DOI: https://doi.org/10.21203/rs.3.rs-1585585/v1
Background: Type 1 diabetes mellitus (T1DM) is a common chronic systemic disease that threatens the health of children worldwide. Diabetic ketoacidosis (DKA) is the most common acute complication of diabetes and can lead to death in severe cases. This study aimed to explore the epidemiological features, clinical manifestations, and risk factors for DKA in children and adolescents newly diagnosed with T1DM in the Department of Endocrinology of the Children’s Hospital of Henan Province.
Methods: Medical records of 683 children and adolescents newly diagnosed with T1DM in our center from March 2014 to November 2021 were retrospectively analyzed. The data included the general condition, laboratory indexes, and clinical symptoms. The patients were divided into three groups according to age: Group I, 0–3 years; Group II, 4–9 years; and Group III, 10 –18years.
Results: The incidence of DKA was 62.96% and was highest in Group I. Group I also had the highest C-peptide, insulin, HbA1c, blood glucose at first diagnosis, and 25 hydroxyvitamin D3 levels; hospitalization lengths and costs; and incidence of clinical symptoms. Logistic regression analysis showed that elevated HbA1c levels, hyperglycemia, and other systemic diseases were independent risk factors for DKA. On the other hand, C-peptide and 25 hydroxyvitamin D were protective factors against DKA.
Conclusions: The incidence of DKA among children and adolescents in Henan Province is very high. Moreover, DKA can be easily misdiagnosed. Newly diagnosed infants with T1DM are more likely to present with DKA, suffer more severe metabolic disorders, endure longer hospital stays, and accrue higher medical costs. Vitamin D supplementation can help reduce the incidence of DKA in children with diabetes.
Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases and major health threats in children. The reported incidence of T1DM ranges from 0.1/100,000 per year in China and Venezuela to 36.8/100,000 per year in Sardinia [1]. In the past few decades, the global annual incidence of T1DM in children has been increasing at a rate of 2–3% per year [2]. The incidence of T1DM among Chinese children is relatively low; however, the number of T1DM cases is large due to the population size of China. This places a heavy burden on families and society.
Of the cases of childhood diabetes, T1DM accounted for about 90%, type 2 diabetes and other Other Special types accounted for about 10%. T1DM, also known as insulin-dependent diabetes, is a chronic autoimmune disease caused by T-cell-mediated islet beta cell destruction and absolute insulin deficiency. The pathogenesis of T1DM is still unclear, and it is believed to be the result of the combined action of genetic, environmental, immune, and other factors [3, 4].
Diabetic ketoacidosis (DKA) is an acute complication characterized by hyperglycemia, acidosis, and ketosis. It presents with dehydration, vomiting, abdominal pain, disturbance of consciousness, and rapid deep respiration. DKA is the leading cause of death in children with T1DM because of hypokalemia, deep vein thrombosis, and cerebral edema [5, 6]. The International Society of Pediatric and Adolescent Diabetes (ISPAD) pointed out that even today, DKA is the most common cause of death in children with diabetes[7], with the highest mortality rate among newly diagnosed patients with T1DM [8]. Nonetheless, DKA is preventable; therefore, awareness among primary physicians and the general public should be enhanced to reduce the incidence of DKA.
There are few large sample epidemiological data and clinical studies on DKA in children are lacking in China. In this study, We retrospectively analyzed the clinical data of 683 children in newly diagnosed T1DM in our center. Our center is a grade III and class A children's hospital in Henan Province(the central region of China), and patients usually come from all over the province.Therefore, Our research helps to understand the disease situation in our province up to a point.
This study included children and adolescents who were newly diagnosed with diabetes mellitus in the Department of Endocrinology of Children's Hospital Affiliated to Zhengzhou University in Henan Province from 2014 to 2021.
The study was approved by the research and ethical committees of the hospital.
According to the American Diabetes Association diagnostic criteria for diabetes (2005), diabetes was diagnosed when any of the following criteria were met: (1) having typical diabetic symptoms (polydipsia, polyuria, polyphagia, and weight loss) and an elevated blood glucose level (≥ 11.1 mmol/L) at any time after a meal, (2) a fasting blood glucose (FPG) level ≥ 7.0 mmol/L, or (3) an oral glucose tolerance test (OGTT) two-hour blood glucose level ≥ 11.1 mmol/L. Patients with type 2 diabetes, secondary diabetes, or special type diabetes were excluded.
