Akito Iwasaki

Lubiprostone improves intestinal permeability in humans, a novel therapy for the leaky gut: A prospective randomized pilot study in healthy volunteers

Background and aims The barrier function of the small intestinal mucosa prevents the introduction of undesired pathogens into the body. Breakdown of this barrier function increases intestinal permeability. This has been proposed to induce not only gastrointestinal diseases, including inflammatory bowel disease and irritable bowel syndrome, but also various other diseases, including allergies, diabetes mellitus, liver diseases, and collagen diseases, which are associated with this so called “leaky gut syndrome.” As such, a method to prevent leaky gut syndrome would have substantial clinical value. However, no drugs have been demonstrated to improve disturbed intestinal permeability in humans to date. Therefore, we investigated whether a drug used to treat chronic constipation, lubiprostone, was effective for this purpose. Methods Healthy male volunteers were treated with lubiprostone (24 μg/day) for 28 days. Intestinal permeability was evaluated by measuring the lactulose-mannitol ratio (LMR) after administration of diclofenac and compared with an untreated group. The examination was conducted three times in total, i.e., at baseline before diclofenac administration and after 14 and 28 days of lubiprostone treatment. Blood endotoxin activity was also evaluated at the same time points. Results The final analysis was conducted on 28 subjects (14 in the lubiprostone group and 14 in the untreated group). The LMR after 28 days of treatment was significantly lower in the lubiprostone group than that in the untreated group (0.017 vs. 0.028, respectively; 95% confidence interval, −0.022–−0.0001; p = 0.049). Blood endotoxin activity exhibited almost no change over time in the lubiprostone and untreated groups and displayed no significant differences at any time point of examination. Conclusions This study is the first to report an improvement in leaky gut using an available drug in humans. The result suggests that lubiprostone may prevent and ameliorate “leaky gut syndrome”. However, a pivotal trial is needed to confirm our finding.

Feasibility of Endoscopic Papillary Large Balloon Dilation in Patients with Difficult Bile Duct Stones without Dilatation of the Lower Part of the Extrahepatic Bile Duct

Background/Aims There is no consensus for using endoscopic papillary large balloon dilation (EPLBD) in patients without dilatation of the lower part of the bile duct (DLBD). We evaluated the feasibility and safety of EPLBD for the removal of difficult bile duct stones (diameter ≥10 mm) in patients without DLBD. Methods We retrospectively reviewed the records of 209 patients who underwent EPLBD for the removal of bile duct stones from October 2009 to July 2014. Primary outcomes were the clearance rate and additional mechanical lithotripsy. Secondary outcomes were the incidence of complications and recurrence rate. Results Fifty-seven patients had DLBD (27.3%), and 152 did not have DLBD (72.7%). There were no significant differences in the overall success rate or the use of mechanical lithotripsy. Success rate during the first session and procedure time were better in the DLBD than the without-DLBD group (75.7% vs 66.7%, 48.1±23.0 minutes vs 58.4±31.7 minutes, respectively). As for complications, there were no significant differences in the incidence of pancreatitis, perforation or bleeding after endoscopic retrograde cholangiopancreatography. The recurrence rate did not differ significantly between the two groups. Conclusions EPLBD is a useful and safe method for common bile duct stone removal in patients without DLBD.

Stent placement above the sphincter of Oddi permits implementation of neoadjuvant chemotherapy in patients with initially unresectable Klatskin tumor

Background and study aims: Neoadjuvant chemotherapy (NAC) may lead to a successful margin-negative resection in patients with initially unresectable locally advanced Klatskin tumor (IULAKT). Use of removable plastic stents is preferable for the safe implementation of NAC in patients with IULAKT to reduce the risk of recurrent cholangitis. Our aim was to evaluate the efficacy associated with the use of plastic stents placed across the stenosis and above the papilla (above stent) during NAC. Patients and methods: In this study, we stratified the patients into two groups chronologically with respect to the period of stent placement: above stent group (n = 17) and across stent group (n = 23) (plastic stent across the sphincter of Oddi). Results: The median stent patency period was 99 days in the above stent group and 31 days in the across stent group (P < 0.0001). The number of stents (P = 0.017) and the rate of emerging undrained cholangitis areas (P = 0.025) were significantly reduced in the above stent group than the counterpart. Regarding time to recurrent biliary obstruction, the above stent group had a longer duration than the across stent group (log rank test, P = 0.004). Length of hospital stay was significantly shorter for the above stent group than the across stent group (P = 0.0475). Multivariate analysis revealed that above stent placement (odds ratio = 33.638, P = 0.0048) was significantly associated with stent patency over a period of 90 days. Conclusions: Above stent placement should be considered for the relief of biliary obstruction and potentially reduces the cost for patients with IULAKT scheduled to receive NAC.

