M-PAST score is better than MAST score for the diagnosis of active fibrotic nonalcoholic steatohepatitis.

BACKGROUND: Clinical trials enroll patients with active fibrotic nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease [NAFLD] activity score ≥ 4) and significant fibrosis (F ≥ 2); however, screening failure rates are high following biopsy. We developed new scores to identify active fibrotic NASH using FibroScan and magnetic resonance imaging (MRI). METHODS: We undertook prospective primary (n = 176), retrospective validation (n = 169), and University of California San Diego (UCSD; n = 234) studies of liver biopsy-proven NAFLD. Liver stiffness measurement (LSM) using FibroScan or magnetic resonance elastography (MRE), controlled attenuation parameter (CAP), or proton density fat fraction (PDFF), and aspartate aminotransferase (AST) were combined to develop a two-step strategy-FibroScan-based LSM followed by CAP with AST (F-CAST) and MRE-based LSM followed by PDFF with AST (M-PAST)-and compared with FibroScan-AST (FAST) and MRI-AST (MAST) for diagnosing active fibrotic NASH. Each model was categorized using rule-in and rule-out criteria. RESULTS: Areas under receiver operating characteristic curves (AUROCs) of F-CAST (0.826) and M-PAST (0.832) were significantly higher than those of FAST (0.744, p = 0.004) and MAST (0.710, p < 0.001). Following the rule-in criteria, positive predictive values of F-CAST (81.8%) and M-PAST (81.8%) were higher than those of FAST (73.5%) and MAST (70.0%). Following the rule-out criteria, negative predictive values of F-CAST (90.5%) and M-PAST (90.9%) were higher than those of FAST (84.0%) and MAST (73.9%). In the validation and UCSD cohorts, AUROCs did not differ significantly between F-CAST and FAST, but M-PAST had a higher diagnostic performance than MAST. CONCLUSIONS: The two-step strategy, especially M-PAST, showed reliability of rule-in/-out for active fibrotic NASH, with better predictive performance compared with MAST. This study is registered with ClinicalTrials.gov (number, UMIN000012757).

Real-world assessment of SmartExam, a novel FibroScan computational method: A retrospective single-center cohort study.

BACKGROUND AND AIM: SmartExam is a novel computational method compatible with FibroScan that uses a software called SmartDepth and continuous controlled attenuation parameter measurements to evaluate liver fibrosis and steatosis. This retrospective study compared the diagnostic accuracy of conventional and SmartExam-equipped FibroScan for liver stiffness measurement (LSM). METHODS: The liver stiffness and the associated controlled attenuation parameters of 167 patients were measured using conventional and SmartExam-Equipped FibroScan as well as reference methods like magnetic resonance elastography (MRE) and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) measurements to assess its diagnostic performance. M or XL probes were selected based on the probe-to-liver capsule distance for all FibroScan examinations. RESULTS: The liver stiffness and controlled attenuation parameter (CAP) correlation coefficients calculated from conventional and SmartExam-equipped FibroScan were 0.97 and 0.82, respectively. Using MRE/MRI-PDFF as a reference and the DeLong test for analysis, LSM and the area under the receiver operating characteristic curve for CAP measured by conventional and SmartExam-equipped FibroScan showed no significant difference. However, the SmartExam-equipped FibroScan measurement (33.6 s) took 1.4 times longer than conventional FibroScan (23.2 s). CONCLUSIONS: SmartExam has a high diagnostic performance comparable with that of conventional FibroScan. Because the results of the conventional and SmartExam-equipped FibroScan were strongly correlated, it can be considered useful for assessing the fibrosis stage and steatosis grade of the liver in clinical practice, with less variability but little longer measurement time compared with the conventional FibroScan.

