Mercy Family Practice SC
Table of Contents
The name Cholesterol comes from the Greek “Chole” meaning bile and “Stereos” meaning solid. It was first identified in 1769 by a French physician named Francois Poulletier as a solid component of gallstones. Cholesterol is a complex organic molecule (C27H45OH) that is mostly manufactured in the liver. It is used as a precursor for hormones and the cell wall. I once had a professor say that if it were not for cholesterol in your body, each of us we would be a puddle of salt water and bones lying on the floor.
The chemical structure of cholesterol is often depicted as a stick diagram. By convention, each vertex of the diagram represents a carbon atom which has four bonds used to link to its neighboring atoms. Two hydrogen atoms are assumed to occupy each carbon atom unless specified by a carbon to carbon double bond, in which case there is only one hydrogen atom. Other atoms are depicted by symbols: H for hydrogen, which has one bond, and Oxygen, which has two bonds. The second most common depiction is a space-occupying diagram. Each atom has electrons that occupy a “cloud” around the nucleus of the atom that interacts with surrounding atoms which forms its characteristic shape.
Figure 1, Cholesterol Molecule
Looking at the stick diagram, the molecule can be divided into three components: the hydroxy group (HO), the ringed structure (red space), and the hydro-carbon tail. The hydroxyl group is an hydrophilic component, which means it is used to link to the water side. The four-ringed central component is the steroid component. The hydro-carbon tail is the lipophilic component which means it is used to link to the lipid side.
Since the hydrophilic side is a combination of an alcohol (HO) and a steroid, cholesterol is considered a sterol. Once the hydrophilic component links to an acid, it forms an ester called a cholesterol ester. This is how the body transports cholesterol in the blood stream.
Figure 2, Ester Compound using Cholesterol
Lipids are fat compounds. The major constituents in the human body are cholesterol and triglycerides. We consume both in our diets. One problem is that lipids do not mix with water. Just fry a slice of bologna on a frying pan, and drip the fat into a glass of water. You will find the fat floats to the surface or sticks to the side of the glass. If you add soap to the water, and stir the glass, you will change it into a turbid fluid, which is called an emulsification. The soap is made of two layers: one that is lipid soluble, and one that is water soluble. Soap forms the interface between these two substances.
The body does the same with the lipids we consume. The molecule that serves as the interface is called a lipoprotein, examples of which are chylomicrons, low density lipoproteins (LDL), and high density lipoproteins (HDL). The major lipoproteins are depicted in the following table:
Table 1, Lipoprotein Characteristic
When you eat a fatty meal, pancreatic enzymes break the lipids into cholesterol and free fatty acids. These are absorbed in the small intestine. The Cholesterol is esterified into cholesterol ester and the fatty acids are linked into three long chains called a triglyceride. These lipid components are packaged into apo B48, which gains components from HDL to form chylomicrons. As the chylomicrons circulate in the blood stream, the triglycerides are removed and stored into fat cells taken up by muscle for energy. The Chylomicron becomes smaller, is called a chylomicron remnant, and is rich in cholesterol esters. The chylomicron remnants are then removed in the liver. The chylomicron remnants still in circulation are small enough to enter through the lining of the artery wall, called the endothelium, where they do not belong. White cells, called Macrophages, then try to remove these chylomicron remnants. Early on, the macrophages swell and are full of lipid particles, which makes them look like foam. These are referred to as foam cells. If there is too much volume, the macrophages die and form a paste like debris that is known as an atheroma. Over time, as the macrophages die, they are calcified, and become hard. This process is known as atherosclerosis.
Once cholesterol and triglycerides end up in the liver, they are metabolized with Apo B first to very low density lipoprotiens (VLDL), then to intermediate density lipoprotiens (IDL) and then to low density lipoproteins (LDL). Inside the liver, cholesterol can be used to make bile acids, and steroid hormones such as testosterone or estrogen. Both cholesterol and triglycerides can be used to manufacture cell membranes.
