Diagnosis And Treatment Of Lipid Disorders PDF

DIAGNOSIS AND TREATMENT OF LIPID DISORDERS  Dyslipidemias: Diseases associated with abnormal lipid concentrations. defined by the clinical characteristics of patients and the results of laboratory tests Include both the overproduction and deficiency of lipoprotei...

DIAGNOSIS AND TREATMENT OF LIPID DISORDERS  Dyslipidemias: Diseases associated with abnormal lipid concentrations. defined by the clinical characteristics of patients and the results of laboratory tests Include both the overproduction and deficiency of lipoproteins caused by malfunctions in : the synthesis transport catabolism of lipoproteins. Due to: genetic abnormalities through environmental/lifestyle imbalances Secondarily of other diseases Hypercholesterolemia most closely linked to heart disease. Familial hypercholesterolemia FH: genetic abnormalities that predispose affected individuals to elevated cholesterol levels These individuals synthesize intracellular cholesterol normally but lack, or are deficient in, active LDL receptors. because there are insufficient receptors to bind the LDL and transfer the cholesterol into the cells. Cells, however, which require cholesterol for use in cell membrane and hormone production, synthesize cholesterol intracellularly at an increased rate to compensate for the lack of cholesterol from the receptor-mediated mechanism. Hypercholesterolemia Homozygotes for FH are fortunately rare (1:1 million in the population) and can have total cholesterol concentrations as high as 800 to 1,000 mg/dL. their first heart attack when still in their teenage years Heterozygotes for the disease are seen much more frequently (1:500 in the population). total cholesterol concentrations in the range of 300 to 600 mg/dL Other symptoms associated with FH include tendinous and tuberous xanthomas, which are cholesterol deposits under the skin, and arcus, which are cholesterol deposits in the cornea. Khodor Ozoor Clin. Chem. 2014 6 Khodor Ozoor Clin. Chem. 2014 7 Pcsk9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a 72-kDa serine protease expressed in the liver, kidney, and intestine that plays an important role in LDL metabolism. The principal route of clearance of circulating LDL-C from the blood is hepatocyte endocytosis, a process mediated by binding of LDL-C to LDL-R on the hepatocyte cell membrane PCSK9 binds to the extracellular epidermal growth factor–like repeat A (EGF-A) domain of LDL-R on the cell surface and is subsequently cointernalized with the LDL-R to lysosomes for degradation of the LDL- R. The binding of PCSK9 thus prevents the receptor from recycling to the plasma membrane, which can occur up to 150 times before it is normally inactivated or degraded. PCSK9 gene inactivation is an attractive target for lipid-lowering therapy. Hypertriglyceridemia Hypertriglyceridemia is generally a result of an imbalance between synthesis and clearance of VLDL in the circulation. The NCEP ATP III has identified borderline high triglycerides as levels of 150 to 200 mg/dL high as 200 to 500 mg/dL very high as greater than 500 mg/dL genetic abnormalities, called FH, or secondary causes, such as hormonal abnormalities associated with the pancreas, adrenal glands, and pituitary, or of diabetes mellitus (increased shunting of glucose into the pentose pathway, causing increased fatty acid synthesis) or nephrosis Hypertriglyceridemia has not been shown as an independent risk factor for CHD, but many CHD patients have moderately elevated triglycerides in conjunction with decreased HDL-C levels.  Triglycerides are influenced by a number of hormones, such as insulin, glucagon, pituitary growth hormone, adrenocorticotropic hormone (ACTH), thyrotropin, and adrenal medulla epinephrine and norepinephrine from the nervous system. Epinephrine and norepinephrine influence serum triglyceride levels by triggering production of hormone-sensitive lipase, which is located in adipose tissue.71 Other body processes that trigger hormone-sensitive lipase activity are cell growth (growth hormone), adrenal stimulation (ACTH), thyroid stimulation (thyrotropin), and fasting (glucagon).  