[Link] [Link] [Link] [Link] [Link] (importanta alimentatiei si a insulinei in aparitia complicatiilor cronice) [Link]

full (e vorba despre factori de risc care influenteaza controlul diabetului) [Link] (modificarile induse de diabet pe sistemul autonom)

Pediatric Diabetes 2007: 8: 163170

All rights reserved

2007 The Authors

Journal compilation

2007 Blackwell Munksgaard

Pediatric Diabetes

ISPAD Clinical Practice Consensus Guidelines 2006 2007

Microvascular and macrovascular complications

Dahl-Jorgensen K. Microvascular and macrovascular

complications.

Pediatric Diabetes 2007: 8: 163170.

Kim C Donaghue
a

, Francesco Chiarelli
b

, Daniela Trotta
b

, Jeremy Allgrove
c

and Knut Dahl-Jorgensen

The Childrens Hospital at Westmead, University of Sydney,

Sydney, Australia;

Department of Paediatrics, University of

Chieti, Chieti, Italy;

Department of Paediatric Endocrinology

and Diabetes, Royal London Hospital, London, UK

Department of Pediatrics, Ulleva

l University Hospital and

Faculty of Medicine, University of Oslo, Oslo, Norway

Corresponding author:

Kim C Donaghue MB BS PhD

The Childrens Hospital at Westmead, Locked Bag 4001,

Westmead, NSW 2145, Australia.

61 2 9845 3172

61 2 9845 3170

e-mail: kimd@[Link]

Acknowledgements: Esko Wiltsh

ire, Gisela Dahlquist, Kenneth

Lee Jones, Edna Roche, Amina Balafrej, and Riccardo Bonfanti.

Editors of the ISPAD Clinical Practice Consensus Guidelines

20062007: Kim Donaghue, Ragnar Hanas, Georgeanna

Klingensmith, and Peter Swift.

The long-term vascular complications of diabetes include retinopathy, nephropat hy, neuropathy, and macrovascular disease. The outcomes are the following:
d

Visual impairment and blindness due to diabetic retinopathy.

Renal failure and hypertension due to diabetic nephropathy.

Pain, paresthesiae, muscle weakness, and autonomic dysfunction due to diabetic neuropathy.
d

Cardiac disease, peripheral vascular disease, and stroke due to macrovascular disease.

Clinically evident diabetes-related vascular complications should be rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease. There has been a declining incidence of complications reported in many areas with specialized clinics (13). This has occurred over a period of time during which there have been major changes in diabetes management, identification of putative risk factors, and the advent of regular screening for complications. There is no evidence that this is a worldwide occurrence: in areas where health care is not optimal, a greater risk of complications will remain.
Interventional studies of intensive glycemic control

The Diabetes Control and Complications Trial (DCCT)

was a multicenter, randomized controlled clinical trial involving 1441 patients with type 1 diabetes conducted in North America from 1983 to 1993 (4). At recruitment, 195 were pubertal adolescents (aged 1317 yr): there were no children (5). After completion of the DCCT (a median of 7.4 yr in the adolescent group) and hence the end of randomization to the two treatment groups (intensive and conventional treatments), the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to follow patients (6). After 4 yr, there was no significant difference in hemoglobin A1c (HbA1c) between the former intensive and conventional treatment groups. The DCCT provided unequivocal evidence that intensive diabetes treatment and improved glycemic control conferred a significant risk reduction for microvascular complications compared with conven-

tional treatment (5) (A). The EDIC study has shown that this positive effect continued after randomization, i.e., there was a memory effect of the improved glycemic control. In addition, it showed a positive effect of intensive therapy for reduction in macrovascular disease (7) (A).
163

In the adolescent cohort, intensive treatment compared with conventional treatment reduced the risk and progression of background retinopathy by 53%, clinical neuropathy by 60%, and microalbuminuria by 54%. The difference in HbA1c was 8.1 vs. 9.8%. The benefits of intensive therapy persisted in the former adolescent cohort during the EDIC study: the previously intensively managed group had 74% less retinopathy, 48% less microalbuminuria, and 85% less albuminuria (6).

