Diagnosis of retinopathy in children younger than 12 years of age: implications for the diabetic eye screening guidelines in the UK.

AimTo assess whether the current starting age of 12 is suitable for diabetic retinopathy (DR) screening and whether diabetes duration should be taken into account when deciding at what age to start screening patients.Materials and methodsA retrospective analysis of 143 patients aged 12 years or younger who attended diabetic eye screening for the first time in the Birmingham, Solihull and Black Country Diabetic Eye Screening Programme was performed.ResultsThe mean age of the patients was 10.7 (7-12) years with 73 out of 143 aged below 12 years and 70 were 12 years of age. 98% had type 1 diabetes and mean diabetes duration was 5 (1 month-11 years) years. For those younger than 12 years, 7/73 (9.6%) had background DR (BDR), of these mean diabetes duration was 7 years (6-8). The youngest patient to present with DR was aged 8 years. In those aged 12 years, 5/70 (7.1%) had BDR; of these mean diabetes duration was 8 years (6-11). No patient developed DR before 6 years duration in either group.ConclusionsThe results show that no patient younger than the age of 12 had sight-threatening DR (STDR), but BDR was identified. Based on the current mission statement of the Diabetic Eye Screening Programme to identify STDR, 12 years of age is confirmed as the right age to start screening, but if it is important to diabetic management to identify first development of DR, then screening should begin after 6 years of diabetes diagnosis.

Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study.

Early case control studies found association of the DRB1 allele, DR3, with Graves' disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10(-3)) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10(-6)). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (chi2 = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; chi2 = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.

The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.

Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus for Graves' disease. The previously reported A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene was, therefore, investigated in a case-control (n = 743) and family-based (n = 179) dataset of white Caucasian subjects with Graves' disease. The relationship between CTLA-4 genotype and severity of thyroid dysfunction at diagnosis was also investigated. An increase in frequency of the G (alanine) allele was seen in Graves' patients compared with control subjects (42% vs. 31.5%, respectively; corrected P<0.0002; odds ratio = 1.58), and a significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi2 = 21.7; corrected P<0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi2 = 5.7; P = 0.025). Circulating free T4 concentrations at diagnosis were significantly associated with CTLA-4 genotype (F = 3.26; P = 0.04). These results support the hypothesis that CTLA-4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves' disease.

Comparison of the hypotensive and metabolic effects of bendrofluazide therapy and a high fibre, low fat, low sodium diet in diabetic subjects with mild hypertension.

Fifty diabetic patients with mild hypertension were treated by a high fibre, low fat and low sodium diet or bendrofluazide for a three-month period. These two well-matched groups had a similar highly significant decrease in both systolic (P less than 0.001) and diastolic blood pressure (P less than 0.001). Both groups lost weight, the weight loss being greater in those receiving dietary therapy. Only dietary therapy was associated with a significant elevation of HDL2 level (P less than 0.05) and decrease in glycosylated haemoglobin (P less than 0.01). Bendrofluazide therapy resulted in significant elevation of glycosylated haemoglobin level (P less than 0.05) and at the end of the study this group had significantly higher glycosylated haemoglobin level (P less than 0.05) than the diet treated group. In those patients who were also hyperlipidaemic, dietary therapy resulted in a significant decrease of mean serum cholesterol (P less than 0.02), triglyceride (P less than 0.01) and glycosylated haemoglobin (P less than 0.01) while bendrofluazide treatment tended to elevate these levels. We conclude that a high fibre, low fat and low sodium dietary regimen lowers blood pressure, improves several other coronary risk factors and appears free of side-effects. This modified diet may be an attractive alternative to thiazide diuretic therapy in the mildly hypertensive diabetic subject.

Hypertension and diabetes.

Hypertension is common in people with diabetes with an estimated prevalence using the new criteria (> or = 140/90) at 70%. The recent large randomized controlled studies in diabetic subjects has clearly shown the benefit of blood pressure lowering with reduction in cardiovascular endpoints and microvascular disease. ACE inhibitors, calcium antagonists, thiazide diuretics and beta-blocking agents have been the agents validated by the trials. The challenge now is to implement antihypertensive therapy to achieve tight blood pressure targets (< or = 140/80), usually requiring dual or even triple therapeutic regimens.

