**Celiac Disease and Diabetes Mellitus Type 1**

Mieczysław Szalecki1,2, Piotr Albrecht3 and Stefan Kluzek4

*1Clinic of Endocrinology and Diabetology, Children's Memorial Health Institute, Warsaw, 2Faculty of Health Sciences, Jan Kochanowski University, Kielce, 3Department of Pediatric Gastroenterology and Nutrition, Warsaw Medical University, 4Sport and Exercise Medicine, Oxford Deanery, Nuffield Orthopaedic Centre, Oxford, 1,2,3Poland 4UK* 

#### **1. Introduction**

A significant increase in autoimmune disease morbidity has been observed in recent years, including disorders manifesting in childhood, concurrent with decreased age of patients at the time of diagnosis. Autoimmune diseases can involve almost every organ system but the endocrine, connective tissue and gastrointestinal systems are the most commonly affected 1, 2, 3.

In terms of epidemiology, autoimmune thyroid diseases (AITD) and diabetes type 1 (T1DM) come to the fore among autoimmune diseases related to the endocrine system, whereas among those unrelated to the endocrine system celiac disease (CD) is one of the more common. These diseases, apart from bronchial asthma, are among the most frequent chronic diseases affecting infants and children and often occur together 1, 3 , 4.

Autoimmune polyendocrinopathy syndrome (APS) or polyglandular autoimmune diseases (PGAD) concern primary deficits in two or more endocrine glands and manifest themselves, except for Graves' disease, as organ hypofunction. The main autoimmune endocrinopathies are: type 1 diabetes mellitus, autoimmune thyroid diseases, autoimmune adrenal failure (Addison disease), hypergonadotropic hypogonadism (premature ovarian failure), autoimmune hypoparathyroidism, and pituitary defects (lymphocytic hypophysitis) 5, 6, 7

Those syndromes are often associated with other non-endocrine autoimmune diseases 5, 6, 7.

For descriptive purposes three to four different types of APS or PGAD have been described. Addison disease is a common element of the first two types i.e. APS-1 Blizzard syndrome, APS-2 Schmidt's syndrome (Carpenter's syndrome). APS-3, on the other hand, is characterised by the presence of autoimmune thyroid disease and diabetes type 1 (3a), pernicious anaemia (3b) or vitiligo, alopecia or other organ specific autoimmune disease (3c).

Some authors also distinguish type 4 disease/syndrome, which comprises varied combinations of autoimmune diseases with the exception of those mentioned above as types 1 and 2. A patient with diagnosed T1DM and CD can be included in this group 5, 6, 7.

Celiac Disease and Diabetes Mellitus Type 1 73

It seems that the development of CD is dependent on the dose, type, timing and method of gluten ingestion. Breastfeeding and small amounts of gluten administered with breast milk are associated with a reduced risk of developing CD 21, 22. Breastfeeding favours the growth of beneficial bacteria, such as *Bifidobacterium,* and therefore decreases the proliferation of

Diet (and gluten intake) related disorders of the intestinal microflora and permeability of the intestinal mucosa appear to play a significant role in the development of T1DM 23. According to Visser et al. 24, the influence of gluten on the development of T1DM is as follows: a high gluten diet is favourable for *Bacteroides,* while a gluten-free casein diet reduces their number. The predominance of *Bacteroides* over *Bifidobacterium* and *Lactobacillus,*  which occurs in breastfed babies, stimulates zonulin release 25. In CD zonulin release is enhanced by gliadin binding to the chemokine receptor CXCR3 18. An excessive concentration of zonulin and its receptor in the enterocyte changes the structure of TJ proteins and increases the passage of antigens from the intestinal lumen to the *lamina propria* where antigens are presented to the T cells by the APC. In conjunction with a genetic predisposition, this may lead to the trafficking and/or activation of autoaggressive T cells, which may provoke autoimmune responses, including destruction of beta cells in T1DM.

A significant role of gliadin in the etiology and pathogenesis of CD and T1DM has also been

Around 4.5% of children and almost 6% of adults with T1DM have concurrent CD 27. This correlation between the two diseases seems to become stronger with increasing age and duration of diabetes. The epidemiological data vary depending on population characteristics as well as on diagnostics criteria. Prevalence of CD among Australian children with newly diagnosed T1DM was 1.2% according to Doolan et al.28. This prevalence was 2.7% among

In similar populations of children in the USA, the prevalence of CD was 5% percent

CD coexists with T1DM in only 1.4% of young adults in Wales 31, while the rate is 7.7% in children in British Columbia, 2% in adults in the Czech Republic 33, 2.6% in children and teenagers in Brazil 34 and 12.3% in adults in Denmark 35. In Iraq it is 11.2% 36, and in Serbia 5.79% 37. Triolo et al. have found tissue transglutaminase antibodies (anti-tTG) in 11.6% of diabetic children, of whom 24.6% had CD 4. In a large study of 28,671 T1DM patients under the age of 30 from Germany and Austria, Warncke et al. 38 demonstrated the presence of anti-tTG in 10.7% patients, which was associated with the duration of T1DM. In a recent study form Greece, Kakleas et al. 39 found an 8.6% prevalence of anti-tTG IgA positivity among T1DM children associated with younger age and a shorter duration of diabetes. The highest prevalence of 13.8% was documented in Italy by Picarelli et al. 40. This study also demonstrated the value of analysing IgA and IgG antibody concentrations simultaneously. The prevalence of CD in the patients with T1DM was 6.4% for IgA-EMA-positive, which

The incidence of CD in Polish children with newly diagnosed T1DM was reported to be 5.7% and 9.4% in those with long-standing T1DM by Mysliwiec et al. 41. There was no

others, including those less beneficial, like *Bacteroides*.

children with long-standing T1DM and 8.4% among adults.

increased to 13.8% when IgG1-EMA was also used for screening.

according to Crone et al, and 3.2% according to Sanchez-Albisua et al 29, 30.

hypothesized by Barbeau et al 26.

**3. Epidemiology** 

In 1969, Walker-Smith and Grigo8 described a child with T1DM and CD for the first time, highlighting the frequent coexistence of these two diseases. What makes CD unique among autoimmune diseases is the fact that the external or initiating factor is known, which is not the case in T1DM or AITD.

#### **2. Pathophysiology**

Recent studies have shown that, apart from environmental causes, such as the ingestion of gluten in celiac disease, other less understood factors like in T1DM, and recent advances in our understanding of genetic predisposition factors, many autoimmune disorders are associated with either primary or secondary disturbances in gastrointestinal mucosal permeability.

