Small Intestinal Mucosal Biopsies Research Articles

Adults with Celiac Disease: Histopathological and Immunohistochemical Analysis of Small Intestinal Biopsies

In this study, we evaluated the immunohistochemical and micromorphological techniques for analyzing small intestinal biopsies from adults suspected of celiac disease. Methods: The study was carried out at the Department of Histopathology, Lady Reading Hospital, Peshawar, from December 2018 to August 2019. Fifty (50) specimens of small intestinal mucosal biopsies were examined in adult celiac disease patients over the age of 14 years. Modified Marsh Criteria were used to record their histomorphology data. Immunohistochemistry was used to determine the kind of intraepithelial lymphocytes. H&E staining and CD3 and CD20 immunostaining were used to count intraepithelial lymphocytes. Results: Seventin (34%) of patients were between the ages of 21 and 30 years, and 22% were between the ages of 41 and 50. Out of total 50 cases, males were 42 (84%). Thirteen (26%) of the cases had focal villous atrophy, 32 (64% of the cases) had partial villous atrophy, and 5 (10%) had total villous atrophy. Antibody to tissue transglutaminase was found to be positive in 21 (42%) of the patients. In all 50 cases, the CD3 immunomarker indicated intraepithelial lymphocytes, while the CD20 immunomarker showed localized positivity in lymphoid follicle development. On both H&E stain and immunostaining CD3 and CD20, the number of intraepithelial lymphocytes was determined to be nearly identical (with a difference of 3 - 4 lymphocytes). Conclusion: Males between the ages of 21 and 30 were the most affected. Partial villous atrophy and lymphocytic enteritis were the most common histological changes. All intraepithelial lymphocytes were distributed in a crescendo-like manner.

Intestinal isosporiasis in patients with acquired immunodeficiency syndrome (AIDS). Pathologic diagnosis in small intestinal mucosal biopsies.

Intestinal isosporiasis in patients with acquired immunodeficiency syndrome (AIDS). Pathologic diagnosis in small intestinal mucosal biopsies.

Challenging in the celiac disease diagnosis; Prague consensus

Celiac disease (CD) was initially a real enigma. There were many questions about what immunogenetics markers could influence the immune response (1). Immunogenetic studies provided important contributions to improve the understanding of critical pathogenetic factors at molecular levels (DQ2, DQ8) (2). An important discovery was the recognition of more precise serological markers for CD, specifically anti-endomysial and anti-tissue transglutaminase antibodies leading to an exploration of their increasingly important role in clinical diagnosis of CD (3). Our aim is to explore new and old challenges with unanswered questions in CD diagnosis. The last Prague consensus report challenges Re-evaluation of CD diagnostic with intestinal biopsy is required in this consesus (4). However, many patients with CD are still inaccurately diagnosed (or remain undiagnosed), even in referral populations whom were evaluated at tertiary care centers: the diagnosis of CD was confirmed in only 64 patients from 107 patients with previous diagnosis of CD (5). Recently, it was noted that even for some experts, the quality of duodenal bulb biopsies was unsatisfactory. This fact may create confusion and false-positive diagnoses which seem to be increasing in the pediatric population(6). However, histopathological classifications of CD have been debated for decades and some investigators have recently expressed concern regarding specific architectural changes, the degree of change and their relevance: Marsh, Marsh modified (Oberhuber), or Corazza classification. (7, 8). As immunologically-based assays evolve, the authors of this paper believe that serological markers are more useful for screening purposes in CD compared to small intestinal mucosal biopsy alone. At present, the gold standard for diagnosis is still small intestinal mucosal biopsy. Although data is still needed, it is conceivable that serological markers may eventually even become more useful for diagnostic purposes in CD compared to small intestinal mucosal biopsy alone (9). But an obvious serological algorithm is not specified. At present, the IgA anti-tissue transglutaminase antibody test appears to be the most sensitive and specific markers of CD screening (10) but a minority of CD patients are seronegative (11). The main task of gastroenterologists was to recognize untreated CD. In countries with weaker economies (i.e., the so-called developing nations), it is generally believed that the rate of diagnosis is low (12). Controversies remain in areas that include application of screening methods and evaluation of high risk groups for the CD, as well as diagnostic tests that lead to a final diagnosis of the CD (13). In addition, a number of immunologically-related challenges in gastroenterology remain for those involved in a CD care. IL-21 was lower in potential CD, than in active CD, so a key role for IL-21 in the progression of mucosal damage in CD needs to be further elucidated (14). Furthermore, HLA DQ8 in Southwest Asia, South America and the Middle East was positive in 49% (n=69) of CD patients and 13% (n=21) of control group, respectively. In conclusion, HLA DQ8 was found to be significantly higher in these geographical regions compared to European countries (15). However, HLA-DQ2 and/or -DQ8 expression: 38.1% in northern, 31.4% in northeastern, and 36.4% in southern India, did not appear to correlate with CD prevalence: 8.53/1,000 and 3.70/1,000 in northern, 4.66/1,000 and 3.92/1,000 in northeastern, and 0.11/1,000 and 1.22/1,000 in the southern India (16). A number of other associated immune-mediated or autoimmune disorders may co-exist with CD, possibly owing to a common genetic background (17). So, novel diagnostic antibodies for CD are neccesary (18).

