Hepatobiliary and pancreatic manifestations in inflammatory bowel diseases: a referral center study.

BACKGROUND: Hepatobiliary and pancreatic manifestations have been reported in patients with Crohn's disease or ulcerative colitis. Our aim was to describe the prevalence of hepatobiliary and pancreatic manifestations in inflammatory bowel disease and their association with the disease itself and the medications used. METHODS: Data were retrospectively extracted from the clinical records of patients followed up at our tertiary IBD referral Center. RESULTS: Our study included 602 IBD patients, with liver function tests at regular intervals. The mean follow-up was 5.8 years (Std. Dev.: 6.72). Abdominal imaging examinations were present in 220 patients and revealed findings from the liver, biliary tract and pancreas in 55% of examined patients (120/220). The most frequent findings or manifestations from the liver, biliary tract and pancreas were fatty liver (20%, 44/220), cholelithiasis (14.5%, 32/220) and acute pancreatitis (0.6%, 4/602), respectively. There were 7 patients with primary sclerosing cholangitis. Regarding hepatitis viruses, one-third of the patients had been tested for hepatitis B and C. 5% (12/225) of them had positive hepatitis B surface antigen and 13.4% had past infection with hepatitis B virus (positive anti-HBcore). In addition, most of the patients were not immune against hepatitis B (negative anti-HBs), while 3% of patients were anti-HCV positive and only one patient had active hepatitis C. Furthermore, 24 patients had drug-related side effects from the liver and pancreas. The side effects included 21 cases of hepatotoxicity and 3 cases of acute pancreatitis. Moreover, there were two cases of HBV reactivation and one case of chronic hepatitis C, which were successfully treated. CONCLUSION: In our study, approximately one out of four patients had some kind by a hepatobiliary or pancreatic manifestation. Therefore, it is essential to monitor liver function at regular intervals and differential diagnosis should range from benign diseases and various drug related side effects to severe disorders, such as primary sclerosing cholangitis.

Presence of pseudopolyps in ulcerative colitis is associated with a higher risk for treatment escalation.

BACKGROUND: Pseudopolyps in ulcerative colitis (UC) are considered as indicators of previous episodes of severe inflammation and ulceration of the mucosa. The aim of the study was to investigate the long-term outcomes of patients treated for UC, with or without pseudopolyps. METHODS: This was a retrospective single-center study. Consecutive patients with UC and available endoscopic data from 2000 until 2016 were eligible for the study and were followed until June 2017. Patients with incomplete medical/endoscopic charts or interrupted follow up were excluded from the study. Primary outcomes included time to treatment escalation, treatment escalation to biological agents or surgery, and UC-related hospitalization. RESULTS: Eighty-three UC patients were included in the study, of whom 25 (30%) had pseudopolyps. The median duration of follow up was 2.8 years (interquartile range: 1.1-4.9). Multiple Cox regression analysis identified the presence of pseudopolyps as the only variable independently associated with treatment escalation (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.2-4.3; P=0.014) and escalation to biological agents or surgery (HR 6.3, 95%CI 1.9-20.7; P=0.002). CONCLUSION: This retrospective single-center study provides the first preliminary evidence that patients with UC and pseudopolyps may represent a subpopulation with a higher inflammatory burden and a greater need for treatment escalation, including to biological agents or surgery. Large, prospective multicenter studies are certainly warranted to confirm these findings.

Hepatobiliary Manifestations and Complications in Inflammatory Bowel Disease: A Review.