Gastrointestinal epithelial cells form the largest body surface area interfacing between an organism and its external environment. Thanks to tight junctions (TJ), a healthy intestinal mucosa serves as a barrier against toxic macromolecules. Under physiological conditions, only a few immunologically active antigens can traverse this barrier. Almost 90% of the proteins that penetrate the barrier via the epithelium are reduced to non-immunogenic, short linear peptides due to the action of lysosomal enzymes. Only a few remain unchanged and are transported by M cells or between the enterocytes through TJ. Breaching of the epithelial barrier by these antigens often results in the development of immunological tolerance rather than triggering the immune response or autoimmunisation 9. An immature or damaged mucosa makes the mucous barrier more permeable, which can result in an allergic or autoimmune reaction in genetically predisposed individuals 9, 10. Uibo et al. 11 detected the lowest expression of tight junction protein 1 (TJP1) mRNA in small bowel mucosa samples from celiac patients with diabetes mellitus type 1, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker of regulatory T cells, when compared with controls and celiac patients 11. Antigen presenting cells (APC), which present antigens to T cells of the intestinal mucosa, are vital to the immunological processes. On their surface, they present glycoproteins encoded by major histocompatibility complex (MHC) class I and II antigens 12, 13. Almost 50 different conditions, including CD and T1DM, are associated with specific MHC class I or II antigen presentation pathways 13. Apart from genetic predisposition, the disease or disorder develops when the immune system is exposed to the antigen. This process may be enhanced by increased permeability of the mucosa due to damaged TJ. According to Fasano et al. 14, 15, 16, 17 an excessive production of zonulin stimulated by gluten, increases permeability of TJ. In CD, this process is presumed to be mediated by gliadin binding to the chemokine receptor CXCR3 18.

Gliadin has lately been speculated to be one of the environmental causes of T1DM. Gliadin, which contains relatively high levels of glutamine and proline, is a source of polypeptides that can penetrate the damaged TJ and presented to T cells by dendritic cells. Activated Th1 lymphocytes can be stimulated to secret gamma interferon (INF-γ) and tumor-necrosis factor-alfa (TNF-α), Th2 lymphocytes to secrete Interleukin-4 (IL-4) and Th17 cells to secrete Interleukin-17A (IL-17A). All these cytokines can stimulate a local inflammatory response, which further augments the permeability of the mucosa 19, 20, hence resulting in a vicious circle that perpetuates damage to the intestinal mucosa.

In 1969, Walker-Smith and Grigo8 described a child with T1DM and CD for the first time, highlighting the frequent coexistence of these two diseases. What makes CD unique among autoimmune diseases is the fact that the external or initiating factor is known, which is not

Recent studies have shown that, apart from environmental causes, such as the ingestion of gluten in celiac disease, other less understood factors like in T1DM, and recent advances in our understanding of genetic predisposition factors, many autoimmune disorders are associated with either primary or secondary disturbances in gastrointestinal mucosal

Gastrointestinal epithelial cells form the largest body surface area interfacing between an organism and its external environment. Thanks to tight junctions (TJ), a healthy intestinal mucosa serves as a barrier against toxic macromolecules. Under physiological conditions, only a few immunologically active antigens can traverse this barrier. Almost 90% of the proteins that penetrate the barrier via the epithelium are reduced to non-immunogenic, short linear peptides due to the action of lysosomal enzymes. Only a few remain unchanged and are transported by M cells or between the enterocytes through TJ. Breaching of the epithelial barrier by these antigens often results in the development of immunological tolerance rather than triggering the immune response or autoimmunisation 9. An immature or damaged mucosa makes the mucous barrier more permeable, which can result in an allergic or autoimmune reaction in genetically predisposed individuals 9, 10. Uibo et al. 11 detected the lowest expression of tight junction protein 1 (TJP1) mRNA in small bowel mucosa samples from celiac patients with diabetes mellitus type 1, indicating an increase in intestinal permeability. Furthermore, these samples displayed the highest expression of forkhead box P3 (FoxP3) mRNA, a marker of regulatory T cells, when compared with controls and celiac patients 11. Antigen presenting cells (APC), which present antigens to T cells of the intestinal mucosa, are vital to the immunological processes. On their surface, they present glycoproteins encoded by major histocompatibility complex (MHC) class I and II antigens 12, 13. Almost 50 different conditions, including CD and T1DM, are associated with specific MHC class I or II antigen presentation pathways 13. Apart from genetic predisposition, the disease or disorder develops when the immune system is exposed to the antigen. This process may be enhanced by increased permeability of the mucosa due to damaged TJ. According to Fasano et al. 14, 15, 16, 17 an excessive production of zonulin stimulated by gluten, increases permeability of TJ. In CD, this process is presumed to be

mediated by gliadin binding to the chemokine receptor CXCR3 18.

circle that perpetuates damage to the intestinal mucosa.

Gliadin has lately been speculated to be one of the environmental causes of T1DM. Gliadin, which contains relatively high levels of glutamine and proline, is a source of polypeptides that can penetrate the damaged TJ and presented to T cells by dendritic cells. Activated Th1 lymphocytes can be stimulated to secret gamma interferon (INF-γ) and tumor-necrosis factor-alfa (TNF-α), Th2 lymphocytes to secrete Interleukin-4 (IL-4) and Th17 cells to secrete Interleukin-17A (IL-17A). All these cytokines can stimulate a local inflammatory response, which further augments the permeability of the mucosa 19, 20, hence resulting in a vicious

the case in T1DM or AITD.

**2. Pathophysiology** 

permeability.

It seems that the development of CD is dependent on the dose, type, timing and method of gluten ingestion. Breastfeeding and small amounts of gluten administered with breast milk are associated with a reduced risk of developing CD 21, 22. Breastfeeding favours the growth of beneficial bacteria, such as *Bifidobacterium,* and therefore decreases the proliferation of others, including those less beneficial, like *Bacteroides*.

Diet (and gluten intake) related disorders of the intestinal microflora and permeability of the intestinal mucosa appear to play a significant role in the development of T1DM 23. According to Visser et al. 24, the influence of gluten on the development of T1DM is as follows: a high gluten diet is favourable for *Bacteroides,* while a gluten-free casein diet reduces their number. The predominance of *Bacteroides* over *Bifidobacterium* and *Lactobacillus,*  which occurs in breastfed babies, stimulates zonulin release 25. In CD zonulin release is enhanced by gliadin binding to the chemokine receptor CXCR3 18. An excessive concentration of zonulin and its receptor in the enterocyte changes the structure of TJ proteins and increases the passage of antigens from the intestinal lumen to the *lamina propria* where antigens are presented to the T cells by the APC. In conjunction with a genetic predisposition, this may lead to the trafficking and/or activation of autoaggressive T cells, which may provoke autoimmune responses, including destruction of beta cells in T1DM.

