|
|
Lipid Disorders |
|
|
Some of these publications require Adobe Acrobat to be installed on your system. Download it free at http://www.adobe.com/acrobat/readstep.html |
|
Lipid
abnormalities |
||||
UNDER construction
Introduction to
Lipid Metabolism
ATPIII,
Adult Treatment Program III. 2001 recommendations for diagnosis and treating lipid
abnormalities issued by the National Institutes of Health. The most
comprehensive and widely adopted set of recommendations. Practically all health
professionals rely on these recommendations.
Diagnostic tests
for lipids
Diagnostic tests
for cardiovascular disease
Lipid Therapy
Therapeutic Diets
Drug therapy
Watch for new strategies
We are finishing exciting research on new diagnostic and treatment approaches to treat hyperlipidemia, particularly for patients with low HDLC, high TG, and family history of premature death (severe disease before 60). If you are one of these patients, would like to consider new options, and can afford the treatment (>$1000 + tests usually covered by conventional insurance), contact us.
Table comparing drugs to treat abnormal lipids. This table is waiting for comments from manufacturers. Errors may exist. Please submit your comments.
Introduction to Lipid Metabolism
See our key definitions + glossary.
There are two major types of “fats”, cholesterol and fatty acids. Fatty acids are the key substance that forms cells, provides protection against cold, and provides energy to the cells and the body. Fatty acids are carried in the blood in many ways. Most often they go together in groups of 3 forming a molecule (substance) called Triglycerides (TG) (Tri = 3). Fatty acids can also be attached to cholesterol molecules (cholesterol-esters), substances called Phospholipids, and many more.
Fat does not dissolve in water. To carry fat in the blood (which is mostly water), the body uses special vehicles or particles that look like balls. The outside of these balls contains chemicals that interact with water so these particles dissolve in water; the inside protects the fats with antioxidants.
The fat in the blood is carried inside particles, called "lipoproteins," manufactured by the liver and the intestine. Researchers have found that some lipoproteins are heavier than others, and have classified lipoproteins according to density.
The lipoproteins are named "VLDL" (very low density lipoproteins), "LDL" (low density lipoproteins), "HDL" (high density lipoproteins), and "IDL" (intermediate density lipoproteins). Using more sophisticated instruments, researchers have found even more lipoproteins of differing densities: Now we have HDL1, HDL2, HDL3, LDL I-IV, and many more. Regardless of density, each lipoprotein contains some cholesterol, cholesterol attached to fatty acids ("cholesterol esters"), triglycerides, phospholipids, vitamins, and apoproteins, a special type of proteins.
Because counting and measuring the lipoproteins is difficult (very difficult to count particles of different size, weight, chemical composition), scientists measure the amount of cholesterol within lipoproteins. Thus, we speak of HDL cholesterol (HDLC).
Notice that there is no such thing as “good cholesterol” or “bad cholesterol”. Instead, there is cholesterol inside HDL, and cholesterol inside LDL. Because higher levels of HDL seem to protect against heart disease, and higher levels of LDL seem to increase the risk of heart disease, HDL is known as the good lipoprotein and LDL is known as the bad lipoprotein.
Due to confusion, instead of speaking about the good or bad lipoprotein, some people speak about the good or bad cholesterol. There is only one type of cholesterol, but where it goes in the body it makes a big difference. When cholesterol is used to protect cells and make useful substances, it is helping the body. When cholesterol forms clumps with fat called plaques or otherwise obstruct arteries, it is being harmful to the body.
Cholesterol is very important to humans; without it we would die very quickly. The body carefully regulates the amounts of cholesterol. When we do not have enough, the body makes more; when we have plenty, the body stops making it. Most people eat too many calories which the body converts and stores as saturated fat. This hard fat makes arteries hard. To keep them soft, the body makes cholesterol. However, over time, the body can make too much cholesterol.
The cells in the body have receptor mechanisms to catch lipoproteins from the blood, absorb the vitamins and essential fats needed from them, and recycle them back into the blood. Many hormones regulate the way the body uses these lipoproteins. In women, menopause causes huge hormonal changes which apparently contribute to higher likelihood of heart disease. People with abnormal genes have abnormal lipoprotein metabolism, and this defect is frequently associated with cardiovascular disease or stroke. A few people have genes that protect them against heart disease, but we do not know how.
The word "hyperlipidemia" literally means high levels of lipids (fats) in the blood. As a general descriptor, it can mean either an elevated number of lipoproteins or an elevated number of lipids (within the lipoproteins). Dyslipidemias are lipid abnormalities, including some with low lipids.
