Chapter 6 - Tissue transglutaminase enzyme and anti-tissue transglutaminase antibodies: implication for acute coronary syndrome

The type II or tissue transglutaminase (TG2) is an ubiquitous enzyme involved in angiogenesis, fibrogenesis, wound healing, cell adhesion/migration, intracellular signaling pathways, respiratory chain assembly, cell proliferation/differentiation, neurite formation, apoptosis, and inflammation. Some years ago, an increased extracellular localization of TG2 has been demonstrated in damaged or inflamed portions of the small intestine from patients with celiac disease (CD). This antigenic overexpression is able to explain, at least in part, the anti-TG2 antibody induction observable in CD patients. On the other hand, anti-TG2 antibodies have been recently described in patients affected from disorders in which the target organ is located at a distance from the intestine, such as acute coronary syndrome (ACS), dilated cardiomyopathy (DCM), valvular heart disease and other causes of end-stage heart failure. In this regard, a cardiac TG2 overexpression has been described in some experimental models of heart failure and in occurrence of myocardial ischemia/reperfusion injury. In the arteries with or without minimal atherosclerosis, TG2 is detectable only in the medium and along the luminal endothelial border while in the atherosclerotic arteries, especially coronaries and carotid vessels, this enzyme is also evident in the fibrous cup and in shoulder regions of the plaque. Consequently, an anti-TG2 antibody-inducing mechanism similar to those taking part in the intestine of CD patients may also occur in the cardiovascular tissues affected from an acute or chronic disorder. Consistent with this hypothesis, anti-TG2 antibodies seem to be related to severity of the acute coronary event, as well as to extent of the myocardial tissue lesion occurring in ACS patients. Furthermore, since TG2 enzymatic activity may result in myocardial wound healing and stabilization of atherosclerotic plaque, anti-TG2 antibodies could have biological effects able to define a prognostic significance. In this light, vulnerable or ruptured atherosclerotic plaque, as well as injured myocardium (following an infarction, myocarditis, etc.) may be sources of TG2 antigen resulting in formation of anti-TG2 antibodies that in turn, by neutralizing TG2 enzymatic activity, could promote destabilization of the plaque or impaired myocardial wound healing, thereby contributing to a chronic disorder such as DCM. The finding that anti-TG2 antibodies are able to induce proliferation and inhibit differentiation of intestinal epithelial cell, increase epithelial permeability, activate monocytes, and disturb angiogenesis in CD patients suggests that they may have a functional role also in cardiovascular disorders. In the near future, these observations and related hypothesis could to become the subject of interesting researches

Chapter 8 - New evidence in the diagnostic procedures of celiac disease. Has time come to change the gold standard?

The diagnosis of celiac disease (CD) is based on three parameters: clinical case identification, serological screening and confirmation test. In agreement with the last European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) criteria, if clinical spectrum and screening tests are suggestive of CD, the evidence of villous atrophy is sufficient to confirm the diagnosis. To complete the diagnostic work-up, a favourable response to the treatment with a gluten-free diet (GFD) is mandatory. However, total villous atrophy is the extreme condition of a modifying spectrum of intestinal damage that can be revealed only in the severe forms of CD. Of consequence, if the histological analysis is the only confirmation test performed, it is possible to highlight false negative results especially in case of patchy atrophy or in absence of intestinal damage, a feature easily found in latent CD. The technical difficulties (sufficient size of the biopsy fragments, correct orientation and cut), the subjective evaluation and the occurrence of villous atrophy in other pathological conditions (e.g., intolerance to proteins other than gluten and tropical sprue) add further limitations to the histology-based diagnosis of CD. In this scenario, HLA-DQ2 and -DQ8 haplotypes have a high negative predictive value and, thus, their absence allows to exclude CD. Instead, the presence of circulating IgA or IgG (respectively, in immunocompetent individuals and in patients with selective IgA deficiency) anti-endomysial (EMA) and/or anti-tissue transglutaminase (anti-tTG) and their disappearance after a GFD, supports the diagnosis. The new developed IgA anti-actin and IgA/IgG anti-deamidated gliadin peptides tests could add further information for the diagnosis and monitoring of CD patients. However, if used alone, the screening tests are insufficient to diagnose CD. On the other hand, it has been demonstrated that EMA and anti-tTG can be detected in culture media of intestinal biopsies from untreated CD patients, as well as in culture media of intestinal biopsies from treated CD patients after in vitro exposure to the specific antigenic stimulus. Since the sensitivity of the organ culture seems to be greater than the histological analysis, this system has been recently proposed as confirmation test in the diagnostic work-up of CD, even if some conflictual opinions have limited its widespread use. In this section, the advances recently achieved to simplify the management and/or improve the performance of both screening and confirmation procedures of CD diagnosis are reported, critically evaluated and compared between them and with each older

Anti-transglutaminase detection followed by endomysium antibody confirmation test on monkey esophagus is the best strategy to screen for celiac disease

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Reactivity to dietary gluten: new insights into differential diagnosis among gluten-related gastrointestinal disorders

The ingestion of dietary gluten sometimes may trigger allergic, autoimmune or nonallergic and nonautoimmune response. The typical gluten-related allergic disorder is the wheat allergy (WA). Celiac disease (CD) is a well-known gluten-related autoimmune condition. The clinical expression of a gluten-related nonallergic and nonautoimmune response is nonceliac gluten sensitivity (NCGS), an emerging condition whose framework is yet unclear and whose diagnosis is suggested only by demonstration of gluten-dependency in patient' symptoms after exclusion of WA and CD. This review discusses the current tools to identify patients suffering from WA, CD, and NCGS, as well as the most recent insights in the differential diagnosis among these gluten-related gastrointestinal disorders

