Hypercholesterolemia is the presence of high levels of
cholesterolCholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
in the blood. It is not a
diseaseA disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
but a
metabolicMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
derangement that can be caused by many diseases, notably
cardiovascular diseaseHeart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. It is closely related to the terms "
hyperlipidemiaHyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...
" (elevated levels of
lipidLipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s in the blood) and "hyperlipoproteinemia" (elevated levels of
lipoproteinA lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
s in the blood).
Elevated cholesterol in the blood is due to abnormalities in the levels of lipoproteins, the particles that carry cholesterol in the bloodstream. This may be related to
dietIn nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...
, genetic factors (such as
LDL receptorThe Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
mutations in
familial hypercholesterolemiaFamilial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein , in the blood and early cardiovascular disease...
) and the presence of other diseases such as
diabetesDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
and
an underactive thyroidHypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
. The type of hypercholesterolemia depends on which type of particle (such as low-density lipoprotein) is present in excess.
Hypercholesterolemia is treated by reducing dietary cholesterol intake, administration of certain medications, and rarely with other treatments including surgery (for particular severe subtypes).
Classification
Classically, hypercholesterolemia was categorized by lipoprotein
electrophoresisElectrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
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 hypercholesterolemiaFamilial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein , in the blood and early cardiovascular disease...
), there is more
often a
family historyIn medicine, a family history consists of information about disorders from which the direct blood relatives of the patient have suffered. Genealogy typically includes very little of the medical history of the family, but the medical history could be considered a specific subset of the total history...
of premature, earlier onset atherosclerosis.
Signs and symptoms
Although hypercholesterolemia itself is
asymptomaticIn medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
, longstanding elevation of serum cholesterol can lead to
atherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. Over a period of decades, chronically elevated serum cholesterol contributes to formation of
atheromatous plaquesIn pathology, an atheroma is an accumulation and swelling in artery walls that is made up of macrophage cells, or debris, that contain lipids , calcium and a variable amount of fibrous connective tissue...
in the arteries. This leads to progressive
stenosisA stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a stricture ....
(narrowing) or even complete
occlusionVascular occlusion is a sudden blockage of a blood vessel, usually with a clot. It differs from thrombosis in that it can be used to describe any form of blockage, not just one formed by a clot. When it occurs in a major vein, it can, in some cases, cause deep vein thrombosis. The condition is...
(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
ischemiaIn medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
(restriction in blood supply) may manifest as specific
symptomA symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s. For example, temporary ischemia of the brain (commonly referred to as a
transient ischemic attackA transient ischemic attack is a transient episode of neurologic dysfunction caused by ischemia – either focal brain, spinal cord or retinal – without acute infarction...
) may manifest as temporary loss of vision,
dizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
and impairment of
balanceEquilibrioception or sense of balance is one of the physiological senses. It helps prevent humans and animals from falling over when walking or standing still. Balance is the result of a number of body systems working together: the eyes , ears and the body's sense of where it is in space ideally...
,
aphasiaAphasia is an impairment of language ability. This class of language disorder ranges from having difficulty remembering words to being completely unable to speak, read, or write....
(difficulty speaking),
paresisParesis is a condition typified by partial loss of voluntary movement or by impaired movement. When used without qualifiers, it usually refers to the limbs, but it also can be used to describe the muscles of the eyes , the stomach , and also the vocal cords...
(weakness) and
paresthesiaParesthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
(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 eyeAmaurosis fugax is a transient monocular visual loss.-Pathophysiology and etiology:...
. Insufficient blood supply to the legs may manifest as
calf pain when walkingClaudication, literally 'limping' , is a medical term usually referring to impairment in walking, or pain, discomfort or tiredness in the legs that occurs during walking and is relieved by rest. The perceived level of pain from claudication can be mild to extremely severe. Claudication is most...
, while in the intestines it may present as
abdominal pain after eating a mealAbdominal angina is postprandial abdominal pain that occurs in individuals with insufficient blood flow to meet mesenteric visceral demands. The term angina is used in reference to angina pectoris, a similar symptom due to obstruction of the coronary artery...
.
Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with
xanthelasma palpebrarumXanthelasma is a sharply demarcated yellowish deposit of cholesterol underneath the skin, usually on or around the eyelids. Although not harmful or painful, these minor growths may be disfiguring and can be removed...