Abnormal Lipids
For diagnostic and treatment purposes, it is useful to distinguish two types of abnormal lipids:
Acquired disorders. This kind
is associated primarily with "bad behaviors." Because of bad diet,
lack of exercise, overweight, and smoking (the leading factors) the body
produces and accumulates excessive levels of cholesterol and triglycerides from
unused calories (calories from any source, often from low fat diets).
The proportion of HDL cholesterol is relatively low. As a result, the ratio of Total/HDL
cholesterol (TC/HDLC) is high. Desirable ratios are below 2.5. Very
dangerous ratios are over 5 (high probability of sudden death). More than 50%
of the adult population in the US has "acquired" abnormal lipid
values.
Genetic disorders. This kind is
primarily associated with "bad genes." These individuals, even
if they were to eat very well and behave well, would still have abnormal lipids
and increased risk of dying from premature death. Many patients in apparently
excellent health and great fitness have severely abnormal lipids. In general,
children with abnormal lipids (unless overweight) and adults with very abnormal
lipids who do not smoke and are less than 5% overweight are likely to have
"bad genes."
Enzymes
The distinction between acquired and genetic disorders is relative and refers to the relative influence of genes vs. behavior. All lipid values (cholesterol, triglycerides) are determined by chemical reactions controlled by enzymes. Enzymes are chemicals that, like tools, help make other chemicals. Some people have many good enzymes that protects against heart disease, aging, cancer, etc. Others have bad enzymes that accelerate diseases. Enzymes work together with other co-factors that make the enzyme more or less active. In that way, enzymes regulate how much the body makes of each substance.
The formation, use, and metabolism of lipids is a very complex process controlled by hundreds (probably thousands) of enzymes with many cofactors (such as vitamins and minerals). Genetic variation among humans causes large variability in enzyme activity. For example, some people may have enzymes that facilitate the formation of HDL (protective effect for heart disease), while others have enzymes that fail to form enough HDL and/or fail to eliminate excessive levels of TGs from the blood.
Enzyme activity also depends on body composition (weight, nutrients stored), diet, exercise, smoking, drugs, and probably thousands of substances in foods and herbs. For reasons poorly understood, some people can use their nutrients extremely well and have excellent lipids and low risk for CAD even when they eat poorly or smoke. Others have abnormal lipids no matter what they do. However, science has taught us that many "undesirable" enzymes may have "desirable" functions even though we do not know these functions yet.
Regardless of the enzymes we have, we can gain weight by eating too many calories and lose weight by eating fewer calories. If we accumulate undesirable weight (= fat), the arteries will get fat (thick) and narrow. It is difficult for arteries to get obstructed if there isn’t enough extra fat for them to grow. Thus, an average diet or even nutrient-deficient diet is unlikely to cause atherosclerosis in slim people.
When you read studies that people in many poor countries do not have heart disease, the reason may not be their diets but the fact that they are very slim. In those countries (such as China, Japan, and many parts of Asia and India), as people become wealthier and eat more food, they gain weight and become more susceptible to heart disease.
As the arteries get fatter they get harder. The body seeks to soften them by incorporating cholesterol in them (cholesterol softens membranes). Over time, the extra cholesterol precipitates and forms crystals and other junk with the extra fat. Special cells try to destroy this “junk” by eating it. Over time the artery accumulates groups of fat, cholesterol, and cells known as “plaques.” A fat and narrow artery reduces the flow of blood and nutrients. It can be obstructed by a group of platelets (clot) that confuse the rough artery with a broken artery and try to “seal” the “hole”. It can also be obstructed by a plaque that ruptures (breaks) from its previous location.
CAD vs CVD; people usually have both, but CAD may be
more painful and obvious
CAD = coronary artery disease refers to hardening and narrowing of the arteries that feed the hear (coronary arteries). These arteries sit on the surface of the heart and provide blood to the muscle in the heart. Cardiovascular disease refers to the consequences of hardening and narrowing of arteries in other parts of the body. Narrowed vessels obstruct blood flow. Hard vessels lack elasticity and the heart needs to pump harder (higher blood pressure) to supply organs far away from the heart (far away in the circulation tree). With lack of blood there is lack of oxygen. Tissues without enough oxygen have ischemia. In the brain we can have a stroke because of ischemia, lack of oxygen that kills cells. Or we can have s troke because a brittle vessel breaks. Similar problems can occur in the kidney and other organs.
An optimal diet can prevent atherosclerosis, but eating too much food forces the body to store fat in the arteries. Thus, eating very well (with plenty of nutrients, vitamins, minerals and lots of supplements) will not prevent atherosclerosis in an overweight person.
