- Email: [email protected]
Microvascular complications in children and adolescents with type 1 diabetes mellitus in Assiut governorate, Egypt
Egyptian Pediatric Association Gazette 66 (2018) 85–90
Contents lists available at ScienceDirect
HOSTED BY
Egyptian Pediatric Association Gazette journal homepage: www.elsevier.com/locate/epag
Microvascular complications in children and adolescents with type 1 diabetes mellitus in Assiut governorate, Egypt
T
Eman B. Kamaleldeena, , Hanaa A. Mohammada, Ebtsam F. Mohameda, Ahmed G. Askarb ⁎
a b
Department of Pediatrics, Faculty of Medicine, Assiut University, Egypt Department of Clinical Pathology, Faculty of Medicine, Assiut University, Egypt
ARTICLE INFO
ABSTRACT
Keywords: Microvascular complications Screening Type 1 diabetes mellitus
Background: Type 1 diabetes mellitus (T1DM) carries a long-term burden of increased microvascular complications in the form of nephropathy, retinopathy, and neuropathy. As the incidence of T1DM continues to rise, the burden of microvascular complications will also increase and negatively influence the prognosis of young patients. Microalbuminuria (MA) represents the earliest clinical indication of diabetic nephropathy and is a predictor of increased cardiovascular morbidity and mortality. Our study’s aim was to determine the prevalence of microvascular complications among type 1 diabetic patients in Assiut University Children Hospital, Upper Egypt and to find out its correlation with various risk factors. Methods: The study was cross-sectional one carried on a sample of 180 type 1 diabetic children and adolescents aged from 6 to 21 years. Patients were subjected to full history taking, physical examination, and investigations of HbA1c, lipid profile, early morning spot urine albumin/creatinine ratio as well as fundus examination. Results: The prevalence of microalbuminuria was 20.5%, macroalbuminuria was 7.8%, diabetic retinopathy was 1.1%, and diabetic neuropathy was 5.5%. Patients with microvascular complications had a significantly higher frequency of DKA (39.2% vs. 10.6%, p = 0.000) and hypoglycemic attacks (47.1% vs. 29.5%, p = 0.001) than those without microvascular complications. Furthermore, studied patients with microvascular complications had significantly higher mean ± SD HbA1c (9.99 ± 1.61 vs. 8.51 ± 1.5, p = 0.000) and serum cholesterol (174.98 ± 48.12 vs. 166.26 ± 43.28, p = 0.05) in comparison to patients without microvascular complications. Conclusion: The prevalence rate of microvascular complications was considerably high among diabetic patients in Assiut governorate, Egypt especially with poor glycemic control and dyslipidemia. Regular screening for microvascular complications is recommended for all diabetic patients, as early treatment is critical for reducing cardiovascular risks and slowing the progression to late stages of diabetic nephropathy.
Introduction Type 1 diabetes mellitus (T1DM) is characterized by a low or absent level of endogenously produced insulin and dependence on exogenous insulin. It accounts for approximately 10% of all cases of diabetes and affecting over 15 million in the world. The incidence of T1DM is increasing in most populations. The annual rate of increase in T1DM rate varies between 2 and 5% in Western European up to 9% in central and Eastern European.1 The current prevalence of T1DM is 1.7/1000 among adolescents according to the third National Health and Nutrition Examination Survey (NHANES).2 In Egypt, the prevalence rate of T1DM among school children in Heliopolis and El Manyal districts was 1.09/ 1000 and 1.12/1000 school children respectively.3 In 2010, the
International Diabetes Federation reported that almost a quarter of all diabetic children in the Middle East and North Africa (MENA) region under the age of 15 years is in Egypt.4 Type 1 diabetes carry a long-term burden of increased microvascular and macrovascular complications. As the incidence of T1DM continues to rise, the load of microvascular complications will also increase and negatively influence the prognosis of young patients. Microvascular complications of diabetes include retinopathy which is the leading cause of blindness in working age people. It also comprises nephropathy which is responsible for up to 40% of cases of renal failure and is a primary determinant of cardiovascular morbidity and mortality. In addition to peripheral neuropathy with risk of foot ulcers, amputations, Charcot joints and autonomic neuropathy causing
Peer review under responsibility of Egyptian Pediatric Association Gazette. ⁎ Corresponding author at: Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut 71515 Egypt. E-mail address: [email protected] (E.B. Kamaleldeen). https://doi.org/10.1016/j.epag.2018.10.003 Received 28 June 2018; Received in revised form 25 September 2018; Accepted 7 October 2018 Available online 24 October 2018 1110-6638/ © 2018 The Egyptian Pediatric Association Gazette. Publishing services provided by Elsevier B.V. All rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
gastrointestinal, genitourinary, and sexual dysfunction.5 Since childhood and adolescence is a period during which intensive education and treatment may prevent or delay the onset and progression of complications, efforts should be steered to screening for early signs of diabetic complications and modifiable risk factors.6 Assiut university children hospital is a large tertiary referral center of Upper Egypt serving a large percentage of the population. Studying the prevalence, the pattern of clinical presentation and factors associated with microvascular complications are crucial for the development of screening practices and might have a connection in disease control. Our study's aim was to find out the rate of microvascular complications in type 1 diabetic children and adolescents and to find out various risk factors associated with it.
morning and before drawing of blood samples using a suitable mercury sphygmomanometer cuff with the patient in the sitting position and the arm supported. Blood pressure was measured two times at 5 min interval and the second measurement was regarded as the blood pressure for the individual. Pubertal stage was assessed using Tanner staging.12 Neurological examination included assessment of muscle power, sensations of a pinprick, touch and temperature, joint position, and ankle reflexes. Feet were checked for ulcers, calluses, and deformities. Patients considered to have neuropathy if they have symptoms and signs of peripheral nerve dysfunction after the exclusion of other causes.13 Fundus examination for detection of diabetic retinopathy defined as any defect on fundal photography or mydriatic ophthalmoscopy.14 Workup The laboratory investigations done included simple urine analysis, serum urea and creatinine, CBC, Glycated hemoglobin, liver function test and fasting serum lipogram. Albumin/Creatinine Ratio (ACR) was estimated in the first early morning spot urine sample collected on awakening (before breakfast or exercise). Micro-albuminuria was measured using ORG5MA Micro-Albumin kit (ORGENTEC DiagnostiKa GmbH, Germany) which is an immunometric Enzyme Immunoassay for quantitative determination of Micro-Albumin in urine. Urinary creatinine was tested on Beckman – AU 480 auto-analyzer. An A/C ratio of 30–300 mcg/mg signifies microalbuminuria and values above 300 mcg/mg are considered as macro-albuminuria. For patients with microalbuminuria, a second urine sample was collected in the same way after 2–3 months to confirm the diagnosis of persistent microalbuminuria.
Materials and methods Patients This cross-sectional study was conducted in the period between July 1st, 2012 till June 30th, 2014, on 180 children and adolescents with T1DM on insulin treatment [twice injection/day (Mixtard), 3 times injection/day (Insulatard and Crystalline Insulin) and 4 times injection/ day (Lantus and Crystalline Insulin)] and diet control. The study cases were recruited after a written informed consent from Endocrinology and Diabetes Unit of Assiut University Children Hospital and the diabetes clinic of Health Insurance Hospital of Assiut governorate (SidiGalal clinic). The sample size was calculated using Epi-info version 7 according to the prevalence of diabetes and diabetic nephropathy. The study earned the ethical clearance and the scientific approval from the Medical Ethical and the Medical Scientific Committees of Faculty of Medicine, Assiut University, Egypt. Eligible criteria for the study included definite diagnosis of T1DM according to the definition of the World Health Organization7, and the estimated C-peptide at the time of diagnosis was < 0.8 ng/ml, at least 5 years disease duration in patients diagnosed before puberty or 2 years in patients diagnosed at puberty8 and the age range was 6–21 years. Criteria of exclusion from the study included children with Type 2 diabetes mellitus (obesity, acanthosis nigricans and high C- peptide level), evidence of secondary diabetes (drugs or pancreatitis), diabetes associated with genetic syndromes or dysmorphic features and diabetic children with urinary tract infection, chronic kidney disease (IgA nephropathy, nephritis) or chronic hepatic, cardiac or CNS diseases.