Direct Comparison of US and MR Elastography for Staging Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: As alternatives to the expensive liver biopsy for assessing liver fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD), we directly compared the diagnostic abilities of magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE), and two-dimensional shear wave elastography (2D-SWE). METHODS: Overall, 231 patients with biopsy-proven NAFLD were included. Intra- and inter-observer reproducibility was analyzed using intraclass correlation coefficient in a sub-group of 70 participants, in whom liver stiffness measurement (LSM) was performed by an elastography expert and an ultrasound expert who was an elastography trainee on the same day. RESULTS: Valid LSMs were obtained for 227, 220, 204, and 201 patients using MRE, VCTE, 2D-SWE, and all three modalities combined, respectively. Although the area under the curve did not differ between the modalities for detecting stage ≥1, ≥2, and ≥3 liver fibrosis, it was higher for MRE than VCTE and 2D-SWE for stage 4. Sex was a significant predictor of discordance between VCTE and liver fibrosis stage. Skin-capsule distance and the ratio of the interquartile range of liver stiffness to the median were significantly associated with discordance between 2D-SWE and liver fibrosis stage. However, no factors were associated with discordance between MRE and liver fibrosis stage. Intra- and inter-observer reproducibility in detecting liver fibrosis was higher for MRE than VCTE and 2D-SWE. CONCLUSIONS: MRE, VCTE, and 2D-SWE demonstrated excellent diagnostic accuracy in detecting liver fibrosis in patients with NAFLD. MRE demonstrated the highest diagnostic accuracy for stage 4 detection and intra- and inter-observer reproducibility. UMIN Clinical Trials Registry No. UMIN000031491.

MRI-Based Quantitative R2* Mapping at 3 Tesla Reflects Hepatic Iron Overload and Pathogenesis in Nonalcoholic Fatty Liver Disease Patients.

BACKGROUND: The role of hepatic iron overload (HIO) in nonalcoholic fatty liver disease (NAFLD) pathogenesis has not been fully elucidated. PURPOSE: This study aimed to investigate the effect of HIO and examine the diagnostic usefulness of magnetic resonance imaging (MRI)-based R2* quantification in evaluating hepatic iron content (HIC) and pathological findings in NAFLD. STUDY TYPE: Prospective and retrospective. POPULATION: A prospective study of 168 patients (age, 57.2 ± 15.0; male/female, 80/88) and a retrospective validation study of 202 patients (age, 57.0 ± 14.4; male/female, 113/89) with liver-biopsy-confirmed NAFLD were performed. FIELD STRENGTH/SEQUENCE: 3 T; chemical-shift encoded multi-echo gradient echo. ASSESSMENT: Using liver tissues obtained by liver biopsy, HIC was prospectively evaluated in 168 patients by atomic absorption spectrometry. Diagnostic accuracies of HIC and R2* for grading hepatic inflammation plus ballooning (HIB) as an indicator of NAFLD activity were assessed. STATISTICAL TESTS: Student's t-test and analysis of variance (ANOVA) with Scheffe's multiple testing correction for univariate comparisons; multivariate logistic analysis. P-value less than 0.05 is statistically significant. RESULTS: HIC was significantly correlated with HIB grades (r = 0.407). R2* was significantly correlated with HIC (r = 0.557) and HIB grades (r = 0.569). R2* mapped an area under the receiver operating characteristic (AUROC; 0.774) for HIC ≥808 ng/mL (median value) with cutoff value of 62.5 s-1 . In addition, R2* mapped AUROC of HIB for grades ≥3 was 0.799 with cutoff value of 58.5 s-1 . When R2* was <62.5 s-1 , R2* correlated weakly with HIC (r = 0.372) as it was affected by fat deposition and did not correlate with HIB grades (P = 0.052). Conversely, when R2* was ≥62.5 s-1 , a significant correlation of R2* with HIC (r = 0.556) and with HIB grades was observed (P < 0.0001) with being less affected by fat deposition. DATA CONCLUSION: R2* ≥ 62.5 s-1 is a promising modality for non-invasive diagnosis of clinically important high grades (≥3) of HIB associated with increased HIC. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Assessment of 10-year changes in liver stiffness using vibration-controlled transient elastography in non-alcoholic fatty liver disease.

