Villous Blunting Research Articles

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.

PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'.

PD-1 inhibitors facilitate immune response against certain tumour types, including melanoma. These drugs have led to prolonged survival but can also result in autoimmune-type side effects, including gastrointestinal inflammation. The histopathological effects of this medication class have not been well studied. We identified 37 gastrointestinal tract biopsies from 20 patients taking a PD-1 or PD-L1 inhibitor and evaluated clinicopathological findings. Diarrhoea was the most common symptom, and endoscopic findings ranged from mild erythema to erosion/ulceration. Common histological findings included lamina propria expansion, villous blunting (if applicable), intra-epithelial neutrophils and increased crypt/gland apoptosis, although intra-epithelial lymphocytes were rarely prominent. A few cases showed crypt rupture with resultant histiocytic/granulomatous response. Most patients responded to drug cessation and/or steroids, but follow-up endoscopies were not performed. PD-1/PD-L1 inhibitors can cause gastritis, enteritis and colitis, similar to other immunomodulatory antibodies (such as CTLA-4 inhibitors and PI3Kδ inhibitors), but the histological findings vary somewhat among drug classes. Clinical history, lack of prominent intra-epithelial lymphocytes and crypt rupture may help to distinguish PD-1 inhibitor gastroenterocolitis from mimics, which include other medication effect, inflammatory bowel disease, graft-versus-host disease, cytomegalovirus infection and autoimmune enteropathy.

Strongyloidiasis: An Uncommon Cause of Villous Blunting

Introduction: We describe an interesting case of villous blunting caused by Strongyloidies stercolaris infection. Case description: 57-year-old female presented with one-week history of myalgias, chills and tactile fever. She also reported chornic diarrhea, intermittent abdominal pain and recent onset dry cough. She denied weight loss, dyspnea, melena, hematochezia, dysuria, pruritus and skin rash. She was originally from Michoacan, Mexico and had lived in United States for several years. She frequently visited a lake near her house in Micohoacan where she enjoyed walking barefoot. Previous travel to Mexico was three years prior to this encounter. Physical exam was notable for mild epigastric tenderness. Lab workup revealed anemia and leukocytosis. Previous workup was significant for peripheral eosinophilia, which had remained unexplained. ESR and CRP values were 36 and 4 respectively. CT scan of abdomen revealed submucosal fatty infiltration in distal duodenum and proximal jejunum. EGD findings were consistent with villous blunting and fissures in mid jejunum. Biopsy of this region revealed larvae of Strongyloides stercolaris. This was confirmed with a positive Strongyloides IgG serology. A diagnosis of Strongyloidiasis was made and treatment with ivermectin was initiated. Discussion: Villi are finger like projections of epithelial lining of intestinal wall, which are involved in absorption of nutrients. Villous blunting is defined by flattening of villi. It can be caused by a various conditions, which include celiac disease, autoimmune enteropathy, common variable immunodeficiency (CVID), peptic duodenitis, food allergies, giardiasis and viral enteritis. Strongyloidiasis can lead to broad range of endoscopic findings in small intestine, which include edema, brown discoloration, subepithilial hemorrhages and megaduodenum1. Strongyloides infection can cause duodenitis which leads to villous blunting and atrophy depending on degree of inflammation. Effects in jejunum have not been well described. Endoscopists must be aware that strongyloidiasis is a cause of villous blunting and keep a high index of suspicion in symptomatic patients who travel frequently to endemic areas, those who are immunosuppressed and recent immigrants.Figure 2Figure 1

