Duodenal Biopsy Specimens Research Articles

Specific Clinical and Morphological Characteristics of Amyloidosis of the Stomach and Duodenum

The aimof the study was to investigate specific clinical and morphological characteristics in biopsy specimens of the stomach and duodenum using immunohistochemical typing.Material and methods.Biopsy specimens – 19 from the stomach and 22 from the duodenum were examined. The specimens were obtained from 27 patients with later pathomorphologically verified amyloidosis. The specimens were fixed in 10% formalin solution, processed with the standard technique of histological tissue making and embedded into paraffin blocks. The tissue sections were stained with H&E and congo red. A broad panel of antibodies to different types of amyloidosis was used for immunohistochemical typing of amyloid deposits.Results.In total, 41 biopsy specimen of the gastric and duodenal amyloidosis was examined. Histological findings included interstitial and vascular amyloid deposits in stomach and duodenum. Based on the results of immunohistochemical typing of 19 gastric biopsy specimens, ALλ amyloidosis was found in 7 cases, AAamyloidosis – in 6, ALλ amyloidosis and transthyretin amyloidosis – in 2 cases each, and mixed type – in 2 biopsy specimens. Among biopsy specimens of the duodenum, ALκ – amyloidosis was diagnosed in 10 cases, AAamyloidosis – in 5, ALλ amyloidosis – in 4, transthyretin amyloidosis – in 2, and mixed type – in one biopsy specimen.Conclusion.Based on the study results, ALκ- and AA-amyloidosis were the most frequent amyloidosis types in the gastric and duodenal biopsy specimens. Immunohistochemical typing was successful in all cases, thus proving that the selected method was adequate for amyloidosis diagnostics.

Duodenal mucosal resurfacing: proof-of-concept, procedural development, and initial implementation in the clinical setting

We aimed to develop duodenal mucosal resurfacing (DMR), a minimally invasive upper endoscopic hydrothermal ablation procedure, to treat insulin-resistant metabolic diseases. We completed a sham-controlled, rodent proof-of-concept study and longitudinal safety study in pigs to demonstrate feasibility to test DMR in humans. Subsequently, the DMR procedure was implemented in an open-label first-in-human (FIH) study of safety and efficacy in patients with type 2 diabetes (T2D). In rats, duodenal abrasion reduced hyperglycemia by 59 mg/dL on average, compared with no change from baseline in the sham treatment arm (P< .05). In pigs, the balloon catheter successfully and safely delivered hydrothermal ablation to the duodenal mucosa and superficial submucosa. Complete mucosal healing was demonstrated by week 6. In the FIH study, hydrothermal ablation was successfully administered with no evidence of perforation, pancreatitis, or hemorrhage. Duodenal biopsy specimens obtained 3 months postprocedure demonstrated full mucosal regrowth. No inflammation was observed, and there was minimal-to-mild collagen banding deposition observed in a proportion of ablation site biopsy specimens with no evidence of fibrotic scarring. Glycemic and hepatic measures improved through 6 months of follow-up. DMR shows potential as an endoscopic intervention that improves glycemic and hepatic parameters in patients with T2D. Further mechanistic and clinical studies are underway to further explore DMR as a treatment for metabolic disease.

Duodenal low-grade inflammation and expression of tight junction proteins in functional dyspepsia.

Duodenal changes in functional dyspepsia (FD) might be related to the development of symptoms. However, relationships among low-grade inflammation, Helicobacter pylori infection, and protein expression by tight junctions (TJs) in the duodenum are unclear. We therefore aimed to determine whether duodenal inflammation and genes associated with TJ proteins are associated with FD. We evaluated inflammatory cell infiltration of the duodenum, Hpylori infection, and genes associated with TJ proteins in duodenal biopsy specimens from 35 patients with FD according to the Rome III diagnostic questionnaire and from 31 asymptomatic controls without structural diseases. We immunohistochemically detected eosinophils and mast cells and counted them. The expression of claudins, occludin, and zonula occludens (ZO)-1 mRNA was evaluated using quantitative RT-PCR. Infection with Hpylori was determined by measuring serum antibodies, rapid urease or urea breath tests, and endoscopic findings. Sex, age, and Hpyloriinfection rates did not differ between patients with FD and controls. The numbers of eosinophils and mast cells were significantly increased in patients with FD compared with controls and were significantly correlated. Inflammatory cell counts in the duodenum were not associated with Hpylori infection status. Claudin-3 mRNA expression was increased in the patients with FD. Subtle inflammation identified in the duodenum of patients with FD might be associated with the onset and persistence of dyspeptic symptoms.

