Adriana Crivelli

Value of a screening algorithm for celiac disease using tissue transglutaminase antibodies as first level in a population-based study.

OBJECTIVE:Serological screening for celiac disease (CD) can detect a large number of otherwise undiagnosed patients based on the sequential evaluation of serological tests and intestinal biopsy. The aim of this study was to compare the screening value for CD of two different protocols for the same community-based population.METHODS:We screened 1000 consecutive subjects (497 women, age range 16–71 yr) attending a centralized laboratory for obligatory prenuptial blood tests. Serum samples obtained from all subjects were processed using two different protocols: 1) a three-level classic screening consisting of the parallel use of IgG and IgA antigliadin antibodies as first level, followed by endomysial antibodies and total serum IgA for positive patients, and finally, intestinal biopsy of positive patients; and 2) a study screening protocol consisting of the parallel use of a commercial guinea pig antitissue transglutaminase antibody and total serum IgA as first line, endomysial antibodies (type IgA and/or IgG) for positive patients, and finally, intestinal biopsy.RESULTS:The classic screening protocol identified five subjects who were eligible for intestinal biopsy, which confirmed the presence of CD in all (prevalence 5.0 × 1000, 95% CI = 1.6–11.6). Using the study algorithm, we detected seven new patients including the five patients detected by the first protocol (prevalence 7.0 × 1000, 95% CI = 2.8–14.4). The two additional patients diagnosed using the proposed algorithm had positive IgG antigliadin antibodies and normal total serum IgA and were not detected by the classic protocol. Both patients were endomysial antibodies positive. The comparative analysis showed that the classic approach was more expensive (U.S.

Risk of fracture in celiac disease: Gender, dietary compliance, or both?

4687 per new patient detected) compared with the proposed study algorithm (U.S.

Telomere Length Study in Celiac Disease

3006).CONCLUSIONS:Our data showed that a new screening protocol using antitissue transglutaminase as first line followed by endomysial antibodies is a cost-effective screening and yielded more realistic figures of prevalence for CD in a community setting than the classic three-level sequential evaluation using antigliadin antibodies.

Analysis of genomic instability in adult-onset celiac disease patients by microsatellite instability and loss of heterozygosis.

AIM To determine the incidence of peripheral fractures in patients with celiac disease (CD) and the effect of treatment on fracture risk. METHODS We compared the incidence and risk of peripheral fractures before and after diagnosis between a cohort of 265 patients who had been diagnosed with CD at least 5 years before study entry and a cohort of 530 age- and sex-matched controls who had been diagnosed with functional gastrointestinal disorders. Data were collected through in-person interviews with an investigator. The overall assessment window for patients was 9843 patient-years (2815 patient-years after diagnosis). RESULTS Compared with the control group, the CD cohort showed significantly higher incidence rate and risk of first peripheral fracture before diagnosis [adjusted hazard ratio (HR): 1.78, 95% CI: 1.23-2.56, P < 0.002] and in men (HR: 2.67, 95% CI: 1.37-5.22, P < 0.004). Fracture risk was significantly associated with the classic CD presentation with gastrointestinal symptoms (P < 0.003). In the time period after diagnosis, the risk of fractures was comparable between the CD cohort and controls in both sexes (HR: 1.08, 95% CI: 0.55-2.10 for women; HR: 1.57, 95% CI: 0.57-4.26 for men). CONCLUSION CD patients have higher prevalence of fractures in the peripheral skeleton before diagnosis. This is associated with male sex and classic clinical presentation. The fracture risk was reduced after the treatment.

