|Year : 2021 | Volume
| Issue : 1 | Page : 28-33
Relationship between serum level of lipoprotein (a) and central macular thickness in diabetic patients
Howaida E Deraz1, Essam Elden S Ahmed2, Ola S El-Shimi3, Elham A Gad2
1 Department of Ophthalmology, Benha Ophthalmology Hospital, Ministry of Health, Egypt
2 Department of Ophthalmology, Faculty of Medicine, Benha University, Benha, Egypt
3 Department of Clinical and Chemical Pathology, Faculty of Medicine, Benha University, Benha, Egypt
|Date of Submission||07-Jul-2020|
|Date of Decision||15-Aug-2020|
|Date of Acceptance||27-Sep-2020|
|Date of Web Publication||24-Mar-2021|
MD Elham A Gad
Department of Ophthalmology, Benha University, Benha 13516
Source of Support: None, Conflict of Interest: None
Background and aim Diabetic retinopathy and maculopathy are major tragedies in ophthalmology. Lipoprotein (Lp) (a) is a pro-atherogenic and a pro-thrombotic risk factor. It has an antifibrinolytic effect with increasing risk of clotting and blood vessel occlusion. Elevated Lp (a) concentrations can also damage the microcirculation by its oxidative effect. The aim of this study was to investigate the relationship between serum level of Lp (a) and the development of maculopathy in diabetic patients by measuring the central macular thickness (CMT) using optical coherence tomography.
Patients and methods This case–control study included one case group of 40 eyes of 20 diabetic patients and one control group of 40 eyes of 20 nondiabetic age-matched and sex-matched patients. All participants were subjected to full ophthalmological examination, including best-corrected visual acuity testing, BMI calculation, glycosylated hemoglobin (HbA1c), serum Lp (a), and CMT measurement by three-dimensional optical coherence tomography.
Results There was no significant difference between the two groups regarding age or sex. Cases group had significantly higher BMI, HbA1c, Lp (a), and CMT than the control group (P<0.001 for all). In addition, cases had significantly lower best-corrected visual acuity than the controls (P<0.001). A significant positive correlation was found between CMT (μm) and each of HbA1c, Lp (a), and BMI (P<0.001, P<0.001, and P=0.002, respectively). Lp (a) level of 11.34 ng/ml or more was found to have a 95% sensitivity, 95% specificity, and 95% overall accuracy in predicting central macular edema (CME). On univariate logistic regression analysis, both of the BMI and Lp (a) were independent significant predictors for CME (P<0.001 and P=0.05, respectively), with odds ratio of 1.569 and 14.482, respectively.
Conclusion Lp (a) was significantly correlated with CMT. It had an excellent sensitivity and specificity in predicting CME and can be used as a potential marker for its detection.
Keywords: diabetic retinopathy, lipoprotein (a), macular thickness, maculopathy
|How to cite this article:|
Deraz HE, Ahmed ES, El-Shimi OS, Gad EA. Relationship between serum level of lipoprotein (a) and central macular thickness in diabetic patients. Delta J Ophthalmol 2021;22:28-33
|How to cite this URL:|
Deraz HE, Ahmed ES, El-Shimi OS, Gad EA. Relationship between serum level of lipoprotein (a) and central macular thickness in diabetic patients. Delta J Ophthalmol [serial online] 2021 [cited 2022 Aug 18];22:28-33. Available from: http://www.djo.eg.net/text.asp?2021/22/1/28/311893
| Introduction|| |
Diabetic retinopathy (DR) is a leading cause of diminution of vision as the global prevalence of diabetes is increasing. Diabetic macular edema (DME) is still representing a usual cause of moderate to severe visual impairment in patients with diabetes and is considered the most serious sight-threatening complication of DR ,.
Risk factors for the appearance and progression of DME have been investigated in details and were confirmed in many clinical studies. The well-known risk factors include blood pressure, glycosylated hemoglobin (HbA1c), and serum lipids ,,,. Raised serum lipid concentrations may enhance the accumulation of hard exudates in the retinal layers . Elevated low-density Lp is associated with a great risk of macular edema, whereas high serum triglyceride levels are associated with increased risk of developing proliferative DR and DME .
