A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH RESULTS: Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 controls from the Japanese population (GWAS-lead variant: rs8098858, p=2.6×10-8). In-silico and in-vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were confirmed in the portal area of the PBC-liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in-vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFN signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Non-liver-related mortality in the DAA era: Insights from post-SVR patients with and without previous HCC history.

BACKGROUND AND AIMS: Mortality after sustained virological response (SVR) with interferon-free direct-acting antiviral (IFN-free DAA) therapy is crucial for optimizing post-SVR patient care, but it remains unclear, especially regarding non-liver-related mortality. METHODS: Consecutive post-SVR patients from 14 institutions were stratified into three cohorts: A (without advanced fibrosis and without prior HCC), B (with advanced fibrosis and without prior HCC), and C (curative HCC treatment). We assessed mortality (per 1000 person-years [/1000PY]) post-SVR. Mortality rates were compared between cohorts A and B and the general population using age- and sex-adjusted standardized mortality ratio (SMR). Comparison of survival between each cohort was performed using propensity-score (PS) matching with sex, age, and comorbidity. RESULTS: In cohort A (n = 762; median age, 65 years), 22 patients died (median follow-up, 36 months); all-cause mortality was 10.0/1000PY, with 86.4% non-liver-related deaths. In cohort B (n = 519; median age, 73 years), 27 patients died (median follow-up, 39 months); all-cause mortality was 16.7/1000PY, with 88.9% non-liver-related deaths. In both cohorts, malignant neoplasm was the most common cause of death; all-cause mortality was comparable to that of the general population (SMR: 0.96 and 0.92). In cohort C (n = 108; median age, 75 years), 15 patients died (median follow-up, 51 months); all-cause mortality was 36.0/1000PY, with 53.3% liver-related deaths. PS matching showed no significant survival differences between cohorts A and B, both of which had better survival than cohort C. CONCLUSIONS: Mortality varies based on HCC history in the DAA era; nevertheless, attention should be paid to non-liver-related deaths in all post-SVR patients.

Safety and Efficacy of Sedation During Emergency Endoscopy for Upper Gastrointestinal Bleeding: A Propensity Score Matching Analysis.

BACKGROUND AND AIM: This study aimed to compare patients with and without sedation during emergency endoscopy for upper gastrointestinal bleeding (UGIB) and to clarify the safety and efficacy of sedation in emergency endoscopy. METHODS: We retrospectively collected 389 patients who underwent emergency endoscopy for UGIB at Ureshino Medical Center from 2016 to 2021. Patients were divided into two groups: sedation group during emergency endoscopy and nonsedation group. Clinical characteristics, patient status on admission, and UGIB etiology were evaluated. Treatment outcomes and adverse events were evaluated using propensity score matching (PSM), and risk factors for mortality from UGIB were investigated using Cox multivariate analysis. RESULTS: The sedation group was significantly younger, composed of a higher proportion of males, and had chronic liver disease. Blood pressure and hemoglobin level on admission were significantly higher in the sedation group. The main cause of bleeding was peptic ulcer, which was significantly higher in the nonsedation group. PSM created 133 matched pairs. The success rate of endoscopic hemostasis was similar in both groups, and procedure time was significantly shorter in the sedation group than in the nonsedation group (17.6 ± 10.0 versus 20.2 ± 10.2 min, P = 0.04). There were no significant differences in adverse events between groups. Cox multivariate analyses revealed that red blood cell transfusion [hazard ratio (HR) 4.45, P < 0.02] and rebleeding (HR 3.30, P = 0.03) were associated with increased risk of 30-day mortality from UGIB. CONCLUSIONS: Sedation reduced the procedure time during emergency endoscopy for UGIB. Sedation during emergency endoscopy for UGIB is acceptable for safe endoscopic procedures.

Usefulness of discharge standards in outpatients undergoing sedative endoscopy: a propensity score-matched study of the modified post-anesthetic discharge scoring system and the modified Aldrete score.

