**3.1 Background and epidemiology**

Celiac disease is an immune-mediated disorder, the only one with a well-established causal agent, resulting from a permanent gluten intolerance triggered by the ingestion of the gliadin fraction of wheat gluten and similar alcohol-soluble proteins named prolamines of barley and rye (Di Sabatino & Corazza, 2009). Gluten intolerance exerts a chronic inflammatory lesion characterized by flattened villi of the small bowel mucosa and submucosa, with a diverse clinical heterogeneity ranging from asymptomatic disease to severe malabsorption syndrome in genetically susceptible individuals (Branski et al., 2006).

Once considered a rare childhood disorder, celiac disease is now known to be a very common condition, even if it remains widely unrecognized and underdiagnosed worldwide both in children and in adults. Availability of new very sensitive and specific serological markers (initially anti-gliadin and anti-reticulin antibodies, and thereafter anti-endomysial and anti-transglutaminase antibodies) allowed more efficient screening, independently from classical clinical picture. Thanks to these serological markers, celiac disease has been identified in a high proportion of children adolescents and adults who did not previously received a correct clinical diagnosis. The prevalence of celiac disease was dramatically increased, and defined as 1 case in 99 schoolchildren in Finland (Mäki et al., 2003), and 1 in 106 in Italy (Tommasini et al., 2004).

#### **3.2 Pathogenesis**

Celiac disease develops from the interplay between a well-defined environmental factor and genetic susceptibility, with the participation of other causative cofactors (drugs like interferon-, infectious agents like intestinal rotavirus, modifications in infant-feeding timing) (Di Sabatino & Corazza, 2009).

*The causal agent*, for CD are specific immunogenic peptides present exclusively in the dietary gluten proteins, from wheat and other cereals like rye and barley. Gluten proteins can be divided into 2 fractions, gliadins and glutenins, both characterized by immunogenicity and by toxicity. Among gluten immunostimolatory peptides, some are more active than others. In particular, a 33 aminoacid immuno-dominant peptide identified from an -gliadin fraction has functional properties attributable to many proline and glutamine residues. Proline increases the peptide resistance to gastrointestinal proteolysis, with more strength binding with HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Glutamine residues are a preferred substrate for transglutaminase-mediated deamination, with subsequent increased immunogenicity (Shan et al., 2002).

*Genetic factors* play an important pathogenetic role, as demonstrated by a concordance rate of 85% in monozygotic twins and by familiar aggregation. HLA-DQ genes, in particular DQ2 variant (alleles DQA1\*05/DQB1\*02) and DQ8 variant (alleles DQA1\*03/DQB1\*0302) are strongly associated to CD. Beside the HLA genes (i.e. COELIAC 1, on chromosome p21), other non-HLA genes are recognized to confer additional susceptibility: COELIAC 2, on chromosome 5q31-33, which contains cytokine gene clusters; COELIAC 3, on chromosome 2q33, which codes the negative co-stimulatory molecule CTLA4; COELIAC 4, on chromosome 19p13.1, which contains the myosin IXB gene variant encoding a myosin that alters actin remodeling (Di Sabatino & Corazza, 2009).

As regards *pathophysiology* od CD, it has been demonstrated that gluten peptides, which are resistant to digestion by gastric and pancreatic enzymes, after crossing intestinal epithelium, are deaminated by tissue transglutaminase and then presented by DQ2+ or DQ8+ antigenpresenting cells to gluten-specific CD4+ T cells. These cells once activated drive a Th1 response, characterized by production of pro-inflammatory cytokines, and responsible for the development of celiac lesions, i.e. lamina propria infiltration of inflammatory cells, crypt hyperplasia and villous atrophy (Di Sabatino & Corazza, 2009).