A significant role of gliadin in the etiology and pathogenesis of CD and T1DM has also been hypothesized by Barbeau et al 26.

#### **3. Epidemiology**

Around 4.5% of children and almost 6% of adults with T1DM have concurrent CD 27. This correlation between the two diseases seems to become stronger with increasing age and duration of diabetes. The epidemiological data vary depending on population characteristics as well as on diagnostics criteria. Prevalence of CD among Australian children with newly diagnosed T1DM was 1.2% according to Doolan et al.28. This prevalence was 2.7% among children with long-standing T1DM and 8.4% among adults.

In similar populations of children in the USA, the prevalence of CD was 5% percent according to Crone et al, and 3.2% according to Sanchez-Albisua et al 29, 30.

CD coexists with T1DM in only 1.4% of young adults in Wales 31, while the rate is 7.7% in children in British Columbia, 2% in adults in the Czech Republic 33, 2.6% in children and teenagers in Brazil 34 and 12.3% in adults in Denmark 35. In Iraq it is 11.2% 36, and in Serbia 5.79% 37. Triolo et al. have found tissue transglutaminase antibodies (anti-tTG) in 11.6% of diabetic children, of whom 24.6% had CD 4. In a large study of 28,671 T1DM patients under the age of 30 from Germany and Austria, Warncke et al. 38 demonstrated the presence of anti-tTG in 10.7% patients, which was associated with the duration of T1DM. In a recent study form Greece, Kakleas et al. 39 found an 8.6% prevalence of anti-tTG IgA positivity among T1DM children associated with younger age and a shorter duration of diabetes. The highest prevalence of 13.8% was documented in Italy by Picarelli et al. 40. This study also demonstrated the value of analysing IgA and IgG antibody concentrations simultaneously. The prevalence of CD in the patients with T1DM was 6.4% for IgA-EMA-positive, which increased to 13.8% when IgG1-EMA was also used for screening.

The incidence of CD in Polish children with newly diagnosed T1DM was reported to be 5.7% and 9.4% in those with long-standing T1DM by Mysliwiec et al. 41. There was no

Celiac Disease and Diabetes Mellitus Type 1 75

has been suggested that in the development of autoimmunity in T1DM, the failure to

At the time of writing this chapter, duodenal biopsy remains the gold standard for CD diagnosis. The diagnostic criteria devised by ESPGHAN in 1989 64 and later modified, consist of finding villous atrophy and crypt hyperplasia in a patient who ingests a sufficient amount of gluten (the Marsh classification 65) and achieves remission after discontinuing gluten from the diet. The diagnosis is further confirmed by positive serology. Highly sensitive and specific IgA and IgG antiendomysial antibodies (EmA) and tissue transglutaminase antibodies (anti-tTG) are most frequently used. Sometimes, deaminated

When evaluating anti-EmA and anti-tTG antibodies only of the IgA class (which is often preferred due to the lower cost), it is important to note the IgA concentration as well, as the frequency of isolated IgA deficiency in celiac patients is almost 2% and 7.7% of patients with

The above criteria are about to change. With exceptionally high levels of antiendomysial antibodies and positive genetic testing (HLA-DQ2, DQ8), CD might be diagnosed without histopathologic examination67. The use of three PCR reactions and a single electophoretic step for DQA1, DQB1 and DRB1 typing provides distinction of CD associated alleles and their homo- or heterozygous status. This analysis reduces reagent costs, personnel and instrument time, while enabling improved allelic assignment through HLA-DR-DQ haplotype association 68. In case of doubt, when the levels of antibodies are low, duodenal

T1DM often coexists with CD. However, the latter is often latent, Larsson et al. suggest that

There is no consensus as to whether all diabetic patients should implement a gluten-free

The ADA recommends screening diabetic patients for CD and placing all children with a confirmed diagnosis of CD on a gluten-free diet (GFD) 70. ISPAD suggests that while it seems sensible to put an asymptomatic child on a GFD to avoid the development of disease complications, evidence supporting this is still not sufficient. Therefore, they recommend that children with confirmed CD and T1DM receive support from a paediatric dietician 71.

Classical presentation of CD can occur in T1DM patients, but many patients with CD and T1DM are either asymptomatic (silent CD) or present with only mild symptoms 72, 73. In a recent study from a North American CD clinic, 71.4% of children with diabetes reported no gastrointestinal symptoms at the time of a positive screen 74. Some patients are overweight or obese at diagnosis; 11.2% of children with CD had a BMI greater than the 90th percentile in a recent US study 72. Based on these data, the ISPAD recommendations for the screening of all T1DM patients for CD appear to be adequate. Screening for CD should be carried out

**6. Evaluation for celiac disease in diabetes mellitus type 1 patients** 

achieve tolerance to autoantigens is attributable to gut related issues 63.

**5. Diagnosing CD in diabetic patients** 

gliadin antibodies (DGP) are also elevated.

isolated IgA deficiency suffer from CD 66.

biopsy is recommended to confirm the diagnosis.

T1DM patients should be screened annually 69.

diet, nor is it clear how often they should be screened for CD.

significant difference between the positivity for anti-tTG IgA and IgG in those groups. Gorska et al. 42 reported 4.1% of newly diagnosed type 1 diabetic children to have positive antibodies and our study 43 showed this to be twice as high among girls (5.62%) than among boys (2.57%). These data are consistent with other studies i.e. the prevalence of CD is twice as high in females as in males.

Patients with CD also have a greater risk for developing T1DM (around 5%) 44 and diabetesassociated antibodies are more commonly detected in these individuals. Galii-Tsinopoulou et al. 45 detected anti-GAD and IA-2 antibodies in 23% of patients with CD. The same authors suggested that a strict gluten-free diet might protect the pancreatic β-cells and thus postpone the onset of T1DM. Initiation of a gluten-free diet in T1DM children is associated with a significantly reduced risk of autoimmunisation. According to Ludvigsson et al.46, early diagnosis of CD (before the age of 2) reduces the risk of developing T1DM before the age of 20 when compared to a group diagnosed between the ages of 3 and 20. The differences, however were not statistically significant.

