Liver Disease-Related Sarcopenia: A Predictor of Poor Prognosis by Accelerating Hepatic Decompensation in Advanced Chronic Liver Disease.

Background Sarcopenia is considered a prognostic factor for advanced chronic liver disease (ACLD) independent of liver function, but the underlying mechanisms are unknown. Here, we investigated whether sarcopenia contributed to hepatic decompensation and worsened prognosis. Methods This was a single-center retrospective study of 708 patients with chronic liver disease who underwent magnetic resonance elastography (MRE). Magnetic resonance imaging (MRI) was used to diagnose sarcopenia and hepatic decompensation (presence of ascites). Results The incidence of sarcopenia (29% overall) and age were significantly correlated to increased liver stiffness (LS) (p < 0.01 each), but age did not differ for LS ≥ 4 kPa. Rates of thrombocytopenia and varices increased at ≥4 kPa, and ascites (n = 52) accounted for 81% of patients with ≥6 kPa LS. Age, alcoholic liver disease, C-reactive protein, sodium level, and controlling nutritional status score were extracted as factors contributing to sarcopenia (all p < 0.05). In ACLD, sarcopenia was an independent predictor of ascites (p < 0.01), and in a follow-up analysis of 163 patients without ascites at baseline, the incidence of ascites in patients with sarcopenia was significantly higher, even after adjusting for LS and liver severity (p < 0.01). The Cox proportional hazards model indicated albumin-bilirubin score and sarcopenia as independent prognostic factors (p < 0.01 each). Conclusions In ACLD, both portal hypertension and liver disease-related sarcopenia were found to occur at ≥4 kPa. Sarcopenia was accompanied by mildly decreased sodium levels and contributed to the early development of ascites and poor prognosis, independent of liver function.

Mildly Low Serum Sodium Levels in Chronic Liver Disease: At Risk for Sarcopenia and Portal Hypertension.

OBJECTIVE: Hyponatremia and sarcopenia in advanced chronic liver disease (ACLD) are both associated with portal hypertension (PHT) and worse prognosis. This study investigated their interrelationship. METHODS: This retrospective study analyzed 751 patients with CLD who underwent magnetic resonance elastography (MRE) at Nippon Kokan Hospital (Kawasaki, Japan). Patients were classified and studied in five groups based on serum sodium (Na) levels: <135, 135-136, 137-138, 139-140, and >140 mEq/L. PHT was assessed by thrombocytopenia, varices, and ascites, and magnetic resonance imaging (MRI) data were used to diagnose sarcopenia. RESULTS: The proportions of the five groups were 3/4/13/32/48 (%), and the mean liver stiffness (LS) was 6.6/5.7/4.2/3.2/3.2 (kPa), with significant progressive increases at Na < 139 (p< 0.01). The incidence of all PHT events and sarcopenia also increased at <139 (each p < 0.01). By contrast, the LS thresholds for predicting thrombocytopenia, varices, and ascites increased from 3.5 to 4.7 and 5.1, respectively, and were the same at 3.4 for low Na (<139) and sarcopenia (all p < 0.01). Multivariate analysis of factors associated with low Na identified LS and sarcopenia as independent factors (p < 0.05 both). In the Cox proportional hazards model, low Na was a significant prognostic factor in ACLD (hazard ratio (HR) 5.33, p < 0.01); however, the albumin-bilirubin (ALBI) score (HR 2.49) and sarcopenia (HR 4.03) were extracted in the multivariate analysis (p < 0.05 both). CONCLUSIONS: Studies using MRE imaging showed that low Na levels in CLD are associated with worse prognosis, not only due to elevated LS (i.e., PHT) but also the strong association with sarcopenia.

Evaluation of the effects of pemafibrate on metabolic dysfunction-associated steatotic liver disease with hypertriglyceridemia using magnetic resonance elastography combined with fibrosis-4 index and the magnetic resonance imaging-aspartate aminotransferase score.

