European Journal of Cardiovascular Medicine

Type 1 Diabetes Mellitus (T1DM) is a chronic autoimmune condition characterized by the destruction of pancreatic β-cells, leading to absolute insulin deficiency and hyperglycemia [1]. It is one of the most common endocrine disorders in children, with an estimated global incidence of 96,000 new cases annually among those under 15 years [2]. In India, approximately 97,700 children live with T1DM, and regional studies, such as the Karnataka T1DM registry, report an incidence of 3.7–4.0 per 100,000 children [3]. Chronic hyperglycemia in T1DM predisposes patients to both acute and chronic complications, including diabetic ketoacidosis (DKA), retinopathy, nephropathy, and potentially hepatopathy [4].

Hepatopathy in diabetes, particularly non-alcoholic fatty liver disease (NAFLD), has garnered increasing attention due to its association with metabolic dysregulation [5]. NAFLD encompasses a spectrum from simple steatosis to non-alcoholic steatohepatitis (NASH), which can progress to fibrosis and cirrhosis [6]. Serum alanine transaminase (ALT) is a widely used biomarker for liver injury, with elevated levels indicating hepatocellular damage [7]. Population-based studies, such as the Third National Health and Nutrition Examination Survey (NHANES III), have linked elevated ALT to impaired glucose metabolism, insulin resistance, and obesity in diabetic populations [8]. In T1DM, the prevalence of elevated ALT is reported to be 3–4 times higher than in the general population, potentially due to glycogen accumulation or lipid deposition in the liver [9].

The pathophysiology of hepatopathy in T1DM is complex. Chronic hyperglycemia induces oxidative stress, activates the polyol pathway, and promotes the formation of advanced glycation end products (AGEs), all of which may contribute to liver damage [10]. Additionally, insulin deficiency disrupts lipid metabolism, leading to increased free fatty acid flux to the liver, which may exacerbate steatosis [11]. However, unlike Type 2 Diabetes Mellitus (T2DM), where insulin resistance is a primary driver, T1DM-related hepatopathy may involve distinct mechanisms, such as glycogenic hepatopathy or autoimmune-mediated liver injury [12]. Studies have suggested that poor glycemic control, as measured by glycated hemoglobin (HbA1c), may correlate with elevated liver enzymes, but data in pediatric T1DM populations are limited [13].

Despite the growing recognition of NAFLD in diabetes, few studies have specifically evaluated serum ALT levels in children with T1DM. A study by Leeds et al. reported a 10.4% prevalence of elevated ALT in T1DM adults, but pediatric data are sparse [14]. Furthermore, the relationship between glycemic control (via HbA1c or fasting blood sugar) and liver enzyme levels remains poorly understood in this population. Understanding this association is critical, as early detection of hepatopathy could guide interventions to prevent long-term liver complications.

This study addresses these gaps by evaluating serum ALT levels in a cohort of children with T1DM and examining their association with glycemic control. By focusing on a pediatric population, the study aims to provide insights into the early manifestations of liver dysfunction in T1DM and inform clinical management strategies. The objectives were to measure serum ALT levels in T1DM children aged 5–18 years and to determine whether these levels correlate with markers of glycemic control, specifically HbA1c and fasting blood sugar (FBS). The findings may contribute to the growing body of evidence on T1DM-related hepatopathy and guide future research into preventive strategies.

Aims

1. To evaluate serum alanine transaminase (ALT) levels in children with Type 1 Diabetes Mellitus (T1DM) aged 5–18 years on insulin therapy.
2. To determine the association between serum ALT levels and glycemic control, as measured by HbA1c and fasting blood sugar (FBS).

Study Design

A cross-sectional study was conducted at Cheluvamba Hospital, Mysuru, India, between February 2022 and February 2023. The study was approved by the Institutional Ethics Committee of Mysore Medical College and Research Institute (EC REG ECR/134/Inst/KA/2013/RR-19), and written informed consent was obtained from parents or guardians of all participants, with assent from children over 13 years.

Study Population

The study included 60 children aged 5–18 years diagnosed with T1DM, as per the International Society for Pediatric and Adolescent Diabetes (ISPAD) criteria, and receiving insulin therapy. Inclusion criteria were: (1) confirmed T1DM diagnosis, (2) age 5–18 years, and (3) on insulin therapy for at least 6 months. Exclusion criteria included: (1) history of viral hepatitis, (2) use of hepatotoxic drugs, (3) chronic liver disease, (4) other metabolic disorders affecting liver function, and (5) history of ICU admission within the past 6 months.

Sample Size Calculation

The sample size was calculated based on the expected prevalence of elevated ALT in T1DM (10.4% from Leeds et al. [14]), with a 95% confidence level and 8% precision. Using the formula for prevalence studies, ( n = \frac{Z^2 \cdot P \cdot (1-P)}{d^2} ), where ( Z = 1.96 ), ( P = 0.104 ), and ( d = 0.08 ), the required sample size was approximately 54. Accounting for a 10% dropout rate, a total of 60 participants were enrolled.

