María Laura Moreno

Stratification of Bone Fracture Risk in Patients With Celiac Disease

BACKGROUND AND AIMS Our objective in this cross-sectional, case-control study was to gain insight into celiac osteopathy by examining a well-defined cohort of patients with a wide clinical spectrum of the disease. METHODS We studied 148 unselected celiac patients and 296 (1:2) age- and sex-matched controls diagnosed with functional gastrointestinal disorders. Based on the clinical history, 53% were classically symptomatic, 36% had subclinical celiac disease, and 11% were silent, detected by screening. The fracture information was obtained through an in-person interview using a pre-designed questionnaire. RESULTS Classically symptomatic patients had an increased number of fractures in the peripheral skeleton (47%) compared with age- and sex-matched controls (15%; odds ratio, 5.2; 95% confidence interval, 2.8-9.8). However, fractures in subclinical/silent celiac cases (20%) were no different from those in controls (14%; odds ratio, 1.7, 0.7-4.4). Compared with the subclinical/silent group, a significantly greater prevalence of fractures was detected in classically symptomatic patients (odds ratio, 3.6, 1.7-7.5). Compared with controls, celiac disease patients had significantly more fractures produced by mild trauma (P < 0.01), but there were no differences in the severity of trauma events that induced fractures. Mean bone density femoral neck z score was higher for subclinical/silent cases compared with classically symptomatic patients (P < 0.05). CONCLUSIONS Celiac patients show a very wide variation in fracture risk, with increased risk in classically symptomatic patients. Diagnostic and therapeutic strategies to prevent bone loss and fracture should be preferentially used in the subgroup of patients with classic clinical disease.

Permeability, zonulin production, and enteropathy in dermatitis herpetiformis

BACKGROUND & AIMS Dermatitis herpetiformis (DH) is characterized by variable degrees of enteropathy and increased intestinal permeability. Zonulin, a regulator of tight junctions, seems to play a key role in the altered intestinal permeability that characterizes the early phase of celiac disease. Our aim was to assess both intestinal permeability and serum zonulin levels in a group of patients with DH having variable grades of enteropathy. METHODS We studied 18 DH patients diagnosed on the basis of characteristic immunoglobulin (Ig)A granular deposits in the dermal papillae of noninvolved skin. Results were compared with those of classic celiac patients, patients with linear IgA dermatosis, and healthy controls. RESULTS According to Marshs classification, 5 patients had no evidence of enteropathy (type 0), 4 patients had type II, 2 patients had type IIIb damage, and 7 patients had a more severe lesion (type IIIc). Intestinal permeability (lactulose/mannitol ratio [lac/man]) was abnormal in all patients with DH. Patients with more severe enteropathy had significantly greater permeability ( P < .05). The serum zonulin concentration (enzyme-linked immunosorbent assay) for patients with DH was 2.1 +/- .3 ng/mg with 14 of 16 (87.5%) patients having abnormally increased values. In contrast, patients with linear IgA dermatosis had normal histology, normal intestinal permeability, and negative celiac serology. CONCLUSIONS Increased intestinal permeability and zonulin up-regulation are common and concomitant findings among patients with DH, likely involved in pathogenesis. Increased permeability can be observed even in patients with no evidence of histologic damage in biopsy specimens. Patients with linear IgA dermatosis appear to be a distinct population with no evidence of gluten sensitivity.

