Celiac Disease Group Research Articles

Standartization of anti-tissue transglutaminase antibody detection and assessment of transglutaminase interactions with fibronectin: Comparison of the results with two commercially available essays

Standartization of anti-tissue transglutaminase antibody detection and assessment of transglutaminase interactions with fibronectin: Comparison of the results with two commercially available essays

Should coeliac disease be considered in the work up of patients with chronic peripheral neuropathy?

Objective: To investigate whether there is an association between chronic peripheral neuropathy and coeliac disease. Methods: The cause of chronic peripheral neuropathy was first investigated in a group of 478...

CTLA4 is differentially associated with autoimmune diseases in the Dutch population

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is an important negative regulator of T-cell response and its genetic association with type 1 diabetes (T1D) has recently been demonstrated. The frequent co-association of autoimmune diseases (AID) and the implication from multiple genome scans that the CTLA4 gene region is a general autoimmune region, led us to study the role of CTLA4 in independent cohorts of T1D, coeliac disease (CD) and rheumatoid arthritis (RA) patients. We present independent data that confirm the association of CTLA4 in Dutch patients with juvenile onset T1D and show differential association of CTLA4 with CD and RA. The CTLA4 gene polymorphisms were tested for association in 350 T1D, 310 CD, 520 RA patients and 900 controls. In addition, 218 families were tested by the transmission disequilibrium test (TDT). T1D patients showed the highest association with the MH30*G: -1147*C: +49*G: CT60*G: JO37_3*G (haplotype 2) in both a case/control cohort (P=0.002, OR=1.42) and by TDT (P=0.02, OR=1.43). In contrast, this haplotype showed no association in the RA and CD cohorts. However, we observed an increased frequency of the MH30*G: -1147*T: +49*A: CT60*G: JO37_3*A (haplotype 3) in the CD patients diagnosed at a young age (OR=1.6, P=0.026, P (c)=0.052). Furthermore, when T1D and CD patients were stratified based on the HLA risk, the T1D susceptible CTLA4 haplotype 2 was over-represented in the high HLA-risk T1D and CD groups. In conclusion, we confirmed association between CTLA4 haplotype 2 and T1D in the Dutch population. Association with another CTLA4 haplotype (haplotype 3) was confirmed for CD, but only in those patients who had an early age of expression. No effect was found between RA and CTLA4. The association of the CTLA4 haplotype 2 with the high-risk HLA genotype in T1D and CD, which share DQ2 as the one of high-risk alleles, might provide a clue to understanding the common genetic background of AID.

Carnitine deficiency in patients with coeliac disease and idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDCM) and coeliac disease (CD) are two pathological conditions which may lead, by different mechanisms, to malabsorption of various micronutrients, including carnitine, active in cardiac metabolism. The aim of the present investigation was primarily to evaluate differences in serum concentrations of total carnitine between IDCM patients and patients with IDCM associated with CD and then also to evaluate, in the latter, the effect of a gluten-free diet on serum concentrations of total carnitine. Serum carnitine was determined by enzymatic spectrophotometric assay in three groups of individuals: group A, 10 patients (5 males, 5 females), mean age 46.5+/-10.8 years, presenting isolated IDCM; group B, 3 patients (2 males, 1 female), mean age 34+/-8 years, with IDCM+CD; and group C, 10 healthy subjects (5 males, 5 females), mean age 38.6+/-11.1 years. All patients with IDCM belonged to class NYHA I-II. Mean concentrations of total serum carnitine in the group of patients with isolated IDCM (group A) were found to be lower than in the controls (group C). The concentrations in patients with IDCM associated with CD (group B) were lower than in the control group and also lower than in the isolated IDCM (group A). After 2 years on a gluten-free diet, patients presenting IDCM associated with CD showed a progressive increase in mean serum carnitine levels compared to values observed prior to the diet. Patients presenting IDCM associated with CD show a greater decrease in serum total carnitine levels than patients presenting the isolated form of IDCM. A gluten-free diet, in these patients, leads to a progressive increase in serum levels of this substance.