Liver and biliary track diseases are common extraintestinal manifestations of inflammatory bowel disease (IBD), reported both in Crohn's disease and ulcerative colitis, and may occur at any time during the natural course of the disease. Their etiology is mainly related to pathophysiological changes induced by IBD, and secondary, due to drugs used in IBD. Fatty liver is considered as the most frequent hepatobiliary manifestation in IBD, while primary sclerosing cholangitis (PSC) is the most correlated hepatobiliary disorder and is more prevalent in patients with ulcerative colitis. PSC can cause serious complications from the liver, biliary tree, and gallbladder and can lead to liver failure. Less frequently, IBD-associated hepatobiliary manifestations include cholelithiasis, granulomatous hepatitis, portal vein thrombosis, IgG4-related cholangiopathy, pyogenic liver abscess, hepatic amyloidosis and primary biliary cirrhosis. Most of the drugs used for IBD treatment may cause liver toxicity. Methotrexate and thiopurines carry the higher risk for hepatotoxicity, and in many cases, dose adjustment may normalize the liver biochemical tests. Reactivation of hepatitis B and C virus during immunosuppressive use, especially during use of biological agents, is a major concern, and adequate screening, vaccination and prophylactic treatment is warranted.

Association of clinical and inflammatory markers with small bowel capsule endoscopy findings in Crohn's disease.

BACKGROUND: Mucosal healing is an established treatment endpoint in Crohn's disease (CD). Still, clinical indices and inflammatory markers are used widely in CD surveillance. AIM: The aim of this study was to investigate the diagnostic performance as well as the relationship of C-reactive protein (CRP) and Crohn's Disease Activity Index (CDAI) with small bowel capsule endoscopy's (SBCE) inflammation scoring index, the Lewis Score (LS). PATIENTS AND METHODS: CDAI, CRP, and SBCE findings of 30 CD patients with isolated small bowel disease were retrieved from our academic institution patient records and were analyzed statistically. RESULTS: SBCE showed significant mucosal inflammation [mean (SD) LS: 1599 (1380)], in nine (60.0%) of 15 patients who were in both clinical and biochemical remission. CDAI and CRP showed a weak and moderate correlation with LS (r=0.317, P=0.088 and r=0.516, P=0.004, respectively). The diagnostic performance of CDAI and CRP in predicting mucosal inflammation was as follows: sensitivity 23.8 and 52.4%; specificity 100 and 66.7%; positive predictive value 100 and 78.6%; and negative predictive value 36.0 and 37.5%. The area under the curve toward endoscopic activity prediction was 0.70 and 0.69, respectively. CONCLUSION: Both CDAI and CRP underestimated endoscopic activity as expressed by the LS in a significant proportion of patients with quiescent disease.

Pseudopolyps in inflammatory bowel diseases: Have we learned enough?

Pseudopolyps are a well described entity in the literature and even though the exact pathogenesis of their formation is not completely understood, they are considered non-neoplastic lesions originating from the mucosa after repeated periods of inflammation and ulceration associated with excessive healing processes. Their occurrence is less common in Crohn's disease than in ulcerative colitis, and their overall prevalence ranges from 4% to 74%; moreover, they are found more often in colon but have been detected in other parts of the gastrointestinal tract as well. When their size exceeds the arbitrary point of 1.5 cm, they are classified as giant pseudopolyps. Clinical evaluation should differentiate the pseudopolyps from other polypoid lesions, such as the dysplasia-associated mass or lesion, but this situation represents an ongoing clinical challenge. Pseudopolyps can provoke complications such as bleeding or obstruction, and their management includes medical therapy, endoscopy and surgery; however, no consensus exists about the optimal treatment approach. Patients with pseudopolyps are considered at intermediate risk for colorectal cancer and regular endoscopic monitoring is recommended. Through a review of the literature, we provide here a proposed classification of the characteristics of pseudopolyps.

The role of small bowel capsule endoscopy and ileocolonoscopy in patients with nonspecific but suggestive symptoms of Crohn's disease.