Duodenal Villous Blunting: Hint for Underlying Malignancy

Introduction: The characteristic changes found during small intestinal remodeling in celiac disease include inflammatory villous blunting or atrophy. Villous blunting with sero-negativity for celiac disease is a diagnostic and therapeutic challenge. Case Description: 66 years old woman was referred to our clinic for the evaluation of chronic diarrhea, unintentional weight loss and malabsorption. She had a history of vitamin B12 deficiency, peripheral neuropathy and frequent falls leading to subdural hematomas. She had tried gluten free diet for a few months without improvement. Laboratory investigations including CBC, CMP, lipase, albumin, Iron, Folate, prothrombin time, vitamin B1, B6, B12 and D were within normal limits. Work up of celiac disease including IgA and IgG Tissue transglutaminase and gliadin peptide were negative. Her intrinsic factor blocking antibody was negative. Biopsies of the duodenal mucosa revealed focal chronic inflammation with villous blunting (Figure 1) which was not pathognomonic for Celiac disease. She was found to be HQ2/HQ8 negative. Magnetic Resonance Enterography (MRE) showed a right ovarian cystic carcinoma with metastatic lymphadenopathy without any bowel inflammation.She was treated by bilateral salphingo- oophorectomy and total hysterectomy, followed by chemotherapy. Discussion: Villous atrophy of the small intestine mucosa occurs most commonly in Celiac disease.The histological changes in celiac disease are best defined by the Modified Marsh classification (Table-1). Villous atrophy (VA) associated with malignancy is infrequently seen and reported. Creamer et al have reported 6 cases of extra intestinal solid malignancies causing villous atrophy. Local tumor infiltration with CD4+ cells and increased production of Th1 cytokines and interferon gamma leads to oligoclonal expansion of CD4+ helper T cells as an antitumor response. Tumor specific T cells can be found to circulate in 50 % of patients with ovarian carcinoma. The small intestine can be affected by this activation of CD4+ T helper 1 cells leading to intraepithelial lymphocytosis (lymphocytic duodenosis) and features of villous atrophy and crypt hyperplasia without gluten hypersensitivity. Conclusion: Villous atrophy without celiac disease can occur in underlying extra intestinal malignancies like ovarian cancer leading to diarrhea, malabsorption and weight loss. Sero- negative celiac disease with villous atrophy should be evaluated for underlying malignancy.Figure 1Table 1: Modified Marsh Classification of Small intestinal changes

Omesartan Induced Sprue-like Enteropathy

Olmesartan is a commonly prescribed antihypertensive that blocks the angiotensin receptor. A serious side effect of sprue-like enteropathy has been documented. Severe chronic diarrhea with substantial weight loss can occur months and up to years after initiation of the drug. Histologically, it is indistinguishable from celiac disease, with villous blunting; however, celiac serology is negative. The infrequency in which it is encountered makes diagnosis difficult; nevertheless, this is a newly recognized and documented side effect seen across the country. A 67-year-old male presented to the hospital with chronic diarrhea. Bowel movements were described as loose, watery, non-bloody voluminous stools without abdominal pain. Stool output was 10-12 liters daily. On admission, workup included infectious, inflammatory, absorptive and autoimmune causes. Secretory causes were ruled out as levels of calcitonin, gastrin, vasoactive intestinal peptide and 5-hydroxyindoleacetic acid were nonremarkable with a negative octreoscan. Infectious causes were ruled out with negative stool studies and viral serologies. The patient's stay was complicated by acute kidney injury, severe protein malnutrition, and pneumatosis intestinalis. Esophagogastroduodenoscopy with duodenal biopsies showed marked villous blunting consistent with celiac disease; however, serology was negative. After extensive workup, it was concluded that the patient's olmesartan was a likely etiology, as studies have shown that the medication can cause sprue-like enteropathy. Olmesartan was discontinued at admission secondary to acute kidney injury, and diarrhea resolved after 4 weeks of hospitalization. This case illustrates the possibility for severe enteropathy with the use of olmesartan and the importance of a medication review in similar cases. Olmesartan induced sprue-like enteropathy can develop months to years after the initiation of therapy and can lead to prolonged hospital stays. One mechanism hypothesized is a cell-mediated immune response. Although very rare, enteropathy is a known adverse effect and prompt recognition is critical to resolve enteropathy, decrease unnecessary tests, and minimize hospital stay length.

Nausea Vomiting and Diarrhea Associated with Small Vessel Fibrinoid Necrotizing Vasculitis: A Brief Review of GI Manifestations of Systemic Vasculitis

