“Plasma lipids are transported in complexes called LIPOPROTEINS. Metabolic disorders that involve elevations in any lipoprotein species are termed HYPERLIPOPROTEINENEMIAS or HYPERLIPIDEMIAS. HYPERLIPIDEMIA denotes increased levels of triglycerides.”
CAUSES OF HYPERLIPIDEMIA:
1. Life style & diet:
Cholesterol levels may be elevated as a result of an individual’s lifestyle for example, by lack of exercise and consumption of a diet containing excess amount of fatty acids.
2. Inheritance:
Hperlipidemias can also can also result from a single inherited gene from a single gene defect in lipoprotein metabolism or, more commonly, from a combination of genetic and lifestyle factors.
3. Other Metabolic factors:
Other risk factors CHD include
Cigarette smoking
Hypertension
Obesity
Diabetes
NORMAL MECHANISM:
LIPOPROTEINS
The lipids of the blood form a heterogeneous group which includes phospholipids (such as lecithin), cholesterol and its esters, neutral fat (glycerol trimesters), free fatty acids, arytenoids, vitamins A, and vitamin E. They are carried in the blood as complexes with each other and with certain plasma proteins called apolipoproteins.
The lipoproteins have been separated and characterized by three important techniques:
1. Chemical analysis.
2. Density, as quantified in the ultracentrifuge and measured in Svedberg units of flotation (Sf).
3. Electrophoresis.
The Apolipoproteins:
The apolipoproteins are a group of proteins that form complexes with the water-insoluble lipids to produce the lipoproteins of the chyle and plasma. They have been divided into groups and labeled alphabetically from A to E, in each there are subdivisions-thus apolipoproteins (apo) A-1, Apo A-II, Apo A-III, Apo-IV, Apo B-48, Apo B-100, Apo C-1, Apo C-II, Apo C-III, Apo D and Apo E.
The lipoprotein surface coating contains ligands for specific enzymes, e.g. Apo C-II activities endothelial cell lipoproteins lipase.
Apo B-48 and Apo E are the important carrier proteins of the chylomicrons and chylomicron remnants. The liver has Apo E receptors. Apo B-100 is found in very-low-density lipoproteins (VLDLs) and low-density lipoproteins (LDLs), while Apo A-I is the important component of the high-density lipoprotein (HDLs). Some tissues have receptors for the apoproteins, and in this way the lipoproteins are taken up by endocytosis and metabolized. Thus the liver has Apo E and Apo B-100 receptors. Finally, it should be noted that the lipoprotein particle can change in composition within the blood stream by donating or receiving lipid or lipoprotein from other particles.
The lipids and lipoprotein in the blood and their metabolism
The study of the lipoprotein is important because abnormalities in their metabolism are associated with a variety of important disease, in particular atherosclerosis and pancreatitis.
Free fatty acid
This is mostly combined with albumen. The fatty acids are derived from the adipose tissues, and are the form in which lipid is transported from the fat deposits to the tissues. They are taken up by cells of high metabolic activity such as muscle, and also by the liver for oxidation or the reformation of triglycerides.
Chylomicrons
These are particles; over 1.0 um is diameter, which on electrophoresis does not migrate from the point of application. They have high neutral fat (triglyceride) content, and are formed in the intestine following the absorption of dietary fat.
Apo B-48, Apo E and Apo C-II are the important surface coating apoproteins. The chylomicrons enter the venous circulation via the lymphatic. In the capillaries of muscles and adipose tissue the chylomicrons adhere to the endothelial lining, and Apo C-II activates the endothelial enzyme lipoprotein lipase. This enzyme causes the hydrolysis of the triglyceride core of the particles, and the release fatty acid is taken up by cells for storage, or muscle fibers for energy production. The chylomicron remnants are now reduced in size, and their main lipid content is cholesterol. The particles are released into the blood, and further enriched with cholesterol esters donated from circulating HDLs. Apo E remains the important carrier proteins. The particles are taken up by the liver, which has Apo E receptors, and their cholesterol content is meta bolised in the liver for storage, bile acid synthesis and lipoprotein formation.
