertriglyceridemia is a risk factor for coronary artery disease (CAD).
Hyperlipidemia (elevation of cholesterol levels and/or triglyceride levels) has been defined by the Fredrickson classification, which is based on a beta-quantification, a process involving ultracentrifugation followed by electrophoresis.1 In this system, all categories except type IIa are forms of hTG.
Table 1. Fredrickson Classification of Hyperlipoproteinemia
Open table in new window
Table
| Type | Serum elevation | Lipoprotein elevation |
| I | Cholesterol and triglycerides | Chylomicrons |
| IIa | Cholesterol | LDL* |
| IIb | Cholesterol and triglycerides | LDL, VLDL** |
| III | Cholesterol and triglycerides | IDL*** |
| IV | Triglycerides | VLDL |
| V | Cholesterol and triglycerides | VLDL, chylomicrons |
| Type | Serum elevation | Lipoprotein elevation |
| I | Cholesterol and triglycerides | Chylomicrons |
| IIa | Cholesterol | LDL* |
| IIb | Cholesterol and triglycerides | LDL, VLDL** |
| III | Cholesterol and triglycerides | IDL*** |
| IV | Triglycerides | VLDL |
| V | Cholesterol and triglycerides | VLDL, chylomicrons |
*LDL (low-density lipoprotein)
**VLDL (very low-density lipoprotein)
***IDL (intermediate-density lipoprotein)
Type I is a rare disorder characterized by severe elevations in chylomicrons and extremely elevated triglycerides, always reaching well above 1000 mg/dL and not infrequently rising as high as 10,000 mg/dL or more. It is caused by mutations of either the lipoprotein lipase gene (LPL), which is critical for the metabolism of chylomicrons and very low-density lipoprotein (VLDL), or of the gene's cofactor, apolipoprotein (apo) C-II.
Counterintuitively, despite exceedingly high elevations of triglyceride and, in some cases, of total cholesterol, these mutations do not appear to confer an increased risk of atherosclerotic disease. This fact may have contributed to the unfounded belief that hypertriglyceridemia is not a risk factor for atherosclerotic disease. Although chylomicrons contain far less cholesterol than other triglyceride-rich lipoproteins do, when serum triglyceride levels are severely elevated, cholesterol levels can also be quite high.
Type IIb is the classic mixed hyperlipidemia (high cholesterol and triglyceride levels), caused by elevations in LDL and VLDL.
Type III is known as dysbetalipoproteinemia, remnant removal disease, or broad-beta disease (see Dysbetalipoproteinemia). Typically, patients with this condition have elevated total cholesterol and triglyceride levels and are easily confused with patients with type IIb hyperlipidemia. Patients with type III hyperlipidemia have elevations in intermediate-density lipoprotein (IDL), a VLDL remnant, and a significant risk for developing coronary artery disease.
Type IV is characterized by abnormal elevations of VLDL, and triglyceride levels are almost always less than 1000 mg/dL. Serum cholesterol levels are normal.
Type V is characterized by elevations of chylomicrons and VLDL. Triglyceride levels are invariably greater than 1000 mg/dL, and total cholesterol levels are always elevated. The LDL cholesterol level is usually low. Given the rarity of type I disease, when triglyceride levels above 1000 mg/dL are noted, the most likely cause is type V hyperlipidemia.
Triglyceride levels greater than 1000 mg/dL increase the risk of acute pancreatitis, and because triglycerides are so labile, levels of 500 mg/dL or greater must be the primary focus of therapy. If a patient also has a high risk for a cardiovascular event, LDL-lowering therapy should be considered.
Pathophysiology
Triglycerides are fats consisting of 3 fatty acids covalently bonded to a glycerol molecule. Triglycerides are synthesized by the liver or, in the case of those derived from dietary sources, are ingested by the liver (as described below); they are subsequently transported throughout the circulation by triglyceride-rich lipoproteins.
By dry weight, triglycerides make up approximately 86%, 55%, and 23% of chylomicrons, VLDLs, and IDLs, respectively, as represented in the image below. Triglycerides are present in LDL and high-density lipoprotein (HDL), but in much smaller quantities of 10% or less.
Composition of triglyceride-rich proteins is shown below.
