Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study.

OBJECTIVE: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis. DESIGN: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina). RESULTS: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10-9, OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10-5, OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10-44). CONCLUSION: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

Artificial-intelligence-based decision support tools for the differential diagnosis of colitis.

BACKGROUND: Whereas Artificial Intelligence (AI) based tools have recently been introduced in the field of gastroenterology, application in inflammatory bowel disease (IBD) is in its infancies. We established AI-based algorithms to distinguish IBD from infectious and ischemic colitis using endoscopic images and clinical data. METHODS: First, we trained and tested a Convolutional Neural Network (CNN) using 1796 real-world images from 494 patients, presenting with three diseases (IBD [n = 212], ischemic colitis [n = 157], and infectious colitis [n = 125]). Moreover, we evaluated a Gradient Boosted Decision Trees (GBDT) algorithm using five clinical parameters as well as a hybrid approach (CNN + GBDT). Patients and images were randomly split into two completely independent datasets. The proposed approaches were benchmarked against each other and three expert endoscopists on the test set. RESULTS: For the image-based CNN, the GBDT algorithm and the hybrid approach global accuracies were .709, .792, and .766, respectively. Positive predictive values were .602, .702, and .657. Global areas under the receiver operating characteristics (ROC) and precision recall (PR) curves were .727/.585, .888/.823, and .838/.733, respectively. Global accuracy did not differ between CNN and endoscopists (.721), but the clinical parameter-based GBDT algorithm outperformed CNN and expert image classification. CONCLUSIONS: Decision support systems exclusively based on endoscopic image analysis for the differential diagnosis of colitis, representing a complex clinical challenge, seem not yet to be ready for primetime and more diverse image datasets may be necessary to improve performance in future development. The clinical value of the proposed clinical parameters algorithm should be evaluated in prospective cohorts.

Digital single-operator pancreatoscopy for the treatment of symptomatic pancreatic duct stones: a prospective multicenter cohort trial.

BACKGROUND: Digital single-operator pancreatoscopy (DSOP)-guided lithotripsy is a novel treatment modality for pancreatic endotherapy, with demonstrated technical success in retrospective series of between 88 % and 100 %. The aim of this prospective multicenter trial was to systematically evaluate DSOP in patients with chronic pancreatitis and symptomatic pancreatic duct stones. METHODS: Patients with symptomatic chronic pancreatitis and three or fewer stones ≥ 5mm in the main pancreatic duct (MPD) of the pancreatic head or body were included. The primary end point was complete stone clearance (CSC) in three or fewer treatment sessions with DSOP. Current guidelines recommend extracorporeal shock wave lithotripsy (ESWL) for MPD stones > 5 mm. A performance goal was developed to show that the CSC rate of MPD stones using DSOP was above what has been previously reported for ESWL. Secondary end points were pain relief measured with the Izbicki pain score (IPS), number of interventions, and serious adverse events (SAEs). RESULTS: 40 chronic pancreatitis patients were included. CSC was achieved in 90 % of patients (36/40) on intention-to-treat analysis, after a mean (SD) of 1.36 (0.64) interventions (53 procedures in total). The mean (SD) baseline IPS decreased from 55.3 (46.2) to 10.9 (18.3). Overall pain relief was achieved in 82.4 % (28/34) after 6 months of follow-up, with complete pain relief in 61.8 % (21/34) and partial pain relief in 20.6 % (7/34). SAEs occurred in 12.5 % of patients (5/40), with all treated conservatively. CONCLUSION: DSOP-guided endotherapy is effective and safe for the treatment of symptomatic MPD stones in highly selected patients with chronic pancreatitis. It significantly reduces pain and could be considered as an alternative to standard ERCP techniques for MPD stone treatment in these patients.

Deep learning-based detection of eosinophilic esophagitis.

BACKGROUND: For eosinophilic esophagitis (EoE), a substantial diagnostic delay is still a clinically relevant phenomenon. Deep learning-based algorithms have demonstrated potential in medical image analysis. Here we establish a convolutional neuronal network (CNN)-based approach that can distinguish the appearance of EoE from normal findings and candida esophagitis. METHODS: We trained and tested a CNN using 484 real-world endoscopic images from 134 subjects consisting of three classes (normal, EoE, and candidiasis). Images were split into two completely independent datasets. The proposed approach was evaluated against three trainee endoscopists using the test set. Model-explainability was enhanced by deep Taylor decomposition. RESULTS: Global accuracy (0.915 [95 % confidence interval (CI) 0.880-0.940]), sensitivity (0.871 [95 %CI 0.819-0.910]), and specificity (0.936 [95 %CI 0.910-0.955]) were significantly higher than for the endoscopists on the test set. Global area under the receiver operating characteristic curve was 0.966 [95 %CI 0.954-0.975]. Results were highly reproducible. Explainability analysis found that the algorithm identified the characteristic signs also used by endoscopists. CONCLUSIONS: Complex endoscopic classification tasks including more than two classes can be solved by CNN-based algorithms. Therefore, our algorithm may assist clinicians in making the diagnosis of EoE.

