Markus Casper

Ursodeoxycholic Acid and Diets Higher in Fat Prevent Gallbladder Stones During Weight Loss: A Meta-analysis of Randomized Controlled Trials

BACKGROUND & AIMS The prevalence of gallstones is increasing in association with the obesity epidemic, but rapid weight loss also increases the risk of stone formation. We conducted a systematic review of the efficacy of strategies to prevent gallbladder stones in adults as they lose weight. METHODS Randomized controlled trials of nonsurgical strategies to prevent gallstones were identified by electronic and manual searches. Our final analysis included 13 trials, comprising 1836 participants undergoing weight loss through dieting (8 trials) or bariatric surgery (5 trials). The trials compared ursodeoxycholic acid (UDCA) or high-fat weight loss diets with control interventions. We performed random-effects meta-analyses and evaluated heterogeneity and bias with subgroup, sensitivity, regression, and sequential analysis. RESULTS UDCA reduced the risk of ultrasound-verified gallstones compared with control interventions (risk ratio, 0.33; 95% confidence interval [CI], 0.18-0.60; number needed to treat, 9). This effect was significantly larger in trials of diets alone (risk ratio, 0.17; 95% CI, 0.11-0.25) than in trials of patients who underwent bariatric surgery (risk ratio, 0.42; 95% CI, 0.21-0.83) (test for subgroup differences, P =.03). UDCA reduced the risk of cholecystectomy for symptomatic stones (risk ratio, 0.20; 95% CI, 0.07-0.53). Diets high in fat content also reduced gallstones, compared with those with low fat content (risk ratio, 0.09; 95% CI, 0.01-0.61). The meta-analyses were confirmed in trials with a low risk of bias but not in sequential analysis. No additional beneficial or harmful outcomes were identified. CONCLUSIONS On the basis of a meta-analysis of randomized controlled trials, during weight loss, UDCA and/or higher dietary fat content appear to prevent formation of gallstones.

MUTYH gene expression and alternative splicing in controls and polyposis patients

Mutational loss of the human DNA repair gene MUTYH in the germline predisposes for colorectal polyposis and cancer, a recessively heritable disease called MUTYH‐associated polyposis. The MUTYH gene shows heavy alternative splicing, but the transcripts relevant for biological function and cancer prevention have not been determined. This knowledge is required to assess the consequences that germline variants of unknown functional significance may have. We therefore quantified expression and investigated patterns of alternative splicing in control individuals, tissue samples, and carriers of two frequent germline alterations. MUTYH expression differed organ dependently, correlating with proliferative activity. Alternative first exons were used tissue specifically; transcripts for mitochondrial proteins predominated in muscle tissues, while ascending colon and testes showed the highest fractions of transcripts for nuclear proteins. Colon cancer cell lines produced predominant transcripts for nuclear protein. Exon skipping was frequent and governed by splice‐site quality. Five transcripts were found to encode the biologically relevant products of the MUTYH gene. Carriers of the disease‐causing mutation c.1187G>A (p.Gly396Asp) showed normal transcript composition, but the frequent single‐nucleotide polymorphism rs3219468:G>C largely reduced one transcript species of MUTYH. Since this alteration decreases protein production of the gene, an increased cancer risk for compound heterozygous carriers is possible. Hum Mutat 33:1067–1074, 2012.

Cancer risk in chronic hepatitis B: Do genome-wide association studies hit the mark?

To identify susceptibility variants for hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC), we conducted a genome‐wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV‐related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 × 10−18). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV‐related HCC, and suggest that KIF1B‐, UBE4B‐ or PGD‐related pathways might be involved in the pathogenesis of this malignancy.

MUTYH hotspot mutations in unselected colonoscopy patients: MUTYH hotspot mutations in unselected colonoscopy patients

Aim  Biallelic MutY human homologue (MUTYH) germline mutations predispose to recessively inherited adenomatous polyposis, designated MUTYH‐associated polyposis (MAP), and colorectal cancer (CRC). The hotspot mutations p.Y179C and p.G396D account for the majority of pathogenic variants of MUTYH in Caucasians. Our aim was to evaluate the prevalence of MUTYH mutations in a prospective cohort of unselected patients with different colorectal diseases.

The INCA trial (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) : study protocol for a randomized controlled trial

BackgroundPatients with liver cirrhosis have a highly elevated risk of developing bacterial infections that significantly decrease survival rates. One of the most relevant infections is spontaneous bacterial peritonitis (SBP). Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis. The aim of the INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) trial is to investigate whether survival of this genetically defined high-risk group of patients with cirrhosis defined by the presence of NOD2 variants is improved by primary antibiotic prophylaxis of SBP.Methods/DesignThe INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms (arm 1: norfloxacin 400 mg once daily; arm 2: placebo once daily; 12-month treatment and observational period). Balanced randomization of 186 eligible patients with stratification for the protein content of the ascites (<15 versus ≥15 g/L) and the study site is planned. In this multicenter national study, patients are recruited in at least 13 centers throughout Germany. The key inclusion criterion is the presence of a NOD2 risk variant in patients with decompensated liver cirrhosis. The most important exclusion criteria are current SBP or previous history of SBP and any long-term antibiotic prophylaxis. The primary endpoint is overall survival after 12 months of treatment. Secondary objectives are to evaluate whether the frequencies of SBP and other clinically relevant infections necessitating antibiotic treatment, as well as the total duration of unplanned hospitalization due to cirrhosis, differ in both study arms. Recruitment started in February 2014.DiscussionPreventive strategies are required to avoid life-threatening infections in patients with liver cirrhosis, but unselected use of antibiotics can trigger resistant bacteria and worsen outcome. Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed. This trial meets this need by suggesting stratified prevention based on genetic risk assessment. To our knowledge, the INCA trial is first in the field of hepatology aimed at rapidly transferring and validating information on individual genetic risk into clinical decision algorithms.Trial registrationsGerman Clinical Trials Register DRKS00005616. Registered 22 January 2014.EU Clinical Trials Register EudraCT 2013-001626-26. Registered 26 January 2015.

