The Role of Non-Invasive Markers of Enterocyte Damage and Increased Permeability in the Pathogenesis of Celiac Disease

Celiac disease (CD) is an immune-mediated enteropathy characterized by atrophy/damage to the mucous membrane of the small intestine in genetically susceptible individuals in response to gluten administration. In CD morphology, atrophy is the result of increased enterocyte apoptosis due to autoimmune inflammation. Since the enterocyte is an anatomical and functional unit of the mucous membrane of the small intestine, responsible for the barrier function and for the absorption of nutrients, to understand the pathogenesis of CD, the study of the processes of restoration of the mucosa is of paramount importance. Antibodies to tissue transglutaminase, antibodies to deamidated gliadin peptides, antibodies to endomysium, which are used to monitor disease activity and represent the body's immune response, can only indirectly indicate the degree of damage/recovery of enterocytes. During histological examination it is not always possible to assess the degree of damage at the cellular level, taking into account the complexity of the interpretation of morphological changes and patchiness of mucosa damage. In recent years, researchers have paid much attention to new markers of mucosa permeability, which include: I-FABP − a marker reflecting damage to enterocytes, citrulline − a marker of the functional mass of enterocytes, zonulin − a marker of increased mucosa permeability and alpha-1-antitrypsin − a marker reflecting the failure of the barrier function of the small intestine and protein loss. Using of these markers will help optimize the algorithm for non-invasive diagnostics of CD, improve monitoring of disease activity, and will also usefull for understanding the processes of mucosa recovery.

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Molecular Biomarkers for Celiac Disease: Past, Present and Future

International Journal of Molecular Sciences ◽

10.3390/ijms21228528 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8528

Author(s):

Aarón D. Ramírez-Sánchez ◽

Ineke L. Tan ◽

B.C. Gonera-de Jong ◽

Marijn C. Visschedijk ◽

Iris Jonkers ◽

...

Keyword(s):

Small Intestine ◽

Celiac Disease ◽

Early Stage ◽

Villous Atrophy ◽

Upper Endoscopy ◽

Gluten Free ◽

Non Invasive ◽

Immune Mediated ◽

Gastrointestinal Complaints ◽

Small Intestinal

Celiac disease (CeD) is a complex immune-mediated disorder that is triggered by dietary gluten in genetically predisposed individuals. CeD is characterized by inflammation and villous atrophy of the small intestine, which can lead to gastrointestinal complaints, malnutrition, and malignancies. Currently, diagnosis of CeD relies on serology (antibodies against transglutaminase and endomysium) and small-intestinal biopsies. Since small-intestinal biopsies require invasive upper-endoscopy, and serology cannot predict CeD in an early stage or be used for monitoring disease after initiation of a gluten-free diet, the search for non-invasive biomarkers is ongoing. Here, we summarize current and up-and-coming non-invasive biomarkers that may be able to predict, diagnose, and monitor the progression of CeD. We further discuss how current and emerging techniques, such as (single-cell) transcriptomics and genomics, can be used to uncover the pathophysiology of CeD and identify non-invasive biomarkers.

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MORPHOLOGICAL CHANGES IN THE SMALL INTESTINE OF RATS WITH ACUTE GENERALIZED PERITONITIS

Вісник наукових досліджень ◽

10.11603/2415-8798.2019.2.10274 ◽

2019 ◽

pp. 110-113

Author(s):

I. Ya. Dzyubanovsky ◽

B. M. Vervega ◽

S. R. Pіdruchna ◽

N. A. Melnyk

Keyword(s):

