Prevalence and natural history of potential celiac disease in adult patients.

OBJECTIVE: Potential celiac disease (PCD) is a form of CD characterized by positive endomysial/tissue transglutaminase antibodies and a preserved duodenal mucosa despite a gluten-containing diet (GCD); it can evolve into flat, active CD. This evolution is, however, not certain. Our aim was to retrospectively study the prevalence and the natural history of adult patients with PCD. METHODS: The clinical notes of all 47 patients with PCD attending our clinic between September 1999 and October 2011 were retrospectively reevaluated. To study their clinical features, patients with active CD, randomly selected and matched for sex and date of birth, served as controls. Symptoms, associated diseases, familiarity, and laboratory data at diagnosis were compared. RESULTS: Prevalence of PCD among all celiac patients directly diagnosed in our center was 42/187, (1/4.4, 18.3%, 95% confidence interval (CI) 13.3-23.4%). Age at diagnosis, laboratory data, prevalence of symptoms, associated diseases, and familiarity for CD did not differ between patients with PCD and those with active CD. Some patients with PCD maintained a normal duodenal mucosa for many years and their symptoms spontaneously improved despite maintaining a GCD. CONCLUSIONS: PCD is not a rare form of CD. Having found no difference at all in age at diagnosis and clinical features between PCD and active CD could suggest that PCD is not a prodrome of CD but is a separate entity that can only subsequently evolve into active CD.

Antibodies to wheat high-molecular-weight glutenin subunits in patients with celiac disease.

BACKGROUND: Wheat gluten comprises gliadins and glutenins. The high-molecular-weight (HMW) glutenin subunits (GS)-1Dy10 are toxic for patients with celiac disease (CD). This study aimed to assess whether CD patients mount a serological response to HMW-GS-1Dy10. METHODS: Recombinant HMW-GS-1Dy10 was deamidated using human recombinant tissue transglutaminase. MALDI-TOF was performed to compare the level of deamidation of glutamine residues between material before and after treatment. Enzyme-linked immunosorbent assays were developed. Sera from patients with untreated CD and gastrointestinal disease controls were tested and receiver operator characteristics were used to calculate cutoffs. RESULTS: MALDI-TOF revealed a number of fragments matching known HMW-GS-1Dy10 sequences within both the deamidated and non-deamidated material. Evidence of deamidation of glutamine residues was found only within the human transglutaminase-treated material. Patients with untreated CD had significantly increased levels of serum antibodies to HMW-GS-1Dy10 compared to controls. Undeamidated HMW-GS-1Dy10 IgA antibodies had sensitivities and specificities of 72.5 and 78.26%, respectively. Deamidated HMW-GS-1Dy10 IgA antibodies had sensitivities and specificities of 76.8 and 65.2%. Undeamidated HMW-GS-1Dy10 IgG antibodies had sensitivities and specificities of 75.3 and 68.1%. Deamidated HMW-GS-1Dy10 IgG antibodies had sensitivities and specificities of 36.2 and 92.8%. CONCLUSION: Patients with untreated CD have raised antibody levels to HMW-GS-1Dy10, indicating the participation of these proteins in the adaptive immune response to gluten. Discrimination between CD patients and controls is not enhanced by deamidation of HMW-GS-1Dy10. Thus antibodies to these proteins are not useful markers for CD detection.

TCRß clonality improves diagnostic yield of TCRγ clonality in refractory celiac disease.

BACKGROUND: Refractory celiac disease (RCD) is a preneoplastic condition as many patients develop an enteropathy-type T-cell lymphoma, a mature T-cell receptor α-ß lymphoma arising in the gut with an ominous outcome. Recently, research focused on a population of intraepithelial intestinal lymphocytes expressing the same lymphoma T-cell receptor variable region (V)γ, as shown by polymerase chain reaction (PCR) analysis and sequencing. Meanwhile, the Biomedicine and Health-2 Concerted Action has made available standardized, highly specific, and sensitive PCR assays not only for Vγ but also for Vß. GOALS: We verified whether analyzing both rearrangements in duodenal biopsies from RCD patients increases the diagnostic accuracy of this method. STUDY: Duodenal biopsies were analyzed from 15 RCD patients, 21 negative controls, and 2 positive controls (enteropathy-type T-cell lymphoma complicating celiac disease). Multiplex clonality analyses were performed according to the Biomedicine and Health-2 protocols. PCR products were cloned and sequenced. RESULTS: Monoclonal rearrangements were found in 5/15 samples from patients with RCD (both rearrangements in 2 cases, Vß only in 2, and only 1 solitary Vγ clonality). Monoclonality was found in 4/8 of the RCD patients who subsequently died, whereas only 1/7 of the patients still alive presented a monoclonal rearrangement. Positive controls revealed both monoclonal rearrangements; rearrangements were not detected in 20 of 21 negative controls. Sequencing of the amplified fragments confirmed the results. CONCLUSIONS: The combined analysis of both rearrangements allowed recognition of monoclonal populations in otherwise negative patients, with detection rates from 20% (Vγ only) to 33% (Vγ and Vß), thus raising the likelihood of early identification of RCD patients at high risk of death.

