University:
Kentucky State University
Course:
BIO 303 | Human Physiology
Academic year:

2019
Views:

454

Pages:

51
Author:

Hundebuchesn

Disorders of lipid metabolism Lipid disorders CH.7 1 Lipids Lipid disorders CH.7 2 Defined on the basis of solubility. Lipids are heterogeneous group of water insoluble (hydrophobic) organic molecules, they are chemically diverse compound but have one feature: water insoluble Functions The biological functions of lipids are divers as their chemistry 1. Lipids in form of a bilayer are essential components of biological membranes. 2. Lipids containing hydrocarbon side chains serve as energy stores. 3. Many intra-and intercellular signaling events involve lipid molecules. Lipid Classification 1. Storage lipids Triglycerides, Waxes and Fatty acids. 2. Structural lipids in membranes Glycerophospholipids, Sphingolipids, Sterols are major structural elements in biological membranes 3. Lipids as signals, cofactors and pigments. These lipids presents in small quantities but play crucial roles - Phosphatidylinositols, Eicosanoids - Prostaglandins. - Thromboxanes. - Leukotrienes. - Steroid hormones carry messages between tissues. - Vitamins A and D are hormone precursors. - Vitamins E and K are oxidation-reduction cofactors. Lipid disorders CH.7 3 Lipid disorders CH.7 4 Lipid disorders CH.7 5 Lipids Disorder • Lipids deficiency (Shortage in Lipids intake) • Lipids exceeding (Overtaking in Lipids intake) 6 Lipid disorders CH.7 Disorders of lipid metabolism…Excess Hyperlipidaemia Lipid disorders CH.7 Clinical manifestation of hyperlipidaemia: • Prolonged hyperlipidaemia results in accumulation of lipid in tissues and causes cell damage. • Lipids may accumulate in: 1. arterial wall, 2. subcutaneous tissue, 3. tendons 4. cornea 1. Arterial walls. -It is the most important manifestation of lipid disorders. -Cholesterol accumulation and associated cellular proliferation and fibrous tissue formation produces atheromatous plaques. -Atherosclerosis is due to deformation and obstruction of the artery that may result from calcification and ulceration of plaques. The small lipoproteins LDL and IDL are atherogenic. 7 2. Subcutaneous tissue The accumulation of lipids in subcutaneous tissue causes xanthomatosis (xanthoma: is a yellow nodule plaque). The nature of the lipid fraction most affected usually determines the clinical appearance: Eruptive xanthomata are crops of : -small, -itchy, -yellow nodules (1-4mm) -yellowish-brown papules. They are associated with very high plasma VLDL or chylomicron (triglyceride) concentrations, which disappear if plasma lipid concentrations fall to normal. Appear over extensors of the elbows and knees, and on the back and buttocks of patients with severe hyperlipidaemia Lipid disorders CH.7 8 Xanthelasma soft yellow-orange plaques on the eyelids are lipid deposits under the periorbital skin and may be associated with high plasma LDL-cholesterol concentrations Lipid disorders CH.7 9 Lipid disorders CH.7 10 3. Tendons Tendinous Xanthomata and usually on Achilles tendons or the extensor tendons of the hands occur in familial hypercholesterolaemia 4. Cornea: Corneal arcus under the age of 40 may be caused by the deposition of lipids and associated with high plasma LDL-cholesterol concentrations. Arcus senilis presents in older subjects. Lipid disorders CH.7 11 Lipid disorders CH.7 12 Classification of Disorders of lipid metabolism Currently there is no satisfactory comprehensive classification of lipoprotein disorders. In practice, lipoprotein disorders are classified as being: 1. Primary-when the disorder is not due to an identifiable underlying disease. Due to: -Genetic factor, -Environmental factor, 2. - A combination of both Secondary-when the disorder is a manifestation of some other disease. Primary lipid Disorders: 1-Genetic classifications: are becoming increasingly complex as different mutations are discovered Familial hypercholesterolaemia (FH), may be due to any of over 500 different mutations of the LDL receptor gene. *The same genotype can be expressed as more