Robert J. Basseri

Hepcidin is a key mediator of anemia of inflammation in Crohn's disease

UNLABELLED Anemia often complicates the course of Inflammatory Bowel Disease (IBD). Hepcidin, a liver-produced peptide hormone, is a key mediator of anemia of chronic disease (ACD). We hypothesized that hepcidin is significantly elevated in anemic CD patients and that hepcidin may cause iron restriction and, therefore, mediate ACD. METHODS We enrolled 17 patients with CD and ACD recruited from the Cedars-Sinai IBD Center. Routine blood tests included hemoglobin (Hgb), hematocrit, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Anemia was defined as hemoglobin <12g/dL and <13.5g/dL, in men and women, respectively. ACD was diagnosed on the basis of a combination of the following: a) normal or elevated ferritin b) lowered serum iron and total iron binding capacity and c) normal percent iron saturation. Serum and urine hepcidin, as well as IL-6 levels were also measured. Patients with documented iron-deficiency anemia were excluded. RESULTS There was an excellent correlation between urine (expressed as ng/mg of creatinine) and serum hepcidin levels expressed as ng/ml (r=0.853, p<0.001). We also found a strong positive correlation between serum hepcidin and ferritin levels (r=0.723, p=0.0015). There was a positive correlation between serum hepcidin and IL-6 levels (r=0.546, p=0.023). We found a strong negative correlation between serum hepcidin concentrations and Hgb levels (r=0.528, p=0.029). CONCLUSION We demonstrate that ACD in CD is characterized by high serum IL-6 and hepcidin levels, which negatively correlate with Hgb levels. Our data support the hypothesis that IL-6-driven hepcidin production mediates ACD in patients with CD.

Colorectal cancer screening and surveillance in Crohn's colitis

AIMS To assess colonoscopic screening and surveillance for detecting neoplasia in patients with long-standing colonic Crohns disease (CD). PATIENTS AND METHODS Colonoscopy and biopsy records from patients with colonic CD were evaluated at the Cedars-Sinai Inflammatory Bowel Disease Center during a 17-year period (1992-2009). RESULTS Overall, 904 screening and surveillance examinations were performed on 411 patients with Crohns colitis (mean 2.2 examinations per patient). The screening and surveillance examinations detected neoplasia in 5.6% of the patient population; 2.7% had low-grade dysplasia (LGD) (n=11), 0.7% had high-grade dysplasia (HGD) (n=3), and 2.2% had carcinoma (anal carcinoma n=3; rectal carcinoma n=6). Mean age of CD diagnosis was 25.6±0.8 years in those with normal examinations, compared to 17.7±2.7 years (p<0.001) in those with HGD, 36.85±1.43 in those with LGD (p=0.021) and 28.32±3.24 years in those with any dysplasia/cancer (p=0.034). Disease duration in patients with normal examinations was 19.1±0.5 years, compared to 36.8±4.4 years (p<0.001) in HGD, 16.88±2.59 in those with LGD (p=0.253) and 30.68±4.03 years in those with any dysplasia/cancer (p=0.152). The mean interval between examinations was higher in HGD (31.5±9.4 months) compared to those with normal colonoscopies (12.92±1.250 months; p=0.002). CONCLUSIONS We detected cancer or dysplasia in 5.6% of patients with long-standing Crohns colitis enrolled in a screening and surveillance program. Younger age at diagnosis of CD, longer disease course, and greater interval between exams were risk factors for the development of dysplasia.

Dysplasia and cancer in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease associated with an increased risk of colorectal cancer (CRC). Although CRC occurs in a minority of IBD patients (1%), it carries a high mortality and accounts for 20% of IBD-related mortality. Established risk factors for the development of CRC in IBD include disease duration of 8 years or more, family history of CRC, extensive colitis and primary sclerosing cholangitis. Meticulous colonoscopy and anti-inflammatory medications can reduce the risk of developing CRC. The future of IBD surveillance involves the use of novel endoscopic techniques (chromoendoscopy, narrow-band imaging, confocal laser endomicroscopy and autofluorescence) to enhance colonoscopic accuracy, in concert with chemopreventative medications to help reduce the risk of CRC in IBD.

History of tonsillectomy is associated with irritable bowel syndrome.