Oral Glucose Mobilizes Triglyceride Stores From the HumanIntestine.

Background & AimsThe small intestine regulates plasma triglyceride (TG) concentration. Within enterocytes, dietary TGs are packaged into chylomicrons (CMs) for secretion or stored temporarily in cytoplasmic lipid droplets (CLDs) until further mobilization. We and others have shown that oral and intravenous glucose enhances CM particle secretion in human beings, however, the mechanisms through which this occurs are incompletely understood.MethodsTwo separate cohorts of participants ingested a high-fat liquid meal and, 5 hours later, were assigned randomly to ingest either a glucose solution or an equivalent volume of water. In 1 group (N = 6), plasma and lipoprotein TG responses were assessed in a randomized cross-over study. In a separate group (N = 24), duodenal biopsy specimens were obtained 1 hour after ingestion of glucose or water. Ultrastructural and proteomic analyses were performed on duodenal biopsy specimens.ResultsCompared with water, glucose ingestion increased circulating TGs within 30 minutes, mainly in the CM fraction. It decreased the total number of CLDs and the proportion of large-sized CLDs within enterocytes. We identified 2919 proteins in human duodenal tissue, 270 of which are related to lipid metabolism and 134 of which were differentially present in response to glucose compared with water ingestion.ConclusionsOral glucose mobilizes TGs stored within enterocyte CLDs to provide substrate for CM synthesis and secretion. Future studies elucidating the underlying signaling pathways may provide mechanistic insights that lead to the development of novel therapeutics for the treatment of hypertriglyceridemia.

Loss of MYO5B Leads to Reductions in Na+ Absorption With Maintenance of CFTR-Dependent Cl– Secretion in Enterocytes

Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), but the physiological cause of the diarrhea associated with this disease is unclear. We investigated whether loss of MYO5B results inaberrant expression of apical enterocyte transporters. We studied alterations in apical membrane transporters in MYO5B-knockout mice, as well as mice with tamoxifen-inducible, intestine-specific disruption of Myo5b (VilCreERT2;Myo5bflox/flox mice) or those not given tamoxifen (controls). Intestinal tissues were collected from mice and analyzed by immunostaining, immunoelectron microscopy, or cultured enteroids were derived. Functions of brush border transporters in intestinal mucosa were measured in Ussing chambers. We obtained duodenal biopsy specimens from individuals with MVID and individuals without MVID (controls) and compared transporter distribution by immunocytochemistry. Compared to intestinal tissues from littermate controls, intestinal tissues from MYO5B-knockout mice had decreased apical localization of SLC9A3 (also called NHE3), SLC5A1 (also called SGLT1), aquaporin (AQP) 7, and sucrase isomaltase, and subapical localization of intestinal alkaline phosphatase and CDC42. However, CFTR was present on apical membranes ofenterocytes from MYO5B knockout and control mice. Intestinal biopsies from patients with MVID had subapical localization of NHE3, SGLT1, and AQP7, but maintained apical CFTR. After tamoxifen administration, VilCreERT2;Myo5bflox/flox mice lost apical NHE3, SGLT1, DRA, and AQP7, similar to germline MYO5B knockout mice. Intestinal tissues from VilCreERT2;Myo5bflox/flox mice had increased CFTR in crypts andCFTR localized to the apical membranes of enterocytes. Intestinal mucosa from VilCreERT2;Myo5bflox/flox mice given tamoxifen did not have an intestinal barrier defect, based on Ussing chamber analysis, but did have decreased SGLT1 activity and increased CFTR activity. Although trafficking of many apical transporters is regulated by MYO5B, trafficking of CFTR is largely independent of MYO5B. Decreased apical localization of NHE3, SGLT1, DRA, and AQP7 might be responsible for dysfunctional water absorption in enterocytes of patients with MVID. Maintenance of apical CFTR might exacerbate water loss by active secretion of chloride into the intestinal lumen.

