RISK FACTORS FOR PROLIFERATIVE

DIABETIC RETINOPATHY

INTRODUCTION

Diabetes Mellitus is a major medical problem throughout the world, number

of diabetics in India will increase from 19 million to 57 million between

1995 and 2005 and around 60% of them are likely to develop diabetic

retinopathy [DR]. (1)

Diabetic retinopathy manifests in various stages, of which Proliferative

diabetic retinopathy [PDR] is a common cause of sudden loss of vision due

to spontaneous vitreous hemorrhage or tractional retinal detachment.

asymptomatic in its most treatable stage. It is conventionally managed with

Panretinal laser photocoagulation, which has been shown in several studies

to reduce the risk of moderate and severe visual loss.

While there is no definitive means of preventing DR, its onset can be

postponed by controlling the important risk factors; namely blood sugar

levels, hypertension, Nephropathy, and serum lipid parameters. However

one of the most important risk factor remains non-modifiable: duration of

diabetes.

Regular fundus examination in diabetics is of utmost important to diagnose

DR at the earliest and institute appropriate management, while establishing

good metabolic control. This promotes stabilization of vision and decreases

the rate of visual loss.

PATIENTS AND METHODS

The present study is a comparative study conducted in the Departments of

Ophthalmology and General Medicine at JIPMER, Pondicherry, between

September 2006 and June 2008. A total of 30 patients with NPDR and 30

patients with PDR were initially enrolled for the study. At the end of the

study, 30 diabetic patients without any retinopathy were included in the

study to serve as controls.

The BP, 24 hr urinary protein and creatinine, and serum lipid profile levels

are recorded and tabulated. The duration of diabetes, type of medication

were also documented. The Ocular status in terms of Visual Acuity, Intra

ocular Pressure, slit lamp examination for neovascularization, fundus picture

on Direct and Indirect ophthalmoscopy and using a +90 D lens, were

recorded and documented. Fluorescein angiography was performed in

patients with PDR and findings noted.

Statistical significance of the parameters under study was tested by t test or

chi square test, depending on the parameter. Analysis of Variance [ANOVA]

was performed to evaluate impact on NPDR and PDR.

OBSERVATIONS :

Majority of the patients belonged to the age group of 51-65 yrs, with a male

preponderance in the PDR group.

Mean duration of diabetes was higher in patients with PDR.

Values of mean systolic and diastolic pressures in the PDR group were

significantly higher than corresponding values in patients with NPDR.

Patients with PDR had higher levels of serum cholesterol and LDL when

compared to the other patients.

Patients with PDR had significantly higher levels of 24 h urinary protein

excretion and blood urea levels than the other patients.

About half of the patients with PDR had serum creatinine level of >1 mg%.

On comparing fasting and postprandial plasma glucose levels, poorer

glycemic control was observed in PDR group.

The groups did not differ with respect to BMI.

The following table illustrates the mean and standard deviation of various

parameters, and the differences across the sexes as well. A p value of <0.05

was taken to b significant.

Table 1. Mean ± Standard Deviation values and Statistical Significance of various parameters under

study

Parameter Groups P Value Sexes P Value

No DR

[I]

NPDR

[II]

PDR

[III]

[I] vs

[II]

[I] vs

[III]

[II] vs

[III]

Males

[A]

Females

[B]

[A] vs [B]

Number of

patients

30 30 30 60 30

Duration of

diabetes, years

4.78 ±

2.2

9.57 ±

4.4

11.61

± 8.3

< 0.05 < 0.05 0.335 9.02 ±

6.6

7.93 ±

5.4

0.440

BP, Systolic, mm

Hg

130.00

± 14.6

128.00

± 17.1

148.5

3 ±

17.6

0.886 < 0.05 < 0.05 136.9±

18.6

132.6±1

8.9

0.301

BP, Diastolic,

mm Hg

88.00 ±

8.4

82.33

± 10.0

90.80

± 10.5

0.067 0.507 < 0.05 88.23

±10.5

84.67 ±

9.3

0.120

Cholesterol, mg

%

144.00

± 27.5

153.37

± 54.6

196.4

7 ±

45.9

0.691 < 0.05 < 0.05 172.1±

49.7

149.5

±45.7

< 0.05

Triglycerides, mg

%

109.00

± 21.5

123.67

± 59.9

144.3

0 ±

61.2

0.508 < 0.05 0.266 127.8±

51.3

121.3±5

5.3

0.586

LDL, mg% 92.00 ±

19.0

91.13

± 36.2

117.4

0 ±

35.4

0.899 < 0.05 < 0.05 104.6±

35.2

91.1

±27.1

0.069

HDL, mg% 35.67 ±

7.4

34.67

± 6.5

42.80

± 5.9

0.832 < 0.05 < 0.05 38.08 ±

7.1

36.97 ±

8.4

0.592

VLDL, mg% 21.50 ±

7.0

22.70

± 11.4

28.47

± 12.4

0.899 < 0.05 24.78

±10.6

23.10

±11.4

0.493

24h Urinary

Proteins, mg

163.67

± 43.1

242.63

±

230.2

991.1

0 ±

1140.