The following data were collected:
(1) General information—age, sex, birth history, feeding pattern, occupation of parents, family history, and onset season.
(2) Laboratory tests—HbA1c, C-peptide, blood glucose, pH, residual alkali, bicarbonate, diabetes autoantibodies, thyroid stimulating hormone (TSH), thyroid autoantibodies, and 25-hydroxyvitamin D (25OHD) level.
(3) Clinical data—symptoms at onset, such as polydipsia, polyuria, polyphagia, and weight loss; duration before diagnosis; complicated ketoacidosis; complicated systemic symptoms; hospital length of stay, and hospitalization cost.
According to the American Diabetes Association, DKA was categorized into three degrees: mild, arterial pH decreased to between 7.25 and 7.30 and serum bicarbonate level decreased to 15–18 mEq/L; moderate, arterial pH of 7.00–7.25 and a bicarbonate level of 10–15 mEq/L; severe, arterial pH below 7.00 and a bicarbonate level below 10 mEq/L.
All the results were processed using SPSS software, version 23.0 (IBM Corp., Armonk, NY, USA). Normally distributed measurement data are expressed as means and standard deviations. Categorical data are presented as percentages. Non-normally distributed data are presented as medians and quartiles. The t-test was used to compare differences in numerical variables between two groups, and univariate analysis of variance was used to compare the mean difference among multiple groups. The Chi-square test was used for comparisons between groups. After univariate analysis, the significant group was entered into a multivariate logistic regression analysis for statistical operation. Bilateral P values < 0.05 were considered statistically significant.
A total of 683 children with T1DM newly diagnosed in the last 5 years were included. Of these, 357 were males and 326 females (male:female ratio, 1.1:1). The average age of onset was 7.91 ± 4.85 years (range, 0.2–18 years). Patients were divided into three groups according to age: Group I, 0–3 years; Group II, 4–9 years; and Group III, 10–18 years. There were 117 males (61.90%) and 72 females (38.10%) in Group I, 124 males (48.44%) and 132 females (51.56%) in Group II, and 116 males (48.74%) and 122 females (51.26%) in Group III. The age and sex distributions are shown in Fig. 1. There were 154 cases (22.55%) in spring, 169 cases (24.74%) in summer, 170 cases (24.89%) in autumn, and 190 cases (27.82%) in winter. The incidence was highest in winter. The distribution of medical visits in each month is shown in Fig. 2. The fathers and mothers of 306 (44.8%) and 277 (40.56%) patients, respectively, were industrial or agricultural workers.
A total of 458 patients (62.96%) were complicated with DKA at onset. Mild DKA accounted for 43.46% of these cases and moderate and severe DKA accounted for 56.54%. A total of 225 patients (32.94%) did not have DKA at first diagnosis. At initial diagnosis, 541 patients (79.21%) had polydipsia, 494 patients (72.33%) had polyuria, only 138 patients (20.2%) had polyphagia, and 225 patients (32.94%) showed weight loss. A total of 198 cases (50.64%) were positive for glutamate decarboxylase antibody (GADAb), while the positive rate for insulin antibody (IAA) was only 4.1%. A total of 130 patients (19.03%) had a family history of diabetes mellitus. A total of 219 cases (32.06%) were complicated with other systemic diseases, among which respiratory symptoms accounted for 53.88%, followed by digestive system symptoms (10.50%) (Fig. 3).
There were no statistical differences in the onset season, family history, GADAb, DKA degree, TPOAb, and TRAb among the three age groups. There were significant differences in sex, incidence of DKA, C-peptide, insulin, glycosylated hemoglobin at first diagnosis, blood glucose at first diagnosis, 25-hydroxyvitamin D(25OHD) level, hospital length of stay, hospitalization costs, and the incidence of polydipsia, polyuria, weight loss, and complicated systemic diseases among the three groups.