than one phenotype in different individuals. i.e different clinical manifestations (signs and symptoms) in different individuals for the same genetic disorder. *These manifestations depend on the severity of the case, and on the life style *Until gene therapy and/or specific substitution therapy become more available, genetic 13 classifications, are unlikely to prove very useful in practice. Lipid disorders CH.7 THE LDL RECEPTOR AND ATHEROSCLEROSIS: Familial Hypercholesterolemia FH Sites for LDL-R defects Normal Mutated Lipid disorders CH.7 14 2. WHO classification: based on -Fredrickson work and -its phenotypic classification: based on the observation pattern of lipoprotein abnormality *The Fredrickson or World Health Organization classification is the most widely accepted for the primary hyperlipidaemias. •It is based on the appearance of fasting plasma sample after standing for 12hr at 4°C and analysis of its cholesterol and TG *The six types by Fredrickson are not equally common. Type I and V are rare, while types IIa, IIb and IV are very common. * As a result, patients with the same genetic defect may fall into different groups, or may change grouping as the disease progresses or treated. * The major advantage of this classification is that it is widely accepted and gives some guidance for treatment 15 Lipid disorders CH.7 Fredrickson (WHO) classification of dyslipidaemia Lipid disorders CH.7 16 Lipid disorders CH.7 17 Lipid disorders CH.7 Genetic classifications: Genetic defect Fredrickson Risk Familial Hypercholesterolemia Reduced number of functional LDL receptors IIa or IIb CHD Familial hypertriglyceridemia Possibly single gene defect IV or V Familal combined hyperlipidemia Possibly single gene defect IIa, IIb, IV or V CHD Lipoprotein lipase deficiency Reduced levels of functional LPL I Pancreatitis Apo C-II deficiency Inability to synthesize apo CII (cofactor of LPL) I Pancreatitis Abetalipoproteinemia Inability to synthesize apo B Normal Fat soluble vitamins deficiencies, neurological deficit Analphalipoproteinemia Inability to synthesize apo A Normal Neurological deficit, CE storage in abnormal places Disease 18 Primary Lipoprotein Disorders Primary hyperlipidaemias Genetic defect Disease Fredrickson (Lipopr mainly affected) Concentration in plasma Cholest TG Familial Hypercholesterolemia Reduced number of functional LDL receptors IIa or IIb (LDL) Familial hypertriglyceridemia Possibly single gene defect IV or V (VLDL+(chylom) or N Cholest TG Familal combined hyperlipidemia Possibly single gene defect IIa, IIb, IV or V (LDL&/orVLDL) or N Cholest or N TG Lipid disorders CH.7 N (or ) Cholest TG 19 Lipid disorders CH.7 20 Predominant hypercholesterolaemia The risk of developing cardiovascular disease increases as the plasma cholesterol concentration rises above 200 mg/dl in the absence of other risk factors this value could be raised Causes of hypercholesterolaemia - Hypercholesterolaemia associated with little or no elevation of plasma triglyceride concentration is almost always due to a raised plasma LDL *The coexistence of an underlying genetic defect or other lipid disorders cause a greater increase in plasma cholesterol with age. Secondary hypercholesterolaemia. Disorders that may produce a secondary increase in plasma total and LDL-cholesterol -primary hypothyroidism, -cholestasis -diabetes mellitus, -drugs (e.g.; thiazides). -nephrotic syndrome, Lipid disorders CH.7 21 Primary hyperlipidaemias Lipid disorders CH.7 Familial hypercholesterolaemia (FH) •This condition is characterized by: high plasma cholesterol concentrations which are present from early childhood and do not depend upon the presence of environmental factors. * Different mutations can affect LDL synthesis, transport, ligand binding, and recycling but all cause a similar phenotype. *The familial incidence of hypercholesterolaemia, often associated with an increased risk of ischemic heart disease, suggests an inherited disorder. * Environmental and dietary factors may determine the expression of the defect. * The risk of developing