Background and Aim: In this retrospective study, we evaluated the effects of pemafibrate treatment in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertriglyceridemia using non-invasive stiffness-based models, including magnetic resonance elastography (MRE) combined with the fibrosis-4 (FIB-4) (MEFIB) index and the magnetic resonance imaging (MRI)-aspartate aminotransferase (AST) (MAST) score. Methods: In total, 179 patients with MASLD treated with pemafibrate were enrolled. We evaluated the effects of 48-week pemafibrate treatment using the MEFIB index, which classifies patients based on the combination of liver stiffness measurement (LSM) on MRE and FIB-4 and the MAST score, which is calculated based on LSM on MRE, MRI-proton density fat fraction (MRI-PDFF), and AST levels. Results: Pemafibrate treatment led to significant reduction in AST, alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) (P = 0.011, <0.001, and <0.001, respectively) and significant improvements in triglyceride and high-density lipoprotein cholesterol levels (P < 0.001 and <0.001, respectively). The MRI-PDFF values were not significantly altered. However, a significant decrease in LSM on MRE was detected (P = 0.003). Evaluation of fibrosis using the MEFIB index and MAST score demonstrated significant improvement (P = 0.004 and <0.001, respectively). Changes in the MAST score showed positive correlation with changes in ALT and GGT levels (r = 0.821, P < 0.001, and r = 0.808, P < 0.001, respectively). Additionally, ALT and GGT levels at baseline were significantly associated with improvements in the MAST score (P < 0.001 and <0.001, respectively). Conclusion: Pemafibrate led to improvements in the MEFIB index and MAST score, as well as liver function. It is a promising therapeutic agent for patients with MASLD and hypertriglyceridemia with the potential to reduce liver-related events.

Diagnosis and Pathogenesis of Sarcopenia in Chronic Liver Disease Using Liver Magnetic Resonance Imaging.

Background Liver magnetic resonance imaging (MRI) is rarely used to evaluate sarcopenia. This study sought to develop new diagnostic criteria for MRI in Asians and investigate the relationship between adipopenia and sarcopenia using MRI proton density fat fraction (PDFF), which is correlated with body fat mass. Methodology This study included 512 patients with chronic liver disease (CLD) who underwent magnetic resonance elastography (MRE). The following parameters were assessed: paraspinal muscle area/height index (PSMI) measured at the level of the superior mesenteric artery and PDFF. The cutoff PSMI and PDFF values for the diagnosis of sarcopenia and adipopenia, respectively, were determined using receiver operating characteristic analysis of Asians with low body mass index. Results Among patients with CLD, the prevalence rates of sarcopenia and adipopenia were 25% and 17%, respectively. We found that sarcopenia increased from stage 3 fibrosis and was inversely correlated with steatosis grade. Multivariate analysis found that MRI-PDFF was associated with sarcopenia. The Kaplan-Meier method in cirrhosis (n = 122) showed that the non-sarcopenia, sarcopenia, and sarcopenia/adipopenia groups had three-year survival rates of 97%, 55% (p < 0.01), and 23%, respectively. The Cox proportional hazards model identified the Child-Pugh score and sarcopenia/adipopenia as independent prognostic factors. Conclusions The new diagnostic criteria for sarcopenia confirmed that the prognosis of cirrhosis can be stratified. Furthermore, sarcopenia with adipopenia was shown to be a phenotype of severe sarcopenia in cirrhosis, and screening for sarcopenia should include cases in the precirrhotic stage.

A Case of Hepatitis C-Related Decompensated Cirrhosis Observed by MRI Imaging Data During Treatment With Direct-Acting Antiviral Agents.

Sofosbuvir/velpatasvir therapy can safely treat hepatitis C virus (HCV)-related decompensated cirrhosis and has been shown to improve liver function at an early stage. However, the pathophysiology of the liver during treatment remains unclear. In this case report, we analyzed hepatic morphology on magnetic resonance imaging during the treatment period and confirmed that liver function and malnutrition were greatly improved with the elimination of HCV, and that rapid hemodynamic changes were occurring in the liver.

