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AIMS Hepatocellular carcinoma (HCC) can still occur in hepatitis C virus (HCV) patients who have achieved a sustained virologic response (SVR), which remains an important clinical issue in the direct-acting antivirals era. The current study investigated the clinical utility of the aMAP score (consisting of age, male, albumin-bilirubin, and platelets) for predicting HCC occurrence in HCV patients achieving an SVR by direct-acting antivirals. METHODS A total of 1113 HCV patients without HCC history, all of whom achieved an SVR, were enrolled for clinical comparisons. RESULTS Hepatocellular carcinoma was recorded in 50 patients during a median follow-up period of 3.7 years. The aMAP score was significantly higher in the HCC occurrence group than in the HCC-free group (53 vs. 47, p

SLC25A13 gene mutations are responsible for diseases related to citrin deficiency (CD), such as neonatal intrahepatic cholestasis caused by citrin deficiency and adult-onset type II citrullinemia (CTLN2). From childhood to adulthood, CD patients are apparently healthy due to metabolic compensation with peculiar dietary habits—disliking high-carbohydrate foods and liking fat and protein-rich foods. Carbohydrate overload and alcohol consumption may trigger the sudden onset of CTLN2, inducing hyperammonemia and consciousness disturbance. Well-compensated asymptomatic CD patients are sometimes diagnosed as having non-obese (lean) non-alcoholic fatty liver disease and steatohepatitis, which have the risk of developing into liver cirrhosis and hepatocellular carcinoma. CD-induced fatty liver demonstrates significant suppression of peroxisome proliferator-activated receptor α and its downstream enzymes/proteins involved in fatty acid transport and oxidation and triglyceride secretion as a very low-density lipoprotein. Nutritional therapy is an essential and important treatment of CD, and medium-chain triglycerides oil and sodium pyruvate are useful for preventing hyperammonemia. We need to avoid the use of glycerol for treating brain edema by hyperammonemia. This review summarizes the clinical and nutritional features of CD-associated fatty liver disease and promising nutritional interventions.

A male hepatitis B virus (HBV) carrier in his 40s under hemodialysis treatment exhibited chronic hepatitis (alanine aminotransferase: 41 IU/L, HBV-DNA: >9.1 log copies/mL). Following discontinuation of the initial treatment with pegylated interferon-α-2a at 24 weeks due to adverse effects, the administration of tenofovirdisoproxil fumarate (TDF) (300 mg/week) led to a rapid improvement in hepatitis markers: HBV DNA became undetectable at month 34, and seroconversion of hepatitis B envelope antigen was confirmed at 45 months. No side effects were recorded during TDF treatment. TDF is a newly approved nucleoside analogue that may cause severe side effects via proximal tubular injury in patients with renal dysfunction. However, few reports have described its use in hemodialysis patients, whose anuric state may render them less susceptible to side effects including kidney injury. Hepatitis improved remarkably without any adverse drug reactions in the present case. TDF may therefore be considered for chronic hepatitis B patients receiving hemodialysis.

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.

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

Killer cell immunoglobulin-like receptors (KIRs) are involved in the activation and inhibition of natural killer cells. Although combinations of KIRs and HLA have been associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection, their roles are not fully understood in the context of hepatocellular carcinoma (HCC) development. We enrolled 787 consecutive patients with chronic HCV infection, which included 174 cases of HCC, and 325 healthy subjects to clarify the involvement of HLA-Bw and C, KIRs, and major histocompatibility complex class I chain-related gene A (MICA) gene polymorphisms (rs2596542 and rs1051792) in chronic HCV infection and HCV-related HCC. We observed a significant association with chronic hepatitis C susceptibility for HLA-Bw4 (P = 0.00012; odds ratio [OR] = 1.66) and significant protective associations for HLA-C2 and KIR2DL1-HLA-C2 (both P = 0.00099; OR = 0.57). When HCC patients were stratified into younger (

