All About Cholesterol

What is cholesterol?

Cholesterol is a chemical compound that is naturally produced by the body and is a combination of lipid (fat) and steroid. Cholesterol is a building block for cell membranes and for hormones like estrogen and testosterone. About 80% of the body's cholesterol is produced by the liver, while the rest comes from our diet. . Dietary cholesterol comes mainly from meat, poultry, fish, and dairy products. Organ meats, such as liver, are especially high in cholesterol content, while foods of plant origin contain no cholesterol. After a meal, dietary cholesterol is absorbed from the intestine and stored in the liver. The liver is able to regulate cholesterol levels in the blood stream and can secrete cholesterol if it is needed by the body.

What are LDL and HDL cholesterol?

LDL cholesterol is called "bad" cholesterol, because elevated levels of LDL cholesterol are associated with an increased risk of coronary heart disease. LDL lipoprotein deposits cholesterol on the artery walls, causing the formation of a hard, thick substance called cholesterol plaque. Over time, cholesterol plaque causes thickening of the artery walls and narrowing of the arteries, a process called atherosclerosis.

HDL cholesterol is called the "good cholesterol" because HDL cholesterol particles prevent atherosclerosis by extracting cholesterol from the artery walls and disposing of them through the liver. Thus, high levels of LDL cholesterol and low levels of HDL cholesterol (high LDL/HDL ratios) are risk factors for atherosclerosis, while low levels of LDL cholesterol and high level of HDL cholesterol (low LDL/HDL ratios) are desirable.

Total cholesterol is the sum of LDL (low density) cholesterol, HDL (high density) cholesterol, VLDL (very low density) cholesterol, and IDL (intermediate density) cholesterol.

What determines the level of LDL cholesterol in the blood?

The liver manufactures and secretes LDL cholesterol into the blood. It also removes LDL cholesterol from the blood by active LDL receptors on the surface of its cells. A decrease number of liver cell LDL receptors is associated with high LDL cholesterol blood levels.

Both heredity and diet have a significant influence on a person's LDL, HDL and total cholesterol levels. For example, familial hypercholesterolemia (hyper= more + cholesterol + emia= in blood) is a common inherited disorder whose victims have a diminished number or nonexistent LDL receptors on the surface of liver cells. People with this disorder also tend to develop atherosclerosis and heart attacks during early adulthood.

Diets that are high in saturated fats and cholesterol raise the levels of LDL cholesterol in the blood. Fats are classified as saturated or unsaturated (according to their chemical structure). Saturated fats are derived primarily from meat and dairy products and can raise blood cholesterol levels. Some vegetable oils made from coconut, palm, and cocoa are also high in saturated fats.

Does lowering LDL cholesterol prevent heart attacks and strokes?

Lowering LDL cholesterol is currently one of the primary public health initiatives preventing atherosclerosis and heart attacks. The benefits of lowering LDL cholesterol include:

• reducing or stopping the formation of new cholesterol plaques on the artery walls;
  
• reducing existing cholesterol plaques on the artery walls and widening the arteries;
  
• preventing the rupture of cholesterol plaques, which initiates blood clot formation and blocks blood vessels;
  
• decreasing the risk of heart attacks; and
  
• decreasing the risk of strokes.

The same measures that decrease narrowing in coronary arteries also may benefit the carotid and cerebral arteries (arteries that deliver blood to the brain).

How can LDL cholesterol levels be lowered?

Therapeutic lifestyle changes to lower cholesterol

Therapeutic lifestyle changes to lower LDL cholesterol involves losing excess weight, exercising regularly, and following a diet that is low in saturated fat and cholesterol.

Medications to lower cholesterol

Medications are prescribed when lifestyle changes cannot reduce the LDL cholesterol to desired levels. The most effective and widely used medications to lower LDL cholesterol are called statins. Most of the large controlled trials that demonstrated the heart attackand stroke prevention benefits of lowering LDL cholesterol used one of the statins. Other medications used in lowering LDL cholesterol and in altering cholesterol profiles include nicotinic acid (niacin), fibrates such as gemfibrozil (Lopid), resins such ascholestyramine (Questran), and ezetimibe, Zetia.

What are "normal" cholesterol blood levels?

