Abstract
Introduction
Celiac disease (CD) is a lifelong immune-mediated condition precipitated by gluten ingestion in genetically predisposed individuals, resulting in intestinal mucosal damage, impaired growth, micronutrient deficiencies, among other gastrointestinal and extraintestinal symptoms. A gluten-free diet (GFD) contributes to the healing of the mucosa and improves nutrient absorption, although recovery patterns may vary.
Aim
The present study aimed to determine changes in anthropometric parameters and micronutrient levels at diagnosis and at six and twelve months following the start of a GFD, and to investigate any associations between these changes and tissue transglutaminase IgA (tTG-IgA) status, the severity of mucosal damage, or clinical characteristics.
Methods
This retrospective investigation involved an assessment of pediatric individuals diagnosed with CD using anthropometric and micronutrient data collected at the point of diagnosis and at subsequent 6- and 12-month intervals following GFD. Dietary adherence was evaluated retrospectively using physician and dietitian follow-up notes, clinical assessment, and serial tTG-IgA measurements.
Results
Among 103 children (64% female), 56% had no comorbidities, and type 1 diabetes was the most common (15%). Height, weight, body mass index, and most micronutrient levels improved during follow-up period. Vitamin D deficiency remained present in 27% of patients at 12 months and overweight prevalence increased from 7.8% to 18.4% during follow-up. Individuals presenting with comorbid CD+type 1 diabetes demonstrated higher SDS for weight and height, and elevated hemoglobin concentrations. The incidence of seronegativity was 55% at six months and 73% at twelve months.
Conclusion
Within a year, GFD enhances growth and resolves the majority of micronutrient deficiencies, however; ongoing nutritional monitoring is crucial due to persistent vitamin D deficiency and an increasing risk of overweight.
Keywords: Celiac disease, Gluten-free diet, Micronutrient status, Growth parameters
Introduction
Celiac disease (CD) is a lifelong, immune-mediated enteropathy triggered by gluten ingestion in genetically susceptible individuals, leading to villous atrophy and impaired nutrient absorption [1]. At the point of diagnosis, children frequently exhibit deficiencies in micronutrients, particularly iron, vitamin D, calcium, and folate. This observation underscores both the intrinsic malabsorption and the common delay in clinical symptom recognition [1, 2]. Despite strict adherence to a gluten-free diet (GFD), prior studies show that nutritional deficiencies might persist, potentially due to an increased reliance on processed gluten-free products with suboptimal nutritional profiles [2, 3].
The influence of a GFD on growth and body mass index (BMI) is still a subject of ongoing debate. A phase of “catch-up growth” is typical for the majority of children; however, the full normalization of nutritional indicators is not universal, and cohort-specific investigations reveal heterogeneous findings regarding alterations in BMI and the prevalence of being overweight during follow-up [4, 5]. Furthermore, long-term follow-up studies reported that hematological anomalies, such as deficiencies in iron and folate, may reappear or newly emerge years after initial diagnosis, even in clinically stable patients. This observation emphasizes the crucial necessity of proactive and persistent laboratory monitoring [6].
The latest European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper recommends a comprehensive, multi-faceted follow-up strategy to monitor growth, serology, and micronutrient status [1]. However, comprehensive longitudinal data detailing the initial recovery path within the first year of treatment, and its interplay with baseline serology, histological severity, and comorbidities, remain limited. Therefore, this study aimed to assess alterations in growth and micronutrient status at 6 and 12 months following the commencement of GFD and to determine whether these results are affected by pre-existing tTG-IgA levels, the degree of mucosal damage, or comorbidities.
Materials and methods
Setting and patients
This retrospective observational cohort study reviewed the records of patients aged 0–18 years who were diagnosed with CD between 2010 and 2017 at our Pediatric Gastroenterology Outpatient Clinic. Patients aged 0–18 years who were diagnosed with CD according to ESPGHAN criteria and had available anthropometric and laboratory data at diagnosis and at least one follow-up visit (6 or 12 months) were included in the study. Patients with incomplete clinical records, those lost to follow-up, or those with alternative causes of villous atrophy were excluded from the analysis.
The diagnosis of CD was determined based on the ESPGHAN guidelines during the study period [7]. All patients underwent serological testing for tTG-IgA, using a commercial enzyme-linked immunosorbent assay (ELISA). A positive result was indicated by values above the manufacturer’s recommended. Total serum IgA levels were assessed for the exclusion of IgA deficiency. Following a positive serology test, patients underwent an upper gastrointestinal endoscopy, and at least four biopsy samples were obtained from the duodenum, including the bulb. An experienced pathologist reviewed the histopathological findings and classified them according to the Marsh–Oberhuber system [8]. Patients exhibiting positive tTG-IgA serology and histopathological evidence of villous atrophy were diagnosed with CD.
Following diagnosis, patients and their families were routinely directed to a registered dietitian with expertise in pediatric CD, and they underwent standardized dietary counseling. No standardized dietary adherence questionnaire was used because of the retrospective design. Adherence was assessed from physician and dietitian follow-up notes, dietary interview records, clinical improvement, and serial tTG-IgA status. Therefore, strict adherence rates could not be calculated objectively and this was considered a limitation.
