25 Hyperlipidemias CLINICAL IMPORTANCE OF LIPOPROTEINS Raised levels of low-density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are independent risk factor for ischemic heart disease Raised levels of triglycerides, and lipoprotein a-lp (a) are linked to the extent and progression of atherosclerosis Lipid lowering plays great role in primary and secondary prevention of coronary events. Important Lipids in the Blood 1. Cholesterol 2. Triglycerides (TGL) 3. Fatty acids (non esterified) 4. Phospholipids. PHYSIOLOGICAL FUNCTIONS OF LIPIDS 1. Lipids synthesize cell membranes. 2. Provide energy. 3. Help in the absorption of fat-soluble vitamins. Transportation in blood: Lipids are transported in blood as lipoproteins since lipids by themselves are insoluble in blood. Hence they are combined with apoproteins and transported. These compounds are called Lipoproteins of which 5 important types are present. CLASSIFICATION OF LIPOPROTEINS BASED ON ULTRACENTRIFUGATION/ELECTROPHORESIS (FIG. 25.1) Classified according to their density: Chylomicrons: Transport dietary TGL from intestine into circulation VLDL- synthesised in liver and intestine: Function is to transport TGL. Intermediate density lipoproteins-idl Low-density lipoproteins LDL: Transport 75% of total plasma cholesterol.
184 Comprehensive Cardiology High-density lipoproteins HDL; synthesized in liver and intestine and are important for mobilization of tissue cholesterol. (TGL-Triglyceride) Note: After overnight fasting chylomicrons disappear from the blood and the lipoproteins measured are VLDL, LDL and HDL. Importance of identification Types: LDL, which transports mainly cholesterol, correlates strongly with the development of myocardial infarction HDL shows a negative correlation and increased levels are desirable The risk of CHD from TGL rise is related to associated abnormalities in glucose tolerance, body weight and HDL cholesterol. Constituents of lipoproteins (Fig. 25.2) Central core of triglycerides and cholesterol esters, surrounded by a coat of phospholipids, cholesterol and proteins called apoproteins or apolipoprotein. APOPROTEINS Fig. 25.1: Electrophoretic separation of lipoproteins Apoproteins constitute a varied collection of proteins with varying structures, e.g. apolipoprotein A, B, C, D and E with various subtypes. They stabilize the lipoprotein particles Have receptor recognizing function Influence enzyme functions activate or inhibit enzymes.
Hyperlipidemias 185 Fig. 25.2: Structure of lipoprotein Apoprotein A is associated with HDL Apoprotein B is associated with LDL and VLDL Apoprotein C is contained in chylomicron Lipoprotein (a) {Lp(a)} resembles LDL cholesterol in composition; this can also accelerate atherosclerosis. Apoprotein B in LDL is another atherogenic factor Lp (a): Lipoprotein little a Lp (a) is a particle of LDL cholesterol. Links to a glycoprotein by a disulphide bond. Importance of Lp (a) 1. It promotes atherogenesis 2. It is structurally similar to plasminogen and so it promotes thrombogenesis 3. It is a major and independent risk factor for atherogenesis. Optimum level should be under 20 mg/dl Currently there is no medicine or drug to effectively lower Lp (a) Drugs being tried to lower Lp (a)- are high doses of niacin and vitamin C Lipid transport in the blood Lipids are macromolecules insoluble in blood Un bound fatty acids have severe toxic effects on the body Some are bound to albumin and are carried in blood but the entire bulk cannot be. More fatty acids can be transported in esterified form- triacyl glycerol These hydrophobic neutral lipids are carried inside the core of specific lipoproteins