Histopathological and Immunohistochemical Analysis of Small Intestinal Biopsies in Adults Suspected of Celiac Disease.

To analyse histomorphological and immunohistochemical analysis of small intestinal biopsies in adults suspected of celiac disease. Descriptive study. Department of Histopathology, Army Medical College, Rawalpindi, from November 2014 to December 2015. Fifty cases of small intestinal mucosal biopsies (duodenal and jejunal) were analysed in adult patients aged above 14 years suspected of celiac disease. Their histomorphological data was recorded using Modified Marsh Criteria. Type of intraepithelial lymphocytes was assessed using immunohistochemistry. Intraepithelial lymphocytes were counted both by H&E stain and immunostain CD3 and CD20. Thirty-four percent patients were aged between 21 - 30 years and 22% patients aged between 41 - 50 years. There were 84% (n=42) males. Thirteen (26%) cases showed focal villous atrophy, 32 (64%) cases showed partial villous atrophy and 5 (10%) cases showed complete villous atrophy. Anti-tissue transglutaminase antibody was positive in 21 (42%) cases. CD3 immunomarker was positive for intraepithelial lymphocytes in all 50 cases while CD20 immunomarker showed focal positivity in areas with lymphoid follicle formation. The count of intraepithelial lymphocytes was found to be almost equal (with a difference of 3 - 4 lymphocytes) on both H&E stain and immunostain CD3 and CD20. Males aged 21 - 30 years were the most commonly affected group. The most frequent change in histology was partial villous atrophy along with lymphocytic enteritis. All the intraepithelial lymphocytes were present in crescendo pattern of distribution.

The role of chronic norovirus infection in the enteropathy associated with common variable immunodeficiency.

A severe enteropathy of unknown etiology can be associated with common variable immunodeficiency (CVID). S tool and archived small intestinal mucosal biopsies from patients with CVID enteropathy were analyzed by PCR for the presence of Norovirus RNA. The PCR products were sequenced to determine the relationship of viral isolates. Stool samples from 10 patients with CVID but no enteropathy served as controls. All eight patients in our CVID cohort with enteropathy showed persistent fecal excretion of Norovirus. Analysis of archived duodenal biopsies revealed a strong association between the presence of Norovirus and villous atrophy over a period of up to 8 years. Analysis of the viral isolates from each patient revealed distinct strains of genogroup II.4. Sequence analysis from consecutive biopsy specimens of one patient demonstrated persistence of the same viral strain over a 6-year period. CVID patients without enteropathy showed no evidence of Norovirus carriage. Viral clearance occurred spontaneously in one patient and followed oral Ribavirin therapy in two further patients, and resulted in complete symptomatic and histological recovery. However, Ribavirin treatment in two further patients was unsuccessful. Norovirus is an important pathogen for patients with CVID and a cause of CVID enteropathy, as viral clearance, symptom resolution, and histological recovery coincide. Ribavirin requires further evaluation as a potential therapy.

