Kirsten Regalia

Defective leukocyte GM-CSF receptor (CD116) expression and function in inflammatory bowel disease.

BACKGROUND & AIMS Inflammatory bowel disease (IBD) refers to 2 chronic inflammatory diseases of the intestine, ie, ulcerative colitis and Crohns disease. IBD results from environmental factors (eg, bacterial antigens) triggering a dysregulated immune response in genetically predisposed hosts. Although the basis of IBD is incompletely understood, a number of recent studies have implicated defective innate immune responses in the pathogenesis of IBD. In this regard, there is much interest in therapies that activate innate immunity (eg, recombinant granulocyte-macrophage colony-stimulating factor). METHODS In this study, we screened expression and function of circulating leukocyte granulocyte-macrophage colony-stimulating factor receptor (CD116) messenger RNA and surface protein in 52 IBD patients and 52 healthy controls. RESULTS Our results show that both granulocyte and monocyte CD116 levels, but not CD114 or interleukin-3Rα, were significantly decreased in IBD compared to control (P<.001) and disease controls (irritable bowel syndrome; P<.001; rheumatoid arthritis; P<.025). IBD-associated CD116 repression was more prominent in patients with ulcerative colitis compared to Crohns disease (P<.05), was independent of disease activity (P>.05), and was not influenced by current medications (P>.05). Receiver operating characteristic curve analysis revealed that leukocyte CD116 expression is a sensitive (85%) and specific (92%) biomarker for IBD. Moreover, granulocyte CD116-mediated function (phosphorylation of signal transducers and activators of transcription 3) paralleled decreased expression of CD116 in IBD granulocytes compared to control (P<.001). CONCLUSIONS These studies identify defective expression and function of CD116 as a distinguishing feature of IBD and implicate an associated defect in innate immune responses toward granulocyte-macrophage colony-stimulating factor.

Use of Esophageal pH Monitoring to Minimize Proton-Pump Inhibitor Utilization in Patients with Gastroesophageal Reflux Symptoms

BackgroundDue to concerns about long-term PPI use in patients with acid reflux, we aimed at minimizing PPI use, either by avoiding initiating therapy, downscaling to other therapies, or introducing endoscopic or surgical options.AimsTo examine the role of esophageal ambulatory pHmetry in minimizing PPI use in patients with heartburn and acid regurgitation.MethodsRetrospective cohort analysis of patients with reflux symptoms, who underwent endoscopy, manometry, and ambulatory pHmetry to define the need for PPI. Patients were classified as: (1) never users; (2) partial responders to PPI; (3) users with complete response to PPI. Patients were then managed as: (1) PPI non-users; (2) PPI-initiated, and (3) PPI-continued.ResultsOf 286 patients with heartburn and regurgitation, 103 (36%) were found to have normal and 183 (64%) abnormal esophageal acid exposure (AET). In the normal AET group, 44/103 had not been treated and were not initiated on PPI. Of the 59 who had previously received PPI, 52 stopped and 7 continued PPI. Hence, PPI were avoided in 96/103 patients (93%). In the abnormal AET group, 61/183 had not been treated and 38 were initiated on PPI and 23 on other therapies. In the 122 patients previously treated with PPI, 24 were not treated with PPI, but with H2RAs, prokinetics, endoscopic, or surgical therapy. Hence, PPI therapy was avoided in 47/183 patients (26%).ConclusionsIn patients with GER symptoms, esophageal pHmetry may avert PPI use in 50%. In the era of caution regarding PPIs, early testing may provide assurance and justification.

Blood and Guts: Diarrhea from Colonic Involvement in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

An 81-year-old male was initially evaluated in a local emergency department for a 6-week history of diarrhea. He had a history of coronary artery disease with remote coronary artery bypass graft and mechanical mitral valve placement, for which he was maintained on warfarin. He also had chronic obstructive pulmonary disease with chronic hypoxemic respiratory insufficiency for which he received continuous oxygen at a rate of 2 L/min. Prior to the onset of diarrhea, he had no chronic gastrointestinal (GI) symptoms. The diarrhea began acutely, was non-bloody, and eventually progressed to more than ten bowel movements daily. While he denied abdominal pain, fevers, chills, or nausea, he sustained a 10-pound weight loss during this time. There was no family history of inflammatory bowel disease. On presentation, his laboratory results included a white blood cell count of 28.0 × 103/μL (of which 44% were atypical lymphocytes), hemoglobin 12.1 g/dL, platelet count 146 × 103/μL, albumin 1.8 g/dL, erythrocyte sediment rate 15 mm/h (normal < 20), C-reactive protein 6.8 mg/dL (normal < 0.9), lactate dehydrogenase 734 U/L (normal < 340), and haptoglobin < 8 mg/dL. Clostridium difficile toxin stool antigen and stool cultures were negative. The remainder of his laboratory results were unremarkable. A computed tomography (CT) scan with intravenous contrast demonstrated significant inflammation and colonic wall thickening and possible narrowing of the rectosigmoid colon with surrounding fat stranding and significant retroperitoneal and mesenteric lymphadenopathy. There was also mesenteric vascular calcification with no vascular obstruction seen. There were no diverticula (Fig. 1). A colonoscopy showed severe inflammation of the rectosigmoid colon with edema and stenosis that could not be traversed. A diagnosis of possible Crohn’s disease was made based on endoscopic appearance, and he was transferred to our institution for further evaluation, treatment, and for consideration of initiation of anti-tumor necrosis factor (TNF) therapy. Upon transfer to our institution, he looked well with stable vital signs but had persistent diarrhea. He had no palpable lymphadenopathy. His laboratory evaluations were stable. We performed a flexible sigmoidoscopy that showed moderate mucosal inflammation, friability, and a few ulcerations, more pronounced in the sigmoid colon. There was no rectal sparing and no clear stricture (Fig. 2). Random biopsies showed a lamina propria expanded by small lymphocytes. Immunohistochemistry revealed the cell populations were cluster-of-differentiation (CD)20 dim, pairedbox containing (Pax)5, CD5, and B cell lymphoma (Bcl)2 positive, but CD10, Bcl1, Bcl6, terminal deoxynucleotidyl transferase (TdT), and lymphoid enhancer-binding factor 1 (LEF1) negative. The Ki67 proliferation index was low at less than 5%. Based on the mucosal appearance, histology, and tumor markers, a diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)-related colitis was made (Fig. 3). Flow cytometry of peripheral blood showed a 47% kappa-restricted monotypic B cell population expressing CD19, with dim expression of CD5, CD20, CD22, CD23, and no expression of CD10 consistent with CLL/SLL. Fluorescence in situ hybridization showed a normal 46YX karyotype without rearrangements. After discussion of prognosis and comorbidities with the patient, he wished to pursue symptomatic support with a focus on palliative care and comfort. A trial of chlorambucil was initiated prior to discharge, with the main goal of improving * George Triadafilopoulos vagt@stanford.edu

