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Abstract

Objective

The aim of this study was to identify factors associated with severe diabetic ketoacidosis (DKA) at the onset of type 1 diabetes mellitus (T1DM) in adult patients.

Methods

We conducted a retrospective analysis over a 10-year period including adults newly diagnosed with T1DM. Eligible participants were diagnosed with DKA at the time of T1DM diagnosis. DKA severity was categorized as mild, moderate, or severe. Data were collected on age, body mass index, family history of diabetes and autoimmune disorders, lifestyle habits, delayed diagnosis, and preceding factors.

Results

A total of 305 participants (69.8% men) with T1DM were included. Overall, 63 patients were admitted with severe DKA (Group 1) and 242 with non-severe DKA (Group 2). Factors associated with severe DKA at diagnosis of T1DM were a long period between symptom onset and first hospitalization, preceding infection, tachypnea, thrombocytopenia, anemia, hepatic cytolysis, polyuria, and tachycardia.

Conclusions

The present findings highlight the need for improving awareness about diabetes symptoms among physicians and the public to reduce the occurrence and severity of DKA at the onset of T1DM.

Keywords

Type 1 diabetes ketoacidosis autoimmunity infection predictive factor cross-sectional study

Introduction

Diabetes mellitus is a chronic disease that represents a major public health problem in the general population and is among the priorities of health care systems worldwide.¹ The rise in diabetes mellitus prevalence persists as a result of widespread adoption of an unhealthy lifestyle, marked by hypercaloric diets and sedentary lifestyle habits.² Diabetes is a main cause of morbidity and mortality, affecting 463 million individuals globally, with projections suggesting that this figure will rise to 578 million by 2030.³

Type 1 diabetes mellitus (T1DM) is the result of autoimmune destruction of beta cells, which produce insulin in the pancreas. Genetic factors, acting together with environmental influences, trigger the onset of this condition. T1DM accounts for approximately 10% of diabetes cases and its incidence is increasing worldwide.^4,5 The current global rise in T1DM incidence, reported at 3% per year, is well documented, and projections suggest that the incidence of T1DM diabetes will be 40% higher in 2010 compared with 1998. This rapid increase strongly implies that environmental factors influencing susceptible genes play an important role in the changing epidemiology of T1DM.⁶

Diabetic ketoacidosis (DKA), resulting from a complete lack of insulin, is the most severe and potentially life-threatening acute complication of T1DM.⁷ The rate of DKA occurrence at the time of T1DM onset ranges from 15% to 67%^5,8,9 and varies with geographic region. DKA accounts for approximately 0.15% to 0.31% of fatalities among individuals with T1DM, although risk factors associated with severe DKA in the adult population are poorly understood.³

The reasons why some individuals develop severe DKA and others do not remain unclear. It is uncertain whether DKA occurrence results from delayed diagnosis and treatment or signifies a more aggressive form of T1DM. Understanding the factors linked to severe DKA at diagnosis and assessing the impact of delayed diagnosis and treatment is crucial. This knowledge could enhance our comprehension of the disease and aid in developing interventions for patients, health care professionals, and the general population to reduce DKA occurrence.

The aim of this study was to identify and analyze the factors associated with severe DKA among adolescent and adult participants diagnosed with T1DM over a decade-long period. Using cross-sectional analysis, we aimed to discern the demographic, clinical, biological, and socioeconomic factors influencing the severity of this acute complication. In doing so, we hope to provide insights that can guide targeted interventions and enhance clinical management approaches.

Methods

A retrospective analysis was conducted between 2010 and 2020 among patients diagnosed with T1DM after age 16 years and who also had medical records for DKA occurrence at the time of T1DM onset. T1DM was confirmed with positive results for one or more circulating pancreatic autoantibodies: anti-glutamic acid decarboxylase antibodies (anti-GAD), anti-tyrosine phosphatase antibodies (anti-IA2), and anti-zinc transporter protein antibodies.

DKA was defined as hyperglycemia (blood glucose >2.5 g/L) associated with acidosis (pH <7.38) with plasma accumulation of ketone bodies. The severity of DKA was categorized based on venous blood pH: severe <7.1; moderate ≥7.1 and <7.2; mild ≥7.2 and <7.3.¹ The study population was divided into two groups based on the severity of DKA: patients in group 1 (G1) presented with a severe form of DKA and those in group 2 (G2) had a non-severe (moderate or mild) form of DKA. Factors preceding DKA in participants from both groups were compared to identify factors associated with a severe form of DKA.