Statistical analysis Data entry and data analysis were done using SPSS (Statistical Package for Social Science) version 19. Data were displayed as numbers and percentages or means and standard deviations. Chi-square test was used to compare categorical variables. Comparison between continuous variables was performed using 2-sample independent student t-test or Mann-Whitney test according to the normality of distribution. Spearman correlations were done to measure correlation between continuous variables. P-value was regarded statistically significant when P < 0.05. Results Demographic and disease-related characteristics of the study population are presented in Table 1 On the assessment of albumin to creatinine ratio (ACR) of the studied cases it was found that 37 patients (20.5%) had ACR 30–300 mcg/mg, i.e., persistent microalbuminuria and 14 patients (7.8%) had ACR > 300 mcg/mg, i.e., macroalbuminuria as shown in Fig. 1. Diabetic retinopathy was found in only two patients (1.1%) out of the studied 180 patients with T1DM, one male patient and normal albumin to creatinine ratio had proliferative diabetic retinopathy, and one girl with microalbuminuria had non-proliferative diabetic retinopathy. Regarding neuropathy, 10 (5.5%) patients out of 180 studied cases had neuropathy. All of them had neuropathy symptoms in the form of numbness, burning feet and pins and needles sensation, three only had signs of stock and glove anesthesia and absent ankle reflex. Comparison of the studied diabetic patients with revealed that those with microvascular complications had significantly higher frequency of DKA; once (13.7%); twice (7.8%) and thrice or more (17.6%) than those without microvascular complications (7.78%, 1.6% and 1.6% respectively) P = 0.000 as shown in Fig. 2 Similarly, patients with microvascular complications had a significantly higher frequency of hypoglycemic attacks twice and thrice or more (11.8% and 11.8%) than those without microvascular complications 0.8% and 4.7%) p = 0.001 Fig. 3. On the other hand, no statistically significant difference was found
Methods All patients were subjected to history taking considering demographic data including age, sex, and residence. Disease-related data including age at onset of diabetes, duration of the disease, family history of diabetes, insulin regimen and insulin dose (U/kg/day), regular checking of blood glucose level, clinic attendance for medical follow up and assessment of HbA1c. History suggestive of neuropathy was acknowledged if there is numbness, burning feet, pins and needles sensations or burning pain. Poor glycemic control history in the past 2 years in the form of either DKA “An episode hyperglycemia > 200 mg/dl with pH ≤7.3 and bicarbonate level < 14“ or hypoglycemia ”blood glucose level of < 3.6 mmol/L (65 mg/dl)“ or symptoms of hypoglycemia as shakiness, sweatiness, headache, drowsiness, difficulty concentrating and irritability. Severe hypoglycemia was defined as an episode of documented or presumed low blood glucose that resulted in the loss of consciousness or seizures.9 Examination of the patients included weight (Weight was measured by Seca Scale), height (body height was measured without shoes using Holtain Stadiometer for children > 3 years and approximated to the nearest 0.1 cm)10 and the body mass index (BMI) was calculated (weight in kg divided by height in square meters) and plotted on Egyptian growth charts.11 Blood pressure was measured early in the 86
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
Table 1 Demographic and disease related characteristics of the studied type 1 diabetic patients in Assiut governorate, Egypt. Item Sex: Male Female Age (years): Mean ± SD Range Residence: Rural Urban Age at onset of diabetes (years): Mean ± SD Range Duration of disease (years): Mean ± SD Range Family history of DM None T1DM T2DM Insulin regimen: Twice injections/day 3 times injection /day 4 times injection /day Insulin dose (U/kg/day): Mean ± SD Range
• • • • • • • • • • • • • •
• • •
•
Number and percentage or mean ± SD 84 (46%) 96 (54%) 13.82 ± 3.23 6–21 125 (69.5%) 55 (30.5%) 7.85 ± 3.54 1.0 – 19
Fig. 3. Frequency of hypoglycemia in the studied type 1 diabetic patients with and without microvascular complications.
6.0 ± 3.08 2 – 14.75 90 (50%) 37(20.5%) 53(29.5%)
Table 2 shows the HbA1c and lipid profile in the studied type 1 diabetic patients with-and without microvascular complications. There was a weak significant positive correlation between albumin to creatinine ratio level &HbA1c (r = 0.324, p < 0.001). Increase HbA1c is associated with increased risk of having albuminuria by 1.63 times (OR: 1.637, 95%CI: 1.302 – 2.058, P < 0.001).
81 (45%) 70 (38.9%) 29 (16.1%) 1.09 ± 0.34 0.35 – 2.3
Discussion Worldwide, from 1990 to 2008, the incidence of type 1 diabetes has been increasing by 2.8–4.0% per year.15 This trend is particularly worrying because type 1 diabetes increases mortality and morbidity population-wide, including young adults.16 People with type 1 diabetes diagnosed before the age of 30 years have a 4.7-fold excess mortality risk and a life expectancy that is shorter by more than a decade.17 This study is the first cross sectional analysis assessing the prevalence of microvascular complications among young diabetic patients in Assiut governorate, Upper Egypt. Assiut University Children Hospital is the largest referral center in Upper Egypt with a capacity of 467 beds and 16,000 admissions annually including 1500 diabetic patients. Results showed that the overall prevalence of microvascular complications in studied children & adolescents aged 5–21 years was 57 patients (31.6%). This result is supported by other studies as Ammari 2004 who found that the prevalence of microvascular complications was 24% in retrospective study of T1DM conducted in Jeddah, Saudi Arabia.18 Diabetic nephropathy (DN) is one of the gravest long-term complications of diabetes. Patients with diabetes plus chronic kidney disease have an increased risk of, cardiovascular mortality and kidney failure. The clinical diagnosis of DN depends on the detection of microalbuminuria, which is, considered the only noninvasive marker of earlyonset diabetic nephropathy.19 The analysis showed that the prevalence of microalbuminuria was 20.5% and macroalbuminuria was 7.8% among the studied patients. This rate was higher than the equivalent rates reported by Ismail and his colleagues who found that prevalence of microalbuminuria was 9.6% in their study conducted in pediatric hospital at Ain Shams University, Cairo.3 The differences could be attributed to poor glycemic control in our patients. Compared to other Arab countries, the prevalence rate of microalbuminuria was 61% among diabetic patients (68) T1DM and 431 T2DM) in the Al-Ain district of the United Arab Emirates (UAE).20 In Kuwait, Al-Eisa and his colleagues reported a prevalence of diabetic nephropathy among T1DM patients, to be around 12%.21 Compared to international rates in type 1 diabetes, our result was far more than reported in many countries worldwide including 3.3% in USA22, 5% in UK, 3.3% in Germany and 5.6% in a Swedish cohort of 426 young patients with T1DM.23 There is a wide contrast in the incidence of microalbuminuria and
Fig. 1. Frequency of different levels of albumin to creatinine ratio in the studied type 1 diabetic patients.
