Diagnostic algorithm based on ratio of ascites-serum tumor markers is superior to tumor markers in the differentiation of benign ascites from malignant ascites.

BACKGROUND: Differential diagnosis between benign ascites and malignant ascites remains challenging in clinical practice, the aim of our study is to determine the differential value of the ratio of ascitic-serum tumor markers between benign ascites and malignant ascites. METHODS: 418 patients with new-onset ascites were retrospectively enrolled in this study. The pertinent data of patients enrolled were collected; diagnostic value of tumor markers, ascites-serum tumor marker ratio, and diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio in patients with ascites were investigated. RESULTS: 81.25% of the patients with benign ascites had low (<1) ratio of ascites-serum tumor markers (Max [A/S CEA, A/S CA15-3, A/S CA19-9]); and 91.88 % of patients with benign ascites had the ratio of ascites-serum tumor marker less than 1.5. On the other hand, 94.96% of the patients with malignant ascites had high (≥1) ratio of ascites-serum tumor markers; and 97.29% of patients with malignant ascites had the ratio of ascites-serum tumor markers more than 0.67. Finally, diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio showed 96.37% of the sensitivity, and 94.37% of the accuracy in the diagnosis of malignant ascites, while ascitic tumor markers with a sensitivity of 78.29%, and an accuracy of 84.93%. CONCLUSIONS: Diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio exhibited an excellent performance in distinguishing benign and malignant ascites, which should be recommended in patients with new-onset ascites in clinical practice.

Hypoalbuminemia contributes to ascites formation via sodium and water retention: Evidence from clinical date and albumin deficient mice.

Albumin infusions improve circulatory and renal function in patients with decompensated cirrhosis. However, there is no convincing evidence that hypoalbuminemia contributes to ascites formation in liver cirrhosis. The aim of our study is to determine the exact role of hypoalbuminemia in the formation of ascites caused by liver cirrhosis and its underlying mechanism. Clinical profiles of patients with liver cirrhosis retrospectively analyzed. The details of albumin involved in ascites formation were investigated in rat model and murine model. Statistical analysis demonstrated hypoalbuminemia was an independent risk factor for ascites formation in patients with liver cirrhosis (OR = 0.722, P < 0.001). In carbon tetrachloride (CCl4)-induced rat model of liver cirrhosis, a significant reduction in serum albumin was observed in rats with ascites (13.37 g/L) compared with rats without ascites (21.43 g/L, P < 0.001). In thioacetamide (TAA)-treated mice, ascites amount of heterozygous albumin (Alb+/-) mice (112.0 mg) was larger than that of wild-type (Alb+/+) mice (58.46 mg, P < 0.001). In CCl4-induced chronic liver injury, ascites amounts of Alb+/- or Alb+/+ mice were 80.00 mg or 48.46 mg (P = 0.001). Further study demonstrated 24-h urinary sodium excretion in Alb+/- mice was lower than that of Alb+/+ mice in TAA/CCl4-induce murine models of liver cirrhosis. Additionally, serum sodium concentration of Alb+/- mice was lower than that of Alb+/+ mice. In cirrhotic mice, higher level of antidiuretic hormone was observed in Alb+/- mice compared with the control; and renal aquaporin (AQP2) expression in Alb+/- mice was significantly higher than that of WT mice. These revealed hypoalbuminemia contributed to the occurrence of ascites in liver cirrhosis through sodium and water retention.

Diagnostic accuracy of magnetically guided capsule endoscopy with a detachable string for detecting oesophagogastric varices in adults with cirrhosis: prospective multicentre study.