Giardia cathepsin B cysteine proteases degrade interleukin‐8 and attenuate interleukin‐8‐induced neutrophil chemotaxis (152.2)

New therapeutic approaches for gastrointestinal inflammatory disorders are sorely needed. Children infected with the protozoan parasite Giardia duodenalis exhibit attenuated gut inflammatory responses via unknown mechanisms. The Giardia genome contains 9 cathepsin B (catB) proteases with anti‐inflammatory potential. Objectives. Using complimentary models of human intestinal biopsies, mice, and human enterocytes in vitro, to determine if Giardia infections attenuate Clostridium difficile toxin‐induced colitis, and if Giardia trophozoites attenuate interleukin‐8 (CXCL8) secretion from intestinal epithelial cells. Results. Reduced neutrophil (PMN) recruitment was observed in Giardia‐infected mice following rectal administration of C. difficile toxins. Co‐incubation of Giardia trophozoites with human small intestinal mucosal biopsy tissues ex vivo, or in vitro Caco‐2 monolayers resulted in attenuated of IL‐1β‐ or Salmonella‐induced CXCL8 secretion via catB‐mediated degradation of CXCL8. Giardia catB proteases also attenuated CXCL8‐induced PMN chemotaxis. Conclusion. Giardia trophozoites secrete catB proteases that degrade CXCL8 and attenuate CXCL8‐induced PMN chemotaxis. Parasitic protease‐mediated reduction of PMN’s may offer a promising therapeutic avenue for intestinal inflammatory disorders. Funding provided by NSERC, AIHS, and CCFC.

PS4 - 5. Administration of Eubacterium hallii improves insulin sensitivity and degree of liversteatosis in male db/db mice

The development of obesity and type 2 diabetes is associated with substantial changes in the composition of (small) intestinal microbiota. Using lean donor fecal transplantations in subjects with metabolic syndrome, we showed that improvement in insulin sensitivity associated with increased levels in small intestinal mucosal biopsies of Eubacterium hallii (an anaerobic butyrate producing bacteria belonging to Clostridium cluster XIVa).

Cleavage of interleukin‐8 and attenuation of neutrophil chemotaxis by a Giardia cathepsin B

Parasitic immunomodulatory molecules are currently undergoing investigation for their potential as anti‐inflammatory therapeutics. Children infected with the small intestinal parasite Giardia duodenalis have attenuated inflammatory responses via unknown mechanisms.ObjectiveTo determine if Giardia trophozoites modulate interleukin‐8 (CXCL8) secretion from intestinal epithelial cells (IECs) resulting in attenuated neutrophil (PMN) chemotaxis.ResultsCo‐incubation of Giardia trophozoites with ex vivo small intestinal mucosal biopsy tissues or in vitro monolayers resulted in attenuation of IL‐1β‐ or S. typhimurium‐induced CXCL8 secretion via parasitic cleavage of CXCL8. Giardia‐mediated cleavage of CXCL8 decreased its chemotactic ability for PMNs. Giardia trophozoites secrete cysteine proteases in the presence or absence of in vitro monolayers. Inhibition of Giardia cysteine proteases with a cysteine protease inhibitor (E‐64d) or a cathepsin B‐specific inhibitor (Ca‐074Me) inhibited Giardia‐mediated cleavage of CXCL8.ConclusionGiardia trophozoites release a cathepsin B‐like protease that cleaves CXCL8 and attenuates PMN chemotaxis. Funding provided by NSERC, AIHS, and CCFC.