MR Imaging in the Evaluation of Placental Abruption: Correlation with Sonographic Findings

To evaluate the accuracy of magnetic resonance (MR) imaging and color Doppler ultrasonography (US) in the diagnosis of abruption, to assess the accuracy of the different MR imaging sequences in the visualization of clots, and to evaluate the correlation between MR imaging findings and clinical outcome. This study protocol was approved by the institutional review board, and written informed consent was obtained from all patients. Between March 2008 and June 2010, 60 consecutive patients (mean gestational age, 30.7 weeks [range, 27-38 weeks]; mean age, 29 years [range, 20-38 years]) who were referred for US and MR imaging owing to a putative diagnosis of abruption were assessed. Multiplanar half-Fourier rapid acquisition with relaxation enhancement, true fast imaging with steady-state precession, three-dimensional T1-weighted gradient-echo MR imaging, and sagittal diffusion-weighted MR imaging were performed. Two radiologists independently reviewed each case, resolving by consensus any diagnostic discrepancy. During a second imaging analysis, the same readers randomly and independently assessed the single sequences. The signal intensity of hematoma was correlated with clinical outcome. The reference standard for abruption was the presence of clots and/or fibrin at inspection of the placenta after delivery. The diagnostic efficacy of US and MR imaging was calculated with 95% confidence intervals. Interobserver agreement was assessed by using the Cohen κ test. The performance of US and MR imaging was calculated in 39 patients who gave birth less than 10 days after MR imaging; these women were considered to have an adequate reference standard. Abruption was found at delivery in 19 patients. Abruption was identified in 10 of the 19 patients (52%) with US and in all 19 (100%) with MR imaging (P = .002), with an interobserver agreement of 0.949. Diffusion- and T1-weighted sequences helped identify 19 (100%) and 18 (95%) of the 19 abruptions, respectively; interrater agreement was very good for all sequences (κ = 0.892-1.0). Hematomas classified as hyperacute or acute worsened to abruption grade II, with the mother being symptomatic or the fetus distressed. MR imaging can accurately depict placental abruption, with excellent interobserver agreement, and should be considered after negative US findings in the presence of late pregnancy bleeding if the diagnosis of abruption would change management. © RSNA, 2011

Extension of the celiac intestinal antibody (CIA) pattern through eight antibody assessments in fecal supernatants from patients with celiac disease

Background: Detection of anti-transglutaminase, anti-endomysium and anti-gliadin antibodies is commonly used to screen celiac disease patients. Besides that in serum, these antibodies are detectable in culture supernatants of oral, duodenal and colonic biopsy samples, saliva, gut lavage fluid samples, and fecal supernatants. Our aim was to extend the intestinal antibody pattern in fecal supernatants from patients with celiac disease. Methods: The fecal supernatants obtained from 25 celiac disease patients and 12 healthy volunteers were used to determine IgA and IgG1 anti-endomysium by immunofluorescence analysis, IgA and IgG anti-transglutaminase, IgA and IgG anti-deamidated gliadin peptides, IgA/IgG anti-transglutaminase/deamidated gliadin peptides and IgA anti-actin by enzyme-linked immunosorbent assay. Results: IgA anti-endomysium were found in 11 of 25 (44.0%) celiac disease patients and in none of healthy volunteers (p=0.0066). The levels of IgA anti-transglutaminase, IgA anti-deamidated gliadin peptides, IgA/IgG anti-transglutaminase/deamidated gliadin peptides and IgA anti-actin determined in celiac disease patients were significantly higher (p=0.0005, p=0.0018, p=0.0061 and p=0.0477, respectively) than those measured in healthy volunteers. The ROC curve analysis showed a diagnostic significance in IgA anti-transglutaminase (AUC=0.862, p<0.0001), IgA anti-deamidated gliadin peptides (AUC=0.822, p<0.0001) and IgA/IgG anti-transglutaminase/deamidated gliadin peptides (AUC=0.783, p=0.0003) fecal tests. Conclusions: Our data extend the intestinal antibody pattern detectable in fecal supernatants, thus increasing the knowledge in the humoral immunity of celiac disease. Further studies are needed to better evaluate the role of fecal antibody tests in identifying celiac disease patients

Anti-transglutaminase detection followed by endomysium antibody confirmation test on monkey esophagus is the best strategy to screen for celiac disease

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Simultaneous detection of IgA/IgG anti-tissue transglutaminase/deamidated gliadin peptides in serodiagnosis of celiac disease

Background: Celiac disease is a common autoimmune disorder that is diagnosed based on clinical case identification, serological screening, and duodenal histology. However, the existence of mild clinical forms, such as seronegative cases with patchy atrophy and potential celiac disease, can make it difficult to determine a definitive diagnosis. The seronegative patients with celiac disease can include those with discordant antibody results and false-negative results, due to unknown origins or selective IgA deficiency. Case presentation: We present two cases with discordant antibody results in order to evaluate if the simultaneous detection of specific antibodies can improve the serodiagnosis of celiac disease. In both patients, the simultaneous detection of IgA/IgG anti-tissue transglutaminase/deamidated gliadin peptides gave discordant positive results by the same antibodies assayed individually. Conclusion: Although further studies are needed to confirm and extend our findings, the simultaneous detection of specific antibodies seems to improve the serodiagnosis of celiac disease in patients with discordant antibody results