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.

2-Step PLT16-AST44 method: Simplified liver fibrosis detection system in patients with non-alcoholic fatty liver disease.

AIM: Accurate detection of the hepatic fibrosis stage is essential to estimate the outcome of patients with non-alcoholic fatty liver disease (NAFLD). Many formulas, biomarkers, and imaging tests are being developed to predict advanced liver fibrosis without performing a liver biopsy. However, these tests do not have high efficiency in detecting early-stage hepatic fibrosis. Therefore, we aimed to detect the presence of hepatic fibrosis (≥F1) merely by using only standard clinical markers. METHODS: A total of 436 patients with NAFLD who underwent liver biopsy were retrospectively enrolled as the discovery cohort (316 patients) and the validation cohort (120 patients). Liver biopsy and laboratory data were matched to extract simple parameters for identifying ≥F1. RESULTS: We developed a novel simplified ≥F1 detecting system, designated as 2-Step PLT16-AST44 method, where (1) PLT of 16 × 104 /µl or less, or (2) PLT greater than 16 × 104 /µl and AST greater than 44 U/L is determined as having ≥F1 fibrosis. The 2-Step PLT16-AST44 method had a sensitivity of 68%, a specificity of 90%, a positive predictive value (PPV) of 97%, a negative predictive value (NPV) of 40%, and an accuracy of 72% to detect ≥F1 fibrosis in the discovery cohort. Validation studies further supported these results. Despite its simplicity, the 2-Step PLT16-AST44 method's power to detect ≥F1 fibrosis in total NAFLD patients was comparable to hyaluronic acid, type 4 collagen 7S, FIB-4, and APRI. CONCLUSIONS: We propose the 2-Step PLT16-AST44 method as a simple and beneficial early-stage hepatic fibrosis detection system.

Serum thrombospondin 2 is a novel predictor for the severity in the patients with NAFLD.

AIM: Thrombospondins are a family of multidomain and secretory glycoproteins. Among them, thrombospondin 2 (TSP2) encoded by TSP2 gene has been reported to be involved in various functions such as collagen/fibrin formation, maintenance of normal blood vessel density and cell adhesion properties. Microarray analyses ranked TSP2 as one of the most highly up-regulated genes in the fibrotic liver in patients with non-alcoholic fatty liver disease (NAFLD). Since TSP2 possesses unique properties as a secretory protein, we hypothesized that hepatic TSP2 gene expression levels would be reflected in serum TSP2 levels. In this study, we examined the relationship between serum TSP2 concentrations and clinicopathological findings in NAFLD patients. METHODS: One hundred and thirty NAFLD patients who had undergone liver biopsy between 2009 and 2015 were retrospectively enrolled. Serum samples were collected at the time of biopsy, and TSP2 was measured by enzyme immunoassays. RESULTS: Serum TSP2 levels moderately correlated with ballooning (r = 0.56, P < .001) and fibrosis stage (r = 0.53, P < .001). The AUC values of TSP2 for predicting mild fibrosis (≧F1), moderate fibrosis (≧F2) and severe fibrosis (≧F3) were 0.73, 0.76 and 0.82 respectively. Additionally, NAFLD activity score (NAS) correlated best with TSP2 (r = 0.52, P < .001) compared to conventional NAFLD-related biomarkers, such as cytokeratin 18 M30, hyaluronic acid, type IV collagen 7S, APRI and FIB-4 index. CONCLUSION: Serum TSP2 levels reflected hepatocyte ballooning, fibrosis and NAS in NAFLD patients. For clinical application of serum TSP2 as a predictor of NAFLD histological activity, additional validation and mechanistic investigations are required.

aMAP score prediction of hepatocellular carcinoma occurrence and incidence-free rate after a sustained virologic response in chronic hepatitis C.

