Claudia Randazzo

Fecal calprotectin in clinical practice: a noninvasive screening tool for patients with chronic diarrhea.

Background: Surrogate markers of colorectal inflammation are increasingly being recognized as important in differentiating organic from functional intestinal disorders. Fecal calprotectin (FC) can be easily measured in the stool, being released by leukocytes in inflammatory conditions. Aim: We evaluated FC as an index of inflammation in consecutive outpatients referred for colonoscopy for chronic, nonbloody diarrhea. Methods: Stool specimens of 346 outpatients with chronic, nonbloody diarrhea, referred for colonoscopy, were measured for FC levels. The proportion of patients correctly diagnosed with the test and the relationship with endoscopic and histologic findings were measured. Results: Abnormal endoscopic findings were detected in 104 patients (30.1%). Histologic findings included 142 patients (41.0%) with inflammation and 204 (59.0%) without inflammation. Fecal excretion of calprotectin significantly correlated with the finding of inflammation at endoscopy and histology (P<0.0001). When 150 mcg/g of stool was used as the upper reference limit, FC showed 75.4% sensitivity and 88.3% specificity, with 81.7% positive and 83.7% negative predictive values for histologic inflammation. Conclusions: In outpatients referred for colonoscopy a measurement of FC is accurate to identify those with histologic inflammation. Assay of FC may be a reliable and noninvasive screening tool to identify inflammatory causes of chronic, nonbloody diarrhea.

Subcutaneous emphysema, pneumomediastinum and pneumoperitoneum after diagnostic colonoscopy for ulcerative colitis: a rare but possible complication in patients with multiple risk factors

Dear Editor: Colonoscopy is regarded as a safe procedure, but complications may occur. The most dreaded are perforation and massive bleeding of the colon. The incidence of perforation is low but, despite increased experience with the procedure, it remains unchanged over time and in a large population study ranges from 0.6 to 1 per 1.000 procedures, depending on the centre and the data source. Few studies have assessed risk factors for colonoscopy-related bleeding and perforation. Gatto et al. have reported that there was a significant trend in the incidence of perforation with increasing age, people aged 75 years or older having a fourfold risk as compared to those aged 65–69 years; same results were obtained by Levin et al. in a series of more than 16.000 colonoscopies. The risk for adverse events has been also associated with comorbidity: diabetes, stroke, cardiovascular disease, chronic obstructive pulmonary disease. Moreover, risk factors for the development of perforations are pre-existing diseases of the colon (polyposis, inflammatory bowel disease, diverticula, strictures, etc.) and conditions related to the procedure itself, bowel cleansing or sedation. An estimated 50% to 100% of patients with a colonic perforation after colonoscopy require a laparotomy for closure of the perforation, with associated major postoperative morbidity and mortality reaching 39% and 25%, respectively. An 80-year-old man with a 6-months history of diarrhoea (six motions/day) with mucus and, occasionally, blood was admitted to our department. Ulcerative colitis (UC) and diverticula had been recently diagnosed, but he did not respond to therapy. Past medical history revealed a cerebrovascular accident and coronary heart disease which requested aortocoronary bypass; for this reason he was on ticlopidine. We carried out colonoscopy according to the standard procedures. About 1 h after endoscopy the patient developed progressive facial and neck swelling, without any pain, dyspnea or stridor. On examination, vital parameters were normal. A clear crepitus was palpated in the head and neck, compatible with subcutaneous emphysema, and the chest was normal. The abdomen was tympanic but not tender, with normal peristalsis. Laboratory tests were normal. X-rays and a total body computed tomography were carried out and showed massive air leakage, with free air intraand retroperitoneal, mediastinal air with limited pneumomediastinum and subcutaneous emphysema extending to the zygoma. The patient was managed conservatively with intravenous fluids and antibiotics (ceftriaxone). Twenty-four hours after onset of symptoms, he developed abdominal pain, fever (38°C) and mild leukocytosis (13.760/mmc); and he was transferred to surgical department. He was submitted to explorative laparoscopy which evidentiated a perforation of the caecum with exudative material in the peritoneum and air trapped into the retroperitoneum forming multiple bubbles. Right hemicolectomy with antiperistaltic ileocolonic anastomosis was carried out. The postoperative course M. Cappello (*) :C. Randazzo : S. Peralta Sezione e U.O.C. di Gastroenterologia, Dipartimento Biomedico di Medicina Interna e Specialistica, Universita di Palermo, Piazza Delle Cliniche 2, 90127 Palermo, Italy e-mail: cmarica@tin.it

Liver Function Test Abnormalities in Patients with Inflammatory Bowel Diseases: A Hospital-based Survey.