#### **4. Genetic determinants and associations**

Most estimates put the prevalence of CD at close to 1% of the general population 47, and recent evidence suggests that serologic prevalence rates have increased fourfold in the past 50 years 48. The concordance rate for CD in monozygotic twins is 75% and it highlights the role of other factors besides genetic predisposition 49. The MHC molecules HLA-DQ2 and HLA-DQ8 are risk factors in the disease. Almost 90% of CD patients carry HLA-DQ2 antigens while most of the rest carry HLA-DQ8 50, 51. HLA-DQ2 molecule is encoded by the DQA1\*0501 and DQB1\*0201 genes 52.

T1DM is strongly associated with HLA DR3-DQ2 and DR4-DQ8 MHC molecules, and associated with DQB1\*0302, DQB1\*0201, DRB1\*0401 and HLA-B alleles 53. Approximately 90% of CD patients share the HLA DR3/DQ2 configuration 54. The prevalence of tissue transglutaminase antibodies has been reported to be as high as 32% in HLA DQ2 homozygous T1DM patients, compared with 2% in patients without DQ2 or DQ8 55.

CD and T1DM also share a number of other genetic susceptibility loci. Out of 8 celiac susceptibility loci, 6 are associated with T1DM. On the other hand, out of 17 diabetessusceptibility loci, 8 are associated with CD 56. At least 8 loci appear to be common for both conditions (CCR3, CCR5, SH2B3, RGS1, TAGAP, PTPN2, IL18RAP, CTLA4) 57. It has been suggested that the immune or inflammatory responses associated with many autoimmune diseases overlap with the function of genes specific for certain diseases, such as IL12A in CD and INS in T1DM 57. Two new CD risk regions were recently identified at chromosomes 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL) 58. Polymorphisms within the TAGAP gene are also related to another autoimmune disease: rheumatoid arthritis 59.

The coexistence of T1DM and CD could be explained by a common genetic factor in the HLA region 60, 61 or by molecular mimicry by which gliadin or tissue transglutaminase C activates T cells that are cross-reactive with various antigens. During active β-cell destruction, transglutaminase C, which is expressed in pancreatic islets, might be presented in an immunogenic form. Such inflammatory responses may have the capacity to persist in susceptible hosts and lead to chronic organ-specific autoimmune disease 62. Furthermore, it

significant difference between the positivity for anti-tTG IgA and IgG in those groups. Gorska et al. 42 reported 4.1% of newly diagnosed type 1 diabetic children to have positive antibodies and our study 43 showed this to be twice as high among girls (5.62%) than among boys (2.57%). These data are consistent with other studies i.e. the prevalence of CD is twice

Patients with CD also have a greater risk for developing T1DM (around 5%) 44 and diabetesassociated antibodies are more commonly detected in these individuals. Galii-Tsinopoulou et al. 45 detected anti-GAD and IA-2 antibodies in 23% of patients with CD. The same authors suggested that a strict gluten-free diet might protect the pancreatic β-cells and thus postpone the onset of T1DM. Initiation of a gluten-free diet in T1DM children is associated with a significantly reduced risk of autoimmunisation. According to Ludvigsson et al.46, early diagnosis of CD (before the age of 2) reduces the risk of developing T1DM before the age of 20 when compared to a group diagnosed between the ages of 3 and 20. The

Most estimates put the prevalence of CD at close to 1% of the general population 47, and recent evidence suggests that serologic prevalence rates have increased fourfold in the past 50 years 48. The concordance rate for CD in monozygotic twins is 75% and it highlights the role of other factors besides genetic predisposition 49. The MHC molecules HLA-DQ2 and HLA-DQ8 are risk factors in the disease. Almost 90% of CD patients carry HLA-DQ2 antigens while most of the rest carry HLA-DQ8 50, 51. HLA-DQ2 molecule is encoded by the

T1DM is strongly associated with HLA DR3-DQ2 and DR4-DQ8 MHC molecules, and associated with DQB1\*0302, DQB1\*0201, DRB1\*0401 and HLA-B alleles 53. Approximately 90% of CD patients share the HLA DR3/DQ2 configuration 54. The prevalence of tissue transglutaminase antibodies has been reported to be as high as 32% in HLA DQ2

CD and T1DM also share a number of other genetic susceptibility loci. Out of 8 celiac susceptibility loci, 6 are associated with T1DM. On the other hand, out of 17 diabetessusceptibility loci, 8 are associated with CD 56. At least 8 loci appear to be common for both conditions (CCR3, CCR5, SH2B3, RGS1, TAGAP, PTPN2, IL18RAP, CTLA4) 57. It has been suggested that the immune or inflammatory responses associated with many autoimmune diseases overlap with the function of genes specific for certain diseases, such as IL12A in CD and INS in T1DM 57. Two new CD risk regions were recently identified at chromosomes 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL) 58. Polymorphisms within the TAGAP gene are

The coexistence of T1DM and CD could be explained by a common genetic factor in the HLA region 60, 61 or by molecular mimicry by which gliadin or tissue transglutaminase C activates T cells that are cross-reactive with various antigens. During active β-cell destruction, transglutaminase C, which is expressed in pancreatic islets, might be presented in an immunogenic form. Such inflammatory responses may have the capacity to persist in susceptible hosts and lead to chronic organ-specific autoimmune disease 62. Furthermore, it

homozygous T1DM patients, compared with 2% in patients without DQ2 or DQ8 55.

also related to another autoimmune disease: rheumatoid arthritis 59.

as high in females as in males.

differences, however were not statistically significant.

**4. Genetic determinants and associations** 

DQA1\*0501 and DQB1\*0201 genes 52.

has been suggested that in the development of autoimmunity in T1DM, the failure to achieve tolerance to autoantigens is attributable to gut related issues 63.

#### **5. Diagnosing CD in diabetic patients**

At the time of writing this chapter, duodenal biopsy remains the gold standard for CD diagnosis. The diagnostic criteria devised by ESPGHAN in 1989 64 and later modified, consist of finding villous atrophy and crypt hyperplasia in a patient who ingests a sufficient amount of gluten (the Marsh classification 65) and achieves remission after discontinuing gluten from the diet. The diagnosis is further confirmed by positive serology. Highly sensitive and specific IgA and IgG antiendomysial antibodies (EmA) and tissue transglutaminase antibodies (anti-tTG) are most frequently used. Sometimes, deaminated gliadin antibodies (DGP) are also elevated.

When evaluating anti-EmA and anti-tTG antibodies only of the IgA class (which is often preferred due to the lower cost), it is important to note the IgA concentration as well, as the frequency of isolated IgA deficiency in celiac patients is almost 2% and 7.7% of patients with isolated IgA deficiency suffer from CD 66.

