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Original Article

Lipoprotein(a) as a risk factor for diabetic retinopathy in patients with type 2 diabetes mellitus

Chopra, Rupali MS; Saramma, Jaison G MS; Mary, John MD; Rebecca, Abraham PhD

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Indian Journal of Ophthalmology: May–Jun 2007 - Volume 55 - Issue 3 - p 195-198
doi: 10.4103/0301-4738.31939
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Abstract

Retinopathy is a serious complication of diabetes mellitus. Several epidemiological risk factors have been identified for the development of diabetic retinopathy such as duration of diabetes, age of the patient at the time of diagnosis, glycemic control, blood pressure, serum lipids and nephropathy. However, the cause for the development and progression of retinopathy could not be explained by the above known factors. Plasma lipids and lipoprotein patterns also have been found to be deranged in patients with type 1 and 2 diabetes mellitus.1

High serum Lipoprotein(a) [Lp(a)] levels have shown to be an independent risk factor for atherogenesis and thromboembolic events in both diabetics and nondiabetics.2 Since capillary occlusion is a frequent finding in diabetic retinopathy, Lp(a) is believed to play an important role in the development and progression of diabetic retinopathy.

The purpose of this study was to estimate serum Lp(a) levels in the Indian population with type 2 diabetes mellitus with and without diabetic retinopathy and to determine the correlation, if any, between serum Lp(a) levels and the severity of diabetic retinopathy.

Materials and Methods

This study was conducted on 200 patients diagnosed to have type 2 diabetes mellitus of five years or more duration. Out of these 200 patients, 100 patients with no retinopathy served as the control group and 100 with retinopathy formed the study group.

Patients included in this study had been diagnosed to have type 2 diabetes mellitus as per the American Diabetes Association criteria.3

The following group of patients was excluded from the study:

  1. Those in whom dilatation of pupils was contraindicated such as angle closure glaucoma
  2. Patients with hazy media which impaired visualization of the fundus
  3. Patients with diabetes of less than five years duration
  4. Patients on hypolipidemic or hyperlipidemic drugs

Pupils of both eyes were dilated with 1% tropicamide eye drops to achieve maximum dilatation. Fundus examination of both eyes was done using direct ophthalmoscopy. Indirect ophthalmoscopy with +20D lens and examination of the macula with +90D Volk's lens was done wherever indicated. Fundus findings were graded as:

  1. No signs of retinopathy
  2. Nonproliferative diabetic retinopathy (NPDR)
  3. Proliferative diabetic retinopathy (PDR). Individuals were classified as having PDR if they had new vessels, vitreous hemorrhage, vitreoretinal traction or retinal detachment believed to be attributable to diabetic neovascularization.

Fasting venous blood samples (5 to 7 ml) were drawn from the patients for estimation of the total lipid profile and Lp(a). Lp(a) levels were measured quantitatively by an immunoturbidimetric method using commercially available kits (CLONITAL). Other routine investigations including glycated hemoglobin, blood urea, serum creatinine and urine analysis were also carried out.

Statistical analysis

Group comparisons involving qualitative measures were carried out using Chi-square test. ANOVA procedure was applied for comparing group means. As the value of Lp(a) was skewed, mean ± standard error of means was calculated for comparison. Logistic regression analysis was performed to find independent factors associated with diabetic retinopathy.

Results

Among the 100 patients forming the study group 86 patients had NPDR and 14 patients had PDR. The average age of patients in the study group was 54.59 years and in the control group 55.1 years. The study group included 60 females and 40 males whereas the control group comprised 43 males and 57 females. Both the study and control group were age and sex-matched.

Table 1 shows the clinical and laboratory characteristics of the subjects. Patients with diabetic retinopathy were found to have a longer duration of the disease. Age, fasting glucose levels, triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol concentrations were comparable in the three groups.

Table 1
Table 1:
Clinical and laboratory characteristics of the subjects

The average Lp(a) levels in patients with retinopathy were 68.5 mg/dl and in the control group 25.1 mg/dl. This difference was found to be statistically significant [Fig. 1].

Figure 1
Figure 1:
Lp(a) levels in patients with diabetic retinopathy and with no diabetic retinopathy.Lp(a) - Lipoprotein(a), Pts - Patients, DR - Diabetic retinopathy

The Lp(a) levels in patients with NPDR were 63.69 mg/dl and in patients with PDR the levels were 104.10 mg/dl. This difference was also found to be statistically significant [Fig. 2]. When logistic regression analysis was performed, diabetic retinopathy was found to be significantly related to serum Lp(a) levels (P<0.01, odds ratio 1.096).

