Circulating myostatin levels as a prognostic biomarker in patients with acute liver failure and late-onset hepatic failure.

AIM: Myostatin is a myokine involved in muscle mass regulation. The associations between circulating myostatin levels and clinical characteristics in patients with acute liver failure (ALF) and late-onset hepatic failure (LOHF) are unclear. METHODS: In this retrospective study, 51 patients with ALF or LOHF were included. Serum myostatin was measured using an enzyme-linked immunosorbent assay. RESULTS: Myostatin levels were significantly lower in patients with ALF and LOHF than in controls (ALF/LOHF: 2522 pg/mL, controls: 3853 pg/mL, p = 0.003). The prevalence of low myostatin in deceased patients was significantly higher than that in spontaneous survivors and patients who underwent liver transplantation. Patients with low myostatin levels had a high incidence of complications. There was a positive correlation between the psoas muscle index and serum myostatin levels. Patients with low myostatin levels had shorter 1-year transplant-free survival and shorter 1-year overall survival than patients with high myostatin levels. Low serum myostatin levels were associated with poor prognosis independent of the Japanese scoring system for ALF ≥3, King's College criteria, or model for end-stage liver disease score >30.5. The combination of serum myostatin levels and prognostic models for ALF significantly stratified patients according to 1-year prognosis. CONCLUSIONS: Low serum myostatin levels were associated with a low psoas muscle index, complication rate, and poor prognosis in patients with ALF and LOHF. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with ALF and LOHF.

Diagnostic guide for immune checkpoint inhibitor-induced liver injury.

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI-induced liver injury) as an immune-related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R-value is useful in deciding treatment strategies for ICI-induced liver injury. Histologically, the most representative feature is an acute hepatitis-like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8-positive T lymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non-obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI-induced cholangitis are classified as non-hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI-induced liver injury.

A low baseline serum myostatin concentration is associated with poor clinical outcome in patients with primary biliary cholangitis.

BACKGROUND AND AIM: Primary biliary cholangitis (PBC) is an autoimmune-mediated cholestatic liver disease that can progress to biliary cirrhosis and liver-related death. The associations between baseline myostatin levels and clinical outcomes in PBC patients are unknown. We aimed to clarify the influence of myostatin levels on the clinical outcomes of PBC patients. METHODS: A total of 119 PBC patients were analyzed in this study. Myostatin levels were measured in stored sera before ursodeoxycholic acid treatment, and their associations with the clinical features and prognosis of PBC patients were analyzed. We analyzed the correlation between serum myostatin and chemokines/cytokines. RESULTS: Serum myostatin was significantly lower in PBC patients (2343 pg/mL) than in healthy controls (4059 pg/mL, P < 0.001). The prevalence of patients with low myostatin levels increased according to the severity of histological fibrosis. The serum myostatin concentration was negatively correlated with the IL-6 and leucine-rich α2 glycoprotein levels, but the chemokine concentration was not correlated with the myostatin concentration. Low myostatin in PBC patients was associated with shorter survival without liver-related complications (hazard ratio [HR], 3.598; 95% confidence interval [CI], 1.27-10.1; P = 0.015) and shorter transplant-free survival (HR, 3.129; 95% CI, 1.02-9.56; P = 0.045) independent of pretreatment GLOBE score. Patients with both high pretreatment GLOBE scores and low myostatin levels had poor prognoses (log-rank test: P < 0.001). CONCLUSIONS: A low serum myostatin concentration at diagnosis was associated with poor clinical outcomes. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with PBC.

Influence of serum Gas6 levels on prognosis in patients with hepatocellular carcinoma.