Histological study of donor's duodenal mucosa biopsy specimens in the diagnosis of pancreatoduodenal complex rejection: the experience of N.V. Sklifosovsky Research Institute for Emergency Medicine

Background. The verification and identification of the transplanted pancreas rejection type requires a morphological examination of the graft tissue. The pancreas graft transcutaneous biopsy procedure is associated with a high risk of surgical and infectious complications, and with the risk of the graft loss. Relatively safe is the biopsy of the donor duodenum mucosa. Objective: to evaluate the efficacy of morphological examination of the donor duodenum mucosa in early diagnosis of an acute rejection crisis of pancreas graft. Material and methods . The study presents a retrospective analysis of 35 donor duodenum mucosa biopsies performed in 19 recipients. In order to assess the correlation between clinical and morphological signs of rejection, the patients were divided into two groups. The first group included 6 patients with clinical signs of graft dysfunction; the second group included 7 patients without signs of rejection. Statistical processing of the study results was made using the descriptive statistics methods. Results . The signs of immunological complications were identified in 18 donor duodenum mucosa biopsies (51.4%) in 12 recipients (63.2%). In most cases (n = 13; 72.2%), the histological signs of mild rejection were found, the signs of moderate and severe rejection were less frequent (n = 3; 16.6% and n = 2; 11.1%, respectively). Morphological signs of acute rejection were found in all the patients of the 1st group (n = 6), including the signs of mild rejection in 4 cases (66.6%), of medium and severe rejection in 1 case each (16.7%). In the 2nd group, morphological signs of mild rejection were found in 3 patients (42.9%). Differences between the groups in the incidence of immunological complications were statistically significant (p < 0.05). Conclusions: the biopsy of donor duodenum mucosa is an important criterion in the diagnosis of an acute rejection crisis of the pancreatoduodenal complex, and also remains a safe method, even in the earliest postoperative period.

Usefulness of IgG4 immunostaining of duodenal papilla biopsy specimens in diagnosis of autoimmune pancreatitis

Usefulness of IgG4 immunostaining of duodenal papilla biopsy specimens in diagnosis of autoimmune pancreatitis

Quantification of the duodenal eosinophil content in adults: a necessary step for an evidence-based diagnosis of duodenal eosinophilia.

The normal content of eosinophils in the adult duodenum remains undefined. Therefore, there is no foundation for evidence-based criteria to diagnose eosinophilic duodenitis. This study aimed at: (1) establishing the range of the eosinophil density in the mucosa of the duodenum of normal adults, and (2) determining the biopsy-based prevalence of isolated eosinophilic duodenitis in a large population of adults. We counted intact eosinophils in three separate high-power fields (hpf area=0.237mm2 each) with the highest densities of eosinophils from the duodenal biopsy specimens of 370 consecutive adults (60% women) with no history of small intestinal disease and a normal duodenal histology. From a large database we also extracted patients with a diagnosis of elevated duodenal eosinophilia and reviewed their biopsies and clinical history. The mean eosinophil count for the 370 patients was 8.2eos/hpf with a standard deviation of±6.3. Twenty-seven of the 370 had eosinophil counts outside the 95% range, which was calculated as: mean + 1.96 × SD=20.4eos/hpf. In a database of 458668 adult subjects, 31 patients (6.8/100000) had elevated duodenal eosinophilia; 21 of these had other gastrointestinal organs involved by eosinophilia, suggesting eosinophilic gastroenteritis. No significant association between duodenal eosinophilia and any specific symptom was observed. This study suggests that in this diverse US population, a cut-off count of 20eos/hpf would be useful to separate patients with normal from those with elevated duodenal eosinophilic infiltrations. The clinical implications of duodenal eosinophilia, particularly when it is not an expression of eosinophilic gastroenteritis, remain to be established.

