Intussuscepted Polypoid Meckel's Diverticulum Presenting With Gastrointestinal Bleeding in a Young Adult.

A 22-year-old female patient with a recent hospitalization for gastrointestinal bleeding presented with recurrent hematochezia and a positive shock index. Previous investigations, including endoscopy and wireless small bowel capsule, were non-diagnostic. CT angiography revealed extravasation in the ileum. Initial tests like technetium-99m scintigraphy and ileocolonoscopy were negative. Repeat wireless small bowel capsule identified a partially ulcerated polypoid mass in the distal ileum. At surgical exploration, an intussuscepted Meckel's diverticulum was identified and resected. A histopathologic examination confirmed the diagnosis. Meckel's diverticulum is a rare cause of gastrointestinal bleeding in adults. Preoperative diagnosis can be challenging. Reports of a polypoid morphology are very scarce in indexed literature and mostly derive from investigation with device-assisted enteroscopy. We report this extremely rare finding at capsule endoscopy to raise clinician awareness and to discuss diagnostic difficulties associated with similar cases, such as the negative scintigraphy result and the optimal timing of repeat capsule endoscopy.

Combination of Percutaneous Transhepatic Balloon-Assisted Transjugular Intrahepatic Collateral Caval Shunt and Embolization for Successful Hemostasis of Lower Gastrointestinal Bleeding Associated With Extremely Enlarged Anorectal Varicose Veins.

Ectopic varices may frequently occur in the rectum in the context of portal hypertension. Although rectal variceal bleeding is not a frequent bleeding situation, it can be life-threatening unless diagnosed and treated immediately. However, there is no specific treatment strategy established so far. We report a case of a man with extrahepatic portal hypertension and severe hematochezia due to rectal variceal bleeding. The patient was diagnosed in the past with portal vein thrombosis, in the context of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome, with ectopic varices in the small intestine, colon, rectum and anal canal, peritoneum and perisplenic veins, treated with mesorenal shunt placement and an oral beta-blocker. After the initial stabilization with fluid replacement and red blood cell transfusion, he underwent endoscopic injection sclerotherapy, with no effect on bleeding episodes, while the large size of the varices precluded the option of endoscopic band ligation. Due to the presence of large collateral veins next to the inferior vena cava, the patient underwent combination therapy with Percutaneous Transhepatic Balloon-Assisted Transjugular Intrahepatic Collateral Caval shunt placement, to decompress portal pressure, followed by angiographic embolization of the feeding vessels resulting in successful hemostasis. Hematochezia ceased, hemoglobin was stabilized and the patient was safely discharged from the hospital. Controlling and treating rectal varices can be a challenging task indicating the need of a multidisciplinary approach. In the absence of well-established treatment guidelines for rectal varices, we highly recommend treatment of refractory ectopic variceal bleeding, non-responsive to endoscopic treatments, with portocaval shunt placement in combination with embolization.

Olmesartan-Induced Enteropathy: A Report of an Unusual Cause of Chronic Diarrhea.

Olmesartan, an angiotensin II receptor blocker indicated in the treatment of hypertension, has been associ-ated with a seronegative sprue-like enteropathy that should be considered in the differential diagnosis of patients with unexplained chronic diarrhoea. It typically presents with severe chronic diarrhoea, considerable weight loss, and villous atrophy on biopsy and may be difficult to recognize because of its clinical and histological similarities to other clinical entities. Practically, discontinuation of the drug leads to dramatic recovery of the symptoms. We report a 76-year-old Caucasian female who was admitted to our hospital with complaints of chronic diarrhea and significant weight loss. Medical history was notable for hypertension being treated with olmesartan. Initially, investigation for all potential infectious causes and celiac disease was negative. Both upper and lower endoscopy was performed with duodenal biopsies revealing total villous atrophy and colonic biopsies showing lymphocytic colitis. In the presence of negative serology for celiac disease and after a thorough review of the patient's medications, olmesartan in-duced-enteropathy was the most possible diagnosis. Olmesartan was discontinued and the symptoms rapidly resolved. A follow-up done a few months later showed no recurrence of the symptoms. In olmesartan-associated enteropathy, discontinuation of olmesartan results in immediate clinical recovery. Although rare, it is considered an emerging and underdiagnosed enteropathy. This case report illustrates the need for a thorough medication history evaluation and regular review during workup. We aim to increase the awareness of olmesartan-induced enteropathy among clinicians and gastroenterologists. We hope it will add to the current literature and help to understand this rare phenomenon in order to avoid unnecessary testing.