The human body makes large amounts of cholesterol (which is essential for life), and the body disposes of unneeded cholesterol. However, if we eat too much cholesterol, we may overwhelm the body's ability to discard excessive amounts, and we may accumulate it in arteries. Depending on our genes and diet, some of us accumulate a lot of cholesterol and fat very fast (accelerated atherosclerosis), while others accumulate it slowly. Accumulation of cholesterol also depends on the types of fats and vitamins we eat. Excessive cholesterol is converted to either innocuous or harmful substances, depending on the relative amounts of vitamins and our genes.
Many foods/herbs contain substances that alter lipid metabolism by affecting the activity of selected enzymes. These substances may help a few people who have abnormalities that are corrected by those substances, and are likely to hurt most others by shifting cholesterol away from the organs that need it. This problem is particularly important in pregnancy. Severe developmental abnormalities can occur in pregnant women who eat substances that interfere with cholesterol metabolism. Read about making a cyclops in our September 98 newsletter (go to the research section).
Lipid disorders
Genetic lipid disorders are also known as "familial diseases" because they usually affect more than one family member. In these diseases, one or more genes are "different" or "defective." As a result, an enzyme which is important to the metabolism of lipoproteins is not made properly, and a small part of the body fails to work. Because the human body is an extraordinarily complex machine, even if one part in 1,000,000 works poorly, the body dies. There are physicians who specialize in the treatment of patients with severely abnormal lipids.
"Familiar hypercholesterolemia"
(highly elevated cholesterol) occurs in about one in 500 persons.
A specific defect in Apolipoprotein B, a
protein that helps to make lipoproteins, occurs in about one in 700 persons.
"Combined hyperlipidemia" (both
elevated triglycerides and cholesterol) occurs in about one in 100 persons.
Low HDLC and high TG is the most common
disorder. My research shows that low HDLC (HDLC < 35 mg/dL) occurs in about
one in five (20%) of total adults, and elevated triglycerides (> 120 mg/dL)
in one of two (50%) of all adults. The combination of low HDLC and high TG is
found in ~5%. This condition appears to account for about 50% of premature
deaths (before age 60) and > 30% of total cardiovascular health care
expenses (because they require very expensive and long term care).
About 15% of people with hyperlipidemia have
at least one defective gene that regulates Apoprotein E4. This protein
regulates the operation of the cell's receptor for LDL. With a bad receptor,
these lipoproteins accumulate in the body. High LDL cholesterol in the blood is
strongly correlated with heart disease.
About 7% of people with hyperlipidemia have
at least one defective gene that regulates Aproprotein E2. This protein
regulates the update of leftover lipoproteins, called "remnants" in
the blood, and also the formation of LDL. Paradoxically, some of these people
may have low cholesterol because they have low LDL cholesterol. However, they
often have high TG.
Humans have two copies of every gene. When only one gene is defective, we say it is a heterozygous defect. When both genes are defective, we say it is a homozygous defect. People who have one defective gene have a mild form of the disease. People with both genes defective have a severe form of the disease.
In addition, people may have more than one defective gene. Each defective gene may affect different aspects of lipid (fat) metabolism. Over the course of evolution, it appears likely that there are many people who have inherited more than one defective gene.
As a general rule, if your cholesterol is over 400 mg/dL or your triglycerides are over 300 mg/dL, or your HDLC is below 35, you probably have an unusual genetic condition that increases your cholesterol or triglycerides or interferes with your body's ability to make HDL. One of the most dangerous combinations is low HDLC and high TG. This combination greatly increases the risk of heart disease. Many people with this combination die of heart disease before they are 60 years old.
Hyperlipidemia
The word "hyperlipidemia" literally means high levels of lipids (fats) in the blood. It means either an inflated number of lipoproteins, or an inflated number of the lipids in the lipoproteins. In medicine, this term traditionally has been used for elevated TC or TG. However, modern research has shown that hyperlipidemia is complex because there are many different types of lipoproteins (some may be present in higher than normal amounts, and others actually may be present in lower than normal amounts). Hyperlipidemias can be acquired disorders, genetic disorders, or (most often) a combination of both. Approximately 5% to 15% of the US population has very high cholesterol (> 400 mg/dL) or very high triglycerides (> 300 mg/dL) (called "severe hyperlipidemia").
Dyslipidemias
Some people have low HDLC (< 35 mg/dL) and another abnormalities of lipid metabolism. These disorders are called "dyslipidemia" or "dyslipoproteinemia," and are most likely caused by genetic defects compounded by bad diets (severe obesity can cause some of these problems).
