Hypercholesterolemia (High Blood Cholesterol)

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Cholesterol is a waxy, fat-like substance that occurs naturally in all parts of the body. Your body needs some cholesterol to work properly. But if you have too much in your blood, it can stick to the walls of your arteries. This is called plaque. Plaque can narrow your arteries or even block them.

High levels of cholesterol in the blood can increase your risk of heart disease. Your cholesterol levels tend to rise as you get older. There are usually no signs or symptoms that you have high blood cholesterol, but it can be detected with a blood test. You are likely to have high cholesterol if members of your family have it, if you are overweight or if you eat a lot of fatty foods.

You can lower your cholesterol by exercising more and eating more fresh fruits and vegetables. You also may need to take a doctor-prescribed cholesterol-lowering medications.



Schematic three dimensional cross section of a cell membrane. There are two major components of this dynamic, fluid, structure: lipids and proteins. A lipid bilayer provides the basic structure within which proteins are free to diffuse. Sugar moieties can be present as part of either proteins (glycoproteins) or lipids (glycolipids). A further important component shown is en:cholesterol; which intercalates between lipid molecules and affects membrane fluidity/stability. The drawing was made by Dana Burns, and can also be found in Scientific American, 1985, 253(4), pages 86-90, in the article "The molecules of the cell membrane" by M.S. Bretscher.



Cholesterol, from the Greek chole- (bile) and stereos (solid) followed by the chemical suffix -ol for an alcohol, is an organic chemical substance classified as a waxy steroid of fat. It is an essential structural component of mammalian cell membranes and is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture of bile acids, steroid hormones, and vitamin D. Cholesterol is the principal sterol synthesized by animals; in vertebrates it is formed predominantly in the liver. Small quantities are synthesized in other eukaryotes such as plants and fungi. It is almost completely absent among prokaryotes, i.e. bacteria.  Although cholesterol is important and necessary for human health, high levels of cholesterol (hypercholesterolemia) in the blood have been linked to damage to arteries and cardiovascular disease.

Hypercholesterolemia is the presence of high levels of cholesterol in the blood.  It is a form of "hyperlipidemia" (elevated levels of lipids in the blood) and "hyperlipoproteinemia" (elevated levels of lipoproteins in the blood).

Cholesterol is a sterol, a sort of fat. It is one of three major classes of lipids which all animal cells utilize to construct their membranes. It is also the precursor of the steroid hormones, bile acids, and vitamin D and can be manufactured by all animal cells.

Since cholesterol is essentially insoluble in water, it is transported in blood in protein particles (lipoproteins). Low density lipoprotein (LDL) is the major carrier of cholesterol in humans.  Elevated levels of cholesterol-containing lipoproteins in the blood may be a consequence of diet, obesity, inherited [genetic] diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as diabetes and an underactive thyroid.

Reducing dietary fat intake reduces total blood cholesterol and LDL cholesterol in adults and it is recommended in people with familial hypercholesterolemia, although dietary change alone is usually insufficient to achieve adequate lowering of cholesterol and medications which reduce cholesterol production or absorption are usually required.  If necessary other treatments, including LDL apheresis or even surgery (for particularly severe subtypes) are performed.

Signs and Symptoms

Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis.  Over a period of decades, chronically elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This leads to progressive stenosis (narrowing) or even complete occlusion (blockage) of the involved arteries.  Blood supply to the tissues and organs served by these stenotic or occluded arteries gradually diminishes until organ function becomes impaired.  It is at this point that tissue ischemia (restriction in blood supply) may manifest as specific symptoms.  For example, temporary ischemia of the brain (commonly referred to as a transient ischemic attack or TIA - mini stroke) may manifest as temporary loss of vision, dizziness and impairment of balance, aphasia (difficulty speaking), paresis (weakness) and paresthesia (numbness or tingling), usually on one side of the body.  Insufficient blood supply to the heart may manifest as chest pain, and ischemia of the eye may manifest as transient visual loss in one eye.  Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal.  Some types of hypercholesterolemia lead to specific physical findings.  For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids), arcus senilis (white or gray discoloration of the peripheral cornea), and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers.  Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.

Causes

Hypercholesterolemia is typically due to a combination of environmental and genetic factors.