#### **3.3 Clinical presentation and diagnosis**

6 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

chronic hyperglycaemia and acute blood glucose fluctuations have a deleterious effect on the metabolic mechanisms involved in the development of microangiopathy, such as protein glycation and oxidative stress. In particular, glucose variability from peaks to nadir, with upward as in the postprandial periods, and nadirs, as in the interprandial periods activates the oxidative stress (Monnier & Colette, 2008). As regards pediatric diabetes, despite better insulin preparations and strict self-management of the disease few children and adolescents maintain mean glycated hemoglobin A1c (HbA1c) levels within the normal ranges, with serious impact on metabolic control and subjects' caregiver quality of life (Rewers et al,

Celiac disease is an immune-mediated disorder, the only one with a well-established causal agent, resulting from a permanent gluten intolerance triggered by the ingestion of the gliadin fraction of wheat gluten and similar alcohol-soluble proteins named prolamines of barley and rye (Di Sabatino & Corazza, 2009). Gluten intolerance exerts a chronic inflammatory lesion characterized by flattened villi of the small bowel mucosa and submucosa, with a diverse clinical heterogeneity ranging from asymptomatic disease to severe

Once considered a rare childhood disorder, celiac disease is now known to be a very common condition, even if it remains widely unrecognized and underdiagnosed worldwide both in children and in adults. Availability of new very sensitive and specific serological markers (initially anti-gliadin and anti-reticulin antibodies, and thereafter anti-endomysial and anti-transglutaminase antibodies) allowed more efficient screening, independently from classical clinical picture. Thanks to these serological markers, celiac disease has been identified in a high proportion of children adolescents and adults who did not previously received a correct clinical diagnosis. The prevalence of celiac disease was dramatically increased, and defined as 1 case in 99 schoolchildren in Finland (Mäki et al., 2003), and 1 in

Celiac disease develops from the interplay between a well-defined environmental factor and genetic susceptibility, with the participation of other causative cofactors (drugs like interferon-, infectious agents like intestinal rotavirus, modifications in infant-feeding

*The causal agent*, for CD are specific immunogenic peptides present exclusively in the dietary gluten proteins, from wheat and other cereals like rye and barley. Gluten proteins can be divided into 2 fractions, gliadins and glutenins, both characterized by immunogenicity and by toxicity. Among gluten immunostimolatory peptides, some are more active than others. In particular, a 33 aminoacid immuno-dominant peptide identified from an -gliadin fraction has functional properties attributable to many proline and glutamine residues. Proline increases the peptide resistance to gastrointestinal proteolysis, with more strength binding with HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Glutamine residues are a preferred substrate for transglutaminase-mediated deamination, with

malabsorption syndrome in genetically susceptible individuals (Branski et al., 2006).

2009).

**3. Celiac disease** 

**3.1 Background and epidemiology** 

106 in Italy (Tommasini et al., 2004).

timing) (Di Sabatino & Corazza, 2009).

subsequent increased immunogenicity (Shan et al., 2002).

**3.2 Pathogenesis** 

The clinical range of celiac disease has a wide spectrum, from asymptomatic to severe malnutrition, with gastrointestinal and extra-intestinal manifestations. The most common feature of celiac disease includes gastrointestinal symptoms (i.e. abdominal pain, increased frequency of bowel movements), weight loss, bone disease, various degree of anemia and weakness.

Different subtypes of celiac disease have been described. Symptomatic or classic celiac disease means typical gastrointestinal symptoms with severe malabsorption syndrome. The term atypical celiac disease is applied to cases with mild or absent gastrointestinal symptoms (colitis or irritable bowel), and characterized by extra-intestinal manifestations, including iron deficient anemia, osteoporosis, failure to thrive. In both cases villous atrophy in observed during endoscopy or intestinal biopsies (Alaedini & Green, 2005). More recently it has been suggested to define celiac disease as silent, minor or major. Silent celiac disease is referred to asymptomatic subjects, sometimes relatives of patients with known celiac disease, or subjects eventually found to be positive at screening procedures. Minor celiac disease is referred to subjects with transient symptoms (dyspepsia, irritable bowel syndrome without malabsorption), anemia, cryptic hypertransaminasemia, infertility, peripheral and central neurological disorders, osteoporosis, dental enamel defects, failure to thrive, dermatitis herpetiformis. Major celiac disease is referred to patients with major gastrointestinal symptoms (Di Sabatino & Corazza, 2009).