AIM The impact of mild drinking habit (less than 20 g/d of ethanol) on the clinical course of non-alcoholic fatty liver disease (NAFLD) has not been determined. We examined the influence of a mild drinking habit on liver carcinogenesis from NAFLD. METHODS A total of 301 patients who had been diagnosed as having NAFLD by liver biopsy between 2003 and 2016 [median age: 56 years, 45% male, 56% with non-alcoholic steatohepatitis, 26% with advanced fibrosis (F3-4)] were divided into the mild drinking group with ethanol consumption of less than 20 g/d (mild drinking group, n = 93) and the non-drinking group (n = 208). Clinicopathological features at the time of liver biopsy and factors related to hepatocellular carcinoma (HCC) occurrence were compared between the groups. RESULTS We observed significant differences in male prevalence (P = 0.01), platelet count (P = 0.04), and gamma-glutamyl transpeptidase (P = 0.02) between the test groups. Over 6 years of observation, the HCC appearance rate was significantly higher in the mild drinking group (6.5% vs 1.4%, P = 0.02). Multivariate survival analysis using Cox’s regression model revealed that hepatic advanced fibrosis (F3-4) (P < 0.01, risk ratio: 11.60), diabetes mellitus (P < 0.01, risk ratio: 89.50), and serum triglyceride (P = 0.04, risk ratio: 0.98) were factors significantly related to HCC in all NAFLD patients, while the effect of a drinking habit was marginal (P = 0.07, risk ratio: 4.43). In patients with advanced fibrosis (F3-4), however, a drinking habit (P = 0.04, risk ratio: 4.83), alpha-fetoprotein (P = 0.01, risk ratio: 1.23), and diabetes mellitus (P = 0.03, risk ratio: 12.00) were identified as significant contributors to HCC occurrence. CONCLUSION A mild drinking habit appears to be a risk factor for hepatocarcinogenesis in NAFLD patients, especially those with advanced fibrosis.

AIM To examine the relationship between serum autotaxin (ATX) concentrations and clinicopathological findings in non-alcoholic fatty liver disease (NAFLD) patients. METHODS One hundred eighty-six NAFLD patients who had undergone liver biopsy between 2008 and 2017 were retrospectively enrolled. Serum samples were collected at the time of biopsy and ATX was measured by enzyme immunoassays. Sera obtained from 160 healthy, non-obese individuals were used as controls. Histological findings were graded according to an NAFLD scoring system and correlations with serum ATX were calculated by Spearman’s test. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUC). Cut-off values were identified by the Youden index, and the nearest clinically applicable value to the cutoff was considered the optimal threshold for clinical convenience. RESULTS Serum ATX levels were significantly higher in NAFLD patients than in controls (0.86 mg/L vs 0.76 mg/L, P < 0.001) and correlated significantly with ballooning score and fibrosis stage (r = 0.36, P < 0.001 and r = 0.45, P < 0.001, respectively). Such tendencies were stronger in female patients. There were no remarkable relationships between ATX and serum alanine aminotransferase, lipid profiles, or steatosis scores. The AUC values of ATX for predicting the presence of fibrosis (≥ F1), significant fibrosis (≥ F2), severe fibrosis (≥ F3), and cirrhosis (F4), were all more than 0.70 in respective analyses. CONCLUSION Serum ATX levels may at least partially reflect histological severity in NAFLD.

AIM Autotaxin (ATX) is a secreted enzyme that is considered to be associated with liver damage as well as fibrosis. This study assessed the ability of ATX to diagnose liver fibrosis in patients with chronic hepatitis B virus (HBV) infection. METHODS Serum ATX levels were retrospectively evaluated in 101 treatment-naive patients with HBV-related chronic hepatitis or cirrhosis, all of whom had undergone liver biopsy at our hospital. RESULTS Serum ATX concentration increased significantly according to liver fibrosis stage in overall (r = 0.46, P

A 21-year-old Japanese man was admitted to our hospital because of severe abdominal pain and jaundice. He had been suffering from abdominal pain attacks and liver dysfunction since 18 years of age. Liver histology showed amorphous brown deposits in the sinusoidal space and significant periportal fibrosis without apparent hepatitis. Increased protoporphyrin in serum and feces and ferrochelatase gene mutation confirmed the final diagnosis of erythropoietic protoporphyria (EPP). Since ursodeoxycholic acid (UDCA) intake and glucose infusion are insufficient to ameliorate jaundice and abdominal attacks, cimetidine and lactulose were added in order to suppress hepatic delta-aminolevulinic acid synthase and limit re-absorption of protoporphyrin, respectively. Afterwards, the jaundice, liver dysfunction and abdominal symptoms improved and UDCA, cimetidine, and lactulose administration was continued. A repeat biopsy at 1.5 years after adding cimetidine/lactulose revealed marked attenuation of periportal fibrosis and protoporphyrin deposits. As far as we know, this is the first demonstration of histological improvement of EPP-induced liver abnormalities due to persistent cimetidine/lactulose administration. These treatments may be useful for EPP-related liver injury.