To the Editor: Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by altered bowel function, abdominal discomfort, and bloating affecting 20% of individuals worldwide. The diagnosis is based on specific clinical criteria in the absence of a detectable organic cause. Interestingly, there is growing literature that patients with IBS have alterations in intestinal microbiota. The human gut is an elaborate ecosystem composed of 10 bacteria established in the first year of life and continuously altered by exogenous factors; however, genetics significantly contribute as well. The general requirement of intestinal colonization is microbial access to the intestinal tract, counteracted by enzymes, gastric acid, and the mucosal immune system. As microbes enter the human digestive tract, the first major encounter with the host immune system is the tonsils. The tonsils are important sentinels in the detection of foreign antigens/bacteria entering the digestive tract, and their removal may influence bacterial colonization/invasion of the alimentary tract. We examined whether a history of tonsillectomy is associated with the presence of IBS. We utilized a prospectively collected dataset of patients referred to a tertiary medical center. Patients with IBS (Rome I criteria) completed a symptom questionnaire to assess bowel symptoms. Bivariate and multivariate analyses were employed to assess associations between IBS, tonsillectomy, GI symptoms, and demographics. A total of 1125 patients (72% female), mean age 44.4±17.5 years were evaluated. Of these, 530 patients had IBS. A history of tonsillectomy was observed in 59.5% and 40.5% of patients with and without IBS, respectively (P=0.001). Confounding variables associated with IBS included age and sex; after controlling for age and sex, tonsillectomy was significantly associated with IBS (P=0.001). This is the first study demonstrating that tonsillectomy is associated with IBS. The rationale for this relationship is unclear, although we have set forth several hypotheses: the health seeking nature of IBS patients and higher rates of other surgeries may explain the higher rate of tonsillectomy, inflammation of the tonsils. Furthermore, the need for tonsillectomy implies an alteration in the host immune response (also found in IBS patients), and the absence of tonsils may enable successful and undetected pathogen penetration into the intestinal tract leading to postinfectious IBS or even bacterial overgrowth. Further investigation is warranted to understand the novel link between tonsillectomy and IBS.

Primary Esophageal B-Cell Lymphoma

e A man with a history of hemophilia and hepatitis C presented to an outside hospital with hematemesis nd concomitant 6-g/dL drop in hemoglobin. He had a history f solid/liquid dysphagia and odynophagia during the last 6 onths. Initial esophagogastroduodenoscopy (EGD) showed arge blood clots in the proximal esophagus that obstructed the iew. A computed tomography scan of the chest showed a eterogeneous density soft tissue mass within the lumen or rising from the wall of the esophagus, likely a clot distending. sophagogram demonstrated a filling defect in the upper thoacic esophagus compatible with known hematoma, and repeat sophagogram showed a marked decrease in the upper thoracic sophageal filling defect suggestive of decreasing hematoma on ischarge. Two weeks later, he presented to an outside hospital comlaining of 2 days of hematemesis and bright red blood per ectum. EGD demonstrated a possible mass of the upper esophgus, without active bleeding. The patient then presented to our nstitution, where an EGD demonstrated a mass extending rom 20 –25 cm from the incisors, involving 50% of the esophgeal circumference with central ulceration (Figure A) suspiious for squamous cell carcinoma. No active bleeding was ppreciated. Endoscopic ultrasound demonstrated a mass inolving and crossing the muscularis propria (Figure B). Biopsies were obtained, which showed aggressive large B-cell lymphoma (Figure C), immunologically characterized by CD20 and coxpression of CD10 and BCL-6 (Figure D). A positron emission tomography (PET) computed tomography scan (Figure E) showed a large, intensely metabolic, active area of thickening of the upper mediastinal esophagus consistent with neoplastic process and no other focal areas of increased activity in the remaining PET scan. This was staged as isolated extranodal large B-cell lymphoma. Thereafter, he received 6 cycles of rituximab– cyclophosphamide, hydroxydaunomycin, Oncovin, and prednisone chemotherapy, resulting in resolution of his dysphagia, gastrointesti-

Autoimmune hemolytic anemia in treatment-naive chronic hepatitis C infection: a case report and review of literature

The hepatitis C virus (HCV) is the most common blood-borne pathogen and currently infects over two hundred and fifty million individuals worldwide. Chronic HCV infection may result in cirrhosis, hepatocellular carcinoma, and liver failure. An exceedingly rare extrahepatic manifestation of HCV is autoimmune hemolytic anemia (AIHA). We discuss an interesting case of direct Coombs’-positive AIHA in a treatment-naive 53-year-old male with a past medical history of HCV cirrhosis, genotype 3a, who presented with fatigue, abdominal pain, and jaundice. Complete blood cell count demonstrated anemia, thrombocytopenia, elevated mean corpuscular hemoglobin and corpuscular volume worrisome for hemolytic anemia. Upon further workup, the patient was found to have increased bilirubin, reticulocyte count, and lactate dehydrogenase with concomitant direct Coombs’-positive test, consistent with the diagnosis of AIHA. A comprehensive workup was conducted to elucidate the underlying etiology of the AIHA, including malignancy, systemic lupus erythematosus (SLE), and medication side-effects. Malignancy was ruled out with an imaging and bone marrow biopsy. SLE was subsequently eliminated with a negative anti-nuclear antibody (ANA), and the patient had never received ribavirin, interferon, cephalosporins or other medications associated with drug-induced immune hemolytic anemia (DI-IHA). While the relationship between DI-IHA and HCV is well-described in the literature, primary AIHA in treatment-naive patients is a rare and intriguing extrahepatic manifestation of HCV and only four reports have been described in the literature. Given the prevalence of HCV and this interesting extrahepatic manifestation, HCV testing should be considered in patients presenting with AIHA with an otherwise negative workup and a history of parenteral or lifestyle risk factors.