The above criteria are about to change. With exceptionally high levels of antiendomysial antibodies and positive genetic testing (HLA-DQ2, DQ8), CD might be diagnosed without histopathologic examination67. The use of three PCR reactions and a single electophoretic step for DQA1, DQB1 and DRB1 typing provides distinction of CD associated alleles and their homo- or heterozygous status. This analysis reduces reagent costs, personnel and instrument time, while enabling improved allelic assignment through HLA-DR-DQ haplotype association 68. In case of doubt, when the levels of antibodies are low, duodenal biopsy is recommended to confirm the diagnosis.

#### **6. Evaluation for celiac disease in diabetes mellitus type 1 patients**

T1DM often coexists with CD. However, the latter is often latent, Larsson et al. suggest that T1DM patients should be screened annually 69.

There is no consensus as to whether all diabetic patients should implement a gluten-free diet, nor is it clear how often they should be screened for CD.

The ADA recommends screening diabetic patients for CD and placing all children with a confirmed diagnosis of CD on a gluten-free diet (GFD) 70. ISPAD suggests that while it seems sensible to put an asymptomatic child on a GFD to avoid the development of disease complications, evidence supporting this is still not sufficient. Therefore, they recommend that children with confirmed CD and T1DM receive support from a paediatric dietician 71.

Classical presentation of CD can occur in T1DM patients, but many patients with CD and T1DM are either asymptomatic (silent CD) or present with only mild symptoms 72, 73. In a recent study from a North American CD clinic, 71.4% of children with diabetes reported no gastrointestinal symptoms at the time of a positive screen 74. Some patients are overweight or obese at diagnosis; 11.2% of children with CD had a BMI greater than the 90th percentile in a recent US study 72. Based on these data, the ISPAD recommendations for the screening of all T1DM patients for CD appear to be adequate. Screening for CD should be carried out

Celiac Disease and Diabetes Mellitus Type 1 77

[3] Craig M, Hattersley A, Donaghue K. ISPAD Clinical Practice Consensus Guidelines 2009.

[4] Triolo TM, Armstrong TK, McFann K, Yu L, Rewers MJ, Klingensmith GJ, Eisenbarth

[5] Betterlre C, Delpra C, Greggio N. Autoimmunity in isolated Addison disease and in

[6] Eisenbarth GS, Gottlieb PA. Autoimmune Polyendocrine Syndromes. New England

[7] Brook CGD, Brown RS. Polyglandular Syndromes in. Handbook of Clinical Pediatric Endocrinology. Blackwell Publishing Inc. Massachusetts USA. 2008:164-171. [8] Walker-Smith JA, Grigor W. Coeliac disease in a diabetic child. Lancet. 1969

[9] Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev

[11] Uibo R, Panarina M, Teesalu K, Talja I, Sepp E, Utt M, Mikeelsar M, Heilman K, Uibo O,

distinct changes in intestinal mucosa. Cell Moll Immunol. 2011;8(2):150-6. [12] Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure

[13] Visser J, Rozing J, Sapone A, Lammers K, Fasano A. Tight junctions, intestinal

[14] Fasano A, Fiorentini C, Donelli G, Uzzau S, Kaper JB, Margaretten K, Ding X,

[15] Fasano A, Uzzau S, Fiore C, Margaretten K. The enterotoxic effect of zonula occludens

[16] Wang W, Uzzau S, Goldblum SE, Fasano A. Human zonulin, a potential modulator of

[17] Baudry B, Fasano A, Ketley J, Kaper JB. Cloning of a gene (zot) encoding a new toxin

[18] Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-

[19] Knip M. Diet, gut, and type 1 diabetes: role of wheat-derived peptides? Diabetes.

[20] Mojibian M, Chakir H, Lefebvre DE, Crookshank JA, Sonier B, Keely E, Scott FW.

intestinal tight junctions. J Cell Sci. 2000;113 Pt 24:4435-40.

produced by *Vibrio cholerae*. Infect Immun. 1992;60(2):428-34.

Vorobjova T. Celiac disease in patient with type 1 diabetes: a condition with

of the human class I histocompatibility antigen, HLA-A2. Nature.

permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms.

Guandalini S, Comstock L, Goldblum SE. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin

toxin on rabbit small intestine involves the paracellular pathway.

Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008;135(1):194-

Diabetes-specific HLA-DR-restricted proinflammatory T-cell response to wheat

GS, Barker JM. Additional autoimmune diseases in 33% of patients at type 1

polyglandular autoimmune diseases type 1, 2 and 4. Annales Endocrinology.

Pediatric Diabetes 2009(S12);10:3-12.

Journal of Medicine. 2004;350:2068-79.

2001;62:193.

17;1(7603):1021.

Immunol. 2003;3(4):331-41.

1987;329(6139):506-12.

Invest. 1995;96(2):710-20.

204.e3

2009;58(8):1723-4.

Ann N Y Acad Sci. 2009;1165:195-205.

Gastroenterology. 1997;112(3):839-46.

diabetes onset. Diabetes Care. 2011;34(5):1211-3.

[10] Fasano A. Intestinal zonulin: open sesame! Gut. 2001;49(2):159-62.

at the time of diagnosis, annually for the first five years and every second year thereafter. More frequent assessment is indicated if the clinical situation suggests the possibility of CD or the child has a first-degree relative with CD 71.

It should be emphasised that both adults and children suffering from CD are at an increased risk for sepsis. The risk is highest for pneumococcal sepsis 75. Therefore it is recommended to vaccinate these patients against pneumococci.

Patients with both CD and T1DM have gastrointestinal symptoms more often than those who suffer from diabetes only. These include stomach pain, bloating, diarrhea, failure to thrive, and decreased appetite. In the study by Naruli et al. 76, this difference was statistically significant (p<0.0005). The symptoms subsided after switching onto a gluten-free diet, which goes to show that CD was in fact not asymptomatic. Patients who observed the diet significantly improved their weight SD score (p=0.008) and BMI SD score (p=0.002) within a year.

In a study by Fröhlich-Reiterer et al. 77, patients with both T1DM and CD (confirmed by a biopsy) were diagnosed with diabetes at a younger age and were of a generally lower height and weight. Those features were statistically significant (p<0.001) and they continued for another five and a half years of observation.

According to Pitocco et al. 78, patients with both diseases are at higher risk of developing atherosclerosis compared to those presenting with diabetes or CD only.

Other recognised side effects associated with untreated CD in patients with T1DM include changes in insulin requirements, frequent hypoglycaemia, failure to thrive, delayed puberty, anaemia, osteopenia, osteoporosis and neurologic complications 79, 80, 81, 82.

The most clinically serious, but rare, complication associated with CD (usually the type resistant to treatment) is the development of small intestinal lymphoma83. The incidence of this malignancy in patients with both CD and T1DM, however, has not been adequately assessed.

