Abstract
Objective
To evaluate the association between bone mineral density (BMD), glycemic control (HbA1c) and celiac autoimmunity in children with type one diabetes (T1D) and in an appropriate control population.
Study design
BMD was assessed cross-sectionally in 252 children with T1D (123 positive for TG and 129 matched children who were negative for transglutaminase [TG]). Additionally, BMD was assessed in 141 children without diabetes who carried T1D-associated HLD-DR,DQ genotypes (71 positive for TG and 70 negative).
Results
Children with T1D who were positive for TG had significantly worse BMD L1-L4 z-score compared with children with T1D who were negative for TG (−0.45 ± 1.22 vs. 0.09 ± 1.10, p=0.0003). No differences in growth measures, urine N-telopeptides, vitamin D 25OH, ferritin, TSH or HbA1c were found. However, both higher HbA1c (β= −1.25 ± 0.85, p=0.0016) and TG (β= −0.13 ± 0.05, p = 0.0056) were significant and independent predictors of lower BMD in multivariate analyses. No differences in BMD or other variables measured were found between children without diabetes who were positive versus negative for TG.
Conclusions
The results suggest a synergistic effect of hyperglycemia and celiac autoimmunity on low BMD.
Keywords: Celiac Disease, Transglutaminases, Diabetes Mellitus–Type 1, Bone Density, Child
Celiac disease (CD) is an autoimmune disease that results in gluten-triggered injury to the small bowel of genetically susceptible individuals (HLA haplotype DR3-DQ2 or DR4-DQ8), leading to malabsorption and a variety of extraintestinal manifestations.(1) Immunoglobulin A (IgA) anti-tissue transglutaminase (TG) antibody is a highly sensitive and specific serological marker for CD and is the preferred screening test for CD.(2) Large cohort studies suggest that up to 12% of individuals with type 1 diabetes mellitus (T1D) screen positive for TG.(3–5) A recent multinational study showed that children with genetic risk for T1D and CD followed from birth develop celiac disease autoimmunity at significant rates that are dependent on specific genotypes; up to 11% of DR3-DQ2 homozygous individuals are already positive by age 5.(6) More than half of screening-identified children found to have CD do not have symptoms,(7) even among those in high risk groups.(8–11) Even though pediatric guidelines recommend testing for TG antibody in symptomatic patients, (2, 12) screening in asymptomatic individuals is more controversial because the natural history of “asymptomatic” celiac disease is not known. Potential long-term effects of untreated celiac disease include iron deficiency anemia, osteoporosis and increased risk for certain malignancies, which may not be obvious during childhood.(12) For this reason, some groups recommend screening of asymptomatic individuals in high-risk groups, including those with T1D or first degree relatives of an individual with a confirmed diagnosis of CD, starting at 3 years of age provided they have had at least 1 year of an adequate gluten-containing diet.(2) Although there is no specific recommendation on how frequently to rescreen children with T1D, it is generally recognized that a previously negative screen does not preclude a later positive screen and development of confirmed CD.(13–15) The benefit of a gluten-free diet in children with screening-identified CD remains to be determined.
We have previously reported that children with T1D who were TG positive on routine screening (defined as persistently elevated TG antibodies, with or without a positive biopsy) had altered body composition and increased markers of bone turnover, but no significant change in bone mineral density (BMD).(16, 17) In addition, these children with T1D did not show increased adverse outcomes when followed over the subsequent two years on a regular diet.(17) As children with T1D are at risk for poor bone mineralization and poor growth, it is unclear whether the presence of T1D is a confounding factor, making detection of a CD effect on bone measures more difficult. (12, 18–22)
The aim of this observational study was to test whether TG positivity is associated with lower bone mineralization in children with and without T1D and T1D influences bone mineralization among patients who were positive for TG.