OBJECTIVE: To evaluate the diagnostic accuracy and safety of using magnetically guided capsule endoscopy with a detachable string (ds-MCE) for detecting and grading oesophagogastric varices in adults with cirrhosis. DESIGN: Prospective multicentre diagnostic accuracy study. SETTING: 14 medical centres in China. PARTICIPANTS: 607 adults (>18 years) with cirrhosis recruited between 7 January 2021 and 25 August 2022. Participants underwent ds-MCE (index test), followed by oesophagogastroduodenoscopy (OGD, reference test) within 48 hours. The participants were divided into development and validation cohorts in a ratio of 2:1. MAIN OUTCOME MEASURES: The primary outcomes were the sensitivity and specificity of ds-MCE in detecting oesophagogastric varices compared with OGD. Secondary outcomes included the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices and the diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices. RESULTS: ds-MCE and OGD examinations were completed in 582 (95.9%) of the 607 participants. Using OGD as the reference standard, ds-MCE had a sensitivity of 97.5% (95% confidence interval 95.5% to 98.7%) and specificity of 97.8% (94.4% to 99.1%) for detecting oesophagogastric varices (both P<0.001 compared with a prespecified 85% threshold). When using the optimal 18% threshold for luminal circumference of the oesophagus derived from the development cohort (n=393), the sensitivity and specificity of ds-MCE for detecting high risk oesophageal varices in the validation cohort (n=189) were 95.8% (89.7% to 98.4%) and 94.7% (88.2% to 97.7%), respectively. The diagnostic accuracy of ds-MCE for detecting high risk oesophagogastric varices, oesophageal varices, and gastric varices was 96.3% (92.6% to 98.2%), 96.9% (95.2% to 98.0%), and 96.7% (95.0% to 97.9%), respectively. Two serious adverse events occurred with OGD but none with ds-MCE. CONCLUSION: The findings of this study suggest that ds-MCE is a highly accurate and safe diagnostic tool for detecting and grading oesophagogastric varices and is a promising alternative to OGD for screening and surveillance of oesophagogastric varices in patients with cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT03748563.

Splenectomy versus non-splenectomy for gastrointestinal bleeding from left-sided portal hypertension: a systematic review and meta-analysis.

Objectives: Left-sided portal hypertension (LSPH) leads to life-threatening gastrointestinal (GI) bleeding. There are no recommendations or consensus about the management of GI bleeding caused by LSPH. This systematic review and meta-analysis were conducted to evaluate the incidence of GI bleeding and the mortality of patients with LSPH receiving different therapeutic strategies. Design: A systematic review and meta-analysis were performed to determine the efficacy of different therapeutic strategies for GI bleeding caused by LSPH. Data sources and methods: All relevant studies were searched from PubMed, Embase, Web of Science, Cochrane Library, Scopus, ScienceDirect, MEDLINE, Google Scholar, CNKI, and Wanfang Data without language restriction through 15 November 2023. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated through RevMan5.3 software. (The Cochrane Collaboration, Copenhagen, Denmark). Results: Seventeen retrospective studies and one prospective study involving 624 patients were included. This systematic review and meta-analysis found that: (1) splenectomy was more effective than non-splenectomy therapeutic strategies in reducing the incidence of GI bleeding caused by LSPH (OR: 0.12; 95% CI: 0.06-0.27); (2) splenectomy was superior to partial splenic artery embolism (PSAE) (OR: 0.06; 95% CI: 0.01-0.62) or endoscopic interventions (OR: 0.04; 95% CI: 0.01-0.19) in the prevention of GI bleeding, respectively; (3) no significant difference in the mortality was observed between splenectomy and non-splenectomy therapeutic strategies (OR: 0.46; 95% CI: 0.20-1.08); and (4) patients receiving preoperative PSAE followed by splenectomy had less intraoperative bleeding and shorter operative time than those receiving splenectomy. Conclusion: This meta-analysis demonstrated that splenectomy is superior to non-splenectomy therapeutic strategies in reducing the incidence of GI bleeding from LSPH, which revealed that splenectomy should be recommended in the management of these patients. Trial registration: This study has been registered on the PROSPERO database with the registration number CRD42023483764.