OBJECTIVE: The prediction of prognosis in hepatocellular carcinoma patients is important for switching treatment. The association between circulating growth arrest-specific 6 levels and prognosis in hepatocellular carcinoma patients is unknown. METHODS: We retrospectively analysed the association between serum growth arrest-specific 6 levels and clinical findings in 132 patients with hepatocellular carcinoma. Serum growth arrest-specific 6 levels were measured using enzyme-linked immunosorbent assay. RESULTS: Amongst 132 patients, the Barcelona Clinic Liver Cancer stage was classified as 0, A, B, C and D in 19, 48, 41, 18 and 6 patients, respectively. Serum growth arrest-specific 6 levels in hepatocellular carcinoma patients were higher than those in healthy controls (28.4 ng/mL vs. 19.6 ng/mL, P < 0.001), and growth arrest-specific 6 levels were positively correlated with soluble Axl levels. In the entire cohort, high growth arrest-specific 6 levels were associated with a shorter survival period (hazard ratio: 1.78 per 20 ng/mL, 95% confidence interval: 1.01-3.16, P = 0.045). In early and intermediate-stage hepatocellular carcinoma patients treated with transcatheter arterial chemoembolization (n = 59), we determined a cut-off value of 36.4 ng/mL based on the receiver operating characteristic curve to predict death within 3 years, and high growth arrest-specific 6 levels were associated with a high cumulative incidence of portal vein tumour thrombosis (Gray's test: P = 0.010) and shorter overall survival (log-rank: P = 0.005). CONCLUSIONS: Serum growth arrest-specific 6 levels were associated with prognosis in hepatocellular carcinoma patients. In early and intermediate-stage hepatocellular carcinoma patients who underwent transcatheter arterial chemoembolization, high growth arrest-specific 6 levels were associated with a high incidence of portal vein tumour thrombosis. Circulating growth arrest-specific 6 levels may be a useful prognostic marker in hepatocellular carcinoma patients.

Characteristics of peripheral blood mononuclear cells and potential related molecular mechanisms in patients with autoimmune hepatitis: a single-cell RNA sequencing analysis.

Autoimmune hepatitis (AIH) is an immune disorder characterized by hypergammaglobulinemia, autoantibodies, and chronic active hepatitis on liver histology. However, immune cell population characteristics in AIH patients remain poorly understood. This study was designed to analyze peripheral blood mononuclear cell (PBMC) characteristics in AIH through single-cell RNA sequencing (scRNA-seq) and explore potential AIH-related molecular mechanisms. We generated 3690 and 3511 single-cell transcriptomes of PBMCs pooled from 4 healthy controls (HCs) and 4 AIH patients, respectively, by scRNA-seq. These pooled PBMC transcriptomes were used for cell cluster identification and differentially expressed gene (DEG) identification. GO functional enrichment analysis was performed on the DEGs to determine the most active AIH immune cell biological functions. Although the PCA-based uniform manifold approximation and projection (UMAP) algorithm was used to cluster cells with similar expression patterns in the two samples, 87 up- and 12 downregulated DEGs were retained in monocytes and 101 up- and 15 downregulated DEGs were retained in NK cells from AIH PBMCs. Moreover, enriched GO terms in the PBMC-derived monocyte and NK cell clusters were related mainly to antigen processing and presentation, IFN-γ-mediated signaling, and neutrophil degranulation and activation. These potential molecular mechanisms may be important targets for AIH treatment.

Association between equol and non-alcoholic fatty liver disease in Japanese women in their 50s and 60s.

BACKGROUND AND AIM: Equol is a metabolite of soy isoflavone and has estrogenic activity. The incidence of non-alcoholic fatty liver disease (NAFLD) increases after menopause in women, which is thought to result in a decrease in estrogen. This study aimed to evaluate the association between equol and NAFLD. METHODS: We evaluated 1185 women aged 50-69 years who underwent health check-ups at four health centers in Fukushima, Japan. Equol producers were defined by a urinary equol concentration of 1.0 µM or more. In addition to comparison between equol producers and non-producers, the association between equol and NAFLD was estimated using logistic regression analysis adjusting for fast walking and eating habits. RESULTS: Of the 1185 participants, 345 (29.1%) women were equol producers. The proportions of women who had NAFLD (34.8% vs 45.2%) were significantly lower in the equol-producing group than in the non-producing group. Multivariable logistic regression analysis showed that equol production was significantly associated with NAFLD (odds ratio = 0.66, 95% confidence interval: 0.51-0.86). CONCLUSIONS: Equol production was significantly associated with NAFLD in women in their 50s and 60s.

Circulating extracellular vesicle-encapsulated microRNA-557 induces a proinflammatory immune response and serves as a diagnostic or relapse marker in autoimmune hepatitis.