Methods
Since 1999, routine TG testing has been performed on patients with T1D who are followed at the Barbara Davis Center.(11) Subjects for this study were recruited from two cohorts: (1) patients followed at the Barbara Davis Center with a diagnosis of T1D and (2) subjects of The Diabetes Autoimmunity Study in the Young (DAISY). DAISY is a prospective study of about 2,500 children at increased risk for T1D who were recruited between 1993 and 2004. DAISY subjects were recruited in two groups. The first group is made up of first-degree relatives of patients with T1D, recruited between birth and 8 years of age (n = 850, 49.8%). The second group was recruited from infants born at St Joseph’s Hospital in Denver, Colorado. This group is representative of the general population of the Denver metropolitan area. These infants were identified as having either moderate or high risk of developing T1D, based on HLA genotype of cord blood sample. Details of the newborn screening, sibling and offspring recruitment, and follow-up of both cohorts have been published previously.(23, 24) Cord blood or the first available blood sample (depending on enrollment group) was sent to Roche Molecular Systems, Inc. for PCR-based HLA class II typing. Subjects who were positive for TG either with T1D (n=123) or without T1D (n=71) were offered enrollment into this observational follow-up study, duodenal biopsy, and consultation with a dietician regarding gluten free diet (GFD). Of the 123 subjects with T1D who were positive for TG, 71 underwent duodenal biopsy; 57 of them were positive, 13 negative and 1 indeterminate. Of the 71 subjects without diabetes who were positive for TG, 36 had biopsy; 28 of these were positive and 8 were negative. The subjects who were positive for TG were frequency matched for sex and age with subjects who were negative for TG either with (n=130) or without (n=70) T1D. In those with T1D, the control group was also matched for duration of T1D. The Colorado Multiple Institutional Review Board approved all study protocols, and parents of all participating children gave informed consent. Assent was obtained from children age ≥7 years.
At the study visit, patients completed a questionnaire for self-report of adherence to gluten-free diet as well as presence, frequency and severity of celiac-associated symptoms. The questionnaire inquired about gastrointestinal symptoms including: diarrhea, abdominal pain, constipation, vomiting, gassiness, abdominal distension, and poor weight gain. Other celiac-associated symptoms queried included: irritability, decreased energy, itching or rash, edema, bleeding or bruising, anemia, pubertal delay, short stature, and bone fractures. Additionally, subjects with T1D self-reported the number of hypoglycemic episodes they encountered between visits and episode severity (loss of consciousness, seizure, glucagon administration, emergency room visit, hospitalization).
Anthropometric data including height, weight, and body mass index (BMI) was converted to age- and sex-specific z-scores.(25, 26) BMD of the lumbar spine (L2-L4) was calculated using Hologic Discovery W S/N 86437 bone densitometer with smart scan as previously described.(16) BMD was converted to age- and sex-specific z-scores. DXA results were defined as “low BMD” if z-score was 2 or more standard deviations below the mean for sex and age.(27)
Laboratory Tests
Screening for anti-tissue TG IgA antibody was performed by radioimmunoassay as previously described with a positive result defined as TG ≥0.05.(11) Urinary cross-linked N-telopeptides of type 1 collagen (NTX) were measured in spot urine sample by EIA (Wampoles Osteomark, Princeton, NJ). Thyroid stimulating hormone (TSH), 25-hydroxyvitamin D, and ferritin were measured using standard laboratory methods.
Statistical analyses
Variables were checked for the distributional assumption of normality. BMD L1-L4, ferritin, urine N-telopeptides, creatinine and TG were treated with a natural log transformation and transformed variables were used in analyses. Independent samples t-test were used to test for differences between study cohorts on continuous variables. Chi Square test of independence or Fisher Exact were used to test categorical variables. ANCOVA was used to test if BMD z-score was related to positive TG duration after adjustment for diabetes status and gluten consumption in the last 2 months. Regression analysis was used to test if BMD z-score was related to the natural log of HbA1c and TG levels, both individually and in a combined model. Data are presented as mean ±SD, geometric mean and 95% CI or frequency (%). BMI, height and weight z-scores were calculated by using the CDC macro using height, weight and sex norms. A p-value < 0.05 was considered significant. All analyses were performed using SAS 9.3.