Fig. 2. Frequency of diabetic ketoacidosis in the studied type 1 diabetic patients with and without microvascular complications.
between the studied patient with and without microvascular complications as regarding demographic data, other disease-related characters, BMI, pubertal stage or raised blood pressure. 87
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
Table 2 Characteristics and laboratory investigations in the studied type 1 diabetic patients with and without Microvascular complications. Patients with microvascular complications (n = 57)
Patients without microvascular complications (n = 123)
No.
No.
Insulin dose (U/kg/day): Mean ± SD Range
% 1.12 ± 0.36 0.4–2.5
P-value
% 1.07 ± 0.33 0.3–2.1
0.464
History of DKA in the past 2 years: No Once Twice Thrice or more
31 7 4 15
60.8 13.8 7.8 26
109 10 2 2
88.6 7.7 1.6 1.6
0.000*
History of hypoglycemia in the past 2 years: No Once Twice Thrice or more
27 12 9 9
52.9 23.5 15.7 15.7
85 31 1 6
69.1 24.0 0.8 4.7
0.001*
Duration of diabetes Mean ± SD Range Puberty: Normal for age Delayed
6.19 ± 3.13 2.0–14.5 101 22
5.82 ± 3.04 1.0–15.0
0.469
82.1% 17.9%
0.535
42 15
73.6% 26.3%
HbA1c (%): < 7.5 7.5 – 10 > 10 Mean ± SD
3 22 32
5.2 38.5 54.9 9.99 ± 1.61
34 72 17
27.6 58.5 13.8 8.51 ± 1.50
Cholesterol (mg/dl): < 200 ≥200 Mean ± SD
33 24
58.8 41.2 174.98 ± 48.12
91 32
74 26 166.26 ± 43.28
0.05*
Triglyceride (mg/dl): < 150 ≥150 Mean ± SD
50 7
87.7 12.2 101.71 ± 44.50
107 16
87 13 100.76 ± 41.64
0.906
HDL (mg/dl): < 40 ≥40 Mean ± SD
13 44
22.8 77.1 50.43 ± 14.21
33 90
27 73 46.03 ± 11.58
0.441
LDL(mg/dl): < 100 ≥100 Mean ± SD
25 32
44 56 104.09 ± 43.03
59 64
48 52 101.67 ± 37.71
0.720
0.000* 0.000*
0.240
0.893
0.033*
0.710
* Significant P value.
adolescence attending pediatric hospital at Ain Shams.25 This low frequency of retinopathy in type 1 diabetic children and adolescents may be attributed to the needed longer duration, around 20 years, from the disease onset for diabetic retinopathy to start to appear.26 In our study we noticed that there are six patients had microvascular complications 1 with retinopathy and 5 with neuropathy without concomitant microalbuminuria, the other six patients had both microalbuminuria and either neuropathy or retinopathy. So, the question here is microalbuminuria a predictor of other microvascular complications or no. A systemic review showed that there is weak if any independent prognostic significance for the incidence of retinopathy and no evidence that it predicts progression of retinopathy.27 Even microalbuminuria as a marker of nephropathy is a major point of dispute in the nephrology literature. Microalbuminuria is suggested to be a risk marker of diabetic inflammation (a variable that identify a pathophysiology state, such as inflammation or infection, and as not necessarily involved, directly or causally, in the genesis of a specified outcome) rather than a risk factor of microvascular disease (involved clearly and consistently with the cause of specified event) supporting this hypothesis is that only 25–30% of diabetic patients who have
macroalbuminuria between different studies. This may be related to the degree of glycemic control in the various studied populations as it is affected by education, socioeconomic status and influence of race/ ethnicity. Furthermore, a technical error in collection and storage of urine samples may affect measured levels of microalbuminuria, as urine proteins are significantly but variably underestimated after storage at −20 °C.24 Regarding neuropathy, 10 (5.5%) patients out of 180 studied cases had neuropathy of whom 5 cases had concomitant microalbuminuria, while the other 5 had neuropathy as the single microvascular complication. Abdel-Motal mentioned in his meta-analysis that the prevalence of peripheral neuropathy among T1DM subjects in the Arab region was estimated as 18%.24 The prevalence was significantly higher in patients with age > 16 years and more than ten years T1DM duration. Prevalence of diabetic neuropathy was 3.1% in a study conducted in pediatric hospital at Ain Shams University, Cairo.3 In this study, only two patients (1.1%), one case with microalbuminuria while the other without from 180 patients with T1DM had diabetic retinopathy. In agreement with our figure, the incidence of diabetic retinopathy was 1.8% in type 1 diabetes mellitus children and 88
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
microalbuminuria will progress to more advanced stage of chronic kidney disease.28 We noticed that patients with microvascular complications had a significantly higher frequency of DKA (39.2%), and higher mean HbA1c (9.99 ± 1.61 vs. 8.51 ± 1.50, p < 0.001) than those without microvascular complications. Furthermore, on stratifying the studied cases according to the level of HbA1c, we found that patients with microvascular complications had a significantly higher frequency of patients having HbA1c > 10% than those without microvascular complications (32 patients versus 17 patients). Allyen and his colleagues mentioned that mean HbA1c was the only significant predictor of persistent microalbuminuria (OR 1.3, 95% CI: 1.0–1.6, P = 0.05) after controlling for age, duration of diabetes, blood pressure, BMI and daily insulin dose (in units/kg)0.29 Chronic hyperglycemia is known to activate several pathways implicated in the damage of vessels: protein glycation increased glucose flux through alternative polyol and hexosamine pathways, increased oxidative stress, which then stimulates secondary intracellular signaling pathways leading to growth factors, cytokines and inflammatory factors production.30 There are lacking information about the relationship between DKA and the development of future long-term complications. Some authors mentioned that DKA indirectly mediated by improved metabolic control. Metabolic control during the whole disease duration seems fundamental in determining microvascular complications in children.31 Patients with microvascular complications had a higher frequency of hypoglycemic attacks than those without microvascular complications. Hypoglycemia has a prominent effect on the development of endothelial dysfunction and the subsequent changes in vascular wall morphology and microvascular complications. The Action in Diabetes and Vascular Disease Modified Release Controlled Evaluation (ADVANCE) study found hypoglycemia to be associated with a 1.8-fold increase in the development of new or worsening nephropathy or retinopathy.32 The relationship between severe hypoglycemia and microvascular disease could be explained by the presence of risk factors common to both. In the present study when we studied the lipid profile of the included patients, we found that serum cholesterol level was higher in patients with microvascular complications in comparison with patients without (mean ± SD 174.98 ± 48.12 versus 166.26 ± 43.28, p = 0.05) as shown in Table 2 High serum cholesterol finding is similar to other studies. Paradoxically, HDL was significantly higher among studied patients with microvascular complications in comparison with patients without (mean ± SD 50.43 ± 14.21versus 46.03 ± 11.58, p = 0.033) as shown in Table 2 This finding agrees with a study by Stone and his colleagues33 but contradicts another study by El Dayem and his colleagues who found that patients with microalbuminuria have low HDL cholesterol level.34 T1DM subjects frequently have regular to high HDL cholesterol levels but suffer from inappropriately high cardiovascular events. Abnormality in the distribution of lipoprotein subclasses has been postulated to explain this seemingly paradoxical finding.2 The metabolism of HDL-C in T1DM may be altered because of abnormal lipoprotein lipase and hepatic lipase activities related to exogenously administered insulin. Additionally, the less efficient handling of heme by the haptoglobin 2–2 genotype in patients with T1DM leaves these complexes less capable of being removed by macrophages, which allows them to associate with HDL, which renders it less functional.35 So, the relation between glycemic control and lipid profile can be explained by worse glycemic control, higher weight, and more insulin resistance are connected with a more atherogenic cholesterol distribution in men and women with T1DM. Better glycemic control can improve or normalize lipid values.35 Through the study we can assess the prevalence of diabetes mellitus (DM) complications in Upper Egypt district and the risk factors for these microvascular complications in children and adolescence with T1DM. There is currently little information available about the prevalence or predictive factors for development of vascular complications of type 1 diabetes among
