Could Capsule Endoscopy Be Useful in Detection of Suspected Small Bowel Bleeding and IBD-10 Years of Single Center Experience.

A retrospective study in patients who underwent video capsule endoscopy (VCE) between 2006 and 2016 was conducted in the Clinic for gastroenterology and Hepatology, University Clinical Center of Serbia. A total of 245 patients underwent VCE. In 198 patients the indication was obscure gastrointestinal bleeding (OGIB), with 92 patients having overt and the other 106 occult bleeding. The remaining 47 patients underwent VCE due to suspected small bowel (SB) disease (i.e., Von Hippel-Lindau syndrome, familial adenomatous polyposis, Peutz Jeghers syndrome, Crohn's disease, prolonged diarrhea, abdominal pain, congenital lymphangiectasia, protein-losing enteropathy, tumors, refractory celiac disease, etc.). VCE identified a source of bleeding in 38.9% of patients (in the obscure overt group in 48.9% of patients, and in the obscure occult group in 30.2% of patients). The most common findings were angiodysplasias, tumors, Meckel's diverticulum and Crohn's disease. In the smaller group of patients with an indication other than OGIB, 38.3% of patients had positive VCE findings. The most common indication is OGIB, and the best candidates are patients with overt bleeding; patients with IBD should be evaluated in this setting.

IBD: From conventional immunosuppression to biological therapy.

Background Inflammatory bowel diseases (IBD) are chronic recurrent inflammatory diseases with partly understood etiology and pathogenesis. The course of IBD, both ulcerative colitis (UC) and Crohn`s disease (CD) is characterized by periods of relapse and remission with the possible occurrence of extraintestinal manifestations. Summary During the last decades therapeutic goals in IBD evolved towards endoscopic remission and mucosal healing creating the need for early administration of disease-modifying agents (DMA). DMA includes conventional immunosuppressants (thiopurines, methotrexate), biological drugs (anti-TNF, anti-integrin, and anti-IL12/23 monoclonal antibodies), and small molecules (JAK inhibitors, S1P receptor modulators). Patients with an aggressive course of disease and risk factors for poor prognosis should be treated with biological therapy early. At the same time, conventional immunomodulators should be used in those with a milder course of disease in the absence of risk factors. Key points Challenges in treating IBD patients include choosing effective yet safe drugs and preventing or overcoming the loss of response.

Successful pregnancies in a patient with Takayasu arteritis and antiphospholipid syndrome, maintained on infliximab corticosteroid-free regimen: case-based review.

Takayasu arteritis (TA) is a large vessel vasculitis affecting predominantly females below the age of 40. Patients with TA seem to be at increased risk for adverse pregnancy outcomes, resulting in mother or child complications. Although few studies analyzed the presence of antiphospholipid antibodies (APLA) in TA patients, an association between antiphospholipid syndrome (APS) and TA is rarely reported in the literature, mainly in the form of case reports. In fact, very few data regarding pregnancy outcomes in patients with TA and APS are available. An active form of Crohn's disease (CD) might be another risk factor strongly affecting the fertility rate. Here, we would like to present a 33-year-old woman with TA, double-positive APS and Crohn's disease (CD). The report is followed by the literature review of the association of APLA and/or APS with TA, focusing on analyzing the pregnancy outcomes. To our knowledge, this is the first case describing two successful, naturally occurring pregnancies, in a patient suffering from TA, APS and CD, and maintained on infliximab, azathioprine, and a corticosteroid-free regimen.

Autoimmune Hemolytic Anemia in Inflammatory Bowel Disease-Report of a Case and Review of the Literature.