[Pathogenic and Compensatory Mechanisms in Epidermis of Sphingomyelin Synthase 2-Deficient Mice].

Sphingomyelin (SM) is a constituent of cellular membranes, while ceramides (Cer) produced from SM on plasma membranes serve as a lipid mediator that regulates cell proliferation, differentiation, and apoptosis. In the skin, SM also is a precursor of Cer, an important constituent of epidermal permeability barrier. We investigated the role of epidermal SM synthase (SMS)2, an isoform of SMS, which modulates SM and Cer levels on plasma membranes. Although SMS2-knockout (SMS2-KO) mice were not neonatal lethal, an ichthyotic phenotype with epidermal hyperplasia and hyperkeratosis was evident at birth, which persisted until 2 weeks of age. These mice showed abnormal lamellar body morphology and secretion, and abnormal extracellular lamellar membranes in the stratum corneum. These abnormalities were no longer evident by 4 weeks of age in SMS2-KO mice. Our study suggests that (1) exposure to a dry terrestrial environment initiates compensatory responses, thereby normalizing epidermal ichthyotic abnormalities and (2) that a nonlethal gene abnormality can cause an ichthyotic skin phenotype.

C-reactive Protein Can Predict Patients with Cirrhosis at a High Risk of Early Mortality after Acute Esophageal Variceal Bleeding.

Objective The aim of this study was to identify patients with a high risk of early mortality after acute esophageal variceal bleeding by measuring the C-reactive protein (CRP) level. Methods We retrospectively evaluated 154 consecutive cirrhotic patients admitted with acute esophageal variceal bleeding. Differences between categorical variables were assessed by the chi-square test. Continuous variables were compared using the Mann-Whitney U-test. Multivariate logistic regression analyses consisting of clinical laboratory parameters were performed to identify risk factors associated with the 6-week mortality. The discriminative ability and the best cut-off value were assessed by a receiver-operating characteristic (ROC) curve analysis. Results Child-Pugh C patients showed a significantly higher 6-week mortality than Child-Pugh A or B patients (38% vs. 6%, p<0.0001). The 6-week mortality in Child-Pugh C patients was associated with the age (p<0.0001), etiology of cirrhosis (p=0.003), hepatocellular carcinoma (p=0.0003), portal vein thrombosis (p=0.005), baseline creatinine (p=0.0001), albumin (p=0.001), white blood cell count (p=0.038), baseline CRP [p=0.0004; area under the ROC (AUROC)=0.765; optimum cut-off value at 1.30 mg/dL] and bacterial infection (p=0.019). We determined that CRP ≥1.30 mg/dL was an independent predictor for 6-week mortality in Child-Pugh C patients [odds ratio (OR)=8.789; 95% confidence interval (CI): 2.080-47.496; p=0.003], along with a creatinine level of 0.71 mg/dL (OR=17.628; 95% CI: 2.349-384.426; p=0.004) (73% mortality if CRP ≥1.30 mg/dL vs. 19% if CRP<1.30 mg/dL, p<0.0001). Conclusion In Child-Pugh C patients with esophageal variceal bleeding, a baseline CRP ≥1.30 mg/dL can help identify patients with an increased risk of mortality.

Development of Gentle Slope Light Guide Structure in a 3.4 µm Pixel Pitch Global Shutter CMOS Image Sensor with Multiple Accumulation Shutter Technology.

CMOS image sensors (CISs) with global shutter (GS) function are strongly required in order to avoid image degradation. However, CISs with GS function have generally been inferior to the rolling shutter (RS) CIS in performance, because they have more components. This problem is remarkable in small pixel pitch. The newly developed 3.4 µm pitch GS CIS solves this problem by using multiple accumulation shutter technology and the gentle slope light guide structure. As a result, the developed GS pixel achieves 1.8 e- temporal noise and 16,200 e- full well capacity with charge domain memory in 120 fps operation. The sensitivity and parasitic light sensitivity are 28,000 e-/lx·s and -89 dB, respectively. Moreover, the incident light angle dependence of sensitivity and parasitic light sensitivity are improved by the gentle slope light guide structure.

