Introduction
There is certainly no shortage of discussion in the media regarding cholesterol as it pertains to general health and more specifically heart disease. What is missing is a more complete appreciation of just what cholesterol is and how the different lipid components interact in your body and impact on your health. This article will define cholesterol and other blood plasma lipids and the importance of these as indicators of risk for heart disease. In addition we will discuss what the results from your cholesterol test, ordered by your physician, mean. The special circumstances surrounding cholesterol in diabetes, hypothyroidism and ovarian hormone therapy will also be discussed in this, part I of a two part series looking at plasma lipids and heart disease. In Part II, next issue, we will discuss steps you can take to modify your plasma lipid level and profile. In addition we will discuss some of the lipid lowering medications currently available.
WHAT IS CHOLESTEROL?
It is important to state that not all fats, or lipids as they are also termed, are bad. In fact your body needs essential lipids in order to synthesize adrenal and gonadal steroids and bile acids as well as extracellular and intracellular messengers. In addition lipids function as a major form of nutrient storage. You should also be aware that blood lipids consist of more than just cholesterol, which is just one type of simple blood lipid. Fatty acids are a second type of simple blood lipid. In the blood about two thirds of the cholesterol has a fatty acid attached to it forming a third simple lipid (cholesterol ester). Complex lipids include triglycerides (TG) and phospholipids, both of which are built largely from fatty acids. These represent the various forms of lipids that your body uses.
Lipids are hydrophobic which means that they are not very soluble in the blood. Yet the lipids must be transported in the blood from the digestive tract or the liver to the various cell tissues where they are required. This is accomplished by combining the lipid with a protein to form a lipoprotein structure that is soluble in the blood. The lipids are generally present in the core of the complex while the protein makes up the outer shell. It is in this form that the lipids are transported through the blood and enter cells in the body, via lipoprotein receptors at cell surfaces. The synthesis and transport of lipids is a very complex and highly regulated process.
There are several different lipoprotein complexes that we define by their densities. In order of increasing density these are:
- Chylomicrons — These are the largest and least dense plasma lipoproteins and are composed of approximately 1-2% protein and 98-99% lipid (about 85-90% triglyceride). Chylomicrons are formed by the cells that line the small intestine. Triglycerides, phospholipids and cholesterol, either synthesized or absorbed by the intestinal cells, are used to form chylomicrons which are eventually released into the circulatory system. In the blood chylomicron TG are broken down releasing free fatty acids that can be taken up by tissue and stored as TG, used as an energy source or re-circulated to the liver for reuse. The chylomicron remnant that remains is rapidly cleared by the liver.
- Very Low Density Lipoproteins (VLDL) — These are large lipoprotein complexes made up of 10-15% protein and 85-90% lipid (about 55% TG, 20% cholesterol and 15% phospholipid). They are synthesized in the liver and released into the blood. Their production is stimulated by high dietary fat or from adipose tissue (fat) during fasting.
- Intermediate Density Lipoproteins (IDL) — As the name implies these lipoprotein complexes are intermediate in size between VLDL and LDL and are present in low concentrations in the plasma. They are thought to be the precursors of LDL and the products of VLDL metabolism. It is believed they are atherogenic.
- Low Density Lipoproteins (LDL) — These are the major cholesterol carrying lipoproteins in the blood plasma. As much as 70% of the total plasma cholesterol is in LDL. They are approximately 7% lipid and 25% protein. Of the 75% lipid about 35% is cholesterol esters, 10% free cholesterol, 10% triglycerides and 20% phospholipid. LDL are considered atherogenic. High LDL levels are often genetically determined though they will be affected by a diet high in fat because a( increased flux of free fatty acids to the liver and b( the LDL receptors are decreased because the body?s cells already have adequate amounts of cholesterol. This key feedback loop is an interesting concept and appears in many finely regulated metabolic pathways. The general idea is that information downstream in a pathway or process is sent back upstream and this information alters the activity in either a positive or negative way. In this case, the cells only require a certain amount of lipid for their metabolic needs. When that concentration is achieved inside the cell it starts to reduce the LDL receptors on the cell surface, decreasing cellular uptake. If the cells in the body are removing less lipid from the blood an increased plasma lipid concentration results.
- High Density Lipoproteins (HDL) — These are the smallest particles and contain about 50% lipid and 50% protein. Higher levels of HDL are actually beneficial and aid in scavenging and transporting free cholesterol. Having given these descriptions you should appreciate that these lipoproteins are not static. In the blood they are represented by a wide range of densities and are constantly in a state of flux being modified by the addition or removal of lipid and/or protein that can dramatically alter their density, stability and function.
The LDL receptors are the primary mechanism whereby plasma cholesterol levels are controlled. These receptors are present on all cells throughout the body and mediate the uptake of cholesterol rich lipoproteins from the blood. They are important for delivery of needed cholesterol to cells as well as removal of excess cholesterol by the liver. Keep in mind that as much as 70% of the total plasma cholesterol is in LDL, one of the reasons why the LDL receptors are so important in regulating blood cholesterol levels.