The non-drug treatment of hypertension in the diabetic patient.

A wide range of non-pharmacological manoeuvres have been tried for the control of BP but the majority of studies have not examined diabetic patients. Alteration of individual dietary components is difficult to achieve and results difficult to interpret. A high fibre, low fat, moderate salt restricted diet is as efficacious as drug therapy in some hypertensive diabetic patients. Similar diets have been recommended for all diabetic patients by the British Diabetic Association and the European Association for the Study of Diabetes. This diet has the added advantage of improving glycaemic control and plasma lipid profiles. The benefits of behavioral modifications are variable, with some being better than placebo. Although there is no evidence for a hypertensive effect of smoking, it should be strongly discouraged in diabetic patients because of the added cardiovascular risk it places upon them. Studies of dietary control of BP indicate that a response should be observed after three months of treatment. If blood pressure remains elevated after this time the patient should be treated with pharmacological agents. Hyperinsulinaemia may be important in the pathogenesis of Type II diabetes, coronary artery disease and essential hypertension. Dietary manoeuvres which reduce plasma insulin levels may prove to be of benefit in all of these conditions, but as yet data are not available to support this hypothesis.

Hypertensive retinopathy: a review of existing classification systems and a suggestion for a simplified grading system.

With the advent of sophisticated ophthalmological investigations and a better understanding of the pathophysiology and clinical or prognostic correlates of the fundal lesions in hypertension, the limitations of early classification schemes using simple ophthalmoscopic appearances are increasingly apparent. This review describes the existing classification systems for hypertensive retinopathy and their limitations, as well as the pathophysiological effects of hypertension on the retinal vasculature. A new and simpler grading system for hypertensive retinopathy is proposed, dividing the features according to prognosis into two categories of non-malignant vs malignant hypertension. Such a simpler, updated system for our medical practice has been long overdue.

Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study.

We have previously demonstrated that modest sodium restriction has a hypotensive effect in hypertensive diabetic subjects. A randomised blind controlled study has therefore been performed to study the effect of replacement of added salt intake using a salt substitute (50% NaCl, 40% KCL, 10% Mg2+, supplied by Cederroth, Sweden), compared to added whole salt intake over a 9 month period of 40 hypertensive Type II diabetic subjects (mean age 62.5 +/- 7.8 years; 24 males and 16 females). After 3 months, there was a significant reduction in systolic blood pressure (SBP) in the salt substitution group (163.2 +/- 24.2 to 153.6 +/- 20.8 mm Hg; P < 0.03) which was maintained at 9 months, when compared to the whole salt group (151.5 +/- 20.6 vs 173 +/- 18.9 mm Hg; P < 0.05). No significant changes were observed in mean weight, fasting lipid or insulin levels or diabetic control (measured by glycosylated haemoglobin). A greater number of patients were withdrawn during the study period owing to consistent BP > 160/95 in the whole salt group (n = 10) compared to salt substitute (n = 4). No significant changes were observed in diastolic pressure, 24-h urine sodium or magnesium excretion, but urine potassium was significantly increased in the salt substitute group (58.8 to 77.3: P < 0.05). The results of this study suggest that substitution of sodium, by potassium and magnesium, produces a clinically significant reduction in SBP in hypertensive Type II diabetic patients, and should be a useful antihypertensive therapy in this patient group.

Randomised blind controlled trial of a high fibre, low fat and low sodium dietary regimen in mild essential hypertension.

Thirty-four patients with essential hypertension were allocated, in a controlled trial, to a treatment diet of high fibre, low fat and low sodium composition, or to a control diet by the hospital dietitian. Clinical observations were made by a separate 'blinded' nursing sister. After three months treatment, the modified diet-treated group showed a significant reduction in mean systolic (169.4 +/- 23.4 to 150.6 +/- 16.1 mmHg) and diastolic blood pressure (101.5 +/- 7.3 to 89.4 +/- 6.8 mmHg), accompanied by significant reductions in urinary sodium excretion (140.4 +/- 34.6 to 93.7 +/- 44 mmol/day) and weight (73.1 +/- 10 to 71.2 +/- 8.4 kg). The changes in control were; systolic 171.2 +/- 14.1 to 162.1 +/- 19.5 mmHg and diastolic pressure 97.2 +/- 10.8 to 91.7 +/- 9.7 mmHg. The mean differences in reductions between treated and control were 8.8 mmHg Systolic (95% confidence intervals: -2.6 to 21.2 mmHg) and 7.0 mmHg diastolic blood pressure (95% confidence intervals: 0.4 to 14.4 mmHg). The number of patients with normal blood pressure in the diet treated group at three months was double that in the control (eleven versus five). No relationships were shown between blood pressure changes and those of weight or urinary sodium excretion during the trial. The findings in this study are broadly in agreement with similar ones in essential hypertension and suggest that this form of dietary regimen has a clinically worthwhile hypotensive effect and this should be readily achievable in routine clinical practice.