Sweet Syndrome Associated With Crohn's Disease Developed After a Combo Therapy With Infliximab and Azathioprine: A Case Report.

Sweet syndrome, also known as Acute Febrile Neutrophilic Dermatosis, is a rare inflammatory condition. The exact pathogenesis of Sweet syndrome is unclear, however, autoimmune and inflammatory conditions including inflammatory bowel disease have been linked as underlying etiologies. Since its description, in 1964, there have been published less than fifty reports of Crohn's-associated Sweet syndrome. We report a 43-year-old male patient with a medical history of Crohn's disease who subsequently developed Sweet syndrome. Two years after the diagnosis of Crohn's disease the patient was administered a combo therapy with Infliximab and Azathioprine followed by deep remission. A few months later the patient manifested with skin lesions with histopathological findings suggestive of Sweet syndrome. Sweet syndrome, although rare, may occur as an extra-intestinal manifestation of Crohn's disease. This report illustrates the need for a thorough investigation of patients with Crohn's disease presenting with skin lesions. We hope it will add to the current literature and help understand this rare phenomenon in order to achieve a proper diagnosis.

Differentially Methylated Ultra-Conserved Regions Uc160 and Uc283 in Adenomas and Adenocarcinomas Are Associated with Overall Survival of Colorectal Cancer Patients.

: Deregulation of the transcribed ultra-conserved regions (T-UCRs) Uc160, Uc283, and Uc346 has been reported in colorectal cancer (CRC) recently. Here, we investigated promoter methylation of these T-UCRs during the adenoma-carcinoma sequence and their clinical significance in CRC patients. Methylation levels were assessed in CRC, adenomas, infiltrated lymph nodes, and metastatic tissue specimens. In situ hybridization was performed in representative tissue specimens. T-UCRs expression levels were also evaluated in HT-29 colon cancer cells before and after the acquired resistance to 5-fluorouracil (5-FU) and oxaliplatin. A gradual increase in T-UCRs methylation levels from hyperplastic polyps to adenomas and to in situ carcinomas (ISC) and a gradual decrease from ISC to infiltrative and metastatic carcinomas was observed (p < 0.001 for Uc160 and Uc283, p = 0.018 for Uc346). Uc160 and Uc283 methylation was associated with the grade of dysplasia in adenoma specimens (p = 0.034 and p = 0.019, respectively). Furthermore, higher Uc160 methylation, mainly in stage III and IV patients, was related to improved overall survival (OS) in univariate (p = 0.009; HR, 0.366) and multivariate analysis (p = 0.005; HR, 0.240). Similarly, higher methylation of Uc283 was associated with longer OS (p = 0.030). Finally, T-UCRs expression was significantly reduced in HT-29 cells after resistance to chemotherapy. This study suggests that promoter methylation of Uc160, Uc283, and Uc346 is altered during CRC development and that Uc160 and Uc283 methylation may have prognostic significance for CRC patients.

Expression of α-Defensins, CD20+ B-lymphocytes, and Intraepithelial CD3+ T-lymphocytes in the Intestinal Mucosa of Patients with Liver Cirrhosis: Emerging Mediators of Intestinal Barrier Function.