Background and Aims Inflammatory bowel diseases (IBD) are frequently associated with altered liver function tests (LFTs). The causal relationship between abnormal LFTs and IBD is unclear. The aim of our study was to evaluate the prevalence and etiology of LFTs abnormalities and their association with clinical variables in a cohort of IBD patients followed up in a single center. Materials and Methods A retrospective review was undertaken of all consecutive IBD in- and outpatients routinely followed up at a single referral center. Clinical and demographic parameters were recorded. Subjects were excluded if they had a previous diagnosis of chronic liver disease. LFT abnormality was defined as an increase in aspartate aminotransferase, (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), or total bilirubin. Results A cohort of 335 patients (179 males, mean age 46.0 ± 15.6 years) was analyzed. Abnormal LFTs were detected in 70 patients (20.9%). In most cases, the alterations were mild and spontaneously returned to normal values in about 60% of patients. Patients with abnormal LFTs were less frequently on treatment with aminosalicylates (22.8 vs. 36.6%, P = 0.04). The most frequent cause for transient abnormal LFTs was drug-induced cholestasis (34.1%), whereas fatty liver was the most frequent cause of persistent liver damage (65.4%). A cholestatic pattern was found in 60.0% of patients and was mainly related to older age, longer duration of disease, and hypertension. Conclusions The prevalence of LFT abnormalities is relatively high in IBD patients, but the development of severe liver injury is exceptional. Moreover, most alterations of LFTs are mild and spontaneously return to normal values. Drug-induced hepatotoxicity and fatty liver are the most relevant causes of abnormal LFTs in patients with IBD.

Adalimumab in Steroid-dependent Crohn's Disease Patients: Prognostic Factors for Clinical Benefit

Background: Corticosteroids are effective in the treatment of Crohns disease but some patients relapse during tapering or after discontinuation. We report data on efficacy and prognostic factors of response of adalimumab in steroid‐dependent patients. Methods: In all, 110 steroid‐dependent patients were treated with adalimumab (80/40 or 160/80 mg every other week followed by 40 mg every other week). Clinical remission was defined as steroid discontinuation without symptomatic recurrence and clinical response as the reduction or maintenance of the initial Crohns Disease Activity Index (CDAI) value reducing steroid dosage but without its discontinuation at week 6 and at the end of follow‐up. Results: At week 6, 91% of patients had a clinical benefit (remission: 45.5%, response: 45.5%). At the end of the follow‐up (mean 14.6 months), 80.9% of responders maintained the clinical benefit (remission: 64.5%, response: 16.4%). At univariate analysis four variables were associated with remission at week 6: age of patients <40 years at baseline, no previous history of surgery, inflammatory pattern, and higher induction regimen. At multivariate analysis only higher induction regimen was related to remission at week 6. At the end of the follow‐up, none of the variables were associated with remission. None of the variables were related to response at 6 weeks and at the end of follow‐up. Adalimumab was well tolerated. Conclusions: This study shows that adalimumab is a powerful and safe weapon for steroid discontinuation in patients with steroid‐dependent Crohns disease. Higher induction regimen dosage is the better therapeutic choice for achieving clinical remission with low risk of clinical relapse. (Inflamm Bowel Dis 2011;)

Liver Biopsy - Indications, Procedures, Results

Liver biopsy (LB) is the most common procedure performed in clinical hepatology. His‐ tological assessment of the liver, and thus, LB is traditionally the “reference standard” in the diagnosis and management of parenchymal liver diseases. Definitive diagnosis of‐ ten depends on LB, and much of understanding of the characteristic features and natu‐ ral history of liver diseases is based on information obtained by serial liver biopsies. During the last 60 years as the result of a better understanding of liver disorders, ap‐ pearance of newer entities and advent of novel hepatic imaging techniques, the indica‐ tions for LB have evolved. Whereas in the past LB was often performed as the initial investigation in the workup of liver disease of unknown aetiology, today the most com‐ mon indication for LB includes staging of chronic hepatitis. A variety of methods exist for getting a liver tissue specimen. These take account of a percutaneous method, a transvenous (transjugular or transfemoral) approach, and intra-abdominal biopsy (laparo‐ scopic or laparotomic). All LB techniques require specific training so as to ensure appro‐ priate-sized specimen retrieval and the lowest rate of complications. However, because LB is an invasive procedure that carries a definite, albeit small, risk of complications, controversy persists with regard to its precise indications in various clinical situations, its clear contraindications, the optimal technique for its performance (and whether cer‐ tain modifications improve its safety), and training requirements for clinicians. The aim of this chapter will be summarize the existing clinical practice of LB with an emphasis on the technique, indications, contraindications, quality of LB specimens and risk of complications.