Prospective antibody case finding of coeliac disease in type‐1 diabetes children: need of biopsy revisited

To evaluate whether coeliac disease (CD) can be diagnosed by measuring autoantibodies without small-intestinal mucosal biopsies in children with type 1 diabetes. Case finding of CD was undertaken in 181 consecutive IgA-competent children with type 1 diabetes using transglutaminase 2 (TG2) and endomysial IgA antibody (EMA) tests in serum and the rapid point of care test in fingertip whole-blood sample. Endoscopy with intestinal biopsies was recommended for patients with high TG2-IgA titres (>96U) and in children with lower positive tests if either the EMA test or the rapid point of care test was additionally positive. The duodenal mucosal biopsies were graded according to the Marsh classification. The TG2-IgA test had a 15.5% and the EMA test a 6.0% seropositivity. All seven biopsied high-titre TG2-IgA-positive children were symptom free and found to have CD (Marsh 3 type lesion). These patients were also positive for EMA and in the rapid point of care test. Lower titre TG2-IgA-positive children had histological Marsh 1 to 3a lesions. None of the type 1 diabetes children with high TG2-IgA titres would have needed endoscopy with duodenal biopsies to reach a CD diagnosis. Lower TG2-IgA-positive patients need to be biopsied.

Gene expression in intestinal mucosal biopsy specimens obtained from dogs with chronic enteropathy

To characterize mucosal gene expression in dogs with chronic enteropathy (CE). 18 dogs with CE and 6 healthy control dogs. Small intestinal mucosal biopsy specimens were endoscopically obtained from dogs. Disease severity in dogs with CE was determined via inflammatory bowel index scores and histologic grading of biopsy specimens. Total RNA was extracted from biopsy specimens and microchip array analysis (approx 43,000 probe sets) and quantitative reverse transcriptase PCR assays were performed. 1,875 genes were differentially expressed between dogs with CE and healthy control dogs; 1,582 (85%) genes were downregulated in dogs with CE, including neurotensin, fatty acid-binding protein 6, fatty acid synthase, aldehyde dehydrogenase 1 family member B1, metallothionein, and claudin 8, whereas few genes were upregulated in dogs with CE, including genes encoding products involved in extracellular matrix degradation (matrix metallopeptidases 1, 3, and 13), inflammation (tumor necrosis factor, interleukin-8, peroxisome proliferator-activated receptor γ, and S100 calcium-binding protein G), iron transport (solute carrier family 40 member 1), and immunity (CD96 and carcinoembryonic antigen-related cell adhesion molecule [CEACAM] 18). Dogs with CE and protein-losing enteropathy had the greatest number of differentially expressed genes. Results of quantitative reverse transcriptase PCR assay for select genes were similar to those for microchip array analysis. Expression of genes encoding products regulating mucosal inflammation was altered in dogs with CE and varied with disease severity. Impact for Human Medicine-Molecular pathogenesis of CE in dogs may be similar to that in humans with inflammatory bowel disease.

MicroRNA Signature of Intestinal Acute Cellular Rejection in Formalin-Fixed Paraffin-Embedded Mucosal Biopsies

Despite continuous improvement of immunosuppression, small bowel transplantation (SBT) is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need to uncover novel insights that will lead to strategies to achieve better control of ACR. We hypothesized that particular miRNAs provide critical regulation of the intragraft immune response. The aim of our study was to identify miRNAs involved in intestinal ACR. We examined 26 small intestinal mucosal biopsies (AR/NR group; 15/11) obtained from recipients after SBT or multivisceral transplantation. We investigated the expression of 384 mature human miRNAs and 280 mRNAs associated with immune, inflammation and apoptosis processes. We identified differentially expressed 28 miRNAs and 58 mRNAs that characterized intestinal ACR. We found a strong positive correlation between the intragraft expression levels of three miRNAs (miR-142-3p, miR-886-3p and miR-132) and 17 mRNAs including CTLA4 and GZMB. We visualized these miRNAs within cells expressing CD3 and CD14 proteins in explanted intestinal allografts with severe ACR. Our data suggested that miRNAs have a critical role in the activation of infiltrating cells during intestinal ACR. These differences in miRNA expression patterns can be used to identify novel biomarkers and therapeutic targets for immunosuppressive agents.