Intestinal parameters of oxidative imbalance in celiac adults with extraintestinal manifestations.

AIMTo evaluate selected intestinal parameters of oxidative stress, and antioxidant capacity in adult celiac disease patients with extraintestinal manifestations.METHODSThe study involved 85 adult patients divided into the following subgroups: (1) patients with newly diagnosed celiac disease (CD) (n = 7); (2) celiac patients not adhering to a gluten-free diet (GFD) (n = 22); (3) patients with CD on the GFD (n = 31); and (4) patients with functional disorders of the gastrointestinal tract, serving as controls (n = 25). Celiac patients presented with non-classic symptoms or extraintestinal manifestations. Standard blood tests including serum antioxidant levels (uric acid, bilirubin, and vitamin D), celiac antibody levels, and histopathological status of duodenal biopsy specimens have been determined. The expression of mRNA for tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 10 (IL-10), superoxide dismutase (SOD), heat-shock protein 70 (HSP-70), hypoxia-inducible factor 1 (HIF-1α), and BAX in the duodenal mucosa of patients was analyzed by reverse transcriptase-polymerase chain reaction.RESULTSThe mean plasma uric acid level in patients with active CD (newly diagnosed and nonadherent patients) and treated celiac patients was significantly higher than in controls (260.17 ± 53.65 vs 190.8 ± 22.98, P < 0.001, and 261.7 ± 51.79 vs 190.8 ± 22.98, P < 0.001, respectively). The mean bilirubin concentration in active and treated celiac patients was significantly lower than in controls (8.23 ± 5.04 vs 10.48 ± 4.08, P < 0.05 and 8.06 ± 3.31 vs 10.48 ± 4.08, P < 0.05, respectively). The mean plasma vitamin D level was significantly lower in active celiac patients than in treated celiac patients and controls (19.37 ± 9.03 vs 25.15 ± 11.2, P < 0.05 and 19.37 ± 9.03 vs 29.67 ± 5.12, P < 0.001, respectively). The expression of TNF-α, IL-10, and HSP-70 mRNAs was significantly elevated in the celiac groups regardless of the diet when compared with controls. Patients on the GFD presented a significantly lower mRNA expression of TNF-α and IL-10 than in newly diagnosed and nonadherent patients (P < 0.05). The expression of SOD mRNA was significantly elevated in celiac patients compared with controls (P < 0.05), with a significant difference between treated and untreated patients (P < 0.05). The expression of HIF-1α mRNA and BAX mRNA was significantly higher in patients with active CD compared with controls and patients on GFD, while no difference was observed between the latter two groups.CONCLUSIONIncreased intestinal expression of HSP-70 despite GFD indicates that GFD only partially reduced oxidative stress. CD patients exhibited an oxidative imbalance and inflammatory response despite GFD. Uric acid may act as an important antioxidant in CD.

Subtypes of chronic gastritis in patients with celiac disease before and after gluten-free diet.

Celiac disease (CD) often manifests with dyspeptic symptoms and chronic gastritis is a common finding. To evaluate the frequency of lymphocytic gastritis (LG), chronic active gastritis (CAG), and chronic inactive gastritis (CIG) in patients with CD, before and after gluten-free diet (GFD). A five-year prospective study including all consecutive patients with a new diagnosis of CD was conducted. Gastric and duodenal biopsy specimens taken both at the time of the CD diagnosis and at the first endoscopic control after 18-24 months on GFD were evaluated. 213 patients with CD were enrolled. At the time of the diagnosis, 42 patients (19.7%) showed normal gastric mucosa, 34 (15.9%) LG, 67 (31.5%) CAG, and 70 (32.9%) CIG. Out of the 34 patients with LG, all were Helicobacter pylori negative and the majority of them showed an improvement both of gastritis (94.1%) and duodenal lesions (82.3%) after GFD. GFD did not show significant effects on CAG and CIG. LG is present in 16% of CD patients, it is not associated with H. pylori infection, and it improves after GFD. Both CAG and CIG are also frequently associated with CD, but fail to respond to a GFD.

