Celiac disease in type 1 diabetes mellitus
© Camarca et al; licensee BioMed Central Ltd. 2012
Received: 14 February 2012
Accepted: 26 March 2012
Published: 26 March 2012
Celiac Disease (CD) occurs in patients with Type 1 Diabetes (T1D) ranging the prevalence of 4.4-11.1% versus 0.5% of the general population. The mechanism of association of these two diseases involves a shared genetic background: HLA genotype DR3-DQ2 and DR4-DQ8 are strongly associated with T1D, DR3-DQ2 with CD. The classical severe presentation of CD rarely occurs in T1D patients, but more often patients have few/mild symptoms of CD or are completely asymptomatic (silent CD). In fact diagnosis of CD is regularly performed by means of the screening in T1D patients. The effects of gluten-free diet (GFD) on the growth and T1D metabolic control in CD/T1D patient are controversial. Regarding of the GFD composition, there is a debate on the higher glycaemic index of gluten-free foods respect to gluten-containing foods; furthermore GFD could be poorer of fibers and richer of fat. The adherence to GFD by children with CD-T1D has been reported generally below 50%, lower respect to the 73% of CD patients, a lower compliance being more frequent among asymptomatic patients. The more severe problems of GFD adherence usually occur during adolescence when in GFD non compliant subjects the lowest quality of life is reported. A psychological and educational support should be provided for these patients.
KeywordsDiabetes Celiac disease Genetic background HLA Dietetic compliance Glycaemic index Gluten free diet Quality of life
Type 1 Diabetes Mellitus (T1D) is frequently associated to other autoimmune conditions. These conditions can severely affect clinical management of the disease, especially in paediatric age.
The most frequent are autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD) and vitiligo. These diseases are associated with organ-specific autoantibodies: AIT with thyroid peroxidase (TPO) and thyroglobulin autoantibodies (TG), CD with endomysial (EMA) and transglutaminase (TTG) autoantibodies, and AD with adrenal autoantibodies. Using these autoantibodies, organ-specific autoimmunity may be often detected before the development of clinical disease, in order to prevent significant morbidity related to unrecognized disease . These diseases are very often clustered in the same individual and a shared genetic background probably explains this association .
The majority of autoimmune endocrine diseases, including T1D, are inherited as complex genetic traits. Multiple genetic and environmental factors interact with each other to confer susceptibility to these disorders. Genetic risk factors associated with T1D, ATD, CD and AD include HLA genes and non-HLA genes.
HLA DR4 and DR3 are strongly associated with T1D and approximately 30-50% of patients are DR3/DR4 heterozygotes. The DR3/DR4 genotype confers the highest diabetes risk with a synergic mode of action, followed by DR4 and DR3 homozygosity, respectively. The HLA-DQ (particularly DQ 2 and DQ8) locus has been found to be the most important determinant of diabetes susceptibility. Approximately 90% of individuals with T1D have either DQ2 or DQ8, compared to 40% of the general population . So, the highest-risk human leukocyte antigen (HLA) genotype for T1D is DR3-DQ2, DR4-DQ8.
DR3-DQ2 shows a strong association with CD; homozygosity for DR3-DQ2 in a population with T1D carries a 33% risk for the presence of TTG autoantibodies .
Non-HLA genes are also involved in the predisposition to T1D and other autoimmune diseases, such as MIC-A, PTPN22, CTLA-4 .
Prevalence of CD in patients with T1D in recent literature (2004-2011)
Cerutti et al. 2004
11.8 ± 4.2
AGA + EMA
Contreas et al. 2004
Sanchez et al. 2005
AGA + EMA
Araujo et al. 2006
Goh et al. 2007
EMA + TG + AGA
Larsson et al. 2008
Karavanaki et al. 2009
12.3 ± 4.6
Djuric et al. 2010
Bhadada et al. 2011
10.81 ± 7.3
Gabriel S et al. 2011
11 ± 4
CD clinical symptoms
The most severe CD-related symptoms are generally related to gastrointestinal malabsorption and include malnutrition, failure to thrive, diarrhea, anorexia, constipation, vomiting, abdominal distension, and pain. These features are more common in children younger than three years of age. Non-gastrointestinal symptoms of CD include short stature, pubertal delay, fatigue, vitamin deficiencies, and iron deficiency anemia and are more commonly observed in older children. The gastrointestinal presentation of CD rarely occurs in T1D patients (< 10%), but many patients with CD and T1D are either asymptomatic (silent CD) or present only mild symptoms [17, 20, 22]. Furthermore, the wide spectrum of CD include also subjects with positive celiac-related antibodies without diagnostic small-bowel mucosal villous atrophy. This condition is defined as potential celiac disease (pot-CD) [23–25]. Data from the majority of childhood diabetes care centers in Italy showed that prevalence of pot-CD patients in this population (higher in females than males) is 12.2%, while the prevalence of pot-CD in the CD control population is 8.4% and only few of them present CD-related symptoms .
