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We reported a female patient with unrecognized celiac disease and multiple extra intestinal manifestations, mainly related to a deranged immune function, including macroamilasemia, macrolipasemia, IgA nephropathy, thyroiditis, and anti-b2-glicoprotein-1 antibodies, that disappeared or improved after the implementation of a gluten-free diet.
The contribution of HLA genes to the genetic risk for celiac disease (CD) has been known for a long time. Recent publications have pointed to the possibility that a second, independent susceptibility locus could be located in the same genomic region, and a triplet repeat polymorphism in exon 5 of the gene MHC class I chain-related protein A (MICA; located between TNFA and HLA-B) has been associated with several autoimmune disorders, including type 1 diabetes mellitus (DM1) and Addison's disease. On the other hand, a single amino acid change in exon 3 of MICA (M129V) has been shown to strongly reduce MICA binding to NKG2D, an activating natural killer receptor expressed also on T cells, and this could have significant effects on autoimmune reactions. In this study, we have analyzed the contribution of these polymorphisms to CD in 37 Basque families, and have constructed MICA-HLA-DRB1 haplotypes to determine whether MICA has an effect independent from the HLA class II conferred risk. In our population, HLA-DRB1*0301 was associated with an increased risk for CD, while HLA-DRB1*1501 conferred protection from the disease (OR: 7.38 and 0.06, respectively). On the other hand, MICA allele A4 was positively associated with the disease (OR: 4.69) whereas allele A9 showed a trend towards protection (OR: 0.18), although significance did not hold after correction. No association of the exon 3 biallelic polymorphism was observed. A positive allelic association was found for haplotypes A5.1-DRB1*0301 (associated with risk for disease), A4-DRB1*0301 and A6-DRB1*07. In view of our results, both HLA-DRB1 and MICA are associated with CD, but stratification analysis did not show any independent contribution of the MICA polymorphisms analyzed to CD risk. Besides, MICA allele A4 (also A5.1 was associated with risk for CD and other diseases) is in strong linkage disequilibrium with HLA-DRB1*0301. Finally, the major histocompatibility complex region's conferred susceptibility to CD, at least in Basque, is very similar to that observed for DM1, with shared risk and protective haplotypes.
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-alpha and a reduction of IL-10 serum levels. CONCLUSIONS: 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.
A 13-year-old boy suffering from celiac disease (CD) developed shortness of breath at exercise and episodes of malaise, fever and acute dyspnea following contact with pigeons. Lung function testing and chest X-ray suggested interstitial lung disease. Serum precipitins and a combined systemic and pulmonary reaction 4 h after challenge with an extract of pigeon droppings confirmed bird-fancier's lung. This case exhibits two points of interest. Extrinsic allergic alveolitis was found in childhood in combination with CD and it may be considered that both these diseases are based on one common immunologic disorder; HLA-typing of the boy's family showed that he carried HLA-DR 3 in a double dose and was therefore homozygous for HLA-DR 3. This is of some interest because extrinsic allergic alveolitis and CD are both associated with HLA-DR 3.
Gastrointestinal injury involves oxidative damage as the result of oxygen-derived free radicals which are formed during the inflammatory reactions. Chylomicrons which are synthesized by the intestine can thus be exposed to lipid peroxidation in celiac disease. Similarly, low-density lipoprotein (LDL) propensity to oxidation may be enhanced as a result of a direct or indirect effect of the oxidative process. To resolve these possibilities, plasma chylomicrons and LDL were isolated from a patient with celiac disease and from a control healthy subject before and 3 h after a fat-rich meal, and their propensity to copper-induced lipid peroxidation was then analyzed. The patient's chylomicrons, its LDL that was obtained before the fat-rich meal and its LDL that was obtained after the meal demonstrated 220, 39 and 48% elevation in their content of thiobarbituric-acid-reactive substances in comparison with the control lipoproteins. After a complete recovery of the patient's intestine, the susceptibility of the patient lipoproteins to in vitro oxidation returned toward normal levels. In the patient LDL fraction (obtained either before or after the fat-rich meal), but not in the patient's chylomicrons, the carotenoid content was reduced by 70%, vitamin E by 45%, and the LDL content of arachidonic acid was increased by 70% in comparison with the control lipoproteins. On recovery of the patient and return of the intestine to its normal morphology, normalization of all of these constituents was achieved.