AIM: Although liver biopsy is the gold standard for the diagnosis and staging of non-alcoholic fatty liver disease (NAFLD), repeated assessment of patients' liver tissue conditions are impractical. We assessed the 10-year changes in liver stiffness measurements (LSM) utilizing vibration-controlled transient elastography in NAFLD patients. METHODS: From January 2006 to September 2007, LSM was carried out for 97 biopsy-proven NAFLD patients. Of these, 34 patients underwent 10-year LSM reassessments (14 of them with paired biopsies). RESULTS: We evaluated the changes in the fibrosis stage as estimated using LSM (FS-LSM). Over a 10-year period, 32.4% had FS-LSM progression, 50% had static disease, and 17.6% had FS-LSM improvement. From among the initially diagnosed non-alcoholic steatohepatitis patients, 18% had progressed to considerable stage 4 (cirrhosis) 10 years later. In this cohort, none of the patients who had been initially diagnosed as FS-LSM stage 0 had progressed to cirrhosis 10 years later. The changes in LSM were correlated with the change in the histological fibrosis stage, the NAFLD activity score, and the change in the sum of the steatosis, activity, and fibrosis score. Improving more than 1 body mass index (kg/m2 ) and having a higher initial aspartate aminotransferase, alanine aminotransferase (ALT), or ALT responder (>30% improvement or reduction to less than 40 IU/L) were factors contributing to LSM improvements (≥2 kPa). CONCLUSIONS: Vibration-controlled transient elastography is likely to become a more clinically important tool for the long-term monitoring of NAFLD patients.

Distribution of liver stiffness in non-alcoholic fatty liver disease with higher fibrosis-4 index than low cut-off index.

BACKGROUND AND AIM: In the condition of high prevalence of non-alcoholic fatty liver disease (NAFLD), a new diagnostic algorithm to efficiently identify NAFLD patients with significant fibrosis is urgently required. We evaluated the predictive ability of the fibrosis-4 index (FIB-4 index) for significant liver fibrosis (F ≥ 2) in a cohort of Japanese patients with NAFLD. METHODS: We prospectively calculated the FIB-4 index in patients who were incidentally diagnosed as fatty liver in medical checkups and then conducted liver stiffness measurement by vibration-controlled transient elastography (VCTE) only in patients in whom the FIB-4 index was more than the low cut-off index (> 1.45). RESULTS: Of the 5929 people who underwent medical checkups, a total of 1374 people were identified as having fatty liver. Among these, we performed VCTE in 106 patients in whom the FIB-4 index was higher than 1.45. The distribution of the fibrosis stage as estimated by VCTE in the patients was as follows: F0, 52.8%; F1, 10.3%; F2, 21.6%; F3, 11.3%; and F4, 3.7%. The positive predictive value of the FIB-4 index for detecting NAFLD with significant fibrosis was 36.6%. The minimum value of the FIB-4 index was constant for each estimated fibrosis stage. CONCLUSIONS: This is the first prospective study to evaluate the usefulness of the FIB-4 index as the first step to screen NAFLD patients with significant fibrosis. In Japan, addition of one further step that combined with the FIB-4 index is necessary to meaningfully reduce the number of patients needing liver stiffness measurement or liver biopsy.

Wisteria floribunda agglutinin-positive Mac-2-binding protein and type 4 collagen 7S: useful markers for the diagnosis of significant fibrosis in patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIM: The fibrosis stage of liver is associated with the long-term outcomes in patients with non-alcoholic fatty liver disease (NAFLD). However, significant fibrosis, defined as fibrosis stages 2-4, is associated with an elevated risk of progression to severe liver disease; there have been scant reports about diagnosing significant fibrosis. We compare the noninvasive method and aim to identify appropriate liver fibrosis markers for detecting significant fibrosis in NAFLD patients. METHODS: We compared the usefulness of liver fibrosis markers (Wisteria floribunda agglutinin-positive Mac-2-binding protein [WFA+ -M2BP], type 4 collagen 7S, etc.), clinical scoring systems, and liver stiffness measurement obtained using vibration-controlled transient elastography and magnetic resonance imaging-based magnetic resonance elastography in the same individuals and identified the most appropriate noninvasive method for detecting significant fibrosis in 165 patients with liver biopsy-diagnosed NAFLD. RESULTS: The area under the receiver operating characteristic curve based on the serum cutoff index values of WFA+ -M2BP/the serum levels of type IV collagen 7S for the diagnosis of significant fibrosis was 0.832 (95% confidence interval: 0.771-0.894)/0.837 (95% confidence interval: 0.778-0.898). "WFA+ -M2BP (cutoff index) ≥ 0.83 or type IV collagen 7S ≥ 5.2 ng/mL" showed a high sensitivity (91.4%) and negative predictive value (87.9%) for the diagnosis of significant fibrosis. CONCLUSIONS: We showed that serum WFA+ -M2BP or type IV collagen 7S levels serve as useful independent markers for detecting significant fibrosis and that use of both WFA+ -M2BP and type IV collagen 7S together increased the sensitivity and negative predictive value for the diagnosis of liver fibrosis. These results need to be validated in larger populations from multiple clinical centers.