186 Comprehensive Cardiology Lipids inside the core are: Most hydrophobic ones TGL, and esterified cholesterol. They are protected from aqueous environment by an outer coat of more hydrophilic lipids, i.e. free cholesterol and glycerol phospholipids. Summary of fatty acid metabolism: Lipid transport system transports hydrophobic lipid molecules from site of synthesis to site of utilization. TGL is transported through digestive system and liver to peripheral sites of utilization (muscle) and storage (adipose tissue) Cholesterol is transported to liver forbile acid synthesis and for excretion from the body. Details of fatty acid metabolism: Two sources of lipids (Flow chart 25.1, Figs 25.3 and 25.4) Lipids originate from two sources: 1. Endogenous lipids synthesized in the liver. 2. Exogenous lipids: Ingested and processed in the intestine. a. Dietary cholesterol and TGL are converted in the intestine to chylomicrons, which enter blood stream via lymphatics. On reaching muscles and fatty tissues, LPL in capillaries breaks them to fatty acids, which then enters the muscle cells to provide energy. b. The remnants of chylomicrons which have lost most of TGL are taken up by the liver cells for disposal. c. Liver: Synthesises cholesterol and TGL, converts them to VLDL and releases them into blood. Theses reach muscles and adipose tissues. VLDL consists mainly of TGL which is hydrolysed by LPL (Lipoprotein Lipase) in capillaries, to fatty acids. They are then released and taken up by surrounding muscles to get energy. Some are taken up by adipose tissue. d. During this, VLDL is made progressively more dense and is converted to LDL. Most of the LDL is taken by liver; some circulate and provide cholesterol to rest of the body tissues. e. HDL is also secreted in liver. It remove surplus cholesterol from tissues, tranfer to LDL, which returns to liver. f. Liver in addition synthesises cholesterol to make bile acids. g. To regulate cholesterol uptake liver varies LDL receptors. HMG CoAR is the rate-limiting enzyme of cholesterol synthesis in liver. DYSLIPIDEMIA / HYPERLIPIDEMIA Hyperlipidemias are abnormalities of lipoprotein levels which promote development of atherosclerosis and coronary heart diseases.
Flow chart 25.1: Normal pathway of lipid transport Hyperlipidemias 187 Types Primary hyperlipidemia. Secondary hyperlipidemia. Primary Caused by genetic abnormalities affecting apoproteins, their receptors and enzymes involved in lipoprotein metabolism. (Frederickson classfication) Secondary Caused by certain clinical conditions. Diabetes, myxedema, renal disease, alcohol abuse, biliary obstruction, acute pancreatitis. Diets Rich in saturated fats also cause hypercholesterolemia by reducing hepatic lipoprotein clearance.
188 Comprehensive Cardiology Fig. 25.3: Exogenous lipoprotein pathways Fig. 25.4: Endogenous lipoprotein pathway Drugs Steroids, oral contraceptive (estrogen containing), thiazides, non-selective beta-blockers, isotretinoin (in acne).
Hyperlipidemias 189 Frederickson/WHO classification identifies 6 phenotypes: Type IIa; It is essentially hypercholesterolemia (LDL chol); normal TGL. Type I, IV and V: These are essentially hypertriglyceridemia ( VLDL and chylomicrons) Type IIb and III: Hypercholesterolemia with hypertriglyceridemia. LDL Cholesterol Level Less than100 mg/dl Optimal 100-129 mg/dl Near optimal/above optimal 130-159 mg/dl Borderline high 160-189 mg/dl High 190 mg/dl and above Very high HDL Cholesterol Level Less than 40 mg/dl Low (increased risk) 60 mg/dl and above High (heart protective) Normal Range of lipid level: Total cholesterol 150-250 mg/dl Triglycerides 70-150 mg/dl LDL cholesterol (100-130 mg) HDL cholesterol (40-60 mg) Lipids Desirable Levels of Blood Lipids Desirable levels Mg/dl of plasma Mmol/L Total cholesterol < 200 < 5 LDL-C < 130 < 3 HDL-C For women > 55 >1 For men > 45 >1 Triglycerides < 130 < 2 Ratio total:hdl-c < 4.5