AIM: The present study investigates the role of innate and adaptive immune system of intestinal mucosal barrier function in cirrhosis. METHODS: Forty patients with decompensated (n = 40, group A), 27 with compensated cirrhosis (n = 27, group B), and 27 controls (n = 27, group C) were subjected to duodenal biopsy. Expression of α-defensins 5 and 6 at the intestinal crypts was evaluated by immunohistochemistry and immunofluorescence. Serum endotoxin, intestinal T-intraepithelial, and lamina propria B-lymphocytes were quantified. RESULTS: Cirrhotic patients presented higher endotoxin concentrations (p < 0.0001) and diminished HD5 and HD6 expression compared to healthy controls (p = 0.000287, p = 0.000314, respectively). The diminished HD5 and HD6 expressions were also apparent among the decompensated patients compared to compensated group (p = 0.025, p = 0.041, respectively). HD5 and HD6 expressions were correlated with endotoxin levels (r = -0.790, p < 0.0001, r = - 0.777, p < 0.0001, respectively). Although intraepithelial T-lymphocytes were decreased in group A compared to group C (p = 0.002), no notable alterations between groups B and C were observed. The B-lymphocytic infiltrate did not differ among the investigated groups. CONCLUSIONS: These data demonstrate that decreased expression of antimicrobial peptides may be considered as a potential pathophysiological mechanism of intestinal barrier dysfunction in liver cirrhosis, while remodeling of gut-associated lymphoid tissue as an acquired immune response to bio-pathogens remains an open field to illuminate.

Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their value for detection of adenomas and adenocarcinomas.

Expression of Transcribed Ultraconserved Regions (T-UCRs) is often deregulated in cancer. The present study assesses the expression and methylation of three T-UCRs (Uc160, Uc283 and Uc346) in colorectal cancer (CRC) and explores the potential of T-UCR methylation in circulating DNA for the detection of adenomas and adenocarcinomas. Expression levels of Uc160, Uc283 and Uc346 were lower in neoplastic tissues from 64 CRC patients (statistically significant for Uc160, p<0.001), compared to non-malignant tissues, while methylation levels displayed the inverse pattern (p<0.001, p=0.001 and p=0.004 respectively). In colon cancer cell lines, overexpression of Uc160 and Uc346 led to increased proliferation and migration rates. Methylation levels of Uc160 in plasma of 50 CRC, 59 adenoma patients, 40 healthy subjects and 12 patients with colon inflammation or diverticulosis predicted the presence of CRC with 35% sensitivity and 89% specificity (p=0.016), while methylation levels of the combination of all three T-UCRs resulted in 45% sensitivity and 74.3% specificity (p=0.013). In conclusion, studied T-UCRs' expression and methylation status are deregulated in CRC while Uc160 and Uc346 appear to have a complicated role in CRC progression. Moreover their methylation status appears a promising non-invasive screening test for CRC, provided that the sensitivity of the assay is improved.

Propranolol reduces systemic oxidative stress and endotoxemia in cirrhotic patients with esophageal varices.

BACKGROUND: The aim of the study was to investigate the effect of propranolol on systemic oxidative stress and endotoxemia in patients with liver cirrhosis and clinically significant portal hypertension evidenced by the presence of esophageal varices. METHODS: Fourteen patients with liver cirrhosis and esophageal varices, not previously been treated with non-selective beta-blockers (NSBB), were prospectively started on propranolol and followed up for three months. Serum early and late lipid peroxidation products (lipid hydroperoxides [LOOH] and malondialdehyde [MDA], respectively), and endotoxin concentrations in peripheral blood were measured. Fourteen age- and sex-matched healthy individuals were used as controls. RESULTS: Patients with liver cirrhosis presented significantly higher systemic oxidative stress and endotoxin concentrations compared to healthy controls (P<0.001). Propranolol treatment for one month significantly reduced serum MDA (P<0.05), LOOH (P<0.01), and endotoxin levels (P<0.01) compared to pre-treatment values, whilst LOOH reached control levels. At three months of propranolol treatment, serum LOOH did not differ significantly from the one-month values, whilst serum endotoxin and MDA levels were further reduced between 3- and 1-month period (P<0.05 and P<0.01, respectively), with the latter reaching control levels. Amelioration of systemic endotoxemia at the one- and three-month follow-up intervals (compared to pre-treatment values) was not correlated with the respective reductions in serum MDA and LOOH. CONCLUSIONS: This is the first study to show that NSBB treatment in liver cirrhosis exerts a significant systemic antioxidant action. This effect seems to be, at least partly, independent of their beneficial effects on intestinal barrier function and endotoxemia.