The mechanism underlying the severity of clinical presentation at present remains unknown. Researchers have shown that neither the degree of duodenal villous atrophy nor the extent of visible enteropathy assessed by capsule endoscopy correlates with presentation (Di Sabatino & Corazza, 2009).

The recognition of a pre-celiac disease state is usually retrospective and this condition has been termed latent celiac disease.

*Potential celiac disease* is characterized by positive antibodies but normal mucosa; there is no evidence to support managing these patients with a gluten-free diet. A higher prevalence of potential CD was found in patients with type 1 diabetes, and this observation may be

Autoimmune Disorders Associated to Type 1 Diabetes Mellitus in Children and Adolescents 9

Gluten consumption could be a common causative factor, as confirmed by the possible diagnosis of both diseases at the same time (Frisk et al. 2008). Moreover the duration of gluten exposure seems to increase the risk of other autoimmune diseases (Ventura et al.., 1999). Dietary gluten could act as a modifier rather than a determinant causative factor, facilitating the progression of other dietary antigens to the small bowel lamina propria, where they can activate the immune response against -cells. Based on this hypothesis, the removal of gluten from diet has been proposed in subjects at risk as prevention trial to reduce the progression to type 1 diabetes mellitus (Pastore et al., 2003). A six-month of gluten-free diet in subjects at risk of type 1 diabetes did not influence -cells autoantibody

Recently, in samples from the small bowel mucosa from patients with celiac disease and type 1 diabetes a low expression of tight junction protein 1 (TJP1) mRNA has been observed, indicating an increase in intestinal permeability that might represent a causative factor. Furthermore, the highest expression of Forkhead box P3 (FoxP3) mRNA, a marker of regulatory T cells was observed, suggesting an increased immunoregolatory mechanisms

The mean prevalence of celiac disease in type 1 diabetes is about 8%, with an extremely variable range (from 1% up to 11%) (Kakleas et al., 2010), almost 10-20 fold higher than observed in general pediatric population (Maki et al., 2003). The different prevalence data could be due to different screening procedures and diagnostic tests used. The prevalence of celiac disease in type 1 diabetes increased over recent decade as compared to the past (Salardi et al., 2008), and seems to be related to changes in environmental factors like dietary habits or infectious diseases. Another possible explanation of this high association could be the same genotypes involved in both diseases.. Three celiac disease loci, i.e. RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12 and TAGAP on chromosome 6q25 were associated with type 1 diabetes mellitus. Moreover, the 32-bp insertion-deletion variant on chromosome 3p21, the PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33 and SH2B3 on chromosome 12q24 are shared by both diseases (Smyth et al., 2008). Younger age at diabetes clinical onset, female gender, and coexistence of another autoimmune disease are

In the majority of patients with type 1 diabetes clinical presentation of celiac disease is usually silent, and thanks to screening procedure is diagnosed (Holmes, 2001, Barera et al, 2002). On the other hand, a detailed medical history allows to identify several signs or symptoms attributable to celiac disease. Extra-intestinal manifestations such as failure to thrive, delayed puberty, iron-deficiency anemia, increased levels of liver enzyme tests, bleeding tendency, precocious osteoporosis, and unexplained hypoglycemic episodes are frequently reported. Gastrointestinal symptoms, i.e. diarrhea and abdominal pain, are reported in 28% and 14% of patients, respectively (Bhadada et al., 2011). Symptoms attributable to celiac disease are more common in children than in adolescents or adults

Type 1 diabetes precedes celiac disease diagnosis (Holmes, 2001); in a small proportion (up to 25%) of cases type 1 diabetes develops in already diagnosed celiac patients (Valerio et

In the majority of cases type 1 diabetes precedes celiac disease diagnosis (Holmes, 2001); in a small proportion of cases (up to 25%) type 1 diabetes develops in patients with already

titer, but only improved endogenous insulin secretion (Pastore et al., 2003).

predictive factors for celiac disease development (Cerutti et al, 2004)

(Uibo et al., 2011).

