Where do cholesterol and triglycerides come from?

There are two sources for these lipids: dietary sources, and endogenous sources (i.e., manufactured within the body).

Dietary cholesterol and triglycerides mainly come from eating animal products and saturated fat. These dietary lipids are absorbed through the gut, assembled there into special packets called chylomicrons, and then are delivered through the bloodstream to the liver, where they are processed.

One of the main jobs of the liver is to make sure all the tissues of the body receive the cholesterol and triglycerides they need to function. Whenever possible (i.e., for about 8 hours after a meal), the liver takes up dietary cholesterol and triglycerides from the chylomicrons produced in the intestines. During times when dietary lipids are not available, the liver produces cholesterol and triglycerides itself.

The liver then packages the cholesterol and triglycerides, along with special proteins, into tiny spheres called lipoproteins. The lipoproteins are released into the circulation, and are delivered to the cells of the body. The cells remove the needed cholesterol and triglycerides from the lipoproteins, as they are needed

What are LDL, HDL, and VLDL?

LDL, HDL and VLDL are the names of the three major varieties of lipoproteins. LDL stands for "low density lipoprotein;" HDL for "high density lipoprotein;" and VLDL for "very low density lipoprotein."

In the bloodstream, "bad" cholesterol is carried in LDL, "good" cholesterol is carried in HDL, and triglycerides are carried in VLDL. Most cholesterol in the blood comes from LDL. Only a small proportion is from HDL cholesterol. Thus, the total cholesterol level in the blood is usually a reflection of the amount of LDL cholesterol.

Why are high cholesterol levels bad?

When LDL cholesterol levels (i.e., the "bad" cholesterol) are too high, the LDL tends to stick the lining of the blood vessels, leading to the stimulation of "atherosclerosis," or hardening of the arteries. Atherosclerotic "plaques" cause narrowing of the arteries, and lead to heart attacks and strokes. Therefore, elevated LDL cholesterol levels (and, since most cholesterol is from LDL, elevated total cholesterol levels) is a major risk factor for heart disease and stroke.

Why is some cholesterol called "good cholesterol"?

Much evidence has now accumulated that increased HDL cholesterol levels are associated with a lower risk of heart disease, and that low HDL cholesterol levels are associated with an increased risk of heart disease. Thus, HDL cholesterol appears to be "good."

Why is HDL cholesterol protective? Nobody knows for sure, but it appears that it's not the cholesterol itself that is good, it's the "vehicle." There is some evidence that the HDL molecule "scours" the walls of blood vessels, and cleans out excess cholesterol. If this is the case, the cholesterol being carried by HDL (that is, the "good" HDL cholesterol) is actually "bad" cholesterol that has just been removed from blood vessels, and is being transported back to the liver for further processing. Apparently, unlike some bad humans, bad cholesterol can be rehabilitated.

Why are triglycerides the Rodney Dangerfield of lipids?

Triglycerides get little respect. Their measurement is part of a standard blood lipid profile, but for the most part doctors don't know what to do when triglyceride levels are modestly elevated.

Why is that? While high triglyceride levels have been associated with heart disease, no study has yet proven that high triglyceride levels are an independent risk factor for heart disease. So doctors don't have the evidence they need to recommend aggressive triglyceride-lowering therapy.

The problem is, patients with elevated triglyceride levels almost invariably have other major risk factors for heart disease (mainly obesity, diabetes, and/or high blood pressure), and so far it has not been possible to sort out whether the triglycerides themselves pose an independent risk.

The most difficult-to-sort-out association is that between triglycerides and HDL cholesterol. It turns out that whenever triglycerides are increased, HDL cholesterol decreases. So is the increased risk seen with high triglycerides due to the triglycerides themselves, or to the associated reduction in "good" cholesterol? So far, nobody can say for sure.

However, recent evidence strongly suggests that an elevated triglyceride level is a significant risk factor for cardiac disease - especially when it is elevated as part of the "metabolic syndrome," sometimes called Syndrome X. (More on the metabolic syndrome below.)

What can cause increased cholesterol?

Elevated cholesterol levels can be caused by several factors, including:

- Increased cholesterol levels can be hereditary.

- A diet high in saturated fat and cholesterol can increase cholesterol levels.

- Being overweight increases LDL cholesterol and decreases HDL cholesterol.