Introduction: Nausea, vomiting, and Diarrhea are common symptoms with a broad differential including systemic diseases. Systemic illnesses such as vasculitis can involve the GI tract, and contribute to nonspecific GI symptoms. Vasculitis and cryoglobulinemia are associated with multiple conditions other than Hep C. Case report: 63 year old woman with a history of Waldenstrom's macroglobulinemia associated with cryoglobulinemia treated with plasmapheresis & Rituxan previously, presented to the hospital with a 3 day history of nausea, vomiting, diarrhea & epigastric abdominal pain, similar to self-limited symptoms that were present a month prior. CT abdomen revealed a segment of small bowel thickening and suspicion for a partial SBO. Subsequently a small bowel follow through study was done which did not reveal any obstruction, but did reveal an edematous small bowel loop corresponding to the abnormal loop on CT scan. EGD and colonoscopy were performed. EGD identified nonspecific gastritis, and colonoscopy revealed mild diffuse loss of vascularity with villous blunting and a transverse colon polyp which was removed. The patient recovered well with supportive management and was discharged home. Pathologically the polyp was composed of granulation tissue of an ulcer caused by small vessel vasculitis with fibrinoid necrosis (fig-1). In follow up a few weeks post discharge patient had minimal symptoms and has been scheduled for continued care with Hem/Onc.Figure 1Discussion: GI vasculitis usually presents as chronic mesenteric ischemia which may be associated with abdominal pain, nausea, vomiting, diarrhea or even GI bleed. Acute mesenteric ischemia, ischemic hepatitis, pancreatitis, cholecystitis, esophagitis, gastritis and appendicitis have also been reported.1 Endoscopy should be performed with caution in the setting of possibly edematous, ischemic bowel.2 Treatment includes treatment of underlying disease, and therapy directed at gastrointestinal symptoms. A high degree of suspicion should be maintained in patients with known history of vasculitis as surgical intervention may be warranted in patients with mesenteric infarction or intestinal perforation.

Celiac Disease Presenting as Myeloneuropathy from Copper Deficiency

Celiac disease is a chronic autoimmune enteropathy triggered by dietary gluten in genetically predisposed individuals. Celiac disease was historically considered a disease of children and young adults, but the diagnosis is made increasingly in an older patient population—approximately 25% of celiac cases are now diagnosed in the seventh decade of life or later. Celiac disease is more likely to present with extraintestinal manifestations in older adults. Patients can present with neurologic manifestations such as ataxia, seizures and peripheral neuropathy resulting from vitamin and trace mineral deficiencies secondary to intestinal malabsorption. Copper deficiency is of particular interest, as it can result in severe myeloneuropathy and has been described in patients with intestinal malaborptive conditions. We present a case of late onset celiac disease presenting as myeloneuropathy likely secondary to copper deficiency. A 76-year-old, previously active, white woman presented with complaints of progressive inability to ambulate and lower extremity numbness of 1 year duration. She was wheelchair dependent at the time of presentation. She also reported several months of watery diarrhea and a 60 lb weight loss. Physical examination revealed decreased sensation to light touch and pinprick along with a positive Babinski sign. Cognitive dysfunction was also apparent. Extensive laboratory evaluation for her myeloneuropathy and chronic diarrhea revealed an elevated IgA anti-tissue transglutaminase antibody level of 22 units/ml (normal 0.0-7.0) and a very low serum copper of 23 micrograms (normal 77-166). The rest for her evaluation was unremarkable. A subsequent EGD revealed diffuse, scalloped mucosa in the examined duodenum and duodenal biopsies showed villous blunting and an increase of intraepithelial lymphocytes confirming the diagnosis of celiac disease. The patient was initiated on a gluten free diet with resolution of diarrhea. Copper supplementation was initiated with minimal improvement in her neurological symptoms Specifically, the patients ataxia and cognitive dysfunction persisted despite improved functional status with rehabilitation. Celiac disease may present late in life and may present with extraintestinal manifestations. Patients with celiac disease are at risk for copper deficiency which can cause severe, permanent myeloneuropathy.

Clinical Vignettes/Case Reports - Small Intestine/Unclassified.