To assess factors associated with severe DKA, we investigated sociodemographic factors as well as factors related to initial symptomatology, clinical examination, patient biology, and clinical progression. This study adhered to all standards of ethics in research. Written consent was obtained from all patients retrospectively. Participants were provided with a form that clearly explained the purpose of the study, the type of information that would be published, and how their data would be used. The anonymity and confidentiality of patient data were respected and we de-identified all patient details. We obtained approval for this retrospective study from the Ethical Committee of the University of Medicine of Sousse (02/11/2023). The study was conducted with strict adherence to medical confidentiality. No fees were received to conduct this study. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.¹⁰

Data were collected on sex; age; lifestyle habits such as smoking, alcohol consumption, and sedentary lifestyle; height and weight; family history of diabetes and autoimmune diseases; cardinal signs; seasonality; delayed diagnosis; preceding factors; and period between symptom onset and first hospitalization. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m²).^11,12 Overweight was defined as BMI 25–30 kg/m²; obesity was defined as BMI >30 kg/m² and categorized as grade 1 obesity with BMI 30–34.9 kg/m², grade 2 obesity with BMI 35–39.9 kg/m², and grade 3 obesity with BMI >40 kg/m². The diagnosis of hypertension was according to whether the participant was already being treated or with systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg.¹³

Laboratory findings were obtained using venous samples collected from individuals on admission, including hemoglobin (HB) level, white blood cell (WBC) count, serum fasting glucose, glycated hemoglobin (HbA1c), venous pH, and bicarbonate (HCO3−) levels; renal and hepatic assessment was also conducted. Anemia was defined as HB level <12 g/dL in female patients and <13 g/dL in male patients. Hyperleukocytosis was defined as WBC count >10,000 cells/mm³, leukopenia as WBC count <4000 cells/mm³, and thrombocytopenia as platelet count <150,000/mm³.¹⁴

The obtained values were coded either in binary mode (yes/no, presence or absence) or according to geometric progression for multiple responses. The necessary data were summarized in a standardized information sheet for all patients. We used IBM SPSS ver. 25.0 (IBM Corp., Armonk, NY, USA) for data entry and analysis. We calculated absolute frequencies and percentages for qualitative variables. We computed means, medians, and standard deviations, and determined extreme values for quantitative variables.

To compare patients from both groups, we used the Student t-test for normally distributed quantitative variables. When normality of the distribution was not met, the Mann–Whitney test was used. The chi-square test was used for qualitative variables. Assessment of the association between two quantitative variables was conducted using the Pearson correlation coefficient. The significance threshold (p) was set to 5%. All variables with a p-value <0.2 in the univariate analysis were introduced into a stepwise descending binary logistic regression model to determine independent factors associated with severe DKA.

Results

A total of 305 patients with T1DM were included in this study. During the study period, which spanned 10 years (2010–2020), the average hospitalization rate was 27.9 participants per year (range: 0–88). The highest number of patients hospitalized for DKA at the onset of T1DM was in 2013. Male individuals comprised 69.8% of the study population, and the sex ratio was 2.31, with a significant male predominance (p < 0.001). Additionally, male sex was significantly associated with the severity of DKA (p = 0.006). The median age of participants was 27 (range: 14–70) years. The most represented age group was 20 to 30 years old with 107 individuals (35.1%) (p < 0.001); 62% of individuals were aged 30 years or younger, and 38% were older than 30 years of age. There was a significant association between younger age and the occurrence of DKA in patients with positive anti-GAD and anti-IA2 (p < 0.001). However, the results of univariate analysis showed that age was not a factor related to the severity of DKA. Among our population, 211 patients (69.2%) lived in an urban area and 94 (30.8%) resided in a rural area (Table 1).

Table 1.

Patients’ demographic characteristics and comorbidities.

Characteristics (N = 305)	n	%
Age (years), mean, (IQR)	27 (20–35.5)
16–19	82	26.9
20–29	107	35.1
30–39	62	20.3
40–49	24	7.9
50–59	20	6.6
60–69	9	3
>70	1	0.3
Male sex	213	69.8
Female sex	92	30.2
Urban residence	211	69.2
Rural residence	94	30.8
Smoking	133	43.6
Alcohol consumption	81	26.6
Sedentary lifestyle	277	90.8
BMI (kg/m²), mean, (IQR)	22.30 (19.37–24.73)
Overweight	36	11.8
Obesity	14	4.6

BMI, body mass index; IQR, interquartile range.