190 Comprehensive Cardiology Recommendation of National Cholesterol Education Program (NCEP) in US: Indications of lipid lowering therapy Clinical state With CHD Free of CHD but two or more risk factors Free of CHD but with one risk factor Level of LDL at which to consider therapy More than 100 mg/dl (2.5 mmol/l) More than 130 mg/dl More than 160 mg/dl TREATMENT OF HYPERLIPIDEMIA Aim; To lower LDL cholesterol and triglycerides and to raise HDL cholesterol. Aggressive treatment required in CHD and when multiple CVS risks are present. Therapy can cause regression of existing atherosclerosis. Desirable levels of total cholesterol < 200 mg/dl (5.2 mmol/l) Stages in therapy for hyperlipidemia Stage I A. Diet therapy Reduce calories in obese to achieve ideal body weight Total fat should be 30% of energy intake Low fat and high carbohydrate diet; avoid refined sugar Avoid saturated fat (dairy products to be avoided) Use high fiber diet Avoid egg yoke, butter, cream, lard, fatty meat, and red meat Use margarine, vegetable oils, chicken and turkey; Recommend intake of oily fish, (mackerel, trout, salomon-) These contain proteins and omega 3 polyunsaturated fats Recommend vegetables, fibers, fruits about 5 portions a day This diet will reduce both cholesterol and TGL If diet fails to reduce/normalize lipids after 6 mths Drugs indicated. B. Exercise: Raises HDL levels. Constitutes important part of therapy. Stage II. Drug therapy Summary Statins for elevated LDL Fibrates for low HDL levels Bile acid sequestrants for women of child-bearing age since statins and fibrates are contraindicated in them. Nicotinic acid and derivatives for hypertriglyceridemia and low HDL.
Hyperlipidemias 191 A. Statins: Drugs Daily dose range Simvastatin 10-40 mg Lovastatin 10-40 mg(bd) Pravastatin 10-40 mg Atorvastatin 10-80 mg Fluvastatin 20-80 mg Cerivastatin 100-300 µg (withdrawn) Rosuvastatin 40 mg These drugs vary in potency and cost (Fluvastatin is weakest, cheaper, Atorvastatin most potent and costly) (All have similar mode of action and side effect). Mode of action of statins: They inhibit HMG CoA reductase which is the rate-limiting enzymein the production of cholesterol by the liver. These agents reduce total cholesterol and LDL (TGL-slightly), Increase, hepatic LDL receptors and HDL Increase in HDL occurs, especially with atorvastatin Maximum effect in 1 month. Side effects: Idiosyncratic and dose related. Elevated LFT results, elevated muscle CPK due to myopathy, rarely rhabdomyolysis this risk increased by cyclosporine. Avoid statins in; liver disease, alcoholism, pregnancy, lactation Stop statins if liver enzyme levels exceeds 3 times normal or - if patient develops muscle pain. Place in therapy; first line drug when LDL cholesterol is high. B. Bile acid binding anion exchange resins Drugs: Cholestyramine 4-8 gm tds Colestipol 5-10 gm tds Colesevelam 625 mg tablets 6 tablets per day. Mode of action: These bind bile acids in the small bowel and -Form an insoluble complex. -Prevent their reabsorption in the distal 200 cm of ileum increasing their excretion This in turn induces more free bile acids to be produced (in the liver) and secreted in the bile. Consequently more hepatic cholesterol is utilized; resulting in depletion of hepatic cholesterol, this leading to increase in LDL receptors on the liver cell, and this in turn increases clearance of LDL from the plasma.