Data collections
Demographic characteristics (gender, age), comorbidities, family history, anthropometric measurements at admission (height, body weight [BW], and body mass index [BMI] with corresponding standard deviation scores [SDS] and percentiles), laboratory parameters (hemoglobin [HGB], iron, total iron-binding capacity [TIBC], vitamin B12, 25-hydroxy [25(OH)] vitamin D, folic acid, calcium, phosphorus, zinc, selenium, and carnitine), serology (tissue transglutaminase antibodies [tTG IgA]), and histopathological findings classified according to the Marsh system were recorded retrospectively.
Hematological parameters were quantified from patient samples with the assistance of the Coulter LH 780 automated hematology analyzer. Standard enzymatic methods in the biochemistry laboratory were used to assess a range of biochemical parameters.
Anemia was defined as HGB levels below − 2 SDS for age and sex; vitamin B12 deficiency as < 200 pg/mL; folic acid insufficiency as < 3 ng/dL; low iron status as ferritin < 12 ng/mL and vitamin D deficiency as serum 25 (OH) vitamin D < 20 ng/mL. The serum levels of calcium, phosphorus, iron, zinc, selenium, and carnitine were determined in relation to the laboratory’s reference values. The tTG IgA level was quantified via enzyme-linked immunosorbent assay (ELISA).
The calculation of BMI SDS was performed utilizing the World Health Organization (WHO) growth standards. For children under the age of five, the WHO Child Growth Standards were employed; for children aged five through nineteen, the WHO Growth Reference served as the applicable guideline. Nutritional status was assessed via BMI SDS, derived from age- and sex-specific reference data. Weight status classifications were established as: underweight (BMI-SDS < − 2), normal weight (BMI-SDS ranging from − 2 to + 1), overweight (BMI-SDS > + 1), and obesity (BMI-SDS > + 2) [9, 10].
Following the initiation of a gluten-free diet (GFD), subsequent evaluations at six and twelve months encompassed measurements of height, BW, BMI, SDS, and percentiles, levels of HGB, iron, TIBC, vitamin B12, 25 (OH) vitamin D, folic acid, calcium, phosphorus, zinc, selenium, carnitine, and tTG IgA were assessed. Micronutrient supplementation, including iron, vitamin D, vitamin B12, folic acid, and calcium, was prescribed when clinically indicated according to baseline deficiency status and physician assessment. However, detailed dose, duration, and adherence data were not consistently available in the medical records. The study diagram is illustrated in Fig. 1.
Fig. 1.
Flow diagram of patient selection and follow-up in the study. Patients aged 0–18 years diagnosed with celiac disease between 2010 and 2017 at the Pediatric Gastroenterology Outpatient Clinic were initially screened (n = 114). Eleven patients were excluded due to incomplete laboratory or follow-up data. The final study cohort consisted of 103 patients who had anthropometric and laboratory data available at diagnosis and during follow-up. All patients included initiated a GFD after diagnosis. Clinical, anthropometric, and laboratory evaluations were performed at three time points: at diagnosis (baseline), at 6 months, and at 12 months after GFD initiation. At follow-up visits, measurements included height, body weight, BMI SDS, hematological parameters, micronutrient levels, and tTG-IgA serology
Patients were categorized based on tTG-IgA -positive and tTG-IgA -negative groups at the 6th and 12th months to allow for a comparative analysis of their hematological and biochemical parameters. Additionally, to address the influence of associated autoimmune conditions, patients were subsequently divided into those with isolated CD and those with CD plus concomitant type 1 diabetes mellitus (T1DM), the most frequent autoimmune comorbidity in this population.
Statistical analysis
Statistical analyses were conducted using IBM SPSS Statistics, version 27. Assessment of distribution normality was performed via the Kolmogorov–Smirnov or Shapiro–Wilk test. The data were presented using mean ± standard deviation (SD) for normally distributed variables, while the median and interquartile range (IQR, 25th–75th percentile) were used for non-normally distributed variables. Categorical variables were described by frequencies (percentages) for categorical variables. Changes in growth parameters (weight, height, and BMI SDS) and laboratory variables at diagnosis, 6, and 12 months were analyzed using repeated measures ANOVA or the Friedman test, as appropriate. Following the observation of overall significance, the Bonferroni correction was applied to pairwise comparisons. Independent samples t-tests or Mann–Whitney U tests were employed for between-group comparisons (CD-only vs. CD+T1DM, and anti-tTG–positive vs. anti-tTG–negative). Analysis of categorical variables was conducted via the chi-square or Fisher’s exact test. Spearman’s rank correlation coefficient was employed to evaluate the relationship between the Marsh classification and laboratory parameters. Statistical significance was established at a two-tailed p-value below 0.05.
Ethic statement
This study adhered to the Declaration of Helsinki, with approval from the local institutional ethics committee (Approval No: 2018/0320, Date 15 August 2018). Due to the retrospective design, the requirement for informed consent was waived by the Istanbul Medeniyet University Clinical Research Ethics Committee, which approved the study protocol (Approval No: 2018/0320; Date: 15 August 2018).
Results
Of the 114 initially identified patients, 11 were excluded due to incomplete follow-up data, including missing anthropometric measurements or laboratory parameters at the 6- or 12-month evaluation. The median age at diagnosis was 7 years (IQR: 4–11), with no significant difference between females (8 years) and males (6 years) (p = 0.607). Demographic, clinical, growth, and baseline laboratory characteristics of the study population are summarized in Table 1.