Gastroesophageal Reflux Symptoms in Patients With Celiac Disease and the Effects of a Gluten-Free Diet

BACKGROUND & AIMS Celiac disease (CD) patients often complain of symptoms consistent with gastroesophageal reflux disease (GERD). We aimed to assess the prevalence of GERD symptoms at diagnosis and to determine the impact of the gluten-free diet (GFD). METHODS We evaluated 133 adult CD patients at diagnosis and 70 healthy controls. Fifty-three patients completed questionnaires every 3 months during the first year and more than 4 years after diagnosis. GERD symptoms were evaluated using a subdimension of the Gastrointestinal Symptoms Rating Scale for heartburn and regurgitation domains. RESULTS At diagnosis, celiac patients had a significantly higher reflux symptom mean score than healthy controls (P < .001). At baseline, 30.1% of CD patients had moderate to severe GERD (score >3) compared with 5.7% of controls (P < .01). Moderate to severe symptoms were significantly associated with the classical clinical presentation of CD (35.0%) compared with atypical/silent cases (15.2%; P < .03). A rapid improvement was evidenced at 3 months after initial treatment with a GFD (P < .0001) with reflux scores comparable to healthy controls from this time point onward. CONCLUSIONS GERD symptoms are common in classically symptomatic untreated CD patients. The GFD is associated with a rapid and persistent improvement in reflux symptoms that resembles the healthy population.

MHC Class I Region Plays a Role in the Development of Diverse Clinical forms of Celiac Disease in a Saharawi Population

OBJECTIVE:The aim of this study was to investigate the association of MHC genes in the development of celiac disease (CD) and its diverse clinical forms in a Saharawi population.METHODS:One hundred and twenty-five CD patients and 98 healthy controls were selected from the Saharawi refugee camps in Tindouf. All were investigated for the presence of antitransglutaminase 2 antibodies. Patients were divided into two groups according to their clinical manifestations: 70 typical and 55 atypical. Patients and controls were typed for HLA-B, DRB1, DQB1, and DQA1, and for MICA transmembrane polymorphism.RESULTS:The frequency of HLA-DQ2 in Saharawi controls was notably increased compared with other populations. No differences in the distribution of DQ2 in either group of patients were found. However, the haplotype B8/DR3/DQ2 was notably overrepresented in atypical patients compared to typical ones (pc= 0.001). The MICA-A5.1 allele was increased in atypical CD patients compared to those with typical forms (pc= 0.0006). Finally, we found that the increased frequency of MICA-A5.1 in the atypical group was independent of the linkage disequilibrium with B8/DR3/DQ2 haplotype (p = 0.02).CONCLUSIONS:The elevated prevalence of CD in Saharawi seems to be related to the high frequency of HLA-DQ2 in this population. However, the development of atypical or typical forms of the disease may be due to a gene or genes located in the class I side of the haplotype B8/DR3/DQ2, especially MICA. This appears not to be implicated in the susceptibility to CD but may play an important role in the development of the different forms of the disease.

Significant bone microarchitecture impairment in premenopausal women with active celiac disease

Patients with active celiac disease (CD) are more likely to have osteoporosis and increased risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) permits three-dimensional exploration of bone microarchitectural characteristics measuring separately cortical and trabecular compartments, and giving a more profound insight into bone disease pathophysiology and fracture. We aimed to determine the volumetric and microarchitectural characteristics of peripheral bones-distal radius and tibia-in an adult premenopausal cohort with active CD assessed at diagnosis. We prospectively enrolled 31 consecutive premenopausal women with newly diagnosed CD (median age 29 years, range: 18-49) and 22 healthy women of similar age (median age 30 years, range 21-41) and body mass index. Compared with controls, peripheral bones of CD patients were significantly lower in terms of total volumetric density mg/cm(3) (mean ± SD: 274.7 ± 51.7 vs. 324.7 ± 45.8, p 0.0006 at the radius; 264.4 ± 48.7 vs. 307 ± 40.7, p 0.002 at the tibia), trabecular density mg/cm(3) (118.6 ± 31.5 vs. 161.9 ± 33.6, p<0.0001 at the radius; 127.9 ± 28.7 vs. 157.6 ± 15.6, p < 0.0001 at the tibia); bone volume/trabecular volume ratio % (9.9 ± 2.6 vs. 13.5 ± 2.8, p<0.0001 at the radius; 10.6 ± 2.4 vs. 13.1 ± 1.3, p < 0.0001 at the tibia); number of trabeculae 1/mm (1.69 ± 0.27 vs. 1.89 ± 0.26, p 0.009 at the radius; 1.53 ± 0.32 vs. 1.80 ± 0.26, p 0.002 at the tibia); and trabecular thickness mm (0.058 ± 0.010 vs. 0.071 ± 0.008, p < 0.0001 at the radius with no significant difference at the tibia). Cortical density was significantly lower in both regions (D comp mg/cm(3) 860 ± 57.2 vs. 893.9 ± 43, p 0.02; 902.7 ± 48.7 vs. 932.6 ± 32.6, p 0.01 in radius and tibia respectively). Although cortical thickness was lower in CD patients, it failed to show any significant inter-group difference (a-8% decay with p 0.11 in both bones). Patients with symptomatic CD (n = 22) had a greater bone microarchitectural deficit than those with subclinical CD. HR-pQCT was used to successfully identify significant deterioration in the microarchitecture of trabecular and cortical compartments of peripheral bones. Impairment was characterized by lower trabecular number and thickness-which increased trabecular network heterogeneity-and lower cortical density and thickness. In the prospective follow-up of this group of patients we expect to be able to assess whether bone microarchitecture recovers and to what extend after gluten-free diet.