An autoimmune predisposition was noted in 22.3% of patients. Celiac disease, vitiligo, and hypothyroidism were the most frequently noted medical histories, in 9.5%, 7.2%, and 3.3% of patients, respectively. Four patients had hyperthyroidism (1.3%), two had pernicious anemia (0.7%), and one had systemic lupus erythematosus (0.3%) (Figure 1). The presence of a family history of diabetes or autoimmune disease was not predictive of DKA severity in our study population.

Figure 1.

Distribution of family history of autoimmunity. SLE, systemic lupus erythematosus.

The median period between symptom onset and first hospitalization was 21 days (range: 3 to 90 days). Most of our participants (n = 77, 25.2%) were admitted during the fourth week of clinical symptoms, 49 (16.1%) were admitted during the second week, and 40 (13.1%) from the third week onward. Polyuria and polydipsia were the most common symptoms, noted in 302 (99%) and 258 (84.6%) patients, respectively. Fatigue ranked second, noted in 234 patients (76.7%). Digestive symptoms (diarrhea and/or vomiting and/or abdominal pain) and dehydration (dry mouth and/or thirst) were present in 66 (21.6%) and 27 (8.9%) patients, respectively, and asthenia was present in 37%. Our study revealed that polyuria and tachycardia were significantly predictive of DKA severity (p < 0.001).

Regarding the initial clinical examination of patients, at admission, 22 participants had vitiligo (7.2%) and four had thyroid goiter (1.3%). HB and platelet levels were inversely associated with DKA severity (p = 0.01; p = 0.002). Leukocyte and neutrophil levels were found to be unrelated to DKA severity, and there was no association between DKA severity and HbA1c or serum fasting glucose levels. Initial admission to the intensive care unit (ICU) was necessary for 10 individuals (3.3%). A severe form of DKA was found in 63 patients (20.7%, G1) versus 242 patients (79.3%, G2) who presented with mild to moderate DKA.

The factors associated with severe DKA were identified by comparing the two groups of patients. The proportion of patients in G1 who developed an infection preceding T1DM was significantly higher than the proportion in G2, with 27 patients (42.9%) versus 66 patients (27.3%), respectively (p = 0.017). The origins of infection were also comparable between the two groups (Figure 2).

Figure 2.

Distribution of infection cases according to origin. ENT, ear, nose, throat.

Exposure to psychological stress was comparable between the two groups, found in 63.5% of patients in G1 versus 51.2% of those in G2. In total, 40 participants in G1 (63.5%) habitually consumed hypertonic drinks versus 136 patients (56.2%) in G2, which was comparable between groups. Thirty-one patients in G1 (49.2%) followed a hypercaloric diet versus 113 patients (46.7%) in G2. Concomitant thyroid dysfunction was detected in five patients in G1 (7.9%) versus 20 patients (8.3%) in G2; this finding was comparable between the groups. Among 40 participants in G2 (16.5%), no unknown factors for DKA were identified, as compared with 5 participants in G1 (7.9%) who had unknown precipitating factors for DKA (Table 2).

Table 2.

Univariate analysis of factors precipitating DKA.

Factor	G1 (n = 63)	G2 (n = 242)	OR	95% CI	p
Infection	27 (42.9)	66 (27.3%)	2	1.12–3.54	0.017
Psychological stress	40 (63.5)	124 (51.2%)	1.65	0.93–2.93	0.082
Hypertonic beverages	40 (63.5)	136 (56.2%)	1.35	0.76–2.4	0.297
Hypercaloric diet	31 (49.2%)	113 (46.7%)	1,1	0.63–1.92	0.722
Endocrine factors	5 (7.9%)	20 (8.3%)	–	–	–
Unidentified factors	5 (7.9%)	40 (16.5%)	0.43	0.16–1.15	0.087

DKA, diabetic ketoacidosis; G1, group 1; G2, group 2; OR, odds ratio; CI, confidence interval.

As for biological factors, thrombocytopenia was significantly associated with severity in 22.2% of G1 patients versus 8.3% of G2 patients (p = 0.002). Anemia was significantly associated with severity in 14.3% of G1 patients versus 4.5% of G2 patients (p = 0.01). The mean fasting glucose was comparable between the two groups (G1: 13.5 vs. G2: 14.72). HbA1c was also comparable between groups (mean: 12.27% in G1 versus 12.42% in G2). Hepatic cytolysis was significantly associated with severity in 39.7% of G1 patients versus 8.3% of G2 patients (p < 0.001) (Table 3). Multivariate analysis did not identify any factors independently associated with the severe form of DKA.