New microwave ablation system for unresectable liver tumors that forms large, spherical ablation zones.

BACKGROUND AND AIM: The aim of this study was to assess the efficacy of a new microwave ablation (MWA) system, the Emprint Ablation System, for the ablation of unresectable large liver tumors (≥ 30 mm). METHODS: Twenty-one hepatic tumors (mean diameter, 34.7 mm) from 21 patients who underwent percutaneous MWA were included in this cross-sectional study. A volume analyzer based on computed tomography imaging was used for all patients within the month before and month after the procedure to evaluate the shape and volume of ablation zones. In addition, computed tomography imaging was performed again 3 months after the procedure to evaluate the presence of residual tumors and local recurrence. RESULTS: Mean ablation time was 11.3 min, and mean overall procedure time was 33.4 min. An ablated adrenal gland-induced Takotsubo (stress) cardiomyopathy occurred immediately after MWA as a major complication in one patient. Roundness index A, B, and C presented a mean value of 0.94, 0.94, and 1.01, respectively (all values near 1 is a perfect sphere), indicating that a spherical ablation zone was achieved. The mean ablation volume was larger than the volume of tumors (24.5 vs 41.7 cm3 ). Residual tumors were confirmed in only 4.8% of tumors after a single ablation session. There was no local recurrence. CONCLUSIONS: In our experience, the new MWA system provides an effective treatment option for unresectable large liver tumors. However, to ablate the liver tumors safely, it is necessary to consider the surrounding organs, such as the adrenal glands.

Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy.

BACKGROUND: Hepatitis C virus (HCV) induces endoplasmic reticulum (ER) stress which, in turn, activates the unfolding protein response (UPR). UPR activates three distinct signalling pathways. Additionally, UPR induces autophagy (UPR-autophagy pathways). On the other hand, it has become clear that some positive-single-strand RNA viruses utilize autophagy. Some groups have used the siRNA silencing approach to show that autophagy is required for HCV RNA replication. However, the mechanism of induction of the UPR-autophagy pathways remain unclear in the cells with HCV. METHOD AND RESULTS: we used a genome-length HCV RNA (strain O of genotype 1b) replication system (OR6) in hepatoma cells (HuH-7-derived OR6 cells). As control, we used OR6c cells from which the HCV genome had been removed by treatment with interferon-α. The UPR-autophagy pathways were activated to a greater degree in the OR6 cells as compared to the OR6c cells. Rapamycin, mTOR-independent autophagy inducer, activated HCV replication in the OR6 cells. On the other hand, HCV replication in the cells was inhibited by 3-methyladenine (3-MA), which is an inhibitor of autophagy. Salubrinal (Eukaryotic Initiation Factor 2(eIF2)-alpha phosphatase inhibitor), 3-ethoxy-5, 6-dibromosalicylaldehyde (X-box binding protein-1 (XBP-1) splicing inhibitor) and sp600125 (c-Jun N-terminal kinases (JNK) inhibitor) inhibited HCV replication and autophagy. Additionally, HCV replication and autophagy were inhibited more strongly by combination of these inhibitors. CONCLUSION: Our results suggest that UPR-autophagy pathways exert an influence on HCV replication. Therefore, control these pathways may serve as a novel therapeutic strategy against replication of HCV.

Transient elastography for monitoring the fibrosis of non-alcoholic fatty liver disease for 4 years.

