Disorders of lipid metabolism Clinical manifestation of hyperlipidaemia: Prolonged hyperlipidaemia results in accumulation of lipid in tissues and causes cell damage. Lipids may accumulate in arterial wall, subcutaneous tissue, tendons and cornea 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

Disorders of lipid metabolism 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.

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

Tendons Tendinous Xanthomata and usually on Achilles tendons or the extensor tendons of the hands occur in familial hypercholesterolaemia Cornea: Corneal arcus under the age of 40 may be caused by the deposition of lipids and associated with high plasma LDL-cholesterol concentrations.

Classification of Disorders of lipid metabolism Currently there is no satisfactory comprehensive classification of lipoprotein disorders. In practice, lipoprotein disorders are classified as being: Primary-when the disorder is not due to an identifiable underlying disease. Secondary-when the disorder is a manifestation of some other disease. Primary lipid Disorders: 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 classifications, are unlikely to prove very useful in practice.

Genetic classifications: Risk Fredrickson Genetic defect Disease CHD IIa or IIb Reduced number of functional LDL receptors Familial Hypercholesterolemia IV or V Possibly single gene defect Familial hypertriglyceridemia IIa, IIb, IV or V Familail combined hyperlipidemia Pancreatitis I Reduced levels of functional LPL Lipoprotein lipase deficiency Inability to synthesize apo C-II (cofactor of LPL) Apo C-II deficiency Fat soluble vitamins deficiencies, neurological deficit Normal Inability to synthesize apo B Abetalipoproteinemia Neurological deficit, CE storage in abnormal places Inability to synthesize apo A Analphalipoproteinemia

WHO classification of dyslipidemia: based on Fredrickson work and it is 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 the appearance of fasting plasma sample after standing for 12 hr at 4°C and analysis of its cholesterol and TG * 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 *The six types by Fredrickson are not equally common. Type I and V are rare, while types IIa, IIb and IV are very common.

Fredrickson (WHO) classification of dyslipidaemia

Fredrickson (WHO) classification of dyslipidaemia

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, -diabetes mellitus, -nephrotic syndrome, -cholestasis -drugs (e.g.; thiazides).

Primary hyperlipidaemias 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, compared with an age- and sex matched population.

Familial (monogenic) hypercholesterolaemia Caused by a LDL receptor defect  reduced cellular uptake of LDL, particularly by the liver  causes an increase in plasma total and LDL- cholesterol concentrations. Plasma triglyceride concentrations are either normal 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 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

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. However, many patients with increased concentrations of VLDL-triglyceride 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, 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, decrease in plasma HDL-cholesterol concentration and hyperuricaemia. * 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

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 in the after the age 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, 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 adults.

Rare disorders associated with lipid metabolism 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: decrease in fat soluble vitamins  lead to neurological defects, for treatment vitamins are given I. V is given 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

Secondary lipid disorders Secondary hyperlipoproteina 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.

Fatty acid  TG  VLDL 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 Acetaladehyde Acetate Alcohol dehydrogenase Aldehyde dehydrogenase NADH

Lipoprotein metabolism in diabetes mellitus Insulin has a major role in the control of fat metabolism. 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

Investigation of lipid disorders Plasma sampling Plasma lipid concentrations and lipoprotein patterns are affected by eating, smoking, alcohol intake, stress and 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. 3) Unless treatment is being monitored, the patient must not be on any drugs designed to lower plasma lipid concentrations

Investigation of lipid disorders Plasma sampling 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 infarction, 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

Lipid profile 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 The ([TG]/5) is used as an estimate of VLDL-cholesterol concentration. It assumes, first, that virtually all of the plasma TG is carried on VLDL, and second, that the TG:cholesterol ratio of VLDL is constant at about 5:1 (Friedewald et al. 1972). Neither assumption is strictly true. Limitations of the Friedewald equation: The Friedewald equation should not be used under the following circumstances: When chylomicrons are present. When plasma triglyceride concentration exceeds 400 mg/dL (4.52 mmol/L). In circumstances in which these conditions apply, LDL-cholesterol should be measured directly.

Reference ranges and laboratory investigation Plasma conc at birth is very low (total chol less than 100 mg/dL 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 are many CHD risk factors Smoking will increase the risk factor There is an inverse correlation between HDL cholesterol and CHD risk. 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 taking in consideration all other CHD risk factors

Coronary Heart Disease Risk Factors Determined By The NCEP (National Cholesterol Education Program) and Adult Treatment Panels

Positive Risk Factors Age:  45 years for men;  55 years or premature menopause for women Family history of premature CHD Current cigarette smoking Hypertension (BP  140/90 mmHg or taking antihypertensive medication) LDL cholesterol concentration  160 mg/dL ( 4.1mmol/L), with ≤ 1 risk factor LDL cholesterol concentration  130 mg/dL (3.4 mmol/L), with ≤ 2 risk factors LDL cholesterol concentration  100 mg/dL (2.6 mmol/L), with CHD or risk equivalent HDL cholesterol concentration < 40 mg/dL (< 1.0 mmol/L) Diabetes mellitus = CHD risk equivalent Negative Risk Factors HDL cholesterol concentration  60 mg/dL ( 1.6 mmol/L) LDL cholesterol < 100 mg/dL (2.6 < mmol/L)

3. A low HDL level (less than 40 mg/dL [men] or 50 mg/dL [women]) Multiple metabolic risk factors A diagnosis of metabolic syndrome is made if a patient has three or more of the following: 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)

6 3 3 2 14 Means 20 of 100 people with this level of risk will have a heart attack in the next 10 years.

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

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 NCEP Guidelines Desirable Borderline Undesirable Total cholesterol Below 200 200 - 240 Aboveor 240 HDL cholesterol Above 60 40 - 59 Below or 40 Triglycerides Below 150 150 - 499 Above or 500 LDL cholesterol Below 130 130 - 160 Above or 160

The End

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