Glutathione S-transferase gene polymorphisms in celiac disease and their correlation with genomic instability phenotype

OBJECTIVES:Telomeres are important structures that are critical for maintaining chromosomal integrity and cell surveillance. The aim of this study was to analyze telomere length in patients with celiac disease (CD), a multifactorial disorder with a strong genetic component that exhibits genomic instability and cancer predisposition, particularly T-cell lymphomas.METHODS:Telomere length measured by telomere restriction fragments (TRF) was studied in small intestinal biopsy (SIB) samples and peripheral blood lymphocytes (PBL) from 20 untreated CD patients, distributed according to the clinical form as four asymptomatic, five monosymptomatic, and 11 polysymptomatic individuals. We also analyzed TRF from normal peripheral blood lymphocytes and normal biopsy samples as normal controls.RESULTS:TRF evaluation showed a significant telomere shortening in SIB samples from CD patients (4.21 ± 0.29 Kb) compared to PBL from the same individuals (9.17 ± 0.35 Kb) (p < 0.0001), independently of clinical form. Mean TRF peak values from normal biopsy samples were significantly higher (8.33 ± 0.38 Kb) than those observed in CD biopsy samples (p < 0.001). No differences between TRF values in CD-PBL and normal peripheral blood lymphocytes (8.89 ± 0.37Kb) were found.CONCLUSIONS:Our findings in patients with CD, a disorder in which the gluten-induced mucosal injury could accelerate telomere shortening, would increase the process of end-to-end fusions resulting in chromosomal changes, supports the hypothesis that genomic instability and telomere reduction may play a role in the cancer predisposition observed in these patients.

Long Term Outcomes after Intestinal Transplantation from a Single South-American Center, Lessons Learned

Background and Aims Malignant complications of celiac disease (CD) include carcinomas and lymphomas. The genetic basis behind cancer development in CD is not known, but acquisition of genetic abnormalities and genomic instability has been involved. The aim of this study was to explore molecular characteristics of genomic instability in CD patients by analyzing microsatellite instability (MSI) and loss of heterozygosis (LOH) with carefully selected microsatellites. Methods We genotyped small bowel biopsies and peripheral blood samples from 20 untreated CD patients using five microsatellites related to MMR genes (panel A), and five repeats associated with tumor suppressor genes, chromosome instability, inflammation, and cancer (panel B). Results Genomic instability was found in seven out of 20 (35%) cases at: D5S107, D18S58, GSTP, TP53 or DCC, being TP53 the most frequently affected (five out of seven cases; 71%). Microsatellite alterations were significantly found using panel B markers (P=0.04). No cases with high frequency of MSI and replication error phenotype were detected. Only one case displayed MSI-L alone. Three patients exhibited LOH and three other cases showed LOH with low level of MSI, being classified as having chromosome instability phenotype. Conclusion Two novel observations were found in this study: first, the finding that non-neoplastic cells from a group of untreated CD patients present genomic instability at nucleotide level; and second, the advantage to use carefully selected microsatellites to identify celiac patients with molecular instability. Our data support the existence of chromosome instability phenotype in CD, suggesting that stable and unstable patients are genomically distinct subtypes that may follow a different evolution.

Case Report: Spleen-preserving Multivisceral Transplant for Peutz–Jeghers Syndrome

BACKGROUND AND OBJECTIVE Genomic instability and reduced glutathione S-transferase (GST) activity have been identified as potential risk factors for malignant complications in celiac disease (CD). In this study, we assessed the possible influence of GST polymorphisms on genome instability phenotypes in a genetically characterised group of celiac patients from previous studies. METHODS The deletion polymorphisms in GSTM1 and GSTT1 genes and the single-nucleotide polymorphism GSTP1 c.313A>G were genotyped using PCR in a set of 20 untreated adult patients with a known genomic instability phenotype and 69 age- and sex-matched healthy individuals. RESULTS The frequencies of variant genotypes in patients were GSTM1-null (30%), GSTT1-null (5%), GSTP1-AG (60%) and GSTP1-GG (15%), and they showed no differences from controls. No significant differences were found in the genotype distribution based on telomere length. Cases with GSTM1-null genotype (83%) and microsatellite stability were more frequent than those with genomic instability. Moreover, carriers of GSTP1-variant genotype (73%) and stable phenotype were significantly increased compared to unstable patients (27%) (P=0.031). No differences were found according to the clinical-pathological characteristics of celiac cases. CONCLUSIONS No association between GST polymorphic variants and celiac-associated genomic instability was proven in our cohort. Future studies should explore the usefulness of other biomarkers to distinguish celiac patients who are susceptible to cancer development.

