Hipertrigliseridemia - Hypertriglyceridemia (hTG)

Introduction
Background


Hypertriglyceridemia (hTG) is a common disorder in the United States. The condition is exacerbated by uncontrolled diabetes mellitus, obesity, and sedentary habits, all of which are more prevalent in industrialized societies, particularly the United States, than in developing nations. In both epidemiologic and interventional studies, hypertriglyceridemia is a risk factor for coronary artery disease (CAD).

Hypertriglyceridemia can be categorized by the Fredrickson classification (analysis of lipids by beta-quantification—ultracentrifugation followed by electrophoresis).1 In this classification, all but one of the hyperlipidemias, type IIa, are characterized by elevated triglycerides: types I, IIb, III, IV, and V. In types I, IIb, III, and V, serum cholesterol levels also are elevated.

Type I is a rare disorder and is characterized by severe elevations in chylomicrons and extremely elevated triglycerides, always well above 1000 mg/dL and as high as 10,000 mg/dL or higher. It is caused by mutations of either the gene lipoprotein lipase (LPL) or its cofactor, apolipoprotein (apo) C-II. Counter-intuitively, despite exceedingly high triglyceride elevations, these mutations do not confer an increased risk of atherosclerotic disease, which may have contributed to the unfounded belief that hypertriglyceridemia is not a risk for atherosclerotic disease. Because chylomicrons also contain a small amount of cholesterol, serum cholesterol levels are also quite high. Type I is the only form of hypertriglyceridemia that does not confer an increased risk for developing coronary artery disease.

Type IIb is the classic mixed hyperlipidemia (high cholesterol and triglycerides) caused by elevations in both low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL).

Type III is also known as dysbetalipoproteinemia, remnant removal disease, or broad-beta disease (see Dysbetalipoproteinemia). Typically, these patients 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 both chylomicrons and VLDL. Triglyceride levels are invariably greater than 1000 mg/dL, and total cholesterol levels are always elevated; however, LDL cholesterol levels are normal. 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. Because triglycerides are so labile, levels of 500 mg/dL or greater become the primary focus of therapy before turning to LDL-lowering therapy.

Pathophysiology

Triglycerides are fats consisting of 3 fatty acids covalently bonded to a glycerol molecule.

Triglyceride-rich lipoproteins transport triglycerides and cholesterol throughout the circulation. By dry weight, triglycerides comprise approximately 86%, 55%, and 23% of chylomicrons, VLDLs, and IDLs, respectively (see Media file 3). Triglycerides are present in LDL and high-density lipoprotein (HDL) but in much smaller quantities of 10% or less.

Triglyceride-rich lipoproteins arise from two 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.

Both chylomicrons and VLDLs are initially metabolized by lipoprotein lipase (LPL), which LPL hydrolyzes the triglycerides, releasing free fatty acids that 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. Unmetabolized chylomicrons are large and are unlikely to be taken up by macrophages that are the precursors of foam cells, which form fatty streaks. Hepatic lipase metabolizes VLDL remnants to form LDL.

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 syndrome.
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 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 (see Media files 1-2). The lesions are caused by accumulations of chylomicrons within macrophages and disappear gradually when triglycerides are kept below 1000 mg/dL.
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.
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. These patients and their families have isolated triglyceride elevations and may have an increased risk of premature coronary artery disease.
Metabolic causes
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.
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.

Differential Diagnoses
Other Problems to Be Considered

When triglycerides are noted to be elevated, a fasting blood sugar should always be checked to rule out one of the most frequent causes of hypertriglyceridemia, uncontrolled diabetes. Management of this condition may make medication to lower the triglycerides unnecessary or, at least, easier to normalize.

