Hypercholesterolemia was once thought to be result of only an unhealthy diet. However, based on new findings, several researches are being conducted to determine the genetic causes of the disease. Several conditions, including abetalipoprotienemia, and familia hypercholesterolemia, have been identified as causes of elevated levels of various types of cholesterol. Along with these discoveries are various techniques, such as DNA tests, that have been developed to asses these diseases.
Due to the other complications of hypercholesterolemia, such as decreased vision, myocardial infarctions, and Alzheimer’s disease, various health experts have conducted several studies to develop a treatment. Currently, two prescription drugs are available and several plant extracts show promise as alternative treatments. In this connection, this review paper examines the genetic causes of hypercholesterolemia and how they relate to health conditions, treatment, and diagnosis.
In conclusion, if a person’s family, such as parents and grandparents, has a genetically-linked history of high cholesterol, it is necessary to conduct tests that would determine the person’s cholesterol level at a young age so as to lessen future health risks and also devise measures that would prevent the disease from worsening. INTRODUCTION Cholesterol or 5-cholesten-3? -ol is the most abundant steroid in animal tissues. An important role of this steroid is in the formation of various substances in the body such as bile acids, vitamin D, progesterone, estrogen, androgens, mineralocorticoid hormones and glucocorticoid hormones.
This substance is also important for normal permeability and cell membrane functions (Dictionary, 2006). However, excess amount of cholesterol, especially low density (LDL) and very low density (VLDL) can have severe detrimental effects. Increased levels of low-density lipoprotein in the blood stream can lead to a build up of cholesterol plaques in arteries as well as amyloid in the brain. The surge of blood cholesterol beyond normal values will increase the risk of obtaining heart disease (NHLBI, 2006).
Many factors can contribute to hypercholesterolemia, including family history, lack of exercise, poor diet, age and gender. Foods high in saturated fats, trans fatty acids, obesity, and lack of exercise increase LDL levels in the blood. Diagnosis of this condition involves lipoprotein profile, a blood test that measures total cholesterol and specific values of LDL, HDL, and triglycerides; and random test for total blood cholesterol level and HDL (NHLBI, 2006). A person that is 20 years old and above needs to have their blood cholesterol levels measured every 5 years (NIH, 2005 )
Causes of Hypercholesterolemia Hypercholesterolemia is a hereditary disease and can also be caused by obesity and a sedentary lifestyle. In these cases a simple life style change is sufficient to treat or prevent the condition (NHLBI, 2006). However, there are several genetic disorders which can override a healthy lifestyle. This review paper focuses on these inherited disorders, including abetalipoproteinemia (ABL), Apo A-I deficiency, and a mutation in an autosomal dominant gene located on chromosome 19, called LDLR gene. ABL is characterized by the presence of HDL and the absence of apoB.
The significance of the increase in HDL levels and decrease inapoB-containing lipoprotein in the plasma includes direct effects in their interlinked metabolism and also the transfer of apolipoproteins and lipids inside the plasma compartment (Katsunori Ikewaki, 2000). Basically, HDL serve as a reservoir for excess phospholipids, cholesterol, and apolipoproteins that have been freed during the lipolysis of the surface of triglyceride-rich proteins, a receiver of excess cholesterol from cells as well as a carrier of cholesterol in the reverse cholesterol transport.
A decrease in the level of HDL apolipoproteins will alter the performance of these functions, hence the accumulation of cholesterol in the blood. This lipoprotein has two major apolipoproteins which are the Apolipoproteins A-I (apoA-I) and Apolipoproteins E. In the case of Abetalipoproteinemia, aside from the absence of apolipoproteins B in the plasma, the levels of HDL and apoA-I are significantly below the normal value. Increased catabolism rate and decrease anabolism of apoA-I are the causes of its decline in blood plasma of ABL patients (Katsunori Ikewaki, 2000).
Familial hypercholesterolemia is a genetic disorder that is due to any mutation of the gene that codes for the proteins that are involved in the functions and metabolism of cholesterol. Other terms of this genetic disorder are Type II hyperlipoproteinemia, Hypercholesterolemic xanthomatosis, and Low density lipoprotein receptor mutation. Patients with this disease have heart attacks at an early age due to increased level of cholesterol starting at birth (Health, 2007).
Heterozygous familial hypercholesterolemia (HeFH) is an inherited genetic condition wherein there is a mutation of the allele of the LDL receptor (LDL-R) gene into a heterozygous state. A normal gene for LDL-R from a parent and abnormal gene for LDL-R from the other is transmitted to the individual. However, only half of the individual’s LDR-R proteins are dysfunctional. The accumulation of blood cholesterol level is because only half the LDR receptors in the liver are removing the LDL particles, thus reducing the function rate by fifty percent.