OBJECTIVES: Ileocolonoscopy (IC) and small bowel capsule endoscopy (SBCE) are essential tools in the investigation of suspected small bowel Crohn's disease (CD). Overutilization of SBCE should be avoided as it leads to unwanted healthcare expenses; thus, it is recommended when IC is normal and CD is still highly suspected. Our aim was to compare the role of SBCE and IC in the investigation of suspected CD irrespective of its location and assess the additional diagnostic benefit of SBCE over IC. METHODS: This was a retrospective study of 91 patients with chronic abdominal pain and/or diarrhea. All patients were evaluated with both colonoscopy (with terminal ileum intubation where possible) and SBCE. The severity of inflammation on SBCE was assessed using the Lewis Score. Endoscopic findings were analyzed toward CD diagnosis. RESULTS: The sensitivity of IC and SBCE in the diagnosis of either small bowel or colonic CD was 81.82 and 63.64%, whereas the specificity was 77.50 and 92.50%, respectively. Positive and negative predictive value was 33.33 and 96.88% for IC, as well as 53.85 and 94.87% for SBCE. Area under receiver operating characteristic curve was 0.797 for IC and 0.781 for SBCE. IC was superior to SBCE in diagnosing small and large bowel CD. SBCE showed the true extent of CD in one patient missed by IC. It identified lesions suggestive of CD in three patients with normal IC, one of whom was finally diagnosed with CD. CONCLUSION: IC should be the initial diagnostic test in patients with nonspecific, but suggestive symptoms of CD. SBCE offers additional information on small bowel mucosa and disease extent.

European experience with methotrexate treatment in Crohn's disease: a multicenter retrospective analysis.

INTRODUCTION: Methotrexate (MTX) has been utilized for the treatment of Crohn's disease (CD) for decades. Nevertheless, current data provide equivocal evidence on the efficacy of MTX in CD.The aims of this study were to describe the efficacy of MTX for maintenance of remission in CD and to identify the factors associated with the probability of steroid-free clinical remission in a multicenter European referral center cohort. PATIENTS AND METHODS: This was a retrospective cohort analysis. Consecutive patients treated with MTX for CD were included from 11 referral centers. Patients receiving concomitant treatment with tumor necrosis factor inhibitors or thiopurines were excluded. The main outcome was steroid-free clinical remission; the secondary outcomes included the rate of complications leading to MTX discontinuation and duration of relapse-free survival in patients achieving the main outcome. RESULTS: Between July 1992 and January 2012, 118 patients were identified for inclusion. MTX administration route was oral for induction in 31.4% and for maintenance in 49.1% of the patients. Steroid-free remission was achieved in 44/118 (37.2%) patients and was maintained relapse free by 28/44 (63.6%) for a median of 12 (3.5-18.5) months. At least one adverse effect was reported by 28.9% of the patients. No clinical or demographic factors were associated with either likelihood of achieving a clinical response or duration of relapse-free survival. CONCLUSION: MTX treatment induced steroid-free clinical remission in over a third of CD patients and maintained it for a year in almost two-thirds of the responders. MTX should be considered a viable therapeutic option in CD patients refractory to other therapies.

Role of wireless capsule endoscopy in the follow-up of inflammatory bowel disease.

The introduction of wireless capsule endoscopy in 2000 has revolutionized our ability to visualize parts of the small bowel mucosa classically unreached by the conventional endoscope, and since the recent introduction of colon capsule endoscopy, a promising alternative method has been available for the evaluation of large bowel mucosa. The advantages of wireless capsule endoscopy include its non-invasive character and its ability to visualize proximal and distal parts of the intestine, while important disadvantages include the procedure's inability of tissue sampling and significant incompletion rate. Its greatest limitation is the prohibited use in cases of known or suspected stenosis of the intestinal lumen due to high risk of retention. Wireless capsule endoscopy plays an important role in the early recognition of recurrence, on Crohn's disease patients who have undergone ileocolonic resection for the treatment of Crohn's disease complications, and in patients' management and therapeutic strategy planning, before obvious clinical and laboratory relapse. Although capsule endoscopy cannot replace traditional endoscopy, it offers valuable information on the evaluation of intestinal disease and has a significant impact on disease reclassification of patients with a previous diagnosis of ulcerative colitis or inflammatory bowel disease unclassified/indeterminate colitis. Moreover, it may serve as an effective alternative where colonoscopy is contraindicated and in cases with incomplete colonoscopy studies. The use of patency capsule maximizes safety and is advocated in cases of suspected small or large bowel stenosis.