Influence of HLA-DQ2 and DQ8 on severity in celiac Disease.

BACKGROUND: HLA-DQB1*02 homozygosity was shown to be more common in patients with complicated rather than uncomplicated celiac disease (CD). GOALS: To study HLA-DQA1 and DQB1 profile in adult patients with different forms of CD, including patients with complicated and potential CD, the most affected and the most preserved histologic end of the pathologic celiac spectrum. STUDY: HLA-DQA1 and DQB1 molecular typing was performed in 218 adult CD patients (169 with uncomplicated CD, 27 with complicated CD, and 22 with potential CD) and 224 healthy stem cell donors. HLA-DQA1 and DQB1 gene polymorphism was analyzed using polymerase chain reaction sequence-specific primers and/or reverse polymerase chain reaction sequence-specific oligonucleotides techniques. RESULTS: As expected, the frequency of HLA-DQB1*02 allele, DQB1*02 homozygosity, and DQB1*0302 gene were statistically different in the 4 groups. However, multivariate analysis demonstrated that patients with potential CD have a higher frequency of both HLA-DQB1*0302 and HLA-DQB1*0603 alleles and a reduced frequency of DQB1*02 homozygosity compared with patients with uncomplicated and complicated CD. CONCLUSIONS: The increased frequency of DQB1*0302 and the reduced frequency of DQB1*02 homozygosity in potential CD is consistent with the idea that different clinical/pathologic evolutions might be related to different immunogeneses. This could be clinically relevant in the future.

The impact of misdiagnosing celiac disease at a referral centre.

In the past few years, the number of celiac disease diagnoses not confirmed at the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, a tertiary referral centre, was particularly high. Therefore, a decision was made to investigate the reasons why these diagnoses were wrong and by whom they had been made. The clinical histories of all celiac patients referred to the centre were re-evaluated. Between December 1998 and January 2007, 614 patients who were diagnosed at other institutions and presumed to be affected by celiac disease attended the tertiary referral outpatient clinic. The histological and serological results allowed for confirmation the diagnosis in 434 patients. In the remaining 180 patients, the initial diagnosis of celiac disease could not be confirmed; therefore, the patients were re-investigated. After re-evaluation, the diagnosis of celiac disease was confirmed in only 61 of these 180 cases. The reasons for incorrect initial diagnosis were analyzed. A mere 80% correct diagnosis rate is a very disappointing result. Although it should be obvious that celiac disease must be investigated with duodenal biopsies and celiac antibody testing, this well-known strategy is not always followed, probably resulting in an incorrect diagnosis.

Dental enamel defects in adult coeliac disease: prevalence and correlation with symptoms and age at diagnosis.

BACKGROUND: Coeliac disease is a condition characterized by a wide spectrum of clinical manifestations. Any organ can be affected and, among others, dental enamel defects have been described. Our aims were to study the prevalence of dental enamel defects in adults with coeliac disease and to investigate a correlation between the grade of teeth lesion and clinical parameters present at the time of diagnosis of coeliac disease. METHODS: A dental examination was performed in 54 coeliac disease patients (41 F, mean age 37 ± 13 years, mean age at diagnosis 31 ± 14 years). Symptoms leading to diagnosis were diarrhoea/weight loss (32 pts.), anaemia (19 pts.), familiarity (3 pts.); none of the patients was diagnosed because of enamel defects. At the time of evaluation, they were all on a gluten-free diet. Enamel defects were classified from grade 0 to 4 according to its severity. RESULTS: Enamel defects were observed in 46/54 patients (85.2%): grade 1 defects were seen in 18 patients (33.3%) grade 2 in 16 (29.6%), grade 3 in 8 (14.8%), and grade 4 in 4 (7.4%). We also observed that grades 3 and 4 were more frequent in patients diagnosed with classical rather than non-classical coeliac disease (10/32 vs. 2/20). However, this was not statistically significant. CONCLUSION: This study confirms that enamel defects are common in adult coeliac disease. Observation of enamel defects is an opportunity to diagnose coeliac disease.