Very low-density lipoprotein (VLDL)
This fraction consists of a core of triglyceride synthesized in the hepatocytes from carbohydrate and lipid sources. A diet rich in carbohydrate enhances this action. Electrophoretically the VLDL migrates between the alpha and the beta bands, and for this reason it has been called the pre-beta-lipoprotein fraction in the blood under fasting condition conditions. Apo B-100 is its most important covering apoprotein, but Apo C-I, Apo C-II,Apo C-III and Apo E are present. The VLDL leaves the liver and interacts with lipoprotein lipase of capillary endothelium, with Apo C-II acting as a cofactor. The triglyceride content is hydrolyzed to provide fatty acids to the muscle and adipose tissue, and the VLDL remnants pass into the blood. About half the remnants are taken up by the liver (using LDL receptor, also known as Apo B, E receptors).The remaining half remains in the plasma, and these remnants circulate as intermediate density lipoprotein (IDL) and are steadily converted into cholesterol rich LDL Apo B -100 remains as the only apoprotein.
High density lipoprotein (HDL)
These particles remove cholesterol from non-hepatic sites. The cholesterol is destined to be transported to the liver, either by a direct route or indirectly via VLDL.Apo A-1 and Apo-II are the important carrier proteins. By the direct cholesterol is taken up directly from the HDL particles in the blood. The particles also donate cholesterol esters to VLDL and return it to the liver either via VLDL remnants or via LDL formed from IDL.
Thus, HDL transports cholesterol from tissues and donates it to the liver. HDL is in fact a heterogeneous group of particles. They have various other properties. They donate cholesterol to other particles. They acquire triglyceride and transport it to liver, and they form a reservoir of some apolipoproteins, e.g. the important Apo C-II, which is necessary for the activation of lipoprotein lipase.
Lipoprotein (a)
Lipoprotein (a) or Lp(a) is made in liver by utilizing LDL and covalently linking it to a glycoprotein called apolipoproteins (a).The concentration in blood varies greatly between individuals, and the level is determined by genetic factors and lifestyle.
ATHEROSCLEROSIS:
The interest in Lp(a) relates to its connection with atherosclerosis. A high blood level is associated with an increased risk of disease.
>.It is a focal disease of large and medium-sized arteries. Atheromatous plaques are present in members of economically developed countries, progress insidiously over many decades and underlie the commonest cause of death (myocardial infarction) and disability (e.g. strokes) in these countries.
>. Fatty streaks are the earliest structurally apparent lesions and progress to fibrous or fatty plaques.
>. Important modifiable risk factors include
(a). hypertension
(b). dyslipidemia
(c). smoking
>. The pathophysiology is of chronic inflammation in response to injury. Endothelial dysfucntioning leads to loss of protective mechanism.
Monocytes/macrophages and T-cell migration, uptake of low-density lipoprotein (LDL) cholesterol and its oxidation, uptake of oxidizes LDL by macrophages, smooth muscle cell migration and proliferation, and deposition of collagen.
>. Plaque rupture leads to platelet activation and thrombosis.
PREVENTION OF ATHEROMATOUS DISEASE:
Antithrombotic drugs reduce arterial thrombosis. Reducing LDL-C is highly effective for prevention of atheromatous.
ABNORMALITIES OF THE PLASMA LIPOPROTEINS:
Hyperlipoprotenaemia:
Hyperlipoprotenaemia is a common finding, and indicates an increase in the level of one or more of the lipoproteins fractions.
GROUPS OF HYPERLIPIDEMIA:
- Primary or familial hyperlipoproteinaemia
- Secondary hyperlipoproteinaemia
The current classification of hyperlipidemias is based on the pattern of lipid abnormality in the blood.
- Primary hyperlipoproteinaemia:
So far as the primary group is concerned, five types have been recognized
- TYPE I HYPERCHYLOMICRONEMIA:
Chylomicrons are not present in the serum of normal individuals who have fasted 10 hours. The recessive traits of deficiency of LPL or its cofactor are usually associated with severe lipemia. (2000-3000 mg/dl of triglycerides when the patient is consuming a typical American diet.) These disorders might not be diagnosed until attack of acute pancreatitis occurs.
