thesis condensation
TRANSCRIPT
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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