(Larsson et al., 2008).

diagnosed celiac disease (Valerio et al., 2002).

al., 2002).

ascribed to the routine screening preformed in these patients, although the influence of genetic factors cannot be excluded. (Franzese et al., 2011).

*Refractory celiac disease* is relatively rare complication occurring approximately from 2% to 5% of patients. It is classified as persistent or recurrent symptoms of malabsorption and enteropathy. Refractory celiac disease is divided into two key categories, type I and type II.

As regards celiac disease diagnosis, it has been demonstrated that case-finding by serological markers detection followed by histological confirmation on duodenal biopsy is an accurate, cost-effective and valid approach for diagnosis, in particular for high-risk subjects, like those affected by other autoimmune conditions, like type 1 diabetes mellitus.

Celiac disease is associated with circulating antibodies against gliadin and endomysial tissue. Anti-endoMysial antibodies showed higher specificity and sensitivity than antigliadin antibodies, and represent a useful means for screening procedures. Anti-reticulin antibodies screening showed less sensibility and it has been replaced by anti-endomysial antibodies. In 1997 the transglutaminase 2 enzyme was found to be the autoantigen for antiendomysial antibodies. Both anti-endomysial and anti-transglutaminase antibodies belong to the IgA class. The first are detected by immunofluorescence staining antibodies and results are qualitative or semiquantitative, while anti-transglutaminase antibodies are detected by an enzyme linked immunosorbent assay (ELISA) or radioimmunoprecipitation, and the results are quantitative. Testing for IgG anti-transglutaminase and antibodies and, more recently for IgG anti-deaminated gliadin peptides are a useful alternative for patients with IgA deficiency (Di Sabatino & Corazza, 2009).

In subjects with serological markers of celiac disease, a small intestinal biopsy is the "gold standard" for diagnosis. The finding of histological picture of villous atrophy with increased number of intraepithelial lymphocytes makes sure diagnosis of celiac disease, irrespective of serological markers result. The Marsh criteria (Marsh et al., 2005) are commonly used for histological staging.

#### **3.4 Treatment**

The only proven treatment for celiac disease is lifelong gluten-free diet. Foods containing gluten from wheat, rye, barley and their derivatives must be avoided since also small amounts of gluten are harmful. It has been reported that no more than 10 mg of gluten ingested can be tolerated.

Compliance to gluten-free diet is sometimes difficult, particularly during adolescence and for patients with silent celiac disease diagnosed by means of screening procedures. Dietary compliance can be evaluated through anti-endomysial and anti-deaminated gliadin antibodies detection. Complications of celiac disease are frequently observed in patients with delayed diagnosis and with poor compliance and include non-Hodgkin lymphoma, probably due to accumulation in the intestinal epithelium of aberrant and clonal intraepithelial lymphocytes (Al-Toma et al., 2007). Other complications include refractory celiac disease and ulcerative jejunoileitis (Rubio-Tapia et al., 2009).

#### **3.5 Celiac disease and type 1 diabetes mellitus**

That celiac disease prevalence is higher in patients with type 1 diabetes mellitus as compared to general population is universally accepted. After autoimmune thyroiditis, the second most commonly reported autoimmune disease in type 1 diabetes is celiac disease (Van den Driessche, 2009).

ascribed to the routine screening preformed in these patients, although the influence of

