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LIPOPROTEIN (a) - IN TYPE 2 DIABETES

Prof K M Prasanna Kumar*,Dr Salim**

* Prof & Head, **Senior Resident- Dept Of Endocrinology & Metabolism,
M S Ramiah Medical college,
Bangalore

INTRODUCTION

Coronary artery disease is the leading cause of death and disability of 20th century in both developed and developing countries. In the past it has been generally conceived that coronary artery disease largely affects the people in the western hemisphere and people at developing countries were at relatively low risk. But during the last two decades there is a significant increase in the incidence of CAD in the Indian sub-continent. The multiple risk factors for the development of coronary artery disease are :-

Age - > 45 in males
> 55 in females
Family history of CAD
Hypertension
Diabetes
Dyslipidemia
Smoking
Obesity

Type 2 diabetic patients have 2-4 fold increase in risk of coronary artery disease relative to non-diabetic subjects. Atherosclerosis, a key factor in the causation of CAD, occurs earlier and is more severe in diabetics than in non-diabetics. But the excess risk of CAD in diabetics is only partly explained by increase in standard risk factors. In this context a host of new risk factors have been described like -

High Lp (a) levels.
Hyperinsulinemia
Increased insulin resistance
Increased upper body obesity
High serum fibrinogen levels
High factor VII levels
High homocysteine levels
Infections with CMV, helicobactor, chlamydiae

Lipoprotein (a) formed by a covalent linkage between apolipo protein (a) and apo B' 100 of LDL, have been found to be associated with atherosclerosis even though no association between high lipo protein (a) levels and macrovascular disease were found in type 2 diabetic patients. Thus studies of relationships of lipo protein (a) to coronary artery disease in diabetic patients have yielded conflicting results. Some studies found lipo protein (a) to be an independent risk factor while others failed to slow significant relationship between lipo protein (a) and coronary artery disease.

Lipoprotein (a)

Structure:

Two apolipoproteins are present in lipoprotein (a) - namely apo B 100 and unique apolipo protein (a) which is linked by a disulphide bond.

Lp (a) closely resembles LDL in content of cholesterol and phospholipids. Partial protein sequencing of apo (a) revealed sequence homology to plasminogen and cloning of apo (a) complementary DNA showed that it contains two types of plasminogen like kringles namely repeated IV like domains and a single kringle V like domain. Further a protease domain was found. The size of plasma apo (a) varies between individuals and is caused by variation in the number of kringle IV coding sequences in the apo (a) gene.

Metabolism

Synthesis - Apo (a) m RNA has been detected in liver cells and the liver is thought to be the major site of Lp (a) production. It's still unclear whether apo (a) joins apo B of LDL to form Lp (a) within the hepatocyte or whether this happens after apo (a) is secreted into the circulation.

Catabolism - Since Lp (a) contains LDL receptor ligand apo B, it has been suggested that the Lp (a) particle like its close relative LDL, is cleared from the circulation via LDL receptor. Moreover HMG - CoA reductase inhibitor and anion exchange resins which increases hepatic LDL receptors expression do not lower Lp (a) concentrations.

Lipid changes in Type 2 diabetes mellitus:

Atherosclerotic vascular disease manifesting itself as coronary - artery disease, cerebro-vascular accident and peripheral vascular disease are the major cause of morbidity and mortality in patients with diabetes. Coronary artery disease mortality is 2-4 fold higher in diabetes than in non-diabetic subjects.

The pathophysiology of dyslipidemia in Type 2 DM results from metabolic disturbances in glucose and lipid metabolism which may be mediated through a common pathophysiological pathway i.e. through resistance to insulin mediated action on both glucose and lipid metabolism.

An atherogenic pattern of lipoprotein changes is often present for years prior to development of fasting hyperglycemia and diagnosis of type 2 DM. So impaired glucose tolerance, a milder abnormality of glucose metabolism is related to abnormality of lipids and lipoprotein metabolism and since asymtomatic impaired glucose tolerance may last for years, this long exposure to multiple risk factors may explain why the excess of coronary artery disease develops early in the course of type 2 DM.

The typical lipoprotein profile associated with type 2 diabetes mellitus includes high triglycerides, low HDL and normal LDL levels. The most consistent change is an increase in very low density lipoprotein - triglyceride level. Lipoprotein (a) concentration varies between racial and ethnic groups, hence generalizing findings from our study population to another may be inappropriate.

Lp(a) levels have been shown to vary considerably in different ethnic groups that have marked differences in prevalence rates of CAD48, 49. It was found in Chinese living in Singapore that they have four fold lower state of CAD with correspondingly lower levels of Lp(a). It was also revealed that South Asians known for higher rates of premature CAD also have elevated levels of Lp(a) compared to Whites50, 51.

In Caucasians, Chinese, Eskimos the distribution of Lp(a) concentrations are highly skewed towards lower levels, while Africans and African Americans, the distribution curve have more Gaussian shape52, 53.

LIPOPROTEIN (A) AS A GENETIC RISK FACTOR:

Lp(a) as a genetic risk factor and ethinicity are interrelated. It has become increasingly clear that genetic predisposition is important in the pathogenesis of anterosclerosis particularly when disease occurs at a relatively young age54.

In several studies it was noted that Lp(a) is genetically determined18, 20 and that high Lp(a) level is a significant genetic risk factor for premature coronary artery disease55. It was also noted that serum Lp(a) levels are largely genetically determined with a single Apo(a) gene localized to the long arm of chromosome to account for more than 90% of variations in its serum level52, 56, 57, 58. Because of strong heritability, Lp(a) is widely recognised as a biological marker for familial CAD and high levels of Lp(a) can be considered to have some importance as a history of premature CAD in parents59-61.