Although severe hypertriglyceridemia (>500 mg/dL )is usually not associated with high risk of CHD, it is a potentially life-threatening abnormality because it can cause acute and recurrent pancreatitis. Severe hypertriglyceridemia is generally caused by a deficiency of LPL located on chromosome 8 or by a deficiency in apo C-II located on chromosome 19, which is a necessary cofactor for LPL activity. Normally, LPL hydrolyzes triglycerides carried in chylomicrons and VLDL to provide cells with free fatty acids for energy from exogenous and endogenous triglyceride sources. A deficiency in LPL or apo C-II activity keeps chylomicrons from being cleared Combined Hyperlipidemia defined as the presence of elevated levels of serum total cholesterol and triglycerides. at increased risk for CHD Genetic familial combined hyperlipidemia FCH is due in part to excessive hepatic synthesis of apoprotein B, leading to increased VLDL secretion and increased production of LDL from VLDL. eruptive xanthomas and are at high risk for developing CHD familial dysbetalipoproteinemia or type III hyperlipoproteinemia: accumulation of cholesterol-rich VLDL and chylomicron remnants as a result of defective catabolism of those particles. The disease is associated with the presence of a relatively rare form of apo E, called apo E2/2. The apo E2/2 cannot bind with hepatic E receptor, and therefore, VLDL and chylomicron remnant uptake is impaired. A ratio derived from the cholesterol concentration in VLDL to total serum triglycerides will be greater than 0.30 in the presence of type III hyperlipoproteinemia Lp(a) Elevation Elevations in the serum concentration of Lp(a), especially in conjunction with elevations of LDL, increase the risk of CHD and CVD Lp(a) are variants of LDL with an extra apolipoprotein, called apo (a); the size and serum concentrations of Lp(a) are largely genetically determined. Non–HDL Cholesterol on–HDL-C reflects total cholesterol minus HDL-C and encompasses all cholesterol present in potentially atherogenic, apo B–containing lipoproteins [LDL, VLDL, IDL, and Lp(a)]. On average, non– HDL-C levels are approximately 30 mg/dL higher than LDL-C levels Recent studies have shown that elevated levels of non–HDL-C are associated with increased CVD risk, even if the LDL-C levels are normal Treatment options Classic bile acid sequestrant drug treatments, such as cholestyramine, colesevelam, and colestipol, work by sequestering cholesterol in the gut so that it is not absorbed; this action enhances conversion of cholesterol into bile acids in the liver, reduces hepatic cholesterol content, and enhances the activity of LDL receptors, and until recently, these were considered to be the only safe drugs for use in children. These bile acid sequestrants lower LDL-C concentrations by 15% to 30% but may increase triglycerides. It is important to note that these agents interfere with the absorption of fat-soluble vitamins and some drugs like digoxin, warfarin, and thyroid supplements, resulting in altered blood concentrations of these drugs and prothrombin times. Bile acid sequestrants are contraindicated in individuals with triglyceride levels greater than 400 mg/dL (4.5 mmol/L). Bile acid sequestrants have uncomfortable adverse effects such as bloating and constipation and are poorly tolerated. Statins The most effective class of drugs for managing patients with dyslipidemia are the HMG-CoA reductase drug inhibitors, such as lovastatin, atorvastatin, and rosuvastatin. These drugs, commonly known as statins, block intracellular cholesterol synthesis by inhibiting HMG-CoA reductase, a rate-limiting enzyme in cholesterol biosynthesis. The reduced level of cholesterol in hepatocytes increases the expression of the LDL receptor, which removes LDL from the circulation, thus reducing the deposition of LDL into vessels and the formation of plaques. The major safety issues with statins are myositis and hepatotoxic effects; Routine monitoring of serum transaminases is recommended and creatine kinase for patients complaining of muscle-related symptoms. These drugs typically reduce LDL-C by as much as 20% to 40%, raise HDL-C by 5% to 10%, and can lower triglyceride by 7% to 43% maximum effects observed after 4 to 6 weeks.  Ezetimibe is a new drug that inhibits the absorption of cholesterol by inhibiting the Niemann-Pick C1-like 1 (NPC1-L1) transporter in the intestine without impacting the absorption of fat-soluble nutrients. Ezetimibe therapy has been shown to decrease LDL-C concentrations by approximately 20%  Fibric acid derivatives, such as clofibrate, gemfibrozil, fenofibrate, and etofibrate, are most often used to reduce triglyceride by 20% to 50% and increase HDL-C levels by 10% to 20%  Niacin or nicotinic acid at high doses (~2 to 6 g/d) is also a potent drug for reducing LDL-C levels (by 5% to 25%) and is the only effective drug at this time for significantly raising HDL-C levels (by 15% to 35% Hypobetalipoproteinemia Hypobetalipoproteinemia is associated with isolated low levels of LDL-C as a result of a defect in the Apo B gene, it is not generally associated with