AIM: This study investigated serum microRNAs (miRNAs/miRs) in autoimmune hepatitis (AIH) and the relationship of these molecules with diagnostic and relapse markers. METHODS: Initially, extracellular vesicle-encapsulated miRNAs (EV-miRNAs) in serum with altered expression in AIH relative to healthy control (HC) samples were identified using microarray analysis. To validate the microarray results, the expression levels of selected EV-miRNAs were determined. RESULTS: Among the 2569 mature miRNAs evaluated in the microarray, EV-miR-557 discriminated patients with AIH from healthy controls (HCs). Validation by digital polymerase chain reaction indicated that serum EV-miR-557 levels were higher in patients with AIH (7.75 copies/µl) than in patients with non-alcoholic steatohepatitis (1.60 copies/µl; p < 0.001), patients with primary biliary cholangitis (2.16 copies/µl; p < 0.005), and HCs (1.86 copies/µl; p < 0.005). The area under the receiver operating characteristic curve values for the probability of AIH using serum EV-miR-557 between the AIH and non-alcoholic steatohepatitis, AIH and primary biliary cholangitis, and AIH and HC groups were 0.81, 0.78, and 0.79, respectively. In addition, serum EV-miR-557 levels >7.69 copies/µl were associated with a significantly higher risk of relapse in patients with AIH (7-year incidence rate: 11.1 vs. 35.4%, log-rank test, p < 0.05). Interestingly, gene expression analysis revealed that increased miR-557 expression following transient transfection of peripheral blood mononuclear cells with a miR-557 mimic resulted in enhanced expression of proinflammatory cytokine-related genes such as interleukin-6, interferon-γ, and tumor necrosis factor. Moreover, miR-557 induced significant tumor necrosis factor-α production (mean: 313.5 vs. 10 642.3 pg/ml, p < 0.05). CONCLUSION: EV-miR-557 may play an important role as a potential biomarker of AIH and may be a promising therapeutic target for AIH.

Risk factors for relapse of autoimmune hepatitis in Japan: A nationwide survey.

AIM: Some autoimmune hepatitis (AIH) patients experience relapse during their clinical course, and some risk factors for relapse have been identified previously using a relatively small sample size. The aim of the present study was to identify the risk factors for relapse in recently diagnosed AIH patients using a nationwide survey in Japan. METHODS: The nationwide survey performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017 was re-evaluated. A total of 614 patients who received corticosteroids were enrolled in the present study. Associations between relapse and patients' characteristics at diagnosis were evaluated using logistic regression analysis. RESULTS: Relapse was identified in 143 (23.3%) patients after remission. At the time of diagnosis of the disease, there were significant differences in the γ-glutamyl transpeptidase (γ-GTP) level, prevalence of liver cirrhosis, and degree of liver fibrosis. Multivariable logistic regression analysis showed that γ-GTP elevation and liver cirrhosis were significantly associated with relapse. CONCLUSION: The γ-GTP level at diagnosis could help identify AIH patients at higher risk of relapse.

Upregulation of complement C1q reflects mucosal regeneration in a mouse model of colitis.

Confirming mucosal healing is important in inflammatory bowel disease treatment. Complement C1q-mediated Wnt signaling activation has recently been suggested to mediate tissue repair and mucosal regeneration. We investigated the involvement of complement C1q and Wnt signaling in intestinal mucosal regeneration using a murine colitis model. The colitis model was established by providing C57BL/6J mice with 4% dextran sodium sulfate (DSS) for 1 week (inflammation phase) followed by regular water for 2 weeks (recovery phase). After 3 weeks, we investigated the relationship between C1q in serum and colonic tissue during the inflammation and recovery phases. We assessed Wnt signaling activity by evaluating ß-catenin expression in mouse intestinal tissue. Serum C1q levels were elevated during the recovery phase. C1q-specific staining indicated high C1q expression in pathological intestinal tissue during the inflammation and recovery phases. C1q mRNA and protein expression was increased during both phases. Interestingly, C1q-expressing cells were consistent with macrophages (F4/80-positive cells). Moreover, the expression of ß-catenin increased in the colonic tissues during the recovery phase of DSS-induced colitis but decreased during the inflammation phase of DSS-induced colitis. C1q expression may mediate Wnt signaling activity and intestinal epithelial regeneration.

Differences in autoimmune hepatitis based on inflammation localization.

Histopathology is essential for the diagnosis and evaluation of disease activity of autoimmune hepatitis (AIH). We aimed to elucidate the characteristics of AIH from the localization of inflammation. We re-evaluated a nationwide survey that was performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017. A total of 303 patients were enrolled, and the clinical and treatment characteristics were compared between the patients with predominantly portal inflammation (230 patients) or lobular inflammation (73 patients). AIH patients with lobular inflammation had a higher probability of being diagnosed with acute hepatitis than those with portal inflammation. Liver enzyme levels were higher in patients with lobular inflammation, whereas immunoglobulin G levels were higher in patients with portal inflammation. The prevalence of an alanine aminotransferase level < 30 U/L after 6 months of treatment was significantly higher in patients with lobular inflammation than in those with portal inflammation (81.7% vs. 67.3%, P = 0.046). The localization of inflammation may be useful for evaluating the onset of AIH.