There was a statistically significant difference in the sex ratio among the three groups (P < 0.05). The proportion of male children was highest in Group I; however, there was no statistical difference in this proportion between Groups II and III. This suggests that the incidence of T1DM in male children was highest among infants.
Group I had the highest incidence of DKA (70.76%). There was no statistically significant difference in the incidence of DKA between Groups II and III.
The lowest C-peptide and HbA1c levels at first diagnosis were found in Group I; however, no statistical difference was found between Groups II and III.
The blood glucose level of Group I an II at first diagnosis was higher than Group III; however, there was no statistical difference between the first two groups.
The 25OHD level in Group I was significantly higher than that in the other two groups; however, there was no statistical difference between the other two groups.
There were differences in hospital length of stay among the three groups: Group I > Group II > Group III. The hospitalization cost in Group I (7481.52 yuan) was significantly higher than that in the other two groups; however, there was no statistical difference between Groups II and III.
The incidence of polydipsia and polyuria in Group I an II was significantly higher thanGroup III. Weight loss was significantly higher in Groups II and III than Group I. Group I had the highest incidence of other systemic diseases (49.58%).
[Insert Table 1 here]
0–3 years (n = 236) |
4–9 years (n = 229) |
10–18 years (n = 218) |
P |
|
---|---|---|---|---|
Sex (male) |
139 (58.9%)a |
113 (49.3%)b |
105 (48.1%)b |
0.04* |
Onset season |
||||
Spring |
49 (20.76%) |
50 (21.83%) |
55 (25.23%) |
0.318 |
Summer |
54 (22.88%) |
65 (28.38%) |
50 (22.94%) |
|
Autumn |
70 (29.66%) |
53 (23.14%) |
47 (21.56%) |
|
Winter |
63 (26.69%) |
61 (26.64%) |
66 (30.28%) |
|
Family history positivity |
48 (20.34%) |
41 (17.90%) |
41 (18.81%) |
0.795 |
DKA positivity |
167 (70.76%)a |
134 (58.52%)b |
129 (59.17%)b |
0.009* |
DKA degree |
||||
Mild |
64 (38.32%) |
64 (47.76%) |
60 (46.51%) |
0.195 |
Moderate and severe |
103 (61.68%) |
70 (52.24%) |
69 (53.49%) |
|
Term infant |
223 (94.5%)a |
194 (84.7%)b |
127 (58.3%)c |
< 0.001* |
Breast milk before 6 months |
190 (80.5%) |
176 (76.9%) |
163 (74.8%) |
0.332 |
HbA1c (%) |
11.19 (2.44)a |
12.36 (2.47)b |
12.24 (3.09)b |
< 0.001* |
C-peptide (nmol/L) |
0.31 (0.14,0.42)a |
0.52 (0.24,0.46)b |
0.74 (0.28,0.75)b |
< 0.001* |
Blood glucose (mmol/L) |
23.43 (6.61)a |
22.94 (7.37)a |
20.36 (7.21)b |
< 0.001* |
25OHD (ng/ml) |
20.73 (9.54)a |
17.79 (7.19)b |
17.08 (6.55)b |
< 0.001* |
Hospital length of stay (days) |
15.88 (6.55)a |
14.32 (6.07)b |
11.60 (5.45)c |
< 0.001* |
Disease course (days) |
5 (0,15.5) |
5 (0,15) |
4.5 (0,12) |
0.922 |
Hospitalization cost (China Yuan) |
7481.52 (6166.42,10495.78)a |
6819.28 (5304,8492.66)b |
6226.4 (4298.39,8570.15)b |
< 0.001* |
Polydipsia |
206 (87.29%)a |
192 (83.84)a |
155 (71.10)b |
0.002* |
Polyuria |
191 (80.93%)a |
179 (78.17)a |
124 (56.88)b |
< 0.001* |
Weight loss |
56 (23.73%)a |
93 (40.61)b |
76 (34.86)b |
< 0.001* |
Comorbid other diseases |
117 (49.58%)a |
73 (31.88%)b |
82 (37.61%)b |
< 0.001* |
a,b,c means Statistical difference between groups | ||||
* means P value < 0.05, statistically significant among the three groups | ||||
25OHD, 25-hydroxyvitamin D; HbA1c, hemoglobin A1C; DKA, diabetic ketoacidosis |
We included age, sex, parental occupation, onset season, family history, HbA1c, C-peptide, blood glucose, 25OHD, and the presence or absence of other systemic comorbidities in the univariate analysis of influencing factors for DKA. Age, HbA1c, 25OHD, C-peptide, and other systemic complications were associated with DKA (Table 2).