Patient Radiation Doses in Therapeutic Endoscopic Retrograde Cholangiopancreatography in Patras and the Key Role of the Operator.

The patient radiation doses, in conjunction with the operator experience, in therapeutic endoscopic retrograde cholangiopancreatography (ERCP) procedures, performed in our hospital, were obtained. Ninety-six patients participated in the study and were divided into 3 groups, based on the operator experience. The dosemetric indices, fluoroscopy time (FT), cumulative dose (Ka,r) and air kerma-area product (PKA), were collected. For the total and weight banding group the third quartile values of the distribution of FT, Ka,r and PKA were 2.90 and 2.92 min, 6.89 and 6.93 mGy and 1.84 and 1.85 Gycm2, respectively, and were comparative or significantly lower than the corresponding values previously reported. Taking as a criterion the operator, the differences in the patient radiation doses were statistically significant, with the highest dose recorded for the operator of the lowest experience degree. The values obtained could contribute in establishing local and national diagnostic reference levels and in optimising ERCP procedure.

PATIENT DOSE DURING THERAPEUTIC ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY PROCEDURE.

Endoscopic retrograde cholangiopancreatography (ERCP) is a standard technique for the diagnosis and treatment of disorders of the pancreas or bile ducts. The aim of this study was the measurement of the radiation dose to patients during therapeutic ERCP procedures, in order to estimate the patient effective dose (ED). Fifteen patients were studied using a fluoroscopy system equipped with automatic brightness control and pulse fluoroscopy mode. Fluoroscopy time (FT), cumulative dose (Ka,r) and air kerma-area product (PKA) were collected for ERCP procedures. The ED was calculated from PKA values. The FT was ranged from 0.68 to 5.57 min, with the mean value of 2.50 min; the Ka,r was ranged from 2.22 to 19.10 mGy, with the mean value of 7.71 mGy; and the PKA was ranged between 0.59 and 5.10 Gycm2, with the mean value of 2.03 Gycm2. The ED ranged from 0.11 to 0.97 mSv, whilst the mean and median ED values were 0.39 and 0.32 mSv, respectively. FT and radiation dose to the patients were either comparative or significantly lower than those previously reported.

OPTIMISATION OF PATIENT DOSE AND IMAGE QUALITY IN ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY: A PHANTOM-BASED EVALUATION.

A phantom-based study is presented aiming to optimise patient dose and image quality (IQ) in endoscopic retrograde cholangiopancreatography procedures, utilising a fluoroscopy system equipped with a flat panel detector. The patient thickness was simulated with various polymethyl methacrylate slabs, whilst IQ was evaluated using the Leeds test object. The main factors evaluated were phantom thickness, distance between phantom and detector, field of view and pulse rate. For all these factors, the dosemetric indices, entrance surface air kerma (ESAK) rate and ESAK per pulse, as well as the IQ parameters, signal-to-noise ratio and high contrast spatial resolution, were measured. Based on these measurements, the figure of merit (FOM) was estimated. The FOM and ESAK rate values indicated the optimum combination of the factors evaluated which could provide adequate clinical information, assuring minimum patient dose.

Intestinal barrier dysfunction in cirrhosis: Current concepts in pathophysiology and clinical implications.

The intestinal lumen is a host place for a wide range of microbiota and sets a unique interplay between local immune system, inflammatory cells and intestinal epithelium, forming a physical barrier against microbial invaders and toxins. Bacterial translocation is the migration of viable or nonviable microorganisms or their pathogen-associated molecular patterns, such as lipopolysaccharide, from the gut lumen to the mesenteric lymph nodes, systemic circulation and other normally sterile extraintestinal sites. A series of studies have shown that translocation of bacteria and their products across the intestinal barrier is a commonplace in patients with liver disease. The deterioration of intestinal barrier integrity and the consulting increased intestinal permeability in cirrhotic patients play a pivotal pathophysiological role in the development of severe complications as high rate of infections, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, variceal bleeding, progression of liver injury and hepatocellular carcinoma. Nevertheless, the exact cellular and molecular mechanisms implicated in the phenomenon of microbial translocation in liver cirrhosis have not been fully elucidated yet.