Upregulation of RACGAP1 is correlated with poor prognosis and immune infiltration in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a primary liver cancer with high mortality worldwide. Even though the patients with HCC received standard therapies, patients with HCC continue to experience unsatisfactory therapy outcomes. Presently, immune therapy acts as a novel therapeutic management for HCC. The aim of this study was to determine overexpressed genes in HCC and evaluate the association between overexpressed genes with the prognosis and immune infiltration. Methods: Gene expression profiles of HCC were analyzed using multiple online databases, and then confirmed by qualitative real time-polymerase chain reaction (RT-qPCR) and immunohistochemical analysis. The correlations of gene overexpression with the prognosis and immune infiltration were determined. Results: Top 11 common differentially expressed genes were identified in HCC, and RACGAP1 was selected for further analysis. RACGAP1 expression was significantly higher in HCC tissues than that in normal tissues. Upregulation of RACGAP1 was correlated with clinical stage and poor prognosis. Additionally, RACGAP1 overexpression was positively related to the infiltration of suppressive immune cells. Moreover, we speculate RACGAP1 may promote tumorigenesis of HCC through immunosuppression mediated by YAP activation. Conclusions: Overexpression of RACGAP1 was associated with unfavorable prognosis and immune infiltration in HCC, which indicated that RACGAP1 could be a molecular target for HCC.

Causal associations between gastroesophageal reflux disease and essential hypertension: A bidirectional Mendelian randomization study.

BACKGROUND: Clinical studies have reported that patients with gastroesophageal reflux disease (GERD) have a higher prevalence of hypertension. AIM: To performed a bidirectional Mendelian randomization (MR) analysis to investigate the causal link between GERD and essential hypertension. METHODS: Eligible single nucleotide polymorphisms (SNPs) were selected, and weighted median, inverse variance weighted (IVW) as well as MR egger (MR-Egger) regression were used to examine the potential causal association between GERD and hypertension. The MR-Pleiotropy RESidual Sum and Outlier analysis was used to detect and attempt to reduce horizontal pleiotropy by removing outliers SNPs. The MR-Egger intercept test, Cochran's Q test and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of single instrumental variable. RESULTS: IVW analysis exhibited an increased risk of hypertension (OR = 1.46, 95%CI: 1.33-1.59, P = 2.14E-16) in GERD patients. And the same result was obtained in replication practice (OR = 1.002, 95%CI: 1.0008-1.003, P = 0.000498). Meanwhile, the IVW analysis showed an increased risk of systolic blood pressure (ß = 0.78, 95%CI: 0.11-1.44, P = 0.021) and hypertensive heart disease (OR = 1.68, 95%CI: 1.36-2.08, P = 0.0000016) in GERD patients. Moreover, we found an decreased risk of Barrett's esophagus (OR = 0.91, 95%CI: 0.83-0.99, P = 0.043) in essential hypertension patients. CONCLUSION: We found that GERD would increase the risk of essential hypertension, which provided a novel prevent and therapeutic perspectives of essential hypertension.

EphB2 promotes enteric nitrergic hyperinnervation and neurogenic inflammation in DSS-induced chronic colitis in mice.

BACKGROUND: Enteric nervous system (ENS) has been closely associated with the neuro-immune response and is currently considered a reliable target for intestinal inflammation. Neuronal nitric oxide synthase (nNOS) nerves are involved in inflammatory diseases by releasing nitric oxide (NO). EphB2 expression and density of innervation of the mucosal layer are positively correlated with the severity of intestinal inflammatory responses. In this study, we hypothesized that a EphB2-mediated mechanism may regulate enteric immunity through modulation of nNOS nerves. METHODS: Firstly, the Western blot (WB) method was employed to quantify EphB2 expression in the intestinal mucosal layer of DSS mice and assess alterations in nerve fiber activation and density. Immunofluorescence (IF) double staining with nNOS and neuronal marker PGP9.5 was conducted to measure nNOS nerve fiber density within the intestinal mucosal layer of mice. Subsequently, in vivo experiments were performed to investigate the inhibitory or activatory effect of EphB2Fc or EphrinB2Fc on EphB2 expression and activation. Immunoprecipitation experiments confirmed the interaction between EphB2 and nNOS nerves. WB and IF experiments were carried out to evaluate both inflammatory conditions of mouse colonic mucosa following intervention with EphB2Fc/EphrinB2Fc as well as changes in nNOS nerve fibers expression. Finally, in vitro experiments, neurally-mediated inflammation was assessed in the organ bath system by activating intestinal mucosal innervation through Veratridine (VER) and electrical field stimulation (EFS) techniques for 3 h. The activation of nNOS nerves was inhibited by nitroindazole (7NI). WB was employed to detect changes in the expression of inflammatory factors in the intestinal mucosal layer in EphB2Fc/EphrinB2Fc treated mice and control group. KEY RESULTS: We found that the expression of EphB2 and density nNOS nerve fibers in the intestinal mucosa were positively correlated with the colitis response. Blocking (EphB2Fc)/activating (EphrinB2Fc) EphB2 in vivo significantly reduced/increased the density of nNOS nerve fibers and expression of inflammatory factors in colonic mucosa of DSS treated mice. In vitro, blocking nNOS nerves activation attenuated the inflammatory reaction induced by either EFS or EphB2. CONCLUSIONS: Our findings provided evidence that EphB2 mediated regulation of innate immunity-ENS crosstalk might represent an attractive target for novel therapeutic strategies in ulcerative colitis.