Quality of life in coeliac patients: Italian validation of a coeliac questionnaire.

BACKGROUND: Coeliac disease (CD) is a chronic condition requiring a gluten-free diet, which is a very demanding diet to maintain on a life-long basis. For this reason it is a condition that can have serious repercussions on the quality of life (QOL). Therefore the need to elaborate a questionnaire on QOL specifically for patients with CD (CDQ): its original language is German, and the translation/validation process represents a considerable challenge involving not only a translation into Italian but also an adaptation to the country's specific cultural differences. METHODS: The questionnaire has been translated according to a "German → Italian → Italian → German" algorithm with reconciliation of the differences. Scores for CDQ are computed overall and over four areas of four items each: emotion, gastrointestinal symptoms, gastrointestinal worries, social problems. RESULTS: CDQ was administered to 171 coeliacs (F 132, mean age 38 yrs ± 14). Completeness was optimal. Item internal consistency was satisfied for 100% and 97% of patients for the specific and generic part, respectively. Cronbach's α coefficient was 0.7 for all scales. The general CDQ was higher in patients reporting subjective well-being (discriminant validity). CONCLUSIONS: The Italian translation of CDQ sounds natural, is easy to understand and reduces possible cultural biases to a minimum. A field test gave results comparable to the original validation, supporting the use of CDQ in cross-national surveys.

Previous immunosuppressive therapy is a risk factor for immune reconstitution inflammatory syndrome in Whipple's disease.

INTRODUCTION: Whipple's disease is a rare chronic infection caused by Tropheryma whipplei. Although most patients respond to antibiotics, in some of them the start of the treatment is followed by recurrence of inflammation. Since polymerase chain reaction is negative for Tropheryma whipplei, this reinflammation cannot be a relapse of Whipple's disease itself. Very recently, it has been recognised as a complication of Whipple's disease and defined immune reconstitution inflammatory syndrome (IRIS). Our aim is to study the prevalence and the clinical features of IRIS in Italian patients with Whipple's disease. METHODS: Evidence of IRIS was retrospectively revaluated in the clinical notes of 22 patients with Whipple's disease. Patients with no evidence of IRIS served as controls for the clinical findings. RESULTS: Recurrence of arthralgia and/or fever allowed a diagnosis of IRIS in 5/22 patients. One patient died. Previous immunosuppressive therapy was found in all patients with IRIS but only in 7/17 controls (Fisher test, p=0.039). Age at diagnosis and diagnostic delay were higher in patients with IRIS compared to controls. However, statistical significance was not reached. CONCLUSIONS: IRIS is a frequent complication of Whipple's disease and it can be fatal. The risk of IRIS is greatly increased in patients previously treated with immunosuppressive therapy.

The significance of duodenal mucosal atrophy in patients with common variable immunodeficiency: a clinical and histopathologic study.

Gastrointestinal manifestations and villous atrophy can be seen in patients with common variable immunodeficiency (CVID). In some patients, infectious agents may be responsible, whereas in others, celiac disease (CD) may be the cause. In this study, we investigate the causes and the histopathologic features seen in patients with CVID. Eleven patients with CVID and villous atrophy underwent duodenal biopsies, human leukocyte antigen (HLA) typing, and testing for all celiac antibodies. Fifteen patients with CVID and normal villi and 6 patients with CD but without CVID served as controls. Histologic response to a gluten-free diet (GFD) allowed a diagnosis of CD in 3 of 11 patients. In the remaining 8, the lack of a histologic response to a GFD or HLA typing excluded CD. Celiac antibodies gave conflicting results and were of no help. Polymorphonuclear infiltrates and lesions like graft-versus-host disease are seen more often in flat mucosa unresponsive to a GFD. However, the specificity of these findings remains to be determined and response to a GFD remains the only diagnostic criteria for CD in these patients. Villous atrophy was gluten-sensitive in 3 of 11 patients with CVID. It was not related to gluten-responsive CD in most patients.