AIMS: Hepatocellular carcinoma (HCC) can still occur in hepatitis C virus (HCV) patients who have achieved a sustained virologic response (SVR), which remains an important clinical issue in the direct-acting antivirals era. The current study investigated the clinical utility of the aMAP score (consisting of age, male, albumin-bilirubin, and platelets) for predicting HCC occurrence in HCV patients achieving an SVR by direct-acting antivirals. METHODS: A total of 1113 HCV patients without HCC history, all of whom achieved an SVR, were enrolled for clinical comparisons. RESULTS: Hepatocellular carcinoma was recorded in 50 patients during a median follow-up period of 3.7 years. The aMAP score was significantly higher in the HCC occurrence group than in the HCC-free group (53 vs. 47, p < 0.001). According to risk stratification based on aMAP score, the cumulative incidence of HCC occurrence for the low-, medium-, and high-risk groups was 0.14%, 4.49%, and 9.89%, respectively, at 1 year and 1.56%, 6.87%, and 16.17%, respectively, at 3 years (low vs. medium, low vs. high, and medium vs. high: all p < 0.01). Cox proportional hazard analysis confirmed aMAP ≥ 50 (hazard ratio [HR]: 2.78, p = 0.014), age≥ 70 years (HR: 2.41, p = 0.028), ALT ≥ 17 U/L (HR: 2.14, p < 0.001), and AFP ≥ 10 ng/mL (HR: 2.89, p = 0.005) as independent risk factors of HCC occurrence. Interestingly, all but one patient (99.5%) with aMAP less than 40 was HCC-free following an SVR. CONCLUSION: The aMAP score could have clinical utility for predicting HCC occurrence in HCV patients achieving an SVR.

Clinical utility of FibroScan as a non-invasive diagnostic test for primary biliary cholangitis.

BACKGROUND AND AIM: Primary biliary cholangitis (PBC) is a chronic, slowly progressive, autoimmune liver disease. Some PBC patients display disease progression regardless of medical treatment. Therefore, it is important to accurately diagnose the clinical stage of PBC. This study investigated clinical merits of vibration-controlled transient elastography using FibroScan for assessing disease stage in PBC. METHODS: A total of 74 treatment-naïve PBC patients (84% female, median age: 64 years), 69 of whom having undergone histological assessment and five clinically diagnosed as at the cirrhosis stage, were enrolled for clinical comparisons of liver stiffness measurement (LSM) with other established indices. RESULTS: The number of patients with Nakanuma stages 1, 2, 3, and 4 was 18, 33, 17, and 6, respectively. The median LSM values for Nakanuma stages 1, 2, 3, and 4 were 5.05, 5.90, 8.90, and 23.70 kPa, respectively, and correlated significantly with disease progression based on Nakanuma's classification (r = 0.501, P < 0.001). LSM was also significantly related to other non-invasive serological markers (Mac-2 binding protein glycosylation isomer: r = 0.606, FIB-4 index: r = 0.493, and aspartate aminotransferase-to-platelet ratio index: r = 0.577; all P < 0.001). The areas under the receiver operating characteristic curve for diagnosing Nakanuma stage ≥ 2, stage ≥ 3, and stage 4 were 0.744, 0.763, and 0.907, respectively. A combination of LSM ≥ 7.0 kPa and Mac-2 binding protein glycosylation isomer ≥ 1.00 cut-off index could predict late-stage PBC (i.e. moderate to advanced disease progression) with a sensitivity of 0.58, specificity of 0.82, and accuracy of 0.74. CONCLUSIONS: Liver stiffness measurement using FibroScan provided simple, accurate, and non-invasive assessment of disease stage in PBC patients.

Biochemical and plasma lipid responses to pemafibrate in patients with primary biliary cholangitis.

