Contrast enhanced endoscopic ultrasound detects early therapy response following anti-TNF-therapy in patients with ulcerative colitis.

BACKGROUND AND AIM: Though colonoscopy plays a crucial role in assessing active ulcerative colitis (aUC), its scope is limited to the mucosal surface. Endoscopic ultrasound (EUS) coupled with contrast-enhancement (dCEUS) can precisely quantify bowel wall thickness and microvascular circulation, potentially enabling the quantitative evaluation of inflammation.We conducted a prospective, longitudinal study to assess therapy response using dCEUS in aUC patients undergoing treatment with adalimumab (ADA) or infliximab (IFX). METHODS: 30 ADA- and 15 IFX-treated aUC patients were examined at baseline and at 2, 6, 14 weeks of therapy and 48 weeks of follow-up. Bowel wall thickness (BWT) was measured by EUS in the rectum. Vascularity was quantified by dCEUS using Rise Time (RT) and Time To Peak (TTP). Therapy response was defined after 14 weeks using the Mayo Score. RESULTS: Patients with aUC displayed a mean BWT of 3.9±0.9 mm. In case of response to ADA/IFX a significant reduction in BWT was observed after 2 weeks (p=0.04), whereas non-responders displayed no significant changes. The TTP was notably accelerated at baseline and significantly normalised by week 2 in responders (p=0.001), while non-responders exhibited no significant alterations (p=0.9). At week 2, the endoscopic Mayo score did not exhibit any changes, thus failing to predict treatment responses. CONCLUSION: dCEUS enables the early detection of therapy response in patients with aUC, which serves as a predictive marker for long term clinical success. Therefore, dCEUS serves as a diagnostic tool for assessing the probability of future therapy success.

Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc).

Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr -/-) mice on a high-fat, high-cholesterol diet independently of low-density lipoprotein (LDL) cholesterol metabolism. Therefore, we allowed compassionate use of olamkicept (600 mg intravenously biweekly for 10 weeks) in a patient with very-high-risk ASCVD. Despite optimal LDL cholesterol under maximum tolerated lipid-lowering treatment, the patient had a remaining very high risk for future cardiovascular events related to significant arterial wall inflammation with lipoprotein (a) [Lp(a)]-cholesterol as the main contributor. 18Fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) measurements were performed before and after the treatment period. Olamkicept reduced arterial wall inflammation in this patient without interfering with lipoprotein metabolism. No clinical or laboratory side effects were observed during or after treatment with olamkicept. Our findings in this patient matched the results from our mechanistic study in Ldlr -/- mice, which were extended by additional analyses on vascular inflammation. Olamkicept may be a promising option for treating ASCVD independently of LDL cholesterol metabolism. A Phase II trial of olamkicept in ASCVD is currently being prepared.

Extensive intrathoracic and intraperitoneal splenosis mimicking mesothelioma: a case report.

BACKGROUND: Splenosis is the heterotopic autotransplantation of splenic tissue after severe splenic trauma and/or splenectomy. The epidemiology is elusive, but splenosis is frequently misdiagnosed as malignant tumors of gastrointestinal, gynecological, or hematological origin before the correct diagnosis is ultimately found. We herein report a rare case of combined, extensive intraabdominal and intrathoracic splenosis initially presenting as pleural mesothelioma. CASE PRESENTATION: A 63-year-old Caucasian male presented with dyspnea and recurring thoracic pain. Initial X-ray and computed tomography scans showed disseminated intrathoracic and intraabdominal lesions. Consequently, thoracoabdominal mesothelioma or a polytopically metastasized cancer of unknown origin was suspected. A thorough examination of the patient's medical history and contrast-enhanced ultrasound by a skilled examiner revealed the diagnosis of extensive abdominal and thoracic splenosis as a consequence of an abdominal gunshot wound with a ruptured diaphragm several decades earlier. Timely diagnosis by noninvasive measures prevented the patient from potential complications of harmful diagnostic procedures, including nuclear imaging and biopsies. The patient is currently treated for hepatitis C and chronic obstructive lung disease, whereas no specific treatment for splenosis is required. CONCLUSIONS: We present a case of rare intrathoracic and intraperitoneal splenosis mimicking mesothelioma. Contrast-enhanced ultrasound and thorough patient history were used for diagnosis and prevented this patient from having to undergo potentially harmful diagnostics. Splenosis can occur after splenic trauma and, consequently, needs to be considered as a rare differential diagnosis to malignant tumors of various origins when a matching patient history is obtained.

Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus.

UNLABELLED: The sterolin locus (ABCG5/ABCG8) confers susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. Genetic mapping utilized patient samples from Germany (2,808 cases, 2,089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls), and China (280 cases, 244 controls). Analysis of allelic imbalance in complementary DNA (cDNA) samples from human liver (n = 22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [(3) H]-cholesterol export assays, analysis of protein expression, and localization of allelic constructs. Through fine mapping in German and Chilean samples, an ∼250 kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding single nucleotide polymorphisms. Subsequent mutation detection and genotyping yielded two disease-associated variants: ABCG5-R50C (P = 4.94 × 10(-9) ) and ABCG8-D19H (P = 1.74 × 10(-10) ) in high pairwise linkage disequilibrium (r(2) = 0.95). [(3) H]-cholesterol export assays of allelic constructs harboring these genetic candidate variants demonstrated increased transport activity (3.2-fold, P = 0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (P = 0.018), Chilean (P = 0.030), and Chinese (P = 0.040) patient samples. CONCLUSION: This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation, thereby drawing a link between "postgenomic" and "pregenomic" pathophysiological knowledge about this common complex disorder. (HEPATOLOGY 2012).

Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians.

UNLABELLED: A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M148I) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M148I) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n = 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n = 210; OR 2.79; P(genotype) = 1.2 × 10(-5) ; P(allelic) = 1.6 × 10(-6) ) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n = 219; OR 2.33; P(genotype) = 0.0085; P(allelic) = 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/week (OR 4.75; P(genotype) = 0.040; P(allelic) = 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P(combined) = 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%. CONCLUSION: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians.

Chronic portal vein thrombosis: transcapsular hepatic collateral vessels and communicating ectopic varices.

PURPOSE: To assess patients with chronic portal vein thrombosis (PVT) with respect to transcapsular collateral veins, the communication between these veins and ectopic varices, and the cause of PVT. MATERIALS AND METHODS: This study was approved by the institutional review committees, and written informed consent was obtained. From November 2003 to March 2008, 145 consecutive patients with chronic PVT due to a variety of causes were assessed for transcapsular collaterals and ectopic varices with ultrasonography (US). Analysis of contingency tables was performed with the Fisher exact test. RESULTS: Transcapsular collaterals were detected in 15 (10.3%) of 145 patients with chronic PVT. They were restricted to patients with a history of hepatobilary surgery, severe pancreatitis, or abdominal surgery (n = 21) and were not detected in patients with liver cirrhosis, systemic coagulopathy, extrahepatic malignancy, idiopathic PVT, chronic pancreatitis, or infectious or inflammatory diseases (n = 124) (P < .001). Ectopic varices were infrequent in 70 patients with liver cirrhosis (n = 2, 3%) but were common in 14 patients with PVT after hepatobiliary surgery (n = 9, 64%) (P < .001, odds ratio = 21.4). Direct communication between transcapsular collaterals and ectopic varices was visible in all nine patients in this cohort. In eight of these patients, ectopic varices were found to be the bleeding source in gastrointestinal hemorrhage. CONCLUSION: Transcapsular collaterals frequently occur in patients with chronic PVT due to hepatobilary surgery or necrotizing pancreatitis. They are associated with ectopic varices; therefore, awareness of transcapsular collaterals in this patient subgroup will help to localize ectopic varices as potential bleeding source.

Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition.

BACKGROUND & AIMS: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones. METHODS: Loci that were identified in a meta-analysis to attain a genome-wide significance level of a P value less than 1.0×10(-7) (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German choleystecomized individuals and 1121 controls and was replicated in 210 cases and 496 controls from South America. RESULTS: By using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1; P = .003), rs4149056 (SLCO1B1; P = .003), and rs4149000 (SLCO1A2; P = .015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model. UGT1A1 (rs6742078; P = .018) was associated with overall gallstone risk. In a sex-stratified analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P = 2.1×10(-7); odds ratio(recessive), 2.34; P(women) = .47). The sex-specific association of rs6742078 was confirmed in samples from South America (P(men) = .046; odds ratio(recessive), 2.19; P(women) = .96). CONCLUSIONS: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required regarding the sex-specific physiology of bilirubin and bile acid metabolism. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men.