BACKGROUND: This study aimed to evaluate the usefulness of discharge standards in outpatients undergoing sedative endoscopy by comparing the modified post-anesthetic discharge scoring system (MPADSS) and the modified Aldrete score. METHODS: We prospectively enrolled 376 outpatients who underwent gastrointestinal endoscopy under midazolam sedation; 181 outpatients were assessed regarding discharge after sedative endoscopy using the MPADSS (group M), and 195 patients were assessed by the modified Aldrete score (group A). The clinical characteristics, types of endoscopy, endoscopic outcomes, and anesthesia outcomes were evaluated between the two groups. We compared discharge score, recovery time, and adverse events using propensity-score matching. RESULTS: Propensity-score matching created 120 matched pairs. The proportion of patients who had a recovery time within 60 min after endoscopy was significantly higher in group A than that in group M (42.5% versus 25.0%, respectively; P < 0.01). The proportion of patients who required > 120 min of recovery time after endoscopy was significantly lower in group A than that in group M (0.0% versus 5.0%, respectively; P = 0.03). However, significantly more patients had drowsiness at discharge in group A compared with group M (19.1% versus 5.0%, respectively; P < 0.01). There was no significant difference in the adverse event rate within 24 h of discharge between the groups. CONCLUSIONS: Patients assessed by the modified Aldrete score were allowed to discharge earlier than those assessed by the MPADSS. However, a patient's level of consciousness should be assessed carefully, especially in patients who visit the hospital alone.

Prognosis of patients with liver cirrhosis: A multi-center retrospective observational study.

AIM: Despite advances in the management of liver diseases and changes in the etiology of cirrhosis, few studies have updated the prognosis of cirrhosis. This study aimed to clarify the recent prognosis of cirrhosis and identify risk factors for death. METHODS: In this retrospective observational study by the Hepatic Disease Network of the National Hospital Organization in Japan, chart reviews were performed to follow patients with cirrhosis beginning in 2011. We conducted Kaplan-Meier survival time analyses stratified by Child-Pugh classification and albumin-bilirubin grade. Cox regression analysis was used to identify risk factors for death. RESULTS: We identified 444 eligible patients from 25 hospitals, including 303 (68%), 110 (25%), and 31 (7%) patients with Child-Pugh classes A, B, and C, respectively. Hepatitis C virus infection was the cause of cirrhosis for 63% of the patients. The 1-year and 5-year cumulative survival rates of patients with Child-Pugh classes A, B, and C were 90% and 61%, 78% and 42%, and 65% and 25%, respectively. The 1-year and 5-year cumulative survival rates of patients with albumin-bilirubin grades 1, 2, and 3 were 98% and 80%, 91% and 56%, and 58% and 23%, respectively. Cirrhosis classification (Child-Pugh and albumin-bilirubin), age, liver cancer, and untreated esophageal varices were associated with increased hazard of death. CONCLUSIONS: Little improvement was observed in the prognosis of cirrhosis compared with previous reports, and the prognosis of Child-Pugh class C cirrhosis remained poor. Untreated esophageal varices were identified as a risk factor for death.

Propofol Sedation in the Endoscopy Room versus Operation Room during Endoscopic Submucosal Dissection for Gastric Tumors: A Propensity Score-Matching Analysis.

BACKGROUND/AIMS: The present study was performed to compare the safety of sedation with propofol during endoscopic submucosal dissection (ESD) for gastric tumors under sedation in the endoscopy room by an endoscopist versus sedation in the operation room by an anesthesiologist. METHODS: In total, 638 patients with gastric tumors who underwent ESD from January 2011 to August 2017 at Ureshino Medical Center and Saga Medical Center Koseikan were retrospectively reviewed. The patients were divided into 2 groups: those who underwent ESD in the endoscopy room (Group E, n = 532) and those who underwent ESD in the operation room (Group O, n = 106). Propensity score matching was applied for evaluation. The treatment outcome of ESD and the adverse events of sedation during ESD (desaturation, hypotension, bradycardia, and arrhythmia) were compared between the 2 groups to consider the safety of ESD. RESULTS: The propensity score-matching analysis created 82 matched pairs. Adjusted comparisons between Groups E and O showed similar treatment outcomes of ESD for gastric tumors. There were no significant differences in the treatment outcomes, anesthesia time, and mean propofol dose between the 2 groups. With respect to adverse events, desaturation occurred more often in Group E than Group O (18.3 vs. 3.7%, respectively; p = 0.005). There were no significant differences in other adverse events (hypotension, bradycardia, and arrhythmia) between the 2 groups. CONCLUSION: Sedation with propofol in the operation room might be required to ensure safer application of ESD for gastric tumors. However, a decrease in the desaturation rate was the only disadvantage of sedation in the endoscopy room.