A diet high in refined carbohydrates can cause hypertriglyceridemia. While cakes, candy, cookies, etc. are an obvious source, the quantity of liquid calories (nondiet soda, juice, alcohol) should be determined.
Workup
Laboratory Studies
Lipid analysis
Elevated triglycerides are determined by direct laboratory analysis of serum or plasma after a 10- to 12-hour fast. Determining which lipoprotein abnormality is the cause of hypertriglyceridemia is less straightforward.
VLDLs are increased and chylomicrons are absent when triglyceride levels are elevated but below 1000 mg/dL. If triglyceride levels are above 1000 mg/dL, both VLDL and chylomicrons are usually present.
If the triglycerides are elevated but less than 1000 mg/dL and the total cholesterol is elevated, the lipoprotein abnormality may be caused by either (1) elevations of both LDL and VLDL, which is type IIb or mixed hyperlipoproteinemia, or (2) increased remnant VLDL or IDL, which is type III hyperlipidemia or dysbetahyperlipoproteinemia.
The 2 disorders may be distinguished by obtaining a direct LDL-c analysis, which is available at most commercial laboratories. If the direct LDL-c is significantly lower than the calculated LDL-c, a diagnosis of type III hyperlipoproteinemia is likely.
The only procedure that reliably distinguishes between a mixed hyperlipoproteinemia (increased LDL-c and triglycerides) and type III hyperlipoproteinemia (increased IDL) is beta quantification. This expensive analysis involves ultracentrifugation followed by electrophoresis. It is not performed by most commercial or hospital laboratories. Specialized lipid centers, such as those at Tufts and JohnsHopkinsMedicalCenters, should be contacted if type IIb or III must be confirmed. In most clinical settings, however, distinguishing between these entities is rarely necessary because the treatment of both conditions is essentially the same. Diet modification, exercise, and appropriate weight loss improve both. Type IIb and III also respond to the same medications—niacin and/or fibric acid derivatives.7 Therefore, no matter which diagnosis applies to a given patient, the treatment is the same.
Chylomicron determination
If the triglyceride levels are greater than 1000 mg/dL and the presence of chylomicrons must be confirmed, the simplest and most cost-effective test involves overnight refrigeration of a tube plasma or serum.
If chylomicrons are present, simple inspection reveals a creamy layer overlying either cloudy or clear serum.
If the infranatant is cloudy, high levels of VLDL are present (type V hyperlipidemia).
If the infranatant is clear, the VLDL content is normal and type I hypercholesterolemia (elevated chylomicrons only) should be suspected.
Type I hyperlipoproteinemia (pure hyperchylomicronemia)
To make a definitive diagnosis of type I hypercholesterolemia, deficiency of either LPL or apo C-II must be confirmed. The presence of LPL activity may be measured in plasma following intravenous heparin administration (50 IU of heparin per kg body weight) or by analysis of muscle or adipose tissue biopsy samples.
Defective or absent apo C-II must be determined at a lipid center that performs 1 of the 3 following assays: (1) gel electrophoresis, (2) radioimmunoassay, or (3) confirmation that LPL added to the patient's plasma is not active.
Other Tests

Rule out secondary causes of hypertriglyceridemia, including diabetes mellitus and hypothyroidism.
Procedures

If the diagnosis of eruptive xanthomas is in doubt, obtaining a biopsy of the suspicious lesions will reveal accumulations of fat (not cholesterol).

Treatment
Medical Care

The latest Adult Treatment Panel guidelines (ATP III) have reclassified serum triglycerides as follows:

Table 1. Classification of Triglycerides (TG)

Open table in new windowClassification TG Level, mg/dL
Normal TG level <150
Borderline-high TG level 150-199
High TG level 200-499
Very high TG level >500


If triglycerides are 500 or above, their treatment takes priority over LDL treatment to prevent pancreatitis.

If the secondary conditions that raise triglyceride levels cannot be managed successfully and if triglycerides are 200-499 mg/dL, the non–HDL-c (total cholesterol - HDLc) can be used as the initial target of using LDL-lowering medication. The non–HDL-c is the sum of the cholesterol carried by the atherogenic lipoproteins, LDL, VLDL, and IDL. The goals for non–HDL-c levels, similar to those for LDL-c levels, are dependent on risk and are 30 mg/dL higher than the corresponding LDL-c goals. The classification of LDL-c and non–HDL-c is as follows:

Table 2. Classification of LDL Cholesterol and Non-HDL Cholesterol

Open table in new windowClassification LDL Goal,
mg/dL Non-HDL Goal,
mg/dL
CHD* and CHD risk equivalent, diabetes mellitus, and the following: 10-year risk for CHD >20% <100 <130
Two or more risk factors and the following: 10-year risk <20% <130 <160
0-1 risk factor <160 <190



*Coronary heart disease

When hypertriglyceridemia is diagnosed, secondary causes should be sought out and controlled. If the triglyceride level is below 500 mg/dL, triglyceride-lowering medication may be withheld while secondary causes are managed. For example, lowering a substantially elevated HbA1c may normalize the triglycerides; or at least facilitate their treatment.