In conclusion, it appears that despite being inconvenient and restrictive, a gluten-free diet should be implemented for all patients suffering from T1DM and CD. There is evidence that this diet might be effective in protecting the pancreatic β-cells and increasing the levels of insulin secretion in newly diagnosed patients 84, 85, 86. A gluten-free diet is beneficial for diabetic patients. It improves the indicators of physical development, reduces the risk of atherosclerosis and sepsis (especially pneumococcal), and relieves the gastrointestinal symptoms associated with untreated CD.

We strongly suggest that annual screening for CD become part of routine practice in patients with T1DM.

#### **7. References**


at the time of diagnosis, annually for the first five years and every second year thereafter. More frequent assessment is indicated if the clinical situation suggests the possibility of CD

It should be emphasised that both adults and children suffering from CD are at an increased risk for sepsis. The risk is highest for pneumococcal sepsis 75. Therefore it is recommended

Patients with both CD and T1DM have gastrointestinal symptoms more often than those who suffer from diabetes only. These include stomach pain, bloating, diarrhea, failure to thrive, and decreased appetite. In the study by Naruli et al. 76, this difference was statistically significant (p<0.0005). The symptoms subsided after switching onto a gluten-free diet, which goes to show that CD was in fact not asymptomatic. Patients who observed the diet significantly improved their weight SD score (p=0.008) and BMI SD score (p=0.002) within a

In a study by Fröhlich-Reiterer et al. 77, patients with both T1DM and CD (confirmed by a biopsy) were diagnosed with diabetes at a younger age and were of a generally lower height and weight. Those features were statistically significant (p<0.001) and they continued for

According to Pitocco et al. 78, patients with both diseases are at higher risk of developing

Other recognised side effects associated with untreated CD in patients with T1DM include changes in insulin requirements, frequent hypoglycaemia, failure to thrive, delayed puberty,

The most clinically serious, but rare, complication associated with CD (usually the type resistant to treatment) is the development of small intestinal lymphoma83. The incidence of this malignancy in patients with both CD and T1DM, however, has not been adequately

In conclusion, it appears that despite being inconvenient and restrictive, a gluten-free diet should be implemented for all patients suffering from T1DM and CD. There is evidence that this diet might be effective in protecting the pancreatic β-cells and increasing the levels of insulin secretion in newly diagnosed patients 84, 85, 86. A gluten-free diet is beneficial for diabetic patients. It improves the indicators of physical development, reduces the risk of atherosclerosis and sepsis (especially pneumococcal), and relieves the gastrointestinal

We strongly suggest that annual screening for CD become part of routine practice in

[1] Anderson MS. Update in endocrine autoimmunity. J Clin Endocrinol Metab.

[2] Van den Driessche A, Eenkhorn V, Van Gaal L, De Block C. Type 1 diabetes mellitus and

autoimmune polyglandular syndrome: a clinical revive. The Netherlands Journal

atherosclerosis compared to those presenting with diabetes or CD only.

anaemia, osteopenia, osteoporosis and neurologic complications 79, 80, 81, 82.

or the child has a first-degree relative with CD 71.

to vaccinate these patients against pneumococci.

another five and a half years of observation.

symptoms associated with untreated CD.

2008;93(10):3663-70.

of Medicine. 2009;67:376-385.

year.

assessed.

patients with T1DM.

**7. References** 


Celiac Disease and Diabetes Mellitus Type 1 79

[37] Djurić Z, Stamenković H, Stanković T, Milićević R, Branković L, Cirić V, Katić V. Celiac

[38] Warncke K, Frochlich-Reiterer EE, Thon A, Hofer SE, Wiemann D, Holl RW, DPV

[39] Kakleas K, Karayjanci C, Cristelis E, Papathanasiou A, Petrou V, Fotinou A, Karavanaki

[41] Myśliwiec M, Balcarska A, Stopiński J. Prognostic factors of celiac disease occurrence in

[42] Górska A, Nazim J, Starzyk J. Ocena częstości wystepowania choroby Hashimoto i

[43] Szalecki M, Ziora K, Biernacka-Florczak I, Domagała Z. Występowanie celiakii u dzieci i

[44] Collin P, Reunala T, Pukkala E, Laippala P, Keyriläinen O, Pasternack A. Coeliac

[45] Galli-Tsinopoulou A, Nousia-Arvanitakis S, Dracoulacos D, Xefteri M, Karamouzis M.

[46] Ludvigsson JF, Ludvigsson J, Ekbom A, Montgomery SM. Celiac disease and risk of

[47] Mäki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, Ilonen J,

[48] Rubio-Tapia A, Kyle RA, Kaplan EL. Increased prevalence and mortality in

[49] Nisticò L, Fagnani C, Coto I, Percopo S, Cotichini R, Limongelli MG, Paparo F,

[50] Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary

[51] Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, Ciclitira PJ, Sollid LM.,

disease--associated disorders and survival. Gut. 1994;35(9):1215-8.

among children in Finland. N Engl J Med. 2003;348(25):2517-24.

undiagnosed celiac disease. Gastroenterology. 2009;137(1):88-93.

type I diabetes mellitus. Clin Exp Immunol. 2005 Oct;142(1):111-5.

Pediatr Int. 2010;52(4):579-83.

2006;16:281-5.

2007;2(19):23-28.

1999;52(3):119-24

Wiss database. Diabetes Care. 2010;33(9):2010-2.

prospektywne. Endokrynol Ped. 2004;3(S3):38.

adolescents. Diabetes Care. 2006;29(11):2483-8.

disease in Italian twins. Gut. 2006;55(6):803-8.

Med. 1989;169(1):345-50.

disease prevalence in children and adolescents with type 1 diabetes from Serbia.

Initiative of the German Working Group for Pediatric Diabetology. Polyendocrinopathy in children, adolescents, and young adults with type 1 diabetes: a multicenter analysis of 28.671 patients from German/Austrian DPV-

K. The prevalence and risk factors for celiac disease among children and adolescents with type 1 diabetes mellitus. Diabetes Res Clin Prac 2010;90(2):202-8. [40] Picarelli A, Sabbatella L, Di Tola M, Vetrano S, Casale C, Anania MC, Porowska B,

Vergari M, Schiaffini R, Gargiulo P. Anti-endomysial antibody of IgG1 isotype detection strongly increases the prevalence of coeliac disease in patients affected by

type 1 diabetes mellitus in children. Pediatr Endocrinol Diabetes Metab.

celiakii wśród dzieci i młodzieży ze świeżo rozpoznaną cukrzycą typu 1 – badanie

młodzieży ze świeżo rozpoznaną cukrzycą typu 1. Endokrynologia Pediatryczna

Autoantibodies predicting diabetes mellitus type 1 in celiac disease. Horm Res.

subsequent type 1 diabetes: a general population cohort study of children and

Laurila K, Dahlbom I, Hansson T, Höpfl P, Knip M. Prevalence of Celiac disease

D'Alfonso S, Giordano M, Sferlazzas C, Magazzù G, Momigliano-Richiardi P, Greco L., Stazi MA. Concordance, disease progression, and heritability of coeliac

association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp

Partanen J; European Genetics Cluster on Celiac Disease. HLA types in celiac

polypeptides in tissue transglutaminase antibody-negative patients with type 1 diabetes. Diabetes. 2009;58(8):1789-96.