A wide spectrum of extraintestinal manifestations (EIMs) can burden patients with inflammatory bowel disease (IBD). EIMs contribute fairly to morbidity and mortality rates in IBD patients. Moreover, EIMs in IBD patients are so frequent that some suggest that IBD should be approached as a systemic disorder. Anemia is very common in IBD patients. The two most common types of anemia in IBD, iron deficiency anemia and anemia of chronic disease, are extraintestinal complications. Autoimmune hemolytic anemia (AIHA) is a rare extraintestinal manifestation of IBD, more frequent in ulcerative colitis (UC) than in Crohn's disease (CD). In this case-based review of the literature, we present a 36-year-old female patient diagnosed with Crohn's disease (CD) and Coombs positive AIHA, complicated by pulmonary thromboembolism and successfully treated with anti-tumor necrosis factor (anti-TNF) therapy. The underlying pathophysiological mechanism of AIHA in IBD is unclear. Treatment options for AIHA in IBD patients before biologic therapy included corticosteroids alone or in combination with azathioprine (AZA), methotrexate, and surgical treatment (colectomy and/or splenectomy). Currently, biologic therapy is a promising therapeutic option, especially in corticosteroid refractory or corticosteroid-dependent IBD patients with AIHA.

Intestinal Ultrasonography as a Tool for Monitoring Disease Activity in Patients with Ulcerative Colitis.

Background: Ultrasonography is a noninvasive, inexpensive, and widely available diagnostic tool. In the last two decades, the development of ultrasound techniques and equipment has significantly increased the usage of intestine ultrasound (US) in the assessment of the gastrointestinal tract in patients with inflammatory bowel disease (IBD). Although current guidelines suggest routine utilization of US in patients with Crohn's disease, data regarding US usage in ulcerative colitis are still scarce. We aimed to assess the reliability of intestinal ultrasonography in the assessment of disease activity and extension of patients with ulcerative colitis. Methods: Fifty-five patients with a histologically confirmed diagnosis of ulcerative colitis, treated at University Clinical Center of Serbia in the period from 2019 to 2022 were included in this retrospective observational study. The data were obtained from the patient's medical records including history, laboratory, US, and endoscopy findings. US examined parameters were as following: bowel wall thickness (BWT), presence of fat wrapping, wall layer stratification, mesenteric hypertrophy, presence of enlarged mesenteric lymph nodes, and absence or presence of ascites. Results: Our results suggest that there is a strong correlation of BWT and colonoscopy findings regarding disease extension (r = 0.524, p=0.01, p < 0.05). Furthermore, our results have shown a statistically significant correlation of BWT with the Mayo endoscopic score (r = 0.434, p=0.01, p < 0.05), disease activity score (r = 0.369,p=0.01, p < 0.05), degree of ulcerative colitis burden of luminal inflammation (r = 0.366, p=0.01, p < 0.05), and Geboes index (r = 0.298, p=0.027, p < 0.05). Overall accuracy of US for disease extension and activity was statistically significant (p < 0.05). Conclusions: Our results suggest that US is a moderately accurate method for the assessment of disease activity and localization in patients with UC.

Profiling of Circulatory Elements Reveals Alteration of Essential and Toxic Trace Metals in Crohn's Disease.

The status of essential and toxic trace metals in the blood of Crohn's disease (CD) patients is unexplained. This study aimed to provide the first elemental profiling of the most recognized essential elements (Mn, Cu, Zn, Se) and selected toxic trace elements (As, Cd, Pb, and U) in sera and cell lysate (CL) samples of CD patients (n = 84). The results were compared with sex- and age-matched samples from the control group (CG). CD sera contained significantly higher levels of Mn, As, Cd, Pb, and U than did CG sera. An identical pattern, with the added inclusion of Cu (also higher in CD patients than in the CG), was obtained for CL samples. However, the most important finding was hypermanganesemia, which indicates that Mn could act as a toxic trace metal in CD. As, Cd, and U were the most significant toxic elements that showed antagonistic effects on the extrusion of essential Mn and Cu. Circulatory system screening markers for CD are hereby proposed (Mn/Cu, Mn/As, and Mn/Pb ratios). These three metal ratios were strongly and significantly correlated with F-Calprotectin levels, and deserve consideration as new markers of CD. The target metals and metal ratios should be taken into consideration as novel initiating and/or modifying factors for CD.

Anemia as a Problem: GEH Approach.