The importance of obesity, a sedentary lifestyle, very high fat diet, and intake of large concentrations of refined carbohydrates should not be underestimated as causes of severe hypertriglyceridemia. Instituting a program of progressive aerobic and toning exercise, weight loss, and dietary management can significantly lower triglyceride levels and, in some cases, normalize them.

During pregnancy, severe hypertriglyceridemia is an unusual complication and may cause pancreatitis.
Many case reports have been published describing interventions to manage this condition.
Most commonly, a very low-fat diet was sufficient to control triglycerides and prevent pancreatitis.
Intermittent and, in persistent cases, continuous total parenteral nutrition has been used—usually in the third trimester.
Reports also have been published describing plasma exchange or apheresis, as well as early third trimester termination of pregnancy by cesarean section.

Consultations

If the primary care provider cannot control a patient's triglycerides, referral should be made to a lipidologist or endocrinologist with expertise in treating severe and difficult-to-manage lipid disorders.

Diet
Total fat intake should be restricted if this intervention assists in weight loss. If triglyceride levels are greater than 1000 mg/dL, allowing no more than 10% of total calories from fat will usually lower triglycerides promptly and dramatically.
Fat restriction is a 2-edged sword. Reducing fat intake causes needed weight loss, and triglycerides usually improve. When triglycerides are severely elevated (>1000 mg/dL), suggesting impaired or absent LPL activity, a low-fat diet decreases chylomicron and VLDL production and improves the metabolism of these triglyceride-rich lipoproteins.
On the other hand, in the setting of stable weight and moderately elevated triglycerides, a very low-fat diet increases triglycerides and may, in addition, decrease HDL-c levels. Patients who are extremely compliant and motivated may choose to follow such a diet in the hope of improving their cholesterol levels. If they have a mixed hyperlipidemia, their LDL-c certainly will decrease. However, such a diet will, if anything, cause further deterioration in the HDL-c and triglycerides. If the patient has an isolated triglyceride elevation and does not lose weight on the diet, the triglycerides may increase. In such cases, addition of a healthy fat (monounsaturated or polyunsaturated fat) lowers triglycerides, increases HDL-c, and sometimes decreases LDL-c.
In cases in which dietary intake of sugar and white flour products is substantial, restricting simple carbohydrates and increasing dietary fiber are important adjuncts that can lower triglycerides substantially.
Large quantities or fruit juice or non-diet soda can increase triglycerides dramatically.
Alcohol should be eliminated or restricted to no more than 1 standard alcoholic beverage per day.
Omega-3 (N-3) fatty acids
The class of polyunsaturated fats known as omega-3 fatty acids, which are derived mainly from fatty fish and some plant products (flax seed), has a unique impact on triglycerides.
In large amounts (10 or more g/d), N-3 fatty acids lower triglycerides 40% or more.
To achieve this dose, purified capsules are usually necessary, but some patients may prefer to eat large quantities of fatty fish. The fish highest in N-3 fatty acids are sardines, herring, and mackerel; daily servings of 1 pound or more may be necessary.
If weight gain ensues, triglyceride lowering will be compromised.
Activity
Exercise, particularly sustained aerobic activity, can have a dramatic impact on triglyceride levels and may increase HDL-c slightly.
The American Heart Association recommends 30-60 minutes of aerobic exercise most days of the week and toning for 20-30 minutes twice a week. This prescription has substantial benefits beyond lipid effects as follows:
Reduced weight
Decreased insulin resistance
Decreased blood pressure
Improved cardiovascular conditioning
Overall reduction in acute cardiovascular events is also a likely benefit of regular exercise.
Toning of large muscles groups (abdomen, back, legs, arms) also improves metabolism of triglyceride-rich lipoproteins and lowers triglycerides.
Medication


Three classes of medications are appropriate for major triglyceride elevations; fibric acid derivatives, niacin, and omega-3 fatty acids. High-doses of a strong statin (simvastatin, atorvastatin, rosuvastatin) also lower triglycerides as much as approximately 50%.