8

0.892 < 0.05 < 0.05 600.0 ±

896.5

197.3 ±

200.9

< 0.05

Urea, mg% 16.83 ±

8.2

28.77

± 11.5

45.83

± 24.2

< 0.05 < 0.05 < 0.05 34.15 ±

21.0

23.13 ±

15.4

< 0.05

BMI, kg/sqm 24.93 ±

2.5

25.48

± 3.3

25.79

± 3.3

0.768 0.530 0.922 25.68 ±

2.9

24.84 ±

3.3

0.226

Fasting Plasma 146.00 139.40 217.4 0.933 < 0.05 < 0.05 166.68 169.50 0.261

Glucose, mg% ± 47.5 ± 53.1 ±

100.8

± 84.4 ± 68.0

Postprandial

Plasma Glucose,

mg%

188.00

± 54.0

215.27

± 79.5

303.8

3 ±

102.8

0.261 < 0.05 < 0.05 242.98

± 96.7

221.13

± 89.7

0.560

Note: The mean difference was taken to be significant at the 0.05 level.

DISCUSSION :

Several large population based epidemiological studies have been carried out

around the world and in India to determine the various risk factors for

diabetic retinopathy. Though PDR per se has not been as extensively

investigated, some hypotheses and conclusions have been put forth by the

various investigators based on the data obtained.

The United Kingdom Prospective Diabetes Study [UKPDS] and a few

studies in India also examined age as a risk factor for severity of retinopathy

and documented positive contributions. (8-14)

In our study, majority of patients belonged to the age group of 51 to 65 yrs.

Overall; the age distribution of patients across the 3 groups was comparable.

Ours was a cross sectional and not a longitudinal study which explains why

no contributory influence of age was documented. Moreover, maintaining a

sample size of 30, all the diabetic patients attending the diabetic clinic could

not be included in the study.

Coming to the influence of the sex of the patient on DR, while the UKPDS

and the CURES study reported higher incidence of retinopathy in males, no

significant relationship existed between sex and prevalence of diabetic

retinopathy as concluded by Davis et al (15) in the ETDRS, Kahn et al on

analysis of Joslin clinic patients (16), Cahill et al (17), and in the Indian studies

conducted at Banaras (9) and by Thapar in 2004. (18)

In our study, there was a male preponderance among the patients studied. In

the PDR group, it leads to the conclusion that PDR is commoner in males,

whereas females were more likely to have NPDR or no DR.

However, fewer females in our study could be because females tend to seek

health care at a later stage than the males, who usually being the earning

members of the family, tend to seek health care earlier, and the females

might be forced to remain at home carrying out domestic duties. Or it could

be just coincidental. Whether there is indeed a difference among the sexes in

predisposition to severe retinopathy, is a question that can be addressed in

larger population based studies. Whether the hormonal differences among

the sexes have a role to play can also be looked into.

With regards to duration of Diabetes as a risk factor, the Arizona study (2),

the WESDR (3-7), the Joslin study (16), the EURODIAB Prospective

Complications Study (PCS) (19) and those conducted at Dublin (17;20), and

Sicily (21) all established duration of diabetes as an important factor

influencing severity and progression of Diabetic retinopathy. Indian studies

such as CURES (20;22), and those conducted at Banaras (9), Ludhiana (18), and

Nagpur (23), also arrived at similar conclusions.

Effect of prolonged duration can be explained on the basis of prolonged

exposure of the body’s end organs to hyperglycemia and the

microangiopathic effects of diabetes. If glycemic levels are within control,

anti diabetic therapy in itself could be an important risk factor. While in the

retina, microangiopathy manifests as worsening retinopathy, the kidneys

show evidence of nephropathy. Each condition two conditions could in turn

promote progression of the other.

The results of our study too agree with those of the above studies. Duration

of diabetes was significantly higher among patients with PDR than those

with no DR (Tables 1). And 15 [50%] of patients with PDR were known

diabetics for 10 yrs or more.

Hypertension is another systemic variable that has been extensively

investigated in various studies. Hypertension per se causes vascular changes

in the fundus, which could be widespread arteriolar attenuation, AV crossing

changes, and exudates. By aggravating the hypoxia caused by diabetic

microangiopathy by hypertensive changes in the vasculature, systemic

hypertension may be one of the main risk factors for PDR.