Differential diagnosis of ascites: etiologies, ascitic fluid analysis, diagnostic algorithm.

Ascites is the pathological accumulation of fluid within the peritoneal cavity. It often occurs as results of liver cirrhosis, malignant neoplasia, tuberculous infection, cardiac insufficiency, renal diseases, etc. Determining the etiology is an essential step in the management of patients with new-onset ascites. Abdominal paracentesis with appropriate ascitic fluid analysis is probably the most cost-effective method of determining the cause of ascites. We performed a literature search of PubMed and identified articles published in the field of ascites, to evaluate diagnostic values of various parameters in defining the etiologies of ascites and then provides diagnostic algorithm for patients with new-onset ascites. In patients with ascites, the constituent ratio of underlying etiology varies between developed and developing countries. It is a challenge to define the etiologies of ascites in developing countries. Routine ascitic fluid analysis should include the serum ascites albumin gradient (SAAG), total protein concentration, cell count and differential. Optional ascitic fluid analysis includes cholesterol, fluid culture, cytology, tumor markers, lactate dehydrogenase, adenosine deaminase (ADA), triglyceride, amylase, glucose, brain natriuretic peptide (BNP), etc. Our review evaluated diagnostic values of the above parameters in defining the etiologies of ascites. Diagnostic algorithm established in this review would provide a practical and convenient diagnostic strategy for clinicians in diagnosing patients with new-onset ascites.

Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1.

Background & Aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients. Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls. Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels. Conclusions: Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH. Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

Interferon-γ secreted by recruited Th1 cells in peritoneal cavity inhibits the formation of malignant ascites.

Type 1 T helper (Th1) cells generate an efficient antitumor immune response in multiple malignancies. The functions of Th1 cells in malignant ascites (MA) have not been elucidated. The distribution of helper T cells in peritoneal fluid and peripheral blood was determined in patients and animal models with malignant ascites. The effects of Th1-derived interferon-γ (IFN-γ) on the formation of malignant ascites were investigated. The mechanism underlying the recruitment of Th1 cells into peritoneal cavity was explored. In patients with malignant ascites and animal models of malignant ascites, the percentage of Th1 cells increased in peritoneal fluid compared with peripheral blood. Next, our experiment demonstrated that Th1 cells inhibited the growth of tumor cells by secreting IFN-γ in vitro. In murine models of malignant ascites, increased peritoneal fluid and shorter survival time were observed in IFN-γ-/- mice compared with wild-type (WT) mice. Then, the levels of C-X-C motif chemokine ligand (CXCL) 9/10 and the ratio of CXCR3+ Th1 cells indicated the involvement of CXCL9, 10/CXCR3 axis in the recruitment of Th1 cells into peritoneal cavity. As expected, in murine models of malignant ascites, the gradient between ascitic Th1 ratio and blood Th1 ratio decreased in CXCR3-/- mice compared with WT mice. IFN-γ secreted by recruited Th1 cells in peritoneal cavity inhibits the formation of malignant ascites. Hence, manipulation of Th1 cells or IFN-γ will provide a therapeutic candidate against malignant ascites.