BACKGROUND: Anemia is present in almost 5% of adults worldwide and accompanies clinical findings in many diseases. Diseases of the gastrointestinal (GI) tract and liver are a common cause of anemia, so patients with anemia are often referred to a gastroenterologist. SUMMARY: Anemia could be caused by various factors such as chronic bleeding, malabsorption, or chronic inflammation. In clinical practice, iron deficiency anemia and the combined forms of anemia due to different pathophysiological mechanisms are most common. Esophagogastroduodenoscopy, colonoscopy, and the small intestine examinations in specific situations play a crucial role in diagnosing anemia. In anemic, GI asymptomatic patients, there are recommendations for bidirectional endoscopy. Although GI malignancies are the most common cause of chronic bleeding, all conditions leading to blood loss, malabsorption, and chronic inflammation should be considered. From a gastroenterologist's perspective, the clinical spectrum of anemia is vast because many different digestive tract diseases lead to bleeding. Key Messages: The gastroenterological approach in solving anemia's problem requires an optimal strategy, consideration of the accompanying clinical signs, and the fastest possible diagnosis. Although patients with symptoms of anemia are often referred to gastroenterologists, the diagnostic approach requires further improvement in everyday clinical practice.

Jaundice as a Diagnostic and Therapeutic Problem: A General Practitioner's Approach.

BACKGROUND: Jaundice is a common clinical finding in clinical practice of hepatologists and general practitioners. It occurs when serum bilirubin levels exceed 3 mg/dL. SUMMARY: In this review, we summarize the pathophysiological mechanism of jaundice, clinical approach to the patient with jaundice, and laboratory and imaging techniques. Clinical presentation of jaundice manifests through yellow skin and sclera coloration. Evaluation of every patient includes detailed medical history and examination. In the laboratory, evaluation of enzymes of hepatic inflammation as well as cholestatic enzymes with serum bilirubin must be included. Additional laboratory analysis and imaging modalities are needed in order to differentiate jaundice etiology. Moreover, imaging is available and needed in further evaluation, and treatment is dependent on the underlying cause. KEY MESSAGES: In this review, we will outline the pathophysiological mechanism of jaundice, clinical approach to the patient with jaundice, and diagnostic and treatment approach to these patients.

Chronic Abdominal Pain: Gastroenterologist Approach.

BACKGROUND: Abdominal pain is a common symptom of gastroenterology examination. Chronic abdominal pain is present for >3 months. SUMMARY: Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal diseases encountered by both gastroenterologists and general practitioners. GERD is usually a chronic disease presented with a set of symptoms including heartburn and/or regurgitation, and less commonly epigastric pain. Epigastric pain syndrome is characterized by the following symptoms: epigastric pain and/or burning. It does not necessarily occur after meal ingestion, may occur during fasting, and can be even improved by meal ingestion. Duodenal ulcers tend to cause abdominal pain that is localized in the epigastric region and commence several hours after eating, often at night. Hunger provokes pain in most of the cases and decreases after meal. Gastric ulcer pain occurs immediately after eating, and consuming food increases pain. Pain is localized in the epigastrium and can radiate to the back. Abdominal pain in irritable bowel syndrome is related to defecation. A typical symptom of chronic pancreatitis is pain that radiates to the back. In Crohn's disease, inflammation causes pain. Key Messages: Pain can occur at different locations with diverse intensity and propagation and is often associated with other symptoms. For any gastroenterologist, abdominal pain is a big challenge.

Diarrhea as a Clinical Challenge: General Practitioner Approach.

BACKGROUND: Diarrhea is defined as the passage of loose stools and increase in stool frequency, weight, or volume. Diarrhea is an important health issue since it accounts for 2.5 million deaths in the world each year. SUMMARY: Diarrhea can be acute, persistent, or chronic. Acute diarrhea (AD) is usually infectious, caused by viruses, less frequently by bacteria and parasites. The majority of cases of AD are self-limiting and do not require diagnostic workup. The use of diagnostic tests in AD should be limited to patients with signs of severe dehydration, bloody stools, persistent fever and those suffering from immunodeficiencies using immunosuppressive therapy or to cases of suspected nosocomial infection. These patients should be referred to gastroenterologists or infectious disease specialists. Therapy in AD consists of early oral refeeding, antidiarrheal medications, antibiotics, and probiotics. Chronic diarrhea (CD) has diverse etiology. The majority of patients have self-limiting symptoms or functional gastrointestinal disorders. Patients with blood in stool, weight loss, clinical and laboratory signs of anemia, and palpable mass in the abdomen (red flag symptoms) need urgent gastroenterology referral. Therapy in CD is possible when the underlying cause of symptoms is identified. KEY MESSAGES: The general practitioner should identify high-risk patients with AD and/or red flag symptoms for urgent gastroenterology referral.

