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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 31  |  Issue : 2  |  Page : 131-137

Correlation of C-reactive protein and glycosylated hemoglobin on severity of diabetic macular edema


1 Department of Ophthalmology, Jubilee Mission Medical College, Thrissur, Kerala, India
2 Department of Endocrinology, Jubilee Mission Medical College, Thrissur, Kerala, India

Date of Web Publication27-Aug-2019

Correspondence Address:
Dr. Geethu Gopinath
Syamantaka 38/356, Arakkakadavu Road, Edappally, Kochi - 682 024, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_38_19

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  Abstract 


Background: Diabetic macular edema (DME) is an important cause of visual impairment in type 2 diabetes. Central macular thickness (CMT) measured using optical coherence tomography (OCT) is a noninvasive method for diagnosis and quantification of DME. OCT not only helps in follow-up and prognosis of macular edema but also aids in early detection of DME, which might not be clinically evident. The study suggests that inflammatory process plays a critical role in retinopathy. C-reactive protein (CRP), an inflammatory marker, is expected to be elevated in patients with poor glycemic control. Furthermore, data on possible association of CRP with diabetic retinopathy are sparse and a limited number of studies reported inconsistent results. The present study is to find the correlation of CRP and glycosylated hemoglobin (HbA1c) on severity of DME. Materials and Methods: This was a case–control study done in a tertiary hospital including 75 cases (type 2 diabetes patients with DME) and 75 controls (diabetics without DME) of diabetic age >5 years. Cases subdivided based on CMT into mild (201–300 μ), moderate (301–400 μ), and severe macular edema (>400 μ). Results: CRP was positive (>0.6 mg/dl) in 32 cases (42.7%) and five controls (6.7%), and positive correlation was obtained between CRP and DME severity. Elevated HbA1c level was associated with increased severity of DME. Conclusion: As inflammation plays a significant role in the pathogenesis of DME, CRP level can be considered as a biomarker to determine the severity of DME along with HbA1c levels.

Keywords: C-reactive protein, central macular thickness, diabetic macular edema, glycosylated hemoglobin, optical coherence tomography


How to cite this article:
Gopinath G, V. Kakkanatt AC, Bisto A A, Mathai MT. Correlation of C-reactive protein and glycosylated hemoglobin on severity of diabetic macular edema. Kerala J Ophthalmol 2019;31:131-7

How to cite this URL:
Gopinath G, V. Kakkanatt AC, Bisto A A, Mathai MT. Correlation of C-reactive protein and glycosylated hemoglobin on severity of diabetic macular edema. Kerala J Ophthalmol [serial online] 2019 [cited 2019 Sep 20];31:131-7. Available from: http://www.kjophthal.com/text.asp?2019/31/2/131/265499




  Introduction Top


India is termed as the “diabetic capital of the world,” with number of patients with diabetes expected to be 60.9 million by 2025.[1],[2] Duration and severity of central macular thickening and extent of fluorescein leakage are major factors accounting for reduced visual acuity and poor prognosis in diabetic retinopathy (DR).[1] Diabetic macular edema (DME) affects 20% of patients of diabetic duration >10 years.

Optical coherence tomography (OCT) is a noninvasive imaging modality based on low coherence interferometry used for in vivo visualization of biological tissues. Central macular thickness (CMT) is the most commonly used parameter to evaluate DME, for management and prognosis. Spectral-domain OCT (SD-OCT) is an imaging modality that has significant impact in the diagnostic evaluation of patients with DME and helps in understanding the precise anatomic alterations and pathophysiology of DME.[3]

Glycosylated hemoglobin (HbA1c) is a predictor of incidence and progression of DR.[4] Increased HbA1c level is the most important risk factor for the development of diabetic complications, including retinopathy and maculopathy.[5] C-reactive protein (CRP), an acute-phase protein, is an inflammatory biomarker involved in endothelial dysfunction and atherogenesis.[6],[7] Elevated CRP is a predictor of development of type 2 diabetes and other metabolic syndromes.[8]


  Materials and Methods Top


This case–control study was conducted in the department of Ophthalmology and Endocrinology, in a tertiary hospital in India from January 2017 to October 2018 which included 150 patients. Patients of type 2 diabetes mellitus (DM) with duration >5 years were included in the study, except those patients with proliferative DR, patients on drugs affecting macula, patients having media opacities interfering OCT examination, patients with other retinal pathologies, patients with other causes for macular edema, and patients with recent intraocular procedures in 1 year, acute infections, autoimmune diseases, and inflammatory bowel disease.