Cholesterol buildup begins at birth then eventually leads to tendon xantomas, corneal stroma and arteriosclerosis (DESCAMPS, 2007). Another type of gene mutation that results in familial hypercholesterolemia is those with mutations in the apolipoproteins B (apoB) or familial defective apolipoprotein B . Glutamine is substituted for arginine in the codes for apolipoproteins B. Heterozygous familial hypercholesterolemia is more severe in terms of LDL cholesterol elevation when compared to familial defective apolipoproteins B(DESCAMPS, 2007).
The next type of familial hypercholesterolemia is a mutation that originates from the mutation of the nucleotide 836 in Exon 9 of the Cholesteryl Ester Transfer Protein (CETP) gene. Functions of CETP are the following: catalysis of hetero-exchange and net mass transfer of cholestyl esters and triacylglycerols between different densities of lipoprotein in the plasma; and contributes to the reverse cholesterol transport pathway in coordination with plasma enzyme lecithin.
The latter function returns cholesterol back to the liver either for reuse or excretion. Large portion of the patients that have this type of mutation are of Japanese ancestry. Manifestations of the condition are: moderate hypercholesterolemia with low LDL cholesterol (Dolphin, 2001). Signs and related health problems: In many cases, various types of high cholesterol, especially of genetic origin, present asymptomatically.
Although obesity, inactivity, and a high fat diet may be a warning sign of possible high cholesterol, these conditions are not that relevant when genetic predispositions, such as familial hypercholesterolemia (FH), are present. In these cases, unhealthy cholesterol levels may be found in ostensibly healthy adults. Much of the time, the only indication of high cholesterol may be found by medical tests, as discussed in the diagnosis section of this review. Despite its commonly asymptomatic nature, high cholesterol has been linked with several serious medical conditions.
One of the oldest and most solid links is with atherosclerosis, and associated cardiovascular events. A recent study clearly demonstrated that high cholesterol, in individuals with FH, was a contributing factor to both intima-media thickness of the carotid artery and the development of arterial stiffness (Cheng 2007). Furthermore, this phenomenon is not unique to the arteries of the hearts. Hypercholesterolemia has been also been demonstrated to cause structural damage to choroids of rabbits (Salazar 2007).
These two instances exemplify a broader pattern of vascular damage caused by cholesterol, especially LDL cholesterol. This damage can lead to medical problems including angina, heart disease, reduced vision, and myocardial infarctions. Also important to note, is that once atherosclerosis has occurred, lowering LDL cholesterol intake and plasma levels does not appear to cause a spontaneous reversal of the cholesterol induced vascular damage (Salazar 2007). Connections have also been made between hypercholesterolemia and Alzheimer’s disease.
A series of autopsies performed on patients over 40 years old, demonstrated a non-linear correlation between hypercholesterolemia and the accumulation of amyloid in the brain. This non-linear correlation suggests that hypercholesterolemia may be one of several factors leading to the accumulation of this Alzheimer’s causing plaque (Pappolla 2003). In addition, cholesterol has been found directly in the cerebral plaques of 24 month old mice genetically predisposed to Alzheimer’s, while at the same time being absent in their control counterparts (Mori 2001).
Several genes, comparable to those in the above mentioned mouse study, have been attributed to increased incidence of Alzheimer’s disease in people. These genes include those responsible for cholesterol transport, cholesterol metabolism, lipoprotein reception and other cholesterol processes within the brain (Carter 2007). More studies are necessary to determine whether it is cholesterol levels, the bodies ability to properly process cholesterol, or a combination of these two factor that determines a persons likelihood of developing Alzheimer’s.
How Is High Blood Cholesterol Diagnosed? Several methods for diagnosing high levels of cholesterol are practiced and new methods are being discovered in the recent years to come. Blood tests are the number one method for testing and because it is simple and cheap. From the blood test, lipoproteins are counted and measured. There are two lipoproteins that are compared, the high density lipoproteins (HDL’s) and the low density lipoproteins (LDL’s). (Mathaway 2006) It is extremely important that a patient follow certain guidelines prior to drawing their blood.
These include avoiding strenuous exercise up to twenty-four hours before the test, do not eat or drink anything but water twelve hours beforehand and if the first test results are abnormal, a second test should be performed between one week and two months after the first test. There are also several home tests and public locations such as shopping malls and pharmacies available. For example, the CholesTrak Test can be taken at home with results in 10 minutes, but it measures only total cholesterol. The BioSafe Cholesterol Panel Test is also a home test, but it needs to be sent to a laboratory.
This test, however, is very accurate and provides a full lipid profile. (Ridgeway 2005) Recently several new skin tests have been approved. This method includes measuring the levels of cholesterol in the skin and this may help determine heart disease and atherosclerosis risks. It is recommended that patients get tested according to age group. All adults starting from the age of twenty should get tested periodically annually, if normal levels are read. Selective screening may be done on children who are at risk for high cholesterol and heart disease or familial hypercholesterolaemia, which is genetically elevated cholesterol.
