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

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

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.

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

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

Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients.

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

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

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

[Successful treatment of X-linked sideroblastic anemia with ALAS2 R452H mutation using vitamin B6].

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) B12 was administered, but his anemia did not respond. However, his hemoglobin level increased from 7 to 11 g/dl with an additional prescription of oral VitB6, which facilitated the patient to undergo phlebotomy to ameliorate organ dysfunctions caused by iron overload. Previous research has revealed that ALAS2 R452 mutations confer poor responses to VitB6 therapy. Hence, accrual of patients with an unexpectedly better response, which was observed in our case, may help elucidate the pathogenesis of and therapies for XLSA.

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

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

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

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

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

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

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.

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

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

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

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

Serum 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.

Serum sodium concentration is associated with increased risk of mortality in patients with compensated liver cirrhosis.

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 (<130 mEq/L). Median MELD-Na score was 10.5 (interquartile range, 8.0-14.3). Cumulative survival rates were significantly lower in patients with Na of less than 139 mEq/L or MELD-Na score of 10.5 or more (log-rank test, P = 0.017 and P = 0.0002, respectively). Several liver function tests, MELD and MELD-Na scores, and the incidence of ascites were all significantly associated with patients having Na of less than 139 mEq/L. 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.

Living donor liver transplantation using a graft with periportal fibrosis.

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.

Serum levels of interleukin-22 and hepatitis B core-related antigen are associated with treatment response to entecavir therapy in chronic hepatitis B.

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 < 0.001), but not HBV DNA, were associated with a favorable treatment outcome. In multivariate analysis, high IL-22 (hazard ratio = 13.67, P = 0.046) and low HBcrAg (hazard ratio = 10.88, P = 0.048) were independently associated with a VR. The levels of IL-22 (P < 0.001), HBsAg (P < 0.001), and HBcrAg (P < 0.001) all decreased from baseline to 24 months of treatment in virological responders. CONCLUSION: Serum IL-22 and HBcrAg are predictive markers of a VR to entecavir therapy in patients with chronic hepatitis B.

Characteristics and prediction of hepatitis B e-antigen negative hepatitis following seroconversion in patients with chronic hepatitis B.

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 (<31 IU/L for at least 1 year) was primarily observed until 2 years following SC, after which it became more infrequent. We next divided patients into abnormal (≥31 IU/L, n = 20) and normal (<31 IU/L, n = 16) groups based on integrated ALT level after the time point of 2 years from SC, and considered the former group as having HBeAg negative hepatitis in the present study. Although changes in median levels of ALT and HBcrAg differed significantly between the groups, multivariate analysis showed ALT normalization within 2 years after SC to be the only significant determining factor for this disease (P = 0.001). We then assessed the 19 patients whose ALT was normal at 2 years following SC, four of whom developed HBeAg negative hepatitis. Increased levels of HBV DNA (P = 0.037) and HBcrAg (P = 0.033) were significant factors of potential relevance. CONCLUSION: ALT abnormality after 2 years of SC may be evaluated as HBeAg-negative hepatitis. ALT, HBV DNA and HBcrAg levels may be useful in predicting the outcome of patients who achieve HBeAg SC.

Laparoscopic findings of congenital hepatic fibrosis: A case report and review of the published work.

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.

Long-term outcome of Japanese patients with type 1 autoimmune hepatitis.

UNLABELLED: 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.

Citrin Deficiency: Clinical and Nutritional Features.

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.