Diagnostic criteria for DM (American Diabetes Association guidelines) were fasting blood sugar of ≥126 mg/dl or 2-h postprandial blood sugar of ≥200 mg/dl or HbA1c ≥6.5%.[9]

After taking informed consent, detailed history and ophthalmological evaluation including best-corrected visual acuity, slit-lamp biomicroscopy, fundus examination, fundus photography, and OCT (using Cirrus HD-OCT) were done for these patients. The diagnosis of DR was based on the modified ETDRS scales.[2]

Based on CMT in OCT, patients with macular edema (including cystoid and spongiform macular edema and excluding tractional macular edema) were classified as Group 1 (CMT >200 μm) and Group 2 [Figure 1] being the patients with no macular edema (CMT ≤ 200 μm).[10]
Figure 1: Optical coherence tomography macula of Group 2 patient (without macular edema)

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Based on CMT, Group 1 patients were further subdivided into mild (1a: CMT: 201–300 μm) [Figure 2], moderate (1b: CMT 301–400 μm) [Figure 3], and severe macular edema (1c: CMT >400 μm) [Figure 4]. Classification was done based on time-domain OCT (TD-OCT) value. As the obtained values are SD-OCT, values were converted into TD-OCT values and then categorized. Conversion was done based on the formula, TD-OCT value = −43.12 + 1.01 × SD-OCT value.[11]
Figure 2: Optical coherence tomography macula of Group 1a patient (mild macular edema)

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Figure 3: Optical coherence tomography macula of Group 1b patient (moderate macular edema)

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Figure 4: Optical coherence tomography macula of Group 1c patient (severe macular edema)

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CRP level was measured by turbidimetry method, and the report was deduced as positive or negative; values >0.6 mg/dl are considered positive. HbA1c level was measured by high-performance liquid chromatography.

Based on hospital prevalence/incidence (5%), the sample was calculated as 68 cases and 68 controls.

Numerical variables were expressed as mean and standard deviation while categorical variables were expressed as frequency and percentages. To test the mean differences of the study variable with macular edema and without macular edema, independent two-sample t-test was applied for parametric variables and Mann–Whitney U-test for nonparametric variable. To test the mean differences of study variables with severity of macular edema, Kruskal–Wallis test was applied. To obtain the association of study variables with groups, Chi-square test was used.

Data obtained from 150 patients were coded and entered into Microsoft Excel sheet and analyzed using SPSS version 20 (IBM, IL, USA). P <0.05 was considered statistically significant. For statistical evaluation, eye with higher CMT of each patient was considered as worse and eye with lower CMT was considered as better eye.


  Results Top


Of 75 cases, 35 patients (46.67%) belonged to Group 1a, 25 patients (33.33%) belonged to 1b, and 15 (20%) belonged to 1c. The mean age in cases was 61.36 ± 6.22 years and in controls was 61.91 ± 6.42 years, and both groups were comparable with respect to age (p > 0.05). Maximum number of patients had duration of diabetes 11–15 years (62 patients).

CRP was positive in four patients of Group 1a (11.4%), 14 patients (56%) of Group 1b, and 14 patients (93.3%) of Group 1c. Combined data represented in [Table 1].
Table 1: C-reactive protein between cases and controls

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HbA1c values were significantly high in patients with DME (P < 0.001) [Table 2].
Table 2: Glycosylated hemoglobin values comparison between cases and controls

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The mean HbA1c value in Group 1a was 7.74 ± 0.96, in Group 1b was 8.35 ± 1.20, and in Group 1c was 10.62% ±0.70% [Table 3].
Table 3: Glycosylated hemoglobin values comparison among case subgroups

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Elevated HbA1c level was associated with increased CMT, with Pearson coefficient showing positive correlation in both eyes [Table 4].
Table 4: Correlation of glycosylated hemoglobin and central macular thickness in cases

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Positive CRP levels were associated with increased CMT in both eyes [Table 5].
Table 5: Comparison of C-reactive protein and central macular thickness in cases

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The mean HbA1c in patients with positive CRP was 9.65% ± 1.42% and in patients with negative CRP was 7.68% ± 0.81%. Patients with positive CRP had significantly elevated levels of HbA1c (P < 0.001) [Table 6].
Table 6: Association between C-reactive protein and glycosylated hemoglobin values in cases

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  Discussion Top


DM is reaching epidemic proportions in the world today. Inflammation is thought to play an inevitable role in DR. In this study, the role of CRP as an inflammatory biomarker on severity of DME along with HbA1c was analyzed. Only limited studies are available comparing degree of macular edema with CRP levels, and few of them have shown inconsistent results. The study also showed that patients with positive CRP were found to have elevated HbA1c values.