Intravenous injection of low-dose flurbiprofen axetil for preventing post-ERCP pancreatitis in high-risk patients: An interim analysis of the trial

Background and study aims: Several meta-analyses and randomized control trials have demonstrated the efficacy of rectal nonsteroidal anti-inflammatory drugs for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). Diclofenac or indomethacin was administered at a dose of 100 mg in those studies, which may be too high for Asian population. In addition, rectal administration can be considered complicated. Patients and methods: This study was a prospective, randomized, placebo-controlled trial. Patients with a PEP risk score ≥ 1 were randomly assigned to receive intravenous injection of 50 mg flurbiprofen axetil (flurbiprofen group) or saline only (placebo group). The primary outcome was reduced PEP. The secondary outcome was amylase level after 2 hours of ERCP as a predictor of PEP. (Clinical Trials.gov, ID UMIN000011322) Results: In total, 144 patients were enrolled from August 2013 to March 2015. We performed an interim analysis of the first 100 patients: 47 received flurbiprofen axetil and 53 received placebo. PEP occurred in 11 patients (11 %): 2 of 47 (4.3 %) in the flurbiprofen group and 9 of 53 (17 %) in the placebo group (P = 0.042). Relative risk reduction was 62.4 %. Hyperamylasemia did not differ significantly (17.0 % vs. 26.4 %, P = 0.109). This analysis resulted in early termination of the study for ethical reasons. Conclusions: Intravenous injection of low-dose flurbiprofen axetil after ERCP can reduce the incidence of PEP in high-risk patients

Differential Diagnosis Between Proximal-Type IgG4-Related Sclerosing Cholangitis and Hilar Cholangiocarcinoma

Indeterminant hilar biliary strictures (IHB) such as IgG4-related sclerosing cholangitis (IgG4-SC) and Klatskin tumor are leading causes and needed to differentiate from each other. Majority of IgG4-SC can be diagnosed without difficulty according to the JHBPS criterion 2012 [1] based on Nakazawa classification [2]. IgG4-SC patients are often associated with other organ involvements such as the pancreas (AIP), major salivary grounds, and/or retroperitoneal organs [1]. IgG4-SC can be divided into two types: the major is IgG4-SC associated with AIP (AIP-SC), and the minor is isolated IgG4-SC (i-SC). Moreover, i-SC consists of intrahepatic/hilar type (proximal, i-SC) and intrapancreatic type, and the characteristic features were still unknown. Proximal-type IgG4-SC, especially Klatskin tumor mimicker, should be excluded because it could be controlled by steroid treatment; besides, Klatskin tumor would be treated by radical surgery or poor prognosis after conservative treatment [3]. Most proximal-type IgG4-SC are associated with AIP; on the other hand, i-SC is cumbersome to rule out cancer. Some proximal IgG4-SC developed as recurrence after remission of AIP. IgG4-SC affects deep lesion of mucosa beyond the epithelium with abundant IgG4-positive lymphoplasma cell infiltration with lateral lesion; besides, Klatskin tumor invades through the mucosa sometimes associated with skip lesion (Fig. 13.1). As endoscopic biopsy tried to detect cancer in the diagnosis of IgG4-SC, it could not evaluate and diagnose IgG4-SC because true lesion is located further in the deep lesion, in which biopsy could not reach the lesion under the mucosa [4]. Steroid trial would be a better option under the situation [1]. This article showed the tips on how to differentiate indeterminant strictures; IgG4-SC and Klastkin tumor in especially on the view point of imaging diagnosis and supplement role of steroid trial.