*Refractory celiac disease* is relatively rare complication occurring approximately from 2% to 5% of patients. It is classified as persistent or recurrent symptoms of malabsorption and enteropathy. Refractory celiac disease is divided into two key categories, type I and type II. As regards celiac disease diagnosis, it has been demonstrated that case-finding by serological markers detection followed by histological confirmation on duodenal biopsy is an accurate, cost-effective and valid approach for diagnosis, in particular for high-risk subjects, like those affected by other autoimmune conditions, like type 1 diabetes mellitus. Celiac disease is associated with circulating antibodies against gliadin and endomysial tissue. Anti-endoMysial antibodies showed higher specificity and sensitivity than antigliadin antibodies, and represent a useful means for screening procedures. Anti-reticulin antibodies screening showed less sensibility and it has been replaced by anti-endomysial antibodies. In 1997 the transglutaminase 2 enzyme was found to be the autoantigen for antiendomysial antibodies. Both anti-endomysial and anti-transglutaminase antibodies belong to the IgA class. The first are detected by immunofluorescence staining antibodies and results are qualitative or semiquantitative, while anti-transglutaminase antibodies are detected by an enzyme linked immunosorbent assay (ELISA) or radioimmunoprecipitation, and the results are quantitative. Testing for IgG anti-transglutaminase and antibodies and, more recently for IgG anti-deaminated gliadin peptides are a useful alternative for patients

In subjects with serological markers of celiac disease, a small intestinal biopsy is the "gold standard" for diagnosis. The finding of histological picture of villous atrophy with increased number of intraepithelial lymphocytes makes sure diagnosis of celiac disease, irrespective of serological markers result. The Marsh criteria (Marsh et al., 2005) are commonly used for

The only proven treatment for celiac disease is lifelong gluten-free diet. Foods containing gluten from wheat, rye, barley and their derivatives must be avoided since also small amounts of gluten are harmful. It has been reported that no more than 10 mg of gluten

Compliance to gluten-free diet is sometimes difficult, particularly during adolescence and for patients with silent celiac disease diagnosed by means of screening procedures. Dietary compliance can be evaluated through anti-endomysial and anti-deaminated gliadin antibodies detection. Complications of celiac disease are frequently observed in patients with delayed diagnosis and with poor compliance and include non-Hodgkin lymphoma, probably due to accumulation in the intestinal epithelium of aberrant and clonal intraepithelial lymphocytes (Al-Toma et al., 2007). Other complications include refractory

That celiac disease prevalence is higher in patients with type 1 diabetes mellitus as compared to general population is universally accepted. After autoimmune thyroiditis, the second most commonly reported autoimmune disease in type 1 diabetes is celiac disease

celiac disease and ulcerative jejunoileitis (Rubio-Tapia et al., 2009).

**3.5 Celiac disease and type 1 diabetes mellitus** 

genetic factors cannot be excluded. (Franzese et al., 2011).

with IgA deficiency (Di Sabatino & Corazza, 2009).

histological staging.

ingested can be tolerated.

(Van den Driessche, 2009).

**3.4 Treatment** 

Gluten consumption could be a common causative factor, as confirmed by the possible diagnosis of both diseases at the same time (Frisk et al. 2008). Moreover the duration of gluten exposure seems to increase the risk of other autoimmune diseases (Ventura et al.., 1999). Dietary gluten could act as a modifier rather than a determinant causative factor, facilitating the progression of other dietary antigens to the small bowel lamina propria, where they can activate the immune response against -cells. Based on this hypothesis, the removal of gluten from diet has been proposed in subjects at risk as prevention trial to reduce the progression to type 1 diabetes mellitus (Pastore et al., 2003). A six-month of gluten-free diet in subjects at risk of type 1 diabetes did not influence -cells autoantibody titer, but only improved endogenous insulin secretion (Pastore et al., 2003).

Recently, in samples from the small bowel mucosa from patients with celiac disease and type 1 diabetes a low expression of tight junction protein 1 (TJP1) mRNA has been observed, indicating an increase in intestinal permeability that might represent a causative factor. Furthermore, the highest expression of Forkhead box P3 (FoxP3) mRNA, a marker of regulatory T cells was observed, suggesting an increased immunoregolatory mechanisms (Uibo et al., 2011).