AIM: Fibrate addition to ursodeoxycholic acid (UDCA) therapy has been shown to improve both liver biochemistry and long-term prognosis in primary biliary cholangitis (PBC) patients showing an incomplete biochemical response to UDCA alone. We herein describe the clinical outcome of seven cases of PBC that received the new selective peroxisome proliferator-activated receptor α modulator, pemafibrate, in combination with UDCA therapy to investigate the biochemical and plasma lipid responses to the drug. METHODS: Of 124 initially enrolled PBC patients, 12 treated with UDCA alone and seven receiving UDCA plus bezafibrate showed alkaline phosphatase (ALP) levels above the upper limit of normal (330 U/L). Ultimately, seven patients with PBC and dyslipidemia who had agreed to biweekly visits at our hospital for UDCA plus pemafibrate combination therapy were retrospectively analyzed. RESULTS: In the four cases that switched from bezafibrate to pemafibrate, ALP became significantly decreased (0.031) and γ-glutamyltransferase tended to decrease (0.063) over the 3 months following pemafibrate addition. Two patients showed a greater than 50% reduction in ALP. No remarkable differences were observed for plasma lipid levels, alanine aminotransferase, aspartate aminotransferase, or the liver fibrosis marker Mac-2 binding protein glycosylation isomer between these time points. No adverse drug reactions were recorded. CONCLUSIONS: Pemafibrate might be another option for PBC patients with an incomplete response to UDCA therapy.

Past history of hepatocellular carcinoma is an independent risk factor of treatment failure in patients with chronic hepatitis C virus infection receiving direct-acting antivirals.

Direct-acting antiviral (DAA) treatment can achieve a high sustained virological response (SVR) rate in patients with hepatitis C virus (HCV) infection regardless of a history of hepatocellular carcinoma (HCC [+]). We examined 838 patients (370 men, median age: 69 years) who were treated with DAAs for comparisons of clinical findings between 79 HCC (+) (9.4%) and 759 HCC (-) (90.6%) patients and associations with treatment outcome. Male frequency was significantly higher in the HCC (+) group (60.8% vs 42.4%, P = 0.006). There were significant differences between the HCC (+) and HCC (-) groups for platelet count (115 vs 152 ×109 /L, P < 0.001), baseline alpha fetoprotein (AFP) (9.9 vs 4.5 ng/mL, P < 0.001) and the established fibrosis markers of FIB-4 index (4.7 vs 3.0, P < 0.001), AST-to-platelet ratio index (APRI) (1.1 vs 0.7, P = 0.009), M2BPGi (3.80 vs 1.78 COI, P < 0.001) and autotaxin (1.91 vs 1.50 mg/L, P < 0.001). The overall SVR rate was 94.7% and significantly lower in the HCC (+) group (87.3 vs 95.5%, P = 0.001). Multivariate analysis revealed that a history of HCC was independently associated with DAA treatment failure (odds ratio: 3.56, 95% confidence interval: 1.32-9.57, P = 0.01). In conclusion, patients with chronic HCV infection and prior HCC tended to exhibit more advanced disease progression at DAA commencement. HCC (+) status at the initiation of DAAs was significantly associated with adverse therapeutic outcomes. DAA treatment for HCV should therefore be started as early as possible, especially before complicating HCC.

Quantitative analysis of serum chemokines associated with treatment failure of direct-acting antivirals in chronic hepatitis C.

Although serum chemokine levels have been reported to influence the outcome of interferon-based treatment in patients with chronic hepatitis C, their effect on the hepatitis C virus (HCV) response to direct-acting antiviral agents (DAAs), which can achieve high rates of a sustained virological response (SVR), is largely unknown. To clarify this relationship, 9 chemokines (eotaxin, GRO-α, IL-8, IP-10, MCP-1, MIP-1α, MIP-1ß, RANTES, and SDF-1α) were quantified before, during, and after DAA treatment using serum samples obtained from 57 patients with chronic hepatitis C. All baseline median chemokine levels were significantly higher in patients with chronic hepatitis C than in healthy subjects (P < 0.05). In particular, lower MIP-1ß (≤71.5 pg/mL) and higher RANTES (>671.5 pg/mL) levels were significantly associated with patients who failed to clear HCV RNA (P = 0.0039 and 0.013, respectively). Prediction of a clinical response based on a combination of these chemokines demonstrated high sensitivity (82%), specificity (85%), negative predictive value (95%), and area under the curve (0.833). The non-SVR rate (56.3%; 9 of 16) was significantly higher in patients with low MIP-1ß and high RANTES compared with other combinations. Moreover, baseline MIP-1ß and RANTES were both additive and independent for predicting a non-SVR. Apart from an increase in eotaxin, all chemokines became decreased in patients with a SVR. In conclusion, a combination of serum MIP-1ß and RANTES levels may be predictive of a treatment response to DAAs in Japanese patients with chronic hepatitis C.