Selected Probiotic Lactobacilli Have the Capacity To Hydrolyze Gluten Peptides during Simulated Gastrointestinal Digestion.

The aim of this study was to demonstrate the capacity of probiotic lactobacilli to hydrolyze immunogenic gluten peptides. Eighteen commercial strains of probiotic lactobacilli with highly variable peptidase activity (i.e., aminopeptidase N, iminopeptidase, prolyl endopeptidyl peptidase, tripeptidase, prolidase, prolinase, and dipeptidase), including toward Pro-rich peptides, were tested in this study. Ten probiotic strains were selected on the basis of their specific enzyme activity. When pooled, these 10 strains provided the peptidase portfolio that is required to completely degrade the immunogenic gluten peptides involved in celiac disease (CD). The selected probiotic mixture was able to completely hydrolyze well-known immunogenic epitopes, including the gliadin 33-mer peptide, the peptide spanning residues 57 to 68 of the α9-gliadin (α9-gliadin peptide 57-68), A-gliadin peptide 62-75, and γ-gliadin peptide 62-75. During digestion under simulated gastrointestinal conditions, the pool of 10 selected probiotic lactobacilli strongly hydrolyzed the wheat bread gluten (ca. 18,000 ppm) to less than 10 ppm after 360 min of treatment. As determined by multidimensional chromatography (MDLC) coupled to nanoelectrospray ionization (nano-ESI)-tandem mass spectrometry (MS/MS), no known immunogenic peptides were detected in wheat bread that was digested in the presence of the probiotics. Accordingly, the level of cytokines (interleukin 2 [IL-2], IL-10, and interferon gamma [IFN-γ]) produced by duodenal biopsy specimens from CD patients who consumed wheat bread digested by probiotics was similar to the baseline value (negative control). Probiotics that specifically hydrolyze gluten polypeptides could also be used to hydrolyze immunogenic peptides that contaminate gluten-free products. This could provide a new and safe adjunctive therapy alternative to the gluten-free diet (GFD).IMPORTANCE This study confirmed that probiotic Lactobacillus strains have different enzymatic abilities for hydrolyzing polypeptides, including the Pro-rich epitopes involved in the pathology of CD. Ten lactobacilli with complementary peptidase activities that hydrolyze gluten peptides during simulated gastrointestinal digestion were selected and tested. The results collected showed the potential of probiotic formulas as novel dietary treatments for CD patients.

Fluorescence In Situ Hybridization for Diagnosis of Whipple's Disease in Formalin-Fixed Paraffin-Embedded Tissue.

Whipple’s disease (WD) is a rare chronic systemic infection with a wide range of clinical symptoms, routinely diagnosed in biopsies from the small intestine and other tissues by periodic acid–Schiff (PAS) diastase staining and immunohistological analysis with specific antibodies. The aim of our study was to improve the pathological diagnosis of WD. Therefore, we analyzed the potential of fluorescence in situ hybridization (FISH) for diagnosing WD, using a Tropheryma (T.) whipplei-specific probe. 19 formalin-fixed paraffin-embedded (FFPE) duodenal biopsy specimens of 12 patients with treated (6/12) and untreated (6/12) WD were retrospectively examined using PAS diastase staining, immunohistochemistry, and FISH. 20 biopsy specimens with normal intestinal mucosa, Helicobacter pylori, or mycobacterial infection, respectively, served as controls. We successfully detected T. whipplei in tissue biopsies with a sensitivity of 83% in untreated (5/6) and 40% in treated (4/10) cases of WD. In our study, we show that FISH-based diagnosis of individual vital T. whipplei in FFPE specimens is feasible and can be considered as ancillary diagnostic tool for the diagnosis of WD in FFPE material. We show that FISH not only detect active WD but also be helpful as an indicator for the efficiency of antibiotic treatment and for detection of recurrence of disease when the signal of PAS diastase and immunohistochemistry lags behind the recurrence of disease, especially if the clinical course of the patient and antimicrobial treatment is considered.

Duodenal biopsies for the diagnosis of coeliac disease: are we adhering to current guidance?