[22] Ivarsson A, Hernell O, Stenlund H. Breast-feeding protects against celiac disease. Am J

[23] Brugman S, Klatter FA, Visser JT, Wildeboer-Veloo AC, Harmsen HJ, Rozing J, Bos NA.

[24] Visser J, Rozing J, Sapone A, Lammers K, Fasano A. Tight junctions, intestinal

[25] Fasano A, Nataro JP. Intestinal epithelial tight junctions as targets for enteric bacteria-

[26] Barbeau WE, Bassaganya-Riera J, Hontecillas R. Putting the pieces of the puzzle

[27] Holmes GK. Screening for coeliac disease in type 1 diabetes. Arch Dis Child.

[28] Doolan A, Donaghue K, Fairchild J, Wong M, Williams AJ. Use of HLA typing in

[29] Crone J, Rami B, Huber WD, Granditsch G, Schober E. Prevalence of celiac disease and

[30] Sanchez-Albisua I, Wolf J, Neu A, Geiger H, Waschler I, Sterm M. Celiac disease in

[31] Li Voon Chong JS, Leong KS, Wallymahmed M, Sturgess R, MacFarlane IA. Is coeliac

[32] Giletti PM, Giletti HR, Israel DM. High prevalence of celiac disease in patients with

[33] Prazny M, Skrha J, Limanova Z. Screening for associated autoimmunity in type 1 diabetes mellitus with respect to diabetes control. Physiol Res 2005;54:41-48. [34] Tanure MG, Silva IN, Bahia M, Penna FJ. Prevalence of celiac disease in Brazilian

[35] Hansen D, Brock-Jacobsen B, Lund E, Bjørn C, Hansen LP, Nielsen C, Fenger C,

[36] Mansour AA, Najeeb AA. Celiac disease in Iraqi type 1 diabetic patients. Arab J

diabetes. Diabetes. 2009;58(8):1789-96.

Clin Nutr 2002;75:914–21.

2002;87(6):495-8.

2005;28(4):806-9.

Nutr. 2003; 37:67-71.

Med. 2005;22:1079-82.

Feb;42(2):155-9.

Diabetologia. 2006;49(9):2105-8.

Ann N Y Acad Sci. 2009;1165:195-205.

diabetes. Med Hypotheses. 2007;68(3):607-19.

mellitus alone? Diabet Med. 2002;19(4):334-7.

transglutaminase. Can J Gastroenterol. 2003;15:297-301.

diabetes (T1D). Ugeskr Laeger. 2007;169(21):2029-32.

Gastroenterol. 2011 Jun;12(2):103-5.

[21] Sollid LM. Breast milk against coeliac disease. Gut. 2002;51(6):767-8.

derived toxins. Adv Drug Deliv Rev. 2004;56(6):795-807.

polypeptides in tissue transglutaminase antibody-negative patients with type 1

Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes?

permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms.

together - a series of hypotheses on the etiology and pathogenesis of type 1

diagnosing celiac disease in patients with type 1 diabetes. Diabetes Care.

follow up to EMA in children with type 1 diabetes mellitus J Pediatr Gastroenterol

children with Type 1 diabetes mellitus: the effect of the gluten-free diet. Diabet

disease more prevalent in young adults with coexisting Type 1 diabetes mellitus and autoimmune thyroid disease compared with those with Type 1 diabetes

type 1 diabetes mellitus detected by antibodies to endomysium and tissue

children with type 1 diabetes mellitus. J Pediatr Gastroenterol Nutr. 2006

Lillevang ST, Husby S. Prevalence of celiac disease (CD) in children with type 1


Celiac Disease and Diabetes Mellitus Type 1 81

[64] Working Group of ESPGAN: Revised criteria for diagnosis of celiac disease. Arch Dis

[65] Marsh MN. Gluten, major histocompatibility complex, and the small intestine: a

[66] Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, Troncone

[67] NIH Consensus Development Conference on Celiac Disease. NIH Consensus State Sci.

[68] Lavant EH, Agardh, Nisson A, CarlsonJA. A new PCR-SSP method for HLA DR-DQ

[69] Larsson K, Carlsson A, Cederwall E, Jönsson B, Neiderud J, Jonsson B, Lernmark A,

[71] Kordonouri O, Maguire AM, Knip M, Schober E, Lorini R, Holl RW, Donaghue KC.

[72] Mahmud FH, Murray JA, Kudva YC. Celiac disease in type 1 diabetes mellitus in a

[73] Rami B, Sumnik Z, Schober E. Screening detected celiac disease in children with type 1

[74] Telega G, Bennet TR, Werlin S. Emerging new clinical patterns in the presentation of

[75] Ludvigsson JF, Olén O, Bell M, Ekbom A, Montgomery SM. Coeliac disease and risk of

[76] Narula P, Porter L, Langton J, Rao V, Davies P, Cummins C, Kirk J, Barrett T, Protheroe

[77] Fröhlich-Reiterer EE, Kaspers S, Hofer S, Schober E, Kordonouri O, Pozza SB, Holl RW;

[78] Pitocco D, Giubilato S, Martini F, Zaccardi F, Pazzano V, Manto A, Cammarota G, Di

Pediatric Gastroenterology and Nutrition. 2005;41(3):317–321.

children with type 1 diabetes. Pediatr Diabetes. 2008;9(4 Pt 2):354-9. [70] Standards of medical care in diabetes—2009. Diabetes Care. 2009;32(S1):13–61.