[Link] (complicatiile cronice sunt influentate de valoarea glicemiei si mai putin de tipul de diabet si de alte elemente precun varsta de aparitie sexul)

Compared with conventional treatment, intensive treatment in the total age group reduced the risk of clinical neuropathy by 60%. Cardiovascular events were reduced by 50% in the previously intensively treated group compared with that of the control group during a mean 17 yr follow-up (7). The DCCT confirmed that improved glycemic control may initially worsen diabetic retinopathy. However, within 1.53 yr, the advantage of intensive treatment is evident (810). In the DCCT, the longterm benefits of intensive insulin treatment greatly outweighed the risk of early retinal deterioration. Ophthalmological monitoring is recommended before initiation of intensive treatment and at 3-month intervals for 612 months thereafter for patients with long-standing poor glycemic control, particularly if

Table 1. Screening, risk factors, and interventions for vascular complications: the levels of evidence for risk factors and

interventions pertaining to adult studies, except for improved glycemic control. For clarity, references for these evidence

levels are included in the text

When to commence

screening? Screening methods Risk factors Potential intervention

Retinopathy Annually from age

11 yr with 2 yr

of diabetes duration

and from 9 yr with

5 yr of duration (E)

Fundal photography or

mydriatic ophthalmoscopy

(less sensitive) (E)

Hyperglycemia (A),

high blood pressure (B),

lipid abnormalities (B),

and higher BMI (C)

Improved glycemic

control (A) and

laser therapy (A)

Nephropathy Annually from age

11 yr with 2 yr

of diabetes duration

and from 9 yr with

5 yr of duration (E)

Urinary albumin/creatinine

ratio or first morning

albumin concentration (E)

High blood pressure (B),

lipid abnormalities (B),

and smoking (B)

Improved glycemic

control (A), ACEI and

AIIRA (A), and blood

pressure lowering (B)

Neuropathy Unclear History and physical

examination

Hyperglycemia (A) and

higher BMI (C)

Improved glycemic

control (A)

Macrovascular

disease

After the age of

12 yr (E)

Lipid profile every 5 yr and

blood pressure annually (E)

Hyperglycemia (A),

high blood pressure (A),

lipid abnormalities (B),

higher BMI (B), and

smoking (B)

Improved glycemic

control (A), blood

pressure control (B),

and statins (A)

ACEI, angiotensin-converting enzyme inhibitors; AIIRA, angiotensin II receptor antagonists; BMI, body mass index.

Table 2. Target levels for different parameters to reduce the risk of microvascular and cardiovascular diseases in children

and adolescents with type 1 diabetes; the levels of evidence pertain to adult studies

Parameter Target level Evidence grade

Hemoglobin A1c (Diabetes Control and

Complications Trial standard)

7.5% without severe hypoglycemia A

Low-density lipoprotein cholesterol

2.6 mmol/L A

High-density lipoprotein cholesterol

1.1 mmol/L C

Triglycerides

1.7 mmol/L C

Blood pressure

90th percentile by age, sex, and height C/B

Body mass index

95th percentile (non-obese) E

Smoking None A

Physical activity

1 h of moderate physical activity daily B

Sedentary activities

2 h daily B

Healthy diet Caloric intake appropriate for age and

normal growth

Fat

30% of caloric intake and saturated

fat

10% of caloric intake

Fiber intake 2535 g daily

Increased intake of fresh fruit and

vegetables

Donaghue et al.
164
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retinopathy severity is at or past the moderate nonproliferative stage at the time of intensification (E).
Other risk factors for the development of complications

Longer duration of diabetes, older age, and puberty are risk factors for complications (11). The prepubertal years of diabetes duration have a significantly lesser impact especially further from the onset of

gonadarche (12) (B). For the same diabetes duration, age and puberty increase the risk for retinopathy and elevated albumin excretion rate (AER) (13) (B). Smoking is associated with an increased risk of developing persistent microalbuminuria or macroalbuminuria (4, 14). The evidence for the effect of smoking on retinopathy is less clear. Type 1 diabetes and smoking interact to produce excess cardiovascular morbidity and mortality (15) (B). Hypertension has a greater impact on cardiovascular disease (CVD) in diabetic patients than in non-diabetic individuals (16). Bl ood pressure control ( , 140/80 mmHg in adults) is effective in decreasing cardiovascular morbidity and mortality in diabetes (17) (A).