LDL is the main lipoprotein that circulates in the blood stream to deliver cholesterol and triglycerides to cells. There is a gradient of density from low to high as you move from VLDL to IDL to LDL. As with chylomicron remnants, LDL is smaller and dense and tends to “leak” into endothelial cells and may cause the same atheroma as described above. Furthermore, chylomicrons only remain in the circulation for a few hours; however, LDL remains in the circulation for days. LDL has a plasma half-life of 2 to 5 days, which means in approximately 3.5 days, if no more LDL is added, that there remains half the original concentration. In four half lives, or approximately 14 days, only 12.5% remains. This means there is more opportunity to cause atherosclerosis. This is why LDL has been coined the “bad cholesterol.”
HDL is the lipoprotein that returns excess cholesterol from the peripheral cells. It is the main “scavenger” protein, and has been coined the “good cholesterol.” In addition, HDL can pick up excess cholesterol in atheromas of endothelial tissue and return it to the liver. Individuals with high levels of HDL have a reverse association with atherosclerosis. In other words, the higher the HDL level, the lower the atherosclerosis.
Association of Coronary Artery Disease with Elevated Cholesterol
During the Korean War, young men were dying in the field. One of the first observational studies looked at the aortas of these men who were as young as 18. They discovered white streaks in the aorta, which is the largest artery in the body, and comes off the heart to circulate blood to the entire body. When they analyzed these white streaks, they found them to be atheromas. In the 1950s, it was a mystery why such young individuals already had the early stages of atherosclerosis.
Only after decades of study did it become evident that the main cause of cardiovascular disease from atherosclerosis was due in large part to elevated levels of cholesterol in the blood. In 1955 a landmark study was conducted called the Framingham Study, named after a suburb west of Boston, MA. This was a randomized, controlled trial (RCT) that studied 4,374 men and women over 18 years. They discovered a correlation between cholesterol levels and death due to coronary artery disease (CAD). For every 10% rise in cholesterol there was a 9% rise in mortality (p < 0.01).
In 1984 the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) was conducted which was another RCT. They studied 3,806 patients with elevated cholesterol free of cardiac disease, and prescribed Cholestyramine to those patients with elevated cholesterol. They showed a reduction in death due to heart attack by 1.6% in those treated with the medication compared to those given a placebo.
After over a half-decade of very well designed studies, it has been shown that LDL highly correlates with cardiac death, and that treatment to lower LDL is associated with a reduction in cardiac death. The studies performed in the last decade are mostly done in patients with well established CAD, and the question raised is how low should cholesterol be reduced and is prolonged exposure to cholesterol lowering agents have a deleterious effect on the liver, or cause cancer. In summary, those at high risk should have their LDL levels lowered to below 70 mg%, and only about 1% of patients have to stop their medication due to adverse events. To date, there is no association of treatment with cancer.
Table 2, Cholesterol Studies Conducted from 1955 through 2011
Diagnosis of Dyslipidemia
Elevated cholesterol may be referred to as dyslipidemia. The list of studies from the previous secretion has given physicians a fairly good understanding regarding what cut off levels to use when deciding to treat dyslipidemia. Because there are so many studies involving a variety of populations, panels of experts convene to give guidelines for physicians and the lay public to follow. One such panel is the National Cholesterol Education, which first convened in 1997, and last met within the last decade. They have published the following values (taken from their web site):
Table 3, NCEP Guidelines for the Public
These levels are taken in the fasting state, which means the patient cannot eat food or liquids with fat or calories for 8 to 12 hours. When asked, before the lab test the patient may only consume water, unsweetened tea or black coffee. In most laboratories, direct measurements are made of total cholesterol, triglycerides and HDL. LDL is calculated by using the formula:
TC = TG/5 + HDL + LDL
where TC= total cholesterol, TG= triglycerides, HDL= high-density lipoproteins, and LDL= low density lipoproteins.
Unfortunately, this equation fails as triglyceride rises above 400 mg%, so that either a direct LDL measurement needs to be done, or a ratio of TC/HDL needs to be calculated.