Ivarsson SA. Skåne Study Group. Annual screening detects celiac disease in

ISPAD Clinical Practice Consensus Guidelines 2009. Pediatric Diabetes

North American community: prevalence, serologic screening, and clinical features.

diabetes mellitus: effect on the clinical course (a case control study). Journal of

celiac disease. Archives of Pediatrics and Adolescent Medicine. 2008;162(2):164–

S. Gastrointestinal symptoms in children with type 1 diabetes screened for celiac

Diabetes Patienten Verlaufsdokumentationssystem-Wiss Study Group. Anthropometry, metabolic control, and follow-up in children and adolescents with type 1 diabetes mellitus and biopsy-proven celiac disease. J Pediatr.

Stasio E, Pedicino D, Liuzzo G, Crea F, Ghirlanda G. Combined atherogenic effects of celiac disease and type 1 diabetes mellitus. Atherosclerosis. 2011;217(2):531-5.

("celiac sprue"). Gastroenterology 1992; 102: 330-354.

disease. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):136-60.

risk for celiac disease. Clin Chim Acta. 2011;11(412):9-10.

Mayo Clinic Proceedings. 2005;80(11):1429–1434.

molecular and immunobiologic approach to the spectrum of gluten sensitivity

R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Mäki M, Ribes-Koninckx C, Ventura A, Zimmer KP; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac

Child 1990; 65:909-911.

Statements. 2004,2,21:1-23.

2009(S12);10:204-210.

sepsis. Gut. 2008 ;57(8):1074-80.

2011;158(4):589-593.e2

disease. Pediatrics. 2009;124(3):489-95.

168.

disease patients not carrying the DQA1\*05-DQB1\*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol. 2003;64(4):469-77.


[52] van Heel DA, Hunt K, Greco L, Wijmenga C. Genetics in coeliac disease. Best Pract Res

[53] Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE, Reynolds P,

[54] Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, Howson JM, Stevens

[55] Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary

[56] Bao F, Yu L, Babu S. One third of HLA DQ2 homozygous patients with type 1 diamina

[57] Heap GA, van Heel DA. The genetics of chronic inflammatory diseases. Hum Mol

[58] Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, Bruinenberg M,

[59] Eyre S, Hinks A, Bowes J, Flynn E, Martin P, Wilson AG, Morgan AW, Emery P, Steer S,

[60] Bilbao JR, Martin-Pagola A, Vitoria JC, Zubillaga P, Ortiz L, Castano L. HLA-DRB1 and

[61] Lopez-Vazquez A, Rodrigo L, Fuentes D. MHC class I chain related gene A (MICA)

[62] Schuppan D. Current concepts of celiac disease pathogenesis. Gastroenterology.

[63] Paronen J, Klemetti P, Kantele JM. Glutamate decarboxylasereactive peripheral blood

heterodimer DQA1\*0501/DQB1\*0201. Gut. 2002;50:336-40.

HLA-B and HLA-A. Nature. 2007 Dec 6;450(7171):887-92.

celiac disease. N Engl J Med. 2008;359(26):2767-77.

2003;64(4):469-77.

1989;169:345-50.

Autoimmun. 1999;13:143-8.

Genet. 2009;18(R1):R101-6.

Ther. 2010;12(5):R175.

2000;119:234-42.

Tissue Antigens. 2002;60:71-6.

integrin. Diabetes. 1997;46:583-8.

signalling. Gut. 2009;58(8):1078-83.

Clin Gastroenterol. 2005;19(3):323-39.

disease patients not carrying the DQA1\*05-DQB1\*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol.

Hardy M, King E, Masters J, Hulme J, Maier LM, Smyth D, Bailey R, Cooper JD, Ribas G, Campbell RD, Clayton DG, Todd JA. Wellcome Trust Case Control Consortium. Localization of type 1 diabetes susceptibility to the MHC class I genes

H, McManus R, Wijmenga C, Heap GA, Dubois PC, Clayton DG, Hunt KA, van Heel DA, Todd JA. Shared and distinct genetic variants in type 1 diabetes and

association of celiac disease to a particular HLA-DQ α/βheterodimer. J Exp Med.

diabetes express celiac disease-associated transglutaminase antibodies. J

Heap GA, Platteel M, Ryan AW, de Kovel C, Holmes GK, Howdle PD, Walters JR, Sanders DS, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, Kelleher D, Barisani D, Bardella MT, McManus R, van Heel DA, Wijmenga C. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB

Hocking LJ, Reid DM, Harrison P, Wordsworth P. Yorkshire Early Arthritis Consortium; Biologics in RA Control Consortium, Thomson W, Worthington J, Barton A. Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease. Arthritis Res

MHC class 1 chain-related A haplotypes in Basque families with celiac disease.

modulates the development of celiac disease in patients with the high risk

lymphocytes from patients with IDDM express gut-specific homing receptor α4β7-


**5** 

Peter Kruzliak1,2

*Bratislava, Slovakia* 

*1 5th Department of Internal Medicine,* 

**Hematologic Manifestations of Celiac Disease** 

*2Department of Physiology and Pathophysiology of the Slovak academy of Sciences* 

Celiac disease is a systemic disease, which is associated with a number of hematologic manifestations. Individuals can present with hematological abnormalities even prior to the diagnosis of celiac disease. Anemia secondary to iron, folic acid and vitamin B12 malabsorption is a common complication of celiac disease. Patients can also present with thrombocytosis, thrombocytopenia, leukopenia, venous thromboembolism, hyposplenism and IgA deficiency. Celiac disease also predisposes to lymphoma development. The highest risk is for enteropathy associated T-cell lymphoma (EATL), an aggressive lymphoma with poor prognosis, however an increased risk for B-cell lymphomas and extraintestinal lymphomas has been described. Strict adherence to a gluten-free diet is known to decrease

Anemia is a frequent finding in patients with celiac disease (CD) and may be the presenting feature. It may also be the only abnormality identified. Anemia was particularly common in patients with untreated CD in the past, but it is still frequently encountered in undiagnosed adults.1,2,3,4 The etiology of anemia in celiac disease is multifactorial. The anemia is usually hypoproliferative, reflecting impaired absorption of essential nutrients like iron and various vitamins. In prior studies, the overall prevalence of anemia at the time of diagnosis of celiac disease has been estimated between 12 and 69%. 5,6,7 Anemias caused by hemolysis are very rarely reported in celiac disease patients. Ivanovski et al. reported an 11-year old girl with untreated celiac disease who had hemolytic anemia and suggested that CD should be serologically screened in patient's with Coombs negative "immune" hemolytic anemia. As in this case the anemia improved after initiating a gluten

A number of causative factors deserve consideration for explaining the mechanism of

**1. Introduction** 

the risk of lymphomas.

**2. Anemia** 

free diet. 8

anemia in celiac disease.

**2.1 Mechanisms of anemia in celiac disease** 

*University Hospital and Medical Faculty of Comenius University* 