Nutritional Status in Adolescents and Young Adults with Screen‐Detected Celiac Disease

To describe the nutritional status in patients with screen-detected celiac disease (CD). Nutritional status was assessed by serum tests and anthropometric measures in 26 subjects (16 to 25 years of age) with biopsy-proven CD and 29 healthy control subjects (16 to 21 years of age) with negative tissue transglutaminase antibodies (16 to 22 years of age); all the subjects were selected from the cohort of 3654 schoolchildren. Compared with control subjects, CD patients had lower median values of whole blood folic acid (91 versus 109 nmol/L; P = 0.01), serum ferritin (14 versus 27 microg/L; P = 0.028) and pre-albumin (0.21 versus 0.28 g/L; P </= 0.001) and higher transferrin receptor (1.3 versus 1.1; P = 0.008) and serum transferrin receptor-ferritin index (1.2 versus 0.7; P = 0.006). Folic acid concentration was subnormal in 31% of the CD subjects (versus 14% of the controls) and iron status (transferrin receptor-ferritin index) was subnormal in 30% (versus 14%). Body mass index was not different in females of the CD and control groups (22 versus 22 kg/m2) or in the males of the respective groups (25 versus 24 kg/m2). Females with CD were shorter than the controls (mean 162 versus 167 cm; P = 0.018), but no difference was found in males. No association was found between the nutritional status and the markers of mucosal injury (villous-crypt measures), but titer of transglutaminase was associated with whole blood folic acid (r = -0.5; P = 0.016) and with transferrin receptor-ferritin index (r = 0.4, P = 0.05). One third of screen-detected adolescent CD subjects have abnormalities in folate or iron status that call for early diagnosis and dietary treatment of the disease to prevent nutritional deficiencies.

Autoimmune cholestatic liver disease in people with coeliac disease: a population-based study of their association

Population data supporting an association between the autoimmune cholestatic liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis and coeliac disease, is limited and at times contradictory. To explore the relationship between coeliac disease and both primary biliary cirrhosis and primary sclerosing cholangitis within the General Practice Research Database, a UK-based longitudinal primary care database. We identified 4732 people with diagnosed coeliac disease and 23 620 age- and sex-matched controls within the General Practice Research Database. We calculated the prevalence of primary biliary cirrhosis and primary sclerosing cholangitis for both the coeliac disease and control group. There was a higher prevalence of primary biliary cirrhosis in adults with coeliac disease, compared with controls [0.17% vs. 0.05%, odds ratio 3.63 (95% confidence interval: 1.46-9.04)]. Primary sclerosing cholangitis was also more common in the coeliac disease group [0.04% vs. 0%, fishers exact test (P = 0.03)]. There was a threefold or greater increase in risk of both primary biliary cirrhosis and primary sclerosing cholangitis in people with coeliac disease compared with the general population. The association with primary biliary cirrhosis was weaker than in some reports and it is difficult on the basis of this study to justify screening patients with coeliac disease for either primary biliary cirrhosis or primary sclerosing cholangitis.

Anthropometry, metabolic control, and thyroid autoimmunity in type 1 diabetes with celiac disease: A multicenter survey

To investigate the influence of celiac disease (CD) on growth and metabolic control in a nationwide cohort of children and adolescents with type 1 diabetes (T1D). We analyzed data from 19,796 pediatric patients with T1D in the German pediatric multicenter DPV-database for occurrence of CD. CD-specific antibodies were present in 1326 patients (6.7%). The diagnosis was confirmed in 127 patients (0.6%) by small-bowel biopsy. Female subjects were significantly more predisposed to have T1D and CD. The CD-affected patients in our cohort were significantly younger at diabetes onset. Furthermore, they had significantly lower height-SDS at onset (-0.49 vs -0.06, P < .05), a difference that increased during the course of the disease (-0.80 vs -0.26 after 9 years of diabetes, P < .05). In addition, body mass index-SDS significantly differed between the groups (0.22 vs 0.47, P < .05). Evidence for thyroid disease was more commonly observed in the T1D with CD group (6.3% vs 2.3%, P < .05). HbA1c values were lower in the patients with T1D and CD. The CD-positive patients were characterized by earlier onset of diabetes and decreased growth and weight gain. These findings emphasize the clinical relevance of celiac disease in patients with autoimmune diabetes.