We selected 38 consecutive celiac disease (CD) patients (from a group of 316 consecutive CD patients) and 91 healthy blood donors, all of whom were HLA-DQ2 (DQA1*0501/DQB1*0201) negative, and investigated the presence of the classically associated alleles HLA-DQ8 and HLA-DRB4. We also studied the distribution of MICA transmembrane alleles in the two clinical forms of the disease. For this reason, these 38 DQ2-negative patients were subdivided into two groups: 18 typical CD patients and 20 atypical CD patients. No differences were found in the distribution of the DRB4 allele between DQ2-negative patients and controls. The HLA-DQ8 heterodimer (DQA1*03xx/DQB1*0302) was increased in CD patients (29%) compared with controls (10%), but no statistical differences were found. No differences were observed in the frequency of these alleles between either group of CD DQ2-negative patients. MICA-A5.1 was increased in atypical CD patients when compared with the typical forms of disease ( P(c)=0.03) and with healthy controls (P(c)=0.002). No other MICA allele was found to be significantly increased in the groups under study. The presence of MICA-A5.1 in atypical CD DQ2-negative patients may indicate a possible role of this allele in the development of CD.
This case report describes the uncommon occurrence of celiac disease and cystic fibrosis in an obese adult patient. Apart from its rarity, the case serves to highlight the elusive nature of these 2 diseases when presenting with atypical clinical features in an adult.
Jejunal mucosa is responsible for the absorption of triglycerides and the production of lipoproteins [chylomicrons, very-low-density lipoprotein (VLDL), high-density lipoprotein (HDL)] and apolipoproteins (B-48, A-I, A-II, A-IV, C-II). Mucosal damage is known to cause fat malabsorption and probably also affects the serum lipid profile. To determine lipoprotein production in states of enterocyte dysfunction, we compared the serum lipid profiles in a group of 12 children with untreated celiac disease (flat jejunal mucosa) with the profiles in a control group of 10 children suffering from other intestinal diseases. Statistically significant differences were found in the following parameters (celiac versus control): plasma levels of triglycerides (70 versus 119 mg/dl), cholesterol content in LDL (107 versus 67.7 mg/dl), protein content in VLDL (6 versus 10 mg/dl), and level of apoprotein A-I (112 versus 140 mg/dl). No significant differences were found between the two groups in the serum levels of total cholesterol, the cholesterol content in VLDL and HDL, the protein content in LDL and HDL, and the level of apoprotein B. Following institution of a gluten-free diet, the lipoprotein profile reverted to normal. These data suggest that the changes in the serum lipoprotein profile in celiac disease are secondary to alterations in enterocyte function and not only a reflection of fat malabsorption.
IgG and IgA antigluten antibodies (Gab) were assayed in 83 celiac disease (CD) patients typed for HLA and Gm markers. Their titer and frequency were lower when a gluten-free diet was given than in active CD; these were significantly correlated, whereas no correlation was found between titer and serum Ig. Persistence of high titers was mainly confined to HLA-DR3 negative females (45% vs 6.7% of DR3 positive females and 19.3% of males). No association was found with any Gm allotype, in contrast with the previously reported involvement of the "fnb" haplotype with both CD susceptibility and Gab persistence in patients on a gluten-free diet. A technical and/or genetic explanation could be given for these differences.
BACKGROUND: Increased urine secretion of peptides has been found in celiac disease, probably resulting from increased intestinal uptake of peptides caused by damage to the small gut mucosa. METHODS: High-performance liquid chromatography of low-molecular-weight peptides in the urine was performed over 6 months, before and after a gluten-free diet was instituted in children who clinically improved while consuming the diet. RESULTS: A significant decrease of peptide levels was observed in children consuming the gluten-free diet. Certain peptide peaks thought to be gluten related decreased the most after the patients began the diet. CONCLUSIONS: Because the peptides decrease in patients consuming a gluten-free diet, it is reasonable to conclude that such peptides have a mostly dietary origin.