Results
There were 252 children with T1D enrolled in the study, 123 who were positive for TG and 129 who were negative. Of the children who were positive for TG, 48% were males, compared with 41% of subjects who were negative for TG (p=0.093). The mean age of the subjects was not different between groups (13.5 ± 3.7 vs 13.9 ± 2.8, p=0.37). The two groups were similar in height, weight and BMI z-scores (Table I). As expected, TG was higher in cases than in controls (p<0.0001). Children with T1D who were positive for TG had a significantly lower BMD z-score than did children with T1D who were negative for TG (p=0.0003). Of those with T1D, more children who were positive for TG had an low BMD on DXA scan than children who were negative for TG (p=0.0076). Thyroid stimulating hormone (TSH) levels were similar between the two groups. There were no differences between subjects with T1D positive versus negative for TG with respect to vitamin D 25OH, ferritin and urine N-telopeptides. TG positive status did not have a significant effect on HbA1c level at study visit (Table I). There was no significant difference in the report of celiac-related symptoms in the subjects with T1D who were positive versus negative for TG.
Table 1.
Demographic and clinical data at enrollment for children with T1D. Comparison of those with (TG+) and without (TG−) serologic evidence of celiac disease.
| T1D, +TG (n=123) | T1D, −TG (n=129) | p-value | |
|---|---|---|---|
| Sex (males) | 59 (48%) | 76 (59%) | 0.082 |
| Age (y) | 13.5 ± 3.7 | 13.9 ± 2.8 | 0.37 |
| Duration of Diabetes (y) | 7.0 ± 4.4 | 6.0 ± 4.3 | 0.078 |
| Height z-score | 0.14 ± 1.28 | 0.24 ± 0.93 | 0.48 |
| Weight z-score | 0.29 ± 0.98 | 0.43 ± 0.94 | 0.24 |
| BMI z-score | 0.07 ± 2.28 | 0.36 ± 1.04 | 0.20 |
| Vitamin D 25OH (ng/mL) | 34 ± 9 | 33 ± 8 | 0.38 |
| Ferritin (ng/mL) | 37 (32–42) | 40 (36–45) | 0.25 |
| Urine N-Telopeptides (nmol BCE/mmol creat) | 223 (188–265) | 239 (205–278) | 0.55 |
| TSH | 2.1 (1.8–2.4) | 2.0 (1.8–2.4) | 0.78 |
| HbA1c (%) | 8.3 (8.1–8.6) | 8.6 (8.3–8.9) | 0.19 |
| BMD L1-L4 z-score | −0.45 ± 1.22 | 0.09 ± 1.10 | 0.0003 |
| Low BMD¶ | 15 (12%) | 4 (3%) | 0.0076* |
| Symptoms | 57 (46%) | 46 (36%) | 0.085 |
Data are presented as mean ± SD, geometric mean and 95% CI or frequency (%).
Fisher Exact P-value due to cell sizes < 5
Low BMD defined by BMD L1-L4 z-score (for age and gender) of ≤ −2 SD.
Effect of TG positive status on BMD in children without T1D
Of the 141 children without T1D enrolled in the study, 71 were positive for TG and 70 were negative. The two groups were similar in height, weight, and BMI z-score (Table IV; available at ww.jpeds.com). The mean age for each group was 13.7 ± 3.3 for the children who were positive for TG and 14.1 ± 3.1 for the children who were negative for TG (p=0.50). There was no significant difference in sex distribution in subjects who were positive versus negative for TG (p=0.21). As expected, the children who were positive for TG had higher levels of TG autoantibodies than the children who were negative for TG (p<0.0001). There was no difference between individuals who were positive versus negative for TG in levels of vitamin D 25-OH, ferritin, urine n-telopeptides or BMD z-scores (Table IV). Although the differences in individual symptoms did not reach statistical significance (data not shown), the subjects who were positive for TG were more likely to report celiac-associated symptoms than controls (36% vs 20%, p=0.038). The most common symptoms reported in those children who were positive for TG were abdominal pain (13% vs 7%, p=0.25), diarrhea (10% vs 3%, p=0.097), constipation (10% vs 3%, p=0.097), and decreased energy (10% vs 1%, p=0.097).
Table 4.