Serum autotaxin is a useful liver fibrosis marker in patients with chronic hepatitis B virus infection.

AIM: Autotaxin (ATX) is a secreted enzyme that is considered to be associated with liver damage as well as fibrosis. This study assessed the ability of ATX to diagnose liver fibrosis in patients with chronic hepatitis B virus (HBV) infection. METHODS: Serum ATX levels were retrospectively evaluated in 101 treatment-naïve patients with HBV-related chronic hepatitis or cirrhosis, all of whom had undergone liver biopsy at our hospital. RESULTS: Serum ATX concentration increased significantly according to liver fibrosis stage in overall (r = 0.46, P < 0.0001), male (r = 0.55, P < 0.0001), and female (r = 0.52, P = 0.0006) patient groups. When analyzed by gender, serum ATX was one of the most reliable markers for all fibrosis stages compared with other tested non-invasive markers, which included hyaluronic acid, type IV collagen 7S, aspartate aminotransferase-to-platelet ratio index, and fibrosis index based on four factors, according to receiver operating characteristic curve analysis. CONCLUSION: Based on this histologically proven data, ATX represents a novel non-invasive biomarker for liver fibrosis in HBV-infected patients.

Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients.

AIM: Postprandial hyperglycemia is frequently accompanied by non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Although α-glucosidase inhibitors (αGIs) can slow glucose absorption from the intestine and suppress the surge of circulating glucose concentration after meals, it remains unclear whether αGIs are also beneficial for NASH. The aim of this prospective study was to examine the efficacy and safety of miglitol, a typical αGI, for NASH. METHODS: Seventeen patients with histologically confirmed NASH and hemoglobin A1c (HbA1c) >6.5% were treated with miglitol (150 mg/day) for 12 months. The changes in clinical parameters and liver histology were analyzed. RESULTS: All patients completed the 12-month miglitol treatment course with no severe adverse events. The treatment significantly decreased body mass index, serum alanine aminotransferase levels, and HbA1c (all P < 0.001). Post-treatment liver biopsy of 11 patients revealed significant improvements in steatosis (from 2.2 ± 0.6 to 1.5 ± 0.7, P = 0.001), lobular inflammation (from 1.8 ± 0.8 to 1.3 ± 0.5, P = 0.014), portal inflammation scores (from 0.6 ± 0.5 to 0.1 ± 0.3, P = 0.025), and NAFLD activity score (from 5.5 ± 1.5 to 3.9 ± 1.4, P = 0.012). Fibrosis and hepatocyte ballooning scores were unchanged. CONCLUSIONS: Miglitol appears to safely ameliorate NASH activity by attenuation of steatosis and lobular/portal inflammation. Appropriately powered controlled trials are warranted to validate our results.

A case of liver abscess co-infected with Desulfovibrio desulfuricans and Escherichia coli and review of the literature.

A 73-year-old woman was admitted with consciousness disturbance following a fever. Abdominal computed tomography revealed a large liver abscess with which the presence of Desulfovibrio desulfuricans and Escherichia coli was confirmed by thorough blood and abscess content culture. Empiric meropenem treatment was switched to cefoperazone/sulbactam, followed by ampicillin/sulbactam based on susceptibility testing. Desulfovibrio desulfuricans is a common bacterium that rarely causes liver abscess and may be overlooked during co-infection due to overgrowth of the accompanying bacteria. Clinicians should bear Desulfovibrio desulfuricans in mind and select the appropriate antibiotics according to susceptibility testing when anaerobic bacteria are detected in a liver abscess.