cardiovascular disease is higher than normal, 22 compared with an age- and sex matched population. Familial (monogenic) hypercholesterolaemia Lipid disorders CH.7 Caused by a LDL receptor defect  reduced cellular uptake of LDL, LDL particularly by the liver  causes an increase extracellular space cytosol LDL in plasma total and LDL- cholesterol concentrations. receptor receptor-mediated Plasma triglyceride concentrations are either normal endocytosis or only slightly increased it is the most lethal of the inherited disorders. In homozygotes LDL receptors are virtually absent and plasma LDL-cholesterol is 3 to 4 times higher than those in normal subjects patients usually die before the age of 20 from ischaemic heart disease. In heterozygotes LDL The number of LDL receptors is reduced by 50% and the plasma cholesterol concentrations are about twice those in normal subjects. They have a 10 to 20-fold higher risk of developing ischaemic heart disease than normal 23 Lipid disorders CH.7 Predominant hypertriglyceridaemia * Elevated plasma triglyceride concentrations may be due to an increase in plasma VLDL, or chylomicrons or both. •Sustained and very high plasma concentrations of chylomicrons are associated with abdominal pain and even acute pancreatitis, as well as eruptive xanthomata. * Many cases of hypertriglyceridaemia are symptom free. These large lipoproteins are unlikely to cause artheroma, per se. (by itself) However, many patients with increased concentrations of VLDLtriglyceride have reduced concentration of plasma HDL and increased plasma concentration of LDL or IDL, which contain cholesterol. * Hypertriglyceridaemia is usually secondary to another disease: -obesity and -excessive carbohydrate intake, -alcohol, 24 -drugs (thiazide diuretics) and -acute pancreatitis. Familial endogenous hypertriglyceridaemia: is caused by hepatic triglyceride overproduction with increased VLDL secretion. * The condition usually becomes apparent only after the fourth decade. * It may be associated with: -obesity, -glucose intolerance, -hyperuricaemia and -decrease in plasma HDL-cholesterol concentration. * Insulin resistance may be a common factor in the above conditions. * High plasma triglyceride concentrations may cause eruptive xanthomata. * primary hypertriglyceridaemia is less than primary hypercholesterolaemia 25 Lipid disorders CH.7 Lipid disorders CH.7 26 27 Lipid disorders CH.7 Lipid disorders CH.7 28 Lipid disorders CH.7 Familial combined hyperlipidaemia: Mixed hyperlipidaemia  It is common disorder  Associated with excessive hepatic production of apoB,  increase LDL and VLDL-triglyceride synthesis due to either a primary or secondary disorder.  Family members have a variety of different phenotypes.  In one-third there is an increase in plasma LDL-cholesterol  In another third there is an increase in both LDL-cholesterol and VLDL-triglycerides  The remaining third have VLDL-hypertriglyceridaemia.  The lipid abnormalities appear significantly after the age of 30  The risk of ischaemic heart disease in all cases is higher  Raised plasma concentrations of both cholesterol and triglycerides are commonest in patients with: -poorly controlled diabetes mellitus, 29 -severe hypothyroidism or -the nephrotic syndrome. Hyperchylomicronaemia * is usually due either to an acquired or inherited deficiency of lipoprotein lipase. * Insulin is needed for optimal enzyme activity  hyperchylomiconaemia may occur in poorly controlled diabetic patients. Inherited lipoprotein lipase deficiency may be due to: A) True deficiency of the enzyme B) Reduced activity of the enzyme because of apo C-II deficiency  Which is an activator for lipoprotein lipase -The plasma is very turbid because of the accumulation of chylomicrons. -True lipoprotein lipase deficiency usually presents during childhood, with signs and symptoms due to an excess of fat at skin, liver (hepatomegaly) retinal vessels and abdomen. - Hyperchylomiconaemia due to apoC-II deficiency is most likely to present in 30 Lipid disorders CH.7 adults. Lipid disorders CH.7 31 Rare disorders