Costs and resource utilization for diagnosis and treatment during the initial year in a European inflammatory bowel disease inception cohort: an ECCO-EpiCom Study.

BACKGROUND: No direct comparison of health care cost in patients with inflammatory bowel disease across the European continent exists. The aim of this study was to assess the costs of investigations and treatment for diagnostics and during the first year after diagnosis in Europe. METHODS: The EpiCom cohort is a prospective population-based inception cohort of unselected inflammatory bowel disease patients from 31 Western and Eastern European centers. Patients were followed every third month from diagnosis, and clinical data regarding treatment and investigations were collected. Costs were calculated in euros (€) using the Danish Health Costs Register. RESULTS: One thousand three hundred sixty-seven patients were followed, 710 with ulcerative colitis, 509 with Crohn's disease, and 148 with inflammatory bowel disease unclassified. Total expenditure for the cohort was €5,408,174 (investigations: €2,042,990 [38%], surgery: €1,427,648 [26%], biologicals: €781,089 [14%], and standard treatment: €1,156,520 [22%)]). Mean crude expenditure per patient in Western Europe (Eastern Europe) with Crohn's disease: investigations €1803 (€2160) (P = 0.44), surgery €11,489 (€13,973) (P = 0.14), standard treatment €1027 (€824) (P = 0.51), and biologicals €7376 (€8307) (P = 0.31). Mean crude expenditure per patient in Western Europe (Eastern Europe) with ulcerative colitis: investigations €1189 ( €1518) (P < 0.01), surgery €18,414 ( €12,395) (P = 0.18), standard treatment €896 ( €798) (P < 0.05), and biologicals €5681 ( €72) (P = 0.51). CONCLUSIONS: In this population-based unselected cohort, costs during the first year of disease were mainly incurred by investigative procedures and surgeries. However, biologicals accounted for >15% of costs. Long-term follow-up of the cohort is needed to assess the cost-effectiveness of biological agents.

Initial disease course and treatment in an inflammatory bowel disease inception cohort in Europe: the ECCO-EpiCom cohort.

BACKGROUND: The EpiCom cohort is a prospective, population-based, inception cohort of inflammatory bowel disease (IBD) patients from 31 European centers covering a background population of 10.1 million. The aim of this study was to assess the 1-year outcome in the EpiCom cohort. METHODS: Patients were followed-up every third month during the first 12 (±3) months, and clinical data, demographics, disease activity, medical therapy, surgery, cancers, and deaths were collected and entered in a Web-based database (www.epicom-ecco.eu). RESULTS: In total, 1367 patients were included in the 1-year follow-up. In western Europe, 65 Crohn's disease (CD) (16%), 20 ulcerative colitis (UC) (4%), and 4 IBD unclassified (4%) patients underwent surgery, and in eastern Europe, 12 CD (12%) and 2 UC (1%) patients underwent surgery. Eighty-one CD (20%), 80 UC (14%), and 13 (9%) IBD unclassified patients were hospitalized in western Europe compared with 17 CD (16%) and 12 UC (8%) patients in eastern Europe. The cumulative probability of receiving immunomodulators was 57% for CD in western (median time to treatment 2 months) and 44% (1 month) in eastern Europe, and 21% (5 months) and 5% (6 months) for biological therapy, respectively. For UC patients, the cumulative probability was 22% (4 months) and 15% (3 months) for immunomodulators and 6% (3 months) and 1% (12 months) for biological therapy, respectively in the western and eastern Europe. DISCUSSION: In this cohort, immunological therapy was initiated within the first months of disease. Surgery and hospitalization rates did not differ between patients from eastern and western Europe, although more western European patients received biological agents and were comparable to previous population-based inception cohorts.

Adult-onset Still's disease preceding Crohn's disease.