- Being sedentary increases LDL cholesterol and decreases HDL cholesterol.

- Age: cholesterol levels increase with age, beginning at about age 20.

- Gender: females prior to menopause have cholesterol levels lower than men at the same age, but when menopause occurs their LDL cholesterol levels increase, as does the risk of heart disease.

Of these causative factors, heredity, age and gender cannot be controlled. The other causative factors can.

"Secondary" elevation of cholesterol

Some people have elevated cholesterol levels as a result of specific diseases or medical conditions. These people are said to have "secondary lipid disorders." In these individuals, treating the underlying medical problem often results in an improvement in cholesterol levels. Conversely, if the underlying medical condition is "missed," successfully reducing cholesterol is difficult if not impossible. Thus, any patient whose cholesterol levels are elevated should be screened for one of these causes of secondary lipid disorders. These causes are: diabetes, hypothyroidism (low thyroid,) obstructive liver disease, chronic renal (kidney) failure, and drugs (anabolic steroids, progesterone drugs, and corticosteroids.)

Who needs to be treated for elevated cholesterol?

Decisions on when to treat cholesterol abnormalities can be based on two factors: lipid levels (total cholesterol levels, LDL levels, and HDL levels,) and the presence of additional risk factors, as follows.

Desirable lipid levels:

Total cholesterol : For total cholesterol, desirable levels are below 200 mg/dL. Total cholesterol is considered "borderline high risk" at levels between 200 and 239, and "high risk" at levels above 240.

LDL cholesterol: Optimal LDL levels are less than 100 mg/dL. Near optimal levels are between 100 and 129 mg/dL. Levels between 130 and 159 are considered "borderline high risk;" and levels between 160 and 189 are considered "high-risk;" and levels of 190 and above are considered "very high risk."

HDL cholesterol: HDL cholesterol levels below 41 mg/dL are considered low.

Additional risk factors that modify cholesterol goals:

- cigarette smoking

- diabetes

- hypertension (high blood pressure)

- low HDL cholesterol

- family history of premature heart disease

- age greater than 45 in men, or greater than 55 in women

- 10-year risk of heart attack greater than 20% (The 10-year risk is calculated from a formula that takes into account the individual's the lipid levels, and the other "additional risk factors" on this list. Click here for the NIH's on-line version of the 10-year risk calculator.)

Based on these two items (i.e., lipid levels and presence of additional risk factors) treatment is recommended as follows:

Risk Category LDL cholesterol goal LDL level at which lifestyle changes should be initiated LDL level at which drug therapy should be strongly considered

Heart disease already present, or 10-year risk greater than 20%, or presence of diabetes less than 100 100 or greater greater than 129

2 or more "additional risk factors" present (see above) less than 130 greater than 129 greater than 159

0 to 1 "additional risk factors" present (see above) less than 160 greater than 159 greater than 189

What about treatment for high triglycerides?

The new guidelines (May, 2001,) for the first time, recommend treating patients who have elevated triglyceride levels. This recommendation is based on recent analyses strongly suggesting that triglycerides are indeed an independent risk factor for coronary artery disease. The decision to treat is generally based on the triglyceride levels themselves. Normal triglyceride levels are less than 150 mg/dL. Borderline high levels are 150-199 mg/dl. High levels are 200 - 499 mg/dL, and very high triglyceride levels are greater than 500 mg/dL.

For people with borderline or high triglyceride levels, treatment should emphasize weight reduction and exercise. Drugs are recommended for people with very high triglyceride levels. Most people who need treatment for high triglyceride levels have "metabolic syndrome" (see below.)

What is metabolic syndrome (syndrome X)?

"Metabolic syndrome" is a recently-recognized set of features that are often seen together, and that, when present, indicate a significantly increased risk of developing cardiac disease. Metabolic syndrome includes the following 5 features: 1) abdominal obesity (that is, excess fat distributed in the waist - the so-called "spare tire;" for men, a waist size of 40 inches and for women, a waist size of 35 inches); 2) elevated triglyceride levels; 3) low HDL cholesterol levels; 4) hypertension; 5) fasting glucose levels greater than 109 mg/dL. The new cholesterol treatment guidelines now recognize the presence of metabolic syndrome as a significant indicator of high risk of heart disease. Patients with metabolic syndrome need to be aggressively treated for their obesity, hypertension, and their lipid disorders.

What other "special circumstances" deserve attention?