Findings of our study were in accordance with results obtained by Kaur et al., who reported that CRP levels were increased in patients with DR as compared to patients without DR.[6] The EURODIAB study also reported that positive CRP level was associated with DR severity after adjusting with sex, age, history of the diabetes, HbA1c level, and systolic blood pressure.[12]

However, some studies have reported no correlation between CRP and DR which is again reason to embark on a new study in the Indian subcontinent.[13],[14] Again, a Chinese study reported by Yang et al. reported inverse relationship between the above-mentioned variables and they also found that it was more prominent among men and not statistically significant in women.[14]

Similar to the present observations, in a study conducted by Kulkarni and Kodliwadmath which included 150 patients, elevated serum high sensitivity-CRP (hs-CRP) levels in diabetics with retinopathy were observed when compared to diabetics without retinopathy. This study concluded that hs-CRP has a role in risk stratification of diabetes.[15]

Mocanu et al. also reported that lower CRP values are associated with higher prevalence of DR but could not give any possible explanations for the same.[13]

The review article by Song et al. including a total of 3679 participants has reported that CRP levels in proliferative DR group were higher than those in the nonproliferative DR group. They concluded that CRP is a useful biomarker to determine the severity of DR.[16]

We assume that CRP being an acute-phase reactant should be positively associated with DR and in turn with DME and its severity. When we correlated with Group 1c patients who had CMT >400 μm, we found that these were also significantly related to CRP values.

Nada and Abdel-Moety reported that CRP was significantly higher in diabetic patients with PDR which was reported after comparing with controls and diabetics without DR. This study did not mention about DME, but PDR being a sight-threatening complication ascertains its significance.[17]

The severity and duration of inadequate glycemic control are seen to be correlated with higher risk of increased severity of retinopathy, from nonproliferative to proliferative DR. Poor glycemic control is derived by the HbA1c value, and this is positively associated with severity of DME also.[1]

In our study, we found significant association with DME and HbA1c values, again showing that a correlation exists with increasing macular thickness and long-standing poor glycemic control.

Fenwick et al. reported a higher odds ratio of DR and DME with poor glucose control. This was again a recently done clinical cross-sectional study on 613 patients.[18] Raman et al. concluded that HbA1c value >8.0% was significantly associated with sight-threatening DR, which was in accordance with our findings that Group 1c patients with highest CMT have a significant correlation with higher HbA1c.[1]

Peng and Tsai studied 124 patients with diabetes and reported contradicting results. They observed that higher HbA1c were correlated with increased CMT in patients without DME, whereas HbA1c values were inversely associated with CMT in patients with DME. Both were found to be statistically significant after adjusting for age, sex, and DR severity in addition to other metabolic factors.[19]


  Conclusion Top


CRP is a useful marker to assess the severity of DME. However, as this acute-phase reactant does increase in a number of other conditions, we must be careful before concluding.

HbA1c is an established marker for assessing glycemic control and also proved to be significantly associated with the severity of DR. Patients with poor glycemic control need to be counseled about earlier development of DR and accelerated progression of severity of DR. Early screening for retinopathy is important as patients may remain asymptomatic till the development of DME and proliferative changes which can be sight-threatening. Our study signifies the critical role of inflammation and metabolic control in the pathogenesis of DR and DME as indicated by CRP and HbA1c. We assume that those patients with elevated CRP might be benefited with anti-inflammatory drug therapy in the management of DME.

Patients with macular edema were treated with intravitreal injections and are under follow-up. Results were not included in the present study, as this was an observational study.

Theoretic assumptions and derived conclusions of our study should be researched in-depth by means of larger randomized control studies.