young adults. Identification of disease complication prevalence and any predictive characteristics will establish a benchmark of these risk factors and may assist healthcare professionals to target appropriate information and support with the aim of deferring or averting their onset.36 Conclusion In conclusion, our findings indicate that chronic diabetic microvascular complications were encountered with high prevalence rate in young age in children and adolescents with T1DM in Assiut governorate especially with poor glycemic control and dyslipidemia. We emphasize the importance of regular complication screening for early detection and treatment. Efforts need to be intensified in the education of health workers and population at large for a quick presentation and prompt diagnosis to predict overt diabetic nephropathy and also to prevent its progression. Disclosure statement The authors declare that they have no conflicts of interest and nothing to disclose. Funding Assiut Faculty of Medicine Research Grants office, Egypt. Acknowledgements None. References 1. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. The Lancet. 2014;383:69–82. 2. Krishnan S, Short KR. Prevalence and significance of cardiometabolic risk factors in children with type 1 diabetes. J Cardiometabolic Syndrome. 2009 Dec 1;4:50–56. 3. Ismail NA, Kasem OM, Abou-El-Asrar M, et al. Epidemiology and management of type 1 diabetes mellitus at the Ain shams university pediatric hospital. J Egypt Public Health Assoc. 2008;83:107–132. 4. Soltesz G, Patterson C, Dahlquist G. Diabetes in the young: a global perspective. IDF Diabetes Atlas. Brussels: International Diabetes Federation; 2009. 5. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013 Jan 1;93:137–188. 6. Donaghue KC, Chiarelli F, Trotta D, et al. Microvascular and macrovascular complications associated with diabetes in children and adolescents. Pediatric Diabetes. 2009 Sep 1;10:195–203. 7. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1, Diagnosis and classification of diabetes mellitus, 1999. 8. International Society for pediatric and Adolescent Diabetes (ISPAD). Clinical practice consensus guidelines for definition, epidemiology and classification of diabetes. Pediatr Diabetes. 2006;7:343–351. 9. Ly TT, Maahs DM, Rewers A, et al. Assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2014 Sep 1;15:180–192. 10. World Health Organization. Training Course on Child Growth Assessment. Geneva: WHO; 2008. 11. Ghalli I, Salah N, Hussien F, Erfan M, El- Ruby M, Mazen I, Sabry M, Abd El-am knack Razik M, Saad M, Hossney L, Ismaail S and Abd El-Dayem S et al.: Egyptian growth curves 2002 for infants, children and adolescents. published aka Sartorio A, Buckler JMH and Marazzi N. Crescere nel mondo. Ferring publisher, 2008. 12. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44:291. 13. Kaur J. An overview of diabetic neuropathy. Annu Rev Res Biol. 2013;3:994–1012. 14. Ghanchi F. Diabetic retinopathy guidelines working group. the royal college of ophthalmologists' clinical guidelines for diabetic retinopathy: a summary. Eye. 2013;27(2):285. 15. Amritanshu K, Kumar A, Anand K, et al. Clinical profile and factors associated with microalbuminuria in type 1 diabetes mellitus in children and adolescents. Int J Res Med Sci. 2017;3:1247–1251. 16. James S, Gallagher R, Dunbabin J, et al. Prevalence of vascular complications and factors predictive of their development in young adults with type 1 diabetes: systematic literature review. BMC Res Notes. 2014;7:593. 17. Livingstone SJ, Levin D, Looker HC, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA. 2015;313:37–44. 18. Ammari F. Long-term complications of type 1 diabetes mellitus in the western area of Saudi Arabia. Diabetologia Croatica. 2004;33:59–63. 19. Navarro-González JF, Mora-Fernández C, De Fuentes MM, et al. Inflammatory
89
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
20. 21. 22. 23. 24. 25.
26. 27.
molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7:327. Al-Maskari F, El-Sadig M, Obineche E. Prevalence and determinants of microalbuminuria among diabetic patients in the United Arab Emirates. BMC Nephrol. 2008;9:1. Al-Eisa AA, Al-Hajri A, Al-Shuaib S, et al. Early-onset microalbuminuria in children with type 1 diabetes in Kuwait. Curr Pediatric Res. 2017;21:254–259. Li L, Jick S, Breitenstein S, et al. Prevalence of diabetes and diabetic nephropathy in a large US commercially insured pediatric population, 2002–2013. Diabetes Care. 2016;39:278–284. Svensson M, Nyström L, Schön S, et al. Age at onset of childhood-onset type 1 diabetes and the development of end-stage renal disease. Diabetes Care. 2006;29:538–542. Abdel-Motal UM, Abdelalim EM, Abou-Saleh H, et al. Neuropathy of type 1 diabetes in the Arab world: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2017;31:172–180. El Samahy MH, Elbarbary NS, Elmorsi HM. Current status of diabetes management, glycemic control and complications in children and adolescents with diabetes in Egypt. Where do we stand now? And where do we go from here? Diabetes Res Clin Pract. 2015;107(3):370–376. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35:556–564. Newman DJ, Mattock MB, Dawnay AB, et al. Systematic review on urine albumin testing for early detection of diabetic complications, 2005.
28. Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care. 2014;37:867–875. 29. Alleyn CR, Volkening LK, Wolfson J, et al. Occurrence of microalbuminuria in young people with Type 1 diabetes: importance of age and diabetes duration. Diabet Med. 2010;27:532–537. 30. Marcovecchio ML, Chiarelli F. Microvascular disease in children and adolescents with type 1 diabetes and obesity. Pediatric Nephrol. 2011;26:365–375. 31. Salardi S, Porta M, Maltoni G, et al. Ketoacidosis at diagnosis in childhood-onset diabetes and the risk of retinopathy 20years later. J Diabetes Complications. 2016;30:55–60. 32. Kilpatrick ES, Rigby AS, Atkin SL, et al. Does severe hypoglycaemia influence microvascular complications in Type 1 diabetes? An analysis of the Diabetes Control and Complications Trial database. Diabet Med. 2012;29:1195–1198. 33. Stone ML, Craig ME, Chan AK, et al. Natural history and risk factors for microalbuminuria in adolescents with type 1 diabetes. Diabetes Care. 2006;29:2072–2077. 34. El Dayem SM, Nazif HK, EI-Kader MA. Study of adiponectin level in diabetic adolescent girls in relation to glycemic control and complication of diabetes. Open Access Macedonian J Med Sci. 2015;3(4):613. 35. De Ferranti SD, De Boer IH, Fonseca V, et al. Type 1 diabetes mellitus and cardiovascular disease. Circulation. 2014;130:1110–1130. 36. James S, Gallagher R, Dunbabin J, Perry L. Prevalence of vascular complications and factors predictive of their development in young adults with type 1 diabetes: systematic literature review. BMC Res Notes. 2014;7:593.