Currently 3 fibrates are used clinically; 2 are available in the United States, gemfibrozil (Lopid), which is now generic, and fenofibrate (multiple brand names). Bezafibrate, available in Europe and elsewhere, has not been approved by the U.S. Food and Drug Administration (FDA).8 The oldest fibrate, clofibrate, is no longer used because of increased morbidity or mortality rates in large placebo-controlled studies (the World Health Organization [WHO] study and the Coronary Drug Project). Moreover, tumorigenicity has been demonstrated in rodents.

Gemfibrozil has been used in 2 major randomized placebo-controlled clinical trials—the Helsinki Heart Study and the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). In a subset of men in the Helsinki study with elevated LDL-c levels and mildly elevated triglycerides greater than 204 mg/dL, a 70% reduction in coronary events was found compared with men with triglycerides less than 204 mg/dL.9 The VA-HIT studied men with coronary heart disease with relatively normal LDL-c and triglyceride levels but with HDL-c levels less than 31 mg/dL. The LDL-c did not change in the treatment group or the control group, but the small increase in HDL-c and decrease in triglycerides experienced by the treatment group resulted in a significant reduction of coronary events compared with controls.10

Niacin (vitamin B-3) in large doses decreases triglycerides at least 40% and can raise HDL-c levels 40% or more. Niacin also reliably and significantly lowers LDL-c levels, and the other major triglyceride-lowering medications do not. In the Coronary Drug Project (a randomized placebo-controlled trial of secondary prevention in men), niacin reduced coronary events compared with placebo.

Niacin has multiple adverse effects, the worst of which is chemical hepatitis. However, at doses of 1.5-2 g/d, complications are unusual. Sustained-release niacin is more hepatotoxic than immediate-release niacin but is better tolerated.11 Flushing, itching, and rash are expected adverse effects that are less common with long-acting formulations. These symptoms are an annoyance but are not life threatening and may be minimized by starting at low doses and increasing slowly. Switching from immediate-release niacin to an equal dose of time-release preparation has been reported to cause severe hepatotoxicity. Niacinamide, also called vitamin B-3, has no lipid-lowering effects; nor does inositol hexanicotinate.

Omega-3 fatty acids are attractive because of their low risk of major adverse effects or interaction with other medications. At very high doses (4 or more g/d), triglycerides are reduced. The triglyceride-lowering impact of fish oils is entirely dependent on the omega-3 content, and, therefore, the number of capsules required for a total dose of 4 g/d requires determining the content of eicosapentaenoic (EPA) and docosahexaenoic (DHA) per capsule. Over the counter fish oil capsules vary in concentration from approximately 0.4 g to 1.0 g of EPA +DHA per capsule. Therefore, a minimum dose of 4 g of omega-3 fatty acids per day may require 8 or more capsules.

A prescription fish oil capsule was approved by the FDA for triglyceride levels greater than 400 mg/dL. Originally called Omacor, it was renamed Lovaza in 2007. One 1-g capsule contains approximately 465 mg of EPA and 375 mg of DHA. High-dose fish oil increases LDL-C levels; the impact on HDL-c levels is variable. The cost is substantially higher than that of over the counter fish oil and is usually not covered by insurance companies.

For patients with mixed hyperlipidemias (elevations of both LDL-c and triglycerides), a moderate dose of a hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor may be appropriate if the amount of triglyceride lowering necessary is only about 20%. Maximum doses of the strongest statins, atorvastatin, simvastatin, rosuvastatin, or cerivastatin (recalled from US market 8/8/01), lower triglycerides approximately 40%, but such doses are not appropriate unless the LDL-c is at least 30% above the desired level.

Bile acid sequestrants (cholestyramine or colestipol) raise triglyceride levels and are not appropriate therapy for hypertriglyceridemia. However, in patients with a mixed hyperlipidemia, resins may be combined with niacin or a fibric acid derivative.

Patients with the metabolic syndrome are often treated with metformin, which not only improves impaired fasting glucose levels, but also lowers triglycerides.
Fibric acid derivatives

Fibric acid derivatives lower triglycerides approximately 40% and increase HDL-c about 20%. Fenofibrate is reported to lower LDL-c levels more reliably than either clofibrate or gemfibrozil, but none of the drugs in this class should be used for isolated LDL-c elevations. The fibrates are commonly used to treat hyperlipidemias types IV (high VLDL) and V (high VLDL and chylomicrons), as well as type III dysbetalipoproteinemia (IDL or VLDL remnant disease).