Dyslipoproteinemia is associated with microalbuminuria and retinopathy developments in the DCCT/ EDIC (18, 19). This included higher total and lowdensity lipoprotein (LDL) cholesterol and higher triglyceride levels for microalbuminuria, as well as larger LDL particle size and apoprotein B in men (B). Family history of complications increases the risk for nephropathy (20) and retinopathy (21) (B). Higher body mass index (BMI) is a risk factor for retinopathy (22), neuropathy (23), microalbuminuria (24), and CVD (25) (B). Lifestyle issues sedentary men with diabetes have higher mortality than active individuals (26) (B).
Diabetic retinopathy

Adolescents have a higher risk of progression to vision-threatening retinopathy compared with adult patients with diabetes (27, 28). The progression may

be rapid, especially in those with poor glycemic control (29). Hence, adolescence is the time when efforts should be directed to screening for early signs of diabetic retinopathy and modifiable risk factors. Regression of retinopathy can also occur (27, 28, 30).
Progression of retinopathy

Background retinopathy is characterized by microaneurysms specific to diabetic retinopathy; hemorrhages both pre-retinal and intraretinal; soft and hard exudates involving microinfarction and protein and lipid leakages, respectively; intraretinal microvascular abnormalities and dilatation; and constriction and tortuosity of vessels. Background retinopathy is not vision threatening and does not invariably progress to proliferative retinopathy. Preproliferative retinopathy is characterized by vascular obstruction, progressive intraretinal micro-

vascular abnormalities, and infarctions of the retinal nerve fibers causing cotton wool spots. Proliferative retinopathy is characterized by neovascularization in the retina and/or vitreous posterior surface. The vessels may rupture or bleed into the vitreoretinal space which is vision threatening. Encasement in connective tissue results in adhesions, which can cause hemorrhage and retinal detachment. High-risk characteristics for visual loss are the location and extent of neovascularization and signs of vitreous or pre-retinal hemorrhage (31). Maculopathy is characterized by decreased vascular competence and microaneurysm formation, which produce exudation and swelling in the central retina.
Assessment of retinopathy

The most sensitive detection methods for retinopathy are stereoscopic fundal photography and fluorescein

angiography. Seven-field stereoscopic fundus photography provides greater sensitivity for detecting both background and proliferative retinopathies compared
Table 3. Recommended threshold values for different parameters for intervention and the primary prevention; the levels

of evidence pertain to adult studies

Threshold value Type of intervention Evidence grade

Blood pressure

90th percentile for age,

gender, and height

Lifestyle intervention B

Blood pressure

90th percentile despite

lifestyle intervention

ACEI E

Blood pressure

95th percentile Lifestyle intervention and ACEI A

LDL cholesterol

2.6 mmol/L Dietary intervention A/C

LDL cholesterol

3.4 mmol/L and one or

more cardiovascular disease risk factors

Statins A/C

ACEI, angiotensin-converting enzyme inhibitors; LDL, low-density lipoprotein.

Consensus Guidelines
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2007:

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165

with direct ophthalmoscopy (28, 32, 33) (A). Fluorescein angiography reveals functional abnormalities (vascular permeability) as well as structural abnor-

malities in the blood vessels, whereas fundal photography reveals only structural abnormalities. Other techniques used in the detection of diabetic retinopathy include indirect ophthalmoscopy and monochromatic single-field photography. In adults with diabetes, mydriasis reduced the technical failure rate over non-mydriatic fundal photography but did not improve sensitivity and specificity for detection of diabetic retinopathy or reduce the need for referral compared with undilated fundal photography of a single field (34). In an incident cohort, after 6 yr of duration with HbA1c of 8.7%, 7-field stereoscopic fundal photography detected early retinopathy (one microaneurysm or hemorrhage) in 8% of children less than 11 yr and 12% of prepubertal children. This compares with retinopathy detection in 25% of adolescents older than 11 yr

and 29% of pubertal adolescents (13) (B). Screening from age 11 yr with 2 yr of diabetes duration or from 9 yr with 5 yr of duration will capture most retinopathy developing in children and adolescents (E).
Laser treatment for retinopathy