90
Contents lists available at ScienceDirect
HOSTED BY
Egyptian Pediatric Association Gazette journal homepage: www.elsevier.com/locate/epag
Microvascular complications in children and adolescents with type 1 diabetes mellitus in Assiut governorate, Egypt
T
Eman B. Kamaleldeena, , Hanaa A. Mohammada, Ebtsam F. Mohameda, Ahmed G. Askarb ⁎
a b
Department of Pediatrics, Faculty of Medicine, Assiut University, Egypt Department of Clinical Pathology, Faculty of Medicine, Assiut University, Egypt
ARTICLE INFO
ABSTRACT
Keywords: Microvascular complications Screening Type 1 diabetes mellitus
Background: Type 1 diabetes mellitus (T1DM) carries a long-term burden of increased microvascular complications in the form of nephropathy, retinopathy, and neuropathy. As the incidence of T1DM continues to rise, the burden of microvascular complications will also increase and negatively influence the prognosis of young patients. Microalbuminuria (MA) represents the earliest clinical indication of diabetic nephropathy and is a predictor of increased cardiovascular morbidity and mortality. Our study’s aim was to determine the prevalence of microvascular complications among type 1 diabetic patients in Assiut University Children Hospital, Upper Egypt and to find out its correlation with various risk factors. Methods: The study was cross-sectional one carried on a sample of 180 type 1 diabetic children and adolescents aged from 6 to 21 years. Patients were subjected to full history taking, physical examination, and investigations of HbA1c, lipid profile, early morning spot urine albumin/creatinine ratio as well as fundus examination. Results: The prevalence of microalbuminuria was 20.5%, macroalbuminuria was 7.8%, diabetic retinopathy was 1.1%, and diabetic neuropathy was 5.5%. Patients with microvascular complications had a significantly higher frequency of DKA (39.2% vs. 10.6%, p = 0.000) and hypoglycemic attacks (47.1% vs. 29.5%, p = 0.001) than those without microvascular complications. Furthermore, studied patients with microvascular complications had significantly higher mean ± SD HbA1c (9.99 ± 1.61 vs. 8.51 ± 1.5, p = 0.000) and serum cholesterol (174.98 ± 48.12 vs. 166.26 ± 43.28, p = 0.05) in comparison to patients without microvascular complications. Conclusion: The prevalence rate of microvascular complications was considerably high among diabetic patients in Assiut governorate, Egypt especially with poor glycemic control and dyslipidemia. Regular screening for microvascular complications is recommended for all diabetic patients, as early treatment is critical for reducing cardiovascular risks and slowing the progression to late stages of diabetic nephropathy.
Introduction Type 1 diabetes mellitus (T1DM) is characterized by a low or absent level of endogenously produced insulin and dependence on exogenous insulin. It accounts for approximately 10% of all cases of diabetes and affecting over 15 million in the world. The incidence of T1DM is increasing in most populations. The annual rate of increase in T1DM rate varies between 2 and 5% in Western European up to 9% in central and Eastern European.1 The current prevalence of T1DM is 1.7/1000 among adolescents according to the third National Health and Nutrition Examination Survey (NHANES).2 In Egypt, the prevalence rate of T1DM among school children in Heliopolis and El Manyal districts was 1.09/ 1000 and 1.12/1000 school children respectively.3 In 2010, the
International Diabetes Federation reported that almost a quarter of all diabetic children in the Middle East and North Africa (MENA) region under the age of 15 years is in Egypt.4 Type 1 diabetes carry a long-term burden of increased microvascular and macrovascular complications. As the incidence of T1DM continues to rise, the load of microvascular complications will also increase and negatively influence the prognosis of young patients. Microvascular complications of diabetes include retinopathy which is the leading cause of blindness in working age people. It also comprises nephropathy which is responsible for up to 40% of cases of renal failure and is a primary determinant of cardiovascular morbidity and mortality. In addition to peripheral neuropathy with risk of foot ulcers, amputations, Charcot joints and autonomic neuropathy causing
Peer review under responsibility of Egyptian Pediatric Association Gazette. ⁎ Corresponding author at: Department of Pediatrics, Faculty of Medicine, Assiut University, Assiut 71515 Egypt. E-mail address: [email protected] (E.B. Kamaleldeen). https://doi.org/10.1016/j.epag.2018.10.003 Received 28 June 2018; Received in revised form 25 September 2018; Accepted 7 October 2018 Available online 24 October 2018 1110-6638/ © 2018 The Egyptian Pediatric Association Gazette. Publishing services provided by Elsevier B.V. All rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
gastrointestinal, genitourinary, and sexual dysfunction.5 Since childhood and adolescence is a period during which intensive education and treatment may prevent or delay the onset and progression of complications, efforts should be steered to screening for early signs of diabetic complications and modifiable risk factors.6 Assiut university children hospital is a large tertiary referral center of Upper Egypt serving a large percentage of the population. Studying the prevalence, the pattern of clinical presentation and factors associated with microvascular complications are crucial for the development of screening practices and might have a connection in disease control. Our study's aim was to find out the rate of microvascular complications in type 1 diabetic children and adolescents and to find out various risk factors associated with it.
morning and before drawing of blood samples using a suitable mercury sphygmomanometer cuff with the patient in the sitting position and the arm supported. Blood pressure was measured two times at 5 min interval and the second measurement was regarded as the blood pressure for the individual. Pubertal stage was assessed using Tanner staging.12 Neurological examination included assessment of muscle power, sensations of a pinprick, touch and temperature, joint position, and ankle reflexes. Feet were checked for ulcers, calluses, and deformities. Patients considered to have neuropathy if they have symptoms and signs of peripheral nerve dysfunction after the exclusion of other causes.13 Fundus examination for detection of diabetic retinopathy defined as any defect on fundal photography or mydriatic ophthalmoscopy.14 Workup The laboratory investigations done included simple urine analysis, serum urea and creatinine, CBC, Glycated hemoglobin, liver function test and fasting serum lipogram. Albumin/Creatinine Ratio (ACR) was estimated in the first early morning spot urine sample collected on awakening (before breakfast or exercise). Micro-albuminuria was measured using ORG5MA Micro-Albumin kit (ORGENTEC DiagnostiKa GmbH, Germany) which is an immunometric Enzyme Immunoassay for quantitative determination of Micro-Albumin in urine. Urinary creatinine was tested on Beckman – AU 480 auto-analyzer. An A/C ratio of 30–300 mcg/mg signifies microalbuminuria and values above 300 mcg/mg are considered as macro-albuminuria. For patients with microalbuminuria, a second urine sample was collected in the same way after 2–3 months to confirm the diagnosis of persistent microalbuminuria.
Materials and methods Patients This cross-sectional study was conducted in the period between July 1st, 2012 till June 30th, 2014, on 180 children and adolescents with T1DM on insulin treatment [twice injection/day (Mixtard), 3 times injection/day (Insulatard and Crystalline Insulin) and 4 times injection/ day (Lantus and Crystalline Insulin)] and diet control. The study cases were recruited after a written informed consent from Endocrinology and Diabetes Unit of Assiut University Children Hospital and the diabetes clinic of Health Insurance Hospital of Assiut governorate (SidiGalal clinic). The sample size was calculated using Epi-info version 7 according to the prevalence of diabetes and diabetic nephropathy. The study earned the ethical clearance and the scientific approval from the Medical Ethical and the Medical Scientific Committees of Faculty of Medicine, Assiut University, Egypt. Eligible criteria for the study included definite diagnosis of T1DM according to the definition of the World Health Organization7, and the estimated C-peptide at the time of diagnosis was < 0.8 ng/ml, at least 5 years disease duration in patients diagnosed before puberty or 2 years in patients diagnosed at puberty8 and the age range was 6–21 years. Criteria of exclusion from the study included children with Type 2 diabetes mellitus (obesity, acanthosis nigricans and high C- peptide level), evidence of secondary diabetes (drugs or pancreatitis), diabetes associated with genetic syndromes or dysmorphic features and diabetic children with urinary tract infection, chronic kidney disease (IgA nephropathy, nephritis) or chronic hepatic, cardiac or CNS diseases.