Serum Gas6 and Axl as non-invasive biomarkers of advanced histological stage in primary biliary cholangitis.

AIM: Advanced histological stage is an important factor in individual risk stratification in patients with primary biliary cholangitis (PBC). Non-invasive biomarkers for advanced histological stage are needed. We assessed the utility of Gas6 and Axl as biomarkers for advanced histological stage in patients with PBC. METHODS: A total of 113 biopsy-proven PBC patients and 20 healthy controls were included in this study. Serum Axl and Gas6 were measured using enzyme-linked immunosorbent assay. The Gas6 / albumin ratio and Axl / albumin ratio were also evaluated as biomarkers of histological stage. RESULTS: Serum Axl (42.6 ng/mL vs. 30.6 ng/mL, P < 0.001) and Gas6 (21.1 ng/mL vs. 18.8 ng/mL, P = 0.007) levels in PBC patients were significantly higher than those in healthy controls. The Axl / albumin ratio was 10.4, and the Gas6 / albumin ratio was 7.6 in patients with PBC. Gas6 and Axl were significantly correlated with aspartate aminotransferase, bilirubin, albumin, and platelets. Gas6 and Axl levels in patients with an advanced Scheuer stage and an advanced Nakanuma stage were significantly higher than those in other patients. The area under the receiver operating characteristic curve (AUROC) of Axl, Gas6, Axl / albumin, and Gas6 / albumin for diagnosing Scheuer stage 4 was 0.733, 0.837, 0.845, and 0.893, respectively. The AUROC of Axl, Gas6, Axl / albumin, and Gas6 / albumin for diagnosing Nakanuma stage 4 was 0.794, 0.834, 0.869, and 0.898, respectively. CONCLUSION: High levels of Gas6 and Axl were associated with advanced histological stage in PBC patients. Furthermore, the Gas6 / albumin ratio and the Axl / albumin ratio showed a high AUROC for diagnosing advanced histological stage.

Acute kidney injury after platinum-based transcatheter arterial chemoembolization and transarterial infusion chemotherapy in patients with hepatocellular carcinoma.

BACKGROUNDS: The incidence of acute kidney injury and the association between acute kidney injury and prognosis have been reported about transcatheter arterial chemoembolization using anthracycline. However, the incidence of acute kidney injury after platinum-based transarterial chemoembolization or transarterial infusion chemotherapy remains unclear. The aim of this study was to investigate association between acute kidney injury after platinum-based transcatheter arterial chemoembolization/transarterial infusion chemotherapy and prognosis in patients with hepatocellular carcinoma. METHODS: We retrospectively analysed 270 sessions in 129 patients who underwent platinum-based transcatheter arterial chemoembolization/transarterial infusion chemotherapy. Acute kidney injury was diagnosed according to the criteria established by the International Club of Ascites. The incidence of acute kidney injury, risk factors for serum creatinine elevation and association between acute kidney injury and prognosis were assessed. RESULTS: Fifteen cases of acute kidney injury (5.6%, 15/270) developed in 14 patients (10.8%, 14/129). Ascites (coefficient: 0.059, P = 0.006), low estimated glomerular filtration rate (coefficient: -0.008, P = 0.029), diabetes (coefficient: 0.072, P < 0.001) and high albumin-bilirubin grade (albumin-bilirubin grade 2: coefficient: 0.053, P = 0.004; and albumin-bilirubin grade 3: coefficient: 0.103, P < 0.001) were significantly associated with an elevation in serum creatinine levels after transcatheter arterial chemoembolization/transarterial infusion chemotherapy. The development of acute kidney injury was associated with poor prognosis (hazard ratio: 3.18, 95%CI: 1.411-7.171, P = 0.005). Patients with acute kidney injury had a significantly lower survival rate than patients without acute kidney injury (log-rank test; P = 0.034). CONCLUSIONS: The incidence of acute kidney injury after platinum-based transcatheter arterial chemoembolization/transarterial infusion chemotherapy was consistent with that after transcatheter arterial chemoembolization using anthracycline, and the development of acute kidney injury was associated with poor prognosis. Ascites, diabetes, low estimated glomerular filtration rate and high albumin-bilirubin grade were risk factors for serum creatinine elevation after platinum-based transcatheter arterial chemoembolization/transarterial infusion chemotherapy.