Environmental factors include:

• obesity, and
• dietary choices.

Genetic contributions are usually due to the additive effects of multiple genes however occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia.  A number of secondary causes exist including:

• diabetes mellitus type 2,
• obesity,
• alcohol,
• monoclonal gammopathy,
• dialysis,
• nephrotic syndrome,
• obstructive jaundice,
• hypothyroidism,
• Cushing’s syndrome,
• anorexia nervosa, and
• medications (thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid).

Diet

Diet has an important effect on blood cholesterol but the size of this effect varies substantially between individuals.  Approximately 50% of dietary cholesterol is absorbed in the intestine, but inter-individual variations in the efficiency of uptake, and the effect of other dietary components such as plant sterols and fiber content affect absorbtion.  Moreover, when dietary cholesterol intake goes down, production (principally by the liver) typically increases, though not always with complete compensation, so that reductions in blood cholesterol can be modest. Reductions in fat intake, particularly saturated fats, also reduce blood cholesterol.  Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia in 2011 were that people with familial hypercholesterolemia should follow the National Cholesterol Education Program (NCEP) Third Adult Treatment Panel (ATP III) Therapeutic Lifestyle Changes (TLC) diet and restrict intakes of total fat to 25-35% of energy intake; that saturated fatty acids should make up less than 7% of energy intake, and that cholesterol intake should be less than 200 mg per day.  There is also evidence that inclusion of 2 g per day of plant stanol or sterol esters and 10 to 20 g per day of soluble fiber decrease dietary cholesterol absorption.  Dietary changes can typically achieve reductions of 10 to 15% in blood cholesterol.

• The most effective approach has been minimizing fat stores located inside the abdominal cavity (visceral body fat) in addition to minimizing total body fat.  Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g. resistin, which increase insulin resistance and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of Diabetes Mellitus.  Maintaining a healthy body weight through increased physical activity and appropriate caloric intake is also important. Overweight or obese individuals can lower blood cholesterol by losing weight - on average a kilogram of weight loss can reduce LDL cholesterol by 0.8 mg/dL.
• Phytosterols are widely recognized as having a proven LDL cholesterol lowering efficacy.  Current supplemental guidelines recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III,FDA) with a recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.
• Insulin induces HMG-CoA reductase activity, whereas glucagon diminishes HMG-CoA reductase activity.  While glucagon production is stimulated by dietary protein ingestion, insulin production is stimulated by dietary carbohydrate. The rise of insulin is, in general, determined by the digestion of carbohydrates into glucose and subsequent increase in serum glucose levels. In non-diabetics, glucagon levels are very low when insulin levels are high; however, those who have become diabetic no longer suppress glucagon output after eating.
• A ketogenic diet may have similar response to taking niacin (lowered LDL and increased HDL) through beta-hydroxybutyrate, a ketone body, coupling the niacin receptor (HM74A).
• Lowering the blood lipid concentration of triglycerides helps lower the concentration of Small LDL particles, because fat rich VLDL particles convert in the bloodstream into Small LDL particles.

Importance of Antioxidants

Because LDL particles appear harmless until they are within the blood vessel walls and oxidized by free radicals, it is postulated that ingesting antioxidants and minimizing free radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.  Some studies have reported the benefits of green tea in helping to reduce LDL; some studies have focused on the antioxidant qualities of the unfermented green tea leaves, others looked at catechins, naturally occurring compounds found in green-tea, which are thought to decrease cholesterol absorption in the gut, and still others compared the effect of 70% dark chocolate with green tea as antioxidants on lipid profiles.

Genetics

Genetic abnormalities are in some cases completely responsible for hypercholesterolemia, such as in familial hypercholesterolemia where there is one or more genetic mutations in, for example, the LDL receptor.  Even when there is no single responsible mutation to explain hypercholesterolemia, genetic predisposition still plays a major role, potentially adding to lifestyle factors and multiplying the risk of late complications. Multiple genes are involved, and hypercholesterolemia where there is probably a genetic predisposition is called polygenic hypercholesterolemia.  A 2006 research article by David Evans* and Frank U Beil "The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women" discusses the genetics of polygenic hypercholesterolemia, and the involvement of multiple abnormalities in LDL metabolism.