Lymphocytic Esophagitis is Uncommon in Adult Inflammatory Bowel Disease

Lymphocytic esophagitis (LE) is a newly described entity characterized histopathologically by peripapillary lymphocytosis (PL) without significant granulocytes (neutrophils and eosinophils) in the esophageal epithelium. It calls into questions the role of lymphocytes (lymphs) in esophageal inflammation. In an initial study, a significant portion of patients with LE suffered from Crohns Disease (CD). A subsequent study revealed LE in 1/4 of children with CD. Aim: To test the hypothesis that LE is associated with adult IBD, and to evaluate for disease variables linking them. Methods: Random esophageal biopsies obtained prospectively from consecutive adults with CD, ulcerative colitis (UC), or indeterminate colitis (IC) were evaluated. Numbers of lymphs, eosinophils, and neutrophils were counted from 3 highpower fields (HPF) in each specimen. Specimens with > 50 lymphs in > 1 HPF were evaluated for features of LE. Associations with age, gender, lifestyle, co-morbidities, and lab data were evaluated. Results: Four of 47 patients (8.5%; 3/30 CD, 1/15 UC, 0/2 IC) had esophageal biopsies with >50 lymphs/HPF (mean 100.5±31.0/HPF). A significant number of granulocytes were seen in biopsies from 3 of the 4 patients, leaving only 1 patient who met the strict criteria for LE. Peripapillary lymphocytosis was associated with elevated ESR (90.3±17.6 vs. 24.5±3.6 mm; p<0.001) and CRP (5.5±2.2 vs. 1.0±0.2 mg/dL; p<0.001); all patients with PL had elevated ESR and CRP. Endoscopic findings in patients with PL included white plaque (n=2) and friable mucosa (n=1). Primary characteristics, disease markers, history of alcohol or tobacco use, and co-morbidities were similar in patients with and without PL. All patients with PL had a relapsing CD course (3 with active disease) and CD phenotypes included inflammatory (n=2), penetrating (n=2), and structuring/penetrating (n=1). Three patients (75%) with PL had a clinical history consistent with GERD (8% in patients without PL; p=0.050). Symptoms in patients with PL included odynophagia (n=1), abdominal pain (n=3), and diarrhea (n=1). Active duodenitis and colitis were each present in two patients with PL, one patient had duodenal lymphocytosis. Conclusions: 1) We found a less frequent association between IBD and LE than was previously reported: according to strict histopathological criteria, 2% of adult patients with IBD had LE. This may be due to differences between pediatric and adult IBD. Alternatively, it may be methodological, because unlike previously we prospectively evaluated consecutive patients with IBD. 2) Peripapillary lymphocytosis was seen in 10% of patients with CD, and was associated with elevated inflammatory markers. These observations suggest PL may be a marker of inflammation. 3) Further evaluation is required to assess the relationships among LE, GERD, and IBD.

Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) of Unknown Primary: A Diagnostic Strategy for Localizing the Primary Lesion

Background: Localization of primary GEP-NETs is a diagnostic challenge of paramount importance, as resection of the primary lesion may increase treatment efficacy and improve prognosis. Aims: To evaluate the diagnostic value of capsule endoscopy (CE), double balloon enteroscopy (DBE), endoscopic ultrasound (EUS), octreotide scan (OS) and PET-CT for localizing primary GEP-NETs. Methods: Retrospective evaluation of patients with metastatic GEP-NETs and an unknown primary per CT or MRI. These patients had at least one of the 5 diagnostic modalities for localization. Tissue diagnosis was used to confirm the primary lesion. Results: 39 patients with biopsy-proven metastatic GEP-NET were referred to our center for a diagnostic evaluation between July 2002 and September 2010. The mean age was 58, 56% female. We ultimately identified the primary in 30 patients (77%) with various combinations of CE, DBE and EUS. CE was positive in 11/22 patients (50%), 8 of whom were confirmed. DBE was positive in 17/27 procedures (63%) and performed in a total of 22 patients. EUS, usually done after a negative intestinal search, was positive in 11/27 (65%). Octreotide scans were positive in 12/23 patients (52%) with 9 confirmations. 7 patients underwent all 3 endoscopic procedures; 6/7 patients (84%) had the primary localized. Overall, the sensitivities of CE, DBE and EUS were 60% 73% and 77%, respectively (see table). OS, typically considered the gold standard, had a sensitivity of only 59%. PET-CT scans were done on 4 patients and all were negative. Conclusions: CE, DBE, and EUS are highly effective in identifying the primary lesion for patients with metastatic GEP-NETs of unknown primary, especially when all three modalities are utilized. OS is imprecise in localizing lesions and may be less sensitive than any of the 3 endoscopic procedures. The value of PET-CT in the search for the primary lesion remains to be determined. Sensitivity, Specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of Each Procedure for Detection of Primary Lesions