Thrombospondin 2 as a Predictive Biomarker for HCC in Hepatitis C Patients: A Longitudinal Study Following DAA Therapy.

This multicentre study investigated the dynamics of thrombospondin 2 (TSP2) levels during direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV) infected patients and evaluated TSP2's potential as a predictive marker for hepatocellular carcinoma (HCC). All 134 participants achieved sustained virological response at 12 weeks (SVR12) with DAA therapy, and serum TSP2 levels significantly decreased from before and after treatment (p < 0.001). During the median follow-up period of 6.0 years, HCC after DAA therapy was observed in 16 patients (11.9%). Patients with serum TSP2 High (≥ 32 ng/mL) at SVR12 had a significantly higher cumulative occurrence of HCC than did those without (26.5% vs. 7.0%, p = 0.0033). A multivariate Cox proportional hazards model identified male gender (HR 4.84, p = 0.005), HCC history (HR 4.61, p = 0.017) and TSP2 High (HR 3.93, p = 0.009) as significant independent predictors of HCC occurrence after DAA therapy. The model had a high concordance index of 0.878. Additionally, combining TSP2 High and FIB-4 High (≥ 3.538) at SVR12 yielded high specificity and negative predictive value (0.941 and 0.917, respectively) for predicting HCC. Kaplan-Meier analysis showed a higher HCC incidence in the TSP2 High + FIB-4 High group (log-rank p < 0.0001). In conclusion, TSP2 may be a promising biomarker for personalised HCC surveillance in DAA-treated hepatitis C patients.

Thrombospondin 2 is a key determinant of fibrogenesis in non-alcoholic fatty liver disease.

OBJECTIVE: Hepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. This study aimed to identify the specific cells expressing THBS2/TSP2 in non-alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 upregulation. DESIGN: Comprehensive NAFLD liver gene datasets, including single-cell RNA sequencing (scRNA-seq), in-house NAFLD liver tissue, and LX-2 cells derived from human hepatic stellate cells (HSCs), were analysed using a combination of computational biology, genetic, immunological, and pharmacological approaches. RESULTS: Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction (qPCR) examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r = .349, p < .001). In support of this, scRNA-seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGFß) pathway and collagen gene activation. Moreover, the activation of LX-2 cells with TGFß increased THBS2/TSP2 and collagen expression independently of the TGFß-SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX-2 cells. CONCLUSIONS: THBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti-fibrotic therapy in NAFLD.

Glycemic control target for liver and cardiovascular events risk in metabolic dysfunction-associated steatotic liver disease.

AIMS: Optimizing glycemic control may prevent liver-related events and major adverse cardiovascular events (MACE) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal hemoglobin A1c (HbA1c) threshold associated with a lower risk of complications, particularly liver-related events as well as MACE is unknown. METHODS: We investigated a nationwide population-based cohort and identified 633 279 patients with MASLD, with a mean follow-up of 4.2 years. Hemoglobin A1c levels were measured annually. The primary endpoint was the risk of liver-related events and MACE and to determine the optimal HbA1c level associated with the risk of complications. RESULTS: Mean HbA1c (per 1%) was associated with liver-related events (subdistribution hazard ratio [sHR] 1.26; 95% confidence interval [CI], 1.12-1.42) as well as MACE (sHR 1.36; 95% CI, 1.32-1.41) after adjustment for confounders. Multivariable sHR (95% CI) for HbA1c of <5.0%, 6.0%-6.9%, 7.0%-7.9%, 8.0%-8.9%, and ≥9.0% (reference, 5.0%-5.9%) were 14 (9.1-22), 1.70 (1.2-2.3), 3.32 (2.3-4.8), 3.81 (2.1-6.8), and 4.83 (2.4-9.6) for liver-related events, and 1.24 (0.8-1.8), 1.27 (1.2-1.4), 1.70 (1.5-2.0), 2.36 (1.9-2.9), and 4.17 (3.5-5.0) for MACE. An HbA1c level of 7% was selected as the optimal threshold for predicting complications (sHR 2.40 [1.8-3.2] for liver-related events and 1.98 [1.8-2.2] for MACE). CONCLUSION: The risk of liver-related events as well as MACE increased in a dose-dependent fashion with an increase in HbA1c levels, except for patients with HbA1c <5.0% for liver-related events. An HbA1c level of 7% was the optimal threshold associated with a lower risk of complications and may be utilized as a target for glycemic control in patients with MASLD.

Kinetics of serum O-glycosylated M-hepatitis B surface antigen with hepatocellular carcinoma history and nucleos(t)ide analogue therapy in hepatitis B patients.