Oral findings in coeliac disease and Sjögren's syndrome

Both coeliac disease (CD) and Sjogren's syndrome (SS) have an autoimmune background and increased risk of oral mucosal and dental abnormalities. Individuals suffering concomitantly from CD and SS could even be at a higher risk. Oral mucosal and dental abnormalities were examined in 20 patients with CD + SS (mean age 61 years) and compared with age- and sex-matched controls with either CD or SS. Oral mucosal changes were most common in SS (80%), followed by CD + SS (65%) and CD (40%). Coeliac-type dental enamel defects were found in 89% in CD + SS and in 88% in CD compared with only 25% in SS (P < 0.001). The median number of teeth was six in the CD + SS, 24 in the CD and 22 in the SS group. The DMF index was higher (P < 0.005) in the CD + SS than in the CD group. CD + SS was characterized by higher salivary flow rate (P < 0.001) and lower inflammatory focus score in the salivary glands (P < 0.01) than SS. The co-occurrence of CD and SS should be recognized because of its effects on dental and oral mucosal health. A lower salivary gland inflammatory focus score and higher salivary flow rate in CD + SS than in SS suggests that a gluten-free diet treatment may alleviate autoimmune inflammation.

MICA response to gliadin in intestinal mucosa from celiac patients

MHC class I chain-related gene A (MICA), a putative independent susceptibility gene in autoimmune diseases, encodes a surface protein present in epithelial cells that binds to NKG2D, an activating receptor of NK, alphabeta and gammadelta T cells, and could function as a stress-inducible activator of the innate immune response. There is no evidence of a long-term implication of MICA in the celiac autoimmune process. However, it could be that gliadin activation of MICA occurs only during the initial stages of the disease. In order to determine whether MICA is activated in response to gliadin in patients with celiac disease (CD), small intestinal mucosa biopsy samples from ten long-standing celiac patients on a gluten-free diet and from five non-celiac individuals were incubated with and without gliadin for 4 h. Total RNA was purified and MICA, IFNG and NKG2D mRNA were quantified by fluorescent real-time RT-PCR. Expression levels were calculated relative to GAPDH. MICA expression was detected in both patients and controls, but incubation with gliadin induced a strong increase in samples from the treated CD group compared with the non-CD controls (P=0.028), while no differences were observed for IFNG or NKG2D mRNA levels. The gliadin-provoked over-expression of MICA in "normalized" tissues from CD patients suggests a role for this stress-induced activator of the immune response in the early stages of organ-specific autoimmune destruction, probably preceding the onset of inflammation.

The role of defective mismatch repair in small bowel adenocarcinoma in celiac disease.