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

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

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/m2 (r = 0.579, P

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

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n = 182) were compared for clinical features and outcomes between first treatment (n = 159) and retreatment (n = 23) G/P groups. Overall, 77 patients (42.3%) were male, the median age was 68 years, and 86/66/1/4 cases had genotype 1/2/1+2/3, respectively. An SVR was achieved in 97.8% (178/182) of cases by intention-to-treat analysis and 99.4% (178/179) of cases by per-protocol analysis. There were no remarkable differences between the first treatment and retreatment groups for male (42.8% vs. 39.1%, p = 0.70), median age (68 vs. 68 years, p = 0.36), prior hepatocellular carcinoma (5.8% vs. 8.7%, p = 0.59), or the fibrosis markers AST-to-platelet ratio index (APRI) (0.5 vs. 0.5, p = 0.80) and fibrosis-4 (FIB-4) index (2.2 vs. 2.6, p = 0.59). The retreatment group had a significantly more frequent history of interferon treatment (12.3% vs. 52.2%, p &lt, 0.01) and the Y93H mutation (25.0% vs. 64.7%, p = 0.02). The number of retreatment patients who had experienced 3, 2, and 1 DAA treatment failures was 1, 3, and 19, respectively, all of whom ultimately achieved an SVR by G/P treatment. In conclusion, G/P was effective and safe for both HCV first treatment and retreatment cases despite the retreatment group having specific resistance mutations for other prior DAAs. As G/P treatment failure has been reported for P32 deletions, clinicians should consider resistance mutations during DAA selection.

Non-alcoholic fatty liver disease (NAFLD) is a major chronic liver disease that can lead to liver cirrhosis, liver cancer, and ultimately death. NAFLD is pathologically classified as non-alcoholic fatty liver (NAFL) or non-alcoholic steatohepatitis (NASH) based on the existence of ballooned hepatocytes, although the states have been known to transform into each other. Moreover, since the detection of ballooned hepatocytes may be difficult with limited biopsied specimens, its clinical significance needs reconsideration. Repeated liver biopsy to assess histological NAFLD activity for therapeutic response is also impractical, creating the need for body fluid biomarkers and less invasive imaging modalities. Recent longitudinal observational studies have emphasized the importance of advanced fibrosis as a determinant of NAFLD outcome. Thus, identifying predictors of fibrosis progression and developing better screening methods will enable clinicians to isolate high-risk NAFLD patients requiring early intensive intervention. Despite the considerable heterogeneity of NAFLD with regard to underlying disease, patient age, and fibrosis stage, several clinical trials are underway to develop a first-in-class drug. In this review, we summarize the present status and future direction of NAFLD/NASH research towards solving unmet medical needs.

A 45-year-old man presented with fatigue and pain in the finger joints. Despite having a history of suspected sideroblastic anemia since the age of 18 years, he had not been followed up for years. Upon presentation, laboratory data revealed microcytic anemia and elevated serum ferritin levels. In addition, ringed sideroblasts were increased in the bone marrow. A liver biopsy revealed hemochromatosis and cirrhosis. Furthermore, genetic analysis revealed that he harbored the ALAS2 R452H mutation, leading to the diagnosis of X-linked sideroblastic anemia (XLSA). Accordingly, oral folate or vitamin (Vit) B

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.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.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.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.

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 β-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.

Fatty liver disease (FLD) increases the risk of diabetes, cardiovascular disease, and steatohepatitis, which leads to fibrosis, cirrhosis, and hepatocellular carcinoma. Thus, the early detection of FLD is necessary. We aimed to find a quantitative and feasible model for discriminating the FLD, based on plasma free amino acid (PFAA) profiles. We constructed models of the relationship between PFAA levels in 2,000 generally healthy Japanese subjects and the diagnosis of FLD by abdominal ultrasound scan by multiple logistic regression analysis with variable selection. The performance of these models for FLD discrimination was validated using an independent data set of 2,160 subjects. The generated PFAA-based model was able to identify FLD patients. The area under the receiver operating characteristic curve for the model was 0.83, which was higher than those of other existing liver function-associated markers ranging from 0.53 to 0.80. The value of the linear discriminant in the model yielded the adjusted odds ratio (with 95% confidence intervals) for a 1 standard deviation increase of 2.63 (2.14–3.25) in the multiple logistic regression analysis with known liver function-associated covariates. Interestingly, the linear discriminant values were significantly associated with the progression of FLD, and patients with nonalcoholic steatohepatitis also exhibited higher values.

