Lipid Metabolism PDF

LIPID METABOLISM  The three main biological classes of lipid are: cholesterol, which is composed of hydrocarbon rings triglycerides (TGs), which are esters composed of glycerol linked to three long-chain fatty acids phospholipids, which are composed of a hydrophobic ‘tail’ consisting of...

LIPID METABOLISM  The three main biological classes of lipid are: cholesterol, which is composed of hydrocarbon rings triglycerides (TGs), which are esters composed of glycerol linked to three long-chain fatty acids phospholipids, which are composed of a hydrophobic ‘tail’ consisting of two long-chain fatty acids linked through glycerol to a hydrophilic head containing a phosphate group. Phospholipids are present in cell membranes and are important signaling molecules. Despite their poor water solubility, lipids need to be absorbed from the gastrointestinal tract and transported throughout the body. This is achieved by incorporating lipids within lipoproteins. Plasma cholesterol and TGs are clinically important because they are major treatable risk factors for cardiovascular disease, while severe hypertriglyceridaemia also predisposes to acute pancreatitis.# We say dyslipidemia and not hypercholesteremia CDL doesn't have cuz to be high , it's otherogenic  Lipids are transported and metabolized by apolipoproteins, which combine with lipids to form spherical or disc-shaped lipoproteins, consisting of a hydrophobic core and a less hydrophobic coat. The structure of some apolipoproteins also enables them to act as enzyme co-factors or cell receptor ligands. Variations in lipid and apolipoprotein composition result in distinct classes of lipoprotein that perform specific metabolic functions. alcohol trauma mumps gallstones introgenic autoimmune, Father causes pancreatitis , , > - , , for , drugs # held lipid deposition Xanthomatas hype triglyceridia causes serve  The main dietary determinants of plasma cholesterol concentrations are the intake of saturated and trans-unsaturated fatty acids, which reduce LDLR levels ,whereas dietary cholesterol has surprisingly little effect on fasting cholesterol levels. Plant sterols and drugs that inhibit cholesterol absorption are effective because they also reduce the re-utilisation of biliary cholesterol. The dietary determinants of plasma TG concentrations are complex since excessive intake of carbohydrate, fat or alcohol may all contribute to increased plasma TG by different mechanisms. Fasting is only need for Thaled cholestral , LDL , HDL , ULDL , not you  Lipids and cardiovascular disease Plasma lipoprotein levels are major modifiable risk factors for cardiovascular disease. Increased levels of atherogenic 3) 2) lipoproteins (especially LDL, but also IDL, and possibly intermediate - # chylomicron remnants) contribute to the development of d Atherosclerosis. A sub-population of LDL particles bears an endothelium additional protein known as apolipoprotein (a), which shares homology with plasminogen. The combination of LDL and apolipoprotein (a) is known as lipoprotein (a) (Lp(a)). It transports oxidized phospholipid and is regarded as atherogenic because its plasma concentration is an independent risk factor for cardiovascular disease. Following chemical modifications such as oxidation, Apo B- containing lipoproteins are no longer cleared by normal mechanisms.* Endothelium has two importantfunctions for CVS-NO production spor mible for v D. , and prostacyclin responsible for antagonizing Thromboxane and platelets - anti platelet  - beneficial , LDL-EDLBAD Conversely, HDL removes cholesterol from the tissues to the liver, where it is metabolized and excreted in bile. HDL may also counteract some components of the inflammatory response, such as the expression of vascular adhesion molecules by the endothelium. Consequently, low HDL cholesterol levels, which are often associated with TG elevation, are also associated with atherosclerosis. They trigger a self-perpetuating inflammatory response, during which they are taken up by macrophages to form foam cells, a hallmark of atherosclerotic lesions. These processes also have an adverse effect on endothelial function. # In general Middle Easters have low HDL ,you cant it by excea Investigations Lipid measurements are usually performed for the following reasons: prevent discuse street it screening for primary or secondary prevention of cardiovascular disease investigation of patients with clinical features of lipid disorders and their relatives monitoring of response to diet, weight control and medication. Abnormalities of lipid metabolism most commonly