There are no established “normal” blood levels for total and LDL cholesterol. In most other blood tests in medicine, normal ranges can be set by taking measurements from large number of healthy subjects. The normal range of LDL cholesterol among “healthy” adults (adults with no known coronary heart disease) in the United States may be too high. The atherosclerosis process may be quietly progressing in many healthy children and adults with average LDL cholesterol blood levels, putting them at risk of developing coronary heart diseases in the future.

What are the current NCEP cholesterol treatment guidelines?

Controlling blood cholesterol levels may decrease the risk of heart attack and stroke. The National Institute of Health, the American Heart Association and the American College of Cardiology publish guidelines to help physicians and patients with this risk reduction. The most recent consensus in 2004 recommended the following: (the expected release date for the new guidelines is the summer of 2010):

1. Consider more intensive LDL cholesterol-lowering for people at very high, high, and moderately high risk for a heart attack. For example, for patients with a very high risk of heart attacks, the LDL cholesterol treatment goal remains at <100mg/dl, but the report advised doctors to consider the option of lowering the LDL cholesterol (usually using a statin plus lifestyle changes) to <70 mg/dl.
   
2. Initiate therapeutic lifestyle changesto modify lifestyle-related risk factors (obesity, physical inactivity, metabolic syndrome, high blood triglyceride levels and low HDL cholesterol levels). Lifestyle changes have the potential to reduce heart attack and stroke risks through several mechanisms beyond the lowering of LDL cholesterol.
   
3. When LDL-lowering medication is used for very high, high or moderately high risk patients, the report advises that the intensity of LDL-lowering drug therapy be sufficient to achieve at least a 30 to 40 percent reduction in LDL cholesterol levels.
   
4. When a very high or high risk patient also has high blood triglyceride or low HDL cholesterol levels, doctors may consider combining nicotinic acid or a fibrate with a statin. Nicotinic acid and fibrates are more effective than statins in loweringtriglycerides and increasing HDL.
   
5. Age should not be a consideration since older persons also benefit from lowering LDL cholesterol. It is never too late or the patient too old to begin lifestyle changes and medications to lower LDL cholesterol. A word of caution is in order. Elderly patients are more likely to have liver and kidney dysfunction, and are also more likely to be on multiple medications some of which may interfere with the breakdown of cholesterol-lowering drugs such as statins. Thus lower dosing may be necessary to avoid adverse side effects.

The 2004 NCEP treatment goals according to risk categories

Risk category	LDL goal	More intense LDL goal option	Initiate TLC if LDL is:	Consider drugs + TLC if LDL is:
High risk	<100 mg/dl		>100 mg/dl	>100 mg/dl
Very high risk	<100 mg/dl	<70 mg/dl	>100 mg/dl	>100 mg/dl
Moderately high risk (10 yr. risk 10%-20%)	<130 mg/dl	<100 mg/dl	>130 mg/dl	>130mg/dl, consider drug option if LDL is 100-129 mg/dl
Moderate risk (10 yr. risk <10%)	<130 mg/dl		>130 mg/dl	>160 mg/dl
Lower risk	<160 mg/dl		>160 mg/dl	>190 mg/dl, consider drug optional if LDL is 160-189 mg/dl

• High risk patients are those who already have coronary heart disease (such as a prior heart attack), diabetes mellitus, abdominal aortic aneurysm, or those who already have atherosclerosis of the arteries to the brain and extremities (such as patients with strokes, TIA's (mini-strokes), and peripheral vascular diseases). High risk patients also include those with 2 or more risk factors (for example, smoking, hypertension, or a family history of early heart attacks) that places them at a greater than 20 percent chance of having a heart attack within 10 years. (A person's chance of having a heart attack can be calculated by using the Framingham Heart Study Score Sheets, at http://nhlbi.nih.gov/about/framingham/riskabs.htm).
  
• Very high -risk patients are those who have coronary heart disease in addition to having either multiple risk factors (especially diabetes), or severe and poorly controlled risk factors (such as continued smoking), or metabolic syndrome (a constellation of risk factors associated with obesity, including high triglycerides and low HDL). Patients hospitalized for acute coronary syndromes are also at very high risk.
  
• Moderately high risk patients are those who have neither coronary heart disease nor diabetes mellitus, but have multiple (2 or more) risk factors for coronary heart disease that put them at a 10 to 20 percent risk of heart attack within 10 years. (Use the Framingham Heart Study Score Sheets, at http://nhlbi.nih.gov/about/framingham/riskabs,htm to calculate the 10 year risk.)
  
