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Hyperlipidemia

Pathophysiology

The pathophysiology of hyperlipidemia is quite complex and involves an interplay of various factors including genetics, the environment, lifestyle and dietary habits (1,2). In order to address the pathophysiology of hyperlipidemia, the normal role of lipid metabolism should be summarized. Cholesterol is water insoluble, and therefore cannot circulate through the blood alone (1,2). It is packaged with triglycerides and phospholipids into a carrier protein known as the lipoprotein (1,2). These are water soluble and allows for the transportation of lipids in the blood (1,2). There are different sizes of lipoproteins, in order of descending size and ascending density are chlymoicrons, very low density lipoprotein, intermediate density lipoprotein, low density lipoprotein, and high density lipoprotein (1). The total serum cholesterol is a function of the total cholesterol molecules in all of these major lipoproteins (1). Each lipoprotein contains various proteins known as apolipoproteins that are attached to the surface (1). They have four functions: 1) They are used to assemble and secrete liporpoteins (Apolipoprotein B-48, and B-100) 2) Serve as major structural components of lipoproteins 3) act as ligands (apolipoprotein B-100 and apolipoprotein E ) that bind to receptors on cell surfaces and 4) are co factors (apolipoprotein C-II) for activating enzymes (such as lipoprotein lipase) that is used to breakdown trigylcerides from chylmicrons and VLDL (1).

Chylomicrons are large triglyceride rich particles that also contain apolipoproteins B-48, B-100, and E (2). These are formed by the dietary fat that is sobulized by bile salts in the intestinal mucosal cells (2). Chylomicrons are catabolized by LPL, (which requires apolipoprotein C-II for activation) to form chylomicron remnants (2). These remnants contain apolipoprotein E and are taken up by the remnant receptor in the liver (2). The free cholesterol is liberated only intracellular after attachment to the remnant receptor (2). The chylomicrons also deliver dietary trigylcerides to the skeletal muscle and adipose tissue (2). When the chylomicrons become remnants, the triglyceride is converted to free fatty acids and apolipoprotein A-1, A-II, A-IV, C-I, C-II, and C-III and phospholipids are transferred to HDL (2). LDL is the major cholesterol transport lipoprotein and contains apolipoprotein B-100 (1,2). If patients fast and consume a normal low fat diet, most the cholesterol is synthesized and used in the extrahepatic organs (1). The majority of the cholestery that is carried by LDL is taken up by the liver for catabolism (1). If patients have homozygous familial hypercholesterolemia, enhanced synthesis of LDL may occur because there is a lack of LDL receptors that reduces the LDL clearance (1). In the normal fasting sate, about 70% of the LDL is cleared through the receptor dependent mechanism (1,2). Eating too much cholesterol and saturated fatty acids such as C12:0, C14:0, and C16:0 is associated with a reduction in the LDL receptor activity, and therefore increased LDL production rate and elevated LDL plasma concentration (2).

A variety of genetic mutations occur during the process of lipoprotein synthesis and metabolism that may lead to lipid disorders (1). In general, disorders that increase serum cholesterol affect the affinity of the LDL receptors, or affect the ability of apolipoprotein B-100 to bind the receptor (known as familial defective apolipoprotein B-100) (1). Elevations of triglycerides are due to overproduction of VLDL (rich in triglycerides, and are secreted by the liver), mutations in apolipoprotein E, or a lack of LPL (1).

Prognosis

Hyperlipidemia is a very important modifiable risk factor for atherosclerosis and cardiovascular disease, especially coronary heart disease (3). The risk of developing atherosclerosis is directly related to increased levels of serum cholesterol (1,3). This plays a major role in plaque formation, which leads to coronary heart disease (3). CHD is the leading cause of death in both men and women in most industrialized nations (2). Developing CHD is a lifelong process that involves years of poor dietary habits, sedentary lifestyle and life-habit risk factors that include smoking and obesity, which contributes to the development of atherosclerosis (2).

Risk factors include obesity, lack of exercise, habitual excessive alcohol use, cholesterol intake greater than 300 mg per day, saturated fat intake per total calories greater than 10% and fat intake per total calories greater than 40% (1,3) The incidence is also higher among men than women (3). Asian Indians have the highest risk, whereas Chinese have the lowest risk (3). Men ≥45 years and women ≥55 years or premature menopause without having estrogen replacement therapy are also at risk (1). A family history of premature CHD (MI, sudden death; before age 55 years in the father or other male first degree relative; or before age 65 years in mother or another female first degree relative), smoking of cigarettes, hypertensive (≥140/90 mm Hg), and low HDL cholesterol (<40 mg/dL) are also risk factors (1). Disease states that also contribute to hyperlipidemia are diabetes, hypothyroidism, Cushing’s syndrome, and renal failure (3). Drugs that are associated with hyperlipidemia include anabolic steroids, birth control pills and estrogens, corticosteroids, thiazide diuretics, beta blockers and protease inhibitors (1,3).

Clinical Presentation

Patients who have hyperlipidemia are generally asymptomatic for many years before the disease is clinically evident (3). If the patient has metabolic syndrome, they may have three or more of the following features: abdominal obesity, atherogenic dyslipidemia, increased blood pressure, insulin resistance with or without glucose intolerance, or a proinflammatory state (1).

Symptoms

The presentation of hyperlipidemia may range from having no symptoms to severe abdominal pain, pancreatitis, peripheral polyneuropathy, high blood pressure, eruptive xanthomas (irregular yellow patch or nodule on the skin, due to deposition of cholesterol) , BMI > 30 kg/m2 , waist size >40 inches in men (35 inches in women) (1,3).

Diagnosis

The first step in diagnosing a lipid disorder is to determine the class or classes of lipoproteins that are increased or decreased in the patient, thus the first step is to obtain a lipoprotein profile (3). A fasting profile in which the patient has fasted for 9 to 12 hours is ideal as an accurate determination of the LDL cholesterol can be performed (1). This is because under fasting conditions, the clearance of triglycerides is by the chlymicrons form circulation is permitted, which allows the VLDL cholesterol to be determined. Laboratory tests include total cholesterol, LDL, triglycerides, apolipoprotein B, C-reactive protein, and HDL (3). They may also include lipoprotein (a), homocysteine, omega 3 index, small dense LDL (pattern B) (2,3). Furthermore, screening for manifestations of vascular disease such as exercise testing, magnetic resonance imaging may be done as well (2,3). Tests for diabetes, such as a fasting glucose or oral glucose tolerance test may be performed as well (2,3). Once the hyperlipidemia is classified, efforts are made to rule out secondary classes of hyperlipidemia (2,3).

Monitoring

LDL-C <2 mmol/L or LDL-C reduction greater or equal to 50% (4). The TC/HDL-C ratio should be less than 4 (4). Trigylcerides should be <1.7 mmol/L. The apolipoprotein B/apolipoprotein A ratio should be less than 0.8. Apolipoprotein B should be less than 0.8 g/L (4).

References

  1. Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT. Pharmacotherapy: Principles and Practice. McGraw-Hill: 2008. p. 385
  2. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2007. p. 175
  3. Zhai XQ, Hodgson, JM, Schlever AM. Hyperlipidemia. MD Consult [online]. Maryland Heights MO: Elsevier Inc. 2011 [cited 2011 Nov 6]. Available from: www.mdconsult.com
  4. Repchinsky C, editor-in-chief. Therapeutic Choices. 6th ed. Canadian Pharmacists Association; 2011. p. 432.

Disclaimer

This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers


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