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

OBJECTIVE Ischemic colitis (IC) often affects the elderly. Proarteriosclerotic factors, such as hypertension and smoking, and cardiovascular disease are considered major contributors to IC. Although a possible link between certain cerebrocardiovascular disorders and meteorological phenomena has been reported, the relationship between IC onset and weather changes remains uninvestigated. This study examined whether specific meteorological factors were associated with the occurrence of IC. PATIENTS AND METHODS We retrospectively enrolled 303 patients who had been diagnosed with IC between January 2003 and June 2010 at Suwa Red Cross Hospital in Nagano Prefecture, Japan. The meteorological data of the days on which IC patients visited the hospital (IC+ days) were compared with those of the days on which IC patients did not (IC- days). RESULTS Univariate analysis indicated that IC+ days had significantly lower air pressure (P

Metabolized by liver sinusoidal endothelial cells, autotaxin (ATX) is a secreted enzyme considered to be associated with liver damage. We sought to clarify the diagnostic ability of ATX for liver fibrosis in 593 biopsy-confirmed hepatitis C virus (HCV)-infected patients. The diagnostic accuracy of ATX was compared with clinical parameters and the established fibrosis biomarkers Wisteria floribunda agglutinin-positive Mac-2-binding protein, FIB-4 index, AST-to-platelet ratio, and Forn’s index. Median ATX levels were consistently higher in female controls and patients than in their male counterparts (P

Aim Although hyponatremia is associated with a poor prognosis in liver cirrhosis, little is known about the clinical significance of serum sodium concentration in cirrhosis in Japan. This study investigated associations of mortality in Japanese cirrhosis patients taking conventional diuretics with serum sodium concentration and other clinical characteristics. Methods A total of 171 consecutive patients with cirrhosis who were taking diuretic medication were enrolled retrospectively. We determined the prevalence of low serum sodium concentration and searched for associations with age, sex, etiology, complications of cirrhosis, liver function tests and Model for End-Stage Liver Disease (MELD) and MELD-Na scores. The predictive ability of sodium level on mortality was also investigated. Results Median serum sodium concentration was 139 mEq/L (interquartile range, 137-141). Only eight of 171 (4.7%) patients had low serum sodium ( Conclusion Serum sodium concentration below 139 mEq/L and MELD-Na score above 10.5 may be predictive markers for mortality in patients with cirrhosis despite being within normal ranges. These markers may help to better assess and manage the prognosis of patients with cirrhosis in Japan.

AIM We sought to clarify the associations between serum cytokines and chemokines, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and hepatitis B virus (HBV) DNA and response to entecavir therapy in chronic hepatitis B. METHODS We analyzed six cytokines (interleukin [IL]-2, IL-6, IL-10, IL-12p70, IL-21 and IL-22) and five chemokines (CCL2, CCL3, CXCL9, CXCL10 and CXCL11) before and at 6, 12 and 24 months during entecavir therapy in 48 chronic hepatitis B patients. Quantitative measurement of HBsAg, HBcrAg and HBV DNA was performed. A virological response (VR) was defined as serum HBV DNA of less than 2.1 log copies/mL by treatment month 24. RESULTS Thirty-nine patients (81%) achieved a VR. Serum IL-6 (P = 0.031), CXCL-9 (P = 0.002), and CXCL-10 (P = 0.001) were high in chronic HBV and correlated positively with transaminases and bilirubin. Before treatment, elevated IL-22 (P = 0.031) and lower HBsAg (P = 0.001) and HBcrAg (P

A 57-year-old woman with familial amyloid polyneuropathy (FAP) was scheduled to undergo living donor liver transplantation (LDLT), but the operation was cancelled because the only potential donor had chronic alcohol-related liver disease. One year later, FAP-related neurological symptoms progressed rapidly, and emergency LDLT was planned. The donor's hepatic function had returned to normal range after 1 year of abstinence. The left liver graft volume was equivalent to 37.7% of the standard liver volume (SLV) of the recipient. However, a liver biopsy revealed mild fibrosis (score, F1). LDLT was successfully performed without any complications. The recipient's neurological findings returned to normal. One year after LDLT, the liver graft volume was equivalent to approximately 90% of the SLV, and the fibrosis had improved. LDLT using a graft with a fibrosis score of up to F1 may be an acceptable alternative for recipients with normal hepatic function.