Table 1.
Demographic, clinical, growth, and baseline laboratory characteristics of the study population (n = 103)
| Variable | Value | Variable | Value |
|---|---|---|---|
| Age at diagnosis, years Median (IQR) | 7 (4–11) | Height percentile at diagnosis | |
| Sex | < 3 percentile | 21 (20.4%) | |
| Female | 66 (64.1%) | 3–10 percentile | 32 (31.1%) |
| Male | 37 (35.9%) | 11–25 percentile | 13 (12.6%) |
| Marsh classification | 26–50 percentile | 18 (17.5%) | |
| Marsh 3 A | 18 (17.5%) | 51–75 percentile | 11 (10.7%) |
| Marsh 3B | 37 (35.9%) | 76–90 percentile | 6 (5.8%) |
| Marsh 3 C | 44 (42.7%) | > 90 percentile | 2 (1.9%) |
| Marsh 4 | 4 (3.9%) | Body weight percentile at diagnosis | |
| Comorbidities | < 3 percentile | 13 (12.6%) | |
| Only celiac disease | 58 (56.3%) | 3–10 percentile | 31 (30.1%) |
| Type 1 diabetes mellitus | 15 (14.6%) | 11–25 percentile | 21 (20.4%) |
| Hypothyroidism | 12 (11.7%) | 26–50 percentile | 17 (16.5%) |
| Down syndrome | 5 (4.9%) | 51–75 percentile | 11 (10.7%) |
| Anthropometric measurements at diagnosis | 76–90 percentile | 6 (5.8%) | |
| Weight SDS Median (IQR) | -1.13 (-1.76 – -0.20) | ||
| Height SDS Median (IQR) | -1.34 (-1.93 – -0.20) | ||
| BMI SDS Median (IQR) | -0.38 (-1.13–0.42) | ||
Abbreviations: BMI Body Mass Index, IQR Interquartile Range, SDS Standard Deviation Score
The final analysis incorporated 103 patients, with eleven individuals excluded due to incomplete data. Of the individuals, 64.1% (n = 66) were female. The study cohort revealed that 56.3% (n = 58) had no comorbidities other than CD. Of the remaining, 14.6% had T1DM, while hypothyroidism (n = 12, 11.7%) and Down syndrome (n = 5, 4.9%).
Growth parameters and body percentiles
At the time of diagnosis, 20.4% and 12.6% of patients had a height and weight below the 3rd percentile, respectively. At diagnosis, nutritional impairment was mainly reflected by low height and weight percentiles rather than BMI-SDS alone. During follow-up, the proportion of children below the 3rd percentile for height and weight decreased, indicating partial nutritional recovery after initiation of the GFD. The proportions experienced a significant decline by the end of the 12-month follow-up, underscoring substantial catch-up growth. In parallel, the number of individuals within the 51st–75th weight percentile range increased, indicating enhanced nutritional status. The Spearman correlation analysis demonstrated a strong positive correlation between height and weight percentiles at all points, with coefficients ranging from 0.773 to 0.914 (p < 0.001).
From diagnosis to the 12-month follow-up, the entire cohort had a significant improvement in their weight, height, and BMI SDS scores. Males demonstrated greater improvement in these metrics within gender-based analyses. Nevertheless, no statistically significant differences between males and females were observed for weight, height, or BMI at any observation interval (p > 0.05 for all comparisons) (Table 2).
Table 2.
Changes in weight, height, and BMI SDS scores at diagnosis, 6th month, and 12th month by gender
| Diagnosis | 6th month | 12th month | P* | P** | ||
|---|---|---|---|---|---|---|
|
Weight (SDS) Median IQR |
Overall | -1.13 (-1.76 - -0.2) | -0.59 (-1.48–0.42) | -0.38 (-1.13–0.6) | < 0.001 | |
| Female | -1.14 (-1.84 - -0.38) | -1.00 (-1.55 - -0.06) | -0.60 (-1.25–0.45) | < 0.001 | 0.057 | |
| Male | -1.03 (-1.53–0.06) | -0.35 (-1.04–0.71) | 0.07 (-0.62–0.8) | < 0.001 | ||
|
Height (SDS) Median IQR |
Overall | -1.34 (-1.93 - -0.2) | -1.10 (-1.78 - -0.03) | -0.95 (-1.51–0) | < 0.001 | |
| Female | -1.36 (-2.11 - -0.06) | -1.15 (-1.83–0.06), | -1.02 (-1.57–0.01) | < 0.001 | 0.281 | |
| Male | -1.29 (-1.92 - -0.45) | -0.94 (-1.67 - -0.26) | -0.77 (-1.35 - -0.12) | < 0.001 | ||
|
BMI (SDS) Median IQR |
Overall | -0.38 (-1.13–0.42) | -0.25 (-0.96–0.53) | 0.15 (-0.78–0.91) | < 0.001 | |
| Female | -0.43 (-1.13–0.35) | -0.37 (-0.98–0.38) | -0.06 (-0.90–0.72) | < 0.001 | 0.241 | |
| Male | -0.24 (-1.01–0.45) | 0.42 (-0.71–0.93) | 0.32 (-0.60–1.05) | < 0.001 | ||
| Anemia n (%) | 61 (58.9%) | 18 (17.8%) | 7 (6.9%) | < 0.001 | NA | |
| Vitamin D deficiency n (%) | 83 (81.0%) | 47 (46.0%) | 28 (27.0%) | < 0.001 | NA | |
| Anti-tTG negativity n (%) | — | 57 (55.0%) | 75 (73.0%) | < 0.001 | NA | |
Abbreviatoins: SDS Standard Deviation Score, IQR Interquartile range, BMI Body Mass Index
Bold values indicate statistically significant differences (p < 0.05)
*Repeated measures ANOVA was used to compare changes over time
** Group comparisons: Student’s t-test (for normally distributed variables) / Mann-Whitney U test (for non-normally distributed variables)
At the time of diagnosis, a total of eight individuals (7.8%) were categorized as overweight (BMI SDS + 1 to + 2), and 3 patients (2.9%) were obese (BMI SDS > + 2). Following six months of a GFD, the proportion of overweight patients increased to 14.6% (n = 15), while the number of patients with obesity remained unchanged at 3 (2.9%). By 12 months, 19 patients (18.4%) were overweight, and 5 patients (4.9%) were obese. Overweight/obesity was observed in 25.0% (3/12) of patients with hypothyroidism and 22.0% (20/91) of those without hypothyroidism, with no statistically significant association between hypothyroidism and overweight/obesity (p = 0.728) (data not shown). Specifically, obesity was observed in two individuals during the follow-up.