Terminal part of thoracic duct: high-resolution US imaging.

PURPOSE: To assess ultrasonographic (US) examination results of the cervical part of the thoracic duct, to provide standard diameters, and to evaluate the diameter of the cervical thoracic duct in certain diseases suspected to involve an abnormal load of chyle (liver, heart, and inflammatory bowel diseases). MATERIALS AND METHODS: The study was approved by the institutional review committee, and written informed consent was obtained from all subjects. Diameter and variations of the cervical thoracic duct were assessed by using US in 265 healthy volunteers (age range, 21-82 years) from a population-based study, in 196 subjects with documented liver cirrhosis (age range, 19-87 years), in 68 subjects with chronic hepatitis (age range, 17-73 years), in 39 subjects with congestive heart failure (age range, 46-85 years), and in 17 subjects with inflammatory bowel disease (age range, 18-66 years). US examinations were performed with high-resolution linear probes (7-12 MHz). RESULTS: A standard imaging approach guided by anatomic structures was established. Dynamic imaging of the chyle flow and valve function was possible. The thoracic duct was visualized in 564 (96%) of 585 examinations. The average thoracic duct diameter in healthy volunteers was 2.5 mm, which was independent of the subjects' age. The diameter was significantly higher in subjects with congestive heart failure (6.3 mm, P < .0001) and liver cirrhosis (5.6 mm, P < .0001). Anatomic variations were present in 27% of subjects. CONCLUSION: High-resolution US with linear probes allows assessment of the cervical thoracic duct with high detection rates. Recognition of local anatomy, diameter, and chyle flow may aid functional assessment.

A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.

With an overall prevalence of 10-20%, gallstone disease (cholelithiasis) represents one of the most frequent and economically relevant health problems of industrialized countries. We performed an association scan of >500,000 SNPs in 280 individuals with gallstones and 360 controls. A follow-up study of the 235 most significant SNPs in 1,105 affected individuals and 873 controls replicated the disease association of SNP A-1791411 in ABCG8 (allelic P value P(CCA) = 4.1 x 10(-9)), which was subsequently attributed to coding variant rs11887534 (D19H). Additional replication was achieved in 728 German (P = 2.8 x 10(-7)) and 167 Chilean subjects (P = 0.02). The overall odds ratio for D19H carriership was 2.2 (95% confidence interval: 1.8-2.6, P = 1.4 x 10(-14)) in the full German sample. Association was stronger in subjects with cholesterol gallstones (odds ratio = 3.3), suggesting that His19 might be associated with a more efficient transport of cholesterol into the bile.

Investigation of the Lith1 candidate genes ABCB11 and LXRA in human gallstone disease.

Genetic susceptibility in the causation of gallbladder diseases was recognized as early as 1937. A major gallstone susceptibility locus (Lith1) was identified in 1995 by quantitative trait locus mapping in mice. Two attractive positional and functional candidate genes in LXRA and ABCB11 are located in this interval. ABCB11 is associated with progressive familial cholestasis. This study was undertaken to investigate LXRA and ABCB11 as candidate genes for gallstone disease in humans. Eight hundred and ten patients who underwent cholecystectomy for symptomatic gallstone disease (median age of onset, 50 years) were compared with 718 sex-matched control individuals. Control individuals were sonographically free of gallstones. Haplotype tagging and all known coding single nucleotide polymorphisms (SNPs) were genotyped for ABCB11 (n=29) and LXRA (n=10). The investigated high-risk patient sample provides a power of greater than 80% for the detection of odds ratios down to 1.55. No evidence of association of the two genes in the single point tagging markers, coding variants or in the sliding window haplotype analysis was detected (all nominal single-point P values>or=.08). In conclusion, in the investigated German sample, no evidence of association of ABCB11 and LXRA to gallstone susceptibility was detected. The gallstone trait is not allelic to progressive familial cholestasis at the ABCB11 locus. Systematic fine mapping of the Lith1 region is required to identify the causative genetic variants for gallstone in mice and humans.