Diagnosis of CD is regularly due to screening protocols which are widely recommended and performed. Actually diagnosis is commonly performed by means of TTG IgA (confirmed by EMA) or TTG-IgG if IgA-deficiency is present. Screening has to performed at followed times: 1) at the time of diabetes onset, 2) yearly in the first 4 years of follow up, 3) each 2 years in the successive 6 years of follow up [27, 28]. In the presence of CD-related antibodies positivity it is mandatory to perform bowel biopsy to confirm diagnosis of CD, even if in very recent guide-lines of ESPGHAN Society  it is proposed that in evident CD-cases it is possible to avoid biopsy (4 main criteria).
GFD should be proposed actually only in patients with mucosal atrophy.
In patients with overt CD, identifying and treating CD with gluten free diet (GFD) surely confer benefit in reducing/resolving malabsorption, infertility, osteoporosis, poor nutrition, impaired growth and long-term malignancy risks and mortality rates [30–32]. Similarly, children with T1D and symptomatic CD benefit from GFD  and also metabolic control of diabetes could be ameliorated .
On the contrary, in symptom-free patients weight gain and bone mineral density (BMD) changes have been non-univocally described as benefit [35–37]. The different viewpoints highlight the need of a prolonged follow up in patients affected by T1D and asymptomatic CD to clarify the role of GFD. Some authors argument that GFD in asymptomatic CD-T1D patients should be opportunely proposed but not excessively stressed [38, 39].
Finally, no definite consensus exists among experts about to treat by GFD pot-CD patients, in whom recently it has been suggested that GFD could be a benefit . Concerning to the natural history of patients whit pot-CD, a recent study shows that 30% of these patients develops overt CD in a three years follow-up and underlines the necessity of re-testing . However no data are available about the follow-up of patients with T1D and pot-CD.
Surprisingly, intestinal inflammation has been described also in T1D patients without CD-related antibodies and structurally normal intestinal mucosa . According to this, our group has observed a gluten-related inflammation either in rectal either in small bowel mucosa of children with T1D [43, 44]. It can be speculated that gluten could be an optimal candidate to stimulate an abnormal innate immune reaction in intestinal mucosa due to its pro-inflammatory characteristics. It remains a crucial issue to establish if the extended intestinal inflammation in T1D is gluten-dependent and whether it precedes the occurrence of the disease.
Bone impairment: a hidden threat
In patients with only T1D it is possible to demonstrate impairment of bone metabolism and structure, specially in relationship with duration and/or poor control of diabetes . Furthermore CD also have been underlined as cause of bone impairment. Clinical observation indicates that clustering of three autoimmune diseases (T1D, CD and generally thyroiditis) significantly increases the occurrence of osteopenia (37.5%). It is possible that bone impairment might be considered not only a complication due to endocrine or nutritional mechanisms, but also a consequence of an immunoregulatory imbalance . In fact osteoclasts are now considered as the innate immune cells in the bone, since they are able to produce and respond to cytokines and chemokines. Bone remodelling involves complex interactions between osteoclasts and other cells in bone microenvironment (marrow stromal cells, osteoblasts, macrophages, T-lymphocytes and marrow cells) . Several cytokines, like the cytokine receptor activator of NFkB ligand (RANKL) and the macrophage colony stimulating factor (M-CSF), can promote osteoclast formation and activity. Also osteoprotegerin (OPG), a circulating secretory glycoprotein, could have a role in bone remodelling in children with T1D because it could promote differentiation, fusion, survival, activation and apoptosis of the osteoblasts. Alterations or abnormalities of the RANKL/OPG system have been implicated in different metabolic bone diseases characterized by increased osteoclast differentiation and activation, and by enhanced bone resorption .
In patients affected by both T1D and CD, the risk of developing osteopenia is also influenced by the compliance to GFD. In fact, osteopenia occurs more frequently in patients with diabetes and CD with poor compliance to GFD . Recent observations indeed indicated an imbalance of cytokines relevant to bone metabolism in untreated celiac patients' sera and the direct effect of these sera on in vitro bone cell activity. In particular the RANKL/osteoprotegerin (OPG) ratio was increased in patients not on gluten-free diet .