AIM: There have been some reports on the use of paired biopsies for monitoring disease progression in non-alcoholic fatty liver disease (NAFLD) patients. Recently, transient elastography has been developed as a non-invasive method for predicting the severity of liver fibrosis. We investigated 4-year disease progression in NAFLD patients by evaluating liver stiffness measurements (LSM) obtained using transient elastography. METHODS: Of 97 biopsy-proven NAFLD patients whose LSM were obtained 4 years prior, we revaluated 36 who were available for follow up and compared their current stage of fibrosis with that at initial assessment. Fibrosis stage was diagnosed according to the cut-off values previously reported by our institution. We also investigated correlations between changes in LSM and changes in non-invasive fibrosis markers obtained by performing biochemical tests and clinical data. RESULTS: A total of nine (25%) patients had fibrosis progression, 17 (47.2%) had static disease and 10 (27.8%) had fibrosis remission. Among patients with stage 0 fibrosis as per initial LSM (n = 16), 11 had static disease and five had fibrosis progression according to LSM obtained 4 years later. Changes in LSM correlated with changes in the FIB4 index (R = 0.519, P = 0.0011) and aspartate aminotransferase-to-platelet ratio index (R = 0.346, P = 0.0412), but not with changes in other non-invasive markers. CONCLUSION: Transient elastography is non-invasive and easy to use; therefore, it can be a useful tool for monitoring the severity of hepatic fibrosis in NAFLD patients.

Hepatic triglyceride lipase plays an essential role in changing the lipid metabolism in genotype 1b hepatitis C virus replicon cells and hepatitis C patients.

AIM: Recently, several studies have shown the existence of associations between lipoprotein profiles and hepatitis C virus (HCV), although only a limited amount of information is available about the mechanisms underlying the changes in the lipoprotein profiles associated with HCV. In this study, we investigated the association between lipoprotein profile, classified according to the particle size, and lipoprotein metabolism. METHODS: We used four kinds of cells for this experiment; full-length genome HCV RNA replicon cells (OR6), sub-genomic HCV RNA replicon cells (sO), and OR6c cells and sOc cells, which were the same cell lines treated with interferon-α. The triglyceride (TG) levels in the lipoprotein subclasses of the culture medium were measured by high-performance liquid chromatography. The mRNA expression levels of several molecules associated with lipoprotein metabolism were measured in the OR6, OR6c, sO and sOc cells. To confirm some of the results obtained using the in vitro system, liver biopsy samples obtained from the patients were also examined. RESULTS: The content of TG in the large low-density lipoprotein (LDL) and medium LDL in the culture medium was increased only in the OR6 cells. The hepatic triglyceride lipase (HTGL) mRNA expression levels were lower in the OR6 cells than in the OR6c cells (P < 0.01). Examination of the HTGL expression levels in the patients' livers revealed a decrease in HTGL expression in the chronic hepatitis C liver as compared with that in the chronic hepatitis B or non-alcoholic steatohepatitis liver (P < 0.01). CONCLUSION: We showed that HCV inhibits HTGL production in hepatocytes, inducing a change of the lipoprotein profile.

Evaluation of the Liver Fibrosis Index calculated by using real-time tissue elastography for the non-invasive assessment of liver fibrosis in chronic liver diseases.

AIM: A rapid and non-invasive method of detecting fibrosis in patients with chronic liver diseases is of major clinical interest. The purpose of this study was to comparatively investigate the effectiveness of the Liver Fibrosis Index (LF Index) calculated using real-time tissue elastography (RTE) in patients with non-alcoholic fatty liver disease (NAFLD) and patients with chronic hepatitis C (CHC). METHODS: Twenty-seven patients with biopsy-proven NAFLD and 93 patients with biopsy-proven CHC were included. They underwent transient elastography (TE), serum liver fibrosis marker testing and RTE to calculate the LF Index. RESULTS: The LF Index showed a stepwise increase with increasing histological severity of fibrosis in CHC patients (P = 0.0102), whereas no significant correlation of the LF Index with the histological severity of liver fibrosis in NAFLD patients (P = 0.852). There was a significant correlation between the LF Index and liver stiffness measured by TE in CHC patients (r = 0.319, P = 0.0009). On the other hand, no such correlation was observed in NAFLD patients. While in CHC patients, the LF Index was correlated with the FIB-4 index, no such correlation was observed in NAFLD patients. CONCLUSION: The LF Index calculated by RTE is effective for assessment of liver fibrosis in patients with CHC. On the other hand, it is not useful in patients with NAFLD. This is the first study to compare the clinical usefulness of RTE as non-invasive assessment of liver fibrosis between CHC and NAFLD. Further investigations are required to refine statistical assessment of RTE.