Demographic and clinical data at enrollment for children without T1D TG+ and TG− serologic evidence of celiac disease.
| No-T1D, TG+ (n=71) | No-T1D, TG− (n=70) | P-value | |
|---|---|---|---|
| Sex (%males) | 27 (38%) | 34 (49%) | 0.21 |
| Age (y) | 13.7 ± 3.3 | 14.1 ± 3.1 | 0.50 |
| Height z-score | 0.41 ± 1.07 | 0.22 ± 1.20 | 0.33 |
| Weight z-score | 0.27 ± 1.05 | 0.17 ± 1.37 | 0.61 |
| BMI z-score | 0.08 ± 1.06 | 0.08 ± 1.14 | 0.98 |
| Vitamin D 25OH (ng/mL) | 34 ± 8 | 33 ± 9 | 0.44 |
| Ferritin (ng/mL) | 34 (29–40) | 35 (30–42) | 0.79 |
| Urine N-Telopeptides | 182 (147–224) | 174 (138–220) | 0.79 |
| (nmol BCE/mmol creat) | |||
| BMD L1-L4 z-score | −0.15 ± 1.08 | −0.04 ± 1.13 | 0.58 |
| Low BMD¶ | 3 (4%) | 2 (3%) | 1.0000* |
| Symptoms | 25 (36%) | 14 (20%) | 0.038 |
Data are presented as mean ± SD, geometric mean and 95% CI or frequency (%).
Fisher Exact P-value due to cell sizes < 5.
Low BMD defined by BMD L1-L4 z-score (for age and gender) of ≤ −2 SD.
Comparison of children with or without T1D who were positive for TG
In the study group as a whole, there were 123 children with T1D who were positive for TG and 71 children without T1D who were positive for TG. Children with and without T1 D who were positive for TG had similar age, height, weight, and BMI z-scores (Table II). Children without T1D who were positive for TG had a similar BMD z-score to those with T1D (p = 0.086). In our study, children without T1D who were positive for TG had significantly lower TG levels than the children with T1D (p=0.026). TG positive duration was longer in the subjects without T1D than in the subjects with T1D (p<0.0001), but it should be noted that those without T1D were tested more frequently over a longer period of time. There was no significant difference in the proportion of subjects who were positive for TG who had eaten gluten over the previous two months between the groups with and without T1D (Table II).
Table 2.
Demographic and clinical data at enrollment for children with and without T1D with positive TG.
| Non-T1D (n=71) | T1D (n=123) | p-value | |
|---|---|---|---|
| Sex (males) | 27 (38%) | 59 (48%) | 0.18 |
| Age (y) | 13.7 ± 3.3 | 13.5 ± 3.7 | 0.70 |
| TG | 0.09 (0.07–0.12) | 0.14 (0.11–0.18) | 0.026 |
| TG+ duration (y) | 8.3 ± 3.4 | 5.5 ± 3.1 | <0.0001 |
| Height z-score | 0.41 ± 1.07 | 0.14 ± 1.28 | 0.13 |
| Weight z-score | 0.27 ± 1.05 | 0.29 ± 0.98 | 0.93 |
| BMI z-score | 0.08 ± 1.06 | 0.07 ± 2.3 | 0.98 |
| Vitamin D 25OH (ng/mL) | 34 ± 8 | 34 ± 9 | 0.83 |
| Ferritin (ng/mL) | 34 (29–40) | 37 (32–42) | 0.47 |
| Urine N-Telopeptides (nmol BCE/mmol creat) | 182 (147–224) | 223 (188–265) | 0.14 |
| BMD L1-L4 z-score | −0.15 ± 1.08 | −0.45 ± 1.22 | 0.086 |
| Low BMD¶ | 3 (4%) | 15 (12%) | 0.075* |
| Eaten gluten in past 2 months? | 48 (68%) | 70 (57%) | 0.14 |
Data are presented as mean ± SD, geometric mean and 95% CI or frequency (%).
Fisher Exact P-value due to cell sizes < 5
Low BMD defined by BMD L1-L4 z-score (for age and gender) of ≤ −2 SD.
Predictors of BMD in Children with T1D
In univariate regression analyses (Table III), higher HbA1c predicted lower BMD z-score (p=0.021). Similarly, higher TG level predicted lower BMD z-score (p=0.015). In a multivariate model, both HbA1c ( p=0.0016) and TG (p = 0.0056) levels independently predicted lower BMD.
Table 3.