By screening the patient list of four Sicilian centers of gastroenterology and those with gluten-free product consumption, 1074 patients (607 females and 467 males) with celiac disease, diagnosed between 1975 and 1989, were identified. A maximum cumulative incidence rate by birth cohort was reached in 1986 (1.65/1000). When the incidence rate was adjusted for the years of follow-up, the actual standardized rate was 3 cases per 1000 live births. Growth failure and chronic diarrhea were the most common symptoms, but a diminishing trend for chronic diarrhea was observed when symptoms were distributed by year of diagnosis. Even though 61.1% of all cases were diagnosed within six months from the onset of symptoms, mean age at diagnosis showed an increasing trend, from less than two years to approximately four years of age. The results of our study showed an increasing incidence of celiac disease due to diagnosis of less typical cases at an older age and also to a steady increase in the rate of diagnosis of cases with a classic clinical picture.
The relationship between adenovirus type 12 (Ad12), celiac disease (CD) and dermatitis herpetiformis (DH) was evaluated by enzyme-linked immunosorbent assay (ELISA). Diagnostic phase serum samples from 44 children with CD, 16 children with DH and 60 matched controls were studied for serum antibodies to synthetic peptides derived from an early E1b protein of Ad12 and A gliadin. Both the patient groups had significantly (p < 0.001) higher IgG antibody levels to the Ad12 E1b peptide than the controls. The difference was especially pronounced for girls (p < 0.005). Antipeptide IgG antibodies to Ad12 E1b and A gliadin posed a synergistic increase in the CD and DH risk suggesting that infection with Ad12 is associated with CD and DH.
Several immunoglobulin allotypes were determined for 42 Finnish children with celiac disease (CD) and for 42 normal controls. The CD patients had been previously HLA typed; all but 2 were positive for HLA B8, DR3 or both. The incidence of HLA B8, DR3 and DR7 was found to be significantly higher in patients than in a control group. No significant association was found between any of the immunoglobulin allotypes and CD either when patients were grouped as a whole or when grouped according to sex. In addition, no association was found between levels of antigliadin antibody and the G2m(23) allotypic marker. This latter finding is in sharp contrast with the report of a significant association in American Caucasians between G2m(23) and the level of antigliadin antibodies by Weiss et al. [J. clin. Invest. 72: 96-101, 1983].
OBJECTIVE: To assess the prevalence of celiac disease (CD) among a group of epileptic patients attending the Epilepsy Clinics of two general hospitals in the city of Brasilia (DF), Brazil. METHOD: Serum samples were collected from 255 epileptic patients (119 children, 136 adults) originating from Epilepsy Clinics, and from a control group composed by 4405 individuals (2034 children, 2371 adults) attending the Laboratory of Clinical Analysis, for routine blood testing. The diagnosis of CD was determined by the antiendomysium antibody (IgA-EMA) test and by small intestine biopsy. RESULTS: two of the 255 epileptic patients (1:127) and fifteen subjects from the control group (1:293) tested positive for the IgA-EMA assay. CONCLUSION: the prevalence of CD was 2.3 times higher in epileptic patients than in controls (7.84 per 1000 versus 3.41 per 1000). Although still not statistically significant, this result is highly suggestive of an increased prevalence of CD among epileptic patients.
The growth pattern of 28 girls and 32 boys with celiac disease was analyzed up to the ages of 10 and 12 years, respectively. Fifty-four patients (90%) were diagnosed before 4 years of age and six patients (10%) between 5 and 9 years of age. At diagnosis, 18 of 60 patients (30%) had a height SD score below -2.0, and 45 of 59 patients (76%) had a weight-for-height below the median. The mean height SD score showed increasing growth retardation in the year before diagnosis, relatively quick catch-up growth in the year after diagnosis, and complete catch-up in 2-3 years. Mean weight-for-height showed a progressive decrease 12-18 months before diagnosis, increased to a maximum at the end of the first year of therapy, and returned to normal 15 months after dietary treatment. Independent of age at diagnosis, initial degree of wasting, diagnostic delay, and strictness of gluten-free diet, catch-up growth was complete in this group of patients who were diagnosed before 9 years of age.