Colorectal endoscopic mucosal resection with submucosal injection of epinephrine versus hypertonic saline in patients taking antithrombotic agents: propensity-score-matching analysis.

BACKGROUND: Endoscopic mucosal resection (EMR) to remove colon polyps is increasingly common in patients taking antithrombotic agents. The safety of EMR with submucosal saline injection has not been clearly demonstrated in this population. AIMS: The present study aimed to evaluate the efficacy and safety of submucosal injection of saline-epinephrine versus hypertonic saline in colorectal EMR of patients taking antithrombotic agents. METHODS: This study enrolled 204 patients taking antithrombotic agents among 995 consecutive patients who underwent colonic EMR from April 2012 to March 2018 at Ureshino Medical Center. Patients were divided into two groups according to the injected solution: saline-epinephrine or hypertonic (10%) saline (n = 102 in each group). Treatment outcomes and adverse events were evaluated in each group and risk factors for immediate and post-EMR bleeding were investigated. RESULTS: There were no differences between groups in patient or polyp characteristics. The main antithrombotic agents were low-dose aspirin, warfarin, and clopidogrel. Propensity-score matching created 80 matched pairs. Adjusted comparisons between groups showed similar en bloc resection rates (95.1% with saline-epinephrine vs. 98.0% with hypertonic saline). There were no significant differences in adverse events (immediate EMR bleeding, post-EMR bleeding, perforation, or mortality) between groups. Multivariate analyses revealed that polyp size over 10 mm was associated with an increased risk of immediate EMR bleeding (odds ratio 12.1, 95% confidence interval 2.0-74.0; P = 0.001). CONCLUSIONS: Two tested solutions in colorectal EMR were considered to be both safe and effective in patients taking antithrombotic agents.

Association of a single nucleotide polymorphism in TNIP1 with type-1 autoimmune hepatitis in the Japanese population.

Several studies reported that autoimmune diseases share a number of susceptibility genes. Of these genes, a SNP rs7708392 in TNIP1 was reported to be associated with systemic lupus erythematosus (SLE). Autoimmune hepatitis (AIH), a rare chronic progressive liver disease, shares some clinical features with SLE. Therefore, we investigated whether the SNP is associated with Japanese AIH. An association study of rs7708392 was conducted in 343 Japanese AIH patients and 828 controls. We found that rs7708392 is associated with AIH (P = 0.0236, odds ratio (OR) 1.26, 95% confidence interval (CI): 1.03-1.54), under the allele model for C allele. Significant differences of clinical characteristics of the AIH patients with or without G allele of rs7708392 were not detected. Of interest, the association was stronger in AIH without HLA-DRB1*04:05 allele (P = 0.0063, Q = 0.0127, OR 1.48, 95% CI: 1.12-1.96), though the association was not detected in AIH with DRB1*04:05. The C allele of rs7708392 was associated with AIH, especially AIH without DRB1*04:05, an already established risk factor.

Association of a single nucleotide polymorphism upstream of ICOS with Japanese autoimmune hepatitis type 1.

Autoimmune hepatitis (AIH) is an uncommon chronic autoimmune liver disease. Several studies reported the association of polymorphisms between CD28, CTLA4 and ICOS gene cluster in 2q33.2 with autoimmune or inflammatory diseases. The previous genome-wide association study on type 1 AIH in a European population has reported a risk G allele of a single nucleotide polymorphism (SNP), rs4325730, in this region. Here, we conducted an association study of this SNP with type 1 AIH in a Japanese population, as a replication study.An association study of rs4325730 was conducted in 343 Japanese AIH patients and 315 controls.We found that rs4325730 is associated with AIH (P=0.0173, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.05-1.62, under the allele model for G allele, P=0.0070, OR 1.62, 95% CI 1.14-2.31, under the dominant model for G allele). This SNP was strongly associated with definite AIH (P=0.0134, OR 1.36, 95% CI 1.07-1.74; under allele model for G, P=0.0035, OR 1.85, 95% CI 1.22-2.81, under dominant model for G).This is the first replication association study of rs4325730 upstream of ICOS with AIH in the Japanese population and rs4325730G is a risk allele.

