High Triglycerides (Hypertriglyceridemia)

Author: Dr Elena Citkowitz Yale University 2008-12-28

Triglycerides are fat molecules. They serve as the body’s primary source of stored energy. However, high levels of triglycerides in the blood are associated with serious health problems (link to Coronary Artery Disease or CAD, link to pancreatitis). Treatment options include diet, exercise, weight loss, and medication.

What is Hypertriglyceridemia?

The term hypertriglyceridemia describes the condition in which triglyceride levels in the blood stream are elevated.  Triglycerides are fat molecules that are composed of three long-chain fatty acids attached to a glycerol ‘backbone’ (Figure 1).  Fat cells accumulate triglycerides, which are the body’s primary source of stored energy.  When energy is required, triglycerides are broken down into its components, glycerol and fatty acids, which are released.  Triglycerides do not travel free in the blood stream but are transported in particles called lipoproteins, which also contain cholesterol, proteins, and phospholipids.  Certain lipoproteins have a higher triglyceride content and are called triglyceride-rich lipoproteins. 

How are Triglycerides evaluated?

Hypertriglyceridemia is associated with many serious health problems that will be discussed below.  Triglycerides alone can be measured by a simple blood test but are most often ordered as part of a standard lipid profile in order to determine risk for coronary artery disease (CAD), a condition that can cause heart attacks and angina.  The term lipid’ refers to fat and fat-like molecules, including cholesterol.  CAD is the buildup of plaque in the arteries of the heart, also called atherosclerosis or “hardening of the arteries”. 

The standard lipid profile is performed after a ten to twelve hours fast and includes the triglycerides, the total cholesterol (a measure of all the cholesterol in the plasma), the cholesterol in a lipoprotein called high-density lipoprotein (HDL), the so-called “good cholesterol” that reduces risk for CAD, and the low-density lipoprotein (LDL), called the “bad cholesterol” because it is a major cause of atherosclerosis

A normal triglyceride level, as defined by the U.S. National Cholesterol Education Adult Treatment Panel III (NCEP ATP III), is less than 150 mg/dL (see Table 1).  In North America, both triglyceride and LDL levels increase from an average of 50-60 mg/dL in children to about 140 in adults.  

Table 1

NCEP ATP III Classification of Serum Triglycerides (mg/dL)

Normal                  <150 mg/dL (1.7 mMol)

Borderline high      150 to 199 mg/dL (1.7 to 2.2 mMol)

High                       200 to 499 mg/dL (2.2 to 5.6 mMol)

Very high               500 mg/dL ( 5.6 mMol)

For LDL classification see the Hypercholesterolemia article (link to Hypercholesterolemia article).

WHY IS IT IMPORTANT TO EVALUATE HYPERTRIGLYCERIDEMIA?

High triglyceride levels are associated, directly and indirectly, with a number of serious diseases.

Why is it important to evaluate hypertriglyceridemia?

High triglyceride levels are associated, directly and indirectly, with a number of serious diseases.

• ·Atherosclerosis

Abundant evidence links high levels of LDL, and low levels of HDL with risk for hardening of arteries (atherosclerosis).  This condition is caused by cholesterol deposition in the linings of arteries and causes blockages leading to circulation problems in the heart, brain or legs.  Atherosclerosis of heart arteries (CAD) causes heart attacks.  The same condition in leg arteries, called claudication, causes calf and sometimes hip pain with walking.  In neck arteries, it causes transient ischemic attacks or strokes.  In the large artery in the abdomen called the aorta, it causes aneurysms.  

    Hypertriglyceridemia is also associated with atherosclerosis but the evidence is less compelling, a situation that     can be explained by the following:
    1)  The variability of triglyceride levels from day to day.  Eating or exercising within 10 hours
         of the test can affect results, as can drinking large quantifies of alcohol.   LDL and HDL
         levels do not shift so easily.  When triglyceride levels are so variable, statistical
         correlations with conditions such as CAD are not accurate.
    2)  The association of the more atherogenic small, dense LDL with high triglycerides and low HDL.
    3)  The association between the metabolism of triglyceride-rich lipoproteins and HDL. 
         Conditions causing elevated triglycerides are accompanied by low HDL levels.
         Medications used to lower triglycerides also raise HDL.
         Several conditions that increase the risk for CAD involve elevated triglycerides.
    4)  Hypertriglyceridemia is also present in two lipid disorders associated with a very high risk for CAD:   

         dysbetalipoproteinemia and familial combined hyperlipidemia. In these  
         conditions, the triglycerides are elevated but the LDL is not.  