CHD Abetalipoproteinemia, which is due to a defect in the microsomal transfer protein used in the synthesis and secretion of VLDL, can also present with low LDL and apo B–like hypobetalipoproteinemia. It is an autosomal recessive disorder and like hypobetalipoproteinemia patients, they are not at an increased risk of cardiovascular disease but can develop several neurologic and ophthalmologic problems from fat-soluble vitamin deficiencies. Hypoalphalipoproteinemia Hypoalphalipoproteinemia indicates an isolated decrease in circulating HDL, typically defined as an HDL-C concentration less than 40 mg/dL (1.0 mmol/L),without the presence of hypertriglyceridemia. alpha denotes the region in which HDL migrates on agarose electrophoresis. LCAT, apo A-I, and ABCA1 transporter gene mutations. An extreme form of hypoalphalipoproteinemia, Tangier disease, is associated with HDL-C concentrations as low as 1 to 2 mg/dL (0.03 to 0.05 mmol/L) in homozygotes, accompanied by total cholesterol concentrations of 50 to 80 mg/dL (1.3 to 2.1 mmol/L). Niacin is somewhat effective in raising HDL-C but can have adverse effects, such as flushing or even hepatotoxicity, Hypoalphalipoproteinemia Acute, transitory hypoalphalipoproteinemia can also be seen in cases of severe physiologic stress, such as acute infections (primarily viral), other acute illnesses, and surgical procedures. HDL-C, as well as total cholesterol, concentrations can be significantly reduced under these conditions but will return to normal levels as recovery proceeds. For this reason, lipoprotein concentrations drawn during hospitalization or with a known disease state should be reassessed in the healthy, nonhospitalized state before intervention is considered. Arteriosclerosis Many, but not all, dyslipidemias, regardless of etiology, are associated with CHD or arteriosclerosis. CHD exceeds all other causes of death combined The relationship between heart disease and dyslipidemias stems from the deposition of lipids, mainly in the form of esterified cholesterol, in artery walls. This lipid deposition first results in fatty streaks, which are thin streaks of excess fat in macrophages in the subendothelial space Fatty streaks can develop over time into plaques that contain increased number of smooth muscle cells, extracellular lipid, calcification, and fibrous tissue, which can partially block or occlude blood flow. established plaque for unknown reasons can become vulnerable to rupture or erosion, triggering a thrombosis that can block circulation.  PVD: plaque in arteries of the arms or legs CAD: in the heart CVD: in the vessels of the brain, it is called cerebrovascular disease. CAD is associated with angina and myocardial infarction, and CVD is associated with stroke. Many genetic and acquired dyslipidemias may also lead to lipid deposits in the liver and kidney, resulting in impaired function of these vital organs. Lipid deposits in skin form nodules called xanthomas, which are often a clue to the presence of an underlying genetic abnormality.  it is estimated that for every 1% decrease in LDL-C concentration, there is a 2% decrease in the risk of developing arteriosclerosis. For patients with established heart disease, studies have shown that aggressive treatment to reduce LDL-C levels below 100 mg/dL is effective in the stabilization and sometimes regression of plaques individuals on a low-fat diet, who continue to have LDL-C levels of 190 mg/dL (4.9 mmol/L) or higher on repeated measurement, will likely benefit from drug intervention Low levels of HDL-C are also associated with increased risk of heart disease  Major Risk Factors for CHD Positive Risk Factors (RF) for CHD – Risk Factors Family history of early CHD – parent or sibling 160 >190 Known CHD Diet/exercise + Diet/exercise +drug Diet/exercise +drug Diet/exercise +drug Consider drug Diabetes (without CHD) Diet/exercise + Diet/exercise +drug Diet/exercise +drug Diet/exercise +drug Consider drug No known CHD but > 2 risk factors ---------------- Diet/exercise Diet/exercise +drug Diet/exercise +drug No known CHD but < 2 risk factors ----------------- ------------------- Diet/exercise Diet/exercise +drug Reference ranges: Total cholesterol < 200 mg/dl HDL: Male: Desirable > 45 Borderline 36-45 high risk < 35 Female: Desirable > 55 Borderline 36-45 high risk < 35 Non-HDL: When TG>200mg/dl, Non-HDL target treatment Goals: < 80 if extreme risk < 100 if Very high risk < 130 if high or moderate risk < 160 if Low riskHgtf Reference ranges: LDL: Treatment Goals: < 55 if extreme risk < 70 if Very high risk < 100 if moderate or high risk < 130 if Low risk Triglycerides: