Chapter (5) Etiology of Low HDL- Cholesterol

Chapter (5) Etiology of Low HDL- Cholesterol

The aim of this chapter is to summarize the different etiological factors mainly the role of life-style and different disease conditions contributing to the development of low HDL cholesterol. CAUSES OF LOW HDL C A. Genetic B. Diseased Conditions 1. Diabetes Mellitus & Metabolic Syndrome. 2. Hyperthyroidism. 3. Liver diseases. 4. Renal diseases. C. Life Style 1. Physical inactivity. 2. Smoking. 3. Overweight and obesity. 4. Diet. D. Drugs 1. Diuretics 2. -Adrenergic blockers

A-CONGENITAL CAUSES Include the following conditions: 1-Tangier Disease: 2- Lecithen Cholesterol Alyl Transferase (LCAT) deficiency. B. DISEASED CONDITIONS 1. Diabetes Mellitus and Metabolic Syndrome Type 2 D.M and insulin resistance syndrome are pathogenetically related to each other and have common dyslipidemic characteristics. Type 2 D.M and insulin resistance patients are typically characterized by hypertriglyceridemia and Low HDL-C levels. LDL-C levels are less consistent in different studies. They were demonstrated to be normal, higher or lower than non diabetic individuals. Low HDL-C / high triglycerides pattern is a better correlator and predictor of CHD than LDL-C level. More over compositional changes of lipid particles are observed. Both LDL-C and HDL-C particles are smaller and denser than average. HDL particle size decreases gradually from non diabetic individuals to prediabetics to patients with D.M. Possible Mechanisms of Diabetic Dyslipidemia Resistance to the antilipolytic effect of insulin leads to an exaggerated flux of free fatty acids into the liver. The increased supply of these molecules to the liver together with a resistance of the hepatic VLDL secretion to the inhibitory effects of insulin lead to hypertriglyceridemia. Hypertriglyceridemia is perhaps the most common lipid abnormality in insulin resistance and is primarily due to increased production of very low density (VLDL) particles. Several investigators have proposed that the lowering of HDL levels observed in insulin resistant states is largely a consequence of the fasting and postprandial hypertriglyceridemia commonly occurring in these states. There is a dynamic interactions between TG-rich lipoproteins and HDL in plasma. 2. Hyperthyroidism It is well known that alterations in thyroid function result in changes in the composition and transport of lipoproteins. while hypothyroidism is associated with normal or elevated HDL-C levels, hyperthyroidism (both overt and subclinical) is accompanied with a decrease in its levels. These changes in the lipid profile are explained by the regulatory effect of thyroid hormones on the activity of some key enzymes of lipoprotein metabolism.

Thyroid hormones stimulate the cholesterol ester transfer protein (CETP), the enzyme which transports cholesteryl esters from HDL2 to the very low density lipoproteins (VLDL) and triglycerides in the opposite direction. moreover, thyroid hormones stimulate the lipoprotein lipase (LPL) which catabolizes triglycerides-rich lipoproteins and hepatic lipase (HL), which hydrolyzes HDL2 to HDL3. Hyperthyroidism constitutes a significant cause of hypobetalipoproteinemia and its treatment results in restoration of these changes to normal. 3. Liver Diseases The liver is the center for the synthesis of the majority of enzymatic and non enzymatic proteins in our body. Apo and lipo-proteins which are involved in the transport and distribution of lipids in tissue systems are also mainly synthesized in the liver. Decreased levels of HDL-C has consistently been observed in a number of liver diseases. A-Acute viral hepatitis: It has long been observed that acute viral hepatitis is associated with low level of apo-a together with hypertriglyceridemia, absence of -and pre -band, on lipoprotein electrophoresis. B-Hepatic cell failure: Decreased level of Apo-A and HDL-C are highly related to the degree of liver injury and this decrease has been suggested to be due to impaired hepatic synthesis. The reduction of HDL-C was found to be more pronounced than that of ApoA1 and the HDL-C: ApoA1 ratio was significantly lower in liver failure patients. 4. Renal Diseases Among other abnormalities, patients with chronic kidney disease have an elevated ratio of LDL-C to HDL-C. LDL-C levels are slightly elevated in patients with chronic kidney disease while HDL-C levels are decreased indicating loss of antiatherogenic effect. C. LIFE STYLE 1. Diet Very low fat-diet can produce HDL-C deficiency. All fats increase HDL-C with the effect of dietary saturated fat being greater than that of unsaturated fats. Monounsaturated (Omega-3) fats are effective in HDL-C increase.

2. Overweight Obesity is frequently associated with HDL-C decrease. However, not all obese persons demonstrate the same phenomenon. In those with obesity and low HDL-C, it has been found that weight reduction generally increase HDL-C level. But this reduction has to be substantial and sustained for its effect on HDL-C level to appear. The exact mechanism of this relationship between body weight and HDL-C level is not clear, but this could be related to elevation of TGDs in some obese individuals which is known to have an inverse relationship to HDL-C level by a mechanism that may involve activity of LPL and CETP. 3. Physical inactivity Physical inactivity is associated with low HDL-C level and regular aerobic exercise causes HDL-C increases, particularly HDL2 subfraction. This increase of HDL-C level induced by physical activity may be due to stimulation of LPL activity. 4. Smoking Smoking reduces the concentration of HDL-C and smoking cessation is associated with an increase in its levels. The mechanism and impact on IHD of smoking-mediated effects on HDL-C is not known, although in vitro, LCAT activity is shown to be inhibited by the serum of smokers. SUMMARY A wide variety of conditions and medical disorders have been documented to be associated with low HDL-C. Most of these conditions are commonly encountered in medical practice. Luckily enough, almost all the etiological factors of low HDL-C (except congenital causes) are modifiable either through life style modification, active medical treatment or both.