Concomitant diagnosis of Crohn's disease and juvenile or adult-onset idiopathic arthritis is rare. It is possible that both conditions share some genetic or immunological defects although sufficient data are lacking. We describe herein the first case of a patient with adult-onset Still's disease who was diagnosed on follow up with concomitant Crohn's disease. A 38-year-old man diagnosed with adult onset Still's disease from the age of 24 was admitted in our hospital because of bloody diarrhea. On admission physical examination was unremarkable and all routine laboratory tests were normal except of Hg at 11.3 gr/dl, erythrocyte sedimentation rate at 27 mm/h and C-reactive protein at 14 mg/dl. Ileocolonoscopy revealed small aphthoid ulcers in the terminal ileum and capsule endoscopy revealed the source of bleeding and small aphthoid ulcers starting from the distal jejunum up to the terminal ileum. Terminal ileum biopsies were diagnostic of Crohn's disease and patient had started on therapy with mesalamine 2 gr/day and azathioprine 2mg/kg and is currently on multidisciplinary follow up. We review all literature on co-existence of Crohn's disease with chronic idiopathic arthritis and we discuss the possible difficulties in diagnosis and therapy of those patients also in the view of the new biological agents.

Coexistence of Crohn's disease in a patient with systemic lupus erythematosus.

The concurrence of inflammatory bowel disease with systemic lupus erythematosus (SLE) is rare. The concomitant diagnosis of Crohn's disease and SLE is even more rare. The patient, a 40-year-old woman, was admitted to our hospital because of relapsing episodes of abdominal pain, diarrheas upper and lower extremities arthralgias, Raynaud's phenomenon with positive antinuclear antibodies, and fever for the last 2 years. The patient was diagnosed elsewhere with SLE and treated with hydroxychloroquine. Her medical history also included tonsillectomy and total hip replacement after a car accident. Family history was unremarkable. Physical examination was unremarkable except of very mild pain at lower left abdominal quadrant. Laboratory tests showed erythrocyte sedimentation rate at 32 mm/h, C-reactive protein at 36 mg/dl, positive rheumatoid factor, and increased C3, C4, positive antinuclear antibodies with the presence of anti-Sm and anti-RNP antibodies. Ileocolonoscopy revealed colonic inflammation with ulcers and pseudopolyps. Subsequent biopsies were diagnostic of Crohn's disease. Patient was diagnosed with Crohn's colitis concomitant to systemic lupus erythematosus and was started on therapy with azathioprine 2 mg/Kg, methylprednisolone 16 mg/d with slow tapering, mesalazine 1.5 g/day, and hydroxychloroquine. Patient is in excellent health status on the six-month follow-up.

Orbital and optic nerve complications of inflammatory bowel disease.

BACKGROUND AND AIMS: Extraintestinal manifestations of inflammatory bowel disease (IBD) can involve the orbit and the optic nerve. Although these manifestations are rare, they can be particularly serious as they can lead to permanent loss of vision. The aim of the review is to present the existing literature on IBD-related optic nerve and orbital complications. METHODS: A literature search identified the publications reporting on incidence, clinical features and management of IBD patients with optic nerve and orbital manifestations. RESULTS: Posterior scleritis and orbital inflammatory disease (orbital pseudotumor) are the most commonly encountered entities affecting the structures of the orbit. On the other hand, the optic nerve of IBD patients can be affected by conditions such as optic (demyelinating) neuritis ("retrobulbar" neuritis), or ischaemic optic neuropathy. Other neuro-ophthalmic manifestations that can be encountered in patients with IBD are related to increased intracranial pressure or toxicity secondary to anti tumour necrosis factor (anti-TNF) agents. CONCLUSIONS: IBD-related optic nerve and orbital complications are rare but potentially vision-threatening. Heightened awareness and close cooperation between gastroenterologists and ophthalmologists are warranted.

Inflammatory bowel disease and lupus: a systematic review of the literature.