Statistical analysis Data entry and data analysis were done using SPSS (Statistical Package for Social Science) version 19. Data were displayed as numbers and percentages or means and standard deviations. Chi-square test was used to compare categorical variables. Comparison between continuous variables was performed using 2-sample independent student t-test or Mann-Whitney test according to the normality of distribution. Spearman correlations were done to measure correlation between continuous variables. P-value was regarded statistically significant when P < 0.05. Results Demographic and disease-related characteristics of the study population are presented in Table 1 On the assessment of albumin to creatinine ratio (ACR) of the studied cases it was found that 37 patients (20.5%) had ACR 30–300 mcg/mg, i.e., persistent microalbuminuria and 14 patients (7.8%) had ACR > 300 mcg/mg, i.e., macroalbuminuria as shown in Fig. 1. Diabetic retinopathy was found in only two patients (1.1%) out of the studied 180 patients with T1DM, one male patient and normal albumin to creatinine ratio had proliferative diabetic retinopathy, and one girl with microalbuminuria had non-proliferative diabetic retinopathy. Regarding neuropathy, 10 (5.5%) patients out of 180 studied cases had neuropathy. All of them had neuropathy symptoms in the form of numbness, burning feet and pins and needles sensation, three only had signs of stock and glove anesthesia and absent ankle reflex. Comparison of the studied diabetic patients with revealed that those with microvascular complications had significantly higher frequency of DKA; once (13.7%); twice (7.8%) and thrice or more (17.6%) than those without microvascular complications (7.78%, 1.6% and 1.6% respectively) P = 0.000 as shown in Fig. 2 Similarly, patients with microvascular complications had a significantly higher frequency of hypoglycemic attacks twice and thrice or more (11.8% and 11.8%) than those without microvascular complications 0.8% and 4.7%) p = 0.001 Fig. 3. On the other hand, no statistically significant difference was found
Methods All patients were subjected to history taking considering demographic data including age, sex, and residence. Disease-related data including age at onset of diabetes, duration of the disease, family history of diabetes, insulin regimen and insulin dose (U/kg/day), regular checking of blood glucose level, clinic attendance for medical follow up and assessment of HbA1c. History suggestive of neuropathy was acknowledged if there is numbness, burning feet, pins and needles sensations or burning pain. Poor glycemic control history in the past 2 years in the form of either DKA “An episode hyperglycemia > 200 mg/dl with pH ≤7.3 and bicarbonate level < 14“ or hypoglycemia ”blood glucose level of < 3.6 mmol/L (65 mg/dl)“ or symptoms of hypoglycemia as shakiness, sweatiness, headache, drowsiness, difficulty concentrating and irritability. Severe hypoglycemia was defined as an episode of documented or presumed low blood glucose that resulted in the loss of consciousness or seizures.9 Examination of the patients included weight (Weight was measured by Seca Scale), height (body height was measured without shoes using Holtain Stadiometer for children > 3 years and approximated to the nearest 0.1 cm)10 and the body mass index (BMI) was calculated (weight in kg divided by height in square meters) and plotted on Egyptian growth charts.11 Blood pressure was measured early in the 86
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
Table 1 Demographic and disease related characteristics of the studied type 1 diabetic patients in Assiut governorate, Egypt. Item Sex: Male Female Age (years): Mean ± SD Range Residence: Rural Urban Age at onset of diabetes (years): Mean ± SD Range Duration of disease (years): Mean ± SD Range Family history of DM None T1DM T2DM Insulin regimen: Twice injections/day 3 times injection /day 4 times injection /day Insulin dose (U/kg/day): Mean ± SD Range
• • • • • • • • • • • • • •
• • •
•
Number and percentage or mean ± SD 84 (46%) 96 (54%) 13.82 ± 3.23 6–21 125 (69.5%) 55 (30.5%) 7.85 ± 3.54 1.0 – 19
Fig. 3. Frequency of hypoglycemia in the studied type 1 diabetic patients with and without microvascular complications.
6.0 ± 3.08 2 – 14.75 90 (50%) 37(20.5%) 53(29.5%)
Table 2 shows the HbA1c and lipid profile in the studied type 1 diabetic patients with-and without microvascular complications. There was a weak significant positive correlation between albumin to creatinine ratio level &HbA1c (r = 0.324, p < 0.001). Increase HbA1c is associated with increased risk of having albuminuria by 1.63 times (OR: 1.637, 95%CI: 1.302 – 2.058, P < 0.001).
81 (45%) 70 (38.9%) 29 (16.1%) 1.09 ± 0.34 0.35 – 2.3
Discussion Worldwide, from 1990 to 2008, the incidence of type 1 diabetes has been increasing by 2.8–4.0% per year.15 This trend is particularly worrying because type 1 diabetes increases mortality and morbidity population-wide, including young adults.16 People with type 1 diabetes diagnosed before the age of 30 years have a 4.7-fold excess mortality risk and a life expectancy that is shorter by more than a decade.17 This study is the first cross sectional analysis assessing the prevalence of microvascular complications among young diabetic patients in Assiut governorate, Upper Egypt. Assiut University Children Hospital is the largest referral center in Upper Egypt with a capacity of 467 beds and 16,000 admissions annually including 1500 diabetic patients. Results showed that the overall prevalence of microvascular complications in studied children & adolescents aged 5–21 years was 57 patients (31.6%). This result is supported by other studies as Ammari 2004 who found that the prevalence of microvascular complications was 24% in retrospective study of T1DM conducted in Jeddah, Saudi Arabia.18 Diabetic nephropathy (DN) is one of the gravest long-term complications of diabetes. Patients with diabetes plus chronic kidney disease have an increased risk of, cardiovascular mortality and kidney failure. The clinical diagnosis of DN depends on the detection of microalbuminuria, which is, considered the only noninvasive marker of earlyonset diabetic nephropathy.19 The analysis showed that the prevalence of microalbuminuria was 20.5% and macroalbuminuria was 7.8% among the studied patients. This rate was higher than the equivalent rates reported by Ismail and his colleagues who found that prevalence of microalbuminuria was 9.6% in their study conducted in pediatric hospital at Ain Shams University, Cairo.3 The differences could be attributed to poor glycemic control in our patients. Compared to other Arab countries, the prevalence rate of microalbuminuria was 61% among diabetic patients (68) T1DM and 431 T2DM) in the Al-Ain district of the United Arab Emirates (UAE).20 In Kuwait, Al-Eisa and his colleagues reported a prevalence of diabetic nephropathy among T1DM patients, to be around 12%.21 Compared to international rates in type 1 diabetes, our result was far more than reported in many countries worldwide including 3.3% in USA22, 5% in UK, 3.3% in Germany and 5.6% in a Swedish cohort of 426 young patients with T1DM.23 There is a wide contrast in the incidence of microalbuminuria and
Fig. 1. Frequency of different levels of albumin to creatinine ratio in the studied type 1 diabetic patients.