associated with lipid metabolism Lipid disorders CH.7 -A few rare disorders, which are associated with reduced plasma lipid concentration but with the accumulation of lipid in tissues - Inherited disorder of HDL deficiency (Tangier disease): -Called also Analphalipoproteinaemia -Associated with premature coronary heart disease. -An abnormal apoA leads to an increased rate of catabolism of HDL. -Plasma HDL concentrations are low and cholesterol esters accumulate in the reticuloendothelial system. Abetalipoproteinaemia (ApoB deficiency): - absence of Apo B - results in impaired synthesis of chylomicrons and VLDL, and therefore of LDL. -lipids cannot be transported from the intestine to the liver. - risk: decraese in fat soluble vitamins  lead to neurological defects, for treatment vitamins are given I.V Hypobetalipoproteinaemia In this condition there is partial deficiency of apo B; CM, VLDL and LDL are present, but in low concentrations. LCAT deficiency: results in accumulation of free, mostly unesterified, cholesterol in tissues 32 Secondary lipid disorders Secondary hyperlipoproteinaemia is a well recognized feature of a number of diseases Common causes of secondary hyperlipidaemia including: obesity and diabetes mellitus management should be directed towards the cause. Lipid disorders CH.7 33 Effect of Alcohol on Lipid profile Large quantity of Ethanol increases the synthesis of Fatty acid,  because of production of NADH and acetate Fatty acid  TG  VLDL Ethanol NADH Alcohol dehydrogenase Acetaladehyde NADH Aldehyde dehydrogenase Acetate Lipid disorders CH.7 34 Lipoprotein metabolism in diabetes mellitus Lipid disorders CH.7 35 Insulin has a major role in the control of fat metabolism, and both type I and type 2 DM are associated with abnormalities of plasma lipids In uncontrolled type I DM •Marked hypertriglyceridaemia, increase in VLDL and often chylomicronaemia as a result of decreased activity of lipoprotein lipase and increased activity of hormone-sensitive lipase  leading to increased flux of free fatty acids from adipose tissue  that act as a substrate for hepatic triglyceride synthesis VLDL synthesis and accumulation  increase LDL. * Both VLDL and chylomicrones need insulin for optimum catalysis. The degree of hypertriglyceridaemia correlates well with glycaemic control and insulin treatment can reverse the hypertriglyceidaemia. * LDL can also be increased, and HDL is decreased. *The VLDL contains increased triglyceride and cholesteryl ester in relation to the amount of apolipoptotein * Glycation of apolipoprotein B may enhance the atherogenicity of LDL by reducing its affinity for the LDL receptor, so leading to increased uptake by macrophage scavenger receptors. * Treatment with lipid-lowering drugs may be appropriate, to reduce the risk of vascular disease The role of insulin and hormone sensitive lipase in lipid metabolism Lipid disorders CH.7 36 Drugs: Thiaziade diuertics and b-blockers  hypertriglyceridaemia since these drugs affect the homeostasis of K+ and Na+ which is important for the conversion of proinsulin into insulin low insulin levels  similar events of diabetes Hypothyrodism  low of T3, T4  decrease the uptake of LDL by the LDL-receptor mediated mechanism Nephrotic syndrome: increase the cholesterol level NS is associated with loss of protein with the urine  This will trigger the body to increase the synthesis of protein including Apo B and other lipoproteins which lead to increase the cholesterol Also may be due to loss of proteins responsible for regulation of lipid metabolism Lipid disorders CH.7 37 Lipid disorders CH.7 Investigation of lipid disorders Plasma sampling • Plasma eating, lipid concentrations smoking, and lipoprotein alcohol intake, patterns stress and are affected by changes in posture. • It is essential that the samples are taken under standard conditions. The following points are important: 1) Plasma cholesterol concentrations are not significantly affected after a fatty meal while plasma triglyceride concentrations are affected. Therefore, specimens for analysis of both should be taken after the patient has fasted for 12 hours. 