Growth arrest and DNA damage-inducible 45α protects against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet.

Growth arrest and DNA damage-inducible 45 α (Gadd45α) is a stress-inducible protein that plays an important role in cell survival/death and DNA repair, but its contribution to the development of nonalcoholic steatohepatitis (NASH) has not been investigated. C57BL/6 Gadd45a-null and wild-type (WT) mice were treated with a methionine and choline-deficient diet (MCD) for eight weeks and phenotypic changes examined. Gadd45a-null mice had more severe hepatic inflammation and fibrosis, higher levels of mRNAs encoding pro-inflammatory, pro-fibrotic, and pro-apoptotic proteins, and greater oxidative and endoplasmic reticulum (ER) stress compared with WT mice. Indeed, Gadd45a mRNA was induced in response to ER stress in primary hepatocytes. Lipidomic analysis of NASH livers demonstrated decreased triacylglycerol (TG) in MCD-treated Gadd45a-null mice, which was associated with increased mRNAs encoding phospholipase D (Pld1/2), phosphatidic acid phosphatase type 2A, and choline/ethanolamine phosphotransferase 1 (Cept1), involved in the phosphatidylcholine-phosphatidic acid-diacylglycerol cycle, and decreased mRNAs encoding fatty acid (FA)-binding protein 1 (Fabp1) and FA transport protein 5. Treatment of cultured primary hepatocytes with tumor necrosis factor α, transforming growth factor ß, and hydrogen peroxide led to the corresponding induction of Fabp1, Pld1/2, and Cept1 mRNAs. Collectively, Gadd45α plays protective roles against MCD-induced NASH likely due to attenuating cellular stress and ensuing inflammatory signaling. These results also suggest an interconnection between hepatocyte injury, inflammation and disrupted glycerophospholipid/FA metabolism that yields a possible mechanism for decreased TG accumulation with NASH progression (i.e., "burned-out" NASH).

Association between serum soluble CD14 and IL-8 levels and clinical outcome in primary biliary cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts that often leads to liver decompensation and liver failure. Although the biochemical response to ursodeoxycholic acid (UDCA) can predict disease outcome in PBC, few biomarkers have been identified as prognostic tools applicable prior to UDCA treatment. We therefore sought to identify such indicators of long-term outcome in PBC in the Japanese population. METHODS: The prebiopsy serum samples and subsequent clinical data of 136 patients with PBC treated with UDCA were analysed over a median follow-up period of 8.8 years. Serum levels of biomarkers related to microbial translocation (sCD14, EndoCAb and I-FABP) were measured along with those of 33 cytokines and chemokines and additional auto-antibodies. Associations between the tested parameters and the clinical outcomes of liver decompensation and liver-related death/liver transplantation were evaluated using the Cox proportional hazards model with stepwise methods and Kaplan-Meier analysis. RESULTS: Elevated levels of serum IL-8, and sCD14 before UDCA therapy were significantly associated with both liver decompensation and liver-related death/liver transplantation. In multivariate analyses, IL-8≥46.5 pg/mL or sCD14≥2.0 µg/mL at enrolment demonstrated the same results. Kaplan-Meier analysis also revealed IL-8 and sCD14 to be significantly associated with a poor outcome. sCD14 was significantly correlated with IL-8. EndoCAb and I-FABP were not related to disease outcome. CONCLUSIONS: Serum IL-8 and sCD14 levels before UDCA therapy represent noninvasive surrogate markers of prognosis in patients with PBC.

Serum Wisteria floribunda agglutinin-positive human Mac-2 binding protein may predict liver fibrosis and progression to hepatocellular carcinoma in patients with chronic hepatitis B virus infection.