Fig. 2. Frequency of diabetic ketoacidosis in the studied type 1 diabetic patients with and without microvascular complications.
between the studied patient with and without microvascular complications as regarding demographic data, other disease-related characters, BMI, pubertal stage or raised blood pressure. 87
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
Table 2 Characteristics and laboratory investigations in the studied type 1 diabetic patients with and without Microvascular complications. Patients with microvascular complications (n = 57)
Patients without microvascular complications (n = 123)
No.
No.
Insulin dose (U/kg/day): Mean ± SD Range
% 1.12 ± 0.36 0.4–2.5
P-value
% 1.07 ± 0.33 0.3–2.1
0.464
History of DKA in the past 2 years: No Once Twice Thrice or more
31 7 4 15
60.8 13.8 7.8 26
109 10 2 2
88.6 7.7 1.6 1.6
0.000*
History of hypoglycemia in the past 2 years: No Once Twice Thrice or more
27 12 9 9
52.9 23.5 15.7 15.7
85 31 1 6
69.1 24.0 0.8 4.7
0.001*
Duration of diabetes Mean ± SD Range Puberty: Normal for age Delayed
6.19 ± 3.13 2.0–14.5 101 22
5.82 ± 3.04 1.0–15.0
0.469
82.1% 17.9%
0.535
42 15
73.6% 26.3%
HbA1c (%): < 7.5 7.5 – 10 > 10 Mean ± SD
3 22 32
5.2 38.5 54.9 9.99 ± 1.61
34 72 17
27.6 58.5 13.8 8.51 ± 1.50
Cholesterol (mg/dl): < 200 ≥200 Mean ± SD
33 24
58.8 41.2 174.98 ± 48.12
91 32
74 26 166.26 ± 43.28
0.05*
Triglyceride (mg/dl): < 150 ≥150 Mean ± SD
50 7
87.7 12.2 101.71 ± 44.50
107 16
87 13 100.76 ± 41.64
0.906
HDL (mg/dl): < 40 ≥40 Mean ± SD
13 44
22.8 77.1 50.43 ± 14.21
33 90
27 73 46.03 ± 11.58
0.441
LDL(mg/dl): < 100 ≥100 Mean ± SD
25 32
44 56 104.09 ± 43.03
59 64
48 52 101.67 ± 37.71
0.720
0.000* 0.000*
0.240
0.893
0.033*
0.710
* Significant P value.
adolescence attending pediatric hospital at Ain Shams.25 This low frequency of retinopathy in type 1 diabetic children and adolescents may be attributed to the needed longer duration, around 20 years, from the disease onset for diabetic retinopathy to start to appear.26 In our study we noticed that there are six patients had microvascular complications 1 with retinopathy and 5 with neuropathy without concomitant microalbuminuria, the other six patients had both microalbuminuria and either neuropathy or retinopathy. So, the question here is microalbuminuria a predictor of other microvascular complications or no. A systemic review showed that there is weak if any independent prognostic significance for the incidence of retinopathy and no evidence that it predicts progression of retinopathy.27 Even microalbuminuria as a marker of nephropathy is a major point of dispute in the nephrology literature. Microalbuminuria is suggested to be a risk marker of diabetic inflammation (a variable that identify a pathophysiology state, such as inflammation or infection, and as not necessarily involved, directly or causally, in the genesis of a specified outcome) rather than a risk factor of microvascular disease (involved clearly and consistently with the cause of specified event) supporting this hypothesis is that only 25–30% of diabetic patients who have
macroalbuminuria between different studies. This may be related to the degree of glycemic control in the various studied populations as it is affected by education, socioeconomic status and influence of race/ ethnicity. Furthermore, a technical error in collection and storage of urine samples may affect measured levels of microalbuminuria, as urine proteins are significantly but variably underestimated after storage at −20 °C.24 Regarding neuropathy, 10 (5.5%) patients out of 180 studied cases had neuropathy of whom 5 cases had concomitant microalbuminuria, while the other 5 had neuropathy as the single microvascular complication. Abdel-Motal mentioned in his meta-analysis that the prevalence of peripheral neuropathy among T1DM subjects in the Arab region was estimated as 18%.24 The prevalence was significantly higher in patients with age > 16 years and more than ten years T1DM duration. Prevalence of diabetic neuropathy was 3.1% in a study conducted in pediatric hospital at Ain Shams University, Cairo.3 In this study, only two patients (1.1%), one case with microalbuminuria while the other without from 180 patients with T1DM had diabetic retinopathy. In agreement with our figure, the incidence of diabetic retinopathy was 1.8% in type 1 diabetes mellitus children and 88
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
microalbuminuria will progress to more advanced stage of chronic kidney disease.28 We noticed that patients with microvascular complications had a significantly higher frequency of DKA (39.2%), and higher mean HbA1c (9.99 ± 1.61 vs. 8.51 ± 1.50, p < 0.001) than those without microvascular complications. Furthermore, on stratifying the studied cases according to the level of HbA1c, we found that patients with microvascular complications had a significantly higher frequency of patients having HbA1c > 10% than those without microvascular complications (32 patients versus 17 patients). Allyen and his colleagues mentioned that mean HbA1c was the only significant predictor of persistent microalbuminuria (OR 1.3, 95% CI: 1.0–1.6, P = 0.05) after controlling for age, duration of diabetes, blood pressure, BMI and daily insulin dose (in units/kg)0.29 Chronic hyperglycemia is known to activate several pathways implicated in the damage of vessels: protein glycation increased glucose flux through alternative polyol and hexosamine pathways, increased oxidative stress, which then stimulates secondary intracellular signaling pathways leading to growth factors, cytokines and inflammatory factors production.30 There are lacking information about the relationship between DKA and the development of future long-term complications. Some authors mentioned that DKA indirectly mediated by improved metabolic control. Metabolic control during the whole disease duration seems fundamental in determining microvascular complications in children.31 Patients with microvascular complications had a higher frequency of hypoglycemic attacks than those without microvascular complications. Hypoglycemia has a prominent effect on the development of endothelial dysfunction and the subsequent changes in vascular wall morphology and microvascular complications. The Action in Diabetes and Vascular Disease Modified Release Controlled Evaluation (ADVANCE) study found hypoglycemia to be associated with a 1.8-fold increase in the development of new or worsening nephropathy or retinopathy.32 The relationship between severe hypoglycemia and microvascular disease could be explained by the presence of risk factors common to both. In the present study when we studied the lipid profile of the included patients, we found that serum cholesterol level was higher in patients with microvascular complications in comparison with patients without (mean ± SD 174.98 ± 48.12 versus 166.26 ± 43.28, p = 0.05) as shown in Table 2 High serum cholesterol finding is similar to other studies. Paradoxically, HDL was significantly higher among studied patients with microvascular complications in comparison with patients without (mean ± SD 50.43 ± 14.21versus 46.03 ± 11.58, p = 0.033) as shown in Table 2 This finding agrees with a study by Stone and his colleagues33 but contradicts another study by El Dayem and his colleagues who found that patients with microalbuminuria have low HDL cholesterol level.34 T1DM subjects frequently have regular to high HDL cholesterol levels but suffer from inappropriately high cardiovascular events. Abnormality in the distribution of lipoprotein subclasses has been postulated to explain this seemingly paradoxical finding.2 The metabolism of HDL-C in T1DM may be altered because of abnormal lipoprotein lipase and hepatic lipase activities related to exogenously administered insulin. Additionally, the less efficient handling of heme by the haptoglobin 2–2 genotype in patients with T1DM leaves these complexes less capable of being removed by macrophages, which allows them to associate with HDL, which renders it less functional.35 So, the relation between glycemic control and lipid profile can be explained by worse glycemic control, higher weight, and more insulin resistance are connected with a more atherogenic cholesterol distribution in men and women with T1DM. Better glycemic control can improve or normalize lipid values.35 Through the study we can assess the prevalence of diabetes mellitus (DM) complications in Upper Egypt district and the risk factors for these microvascular complications in children and adolescence with T1DM. There is currently little information available about the prevalence or predictive factors for development of vascular complications of type 1 diabetes among