Composition of triglyceride-rich lipoproteins.
Triglyceride-rich lipoproteins come from 2 sources, often described as the endogenous and exogenous pathways. In the exogenous pathway, dietary fats (triglycerides) are hydrolyzed to free fatty acids (FFAs) and monoglycerides and are absorbed, with cholesterol, by intestinal cells. They are then reesterified and combined with apolipoproteins and phospholipids to form a nascent chylomicron, a process requiring microsomal triglyceride transfer protein (MTP). The initial apolipoproteins are apo A, which are soluble and can transfer to HDL; and apolipoprotein B48, a structural apolipoprotein that is not removed during catabolism of the chylomicron. Chylomicrons enter the plasma via the thoracic duct, where they acquire two other soluble apolipoproteins, apo C and apo E, from high-density lipoprotein (HDL).
VLDLs are produced by a process analogous to the exogenous pathway. Triglycerides may derive from de novo free fatty acid synthesis in the liver or from the uptake of remnant chylomicrons, VLDL, or free fatty acids from the plasma. Precursor VLDL combines triglycerides, the structural apolipoprotein apo B100, and phospholipids, as well as cholesterol and some apo Cs and Es. The formation of the immature VLDL requires MTP. Once secreted into the plasma, VLDLs acquire more apo Cs and Es.
Any disturbance that causes increased synthesis of chylomicrons and/or VLDLs or decreased metabolic breakdown causes elevations in triglyceride levels. That disturbance may be as common as dietary indiscretion or as unusual as a genetic mutation of an enzyme in the lipid metabolism pathway.
As shown in the images below, chylomicrons and VLDLs are initially metabolized by lipoprotein lipase (LPL), which hydrolyzes the triglycerides, releasing free fatty acids; these fatty acids are stored in fat and muscle. With normal LPL activity, the half-lives of chylomicrons and VLDLs are about 10 minutes and 9 hours, respectively. Because of the large size of unmetabolized chylomicrons, they are unlikely to be taken up by macrophages, which are the precursors of foam cells. Foam cells promote fatty streak formation, the precursor of atherosclerotic plaque. LPL activity produces chylomicron remnants that are small enough to take part in the atherosclerotic process. Chylomicron remnants are taken up by the LDL receptor or the LDL receptor-related protein.2
Lipoprotein lipase (LPL) releases free fatty acids from chylomicrons and produces chylomicron remnants that are small enough to take part in the atherosclerotic process.
Once very low-density lipoprotein (VLDL) has been metabolized by lipoprotein lipase, VLDL remnants in the form of intermediate-density lipoprotein (IDL) can be metabolized by hepatic lipase, producing LDL, or they can be taken up by the LDL receptor via either apolipoprotein B (apo B) or apo E.
VLDL remnants have 1 of 2 fates: they can be metabolized by hepatic lipase, which further depletes triglycerides, producing LDL, or they can be taken up by the LDL receptor via either apo B or apo E. VLDL remnants are not only triglyceride-poor, they are also cholesterol enriched, having acquired cholesterol ester from HDL via the action of cholesterol ester transfer protein (CETP), which facilitates the exchange of VLDL triglycerides for cholesterol in HDL. This pathway may promote HDL's reverse cholesterol transport activity, but only if VLDL and LDL return cholesterol to the liver. If these lipoproteins are taken up by macrophages, the CETP transfer results in increased atherogenesis.
Chylomicron remnants, VLDL, VLDL remnants, and LDL are all atherogenic.
Frequency
United States
The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) defined elevated triglycerides as 150 mg/dL and higher.2 Using that criterion, the Third National Health and Nutrition Examination Survey (NHANES) found that the prevalence of hypertriglyceridemia in US adults age 20 years and older was approximately 35% in men and 25% in women. Triglyceride levels in African American men and women were 21% and 14%, respectively; 40% and 35% in Mexican American men and women, respectively; and in 37% and 25% in white American men and women, respectively.
Prevalence of severe hypertriglyceridemia, defined as triglycerides greater than 2000 mg/dL, is estimated to be to be 1.8 cases per 10,000 white adults, with a higher prevalence in patients with diabetes or alcoholism.