DKA (n = 430) |
Non DKA (n = 253) |
P value |
|
---|---|---|---|
Age (years) |
0.009* |
||
0–3 years |
167 (38.8%) |
69 (27.3%) |
|
4–9 years |
134 (31.1%) |
95 (37.5%) |
|
10–18 years |
129 (30%) |
89 (35.2%) |
|
Sex (male) |
220 (51.2%) |
137 (31.9%) |
0.45 |
Father occupation |
0.664 |
||
Industrial and agricultural workers |
201 (46.7%) |
105 (41.5%) |
|
Service workers |
22 (5.1%) |
14 (5.5%) |
|
Civil servants and employees of enterprises and institutions |
43 (10%) |
22 (8.7%) |
|
Professional and technical staff |
10 (2.3%) |
8 (3.2%) |
|
Self-employment |
72 (16.7%) |
45 (17.8%) |
|
Other |
82 (19.1%) |
59 (23.3%) |
|
Mother occupation |
0.717 |
||
Industrial and agricultural workers. |
181 (42.1%) |
96 (37.9%) |
|
Service workers |
15 (3.5%) |
13 (5.1%) |
|
Civil servants and employees of enterprises and institutions |
45 (10.5%) |
22 (8.7%) |
|
Professional and technical staff |
6 (1.4%) |
4 (1.6%) |
|
Self-employment |
61 (14.2%) |
40 (15.8%) |
|
Other |
122 (28.4%) |
78 (30.8%) |
|
Onset season |
0.167 |
||
Spring |
94 (21.9%) |
60 (23.7%) |
|
Summer |
98 (22.8%) |
71 (27.4%) |
|
Autumn |
118 (27.4%) |
52 (20.5%) |
|
Winter |
120 (27.9%) |
70 (27.7%) |
|
Family history positivity |
76 (17.7%) |
54 (21.3%) |
0.238 |
HbA1c at onset (%) |
12.11 ± 2.66 |
11.59 ± 2.80 |
0.017* |
C-peptide at onset (nmol/L) |
0.28 (0.16,0.43) |
0.42 (0.28,0.67) |
< 0.001* |
Blood glucose at onset (mmol/L) |
23.43 ± 6.91 |
20.34 ± 7.21 |
< 0.001* |
25OHD (ng/mL) |
17.99 ± 7.72 |
19.57 ± 8.50 |
0.013* |
Complicated with other diseases |
200 (46.5%) |
72 (28.5%) |
< 0.001* |
* means P value < 0.05, statistically significant between the two groups | |||
25OHD, 25-hydroxyvitamin D; HbA1c, hemoglobin A1C; DKA, diabetic ketoacidosis |
[Insert Table 2 here]
Further logistic regression analysis found that the independent risk factors for DKA included elevated HbA1c levels, elevated blood glucose levels, and comorbid other diseases. On the other hand, 25OHD and C-peptide were protective factors against DKA (Table 3). Children with more serious islet function impairment and other systemic diseases at first diagnosis were more prone to DKA. The incidence of DKA was lower in children with T1DM with high levels of vitamin D and less serious impairment of islet function.