Peripheral T-Cell Lymphoproliferative Disorder (PTCL) is a rare group of neoplasms and represents less than 5% of all Non-Hodgkin Lymphomas. They occur more commonly in adults with a median age of 60 years but rarely reported in the oldest old (more than 85 years). Usually it's described as diffuse pattern of infiltration by polymorphic atypical neoplastic T-cells. This entity has vague clinical presentation including fever, night sweats and weight loss, frequently difficult to diagnose. This is a functionally independent 86 year old Jamaican Female with history of esophageal reflux known patient of our Gastroenterology service, who came for evaluation of early morning satiety, nausea and significant progressive weight loss in a period of 6 months. Her physical examination was significant only for mild epigastric discomfort. Family and Social history, surgical procedures, laboratory findings, chest radiography and abdominal ultrasound were unremarkable. In the previous year, CT-Scans and MRI of the abdomen because of reflux symptoms were normal. The current imaging found a soft tissue mass 3.9x7 cm in the mid abdomen rising from the small bowel, abnormal loops with thickened wall, indistinct margins and extensive mesenteric and retroperitoneal adenopathy (Figure I). She underwent push enteroscopy exposing a partially circumferential frond-like/villous jejunal friable mass with no bleeding at 50cm beyond the ligament of Treitz, extending 5 cm with non-obstructing characteristics (Figure II). The histology revealed villous blunting, ulceration and mixed inflammatory erosion in the lamina propia and a heavy atypical lymphoid infiltration deeper in the submucosa. The immunohistochemical analysis confirmed positive CD-3 with CD5 & CD4: T-Cell phenotype with negative CD30 and ALK-1. In accordance with the Ann Arbor system, this is considered stage IIE lymphoproliferative disorder. Further evaluation to obtain a final diagnosis was attempted but declined by the patient and the inability to undergo surgical resection considering her very poor pulmonary status. On follow up, no new symptoms were reported. Peripheral T-Cell Lymphoproliferative disorder presenting in the G.I. system is rare and has not been reported in the oldest old (more than 85 years old). Its differential diagnosis includes HTLV-1 or Enteropathy Associated T Cell Lymphoma. The value of this case is its unusual presentation in such uncommon pathology for the geriatric population.Figure 1Figure 2

Asymptomatic Cholecystocolonic and Cholecystoduodenal Fistulae in the Same Patient: A Unique Presentation

Background: Incidental findings of cholecystocolonic fistulae (CCF) are rarely reported and a review of 160 articles, published between 1950 and 2006 by Costi et al, revealed only 231 such cases. In patients with repeated episodes of cholecystitis associated with CBD stones1 and absence of pathognomic symptoms like chronic watery diarrhea2, malabsorption of fat-soluble vitamins, especially Vitamin D3 and pneumobilia, suspicion for a CCF must be considered4. We present a case of an asymptomatic 67 year old female who was found to have cholecystocolonic and cholecystoduodenal fistulae during a routine colonoscopy. Case Report: A 67 year Caucasian female with history of prediabetes and hypertension presented to our facility for a routine surveillance colonoscopy. During her colonoscopy, a small fistula was found in the transverse colon (figure 1). This was an incidental finding as the patient did not have any concerning symptoms such as diarrhea or weight loss. She underwent a lower gastrointestinal series which confirmed the presence of a fistulous tract connecting the hepatic flexure of the colon to a contracted gallbladder with subsequent filling of the biliary tree. Additionally, a second smaller fistula was visualized which extended from the larger fistula near the hepatic flexure of the colon to the duodenum (Figure 2). An MRCP following this showed an open mouth communication from the gallbladder fundus to the transverse colon and posterior to this communication, there was an additional fistulous tract extending from the second portion of the duodenum to the gallbladder (Figure 3). Biopsies of the fistula revealed villous blunting with pseudopyloric metaplasia, increased lamina propria inflammation and mild active inflammation negative for granulomas and dysplasia. Following colo-cystic and coloduodenal fistula take down surgery, she was discharged home and has had an uneventful recovery thus far.Figure 1Figure 2Figure 3Discussion: Internal biliary enteric fistulas (IBFs) are a rare collection of biliary tract pathologies which have previously only been sparsely reported in literature. They have a 0.2-0.9% detection rate during biliary tract operations. A classic triad of pneumobilia, chronic bile acid induced diarrhea and malabsorption of fat-soluble vitamins like Vitamin D often provides high clinical suspicion of these fistulas which then need confirmation with endoscopic evaluation. However, asymptomatic IBFs are rare and their occurance warrants reporting.

Olmesartan-Associated Enteropathy Without Chronic Diarrhea: An Atypical Presentation of a Difficult Diagnosis