The most severe form of hypertriglyceridemia, LPL deficiency, occurs in approximately 1 case per 1 million; the frequency of apo C-II deficiency is even lower.
International
The worldwide incidence of LPL deficiency is similar to that in the United States with the exception of small populations such as in Quebec, Canada, where the number is significantly higher, probably due to the founder effect.
Apo C-II is infrequent in all populations studied to date.
Mortality/Morbidity
- Hypertriglyceridemia is correlated with an increased risk of cardiovascular disease (CVD), particularly in the setting of low HDL cholesterol (HDL-c) levels and/or elevated LDL cholesterol (LDL-c) levels. When low HDL-c levels are controlled for, some studies demonstrate that elevated triglycerides do not correlate with risk of cardiovascular disease. Others suggest that high triglyceride levels are an independent risk factor. Because metabolism of the triglyceride-rich lipoproteins (chylomicrons, VLDL) and metabolism of HDL are interdependent and because of triglycerides are very labile, the independent impact of hypertriglyceridemia on cardiovascular disease risk is difficult to confirm. However, randomized clinical trials using triglyceride-lowering medications have demonstrated decreased coronary events in both the primary and secondary coronary prevention populations.
- An understanding of lipoprotein catabolism provides an explanation for the absence of increased risk of cardiovascular disease in patients with the most severe form of hypertriglyceridemia, type I hyperlipoproteinemia. The atherogenicity correlated with elevated triglyceride levels is thought to be secondary to increased levels of chylomicron and VLDL remnants. Remnants are smaller, richer in cholesterol, and more readily taken up by macrophages, which are converted to plaque-forming foam cells. The chylomicrons in patients with type I disease cannot be converted to remnants and, therefore, should not be atherogenic.
- Extreme elevations of triglycerides, usually well above 1000 mg/dL, may cause acute pancreatitis and all the sequelae of that condition (see Pancreatitis, Acute). The NCEP ATP III guidelines stipulate that if triglycerides are ≥500 mg/dL, the initial management should be to lower the triglycerides to prevent pancreatitis. Only when the triglyceride level is below 500 should LDL-lowering be addressed.
- The chylomicronemia syndrome3,4 is an often unrecognized and less severe condition than pancreatitis that is usually caused by triglyceride levels greater than 1000 mg/dL. Abdominal pain is the most common presenting symptom, but chest pain and dyspnea may sometimes occur. Amylase and lipase are minimally, if at all, elevated. Symptoms resolve when triglyceride levels decrease well below 1000.
Race
- Triglycerides are lower in African Americans than in whites.
- Racial predisposition has been not described for LPL deficiency or apo C-II deficiency.
Sex
- In the Prospective Cardiovascular Munster study (PROCAM), a large observational study, mild hypertriglyceridemia (triglycerides >200 mg/dL) was more prevalent in men (18.6%) than in women (4.2%).5
- Genetic mutations in both LPL and apo C-II affect males and females in equal numbers.
Age
- Triglycerides increase gradually in men until about age 50 years and then decline slightly. In women, they continue to increase with age.
- Mild hypertriglyceridemia (triglycerides >150 mg/dL) is slightly more prevalent in men beginning at age 30 years and women starting at age 60 years.
- LPL deficiency and apo C-II deficiency are caused by homozygous autosomal recessive genes present at conception. The manifestations of LPL and apo C-II deficiency (severe hypertriglyceridemia) usually are detected in childhood, although defective apo C-II sometimes presents in early adulthood.
Clinical
History
- Hypertriglyceridemia is usually asymptomatic until triglycerides are greater than 1000-2000 mg/dL.
- A history of recurrent episodes of acute pancreatitis is common in patients with severe and uncontrolled hypertriglyceridemia.6 Triglyceride levels often exceed 5000 mg/dL at the onset of pancreatitis.
- Severe hypertriglyceridemia may cause eruptive xanthomas, which is a benign condition.
- Patients with recurrent episodes of abdominal pain that is less severe than acute pancreatitis may experience the chylomicronemia syndrome7 .
- These patients usually have triglyceride elevations greater than 2000 mg/dL at the onset of symptoms and provide a history of recurrent episodes of abdominal pain, sometimes with nausea, vomiting, or dyspnea.