• The Metabolic Syndrome

Hypertriglyceridemia is also associated with CAD risk in another condition called the metabolic syndrome.   As defined by the NCEP guidelines, the syndrome is defined as having at least three of the five following conditions: elevated triglycerides levels (above 150 mg/dL), elevated blood pressure, elevated blood sugar, abdominal obesity, and low HDL.  The metabolic syndrome increases the risk for developing diabetes as well as CAD.  The recommended initial treatment for this condition is weight loss and increased physical activity both of which are key interventions to lower triglycerides. 

Unexpectedly, a very rare condition called type I hyperlipidemia, which causes extremely high levels of triglycerides, usually in the multi thousands, is not associated with an increased risk of atherosclerosis.  The lack of association of the dramatically increased triglycerides with increased risk for CAD may be partly responsible for the belief that hypertriglyceridemia is unrelated to atherosclerosis.  The explanation for this seeming contradiction lies in the fact that the chylomicrons are not metabolized to smaller chylomicron remnants and are, therefore, too large to be taken up by the cells that damage the artery lining. 

• Pancreatitis

Aside from the risk of CAD, patients with high triglycerides are at risk for another life threatening condition called pancreatitis, which usually causes severe upper abdominal pain, sometimes accompanied by nausea, vomiting and other symptoms (Link to Google Pancreatitis article). Very high triglycerides are defined as levels of 500 mg/dL or higher and the guidelines strongly advise that they be promptly lowered to prevent pancreatitis.  Although it is highly unlikely that triglyceride levels below 1000 mg/dL cause pancreatitis, triglycerides can change so quickly that simple lifestyle changes (listed in table 3) could easily drive the triglyceride levels to several thousand in a matter of days. 

•       Hyperchylomicronemia

The most severe form of hypertriglyceridemia occurs when levels rise above 1000 mg/dL, a condition called hyperchylomicronemia.  When the triglycerides are greater than 2000 mg/dL, a constellation of symptoms may occur called the chylomicronemia syndrome.  Pancreatitis is not always the cause of abdominal pain although it is frequently a part of the syndrome.  The symptoms may also be confused with appendicitis or a gall bladder attack.  Other common symptoms include shortness of breath and changes in mental status.  

The chylomicronemia syndrome includes physical findings as well.  Examination of the retina reveals a condition called lipemia retinalis.  The retina is pale orange and the blood vessels are white (Figure 2).  Similarly, blood withdrawn from a vein also has a white or milky appearance and is described as lipemic (Figure 3).  In prolonged chylomicronemia, small, pimple-like lesions may appear, most prominent on the trunk, arms, and legs.  These are eruptive xanthomas and will resolve when triglyceride levels remain below 500 mg/dL for an extended period (Figure 4).

When should I get my triglycerides evaluated?

The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines suggest screening fasting lipids starting at age 20.  If a younger person has significant risk factors for coronary artery disease (CAD) (e.g. high blood pressure, smoking or a parent with premature CAD) or has a parent or sibling with significant hyperlipidemia, screening should start earlier.  The United States Preventive Services Task Force recommends initial screening at age 35 in men and 45 in women and as early as age 20 in those with major risk factors for CAD.

Where do Triglycerides come from?