Intestinal mucosal proliferation, apoptosis and oxidative stress in patients with liver cirrhosis.

BACKGROUND: Intestinal mucosal barrier dysfunction in liver cirrhosis and its implicated mechanisms is of great clinical importance because it is associated with the development of serious complications from diverse organs through promotion of systemic endotoxemia. AIM: The present study was designed to investigate whether enterocytes' proliferation, apoptosis and intestinal oxidative stress are altered in the intestinal mucosa of patients with compensated and decompensated liver cirrhosis. MATERIAL AND METHODS: Twelve healthy controls (group A) and twenty four cirrhotic patients at a compensated (n = 12, group B) or decompensated condition (n = 12, group C) were subjected to duodenal biopsy. In intestinal specimens mucosal apoptotic and mitotic activity and their ratio were recorded by means of morphological assessment and mucosal lipid hydroperoxides were measured. Plasma endotoxin concentration, an index of gut barrier function, was also determined. RESULTS: Cirrhotic patients presented significantly higher serum endotoxin concentrations as compared to healthy controls (P < 0.001), whilst endotoxemia was higher in decompensated disease (P < 0.05 vs. compensated cirrhosis). Intestinal mucosal mitotic count was significantly lower in patients with compensated and decompensated cirrhosis compared to controls (P < 0.01, respectively), whilst a trend towards increased apoptosis was recorded. The mitotic/apoptotic ratio was significantly reduced in groups B (P < 0.05) and C (P < 0.01) as compared to controls. Intestinal lipid peroxidation was significantly increased in decompensated cirrhotics (P < 0.001 vs. groups A and B). CONCLUSIONS: The present study demonstrates for the first time that human liver cirrhosis is associated with decreased intestinal mucosal proliferation and proliferation/apoptosis ratio even at early stages of cirrhosis and increased intestinal oxidative stress in advanced liver disease.

Altered intestinal tight junctions' expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability.

BACKGROUND: Increased intestinal permeability in cirrhosis exerts a pivotal role in the pathogenesis of spontaneous bacterial peritonitis and other complications of cirrhosis through promotion of systemic endotoxemia. This study was designed to investigate whether the expression of tight junction (TJ) proteins, which regulate gut paracellular permeability, is altered in the intestinal mucosa of patients with liver cirrhosis and study its potential association with the stage of liver disease and the development of systemic endotoxemia. DESIGN: Twenty-four patients with cirrhosis at a decompensated (n = 12, group A) or compensated condition (n = 12, group B) and 12 healthy controls (group C) were subjected to duodenal biopsy. The expression of the TJ proteins occludin and claudin-1 in the intestinal epithelium was evaluated by immunohistochemistry. Plasma endotoxin concentrations were also determined. RESULTS: Patients with cirrhosis presented significantly higher serum endotoxin concentrations as compared to healthy controls (P < 0·001), whilst endotoxemia was higher in decompensated disease (P < 0·05 vs. compensated cirrhosis). Patients with decompensated and compensated cirrhosis presented significantly reduced expression of occludin and claudin-1 as compared to controls (P < 0·01, respectively). These alterations were significantly more pronounced in decompensated patients as compared to compensated (P < 0·05). Regarding occludin, in patients with cirrhosis, a specific pattern of expression in the intestinal epithelium was observed, with a gradually increasing loss of expression from crypt to tip of the villi. Occludin and claudin-1 expression were inversely correlated with Child-Pugh score (P < 0·001), the grade of oesophageal varices (P < 0·01) and endotoxin concentrations (P < 0·001). CONCLUSIONS: This study demonstrates for the first time that human liver cirrhosis induces significant alterations in enterocytes' TJs. These changes might represent an important cellular mechanism for intestinal barrier dysfunction and hyperpermeability in patients with liver cirrhosis.

Intestinal epithelial cell proliferation, apoptosis and expression of tight junction proteins in patients with obstructive jaundice.