Hematological and biochemical parameters
The hematological and biochemical parameters were significantly improved during the 12-month follow-up. The prevalence of participants presenting with HGB levels below the established age- and sex-adjusted normal range decreased from 58.9% at diagnosis to 17.8% at six months and 6.9% at twelve months.
At diagnosis, 81% of patients had a vitamin D deficiency, and this proportion significantly decreased to 46% at 6 months and 27% at 12 months following initiation of the GFD. Moreover, the levels of serum iron, vitamin B12, folic acid, calcium, and phosphorus also increased significantly, while the TIBC decreased, reflecting improvement in iron status and overall nutritional recovery (all p < 0.001). Overall, the majority of children demonstrated nutritional recovery during follow-up, as reflected by improvements in anthropometric indices, normalization of hematological parameters, and a marked reduction in micronutrient deficiencies. Detailed laboratory values are summarized in Table 3.
Table 3.
Changes in hematological and biochemical parameters from diagnosis to the 12th month
| Diagnosis | 6th month | 12th month | p | |
|---|---|---|---|---|
| Hemoglobin (Hb)Mean ± SD | 11.2 ± 1.7 | 12.4 ± 1.3 | 12.9 ± 1.1 | < 0.001 |
| Serum Iron Median (IQR) | 31 (17–51) | 65 (41.5–76) | 81 (68–102) | < 0.001 |
| Total Iron-Binding Capacity (TIBC) Mean ± SD | 386.1 ± 56.5 | 370.8 ± 49.4 | 356.9 ± 48.0 | < 0.001 |
| Serum Ferritin Median (IQR) | 8.1 (4.5–14.8) | 15 (11.4–23.3) | 21.6 (15–30) | < 0.001 |
| Vitamin B12 Median (IQR) | 261 (218.5–330) | 327 (260–401) | 370 (314.5–468.5) | < 0.001 |
| 25-Hydroxyvitamin D (25-OH Vit. D) Median (IQR) | 13.8 (10–19.3) | 21.1 (16.3–25.9) | 24.5 (19.5–29.2) | < 0.001 |
| Serum Calcium Median (IQR) | 9.1 (8.5–9.7) | 9.8 (9.5–10.1) | 10.0 (9.8–10.1) | < 0.001 |
| Serum Phosphorus Median (IQR) | 4.5 (4.1–4.9) | 5.0 (4.5–5.5) | 5.2 (4.8–5.5) | < 0.001 |
| Serum Folic Acid Median (IQR) | 5.1 (4.0–8.2) | 8.3 (6.05–12) | 12.05 (8.67–15) | < 0.001 |
Bold values indicate statistically significant differences (p < 0.05)
*Repeated measures ANOVA was used to compare changes over time
Comparison between CD-Only and CD+T1DM groups
The median age at diagnosis was significantly higher in the CD+T1DM group than in the CD-only group (9.0 years [IQR: 5.5–12.0] vs. 6.0 years [IQR: 3.3–10.0], p = 0.038). A notable enhancement in growth parameters was observed in patients with CD+T1DM than in those with CD alone. The comorbid group exhibited significantly elevated SDS values at diagnosis, and this difference persisted at 6 and 12 months. The age at CD diagnosis was also compared between the CD-only and CD+T1DM groups to explore whether earlier diagnosis might explain the more favorable growth profile in the comorbid group. In parallel, the CD+T1DM group consistently displayed significantly higher height SDS values at every measured time point. Despite a higher BMI SDS at diagnosis within this cohort, the differences during follow-up did not reach statistical significance (Table 4).
Table 4.