They can also be used to treat type IIb mixed hyperlipidemia if used in conjunction with an LDL-lowering medication such as a resin.


Gemfibrozil (Lopid)

Lowers TGs and raises HDL-c. LDL-c is usually is unaffected but may increase if initially low or decrease if initially high. Available in generic formulation, most cost-effective fibrate at this time. FDA-approved indications are for type IV and V hyperlipidemia, ie, elevations in VLDL only or both VLDL and chylomicrons.

Fenofibrate (Tricor)

Similar to other fibric acid derivatives in TG-lowering and HDL-raising effects. Differs in that modest LDL-lowering can be expected with greater frequency than with gemfibrozil. The FDA-approved indications are for hypertriglyceridemia and hypercholesterolemia, but this difference does not qualify fenofibrate for treatment of isolated LDL-c elevations. Taken once a day. May increase compliance.

Niacin (nicotinic acid)

At least 1.5 g/d decreases triglycerides as much as about 50%. Substantial HDL-c increases of 30% or more can be achieved, particularly at higher doses. LDL-c will decrease 15-25%. Whether OTC or by prescription, it costs less than any other lipid-lowering medication. For reasons not clearly understood, changing brands during treatment is more likely to cause hepatotoxicity, occurring more so with time-release than immediate-release niacin.

Sustained-release niacin (Vitamin B-3)

More hepatotoxic than immediate-release niacin. Patients strongly advised against switching formulations or brands during treatment. Both OTC and prescription formulas are available. OTC brands cost less, but only reliable manufacturers should be recommended. Slo-Niacin is OTC formulation available in 250-mg, 500-mg, and 750-mg tablets. Sundown is another manufacturer. Prescription SR niacin (Niaspan) is available in 375-mg, 500-mg, and 1000-mg tabs.

Immediate-release niacin (Niacor and Nicolar)

Less hepatotoxic than SR niacin but less well tolerated by patients due to prostaglandin-mediated flushing, itching, and rash. Therapy started at a low dose, such as 100 mg tid pc, and increased gradually over several weeks will allow some patients to accommodate adverse effects. At high doses (4-6 g/d), it is less hepatotoxic than SR niacin. Changing formulation at high dose may increase risk of hepatotoxicity. Niacor and Nicolar are prescription formulations that, while more expensive than OTC brands, may have an advantage in making it less likely that the patient switches brands.

Omega-3 fatty acids

These agents reduce triglyceride biosynthesis.

Omega-3-acid ethyl esters (Lovaza)

First prescription omega-3-acid. Each 1-g cap contains at least 900 mg of omega-3-acid ethyl esters, predominantly a combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Theorized to reduce triglyceride synthesis in the liver. EPA and DHA are poor enzyme substrates for triglyceride synthesis in the liver, and they inhibit esterification of other fatty acids. Potential mechanisms of action include acyl CoA:1,2-diacylglycerol acyltransferase inhibition, increased hepatic mitochondrial and peroxisomal beta-oxidation, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity.
Clinical trials show significant reduction in non–high-density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, very low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein B levels from baseline when combined with simvastatin compared with simvastatin and placebo. Monotherapy with omega-3-acid ethyl esters reduce median triglyceride, VLDL-C, and non–HDL-C levels from baseline.
Indicated as adjunctive treatment to diet to reduce very high triglyceride levels (ie, >500 mg/dL).