Two sources produce triglyceride-rich lipoproteins: the small intestine and the liver.  In the intestine, dietary fat is broken down into free fatty acids and monoglycerides, which are taken up by intestinal cells that synthesize triglycerides and assemble them into very large lipoproteins called chylomicrons.
The liver performs an analogous function by synthesizing triglycerides and packaging them into VLDL.  The triglyceride content of VLDL is much less than that of chylomicrons because of its smaller size but also because the percent triglyceride content is less.  VLDL remnants, also called intermediate density lipoprotein (IDL), are further metabolized to low density lipoprotein.  
VLDL, VLDL remnants, LDL, and chylomicron remnants can be taken up by the liver but they all have the ability to taken up by cells that deposit cholesterol in the linings of arteries causing atherosclerosis or hardening of the arteries.  Chylomicrons that have not been metabolized to remnants are so large that they cannot enter cells and, therefore, are thought not to increase the risk for CAD.
Elevated triglycerides occur either when too many chylomicrons and/or VLDLs are synthesized or their metabolic breakdown is slowed, or both.   Approximately 30% of the U.S. population has elevated fasting triglycerides, defined by ATP III as levels greater than 150 mg/dL (Table 1)

Causes of Hypertriglyceridemia (Table 2)

Causes of hypertriglyceridemia are divided into primary inherited disorders and secondary disorders caused by modifiable factors.   This distinction is somewhat misleading in that even the secondary disorders have some underlying genetic, i.e. inherited component.  While obesity, lack of exercise and a diet dominated by cookies and soda can cause hypertriglyceridemia, many individuals with these characteristics have normal triglycerides (much to the dismay of those afflicted with high triglyceride levels).  Unidentified genes or gene clusters underlie these variable responses to environmental factors. 
As already mentioned, two inherited primary disorders, familial combined hyperlipidemia and dysbetalipoproteinemia, are strongly associated with CAD.  In families with early, premature CAD, 14% have been found to have familial combined hyperlipidemia.        
The medical conditions, lifestyle factors, and medications that cause hypertriglyceridemia are listed in Table 2.  Diabetes and pre-diabetic conditions are among the most common causes of the modifiable causes of hypertriglyceridemia.  Acute pancreatitis, when caused by something other than severe hypertriglyceridemia, may itself cause mild hypertriglyceridemia.    

Table 2.   Selected Causes of Hypertriglyceridemia

• Inherited Syndromes

         Familial combined hyperlipidemia - common disorder, strong risk for CAD

       Familial hypertriglyceridemia - may not increase risk for CAD
       Familial dysbetalipoproteinemia - strong risk for CAD
       Familial chylomicronemia - exceedingly rare with very high risk for pancreatitis but not CAD

• Medical Conditions

       Diabetes mellitus, particularly if not well controlled  
       Kidney disease (chronic renal failure, nephrotic syndrome)
       Hypothyroidism, untreated
       Human immunodeficiency disease
       Pregnancy
       Obesity, particularly central (male-pattern) obesity
       Acute pancreatitis

 

• Lifestyle

         Lack of exercise
       Diet very high in simple carbohydrates (sugar, juice, soda, white flour, white rice)
       Alcohol
       Very high-fat meal

 

 

Treatment to Lower Triglycerides

Goals

In the ATP III guidelines, unless the triglycerides are at least 500 mg/dL (5.64 mMol) LDL-lowering precedes treatment for hypertriglyceridemia.  LDL goals and treatment are based on the patient’s risk for CAD (link to Google Hypercholesterolemia article).   For borderline high triglyceride levels (150- 199 mg/dL, 1.69-2.25 mMol), treatment is focused on weight management and increased physical activity, and, if necessary, medication to lower the LDL.  If the LDL is at goal and triglycerides are 200-499 mg/dL (2.26-5.63 mMol), a secondary goal called the non-HDL cholesterol is calculated by subtracting the HDL from the total cholesterol.  This value includes all the atherogenic lipoproteins: LDL, VLDL, VLDL remnants/IDL, and chylomicron remnants.  The non-HDL goal is 30 points higher than the patient’s LDL goal.  Lifestyle changes are again recommended and, if necessary, medication to lower either the LDL or lower the triglycerides.