Comparison of growth and hematological/biochemical parameters between only celiac and celiac + diabetes mellitus groups at diagnosis, 6th month, and 12th month
| Parameter | Time Point | Only Celiac Mean ± SD/ Median (IQR) |
Celiac + T1DM Mean ± SD/ Median (IQR) |
p-value |
|---|---|---|---|---|
| Age (years) | Diagnosis | 6.0 (3.3–10.0) | 9.0 (5.5–12.0) | 0.038 |
| Body Weight SDS | Diagnosis | -1.27 ± 1.04 | 0.00 ± 0.75 | < 0.001 |
| 6th Month | -1.04 (-1.64 - -0.27) | 0.18 (-0.27–0.66) | 0.001 | |
| 12th Month | -0.57 (-1.27–0.37) | 0.27 (-0.07–0.55) | 0.034 | |
| Height SDS | Diagnosis | -1.34 ± 1.26 | -0.28 ± 0.96 | 0.001 |
| 6th Month | -1.05 ± 1.19 | -0.15 ± 0.96 | 0.003 | |
| 12th Month | -0.84 ± 1.19 | -0.13 ± 0.94 | 0.009 | |
| BMI SDS | Diagnosis | -0.84 (-1.35 - -0.28) | 0.25 (-0.26–0.45) | 0.001 |
| 6th Month | -0.54 (-0.97–0.24) | 0.16 (-0.32–0.54) | 0.054 | |
| 12th Month | 0.07 (-0.78–0.91) | 0.16 (-0.36–0.55) | 0.349 | |
| Hemoglobin (Hb) (g/dL) | Diagnosis | 10.9 ± 1.6 | 12.4 ± 1.5 | 0.002 |
| 6th Month | 12.2 ± 1.2 | 13.1 ± 1.2 | 0.005 | |
| 12th Month | 12.7 ± 1.0 | 13.5 ± 1.0 | 0.002 | |
| Serum Iron (µg/dL) | Diagnosis | 20 (16.3–33) | 47.0 (34.0–56.3) | 0.013 |
| 6th Month | 55 (41.3–76.5) | 68 (45–73) | 0.500 | |
| 12th Month | 75 (68–97) | 97.5 (80–113) | 0.174 | |
| Total Iron-Binding Capacity (TIBC) (µg/dL) | Diagnosis | 381 (342.5–423.75) | 367.5 (332.5–414) | 0.292 |
| 6th Month | 373.2 ± 47.9 | 359.9 ± 50.5 | 0.322 | |
| 12th Month | 359.3 ± 47.3 | 347.6 ± 41.4 | 0.322 | |
| Ferritin (ng/mL) | Diagnosis | 6.3 (3.9–12.2) | 9.0 (7.5–19.1) | 0.029 |
| 6th Month | 15.0 (10.3–22.8) | 18.0 (13.5–32.5) | 0.115 | |
| 12th Month | 20.5 (15.0–27.1) | 30.0 (18.6–43.8) | 0.072 | |
| Vitamin B12 (pg/mL) | Diagnosis | 267 (218–328) | 293 (232.5–341.3) | 0.264 |
| 6th Month | 315 (251–386) | 344 (297.5–413.5) | 0.097 | |
| 12th Month | 370 (310–450) | 384 (328–498) | 0.279 | |
| 25-OH Vitamin D (ng/mL) | Diagnosis | 13.9 (10.0–20.0) | 13.1 (9.4–15.9) | 0.281 |
| 6th Month | 21.6 (16.3–26.9) | 23.5 (16.1–30.9) | 0.647 | |
| 12th Month | 23.1 (20.2–29.1) | 20.3 (14.5–28.1) | 0.185 | |
| Calcium (mg/dL) | Diagnosis | 9.2 (8.5–9.7) | 9.0 (8.6–9.8) | 0.907 |
| 6th Month | 9.8 (9.5–10.1) | 9.7 (9.5–9.9) | 0.480 | |
| 12th Month | 10.0 (9.7–10.3) | 9.9 (9.7–10.1) | 0.361 | |
| Phosphorus (mg/dL) | Diagnosis | 4.6 (4.1–5.1) | 4.3 (3.9–4.7) | 0.147 |
| 6th Month | 5.0 (4.5–5.5) | 5.0 (4.6–5.2) | 0.376 | |
| 12th Month | 5.1 (4.8–5.4) | 5.2 (4.7–5.7) | 0.103 | |
| Folic Acid (ng/mL) | Diagnosis | 5.0 (3.9–6.7) | 8.2 (4.8–10.3) | 0.027 |
| 6th Month | 7.7 (5.8–11.0) | 10.0 (8.0–12.0) | 0.135 | |
| 12th Month | 10.4 (8.3–15.0) | 12.8 (12.1–13.6) | 0.544 |
Group comparisons: Student’s t-test / Wilcoxon test
Abbreviations: SDS Standard Deviation Score, IQR Interquartile range, BMI Body Mass Index
Bold values indicate statistically significant differences (p < 0.05)
HGB measurements demonstrated a consistent elevation in the CD+T1DM group when compared to other hematological markers at each assessment point. Serum iron and ferritin levels were significantly higher at diagnosis in the comorbid group (p = 0.013 and p = 0.029, respectively), but these differences were no longer significant during follow-up. There were no statistically significant differences in the levels of calcium, phosphorus, vitamin B12, folic acid, or 25-OH vitamin D when comparing the groups (Table 4).