Predictors of BMD z-score in patient s with T1D
| β-coefficient | p-value | |
|---|---|---|
| Model 1 | ||
| TG | −0.81 ± 0.33 | 0.015 |
| Model 2 | ||
| HbA1c | −0.89 ± 0.38 | 0.021 |
| Model 3 | ||
| TG | −0.13 ± 0.05 | 0.0056 |
| HbA1c | −1.25 ± 0.85 | 0.0016 |
Adherence to Gluten-Free Diet
At the first visit, subjects were asked questions regarding adherence to a gluten-free diet. Of subjects with T1D who were positive for TG, 56% were on a regular diet, reporting having eaten gluten in the previous 2 months. This was significantly different than the subjects who were negative for TG, all of whom had eaten gluten in the previous month (p<0.0001). Among the subjects without T1D who were positive for TG, the majority (68%) also did not follow a gluten-free diet, with only 32% reporting no gluten-containing foods over the 2 months prior to study. This was significantly different than the subjects who were negative for TG, all of whom had eaten gluten in the previous month (p<0.0001).
Discussion
Both T1D and CD individually have known effects on lowering BMD and altering bone metabolism.(28–30) Previous studies have examined BMD in children with celiac autoimmunity and in T1D; however, none have studied controls without T1D who are not only similar in age, but also in HLA genotypes.(16, 17, 31) In our study, subjects with T1D who were positive for TG had significantly lower lumbar BMD, and a greater number of children had low BMD on DXA scan (BMD L1-L4 z-score ≤ −2) compared with subjects with T1D who were negative for TG. These findings are consistent with our previous study, which showed children with T1D with sustained and substantial (TG>0.50) elevation in TG over 2 year follow up had decreased lumbar BMD.(17) These findings raise the question of whether there is a role for higher TG index as a predictor of bone density in T1D, in contrast to a previous study in children with celiac disease alone which showed in that population the magnitude of TG index did not predict BMD.(32) As both T1D and celiac disease have known effects on bone health, our findings may also represent a synergistic negative effect of suboptimal glycemic control and celiac autoimmunity on bone density in children with T1D.(28–30) This is supported by the different findings relative to BMD between the groups with and without T1D.
Unlike our previous findings in children with T1D, in the groups with and without T1D, there was no difference in weight or BMI when compared with controls who were negative for TG. It should be noted that the subjects with T1D who were positive for TG in this study had a wide variability in BMI z-score. This may reflect the older age of this group relative to our previously studied group.(16, 17) In addition, and our previous work showed changes in markers of turnover but no differences in BMD, in this older cohort, we now see differences in BMD. As puberty plays a major role in BMI changes as well as the accrual of BMD, the inclusion of a substantial portion of subjects of pubertal age may be a contributing factor to these differences.
Our previous findings showed delaying gluten-free diet over two years of follow up in patients with T1D and TG positive status did not result in worsening weight, height and HbA1c.(17) Other studies, however, have suggested that 12 to 48 months of gluten-free diet may improve height, weight, BMI and BMD in those with evidence of severe villous atrophy on intestinal biopsy.(33) Our current findings raise the question of whether TG and HbA1c levels may be used to identify those at risk for detrimental effects on bone density, thereby selecting children who may most benefit from a gluten-free diet and those in whom it may not be necessary.
This study had several limitations. A number of subjects did not undergo duodenal biopsy and of those who did, some biopsy results were negative. For this reason, these results apply to the broader group of children with positive TG antibody status, regardless of histologic signs of inflammation. Another limitation is the effect of gluten free diet on the ability to detect differences between the groups who were positive versus negative for TG. A substantial minority of children with and without T1D wo were positive for TG were avoiding gluten for at least two months prior to enrollment; however, even among those who were avoiding gluten to some degree, there was significant variability in how frequently the individuals were adhering to recommended behaviors for a strict gluten-free diet. This makes the actual gluten exposure difficult to estimate and this was beyond the scope of this study. Another potential limitation of this study was the difference in duration of TG positivity between the subjects with and without T1D. This difference was likely due to ascertainment bias, as the subjects without T1D were recruited as part of the DAISY prospective study and were tested for TG more frequently and over a longer period of time than the subjects with T1D, who were typically first tested upon diagnosis with T1D. When comparing the effect of TG positive status in children with and without T1D, there was no difference in BMD in children with T1D relative to those without T1D, despite a longer duration of TG positivity in the subjects without T1D. Separate analysis showed that length of time with TG positive status was not significantly related to BMD (data not shown). Finally, the BMD z-scores were normalized to chronologic age; however, chronic inflammation could lead to delayed bone age. This could be a confounding factor making BMD appear lower for some individuals.