MICA molecules interact with the NKG2D-activating receptor on human NK and CD8 T cells. We investigated the participation of the MICA/NKG2D pathway in the destruction of intestinal epithelium by intraepithelial T lymphocytes (IEL) in Celiac disease and its premalignant complication, refractory sprue. We show that MICA is strongly expressed at epithelial cell surface in patients with active disease and is induced by gliadin or its p31-49 derived peptide upon in vitro challenge, an effect relayed by IL-15. This triggers direct activation and costimulation of IEL through engagement of NKG2D, leading to an innate-like cytotoxicity toward epithelial targets and enhanced TCR-dependent CD8 T cell-mediated adaptive response. Villous atrophy in Celiac disease might thus be ascribed to an IEL-mediated damage to enterocytes involving NKG2D/MICA interaction after gliadin-induced expression of MICA on gut epithelium. This supports a key role for MIC/NKG2D in the activation of intraepithelial immunity in response to danger.
BACKGROUND & AIMS: Studies of cancer risk in celiac disease (CD) or dermatitis herpetiformis (DH) indicate increased risks for malignant lymphoma and occasionally other neoplasms, but are characterized by small numbers, lack of systematic cancer assessment, and subjects identified from referral institutions. METHODS: By using Swedish population-based inpatient and cancer registry data, we followed-up 12,000 subjects with CD or DH, and evaluated cancer incidence by using standardized incidence ratios (SIR). RESULTS: Adults (but not children and adolescents) with CD had an elevated overall risk for cancer (SIR = 1.3) that declined with time and eventually reached unity. Elevated risks were found for malignant lymphomas, small-intestinal, oropharyngeal, esophageal, large intestinal, hepatobiliary, and pancreatic carcinomas. The excess occurrence of malignant lymphomas was confined to adults, decreased with time of follow-up evaluation, and decreased over successive calendar periods. Decreased risks were found for breast cancer. Subjects with DH had a slightly increased overall cancer risk (SIR = 1.2) owing to excesses of malignant lymphoma and leukemia, but no increases of gastrointestinal carcinomas. CONCLUSIONS: Albeit increased, the relative risks for lymphomas and gastrointestinal cancers in this study are lower (and declining) than in most previous reports. The overall cancer risk is only moderately increased, and nonelevated during childhood and adolescence.
BACKGROUND & AIMS: Celiac disease (CD) is a common gluten-sensitive enteropathy associated with human leukocyte antigen (HLA)-DQ2 and HLA-DQ8. The aim of this study was to determine if a particular HLA-DQ subtype predisposes to complications such as refractory CD with (RCD II) or without aberrant T cells (RCD I), and enteropathy-associated T-cell lymphomas (EATL). METHODS: Molecular HLA-DQ typing was performed on 43 RCD I, 43 RCD II, and 30 EATL patients, and compared with age-matched groups of 121 patients with histologically defined uncomplicated CD and 183 healthy controls. All individuals were Dutch Caucasians and were at least 21 years of age. RESULTS: HLA-DQ2 was present in 79% of RCD I, 97.7% of RCD II, and 96.6% of EATL patients. The differences were significant when compared with 28.9% in controls but not with 91.7% in uncomplicated CD. Homozygosity for HLA-DQ2 was observed in 25.5% of RCD I, 44.1% of RCD II, and 53.3% of EATL patients vs 20.7% of uncomplicated CD patients and 2.1% of controls. HLA-DQ8 was present in 10.7% of CD, 16.2% of RCD I, 9.3% of RCD II, and 6.6% of EATL patients vs 20.2% of controls. CONCLUSIONS: Homozygosity for HLA-DQ2 is associated with RCD II and EATL. Early identification of HLA-DQ2 homozygous CD patients may help to recognize CD patients at risk for developing these severe complications.