BackgroundThe British Society of Gastroenterology guidelines recommend taking at least four duodenal biopsy specimens at the time of upper gastrointestinal (UGI) endoscopy if coeliac disease (CD) is suspected and it...

Disaccharidase deficiency and functional bowel diseases

To elucidate the role of intestinal carbohydrases (glucoamylase, maltase, sucrose, and lactase) in the etiology and pathogenesis of functional bowel diseases (FBD). 74 patients (36 men and 38 women) aged 18 to 50 years with FBD were examined. According to Rome IV criteria (2016), there was diarrhea-predominant irritable bowel syndrome (IBS) in 21 patients, functional diarrhea (FD) in 33, constipation-predominant IBS in 6, functional constipation (FC) in 4, and mixed IBS in 10. The activity of carbohydrases in the small intestine mucosa (SIM) was investigated by the Dahlquist method modified by Trinder in the duodenal biopsy specimens obtained during esophagogastroduodenoscopy. Lactase deficiency was identified in 87.8% of the patients; maltase deficiency in 48.6%; sucrose deficiency in 51.3%; and glucoamylase deficiency in 85.1%. The activity of all the investigated enzymes was reduced in 23 (31.1%) patients with FBD; deficiency of 1-3 carbohydrases was found in 47 (63.5%). Normal enzymatic activity was established in 4 (5.4%) patients. In the majority of patients with FBD, the intestinal symptoms are caused by the decreased activity of SIM carbohydrases. Therefore, disaccharidase deficiency associated with an established damaging agent (nonsteroidal anti-inflammatory drugs, antibiotics, acute intestinal infections, etc.) should be considered to be a more precise diagnosis.

Celiac disease in non-clinical populations of Japan.

Celiac disease is a chronic autoimmune enteropathy caused by gluten ingestion. While its prevalence in Western countries is reported to be as high as 1%, the prevalence has not been evaluated in a large-scale study of a Japanese population. The aim of our study was to clarify the possible presence of celiac disease in a Japanese non-clinical population as well as in patients showing symptoms suggestive of the disease. Serum samples were collected from 2008 non-clinical adults and 47 patients with chronic unexplained abdominal symptoms between April 2014 and June 2016. The anti-tissue transglutaminase (TTG) immunoglobulin A antibody titer was determined as a screening test for celiac disease in all subjects, and individuals with a value of >2U/mL subsequently underwent testing for the presence of serum endomysial IgA antibody (EMA) as confirmation. Those testing positive for EMA or with a high concentration (>10U/mL) of TTG were further investigated by histopathological examinations of duodenal mucosal biopsy specimens and HLA typing tests. Of the 2008 non-clinical adults from whom serum samples were collected, 161 tested positive for TTG, and all tested negative for EMA. Four subjects who had a high TTG titer were invited to undergo confirmatory testing, and the histopathological results confirmed the presence of celiac disease in only a single case (0.05%). Of the 47 symptomatic patients, one (2.1%) was found to have a high TTG titer and was diagnosed with celiac disease based on duodenal histopathological findings. The presence of celiac disease in a non-clinical Japanese population was low at 0.05% and was rarely found in patients with unexplained chronic abdominal symptoms.

Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections.

Whipple's disease is a rare infectious disease that can be fatal if left untreated. The disease is caused by infection with Tropheryma whipplei, a bacterium that may be more common than was initially assumed. Most patients present with nonspecific symptoms, and as routine cultivation of the bacterium is not feasible, it is difficult to diagnose this infection. On the other hand, due to the generic symptoms, infection with this bacterium is actually quite often in the differential diagnosis. The gold standard for diagnosis used to be periodic acid-Schiff (PAS) staining of duodenal biopsy specimens, but PAS staining has a poor specificity and sensitivity. The development of molecular techniques has resulted in more convenient methods for detecting T. whipplei infections, and this has greatly improved the diagnosis of this often missed infection. In addition, the molecular detection of T. whipplei has resulted in an increase in knowledge about its pathogenicity, and this review gives an overview of the new insights in epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Tropheryma whipplei infections.