Most Americans are overweight and have cholesterol levels that are elevated. Whether or not to treat comes down to making an assessment of the patient's 10-year risk for CAD. Fortunately, the NECP has a web-based calculator (http://www.nhlbi.nih.gov/guidelines/cholesterol) that can be used to make this assessment based on the main characteristics that lead to heart disease: age, gender, lipid values, smoking history, and high blood pressure. Those with a risk > 20% should be on cholesterol lower medication, and those < 20% should maintain life-style changes (see below). Patients with established medical histories of Diabetes Mellitus, CAD, or other vascular diseases are automatically in the high-risk category and should be on treatment.
Patients with two or more risk factors with borderline elevated levels should consider treatment as well. Risk factors for CAD include the following:
Dietary Treatment for Elevated Cholesterol
The first observations were made years ago that certain cultures such as the Inuit Indians of North America and many Mediterranean countries had lower rates of CAD than did those of other nationalities such as the Americans and Northern Europeans.
In 2008, Katcher published an article entitled “Lifestyle Approaches and Dietary Strategies to Lower LDL-Cholesterol and Triglycerides and Raise HDL-Cholesterol.” She does a meticulous job of documenting the studies over the years that support a dietary approach to lowering cholesterol. She compares the diets of seven countries and correlates the amount of trans-saturated and saturated fats in the diet with the level of elevation of LDL in the population. In particular, diets that rely on high concentrations of egg yolk demonstrate increased levels of LDL cholesterol. Katcher also demonstrates that foods high in Omega-3 fatty acids and modest amounts of alcohol intake have the opposite effect. Her findings support the Mediterranean diet as a healthy that relies on high levels of Omega-3 fatty acids from olive oil and fish.
Figure 3, Results of several randomized studies showing the correlation between dietary intake of fat and LDL:HDL ratio
Table 4, Saturated Fat (SF) Content of Certain Foods
A fatty acid is a long hydro-carbon chain with an acid (CO-OH) configuration on it end. There are no double bonds along the chain. Stearic acid is a saturated fat found in animal fats. A trans-fatty acid refers to a fatty acid that has one (mono-unsaturate) or more (poly-unsaturate) double bonds. Two examples of mono-saturated fats are Elaidic acid and Oleic acid. Elaidic acid is found in vegetable oil and Oleic acid is the main ingredient of olive oil. For some reason, the bent nature of Oleic acid makes it favorable over Elaidic acid.
Figure 4, Saturated vs Mono-saturated Fats
As you include more double bonds, there are more places for the body chemistry to link to thereby making it easier for the body to metabolize and eliminate the chemical compound. These are called poly-unsaturated fats. The poly-unsaturated compounds that have received the most attention are thosed referred to as Omega-3 fatty acids. The three most important are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).
Figure 5, Omega-3 Fatty Acids
Katcher sites several studies that have demonstrated that as Omega-3 fatty acid consumption increases, triglycerides levels drop and HDL levels rise. Specifically, she sites the Diet and Reinfarction Trial (DART) and the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione Study. In the DART study, diets high in Omega-3 fatty acids are associated with a 29% reduction in 2-year all-cause mortality in those patients who recovered from a heart attack.
ALA is an essential fatty acid because it cannot be produced by humans. Therefore, it must be consumed in the diet. Major sources of ALA are vegetable oils, nuts, and seeds, particularly flaxseed. Other sources of ALA include canola, soybean oils, and walnuts. EPA and DHA can be found in fatty fish, fish oil, fortified foods, and more recently, DHA-rich algal oil supplements. The Institute of Medicine recommends between 0.6% and 10% of total calories come from Omega-3 fatty acids. You can obtain this level by either consuming two servings of fatty fish (8 oz total) per week or by consuming 1 to 2 teaspoons per day of flaxseed oil.