Early effect of oral administration of omeprazole with mosapride as compared with those of omeprazole alone on the intragastric pH.

BACKGROUND: The ideal medication for acid-related diseases should have a rapid onset of action to promote hemostasis and cause efficient resolution of symptoms. The aim of our study was to comparatively investigate the inhibitory effect on gastric acid secretion of a single oral administration of omeprazole plus mosapride with that of omeprazole alone. METHODS: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 hours after a single oral administration of omeprazole 20 mg or that of omeprazole 20 mg plus mosapride 5 mg (the omeprazole being administered one hour after the mosapride). Each administration was separated by a 7-days washout period. RESULTS: The average pH during the 6-hour period after administration of omeprazole 20 mg plus mosapride 5 mg was higher than that after administration of omeprazole 20 mg alone (median: 3.22 versus 4.21, respectively; p = 0.0247). CONCLUSIONS: In H. pylori -negative healthy male subjects, an oral dose of omeprazole 20 mg plus mosapride 5 mg increased the intragastric pH more rapidly than omeprazole 20 mg alone.

Combination of tofogliflozin and pioglitazone for NAFLD: Extension to the ToPiND randomized controlled trial.

The incidence of nonalcoholic fatty liver disease (NAFLD) has recently increased and is related to obesity and the associated surge in type 2 diabetes mellitus (T2DM) and metabolic syndromes. This trial follows up on our previous work and forms part of the ToPiND study. We aimed to combine tofogliflozin and pioglitazone treatment for hepatic steatosis in patients with NAFLD and T2DM. In this open-label, prospective, single-center, randomized clinical trial, patients with NAFLD with T2DM and a hepatic fat fraction of ≥10% were assessed based on magnetic resonance imaging proton density fat fraction. Eligible patients received either 20 mg tofogliflozin or 15-30 mg pioglitazone orally, once daily for 24 weeks, followed by combination therapy with both medicines for an additional 24 weeks. The effects on diabetes mellitus and hepatic steatosis were examined at baseline and after the completion of monotherapy and combination therapy. Thirty-two eligible patients received the combination therapy of tofogliflozin and pioglitazone. The combination therapy showed additional improvement in glycated hemoglobin compared with each monotherapy group and showed improvement in steatosis, hepatic stiffness, and alanine aminotransferase levels compared with the tofogliflozin monotherapy group. Pioglitazone monotherapy-mediated increase in body weight decreased following concomitant use of tofogliflozin. The combination therapy resulted in lower triglyceride, higher high-density lipoprotein cholesterol, higher adiponectin, and higher ketone body levels. Conclusion: In addition to the additive effects of tofogliflozin and pioglitazone in patients with T2DM and NAFLD, combination therapy was suggested to reduce weight gain and induce cardioprotective effect. Further studies with more patients are needed to investigate the combination therapy of various drugs.

Gastroesophageal varices evaluation using spleen-dedicated stiffness measurement by vibration-controlled transient elastography.