Splenic tuberculosis in a patient with Crohn's disease on infliximab: Case report

To the Editor: An increased risk of reactivation of latent tuberculosis (TB) during therapy with tumor necrosis factor alpha (TNFa)-antagonists was first reported in 2001. Therefore, screening for the presence of latent Mycobacterium tuberculosis infection by purified protein derivative test (PPD) and chest x-ray is now routinely performed before starting treatment with anti-TNFa. Nevertheless, cases of TB, especially extrapulmonary, are still reported during anti-TNFa treatment. This may be related to the limited sensitivity of the PPD skin test in patients who are already immunosuppressed as the result of previous treatment. This has led to the development of more accurate tests. We report a case of a patient with Crohn’s disease (CD) treated with infliximab who, in spite of negative screening tests, developed fever and splenic focal lesions that were initially interpreted as lymphoma leading to splenectomy. Splenic TB was diagnosed on the resected specimen. A 34-year-old man with ileocolonic CD was admitted to the Gastroenterology and Hepatology Unit in June 2008. In 2002, because of recurrent abdominal pain, he underwent a follow-up colonoscopy that showed a stenosis of the ileocecal valve and was treated with a course of oral prednisone. The patient was asymptomatic from 2004 to 2006. In May 2007 he experienced a new relapse complicated by an abdominal abscess. He received total parenteral nutrition associated with intravenous steroids and underwent an ileocecal resection with ileocolonic anastomosis. An early clinical and endoscopic anastomotic relapse, complicated by enteromuscular fistula and abscess in the right iliac fossa, occurred 6 months after the operation. The patient was treated with antibiotics and steroids, obtaining resolution of the abscess. Since the fistula remained active, in April 2008 he started induction therapy with infliximab (Remicade, Schering-Plough, Milan, Italy) 5 mg/kg at weeks 0, 2, 6. Screening with the PPD test, chest x-ray, and hepatitis virus C and B markers was negative. No infusion reaction or delayed hypersensitivity-like reaction was observed. After the third infliximab infusion the fistula closed and the patient was in clinical remission and was able to stop steroids. In June 2008 he presented to our clinic with high fever (up to 39 C) that had developed 2 weeks after the last infliximab infusion. There was no history of prior infection, foreign travel, or infectious contacts. A physical examination revealed tachycardia and splenomegaly. He had no intestinal symptoms and magnetic resonance imaging (MRI) confirmed fistula closure. Laboratory tests showed an elevated erythrocyte sedimentation rate (90 mm/h) and C-Reactive Protein (7 mg/dL; normal <1). Ultrasonography (US) revealed multiple hypoechoic splenic focal lesions. There was no evidence of abdominal abscess. Chest x-ray as well as serologic tests for Brucella, Salmonella, human immunodeficiency virus (HIV), and cytomegalovirus and blood and urine cultures were negative. Polymerase chain reaction (PCR) for mycobacteria on blood and urine samples was negative. Abdominal MRI confirmed an enlarged spleen (14 cm) and multiple focal lesions that were isointense lesions (<1 cm) on T1and T2-weighted images and, on dynamic contrastenhanced images, hypointense with peripheral enhancement (Fig. 1). Image findings suggested lymphoma but a bone marrow biopsy was negative. A chest computed tomography (CT) revealed paratracheal, hilar, pretracheal, and subcarinal lymphnodes (diameter 1.5–2.5 cm), confirmed on positron emission tomography (PET) scan. The PET scan did not show abnormal uptake of the radioisotope in the spleen. Fever disappeared after a 7-day course of empiric treatment with piperacilline-tazobactam (4 g/day), ceftazidime (4 g/day), metronidazole (1.5 g/day), and fluconazole (100 mg/day) and the patient was initially discharged, but follow-up CT 2 months later showed persistent splenic hypodense lesions and mediastinal lymphnodes. We decided to perform a splenectomy. On the resected organ diffuse caseating granulomas were shown but Ziehl–Neelsen staining was negative. PCR on splenic tissue revealed, however, the presence of mycobacteria. The QuantiFeron-TB, an in vitro whole-blood assay for the detection of IFN-c production in response to M. tuberculosis-specific antigens, was positive: IFN-c level 8.84 IU/ml (normal <0.35). The patient was placed on a regimen of isoniazid (300 mg/day), rifampicin (600 mg/day), ethambutol (1200 mg/day), and pyrazinamide (1000 mg/day) associated with B6 vitamin supplementation. Patients treated with infliximab are at increased risk for infectious complications. In a report by Keane et al involving 70 cases of TB occurring during infliximab therapy in 147,000 patients, extrapulmonary and disseminated TB was observed in 57% and 24% of patients; these rates are considerably higher than those observed in the general population. Apart from the extent of infection, the clinical presentation of TB occurring during treatment with TNF antagonists can be unusual and constitute a diagnostic dilemma. The patient in this report had ileocolic CD and infliximab was used for fistulizing disease refractory to conventional CopyrightVC 2009 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20998 Published online 9 July 2009 in Wiley InterScience (www.interscience.wiley.com).