Quantification of Intraepithelial Lymphocytes in Normal Pediatric Small Intestinal Allograft and Native Ilea

Background The small bowel acts as one of the first lines of defense against intraluminal infections and antigenic stimuli. Pediatric small bowel transplant patients are at particular risk from such agents, especially viral enteridities. Quantification of intraepithelial lymphocytes (IEL) in architecturally normal small intestinal mucosal biopsies plays an important role in the diagnosis of conditions such as celiac disease and some viral infections. No studies to date have been done to quantify IEL numbers in pediatric small bowel allografts and in native pediatric ilea. Our study investigated the IEL:enterocyte (EC) ratio in pediatric allograft and native ilea. Methods Hematoxylin and eosin slides from 50 surveillance endoscopic biopsies of small bowel allografts taken from patients <8 years of age and 50 terminal ileal biopsies from aged-matched control populations were reviewed. IEL:EC ratios were averaged from five well-oriented villi in each case. IEC numbers were compared between biopsies from proximal (afferent) and distal (efferent) limbs of double-barrel allograft stomas, as well as native terminal ilea. Results Within small bowel allografts, the average number of villus tip IELs was 1.3/20 ECs (standard deviation [SD] 0.6) in the proximal limb and 1.0/20 ECs in the distal (SD 0.6 P < .01). This value was significantly lower than in the control ilea (2.1/20 EC [SD 0.6]; P < .01, each). The overall distribution of lymphocytes was in a similar pattern throughout the villus with IEL:EC ratios on villus sides from proximal allografts, distal allografts, and native ilea being 1:20, 0.8:20, and 2:20, respectively. Conclusions The results suggest that approximately one to two IEL per 20 ECs at villus tips may represent a “normal” intraepithelial inflammatory cell population in small bowel allografts. The value is lower than that seen in age-matched native ileal biopsies. IEL numbers are significantly higher in the proximal limb compared to the distal limb of double-barrel stomas.

The role of endoscopy in the management of patients with diarrhea

The role of endoscopy in the management of patients with diarrhea

Correlation between Clinical and Morphological Signs of Gastrointestinal Disorders in Patients with Degenerative Spine and Hip Disease

Objective. To analyze correlation between clinical signs of gastrointestinal disorder and endoscopic and morphological findings in patients with spine and hip degenerative disease. Material and Methods. The study included data on 648 patients with spine and hip degenerative diseases. Clinical analysis of gastrointestinal function, gastrofibroscopy, intestinal fibroscopy, chronographic study, and morphological examination of small-intestinal mucosal biopsy specimens were performed in all examined patients. Results. The obtained data demonstrate sufficiently close correlation between clinical signs of gastrointestinal disorder and changes in mucosal endoscopic pattern and histological structures. Conclusion. Patients with degenerative spine and hip diseases have a comorbid condition presented by clinically significant complex of gastrointestinal disorders correlated with endoscopic and morphological changes in the intestinal wall.

Gene Expression Profiling of MicroRNAs in Small-Bowel Transplantation Paraffin-Embedded Mucosal Biopsy Tissue