A higher incidence of proliferative retinopathy, after controlling for age, sex,

and diabetes duration, was associated with hypertension, as reported by

Nelson and coworkers in the Arizona study on incidence of PDR. (2)

However, there is less consensus on the contribution of hypertension

towards progression of PDR as reported in the Indian studies.

In our study, Systolic and diastolic BP in patients with PDR (149/91 mm

Hg) was significantly higher than the other groups (Tables 1).

Abnormal serum lipid parameters are being intensely investigated as

possibly risk factors for PDR. Results of the other studies reveal no

consensus at present, and hence further investigation in larger population

based trials is warranted.

In our study, levels of cholesterol, triglycerides and LDL were compared

among the groups of patients. Cholesterol, LDL, HDL and VLDL levels

among patients with PDR were significantly higher than those with no DR

and NPDR (Tables 1). In addition, males, regardless of groups, tended to

have significantly higher cholesterol level than females.

Higher cholesterol and triglyceride levels have been known to predispose to

hard exudates in the retina. However it is difficult at this point to justify a

direct link to PDR. One mechanism could be widespread atheromatous

changes in the vasculature of patients with elevated lipid profile levels,

leading to decreased perfusion of the retina. In eyes with baseline severe

retinopathy such as NPDR, further hypoxia could induce Neovascularization

and thus PDR. However, further investigation is necessary to establish the

most possible mechanism of pathogenesis.

The higher levels found in males in our study may be due to a difference in

diet.

Diabetic Nephropathy is another parameter which has been implicated in

various studies conducted worldwide as a risk factor for retinopathy

progression. This greater risk can be explained based on the various

systemic effects of the nephropathy per se. Nephropathy may contribute to

the development of proliferative retinopathy by increasing blood pressure

and fibrinogen, by altering the lipoprotein profile, and possibly through

other mechanisms. Moreover, patients with micro and macroalbuminuria

usually have significantly elevated blood sugars and blood pressures, which

compound the risk.

A higher incidence of proliferative retinopathy, after controlling for age, sex,

and diabetes duration, was associated with proteinuria and renal

insufficiency in the Arizona study. (2)

In our study, 24 h Urine protein excretion was significantly higher in

patients with PDR. Thus blood levels of urea and creatinine were

significantly higher these patients. Interestingly, females were found to have

significantly lower urea and creatinine levels than males

The differences between males and females with regard to predisposition to

developing nephropathy, and the level of nephropathy at which DR

progresses to PDR needs larger studies for evaluation.

Coming to the Body Mass Index, although BMI was > 25 kg/sqm in patients

with NPDR and PDR in our study, the difference amongst them was not

statistically significant (Table 1). As the majority of our patients are above

50 yrs of age, a sedentary lifestyle without exercise could explain the BMI

being above 25 in them. Moreover, being overweight [>120% of expected

body weight] is a component of the definition of type 2 diabetes (7). The

higher body mass also contributes to the high BMI. However, a larger study

is required to investigate the importance of BMI.

Along with duration of diabetes, poor glycemic control is another risk factor

studied extensively around the world for its deleterious effect on diabetic

retinopathy.

The ETDRS (15), WESDR (3-7), UKPDS (24;25), studies conducted at Joslin (16)

and Pennsylvania (26), CURES (20;22), and other Indian studies (9-11;18;23)

uniformly concluded that uncontrolled diabetes as measured in terms of

raised HbA1C levels, or raised fasting and post prandial glucose levels was

an important risk factor for progression to PDR.

In our study, fasting and post prandial plasma glucose levels of the patients

with PDR were higher than those with NPDR (Table 1).

This effect of hyperglycemia can be explained to be due to the action of

Aldose reductase. Aldose reductase is the initial enzyme in the intracellular

polyol pathway. This pathway involves the conversion of glucose into

glucose alcohol (sorbitol). High glucose levels increase the flux of sugar

molecules through the polyol pathway, which causes sorbitol accumulation

in cells. Osmotic stress from sorbitol accumulation has been postulated as an

underlying mechanism in the development of diabetic microvascular

complications, including diabetic retinopathy.

CONCLUSION:

Proliferative Diabetic Retinopathy remains the most common cause of

sudden onset of visual loss among adults. While established risk factors

include Duration of Diabetes, poor glycemic control, Hypertension and

Nephropathy, hyperlipidemia and BMI are under intense investigation. By

ensuring a good metabolic control in place, progression of DR to the

proliferative stage can be postponed. The importance of regular fundus

examinations cannot be stressed enough, in order to pick up retinal lesions at

the earliest, and institute treatment in the form of panretinal

photocoagulation when indicated.

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