In conclusion osteopenia seems to be a new occult problem in CD patients, in T1D patients and in patients with two or three immunological diseases, depending also on GFD.
Variations of HbA1c, BMI gain and height velocity after GFD in children with T1D-CD
Westman et al.
Saukkonen et al.
Amin et al.
Saadah et al.
Valletta et al.
GI of some gluten-free foods, compared to glucose and white bread
GI glucose = 100
GI bread = 100
Gluten-free multigrain bread
79 ± 13
Gluten-free white bread
76 ± 5
108 ± 7
Gluten-free fiber enriched bread
73 ± 4
104 ± 5
GI of gluten-free foods evaluated in vivo, compared to white bread (= 100)
Nutritional composition of gluten free and containing gluten foods
Crackers containing gluten
Cereal flakes containing gluten
Gluten-free cereal flakes
Rusks containing gluten
Pasta containing gluten
Portion size, macronutrient and micronutrient composition of test meal.
GF white Unsliced bread
GF fibre Sliced bread
GF white Sliced bread
GF fibre Unsliced bread
Weight of meal and nutrient composition of 50 g available carbohydrate portions of the foods studied as served.
Weight of meal (g)
Total dietary fibers (g)
Compliance/adherence to GFD and quality of life (QOL)
Adherence to the GFD in children with T1D-CD
Acerini et al.
Westman et al.
Valerio et al.
Saadah et al.
Studies on the compliance/adherence to GFD in non diabetic people showed that, in relation to the social life, children usually have a better compliance to GFD than adults . In a follow-up of 10 years in the Netherlands conducted on children from 2 to 4 years who received CD diagnosis by screening, authors described a general improvement of health without deterioration in QOL . In concordance Kolsteren showed that the QOL of celiac children is quite similar to that of other children . Usually the difficulty with the diet occurs when the patient became adolescent, because she/he needs to feel equal to peers, especially when she/he decides to go out to eat and more acutely she/he feels limits imposed by GFD. According to Wagner et al.  celiac adolescents non compliant with GFD reported a lower general QOL, more physical problems, a higher burden of illness, more family troubles, and more problems in leisure time than adolescents who are compliant with GFD. No differences between compliant patients with CD and adolescents without any chronic condition were found in all QOL aspects.
It is also important remark that the balance between GFD adherence and daily life is difficult to achieve for the child/adolescent who is also affected by an other chronic disease such as T1D. The need to coordinate insulin therapy with proper nutrition and a healthy lifestyle, in order to maintain adequate metabolic control, is already a considerable effort for the young T1D-patient and families . Rebellions are frequent especially in adolescents, who are already feeling diabetes as very "invasive" for all the aspects of daily life and who receive a further "restriction" constituted by the GFD. Consequently there it could be the risk, especially if this proposal is not properly, to elicit a response of complete rebellion which will endanger not only the adherence to the GFD [36, 54, 55], but also the entire management of T1D, causing a sharp deterioration of general compliance and increasing the risk of severe acute complications (recurrent ketoacidosis, unawareness hypoglycemia). In addition it is possible to think that this further limit could be a trigger also of eating disorders in adolescent patients, being eating disorders not rare and previously reported in diabetes. Regarding QOL, Sud et al.  in children with T1D-CD showed that the double diagnosis appears to have a minimal impact on QOL, even if patients' parents reported a very important difficulty on management. It is interesting that not significant differences in QOL were observed with regard to age at CD diagnosis and duration, or on the basis of adherence with a GFD. Furthermore parents of T1D-CD children did express greater concern about their child's social functioning.
Prevalence of CD among children with T1D is significantly higher than in non diabetic children. In a large proportion CD is asymptomatic or characterized by modest/atypical symptoms. Periodic screening of CD auto-antibodies is mandatory. CD diagnosis requires the biopsy confirmation and it is necessary to prescribe GFD in the presence of mucosa impairment. Concerning the clinical benefits of GFD in T1D-CD patients, data are contrasting, except in severely symptomatic patients.
Osteopenia seems to be a new occult problem in CD patients, in T1D patients and in patients with two or three immunological diseases, depending also on GFD.
It is unclear whether GFD composition could present any disadvantages regarding of glycemic index, fibers, percentage of fat and micro-nutrients. Data are not univocal on this point.
Communication of the need of GFD in patients with T1D-CD is particularly delicate, especially in adolescents where it is possible to trigger rebellion behaviors. The coexistence of these two diseases in the same patient requires care by clinicians and probably a specific psychological approach.
Autoimmune thyroid disease
Bone mineral density
Human leukocyte antigen
Potential celiac disease
Quality of life
Type 1 diabetes
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