Follow-up
Deterrence/Prevention
Patients with hypertriglyceridemia, particularly if the HDL-c level is low, are at risk for cardiovascular events. They should be treated, not only for their lipid disorder, but also for other modifiable cardiovascular risk factors, such as hypertension, diabetes, smoking, sedentary lifestyle, and obesity.
While the rare inherited disorders of severe hypertriglyceridemia require heroic restrictions in dietary fat, most elevated triglycerides can be controlled, at least partially, by a program of diet, exercise, and weight loss. Therefore, prevention entails pursuing an active lifestyle with regular aerobic and toning exercise; eating a diet low in simple carbohydrates and alcohol, and if the triglycerides are well above 1000 mg/dL low in fat; and maintaining a lean body habitus. These habits have the added benefit of reducing the probability of developing type 2 diabetes mellitus and hypertension. Lifestyle modification can be more effective than a triglyceride-lowering medication if the habits are in need of intervention and the patient is willing and able to make significant changes.
Patients with modest triglyceride elevations may develop severe hypertriglyceridemia and risk of pancreatitis if an aggravating agent is instituted. Drugs such as oral isotretinoin and unopposed oral estrogen replacement therapy should be used with caution.
Complications
Triglycerides do not cause complications until elevations of 1000 mg/dL or more are reached. However, as suggested by the NCEP ATP III, triglycerides are so labile that a level between 500 and 1000 mg/dL may in certain settings increase dramatically and should be a target of treatment even before ensuring that the LDL goal is reached.
Pancreatitis: Triglycerides do not cause pancreatitis below levels of greater than 1000 mg/dL. However, many patients tolerate triglycerides of 4000 mg/dL or higher without developing symptoms.12
The chylomicronemia syndrome
The chylomicronemia syndrome, a less recognized diagnosis usually occurring when triglycerides are 800 mg/dL or higher, causes recurrent episodes of ill-defined abdominal pain that may be accompanied by nausea and vomiting.
Amylase and lipase levels are normal in this setting.
The symptoms resolve when triglycerides are lowered.
Other presentations include dyspnea, chest pain, and/or back pain.
Prognosis
Patients' risk of cardiovascular disease is diminished with aggressive treatment to lower triglycerides, particularly in the setting of low HDL-c levels.
The risk of recurrent pancreatitis secondary to hypertriglyceridemia can be avoided entirely by ensuring that levels are maintained well below 700 mg/dL. Because triglyceride levels are so labile, simply moderating levels to less than 1000 mg/dL does not decrease risk substantially because the slightest metabolic imbalance or dietary indiscretion may push levels several hundred points higher.
Patient Education
Patients often do not understand that triglycerides are a blood lipid that may be analyzed along with cholesterol. They should be educated regarding the separate risks of hypertriglyceridemia —increased risk of a cardiovascular event and risk of pancreatitis if levels are close to or above 1000 mg/dL.
Patients should be informed that triglycerides respond to the simple interventions of diet control, exercise, and appropriate weight loss. Stress the importance of alcohol intake of no more than 1 drink per day.
For excellent patient education resources, visit eMedicine's Statins Center. Also, see eMedicine's patient education articles High Cholesterol, Understanding Your Cholesterol level, Lifestyle Cholesterol Management, Understanding Cholesterol-Lowering Medications, and Statins and Cholesterol.
Miscellaneous
Medicolegal Pitfalls
Failure to treat patients with elevated triglycerides, thereby increasing their risk of pancreatitis or of a cardiovascular event
Starting medications that may cause severe hypertriglyceridemia without first checking baseline triglycerides
These drugs may be used in patients with mildly elevated triglycerides and are not absolutely contraindicated in patients with significantly elevated triglycerides.
Patients must be closely monitored, and a triglyceride-lowering medication should be instituted, if necessary.
Combining a statin with either niacin or a fibric acid derivative
The increased risk of myositis is not an absolute contraindication except in the case of combining the statin, cerivastatin (recalled from US market 8/8/01), with a fibric acid.
A patient with a mixed hyperlipidemia and other risk factors for coronary artery disease may warrant a niacin-statin or gemfibrozil-statin combination when the risks versus benefits are considered.
Special Concerns
Pregnancy
Women with elevated triglycerides before conception may develop severe hypertriglyceridemia, with triglyceride levels well above 1000 mg/dL, and the concomitant risk of pancreatitis. These women should be counseled regarding diet, exercise, and weight management before becoming pregnant and must be monitored closely during their pregnancies.13 All pregnancies require occasional triglyceride monitoring. Simple inspection to rule out lipemic serum is all that is necessary.
Most of the medications to treat hypertriglyceridemia are contraindicated during pregnancy, although treatment with gemfibrozil in a patient with severe hypertriglyceridemia and pancreatitis has been reported. Omega-3 fatty acids may be a more acceptable intervention, but the safety of high-dose N-3 fatty acids has not been proven.

http://emedicine.medscape.com/article/126568-overview