Figure 2
Figure 2:
Lp(a) levels in NPDR vs. PDR.Lp(a) - Lipoprotein(a), NPDR - Nonproliferative diabetic retinopathy, PDR - Proliferative diabetic retinopathy

Discussion

Diabetic retinopathy is one of the most important complications in both type 1 and type 2 diabetes. The duration of diabetes and the glycemic control are the two most important factors in the development of retinopathy.4 However, these factors alone do not explain the occurrence of retinopathy. It may be absent in some with poor glycemic control even over a long period of time, while others may develop retinopathy in a relatively short period despite good metabolic control. This raises the possibility of other factors playing a role in the development of diabetic retinopathy. Thus the above study was undertaken to evaluate the role of Lp(a), a subfraction of LDL cholesterol in the development of diabetic retinopathy.

Our study showed the average serum Lp(a) levels in patients with diabetic retinopathy significantly higher than in those with no retinopathy which was in accordance with the studies conducted in Japan which reported high serum Lp(a) concentrations in type 2 diabetic patients with retinopathy.56

On the contrary, several studies in Caucasians mostly done in patients with type 1 diabetes showed that Lp(a) levels are not related to retinopathy.78

Regarding the association of serum Lp(a) levels and severity of diabetic retinopathy our study showed that Lp(a) levels increase with increasing severity of retinopathy. The average Lp(a) levels in patients with PDR were significantly higher than in patients with NPDR. This is in accordance with the study conducted by Kim et al.9 which showed that Korean type 2 diabetic patients with PDR had higher serum Lp(a) levels.

Maioli et al.10 also reported raised serum apolipoprotein(a) levels in the active diabetic retinopathy group (severe NPDR and PDR) compared with no retinopathy group. Heesen et al.11 also reported higher prevalence of preproliferative retinopathy with increasing Lp(a) levels in type 2 diabetic patients. Verrotti et al.12 studied the serum lipids and lipoprotein concentrations in young adults with insulin-dependent diabetes mellitus and different degrees of retinopathy. They also reported significantly higher Lp(a) values in patients with preproliferative and PDR as compared to patients with background diabetic retinopathy.

On the other hand the two Japanese studies by Onuma et al. and Morisaki et al.56 showed no significant difference in the Lp(a) levels between patients with NPDR and PDR.

The causes for such discrepancies are not clear at present, but differences in type of diabetes, ethnic groups or classification of diabetic retinopathy may be responsible. Also, Lp(a) is a genetically determined molecule. In normal subjects plasma levels of Lp(a) are controlled by apolipoprotein(a) gene localized on the long arm of chromosome 6. Plasma levels in healthy subjects are highly variable and also depend on the ethnic group studied.13 Indians, both immigrant and native, display high plasma levels of Lp(a).14

The mechanism of association between diabetic retinopathy and high serum Lp(a) levels is the close homology of Lp(a) with plasminogen. The pathogenesis of diabetic retinopathy is believed to be occlusion of the small retinal vessels. Sequencing of cloned human apo Lp(a) complementary DNA showed that apo Lp(a) is strikingly similar to human plasminogen. It contains a serine protease domain and two types of kringle domains similar to pringle 4 and 5 in plasminogen.15 The various coding and untranslated sections of human apo Lp(a) gene are identical to human plasminogen gene.16

This striking homology endows Lp(a) with the capacity to bind to fibrin and to membrane proteins of endothelial cells and monocytes through plasminogen receptors thereby inhibiting plasminogen binding and plasmin generation. This inhibition of plasmin generation and accumulation of Lp(a) on the surface of cell membranes favors fibrin and cholesterol deposition causing vascular occlusion.

Lp(a) is believed to have an antifibrinolytic effect,17 so it may contribute to occlusion of small retinal vessels.

Conclusion

We conclude that Lp(a) levels are significantly raised in patients with diabetic retinopathy as compared to patients with no retinopathy. Hence Lp(a) might be an independent risk factor for diabetic retinopathy.

Source of Support:

Nil

Conflict of Interest:

None declared.

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Keywords:

Diabetic retinopathy; lipoprotein(a); type 2 diabetes mellitus

© 2007 Indian Journal of Ophthalmology | Published by Wolters Kluwer – Medknow