Coexistence of systemic lupus erythematosus (SLE) should be considered in patients with inflammatory bowel disease (IBD) and complex extraintestinal manifestations and the diagnosis of IBD could be established either before or after the diagnosis of SLE. Differential diagnosis of concomitant SLE and IBD is difficult and should always exclude infectious conditions, lupus-like reactions, visceral vasculitis and drug-induced lupus. The underlying mechanism by which 5-ASA/sulphasalazine induces SLE or lupus-like syndromes is not clear and high awareness for possible predictive factors is demanded for early prevention. In most cases the symptoms from drug-induced lupus have been reversible after the discontinuation of the drug and response to steroids is favorable. Treatment of patients co-diagnosed with SLE and IBD may include corticosteroids, immunosupressants and hydroxychloroquine. In severe lupus and IBD patients cyclophosphamide pulse may be of benefit while infliximab may be beneficiary in patients with lupus nephritis. However, the role TNFalpha plays in humans with SLE and IBD is controversial and data on the likely effects of blocking TNFalpha on anti-DNA autoantibody production is always of interest.

Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites.

Circulating levels of endotoxin, interleukin (IL)-6, and tumor necrosis factor (TNF)-α increase with intestinal bacterial overgrowth and translocation, and are believed to be involved in the pathogenesis of hyperdynamic circulatory syndrome and functional renal failure in patients with advanced cirrhosis. We investigated the effects of the antibiotic rifaximin on systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. We measured mean arterial pressure, cardiac output (CO) by Doppler ultrasound, systemic vascular resistance (as the ratio of mean arterial pressure:CO), plasma renin activity, levels of plasma aldosterone, the glomerular filtration rate by plasma clearance of technetium-99m-DTPA, natriuresis, levels of plasma endotoxin, and serum levels of IL-6 and TNF-α in 13 patients at baseline and after 4 weeks of treatment with rifaximin. Rifaximin treatment significantly reduced CO and significantly increased systemic vascular resistance, in association with a significant decrease in plasma rennin activity. The therapy also significantly increased the glomerular filtration rate and natriuresis while reducing levels of endotoxin, IL-6, and TNF-α. Intestinal decontamination with rifaximin improved systemic hemodynamics and renal function in patients with advanced cirrhosis.

Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response.

BACKGROUND: Intensifying infliximab therapy is often practiced in Crohn's disease (CD) patients losing response to the drug but there are no data if halving the interval is superior to doubling the dose. We aimed to assess the efficacy of infliximab dose intensification by interval-halving compared with dose-doubling. METHODS: A multicenter retrospective study of CD patients losing response to infliximab was undertaken. The clinical outcome of patients whose infusion intervals were halved (5 mg/kg/4 weeks) was compared with patients treated by dose-doubling (10 mg/kg/8 weeks). RESULTS: In all, 168 patients were included from 18 centers in Europe, USA, and Israel. Of these, 112 were intensified by dose-doubling and 56 received interval-halving strategy. Early response to dose-escalation was experienced by 86/112 (77%) patients in the dose-doubling group compared with 37/56 patients (66%) in the interval-halving group (odds ratio [OR] 1.7, 95% confidence interval [CI] 0.8-3.4, P = 0.14). Sustained clinical response at 12 months postescalation was maintained in 50% of patients in the dose-doubling group compared with 39% in the interval-halving group (OR 1.5, 95% CI 0.8-2.9, P = 0.2). On multivariate analysis, predictors of long-term response to escalation were a nonsmoking status, CD diagnosis between 16-40 years of age, and normal C-reactive protein (CRP). CONCLUSIONS: Dose intensification leads to a sustained regained response in 47% of CD patients who lost response to standard infliximab dose, but halving the infusion intervals is probably not superior to dose-doubling. Given the costs and patient inconvenience incurred by an additional infusion visit, the dose-doubling strategy may be preferable to the interval-halving strategy.

Role of genetics in the diagnosis and prognosis of Crohn's disease.

Considering epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have been so far related to the diagnosis of Crohn's disease. Those genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the most strong and replicated associations with Crohn's disease have been done with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in prognosis of Crohn's disease and many attempts have been made to classify genetic profiles in Crohn's disease. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding on Crohn's disease genetics is important but when combining genetic data with functional data the outcome could be of major importance to clinicians.