come to light following these tests. Non-fasting measurements of total cholesterol (TC) and HDL cholesterol (HDL-C) allow estimation of non-HDL cholesterol (non-HDLC, calculated as TC − HDL-C), but a 12-hour fasting sample is required to standardize TG measurement and allow calculation of LDL cholesterol (LDL-C) according to the Friedewald formula: LDL-C = TC −HDL-C − (TG/2.2)mmol/L or LDL-C = TC −HDL-C − (TG/5)mg/dL is su Th normal The formula becomes unreliable when TG levels exceed 4 mmol/L (350 mg/dL). Measurements of non-HDLC or Apo B100 may assess risk of cardiovascular disease more accurately than LDL-C, particularly when TG levels are increased. The use of non-fasting samples is increasing X because non-fasting TG is a more sensitive marker of the risk of cardiovascular disease. Nevertheless, a 12-hour fast is required for formal diagnosis of the presence of hypertriglyceridaemia or use of the Friedewald equation. Consideration must be given to confounding factors, such as recent illness, after which cholesterol, LDL and HDL levels temporarily decrease in proportion to severity. Results that will affect major decisions, such as initiation of drug therapy, should be confirmed with a repeat measurement. Elevated levels of TG are common in obesity, diabetes and insulin resistance, and are frequently associated with low HDL and increased ‘small, dense’ LDL. Under these circumstances, LDL-C may under-estimate risk. This is one situation in which measurement of non-HDLC or Apo B may provide more ↑ ↑ ~ ~ ~ ~ ~ - ~ - Y ~  ! ↳ Achilles Fender Xanthoma Hypercholesterolaemia - Hypercholesterolaemia is a polygenic disorder that is the most common cause of a mild to moderate increase in consanguineous marriage. Homozygosity results in more extensive xanthomas and precocious cardiovascular disease, often in childhood. Physical signs, such as corneal arcus and xanthelasma, may be found in this as well as other forms of lipid disturbance. The risk of cardiovascular disease is proportional to the degree of LDL-C (or Apo B) elevation, but is modified by other major risk factors, including low HDL-C and high Lp(a). = Safe Hypertriglyceridaemia Hypertriglyceridaemia also usually involves polygenic factors. Other common causes include excess alcohol intake, medications (such as β-blockers and retinoids), type 2 diabetes, impaired glucose tolerance, central obesity or other manifestations of insulin resistance and impaired absorption of bile acids. It is often accompanied by post- prandial hyperlipidaemia and reduced HDL-C, both of which may contribute to cardiovascular risk. Excessive intake of alcohol or dietary fat, or other exacerbating factors, may precipitate a massive increase in TG levels, which, if they exceed 10 mmol/L (880 mg/dL), may pose a risk of acute pancreatitis. They can present in childhood and may be associated with episodes of acute abdominal pain and pancreatitis. In common with other causes of severe hypertriglyceridaemia, hepatomegaly, lipaemia retinalis and eruptive xanthomas may occur. Mixed hyperlipidaemia The term ‘mixed’ usually implies the presence of hypertriglyceridaemia, as well as an increase in LDL- C or IDL. Treatment of massive hypertriglyceridaemia may improve TG faster than cholesterol, Primary mixed hyperlipidaemia is usually polygenic and, like predominant hypertriglyceridaemia, often occurs in association with type 2 diabetes, impaired glucose tolerance, central obesity or other manifestations of insulin resistance. Both components of mixed hyperlipidaemia may contribute to the risk of cardiovascular disease. Principles of management Lipid-lowering therapies have a key role in the secondary and primary prevention of cardiovascular diseases. Assessment of absolute risk of cardiovascular disease, treatment of all modifiable risk factors and optimization of lifestyle, especially diet and exercise, are central to management in all cases. Patients with the greatest absolute risk of cardiovascular disease derive the greatest absolute benefit from treatment. Public health organizations recommend thresholds for the introduction of lipid- lowering therapy based on the identification of patients in very high-risk categories, or those calculated to be at high absolute risk according to algorithms or tables such as the Joint British Societies Coronary Risk Prediction Chart.  * DM is indicationfor statin * #BB is indicative forD # Less than 33yrs old , usually diastolic HPT while with and results ingaping ! aging SBP9 [ > - Age /BP / hipid profile - smoke or not ~ In general, patients who have cardiovascular disease, diabetes mellitus, chronic renal impairment, familial hypercholesterolaemia or an absolute risk of cardiovascular disease of more than 20% in the ensuing 10 years are arbitrarily regarded as having sufficient risk to justify drug treatment. Age is such an overwhelming determinant of absolute cardiovascular risk that some recent recommendations consider ‘lifetime’ risk. Public health organizations also recommend target levels for patients receiving drug treatment. High- risk patients should aim for HDL-C > 1 mmol/L (38 mg/dL) and fasting TG < 2 mmol/L (approximately 180 mg/dL), while target levels for LDL-C have been reduced to 1.8 mmol/L (76 mg/dL) or less. In general, total cholesterol should be < 5 mmol/L (190 mg/dL) during treatment, and < 4 mmol/L (approximately 150 mg/dL) in high-risk patients and in secondary prevention of cardiovascular disease. Recent trials have demonstrated continuous benefit of LDL-C reduction to a level of 1.4 mmol/L (54 mg/dL), so further reduction in treatment targets may be anticipated. Non-pharmacological management Patients with lipid abnormalities should receive medical advice and, if necessary, dietary counselling to: reduce intake of saturated and trans-unsaturated fat to less than 7–10% of total energy reduce intake of cholesterol to < 250 mg/day replace sources of saturated fat and cholesterol with alternative foods, such as lean meat, low-fat dairy products, polyunsaturated spreads and low-glycaemicindex carbohydrates reduce energy-dense foods such as fats and soft drinks, while increasing activity and exercise to maintain or lose weight increase consumption of cardioprotective and nutrientdense foods, such as vegetables, unrefined carbohydrates, fish, pulses, nuts, legumes, and fruit adjust alcohol consumption, reducing intake if excessive or if associated with hypertension, hypertriglyceridaemia or central obesity achieve additional benefits with preferential intake of foods containing lipid-lowering nutrients such as n-3 fatty acids, dietary fibre and plant sterols. The response to diet is usually apparent within 3–4 weeks but dietary adjustment may need to be introduced gradually. Although hyperlipidaemia in general, and hypertriglyceridaemia in particular, can be very responsive to these measures, LDL-C reductions are often only modest in routine clinical practice. Explanation, encouragement and persistence are often required to assist patient adherence. Even minor weight loss can substantially reduce cardiovascular risk, especially in centrally obese patients.  Pharmacological management colestrymine PC19 Statis Ezetimibe , Ir ↳ , , Libitor's Hypercholesterolaemia combination therapy & Hypercholesterolaemia can be treated with one or more of the cholesterol-lowering drugs as described below. Statins > - myopathy taken causes night , at These reduce cholesterol synthesis by inhibiting the HMGCoA reductase enzyme. The reduction in cholesterol synthesis up-regulates production of the LDLR, which increases clearance of LDL and its precursor, IDL, resulting in a secondary reduction in LDL synthesis. Statins reduce LDL-C by up to 60%, reduce TG by up to 40% and increase HDL-C by up to 10%. They also reduce the concentration of intermediate metabolites such as isoprenes, which may lead to other effects such as suppression of the inflammatory response. There is clear evidence of protection against total and coronary mortality, stroke and cardiovascular events across the spectrum of cardiovascular disease risk. figa mindges I , Silvastatin - Acrostatin - use lipophilic leading to myopathy  Statins are generally well tolerated and serious side-effects are rare (well below 2%). Liver function test abnormalities and muscle problems, such as myalgia, asymptomatic increase in creatine kinase (CK), myositis and, infrequently, rhabdomyolysis, are the most common. Side-effects are more likely in patients who are elderly, debilitated or receiving other drugs that interfere with statin degradation, a avoi Macrolideso Le which usually involves cytochrome P450 3A4 or glucuronidation. pts totitor We have Enty leading e 3 -- S Massure CI it so times Simple my spathy on Rhabdomyolisis sitis. = - elevated above normal , then Stopp stop Ezetimibe Ezetimibe inhibits activity of the intestinal mucosal transporter NPC1L1, which is responsible for absorption of dietary and biliary cholesterol. The resulting depletion of hepatic cholesterol up- regulates hepatic LDLR production. This mechanism of action is synergistic with the effect of statins. Monotherapy in a 10 mg/day dose reduces LDL-C by 15–20%. Slightly greater (17–25%) incremental LDL-C reduction occurs when ezetimibe is added to statins. Ezetimibe is well tolerated, and evidence of a beneficial effect on cardiovascular disease endpoints is now available. Plant sterol- supplemented foods, which also reduce cholesterol absorption, lower LDL-C by 7–15%.  