Table 3.

Univariate analysis of biological signs associated with severe DKA.

Biological parameters	G1 (N = 63) n (%)	G2 (N = 242) n (%)	OR	95% CI	p
WBC (/mm³), median	7500	6800	–	–	–
Leukocytosis	11 (17.5)	30 (12.4)	1.49	0.7–3.17	0.294
Leukopenia	1 (1.6)	6 (2.5)	–	–	1
Hemoglobin (g/dL) median	12.9	13.8	–	–	1
Anemia	9 (14.3)	11 (4.5)	2.5	1.38–8.86	0.01
Platelets (/mm³), median	207,000	213,000	–	–	1
Thrombocytopenia	14 (22.2)	20 (8.3)	3.17	1.49–6.71	0.002
Creatinine (µmol/L), median	57.11	58.42	–	–	1
Hepatic cytolysis	25 (39.7)	20 (8.3)	7.3	3.69–14.43	<0.001
Fasting blood glucose (mmol/L), mean	13.5	14.72	–	–	>0.99
Hb1Ac (%), mean	12.27	12.42	–	–	>0.99
Thyroid disorders	9 (14.3)	32 (13.2)	1.09	0.49–2.42	0.826

DKA, diabetic ketoacidosis; WBC, white blood cell; HbA1c, glycated hemoglobin; OR, odds ratio; CI, confidence interval.

Discussion

Several studies have demonstrated a decrease in the average age at diagnosis of adult T1DM.¹⁴ DKA often occurs in young adults diagnosed with T1DM.^15–17 Per the results of our analysis, the median patient age (interquartile range) was 27 (20–35.5) years, which is consistent with the literature. In univariate analysis, we concluded that age was not a factor related to the severity of DKA, consistent with the literature.^18–20 The sex ratio in our study population revealed a marked and significant male predominance (69.8%, p < 0.001), corroborating observations from several Chinese and African research teams.^21–24 Male sex was significantly associated with the severity of DKA (p = 0.006), but there are very few related studies with which to compare this finding. A study by Bogale et al. showed no significant difference in the severity of DKA between the two sexes.²⁴

Several studies have emphasized that the absence of a family history of diabetes or autoimmune disorders is a not risk factor for the development of DKA;^25,26 this may be owing to a lack of knowledge about the cardinal signs of diabetes and possible modes of presentation. In a literature review by Sadauskait-Kuehne et al., the authors concluded that children with at least one first-degree parent who has diabetes have laboratory values closer to normal at the time of diagnosis than sporadic cases of DKA.²⁷ In our study, the presence of a family history of diabetes or autoimmune disease was not predictive of DKA severity.

T1DM and celiac disease share a common genetic background and abnormal immune response at the level of the small intestine, characterized by inflammation and varying degrees of enteropathy.²⁸ The prevalence of celiac disease in T1DM ranges from 3% to 16%, with an average prevalence of 8%, which was comparable to our results where 9.5% of patients had celiac disease.²⁹ It is essential to conduct regular nutritional education and provide psychological support to these patients.

The presence of an infectious episode preceding T1DM diagnosis was significantly predictive of DKA severity. A meta-analysis conducted by Usher-Smith et al. in 2011, including over 24,000 children from 31 countries, demonstrated that the presence of a recent infection was statistically associated with a three-fold higher risk of developing DKA at the time of T1DM diagnosis.³⁰ Regarding the clinical presentation of DKA, several studies have reported cardinal signs preceding the onset of inaugural DKA in T1DM, mainly including polyuria, asthenia, weight loss, and digestive symptoms.^17,31,32 Similar to a study where polyuria was the most common symptom (89%) followed by general condition alteration with asthenia (54%), polyuria ranked first among our patients (99%), followed by weight loss (84.6%) and asthenia (37%). On average, our patients experienced a diagnostic delay of 21 days from the onset of the first diabetes-related symptoms, which was close to that reported in the literature.^29,31