Olmesartan-associated enteropathy (OAE) is a recently identified sprue-like enteropathy and clinical syndrome that presents primarily with chronic diarrhea and significant weight loss accompanied by abdominal pain, nausea, vomiting, bloating or fatigue. This report describes an atypical clinical presentation of olmesartan-associated enteropathy. An 82-year-old woman presented to clinic with approximately 5 months of poor appetite followed by sudden onset of frequent nausea, vomiting, epigastric abdominal pain and 40-pound weight loss. She had no diarrhea. She had several previous admissions at other hospitals with extensive work-up that was ultimately unrevealing (included multiple abdominal CTs, multiple EGDs, and colonoscopy). Olmesartan was on her home medication list but had been replaced by another hospital formulary angiotensin receptor blocker (ARB) on admission. While endoscopically unrevealing, duodenal biopsy at this admission demonstrated marked villous blunting and chronic inflammation. Serologies for celiac disease were negative, which was consistent with OAE. All ARBs were discontinued and the patient's nausea and abdominal pain improved. This case differed from the clinical pattern of symptoms noted in prior reports of OAE as the patient was entirely without diarrhea. A literature review identified numerous cases with nausea, vomiting and abdominal pain in addition to diarrhea and weight loss, but to our knowledge this is the first described case of OAE without symptoms of diarrhea (although constipation is not uncommon in celiac disease). Additionally, this case calls attention to a standard practice that influences the potential for missed diagnoses related to medication side effects. The admission process of substituting medications to comply with hospital formularies creates an opportunity for medications, such as olmesartan, to be overlooked. This case emphasizes the importance of thorough medication reconciliation at the time of a new hospitalization. Rubio-Tapia, Alberto, et al. “Severe spruelike enteropathy associated with olmesartan.” Mayo Clinic Proceedings. Vol. 87. No. 8. Elsevier, 2012. Marietta, E. V., et al. “Immunopathogenesis of olmesartan-associated enteropathy.” Alimentary pharmacology & therapeutics 42.11-12 (2015): 1303-1314. Burbure, Nina, et al. “Olmesartan associated sprue-like enteropathy: a systematic review with emphasis on histopathology.” Human Pathology (2015).Figure 1

Demonstration of Trophozoites of G. Lamblia in Ileal Mucosal Biopsy Specimens May Reveal Giardiasis in Patients With Significantly Inflamed Parasite-free Duodenal Mucosa

In the majority of individuals, infestation with trophozoites of Giardia lamblia (synonymous G. duodenalis or G. intestinalis) leads to a self-limited disease. Whereas most duodenal biopsies with chronic giardiasis show little or no inflammatory reaction, some patients may develop a severe disease with significant mucosal inflammation and various degrees of villous blunting. Occasionally, the histologic changes may resemble those of celiac disease. In this paper, we describe 11 patients, 5 of them female, with chronic giardiasis and demonstrable G. lamblia in ileal biopsies. The median age was 45 years (35 to 62 y), with male patients being at least 10 years younger than female patients. All of the duodenal biopsies showed at least mild villous blunting (grading: mild, marked, or total). In the mucosa an increased number of plasma cells and lymphocytes was observed. Furthermore, varying numbers of granulocytes were found in the lamina propria and in the epithelial layer. In 1 case only, the number of intraepithelial lymphocytes was >40/100 epithelial cells thus mirroring the histologic picture of celiac disease with a flat mucosa (with negative celiac disease-specific serological findings). Interestingly enough, all mucosal biopsy specimens from the duodenum were parasite free. Therefore, giardiasis could only be revealed by the demonstration of trophozoites of G. lamblia in biopsy specimens from the terminal ileum, which had been taken simultaneously or several weeks later. In contrast to duodenal biopsies, the ileal mucosa appeared either normal or only mildly inflamed in this setting. All patients but 1 were symptomatic, with chronic diarrhea being the leading symptom. Symptoms resolved after antibiotic therapy. This study demonstrates that giardiasis may be associated with a significant duodenal pathology in biopsy specimens without discernible parasites. In the cases described here infestation with G. lamblia was only proven histologically by examination of mucosal biopsy specimens taken from the terminal ileum.

Environmental Enteric Dysfunction in Children.

Diarrheal diseases are a major cause of childhood death in resource-poor countries, killing approximately 760,000 children younger than 5 years each year. Although deaths due to diarrhea have declined dramatically, high rates of stunting and malnutrition have persisted. Environmental enteric dysfunction (EED) is a subclinical condition caused by constant fecal-oral contamination with resultant intestinal inflammation and villous blunting. These histological changes were first described in the 1960s, but the clinical effect of EED is only just being recognized in the context of failure of nutritional interventions and oral vaccines in resource-poor countries. We review the existing literature regarding the underlying causes of and potential interventions for EED in children, highlighting the epidemiology, clinical and histologic classification of the entity, and discussing novel biomarkers and possible therapies. Future research priorities are also discussed.