• Moderate risk patients are those who have neither CHD nor diabetes mellitus, but have 2 or more risk factors for coronary heart disease that put them at a <10% risk of heart attack within 10 years.
  
• Lower risk patients are those with 0 to 1 risk factor for coronary heart disease.

Why is HDL the good cholesterol?

HDL is the good cholesterol because it protects the arteries from the atherosclerosis process. HDL cholesterol extracts cholesterol particles from the artery walls and transports them to the liver to be disposed through the bile. It also interferes with the accumulation of LDL cholesterol particles in the artery walls.

The risk of atherosclerosis and heart attacks is strongly related to HDL cholesterol levels. Low levels of HDL cholesterol are linked to a higher risk, whereas high HDL cholesterol levels are associated with a lower risk.

Very low and very high HDL cholesterol levels can run in families. Families with low HDL cholesterol levels have a higher incidence of heart attacks than the general population, while families with high HDL cholesterol levels tend to live longer with a lower frequency of heart attacks.

Like LDL cholesterol, life style factors and other conditions influence HDL cholesterol levels. HDL cholesterol levels tend to be lower in persons who smoke cigarettes, are overweight and inactive, and in people with type II diabetes mellitus.

HDL cholesterol is higher in people who are lean, exercise regularly, and do not smoke cigarettes. Estrogen increases a person's HDL cholesterol, which explains why women generally have higher HDL levels than men do.

For individuals with low HDL cholesterol levels, a high total or LDL cholesterol blood level further increases the incidence of atherosclerosis and heart attacks. Therefore, the combination of high levels of total and LDL cholesterol with low levels of HDL cholesterol is undesirable whereas the combination of low levels of total and LDL cholesterol and high levels of HDL cholesterol is favorable.

What are LDL/HDL and total/HDL ratios?

The total cholesterol to HDL cholesterol ratio (total chol/HDL) is a number that is helpful in estimating the risk of developing atherosclerosis. The number is obtained by dividing total cholesterol by HDL cholesterol. (High ratios indicate a higher risk of heart attacks, whereas low ratios indicate a lower risk).

High total cholesterol and low HDL cholesterol increases the ratio and is undesirable. Conversely, high HDL cholesterol and low total cholesterol lowers the ratio and is desirable. An average ratio would be about 4.5. Ideally, one should strive for ratios of 2 or 3 (less than 4).

What are the treatment guidelines for low HDL cholesterol?

In clinical trials involving lowering LDL cholesterol, scientists also studied the effect of HDL cholesterol on atherosclerosis and heart attack rates. They found that even small increases in HDL cholesterol could reduce the frequency of heart attacks. For each 1 mg/dl increase in HDL cholesterol, there is a 2% to 4% reduction in the risk of coronary heart disease. Although there are no formal NCEP (please see discussion above) target treatment levels of HDL cholesterol, an HDL level of <40 mg/dl is considered undesirable and measures should be taken to increase it.

How can levels of HDL cholesterol be raised?

The first step in increasing HDL cholesterol levels (and decreasing LDL/HDL ratios) is therapeutic life style changes. When these modifications are insufficient, medications are used. In prescribing medications or medication combinations, doctors have to take into account medication side effects as well as the presence or absence of other abnormalities in cholesterol profiles.

Regular aerobic exercise, loss of excess weight (fat), and cessation of smoking cigarettes will increase HDL cholesterol levels. Regular alcohol consumption (such as one drink a day) will also raise HDL cholesterol. Because of other adverse health consequences of excessive alcohol consumption, alcohol is not recommended as a standard treatment for low HDL cholesterol.

Medications that are effective in increasing HDL cholesterol include nicotinic acid (niacin), gemfibrozil (Lopid), estrogen, and to a much lesser extent, the statin drugs (discussed below). A newer medicine, fenofibrate (Tricor) has shown much promise in selectively increasing HDL levels and reducing serum triglycerides.

What are triglycerides and VLDL?

Triglyceride is a fatty substance that is composed of three fatty acids. Like cholesterol, triglyceride in the blood either comes from the diet or the liver. Also, like cholesterol, triglyceride cannot dissolve and circulate in the blood without combining with a lipoprotein.

The liver removes triglyceride from the blood, and it synthesizes and packages triglyceride into VLDL (very low-density lipoprotein) particles and releases them back into the blood circulation.

Do high triglyceride levels cause atherosclerosis?