young adults. Identification of disease complication prevalence and any predictive characteristics will establish a benchmark of these risk factors and may assist healthcare professionals to target appropriate information and support with the aim of deferring or averting their onset.36 Conclusion In conclusion, our findings indicate that chronic diabetic microvascular complications were encountered with high prevalence rate in young age in children and adolescents with T1DM in Assiut governorate especially with poor glycemic control and dyslipidemia. We emphasize the importance of regular complication screening for early detection and treatment. Efforts need to be intensified in the education of health workers and population at large for a quick presentation and prompt diagnosis to predict overt diabetic nephropathy and also to prevent its progression. Disclosure statement The authors declare that they have no conflicts of interest and nothing to disclose. Funding Assiut Faculty of Medicine Research Grants office, Egypt. Acknowledgements None. References 1. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. The Lancet. 2014;383:69–82. 2. Krishnan S, Short KR. Prevalence and significance of cardiometabolic risk factors in children with type 1 diabetes. J Cardiometabolic Syndrome. 2009 Dec 1;4:50–56. 3. Ismail NA, Kasem OM, Abou-El-Asrar M, et al. Epidemiology and management of type 1 diabetes mellitus at the Ain shams university pediatric hospital. J Egypt Public Health Assoc. 2008;83:107–132. 4. Soltesz G, Patterson C, Dahlquist G. Diabetes in the young: a global perspective. IDF Diabetes Atlas. Brussels: International Diabetes Federation; 2009. 5. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013 Jan 1;93:137–188. 6. Donaghue KC, Chiarelli F, Trotta D, et al. Microvascular and macrovascular complications associated with diabetes in children and adolescents. Pediatric Diabetes. 2009 Sep 1;10:195–203. 7. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1, Diagnosis and classification of diabetes mellitus, 1999. 8. International Society for pediatric and Adolescent Diabetes (ISPAD). Clinical practice consensus guidelines for definition, epidemiology and classification of diabetes. Pediatr Diabetes. 2006;7:343–351. 9. Ly TT, Maahs DM, Rewers A, et al. Assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2014 Sep 1;15:180–192. 10. World Health Organization. Training Course on Child Growth Assessment. Geneva: WHO; 2008. 11. Ghalli I, Salah N, Hussien F, Erfan M, El- Ruby M, Mazen I, Sabry M, Abd El-am knack Razik M, Saad M, Hossney L, Ismaail S and Abd El-Dayem S et al.: Egyptian growth curves 2002 for infants, children and adolescents. published aka Sartorio A, Buckler JMH and Marazzi N. Crescere nel mondo. Ferring publisher, 2008. 12. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44:291. 13. Kaur J. An overview of diabetic neuropathy. Annu Rev Res Biol. 2013;3:994–1012. 14. Ghanchi F. Diabetic retinopathy guidelines working group. the royal college of ophthalmologists' clinical guidelines for diabetic retinopathy: a summary. Eye. 2013;27(2):285. 15. Amritanshu K, Kumar A, Anand K, et al. Clinical profile and factors associated with microalbuminuria in type 1 diabetes mellitus in children and adolescents. Int J Res Med Sci. 2017;3:1247–1251. 16. James S, Gallagher R, Dunbabin J, et al. Prevalence of vascular complications and factors predictive of their development in young adults with type 1 diabetes: systematic literature review. BMC Res Notes. 2014;7:593. 17. Livingstone SJ, Levin D, Looker HC, et al. Estimated life expectancy in a Scottish cohort with type 1 diabetes, 2008–2010. JAMA. 2015;313:37–44. 18. Ammari F. Long-term complications of type 1 diabetes mellitus in the western area of Saudi Arabia. Diabetologia Croatica. 2004;33:59–63. 19. Navarro-González JF, Mora-Fernández C, De Fuentes MM, et al. Inflammatory
89
Egyptian Pediatric Association Gazette 66 (2018) 85–90
E.B. Kamaleldeen et al.
20. 21. 22. 23. 24. 25.
26. 27.
molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7:327. Al-Maskari F, El-Sadig M, Obineche E. Prevalence and determinants of microalbuminuria among diabetic patients in the United Arab Emirates. BMC Nephrol. 2008;9:1. Al-Eisa AA, Al-Hajri A, Al-Shuaib S, et al. Early-onset microalbuminuria in children with type 1 diabetes in Kuwait. Curr Pediatric Res. 2017;21:254–259. Li L, Jick S, Breitenstein S, et al. Prevalence of diabetes and diabetic nephropathy in a large US commercially insured pediatric population, 2002–2013. Diabetes Care. 2016;39:278–284. Svensson M, Nyström L, Schön S, et al. Age at onset of childhood-onset type 1 diabetes and the development of end-stage renal disease. Diabetes Care. 2006;29:538–542. Abdel-Motal UM, Abdelalim EM, Abou-Saleh H, et al. Neuropathy of type 1 diabetes in the Arab world: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2017;31:172–180. El Samahy MH, Elbarbary NS, Elmorsi HM. Current status of diabetes management, glycemic control and complications in children and adolescents with diabetes in Egypt. Where do we stand now? And where do we go from here? Diabetes Res Clin Pract. 2015;107(3):370–376. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35:556–564. Newman DJ, Mattock MB, Dawnay AB, et al. Systematic review on urine albumin testing for early detection of diabetic complications, 2005.
28. Bakris GL, Molitch M. Microalbuminuria as a risk predictor in diabetes: the continuing saga. Diabetes Care. 2014;37:867–875. 29. Alleyn CR, Volkening LK, Wolfson J, et al. Occurrence of microalbuminuria in young people with Type 1 diabetes: importance of age and diabetes duration. Diabet Med. 2010;27:532–537. 30. Marcovecchio ML, Chiarelli F. Microvascular disease in children and adolescents with type 1 diabetes and obesity. Pediatric Nephrol. 2011;26:365–375. 31. Salardi S, Porta M, Maltoni G, et al. Ketoacidosis at diagnosis in childhood-onset diabetes and the risk of retinopathy 20years later. J Diabetes Complications. 2016;30:55–60. 32. Kilpatrick ES, Rigby AS, Atkin SL, et al. Does severe hypoglycaemia influence microvascular complications in Type 1 diabetes? An analysis of the Diabetes Control and Complications Trial database. Diabet Med. 2012;29:1195–1198. 33. Stone ML, Craig ME, Chan AK, et al. Natural history and risk factors for microalbuminuria in adolescents with type 1 diabetes. Diabetes Care. 2006;29:2072–2077. 34. El Dayem SM, Nazif HK, EI-Kader MA. Study of adiponectin level in diabetic adolescent girls in relation to glycemic control and complication of diabetes. Open Access Macedonian J Med Sci. 2015;3(4):613. 35. De Ferranti SD, De Boer IH, Fonseca V, et al. Type 1 diabetes mellitus and cardiovascular disease. Circulation. 2014;130:1110–1130. 36. James S, Gallagher R, Dunbabin J, Perry L. Prevalence of vascular complications and factors predictive of their development in young adults with type 1 diabetes: systematic literature review. BMC Res Notes. 2014;7:593.
90