Carotid intima media thickness in a girl with sitosterolemia carrying a homozygous mutation in the ABCG5 gene.

BACKGROUND: Sitosterolemia is a rare lipid metabolism disorder that involves storage of plant sterols. This disease is associated with atherosclerosis, but detailed vascular endothelial assessment is difficult. CASE PRESENTATION: We report a 5-year-old girl with sitosterolemia who presented with xanthomas at 23 months of age. Her total cholesterol was 868 mg/dL, and her plasma sitosterol level was 9.48 mg/dL. Direct sequencing detected a homozygous mutation in gene ABCG5 (p.Arg389His). Echocardiographic examination revealed that the carotid artery intima media thickness (cIMT) was 0.4 mm with heterogenous hyperechogenicity inside the arterial wall. She was treated using dietary therapy and ezetimibe, which effectively lowered her sitosterol levels. After 3 years of treatment, her cIMT was stable in diameter and arterial wall echogenicity had improved. CONCLUSIONS: Sitosterolemia is a unique disorder in which it is difficult to avoid premature atherosclerosis because of high sitosterol levels. cIMT measurement with arterial wall assessment may improve management.

Early Prediction of the Outcome Using Tumor Markers and mRECIST in Unresectable Hepatocellular Carcinoma Patients Who Underwent Transarterial Chemoembolization.

OBJECTIVE: We examined early predictors of the outcome in hepatocellular carcinoma (HCC) patients after transarterial chemoembolization (TACE). METHODS: We analyzed 116 patients with unresectable HCC treated with initial TACE. α-Fetoprotein (AFP) or des-γ-carboxy prothrombin (DCP) response was assessed in patients who had baseline AFP levels ≥200 ng/ml or DCP ≥60 mAU/ml; a positive response was defined as a reduction of >50% compared to baseline 1 month after TACE. RESULTS: A baseline AFP level ≥200 ng/ml was associated with a poor overall survival (OS) (29.4 vs. 6.1 months; p <0.0001). AFP response had no significantly prognostic effects on the OS. Conversely, although the baseline DCP did not influence the OS, DCP responders showed a significantly better OS than nonresponders (67.0 vs. 19.8 months, p = 0.020). The baseline AFP (p = 0.004) and initial tumor response evaluated by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) (p = 0.012) were found to be independent predictors of the OS. The combination of the baseline AFP and initial assessment by mRECIST allowed stratification of the OS. CONCLUSIONS: The combination of the baseline AFP level and mRECIST is useful for the early prediction of the OS in HCC patients who underwent TACE.

[Liver injury and hepatic encephalopathy induced by the herbal medicine Hochuekkito].

A 57-year-old man was admitted with pruritus and jaundice following treatment for fatigue with the herbal medicine Hochuekkito. The patient was prescribed prednisolone and ursodeoxycholic acid, but he developed progressive cholestasis that required intravenous methylprednisolone pulse therapy. After treatment with plasma exchange for prolonged prothrombin time, the patient recovered; however, his liver function deteriorated because of liver injury induced by trimethoprim-sulfamethoxazole for pneumocystis pneumonia. After reduction of trimethoprim-sulfamethoxazole, his liver function almost returned to normal by day 130 of admission. It has remained normal for 10 months since then. Therefore, when prescribing Hochuekkito, the possibility of drug-induced liver injury should be taken in account.

Transforming growth factor-α attenuates hepatic fibrosis: possible involvement of matrix metalloproteinase-1.