It is not associated with coronary heart disease.
Treatment: low fat diet, no drug therapy is effective.
2. TYPE II A (HYPERCHOLESTEROLEMIA):
Elevated LDL with normal VLDL levels due to a block in LDL degradation,
Result in increased serum cholesterol but normal Triglyceride level. It is caused by
Defects in the synthesis or processing of LDL receptors.
Treatment: diet, heterozyggotes: niacin, statin, cholestyramie.
3. TYPE II B [FAMILIAL COMBINED (MIXED) HYPERLIPIDEMIA]:
Increased level of LDL and VLDL resulting in elevated serum as well as cholesterol levels.
Caused by over production of VLDL by liver.
Treatment: diet, drug therapy niacin, statin
4. TYPE III [FAMILIAL DYSBETALIPOPRTEINAEMIA]:
Serum concentration of ILD are increased, resulting in elevated serum as well as
Cholesterol levels.
Its cause is overproduction or underutilization of IDL due to mutant apolipoproteins
Xanthomas and accelerated vascular disease develop in patients by
Middle age.
Treatment: Diet. Drug therapy includes niacin and fenofibrate, or a statin.
5. [FAMILIAL HYPERTRIGLYCERIDEMIA]
VLDL levels are increased, whereas LDL levels are normal or decreased, resulting
In normal to elevated cholesterol, and greatly elevated circulating TG levels.
Its cause is overproduction and/or decreased removal of VLDL TG in serum.
This is a relatively common disease. It has few clinical manifestations other
Than accelerated ischemic heart disease.
Patient with this disorder are frequently obese diabetic, and hyperuricemic.
Treatment: Diet. If necessary, drug therapy includes niacin and/or fenofibrate.
6. [FAMILIAL MIXED HYPERTRIGLYCERIMEDEMIA]
Serum VLDL and chylomicrons are elevated. LDL is normal or decreased. This results in elevated cholesterol and greatly elevated TG levels.
Cause is either increased production or decreased clearance of VLDL and chylomicrons; usually it is a genetic defect.
Occurs most commonly in adults who are obese and/or diabetic.
Treatment: diet. If necessary, drug therapy includes niacin and/or fenofibrate, or statin.
SECONDARY HYPERLIPOPROTEINAEMIA
In secondary hyperlipoproteinaemia, apart from type III, the same spectrum of lipoprotein pattern is found. Thus, in obstructive jaundice there is an increase in plasma cholesterol and LDL, whereas in diabetes mellitus it is the chylomicrons and LDL that are elevated. Other diseases characterized by hyperlipoproteinaemia are
>.acute alcoholism
>.hyperthyroidism
>.nephritic syndrome
As with the primary group the lipid pattern is influenced by diet, and there may be a change from one type to another.
DIAGNOSIS OF LIPOPROTEIN DISORDER
Lipoprotein disorders are detected by measuring lipids in serum after a 10 hour fast. Risk of heart disease increases with the concentration of the atherogenic lipoproteins. Is inversely related to levels of HDL, and is modified by other risk factors. Evidence from clinical trials suggests that LDL cholesterol levels of 60 mg/dl may be optimal for patients with coronary disease. Ideally, triglycerides should be below 120 mg/dl. Differentiation of the disorder requires identification of the lipoproteins involved. Diagnosis of a primary disorder usually requires further clinical and genetic data as well as ruling out secondary hyperlipidimias.
Treatment of hyperlipoproteinaemias:
Apart from correlating the various types of hyperlipoproteinaemia with the presence of arterial disease and various types of xanthomas, the classification is useful because it indicates a line of treatment. Thus, if there is an increase in the level of chylomicrons containing triglyceride of exogenous origin, as in types I and V, limitation of dietary fat is indicated. If the VLDL level is elevated, as in type IV, carbohydrate restriction is likely to be effective.
In addition, a variety of drugs are available for treating the various types of hyperlipidaemia e.g.,
>.Statins
>. Niacin
>.Bile acid resins
>.Fibrates
>.Cholesterol absorption inhibitors.
BY
Name. Komal Hassan
Dp_01083_210
Department of pharmacy
The University of Lahore.