A genetic polymorphism of the newly discovered interferon-λ 4 (IFNL4) gene was associated with hepatitis C virus (HCV) clearance in individuals of African ancestry. To assess whether a dinucleotide variant of IFNL4 (ss469415590) also affected treatment outcome of antiviral therapy in Japan, we genotyped 213 patients with chronic genotype 1 HCV infection and 176 healthy subjects. The ΔG allele was associated with treatment failure [odds ratio (OR) 4.73, P = 0.019], as was the IFL3 rs8099917 single nucleotide polymorphism (SNP) (OR 5.06, P = 0.068). The correlation between ss469415590 and rs8099917 was high (r(2) = 0.92, D' = 0.98). Multivariate analysis revealed that the rs8099917 SNP was independently associated with treatment failure (OR 5.28, P = 0.009). Therefore, ss469415590 may be another predictive marker of antiviral therapy outcome in the Japanese population.

Aim We analyzed the characteristics of alanine aminotransferase (ALT) abnormality after achieving hepatitis B e-antigen (HBeAg) seroconversion (SC) and other factors associated with the occurrence of HBeAg negative hepatitis. Methods We followed 36 patients with chronic hepatitis B from 3 years prior to at least 3 years after SC (mean, 11.6 years) and examined ALT, hepatitis B virus (HBV) DNA, HB surface antigen, HB core-related antigen (HBcrAg) levels and mutations related to HBeAg SC. Results ALT normalization (

A 33-year-old man visited a hospital after vomiting blood. Emergent esophagogastroduodenoscopy revealed the presence of varices in the lower esophagus. The patient did not have a past history of alcohol consumption and was negative for hepatitis B and C viruses. He was referred to our hospital for closer examination. Portal hypertension was detected by conventional imaging modalities, but signs of liver cirrhosis, thrombosis, stenosis, malformation of the portal vein and bile duct abnormalities were not observed. We performed laparoscopy-guided liver biopsy to examine the cause of portal hypertension. In addition to prominent development of collateral vessels on hepatic ligaments and the omenta, marbled whitish markings with black-green spots were dispersed over the liver surface, but nodular formation and lymphatic vesicles were not found. Biopsied specimen demonstrated severe dense fibrosis in portal areas and von Meyenburg complexes (vMC). Based on these findings, the diagnosis of congenital hepatic fibrosis (CHF) was made. Post-biopsy hemostasis was confirmed under laparoscopy and no major complications occurred after biopsy. We reviewed 11 cases of CHF which had undergone laparoscopy in Japan, including our case. Marbled whitish markings, black-green spots and collateral vessels were seen in 11, five and seven cases, respectively. When we encounter the patients having portal hypertension of unknown etiology, laparoscopy-guided liver biopsy should be considered as a safe and useful diagnostic procedure. Black-green spots in marbled whitish markings, which reflect vMC in broad fibrotic areas, are laparoscopic characteristics of CHF.

Primary biliary cirrhosis (PBC) is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts that often result in liver failure. Toll-like receptor (TLR) 4 recognizes lipopolysaccharides of Gram-negative bacteria. Infectious agents have been suspected to play a crucial role in PBC pathogenesis since TLR4 expression was found in bile duct epithelial cells and periportal hepatocytes in liver tissues of PBC. To assess the potential contribution of TLR4 SNPs to the development of this disease, we genotyped five SNPs in TLR4 in 261 PBC patients and 359 controls using a TaqMan assay. No significant positive associations with either PBC susceptibility or progression were uncovered. These results indicate that TLR4 polymorphisms do not play a prominent role in the development of PBC in Japanese patients. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved., Article, HUMAN IMMUNOLOGY. 74(2):219-222 (2013)

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

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.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 intake20 g/day, n = 31), non-alcoholic fatty liver group (steatosis5% and ethanol intake20 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.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.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.