- Pancreatitis is not necessarily present.
- Pain is commonly mid epigastric but may occur in other regions, including the chest or back.
- The presentation of hyperchylomicronemia may be confused with conditions such as acute myocardial syndromes or biliary colic.
Physical
When triglycerides are less than 1000 mg/dL, the physical findings are normal unless the underlying condition is dysbetalipoproteinemia, type III hyperlipoproteinemia. In this condition, palmar xanthomas may be discerned infrequently.
When triglycerides are acutely and massively elevated, physical findings may be absent except on funduscopic examination. Therefore, physical findings in patients with severe hypertriglyceridemia are variable, ranging from normal to one or more of the following findings:
- Dermatological
- Eruptive xanthomas (seen below) are sometimes found when sustained elevated triglycerides are well above 1000 mg/dL. These are 1- to 3-mm yellow papules on an erythematous base. They are most prominent on the back, buttocks, chest, and proximal extremities. The lesions are caused by accumulations of chylomicrons within macrophages and disappear gradually when triglycerides are kept below 1000 mg/dL.
Eruptive xanthomas on the back of a patient admitted with a triglyceride level of 4600 mg/dL and acute pancreatitis.
Close-up of eruptive xanthomas.
- Patients with dysbetalipoproteinemia (type III) may have palmar xanthomas (yellowish creases of the palms). This type of xanthoma is considered pathognomonic for this disorder. Tuberous or tuberoeruptive xanthomas, which also may occur in other hyperlipidemias, may arise on the elbows, knees, or buttocks.
- Eruptive xanthomas (seen below) are sometimes found when sustained elevated triglycerides are well above 1000 mg/dL. These are 1- to 3-mm yellow papules on an erythematous base. They are most prominent on the back, buttocks, chest, and proximal extremities. The lesions are caused by accumulations of chylomicrons within macrophages and disappear gradually when triglycerides are kept below 1000 mg/dL.
- Gastrointestinal
- If pancreatitis or the chylomicronemia syndrome is present, the mid epigastric area or upper right or left quadrants are tender to palpitation.
- Hepatomegaly and, less commonly, splenomegaly may be appreciated.
- Ophthalmologic: Triglyceride levels of 4000 mg/dL or higher may cause a condition known as lipemia retinalis, in which funduscopic examination reveals retinal blood vessels (and occasionally the retina) that have a pale pink, milky appearance.
- Neurological: Memory loss, dementia, and depression have been reported in patients with the chylomicronemia syndrome.
Causes
Hypertriglyceridemia has many causes, including familial and genetic syndromes, metabolic disease, and drugs.
- Genetic causes: Abnormalities of the enzyme pathway for chylomicron metabolism are the best-characterized genetic causes of hypertriglyceridemia. However, less clearly defined inheritable disorders are more frequent causes of elevated triglycerides.
- Type I hyperlipoproteinemia is the best-characterized genetic cause of hypertriglyceridemia and is caused by a deficiency or defect in either the enzyme LPL or its cofactor, apo C-II.
- LPL hydrolyzes triglycerides in chylomicrons and VLDL, releasing free fatty acids. The enzyme is found in the endothelial cells of capillaries and can be released into the plasma by heparin. LPL is essential for the metabolism of chylomicrons and VLDL, transforming them into their respective remnants. Apo C-II, an apolipoprotein present in both chylomicrons and VLDL, acts as a cofactor in the action of LPL.
- The above pathway is affected by other genetic disorders, particularly type 1 or type 2 diabetes, because LPL requires insulin for full activity.
- Two triglyceride disorders are genetically controlled, but the mechanisms are not clearly defined.
- Familial combined hyperlipidemia is an autosomal dominant disorder characterized by patients and their first-degree relatives who may have either isolated triglyceride or LDL-c elevations or both. Diagnosis of the disorder in a particular patient requires a family history of premature coronary artery disease (CAD) in 1 or more first-degree relatives and a family history for elevated triglycerides with or without elevated LDL-c levels. The diagnosis is important for prognosis; 10-20% of patients with premature CAD have familial combined hyperlipidemia.