Diagnosis

There is not an absolute cutoff between normal and abnormal cholesterol levels and interpretation of values needs to occur in relation to other health factors. The ideal cholesterol level should be less than 4 mmol/l with a LDL cholesterol less than 2 mmol/l in those at high risk of cardiovascular disease.

Higher cholesterol levels lead to increased risk of several diseases, most notably cardiovascular diseases. Specifically, high levels of small LDL cholesterol particles are associated with increased risk.  Larger LDL particles do not carry the same risk.

When measuring cholesterol, it is important to measure its subfractions before drawing a conclusion as to the cause of the problem. The subfractions are LDL, HDL and VLDL. In the past, LDL and VLDL levels were rarely measured directly due to cost concerns. VLDL levels are reflected in the levels of triglycerides (generally about 45% of triglycerides is composed of VLDL). LDL was usually estimated from the other fractions using the equation LDL total cholesterol - HDL - (0.2 x triglycerides). This formula is known as the Friedewald equation.

Less expensive (and usually less accurate) home test kits are available in a range of prices, with most being less than $300 US dollars.  If you choose to have a lipid profile analysis done through your local hospital lab, medicare and most private insurance will generally pay all or most of the price of the test. 

Advanced laboratory analyses that do measure LDL and VLDL particle sizes and levels have been developed, and at far lower cost. These have partly been developed and become more popular as a result of the increasing clinical trial evidence that intentionally changing cholesterol transport patterns, including to certain abnormal values compared to most adults, often has a dramatic effect on reducing, even partially reversing, the atherosclerotic process. With ongoing research and advances in laboratory methods, the prices for more sophisticated analyses have markedly decreased, by some labs, and with simultaneous increases in the accuracy of measurement for some of the methods.

Hyperlipidemia

Classically, hypercholesterolemia was categorized by lipoprotein electrophoresis and the Fredrickson classification. Newer methods, such as lipoprotein subclass analysis have offered significant improvements in understanding the connection with atherosclerosis progression and clinical consequences.  If the hypercholesterolemia is hereditary (familial), there is more often a family history of premature, earlier onset atherosclerosis.

Screening

The US Preventive Services task Force (USPSTF) strongly recommends screening for lipid disorders in adults.  According to The Public Healthy Agency of Canada website, the 2003 recommendations for the management of dyslipidemia and the prevention of cardiovascular disease says that men 40 years of age and older and women who are postmenopausal or over 50 years of age be screened for high cholesterol levels.  In those with normal cholesterol levels screening is recommended once every five years.  Once people are on a statin further testing provides little benefit except to possibly determine compliance with treatment.

Treatment

Treatment guidelines for hypercholesterolemia for primary prevention and secondary prevention have been published. For those at high risk a combination of lifestyle modification and statins has been shown to decrease mortality.

Lifestyle

A number of lifestyle changes are recommended in those with high cholesterol including: smoking cessation, limiting alcohol consumption, increasing physical activity, maintaining a healthy weight, and changing to a diet low in saturated fats, trans fat-free and low cholesterol foods.  In strictly controlled surroundings, a diet can reduce cholesterol levels by 15%. In practice, dietary advice can provide a modest decrease in cholesterol levels and may be sufficient in the treatment of mildly elevated cholesterol.

Cholesterol-lowering Medications

• Statins* reduce high levels of LDL particles by inhibiting the enzyme HMG-CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To compensate for the decreased cholesterol availability, synthesis of hepatic LDL receptors is increased, resulting in an increased clearance of LDL particles from the blood.
• Ezetimibe reduces intestinal absorption of cholesterol, thus can powerfully reduce LDL particle concentrations when combined with statins.
• Niacin (B3), lowers LDL by selectively inhibiting hepatic diacyglycerol acyltransferase 2, reducing triglyceride synthesis and VLDL secretion through a receptor HM74 and HM74A or GPR109A.
• Clofibrate is effective at lowering cholesterol levels, but has been associated with significantly increased cancer and stroke mortality, despite lowered cholesterol levels.  Other, more recently developed and tested fibrates, e.g. fenofibric acid have had a better track record and are primarily promoted for lowering VLDL particles (triglycerides), not LDL particles, yet can help some in combination with other strategies.
• Some Tocotrienols, especially delta- and gamma-tocotrienols, are being promoted as statin alternative non-prescription agents to treat high cholesterol, having been shown in vitro to have an effect. In particular, gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor, and can reduce cholesterol production.  As with statins, this decrease in intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-regulation, also decreasing plasma LDL levels. As always, a key issue is how benefits and complications of such agents compare with statins—molecular tools that have been analyzed in large numbers of human research and clinical trials since the mid-1970s.