Medical conditions underlying retinal vein occlusion in patients with glaucoma or ocular hypertension.

Forty-three patients with glaucoma and 24 patients with ocular hypertension presenting with a retinal vein occlusion were medically assessed. The prevalence of systemic hypertension was 60.5% in those with glaucoma and 66.6% with ocular hypertension. The prevalence of hyperlipidaemia was 38.1% in those with glaucoma and 37.5% in those with ocular hypertension. These findings were compared with those from a carefully age-sex matched group of patients presenting with a retinal vein occlusion without evidence of glaucoma or ocular hypertension. There were no statistical differences between any of the groups (52.2% had systemic hypertension and 28.8% had hyperlipidaemia). There was also a strikingly high prevalence of systemic hypertension (89%) and hyperlipidaemia (55.5%) in nine of the patients who had evidence of a recurrent retinal vein occlusion associated with glaucoma, and these prevalence rates were strikingly similar to the rates in patients with recurrence but without glaucoma. The data suggest that glaucoma or ocular hypertension has a less prominent aetiological role in the development of a retinal vein occlusion than underlying medical causes and that full medical assessment is worthwhile.

Medical conditions underlying recurrence of retinal vein occlusion.

Seventeen patients with recurrent retinal vein occlusion were investigated for underlying medical conditions and compared with 61 patients with single retinal vein occlusion (26 with central, 35 with branch vein occlusion). The two study groups were comparable for age, sex, and weight. Patients with recurrence had a significantly increased prevalence rate of hypertension (88% versus 48%: p less than 0.01), with a trend to increased hyperlipidaemia (47% versus 33%) compared with patients with a single episode. A significantly raised mean systolic (p less than 0.05) but not diastolic blood pressure was found in patients with recurrence. Other cardiovascular risk factors in patients with recurrence were also found and included lower mean levels of high density lipoprotein (HDL)-cholesterol (p less than 0.02) and the HDL2 subfraction (p less than 0.001), and a significantly increased proportion of patients with regular alcohol intake (p less than 0.01). We conclude that hypertension and hyperlipidaemia with an increase in other cardiovascular risk factors are commonly found in patients with recurrent retinal vein occlusion and may therefore be important aetiological factors. The possible benefits of treatment of these underlying conditions to prevent recurrence need to be assessed in well designed prospective studies.

Retinal vein occlusion and the prevalence of lipoprotein abnormalities.

Ninety-nine patients with retinal vein occlusion (40 with central, 59 with branch vein occlusion) were investigated for the prevalence of associated diseases for comparison with an age-matched control group. There was a significantly increased prevalence of hyperlipidaemia (p less than 0.001) and hypercholesterolaemia (p less than 0.001) in the group with branch retinal vein occlusion and of hyperlipidaemia (p less than 0.001) and hypercholesterolaemia (p less than 0.02) in the group with central retinal vein occlusion compared with controls. An increased prevalence of hypertriglyceridaemia (p less than 0.001) was also found in patients with central vein occlusion. Other associations were noted (hypertension and oestrogen therapy). Increased serum cholesterol concentrations were found in patients with central vein occlusion (p less than 0.05) and branch vein occlusion (p less than 0.001) compared with controls, and similar tendencies were noted for levels of LDL and HDL cholesterol. Patients with central vein occlusion also had raised levels of serum triglyceride (p less than 0.001) and VLDL-triglyceride (p less than 0.05). The occurrence of both central and branch vein occlusions may be associated with an increased prevalence of hyperlipidaemia and hypertension. Increase of serum lipids may contribute to the aetiology of vein occlusion by altering plasma viscosity or affecting platelet function.

beta-thromboglobulin and platelet factor 4 levels in retinal vein occlusion.