Correlation of Patient-Reported Outcome (PRO-2) with Endoscopic and Histological Features in Ulcerative Colitis and Crohn's Disease Patients.

METHODS: A cross-sectional study was conducted in consecutive newly diagnosed patients with inflammatory bowel disease in a tertiary care referral center. The initial evaluation included patient-reported outcome for stool frequency subscore and rectal bleeding. Endoscopic activity was determined using the Mayo scoring system for ulcerative colitis and the Simple Endoscopic Score for Crohn's disease. Histopathological activity was assessed using a validated numeric scoring system. RESULTS: We included 159 patients (63 Crohn's disease with colonic involvement and 96 with ulcerative colitis). We found significant correlation between the Mayo endoscopic subscoring system and histology activity in ulcerative colitis, while no correlation was found in patients with Crohn's disease. Patient-reported outcome showed inverse correlation with endoscopic and histological activity in Crohn's disease (r s = -0.67; r s = -0.72), while positive correlation was found in ulcerative colitis (r s = 0.84; r s = 0.75). Interpretation and Conclusions. Patient-reported outcome is a practical and noninvasive tool for assessment of disease activity in ulcerative colitis patients but not in Crohn's disease.

Exploring inflammatory and apoptotic signatures in distinct Crohn's disease phenotypes: Way towards molecular stratification of patients and targeted therapy.

BACKGROUND: Crohn's disease (CD) is chronic inflammatory bowel disease with different phenotypic characteristics influencing disease prognosis and therapeutic strategies. The aim of this pilot study was to analyze selected inflammatory and apoptotic markers in non-inflamed and inflamed samples of ileal mucosa of non-stricturing/non-penetrating (NS/NP) and stricturing (S) CD mucosal phenotypes in order to characterize their distinct profiles. METHODS: From twenty CD patients (9 NS/NP, 11 S) paired non-inflamed and inflamed ileal biopsies were collected and used for analysis of cytokine (TNF and IL6) and apoptotic (Bcl2, Bax, Fas and FasL) genes' expression levels by real-time PCR, while NFκB transcriptional potency was assessed by electromobility gel shift assay. RESULTS: Our results demonstrated significant upregulation of TNF and IL6 in inflamed area of both NS/NP (p = 0.03, p = 0.01) and S phenotypes (p = 0.04, p = 0.04), respectively. However, TNF increase was more prominent in NS/NP compared to S inflamed mucosa (p = 0.02). Also, level of proapoptotic Bax was significantly higher in NS/NP compared to S inflamed mucosa (p = 0.01). Opposing transcription potency of NFκB has been detected between two phenotypes: being decreased in NS/NP (p = 0.07) and increased in S (p = 0.1) inflamed compared to non-inflamed mucosa, demonstrating trend towards statistical significance. CONCLUSIONS: We found that two distinct CD phenotypes have specific molecular signatures. Obtained results could direct improvement of current and development of new therapeutic strategies based on more specific molecular stratification of CD patients.

Metabolic Syndrome in Inflammatory Bowel Disease: Association with Genetic Markers of Obesity and Inflammation.

Background: This study analyzed poorly understood relationship of two overlapping conditions: metabolic syndrome (MeS) and inflammatory bowel disease (IBD), both associated with inflammation in the visceral adipose tissue. Methods: Newly diagnosed 104 IBD patients, of which 50 Crohn's disease (CD) and 54 ulcerative colitis (UC), and 45 non-IBD controls were examined for MeS-related obesity and lipid markers. Th-17 immune genes IL17A, IL17F, IL23A, and TLR9 mRNAs were measured in intestinal mucosa by qRT-PCR. Subjects were genotyped for obesity-associated FTO variant rs9939609 by polymerase chain reaction-amplification refractory mutation system. Results: CD was associated with MeS (P = 0.01), while both CD and UC were associated with central obesity (P = 10-5, P = 0.002, respectively) and low levels of high-density lipoprotein (HDL) cholesterol (P = 5 × 10-6, P = 6 × 10-6, respectively). IBD lipid profile was characterized by decreased total and HDL cholesterol, while low-density lipoprotein cholesterol was reduced only in CD. Negative correlations were found between total cholesterol and CD activity index (P = 0.005), waist circumference and IL17A as well as IL17F mRNA levels in inflamed CD colon (P = 0.003, P = 0.001, respectively). Carriers of FTO rs9939609 AA genotype showed increased risk of CD (OR 2.6, P = 0.01). Conclusions: MeS, central obesity, and dyslipidemia could be important for IBD pathogenesis. This could influence therapeutic approaches and prevention strategies in high-risk groups.