Celiac disease serology in patients with different pretest probabilities: Is biopsy avoidable?

Introduction In many countries, intestinal failure patients (IF pts) had the only option of parenteral nutrition (PN) as available treatment until intestinal transplantation (ITx) evolves as part of a multidisciplinary team. We would like to report the long-term outcomes of a series of ITx performed in children and adults at a single center, 9 years after its creation. Material and Methods retrospective analysis of all consecutive ITx performed between May 2006 and Oct 2017. Diagnoses, pre ITx mean time on PN, indication for ITx, time on the waiting list (WL), type of ITx, mean total ischemia time (TIT), and warm ischemia time (WIT), time for PN discontinuation, 5-year actuarial patient survival are reported. Results 44 patients received 47 ITx. The mean time on PN for the Tx group was 1604 days*. The main indication for ITx was: lack of central venous accesses followed by PN associated liver disease, and catheter related infectious complications. The mean time on the WL was 222 days (SD: 195 days). ITx were performed in 28 children and 16 adults. Thirty-seven procedures were isolated ITx; 10 multiorgan (MTO) (4 combined, 7 multivisceral - 2 with kidney); 4 (8,5%) were re-transplants: 3 isolated, 1 multivisceral; 8 included right colon. Sixteen pts (36%) received the abdominal rectus fascia. All procedures were performed by the same team; TIT was 7:36±2:10 hs, WIT was 39.1±10.5 min. Mean length of implanted intestine: 325 ± 59.5 cm, BC ileostomy were performed in 59.5% of the cases. 18/47 Tx required early re-operations. The overall mean follow up time is 49±45.2 months; the mean time to be off PN was 68 days (* p: 0,001); the overall 5 year pt survival is 55.1%; 60.5% for Isolated ITx vs 35% for MTO (p=0,01); 60.3% for ped recipient’s vs 44.9% for adults (p=NS). Conclusions After 11 years of establishing a dedicated adult and ped IF program, we proved that ITX is a valid therapeutic alternative for pediatric and adult candidates. Long term results are comparable to a large series reported from centers of develop countries or the ITR.

Medical and surgical rehabilitation in adult patients with intestinal failure type III. Report of the long term outcomes from a single center

CASE REPORT A 24-year-old man diagnosed with Peutz-Jeghers syndrome as a child underwent multiple surgeries owing to intussusception. Pretransplant workup showed >150 polyps along the gastrointestinal (GI) tract, some of them with high-grade dysplasia. Despite having intestinal sufficiency, a modified multivisceral transplantation was offered. PROCEDURE An 18-year-old donor was procured using University of Wisconsin solution. The recipients surgery started with a midline incision. Mobilization of the right colon and the root of the mesentery was done to isolate the superior mesenteric artery. The same maneuver was done with the left and sigmoid colon. The common bile duct was then isolated and transected at the cystic duct level. The abdominal portion of the esophagus and the proximal stomach were isolated and divided at the gastroesophageal junction. After that, the pancreas was mobilized, preserving the spleen with the splenic vessels. The distal GI tract was transacted at the level of the proximal rectum. For engraftment, an arterial conduit was placed in the infrarenal aorta and anastomosed to the grafts aortic patch. End-to-side portal reconstruction was made at the level of the portal vein, allowing performing a duct-to-duct biliary reconstruction over a 5-Fr T-tube. A hand-sewn gastrogastric anastomosis and piloroplasty were performed; the distal anastomosis was done with circular staplers. A gastrojejunostomy and a loop ileostomy were the final steps of the procedure. RESULTS The patient stayed in intensive care for 2 days and enteral feeds were started on day 7. Currently, 23 months after transplant he is alive with an excellent quality of life.