*While statins are effective in decreasing mortality in those who have had previous cardiovascular disease, there is debate over whether or not they are effective in those with high cholesterol but no other health problems.  One review did not find a mortality benefit in those at high-risk but without prior cardiovascular disease.  Other reviews concluded that there is a mortality benefit but there were concerns regarding the quality of the evidence.  With respect to quality of life there is limited evidence of improvement when statins are used for primary prevention.  No studies as of 2010 show improved clinical outcomes in children with high cholesterol even though statins decrease cholesterol levels.  Effects appear similar regardless of the statin used.  Other agents that may be used for elevated cholesterol levels including: fibrates, nicotinic acid and cholestyramine.  These however are only recommended for primary prevention if statins are not tolerated.

Guidelines

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The American College of Physicians (ACP) has addressed hypercholesterolemia in patients with diabetes.  Their four recommendations are:

1. Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.
2. Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
3. Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d; or an equivalent dose of another statin").
4. For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

The National Cholesterol Education Program revised their guidelines; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.  In the UK, the National Institute for Health and Clinical Excellence (NICE) has made recommendations for the treatment of elevated cholesterol levels, published in 2008.

Complementary and Alternative Medicine (CAM) Therapies

According to a survey in 2002, CAM therapies were used in an attempt to treat cholesterol by 1.1% of U.S. adults. Consistent with previous surveys, this one found that the majority of individuals (i.e., 55%) used it in conjunction with conventional medicine.  A review trials of phytosterols and/or phytostanols reported an average of 9% lowering of LDL-cholesterol.  In 2000 the US Food and Drug Administration (FDA) approved the labeling of foods containing specified amounts of phytosterol esters or phytostanol esters as cholesterol lowering; in 2003 an FDA Interim Health Claim Rule extended that label claim to foods or dietary supplements delivering more than 0.8 grams/day of phytosterols or phytostanols.  Some researchers, however, are concerned about diet supplementation with plant sterol esters and draw attention to lack of long-term safety data. 


External Links

Cholesterol - Food and Drug Administration (FDA).
High Blood Cholesterol: What You Need to Know - National Heart, Lung, and Blood Institute.
High Cholesterol: Understand Your Risks - Centers for Disease Control and Prevention (CDC).
High Cholesterol - FamilyDoctor.org.
Levels of Cholesterol - American Heart Association.
Countries' Economy, Healthcare System Linked to Cholesterol Rates - American Heart Association.
FDA Expands Advice on Statin Risks - Food and Drug Administration (FDA).

Diagnosis/Symptoms

Get Your Cholesterol Checked - Healthfinder.gov.
How to Get Your Cholesterol Tested - American Heart Association.
What Your Cholesterol Levels Mean - American Heart Association.

Treatment

Drug Therapy for Cholesterol - American Heart Association.
High Cholesterol: Cholesterol-Lowering Medicines - FamilyDoctor.org.
High Cholesterol: Medicines to Help You - Food and Drug Administration (FDA).
Making Sense of Vytorin Concerns - Food and Drug Administration (FDA).
Niacin to Boost Your HDL 'Good' Cholesterol - Mayo Foundation for Medical Education and Research.
Treating High Cholesterol: A Guide for Adults - Agency for Healthcare Research and Quality.
Lowering Your Cholesterol with TLC (Therapeutic Lifestyle Changes) - National Heart, Lung, and Blood Institute - PDF.

Prevention/Screening

Cholesterol Test - American Association for Clinical Chemistry.
HDL Cholesterol Test - American Association for Clinical Chemistry.
High Blood Cholesterol Prevention - Centers for Disease Control and Prevention (CDC).
Home-Use Tests > Cholesterol - Food and Drug Administration (FDA).
LDL Cholesterol Test - American Association for Clinical Chemistry.