Celiac disease is associated with an increased risk of small bowel adenocarcinoma. The aims of this study were to investigate the molecular basis, assess outcomes, and identify clinicopathologic characteristics of small bowel adenocarcinoma in celiac disease. Retrospective case control cohort study of all celiac disease patients treated at our institution for small bowel adenocarcinoma and matched control patients with sporadic small bowel adenocarcinoma from July 1960 to November 2002. Mismatch repair (MMR) status was accessed by testing tissue for microsatellite instability (MSI) and for hMLH1 and hMSH2 protein expression. Over a 40-year time period, 18 patients with small bowel adenocarcinoma and celiac disease were treated at the Mayo Clinic. One celiac disease patient was excluded. High-frequency MSI (MSI-H) was identified in 8 of 11 (73%) and 2 of 22 (9%) available small bowel adenocarcinoma specimens in the celiac disease and control groups, respectively. In the celiac disease group, MSI-H was associated with loss of hMLH1 and hMSH2 in 6 and 1 specimens, respectively. Loss of hMLH1 occurred in both control tumors. Stage was associated with celiac disease status (P = 0.018), and 78% of controls were stage III or IV compared with 47% of celiac disease patients. Overall, survival was better (P = 0.025) in the celiac disease group compared with stage-matched controls. Celiac disease patients with small bowel adenocarcinoma had a high incidence defective MMR (73%) compared with controls and had better survival compared with stage-matched controls. In addition, celiac disease patients presented more frequently with early-stage small bowel adenocarcinoma. The better survival and earlier presentation of small bowel adenocarcinoma in celiac disease appears to be biologically associated with defective MMR.

Neurologic Complications of Celiac Disease

Source: Zelnik N, Pacht A, Obeid R, et al. Range of neurologic disorders in patients with celiac disease. Pediatrics. 2004;113:1672–1676.Investigators at the Carmel Medical Center in Haifa, Israel, sought to study the neurologic complications of celiac disease (CD) among a cohort of patients evaluated between 1977 and 2001. Patients with celiac disease [n=111] and controls [n=211] matched for age and gender were questioned regarding neurologic disorders, had their charts reviewed, and received neurologic evaluations, including brain imaging or electroencephalography, if indicated. Prior to 1988, diagnosis of CD was based on 3 consecutive intestinal biopsies. After 1988, the diagnostic approach was simplified and was based on immunoglobulin A antiendomysial antibodies and 1 intestinal biopsy. The mean age of patients and controls was 20.1 ± 9 years, and the male to female ratio was 2:3. The CD was classical infantile (diagnosed at 1.8 years) in 58 (52.3%) patients and later in onset (diagnosed at 14.8 years) in 53 (47.7%) patients. Neurologic disorders were found in 57/111 (51.4%) of patients with CD, whereas only 42/211 (19.9%) control subjects had abnormal neurologic findings. Patients with late-onset CD had more neurologic complications than the classical CD group (54.7% versus 48.3%), but the difference was not significant. Neurologic abnormalities and their frequency compared to controls included: hypotonia, 21.6% versus 3.8% (P<.01); developmental delay, 15.5% versus 3.3% (P<.01); seizures, 7.2% versus 0.8% (P<.09); learning disabilities and ADHD, 20.7% versus 10.5% (P<.01); headache, 27.9% versus 8.1% (P<.01); ataxia, 5.4% versus 0% (P<.01); and tics, 0.9% versus 2.4% (P=.67). Seizure disorders were more frequent with CD but not significantly, and tic disorders showed no increased prevalence. The gluten-free diet only benefited those CD patients with infantile hypotonia and migraine headache.The range of neurologic disorders associated with CD is wider than previously reported and includes chronic migraine headache, developmental delay, hypotonia in infants, learning disabilities, ADHD,1,2 and seizures. Apart from cases of epilepsy with occipital calcifications, recurrent seizures were not significantly correlated with CD.In occipital lobe seizures related to CD, the CD may be clinically asymptomatic.3 The incidence of silent CD in children with idiopathic localization epilepsies and the indications for routine CD screening were established in a study of 72 patients (mean age, 12.6 years) observed over a 5-year period.4 Two (8%) of 25 patients with childhood partial epilepsy with occipital paroxysms (CPEO) had positive IgA-antiendomysium antibodies, and jejunal biopsies showed villous atrophy and crypt hyperplasia, confirming the diagnosis of CD. Brain CT showed occipital calcifications in one. Seizures were controlled by treatment with a gluten-free diet, and no brain calcifications developed in the patient with a normal CT after a 3-year follow-up on a gluten-free diet.Forty-seven patients with childhood partial epilepsy with centrotemporal spikes (CPEC) had negative antibody tests for CD.4 CD screening is recommended in children with CPEO but not in those with CPEC and extraoccipital spikes. Early diagnosis and dietary intervention may reverse the tendency to seizures and brain calcifications. The gluten-free diet was also successful in the relief of migraine headaches. Wheat cereal is a known migraine trigger in some children5 and positive reactors should be screened for CD.The underlying pathophysiology linking gluten to neurologic disorders is not well characterized in this study, which refers only to its non-specific immunologic and inflammatory effects. Nonetheless, the association between gluten and brain disorders appears to be very strong, and some patients’ neurologic symptoms remit when gluten is removed from their diet. Thus, to separate the wheat of celiac disease-associated neurologic disorders from the chaff of the truly idiopathic, we must consider celiac disease as a possible etiology for a variety of neurologic presentations.