biliary of Bile acid-sequestering resins rhosis > itchie in - Drugs in this class include colestyramine, colestipol and colesevelam. These prevent the reabsorption of bile acids, thereby increasing de novo bile acid synthesis from hepatic cholesterol. As with ezetimibe, the resultant depletion of hepatic cholesterol up-regulates LDL receptor activity and reduces LDL-C in a manner that is synergistic with the action of statins. PCSK9 inhibitors Highly effective Monoclonal antibodies have been developed that neutralise PCSK9, an enzyme that degrades the LDLR. This causes levels of LDLR to increase, which markedly reduces LDL-C. The PCSK9 inhibitors currently available are evolocumab and alirocumab, which are administered by subcutaneous injection every 2–4 > weeks. These drugs are well tolerated and highly - effective. Reductions in LDL-C of about 50–60%. Nicotinic acid > - ToMADL but poorlytelerated Pharmacological doses reduce peripheral fatty acid release, with the result that VLDL and LDL decline while HDL-C increases.  Combination therapy ↓ In many patients, treatment of predominant hypercholesterolaemia can be achieved by diet plus the use of a statin in sufficient doses to achieve target LDL-C levels. Patients who do not reach LDL targets on the highest tolerated statin dose, or who are intolerant of statins, may receive ezetimibe, plant sterols, or resins. Ezetimibe and resins are safe and effective in combination with a statin because the mechanisms of action of individual therapies complement each other while blunting each other’s compensatory mechanisms. Hypertriglyceridaemia Fibrates Fibrates reduce TG by up to 50% and increase HDL-C by up to 20%, but LDL-C changes are variable. Fibrates are usually well tolerated but share a similar side-effect profile to statins. In addition, they may increase the risk of cholelithiasis and prolong the action of anticoagulants. Accumulating evidence suggests that they may also have a protective effect against diabetic microvascular complications. f Highly polyunsaturated long-chain n-3 fatty acids EPA and DHA are potent inhibitors of VLDL TG formation. Intakes of more than 2 g n-3 fatty acid (equivalent to 6 g of most forms of fish oil) per day lower TG in a dose-dependent fashion. Up to 50% reduction in TG may be achieved with 15 g fish oil per day. Changes in HDL-C are variable but fish oils do not routinely reduce LDL-C. LPatients with predominant hypertriglyceridaemia who do not respond to lifestyle intervention can be treated with fibrates or fish oil, depending on individual response and tolerance. If target levels are not achieved, the fibrates, fish oil and possibly nicotinic acid can be combined. Massive hypertriglyceridaemia may require more aggressive limitation of dietary fat intake (< 10–20% energy as fat). Any degree of insulin deficiency should be corrected because insulin is required for optimal activity of lipoprotein lipase. The initial target for patients with massive hypertriglyceridaemia is TG < 10 mmol/L (880 mg/dL), to reduce the risk of acute pancreatitis. *  * If hiver functions are normal with Monitoring of therapy stations statin after repeat buls , need no to it ! - The effects of lipid-lowering therapy should be assessed after 6 weeks (12 weeks for& - fibrates). At this point, it is prudent to review side-effects, lipid response (see target levels above), CK and liver function tests. During longer-term follow-up, adherence to treatment, diet and exercise should be assessed, with monitoring of weight, blood pressure and lipid levels. The presence of cardiovascular symptoms or signs should be noted and absolute cardiovascular risk assessed periodically. Effective statin therapy may be associated with a paradoxical and as yet unexplained increase in coronary calcium score. It is not necessary to perform routine checks of CK and liver function unless symptoms occur, or if statins are used in combination with fibrates, or other drugs that may interfere with their clearance. If myalgia or weakness occurs in association with CK elevation over 5–10 times the upper limit of normal, or if sustained alanine aminotransferase (ALT) elevation more than 2–3 times the upper limit of normal occurs that is not accounted for by fatty liver, treatment should be discontinued and alternative therapy sought.