BACKGROUND: The effect of transforming growth factor (TGF)-α on fibrosis varies between cell types and the role of TGF-α in hepatic fibrosis has not been fully elucidated. METHODS: We examined the effect of TGF-α on hepatic fibrosis using TGF-α-expressing transgenic mice fed a methionine- and choline-deficient (MCD) diet and human hepatic stellate cells (HSCs) line LX-2, rat and human primary HSCs. RESULTS: Although the expression levels of the tissue inhibitor of metalloproteinases-1 and α1(I) collagen mRNA were unchanged, feeding the TGF-α transgenic mice the MCD diet resulted in greater expression of the murine functional analogue of matrix metalloproteinase-1 (MMP-1), MMP-13 mRNA and protein and attenuated hepatic fibrosis compared with wild-type mice. TGF-α overexpression did not affect the extent of the steatosis, oxidative stress and hepatic inflammation in the MCD diet-fed mice. The effect of TGF-α on the fibrogenic and anti-fibrogenic gene expressions varied between cell types in vitro. TGF-α increased MMP-1 mRNA expressions that were completely blocked by gefitinib in LX-2 cells. The extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase and p38 pathways were involved in MMP-1 mRNA expression in LX-2 cells. Although TGF-α increased the phosphorylation of p38, the p38 inhibitor activated the RAS-ERK pathway and increased TGF-α-induced MMP-1 mRNA expression, which suggested that there may be a crosstalk between the RAS-ERK and the p38 pathways in LX-2 cells. CONCLUSIONS: The TGF-α may attenuate hepatic fibrosis in part because of upregulation of the expression of MMP-1. The balance between fibrogenic and anti-fibrogenic gene expression and between the activity of the RAS-ERK and the p38 pathways may be crucial for the fibrotic process.

Clinical characteristics of null responders to Peg-IFNα2b/ribavirin therapy for chronic hepatitis C.

AIM: To predict which chronic hepatitis C patients are likely to be late-responders, we herein investigated the clinical characteristics of null-responders at 36 wk with hepatitis C virus (HCV) genotype Ib and a high viral load during the course of pegylated interferon (Peg-IFN)/ribavirin therapy. METHODS: One hundred forty-two patients with genotype Ib HCV and a high viral load were included in this study. Peg-IFNα2b (1.5 µg/kg once a week) and ribavirin (600-1000 mg per day according to body weight) were administered for 48 wk. We defined null-responders as the cases that never cleared serum HCV RNA as determined using RT-PCR until 36 wk. Other patients were defined as responders. We compared the clinical characteristics (age, gender, body mass index, previous treatment) and HCV RNA titer during the therapy between null-responders and responders. RESULTS: The HCV RNA clearance rate was 17.9% (24/134), 46.3% (62/134), 60.6% (86/142), 86.6% (123/142), and 88.0% (125/142) at 4, 8, 12, 24, and 36 wk, respectively. There were 17 patients (12.0%) who were still null-responders at 36 wk. There were no differences in the clinical characteristics between the responders and null-responders except for the titer and decline rates of HCV RNA at 1 wk and 4 wk. The HCV RNA titers at 1 wk and after 4 wk of treatment were significantly higher in the null-responders in comparison to the responders (P <0.01). The serum HCV RNA titers of the responders decreased by 1.3 log after 1 wk of treatment, and 1.6 log after 4 wk of treatment, respectively. On the other hand, the titers of the null responders decreased by only 0.5 log after 1 wk, and 0.7 log after 4 wk of treatment, respectively. The decrease rates of HCV RNA after 1 and 4 wk of treatment were significantly worse for null responders than for the responders (P <0.01). CONCLUSION: The HCV RNA titer at 1 wk and 4 wk after initiating treatment may be useful for predicting null-responders to Peg-IFNα2b/ribavirin therapy. However, further investigation is needed to determine the optimal time at which the decision to discontinue the Peg-IFNα2b/ribavirin therapy for null-responders can be made.

Clinical characteristics and treatment for patients presenting with bleeding duodenal varices.