Patients with very high LDL cholesterol levels (greater than 189 mg/dL): These patients often have a genetic form of lipid disorder. Not only do they have a high risk of premature heart disease without aggressive therapy, but also their family members should be screened for elevated cholesterol levels, and those with high cholesterol levels also need to be treated.

Patients with low HDL cholesterol levels (less than 40 mg/dL): The new guidelines now recognize low HDL levels as a strong independent risk factor for coronary artery disease. Many of patients with low HDL will have diabetes or "metabolic syndrome" (see above.) They are often overweight and physically inactive. Other causes of low HDL levels are smoking, very high carbohydrate diets (greater than 60% of calories), and drugs (anabolic steroids, progesterone, and beta blockers). Unfortunately, current drug therapy usually does not markedly increase HDL levels. Treatment for patients with low HDL levels is usually aimed at weight reduction, smoking cessation, exercise, and controlling other risk factors (such as hypertension, LDL cholesterol, and triglycerides.)

How are elevated cholesterol and triglycerides treated?

The primary method of treating elevated cholesterol (and triglycerides) is with diet, exercise, and weight loss. Recommended dietary changes include incorporating low total fat, low saturated fat, low dietary cholesterol, and increased starch and fiber. Physical activity should ideally consist of at least 20 minutes of aerobic exercise three to five times per week, but in fact any increase in physical activity is helpful. Patients who are obese can often significantly reduce their LDL cholesterol and triglyceride levels by losing weight.

Cholesterol levels should be re-measured 3 - 6 months after undertaking these non-pharmaceutical efforts. If lipid levels are still not satisfactory, drug therapy should then be considered.

What drugs are used to treat cholesterol and triglycerides?

These drugs include four major categories:

Bile acid binding resins: Cholestyramine and cholestipol - these drugs prevent the cholesterol in bile (the digestive product secreted from the gallbladder) from being reabsorbed in the gut. Their side effects include intestinal gas and gallstones, which significantly limit their usefulness. The bile acid binding resins can also cause a decrease in absorption of other drugs, and vitamin deficiencies. In addition, these drugs can occasionally cause significant increases in triglyceride levels.

Niacin: Niacin is one of the B vitamins. When used in large doses, it can significantly reduce LDL cholesterol and increase HDL cholesterol, by mechanisms that are poorly understood. Its major side effects include skin flushing and severe itching, along with gastrointestinal disturbances. Nicacin is very effective, but because of side effects tends to be poorly tolerated.

Fibric acid derivatives: Gemfibozil and clofibrate are fibric acid derivatives. The chief benefit of these drugs is that they lower triglycerides. Their ability to reduce LDL cholesterol is much more modest. They can cause gastrointestinal side effects and gallstones.

Statins: Several statin drugs are now on the market, including lovastatin, pravastatin, atorvastatin and simvastatin. These drugs inhibit the liver enzyme HMG-CoA reductase, which significantly reduces the production of cholesterol by the liver. These drugs result in a significant reduction in LDL cholesterol, with a modest decrease in triglycerides, and a modest increase in HDL cholesterol. They tend to be well-tolerated in general, but can cause elevations in liver enzymes (which therefore need to be monitored). They can also cause a muscle disorder which can be severe in rare individuals. The muscle disorder (myopathy) is particularly likely when statins are used in combination with gemfibrozil.

Of these drug choices, the statins are not only more effective than other categories, they also tend to be much better tolerated. Furthermore, evidence is accumulating that the aggressive use of statins can actually arrest the progression of coronary artery disease, and in some circumstances can be used instead of more invasive procedures such as angioplasty.

The treatment of abnormal lipid levels can be summarized as follows: First, dietary changes, weight loss, and exercise should be tried. If that fails to restore adequate lipid levels, then most doctors will try statins. If statins fail, or if they are not tolerated, an agent from another class of the lipid-lowering drugs can be tried.

Summary:

Traditional medicine is often accused of ignoring the prevention of disease, favoring instead to let disease develop, and then reap the rewards of treating the disease with expensive high-tech methods. But "traditional medicine" has expended tremendous efforts to identify ways of preventing atherosclerotic cardiac disease, still the major killer in the United States. The new methods of treating cholesterol, and the accumulating evidence that doing so can prevent and even halt the progression of coronary artery disease, is perhaps the best answer to such accusations.