Comparison of sedation between the endoscopy room and operation room during endoscopic submucosal dissection for neoplasms in the upper gastrointestinal tract.

BACKGROUND: The present study was performed to compare the safety of sedation during endoscopic submucosal dissection (ESD) in the endoscopy room versus operation room. METHODS: In total, 297 patients with gastrointestinal tumors who underwent ESD from January 2011 to December 2016 were retrospectively reviewed. The patients were divided into two groups: those who underwent ESD in the endoscopy room without propofol (Group E) versus operation room with propofol (Group O). The patient, tumor, and procedure characteristics; adverse events; and treatment outcomes were compared between the two groups. RESULTS: The patient and tumor characteristics, including age (73.6 ± 8.2 vs. 72.5 ± 9.1 years), comorbidities, and tumor size and histology, were not different between Groups E and O. The ESD procedure time was comparable between Groups E and O (105.4 ± 70.4 vs. 106.5 ± 64.4 min), and the anesthesia time was equivalent (138.3 ± 78.1 vs. 148.4 ± 68.8 min). There were no significant differences in adverse events between the two groups. During the ESD procedure, desaturation occurred significantly more often in Group E than O (12.9% vs. 4.0%, P = 0.021, odds ratio: 3.53, 95% CI: 1.17-14.4). The recovery time after ESD was significantly longer in Group E than O (180 (100-360) vs. 90 (0-180) min, P < 0.001). CONCLUSIONS: A decreased desaturation rate and shorter recovery time after ESD were the advantages of sedation in the operation room with propofol compared with sedation in the endoscopy room. These findings warrant further exploration of the advantages of safe and effective ESD for upper gastrointestinal neoplasms in the operation room.

Successful endoscopic closure with an over-the-scope clip for sigmoid colon perforation due to bile duct stent migration.

An 86-year-old woman presented with a history of endoscopic papillary sphincterotomy for bile duct stones and diverticulitis. The patient was admitted as an emergency case of acute cholangitis due to choledocholithiasis, underwent endoscopic bile duct stenting, and was discharged with a plan for endoscopic lithotripsy. One month later, the patient was readmitted owing to abdominal pain. Abdominal computed tomography at admission showed that the bile duct stent had migrated to the sigmoid colon and the presence of a small amount of extraintestinal gas, suggesting a colonic perforation. Lower gastrointestinal endoscopy showed adhesions and intestinal stenosis in the sigmoid colon, probably after diverticulitis, and the bile duct stent that had perforated the same site. The stent was removed and endoscopic closure of the perforation was performed using an over-the-scope clip. Abdominal computed tomography 8 days after the closure showed no extraintestinal gas. The patient resumed eating and was discharged on the 14th day of admission. There was no recurrence of abdominal pain. Endoscopic closure of sigmoid colon perforation due to bile duct stent migration using an over-the-scope clip has not been reported thus far, and it may be a new treatment option in the future.

A case of pancreatic endocrine carcinoma with a different clinical diagnosis before chemotherapy and pathological autopsy.

We encountered a case of pancreatic neuroendocrine carcinoma (pNEC) diagnosed via pathological autopsy that was initially diagnosed clinically as G3 pancreatic neuroendocrine tumor (G3 pNET) and discussed the differences between these entities in the literature. A 76-year-old man was admitted to our department because of jaundice. Computed tomography revealed multiple round nodules in both lung fields, suggesting metastasis, and a mass lesion was detected in the head of the pancreas with poor contrast in the arterial phase and slight contrast enhancement in the equilibrium phase. Biopsy of the lungs and pancreas led to a diagnosis of multiple pulmonary metastases of G3 pNET. Because the lesions were unresectable, chemotherapy was administered. Treatment was started with everolimus for 5 weeks. However, the patient experienced severe loss of appetite and malaise, and the lung lesions progressed, prompting treatment discontinuation. Subsequently, the patient's disease progressed rapidly, and he died 99 days after the start of chemotherapy. We performed a pathological autopsy with the consent of the family because of the rapid tumor growth. A pathological autopsy revealed a final diagnosis of pNEC, which differed from the clinical diagnosis.