Endothelial Cells ◽

Small Intestine ◽

Mucous Membrane ◽

Morphological Changes ◽

Histological Study ◽

Abdominal Cavity ◽

Inflammatory Infiltration ◽

Generalized Peritonitis ◽

White Rats ◽

Fecal Suspension

The main cause of mortality in acute generalized peritonitis (AGP) is the development of multiple organ insufficiency. The intestine is the organ where the first changes develop in this pathology. The aim of the study – to research and evaluate the morphological changes in the small intestine wall of animals with experimental AGP. Materials and Methods. 32 white rats were used in this study. Acute peritonitis was modeled by introduction of 10 % fecal suspension in the dosage of 0.5 ml per 100 g of the animal's weight into the abdominal cavity of rats by puncture. The terms of observation: the 1st, 3rd and the 7th days from the beginning of the peritonitis modeling. For histological study the intestinal tissue was taken. The resulting pieces of the organ were fixed in a 10 % neutral formalin solution, which were then stained with hematoxylin and eosin. Results and Discussion. On the 3rd day of the experiment in animals with a modeled AGP, vascular changes were manifested first of all by the rounding (retraction) of endothelial cells or their desquamation and the appearance of defects, that allow plasma proteins and the formed elements of blood to leave circulation boundaries of the vascular bed. On the 7 th day in animals with a modeled AGP increased vascular permeability of the mucous membrane of the small intestine was accompanied by a significant edema of the stroma of the villi and by focal hemorrhages. Conclusion. Consequently, the distinct inflammatory changes in all terms of the injury were seen in the wall of the small intestine at the simulated AGP. The significant expansion of the capillaries and venules against the background of inflammatory infiltration in the stroma of the glandular component of the small intestine was noted on the 1st day from the beginning of the experiment. An increase in the height of intestinal villus and a crypt with retraction and desquamation of endothelial cells in the wall of vessels, which caused platelet adhesion in the areas of destruction was observed on the 3rd day. The areas of focal necrosis of the superficial epithelium, which were accompanied by multiple hemorrhages per diapedesis in the perivascular space of the mucous membrane, were seen in the wall of the small intestine of animals with a simulated AGP on the 7th day.

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Diagnosis of celiac disease in routine clinical practice

Pediatrician (St Petersburg) ◽

10.17816/ped5214-18 ◽

2014 ◽

Vol 5 (2) ◽

pp. 14-18 ◽

Cited By ~ 1

Author(s):

Lyubov Aleksandrovna Reshetnik ◽

Oksana Viktorovna Antsiferova ◽

Tatyana Anatolyevna Spasich ◽

Sergey Stepanovich Golubev

Keyword(s):

Celiac Disease ◽

Mucous Membrane ◽

Tissue Transglutaminase ◽

Disease Diagnosis ◽

Membrane Thickness ◽

Morphological Investigation ◽

Biopsy Material ◽

Selective Sampling ◽

Celiac Disease Diagnosis ◽

Endoscopic Investigation

During 10 years there has been conducted the purposeful clinical and laboratory investigation of 1775 children aged from 6 months to 18 years. In all patients antibodies to glyadin and tissue transglutaminase have been defined. 494 (27,83 %) children with positive serological markers have been send to endoscopic investigation with subsequent morphological investigation of biopsy material. In selective sampling of children the morphologically confirmed celiac disease is occurred with the frequency 1 to 40. Morphometric indices of duodenum mucous membrane are characterized with decrease of mucous membrane thickness, height of villi, ratio of villi height to depth of crypts. As a compensation crypts depth and a number of interepithelial lymphocytes are increased. Small changes correspond to manifest form of celiac disease. Probability of morphological confirmation of celiac disease diagnosis is higher in children to 7 years old.

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High Prevalence of Celiac Disease in Patients with Type 1 Diabetes Detected by Antibodies to Endomysium and Tissue Transglutaminase

Canadian Journal of Gastroenterology ◽

10.1155/2001/640796 ◽

2001 ◽

Vol 15 (5) ◽

pp. 297-301 ◽

Cited By ~ 60

Author(s):

PM Gillett ◽

HR Gillett ◽

DM Israel ◽

DL Metzger ◽

L Stewart ◽

...