Hepatocellular carcinoma as extracolonic manifestation of Lynch syndrome indicates SEC63 as potential target gene in hepatocarcinogenesis.

Abstract Objective. Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes with microsatellite instability (MSI) as its molecular hallmark. Hepatocellular carcinoma (HCC) has not been considered part of the tumor spectrum. The aim was to provide a detailed molecular characterization of an HCC associated with Lynch Syndrome (Muir-Torre variant). Materials and methods. HCC samples were analyzed for MSI, MMR protein expression and coding microsatellite instability (cMSI). Since cMSI also affected SEC63 coding for an endoplasmic reticulum membrane protein with implications for intracellular protein translocation, its impact on hepatocyte growth control was assessed in an established short-term model. Recombinant inbred mouse lines (BXD) showing different basal SEC63 expression levels were treated with the chemocarcinogen diethylnitrosamine (DEN) intraperitoneally. Proliferation and apoptosis of hepatocytes were determined after 48 h using Ki67 and TUNEL assays. Results. The HCC was high-grade microsatellite unstable with loss of MSH2 expression. cMSI was detected in four genes (ASTE1, SEC63, TAF1B, TGFBR2). However, only TGFBR2 is known to be involved in hepatocarcinogenesis. When investigating the impact of SEC63 expression on hepatocyte growth control in the murine model, low hepatic expression correlated significantly (p < 0.05) with a decrease in apoptosis and increased proliferative activity. Conclusions. For the first time, an HCC with characteristic molecular features of association with Lynch syndrome is described. The pro-carcinogenic growth behavior of hepatocytes with low SEC63 expression in the murine model indicates a potential role for SEC63 in hepatocarcinogenesis in general, but this needs further functional validation.

Multidisciplinary treatment of desmoid tumours in Gardner’s syndrome due to a large interstitial deletion of chromosome 5q

BACKGROUND AND AIMS Classic autosomal-dominant familial adenomatous polyposis (FAP) is clinically defined by the development of hundreds to thousands of colorectal adenomas beginning in childhood and adolescence. A variant of FAP characterized by polyposis in combination with osteomas or soft tissue tumours is called Gardners syndrome. FAP is caused by germline inactivation of the APC (adenomatous polyposis coli) tumour-suppressor gene located on the long arm of chromosome 5 (5q21-5q22). Cytogenetically visible deletions of chromosome 5q encompassing APC have very rarely been reported. Here, we aimed to phenotypically and genetically characterize a patient with a heterozygous 5q deletion resulting in Gardners syndrome. METHODS AND RESULTS A 26-year-old female patient with mild mental handicap and dysmorphic features due to a cytogenetically visible deletion on chromosome 5q (microscopically estimated region 5q14-5q23) presented at our tertiary referral centre because of mild adenomatous polyposis (<500 polyps). Twenty months after prophylactic proctocolectomy with definitive ileostomy, three rapidly growing desmoids were observed. Tumour-associated complications necessitated a multidisciplinary approach including medical treatment, surgery and radiation therapy. The characterization of the deletion by comparative genomic hybridization identified a large 5q deletion expanding over a 20-Mb region (5q21.3-5q23.3) including the APC gene. CONCLUSION Chromosome deletions must be suspected in patients presenting with FAP together with mental handicap and dysmorphic features. This case also impressively shows that FAP-associated desmoids need multimodal treatment taking into account the patients individual symptoms, disease progression and tumour location.

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

OBJECTIVES: Variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O‐acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol‐related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC. METHODS: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol‐related cirrhosis and HCC and in 1165 controls with alcohol‐related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression. RESULTS: The development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55‐2.18], p = 1.85 × 10‐12) and TM6SF2 rs58542926 (ORadjusted 1.66 [1.30‐2.13], p = 5.13 × 10‐05), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (ORadjusted 1.04 [0.88‐1.24], p = 0.61) was not significant. The population‐attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined. CONCLUSIONS: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol‐related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk‐stratification of patients with alcohol‐related cirrhosis, and genotype‐guided screening algorithms would optimize patient care.

How to improve success rates of endoscopic management for buried bumper syndrome

Background Buried bumper syndrome (BBS) is a rare complication of percutaneous endoscopic gastrostomy. Complete BBS without visible parts of the inner bumper is a challenge for endoscopic treatment. Methods and Aims Data base analysis of all procedures performed at our tertiary university endoscopy center between 2000 and 2015 was conducted. Our aim was to improve the success rates of endoscopic treatment using a standardized approach and a pull-modification of the papillotome-based extraction technique in a prospective cohort. Results Retrospectively, 55 patients were identified (37 men; age 54 ± 16 years). The prospective series comprised 11 patients (8 men; age 63 ± 27 years). Patients with partial BBS were effectively treated by endoscopy in both cohorts (24/25 and 4/4 patients, respectively). For complete BBS (Cyrany grade 3), success rates of endoscopic therapy differed significantly between the cohorts (P = 0.017). In the retrospective cohort, only 38% of patients (9/24 patients) were successfully treated. In the prospective cohort, all six patients (deep-type in five cases) were managed without complications. Patients with extra-gastric tubes underwent primary surgery in both cohorts (six and one patients, respectively). Conclusion A structured approach improved success rates of endoscopic treatment. All patients with an internal bumper verified to lie within the gastric wall can be treated by an experienced investigator using a papillotome-based technique.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

Objective Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. Design We analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. Results The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). Conclusion The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.