AIM: Serum glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) is a reliable, non-invasive marker of liver fibrosis. This study assessed the ability of WFA+ -M2BP to diagnose liver fibrosis in patients with chronic hepatitis B virus (HBV) infection and evaluated WFA+ -M2BP as a predictor of hepatocellular carcinoma (HCC) development. METHODS: Serum WFA+ -M2BP values were retrospectively evaluated in 112 treatment-naïve patients with HBV-related chronic hepatitis and cirrhosis who had undergone liver biopsy at our hospital. RESULTS: Serum WFA+ -M2BP levels were significantly related with liver fibrosis (r = 0.3725, P = 0.001). Fibrosis stage F2, F3, and F4 had a cut-off index of 0.94, 1.26, and 1.26, respectively. For diagnosing F ≥ 2 fibrosis, the area under the receiver-operating characteristic curve for WFA+ -M2BP was 0.713 and comparable with those of other non-invasive fibrosis markers, such as hyaluronic acid, type IV collagen 7S, aspartate aminotransferase-to-platelet ratio index, fibrosis-4 index, serum albumin, and platelet count. Multivariate analysis identified male, WFA+ -M2BP ≥0.71, alanine aminotransferase ≥80 IU/L, and platelet count <14.5 × 109 /L as independent risk factors for the development of HCC in patients with HBV infection. CONCLUSIONS: Serum WFA+ -M2BP values appear to be useful for assessing liver fibrosis stage and are independently associated with HCC development in patients with chronic HBV infection.

Clinicopathological characteristics of non-B non-C hepatocellular carcinoma without past hepatitis B virus infection.

AIM: Past hepatitis B virus (HBV) infection is considered a risk factor for hepatocarcinogenesis, but the clinicopathological characteristics of non-B non-C hepatocellular carcinoma (NBNC-HCC) excluding past HBV infection have not been investigated. This study aimed to clarify the clinicopathological features of strictly defined NBNC-HCC. METHODS: Among HCC patients who underwent surgical resection at our affiliated hospitals in Nagano prefecture, Japan, between 1996 and 2012, 77 were negative for serum anti-HBV core/surface antibodies in addition to HBV surface antigen and anti-hepatitis C virus antibody without signs of autoimmune liver disease, Wilson disease, or hemochromatosis. These patients were divided into the alcohol intake-positive group (ethanol intake >20 g/day, n = 31), non-alcoholic fatty liver group (steatosis >5% and ethanol intake <20 g/day, n = 30), and cryptogenic group (no ethanol intake or steatosis, n = 16). Preoperative clinical parameters, tumor and background liver pathology, and prognosis were analyzed. RESULTS: Advanced fibrosis and steatosis were detected in 64% and 60% of all patients, respectively. Approximately 85% of the alcohol intake-positive patients had advanced fibrosis. Non-alcoholic fatty liver HCC subjects had the highest body mass index and prevalence of diabetes, but 30-40% had none to mild fibrosis. The cryptogenic group of HCC patients had the lowest incidence of accompanying hepatic inflammation/fibrosis but the largest tumor size. Recurrence/survival rates were comparable among the groups. CONCLUSIONS: Liver fibrosis and steatosis are risk factors of HCC regardless of past HBV infection and ethanol consumption. The present results also indicate the possibility of hepatocarcinogenesis independent of hepatic steatosis, inflammation and fibrosis, ethanol intake, and past HBV infection.

Liver stiffness-spleen size-to-platelet ratio risk score identifies esophageal varices in Japanese patients with chronic hepatitis C.