In a literature review, initial clinical examination of patients admitted for DKA revealed various clinical manifestations such as Kussmaul breathing, tachycardia, signs of dehydration, ketone breath odor, and consciousness disorders including coma.³³ Our study revealed that polyuria and tachycardia were significantly predictive of DKA severity (p < 0.001), similar to the results of a study by Ben Salah et al. among patients admitted for DKA to an emergency department.^34–36

In our study, HB and platelet levels were inversely associated with DKA severity (p = 0.01; p = 0.002), consistent with the results of several cohort studies, such as that by Mousa et al. Those authors concluded that mean platelet volume and platelet distribution width were significantly altered in patients with DKA, and these levels markedly improved upon DKA resolution.^37–39 Leukocytosis, a common biological abnormality in DKA, is not necessarily associated with infectious syndrome.³⁹ Numerous studies have reported its association with DKA severity, such as the study by Xu et al., where leukocyte and neutrophil levels were significantly higher in severe DKA cases compared with mild or moderate cases (p < 0.05).⁴⁰ This is contrary to our study where leukocyte and neutrophil levels were found to be unrelated to DKA severity.

Hepatic cytolysis was observed in 6.2% of patients and was significantly associated with DKA severity (p < 0.001). This finding is comparable to results reported by Tiercelin et al., where 38% of patients had elevated transaminases (1.02 to 20 times the upper limit), and this cytolysis was related to the severity of renal tubular acidosis. This situation could be explained by hepatic glycogenosis, a condition with a spontaneously favorable course.^41,42

The prevalence of severe DKA in children and adolescents with T1DM remains notably high.^43,44 Studies indicate that severe DKA occurs in approximately 20% to 30% of pediatric patients at the time of T1DM diagnosis.^45–47 This high prevalence underscores the critical need for timely recognition and intervention. The rates of ICU admission in these young patients are also high. Admission to the ICU is often required to manage the acute complications associated with severe DKA, especially in recent years, which is probably attributable to COVID-19.^48,49 When compared with adult populations, children and adolescents with T1DM exhibit higher rates of severe DKA and ICU admission, likely owing to various factors including delayed diagnosis and differences in disease management practices. Understanding these discrepancies is crucial for improving outcomes and tailoring prevention strategies to different age groups.

There are several limitations to our study. As a cross-sectional analytical study, we captured data at a single point in time, which limits the ability to infer causality or observe changes over time. This study was conducted at a single center, which may limit the generalizability of the findings to other settings or populations. Furthermore, the retrospective nature of data collection from hospital records introduces the potential for selection bias and information bias owing to incomplete or inaccurate documentation.

Conclusions

The severity of the clinical presentation of DKA varies, ranging from simple ketosis to severe DKA, with potential complications including cerebral edema leading to coma or even death. In this cross-sectional study, we sought to describe the epidemiological, clinical, and biological characteristics of patients hospitalized for DKA, heralding T1DM, and to identify factors associated with the severity of DKA. We aimed to clarify predictive factors for the occurrence of inaugural DKA in T1DM. These factors mainly involve infection or acute psychological stress and can even be triggered by physical trauma, surgery, or road accidents, among others. However, many factors that can predict DKA remain unknown. In our univariate analysis, we identified several predictive factors for severe DKA among hospitalized patients with inaugural T1DM, including male sex, an infection preceding T1DM, tachypnea, thrombocytopenia, anemia, hepatic cytolysis, polyuria, and tachycardia.

The treatment of DKA should primarily focus on preventive measures based on early diagnosis of diabetes according to a thorough understanding of the cardinal signs of diabetes and proper management thereafter. All efforts should be centered on educating physicians and families to provide the necessary knowledge for diagnosing diabetes. Increased focus on and implementation of prevention strategies are warranted, particularly for individuals with ketosis-prone atypical diabetes.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241281654 - Supplemental material for Factors associated with severe diabetic ketoacidosis in patients diagnosed with type 1 diabetes: a decade-long cross-sectional analysis

Supplemental material, sj-pdf-1-imr-10.1177_03000605241281654 for Factors associated with severe diabetic ketoacidosis in patients diagnosed with type 1 diabetes: a decade-long cross-sectional analysis by Ach Taieb, Ghali Hela, Achour Salsabil, Gorchane Asma and Ach Koussay in Journal of International Medical Research

Footnotes

Author contributions

Ach Taieb drafted the manuscript. All authors helped in patient care and read and approved the final manuscript.

Availability of data and materials

The collected data are available upon request from the corresponding author.

Declaration of conflicting interest

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

ORCID iD

Ach Taieb

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