Comparison to tTG-IgA positivity
Seronegativity was observed in 55% (n = 57) of the participants at 6 months, increasing to 73% (n = 75) by 12 months. No significant differences in growth parameters were observed between patients with positive and negative anti-tTG status at each assessment point (all p > 0.05). Despite higher BMI SDS values in the anti-tTG-negative group at both 6 and 12 months, these differences were not statistically significant (Table 5).
Table 5.
Comparison of clinical, anthropometric, and laboratory parameters according to Anti-tTG status at 12 months
| Variable | Anti-tTG Positive (n = 28) | Anti-tTG Negative (n = 75) | p value |
|---|---|---|---|
| Age at diagnosis (years) | 7 (4–11) | 7 (4–11) | > 0.05 |
| Female sex, n (%) | 18 (64.3%) | 48 (64.0%) | > 0.05 |
| Body Weight SDS, mean ± SD | -0.44 ± 0.88 | -0.33 ± 0.92 | > 0.05 |
| Height SDS, mean ± SD | -0.98 ± 1.10 | -0.93 ± 1.07 | > 0.05 |
| BMI SDS, median (IQR) | 0.07 (-0.88–0.74) | 0.21 (-0.71–0.96) | > 0.05 |
| Hemoglobin (g/dL), mean ± SD | 12.4 ± 1.1 | 12.7 ± 1.0 | > 0.05 |
| Serum iron (µg/dL), median (IQR) | 74.5 (56.5–91.5) | 87 (69–110.5) | 0.004 |
| Total Iron-Binding Capacity (µg/dL), mean ± SD | 352.1 ± 45.8 | 358.6 ± 47.3 | > 0.05 |
| Ferritin (ng/mL), median (IQR) | 23 (12–41) | 27 (14–46) | > 0.05 |
| Vitamin B12 (pg/mL), median (IQR) | 331 (256–410) | 347 (270–432) | > 0.05 |
| Folate (ng/mL), median (IQR) | 9.1 (6.8–12.4) | 9.7 (7.2–13.1) | > 0.05 |
| 25-OH Vitamin D (ng/mL), median (IQR) | 22 (15–29) | 24 (17–32) | > 0.05 |
| Calcium (mg/dL), median (IQR) | 9.4 (9.1–9.7) | 9.5 (9.2–9.8) | > 0.05 |
| Phosphorus (mg/dL), median (IQR) | 4.5 (4.1–5.0) | 4.6 (4.2–5.1) | > 0.05 |
| Zinc (µg/dL), median (IQR) | 86 (73–95) | 90 (78–99) | > 0.05 |
| Overweight, n (%) | 4 (14.3%) | 15 (20.0%) | > 0.05 |
| Obesity, n (%) | 1 (3.6%) | 4 (5.3%) | > 0.05 |
Abbreviations: SDS Standard Deviation Score,IQR Interquartile range, BMI Body Mass Index
Bold values indicate statistically significant differences (p < 0.05)
Most of the hematological and biochemical parameters did not demonstrate statistically significant differences according to anti-tTG status at both the 6th and 12th months. Nevertheless, serum iron concentrations at 12 months showed a statistically significant elevation in the anti-tTG-negative group (median 87 µg/dL; IQR 69–110.5) compared with the anti-tTG-positive group (median 74.5 µg/dL; IQR 56.5–91.5) (p = 0.004).
Correlation between marsh classification and growth and micronutrient parameters
There were no significant differences in growth parameters such as weight, height, and BMI observed between the Marsh classification groups (data not shown). The Spearman correlation analysis showed no statistical relationships between Marsh classification and the measured levels of HGB, iron, TIBC, ferritin, 25 (OH) vitamin D, calcium, or phosphorus (all p > 0.05). However, significant negative correlations were observed between Marsh classification and vitamin B12 levels at diagnosis (r = − 0.253, p = 0.010) and at 6 months (r = − 0.202, p = 0.043). A significant negative correlation was also found between Marsh classification and folic acid levels at diagnosis (r = − 0.221, p = 0.028), whereas correlations at later follow-up points were not significant (Table 6). Time-based correlation matrix between marsh classification and biochemical ındices is presented in Fig. 2.
Table 6.
Correlation between marsh classification and hematological/biochemical parameters over time
| Marsh Classification | ||||||
|---|---|---|---|---|---|---|
| Diagnosis | 6th Month | 12th Month | ||||
| Hemoglobin | r | 0.001 | r | 0.102 | r | 0.168 |
| p | 0.989 | p | 0.307 | p | 0.095 | |
| Iron | r | 0.057 | r | 0.066 | r | -0.075 |
| p | 0.576 | p | 0.524 | p | 0.486 | |
| Total Iron-Binding Capacity (TIBC) | r | -0.088 | r | -0.038 | r | -0.090 |
| p | 0.396 | p | 0.714 | p | 0.407 | |
| Ferritin | r | 0.000 | r | -0.027 | r | 0.091 |
| p | 0.998 | p | 0.784 | p | 0.374 | |
| Vitamin B12 | r | − 0.253 | r | − 0.202 | r | -0.136 |
| p | 0.010 | p | 0.043 | p | 0.178 | |
| 25-OH Vitamin D | r | -0.013 | r | -0.156 | r | -0.151 |
| p | 0.894 | p | 0.118 | p | 0.139 | |
| Calcium | r | 0.023 | r | 0.127 | r | 0.028 |
| p | 0.821 | p | 0.203 | p | 0.786 | |
| Phosphorus | r | -0.001 | r | -0.042 | r | -0.132 |
| p | 0.991 | p | 0.672 | p | 0.203 | |
| Folic Acid | r | − 0.221 | r | 0.092 | r | -0.035 |
| p | 0.028 | p | 0.363 | p | 0.740 | |
Bold values indicate statistically significant differences (p< 0.05)
Fig. 2.