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes

Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin-IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin-IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin-IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4+ T cells. We now show that gluten-specific CD4+ T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin-IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4+ T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-xL Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4+ T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin-IELs and CD3-CD56+ IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4+ T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.

Intraepithelial lymphocytes, scores, mimickers and challenges in diagnosing gluten-sensitive enteropathy (celiac disease).

The upper digestive tract is routinely scoped for several causes of malabsorption, and the number of duodenal biopsy specimens has increased notably in the last 10 years. Gluten-sensitive enteropathy (GSE) is an autoimmune disease, which shows an increasing prevalence worldwide and requires a joint clinico-pathological approach. The classical histopathology of GSE with partial or total villous blunting is well recognized, but the classification of GSE is not straightforward. Moreover, several mimickers of GSE with intraepithelial lymphocytosis have been identified in the last 20 years, with drug interactions and medical comorbidities adding to the conundrum. In this review, we report on the normal duodenal mucosa, the clinical presentation and laboratory diagnosis of GSE, the duodenal intraepithelial lymphocytes and immunophenotype of GSE-associated lymphocytes, the GSE mimickers, the differences “across oceans” among guidelines in diagnosing GSE, and the use of a synoptic report for reporting duodenal biopsies in both children and adults in the 21st century.

Accuracy of biopsy for the preoperative diagnosis of superficial nonampullary duodenal adenocarcinoma

Endoscopic biopsy sampling for the diagnosis of duodenal adenocarcinoma is not perfect. We investigated the accuracy of biopsy specimen diagnoses of superficial nonampullary duodenal epithelial tumors (NADETs). Clinicopathologic data were retrospectively reviewed for 95 superficial NADETs from 95 patients who underwent endoscopic resection. Preoperative diagnoses based on biopsy specimens were compared with histologic diagnoses of resected specimens. Among the 21 lesions with biopsy specimen diagnoses of carcinoma, 12 (57.1%) were histologically diagnosed as adenomas after resection. Among the 74 lesions with biopsy specimen diagnoses of adenoma, 15 (20.3%) were histologically diagnosed as carcinomas after resection. The duodenal biopsy specimen predicted final histologic diagnoses of carcinoma with a sensitivity of 37.5% (95% CI, 18.8-59.4), specificity of 83.1% (95% CI, 72.3-91.0), accuracy of 71.6% (95% CI, 61.4-80.4), positive predictive value of 42.9% (95% CI, 21.8-66.0), and negative predictive value of 79.7% (95% CI, 68.8-88.2). Among 61 cases considered suitable for EMR, treatment modality was converted from EMR to endoscopic submucosal dissection because of the nonlifting sign in 15 cases (24.6%). The accuracy of duodenal biopsy sampling was relatively low. Duodenal biopsy sampling may induce unexpected fibrosis. New endoscopic modalities that can improve preoperative diagnosis yield of NADETs are eagerly awaited.

Suspected Nonceliac Gluten Sensitivity Confirmed in FewPatients After Gluten Challenge in Double-Blind, Placebo-Controlled Trials.

A double-blind, placebo-controlled, gluten challenge has been proposed to confirm a diagnosis of nonceliac gluten sensitivity (NCGS) in patients without celiac disease who respond to a gluten-free diet. To determine the accuracy of this approach, we analyzed data from 10 double-blind, placebo-controlled, gluten-challenge trials, comprising 1312 adults. The studies varied in the duration of the challenge (range, 1 d to 6 wk), daily doses for the gluten challenge (range, 2-52 g; 3 studies administered <8 g/d), and composition of the placebo (gluten-free products, xylose, whey protein, rice, or corn starch containing fermentable carbohydrates). Most of the studies found gluten challenge to significantly increase symptom scores compared with placebo. However, only 38 of 231 NCGS patients (16%) showed gluten-specific symptoms. Furthermore, 40% of these subjects had a nocebo response (similar or increased symptoms in response to placebo). These findings reveal heterogeneity and potential methodology flaws among studies of gluten challenge, cast doubt on gluten as the culprit food component in most patients with presumptive NCGS, and highlight the importance of the nocebo effect in these types of studies.