Patients already diagnosed with high cholesterol should be tested every two to six months. How Is High Blood Cholesterol Treated? When genetic factors are not involved it is generally found that exercise and dietary changes are sufficient to lower cholesterol to acceptable level. However, when there are genetic influences such as familia, hypercholesterolemia, and additional treatments are often necessary. Currently studies are suggesting two categories of prescription drugs, statins and bile acids. In addition, there is compelling evidence to suggest that plants, sterols and stenils can be used as an alternative treatment.
The discovery of statins in 1987 was key to understanding the pathological effects of hypercholesterolemia. It was unclear whether cholesterol lowering improved cardiovascular health although studies had identified that high blood cholesterol was a risk factor and because total cholesterol levels were less than 300 mg/dL in patients tested, physicians were not convinced that this was abnormal. Statins helped demonstrate the importance of cholesterol reduction, reducing total mortality and vascular disease.
Since the discover of statins, experimental trials using statins have reported lower low-density lipoprotein ( LDL) cholesterol levels in patients on these drugs since low LDL levels reduce the risk of heart attacks and other cholesterol related diseases in patients. Another study in clinical trials found that HDL cholesterol levels in patients receiving statins was predictive of major cardiovascular events in patients treated with statins, even when LDL levels were below 70 mg per deciliter, those in the highest quintile of HDL cholesterol levels were at less risk for major cardiovascular events than those in the lowest quintile .
There are currently five statin drugs available in the United States to treat high blood cholesterol: lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin . The major effect of the statins is to lower the LDL-cholesterol levels by inhibiting the HMG-CoA reductase enzyme that controls the rate of cholesterol by slowing down the production of cholesterol and by increasing the liver’s ability to remove the LDL-cholesterol already in the blood. According to National Heart, Lung, and Blood Institute, these drugs are successful in reducing the number of heart attacks and heard disease deaths.
The other cholesterol lowering medication is bile-acid. There are different types of bile-acid sequestrants, including cholestyramine powder, colestipol and colesevelam. Bile-acid sequestrants work by lowering the LDL (or bad) cholesterol. They bind bile acids in the intestines and excrete them through the stool. The liver then converts cholesterol into more bile acids, lowering cholesterol levels. Bile-acid sequestrants are often used in conjunction with a statin or niacin drug.
Although hypercholesterolemia is treated with medications such as statins and bile acids, there are other alternative cures for the disease. The most effective alternative is diet and exercise. A study designed to test for disease patterns associated with health behaviors in different ethnicities. Although the experiment was focused on different racial and socioeconomic determinants for chronic diseases such as high blood cholesterol levels, the overall finding suggested that healthy diet and regular exercise reduces the risk of heart disease and other health related illnesses.
In addition to healthy diet and exercise, another source of controlling hypercholesterolemia is with the use of plant stanols and sterols. Research has shown that plant sterols and stanols included with a healthy diet may reduce the risk of heart disease. Sterols and stanols work by blocking the absorption of cholesterol in the small intestine. This lowers the low density cholesterol known as the ‘bad’ cholesterol (LDL) by 6-15%, without lowering the good cholesterol known as the high density cholesterol (HDL).
Clinical research trials have documented safety and effectiveness for the use of plant stanols and sterols without the interference of cholesterol lowering medications. The National Cholesterol Education/Adult Treatment III program guidelines recommend plant sterols/plant stanols as part of a heart healthy eating plan. Eating a heart healthy low fat diet that include eating plenty of fruits, vegetables, whole grain foods, plant sterols/stanols, plus regular physical activity help reduce the risk of heart disease.
The Food & Drug Administration approved the health claim regarding the role of plant sterols esters in reducing risk of heart disease. CONCLUSION In conclusion, since the diagnosis and treatment hypercholesterolemia varies depending on the genetic make-up of the person, it is necessary to follow the treatment and medications prescribed by the doctor. Generally, most cholesterol-related diseases can be treated through proper diet and sufficient exercise. Inherited cholesterol diseases do not really hinder or impede the treatment of a patient with high cholesterol.
It only modifies the treatment of the disease. Moreover, since the medications, such as lovastatin, simvastatin, pravastatin, fluvastatin, and atorvastatin used to treat genetically-inherited cholesterol diseases have been proven safe and effective by recognized medical and health institutions, there is basically no need to worry about side-effects and other risks. In addition, since bile-acid sequestrants, including cholestyramine powder, colestipol and colesevelam have been proven to lower bad cholesterol, there are basically a number of options to treat hypercholesterolemia.
Furthermore, despite the availability and existence of these medications, it can be concluded that the best way to treat high-cholesterol related diseases is to observe a healthy diet and engage in exercises. Whether the cholesterol disease is genetically-linked or not, it has been proven that diet and exercise are cheap and effective ways to lower cholesterol levels. Lastly, the success of both the diet and the exercise largely depends on the discipline of the patient to follow them.