Genetic predisposition to thrombophilia in inflammatory bowel disease.

Background Inflammatory bowel disease (IBD) is linked to a definite risk of thromboembolic events (TE), but data on the role of prothrombotic genetic mutations are conflicting. Study Fourteen genetic factors involved in TE pathogenesis were investigated in a homogeneous cohort of Sicilian patients with IBD with and without history of TE and in healthy controls. Forty IBD patients (21 CD, 19 UC) and 20 healthy individuals were enrolled. Genetic testing was based on the reverse hybridization principle by a commercial assay that analyzes 14 polymorphisms involved in thrombophilia and cholesterol metabolism. The rate of genetic polymorphisms and mutations was compared between IBD patients and healthy controls. Results No significant difference in allelic frequency was found between IBD patients and controls except AGT T/T, though a trend toward significance was found also for ACE D/D. Eight out of 9 patients with earlier history of TE had more than 1 polymorphism, compared with 12 out of 31 without TE. In patients with IBD the mutation AGT T/T was related to male sex (P<0.0259) and, marginally, to arterial hypertension (P<0.06) and diabetes (P<0.09). Conclusions Our data confirm a definite risk of TE in IBD (22.5% of our series). An increased frequency of the genotypes ACE D/D and AGT T/T, never reported so far, was found. In IBD patients TE has a multifactorial genesis with involvement of several genes as well and acquired factors. Genetic screening for prothrombotic factors could help segregate IBD patients at higher risk of TE.

Drugs and Toxins Effects on the Liver

Drug induced hepatotoxicity can be defined as a liver injury caused by drug or herbal medicines leading to liver test abnormalities or to a liver dysfunction with a reasonable exclusion of the other competing aetiologies. The liver has a central function in the metabolism of the xenobiotics, and as a result it may be susceptible to its toxic or idiosyncratic effects. While the overall incidence of drug induced liver injury (DILI) is infrequent (1 in 10.000 to 100.000 persons exposed), the impact is significant in the general population, with broad implications for patients, physicians, pharmaceutical industries and governmental regulatory agencies. DILI is the principle reason for the termination in clinical trials and the most frequent adverse event leads to drug non approvals, withdrawals or to a restriction of prescription drug use after an initial approval and postmarketing regulatory decisions. DILI has been shown to have a dose-dependent component. However, most of the cases of DILI are due to idiosyncratic reactions: over 1000 drugs and herbal products have been associated with idiosyncratic hepatotoxicity. It is difficult to establish a diagnosis of DILI. In fact, there is no single pathognomonic test to establish that a given drug in a given subject is the cause of liver injury. Furthermore, the clinical presentation of DILI may considerably vary. It can mimic other known forms of acute and chronic liver diseases and the severity may range from asymptomatic elevations of hepatic enzymes to fulminant hepatic failure. Because of these factors, a diagnosis of DILI is frequently delayed or may be entirely missed. So, the study of DILI is confounded by the heterogeneity of its clinical presentation and by the course of the injury, the delay in establishing diagnosis as it requires exclusion of other causes of liver injury, the lack of standardized criteria or specific ‘gold standard’ diagnostic tests and underreporting of cases of DILI or their final outcomes. The aim of this chapter is to provide a review and an update of DILI.