The mean prevalence of celiac disease in type 1 diabetes is about 8%, with an extremely variable range (from 1% up to 11%) (Kakleas et al., 2010), almost 10-20 fold higher than observed in general pediatric population (Maki et al., 2003). The different prevalence data could be due to different screening procedures and diagnostic tests used. The prevalence of celiac disease in type 1 diabetes increased over recent decade as compared to the past (Salardi et al., 2008), and seems to be related to changes in environmental factors like dietary habits or infectious diseases. Another possible explanation of this high association could be the same genotypes involved in both diseases.. Three celiac disease loci, i.e. RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12 and TAGAP on chromosome 6q25 were associated with type 1 diabetes mellitus. Moreover, the 32-bp insertion-deletion variant on chromosome 3p21, the PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33 and SH2B3 on chromosome 12q24 are shared by both diseases (Smyth et al., 2008). Younger age at diabetes clinical onset, female gender, and coexistence of another autoimmune disease are predictive factors for celiac disease development (Cerutti et al, 2004)

In the majority of patients with type 1 diabetes clinical presentation of celiac disease is usually silent, and thanks to screening procedure is diagnosed (Holmes, 2001, Barera et al, 2002). On the other hand, a detailed medical history allows to identify several signs or symptoms attributable to celiac disease. Extra-intestinal manifestations such as failure to thrive, delayed puberty, iron-deficiency anemia, increased levels of liver enzyme tests, bleeding tendency, precocious osteoporosis, and unexplained hypoglycemic episodes are frequently reported. Gastrointestinal symptoms, i.e. diarrhea and abdominal pain, are reported in 28% and 14% of patients, respectively (Bhadada et al., 2011). Symptoms attributable to celiac disease are more common in children than in adolescents or adults (Larsson et al., 2008).

Type 1 diabetes precedes celiac disease diagnosis (Holmes, 2001); in a small proportion (up to 25%) of cases type 1 diabetes develops in already diagnosed celiac patients (Valerio et al., 2002).

In the majority of cases type 1 diabetes precedes celiac disease diagnosis (Holmes, 2001); in a small proportion of cases (up to 25%) type 1 diabetes develops in patients with already diagnosed celiac disease (Valerio et al., 2002).

Autoimmune Disorders Associated to Type 1 Diabetes Mellitus in Children and Adolescents 11

through screening procedures. Moreover, gluten-free diet can exert an increased insulin requirement since persistent hyperglycemia can occur. Gluten-free diet exerts in increased weight and height (Goh et al., 2010), as well as serum ferritin and hemoglobin (Hansen et al., 2006). Moreover improvement of bone status in patients with type 1 diabetes and adherence

Autoimmune thyroid diseases include many thyroid gland disorders, with different histological and clinical pictures ranging from the hypothyroidism of chronic lymphocytic

As other autoimmune diseases, **chronic lymphocytic thyroiditis** (also defined Hashimoto's thyroiditis from the physician who firstly described this condition) derives from a combination of genetic susceptibility and some environmental trigger factors (Pearce et al,

Hashimoto's thyroiditis is more frequent in females than in males (3.5 cases/1000 people/year versus 0.8 cases/1000 people/year, respectively), and global prevalence is

Hashimoto thyroiditis is the most common cause of acquired hypothyroidism in children and adolescents (formerly called "adolescent" or "simple" goiter), and usually presents itself during early adolescence or among schoolchildren, with or without gout, with a

Susceptibility to Hashimoto's thyroiditis is determined by individual genetic background,

Associations have been reported between Hashimoto's thyroiditis and HLA- DR3, HLA-DR4, or HLA-DR5. Furthermore, in children and adolescents paternal alleles and antibodies status have been shown to influence susceptibility to autoimmune thyroid disease. The expression of HLA-DR antigens on thyroid cells have a potential role in perpetuating the immune response, related to certain HLA-DR subtypes. As regards non-HLA susceptibility genes, several studies demonstrated the association between a polymorphism of the CTLA-4