Skeletal muscle volume loss during transarterial chemoembolization predicts poor prognosis in patients with hepatocellular carcinoma.

AIM: Sarcopenia has a negative impact on the prognosis of patients with hepatocellular carcinoma (HCC). We investigated the significance of skeletal muscle volume and its changes in HCC patients receiving transarterial chemoembolization (TACE). METHODS: We retrospectively analyzed 179 HCC patients receiving TACE from 2006 to 2017. Skeletal mass index was calculated as the left-right sum of the major × minor axis of the psoas muscle at the third lumbar vertebra, divided by height squared (psoas muscle index [PMI]). Patients were classified into two groups (low and normal PMI) depending on an index <6.0 and <3.4 cm2 /m2 for men and women, respectively. We assessed overall survival (OS) and TACE period (between the first TACE [Pre] and the time of TACE refractoriness [Post]). Changes in PMI per month during the TACE period (CPMI; (PMI [Pre] - PMI [Post]) / TACE period) were calculated as an index of progressive muscle atrophy. RESULTS: There were no significant differences in OS between groups with low and normal PMI at Pre. Multivariate analysis showed that CPMI was significantly associated with poor OS (hazard ratio, 1.884; P = 0.001). Patients with severe muscle atrophy (CPMI above the upper quartile) had a significantly lower OS than those with mild muscle atrophy (CPMI below the upper quartile). Compared with patients with mild muscle atrophy, patients with severe muscle atrophy had a significant loss of liver function reserves at Post. CONCLUSION: Progressive loss of skeletal muscle volume is an important predictor of poor prognosis in HCC patients treated with TACE.

Changes in serum levels of leucine-rich α2-glycoprotein predict prognosis in primary biliary cholangitis.

AIMS: A non-invasive biomarker for patients with primary biliary cholangitis (PBC) is needed. The association between leucine-rich α2 glycoprotein (LRG) and PBC has not been investigated. We aimed to assess the predictive value of LRG for the development of cirrhosis-related conditions in PBC. METHODS: We retrospectively reviewed clinical data of 129 individuals with biopsy-confirmed PBC. Leucine-rich α2 glycoprotein was analyzed by enzyme-linked immunosorbent assays using stored sera at biopsy (n = 129) and after treatment (n = 80). RESULTS: Levels of LRG decreased significantly after treatment (55.8 µg/mL vs. 39.8 µg/mL, P < 0.001). Neither LRG nor delta-LRG was associated with transaminase or histological findings. Delta-LRG >0 (hazard ratio [HR] 4.61, P = 0.013), delta-LRG >0 and an aspartate aminotransferase/platelet ratio index (APRI) >0.76 (HR 458, P < 0.001) were associated with the development of a cirrhosis-related condition. Patients with a delta-LRG >0 and an APRI >0.76 had a significantly increased rate of developing cirrhosis-related conditions (P < 0.001). CONCLUSIONS: Changes in LRG levels after treatment predicted PBC prognosis but were not associated with histological stage. Changes in LRG in addition to the APRI could be a useful combination of tools for clinicians as a non-invasive biomarker.

Association between sarcopenia and osteoporosis in chronic liver disease.

AIM: Sarcopenia and osteoporosis are important complications in chronic liver disease (CLD). The aim of this study was to investigate the relationship between sarcopenia and osteoporosis in patients with CLD. METHODS: We retrospectively investigated the relationship between sarcopenia and osteoporosis in 112 CLD patients (57 men and 55 women), including 40 cirrhotic patients (36%), by measuring the appendicular skeletal muscle mass index (ASMI) using bio-impedance analysis. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. RESULTS: The sarcopenia rate was 13% (14/112), and the osteoporosis and osteopenia rates were 17% (19/112) and 65% (73/112), respectively. The rate of osteoporosis was significant and high in patients with sarcopenia or cirrhosis. In linear regression analysis, sarcopenia was significantly associated with the BMD of the lumbar spine (coefficient = -0.149, P = 0.014) and the femur neck (coefficient = -0.110, P = 0.003). Cirrhosis was also significantly associated with low BMD of the lumbar spine (coefficient = -0.160, P < 0.001) and the femur neck (coefficient = -0.066, P = 0.015). In the logistic analysis, sarcopenia (odds ratio = 6.16, P = 0.039) and cirrhosis (odds ratio = 15.8, P = 0.002) were independent risk factors for osteoporosis. The ASMI cut-off values for osteoporosis were 7.33 kg/m2 in men and 5.71 kg/m2 in women. CONCLUSIONS: Sarcopenia was closely associated with osteoporosis, and a low ASMI was a potential predictor of osteoporosis in CLD patients. Screening for BMD might be required to detect osteoporosis in cirrhotic patients.