Once sight-threatening retinopathy has been detected, the treatment options are limited. Panretinal photocoagulation, commonly known as laser therapy, consists of multiple discrete outer retinal burns throughout the mid and far peripheral areas but sparing the central macula. It has been proven to reduce the progression of visual loss by more than 50% in patients with proliferative retinopathy (31, 35) (A). However, photocoagulation is not indicated for eyes with mild or moderate non-proliferative retinopathy (36). Side effects of treatment are decreased night and peripheral

visions and subtle changes in color perception. Complications of laser therapy are vitreal and choroidal hemorrhages or visual sequelae of misplaced burns.
Diabetic nephropathy

Diabetic nephropathy is defined as persistent proteinuria greater than 500 mg/24 h or albuminuria greater than 300 mg/24 h and is usually associated with hypertension and a diminishing glomerular filtration rate (37). Endstage renal failure may occur many years later and requires dialysis or kidney transplantation. Diabetic nephropathy is a major cause of morbidity and mortality among young adults with type 1 diabetes (38, 39).
Assessment of incipient nephropathy

The first clinical sign is microalbuminuria. This is defined (37) as any of those below:
d

AER between 20 and 200

m g/min or AER 30300 mg/24 h in 24-h urine collections.

Albumin concentration (AC) 30300 mg/L (in early morning urine sample).
d

Albumin/creatinine ratio (ACR) 2.525 mg/mmol or 30300 mg/g (spot urine) in males and 3.525 mg/ mmol in females (because of lower creatinine excretion). Other definitions have also been used in longitudinal studies. Microalbuminuria is confirmed by finding two or all three samples abnormal over a period of 36 months. Persistent microalbuminuria has been shown to

predict the progression to end-stage renal failure (2, 30, 31, 4042) and is associated with an increased risk of macrovascular disease (43, 44) (B). An increase of AER within the microalbuminuric range identifies patients at risk of progression to renal damage (24, 45, 46) (B). Loss of nocturnal dipping on 24-h blood pressure monitoring is an early marker of diabetic renal disease preceding microalbuminuria (47). Microalbuminuria can also regress (48), especially in adolescents (24, 49). Progression to microalbuminuria is preceded by renal hypertrophy (50) (B). Confounders exercise increases the AER in nondiabetic individual and increases it more markedly during diabetes. Even moderate exercise may interfere with the interpretation of data (37). For interpretation of persistently elevated AER values, especially in children with short diabetes duration, it is essential to

exclude other causes of albuminuria such as immunoglobulin A or other types of nephritis common in childhood. In an incident cohort, after 6 yr of duration, early elevation of AER (greater than 7.5 m g/min) was detected in 5% of children younger than 11 yr and 5% of prepubertal children: no microalbuminuria was detected. This compared with early elevation of AER in 25% adolescents older than 11 yr and 26% of pubertal adolescents. (13). Screening from age 11 yr with 2 yr of diabetes duration and from 9 yr with 5 yr of duration will capture most evolving microalbuminuria in children and adolescents (E).
Antihypertensive treatment for prevention of nephropathy

Effective antihypertensive therapy in patients with nephropathy prolongs the time to end-stage renal disease (51) (B). A recent prospective study has shown improved prognosis of renal function from 5 to 7 yr from onset of nephropathy to a median of 21.7 yr (52), predominantly due to aggressive antihypertensive treatment, with smaller contributions from improved glycemic control and smoking cessation (B). Donaghue et al.
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Blood pressure values between the 90th and 95th percentiles are defined as prehypertension (53, 54). Protocols and reference values for 24-h ambulatory blood

pressure monitoring in ch ildren have also been published (21, 47). Angiotensinconverting enzyme inhibitors (ACEI) are recommended for use in children and adolescents with hypertension (55). They have been effective and safe in childr en in short-term studies (28, 56). The clinical beneficial effect of angiotensin II receptor antagonists (AIIRA) in hypertension is similar to that observed with ACEI but have not been used extensively in children. ACEI and AIIRA reduce progression from microalbuminuria to macroalbuminuria and increase the regression rate to normoalbuminuria (57) (A). For