(yellowish patches underneath the skin around the eyelids),
arcus senilisArcus senilis is a white or gray, opaque ring in the corneal margin , or white ring around the iris. It is present at birth, but then fades; however, it is quite commonly present in the elderly...
(white or gray discoloration of the peripheral
corneaThe cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
), and
xanthomaA xanthoma , from Greek xanthos, ξανθος, "yellow", is a deposition of yellowish cholesterol-rich material in tendons or other body parts in various disease states...
ta (deposition of yellowish cholesterol-rich material) of the
tendonA tendon is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension. Tendons are similar to ligaments and fasciae as they are all made of collagen except that ligaments join one bone to another bone, and fasciae connect muscles to other...
s, 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:
obesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
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 2Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
,
obesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
,
alcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
,
monoclonal gammopathyMonoclonal gammopathy is a synonym for paraproteinemia.- External links :*...
,
dialysisIn medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
,
nephrotic syndromeNephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
, obstructive jaundice,
hypothyroidismHypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
, Cushing’s syndrome,
anorexia nervosaAnorexia nervosa is an eating disorder characterized by refusal to maintain a healthy body weight and an obsessive fear of gaining weight. Although commonly called "anorexia", that term on its own denotes any symptomatic loss of appetite and is not strictly accurate...
, medications (thiazide diuretics,
ciclosporinCiclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
, glucocorticoids, beta blockers,
retinoic acidRetinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
).
Diet
While part of the circulating cholesterol originates from diet, and restricting cholesterol intake may reduce blood cholesterol levels, there are various other links between the dietary pattern and cholesterol levels.
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 receptorThe Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...
.
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. The involved genes have yet to be discovered.
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 calculation
Less expensive (and less accurate) laboratory methods and the Friedewald calculation have long been used because of the complexity, labor, and expense of the
electrophoreticElectrophoresis, also called cataphoresis, is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. This electrokinetic phenomenon was observed for the first time in 1807 by Reuss , who noticed that the application of a constant electric...
methods developed in the 1970s to identify the different lipoprotein particles that transport cholesterol in the blood. In 1980, the original methods, developed by research work in the mid-1970s cost about $5,000, in US 1980 dollars, per blood sample/person.
With time, more 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, to less than $100, US 2004, by some labs, and with simultaneous increases in the accuracy of measurement for some of the methods.
Screening
The
U.S. Preventive Services Task ForceThe U.S. Preventive Services Task Force is "an independent panel of experts in primary care and prevention that systematically reviews the evidence of effectiveness and develops recommendations for clinical preventive services." The task force, a panel of primary care physicians and...
(USPSTF) has strongly recommends routine screen for men 35 years and older and women 45 years and older for lipid disorders and the treat of abnormal lipids in people who are at increased risk of coronary heart disease. They also recommend routinely screening men aged 20 to 35 years and women aged 20 to 45 years if they have other risk factors for
coronary heart diseaseCoronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
. In Canada screening is recommended for men 40 and older and women 50 and older. 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
Recommendations for both 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, physical activity, maintaining a healthy weight, and a diet low in saturated fats.
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.
Medication
While statins are effective in decreasing mortality in those who have had previous
cardiovascular diseaseHeart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, 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 was concerns regarding the quality of the evidence. With respect to
quality of lifeThe term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
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.
Guidelines
Various clinical practice guidelines have addressed the treatment of hypercholesterolemia. The
American College of PhysiciansThe American College of Physicians is a national organization of doctors of internal medicine —physicians who specialize in the prevention, detection, and treatment of illnesses in adults. With 130,000 members, ACP is the largest medical-specialty organization and second-largest physician group in...
has addressed hypercholesterolemia in patients with diabetes. Their four recommendations are:
- 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.
- 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.
- 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").
- 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 ProgramThe National Cholesterol Education Program is a program managed by the National Heart, Lung and Blood Institute, a division of the National Institutes of Health. Its goal is to reduce increased cardiovascular disease rates due to hypercholesterolemia in the United States of America...
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 ExcellenceThe National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...
(NICE) has made recommendations for the treatment of elevated cholesterol levels, published in 2008.
Alternative medicine
According to a survey in 2002,
alternative medicineAlternative medicine is any healing practice, "that does not fall within the realm of conventional medicine." It is based on historical or cultural traditions, rather than on scientific evidence....
was 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 Food and Drug Administration 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 significant safety issues.
Health CanadaHealth Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies:Health Canada...
does not allow the sale of foods enriched with plant sterol esters.