Enoxaparin attenuates pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome by inhibiting oncostatin M expression.

BACKGROUND AND AIMS: The definitive treatment for pyrrolizidine alkaloids (PAs)-induced hepatic sinusoidal obstruction syndrome (HSOS) is not available. The effectiveness of anticoagulation therapy remains controversial. The efficacy of low molecular weight heparin (LMWH) should be investigated in patients and animal models, and the underlying mechanism should be explored. METHODS: The prognosis of patients with PAs-HSOS who received anticoagulation therapy was retrospectively analysed. The effect of enoxaparin on the liver injury was determined in animal models of monocrotaline (MCT)-induced HSOS was determined, and the underlying mechanism was investigated using a murine model. RESULTS: The cumulative survival rate of patients with PAs-induced HSOS was 60.00% and 90.90% in the non-anticoagulation group and anticoagulation group. Enoxaparin attenuated liver injury effectively in a rat model of MCT-induced HSOS. Additionally, the improvement of severe liver injury was observed in MCT-treated mice after the administration of enoxaparin (40 mg/kg). The alleviation of liver injury was observed in mice with hepatocyte-specific deletion of oncostatin M (Osm△Hep ). In MCT-treated mice administrated with enoxaparin, no significant differences in liver injury were observed between Osm△Hep mice and Osmflox/flox mice. Additionally, adenovirus-mediated overexpression of Osm resulted in severe liver injury in MCT-induced mice after the administration of enoxaparin. CONCLUSIONS: LMWH attenuated severe liver injury in patients with PAs-Induced HSOS and animal models of MCT-induced HSOS, which provides a rationale for the application of anticoagulation therapy.

Retrorsine Cooperates with Gut Microbiota to Promote Hepatic Sinusoidal Obstruction Syndrome by Disrupting the Gut Barrier.

Background and Aims: Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening syndrome, and a cause is exposure to pyrrolizidine alkaloid (PA)-containing products. It is well-established that retrorsine (RTS), a representative Pas, insults hepatic sinusoidal endothelial cells and ensues congestion of hepatic sinusoids. However, little known about the impact of Pas on gut microbiota and intestinal barrier and inflammation in HSOS. Methods: Mice were gavaged with or without nonabsorbable antibiotics (ABX), followed by a single dose of RTS. The gut microbiota was examined by 16S rDNA sequencing. Results: ABX pretreatment significantly reversed RTS-induced liver damage. RTS altered gut microbiota composition, increasing Gram-negative bacteria and resulting in a sharp elevation of circulating lipopolysaccharides (LPS) in HSOS mice. Gut decontamination with ABX alleviated RTS-induced intestine inflammation, protected against disruption of the intestinal epithelial barrier and gut vascular barrier (GVB), and suppressed hepatic LPS-NF-κB pathway activation in RTS-induced HSOS. Importantly, the LPS level was positively correlated with MELD score in patients with HSOS. Elevated LPS in patients with HSOS confirmed that Gram-negative bacteria were involved in the pathogenesis of HSOS. Conclusions: RTS, a PA, cooperated with gut dysbiosis to cause intestinal inflammation and gut barrier compromise that increased transport of gut-derived LPS into the liver through the portal vein, which contributed to the pathology of HSOS. Modulating the gut microbiota, protecting the intestinal barrier, and suppressing intestinal inflammation with prebiotics or antibiotics might be a useful pharmacologic intervention in HSOS.

Utility of ascitic tumor markers and adenosine deaminase for differential diagnosis of tuberculous peritonitis and peritoneal carcinomatosis.