Adalimumab in Steroid-Dependent Crohn's Disease Patients: Analisys of Efficacy, Prognostic Factors for Clinical Benefit and Safety

EFFICACY AND SAFETY OF INFLIXIMAB IN THE LONG-TERM IN CROHN’S DISEASE W. Fries ∗ ,1, A.C. Privitera2 , M.A. Lo Presti 1, M. Mastronardi 3 , M. Cappello 4 , L. Grossi 5, A. Lauria6, M. Principi 7, N. Della Valle8, N. Buccianti 9 1Dip. di Medicina Interna, Policlinico, Messina, Italy; 2Dip. di Scienze Chirurgiche, Trapianti D’Organo e Tecnologie Avanzate, U.O.C. di Chirurgia Generale e Serv. Endoscopia, Az. Osp. Per L’emergenza “cannizzaro”, Catania, Italy; 3UOC Gastroenterologia ed Endoscopia Digestiva, Irccs “S. De Bellis”, Castellana Grotte (BA), Italy; 4Gastroenterologia Ed Epatologia, Policlinico, Palermo, Italy; 5Unita di Fisiopatologia Digestiva All’Ospedale Spirito Santo, Pescara, Italy; 6Gastroenterologia e Endoscopia Digestiva A.O. Bianchi-Melacrino-Morelli, Reggio Calabria, Italy; 7Sezione di Gastroenterologia Ed Endoscopia Digestiva, Policlinico, Bari, Italy; 8Gastroenterologia, Policlinico, Foggia, Italy; 9UOC di Medicina Interna, Azienda Ospedaliera S. Carlo, Potenza, Italy

Non-Organ Specific Autoantibodies (NOSA) Induced by Anti-Tumor Necrosis Factor-Alpha Agents for Inflammatory Bowel Disease (IBD) Are Not Associated With Overt Autoimmune Disease

Background: Hepatosplenic T-cell lymphoma is a feared complication of thiopurine treatment for Inflammatory Bowel Disease. While estimates of the risk of Hepatosplenic T-cell lymphoma have been stated in the past, it has not been possible to calculate an estimated incidence as no population based studies of patients with IBD on thiopurines has yet reported a case of HSTCL. Aims: Here we aim to calculate the incidence of HSTCL via a meta-analysis of three population based studies of IBD patients taking thiopurine therapy. We also aim to calculate the relative risk of HSTCL. Methods: We included three population based studies in our analysis, a study from the UK, (Armstrong 2010 Am J of Gastro), one from France (CESAME; Beaugerie 2009 Lancet), and one from Spain (Gisbert Gastro 2010). In our study data were extracted from the Spanish collaborative registry ENEIDA (of which the Gisbert study was published). We examined overall incidence, the incidence in men, those less than 36 years old, and men under 36 years old. 95% confidence intervals (CIs) were estimated by summing observed and expected cases of lymphoma. CIs assumed a Poisson distribution. To examine for heterogeneity, the deviance statistic from Poisson regression models was examined. All patient studies were in compliance with the Helsinki Protocol. Results: One case of HSTCL was present among the three studies, (in ENEIDA). The overall incidence was 1.32 cases per 100,000 person-years with a number needed to harm (NNH) of 1:75,488 patients per year. For men, the incidence was 2.69 cases per 100,000 person-years with an NNH of 1:37,208 per year, and in those under 36 years of age the incidence was 3.63 cases per 100,000 person years with an NNH of 1:27,528. In men under 36, the incidence was 7.93 cases per 100,000 person years with an NNH of 1:12,616 patients per year. Confidence intervals were very large secondary to only one patient being described and there was no significant heterogeneity (see Table 1). Conclusion: In a recent systematic review of HSTCL in IBD (Kotlyar 2010, Clin Gastroenterol Hepatol), while incidence could not be estimated, the absolute risk was estimated at being 1:44,444 overall and 1:7404 in men under 35. These estimates accord with calculated numbers needed to harm of 1:75,488 per year overall and 1:12,616 per year in men under 36. Confidence Interval for Incidence and Tests for Heterogeneity