Lifestyle Changes

• Weight loss
• Exercise – brisk walking or the equivalent, minimum 30 minutes 4 days/week,

               optimally 60 minutes 7 d/week

• Elimination of simple carbohydrates
• Avoidance of extremely high fat meals if triglycerides greater than 1000 mg/dL 

Lifestyle intervention is more effective than medication in lowering triglyceride levels.  With sufficient changes in diet, physical activity, and weight, triglycerides can decrease over 1000 mg/dL in a matter of weeks.  Controlling medical conditions, particularly diabetes, can also dramatically lower triglyceride levels.  The same cannot be said for lowering the LDL where medication usually has a substantially greater impact than does lifestyle intervention.  And only the most dramatic changes in exercise and weight will increase HDL levels substantially, while medication is almost as ineffective.
While a weight loss program can produce excellent results, it should not be undertaken without understanding the long-term commitment required to maintain it.  A better strategy would be to make the changes in diet and exercise described below, which should slowly decrease percent body fat and increase lean body weight.  Rather than using a scale to assess loss of fat, a better gauge is a decrease in waist circumference.   
A minimum of 30 minutes of aerobic exercise most days of the week is necessary.  Sustained exercise is preferred but can be broken up into 10 minute sessions if necessary.   
Sweets, white bread, white potatoes, and white rice should be eliminated or sharply reduced.   “Liquid calories” (soda, juice, coffee or tea sweetened with sugar or honey) are easy to consume in large quantities and have little effect on appetite and should be eliminated or sharply reduced.  Regular (non-diet) soda and juice are equally high in calories, carbohydrates, and sugar; 12-oz of either contains 150 calories or more.

Medications

  

• Fibrates

Fibrates improve the metabolism of triglyceride-rich lipoproteins.  Only two fibrates, gemfibrozil and fenofibrate, have been approved by the U.S. Food and Drug Administration.  Bezafibrate, ciprofibrate, and clofibrate are available in other countries.  Fibrates lower triglycerides and raise HDL, but their impact on LDL is unpredictable.  A study that compared gemfibrozil to placebo in men with CAD who had low HDL cholesterol and mildly elevated triglycerides and LDL levels, showed that only gemfibrozil lowered the risk of cardiac events (heart attack, etc.) .  At the end of the study, the

HDL was slightly higher and the triglycerides slightly lower.  The LDL hadn’t changed.

Fibrates raise HDL approximately 15% and lower triglycerides about 50%, with variable changes in LDL.  Some patients experience mild stomach upset. Fibrates should not be taken by those with gall bladder disease, severe liver disease or kidney disease; and parameters for clotting should be monitored more closely in patients on certain types of blood thinners

Fibrates have only a small risk of causing muscle injury but if combined with the powerful class of LDL lowering medications called statins, the risk is increased, though less with fenofibrate than with gemfibrozil.  

• ·Niacin 

Niacin, also called nicotinic acid, is vitamin B3, and at the recommended daily allowance of 20 mg has no impact on lipids or any harmful side effects.  It is the most effective agent for raising HDL and, unlike the fibrates, reliably lowers LDL.  It suppresses release of free fatty acids from fat tissue, which reduces VLDL production, and impacts directly on HDL metabolism.  The dose required to lower triglycerides is 50 or more times greater than the recommended daily allowance.  Another form of vitamin B3 is called niacinamide and is ineffective in lowering triglycerides as are several formulations advertised as “no-flush” niacin, such as inositol hexanicotinate.   Niacin can be bought without a prescription.  Taking less than l000 mg is probably safe but will do little for the lipids.  But a dose sufficient to significantly lower triglycerides entails the risk of suffering from one or more of niacin’s many adverse reactions.  Taking more than 1000 mg/day should be undertaken only under the supervision of a physician.  High-dose immediate-release niacin increases the likelihood of liver dysfunction, gout, elevated blood sugar, and possibly stomach ulcers.  The time-release and extended-release formulations, which were designed to prevent harmless but bothersome side effect including flushing, itching, rash and stomach, are more likely to have serious medical consequences. Physician oversight allows symptoms and laboratory tests to be monitored and, if necessary, acted upon.

Niacin is the best HDL-raising medication and has been shown to reduce plaque and decrease cardiac events.  The approximate lipid changes in response to 2000 mg niacin are a 50% decrease in triglycerides, 35% increase in HDL, and 25% decrease in LDL.  Higher doses may increase HDL even more.  