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

BACKGROUND AND AIMS: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

Isolated bacterial infection without decompensation has no impact on survival of compensated patients with cirrhosis.

BACKGROUND & AIMS: Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was to evaluate the impact of BI on the natural history of compensated cirrhosis. METHODS: We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI. RESULTS: About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline. CONCLUSIONS: In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.

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.

The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis.

BACKGROUND AND AIMS: Protein and organelle turnover by autophagy is a key component to maintain cellular homeostasis. Loss of the autophagy protein ATG16L1 is associated with reduced bacterial killing and aberrant interleukin-1ß production, perpetuating inflammation and carcinogenesis. Here we hypothesized that the functional p.T300A gene variant in ATG16L1 is associated with an increased risk for hepatocellular carcinoma (HCC) in cirrhosis. METHODS: A case-control study was performed using a prospective derivation cohort (107 patients with HCC and 101 controls) and an independent validation cohort (124 patients with HCC and 108 controls) of patients with cirrhosis of any aetiology. ATG16L1 p.T300A (rs2241880) and PNPLA3 p.I148M (rs738409) variants were determined by real-time PCR. RESULTS: The G allele of the ATG16L1 p.T300A variant was more frequent in patients with HCC compared to controls without HCC in the derivation cohort (0.62 vs. 0.51, P = .022) and in the validation cohort (0.59 vs. 0.50, P = .045). In combined analysis, the odds ratios (OR) were 1.76 (95% CI: 1.07-2.88) for G allele positivity and 2.43 (95% CI: 1.37-4.31) for p.T300A G allele homozygosity. This association was independent from the presence of a PNPLA3 variant, which was also associated with HCC (OR 2.10; 95% CI: 1.20-3.66), and it remained significant after adjustment for male sex, age and aetiology in multivariate analysis. CONCLUSION: The common germ-line ATG16L1 gene variant is a risk factor for HCC in patients with cirrhosis. Personalized strategies employing the genetic risk conferred by ATG16L1 and PNPLA3 may be used for risk-based surveillance in cirrhosis.

Correction: Genetic Variants in PNPLA3 and TM6SF2 Predispose to the Development of Hepatocellular Carcinoma in Individuals With Alcohol-Related Cirrhosis.

Author Pierre Deltenre, MD should appear in the author list in position 25, between Felix Braun and Thomas Berg. He should also have a PhD degree added to his name.

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.

A Variant of COL3A1 (rs3134646) Is Associated With Risk of Developing Diverticulosis in White Men.

BACKGROUND: Colonic diverticulosis is one of the most common gastroenterological disorders. Although diverticulosis is typically benign, many individuals develop diverticulitis or other aspects of diverticular disease. Diverticulosis is thought to stem from a complex interaction of environmental, dietary, and genetic factors; however, the contributing genetic factors remain unknown. OBJECTIVE: The aim of our present study was to determine the role of genetic variants within genes encoding for collagens of the connective tissue in diverticulosis. DESIGN: This was a transsectional genetic association study. SETTINGS: This study was conducted at three tertiary referral centers in Germany and Lithuania. PATIENTS: Single-nucleotide polymorphisms in COL3A1 (rs3134646, rs1800255) and COL1A1 (rs1800012) were genotyped in 422 patients with diverticulosis and 285 controls of white descent by using TaqMan assays. MAIN OUTCOME MEASURES: The association of colonoscopy-proven diverticulosis with genetic polymorphisms with herniations was assessed in multivariate models. RESULTS: The rs3134646, rs1800255, and rs1800012 variants were significantly associated with the risk of developing diverticulosis in the univariate model; however, these associations were not significant in the multivariate logistic regression analysis including additional nongenetic variables. When selectively analyzing sexes, the genotype AA (AA) in rs3134646 remained significantly associated with diverticulosis in men (OR, 1.82; 95% CI, 1.04-3.20; p = 0.04). LIMITATIONS: Because a candidate approach was used, additional relevant variants could be missed. Within our cohort of patients with diverticulosis, only a small proportion had diverticular disease and thus, we could not examine the variants in these subgroups. Functional studies, including the analysis of the involved collagens, are also warranted. CONCLUSIONS: Our study shows that a variant of COL3A1 (rs3134646) is associated with the risk of developing colonic diverticulosis in white men, whereas rs1800255 (COL3A1) and rs1800012 (COL1A1) were not associated with this condition after adjusting for confounding factors. Our data provide novel valuable insights in the genetic susceptibility to diverticulosis. See Video Abstract at http://links.lww.com/DCR/A504.

Selective association of nonaspirin NSAIDs with risk of diverticulitis.