The role of defective mismatch repair in small bowel adenocarcinoma in celiac disease

Abstract Introduction: Celiac Disease (CD) is associated with an increased risk of small bowel (SB) adenocarcinoma. The aims of this study were to investigate the molecular basis and assess outcomes of SB adenocarcinoma in CD. Methods: We performed a retrospective case control study of 18 biopsy-proven CD patients with SB adenocarcinoma, 51 age- and gender-matched control patients, and 40 age-, gender-, and stage-matched control patients with SB adenocarcinoma treated at our institution from 7/1960 to 11/2002. Mismatch Repair (MMR) status was assessed by microsatellite instability (MSI) and hMLH1 and hMSH2 protein expression by immunohistochemistry. Results: One CD patient was excluded due to postmortem diagnosis of cancer. High frequency MSI (MSI-H) was identified in 8/11 (73%) tumors in the CD group and 2/22 (9%) in the control groups. Expression of hMLH1 was lost in 6/8 and 2/2 MSI-H tumors in the CD and control groups, respectively. One MSI-H tumor lost hMSH2 expression in the CD group. CD patients presented with lower stage cancer compared to controls (P = 0.018). Survival was improved in the CD group when compared to stage-matched controls (5-year survival 64% versus 24%, P=0.025), and was not associated with stage in the CD group. Conclusions: CD patients with SB adenocarcinoma had remarkably high incidence of defective MMR and better survival compared to stage-matched controls. CD patients presented with earlier stage cancers and stage was not a strong prognostic indicator. Improved survival and earlier presentation of SB adenocarcinoma in CD may be biologically linked to defective MMR.

Characteristics and Quality of Illness Behavior in Celiac Disease

The study evaluated the illness behavior of patients with celiac disease and the influence of the disease and its treatment on key personality components and adherence to dietary recommendations. Twenty-nine adult patients with celiac disease and 47 matched healthy comparison subjects participated in the study. More than 70% of the celiac disease group scored in the pathological range on at least one scale of the Illness Behavior Questionnaire. Patients who received the diagnosis in adulthood had a lower score for nonconformism, a greater tendency to pretend to be sociable, and higher levels of psychophysiological reactiveness, relative to the comparison subjects. The results suggest that celiac disease may be associated with changes in personality that may interfere with patients' adaptation to living with a chronic disease.

Abnormalities of Th 1 function in non-IgE food allergy, celiac disease, and ileal lymphonodular hyperplasia: a new relationship?