2) The patient should be taking a 'normal' diet and his weight should have remained constant for about two weeks before the tests. 38 Cont. Investigation of lipid disorders 3) Unless treatment is being monitored, the patient must not be on any drugs designed to lower plasma lipid concentrations 4) Lipoprotein concentrations, like those of all large particles, are affected by venous stasis and posture. A standardized collection procedure is important if serial estimations to assess the effect of treatment are used. 5) Stress may affect plasma lipid concentrations like myocardial infarct, major operation, or any serious illness. 6) The blood sample should not be heparinized and plasma or serum must be separated from cells as soon as possible 39 Lipid disorders CH.7 LDL-cholesterol is most commonly estimated from quantitative measurements of total and HDL-cholesterol and plasma triglycerides (TG) using the empirical relationship of Friedewald et al. (1972) [LDL-chol] = [Total chol] - [HDL-chol] - ([TG]/5) where all concentrations are given in mg/dL Lipid disorders CH.7 40 Reference ranges and laboratory investigation Plasma conc at birth is very low (total chol less than 2.6 mmol/L) and there is rapid increase in in first year of life Elevated plasma chol is a major risk factor for CHD There is an inverse correlation between HDL cholesterol and CHD risk. Smoking will increase the risk factor There are many CHD risk factors So it is inappropriate to define a reference range for plasma chol concentration. But it is preferable to consider an individual person's chol concentration in terms of what is ideal or desirable for that individual, i.e taking in consideration CHD risk factors Lipid disorders CH.7 41 Lipid disorders CH.7 42 Lipid disorders CH.7 Coronary Heart Disease Risk Factors Determined By The NCEP (National Cholesterol Education Program) and Adult Treatment Panels 43 Positive Risk Factors 1. Age:  45 years for men;  55 years or premature menopause for women 2. Family history of premature CHD 3. Current cigarette smoking 4. Hypertension (BP  140/90 mmHg or taking antihypertensive medication) 5. LDL cholesterol concentration  160 mg/dL ( 4.1mmol/L), with ≤ 1 risk factor 6. LDL cholesterol concentration  130 mg/dL (3.4 mmol/L), with ≤ 2 risk factors 7. LDL cholesterol concentration  100 mg/dL (2.6 mmol/L), with CHD or risk equivalent 8. HDL cholesterol concentration < 40 mg/dL (< 1.0 mmol/L) 9. Diabetes mellitus = CHD risk equivalent Lipid disorders CH.7 44 Multiple metabolic risk factors A diagnosis of metabolic syndrome is made if a patient has three or more of the following: 1. Abdominal obesity (a waist circumference of more than 40 inches [men] or 35 inches [women]) 2. An elevated triglyceride level (150 mg/dL or higher) 3. A low HDL level (less than 40 mg/dL [men] or 50 mg/dL [women]) 4. A high-normal or high blood pressure level (130/85 mm Hg or higher) 5. A high fasting glucose level (110 mg/dL or higher) Negative Risk Factors • HDL cholesterol concentration  60 mg/dL ( 1.6 mmol/L) • LDL cholesterol < 100 mg/dL (2.6 < mmol/L) Lipid disorders CH.7 45 Lipid disorders CH.7 46 6 3 3 1 2 15 Means 20 of 100 people with this level of risk will have a heart attack in the next 10 years. Lipid disorders CH.7 47 Lipid disorders CH.7 Risk Factor Intervention •Target treatment based on risk –High:10 year risk > 20% –Intermediate:10 year risk 10 –20% –Low:10 year risk < 10% •Preventive strategies differ depending on risk category –Aspirin –Cholesterol lowering Risk Level LDL Goal (mg/dl) Consider Drug Therapy ___________________________________________________ High > 20% < 70 ≥100 Intermediate 10 –20% < 10% < 100 ≥160 Low < 160 ≥190 48 Risk Assessment Tool for Estimating Your 10-year Risk of Having a Heart Attack 10-Year Risk Calculator http://hp2010.nhlbihin.net/atpiii/calculator.asp 10-Year Risk Calculator Results Lipid disorders CH.7 49 Lipid disorders CH.7 50 Anabolic effect of Insulin Lipid disorders CH.7 52

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