Successful retrograde transvenous embolization under balloon occlusion for rectal arteriovenous malformation.

A 57-year-old man was admitted to our hospital because of frequent hematochezia. Colonoscopy exhibited a submucosal tumor-like lesion in the lower rectum. Abdominal contrast-enhanced computed tomography showed a rectal arteriovenous malformation (AVM) on the right side wall of the lower rectum. The feeder was the superior rectal artery, with early venous return. Embolization of the draining vein and feeding artery of the AVM with N-butyl-2-cyanoacrylate under balloon occlusion was planned. Angiography of the superior rectal artery showed the nidus in the rectum with early venous return of contrast material. The portal vein was punctured percutaneously under ultrasound guidance, and a balloon catheter advanced to the distal part of the superior rectal vein. Venography under balloon occlusion showed the outflow vein and nidus. Transvenous and transarterial nidus embolization with N-butyl-2-cyanoacrylate under balloon occlusion was then performed. Since the embolization, there have been no further episodes of bleeding. There is no established treatment for AVMs. Successful treatment requires targeting and eradication of the nidus. We successfully performed embolization therapy for a rectal AVM via a retrograde transvenous approach. This technique may be suitable for completely eradicating the nidus without the risk of embolism.

Whole-body insulin sensitivity index is a highly specific predictive marker for virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients with genotype 1b and high viral load.

Insulin resistance is a candidate predictive factor for virological response to peginterferon plus ribavirin (PEG/RBV) therapy in chronic hepatitis C patients. We examined whether indices of insulin resistance could serve as a predictor of sustained virological response (SVR). Fifty-one patients with genotype 1b and high viral load who received PEG/RBV therapy for 48 weeks were included. Homeostasis model assessment of insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI) calculated from the 75-g oral glucose tolerance test and serum levels of soluble tumor necrosis factor receptor 2 (sTFNR2) were evaluated before therapy. Patients who achieved SVR had significantly lower HOMA-IR and sTNFR2 levels and a higher WBISI compared with non-SVR patients. The positive predictive value for SVR was 0.653 for a HOMA-IR of <2 and 0.846 for a WBISI of 6 or higher. WBISI may serve as a highly specific predictor for SVR in PEG/RBV therapy.

Presence of esophageal varices is a risk factor for non-hemorrhagic death of hepatocellular carcinoma patients treated with radiofrequency ablation.

BACKGROUND/AIMS: The presence of esophageal varices (EVs) is believed to be a factor that affects the prognosis of patients with hepatocellular carcinoma (HCC). We examined whether the presence and severity of EVs affected either survival prognosis or the cause of death in HCC patients treated with radiofrequency ablation (RFA). METHODOLOGY: The study included 89 HCC patients treated with RFA who were endoscopically evaluated for EVs before treatment. To determine factors associated with survival, we performed univariate and multivariate analyses of variables including demographics, tumor stage, Child-Pugh class and status of EVs. Furthermore, we investigated the association between the presence of EVs and causes of death. RESULTS: Multivariate analyses showed both Child-Pugh class B (odds ratio: 2.654; p = 0.017) and EVs (odds ratio: 3.18; p = 0.004) to be independent factors of poor prognosis. Of 34 patients who died during the period of observation, one died because of an EV rupture. CONCLUSIONS: The existence of EVs may affect survival prognosis of HCC patients treated with RFA independently of Child-Pugh status, but is not associated with hemorrhagic death.