In conclusion, we found a significantly lower BMD in subjects who were positive for TG compared with subjects who were negative for TG only when there was concurrent T1D. This data supports screening patients with T1D for TG in order to identify those with higher risk of adverse effects, specifically on bone health. The utility of screening of children identified solely by genetic risk remains uncertain. Further longitudinal study is necessary to evaluate the role of GFD on long-term bone health, particularly in the population with T1D.
Acknowledgments
Supported by the National Institutes of Health (R01 DK50979, DK32083, DK32493, 5K12DK094712), Diabetes Endocrinology Research Center (P30 DK57516), and the National Centers for Research Resources, General Clinical Research Centers Program (M01RR00069).
Abbreviations
- BMD
bone mineral density
- CD
celiac disease
- DXA
dual-energy x-ray absorptiometery
- HbA1c
Hemoglobin A1c
- IgA
Immunoglobulin A
- T1D
type 1 diabetes
- TG
transglutaminase
- TSH
Thyroid stimulating hormone
Footnotes
The authors declare no conflicts of interest.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- 1.Green PH, Jabri B. Coeliac disease. Lancet. 2003;362(9381):383–91. doi: 10.1016/S0140-6736(03)14027-5. [DOI] [PubMed] [Google Scholar]
- 2.Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA American College of G. ACG clinical guidelines: diagnosis and management of celiac disease. The American journal of gastroenterology. 2013;108(5):656–76. doi: 10.1038/ajg.2013.79. quiz 77. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Aktay AN, Lee PC, Kumar V, Parton E, Wyatt DT, Werlin SL. The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin. Journal of pediatric gastroenterology and nutrition. 2001;33(4):462–5. doi: 10.1097/00005176-200110000-00008. [DOI] [PubMed] [Google Scholar]
- 4.Rewers M, Liu E, Simmons J, Redondo MJ, Hoffenberg EJ. Celiac disease associated with type 1 diabetes mellitus. Endocrinology and metabolism clinics of North America. 2004;33(1):197–214. xi. doi: 10.1016/j.ecl.2003.12.007. [DOI] [PubMed] [Google Scholar]
- 5.Bhadada SK, Kochhar R, Bhansali A, Dutta U, Kumar PR, Poornachandra KS, et al. Prevalence and clinical profile of celiac disease in type 1 diabetes mellitus in north India. Journal of gastroenterology and hepatology. 2011;26(2):378–81. doi: 10.1111/j.1440-1746.2010.06508.x. [DOI] [PubMed] [Google Scholar]
- 6.Liu E, Lee HS, Aronsson CA, Hagopian WA, Koletzko S, Rewers MJ, et al. Risk of pediatric celiac disease according to HLA haplotype and country. The New England journal of medicine. 2014;371(1):42–9. doi: 10.1056/NEJMoa1313977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kinos S, Kurppa K, Ukkola A, Collin P, Lahdeaho ML, Huhtala H, et al. Burden of illness in screen-detected children with celiac disease and their families. Journal of pediatric gastroenterology and nutrition. 2012;55(4):412–6. doi: 10.1097/MPG.0b013e31825f18ff. [DOI] [PubMed] [Google Scholar]
- 8.Lorini R, Scotta MS, Cortona L, Avanzini MA, Vitali L, De Giacomo C, et al. Celiac disease and type I (insulin-dependent) diabetes mellitus in childhood: follow-up study. Journal of diabetes and its complications. 1996;10(3):154–9. doi: 10.1016/1056-8727(96)00056-6. [DOI] [PubMed] [Google Scholar]