OR |
SE |
P |
95%CI |
||
---|---|---|---|---|---|
Age (0–3 years as reference) |
0.091 |
||||
4–9 years |
1.209 |
0.114 |
0.409 |
0.77 |
1.900 |
10–18 years |
0.759 |
0.165 |
0.192 |
0.501 |
1.148 |
HbA1c |
1.067 |
0.032 |
0.042 |
1.002 |
1.137 |
C-peptide |
0.415 |
0.213 |
< 0.001 |
0.273 |
0.631 |
Blood glucose |
1.055 |
0.012 |
< 0.001 |
1.030 |
1.081 |
25OHD |
0.970 |
0.011 |
0.007 |
0.949 |
0.992 |
Complicated with other diseases |
0.444 |
0.184 |
< 0.001 |
0.310 |
0.638 |
OR, odds ration; SE, standard error; 25OHD, 25-hydroxyvitamin D; HbA1c, hemoglobin A1C; 95%CI, 95% confidence interval |
There was no apparent peak age for newly diagnosed type 1 diabetes in Henan Province. In Iran, the peak age of onset is between 5 and 9.9 years [9]. while in Beijing, Japan, and Uzbekistan, it was in adolescence [11, 12, 13]. Contrary to these findings, infant diabetes accounted for 34.5% of the children with diabetes in our study. The incidence of infant diabetes is high in our center because ours is the largest third-level and first-class specialized children's hospital in Henan Province, with advanced professional technology. Thus, parents of young children, especially infants and toddlers, tend to choose our hospital, while those of older children may choose other general hospitals.
The incidence of T1DM peaked in winter, which may be related to the high incidence of virus infections in this season. The seasonal pattern of T1DM onset is well known and has been confirmed repeatedly. In a study from Sweden, the incidence was higher from January to March and lowest from May to July [14]. However, studies from Iraq have shown higher rates in summer [15], which may be linked to different environmental factors. The seasonal distribution of T1DM among children aged 4–9 years in this study was consistent with the results found in Jiangxi Province in China.
The main symptoms before hospital visit were polyuria (72.33%) and polydipsia (79.21%), followed by weight loss (32.94%) and polyphgia (20.2%). A study from Taiwan showed that the most common symptoms were polyuria (96%), polydipsia (92%), dry lips (81%), weight loss (79%)[16]. In this study, it was found that polydipsia and polyuria were more common in infants and school-age children with T1DM, while weight loss was more common in adolescent children. This may be related to the strong self-consciousness of adolescent children and the difficulty in timely detection of symptoms.
One major finding is that 62.96% of the children presented with DKA in this study, and that severe DKA accounted for more than half of the DKA cases. The 0–3-year-olds group had the highest incidence of DKA (70.76%), and no statistical differences were observed between the other two groups. The incidence of DKA varies in different countries and regions [17], with the lowest incidence reported in Denmark (14.7%) and the highest in Saudi Arabia (79.8%). An Iranian study showed a 24% incidence of DKA, of which 54.5% of the cases were severe [9]. Results of multi-center epidemiological investigations are lacking in China. The incidence of DKA in Beijing and Tianjin was 41.1% and 45.6% respectively, among newly diagnosed type 1 diabetes children [10], and there was no statistical difference between different age groups. Studies from Jiangxi Province of China and France showed that the incidence of severe DKA was highest in children aged 0–4 years, which is similar to our findings. However, studies from Finland and New Zealand showed that the incidence of DKA was higher in adolescence [5, 18], which may be related to the lack of detection of symptoms due to the stronger self-consciousness of adolescent children.
About one-third of the children with DKA were complicated with other systemic complications, mainly those of the respiratory and digestive systems. In addition, children could not accurately express the typical symptoms of diabetes, such as polydipsia and polyuria, and caregivers and doctors had insufficient knowledge of the disease; therefore, the diagnosis of DKA was easily delayed, especially in younger children.
In this study, the highest incidence of DKA was found in the 0–3-year-olds group. This group also had the highest blood glucose levels and the lowest C-peptide levels. This reflected that the islet beta-cell function damage and metabolic disorders were more serious at onset in the young age group. Interestingly, the 0–3-year-olds group had the lowest HbA1c levels. This also prompted the more rapid and severe damage of insulin beta cells caused by immune injury, leading to a more serious metabolic disorder. This is consistent with the results of a study conducted in Taiwan [16].
Hospital length of stay and hospitalization costs were highest in the youngest age group. This was possibly related to the high morbidity of DKA and the complications with other systemic diseases in children in the young age group.