Complementary and Alternative Medicine (CAM) Therapy

Cholesterol-Lowering Supplements: Lower Your Numbers without Prescription Medication - Mayo Foundation for Medical Education and Research.
Flaxseed and Flaxseed Oil - National Center for Complementary and Alternative Medicine.
Garlic - National Center for Complementary and Alternative Medicine.
Grape Seed Extract - National Center for Complementary and Alternative Medicine.
Green Tea - National Center for Complementary and Alternative Medicine.
Lower Your Cholesterol with Plant Sterols and Stanols - Joslin Diabetes Center.
Red Clover - National Center for Complementary and Alternative Medicine.
Soy - National Center for Complementary and Alternative Medicine.

Nutrition

Cholesterol: Top 5 Foods to Lower Your Numbers - Mayo Foundation for Medical Education and Research.
Cooking for Lower Cholesterol - American Heart Association.
Fats and Cholesterol: Out with the Bad, In with the Good - Harvard School of Public Health.
Heart-Healthy Home Cooking: African American Style - National Heart, Lung, and Blood Institute - PDF.
Dining Out > Tips by Cuisine - American Heart Association.
Trans Fat Now Listed with Saturated Fat and Cholesterol on the Nutrition Facts Label - Food and Drug Administration (FDA).

Disease Management

Lifestyle Changes and Cholesterol - American Heart Association.
Tips to Sticking with Lifestyle Changes - American Heart Association.

Specific Conditions

HDL Cholesterol: How to Boost Your 'Good' Cholesterol - Mayo Foundation for Medical Education and Research.
Hyperlipidemia - American Heart Association.
Overview of Cholesterol and Lipid Disorders - Merck & Co., Inc.

Related Issues

Cholesterol Level: Can It Be Too Low? - Mayo Foundation for Medical Education and Research.
Common Misconceptions about Cholesterol - American Heart Association.
Xanthelasma Palpebrarum - Logical Images, Inc.

Health Check Tools

Cholesterol IQ Quiz - American Heart Association.
Risk Assessment Tool for Estimating Your 10-Year Risk of Having a Heart Attack - National Heart, Lung, and Blood Institute.
Test Your Lipid IQ - Foundation of the National Lipid Association.

Tutorials

High Blood Cholesterol - National Heart, Lung, and Blood Institute.

Videos

Bad Fats Brothers - American Heart Association.
Better Fats Sisters - American Heart Association.
"If I Had - Abnormal Cholesterol on Routine Blood Work" Dr. Lori Mosca, NewYork Presbyterian Hospital; Columbia University Medical Center - Insidermedicine.

Anatomy/Physiology

What Do Fats Do in the Body? - National Institute of General Medical Sciences (NIGMS).

Clinical Trials

ClinicalTrials.gov: Hypercholesterolemia, Hyperlipidemia-Familial Combined, Hyperlipidemias, Hyperlipoproteinemia Type III, Hyperlipoproteinemia Type II - National Institutes of Health.

Genetics

Genetics Home Reference: Hypercholesterolemia - National Library of Medicine.
Genetics Home Reference: Tangier disease - National Library of Medicine.
Learning about Familial Hypercholesterolemia - National Human Genome Research Institute.

Research

Does LDL Cholesterol Influence the Relationship Between HDL Cholesterol and Cardiovascular Risk in Women? - American College of Physicians - PDF

Organizations

American Heart Association.
National Heart, Lung, and Blood Institute.

Statistics

CDC Vital Signs: High Blood Pressure and Cholesterol - Centers for Disease Control and Prevention.
Cholesterol Facts and Statistics - Centers for Disease Control and Prevention.

Children

Cholesterol and Your Child - Nemours Foundation.
What's Cholesterol? - Nemours Foundation.

Teenagers

Dietary Fat and Cholesterol - Children's Hospital Boston.
What Is Cholesterol? - Nemours Foundation.

Women

Women and Cholesterol - American Heart Association.

Seniors

High Blood Cholesterol - National Heart, Lung, and Blood Institute.


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