• Fish oil supplements                                                                                 

The components in fish oil that lower triglycerides are called omega-3 fatty acids.  The omega-3 fatty acids in fish oil are eicosapentaenoic (EPA) and docosahexaenoic acid (DHA).  Some plants also contain a substantial amount of an omega-3 fatty acids called alpha-linolenic acid.  Less evidence is available regarding its benefits.  High-dose fish oil appears to decrease VLDL synthesis but the mechanism has not been well defined. 

 Four grams of EPA plus DHA lower triglyceride levels up to 50%; but LDL levels may increase more than 40%, while HDL levels are unchanged or minimally increased.  Many brands of fish oil capsules are available without prescription; a prescription is required for a particularly high-strength formulation.  A bottle of fish oil capsules labeled 1000 or 1200 mg usually contains 50% or less of EPA and DHA combined; the content is listed on the back of the bottle.  The capsules may be taken once per day.  They sometimes cause a fishy after taste or mild stomach upset; side effects that may lessen if taken with a meal.   Getting sufficient omega-3 fatty acids by eating fish is difficult.  A daily diet of 5 to 8 ounces of one of the five fattest fish would be necessary (Table 4).  However, low doses of fish oil, 850 to 1000 mg of EPA plus DHA per day, while not improving hypertriglyceridemia, have been shown to lower the risk of fatal cardiac events, a finding that has prompted the American Heart Association to recommend eating (preferably fatty) fish at least at least twice a week. 

 

Table 3  Omega-3 Fatty Acid Content of Fatty Fish

Raw Fish 3.5 oz     Grams of omega-3 fatty acids

Mackerel                           2.5 Sardines (canned)              1.7 Herring (Atlantic)               1.6 Trout (Lake)                      1.6 Salmon (Chinook)               1.4

  

 

• Statins

Statins are powerful medications used to treat high LDL levels.  If an LDL level is sufficiently high to mandate a high dose of one of the stronger statins (simvastatin, atorvastatin, rosuvastatin) the triglyceride level will decrease up to 50%, as will the LDL.  Such high-dose statins should not be given for isolated triglyceride elevations.  Whether or not statins cause significant liver injury is debatable; but severe muscle toxicity, though quite rare, can be life-threatening.  This risk is increased when statins are given with certain other medications, including the fibrates.  While a list of other medications that increase the risk of statin toxicity is beyond the scope of this article (Link to article on Hypercholesterolemia), mention should be made of the “grapefruit warning”.   A quart of grapefruit juice is a concern; one grapefruit or an 8 ounce glass of juice is safe. 

Links

1.  American Heart Association: What is atherosclerosis?
http://www.nhlbi.nih.gov/health/dci/Diseases/Atherosclerosis/Atherosclerosis_WhatIs.html
2.  WHO/Frederickson Classification with multiple links to sources of information about triglycerides.
http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20020617063512021840
3.   Centers for Disease Control and Prevention (CDC)
Information on physical activity, nutrition, weight
http://www.cdc.gov/nccdphp/dnpa/physical/index.htm 
4.  American Heart Association: Why Lose Weight?
http://www.americanheart.org/presenter.jhtml?identifier=3040449      

References

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   (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
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2. Brunzell , JD.  Hypertriglyceridemia.  N Engl J Med 2007;357:1009-1017
3. Dunbar RD, Rader DJ.  Demystifying triglycerides: A practical approach for the clinician. 
    Cleve Clin J Med 2005;72:661-675. 
4. Jacobson TA, Miller M, Schaefer EJ.  Hypertriglyceridemia and cardiovascular risk reduction. 
    Clin Ther. 2007;29:763-777.
5. Haskell WL, et al.  Physical Activity and Public Health. Updated Recommendation for Adults
    from the American College of Sports Medicine and American Heart Association. 
    Circulation 2007;116:1081-1093.  
    http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.107.185649
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     Adults from the American College of Sports Medicine and American Heart Association.
    Circulation 2007;116:1094-1105.  
    http://circ.ahajournals.org/cgi/reprint/CIRCULATIONAHA.107.185650