ATHEROSCLEROSIS
Atherosclerosis is a disease that leads to partial or complete obstruction of blood vessels. As a result blood flow is reduced and insufficient transport of oxygen and nutrients to affected organs results. When this happens with the heart, angina (chest pain) or even a myocardial infarction (heart attack) can result. The Cholesterol-Diet-Heart Hypothesis states that 1. increased plasma cholesterol concentrations increase the risk of coronary heart disease (CHD), 2. diets high in fat (especially saturated fat) and cholesterol increase levels of plasma cholesterol and 3. lowering plasma cholesterol levels results in a decreased risk of CHD. Evidence supporting this hypothesis has been accumulating for several decades and is now irrefutable. Numerous large scale, multi-centered studies have consistently demonstrated the link between elevated plasma lipoproteins (especially LDL) and coronary heart disease.
HOW DOES ATHEROSCLEROSIS OCCUR?
It is generally accepted that atherosclerosis occurs as a result of two processes. One is the infiltration of the endothelium (the cells lining your blood vessels) by lipoproteins and the second is the formation of a lesion on the endothelium which leads to thickening of the arterial wall. Initially these were two separate models but it now accepted that both of these processes occur and that lipids can be deposited in intact endothelial cells prior to lesion formation. A brief overview of how this occurs is as follows and is depicted in Figure 1.
One of the initial events that starts the atherosclerotic ball rolling is the attachment of circulating monocytes (a type of white blood cell) to the endothelium. Although it is not certain, monocyte attachment may be triggered by LDL in or near the endothelium or by small areas of endothelial injury. The monocytes alter the endothelial surface and eventually enter the subendothelial space. It is worthwhile to note that at this stage there can be thickening of the artery wall with no change in the lumen of the artery. Monocytes are converted to macrophages (a monocyte that has left the circulation and settled in tissue) and there is a continued accumulation of LDL and other lipoproteins in this space. These lipoproteins undergo oxidation and are taken up by the macrophages that take on the appearance of foam cells. These initial steps occur on a very small scale but can lead to the first visible lesion, called a fatty streak. It is thought that fatty streaks come and go depending on the stimuli present in the area of the arterial wall. If the fatty streak progresses rather than regresses it can form a fibrous lesion (plaque) with further thickening of the smooth muscle of the arterial wall. Depending on the severity the lesion can obstruct the blood vessel to varying degrees interfering with normal blood flow. Further maturation of the lesion leads to continued wall thickening and lipid deposition, eventually reducing the elasticity of the artery wall. In this unstable form the lesion can potentially swell or rupture leading to complete blockage of the blood vessel. This is a simplified version of a very complex process. In a high percentage of cases even a relatively minor lesion can rupture and completely block a blood vessel leading to angina or a heart attack. The most important thing to remember from this is that if the atherogenic stimulus (high LDL, VLDL and TG, elevated glucose) is removed the plaque can regress and leaves behind a relatively inert scar that is devoid of lipid. It is never too late to try to reduce the atherosclerotic stimulus as numerous research trials have shown significant plaque regression even in patients with extensive atherosclerosis.
INTERPRETING BLOOD LIPID TEST RESULTS
One of the first things that your physician will consider is your total cholesterol (TC). Quite often this is the only component that is measured since a complete profile, because of cost, is not permitted by MSP if there is no history of vascular disease or if there are few risk factors for vascular disease. The generally accepted upper limit normal for TC is 5.2 mML-1 for men and 5.4 mML-1 for women. These numbers are simply a guide and risk factors must also be considered. A number of risk factors are presented in Table 1. One or more of these risk factors means that your physician should take even moderately elevated cholesterol levels seriously. This is especially true for diabetics as we will discuss later. Other factors such as hypertension,family history and obesity must also be considered.
If your physician feels it is warranted a complete profile can be requested. This can provide additional information when trying to assess your overall status and, once again, interpretation of the results is influenced by the risk factors mentioned above.
Low density lipoproteins (LDL), “bad” cholesterol, has an accepted upper limit normal of 3.4 mML-1 for men and women. This upper limit normal is generous and given the overwhelming evidence implicating elevated LDL in the progression of atherosclerosis, from an epidemiologic point of view a level less than 3.0 mML-1 would be desirable.
Since elevated levels of high density lipoprotein (HDL) are considered beneficial we use a lower limit to assess risk. Any value lower than 0.90 mML-1 for men and 1.0 mML-1 for women would suggest that some action should be taken, involving modifications in diet and exercise.
Total Cholesterol:High Density Lipoprotein (TC:HDL) has been used for some time now as a guide to assess the risk of heart disease associated with a given profile. While the total cholesterol level is a rough indicator the ratio is a more accurate predictor of heart disease risk. The upper limit normal TC:HDL ratio is 4.9 for men and 4.4 for women. Since higher HDL reduces this ratio an individual with a higher total cholesterol but plenty of HDL may have a lower risk profile than someone with acceptable TC (but lower HDL) simply because the higher HDL reduces the ratio.
The accepted upper limit normal for triglycerides is 2.3 mmolesL-1. TG levels are rapidly influenced by diet and can be quite variable compared to other components of your blood lipid profile. High amounts of sugar and alcohol in the diet in addition to fats can increase TG levels.