Impaired Bone Microarchitecture Improves After One Year On Gluten-Free Diet: A Prospective Longitudinal HRpQCT Study in Women With Celiac Disease.

We have recently identified a significant deterioration of bone microarchitecture in premenopausal women with newly diagnosed celiac disease (CD) using high‐resolution peripheral quantitative computed tomography (HRpQCT). The aim of this work was to assess changes in bone microarchitecture after 1 year on a gluten‐free diet (GFD) in a cohort of premenopausal women. We prospectively enrolled 31 consecutive females at diagnosis of CD; 26 of them were reassessed 1 year after GFD. They all underwent HRpQCT scans of distal radius and tibia, areal BMD by DXA, and biochemical tests (bone‐specific parameters and CD serology) at both time points. Secondary, we compared 1‐year results with those of a control group of healthy premenopausal women of similar age and BMI in order to assess whether the microarchitectural parameters of treated CD patients had reached the values expected for their age. Compared with baseline, the trabecular compartment in the distal radius and tibia improved significantly (trabecular density, trabecular/bone volume fraction [BV/TV] [p < 0.0001], and trabecular thickness [p = 0.0004]). Trabecular number remained stable in both regions. Cortical density increased only in the tibia (p = 0.0004). Cortical thickness decreased significantly in both sites (radius: p = 0.03; tibia: p = 0.05). DXA increased in all regions (lumbar spine [LS], p = 0.01; femoral neck [FN], p = 0.009; ultradistal [UD] radius, p = 0.001). Most parameters continued to be significantly lower than those of healthy controls. This prospective HRpQCT study showed that most trabecular parameters altered at CD diagnosis improved significantly by specific treatment (GFD) and calcium and vitamin D supplementation. However, there were still significant differences with a control group of women of similar age and BMI. In the prospective follow‐up of this group of patients we expect to be able to assess whether bone microarchitecture attains levels expected for their age.