Association of soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) and mac-2 binding protein glycosylation isomer (M2BPGi) in patients with autoimmune hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver injury progress to cirrhosis or hepatocellular carcinoma (HCC). The aim of the present study was to determine whether circulating soluble TIM3 (sTIM3) is elevated in patients with AIH patients and whether sTIM-3 levels are associated with clinical parameters of AIH. METHODS: We enrolled 123 Japanese patients with AIH who were identified from the National Hospital Organization-AIH-liver-network database, as well as 32 patients with chronic hepatitis C (CHC), 30 patients with primary biliary cholangitis (PBC) and healthy control subjects. Serum sTIM-3 concentrations were quantified by ELISA. RESULTS: Serum levels of sTIM-3 were significantly higher in AIH patients (median 4865 pg/ml; [interquartile range (IQR); 3122-7471]) compared to those in CHC (1026 pg/ml [IQR: 806-1283] p<0.001), PBC (2395 pg/ml [IQR: 2012-3422] p<0.001) or healthy controls (1285 pg/ml [IQR: 1098-1812] p<0.001). In AIH group, serum sTIM-3 were correlated with alanine aminotransferase (ALT), or total bilirubin (TB) and negatively correlated with serum levels of albumin (Alb). Serum levels of sTIM-3 were also strongly correlated with Mac-2 binding protein glycosylation isomer (M2BPGi) levels, but did not correlate with the histological grade of liver fibrosis. Steroid treatment of AIH patients significantly reduced serum sTIM-3 levels (2147±623pg/ml versus 1321±378pg/ml, p<0.001). CONCLUSIONS: Circulating sTIM-3 levels were elevated in AIH patients and are associated with AIH disease activity and AIH-related liver damage. These findings indicate that serum sTIM-3 correlated with disease status of AIH and could be useful biomarkers to detect autoimmune-mediated liver injury. Our data suggest a possible link between the TIM-3/GAL-9 pathway and AIH severity or phenotype, and further investigations of the TIM-3 pathway and AIH pathophysiology is warranted.

Eradication of hepatitis C virus by interferon improves whole-body insulin resistance and hyperinsulinaemia in patients with chronic hepatitis C.

BACKGROUND/AIMS: To investigate whether eradication of hepatitis C virus (HCV) by interferon (IFN) therapy influences systemic glucose metabolism. METHODS: Seventy-two patients with chronic hepatitis C were enrolled in this study. Patients received IFN therapy and were classified into two groups: sustained responders (n=48) and nonsustained responders (n=24). We analysed systemic glucose metabolism in terms of the following indices: homeostasis model assessment for insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta), insulinogenic index (II), composite insulin sensitivity index (ISI composite) and the area under the curve of plasma glucose (PG-AUC) and serum insulin (SI-AUC) in oral glucose tolerance tests. In 28 sustained responders and 16 nonsustained responders, serum levels of soluble tumour necrosis factor receptor 2 (sTNFR2) were measured. Indices were determined before and 6 months after therapy. RESULTS: In the sustained responders, HOMA-beta (P=0.0004) and SI-AUC (P=0.002) were significantly decreased and the ISI composite was increased (P=0.009), although there were no significant changes in HOMA-IR, II or PG-AUC. Serum sTNFR2 levels decreased significantly after therapy in sustained responders (P=0.001). In the nonsustained responders, there were no changes in any index. CONCLUSIONS: Eradication of HCV by IFN therapy could improve whole-body insulin resistance and insulin hypersecretion with reduced serum TNF-alpha levels.

Hepatitis C virus infection enhances insulin resistance induced by visceral fat accumulation.

BACKGROUND/AIMS: To clarify the impact of visceral obesity on hepatitis C virus (HCV)-infected patients, we examined the relationship between insulin resistance development and visceral fat accumulation. METHODS: We analyzed 87 HCV-infected patients with mild fibrosis (stage 1 or 2) in comparison with 125 sex- and age-matched patients with non-alcoholic fatty liver disease (NAFLD). The degree of visceral fat area (VFA; cm(2)) at the umbilical level was measured by abdominal computed tomography and divided into two grades: no visceral obesity, VFA<100 and visceral obesity, VFA>/=100. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). Pancreatic beta-cell function was evaluated by homeostasis model assessment of beta-cell function (HOMA-beta). Serum soluble tumour necrosis factor (TNF)-receptors 1 and 2 and adiponectin were measured. RESULTS: Insulin resistance evaluated by HOMA-IR and QUICKI was correlated with visceral fat accumulation, and was higher in HCV patients than in NAFLD patients with visceral obesity. HOMA-beta was higher in HCV patients than in NAFLD patients for each VFA grade. Serum-soluble TNF-receptors 1 and 2 were higher in HCV patients than in NAFLD patients with visceral obesity. CONCLUSIONS: Hepatitis C virus infection is a risk factor for development of insulin resistance, particularly in patients with visceral obesity.