Baclofen and gastroesophageal reflux disease: seeing the forest through the trees

Baclofen has been shown to decrease reflux events and increase lower esophageal sphincter pressure, yet has never established a clear role in the treatment of gastroesophageal reflux disease (GERD). Lei and colleagues have shown in a recent elegant study that baclofen reduces the frequency and initiation of secondary peristalsis and heightens esophageal sensitivity to capsaicin-mediated stimulation. These findings may help explain both the benefit of baclofen in conditions such as rumination and supragastric belching, as well as the apparent lack of benefit of baclofen and other GABAB agonists in long-term treatment of GERD.

Pulmonary Crohn’s Disease

A 31-year-old man of Northern European ancestry who was born and raised in California was well until 2013 when he developed a perianal fistula. At that time, he had no diarrhea, abdominal pain, or weight loss. Anal examination under anesthesia revealed a deep right, transsphincteric hemi-horseshoe anal fistulous tract that extended from the right posterior to the right anterior midline. Laboratory evaluation was notable for a normal complete blood count and comprehensive metabolic panel, although serum inflammatory markers were mildly elevated (ESR 33 mm/ h, CRP 1.5 mg/dL). Since the draining fistula failed to heal, the diagnosis of Crohn’s perianal fistulizing disease was suspected. Magnetic resonance enterography (MRE) demonstrated normalappearing small bowel and colon, with inflammation in the right ischio-rectal fossa, consistent with the patient’s known history of perianal fistula (Fig. 1). Colonoscopy revealed multiple scattered ulcers in the right and midcolon with sparing of the rectum and sigmoid colon, with a normal-appearing terminal ileum (Fig. 2). Histopathologic examination revealed crypt abscesses and architectural distortion without granulomata. He was diagnosed with Crohn’s disease complicated by colitis and severe fistulizing perianal disease; treatment with infliximab and azathioprine was planned. Nevertheless, before treatment was initiated, he complained of leftsided pleuritic chest pain, low-grade fevers, night sweats, and loose, frequent stools. Laboratory examination now revealed a new iron-deficiency anemia with hemoglobin of 12.0 g/dL and transferrin saturation of 7 %. Furthermore, his serum albumin was low at 3.0 g/dL, and his inflammatory markers were higher than they were previously (ESR 51 mm/h, CRP 7.6 mg/dL). Chest computed tomography (CT) with intravenous contrast demonstrated multiple pulmonary nodules in both lower lobes, with a few areas of peripheral nodular consolidation in the left lower lobe measuring up to 3.5 cm in size and without evidence of pulmonary emboli (Fig. 3). Comparison of his chest CT to the lung base images visualized on his MRE from 6 months prior verified his pulmonary lesions to be new. Because of concern for an underlying pulmonary infection, the patient underwent CT-guided fine needle aspiration with a 21-gauge needle, followed by the acquisition of 8 core biopsy samples using a 20-gauge core biopsy device. Histopathology revealed scattered epithelioid granulomas, multinucleated giant cells, and mixed chronic inflammation, without significant necrosis or evidence of malignancy. Stains for Gomori methenamine silver (GMS), acid-fast bacilli (AFB), and Fite were negative for fungal and mycobacterial organisms. The differential diagnosis for causes of his granulomatous lung disease included inflammatory (Crohn’s), infectious (tuberculosis, histoplasmosis, coccidiomycosis, and cryptococcal disease), or noninfectious (sarcoidosis, Wegener’s granulomatosis, hypersensitivity pneumonitis). The single unifying diagnosis to explain the near simultaneous onset of a poorly healing perianal fistula, a patchy & Christine A. Cartwright cart@stanford.edu