Non-IgE mechanisms may also be involved food allergy (FA). Our group has been studying the immunopathogenesis clinical entities in children with gastro-intestinal symptoms and in whom biopsies of the terminal ileum show lymphoid tissue masses referred to as ileal lymphonodular hyperplasia. Our more recent studies have demonstrated Th1/Th2 cytokine profiles associated with non-IgE FA and other clinical entities. We investigated 12 subjects with non-IgE FA (group 1) and 4 subjects with celiac disease (group 2). Cytokine profiles and immunologic studies of lymphocytes in peripheral blood and from gastro-intestinal biopsy tissues from patients in groups 1 and 2 were also evaluated. Group 1 consisted of 12 children with clinical symptoms of anorexia, diarrhea, and abdominal pain. The diagnosis of non-IgE FA was established by positive double-blind, placebo-controlled food challenge and reduced or negative immediate-type skin testing and negative IgE radioallergosorbent tests. Group 2 consisted of four patients with celiac disease and three adult females with biopsy-proven clinical symptoms of celiac disease. In group 1, peripheral blood CD4 and CD8 lymphocyte distributions were normal, with a predominance of CD4+ cells with a decreased intracellular Th1 cytokine pattern and a normal Th2 intracellular cytokine pattern. In contrast, all four patients in group 2 not only displayed abnormal CD4 and CD8 peripheral blood lymphocyte distributions (CD8 > CD4), but also an abnormal predominance of CD4+ cells with an increased Th1 and a normal Th2 cytokine pattern. A similar abnormal pattern of CD4 > CD8 ratio was observed in intestinal biopsies. All 12 patients in group 1 showed lymphonodular hyperplasia in each of the biopsies and by ileoscopy. These studies suggest that abnormalities in Th1 function may not only play a role in some patients with non--IgE-mediated FA in whom decreased Th1 function is seen, but also in patients with celiac disease in whom an increased Th1 function is seen. The studies also suggest that lymphonodular hyperplasia may be a hallmark histologic lesion in patients with non--IgE-mediated FA.

Increased Prevalence of Autoimmune Diseases in First-Degree Relatives of Patients With Celiac Disease

The prevalence of autoimmune disorders is increased in patients with celiac disease (CD), and it is unknown whether their first-degree relatives also have a high risk of autoimmune disorders. To assess the prevalence of autoimmune diseases in first-degree relatives of CD patients, the authors looked for autoimmune disorders in 225 first-degree relatives of 66 children with CD (group A) and in 232 first-degree relatives of 68 healthy children (group B). For both groups, serologic screening for CD was performed through antiendomysium (EMA) and tissue transglutaminase autoantibodies (tTGAA). EMA- and tTGAA-positive subjects were offered an intestinal biopsy. The age at onset of autoimmune diseases was also recorded in group A. The prevalence of autoimmune disorders was significantly (P = 0.028) higher in group A (11 of 225, 4.8%) than in group B (2 of 232, 0.86%). In relatives of CD patients, the prevalence increased with age (chi2 for trend, 43.5; P < 0.0001). Serologic screening for CD was only positive in group A (15 of 225 subjects). An intestinal biopsy was performed in 13 of these 15 relatives (2 refused biopsy). Eleven of 13 had flat mucosa, with subclinical or silent forms of CD. The prevalence of autoimmune diseases in the EMA- and tTGAA-positive relatives of CD patients was significantly higher (3 of 15, 20%; P = 0.028; odds ratio, 6.3; 95% CI, 1/0.21-1/0.11, 4.9-7.6) than in those who were EMA and tTGAA negative (8/210, 3.8%). The first-degree relatives of CD patients have an increased risk of autoimmune diseases, most likely connected with unrecognized subclinical or silent forms of CD.

Increased Prevalence of Autoimmune Diseases in First‐Degree Relatives of Patients With Celiac Disease