Time-based correlation matrix between marsh classification and biochemical indices. Abbreviations Hb: Hemoglobin, TIBC: Total Iron Binding Capacity
Discussion
Previous research has investigated the micronutrient deficiencies detected at the point of CD diagnosis, yet limited attention has been given to the evolution of vitamin and mineral levels following initiation of a GFD [2, 3, 11]. The current study assessed micronutrient levels in children diagnosed with CD both at the time of diagnosis and at six and twelve months following the commencement of a GFD. Concurrently, we examined alterations in growth indicators and clinical factors associated with recovery. Similarly, Perez-Junkera et al. [12] reported that ongoing nutritional counselling during the first year after diagnosis improved dietary habits and emphasized the importance of continuous nutritional supervision beyond gluten avoidance alone. These findings support our results highlighting the need for regular nutritional monitoring during follow-up.
The most recent studies into BMI and developmental metrics among pediatric individuals diagnosed with CD reported heterogeneous findings [13–15]. The initiation of a GFD within our cohort correlated with evident improvements in anthropometric indicators. Significant elevations were observed in median weight and BMI SDS throughout the 12-month follow-up, while height SDS also showed improvement, but it did not fully normalize within this timeframe. This observation aligns with prior research suggesting that sustained restoration of linear growth necessitates extended post-treatment follow-up [13, 16]. Delayed catch-up growth may occur in children diagnosed later or presenting with severe mucosal damage, and the normalization of growth velocity might extend for multiple years following the initiation of treatment [16, 17]. As a result, although a 12-month follow-up suffices for illustrating early nutritional recovery, it might not fully capture the protracted influence of a GFD on longitudinal growth. Children who show inadequate height recovery despite good dietary adherence and serological improvement may require further evaluation for alternative or additional causes of growth failure, including growth hormone deficiency, thyroid dysfunction, poor dietary adherence, and persistent intestinal inflammation.
The prevalence of overweight and obesity also increased during the follow-up. The findings from prior investigations suggest that a GFD, though beneficial for correcting malnutrition in CD patients, could conversely contribute to weight gain in a subset of these individuals [3–5]. Our findings mirrored those of Patwari et al. [16], who reported a normalization of body mass alongside an incomplete recovery of height. Moreover, studies have found that pediatric patients with CD often present with obesity at the time of diagnosis [18]. Recent studies suggest that normal or elevated BMI does not preclude the presence of CD, and a growing number of pediatric cases are presenting with overweight or obesity at diagnosis [19, 20]. Systematic reviews indicate that the increase in BMI observed post-GFD initiation often signifies a recovery from antecedent nutritional deficiencies rather than a true rise in obesity risk, particularly in children [5]. Notwithstanding, the high fat and simple carbohydrate composition found in numerous gluten-free products may be a factor in significant weight gain among certain individuals [3]. These findings highlight the significance of comprehensive dietary guidance and consistent anthropometric assessment for children adhering to a GFD. In our cohort, hypothyroidism was not associated with overweight or obesity during follow-up. Nevertheless, given the known effects of thyroid dysfunction on metabolism and growth, thyroid status should continue to be considered during nutritional surveillance. In the present cohort, the increase in overweight may reflect catch-up weight gain after treatment, improved intestinal absorption, and possible increased consumption of calorie-dense processed gluten-free products. Therefore, follow-up should focus not only on correction of deficiencies but also on diet quality and prevention of excessive weight gain.
The most prevalent extra-gastrointestinal sign of CD is anemia, which is typically associated with compromised iron absorption within the duodenum [21]. Within our cohort, 58.9% of children exhibited anemia at diagnosis, a prevalence aligning with prior pediatric studies that have reported rates ranging from 12% to 69% [22, 23]. The prevalence reported in the present study is notably higher than the 27% to 40% prevalence found in population-based studies of healthy Turkish children [24].
Post-intervention analysis revealed significant positive changes in HGB, ferritin, and related micronutrient metrics after the initiation of a GFD. A dramatic decrease in anemia was observed, with prevalence falling from 58.9% at diagnosis to 6.9% after one year of treatment. The present findings are in agreement with previous research indicating that the restoration of mucosal integrity through a GFD successfully reinstates iron absorption and erythropoiesis in pediatric patients [21, 22]. Nevertheless, a subset of patients has experienced persistent anemia despite prolonged therapeutic interventions. Valvano et al. [25] reported that approximately 4.4% of pediatric patients remained anemic 8–10 years after initiating a GFD. The persistence of anemia, despite histological recovery, may be attributable to understated enterocyte structural alterations that impair nutrient absorption [22, 26].