BACKGROUND: Intestinal hyperpermeability has been repeatedly confirmed in patients with obstructive jaundice and is considered a pivotal factor in the development of septic and renal complications in these patients. However, little is known on the mechanism(s) leading to this phenomenon. This study was undertaken to investigate the cellular and subcellular intestinal alterations in patients with obstructive jaundice. DESIGN: Sixteen patients with obstructive jaundice of malignant (n = 8, group A) or benign (n = 8, group B) aetiology, without concomitant cholangitis, and eight healthy controls (group C) were subjected to duodenal biopsy distal to the ampulla of Vater. Specimens were examined histologically and the apoptotic activity in the cryptal epithelium was recorded. Epithelial proliferation was evaluated by immunohistochemical expression of Ki67 antigen. The expression of the tight junction (TJ) proteins occludin, claudin-1, claudin-4 and claudin-7 in the intestinal epithelium was also evaluated by immunohistochemistry. RESULTS: Patients with malignant or benign obstructive jaundice presented significantly decreased intestinal epithelial cell proliferation rates compared with controls (P < 0·05), whereas no differences were detected in apoptotic activity. In a semiquantitative analysis of TJ protein expression, occludin, claudin-1 and -7 were significantly decreased (P < 0·001), whereas claudin-4 was significantly increased (P < 0·01) in jaundiced patients and their distribution was altered. No differences were detected between patients with malignant or benign obstructive jaundice for all intestinal barrier parameters studied. CONCLUSION: Decreased enterocyte proliferation and altered TJ protein expression might represent important mechanisms for intestinal barrier dysfunction and hyperpermeability in patients with extrahepatic cholestasis. The potential pharmacological modulation of these factors may lead to better control of intestinal permeability in the jaundiced patient with improved clinical outcome.

Pentoxifylline: a first line treatment option for severe alcoholic hepatitis and hepatorenal syndrome?

Although favourable results of pentoxifylline (PTX) used in treatment of severe alcoholic hepatitis patients with a Maddrey discriminant function score > or = 32 have been previously reported, it is not currently recommended as a first line treatment for alcoholic hepatitis owing to lack of evidence for its efficacy as compared to the standard treatment with corticosteroids. In a very recent issue of World Journal of Gastroenterology, Dr. De BK and colleagues compared for the first time the two treatment modalities head to head in a randomized controlled study, demonstrating the advantage of PTX over corticosteroids in terms of patients' survival and risk-benefit profile. The advantage of PTX over corticosteroids in survival of patients with severe alcoholic hepatitis was found to be related to the prevention of hepatorenal syndrome in their study. This study raises the question of the use of PTX as a standard treatment for severe alcoholic hepatitis. Considering the fact that PTX presented a spectacular efficiency in prevention of hepatorenal syndrome in their study as well as that previous studies have shown that this effect is possibly related to a primary renoprotective action because it is irrelevant of tumor necrosis factor-alpha synthesis inhibition or improved liver function, we tempted to speculate that PXT might be an effective option for prevention and/or treatment of hepatorenal syndrome complicating other forms of advanced liver disease. This attractive theory remains to be elucidated by pressing future studies in view of the lack of effective treatment modalities for hepatorenal syndrome.

Management of Αcute Non-Variceal Upper Gastrointestinal Bleeding: Drugs, Endoscopic Hemostasis, or Both?

Acute upper gastrointestinal bleeding remains one of the most frequent and emergent conditions in everyday clinical practice and a challenge for doctors. Peptic ulcer is responsible for more than half of acute upper gastrointestinal bleeding and is the most frequent cause of serious non-variceal bleeding. Despite progress in diagnosis and management in these patients, the recurrence of bleeding remains an important problem. Several drugs and endoscopic techniques, alone or in combination, have been evaluated in many studies and there is presently enough experience in terms of their efficacy. Endoscopic hemostasis is more effective than any other therapeutic intervention in the treatment of patients with non-variceal upper gastrointestinal bleeding. In patients with high risk of rebleeding spots, the combination of endoscopic hemostasis with high dose proton pump inhibitors is the most effective strategy to reduce bleeding recurrences and the need for surgery.