Figure 6, Omega-3 Fatty Acids vs Triglyceride Levels
Figure 7, Composition of Fats used for Cooking
It is logical to substitute foods high in cholesterol with those food that do not contain cholesterol, such as fruits, vegetables, beans, grains, nuts, and seeds. Furthermore, there are foods that actually reduce LDL cholesterol such as soluble fiber and phytosterols.
Fiber is the nondigestible carbohydrates found in plants. It is believed that fiber reduces LDL cholesterol by reducing cholesterol absorption. It is recommended to consume 10 to 25 grams per day of fiber in any of the following forms: psyllium husk, oats or barley which may reduce LDL cholesterol by 5%.
Stanols & Sterols
Phytosterols (sterols & stanols) are plant sources that share a similar chemical structure to cholesterol (see figure 4). Phytosterols are present in nuts, seeds and vegetable oils, as well as orange juice, yogurt, margarin spreads, salad dressings, breads, cereals, milk and granola bars. They are also produced in soft-gel pills. The most common form of phytosterols are beta-sitosterol, ampesterol, and stigmasterol. A meta-analysis shows that 2 grams per day of phytosterols reduces LDL cholesterol by 10%. Most americans comsume less than 400 mg per day. The mechanism of action is the simple displacement of cholesterol from the lipoprotein carrier molecule.
Figure 8, Phytosterols
As phytosterol consumption increases, there is a decrease in beta-carotene. Although it may not be clinically relavant, it has been recommended that people consuming high levels of phytosterols should also consume foods high in carotenoids, such as carrots, pumpkin, apricots, spinach and broccoli.
Soy protein accounts for 36% of the soybean. It contains all of the essential amino acids requied of the body. Metabolism of soy protein in the intestines into isoflavones act as phytoestrogens (plant forms of estrogen). Only 30-50% of the population are capable of this phytoestrogen conversion.
The cholesterol lowering ability of soy is less significant that that of fiber and phytosterols (see above). Meta-analysis from the 1995 shows that a diet consuming 47 grams per day lowered LDL cholesterol from 9.3 to 12.9%. Another meta-analysis in 2005 shows that a diet consuming 80 gm per day lowered LDL cholesterol by 3.8 to 7.3%. The mechanism is less clear, but research suggests that soy protein down-regulates the activity of sterol regulatory element binding protein (SREBP-1) which reduces production of triglycerides and LDL cholesterol from the liver.
Alcohol consumption lowers cardiovascular risk in three ways: (1) lowers fibrinogen levels, (2) increases plasminogen activator, thereby decreasing blood clot formation, and (3) increases HDL cholesterol. The American Heart Association (AHA) defines a drink as 12 ounces of beer, 4 ounces of wine, 1.5 ounces of 80-proof spirits, or 1 ounce of 100-proof spirits. Red wine is considered the more favorable alcoholic drink to consume. It should be stressed that consumption of more than two alcoholic drinks per day increases the risk for liver cirrhosis, alcoholism, obesity, hypertension, suicide, stroke, and breast cancer.
A meta-analysis has demonstrated that consumption of one to two alcoholic drinks per day reduces CVD by a relative risk (RR) of 0.68 for wine and 0.78 for beer, where RR < 1 is favorable, and the lower the better. The Third National Health and Nutrition Examination Survey (NHANES III) studied 8,125 people and looked at the relationship between alcohol intake and the prevalence of metabolic syndrome, which is often considered a pre-diabetic state. The major benefit of alcohol consumption is the rise in HDL levels. The NHANES III generated the following chart:
Table 5, Multivariate adjusted Odds Ratio for the Prevalence of Metabolic Syndrome
In the last three decades, an increasing percentage of Americans are overweight. A reduction in weight by 5 to 10% will result in a reduction of LDL cholesterol by 15%, a reduction of triglycerides by 20%, and an increase in HDL cholesterol by 9%, the latter of which is a delayed effect.