Treatment
When you are diagnosed with a genetic disorder of lipid metabolism, you will need to follow a very strict and complex diet, and you may also have to take drugs. This is a situation where you must be seen by a lipids specialist rather than a regular physician. Because each of these disorders is fairly unique and manifests differently in different patients, you need to work with your health provider to develop the optimal plan.
§ Treatment involves a combination of different strategies:
§ Weight loss. This is the most important strategy for overweight people.
§ Diet low in calories, high in nutrients, essential fats. Adequate in vitamins and minerals.
§ Exercise.
§ Combination of drugs.
Drugs come in several categories, Each category is particularly useful for a specific type of disorder. Some help increase HDL and decrease TGs; others lower LDL and total cholesterol. A doctor needs to spend considerable time analyzing your problem to determine the cause of your lipid abnormality and the best types of drugs for your condition.
Once a decision is made about the types of drugs to be used, one needs to decide the specific drug within each type and the dose. These decisions involve more subtle aspects of each person’s condition. Sometimes one must try a drug for a while, and then change to a different type to see which one works better and has fewer side effects. Alternatively, changing drugs may minimize side effects.
A combination of drugs may allow a doctor to prescribe lower doses of individual drugs, thereby decreasing the risk of side effects. Remember: Each drug has side effects, and many of the long term side effects cannot be known because each person has different genes and likely responds differently to each drug.
Treatment of low HDLC and high
triglycerides
The combination of low HDLC (<40) with high TG (>150) is one of the most lethal combinations. Scientists do not know the biochemical basis or cause for these problems. There are many known causes, the most common ones being overweight and diabetes. However, many slim and otherwise healthy people have low HDLC and high TG, often with a family history of premature CVD (before age 60). These individuals are at very high risk of premature (and often sudden) CVD or death. See low HDL and high TG for research articles on these topics.
Many drugs are useful, but some patients do not respond to drugs; for young people drugs could be harmful (the dangers of 20+ years on drugs is not known); many of these drugs disrupt cholesterol metabolism and are highly likely to negatively affect development (pregnant and nursing women should not use them). Pregnant women with lipid abnormalities may develop preeclampsia or their baby could have suboptimal brain development. Read my pregnancy, the case of a pregnant woman with abnormal lipids.
After 20+ years of research, Dr. Siguel has identified a biochemical defect that explains in part why some people cannot make HDLC and accumulate TGs. He will soon announce a new therapy.
Some of the factors to consider to determine whether you have a genetic abnormality that predisposes to premature death:
- Family history (person related by blood, siblings, parents, grandparents,
uncles, aunts) of cardiovascular disease (heart disease, stroke,
substantial hypertension, angina) before age 50, or a heart attack or need
for surgery before age 60.
- Abnormal lipids, primarily low HDLC, high TG, high TG/HDLC,
high TC/HDLC.
- Lipid values oscillate, with HDLC frequently moving below 40
mg/dl and TG frequently found > 150 mg/dl (fasting samples). Notice
that a relatively low TC < 200 mg/dl is not sufficient to prevent
disease.
- Abnormal lipid values even though you are not significantly
overweight (< 5% above ideal weight).
- You eat a reasonably healthy diet, better than the average
American.
Example. A 55 yo man has no significant heart abnormalities. His HDLC = 42,
TG = 156, TC = 198. Weight = 165, height = 5'7". Over a period of several
years, in response to various diets, his HDLC fluctuated between 35 and 48, and
TGs fluctuated between 140 and 180 mg/dL. He eats a diet with total fat <
30% of calories (vs ~ 35%+ for most Americans), and exercises continuously >
1/2 hr per day (on average). [Everybody moves during the day-- exercise refers
to a continuous period of active exercise rather than opening the
refrig. door or getting up to get the remote control.] In response to a dietary
treatment program by his doctor, his TC declined from 220 to 198, but his HDLC
also declined from 48 to 41. Unfortunately, the TC/HDLC and the TG/HDLC
increased in response to treatment.
The fact that he gets worse in response to a new diet may merely reflect that
the diet was too low in fat. He is 10 to 15 lbs overweight, which accounts for
some of the elevated TG and lower HDLC. However, a desirable level for HDLC is
> 55 mg/dl. He exercises an acceptable amount and eats a fairly balanced
diet (including lean chicken, fish and vegetables) estimated at 2900 calories
per day. He does not smoke or drink. He is a successful business person in an
excellent economic situation and enjoys what he does (stress reasonable). He
takes a multivitamin supplement every day. He is unlikely to have nutritional
abnormalities more severe than those of many people with better risk factors.
If he has a family history of premature death, he is likely to be at high risk
for premature death. If his HDLC were > 35 and TG > 200, he would likely
be at risk for premature death even without a family history of premature
death.