Dysphagia as the Sole Initial Presentation of Celiac Disease

Several studies have described celiac disease patients presenting with esophageal symptoms. We present the case of a 33-year-old Caucasian woman who presented with three months of strictly dysphagia to solids. She reported no weight loss, abdominal pain, or diarrhea and reported no heartburn symptoms. Labs revealed a tissue transglutaminase IgA of >100 units. Biopsies revealed moderate to severe villous blunting and increased intraepithelial lymphocytosis consistent with Marsh 3 celiac disease in the 2nd and 3rd portions of the duodenum. To the best of our knowledge, this case represents the first reported case of dysphagia as initial and sole presentation of celiac disease completely resolved by gluten-free diet.

Intraepithelial lymphocytosis is a frequent finding in biopsies from ileal pouch–anal anastomoses

Following restorative proctocolectomy with an ileal pouch-anal anastomosis, the small bowel mucosa undergoes several specific histologic adaptions, which may be unrelated to the underlying disease or symptoms of pouchitis. An increase in intraepithelial lymphocytes (IELs) has not been described as part of this spectrum. Mucosal biopsies of the ileal pouch and afferent limb of 230 patients (mean age: 45.7y [18.3-74.7], gender [female/male]: 117/113) with a functioning ileal pouch-anal anastomosis (mean time since ileostomy closure: 10.8months) and associated clinically annotated outcome data were assessed for IELs/100 enterocytes. Forty-two patients (18.3%) showed an increase in IELs (≥20 IELs/100 enterocytes [range 20-39]), in pouch and/or afferent limb biopsies. Intraepithelial lymphocytosis was more commonly observed in afferent limb compared to pouch biopsies (18.8% vs 8.3%; P = .42) and in familial adenomatous polyposis compared to ulcerative colitis patients (16% vs 8%; P = 0.36), but neither difference reached statistical significance. No cases with increased IELs displayed severe villous blunting. Increased IELs were not significantly associated with age, sex, ethnicity, smoking history, time since ileostomy, use of antibiotics, biologic agents, anti-diarrheal agents or probiotics, C-reactive protein levels or differential white cell count. None of the 42 patients with increased IELs had positive celiac serology (anti-human tissue transglutaminase IgA [ELISA] with corresponding total serum IgA). Intraepithelial lymphocytosis in pouch biopsies may represent a subclinical response to an altered bacterial microenvironment. Pathologists should be aware that intraepithelial lymphocytosis is part of the spectrum of changes in pouch biopsies, and only rarely is due to celiac disease.

Novel Gut Barrier Modulatory Effect of Vildagliptin in Amelioration of Bacterial Translocation in Cholestatic Rats

Intestinal barrier dysfunction is frequently implicated in the etiology of septic complications following obstructive jaundice. The present study was conducted to investigate the potential gut barrier modulating effect of vildagliptin (VLD), a dipeptidyl peptidase‐IV (DPP‐IV) inhibitor, on common bile duct ligation (CBDL) in rats. VLD (10 mg/kg/d; p.o) was administered for 10 successive days after CBDL in male Sprague‐Dawley rats. VLD reduced portal endotoxemia induced by CBDL and suppressed rectal temperature elevation, body weight loss and colon and spleen indices to different extends. Moreover, it reversed villous blunting, low villous density, mucosal thinning and inflammatory cell infiltration noticed microscopically in the ileal segments of the CBDL rats. These events were accompanied by the reduction of intestinal myeloperoxidase activity and lipid peroxidation, the elevation of the major anti‐oxidant molecule, glutathione, as well as the normalization of ileal nitric oxide level. Furthermore, ileal DPP‐IV was inhibited in association with the rise in ileal glucagon‐like peptide‐1 (GLP‐1) and insulin‐like growth factor‐1 (IGF‐1) levels in VLD treated animals. The current findings suggest that VLD anti‐oxidant, anti‐inflammatory, as well as enhancements of incretin and IGF‐1 account for the hardwearing of the intestinal barrier that functions competently in the absence of the supporting bile elements.

Idelalisib-associated Enterocolitis: Clinicopathologic Features and Distinction From Other Enterocolitides.