Whether elevated triglyceride levels in the blood lead to atherosclerosis and heart attacks is controversial. While abnormally high triglyceride levels may be a risk factor for atherosclerosis, it is difficult to conclusively prove that elevated triglyceride by itself can cause atherosclerosis. Elevated triglyceride levels are often associated with other conditions that increase the risk of atherosclerosis, including obesity, low levels of HDL- cholesterol, insulin resistance and poorly controlled diabetes mellitus, and small, dense LDL cholesterol particles.

What are the causes of elevated triglyceride levels?

High triglyceride levels may be genetic or they may be acquired. Examples of inherited hypertriglyceridemia (hyper=high + triglyceride + emia= in blood) disorders include mixed hypertriglyceridemia, familial hypertriglyceridemia, and familial dysbetalipoproteinemia.

Hypertriglyceridemia can often be caused by non-genetic factors such as obesity, excessive alcohol intake, diabetes mellitus, kidney disease, and estrogen- containing medications such as birth control pills.

How can elevated blood triglyceride levels be treated?

Diet is the first step in treating hypertriglyceridemia. A low fat diet, regular aerobic exercise, loss of excess weight, reduction of alcohol consumption, and stopping cigarette smoking may be enough to control triglyceride levels in the blood. In patients with diabetes mellitus, meticulous control of elevated blood glucose is also important.

When medications are necessary, fibrates (such as Lopid), nicotinic acid, and statin medications can be used. Lopid not only decreases triglyceride levels but also increases HDL cholesterol levels and LDL cholesterol particle size. Nicotinic acid lowers triglyceride levels, increases HDL cholesterol levels and the size of LDL cholesterol particles.

The statin drugs have been found effective in decreasing triglyceride as well as LDL cholesterol levels and, to a lesser extent, in elevating HDL cholesterol levels.

What medications are available to lower cholesterol, lipids, and triglycerides?

Lipid altering medications are used in lowering blood levels of undesirable lipids such as LDL cholesterol and triglycerides and increasing blood levels of desirable lipids such as HDL cholesterol. Several classes of medications are available in the United States, including HMG CoA reductase inhibitors (statins), nicotinic acid, fibric acid derivatives, and medications that decrease intestinal cholesterol absorption (bile acid sequestrants and cholesterol absorption inhibitors). Some of these medications are primarily useful in lowering LDL cholesterol, others in lowering triglycerides, and some in elevating HDL cholesterol. Medications also can be combined to more aggressively lower LDL, as well as in lowering LDL and increasing HDL at the same time.

Lipid altering medications commonly used in the United States

Medication class	Medication examples	Effects on blood lipids
Statins	pravastatin sodium (Pravachol),lovastatin (Mevacor), atorvastatin calcium (Lipitor), fluvastatin sodium (Lescol),rosuvastatin (Crestor), simvastatin(Zocor)	Most effective in lowering LDL, mildly effective in increasing HDL, mildly effective in lowering triglycerides
Nicotinic acid(Niacin)	Niacin, Niaspan, Slo-Niacin	Most effective in increasing HDL, effective in lowering triglycerides, mildly to modestly effective in lowering LDL
Fibric acid	Lopid, Tricor	Most effective in lowering triglycerides, effective in increasing HDL, minimally effective in lowering LDL
Bile acid sequestrants	cholestyramine (Questran), colestipol(Colestid), and colesevelam (Welchol)	Mildly to modestly effective in lowering LDL, no effect on HDL and triglycerides
Cholesterol absorption inhibitors	ezetimibe (Zetia)	Mildly to modestly effective in lowering LDL, no effect on HDL and triglycerides
Combining nicotinic acid with statin	lovastatin+niaspan (Advicor)	Effective in lowering LDL and triglycerides and increasing HDL

Is lowering LDL cholesterol enough?

LDL cholesterol reduction is only half of the battle against atherosclerosis. Individuals who have normal or only mildly elevated LDL cholesterol levels can still develop atherosclerosis and heart attacks even in the absence of other risk factors such as cigarette smoking, high blood pressure, and diabetes mellitus. It is clear that while lowering LDL cholesterol below NCEP target levels is an important step, there are other factors involved in heart disease that are yet to be discovered.

REFERENCES:

Fauci, Anthony S., et al. Harrison's Principles of Internal Medicine. 17th ed. United States: McGraw-Hill Professional, 2008.

National Heart Lung and Blood Institute, National Institutes of Health. "Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)."