BACKGROUND AND AIM: Liver stiffness measurement (LSM) and spleen stiffness measurement (SSM@50 Hz) using standard vibration-controlled transient elastography (VCTE) have been studied as a noninvasive test for screening of gastroesophageal varices (GEV) in chronic liver disease (CLD). Recently, a novel spleen-dedicated VCTE (SSM@100 Hz) has been developed. We evaluated the diagnostic performance of SSM@100 Hz, SSM@50 Hz, LSM, and other noninvasive tests using esophagogastroduodenoscopy (EGD) as the reference as well as the correlation with hepatic venous pressure gradient (HVPG). METHODS: A total of 123 patients with CLD enrolled in this cross-sectional study. SSM@100 Hz, SSM@50 Hz, and LSM were determined by VCTE. EGD and HVPG were performed within 12 weeks before or after VCTE. RESULTS: GEV were present in 60 patients. Failure or suboptimal SSM were fewer at 100 Hz (4.0%) than at 50 Hz (17.7%). All SSM values obtained at 100 Hz were lower than the 100 kPa ceiling threshold, but 10 patients reached the 75 kPa ceiling threshold for SSM@50 Hz. SSM@100 Hz was most accurate (area under the receiver operating characteristic [AUROC] = 0.944) for the diagnosis of GEV compared to SSM@50 Hz, LSM, and scoring systems. AUROC of SSM@100 Hz for diagnosis of high-bleeding risk varices (HRV) was 0.941, which was significantly higher than that of SSM@50 Hz (AUROC = 0.842, P = 0.002). SSM@100 Hz showed higher specificity (82.0%) for diagnosis of HRV than SSM@50 Hz (specificity = 67.1%). SSM@100 Hz was significantly correlated with HVPG (r = 0.71, P < 0.001). CONCLUSIONS: The novel spleen-dedicated VCTE examination can be used for noninvasive assessment of GEV and HVPG in CLD. Japan Registry of Clinical Trials Registry No. jRCTs032200119.

Diagnostic comparison of vibration-controlled transient elastography and MRI techniques in overweight and obese patients with NAFLD.

Non-invasive imaging techniques have greatly advanced the assessment of liver fibrosis and steatosis but are not fully evaluated in overweight patients. We evaluated the diagnostic performance of vibration-controlled transient elastography (VCTE) and magnetic resonance elastography (MRE) to assess fibrosis and controlled attenuation parameter (CAP) and MR imaging (MRI)-proton density fat fraction (MRI-PDFF) to assess steatosis in overweight and obese patients with non-alcoholic fatty liver disease (NAFLD). We included 163 biopsy-proven patients with NAFLD who underwent VCTE, MRE/MRI-PDFF, and liver biopsy (years 2014-2020) who were classified according to their body mass index (BMI) as normal (BMI < 25 kg/m2, n = 38), overweight (25 ≤ BMI < 30 kg/m2, n = 68), and obese (BMI ≥ 30 kg/m2, n = 57). VCTE and MRE detected fibrosis of stages ≥ 2, ≥ 3, and 4 with an area under the receiver operating curve (AUROC) of 0.83-0.94 (VCTE) and 0.85-0.95 (MRE) in all groups, without considerable differences. MRI-PDFF detected steatosis of grades ≥ 2 and 3 with high AUROC in all groups (0.81-1.00). CAP's diagnostic ability (0.63-0.95) was lower than that of MRI-PDFF and decreased with increasing BMI compared to MRI-PDFF. VCTE and MRE similarly accurately assess fibrosis, although MRI-PDFF is more accurate than CAP in detecting steatosis in overweight and obese patients with NAFLD.

Novel findings for the development of drug therapy for various liver diseases: Liver microsomal triglyceride transfer protein activator may be a possible therapeutic agent in non-alcoholic steatohepatitis.

The factors involved in the progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH) are not fully understood and thus it is urgently needed to elucidate these factors. Steatosis is not causal in the development of NASH, but rather it sensitizes the liver to the damaging effects of second hits such that stressors innocuous to a healthy liver lead to the development of NASH in the steatotic liver. In the previous study, most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, very-low-density lipoprotein (VLDL) synthesis, especially hepatic microsomal triglyceride transfer protein (MTP) mRNA expression, was impaired in the NASH group. Moreover, NASH showed significantly higher incidence of minor alley appearance compared with NAFL, indicating the possibility of association between NASH pathogenesis and decreased congenital MTP activity. MTP is one of the enzymes that transfer triglycerides to nascent apolipoprotein B, producing VLDL and removing lipid from the hepatocyte. A growing body of literature suggests that the measurement of hepatic MTP expression may be helpful for diagnosis; and moreover, hepatic MTP activator may be a possible therapeutic agent for the treatment of NASH.