Appropriate Management of Attenuated Familial Adenomatous Polyposis: Report of a Case and Review of the Literature.

Hereditary polyposis syndromes in which APC gene germline mutations can lead to colorectal carcinogenesis are familial adenomatous polyposis (FAP), attenuated FAP (AFAP) and MUTYH-associated polyposis. All 3 syndromes increase the potential for the development of colorectal cancer. AFAP is diagnosed if less than 100 adenomas are detected in the colon at presentation. AFAP is inherited in an autosomal dominant manner. We present a case of a 22-year-old female with AFAP who was treated with endoscopic polypectomy and surveilled by annual colonoscopy. Guidelines for AFAP surveillance suggest annual colonoscopy with endoscopic polypectomy in asymptomatic individuals. Indications for immediate surgery include documented or suspected cancer or significant symptoms. Preferred surgical option in AFAP is colectomy and ileo-rectal anastomosis. Surveillance of the AFAP patients should include upper GI endoscopy and duodenoscopy with random biopsies of fundic gland polyps and endoscopic resection of detected adenomas. Annual thyroid ultrasound is indicated due to increased risk for thyroid cancer. In pediatric patients tested positive for germline mutation of APC gene screening for hepatoblastoma using alpha-fetoprotein and liver ultrasound should be performed.

Importance of TLR9-IL23-IL17 axis in inflammatory bowel disease development: Gene expression profiling study.

BACKGROUND AND AIMS: Mucosal gene expression have not been fully enlightened in inflammatory bowel disease (IBD). Aim of this study was to define IL23A, IL17A, IL17F and TLR9 expression in different IBD phenotypes. METHODS: Evaluation of mRNA levels was performed in paired non-inflamed and inflamed mucosal biopsies of newly diagnosed 50 Crohn's disease (CD) and 54 ulcerative colitis (UC) patients by quantitative real-time PCR analysis. RESULTS: IL17A and IL17F expression levels were significantly increased in inflamed IBD mucosa. Inflamed CD ileal and UC mucosa showed increased IL23A, while only inflamed CD ileal samples showed increased TLR9 mRNA level. Correlation between analysed mRNAs levels and endoscopic and clinical disease activity were found in UC, but only with clinical activity in CD. CONCLUSION: Both CD and UC presented expression of Th17-associated genes. Nevertheless, expression profiles between different disease forms varies which should be taken into account for future research and therapeutics strategies.

Genetic and environmental factors significant for the presentation and development of inflammatory bowel disease.

OBJECTIVES: The aim of the study was to evaluate associations between inflammatory bowel disease (IBD) presentation and variants in NOD2, TLR4, TNF-α, IL-6, IL-1ß, and IL-RN genes in order to identify possible environmental factors that may affect IBD occurrence, investigate potential predictors for surgical treatment of IBD, and correlate the presence of granulomas in biopsy specimens with clinical characteristics of Crohn's disease (CD) patients. PATIENTS AND METHODS: We genotyped 167 IBD patients using PCR-based methodology and tested for disease genotype-phenotype associations. RESULTS: In CD patients ileal localization of disease was more frequent in NOD2 variant carriers. Ileal CD was associated with IL-6 GC+CC genotypes, identifying C allele as a possible marker of increased risk for ileal CD. In CD patients a positive family history for IBD was related to earlier onset of disease, higher risk for CD-related surgery, and appendectomy. CD patients who are TLR4 299Gly carriers are at higher risk for surgery at onset of the disease compared with TLR4 299Asp variant carriers. The presence of granuloma in biopsy specimens was more frequent in patients in whom a diagnosis of CD was made during emergency surgery. Multivariate analysis showed that CD carriers of the 299Gly allele had a 4.6-fold higher risk for emergency surgery before CD diagnosis is established compared with noncarriers, suggesting an aggressive disease course. Granuloma in endoscopic biopsies is detected 5.4-fold more frequently in patients treated surgically at the time of diagnosis. CONCLUSION: Genetic variants together with epidemiological and clinical data of IBD patients could potentially be used as predictors of the disease course.