Keyword(s):

British Columbia ◽

Type 1 Diabetes ◽

Celiac Disease ◽

Growth Parameters ◽

Morphological Changes ◽

Tissue Transglutaminase ◽

Immunoglobulin A ◽

Gluten Free Diet ◽

Gluten Free

OBJECTIVE: To establish the prevalence of celiac disease (CD) in children with type 1 diabetes in British Columbia.PATIENTS AND METHODS: Two hundred thirty-three children with type 1 diabetes were prospectively screened for CD using blind testing with the current 'gold standard', immunoglobulin A endomysium antibody (EmA), and the novel immunoglobulin A tissue transglutaminase (tTG) antibody. Those children with positive results were offered small bowel biopsy; a gluten-free diet was recommended if CD was confirmed.RESULTS: Nineteen children were positive for EmA and had an elevated tTG level. One patient from this group was already known to have CD, and the other 18 patients consented to biopsy. One biopsy was normal, three biopsies demonstrated elevated intraepithelial lymphocyte counts with normal morphology and 14 biopsies had morphological changes consistent with CD. Growth parameters were normal in all patients, and nine of 19 children who were positive for EmA were asymptomatic. Seven patients had mild elevation of tTG levels alone. Two children from this latter group had normal biopsies, and five declined biopsy.CONCLUSIONS: At least 14 new cases of CD were detected in addition to four known cases, yielding an overall biopsy-confirmed prevalence of CD of 7.7% (18 of 233). The present study confirms that CD is as prevalent in the pediatric type 1 diabetic population in British Columbia as it is in Europe. Serological screening of these children is important because many children have no symptoms or signs suggestive of CD. This study suggests that tTG serology may also be useful in monitoring response and compliance with a gluten-free diet.

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Morphological changes in the mucous membrane of the small intestine following administration of acth and hydrocortisone

Bulletin of Experimental Biology and Medicine ◽

10.1007/bf00784857 ◽

1967 ◽

Vol 63 (1) ◽

pp. 86-88

Author(s):

L. K. Leonova

Keyword(s):

Small Intestine ◽

Mucous Membrane ◽

Morphological Changes

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Gastrointestinal risk factors for anemia in children with celiac disease

Pediatrician (St Petersburg) ◽

10.17816/ped1055-12 ◽

2020 ◽

Vol 10 (5) ◽

pp. 5-12

Author(s):

Natalia S. Shapovalova ◽

Valeriya P. Novikova ◽

Maria O. Revnova ◽

Olga P. Gurina ◽

Elena A. Dementieva ◽

...

Keyword(s):

Risk Factors ◽

Celiac Disease ◽

Mucous Membrane ◽

Tissue Transglutaminase ◽

Hemoglobin Level ◽

Histological Evaluation ◽

Additional Risk Factor ◽

Additional Risk ◽

Gastrointestinal Risk

With oral intake, iron absorption in patients with celiac disease (CD) is reduced due to the decreased absorption surface of the atrophic small intestine mucous membrane. Besides, there are additional risk factors for anemia whose mechanisms are unclear.The aimof this study was to evaluate gastrointestinal risk factors for anemia in children. Materialsand methods.The first group consisted of 58 children with newly diagnosed CD who did not adhere to the gluten-free diet(GFD). The second group included 49 children with CD who hasnt been adhering to the GFD. The third group included 69children with chronic gastritis (CG) without CD. In addition to the standard examination, which includes the determination of antibodies to tissue transglutaminase and histological examination of the duodenum mucous membrane, a histological evaluation of the gastric mucosa, determination of pepsinogen 1 and 2 and their ratio, antibodies to Castles intrinsic factor were performed. Results.The mean level of hemoglobin in the group 1114,71120,10125,50g/l, in the group 2124,37128,74133,10g/l, in the group 3130,12133,78137,43g/l (p1,2=0.013;p1,3=0,000;p2,3=0.083). A correlation analysis of the hemoglobin level and morphological parameters of the duodenal mucosa among the studied patients revealed an inverse moderate correlation between the hemoglobin level and the degree of the small intestinal atrophy according to Marshr=0.331,p=0,000, crypt depthr=0,439,p=0,000, and a moderate direct with the ratio of villi:cryptr=0.417,p=0.000, with the height of the villir=0.366,p=0,000. Additionally, a moderate direct correlation between the level of hemoglobin and the number of parietal cells was found to ber=0.354,p=0.037. In group 1, a significant inverse correlation between the level of hemoglobin and the level of antibodies to Castles factorr=0.529,p=0.006, was obtained for the level of antibodies in the Castles factor. Conclusion.Autoimmune gastritis may be an additional risk factor in combination with malabsorption, as a possible cause of anemia in children with CD.