Acknowledgments

We would like to acknowledge the support from Jubilee Mission Medical College, Thrissur.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Raman R, Verma A, Pal SS, Gupta A, Vaitheeswaran K, Sharma T. Influence of glycosylated hemoglobin on sight-threatening diabetic retinopathy: A population-based study. Diabetes Res Clin Pract 2011;92:168-73.  Back to cited text no. 1
    
2.
Raman R, Rani PK, Kulothungan V, Rachepalle SR, Kumaramanickavel G, Sharma T. Influence of serum lipids on clinically significant versus nonclinically significant macular edema: SN-DREAMS report number 13. Ophthalmology 2010;117:766-72.  Back to cited text no. 2
    
3.
Bhende M, Shetty S, Parthasarathy MK, Ramya S. Optical coherence tomography: A guide to interpretation of common macular diseases. Indian J Ophthalmol 2018;66:20-35.  Back to cited text no. 3
[PUBMED]  [Full text]  
4.
Corcóstegui B, Durán S, González-Albarrán MO, Hernández C, Ruiz-Moreno JM, Salvador J, et al. Update on diagnosis and treatment of diabetic retinopathy: A Consensus guideline of the working group of ocular health (Spanish society of diabetes and Spanish vitreous and retina society). J Ophthalmol 2017;2017:8234186.  Back to cited text no. 4
    
5.
Kocak Altintas AG, Citirik M, Gulpamuk B. Relationship of serum HbA1c and fasting serum lipids with central macular thickness in patients with Type 2 diabetes mellitus. J Clin Res Ophthalmol 2016;3:23-6.  Back to cited text no. 5
    
6.
Kaur S, Singh P, Grewal RK, Kaur N, Agarwal A. Serum haptoglobin, ceruloplasmin and CRP levels: Markers of diabetic retinopathy. Global Journal of Medical Research 2012;12:1-4.  Back to cited text no. 6
    
7.
Laursen JV, Hoffmann SS, Green A, Nybo M, Sjølie AK, Grauslund J. Associations between diabetic retinopathy and plasma levels of high-sensitive C-reactive protein or von Willebrand factor in long-term type 1 diabetic patients. Curr Eye Res 2013;38:174-9.  Back to cited text no. 7
    
8.
Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol 2018;9:754.  Back to cited text no. 8
    
9.
American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care 2017;40 Suppl 1:S11-24.  Back to cited text no. 9
    
10.
Brown JC, Solomon SD, Bressler SB, Schachat AP, DiBernardo C, Bressler NM, et al. Detection of diabetic foveal edema: Contact lens biomicroscopy compared with optical coherence tomography. Arch Ophthalmol 2004;122:330-5.  Back to cited text no. 10
    
11.
Diabetic Retinopathy Clinical Research Network Writing Committee, Bressler SB, Edwards AR, Chalam KV, Bressler NM, Glassman AR, et al. Reproducibility of spectral-domain optical coherence tomography retinal thickness measurements and conversion to equivalent time-domain metrics in diabetic macular edema. JAMA Ophthalmol 2014;132:1113-22.  Back to cited text no. 11
    
12.
Schram MT, Chaturvedi N, Schalkwijk CG, Fuller JH, Stehouwer CD; EURODIAB Prospective Complications Study Group. Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes – The EURODIAB prospective complications study. Diabetologia 2005;48:370-8.  Back to cited text no. 12
    
13.
Mocanu V, Timar R, Horhat R, Bucur A, Şerban V. C-reactive protein and body mass index in patients with type -2 diabetes mellitus and diabetic retinopathy. Romanian J Diabetes Nutr Metab Dis 2013;20:127-33.  Back to cited text no. 13
    
14.
Yang XF, Deng Y, Gu H, Lim A, Snellingen T, Liu XP, et al. C-reactive protein and diabetic retinopathy in Chinese patients with type 2 diabetes mellitus. Int J Ophthalmol 2016;9:111-8.  Back to cited text no. 14
    
15.
Kulkarni DR, Kodliwadmath DM. Oxidative stress and high sensitivity C reactive protein in diabetic retinopathy. Int J Pharm Bio 2013;4:1306-10.  Back to cited text no. 15
    
16.
Song J, Chen S, Liu X, Duan H, Kong J, Li Z. Relationship between C-reactive protein level and diabetic retinopathy: A systematic review and meta-analysis. PLoS One 2015;10:e0144406.  Back to cited text no. 16
    
17.
Nada WM, Abdel-Moety DA. Serum C-reactive protein and diabetic retinopathy. Open J Ophthalmol 2017;7:73-8.  Back to cited text no. 17
    
18.
Fenwick EK, Xie J, Man RE, Sabanayagam C, Lim L, Rees G, et al. Combined poor diabetes control indicators are associated with higher risks of diabetic retinopathy and macular edema than poor glycemic control alone. PLoS One 2017;12:e0180252.  Back to cited text no. 18
    
19.
Peng YJ, Tsai MJ. Impact of metabolic control on macular thickness in diabetic macular oedema. Diab Vasc Dis Res 2018;15:165-8.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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