A newly developed O-glycosylated M-hepatitis B surface antigen (HBsAgGi) measurement system can detect hepatitis B surface antigen (HBsAg) associated with infectious particles. We investigated the association of HBsAgGi levels with clinical parameters and a history of hepatocellular carcinoma (HCC) development in a cross-sectional cohort analysis (Study 1) as well as the quantitative changes in HBsAgGi during nucleos(t)ide analogue (NA) therapy in a longitudinal cohort analysis (Study 2). A total of 124 patients with genotype C chronic HBV infection were analysed in Study 1 to evaluate correlations of HBsAgGi with conventional HBV markers and HCC history. Among those, 36 patients receiving NA therapy were enrolled in Study 2 for quantitative comparisons between pre-treatment baseline and 48 weeks of NA therapy. In Study 1, serum HBsAgGi was significantly associated with HBsAg (r = .5857, p < .00001) and weakly but significantly correlated with HBV DNA (r = .2936, p = .001). Although HBsAgGi (p = .111) was comparable between HCC history (+) group and HCC history (-) group, the HBsAgGi/HBsAg ratio (p = .011) was significantly higher in HCC history (+) patients. In Study 2, HBsAgGi was significantly decreased after 48 weeks of NA therapy (p < .001). HBsAg findings were similar (p = .005) along with an HBV DNA reduction (p < .001). In the baseline hepatitis B e antigen (HBeAg) (+) subgroup, HBsAgGi decreased significantly between baseline and 48 weeks of NA (p = .005), while HBsAg was comparable (p = .051). Low HBsAg and high HBsAgGi were associated with a history of HCC development. HBsAgGi decreased significantly by 48-week NA therapy.

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.

Impact of Dietary Fat on the Progression of Liver Fibrosis: Lessons from Animal and Cell Studies.

Previous studies have revealed that a high-fat diet is one of the key contributors to the progression of liver fibrosis, and increasing studies are devoted to analyzing the different influences of diverse fat sources on the progression of non-alcoholic steatohepatitis. When we treated three types of isocaloric diets that are rich in cholesterol, saturated fatty acid (SFA) and trans fatty acid (TFA) with hepatitis C virus core gene transgenic mice that spontaneously developed hepatic steatosis without apparent fibrosis, TFA and cholesterol-rich diet, but not SFA-rich diet, displayed distinct hepatic fibrosis. This review summarizes the recent advances in animal and cell studies regarding the effects of these three types of fat on liver fibrogenesis.

A trans-fatty acid-rich diet promotes liver tumorigenesis in HCV core gene transgenic mice.

Excess consumption of trans-fatty acid (TFA), an unsaturated fatty acid containing trans double bonds, is a major risk factor for cardiovascular disease and metabolic syndrome. However, little is known about the link between TFA and hepatocellular carcinoma (HCC) despite it being a frequent form of cancer in humans. In this study, the impact of excessive dietary TFA on hepatic tumorigenesis was assessed using hepatitis C virus (HCV) core gene transgenic mice that spontaneously developed HCC. Male transgenic mice were treated for 5 months with either a control diet or an isocaloric TFA-rich diet that replaced the majority of soybean oil with shortening. The prevalence of liver tumors was significantly higher in TFA-rich diet-fed transgenic mice compared with control diet-fed transgenic mice. The TFA-rich diet significantly increased the expression of pro-inflammatory cytokines, as well as oxidative and endoplasmic reticulum stress, and activated nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (NRF2), leading to high p62/sequestosome 1 (SQSTM1) expression. Furthermore, the TFA diet activated extracellular signal-regulated kinase (ERK) and stimulated the Wnt/ß-catenin signaling pathway, synergistically upregulating cyclin D1 and c-Myc, driving cell proliferation. Excess TFA intake also promoted fibrogenesis and ductular reaction, presumably contributing to accelerated liver tumorigenesis. In conclusion, these results demonstrate that a TFA-rich diet promotes hepatic tumorigenesis, mainly due to persistent activation of NF-κB and NRF2-p62/SQSTM1 signaling, ERK and Wnt/ß-catenin pathways and fibrogenesis. Therefore, HCV-infected patients should avoid a TFA-rich diet to prevent liver tumor development.

A high-cholesterol diet promotes steatohepatitis and liver tumorigenesis in HCV core gene transgenic mice.

Previous epidemiological studies have suggested a link between high-cholesterol intake and liver disease progression, including hepatocellular carcinoma (HCC). However, the precise mechanism of hepatotoxicity and hepatocarcinogenesis caused by excessive cholesterol consumption remains unclear. We aimed to investigate the impact of dietary cholesterol using hepatitis C virus core gene transgenic (HCVcpTg) mice, which spontaneously developed HCC with age. Male HCVcpTg mice were treated for 15 months with either a control diet or an isocaloric diet containing 1.5% cholesterol, and liver phenotypes and tumor-associated signaling pathways were evaluated. The high-cholesterol diet-fed HCVcpTg mice exhibited a significantly higher incidence of liver tumors compared with the control diet mice (100% vs. 41%, P < 0.001). The diet induced steatohepatitis with pericellular fibrosis and evoked higher mRNA expression of pro-inflammatory and pro-fibrotic mediators along with enhanced hepatocyte proliferation and greater oxidative and endoplasmic reticulum stress in the liver. Moreover, long-term consumption of cholesterol-rich diet activated nuclear factor-kappa B (NF-κB) and p62/sequestosome 1 (Sqstm1)-nuclear factor erythroid 2 (NRF2) axis, enhanced fibrogenesis, and consequently accelerated hepatic tumorigenesis. In conclusion, these results demonstrate that a high-cholesterol diet facilitates liver tumorigenesis by inducing steatohepatitis, promoting hepatocyte division, and up-regulating cellular stress and pro-inflammatory NF-κB and detoxifying p62/Sqstm1-NRF2 signals. Therefore, high dietary cholesterol should be avoided in HCV-infected patients to prevent development of steatohepatitis, liver fibrosis, and HCC.