Utility of magnetic resonance elastography for predicting ascites in patients with chronic liver disease.

OBJECTIVE: This study aimed to evaluate the utility of magnetic resonance elastography (MRE) as a non-invasive method for predicting ascites in patients with chronic liver disease (CLD). METHODS: A total of 208 CLD patients underwent MRE to measure liver stiffness (LS) at our institution from March 2013 to June 2015. We evaluated the diagnostic performance of MRE for predicting the presence of ascites using receiver-operating characteristic (ROC) curve analysis and compared the performance with that of serum fibrosis markers. Multivariate logistic regression analysis was performed to identify factors associated with the presence of ascites. The cumulative incidence of ascites was examined in patients without ascites at baseline. The pathological stage of liver fibrosis was evaluated in 81 CLD patients using histopathologic diagnosis. RESULTS: Of the 208 patients, 41 had ascites. The optimal cut-off LS value for the presence of ascites was 6.0 kPa (area under the ROC curve = 0.87). The area under the ROC curve for the presence of ascites was significantly higher for MRE than that for fibrosis markers. Multivariate analysis revealed that LS >6.0 kPa is an independent risk factor for the presence of ascites. The cumulative incidence of ascites was significantly higher among those with LS values >6.0 kPa. There was significantly greater diagnostic accuracy for liver fibrosis stage ≥4 with MRE than that with fibrosis markers. CONCLUSIONS: Compared with serum fibrosis markers, MRE has higher diagnostic performance in predicting the presence of ascites. MRE-based LS has the potential to predict the presence of ascites in CLD patients.

Serum levels of a cell death biomarker predict the development of cirrhosis-related conditions in primary biliary cholangitis.

Non-invasive predictors for the development of cirrhosis-related conditions are needed for patients with primary biliary cholangitis (PBC). We investigated the association between cytokeratin-18 fragments (M30 and M65) and liver histology, treatment response and the development of cirrhosis-related conditions in patients with PBC. We retrospectively reviewed the clinical data of 111 individuals with biopsy-proven PBC. Serum M30 and M65 levels were measured using stored sera. M30 were significantly decreased after treatment, but there was no significant change in the M65 levels. M65 was significantly higher in non-responders according to the Paris-I and Paris-II definitions. In the multivariate analysis, high levels of M65 were significantly associated with advanced Scheuer stage (odds ratio 5.86; 95% confidence interval 0.55-22.2; P = 0.009) and with the development of cirrhosis-related conditions (hazard ratio 3.94; 95% confidence interval: 1.06-14.5, P = 0.039). Among PBC patients without cirrhosis, those with high serum M65 levels at baseline were at higher risk of developing cirrhosis-related conditions (log-rank test; P = 0.001). High levels of serum M65 may be a non-invasive and early predictor of the development of cirrhosis-related conditions in PBC patients. Our findings may help initiate therapies earlier for those at risk for cirrhosis.

Reduced frontal activation during verbal fluency task in chronic hepatitis C patients with interferon-based therapy as measured by near-infrared spectroscopy.

AIM: Psychiatric side-effects are the main reason for discontinuation of interferon (IFN)-based therapy. Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders. We prospectively evaluated brain activation in 20 chronic hepatitis C patients with or without IFN-based therapy by using NIRS during a verbal fluency task (VFT). METHODS: The relative concentrations of oxygenated hemoglobin were measured while patients completed a questionnaire survey at the start of treatment and at 4 and 12 weeks during treatment, using NIRS. RESULTS: The VFT performance did not change among the two groups. Patients with IFN-based therapy showed significantly lower activation during VFT in frontal channels at 12 weeks than those at the start of treatment and control (P < 0.05). Their Center for Epidemiologic Studies Depression Scale scores were significantly higher at 12 weeks than those at the start of treatment, although major depressive symptoms were not found (8.3 ± 7.9 vs. 13.2 ± 6.0, P < 0.001). CONCLUSION: The decrease in oxygenated hemoglobin concentrations of the frontal lobe detected using NIRS in this study reflects hypofunction of the frontal lobe. This functional decline that was caused by IFN-based therapy may be associated with the prodromal phase of depression.