AIM: Non-invasive methods are needed to identify esophageal varices (EV) in patients with chronic liver disease. To this end, we evaluated liver stiffness (LS)-spleen diameter-to-platelet ratio risk score (LSPS) in predicting EV among Japanese chronic hepatitis C patients. METHODS: A total of 99 patients with chronic hepatitis C who had undergone endoscopy, LS measurement and ultrasonography between 2013 and 2014 were enrolled. Clinical data were compared with those for other non-invasive markers (platelet count, aspartate aminotransferase-to-platelet ratio, FIB-4 index and platelet-to-spleen ratio), spleen size, LS and controlled attenuation parameter. Diagnostic applicability was assessed by the area under the receiver-operator curve (AUC) and predictive values along with multivariate logistic regression. RESULTS: LSPS was significantly correlated to the grade of EV (ρ = 0.617, P < 0.001) and was superior to the other non-invasive indices for determination of EV. LSPS was independently associated with EV by multivariate logistic regression analysis (odds ratio, 3.079; 95% confidence interval [CI], 2.137-4.438; P < 0.001). The cut-off value of LSPS for EV was 0.7, for which the AUC, sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 0.928 (95% CI, 0.876-0.980), 86.3%, 89.6%, 70.4%, 95.8% and 88.9%, respectively. CONCLUSION: LSPS may also identify EV in patients with chronic hepatitis C in Japan. The clinical values of LSPS for EV risk merit further validation in larger prospective studies.

Controlled attenuation parameter is correlated with actual hepatic fat content in patients with non-alcoholic fatty liver disease with none-to-mild obesity and liver fibrosis.

AIM: Non-invasive steatosis-quantifying methods are required for non-alcoholic fatty liver disease (NAFLD) patients in order to monitor disease severity and assess therapeutic efficacy. Controlled attenuation parameter (CAP) evaluated with vibration-controlled transient elastography can predict the presence of steatosis, but its application to absolute hepatic fat quantitation remains unclear. The aim of this st\udy was to examine whether CAP is correlated with real hepatic fat content in NAFLD patients. METHODS: Eighty-two NAFLD patients who had undergone percutaneous liver biopsy were enrolled. CAP was measured using FibroScan(®) just before liver biopsy. The percentage of fat droplet area to hepatocyte area in biopsied specimen was determined morphometrically using computerized optical image analyzing system. The correlation between CAP and liver histology was examined. RESULTS: CAP showed an excellent correlation with actual liver fat percentage in the NAFLD patients with body mass index (BMI) of less than 28 kg/m(2) (r = 0.579, P < 0.0001), especially less than 25 kg/m(2) (r = 0.708, P < 0.01), but the meaningful correlation disappeared in the patients with BMI of 28 kg/m(2) or more. In the patients with BMI of less than 28 kg/m(2) , CAP quantitativeness was affected by the presence of stage 2-4 fibrosis, but not the presence of hepatocyte ballooning and severity of lobular inflammation. CONCLUSION: CAP may be a promising tool for quantifying hepatic fat content in NAFLD patients with none-to-mild obesity and liver fibrosis. Further improvement of CAP performance is needed for the NAFLD patients with BMI of more than 28 kg/m(2) or significant hepatic fibrosis.

Serum autotaxin is a prognostic indicator of liver-related events in patients with non-alcoholic fatty liver disease.

BACKGROUND: Circulating autotaxin (ATX) levels have been reported to correlate with liver inflammation activity and liver fibrosis severity in patients with non-alcoholic fatty liver disease (NAFLD). The objective of this study is to investigate whether serum ATX could predict liver-related events (LRE) in NAFLD patients. METHODS: This retrospective investigation includes 309 biopsy-proven NAFLD patients registered at Shinshu University Hospital. All patients are followed for at least 1 year, during which time the prevalence of LRE, including newly developing hepatocellular carcinoma, hepatic encephalopathy, ascites, and esophagogastric varices, is investigated in relation to ATX levels at the time of liver biopsy. RESULTS: During the median follow-up period of 7.0 years, LRE are observed in 20 patients (6.5%). The area under the receiver operating characteristic curve and cut-off value of serum ATX for predicting LRE are 0.81 and 1.227 mg/l, respectively. Multivariate Cox proportional hazards models for LRE determine ATX and advanced fibrosis as independently associated factors. Furthermore, in a competing risk analysis that considered non-liver-related death as a competing event, ATX (HR 2.29, 95% CI 1.22-4.30, p = 0.010) is identified as an independent factor associated with LRE, along with advanced fibrosis (HR 8.01, 95% CI 2.10-30.60, p = 0.002). The predictive utility of ATX for LRE is validated in an independent cohort. CONCLUSIONS: Serum ATX may serve as a predictive marker for LRE in patients with NAFLD.