The National Cholesterol Education Program (NCEP) give the following recommendation for what they call the Therapeutic Lifestyle Changes (TLC) Diet outlined in the following table:
Table 6, Components of Life Style Changes
The American Heart Association (AHA) has made the following recommendations:
Table 7, AHA Dietary Recommendations
Abbreviations: DASH= dietary approaches to stop hypertension; TLC= Therapeutic Lifestyle Changes; d= day; sv= serving
There has been a lot of discussion over various diets which includes the Pritikin Diet, the South Beach Diet, and others. None of these have any studies to back up their efficacy. However, the Mediterranean Diet does have data to show its benefit. This diet includes many cultures that live along the Mediterranean, the most noted of which are the Greeks. Nonetheless, there are several characteristics that separate them from the American Diet. These are as follows:
The PREDIMED study randomized 9000 individuals, early results show a reduction in LDL cholesterol from 3.8 to 5.8 mg% and a reduction in triglycerides of 7.6 mg%. A much smaller study, Esposito Study, only had 180 subjects over two years, showed a reduction in triglycerides by 19 mg% (p = 0.001) and an increase in HDL cholesterol of 3 mg% (p = 0.03). Finally, the Lyon Diet Heart Study randomized individuals who survived a heart attach and compared the Mediterranean Diet to a “prudent” American Diet over a period of 46 months. Those on the Mediterranean diet had a significant reduction in recurrent heart disease by 50-70%.
Medical Treatment for Elevated Cholesterol
As noted in Table 8, there have been a long list of studies showing the benefit of the following medications: Atorvastatin, Cholestyramine, Ezetimibe, Lovastatin, Pravastatin, Rosuvastatin and Simvastatin. The “statin” drug are the most potent group of medications tested. Most high-risk patients who cannot reduce their cholesterol by life-style changes will be placed on a statin medication. It works by reducing an enzyme called 3-hydroxy-3-methyl-glutaryl-CoA (HMGCoA) reductase, which is the rate-limiting co-enzyme in the production of cholesterol from the liver and other cells.
Table 8, Synthesis of Cholesterol and Location of HMG-CoA
There are few head-to-head trials pitting one statin drug against another. Therefore, the choice of which drug to use is mostly based on price and efficacy. Lovastatin (Mevacor), Pravastatin (Pravachol) and Simvastatin (Zocor) are generic medications that have a long list of studies to back up their efficacy. Atorvastatin (Lipitor) is supposed to be generic by the end of 2011 and Rosuvastatin (Crestor) is supposed to go generic by early 2012. Rosuvastatin is unique in that it is the most potent and lower LDL and also is the only drug in its class to raise HDL. As you can see from the following table, there is considerable variation in the cost of these medications. The major side effect of statin drugs are two-fold: muscle aches and liver toxicity. The above studies show that these drugs are well tolerated and are only discontinued in between 1-2% of cases.
Table 9, Statin Medications Available by Prescription
One common strategy is to combine modalities. Your physician will commonly tell you to exercise, change your diet, and lose weight. A simple statement such as this incorporates a lot of life-style modifications (see the above sections). The most potent life-style changes are weight reduction and fiber supplementation. Adding a statin drug is an additional modality. Above in Table 9, you will notice a combination medication Vytorin, which adds ezetimibe, also known as Zetia, which lowers cholesterol by interfering with cholesterol absorption by the gastro-intestinal tract at the brush border where cholesterol is absorbed. For this reason, diarrhea is the most common side effect, along with upper respiratory tract infections and arthralgias (joint aches).
Anderson KM, et al, Cholesterol and Mortality, 30 Years of Follow-up From the Framingham Study; JAMA 1987, 257:2176-2180.
Baik, I et al, Intake of Fish and n-3 Fatty Acids and Future Risk of Metabolic Syndrome, 2010; J Am Diet Assoc. 2010;110:1018-1026.
Cannon, CP et al, Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes (PROVE-IT), N Engl J Med 2004;350:1495-504.
Cannon, CP et al, Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes (IMPROVE-IT), Am Heart J 2008;156:826-32.