Correction to: A high-cholesterol diet promotes steatohepatitis and liver tumorigenesis in HCV core gene transgenic mice.

In the original publication of the article.

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.

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.

Hepatic Angiosarcoma with Kasabach-Merritt Phenomenon: A Case Report and Review of the Literature.

A 76-year-old woman was referred to our hospital due to massive gingival bleeding following teeth extraction. Laboratory findings suggested disseminated intravascular coagulopathy (DIC). Enhanced computed tomography and magnetic resonance imaging disclosed multiple hypervascular liver masses of 2-6 cm in diameter, the largest of which displaying an irregular enhancement pattern. We considered that her DIC was caused by the multiple liver masses and commenced repeated erythrocyte/fresh frozen plasma infusión and gabexate mesilate administration. However, the DIC proved uncontrollable and trans-arterial embolization could not be attempted. The patient eventually died 4 months after admission due to spontaneous hepatic tumor rupture and hepatic failure. Post-mortem hepatic tumor biopsy led to a final diagnosis of hepatic angiosarcoma with Kasabach-Merritt phenomenon (KMP). Among the 7 cases of hepatic angiosarcoma representing KMP found in the literature, mortality occurred within 4 months of the appearance of bleeding tendency primarily due to abdominal bleeding and hepatic failure. The possibility of hepatic angiosarcoma should be considered in patients with DIC and hypervascular liver tumors. Since treatment is uncertain and prognosis is poor, novel diagnostic and therapeutic advances are needed for angiosarcoma.

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.

Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial ß-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα.

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.

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.

Gastrointestinal post-transplant lymphoproliferative disorder with rapidly forming characteristic lesions after cord blood transplantation: a report of two cases.

Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) frequently involves the gastrointestinal tract, but the endoscopic characteristics of this condition have not been discussed in detail. We report two cases of EBV-related PTLD involving rapidly forming characteristic lesions. Case 1 was a 60-year-old man with acute myeloid leukemia who underwent cord blood transplantation (CBT) after which he initially achieved complete remission (CR). He developed nausea and vomiting on day 99. Gastrointestinal endoscopy showed no tumor-like lesions in his stomach. However, a second endoscopic evaluation, which was performed 7 days after the first, revealed multiple raised lesions in his stomach, and a histopathological examination of the biopsy specimen resulted in a diagnosis of EBV-related PTLD. Case 2 was a 36-year-old man with acute myeloid leukemia who underwent CBT after achieving his second CR. He suffered nausea and pharyngalgia on day 309. Although the initial gastrointestinal endoscopic examination showed only multiple erosive or small ulcerative lesions, a second endoscopic evaluation, which was performed 10 days after the first, revealed a raised lesion with a central ulcer in the duodenum. Histopathological examination of the biopsy specimen yielded a diagnosis of EBV-related PTLD. Both patients were successfully treated by reducing the dose of immunosuppressive agents and administering rituximab.

Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis.

OBJECTIVES: Noninvasive markers of liver fibrosis in patients with primary biliary cirrhosis (PBC) are needed for predicting disease progression. As the Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA(+)-M2BP) was recently established as a liver fibrosis glycobiomarker in chronic hepatitis C, we assessed its efficacy in evaluating liver fibrosis stage and disease progression in PBC. METHODS: A total of 137 patients with PBC who underwent liver biopsy and serological tests for WFA(+)-M2BP were enrolled. All patients were treated with ursodeoxycholic acid. Clinical data were compared with those for other noninvasive markers (aspartate aminotransferase-to-platelet ratio, FIB-4 index, aspartate aminotransferase/alanine aminotransferase ratio, Forn's index, and Mayo score) for estimating liver fibrosis using receiver operating characteristic analysis. The association between WFA(+)-M2BP and clinical outcome (liver decompensation, liver transplantation, or death) was evaluated using the Cox proportional hazards model with stepwise method. RESULTS: WFA(+)-M2BP was independently associated with liver fibrosis stage as determined by liver biopsy. The cutoff values of WFA(+)-M2BP for fibrosis stages ≥F1, ≥F2, ≥F3, and F4 were 0.7, 1.0, 1.4, and 2.0, respectively. The area under the receiver operating characteristic curve values for significant fibrosis, severe fibrosis, and cirrhosis were 0.979, 0.933, and 0.965, respectively. WFA(+)-M2BP was significantly superior to the other indices for the determination of significant and severe fibrosis stages. Furthermore, the WFA(+)-M2BP level at enrollment was strongly and independently associated with clinical outcome (hazard ratio 18.59, P=0.021). CONCLUSIONS: Baseline measurements of WFA(+)-M2BP represent a simple and reliable noninvasive surrogate marker of liver fibrosis and prognosis in patients with PBC.