- Familial hypertriglyceridemia is also an autosomal dominant trait.8 These patients and their families have isolated triglyceride elevations and may have an increased risk of premature coronary artery disease.
- Type I hyperlipoproteinemia is the best-characterized genetic cause of hypertriglyceridemia and is caused by a deficiency or defect in either the enzyme LPL or its cofactor, apo C-II.
- Metabolic causes8
- Diabetes: Uncontrolled diabetes mellitus, both type 1 and type 2, is one of the most common causes of hypertriglyceridemia, and it is often severe in patients presenting with ketosis.
- Patients with type 1 diabetes mellitus are insulin deficient, and LPL is largely ineffective. Control of these patients' diabetes mellitus with insulin will restore LPL function, reducing triglyceride levels and restoring diabetes mellitus control.
- In patients with uncontrolled type 2 diabetes mellitus and hyperinsulinemia, triglycerides are elevated for several reasons. (1) LPL is less effective in the insulin-resistant state. (2) Overproduction of VLDL by the liver is common in patients with diabetes who are often overweight. (3) Diabetes mellitus is one of the conditions that leads to incomplete metabolism of VLDL, causing increased remnant VLDL or IDL observed in dysbetalipoproteinemia (see Dysbetalipoproteinemia).
- Obesity: Mild-to-moderate elevations in triglycerides are common in obese patients, largely secondary to reduced efficacy of LPL and overproduction of VLDL.
- Hypothyroidism: It commonly causes LDL-c elevations but also may lead to mixed hyperlipidemia or isolated triglyceride elevations. Reduced hepatic lipase activity slows VLDL remnant catabolism. As with diabetes mellitus, untreated hypothyroidism may cause dysbetalipoproteinemia in patients with homozygous apolipoprotein E-2.
- Nephrotic syndrome: It is thought to increase hepatic synthesis of VLDL and also may slow catabolism of both LDL and VLDL. As in hypothyroidism, elevated LDL-c levels are more common in this condition, but mixed hyperlipidemia or isolated triglyceride elevations may be observed. Higher levels of proteinuria are correlated with more severe hyperlipidemia.
- Diabetes: Uncontrolled diabetes mellitus, both type 1 and type 2, is one of the most common causes of hypertriglyceridemia, and it is often severe in patients presenting with ketosis.
- Drugs
- High-dose thiazide diuretics or chlorthalidone
- High-dose beta-adrenergic blocking agents, excluding those with intrinsic sympathomimetic activity.
- Unopposed oral estrogen replacement therapy
- Oral contraceptives with high estrogen content
- Tamoxifen
- Glucocorticoids
- Oral isotretinoin
- Antiretroviral therapy (including some protease inhibitors, nonnucleoside reverse transcriptase inhibitors)
- Atypical antipsychotics
- Other causes of hypertriglyceridemia
- Alcohol: Excessive alcohol intake and high-carbohydrate diets (>60% of caloric intake) are frequent causes of hypertriglyceridemia.
- High-carbohydrate diets (>60% of caloric intake)
- Acute pancreatitis: It may cause substantial elevations in triglycerides by unknown mechanisms. However, much more frequently, severe hypertriglyceridemia causes acute pancreatitis. In patients presenting with acute pancreatitis and triglycerides greater than 1000 mg/dL, not assuming that the triglycerides are the cause of the pancreatitis is prudent. Other causes, such as common bile duct obstruction and alcoholism, must be considered as possible etiologies.
- Pregnancy: In patients with mildly-to-moderately elevated triglycerides in the nonpregnant state, hypertriglyceridemia (sometimes severe) may occur. Such patients should be monitored closely, particularly in the third trimester. In fact, simply looking for laboratory notation of lipemic serum in routine blood tests during pregnancy will avoid unexpected complications resulting from unrecognized and untreated hypertriglyceridemia during pregnancy.
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Further Reading
Keywords
hypertriglyceridemia, hypercholesterolemia, hyperlipidemia, high triglycerides, high LDL, high HDL, elevated LDL, elevated triglycerides, chylomicrons, chylomicron, hyperlipoproteinemia, high LDL cholesterol, high HDL cholesterol, dysbetalipoproteinemia, chylomicronemia