Data Collection

Participants underwent a detailed clinical assessment, including history of symptoms (icterus, nausea, fatigue, loss of appetite), past medical history, and insulin therapy details (type, duration, regimen, compliance). Physical examination included height, weight, body mass index (BMI), and systemic findings (respiratory, cardiovascular, gastrointestinal, and neurological). Blood samples were collected for serum ALT, HbA1c, fasting blood sugar (FBS), and postprandial blood sugar (PPBS). Serum ALT was measured using the UV kinetic method on an automated analyzer (normal range: <40 IU/L). HbA1c was determined by high-performance liquid chromatography (HPLC), and blood glucose levels were measured using a glucometer.

Children with elevated ALT levels (>40 IU/L) underwent ultrasonography of the liver to assess for NAFLD or other abnormalities. These participants received strict glycemic control as per ISPAD 2018 guidelines, including optimization of insulin regimens (basal-bolus or continuous subcutaneous insulin infusion) and dietary counseling. Follow-up assessments were conducted at 6 months to evaluate changes in ALT levels.

Statistical Analysis

Data were analyzed using SPSS version 25. Continuous variables (age, ALT, HbA1c, FBS) were expressed as mean ± standard deviation (SD). Categorical variables (gender, systemic findings) were presented as frequencies and percentages. Pearson’s correlation coefficient was used to assess the association between serum ALT and glycemic parameters (HbA1c, FBS). A P-value < 0.05 was considered statistically significant.

The study enrolled 60 children with T1DM, with a mean age of 11.87 ± 2.97 years and a mean duration of diabetes of 6.85 ± 3.00 years. The cohort included 24 males (40%) and 36 females (60%).

Table 1: Distribution of Study Population Based on Age

Table 2: Distribution of Study Population Based on Gender

Table 3: Distribution of Study Population Based on Duration of Insulin Therapy

Table 4: Distribution of Study Population Based on Glycemic Parameters

Table 5: Distribution of Study Population Based on Serum ALT Levels

The mean serum ALT level was 16.40 ± 8.01 IU/L, within the normal range (<40 IU/L). Only three participants (5.0%) had elevated ALT levels (>40 IU/L). Ultrasonography in these cases showed no evidence of NAFLD or other liver abnormalities. After 6 months of strict glycemic control, repeat ALT measurements showed no significant change (mean: 41.2 ± 2.1 IU/L to 39.8 ± 1.9 IU/L, P = 0.412).

Correlation analysis revealed no significant association between serum ALT and HbA1c (r = 0.132, P = 0.273). However, a statistically significant correlation was observed between ALT and FBS (r = 0.456, P < 0.001). No significant associations were found between ALT and other parameters, such as BMI (P = 0.521) or duration of insulin therapy (P = 0.389).

This study evaluated serum ALT levels in 60 children with T1DM and their association with glycemic control. The mean ALT level of 16.40 ± 8.01 IU/L was within the normal range, and only 5.0% of participants had elevated levels, suggesting a low prevalence of hepatopathy in this cohort. These findings contrast with previous studies reporting higher rates of elevated ALT in T1DM. For instance, Leeds et al. found a 10.4% prevalence of elevated ALT in T1DM adults (P < 0.05 compared to controls) [14]. Similarly, Al-Hussaini et al. reported a 15.6% prevalence of hepatopathy in T1DM children, with 8% showing NAFLD on ultrasonography [15]. The lower prevalence in our study may reflect differences in population characteristics, such as lower BMI (mean: 18.2 ± 2.5 kg/m²) or shorter diabetes duration compared to other cohorts.

The lack of correlation between ALT and HbA1c (P = 0.273) suggests that chronic glycemic control does not significantly influence liver enzyme levels in T1DM children. This finding aligns with El-Sayed et al., who reported no association between HbA1c and ALT in T1DM adolescents (P = 0.321) [13]. However, it contrasts with studies in T2DM, where poor glycemic control is strongly linked to NAFLD (e.g., Targher et al., 25% prevalence of NAFLD in T2DM with HbA1c >7%, P < 0.01) [9]. The significant correlation between ALT and FBS (P < 0.001) in our study suggests that acute hyperglycemia may induce transient liver stress, possibly via oxidative stress or glycogen accumulation, as proposed by Sherigar et al. [12].

The absence of NAFLD on ultrasonography in participants with elevated ALT is notable. This may indicate glycogenic hepatopathy, a reversible condition in T1DM caused by glycogen accumulation, rather than NAFLD [12]. Alternatively, the small number of cases with elevated ALT (n=3) may have limited the detection of NAFLD. Larger studies, such as Stadler et al., reported a 12% prevalence of NAFLD in T1DM adults using transient elastography (P < 0.05) [11], highlighting the need for advanced imaging in future research.

Limitations of this study include the small sample size and single-center design, which may limit generalizability. Additionally, the reliance on ultrasonography rather than liver biopsy may have underestimated NAFLD prevalence. Future studies should incorporate longitudinal designs and advanced diagnostic tools, such as magnetic resonance elastography, to better characterize hepatopathy in T1DM.

This study found that serum ALT levels in children with T1DM were generally within the normal range, with a low prevalence of elevation (5.0%). No significant association was observed between ALT and HbA1c, indicating that chronic glycemic control may not directly influence liver enzyme levels in this population. However, the significant correlation with FBS suggests that acute hyperglycemia may contribute to liver stress. These findings highlight the need for regular monitoring of liver function in T1DM children, particularly during periods of poor glucose control. Larger, multicenter studies are warranted to confirm these results and explore the mechanisms underlying T1DM-related hepatopathy.

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