Lipoprotein (a) [Lp (a)] is an low-density Lp-like molecule formed of an apolipoprotein B100 particle held by a disulfide bridge to apo (a). Lp (a) plasma concentrations are inherited and controlled by the apo (a) gene, which is located on chromosome 6q26-27 . The kringles of apo (a) are homolog of the kringle IV of plasminogen to a great extent. Lp (a) competes with plasminogen for binding to fibrin and plasminogen receptors, which are located on the surface of monocytes and vascular endothelial cells. This may attenuate the production of plasmin and decrease the fibrinolytic activity in the circulation .
Optical coherence tomography (OCT) has been introduced as one of the principal methods used to identify the presence and severity of DME. OCT allows quantitative measurement of DME and is mainly useful in clinical studies. It is an objective manner and a highly sensitive method to detect retinal changes in diabetic patients such as macular thickness .
The aim of this study was to investigate the correlation between macular thickness and volume measured by OCT and serum level of Lp (a) in type 2 diabetic patients.
| Patients and methods|| |
This is a case–control study that was carried out from May 2019 to April 2020. The patients were recruited from the Outpatient Clinic of the Ophthalmology Department, Benha University Hospital, Benha, Egypt. The study was approved by the Ethical Committee of the Faculty of Medicine, Benha University, and was done in accordance to the Declaration of Helsinki and its later amendments. An informed written consent to participate and to publish data of the study was taken from every participant before the study.
Study groups and sampling were as follows:
- Case group included 40 eyes of 20 diabetic patients diagnosed with DR associated with DME.
- Control group included 40 eyes of 20 apparently healthy, nondiabetic, age-matched and sex-matched patients.
The following were the inclusion criteria:
- Age: 21 years or more.
- For cases: type 2 diabetic patient diagnosed at least 5 years before the study.
The following were the exclusion criteria:
- Any systemic condition or drugs that can affect the level of Lp (a) such as chronic liver/kidney diseases, hypothyroidism, familial hypercholesterolemia, lipid-lowering drugs or glitazones, pregnancy, oral contraceptive pills, or hormonal therapy.
- Any local retinal condition that may affect the OCT quality or diagnosis such as age-related macular degeneration, complicated cataract surgery with Irvine Gass syndrome, uveitis, glaucoma, significant cataract, or vitreous hemorrhage.
All the participants were subjected to the following:
- Full history taking: including personal and disease history.
- BMI calculation: weight (kg)/height (m2).
- Complete ophthalmological examination including anterior and posterior segment examination with the slit lamp and 90 D Volk lens (Volk Optical, Mentor, Ohio, USA).
- Visual acuity testing: uncorrected and best-corrected visual acuity (BCVA) testing using automated chart projector with decimal notation.
- Laboratory investigations including fasting blood sugar, HbA1c, and serum LP (a) (ng/ml).
- Central macular thickness (CMT) measurement: using 3D-OCT 2000 Topcon (Topcon Corporation, Tokyo, Japan).
Raw data were coded and entered into the computer by the researcher using the SPSS (Statistical Package for Social Sciences), version 21 (SPSS Inc. Released 2015, IBM SPSS statistics for Windows, version 23.0; IBM Corp., Armonk, New York, USA). Graphs were done for visual presentation using SPSS and Microsoft excel software. Descriptive statistics were carried out, in the form of frequency distribution tables (frequencies and percentages) and summary statistics (mean, SD, median, and range) as appropriate. Tests of Kolmogorov–Smirnov and Shapiro–Wilk were used to test normality of distribution of numerical variables. Pearson’s χ2 was used as a test of significance of association between two categories. Whenever more than 20% of the expected values were less than 5, Fisher’s exact test was used instead. Mann–Whitney test was used to compare ranks among two groups, for skewed numerical data. Spearman correlation was used to quantify the relation between skewed numerical variables. Validity of Lp (a) was tested by receiver operating characteristics (ROC) curve and area under the curve to calculate its sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy. Univariate logistic regression analysis with odds ratio at 95% confidence interval (CI) was used to determine the predictors of DME. The level of significance of all data was 95%. So, a P value less than 0.05 was considered statistically significant.