those with microalbuminuria, ACEI and AIIRA reduce the doubling of serum creatinine. While ACEI reduces all-cause mortality, AIIRA use was associated with higher all-cause mortality compared with placebo (A). Despite the above evidence mainly in adults, there are still some concerns regarding the use of ACEI in protecting long-term renal function in young individuals without hypertension. In meta-analysis of individual patient data, the beneficial effects were more modest in those with the lowest levels of microalbuminuria (58) (A). Young people with microalbuminuria would potentially be taking ACEI for decades. Side effects include cough, hyperkalaemia, headache, and impotence (57). Furthermore, an increase in major congenital malformations has recently been reported after first-trimester exposure to ACEI

but not with other antihypertensive agents in nondiabetic women (59).

Diabetes can affect the somatic and autonomic nervous systems. The somatic ne uropathies associated with diabetes fall into the following two broad categories: Focal neuropathies include mononeuropathies such as carpal tunnel syndrome, palsy of the peroneal nerve, palsy of the third cranial nerve, and proximal nerve conditions (e.g., diabetic amyotrophy). Diabetic sensorimotor polyneuropathy is the most common generalized neuropathy, and, for this reason, the simplified term diabetic neuropathy is commonly used. It is a polyneuropathy because of the diffuse damage to all peripheral nerve fibers motor, sensory,

and autonomic. Such damage occurs insidiously and progressively and is characterized at first by sensory loss and later by loss of motor function, in a stocking and glove distribution. Autonomic neuropathy can cause postural hypotension, vomiting, diarrhea, bladder paresis, impotence, sweating abnormalities, impaired light reflex, impotence, and retrograde ejaculation. Abnormal heart rate responses and prolonged QT intervals have been associated with increased risk of sudden death (60).
Assessment of neuropathy

Clinical assessment involves history taking especially of numbness, persistent pain, or paresthesia and physical examination of ankle reflexes and vibration and light touch sensations (by conventional neurological examination or by graduated monofilaments).

Autonomic nerve tests include heart rate response to deep breathing, standing from a lying position, Valsalva maneuver, heart rate variation at rest, QT interval, postural changes in blood pressure, and pupillary responses to light and dark adaptation. Peripheral nerve tests include quantitating vibration and thermal discrimination thresholds and nerve conduction. These are mostly used in research settings. Age- and gender-specific normal ranges need to be applied where relevant when interpreting results. Nerve function test abnormalities have not decreased in an adolescent population in which retinopathy and microalbuminuria have decreased over the same time: peripheral nerve abnormalities actually increased (3). This is probably due to the increasing BMI which has occurred over the same time (B).
Macrovascular disease

The mortality and morbidity of CVD are markedly increased in diabetic individuals compared with that in non-diabetic population (61) (B). Hypertension has a greater impact on CVD in diabetic patients than in non-diabetic individuals (16). Blood pressure control ( , 140/80 mmHg in adults) reduces cardiovascular morbidity and mortality in diabetes (17) (A). A family history of early CVD (before 55 yr of age), lipid disturbances, type 2 diabetes, hypertension (10), and smoking place the individual with diabetes at higher risk (B). Atherosclerosis starts in childhood and adolescence as shown by intimamedia thickness of the carotids and aorta (62) and silent coronary atherosclerosis

measured by intravascular ultrasound in young adults with childhood-onset diabetes (9) (B). Silent coronary atherosclerosis (9) and cardiovascular events (7) are strongly associated with poor glycemic control (A). Cholesterol plays an important role in the initiation and progression of atherosclerosis (53). Well-controlled type 1 diabetes is not associated with gross blood lipid disturbances, but more advanced lipoprotein subclass examinations reveal atherogenic profiles (18). Poor glycemic control was associated with a potentially more atherogenic lipoprotein profile (63). Consensus Guidelines
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167