- 9.Calero P, Ribes-Koninckx C, Albiach V, Carles C, Ferrer J. IgA antigliadin antibodies as a screening method for nonovert celiac disease in children with insulin-dependent diabetes mellitus. Journal of pediatric gastroenterology and nutrition. 1996;23(1):29–33. doi: 10.1097/00005176-199607000-00006. [DOI] [PubMed] [Google Scholar]
- 10.Kordonouri O, Dieterich W, Schuppan D, Webert G, Muller C, Sarioglu N, et al. Autoantibodies to tissue transglutaminase are sensitive serological parameters for detecting silent coeliac disease in patients with Type 1 diabetes mellitus. Diabetic medicine : a journal of the British Diabetic Association. 2000;17(6):441–4. doi: 10.1046/j.1464-5491.2000.00291.x. [DOI] [PubMed] [Google Scholar]
- 11.Hoffenberg EJ, Bao F, Eisenbarth GS, Uhlhorn C, Haas JE, Sokol RJ, et al. Transglutaminase antibodies in children with a genetic risk for celiac disease. The Journal of pediatrics. 2000;137(3):356–60. doi: 10.1067/mpd.2000.107582. [DOI] [PubMed] [Google Scholar]
- 12.Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Journal of pediatric gastroenterology and nutrition. 2005;40(1):1–19. doi: 10.1097/00005176-200501000-00001. [DOI] [PubMed] [Google Scholar]
- 13.Maki M, Huupponen T, Holm K, Hallstrom O. Seroconversion of reticulin autoantibodies predicts coeliac disease in insulin dependent diabetes mellitus. Gut. 1995;36(2):239–42. doi: 10.1136/gut.36.2.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Saukkonen T, Savilahti E, Reijonen H, Ilonen J, Tuomilehto-Wolf E, Akerblom HK. Coeliac disease: frequent occurrence after clinical onset of insulin-dependent diabetes mellitus. Childhood Diabetes in Finland Study Group. Diabetic medicine : a journal of the British Diabetic Association. 1996;13(5):464–70. doi: 10.1002/(SICI)1096-9136(199605)13:5<464::AID-DIA101>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
- 15.Barera G, Bonfanti R, Viscardi M, Bazzigaluppi E, Calori G, Meschi F, et al. Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics. 2002;109(5):833–8. doi: 10.1542/peds.109.5.833. [DOI] [PubMed] [Google Scholar]
- 16.Simmons JH, Klingensmith GJ, McFann K, Rewers M, Taylor J, Emery LM, et al. Impact of celiac autoimmunity on children with type 1 diabetes. The Journal of pediatrics. 2007;150(5):461–6. doi: 10.1016/j.jpeds.2006.12.046. [DOI] [PubMed] [Google Scholar]
- 17.Simmons JH, Klingensmith GJ, McFann K, Rewers M, Ide LM, Taki I, et al. Celiac autoimmunity in children with type 1 diabetes: a two-year follow-up. The Journal of pediatrics. 2011;158(2):276–81. e1. doi: 10.1016/j.jpeds.2010.07.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Penfold J, Chase HP, Marshall G, Walravens CF, Walravens PA, Garg SK. Final adult height and its relationship to blood glucose control and microvascular complications in IDDM. Diabetic medicine : a journal of the British Diabetic Association. 1995;12(2):129–33. doi: 10.1111/j.1464-5491.1995.tb00443.x. [DOI] [PubMed] [Google Scholar]
- 19.Gunczler P, Lanes R, Paz-Martinez V, Martins R, Esaa S, Colmenares V, et al. Decreased lumbar spine bone mass and low bone turnover in children and adolescents with insulin dependent diabetes mellitus followed longitudinally. Journal of pediatric endocrinology & metabolism : JPEM. 1998;11(3):413–9. doi: 10.1515/jpem.1998.11.3.413. [DOI] [PubMed] [Google Scholar]
- 20.Heap J, Murray MA, Miller SC, Jalili T, Moyer-Mileur LJ. Alterations in bone characteristics associated with glycemic control in adolescents with type 1 diabetes mellitus. The Journal of pediatrics. 2004;144(1):56–62. doi: 10.1016/j.jpeds.2003.10.066. [DOI] [PubMed] [Google Scholar]