Capsule endoscopy is useful diagnostic tool for diagnosing Meckel's diverticulum.

OBJECTIVE: Meckel's diverticulum (MD) is the most common congenital anomaly of the gastrointestinal tract. Although a majority of patients remain asymptomatic, complications may occur in a subset of patients. MD is a rare cause of gastrointestinal bleeding (GIB) in adults. We aimed to clarify the possible role of capsule endoscopy (CE) in the identification of Meckel's diverticulum. PATIENTS AND METHODS: From October 2004 to December 2010, 157 CEs were performed (83 male individuals, mean age 51±20 years; range 3-83 years) for obscure GIB. Before CE, all patients underwent nonconclusive upper and lower endoscopy at least two times and barium follow-through. RESULTS: CE identified the source of bleeding in 70/157 patients (44.6%). MD was diagnosed in 13/70 (18.6%) patients (11 male individuals, mean age 35±20 years, range, 3-69 years) after CE. Nine patients presented with obscure overt and four with obscure occult bleeding. The mean duration of obscure GIB history was 13 months (range 1-72 months). The mean hemoglobin concentration at the time of the procedure was 115±12 g/l. The findings of MD on CE were double lumen sign (13/13), visible blood (7/13), and diaphragm sign (6/13). All patients were operated upon, and MD histologically verified in 11. In two patients CE was false-positive and in two patients, false-negative. Capsule endoscopy had a positive predictive value of 84.6% for the diagnosis of MD. CONCLUSION: MD should be considered in the differential diagnosis of obscure GIB in adults. CE is an effective and promising modality for diagnosing MD in patients with obscure GIB.

[Recommendation for gastroprotection in gastrointestinal bleeding prevention].

Incidence of gastrointestinal bleeding in most populations is about 1 per 1,000 inhabitants. More than 65% of all bleeding episodes are associated with drug use. The most often involved are non-steroidal antiinflammatory drugs and low doses of acetyl-salicylic acid. The mortality within the first month after the bleeding episode is about 10­12%, and has not significantly changed in the last decade. Therefore, bleeding prevention is of major importance. Appropriate selection of patients, proper drug choice, application of lowest efficient doses of potentially ulcerogenic drugs, and use of drugs that inhibit gastric acid secretion remain cornerstone preventive measures of gastrointestinal bleeding.

Role of Helicobacter pylori infection in gastric carcinogenesis: Current knowledge and future directions.

Helicobacter pylori (H. pylori) plays a role in the pathogenesis of gastric cancer. The outcome of the infection depends on environmental factors and bacterial and host characteristics. Gastric carcinogenesis is a multistep process that is reversible in the early phase of mucosal damage, but the exact point of no return has not been identified. Therefore, two main therapeutic strategies could reduce gastric cancer incidence: (1) eradication of the already present infection; and (2) immunization (prior to or during the course of the infection). The success of a gastric cancer prevention strategy depends on timing because the prevention strategy must be introduced before the point of no return in gastric carcinogenesis. Although the exact point of no return has not been identified, infection should be eradicated before severe atrophy of the gastric mucosa develops. Eradication therapy rates remain suboptimal due to increasing H. pylori resistance to antibiotics and patient noncompliance. Vaccination against H. pylori would reduce the cost of eradication therapies and lower gastric cancer incidence. A vaccine against H. pylori is still a research challenge. An effective vaccine should have an adequate route of delivery, appropriate bacterial antigens and effective and safe adjuvants. Future research should focus on the development of rescue eradication therapy protocols until an efficacious vaccine against the bacterium becomes available.