Many studies have shown that young age, race, residing in a rural area, and lack of health insurance are the main risk factors for DKA [19, 20]. However, domestic studies have found that rural residence, blood sodium, blood glucose, blood triglyceride and infection are risk factors for DKA [21]. While our findings are different with the domestic studies. In this study, age, HbA1c, C-peptide, 25OHD, and the presence of other systemic comorbidities were all factors associated with DKA. However, we found that age was not an independent risk factor for DKA after multivariate logistic regression analysis. This suggested that age was a confounding factor for DKA.
According to our findings, vitamin D deficiency is widely prevalent in children with T1DM in Henan Province. The serum 25OHD levels among the children in the 0–3-year-olds group were significantly higher than those of the children in the other two groups. Further, there was no statistical difference between the other two groups. A large number of studies have shown that 25OHD has a protective effect on islet β cell function and islet autoimmune and inflammatory responses [22]. Vitamin D deficiency has been linked to an increased incidence of T1DM worldwide, and new research suggests that vitamin D is associated with the incidence of DKA. In a study of 185 children with T1DM in the United States, 33% of the patients had DKA. Out of these cases, the incidence of DKA was 44% in the low vitamin D group and 18% in the vitamin D adequate group: the incidence of DKA in the vitamin D deficient group was significantly higher than that in the vitamin D adequate group [23]. However, an Australian study of the relationship between 25OHD and acidosis showed that acidosis may lead to impaired 1-α-hydroxylase activity to affect the metabolism of vitamin D, or low levels of vitamin D may be T1DM children merger risk factors of DKA, remains to be further discussed [24]. Logistic regression analysis in this study showed that 25-hydroxyvitamin D3 was an independent factor for DKA, which is consistent with the findings of other studies. The incidence of DKA was lowest in children with T1DM with high vitamin D levels; therefore, we recommend that children with T1DM receive vitamin D supplementation.
Compared with other countries, the incidence of DKA in children and adolescents aged 0–18 years in our province, and even in other regions of China, is high. It is easy for DKA to be misdiagnosed and incorrectly treated, which places a heavy burden on children with T1DM, their families, and society. Thus, DKA needs attention from all sectors of our society. Younger children with T1DM are more likely to have DKA, more serious metabolic disorders, and other systemic diseases. This leads to longer hospital stays and higher medical costs. Vitamin D supplementation is important in children with diabetes. We should increase the education and popularization of diabetes knowledge among parents, kindergarten teachers, and pediatricians to facilitate early identification and timely diagnosis and treatment of diabetes in infants. However, family income, body mass index, blood lipids, electrolytes, and other indicators were not included in this study. These should be assessed further in future studies.
25OHD: 25-hydroxyvitamin D
DKA: Diabetic ketoacidosis
FPG: fasting blood glucose
GADAb: glutamate decarboxylase antibody
HbA1c: hemoglobin A1C
IAA: insulin antibody
ISPAD: International Society of Pediatric and Adolescent Diabetes
MODY: maturity-onset diabetes of the young
OGTT: oral glucose tolerance test
T1DM: type 1 diabetes mellitus
TSH: thyroid stimulating hormone
Ethics approval and consent to participate
The study was approved by the ethics committee of Henan Children's Hospital, respecting the Declaration of Helsinki for human subjects. As the study is retrospective, Ethics committee of Henan Children's Hospital waived the need for informed consent (Ethical number: 2022–K–019).
Consent for publication
Not applicable.
Availability of data and materials
Due to our need for subsequent studies, the datasets generated and/or analyzed in the current study are not publicly available, but are available at the reasonable request of the corresponding author.
Competing interests
The authors declare that they have no competing interests.
Funding
The study was supported by a grant from the Henan Province Science and Technology Department, Zhengzhou, China.(Project: Molecular genetic etiology and clinical diagnosis optimization of infantile type 1 diabetes mellitus)
Authors' contributions
AH, HW and QC :Concept and designed the study, analysed data and drafted. AH, QC,WY,YC;Collected the data,supervised at site,analysed and interpreted the data. AH,QW,HW: Collected the data and helped in data analysis.AH wrote the main manuscript text. All authors reviewed the systematic review and revised the manuscript. All authors have read and approved the final manuscript.
Acknowledgments
The authors thank Professor Yan Liang from the Department of Pediatrics of Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, for her great help in the current study. The authors would like to thank Editage (www.editage.cn) for English language editing.