| Results|| |
Each group included 40 eyes of 20 participants. There was no statistically significant difference between the two groups regarding the mean age or sex distribution. The mean age of the cases was 53.75±4.84 years, and of the controls was 51.65±5.58 years (P=0.212). Males represented 50% of the cases and 45.0% of the controls (P=0.212). The cases group had significantly higher mean BMI (30.71±2.63) than the controls (26.47±3.29) (P<0.001) ([Table 1]). The mean duration of diabetes mellitus (DM) among the cases was 11.45±4.48 years (range=5–20 years). The mean HbA1c level was significantly higher among the cases (7.76±0.94) than the controls (5.98±0.20) (P<0.001). Moreover, the mean Lp (a) was significantly higher among the cases (16.09±2.60 ng/ml) than the controls (9.17±1.53 ng/ml) (P<0.001) ([Table 1]).
The cases had significantly worse BCVA (0.31±0.18) than the controls (0.97±0.06) (P<0.001). They also had significantly higher mean CMT (410.77±100.77 μm) than the controls (201.70±30.34 μm) (P<0.001) ([Table 1]).
There was a significant positive correlation between CMT with each of HbA1c (rho=0.793, P<0.001), serum Lp (a) ([Figure 1] and [Figure 2]) (rho=0.734, P<0.001), BMI (P=0.002), and DM duration (rho=0.489, P=0.029), whereas it had a significant negative correlation with BCVA (rho=0.696, P<0.001) ([Table 2]). The Lp (a) showed a significant positive correlation with HbA1c (P<0.001), BMI (P=0.017), and DM duration (P=0.27) but a significant negative correlation with BCVA (P<0.001) ([Table 2]).
|Figure 1 Scatter plot of central macular thickness (CMT) (μm) and lipoprotein (a) [LP (a)] (ng/ml).|
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|Figure 2 Optical coherence tomography (OCT) scans of two diabetic patients. Case 1 is a 60-year-old diabetic male patient. BMI is 29.34, DM duration is 16 years, HbA1c is 7.5, Lp (a) 15.42 ng/ml, and central macular thickness (CMT) is 350 μm. Case 2 is a 67-year-old male patient. BMI is 33.06, DM duration is 14 years, HbA1c 8.4, Lp (a) is 18.96 ng/ml, and CMT is 540 μm. DM, diabetes mellitus; HbA1c, glycosylated hemoglobin; Lp, lipoprotein.|
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|Table 2 Spearman correlation of central macular thickness and lipoprotein (a) with potential risk factors|
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ROC curve analysis of serum Lp (a) was conducted to predict its role in developing DME ([Figure 3]). It revealed an excellent area under the curve (0.998, P<0.001). At a cutoff value of/or more than 11.34 ng/ml, it had a 95.0% sensitivity, 95.0% specificity, 95% positive predictive value, 95.0% negative predictive value, and 95.0% overall accuracy.
|Figure 3 ROC curve of the predictive ability of LP (a) diabetic retinopathy. Lp, lipoprotein; ROC, receiver operating characteristics.|
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A univariate binary logistic regression analysis was performed to estimate the odds ratio and 95% confidence intervals to examine the risk factors/predictors of DME. BMI and serum Lp (a) were significant risk factors in univariate analysis, whereas other variables were not ([Table 3]).
|Table 3 Univariate logistic regression analysis for detection of risk factors associated with diabetic retinopathy|
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| Discussion|| |
The association between Lp (a) and type 2 DM and the development of DR has been a debate in the past two decades. Some investigators have found a positive association ,, whereas others have found an inverse one ,.
In this study, diabetic cases with DME were found to have a significantly elevated level of Lp (a) than the nondiabetic controls. Among diabetic patients, Lp (a) showed a significantly positive correlation with CMT measured by OCT, HbA1c level, BMI, and DM duration. However, it showed a significant negative correlation with BCVA. The univariate analysis showed that BMI and Lp (a) were significant independent risk factors and predictors of the CMT.