In non-alcoholic fatty liver disease (NAFLD), fat accumulates and can cause damage within the liver. The disease is becoming increasingly common worldwide. It is therefore important to identify individuals with NAFLD who are at higher risk of developing severe liver complications. In this study, we found that NAFLD patients with elevated levels of a substance called autotaxin (ATX) in their blood were more prone to liver-related issues. Thus, it is crucial for doctors to give special attention to NAFLD patients exhibiting high ATX levels. Through close ATX monitoring and appropriate treatment, doctors can potentially enhance their health outcomes and prevent the onset of more severe liver complications.

Prognostic Significance of C-Reactive Protein in Lenvatinib-Treated Unresectable Hepatocellular Carcinoma: A Multi-Institutional Study.

BACKGROUND: Serum C-reactive protein (CRP) is an established biomarker for acute inflammation and has been identified as a prognostic indicator for hepatocellular carcinoma (HCC). However, the significance of the serum CRP level, specifically in HCC patients treated with lenvatinib, remains unclear. METHODS: We retrospectively analyzed 125 HCC patients who received lenvatinib treatment at six centers. Clinical characteristics were assessed to identify clinical associations between serum CRP and HCC prognosis. RESULTS: The median overall serum CRP level was 0.29 mg/dL. The cohort was divided into two groups: the low-CRP group with a serum CRP < 0.5 mg/dL and the high-CRP group with a serum CRP ≥ 0.5 mg/dL. The low-CRP group exhibited significantly longer overall survival (OS) than the high-CRP group (22.9 vs. 7.8 months, p < 0.001). No significant difference was observed for progression-free survival (PFS) between the high- and low-CRP groups (9.8 vs. 8.4 months, p = 0.411), while time-to-treatment failure (TTF) was significantly longer in the low-CRP group (8.5 vs. 4.4 months, p = 0.007). The discontinuation rate due to poor performance status was significantly higher in the high-CRP group (p < 0.001). CONCLUSION: A baseline serum CRP level exceeding 0.5 mg/dL was identified as an unfavorable prognostic factor in HCC patients receiving lenvatinib treatment.

Non-alcoholic fatty liver disease later diagnosed as myotonic dystrophy.

BACKGROUND: Myotonic dystrophy (MD) is sometimes accompanied by metabolic/endocrine disorders, including dyslipidemia, central obesity, and hypogonadism. Due to considerable individual differences in the severity and progression of myopathy, MD patients with minimal-to-mild muscle symptoms might be followed as having other diseases, such as non-alcoholic fatty liver disease (NAFLD). CASE SUMMARY: A 40-year-old non-obese man without a history of regular ethanol consumption was referred to our hospital due to persistent liver dysfunction and hyperlipidemia. His body mass index was 23.4 kg/m2. Liver histology demonstrated macrovesicular steatosis, ballooned hepatocytes with eosinophilic inclusion bodies, and perisinusoidal fibrosis, leading to the diagnosis of non-alcoholic steatohepatitis (NASH). Although he had no discernable muscle pain or weakness, persistently high serum creatine kinase (CK) and myoglobin levels as well as the presence of frontal baldness, a hatched face, history of cataract surgery, and grip myotonia indicated the possibility of MD. Southern blotting of the patient's DNA revealed the presence of CTG repeats, confirming the diagnosis. CONCLUSION: When gastroenterologists encounter NAFLD/NASH patients, serum CK should be verified. If hyperCKemia, frontal baldness, a hatched face, history of cataract surgery, and grip myotonia are noted, the possibility of MD may be considered.