192 Comprehensive Cardiology Hence higher level of cholesterol is absorbed from plasma to synthesis more bile salts. Side effects: Cause little systemic effects since they are not absorbed from intestine Nausea, vomiting, constipation, bloating, flatulence, hemorrhoids, intestinal obstruction these GI effects, since they are to be taken in high doses (upto 30 gm/day) Fat-soluble vitamin supplementation may be needed. Drug absorption reduced, e.g. of digoxin, thyroxin, warfarin. Can raise serum triglycerides level. Colesevelam-causes less GI tract side effects. Place in therapy: Indicated in premenopausal women-as fibrates and statins are contraindicated in pregnancy and at time of conception. Fibrates Fibric acid derivatives Primarily drugs for hypertriglyceridemia and when LDL cholesterol is low Drugs: Gemfibrozil, gemfibrozil, clofibrate, ciprofibrate, feno fibrate, beza fibrate. Action; exact mechanism not known. Suggestions mechanisms Stimulate lipoprotein lipase this enzyme catalyses VLDL, i.e. they increase VLDL catabolism and decrease VLDL production They also induce changes in LDL composition, which makes it less atherogenic and enhance fibrolysis. Place in therapy for fibretes: Primary drug for hypertriglyceridemia; mainly used in type IIb and III hyperlipidemia. Side effects: GI disturbances, risk for muscle toxicity leading to myoglobinuria causing renal failure especially if combined with statins or with excessive alcohol use. Avoid in liver and renal disease, children, pregnant women. Risk for gallstones, as increased amount of cholesterol is excreted in bile. Dose: Bezafibrate 200 mg tds after food; Clofibrate (Atromid) (not used nowadays) 500 mg tds; Gemfibrozil (Lopid) 600 mg bd. C. Nicotinic acid Action: It reduces both cholesterol and TGL in plasma; but high doses are required. Acts by reducing synthesis of VLDL in liver; Decreases LDL synthesis by reducing apoprotein B in liver.
Hyperlipidemias 193 Side effects; GI disturbances, pruritis, flushing, hyperglycemia, hyperurecemia, rise in liver enzymes. Rarely hyperpigmentation, acanthosis nigricans: Flushing is reduced by adding small doses of aspirin Dose: Start with 100 mg tds; gradually increase to1gm tds. Maximum recommended dose is 2 gm per day. Avoid in: Liver disease, gout, and h/o recent peptic ulcer LFT to be monitored. Omega 3 polyunsaturated fatty acids; Occur in purified fish oils Contain long chain fatty acids. Inhibit thrombosis Competitively antogonise thromboxanea 2 Lower the plasma triglyceride levels. Dose: 3-6 gm/day. D. Other modalities of treatment Indications: Reserved for hyperlipedemia is refractory to diet and drug therapy. For example, in those with homozygous hypercholesterolemia, (usually children): with very high levels. I. LDL apheresis Extracorporeal removal of LDL similar to plasma exchange every 2 to 3 weeks and similar to renal dialysis very expensive. Plasma exchange with LDL immunoabsorber column. II. Surgery Resection of distal 200 cm of ileum or bypassing of this segment. Porta caval shunt-less hazardous than liver transplant; Reduces LDL-C levels by 50%; exact mechanism not known. Liver and heart transplant Liver transplant provides new LDL receptors. Heart transplant required if in very early childhood severe premature CHD develops. III. Gene Therapy Involves replacement of abnormal LDLr gene with a normal gene; - Hepatocytes are obtained from patient s left lobe, cultured and these are transfected with a recombinant retrovirus containing normal human LDLr gene; These cells are transferred back to patient via a porto venous catheter: risk involved in surgery is more than the benefit. Another method of gene therapy: To enable liver to express VLDL receptor by transfection of VLDL receptor gene. Regression of coronary lesions on treatment Regression of coronary atherosclerotic lesion has been shown to occur with vigorous therapy to lower serum LDL cholesterol, in various trials.
194 Comprehensive Cardiology RECENT ADVANCES More potent statins: are being developed. MTP inhibitors: MTP transfers TGL to apoprotein. It is essential for the synthesis of chylomicrons and VLDL. Dietary and biliary cholesterol absorption inhibitor Ezetimibeanother drug launched, and found effective and is extensively used. ACAT inhibitor: Have failed to reach the market yet.