Role of deleterious single nucleotide variants in the coding regions of TNFAIP3 for Japanese autoimmune hepatitis with cirrhosis.

Autoimmune hepatitis (AIH) is an autoimmune liver disease and cirrhosis is sometimes complicated with AIH at diagnosis, influencing its prognosis. TNFAIP3 gene encodes A20, an inhibitor of nuclear factor-κB pathway, and is a susceptibility gene for autoimmune diseases. We investigated deleterious variants in the coding regions of TNFAIP3 gene of Japanese AIH patients or those with cirrhosis. The deleterious variants in the coding regions of TNFAIP3 gene were analyzed by the cycle sequencing method and the frequencies of deleterious TNFAIP3 alleles of AIH or AIH with cirrhosis were compared with those of Japanese controls. The deleterious alleles in TNFAIP3 were not associated with AIH. A significant association was shown for the deleterious alleles in TNFAIP3 (P = 0.0180, odds ratio (OR) 4.28, 95% confidence interval (CI) 1.53-11.95) with AIH with cirrhosis at presentation. The serum IgM levels in AIH patients with deleterious alleles in TNFAIP3 were tended to be lower than those without (P = 0.0152, Q = 0.1216). The frequency of deleterious alleles in TNFAIP3 was higher in the AIH subset without the DRB1 risk alleles than that with (P = 0.0052, OR 5.10, 95%CI 1.55-16.74). The deleterious alleles in TNFAIP3were associated with AIH with cirrhosis.

Galectin-9 in autoimmune hepatitis: Correlation between serum levels of galectin-9 and M2BPGi in patients with autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver damage progresses to cirrhosis or hepatocellular carcinoma (HCC). The mainstay therapy for AIH is steroids and other immunosuppressive treatments. Currently, there are no validated markers for monitoring immune-mediated hepatic inflammation. Galectin-9 has recently been identified as a potential biomarker in patients with chronic liver disease. The objective of this study was to determine whether Galectin-9 and other serum proteins are associated with active disease in AIH patients.We enrolled 77 Japanese patients with well-documented AIH who were identified from the National Hospital Organization-AIH-liver-network database, as well as 32 patients with chronic hepatitis C (CHC), 27 patients with SLE, and 17 healthy control subjects. Serum levels of galectin-9, and markers of liver injury were measured and compared between groups.Serum levels of galectin-9 were significantly higher in AIH patients than in CHC patients (13.8 ±â€Š4.9 ng/mL vs 8.9 ±â€Š3.0 ng/mL, P < .001) or healthy controls (13.8 ±â€Š4.9 ng/mL vs 5.0 ±â€Š1.3 ng/mL, P < .001). In AIH group, serum galectin-9 levels weakly correlated with alanine aminotransferase levels or total bilirubin (TB) and strongly correlated with C-X-C motif chemokine 10 (CXCL10) and Mac-2 binding protein glycosylation isomer (M2BPGi) levels, but did not correlate with the histological grade of liver fibrosis. Steroid treatment of AIH patients significantly reduced serum galectin-9 levels (14.1 ±â€Š4.9 ng/mL vs 8.3 ±â€Š3.8 ng/mL, P < .001). SLE patients exhibited higher galectin-9 levels, whereas the galectin-9 levels did not correlate with liver function tests such as alanine aminotransferase levels.Serum galectin-9 correlated with disease status in AIH patients and could thus be useful biomarkers to detect hepatic autoimmunity. Because circulating galectin-9 reflects autoimmune-mediated inflammation, it may have additional utility as a biomarker for other autoimmune disorders.