Background The molecular mechanisms and regulation of immune-mediated rejection of organ allografts remains unclear. Recent studies have reported that small non-coding RNAs, microRNAs (miRNAs) play a critical role in the immune system via modulation of transcription and translation. Purpose We hypothesized that particular miRNAs provide regulation of an ensuing intragraft immune effector response. The aim of our study was to detect miRNAs involved in acute cellular rejection (AR) in human small intestinal allografts. Materials We examined 12 small intestinal mucosal biopsies (AR, 7 cases, all grade 2 or 3) and non-rejecting (NR) allografts (5 cases, all grade 0) obtained from recipients after small bowel or multivisceral transplantation. RNA was isolated from the formalin-fixed paraffin-embedded (FFPE) biopsy samples and transcribed to cDNA. After preamplification we utilized a PCR based TaqMan Low Density Array (TLDA) containing 365 mature human miRNAs. Relative quantification was done based on pooled normal intestine using a comparative Ct method. Results We identified 62 miRNA upregulated genes in small bowels with ACR, and 35 were downregulated. Forty-two miRNA genes were upregulated in non-ACR small bowel biopsy samples (grade IND), and 45 were downregulated. The relative fold change ratio of ACR to non-ACR was calculated, and 50 upregulated and 8 downregulated miRNAs were detected as significant. Several interesting miRNAs will be evaluated further from this preliminary study. Our data suggests that intragraft miRNAs are potentially involved in the activation of a host alloimmune response to donor. These miRNAs may serve as targets for appropriate intervention and may be useful to monitor the allograft status.

COMPARISON OF ULTRASONOGRAPHIC FINDINGS WITH CLINICAL ACTIVITY INDEX (CIBDAI) AND DIAGNOSIS IN DOGS WITH CHRONIC ENTEROPATHIES

Intestinal wall thickness is neither a specific nor sensitive ultrasound parameter for detecting intestinal inflammation. We hypothesize that mucosal echogenicity, lymphadenomegaly, and secondary findings of the gastrointestinal tract would be more sensitive and specific markers for detecting and differentiating causes of chronic inflammatory bowel disease in dogs. Fifty-six client-owned dogs with chronic diarrhea and 10 control dogs were examined with two-dimensional, gray-scale ultrasound (time 0, 4, and 10 weeks post therapy) and small intestinal mucosal biopsies were performed at the 0- and 4-week time points. The clinical activity was assessed at each time point using the canine inflammatory bowel disease activity index (CIBDAI). Fifty-one dogs had inflammatory infiltration of the duodenal mucosa and were divided into three groups, food-responsive disease, idiopathic inflammatory bowel disease, and protein-losing enteropathy, based on their response to the different treatments and histology. Two different patterns of increased echogenicity of the mucosa were detected: hyperechoic speckles and hyperechoic striations. A normal, hypoechoic bowel mucosa in dogs with chronic diarrhea had a sensitivity of 80% and a specificity of 81% for the diagnosis of food-responsive disease. Hyperechoic striations had a sensitivity of 75% and a specificity of 96% for dogs with protein-losing enteropathy. Hyperechoic speckles were non-specific for diagnosing inflammatory bowel disease. There was a significant relationship between ultrasound score and CIBDAI at t0, but not following therapy. Mucosal echogenicity may be a better parameter for detecting inflammatory bowel disease than bowel wall thickness in dogs with chronic diarrhea.

Lactose malabsorption in the elderly: Role of small intestinal bacterial overgrowth

Objective. The prevalence of lactose malabsorption (LM) is increased in the elderly, although the mechanisms responsible are still a matter of speculation. The objective of this study was to investigate the possible roles of reduced functional small intestinal absorptive area, lactase deficiency and small intestinal bacterial overgrowth (SIBO). Material and methods. Twenty Caucasian (Anglo-Celtic), asymptomatic, well-nourished, elderly volunteers (median age 79 years, range 70–94 years) with no clinically apparent predisposition to SIBO underwent a 50 g lactose breath hydrogen test (LBHT) and mannitol absorption test, the latter as an index of functional small intestinal absorptive area. Those with LM additionally underwent bacteriological assessment of small intestinal secretions and mucosal biopsy, to assess the contribution of SIBO and lactase deficiency, respectively, to the pathogenesis of LM in individual cases. The prevalence of SIBO was also determined in elderly subjects without LM. Twenty asymptomatic younger subjects (median age 29 years, age range 18–35 years) served as controls. All subjects were “hydrogen producers” in response to lactulose. Results. LM was evident in 10/20 (50%) elderly subjects and 1/20 (5%) younger subjects (p=0.003). Mannitol absorption did not differ significantly in elderly and younger subjects or in elderly subjects with and without LM. SIBO was documented in 9/10 (90%) elderly subjects with LM; eradication was associated with resolution of LM. Lactase deficiency was evident in only one elderly subject with LM. SIBO was evident in 2/10 (20%) elderly subjects without LM (p=0.005 compared to those with LM). Lactulose breath hydrogen test identified only 2/11 (18%) elderly subjects with SIBO. Conclusions. Increased prevalence of LM in the elderly is mostly due to clinically non-apparent SIBO, rather than mucosal factors. The lactulose breath hydrogen test cannot be relied upon to identify elderly subjects with SIBO, even in those without an anatomical predisposition.

AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease

Celiac disease is a permanent intolerance to gluten, a term that is broadly used to describe the storage proteins in wheat, rye, and barley. Celiac disease is characterized by a chronic inflammatory state of the proximal small intestinal mucosa, which can impair digestion and absorption of macronutrients and micronutrients and results in increased net secretion of water and solute. Celiac disease can present with intestinal symptoms, can present with extraintestinal symptoms (including the intensely pruritic skin rash dermatitis herpetiformis), or may be detected in individuals who are asymptomatic as part of the screening of populations at increased risk for celiac disease. There is a spectrum of small intestinal mucosal injury that ranges from minimal with an increase in intraepithelial lymphocytes to total villous atrophy. However, most symptomatic patients with celiac disease have some degree of villous atrophy. The HLA class II DQ molecules DQ2 or DQ8 are necessary, although not sufficient, for the phenotypic expression of celiac disease.

Management of celiac disease in childhood and adolescence: Unique challenges and strategies

Celiac disease (CD) is a common condition that occurs in genetically predisposed individuals when they ingest products containing wheat, barley, or rye. It produces an autoimmune-mediated enteropathy with characteristic histologic features on small intestinal mucosal biopsy. The clinical manifestations of CD are highly variable and initially may be unrelated to the gastrointestinal system. The condition is also strongly associated with other autoimmune and nonautoimmune conditions. Physicians caring for children and adolescents are challenged with identifying those who might have CD and require referral for definitive testing, recognizing the potential pitfalls in the diagnostic work-up of the pediatric patient, and providing ongoing care for those with a positive diagnosis. Confirmation of the diagnosis mandates that the individual be placed on a strict gluten-free diet (GFD) for life, as this is the only treatment currently available for CD. This article will discuss the immunopathogenesis, epidemiology, and clinical manifestations of CD and will outline a strategy of active case-finding using serological tests to identify those who require an intestinal biopsy for definitive diagnosis. The need for lifelong treatment by means of a GFD and for continued follow-up of children and adolescents after diagnosis is emphasized.

Intraepithelial Lymphocytosis in Architecturally Preserved Proximal Small Intestinal Mucosa: An Increasing Diagnostic Problem With a Wide Differential Diagnosis

An increased intraepithelial lymphocyte density in an architecturally normal proximal small intestinal mucosal biopsy is a common finding facing surgical pathologists dealing with gastrointestinal biopsy specimens. Approximately 1% to 2% of all proximal small intestinal biopsies will show this change. It is increasingly recognized by surgical pathologists that gluten-sensitive enteropathy is an important cause of this pattern; however, gluten-sensitive enteropathy accounts for the minority of all cases. A wide variety of immunologic stimuli can raise intraepithelial lymphocyte numbers. Among the other common associations are enteric infection, autoimmune disease, drugs, and gastric Helicobacter infection. To outline the causes of intraepithelial lymphocytosis, to highlight the importance and the difficulties faced in establishing gluten-sensitive enteropathy as the cause, and to aid the surgical pathologist in the routine sign out of these cases. A review of the literature detailing the causes or associations of proximal small intestinal intraepithelial lymphocytosis is presented. Increased lymphocyte numbers in the epithelium of architecturally preserved proximal small intestinal biopsies is a morphologic feature associated with a broad differential diagnosis.