BACKGROUND: Differential diagnosis between tuberculous peritonitis and peritoneal carcinomatosis remains challenging in clinical practice; thus, in-patients diagnosed with tuberculous peritonitis or peritoneal carcinomatosis were retrospectively enrolled, and diagnostic values of ascitic tumor markers and adenosine deaminase were determined. METHODS: Consecutive patients diagnosed with tuberculous peritonitis or peritoneal carcinomatosis were retrospectively enrolled. The pertinent data of 169 patients enrolled were collected. RESULTS: A panel of ascitic tumor makers (CEA, CA15-3, CA19-9) had high specificity (96.83%) and accuracy (94.67%) in the differentiation of peritoneal carcinomatosis from tuberculous peritonitis; and ascitic ADA was a good discriminator between these patients, with an accuracy of 91.72%. Combined use of ascitic tumor makers and ADA (ascitic ADA < 22.5 IU/L or ascitic CEA > 3.65 ng/mL or CA15-3 > 42.70 U/mL or CA19-9 > 25.10 U/mL) performed high sensitivity (99.06%) and accuracy (94.08%) for the diagnosis of peritoneal carcinomatosis. In addition, combined ascitic ADA and tumor marker (positive ascitic tumor makers and ADA < 22.50 IU/L) had 100% of the specificity in diagnosing peritoneal carcinomatosis. CONCLUSIONS: Combined use of ascitic tumor markers and adenosine deaminase showed excellent efficiency in the differential diagnosis between tuberculous peritonitis and peritoneal carcinomatosis, thus these two simple and cost-effective parameters should be determined when tuberculous peritonitis or peritoneal carcinomatosis was suspected in clinic practice.

Difference between type 2 gastroesophageal varices and isolated fundic varices in clinical profiles and portosystemic collaterals.

BACKGROUND: There is significant heterogeneity between gastroesophageal varices (GOV2) and isolated gastric varices (IGV1). The data on the difference between GOV2 and IGV1 are limited. AIM: To determine the etiology, clinical profiles, endoscopic findings, imaging signs, portosystemic collaterals in patients with GOV2 and IGV1. METHODS: Medical records of 252 patients with gastric fundal varices were retrospectively collected, and computed tomography images were analyzed. RESULTS: Significant differences in routine blood examination, Child-Pugh classification and MELD scores were found between GOV2 and IGV1. The incidence of peptic ulcers in patients with IGV1 (26.55%) was higher than that of GOV2 (11.01%), while portal hypertensive gastropathy was more commonly found in patients with GOV2 (22.02%) than in those with IGV1 (3.54%). Typical radiological signs of cirrhotic liver were more commonly observed in patients with GOV2 than in those with IGV1. In patients with GOV2, the main afferent vessels were via the left gastric vein (LGV) (97.94%) and short gastric vein (SGV) (39.18%). In patients with IGV1, the main afferent vessels were via the LGV (75.61%), SGV (63.41%) and posterior gastric vein (PGV) (43.90%). In IGV1 patients with pancreatic diseases, spleno-gastromental-superior mesenteric shunt (48.15%) was a major collateral vessel. In patients with fundic varices, the sizes of gastric/esophageal varices were positively correlated with afferent vessels (LGVs and PGVs) and efferent vessels (gastrorenal shunts). The size of the esophageal varices was negatively correlated with gastrorenal shunts in GOV2 patients. CONCLUSION: Significant heterogeneity in the etiology and vascular changes between GOV2 and IGV1 is useful in making therapeutic decisions.

Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. APPROACH AND RESULTS: We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10-73 ). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10-9 ) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10-9 ). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10-7 ), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10-7 ), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10-6 ), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10-6 ) had suggestive association signals with AIH. CONCLUSIONS: Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.

MS275 as Class I HDAC inhibitor displayed therapeutic potential on malignant ascites by iTRAQ-based quantitative proteomic analysis.