At the time of diagnosis, a significant number of patients also exhibited a deficiency in vitamin D. Despite a decrease in vitamin D deficiency after initiation of a GFD, a considerable proportion of participants still exhibited deficiency after 12 months. Prior investigations have documented conflicting outcomes regarding enhancements in 25 (OH) vitamin D status following gluten withdrawal [27, 28]. These discrepancies may reflect differences in dietary intake, supplementation practices, seasonal and geographic factors, as well as underlying genetic predispositions affecting vitamin D metabolism [27, 28]. Given the established involvement of 25 (OH) vitamin D in immune system modulation and intestinal barrier function, persistent deficiency emphasizes the significance of systematic monitoring and suitable supplementation for children diagnosed with CD [29].
Diagnostic delay remains an important issue in pediatric CD. Previous studies suggest that the diagnostic delay, from the onset of symptoms to a confirmed diagnosis, may range from several months to over a year, especially when symptoms are atypical or extraintestinal [30–32]. Our study revealed that children concurrently affected by CD+T1DM demonstrated enhanced growth and hematological markers in comparison to those who had CD alone. Although routine screening in children with T1DM could theoretically lead to earlier recognition of CD, this explanation was not supported by our cohort. Although routine screening for CD in children with T1DM has been proposed as a possible explanation for their more favorable growth outcomes, our data did not support earlier diagnosis in this subgroup. In fact, the median age at diagnosis was significantly higher in children with CD+T1DM than in those with CD alone (9.0 vs. 6.0 years, p = 0.038). Therefore, factors other than earlier diagnosis may contribute to the observed differences in growth parameters. However, because symptom duration and diagnostic delay were not consistently available in our retrospective records, this interpretation should be considered hypothesis-generating.
The evaluation of treatment response and dietary adherence during follow-up commonly involves the utilization of serological monitoring. Seronegativity was achieved by 73% of patients in the present study during the first year. Despite this, serological response and growth parameters were not significantly associated. Prior research indicates that overall nutritional recovery and dietary adherence may exert a stronger impact on growth results compared to serological indicators alone [11]. Recent recommendations emphasize that serological markers should not be used as the sole measure of dietary adherence, but should instead be interpreted together with dietary assessment, clinical evaluation, growth monitoring, and nutritional follow-up [33]. In accordance with current ESPGHAN guidelines, routine surveillance of symptomatic indicators and serological markers is recommended during the follow-up period [1, 7]. However, seronegativity does not necessarily indicate complete mucosal healing. In a meta-analysis, Silvester et al. [34] found that tissue transglutaminase and endomysial antibodies sometimes missed persistent villous atrophy in patients following a GFD. At 12 months, the anti-tTG-negative group showed considerably higher serum iron levels, which might be due to iron absorption associated with mucosal recovery in the proximal small intestine [22].
The study also highlighted an inverse association between histological severity and folate and vitamin B12 concentrations. The diminished levels of these vitamins, concurrent with escalating histological damage, indicate their potential sensitivity as markers for mucosal injury, given their absorption in the small intestine [35]. In contrast, systemic storage and metabolic control may influence markers like HGB, ferritin, 25 (OH) vitamin D, zinc, calcium, and phosphorus, offering a reason for their occasional lack of direct correlation with histological severity [1, 21].
Limitations
This study has several limitations. First, its retrospective single-center design may have introduced selection and information bias because all data were obtained from existing medical records. Second, patients with incomplete follow-up data were excluded from the analysis, which may have resulted in selection bias and may limit the generalizability of our findings. Third, although gluten-free diet adherence was assessed using physician and dietitian follow-up notes, dietary interviews, clinical improvement, and serial tTG-IgA measurements, no standardized adherence questionnaire was available and strict adherence could not be objectively quantified. In addition, detailed information regarding the dose, duration, and adherence to micronutrient supplementation was not consistently available. Finally, the 12-month follow-up period may not be sufficient to fully evaluate long-term nutritional recovery, particularly linear growth trajectories, which may require several years to normalize after initiation of a gluten-free diet. Therefore, prospective multicenter studies with longer follow-up periods and standardized dietary assessment tools are needed to better characterize long-term nutritional outcomes in pediatric celiac disease.
Conclusion
In the current study, children with CD experienced significant growth restoration and correction of most micronutrient deficiencies within one year of starting a GFD. Nonetheless, ongoing vitamin D deficiency and increasing rates of being overweight or obese emphasize the necessity of careful nutritional monitoring. Children with concomitant T1DM showed more favorable growth and hematological profiles; however, the underlying mechanisms remain unclear and cannot be attributed solely to earlier diagnosis. Lower vitamin B12 and folate levels may reflect greater histological severity, although this finding should be interpreted cautiously and confirmed in prospective studies. These findings underscore the importance of a holistic approach to CD treatment, which includes both gluten avoidance and complete nutritional care.
Acknowledgements
None.
Authors’ contributions
All authors contributed to the study conception and design. Material preparation and data collection were performed by Seyhan Yılmaz and Sebahat İmamoğlu Çam. Seyhan Yılmaz conducted the statistical analysis and interpreted the data. The first draft of the manuscript was written by Seyhan Yılmaz, and Sebahat İmamoğlu Çam reviewed and commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
No funding was received for this study.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study adhered to the Declaration of Helsinki, with approval from the local institutional ethics committee (Approval No: 2018/0320, Date 15 August 2018). Due to the retrospective design, the requirement for informed consent was waived by the Istanbul Medeniyet University Clinical Research Ethics Committee, which approved the study protocol (Approval No: 2018/0320; Date: 15 August 2018). Before analysis, all patient data underwent anonymization.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.