ABSTRACTBackgroundThe prevalence of autoimmune disorders is increased in patients with celiac disease (CD), and it is unknown whether their first‐degree relatives also have a high risk of autoimmune disorders.MethodsTo assess the prevalence of autoimmune diseases in first‐degree relatives of CD patients, the authors looked for autoimmune disorders in 225 first‐degree relatives of 66 children with CD (group A) and in 232 first‐degree relatives of 68 healthy children (group B). For both groups, serologic screening for CD was performed through antiendomysium (EMA) and tissue transglutaminase autoantibodies (tTGAA). EMA‐ and tTGAA‐positive subjects were offered an intestinal biopsy. The age at onset of autoimmune diseases was also recorded in group A.ResultsThe prevalence of autoimmune disorders was significantly (P = 0.028) higher in group A (11 of 225, 4.8%) than in group B (2 of 232, 0.86%). In relatives of CD patients, the prevalence increased with age (χ2 for trend, 43.5;P &lt; 0.0001). Serologic screening for CD was only positive in group A (15 of 225 subjects). An intestinal biopsy was performed in 13 of these 15 relatives (2 refused biopsy). Eleven of 13 had flat mucosa, with subclinical or silent forms of CD. The prevalence of autoimmune diseases in the EMA‐ and tTGAA‐positive relatives of CD patients was significantly higher (3 of 15, 20%;P = 0.028; odds ratio, 6.3; 95% CI, 1/0.21–1/0.11, 4.9–7.6) than in those who were EMA and tTGAA negative (8/210, 3.8%).ConclusionsThe first‐degree relatives of CD patients have an increased risk of autoimmune diseases, most likely connected with unrecognized subclinical or silent forms of CD.

Cytokine genotyping (TNF and IL-10) in patients with celiac disease and selective IgA deficiency.

Selective IgA deficiency (IgAD) and celiac disease (CD) are frequently associated and share the ancestral haplotype human leukocyte antigen (HLA)-8.1, which is characterized by a peculiar cytokine profile. The aim of this study was to evaluate the role of tumor necrosis factor (TNF) and interleukin (IL)-10 alleles in CD and CD-IgAD. The distribution of some biallelic polymorphisms of both cytokine promoters (-308G-->A and -863C-->A at TNF promoter sequence and -1082G-->A, -819C-->A, and -592C-->T at IL-10 promoter) were typed using biotilinated specific probes in 32 celiac patients, in 34 CD-IgAD patients, and in 96 healthy controls. In CD and CD-IgAD, the -308A allele was significantly more frequent than in controls, whereas no significant differences were observed for the biallelic polymorphisms at the -863 and for the three IL-10 promoter polymorphisms. The evaluation of combined TNF and IL-10 genotypes showed in CD-IgAD a significant reduction of -308G/-1082G homozygous subjects and both in CD and CD-IgAD groups an increase of 308AA/1082GG. Accordingly, CD-IgAD patients positive both for -308A TNF and -1082A IL-10 showed an increase of TNF-alpha and a reduction of IL-10 serum levels. Genetically determined increased production of TNF-alpha and reduction of IL-10 may be relevant for susceptibility to CD, mainly in IgAD, as the different allele expression at TNF and IL-10 loci seems to influence cytokine production profile.

Cytokine genotyping (TNF and IL-10) in patients with celiac disease and selective IgA deficiency

Objective Selective IgA deficiency (IgAD) and celiac disease (CD) are frequently associated and share the ancestral haplotype human leukocyte antigen (HLA)-8.1, which is characterized by a peculiar cytokine profile. The aim of this study was to evaluate the role of tumor necrosis factor (TNF) and interleukin (IL)-10 alleles in CD and CD-IgAD. Methods The distribution of some biallelic polymorphisms of both cytokine promoters (−308G→A and −863C→A at TNF promoter sequence and −1082G→A, −819C→A, and −592C→T at IL-10 promoter) were typed using biotilinated specific probes in 32 celiac patients, in 34 CD-IgAD patients, and in 96 healthy controls. Results In CD and CD-IgAD, the −308A allele was significantly more frequent than in controls, whereas no significant differences were observed for the biallelic polymorphisms at the −863 and for the three IL-10 promoter polymorphisms. The evaluation of combined TNF and IL-10 genotypes showed in CD-IgAD a significant reduction of −308G/−1082G homozygous subjects and both in CD and CD-IgAD groups an increase of 308AA/1082GG. Accordingly, CD-IgAD patients positive both for −308A TNF and −1082A IL-10 showed an increase of TNF-α and a reduction of IL-10 serum levels. Conclusions Genetically determined increased production of TNF-α and reduction of IL-10 may be relevant for susceptibility to CD, mainly in IgAD, as the different allele expression at TNF and IL-10 loci seems to influence cytokine production profile.