Fifty-six patients with retinal vein occlusion--35 with central and 21 with branch vein occlusion--were investigated for comparison with an age and sex matched control group. Mean levels of beta-thromboglobulin and platelet factor 4 were significantly higher (p less than 0.001) in both the group with central and the group with branch retinal vein occlusion than in the control group. A significant increase of beta-thromboglobulin (p less than 0.001) was also found in the retinal vein occlusion group in those patients who were not hyperlipidaemic or diabetic (n = 39). Weak correlations were found between levels of lipoprotein cholesterol and plasma beta-thromboglobulin. Increased platelet aggregation may contribute to the aetiology of retinal vein occlusion.

Does type II diabetes predispose to retinal vein occlusion?

Retinal vein occlusion (RVO) not infrequently occurs in diabetic patients. Although the aetiology is unclear, it could relate to the other microvascular complications of diabetes. In the non-diabetic, both the central (CRVO) and branch (BRVO) forms are commonly associated with hypertension and hyperlipidaemia. We have therefore studied fifty type II diabetic patients with RVO compared to a carefully matched diabetic control group (n = 50) to elucidate underlying medical conditions and hence the aetiology of RVO in diabetic patients. The two groups were well matched. Diabetics with RVO showed a strikingly high prevalence of hypertension compared to the controls (72% versus 32%: p < 0.001) and a trend to increased hyperlipidaemia (54% versus 36%). Diabetic microvascular complications were more common in the control group (diabetic retinopathy and proteinuria). No significant differences were observed in mean HbA1 or weight, but current smoking habits and blood pressure levels were increased in the diabetics with RVO. 80% of diabetic patients with the BRVO form, were hypertensive. We conclude that the main underlying medical conditions for RVO in diabetics are hypertension and hyperlipidaemia, and these may be important in the aetiology as in the non-diabetic. RVO is more common in type II rather than type I diabetes, and does not associate with the presence of diabetic microvascular complications. Clinical assessment for hypertension and hyperlipidaemia is therefore important in diabetic patients with RVO, especially if recurrence of the condition and further visual loss is to be prevented.

Sodium restriction and blood pressure in hypertensive type II diabetics: randomised blind controlled and crossover studies of moderate sodium restriction and sodium supplementation.

OBJECTIVE: To determine the effect of moderate dietary sodium restriction on the hypertension of non-insulin-dependent (type II) diabetes. DESIGN: Randomised parallel controlled study of moderate sodium restriction for three months compared with usual diabetic diet, followed by randomised double blind crossover trial of sustained release preparation of sodium for one month versus placebo for one month in patients continuing with sodium restriction. SETTING: Patients attending diabetic outpatient clinic of city hospital. PATIENTS: Thirty four patients with established type II diabetes complicated by mild hypertension (systolic blood pressure greater than 160 mm Hg or diastolic pressure greater than 95 mm Hg on three consecutive occasions). Patients already taking antihypertensive agents (but not diuretics) not barred from study provided that criteria for mild hypertension still met. Conditions precluding patients from study were diabetic or hypertensive nephropathy, cardiac failure, and pregnancy. INTERVENTIONS: After run in phase with recordings at seven weeks, three weeks, and time zero patients were allocated at random to receive moderate dietary sodium restriction for three months (n = 17) or to continue with usual diabetic diet. Subsequently nine patients in sodium restriction group continued with regimen for a further two months, during which they completed a randomised double blind crossover trial of sustained release preparation of sodium (Slow Sodium 80 mmol daily) for one month versus matching placebo for one month. END POINT: Reduction in blood pressure in type II diabetics with mild hypertension. MEASUREMENTS AND MAIN RESULTS: Supine and erect blood pressure, body weight, and 24 hour urinary sodium and potassium excretion measured monthly during parallel group and double blind crossover studies. After parallel group study sodium restriction group showed significant reduction in systolic blood pressure (supine 19.2 mm Hg, erect 21.4 mm Hg; p less than 0.001) and mean daily urinary sodium excretion (mean reduction 60 mmol/24 h). There were no appreciable changes in weight, diabetic control, or diastolic pressure. No significant changes occurred in controls. In double blind crossover study mean supine systolic blood pressure rose significantly (p less than 0.005) during sodium supplementation (to 171 mm Hg) compared with value after three months of sodium restriction alone (159.9 mm Hg) and after one month of placebo (161.8 mm Hg). CONCLUSIONS: Moderate dietary restriction of sodium has a definite hypotensive effect, which may be useful in mild hypertension of type II diabetes.

Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies.

The approach of all ophthalmologists, diabetologists and general practitioners seeing patients with diabetic retinopathy should be that good control of blood glucose, blood pressure and plasma lipids are all essential components of modern medical management. The more recent data on the use of fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye studies is reviewed. In FIELD, fenofibrate (200 mg/day) reduced the requirements for laser therapy and prevented disease progression in patients with pre-existing diabetic retinopathy. In ACCORD Eye, fenofibrate (160 mg daily) with simvastatin resulted in a 40% reduction in the odds of retinopathy progressing over 4 years, compared with simvastatin alone. This occurred with an increase in HDL-cholesterol and a decrease in the serum triglyceride level in the fenofibrate group, as compared with the placebo group, and was independent of glycaemic control. We believe fenofibrate is effective in preventing progression of established diabetic retinopathy in type 2 diabetes and should be considered for patients with pre-proliferative diabetic retinopathy and/or diabetic maculopathy, particularly in those with macular oedema requiring laser.

Does microvascular disease predict macrovascular events in type 2 diabetes?

AIM: Population studies suggest a link between albuminuria, reduced glomerular filtration rate (GFR) and retinopathy and macrovascular events in type 2 diabetes. The aim of this review was to investigate whether this association extended to the presence of any diabetic microvascular complication. METHOD AND RESULTS: PUBMED was searched from 1999 to 2010 using the terms 'albuminuria', 'nephropathy', 'chronic kidney disease', 'estimated GFR', 'retinopathy', 'autonomic neuropathy', 'peripheral neuropathy', or 'microvascular' and 'cardiovascular disease', 'stroke', 'coronary heart disease' or 'peripheral vascular disease' and 'type 2 diabetes' and MESH equivalents. Prospective studies with at least 200 type 2 diabetes subjects that evaluated hard cardiovascular endpoints were selected. In 25 studies (n=54,117) included in the review there was evidence of an association between microvascular complications (notably retinopathy or nephropathy) and cardiovascular events. Diabetic retinopathy was associated with ∼ 1.7-fold increased risk for cardiovascular events, and albuminuria or reduced GFR associated with ∼ two-fold increased risk for cardiovascular events. In the presence of more than one complication, this risk was accentuated. These associations remained even after adjustment for conventional cardiovascular risk factors, diabetes duration and glycaemic control. These data suggest that similar mechanisms may be relevant to the pathogenesis of both micro- and macrovascular disease in type 2 diabetes. It is likely that endothelial dysfunction, low-grade inflammation and rheological abnormalities are common mechanistic denominators. CONCLUSIONS: This review highlights the association between micro- and macrovascular disease in type 2 diabetes, underlining the importance of early detection of microangiopathy for vascular risk assessment in type 2 diabetes.

Diabetic retinopathy and blockade of the renin-angiotensin system: new data from the DIRECT study programme.

The pathogenesis and medical management of diabetic retinopathy is reviewed. The importance of good control of blood glucose and blood pressure remain key elements in the prevention and treatment of diabetic retinopathy, and a number of specific metabolic pathways have been identified that may be useful additional targets for therapeutic intervention. Trial data, however, aimed specifically to answer the questions of optimum medical management are limited, so the DIRECT study of renin-angiotensin blockade using oral candesartan 32 mg daily is a welcome addition to our knowledge. This arose from the promising improvement of retinopathy outcomes in the EUCLID study of lisinopril in type I diabetes. In DIRECT, 5 years of candesartan treatment in type I diabetes reduced the incidence of retinopathy by two or more steps (EDTRS) in severity by 18% (P=0.0508) and, in a post hoc analysis, reduced the incidence of retinopathy by three-step progression by 35% (P=0.034). In type I diabetes patients there was no effect on progression of established retinopathy. In contrast, in type II diabetes, 5 years of candesartan treatment resulted in 34% regression of retinopathy (P=0.009). Importantly, an overall significant change towards less-severe retinopathy was noted in both type I and II diabetes (P