PURPOSE: The purpose of this study is to investigate the association of intake of nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular nonaspirin NSAIDs and compare it with other risk factors for the progression of diverticulosis to diverticulitis in patients who underwent colonoscopy. METHODS: A total of 194 patients who underwent complete colonoscopy in our center between 2012 and 2016 were recruited: 144 with diverticulosis without prior diverticulitis (median age 71 years, 59.7% men) and 50 with diverticulitis (median age 64 years, 54.0% men). Data concerning current and previous medication as well as concomitant diseases were collected using a structured questionnaire and by revision of patients medical charts. RESULTS: Patients with diverticulitis were significantly (p < 0.001) younger as compared to individuals with plain diverticulosis (median age 64 versus 71 years, respectively). The intake of NSAIDs significantly (p = 0.002) increased the risk of prior diverticulitis (OR 3.2, 95% CI 1.5-6.9). In the multivariate model, both age (p < 0.001) and NSAIDs (p = 0.03) proved to be independent determinants of diverticulitis. When analyzing aspirin intake, it was not associated with diverticulitis. CONCLUSIONS: Our study demonstrates, in line with previous reports, that intake of NSAIDs is associated with diverticulitis. We show in particular that nonaspirin NSAIDs might be selectively associated with diverticulitis. These results point to divergent role of aspirin and nonaspirin NSAIDs in the development of diverticulitis.

[Acute liver failure as a rare case of a frequent disease]. / Akutes Leberversagen als seltene Manifestation einer häufigen Erkrankung.

Here we report the case of a 63-year-old female patient who was admitted with acute liver failure. The etiology turned out to be an acute fulminant hepatitis caused by hepatitis C virus (HCV) infection of unknown origin. Fulminant hepatitis due to acute hepatitis C is very rare and hardly reported but a potential cause of acute liver failure due to massive hepatic necrosis, which may lead to encephalitis and multi-organ-failure. During follow-up spontaneous virological clearance was observed. The case illustrates that acute HCV infection, which is confirmed by the detection of HCV-RNA, has to be considered in the differential diagnosis of acute liver failure.

Cancer-associated circulating large extracellular vesicles in cholangiocarcinoma and hepatocellular carcinoma.

BACKGROUND & AIMS: Large extracellular vesicles, specifically AnnexinV+ EpCAM+ CD147+ tumour-associated microparticles (taMPs), facilitate the detection of colorectal carcinoma (CRC), non-small cell lung carcinoma (NSCLC) as well as pancreas carcinoma (PaCa). Here we assess the diagnostic value of taMPs for detection and monitoring of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Specifically, the aim of this study was to differentiate liver taMPs from other cancer taMPs, such as CRC and NSCLC. METHODS: Fluorescence-activated cell scanning (FACS) was applied to detect various taMP populations in patients' sera that were associated with the presence of a tumour (AnnexinV+ EpCAM+ CD147+ taMPs) or could discriminate between cirrhosis (due to HCV or HBV) and liver cancers (AnnexinV+ EpCAM+ ASGPR1+ taMPs). In total 172 patients with liver cancer (HCC or CCA), 54 with cirrhosis and no liver neoplasia, and 202 control subjects were enrolled. RESULTS: The results indicate that AnnexinV+ EpCAM+ CD147+ taMPs were elevated in HCC and CCA. Furthermore, AnnexinV+ EpCAM+ ASGPR1+ CD133+ taMPs allowed the distinction of liver malignancies (HCC or CCA) and cirrhosis from tumour-free individuals and, more importantly, from patients carrying other non-liver cancers. In addition, AnnexinV+ EpCAM+ ASGPR1+ taMPs were increased in liver cancer-bearing patients compared to patients with cirrhosis that lacked any detectable liver malignancy. The smallest sizes of successfully detected cancers were ranging between 11-15mm. AnnexinV+ EpCAM+ ASGPR1+ taMPs decreased at 7days after curative R0 tumour resection suggesting close correlations with tumour presence. ROC values, sensitivity/specificity scores and positive/negative predictive values (>78%) indicated a potent diagnostic accuracy of AnnexinV+ EpCAM+ ASGPR1+ taMPs. CONCLUSION: These data provide strong evidence that AnnexinV+ EpCAM+ ASGPR1+ taMPs are a novel biomarker of HCC and CCA liquid biopsy that permit a non-invasive assessment of the presence and possible extent of these cancers in patients with advanced liver diseases. LAY SUMMARY: Microparticles (MPs) are small vesicles that bleb from the membrane of every cell, including cancer cells, and are released to circulate in the bloodstream. Since their surface composition is similar to the surface of their underlying parental cell, MPs from the bloodstream can be isolated and by screening their surface components, the presence of their parental cells can be identified. This way, it was possible to detect and discriminate between patients bearing liver cancer and chronic liver cirrhosis.