Idelalisib is a highly specific small-molecule phosphoinositide-3-kinase δ inhibitor that was recently approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. The known side effects of idelalisib include severe diarrhea and colitis. Here we report the histologic findings in idelalisib-associated enterocolitis in 11 patients with chronic lymphocytic leukemia or follicular lymphoma receiving idelalisib over a 5-year period (2011 to 2015) at our institution. All 11 patients were receiving idelalisib and underwent colonoscopy for the evaluation of diarrhea. None of the patients had previously received a stem cell transplant. Histologically, the colon biopsies in all 11 cases showed some degree of apoptosis within crypts, with 5 cases showing moderate to severe apoptosis involving the majority of the crypts with loss of goblet cells. No viral inclusions were seen in any case and immunohistochemical stains for cytomegalovirus performed in 9/11 cases were negative. All cases showed at least focal acute cryptitis, and 8 of these cases showed mild architectural distortion. Increased inflammation within the lamina propria was seen in 7 cases, and increased intraepithelial lymphocytes within crypts was seen in 8 cases; the lymphocytes were mostly T cells with a predominance of CD8 T cells, with the majority expressing the α/β T-cell receptor. Diagnoses of graft-versus-host disease, autoimmune enteropathy, infectious enterocolitis, and although thought to be less likely, inflammatory bowel disease were considered in each case. The presence of numerous intraepithelial lymphocytes in addition to severe villous blunting and apoptosis in the small intestinal biopsies from a subset of these patients additionally raised the possibility of autoimmune enteropathy, common variable immunodeficiency, or less likely, celiac disease. Awareness of the histologic features of idelalisib-associated enterocolitis is important to distinguish it from potential mimics, particularly graft-versus-host disease, autoimmune enteropathy, and cytomegalovirus/infectious enterocolitis.

A case report of adult autoimmune enteropathy and literature review

One case was selected from our hospital and another 31 cases from literature. Symptoms, endoscopic and pathological manifestations and autoimmune examinations of all cases were summarized and analyzed. Their major symptoms were prolonged diarrhea (100%) and malabsorption (100%). Specific small bowel histology indicated villous blunting and minimal intraepithelial lymphocytosis. And 15 of them had some other autoimmune diseases. And many positive autoimmune antibodies were detected, including anti-enterocyte antibodies (n=20), anti-intestinal goblet cell antibody (n=7) and anti-nuclear antibody (n=9). Most patients (27/32) responded to corticosteroids. Adult autoimmune enteropathy is a rare syndrome with intractable diarrhea and malabsorption. And it may be accompanied by other autoimmune diseases in some cases. Key words: Diagnosis; Treatment; Adult autoimmune enteropathy

Diffuse Nodular Lymphoid Hyperplasia Associated With Giardia Infection

30 y.o M presented with nausea, vomiting, weight loss and diarrhea for three weeks. The patient had no other systemic symptoms. His medical history was notable for occasional upper respiratory infections and prior episodes of spontaneously resolved diarrhea over the last several years. Family history was unremarkable. Labs were notable for microcytic anemia. Initial stool studies and fecal WBC were negative. CT imaging was notable for mesenteric lymphadenopathy and inflammation of the small bowel concerning for enteritis. Endoscopic evaluation revealed mucosal abnormalities (fig 1-2) which were biopsied. Pathology revealed lymphoid hyperplasia with villous blunting. Subsequent stool studies were positive for Giardia. Immunoglobulin testing was notable for low IgG and IgA levels consistent with CVID. The patient was placed on Flagyl and had resolution of symptoms after completion of therapy.Figure 1Figure 2Discussion: Diffuse nodular lymphoid hyperplasia of the gastrointestinal tract is a rare, benign, usually asymptomatic, disorder of unclear pathogenesis. A common hypothesis is that an intestinal antigenic trigger leads to repetitive stimulation and hyperplasia of lymphoid follicles. DNLH is most commonly characterized by multiple small nodules in the small intestine, although it can be found anywhere along the GI tract. DNLH has been most strongly associated with common variable immunodeficiency and Giardia, although there have been reported links with HIV, IgA deficiency, celiac disease, H. pylori, EBV, and CMV. Common clinical presentations are nausea, vomiting, diarrhea, abdominal pain, obstruction, with or without malabsorption and weight loss. DNLH is diagnosed by endoscopy and confirmed by histology showing hyperplastic lymphoid follicles. It is important to perform immunologic screening after the diagnosis of DNLH. DNLH is found in 20% of CVID patients. Despite appropriate antibiotic therapy, lymphoid hyperplasia and symptoms may persist. Although DNLH is often a benign course, patients with this disease may have an increased risk of intestinal lymphoma. For this reason, more investigation is warranted in regard to possible surveillance modalities and intervals.