Wairokpam and Devi  studied two groups of diabetic patients: one group with DR and one group without. They found that all lipid parameters except high-density lipoprotein were significantly elevated among the retinopathy group. They also found the mean value of Lp (a) to be significantly elevated among the retinopathy group (P<0.001) as well. The same was reported also by Chopra et al.  (P<0.001), Malaguarnera et al.  (P<0.001), and Tu et al.  (P<0.001).
On the contrary, a cross-sectional study done by Chandni and Ramamoorthy  observed abnormal Lp (a) levels in 26.4% of the studied patients (144 type 2 diabetic patients). However, there was no significant difference of Lp (a) levels among patients with DR and patients without retinopathy. In addition, Ergün et al.  found similar Lp (a) levels in patients with DR and patients without. Verrotti et al.  studied the lipid profile and Lp (a) in 42 adolescent and young diabetic patients (range=12.8–27.9 years) with type 1 DM. They found no significant difference between patients with retinopathy and patients without. However, among patients with retinopathy, patients with pre-proliferative or proliferative DR had significantly higher Lp (a) levels than patients with background DR (P<0.001).
A follow-up study of 787 diabetic patients without retinopathy was carried out by Yun et al.  for more than 11 years. Their patients who developed DR were found to have significantly higher levels of Lp (a) than patients who did not develop DR (P<0.001). A very recent study by Moosaie et al.  included 1057 diabetic patients who were followed up for 5 years. They found a significant positive association between Lp (a) and the presence of DR (odds ratio=3.46, P<0.001).
In addition to Lp (a), other risk factors have been associated with DR in the current study. These included BMI and HbA1c level. There was a significant positive correlation between CMT and each of BMI and DM duration. On performing univariate regression analysis for predictors of CMT, BMI, and Lp (a) continued to be significant risk factors but HbA1c was not. This is in agreement with many studies, which reported positive association between the duration of DM and the presence/severity of DR ,,. In addition, Mociran et al.  found that the prevalence of diabetic maculopathy was greatest in those with duration of diabetes of more than 5 years. Jew et al.  found that HbA1c in the clinically diabetic maculopathy group was significantly higher (P<0.001) compared with the nondiabetic maculopathy group. Katusić et al.  and Kaštelan et al.  demonstrated that significant increases in high-density lipoprotein cholesterol and blood pressure were observed in higher BMI individuals, which are risk factors for DR.
| Conclusion|| |
Lp (a) level was significantly higher among diabetic cases than in controls. It was significantly correlated with CMT. It had an excellent sensitivity and specificity and was proved as an independent predictor for DME by ROC curve and logistic regression analysis. Hence, it can be used as a potential marker for diabetic maculopathy detection.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Joussen A, Smyth N, Nissen C. Pathophysiology of diabetic macular edema. Dev Ophthalmol 2007; 39:1–12.
Ding J, Wong T. Current epidemiology of diabetic retinopathy and diabetic macular edema. Curr Diab Rep 2012; 12:346–354.
Matthews D, Stratton M, Aldington J, Holman R, Kohner M. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol 2004; 122:1631–1640.
Miljanovic B, Glynn R, Nathan D, Manson J, Schaumberg D. A prospective study of serum lipids and risk of diabetic macular edema in type 1 diabetes. Diabetes 2004; 53:2883–2892.
Rema M, Srivastava B, Anitha B, Deepa R, Mohan V. Association of serum lipids with diabetic retinopathy in urban South Indians − the Chennai Urban Rural Epidemiology Study (CURES) Eye Study-2. Diabet Med 2006; 23:1029–1036.
Raman R, Rani P, Kulothungan V, Rachepalle S, Kumaramanickavel G, Sharma T. Influence of serum lipids on clinically significant versus nonclinically significant macular edema: SN-DREAMS Report number 13. Ophthalmology 2010; 117:766–772.
Aiello L, Avery R, Arrigg P, Keyt B, Jampel H, Shah S. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331:1480–1487.
Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, Seitz C. Lp (a) glycoprotein phenotypes. Inheritance and relation to Lp (a)-lipoprotein concentrations in plasma. J Clin Invest 1987; 80:458–465.
Hajjar K, Gavish D, Breslow J, Nachman R. Lipoprotein (a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature 1989; 339:303–305.
Massin P, Bandello F, Garweg J, Hansen L, Harding S, Larsen M et al.
Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 2010; 33:2399–2405.
Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City. Circulation 2008; 117:176–184.
Mora S, Kamstrup PR, Rifai N, Nordestgaard BG, Buring JE, Ridker PM. Lipoprotein(a) and risk of type 2 diabetes. Clin Chem 2010; 56:1252–1260.
Habib SS, Aslam M. Lipids and lipoprotein(a) concentrations in Pakistani patients with type 2 diabetes mellitus. Diabetes Obes Metab 2004; 6:338–343.
Singla S, Kaur K, Kaur G, Kaur H, Kaur J, Jaswal S. Lipoprotein (a) in type 2 diabetes mellitus: relation to LDL: HDL ratio and glycemic control. Int J Diabetes Dev Ctries 2009; 29:80–84.
Wairokpam T, Devi KS. Lipoprotein A in diabetic retinopathy. IOSR J Dent Med Sci 2017; 16 (6 Ver. IX):05–09.
Chopra R, Saramma JG, Mary J, Rebecca A. Lipoprotein(a) as a risk factor for diabetic retinopathy in patients with type 2 diabetes mellitus. Indian J Ophthalmol 2007; 55:195–198.
] [Full text]
Malaguarnera G, Gagliano C, Bucolo C, Vacante M, Salomone S, Malaguarnera M. Lipoprotein(a) serum levels in diabetic patients with retinopathy. Biomed Res Int 2013; 2013:943505.
Tu WJ, Liu H, Liu Q, Cao JL, Guo M. Association between serum lipoprotein(a) and diabetic retinopathy in Han Chinese patients with type 2 diabetes. J Clin Endocrinol Metab 2017; 102:2525–2532.
Chandni R, Ramamoorthy KP. Lipoprotein(a) in type 2 diabetic subjects and its relationship to diabetic microvascular complications. World J Diabetes 2012; 3:105–109.
Ergün UG, Oztüzün S, Seydaoglu G. Lipoprotein (A) levels in type 2 diabetic patients with diabetic retinopathy. Med J Malaysia 2004; 59:406–410.
Verrotti A, Lobefalo L, Chiarelli F, Mastropasqua L, Pallotta R, Colangelo L et al.
Lipids and lipoproteins in diabetic adolescents and young adults with retinopathy. Eye (Lond) 1997; 11 (Part 6):876–881.
Yun JS, Lim TS, Cha SA, Ahn YB, Song KH, Choi JA et al.
Lipoprotein(a) predicts the development of diabetic retinopathy in people with type 2 diabetes mellitus. J Clin Lipidol 2016; 10:426–433.
Moosaie F, Davatgari RM, Firouzabadi FD, Esteghamati S, Deravi N, Meysamie A et al.
Lipoprotein (a) and apolipoproteins as predictors for diabetic retinopathy and its severity in adults with type 2 diabetes: a case-cohort study. Can J Diabetes 2020; 44:414–421.
Mociran M, Drago ŞC, Hâncu N. Risk factors and severity of diabetic retinopathy in Maramureş. Appl Med Informatics 2009; 24:47–52.
Jew OM, Peyman M, Chen TC, Visvaraja S. Risk factors for clinically significant macular edema in a multi-ethnic population with type 2 diabetes. Int J Ophthalmol 2012; 5:499–504.
Katusić D, Tomić M, Jukić T, Kordić R, Sikić J, Vukojević N et al.
Obesity − a risk factor for diabetic retinopathy in type 2 diabetes?. Coll Antropol 2005; 29 (Suppl 1):47–50.
Kaštelan S, Tomić M, Gverović Antunica A, Ljubić S, Salopek Rabatić J, Karabatić M. Body mass index: a risk factor for retinopathy in type 2 diabetic patients. Mediators Inflamm 2013; 2013:436329.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]