BACKGROUND: Malignant ascites is a manifestation of end stage events in a variety of cancers and is associated with significant morbidity. Epigenetic modulators play a key role in cancer initiation and progression, among which histone deacetylases (HDACs) are considered as one of the most important regulators for various cancer development, such as liver cancer, ovarian cancer, and pancreatic cancer et al. Thus, in this paper, we sought to explore the therapeutic effect of HDAC inhibitor on malignant ascites. METHODS: In this report, we tested the therapeutic effect of different isoform selective HDAC inhibitors (Class I HDACI MS275, Class IIa HDACI MC1568, pan-HDAC inhibitors SAHA) on malignant ascites in vitro and in vivo. We further used proteome analysis to find the potential mechanisms for malignant ascites therapy. RESULTS: Among the different isoform-selective HDAC inhibitors, the class I selective HDACI, MS275, exhibited preferential inhibition on various ascites cells. MS275 could induce cell cycle arrest in G0/G1 phase and promote apoptosis on ascites cells. Through proteome analysis, we found MS275 could downregulate proteins related to cell cycle progression, such as CDK4, CDC20, CCND1; MS275 could upregulate pro-apoptosis proteins such as PAPR1, LMNB2 and AIFM1; in addition, MS275 could change the expression of tumorigenic proteins related to the specific malignant ascites bearing tumors, such as TSP1 and CDK4 for bladder cancer. We then confirmed that abemaciclib (CDK4/6 selective inhibitor) could inhibit the proliferation of ascites cells, and the combination of abemaciclib and MS275 had synergistic anti-tumor effect. Finally, we found that MS275 could in vivo inhibit malignant ascites progression (ascites volume: 2.9 ± 1.0 mL vs 7.5 ± 1.2 mL, p < 0.01), tumor growth, and prolong 66% of the life-span when compared with the untreated group. CONCLUSION: This present research revealed that the class I selective HDAC inhibitor, MS275, could effectively inhibit malignant ascites development and tumor growth via multiple pathways. These results indicated that HDACI could have great potential for clinical therapy of malignant ascites.

Predictive Model of Ursodeoxycholic Acid Treatment Response in Primary Biliary Cholangitis.

BACKGROUND AND AIMS: Although ursodeoxycholic acid (UDCA) treatment in primary biliary cholangitis is effective in many patients, there are still many people who respond poorly to it. Identifying and intervening these patients early is important. Therefore, exploring the risk factors and proposing a predictor index to predict the UDCA treatment nonresponse earlier among primary biliary cholangitis patients were the aims of this research. METHODS: A total of 135 primary biliary cholangitis patients treated with UDCA (13-15 mg/kg/d) were enrolled in this retrospective study. The response to treatment was evaluated based on Paris I criteria. The univariate and logistic multivariate regression analyses were adopted to determine the independent risk factors and propose a predictor index. Receiver operating characteristic curve was used to evaluate the predictive ability of the predictor index. RESULTS: Total bilirubin, albumin, globulin, immunoglobin M, and aspartate aminotransferase-to-platelet ratio index were the five independent risk factors associating with early biochemical nonresponse to UDCA treatment. Based on these factors, we established a predictor index with the predictive value being 0.886 (sensitivity: 82.80%, specificity: 84.40%). CONCLUSIONS: We developed a predictor index that had an accurate prediction of the early biochemical nonresponse to UDCA treatment, which is expected to provide valuable information for the high-risk group before treatment begins.

Quantitative CT assessment by histogram and volume ratio in pyrrolizidines alkaloids-induced hepatic sinusoidal obstruction syndrome.

OBJECTIVE: To quantitatively assess hypoattenuation volume ratio and hepatic parenchymal hypoattenuation on contrast enhanced computed tomography (CECT) in patients with pyrrolizidines alkaloids (PAs)-induced hepatic sinusoidal obstruction syndrome (HSOS), and evaluate the correlations of the CT-based quantitative values with clinical factors. METHODS: Thirty-five patients with PAs-induced HSOS who underwent CECT were retrospectively enrolled. The ratio of hypoattenuation volume to total liver volume, and changes in damaged area-to-normal liver density ratio (ΔDR) derived from histogram on portal venous phase were quantitatively measured. Heterogeneous hypoattenuation (CT score) scored by hypoattenuation volume ratio and ΔDR were calculated. The correlation between imaging findings and clinical factors was analyzed using Pearson correlation test. RESULTS: Liver function tests were abnormal in most patients, the mean Hounsfield unit (HU) of damaged area (58.68 ± 17.3) was significantly lower (P < 0.001) than the corresponding normal liver (82.27 ± 23.97). Heterogeneous hypoattenuation were mild in 13 patients (37 %), moderate in 16 patients (46 %), and severe in 6 patients (17 %). ΔDR derived from histogram was positively correlated (weakly to moderately) with total bilirubin (r = 0.341, P = 0.045), direct bilirubin (r = 0.385, P = 0.022), and alkaline phosphatase (r = 0.491, P = 0.003), while such correlation was not observed in hypoattenuation volume ratio. The severity of heterogeneous hypoattenuation scored by hypoattenuation volume ratio and ΔDR was positively correlated (weakly) with prothrombin time (r = 0.357, P = 0.035), international normalized ratio (r = 0.363, P = 0.032), alkaline phosphatase (r = 0.359, P = 0.034), and model for end-stage liver disease (MELD) score (r = 0.347, P = 0.041). CONCLUSION: Heterogeneous hypoattenuation scored by volume ratio and ΔDR on CECT provides a non-invasive approach in evaluating the severity of PAs-induced HSOS.