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Intestine wall histostructure peculiarities with peritonitis and mechanical intestine obstruction (experimental study)

Biomedical and Biosocial Anthropology ◽

10.31393/bba36-2019-05 ◽

2020 ◽

pp. 27-34

Author(s):

Т. I. Tamm ◽

V. V. Nepomnyaschy ◽

O. А. Shakalova ◽

А. Ya. Barduck

Keyword(s):

Small Intestine ◽

Mucous Membrane ◽

Morphological Changes ◽

Abdominal Cavity ◽

Statistical Processing ◽

Intestinal Wall ◽

Control Group ◽

Mechanical Ileus ◽

Fecal Suspension ◽

Dynamic Ileus

Today, the histological criteria for differential diagnosis of dynamic ileus due to peritonitis and mechanical obstruction of the intestine remain undeveloped. In this regard, the aim of the work was to establish the difference in morphological changes occurring in the intestinal wall during dynamic and mechanical ileus in the experiment. The experiment was conducted on 33 sexually mature Wistar rats. In 15 animals of the first group, mechanical ileus was modeled by ligation of the lumen of the small intestine at the middle of the distance between the duodenojejunal junction and the ileocecal angle. In 15 rats of the second group, a dynamic ileus model was formed in the form of peritonitis by introducing fecal suspension into the lumen of the abdominal cavity. The control group included 3 animals who underwent laparotomy without the formation of mechanical ileus and peritonitis. For histological examination, fragments of the intestinal wall were sampled 1 cm above the site of the obstruction with mechanical ileus and the portion of the small intestine with peritonitis. Statistical processing was performed in an Excel package using parametric statistics methods. It was stated that with mechanical ileus purulent inflammation develops in the intestine wall beginning from the mucous membrane spreading over wall thickness which can cause its destruction within 48 hours; with dynamical ileus purulent inflammation develops in the intestine wall, it captures particularly serous and muscle layers without causing violations of mucosa cover structure and without intestine wall destruction within 48 hours. Under experimental dynamic ileus, changes in the mucous membrane were reactive in nature and consisted of manifestations of compensatory-adaptive and regenerative processes in response to a violation of the trophism of various structures of the intestinal wall.

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Serum Markers in the Clinical Management of Celiac Disease

Digestive Diseases ◽

10.1159/000371405 ◽

2015 ◽

Vol 33 (2) ◽

pp. 236-243 ◽

Cited By ~ 16

Author(s):

Marlou Adriaanse ◽

Daniel A. Leffler

Keyword(s):

Celiac Disease ◽

Disease Activity ◽

Patient Care ◽

Dynamic Range ◽

Intestinal Inflammation ◽

Tissue Transglutaminase ◽

Intestinal Biopsy ◽

Intestinal Damage ◽

Fatty Acid Binding ◽

Serologic Tests

The advent of highly reliable noninvasive celiac diagnostic tests has transformed the field of celiac disease, from diagnosis, to evaluation of epidemiology, to clinical and translational research. Serologic tests in their modern forms are highly sensitive and specific for diagnosis, allowing for consideration of avoidance of diagnostic intestinal biopsy in some settings. On the other hand, as predictors of intestinal damage and for use in monitoring disease activity, currently available noninvasive tests have been disappointing. Serologic tests, while a measure of disease activity, do not correlate well with histology or symptomatology, and it is unclear if they predict long-term risk. Additionally, while the many clinically available tests have improved accessibility, they can have widely different cutoff levels and overall performance, making the comparison of levels in individual patients over time and across populations quite difficult. In the future, we can expect to see improvement in the currently available serologic tests including tissue transglutaminase and deamidated gliadin peptide with expansion of the dynamic range of the tests, and the celiac care community should push for a standardization of assays that would simplify research and patient care. Additionally, current serologic tests are measures of the adaptive immune response in celiac disease but do not directly measure intestinal inflammation. Promising work on intestinal fatty acid-binding protein and other assays which directly measure intestinal damage may complement traditional serologic tests and further improve our ability to noninvasively diagnose and monitor celiac disease. The coming years hold promise for the continuing evolution of serum-based tests in celiac disease with the possibility of substantial improvement of patient care and clinical research.

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