Losing weight is the first no-brainer. There is no side effect. He can easily
lose 15 lbs, maybe even 20 lbs. Being thin protects against heart disease and
cancer. However, it is possible that these steps will not dramatically improve
his lipid risk factors and he may be at risk for sudden premature death.
The next steps are complex and expensive. Non-invasive analysis of the heart
and its arteries could be used to determine whether or not there is an incipient
obstruction or a plaque that could disrupt and cause an obstructions. If the
heart and arteries suggest an immediate risk of premature death, he may start
on anticoagulant therapy (such as one baby aspirin per day) and other steps (to
be discussed in 1999) to reduce the risk of premature death.
If the arteries look reasonably clean, then he can start a new therapy to
reverse the risk of premature death by manipulating the lipid composition of
his tissues. These issues will be presented in 1999.
We are looking for doctors with interesting patients to report their experiences or collaborate with us trying new dietary therapies.
Treatment of high TC/HDLC
Our treatment for high TC/HDLC seeks to normalize the fatty acid profile. Read:
Siguel, E. A new
relationship between PUFAs and TC/HDLC. Lipids, 1996; 31, S51-S56.
Insulin Resistance Syndrome
Insulin resistance is characterized by high glucose levels (and often high insulin levels) in blood, where the cells do not seem to respond appropriately to insulin. Insulin resistance syndrome has many forms. For most people, insulin resistance is due to genetic factors and lifestyle. Insulin resistance usually occurs in Type II diabetes.
High glucose is a symptom of the disease, not its cause. Treating high glucose with drugs may prevent some of the complications caused by high glucose, but does not correct the underlying problem.
Patients with type 1 diabetes do not produce enough insulin.
Patients with type 1 and 2 diabetes, insulin resistance, and syndrome X are at increased risk of developing CVD. Patients with type 2 diabetes are at increased risk of developing hypertension, while hypertensive people are more likely than usual to develop type 2 diabetes.
Insulin resistance is a major risk factor for heart disease and a cause of low HDLC and high TG. Insulin resistance is associated with non-insulin-dependent diabetes mellitus (NIDDM), hyperlipidemia, hypertension, obesity, and cardiovascular disease ['insulin-resistance syndrome' (Syndrome X)].
Typical treatment for the abnormal lipids in these patients is calorie restriction/weight loss. Hypertension and diabetes may increase CAD risk by increasing TG and causing low HDLC. "These abnormalities appear to result from increased hepatic secretion of VLDL particles due to increased concentrations of free fatty acids and glucose, reduced VLDL clearance due to reduced activity of lipoprotein lipase, and reduced LDL clearance due to glycosylation of ligand proteins." (McKenney JM. "Understanding and Treating Dyslipidemia Associated with Non-Insulin Dependent Diabetes Mellitus and Hypertension." Pharmacotherapy 1993 ;13(4):340-352.) "Increased free fatty acid transport in plasma, a common abnormality in insulin-resistant states, may be the underlying driving force for the two common lipid abnormalities seen in diabetes, low HDLC and high TG" (Ginsberg HN. "Diabetic Dyslipidemia: Basic Mechanisms Underlying the Common Hypertriglyceridemia and Low HDL Cholesterol Levels." Diabetes 1996 Jul; 45 Suppl 3:S27-S30.). McKenney's treatment follows NCEP guidelines, including restricting saturated fat and cholesterol in the diet.
We are developing a new treatment for insulin resistance.
Syndrome X
Refers to the combination of low HDLC, high TG, insulin resistance, and hypertension.
Clustering of abnormalities
Patients are likely to develop a group of various abnormalities such as diabetes, hypertension, obesity, insulin resistance, low HDLC, high TG, high cholesterol, abnormal glucose.
Lipid Drug Therapy
Review table with summary of key drugs, mode of action, doses, links to manufacturers. Lipid Drug Therapy
We welcome comments and help to make this information more complete and accurate.
NIH recommendations for lipid treatment.
TO BE CONTINUED
Note. We are working on several patent applications for diagnosis and treatment of lipid abnormalities and syndrome X. Companies or individuals interested in collaborative research or licensing are welcomed to contact us. We also need product information, graphic aids, etc. If you make products/drugs or oils to treat cardiovascular disease or lipid abnormalities, please contact us at lipids@efafood.com; PO Box 10187 Dept L, Gaithersburg, MD 20898
|
By
reading this web site, you agree to read & comply with the following
instructions: You agree to pay us $300 for each unsolicited communication to sell us unsolicited products/services (by e-mail, mail, phone, etc.). Read details. |
|
|
© 1998 Edward N. Siguel. All rights
reserved |
modified 1/15/00 |