Serum nitric oxide metabolite as a biomarker of visceral fat accumulation: clinical significance of measurement for nitrate/nitrite.

BACKGROUND: A visceral fat area of more than 100 cm2 as measured by computed tomography (CT) at the umbilical level has been included as a criterion for obesity in all the proposed criteria for metabolic syndrome. However, CT cannot be used frequently because of radiation exposure. We evaluated the usefulness of measurement of the serum levels of nitric oxide (NO), instead of CT and the waist circumference, as a marker of abdominal visceral fat accumulation. MATERIAL/METHODS: The study was carried out in 80 subjects. The serum levels of NO metabolites (nitrate/nitrite) were measured using the Griess reagent. RESULTS: Simple and multiple regression analysis revealed that the serum levels of NO metabolites showed the greatest degree of correlation with the visceral fat area (r = 0.743, p<0.0001), and corresponded to a visceral fat area of 100 cm2, as determined using the ROC curve, was 21.0 µmol/ml (sensitivity 88%, specificity 82%); this method was more sensitive than the waist circumference for evaluation of the visceral fat accumulation. CONCLUSIONS: Measurement of the serum levels of NO metabolites may be a simple, safe, convenient and reliable method for the evaluation of visceral fat accumulation in clinical diagnostic screening.

Early effects of oral administration of lafutidine with peppermint oil, compared with lafutidine alone, on intragastric pH values.

BACKGROUND/AIMS: Ideally, medications for the treatment of acid-related diseases should have a rapid onset of action to promote hemostasis and the resolution of symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of lafutidine alone or combined with peppermint oil. METHODOLOGY: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 4 hours after a single oral administration of lafutidine (10 mg) or the administration of lafutidine (10 mg) with peppermint oil (0.64 mL). Each administration was separated by a 7-day washout period. RESULTS: No significant difference in the average pH was observed during the 4-hour period after the combined administration of lafutidine and peppermint oil and after the administration of lafutidine alone (median gastric pH: 5.09 versus 5.29; p = 0.3122). CONCLUSIONS: In H. pylori-negative healthy male subjects, an oral dose of lafutidine combined with peppermint oil did not increase the intragastric pH faster than lafutidine alone.

Discrimination between sclerosing cholangitis-associated autoimmune pancreatitis and primary sclerosing cholangitis, cancer using intraductal ultrasonography.

BACKGROUND AND AIM: Differentiation of sclerosing cholangitis-associated autoimmune pancreatitis (SC-AIP), primary sclerosing cholangitis (PSC) and cancer of the hilar part of the bile duct (CHB) has been challenging. The aim of the present study was to evaluate characteristic intraductal ultrasonography (IDUS) features that could be used to discriminate SC-AIP from PSC and CHB. METHODS: Six patients with SC-AIP, 10 patients with PSC and 12 patients with CHB were identified. We reviewed the following bile duct features observed using IDUS to determine their usefulness for differentiating SC-AIP from PSC and CHB: presence of symmetrical wall thickness, wall thickness, presence of homogeneous internal foci and presence of lateral mucosal lesions continuous to the hilar. RESULTS: IDUS results (SC-AIP, PSC, CHB) were as follows: wall thickness (mm), 3.7±0.9, 2.6 ±0.9, 2.8±0.0.6; presence of symmetrical wall thickness, 100% (6/6), 20% (2/10), 8.3% (1/12); presence of homogeneous internal foci, 100% (6/6), 10% (1/10), 8.3% (1/12); and presence of lateral mucosal lesions continuous to the hilar, 83.3% (5/6), 40%(4/10), 25% (3/12). Symmetrical wall thickness of the bile duct, homogeneous internal foci and lateral mucosal lesions continuous to the hilar were detected significantly more often among the patients with SC-PSC than among the patients with PSC or CHB (P<0.05). CONCLUSIONS: IDUS findings, such as symmetrical wall thickness, presence of homogeneous internal foci and presence of lateral mucosal lesions continuous to the hilar can facilitate the differential diagnosis of SC-AIP from PSC and CHB.