Cleeman JI, et al, National Cholesterol Education Program (NCEP) Recommendations for Cholesterol Testing in Young Adults, Circulation. 1997;95:1646-1650.
Cleeman JI, Grundy SM, National Cholesterol Education Program Recommendations for Cholesterol Testing in Young Adults, Circulation. 1997;95:1646-1650.
Colhoun, HM et al, Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, The Lancet, 8/21/2004, 364: pp 685-696.
Downs JR et al, Primary Prevention of Acute Coronary Events With Lovastatin in Men and Women With Average Cholesterol Levels Results of AFCAPS/TexCAPS, JAMA, May 27, 1998, Vol 279, No. 20.
Glynn, RJ et al, Tracking of High-Sensitivity C-Reactive Protein after an Initially Elevated Concentration: The JUPITER Study, 2009, Clinical Chemistry 55:2, 305–312
Goldman L, Cecil Medicine, 23rd ed, Chapter 217, Disorders of Lipid Metabolism, 2008 (Saunders: Philadelphia, PA)
Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial, Lancet 2002; 360:7-22.
Katcher, Heather I, et al, Lifestyle Approaches and Dietary Strategies to Lower LDL-Cholesterol and Triglycerides and Raise HDL-Cholesterol, Endocrinol Metab Clin N Am 38 (2009) 45–78
Katcher, HI et al, Lifestyle Approaches and Dietary Strategies to Lower LDL-Cholesterol and Triglycerides and Raise HDL-Cholesterol, Endocrinol Metab Clin N Am 2009, 38: 45–78.
Koren MJ, et al, Clinical Outcomes in Managed-Care Patients With Coronary Heart Disease Treated Aggressively in Lipid-Lowering Disease Management Clinics, The ALLIANCE Study, J Am Coll Cardiol 2004;44:1772–9.
LaRosa JC, et al, Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease, Treating to New Targets (TNT), N Engl J Med 2005;352:1425-35.
Lipid Research Clinics Program, Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), I. Reduction in Incidence of Coronary Heart Disease, JAMA, Jan 20 1984, Vol 251, No 3, pp. 351-364.
LIPID Study Group, Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels, The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group, (N Engl J Med 1998;339: 1349-57.
McGill, HC et al, Effects of Serum Lipoproteins and Smoking on Atherosclerosis in Young Men and Women, Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:95-106.
Neaton JD, et al, Serum cholesterol, blod pressure, cigarette smoking, and death from coronary heart disease. Oveall findings and differences by age for 316,099 white men, Multiple Risk Factor Intervention Trial Research (MRFIT), Arch Int Med, 1992, 152: 56-64.
Pasternak, R, Adult Treatment Panel II Versus Adult Treatment Panel III: What Has Changed and Why?, Am J Cardiol 2002;89(suppl):3C–7C.
Pedersen, TR et al, Follow-Up Study of Patients Randomized in the Scandinavian Simvastatin Survival Study (4S) of Cholesterol Lowering, Am J Cardiol 2000;86:257–262.
Pedersen, TR et al, High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction The IDEAL Study: A Randomized Controlled Trial, JAMA. 2005;294:2437-2445.
Ridker, PM et al, HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial, 2010 [Abstract]
Sacks et al, The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels, Cholesterol and Recurrent Events (CARE), N Engl J Med 1996; 335:1001-9.
Schwartz et al, Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes, The MIRACL Study: A Randomized Controlled Trial, JAMA, April 4, 2001—Vol 285, No. 13 1711-1718.
Shepherd et al, Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia, (N Engl J Med 1995;333:1301-7.
VanHorn, L et al, The Evidence for Dietary Prevention and Treatment of Cardiovascular Disease, J Am Diet Assoc. 2008;108:287-331.
Wiviott, SD et al, Safety and Efficacy of Achieving Very Low Low-Density Lipoprotein Cholesterol Levels With Rosuvastatin 40 mg Daily (from the ASTEROID Study), Am J Cardiol 2009;104:29–35.
1500 Heritage Rd Suite A/ De Pere, WI 54115