In literature are reported linkage with loci on the X chromosome and on chromosome 20 or 14. Observations in twins are correlated with a genetic predisposition to thyroid autoimmunity. There are several cases of identical twins where one twin showed Graves' disease and the others Hashimoto's thyroiditis. It is common to find family clusters with HT and the incidence in parents or siblings of patient with HT can reach about 25% (Lorini et

There is no evidence that a clear infectious agent is responsible for autoimmune thyroiditis. However, long-term follow-up of patients with subacute thyroiditis showed a possible reaction to viral infection with signs of persistence thyroid autoimmune disease. To this purpose, hepatitis C can act as a trigger for the development of autoimmune thyroiditis through thyroid follicular cell apoptosis. Potential mechanisms of infectious triggers include cell damage with the release of auto-antigens, expression of new antigens and molecular

including both major histocompatibility complex (MHC) and non-MHC genes.

to gluten-free diet has been reported (Valerio et al., 2008).

**4. Autoimmune thyroid disease** 

**4.1.1 Background and genetic susceptibility** 

thyroiditis to the hyperthyroidism of Graves' disease.

prevalence of 1% among schoolchildren (Lorini et al, 2003).

gene and autoimmune thyroid disease (Barker, 2006).

**4.1 Hashimoto's thyroiditis** 

2003).

al., 2003).

**4.1.2 Pathogenesis** 

mimicry mechanisms.

increasing with age.

Positivity for disease-related antibodies allows identification of patients with suspected celiac disease who must undergo intestinal biopsy. IgA-transglutaminase antibodies show the highest sensitivity and allow to identify around 98% of patients with celiac disease, while their specificity is lower, especially at a low titer (Salardi et al., 2008). IgA-antiendomysial antibodies show lower sensitivity (98%) but higher specificity. Fluctuating positivity for anti-endomysial antibodies at a low titer can be detected at time of diabetes clinical onset, and in absence of signs or symptoms related to celiac disease only periodical screening is recommended .

Total IgA screening is mandatory before celiac disease-related antibodies detection. Patients with IgA deficiency benefit from IgG anti-transglutaminase antibody detection (Lenhardt et al., 2004) and, as recently reported, by IgG anti-deaminated gliadin peptides (Volta et al., 2010). IgA deficiency deserves attention, since this condition is more frequent in patients with celiac disease (1.7%) as compared to control population (0.25%)(Cataldo et al., 1997).

As regards timing of screening, it has been reported that the serological screening of celiac disease allows diagnosing 1% of patients with celiac disease. The frequency of diagnoses increases to 5% when screening is performed in the next 5 years after diabetes diagnosis (Larsson et al., 2008). It has been reported that up to 85% of cases of celiac disease is diagnosed 2-5 years after type 1 diabetes clinical onset (Saukkonen et al., 1996). Markers of celiac disease can appear within 10 years, so it is recommended to perform screening yearly for the first 4 years after diabetes diagnosis, and every 2 years in the following 6 years (Kordonouri et al., 2009).

Fig. 1. Linear growth in a girl with type 1 diabetes and concomitant celiac disease, who developed autoimmune thyroiditis

Diagnosis of celiac disease by intestinal biopsy requires a lifelong gluten-free diet. Major problems related to gluten-free diet include quality of life, impairment of social life, poor compliance especially in adolescents and in patients with silent celiac disease diagnosed through screening procedures. Moreover, gluten-free diet can exert an increased insulin requirement since persistent hyperglycemia can occur. Gluten-free diet exerts in increased weight and height (Goh et al., 2010), as well as serum ferritin and hemoglobin (Hansen et al., 2006). Moreover improvement of bone status in patients with type 1 diabetes and adherence to gluten-free diet has been reported (Valerio et al., 2008).