Though the inherited serum levels of Lp(a) are susceptible to change due to associated factors like hypothyroidism, hormonal treatment with estrogens and growth hormone, nephrotic syndrome and end stage renal disease and consumption of trans fatty acids and alcohol. These levels are not significantly influenced by sex, diet, environmental factors, anthropometric measurements, other lipoproteins or associated coronary risk factors18, 62-65.

LIPOPROTEIN (a) AS A DUAL CARDIO VASCULAR PATHOGEN

Proatherogenic role

Lp(a), unlike LDL is a poor ligand for LDL receptor and is consequently taken up by macrophages presumably through scavenger - receptor pathway. These macrophages would then be transformed into foam cells potentially leading to formation of atherosclerotic plaque52, 66.

Lp(a) traverses the endothelium of arterial wall and reach the intima where it can undergo complexation with such tissue matrix components as proteo glycans, glycosamino glycans and collagen as well as fibrin contributing to the formation of atherosclerotic plaque. The magnitude of transfer of Lp(a) from the plasma compartment to the arterial wall could be predicted to be larger when plasma Lp(a) levels are elevated, because of a gradient effect or because of possible direct action of Lp(a) on arterial permeability67.

Another possible mechanism is by increase in the potential oxidative modifications of LDL by lipo protein (a).

K1 plasmin mediated activation of the cytokine transforming growth factor (b-TGE) is impaired by Lp(a) in vitro resulting in increased migration and proliferation of vascular smooth muscle cells and thus pro atherogenic68.

Prothrombic Role

The close structural similarity between apo(a) and plasminogen has stimulated research aimed at defining whether and why Lp(a) may be thrombogenic.

Lp(a) can compete with the binding of plasminogin to fibrin and with the binding of plasminogen to the plasminogen receptors66.

Lp(a) also competes with the streptokinase mediated activation of plasminogen and the tissue plasminogen activator-mediated lysis of fibrin clot69.

Exponential adverse effects of Lp(a) with.other lipoproteins

Premature atherosclerosis is frequently seen in the presence of high plasma Lp(a), high plasma LDL and low plasma HDL levels in patients in their thirties.

Correlation coefficient of Lp(a) with total cholesterol, LDL cholesterol HDL cholesterol, fasting triglycerides, apo A-1, apo A-II, apo - B ranged from 0.16 to 0.17, values of 0.26 and 0.20 were found for total and LDL cholesterol respectively38.

It was found out that isolated elevation of Lp(a) above threshold value of 30 mg/dl increase the risk of premature CAD 2-3 folds in men15,70, also that when serum LDL level is also elevated along with elevated Lp(a), the risk increased 6 folds15. It was also noted that men with LDL values of > 317 mg/dl and Lp(a) values of > 30 mg/dl have a 16 fold increase in their odds ratio of having CAD when compared to those having an LDL level of < 130 mg/dl and Lp(a) level of < 10 mg/dL70.

In women the risk of premature CAD increases by 100 folds when the total cholesterol (TC)/HDL ratio is > 16 along with an Lp(a) level of > 55 mg/dL when compared to women with TC/HDL ratio of 4 and Lp(a) value of < 15 mg/dL71.

Comprehensive Lipid Tetrad Index.

In a large multicentre study in Europe, it was found out that the most severe abnormalities of all four lipids were associated with most extensive coronary artery disease72.

Recently Enas et al proposed a comprehensive lipid tetrad index to best estimate the total burden of dyslipidemias. It is the product of cholesterol, triglycerides and Lp(a) values divided by the HDL level. A high index would indicate the presence of a highly atherogenic lipid profile.

Lipoprotein (a) As A Predictor Of Coronary Artery Disease

Several studies have suggested lipoprotein (a) as an independent risk factor for coronary artery disease.

Initial studies in the early 70s, indicated an association between high Lp (a) levels and atherosclerotic heart disease, a discovery since then confirmed in many studies.

Later it was found that a high Lp (a) level particularly increase the risk of CAD in the presence of high LDL level even in the absence of the classic hyper cholesterolemia suggesting that in addition to being a genetic risk factor in its own right, a high Lp (a) level increases the risk of overt CAD in patients with familial hyper cholesterolemia or a modulately high LDL level.

In late 80's it was found that coronary artery disease in Asian Indians occur prematurely is at least a decade or two earlier than that seen in Europeans . Later several studies suggested that lipo protein (a) may be an independent risk factor for coronary artery disease in these population

It was also noted that in angiographically documented cases with normal lipid parameters including apolipoproteins, Lp (a) may be the only abnormal parameter .

Studies in the past have shown that high rates of CAD in Asian Indians are accompanied by a paradoxically low prevalence of conventional risk factors like hypertension, hypercholesterolemia and cigarette smoking, as found out by studies analyzing the risk factors for CAD among Asian Indian physicians in US which suggested that the presence of a powerful risk factor unaffected by even maximum modification of life style like insulin resistance syndrome, elevated Lp (a) levels .

Lp (a) Levels in type 2 DM:

Results of studies assessing Lp (a) levels in patients with Type 2 DM have been inconsistent. Large population studies and small longitudinal studies showed no difference in Lp (a) concentration in type 2 DM with and without coronary artery disease and no relationship with glycemic control. While a few other studies showed that Lp (a) levels are noted to be high in type 2 DM especially with poor glycemic control and some even suggested that Lp (a) may be an independent risk factor for CAD. BIBLIOGRAPHY

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