Changes in lipids associated with increased cardiovascular risk are also associated with central obesity in type 1 diabetes (as well as type 2 diabetes) (64). Individuals with type 1 diabetes are as much at risk for hypercholesterolemia as the non-diabetic population. The prevalence approached 50% of young adults in one study (65). The prevalence of elevated nonhigh-density lipoprotein cholesterol was 25% in a study of individuals younger than 21 yr of age with type 1 diabetes (66). In adults, statins are effective in the primary and secondary preventions of major cardiovascular events, stroke, and limb revascularization in patients with diabetes (67) (A). The Heart Protection Study was a 5-yr interventional study of 5963 patients with diabetes, in which 10% had type 1 diabetes. This effect was independent of glycemic control and

cholesterol levels. Short-term trials have shown that simvastatin, lovastatin, and pravastatin are effective and safe in children and adolescents (6870). No significant side effects were observed in terms of growth, pubertal Tanner grading, testicular volume, menarche, endocrine function parameters, or liver or muscle enzymes. The efficacy and safety of statins in children with type 1 diabetes still need to be determined in randomized trials, as does the age at which treatment should be initiated. Special attention should be paid to symptoms associated with muscles and connective tissues, as there is an increased risk of rhabdomyolysis (71).
Screening for and prevention of complications

Screening for diabetes complications aims to detect subclinical complications, which may be treated to delay progression to clinical disease.

Improvement in glycemic control will reduce the risk for onset and progression of diabetes vascular complications (A).
d

Initial eye examination should occur shortly after diagnosis to detect cataracts or major refractive errors that require treatment for binocular vision (E).
d

Screening for retinopathy and microalbuminuria should start from 11 yr with 2 yr of diabetes durationandfrom 9yrwith 5yrofdurationandafter 2 yr of diabetes duration in an adolescent (13) (E).
d

Minimum assessment for retinopathy should be by ophthalmoscopy through dilated pupils by an experienced observer (E).
d

The frequency of retinopathy screening in general should occur annually but should be more frequently if there are high-risk features for visual loss. For those with duration less than 10 yr, minimal background retinopathy on fundal photography and reasonable glycemic control, biennial assessment by fundal photography, can occur (27) (E).
d

Laser treatment reduces the rate of visual loss for vision-threatening retinopathy (A).
d

Annual screening for microalbuminuria should be undertaken by any of the methods below (13):
d

First morning urine samples (AC).

Spot urine: ACR.

Timedurinecollections(AER).Timedovernighturine collections are generally easier for adolescents and are less subject to the effects of exercise and posture.
d

Because of biological variability, two of three consecutive collections should be used as evidence of microalbuminuria. Confounders are exercise and menstrual bleeding.
d

Abnormal screening tests should be repeated, as microalbuminuria may disappear and not be persistent.
d

When persistent microalbuminuria is confirmed, screening for retinopathy, neuropathy, and lipid abnormalities is also recommended (E).
d

ACEI are recommended for use in children with

hypertension (55) (E). They have been effective and safe in children in short-term studies (28, 56) but are not safe during pregnancy.
d

ACEI or AIIRA agents should be used in patients with persistent microalbuminuria to prevent progression to proteinuria (E) in adolescents.
d

Blood pressure should be measured at least annually. (E) Confirmation of hypertension may be assisted by 24-h ambulatory blood pressure measurements (E).
d

Blood pressure values should be compared with age-appropriate centile charts (55). Blood pressure should be maintained at less than the 95th centile for age as in all children with hypertension (55) (E).
d

Screening for fasting blood lipids should be performed soon after diagnosis (when diabetes stabilized) in all children with type 1 diabetes older than 12 yr (E). If normal results are obtained, this should be repeated every 5 yr. If there is a family history of hypercholesterolemia, early CVD, or if the family history is unknown, screening should start at 2 yr of age (8) (E).
d

Target level for LDL cholesterol should be lower than 2.6 mmol/L. If interventions to improve metabolic control and dietary changes cannot help reach the target level, statins should be considered, although long-term safety is not established (55) (E).
d

Cessation of smoking/never initiating smoking will reduce progression of microalbuminuria and CVD

(52) (B).
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[Link] (factori de risc care influenteaza progresia NPDR IN PDR) [Link] (importanta controlului strict al diabetului in progresti retinopatiei diabetice) [Link] (principali factori de risc ce duc la progresia de la normoalbuminurie la brc) [Link] (efectul mersului pe jos/activitatii fizice asupra glicemiei postprandiale) [Link] (in introducere pot lua date despre evolutia in timp a diabetului incidenta)