Riluzole-induced acute pancreatitis

hyperplastic epithelium. Instead, there was a moderate expression of p53 in some of the largest hyperplastic polyps. These cells also revealed an increased reactivity of bcl-2, whereas the neoplastic epithelium was completely bcl-2 negative. Colorectal cancer arising within an hyperplastic polyp has been described, and most cases followed the progression from hyperplasia to serrated/adenomatous dysplasia to adenocarcinoma. Cancer developing in a pure hyperplastic lesion is rare and was first reported in 1982 (7). In our case, the adenocarcinoma showed clear histological evidence of a direct origin from the hyperplastic epithelium. Moreover, the neoplastic foci were deeply seated and not superficially seated, as happens in the common degenerated adenomatous polyp, an unusual feature that has already been described (7). The presence of multiple hyperplastic polyps was a further interesting feature of our case. The hyperplastic polyposis syndrome is an uncommon condition that seems to be strongly associated with adenocarcinoma of the colon, representing in the opinion of some authors the morphological expression of a distinct pathway of colorectal carcinogenesis characterized by sporadic or hereditary defective DNA mismatch repair and defined genetically by microsatellite instability (6). In our case microsatellite instability did not play any role, in agreement with the findings of Hawkins et al. (2), who reported loss of p53 and development of chromosomal instability, a pathway of neoplastic progression observed in the so-called common form of colorectal carcinoma (2). Unfortunately, no exhaustive studies on the topic are available, despite the fact that hyperplastic polyps are very frequent and that the biology of these lesions, whether isolated or multiple, is of major clinical interest because of their possible malignant degeneration.

Bifidobacterium infantis NLS Super Strain Reduces the Expression of α-Defensin-5, a Marker of Innate Immunity, in the Mucosa of Active Celiac Disease Patients.

Background: We have previously shown a reduction of gastrointestinal symptoms after the oral administration of Bifidobacterium infantis Natren Life Start super strain (NLS-SS) in untreated celiac disease (CD) patients. The symptomatic improvement was not associated with changes in intestinal permeability or serum levels of cytokines, chemokines, or growth factors. Therefore, we hypothesized that the beneficial symptomatic effect observed previously in patients with CD treated with B. infantis may be related to the modulation of innate immunity. Goals: To investigate the potential mechanisms of a probiotic B. infantis Natren Life Start super strain on the mucosal expression of innate immune markers in adult patients with active untreated CD compared with those treated with B. infantis×6 weeks and after 1 year of gluten-free diet (GFD). Methods: Numbers of macrophages and Paneth cells and &agr;-defensin-5 expression were assessed by immunohistochemistry in duodenal biopsies. Results: We showed that GFD decreases duodenal macrophage counts in CD patients more effectively than B. infantis. In contrast, B. infantis decreases Paneth cell counts and expression of &agr;-defensin-5 in CD (P<0.001). Conclusions: The results identify differential innate immune effects of treatment with B. infantis compared with 1 year of GFD. Further studies are needed to investigate synergistic effects of GFD and B. infantis supplementation in CD.

Should ESPGHAN Guidelines for Serologic Diagnosis of Celiac Disease be Used in Adults? A Prospective Analysis in an Adult Patient Cohort With High Pretest Probability

Should ESPGHAN Guidelines for Serologic Diagnosis of Celiac Disease be Used in Adults? A Prospective Analysis in an Adult Patient Cohort With High Pretest Probability

Altered Esophageal Mucosal Structure in Patients with Celiac Disease

Background/Aim. Reflux symptoms (RS) are common in patients with celiac disease (CD), a chronic enteropathy that affects primarily the small intestine. We evaluated mucosal integrity and motility of the lower esophagus as mechanisms contributing to RS generation in patients with CD. Methods. We enrolled newly diagnosed CD patients with and without RS, nonceliac patients with classical reflux disease (GERD), and controls (without RS). Endoscopic biopsies from the distal esophagus were assessed for dilated intercellular space (DIS) by light microscopy and electron microscopy. Tight junction (TJ) mRNA proteins expression for zonula occludens-1 (ZO-1) and claudin-2 and claudin-3 (CLDN-2; CLDN-3) was determined using qRT-PCR. Results. DIS scores were higher in patients with active CD than in controls, but similar to GERD patients. The altered DIS was found even in CD patients without RS and normalized after one year of a gluten-free diet. CD patients with and without RS had lower expression of ZO-1 than controls. The expression of CLDN-2 and CLDN-3 was similar in CD and GERD patients. Conclusions. Our study shows that patients with active CD have altered esophageal mucosal integrity, independently of the presence of RS. The altered expression of ZO-1 may underlie loss of TJ integrity in the esophageal mucosa and may contribute to RS generation.