Increased Post-Prandial Intragastric and Duodenal Acidity in Patients With Chronic Pancreatitis Could Result in Duodenitis

A 29 year old Hispanic male with history of DM type 1, Type V hyperlipoproteinemia, and chronic pancreatitis with exocrine insufficiency came to the ER complaining of abdominal pain. His abdominal pain had started 2 days ago, 6/10, periumbilical, radiated to the back, dull in nature, not related to food, intermittent at first, but was constant for the last 1 day. On review of systems, he complained of subjective fever, chills, diaphoresis, nausea, 2-3 episodes of non-bloody, non-bilious vomiting, loss of appetite, about 20 lbs wt loss over 3 months, and dark-colored stools. Pertinent findings on physical examination were no pallor or icterus, diffuse abdominal tenderness on palpation without rebound or guarding with good bowel sounds and no organomegaly, and digital rectal examination showed good anal sphincter with no gross blood. His significant laboratory findings were hemoglobin and hematocrit of 8.7/25.4 with lipase of 28. He was admitted to general medical floor for acute on chronic pancreatitis. He was aggressively treated with intravenous normal saline. In view of his anemia, esophagogastroduodenoscopy (EGD) was performed. EGD showed erythema antrum of the stomach and duodenitis and biopsy showed mild chronic inflammation in the gastric mucosa but no helicobacter pylori and no villous blunting in the duodenum. Subsequently, he was started on protonix 40mg po daily and iron supplements. Furthermore, his symptoms improved and he tolerated oral diet and was discharged home to follow-up in GI clinic. In the postprandial periods intraduodenal pH has been shown to be markedly reduced in chronic pancreatitis patients. Intragastric pH is also lower in chronic pancreatitis patients. When focusing on the percentage of postprandial time with pH below five in the duodenum and pH below three in the stomach, chronic pancreatitis patients were exposed to acid in stomach and duodenum for a significantly longer period. Several previous studies have measured intraduodenal pH in patients with chronic pancreatitis and all have observed an abnormally low intraduodenal pH with reduced acid neutralizing capacity.

Concomitant Lymphocytic Gastritis, Enteritis, and Colitis

A sixty-two year old male with a past history of hypertension, hypothyroidism, hypogonadism, and recent right renal cell carcinoma presented with a history of diarrhea present since the 2 months ago. The diarrhea was 4-8 times per day, watery, and without blood. He had reported weight loss of twenty-five pounds since the onset of the diarrhea. The patient denied abdominal pain, nausea / vomiting, fevers, arthralgias, rash, mouth sores, or eye redness. There was no family history of inflammatory bowel disease (IBD) or autoimmune. C-reactive protein was not elevated at 1.21. The tissue transglutaminase antibody was negative. Esophagogogastroduodenostomy (EGD) showed erythema throughout the entire examined stomach and a 2 cm hiatal hernia. The esophagus and duodenum were otherwise normal. Colonoscopy showed sigmoid diverticulosis, internal hemorrhoids, and two sub-centimeter polyps in the sigmoid colon. Biopsies from the stomach, duodenum, terminal ileum, and random colon (right and left) showed significant intra-epithelial lymphocytic infiltrate with severe villous blunting of the duodenum, and terminal ileum. There was no evidence of collagenous gastritis or colitis. The patient was started on prednisone 40 mg per day, which resulted in resolution of diarrhea with one formed bowel movement per day and stabilization of the weight. Tapering prednisone to 20 mg caused recurrent diarrhea. The patient was transitioned to budesonide 9 mg orally per day and was able to come off the prednisone. Increased numbers of intra-epithelial lymphocytes can be found in the esophagus, stomach, small intestine, and colon in a variety of clinical circumstances. In the stomach, it is important to exclude celiac disease (CD) and H. pylori gastritis prior to making the diagnosis of lymphocytic gastritis. In our patient, serologic workup for CD was negative. In the duodenum, causes of lymphocytosis may be secondary to CD, autoimmune enteropathy, common variable immune deficiency, or medication induced (i.e NSAIDs). Similarly, terminal ileum causes are CD, IBD, medication induced, or secondary to autoimmune causes. Colonic lymphocytosis may be secondary to autoimmune diseases such as Hashimoto's thyroiditis, drug-induced, or CD. Concomitant occurrence of lymphocytosis in the stomach, small bowel (duodenal and ileum), and colon is exceedingly rare. Our patient responded well to prednisone therapy and was successfully switched to budesonide therapy.Figure 1Figure 2Figure 3