Serum glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFASerum WFASerum WFASerum WFA

The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4–positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment. Conclusion: Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse. (HEPATOLOGY 2012)

Methods. We quantified a total of 8 serum cytokines before, during, and after treatment in 79 genotype 1 chronic HCV patients. Viral ISDR and core region variants were determined by direct sequencing. Results. High levels of interleukin (IL)-12 and IL-18 and more than 2 mutations in the ISDR were associated with a sustained virological response (SVR). Conversely, high baseline IL-10 levels and glutamine at amino acid 70 of the HCV core protein (Gln70) were significantly associated with a nonresponse to treatment, and patients with Gln70 had significantly higher IL-10 levels. In multivariate analysis, low IL-10, high IL-12, and high IL-18 levels were independently associated with an SVR. These 3 cytokine levels were decreased from baseline levels 4 weeks into treatment and remained low in patients with an SVR. Conclusion. Serum IL-10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR and core region., Article, JOURNAL OF INFECTIOUS DISEASES. 203(8):1087-1095 (2011)

Hepatic steatosis may develop after pancreatic resection, but its clinicopathological features remain unclear. We explored the clinical characteristics of newly appearing nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD), designated as de novo NAFLD after PD.Of 83 patients who underwent PD between 2001 and 2006, the patients with regular alcohol consumption after PD (n = 3), those who were unavailable for regular abdominal computed tomography follow-up (n = 12), and those who died within 6 months of PD (n = 8) were excluded from the study. In the remaining 60 patients, the prevalence and clinical features of de novo NAFLD after PD were examined.NAFLD developed after PD in 14 (23%) patients in our cohort. Liver biopsy was performed in 8 patients and all showed typical steatohepatitis. Compared with the patients who had conventional nonalcoholic steatohepatitis (NASH), patients with post-PD de novo NASH demonstrated significant decreases in body mass index and lower levels of serum albumin, cholesterol, apolipoprotein B, and homeostasis model assessment for insulin resistance. Multivariate logistic regression analysis revealed that pancreatic head cancer was associated with an increased risk of developing NAFLD after PD (odds ratio 12.0, 95% confidence interval 2.0-71.4, P = 0.006). Increased dosage of oral pancreatic enzymes significantly ameliorated the steatosis, as well as leading to the recovery of body weight loss and resolution of the biochemical abnormalities.De novo NAFLD/NASH after PD is characterized by non-obesity and lack of hyperlipidemia and insulin resistance and is associated with pancreatic exocrine insufficiency. In such patients, intensifying pancreatic enzyme supplementation may be useful.

Background & Aims It is well-known that hepatic triglycerides (TG) diminish with the progression of non-alcoholic steatohepatitis (NASH), which has been designated as burned-out NASH, but its mechanism remains unclear. We aimed to explore the changes in hepatic fatty acid (FA) and TG metabolism with disease progression. Methods Hepatic expression of key genes in healthy individuals ( n =6) and patients with simple steatosis (SS, n =10), mild NASH (fibrosis stage 1–2, n =20), and advanced NASH (fibrosis stage 3–4, n =20) were assessed by quantitative polymerase chain reaction. Results Hepatic expression of genes related to FA uptake and oxidation and very-low-density lipoprotein synthesis/export did not differ among the groups. However, the mRNA levels of sterol regulatory element-binding protein (SREBP)-1c and its downstream genes FA synthase, acetyl-coenzyme A carboxylase 1, and diacylglycerol acyltransferase 1 were inversely correlated with fibrosis stage. Immunoblot analysis revealed a remarkable reduction in mature SREBP-1c levels in advanced NASH. Furthermore, hepatic expression of tumor necrosis factor-α increased in accordance with fibrosis progression, which was possibly related to the decrease in hepatic SREBP-1c expression. Conclusions Down-regulation of SREBP-1c and lipogenic enzymes may be associated with the development of burned-out NASH.

To assess the degree of hepatic fat content, simple and noninvasive methods with high objectivity and reproducibility are required. Magnetic resonance imaging (MRI) is one such candidate, although its accuracy remains unclear. We aimed to validate an MRI method for quantifying hepatic fat content by calibrating MRI reading with a phantom and comparing MRI measurements in human subjects with estimates of liver fat content in liver biopsy specimens. The MRI method was performed by a combination of MRI calibration using a phantom and double-echo chemical shift gradient-echo sequence (double-echo fast low-angle shot sequence) that has been widely used on a 1.5-T scanner. Liver fat content in patients with nonalcoholic fatty liver disease (NAFLD, n = 26) was derived from a calibration curve generated by scanning the phantom. Liver fat was also estimated by optical image analysis. The correlation between the MRI measurements and liver histology findings was examined prospectively. Magnetic resonance imaging measurements showed a strong correlation with liver fat content estimated from the results of light microscopic examination (correlation coefficient 0.91, P < 0.001) regardless of the degree of hepatic steatosis. Moreover, the severity of lobular inflammation or fibrosis did not influence the MRI measurements. This MRI method is simple and noninvasive, has excellent ability to quantify hepatic fat content even in NAFLD patients with mild steatosis or advanced fibrosis, and can be performed easily without special devices., Article, JOURNAL OF GASTROENTEROLOGY. 45(12):1263-1271 (2010)