- 21.Liu EY, Wactawski-Wende J, Donahue RP, Dmochowski J, Hovey KM, Quattrin T. Does low bone mineral density start in post-teenage years in women with type 1 diabetes? Diabetes care. 2003;26(8):2365–9. doi: 10.2337/diacare.26.8.2365. [DOI] [PubMed] [Google Scholar]
- 22.Strotmeyer ES, Cauley JA, Orchard TJ, Steenkiste AR, Dorman JS. Middle-aged premenopausal women with type 1 diabetes have lower bone mineral density and calcaneal quantitative ultrasound than nondiabetic women. Diabetes care. 2006;29(2):306–11. doi: 10.2337/diacare.29.02.06.dc05-1353. [DOI] [PubMed] [Google Scholar]
- 23.Rewers M, Bugawan TL, Norris JM, Blair A, Beaty B, Hoffman M, et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY) Diabetologia. 1996;39(7):807–12. doi: 10.1007/s001250050514. [DOI] [PubMed] [Google Scholar]
- 24.Norris JM, Yin X, Lamb MM, Barriga K, Seifert J, Hoffman M, et al. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA : the journal of the American Medical Association. 2007;298(12):1420–8. doi: 10.1001/jama.298.12.1420. [DOI] [PubMed] [Google Scholar]
- 25.Frisancho A. Anthropometric standards for the assessment of growth and nutritional status. Ann Arbor: The University of Michigan Press; 1990. pp. 39–55. [Google Scholar]
- 26.Boot AM, de Ridder MA, Pols HA, Krenning EP, de Muinck Keizer-Schrama SM. Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. The Journal of clinical endocrinology and metabolism. 1997;82(1):57–62. doi: 10.1210/jcem.82.1.3665. [DOI] [PubMed] [Google Scholar]
- 27.Crabtree NJ, Arabi A, Bachrach LK, Fewtrell M, El-Hajj Fuleihan G, Kecskemethy HH, et al. Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD Pediatric Official Positions. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2014;17(2):225–42. doi: 10.1016/j.jocd.2014.01.003. [DOI] [PubMed] [Google Scholar]
- 28.Onder A, Cetinkaya S, Tunc O, Aycan Z. Evaluation of bone mineral density in children with type 1 diabetes mellitus. Journal of pediatric endocrinology & metabolism : JPEM. 2013;26(11–12):1077–81. doi: 10.1515/jpem-2012-0369. [DOI] [PubMed] [Google Scholar]
- 29.Jatla M, Zemel BS, Bierly P, Verma R. Bone mineral content deficits of the spine and whole body in children at time of diagnosis with celiac disease. Journal of pediatric gastroenterology and nutrition. 2009;48(2):175–80. doi: 10.1097/MPG.0b013e318177e621. [DOI] [PubMed] [Google Scholar]
- 30.Szymczak J, Bohdanowicz-Pawlak A, Waszczuk E, Jakubowska J. Low bone mineral density in adult patients with coeliac disease. Endokrynologia Polska. 2012;63(4):270–6. [PubMed] [Google Scholar]
- 31.Joshi AS, Varthakavi PK, Bhagwat NM, Chadha MD, Mittal SS. Coeliac autoimmunity in type I diabetes mellitus. Arab J Gastroenterol. 2014;15(2):53–7. doi: 10.1016/j.ajg.2014.04.004. [DOI] [PubMed] [Google Scholar]
- 32.Trovato CM, Albanese CV, Leoni S, Celletti I, Valitutti F, Cavallini C, et al. Lack of Clinical Predictors for Low Mineral Density in Children With Celiac Disease. Journal of pediatric gastroenterology and nutrition. 2014 doi: 10.1097/MPG.0000000000000541. [DOI] [PubMed] [Google Scholar]
- 33.Artz E, Warren-Ulanch J, Becker D, Greenspan S, Freemark M. Seropositivity to celiac antigens in asymptomatic children with type 1 diabetes mellitus: association with weight, height, and bone mineralization. Pediatric diabetes. 2008;9(4 Pt 1):277–84. doi: 10.1111/j.1399-5448.2008.00386.x. [DOI] [PMC free article] [PubMed] [Google Scholar]