Prognostic factors for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: a multicenter study in China.

BACKGROUND: In China, one of the major causes of hepatic sinusoidal obstruction syndrome (HSOS) is the intake of herbals containing pyrrolizidine alkaloid (PA). However, prognostic factors for PA-induced HSOS are poorly understood. The aim of this study was to identify the independent prognostic factors for PA-induced HSOS using a multi-center study. METHODS: A total of 117 PA-induced HSOS patients were enrolled for data collection in three university hospitals from November 2003 to September 2018. Univariate and multivariate Cox proportional hazards analysis were used to determine prognostic factors for PA-induced HSOS. RESULTS: The median age of the PA-induced HSOS patients was 61 years (range, 21-88 years), and 64% of them were male. The survival rates at 1, 3, and 36 months were 89.71%, 72.60%, and 69.19%, respectively. Significant differences in prothrombin time (PT), international normalized ratio, total bilirubin, severity grading [new criteria for severity grading of hematopoietic stem cell transplantation (HSCT)-related HSOS in adults] were found between patients who survived and those who died. Univariate and multivariate survival analysis using Cox's regression model demonstrated low serum albumin (<35 g/L), elevated serum urea (>8.2 mmol/L) and severe or very severe HSOS (European Society for Blood and Marrow Transplantation 2016 criteria) were independent prognostic factors of survival. CONCLUSIONS: Serum albumin, serum urea, and severity grading were independent prognostic factors for patients with PA-induced HSOS, and can contribute to identifying potentially high-risk patients for early effective intervention. TRIAL REGISTRATION: ChiCTR-DRD-17010709 (www.chictr.org.cn).

Liver injury in patients with COVID-19: clinical profiles, CT findings, the correlation of the severity with liver injury.

BACKGROUND AND AIMS: Liver injury is found in some of patients with COVID-19. Liver injury of COVID-19 patients based on severity grading and abdominal radiological signs have not been reported until now. The aim of our study is to determine clinical profiles of the patients based on severity grading, describe abdominal radiological signs, and investigate the correlations of the severity with clinical profiles and radiological signs. METHODS: This retrospective cohort study included 115 patients with COVID-19 from Jan 2020 to Feb 2020. Medical records of the patients were collected and CT images were reviewed. RESULTS: Common clinical manifestations of patients with COVID-19 were fever (68.70%), cough (56.52%), fatigue (31.30%); some of them had gastrointestinal symptoms (diarrhea, 12.17%; nausea or vomiting 7.83%; inappetence, 7.83%). Abnormal liver function was observed in some of patients with COVID-19. Significant differences in the levels of AST, albumin,CRP were observed among different groups classified by the severity. Common findings of upper abdominal CT scan were liver hypodensity (26.09%) and pericholecystic fat stranding (21.27%); liver hypodensity was more frequently found in critical cases (58.82%). The severity of COVID-19 correlated with semi-quantitative CT score of pulmonary lesions, CT-quantified liver/spleen attenuation ratio in patients with COVID-19. CONCLUSIONS: Some of the patients with COVID-19 displayed liver damage revealed by liver functional tests and upper abdominal CT imaging, and the severity of COVID-19 patients correlated with some of liver functional tests and CT signs; thus, it will allow an earlier identification of high-risk patients for early effective intervention.