A 33-year-old man presented with pain and palsy of the leg in 2008 for treatment of hepatocellular carcinoma with huge distant metastases. The patient's tumors had slowly enlarged despite several treatments. Oral administration of sorafenib at 800 mg/day with careful observation was commenced in 2009. Laboratory investigations on day 7 showed massive tumor lysis. An abdominal CT showed multiple low density areas and tumor markers decreased, indicating extended tumor necrosis. In conclusion, clinicians should bear in mind not only the published adverse effects, but also massive tumor lysis, when treating patients with large tumor burden by sorafenib., Article, INTERNAL MEDICINE. 49(11):991-994 (2010)

The original publication is available at www.springerlink.com, Background: Hepatoprotective therapies that include regular glycyrrhizin injection (GI) are beneficial for chronic hepatitis C patients, but are sometimes unable to normalize serum alanine aminotransferase (ALT) levels. Here, we evaluated whether the addition of minor bloodletting, named petit phlebotomy (PP), prior to each GI could further reduce serum ALT concentrations in such patients. Methods: Seventy-six HCV-infected patients receiving regular GI with persistently abnormal serum ALT levels were randomly divided into GI+PP or GI groups and monitored for 12 months. PP was performed before every GI to a total 60 ml of blood a week. The primary PP endpoint was serum ferritin levels of less than 20 ng/ml. PP was suspended upon reaching the endpoint, but was resumed as needed. The efficacy of the addition of PP was evaluated by measuring changes in serum ALT levels. Results: Two patients in each group dropped out because of apparition of hepatocellular carcinoma. The remainder completed the 12-month treatment with no serious adverse events. Serum ALT and ferritin levels were significantly decreased in the GI+PP group (from 67 + 34 to 44 + 14 U/l and from 163 + 127 to 25 + 21 ng/ml, respectively, both P, Article, Journal of Gastroenterology 44(6): 577-582(2009)

We here report the first case of cholangiolocellular carcinoma (CoCC) visualized with contrast-enhanced ultrasonography (CEUS) using a second-generation contrast agent, Sonazoid. A 76-year-old man was admitted to our hospital for evaluation of a hepatic tumor. The tumor was described as having hyper-enhancement in the early phase and persistent enhancement in the late phase by contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), as well as hypervascularity by angiography. CEUS assessment of the nodule showed diffuse and homogeneous enhancement in the pure arterial phase, which became progressively hypoechoic relative to the adjacent liver parenchyma during the portal vein and late phases (mixed vascular phase), and showed a contrast defect with an unclear border in the Kupffer phase. Histologically we diagnosed this hepatic tumor as CoCC. In light of the above findings and the rarity of CoCC, it is helpful to incorporate the results of several imagings, such as CT, MRI, angiography and CEUS with a second-generation contrast agent when clinically diagnosing CoCC.

症例は68歳，女性．B型肝硬変にて治療中2004年に肝細胞癌（HCC）を初発し肝切除術を施行．その後再発に対して3回の肝動脈塞栓術（TAE）を施行した．2008年5月にCT上S4領域に径20 mmの再発病変を認めたが，肝動脈門脈シャントのためTAEができず，局所療法目的に当院紹介となった．CT, MRIではTAE後の結節と再発病変が混在していた．超音波（US）では，Bモードで多発する低エコー領域を認め質的診断は困難だったが，ソナゾイドTM造影USを追加したところ，一部に動脈相で濃染しKupffer相で低エコーを示すHCCに合致する病変を認め，局所療法が可能となった．3カ月後の造影USでは新たな再発を認めたが，やはり診断可能であり局所療法を行った．肝切除後の再発病変に複数回の再発治療を施行した症例であっても，造影USを施行することでBモードで評価困難な再発病変を診断でき，効果的な治療が可能であった.