Prevalence of autoimmune disorders in relatives of patients with celiac disease.

Celiac disease (CD) is frequently associated with an autoimmune disorder (AD). The aim of the study was to establish if an AD is more frequent than expected in relatives of CD patients and, in particular, if it is related to the presence of silent unrecognised CD. We also evaluated the prevalence of ADs in CD patients and compared it with that in a control series. A structured questionnaire was used to evaluate the prevalence of ADs in 125 (51 males and 74 females with a mean age of 8.9 years) children with CD (group A), 125 (67 males and 58 females with a mean age of 8.1 years) matched "healthy" children (group B), all 1352 first- and second-degree relatives of the 125 children with CD (group C), all 1238 first- and second-degree relatives of the control group B of "healthy" children (group D), and all 205 first- and second-degree relatives of 20 children with AD (group E). We also used the antiendomysium antibody assay to screen 354 of the 373 first-degree relatives of group C. An AD was present in 9 of the 125 (7.2%) children with CD (group A), in 1 of the 125 (0.8%) healthy children (group B), in 67 of the 1352 (4.9%) relatives of CD patients (group C), in 14 of the 1238 (1.1%) relatives of healthy children (group D), and in 7 of the 205 (3.4%) of relatives of patients with AD (group E). Clinically silent CD was found in 20 of the 354 first-degree relatives of CD patients (5.6%), and the risk of silent CD was significantly higher, reaching 25% (4/16) in the subgroup of relatives also affected by another AD. Relatives of CD patients had an increased prevalence of AD compared to control groups, and relatives of CD patients with ADs, have a risk as high as 25% of being silent celiacs: they should thus be screened for CD.

Bone mineral density and importance of a gluten-free diet in patients with celiac disease in childhood.

Celiac disease (CD), a common cause of malabsorption, is known to be associated with disorders of the skeleton, but there are conflicting data about the effect of diet on bone metabolism. The aims of this study were to investigate the prevalence of osteopenia; to identify the relationship between bone mineral density (BMD), serum calcium, and parathyroid hormone levels; and to determine the effect of gluten-free diet on BMD in children with celiac disease. The study included 32 patients with CD (group 1) and 82 healthy controls (group 2). The patients with CD were evaluated under 2 subgroups, ie, 16 patients with recent diagnosis (group 1a) and 16 patients who follow their diet strictly (group 1b). BMD values and concentrations of calcium, phosphorus, alkaline phosphatase, and intact parathyroid hormone were determined on entry to the study and at 12 months in celiac patients. These values were compared with those of healthy control participants. BMD and bone mineral content values in patients with recent diagnosis were found to be significantly lower than the control group. The BMD values in patients with recent diagnosis were significantly increased after a gluten-free diet for 1 year. Osteopenia was found more commonly in patients with recent diagnosis than patients in whom a gluten-free diet had been instituted. At 1-year follow-up, osteopenia was not resolved with the gluten-free diet, and this was especially true in patients without gastrointestinal manifestation. In patients with recent diagnosis (group 1a), the mean calcium level was found to be lower than the patients who follow their diet strictly (group 1b). There was a positive correlation between calcium level and BMD and bone mineral content. BMD is almost invariably low in newly diagnosed celiac patients in childhood. We therefore recommend that BMD should be evaluated in patients with CD. Strict gluten avoidance promoted a significant increase in BMD. However, values still remained markedly low after 1 year of follow-up in some patients. These patients should be followed for longer periods of time with yearly BMD evaluation, as 1 year of diet therapy was found to be insufficient for osteopenia to be resolved.