In summary the easiest way to remember these concepts is that higher high density and lower low density lipoproteins is the healthier profile. Triglycerides should also be kept low. Keeping the atherogenic lipoproteins low makes sense now that you appreciate that these lipoproteins actually penetrate your artery walls and accelerate progression of atherosclerosis as outlined in the previous discussion.
SPECIAL CIRCUMSTANCES FOR PLASMA LIPIDS
GENETICS
Genetics plays a role in many different types of dyslipidemia and cannot be fully discussed here for lack of space. Briefly, however, genetic mutations can alter metabolic pathways and receptor recognition processes and result in a variety of lipid disorders. Some are as simple as moderately elevated LDL while others are far more complex, potentially lethal and affect a whole array of physiological processes, not simply lipid metabolism. A complete lipid profile and detailed family history can sometimes shed light on whether there is a genetic basis for dyslipidemia. Generally speaking the lipids will be dramatically elevated (two or more times the upper limit normal for total cholesterol and/or LDL) in cases with a genetic basis. Your physician may suggest you see a specialist if this is the case.
OVARIAN HORMONE THERAPY
Estrogen Therapy
Estrogen therapy, either conjugated equine estrogen (premarin) or 17b-estradiol, has been shown to lower the plasma levels of LDL , by as much as 15%, likely via increasing the clearance from the circulation. HDL cholesterol is increased by estrogen therapy by more than 15% which, when combined with lower LDL can significantly improve the TC:HDL ratio discussed previously. As a result it has been felt that the net effect of estrogen therapy is a significant reduction in the risk for heart disease. The only well designed clinical trial to formally test this hypothesis, however, failed to show any reduction in heart disease for the women who were treated with estrogen. The one drawback is that estrogen therapy often results in increased triglycerides and evidence to date suggests that this is dose related. Generally speaking, however, the TG levels stay within the normal range.
Estrogen Therapy
Very little is known about the effects of progesterone alone on the plasma lipids. What is known is teased out of studies looking at estrogen combined with either medroxy-progesterone acetate (provera, a progesterone analogue) or micronized progesterone (natural progesterone). In these cases progesterone’s effects are assessed on the basis of impact on the benefits of estrogen therapy. In cases of combined therapy natural progesterone is shown to maintain the benefits of estrogen while provera actually reduces the beneficial increase in HDL caused by estrogen. Neither form of progesterone alters the increase seen in TG levels. This would suggest that when combined therapy is administered the more expensive natural progesterone should be chosen rather than provera.
THYROID FUNCTION
Changes in thyroid function can have dramatic effects on the levels of the plasma lipids. Anyone with significantly elevated blood lipids should be tested for hypothyroidism, a simple test that measures the level of your thyroid stimulating hormone (TSH). An under-active thyroid typically results in elevated LDL levels but may also include elevated TG. HDL usually remains unchanged or slightly lowered. In cases where hypothyroid symptoms are not yet present but metabolic abnormalities are, hypercholesterolemia will respond to thyroid hormone treatment. The elevation of LDL in cases of hypothyroidism once again represents an increased risk for artherosclerosis.
DIABETES
Diabetes mellitus has profound effects on plasma lipid metabolism. Elevated triglycerides are found in one third of all diabetics. In addition diabetics often have high levels of LDL and IDL (both atherogenic components) and low plasma HDL. This predisposes then to premature coronary heart disease, the leading cause of death in diabetics. For these reasons hyperlipidemia in diabetics is often treated more aggressively than in the general population. For example, acceptable upper limits for levels of LDL and TG are more likely in the range of 2.7 and 1.8 mmolesL-1, respectively. Especially for type II (late-onset) diabetes improving glycemic control and modifying diet are often not enough to keep the lipid levels acceptable and for this reason cholesterol lowering medications are becoming an essential component of diabetic lipid therapy.
Summary
Hopefully you now have a basic understanding of cholesterol as one of several forms of lipids in your blood and the role these lipids play in the progression of atherosclerosis. You can now appreciate the significance of the lipid results that you and your doctor discuss and their potential impact on your health. Next issue we will discuss some of the things you can do to improve your lipid profile through lifestyle modifications and, if necessary, through the use of lipid lowering medications.
Eric Norman is a research scientist investigating heart disease in post-menopausal women using ovarian hormone therapy and in type II diabetics.
References
- Manual of Lipid Disorders. Reducing the risk for coronary heart disease. Antonio M. Gotta Jr.; Henry J. Pownall. Second Edition. Publisher: Williams and Wilkins. 1999.
- Disorders of Lipid Metabolism. Chapter 23.Mahley,R.W.; Weisgraber,K.H.; Farese,R.V. in Williams Textbook of Endocrinology,Ninth Edition. Editors: Wilson,J.D.; Foster, D.W.; Kronenberg,H.M.; Larsen,P.R.. Publisher: W.B. Saunders Company. 1998.
- Effects of Estrogen or Estrogen/Progestin Regimens on Heart Disease Risk Factors in Postmenopausal Women. PEPI Trial. J of Amer Med Assoc. Vol. 273:199-208. 1995.