BACKGROUND AND AIM: Bleeding from ectopic varices, including duodenal varices, is uncommon, but it can be difficult to manage. The clinical data of patients diagnosed and treated for duodenal varices were reviewed to investigate the strategy for treatment. METHODS: The present study reviewed the clinical data of 10 patients with duodenal varices (mean age, 58.2 ± 15.6 years) at our associated institutes during the period between January 1996 and December 2008. RESULTS: Nine patients had duodenal varices located in the second portion, whereas in one case they were located in the duodenal bulbus. The underlying diseases included liver cirrhosis in eight patients, and extrahepatic portal vein obstruction in two patients. The lesions were identified with bleeding from varices in eight of 10 patients. Initial hemostasis was achieved in all eight patients. However, among four patients treated endoscopically only, two patients died from rebleeding from varices and two died from hepatic failure resulting from variceal bleeding. Additional interventional radiology (IVR) was used in three patients and additional surgery was carried out in one case. One patient who was treated with balloon-occluded retrograde transvenous obliteration rebled during IVR and died from bleeding. Two patients who underwent double balloon-occluded embolotherapy and one case who had surgery achieved good clinical outcomes. CONCLUSIONS: Although endoscopic treatment is useful for initial hemostasis of hemorrhagic duodenal varices, the patients who underwent additional IVR after endoscopic treatment achieved good outcomes.

Antioxidative activities of Oxindole-3-acetic acid derivatives from supersweet corn powder.

The components contributing to the antioxidative activity of supersweet corn powder (SSCP), which is commonly used in corn soup and snacks in Japan, were clarified and the effects investigated. 7-(O-ß-Glucosyloxy)oxindole-3-acetic acid (GOA) was found to be the component most strongly contributing to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity of the 80% ethanol extract of SSCP, and the presence of its aglycone, 7-hydroxy-oxindole-3-acetic acid (HOA) was confirmed. GOA and HOA respectively contributed 35.1% and 10.5% to the DPPH radical-scavenging activity of the 80% ethanol extract of SSCP. Mice orally administered with HOA at doses of both 500 and 1500 mg/kg showed a significantly lower (p<0.05) level of thiobarbituric acid reactive substances (TBARS) in the plasma than the vehicle-treated control. These results suggest that GOA and HOA were at least partly involved in the antioxidative activity of SSCP in vitro and that HOA might have possessed antioxidative activity in vivo.

Histone deacetylase inhibitors induce cytochrome P450 2B by activating nuclear receptor constitutive androstane receptor.

Valproic acid, a histone deacetylase (HDAC) inhibitor, induces the cytochrome P450 2B subfamily. However, the effects of HDAC inhibitors on CYP2B induction are still not fully understood. Nuclear receptor constitutive androstane receptor (CAR) is a key regulator of CYP2B induction. In this study, we investigated the effect of HDAC inhibitors on CAR-mediated CYP2B induction. The expression of CYP2B6 mRNA was induced in HepG2 cells stably expressing mouse CAR (Ym17) by HDAC inhibitors including valproic acid, phenylbutyrate, and trichostatin A. HDAC inhibitors activated the phenobarbital-responsive enhancer module of the CYP2B6 promoter in transient transfection reporter assays with Ym17 cells. Furthermore, HDAC inhibitors synergistically augmented the effect of the CAR ligand, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, in the transactivation of CYP2B6 mRNA and the promoter assay in Ym17 cells. Intraperitoneal injection of HDAC inhibitors induced Cyp2b10 mRNA in wild-type mice. However, such induction was not observed in CAR(-/-) mice. Immunoprecipitation demonstrated that CAR formed a complex with HDACs. HDAC inhibitors diminished the binding between CAR and HDAC1 and augmented the binding of steroid receptor coactivator-1 (SRC-1) to CAR. Furthermore, small interfering RNA knockdown of HDAC1 increased CYP2B6 mRNA expression. These results provide novel insight into the mechanism by which HDAC inhibitors affect gene expression of CYP2B6. HDAC inhibitors have the potential to up-regulate CYP2B6 through the dissociation of HDAC1 and recruitment of SRC-1 to receptor CAR.

[A case of autoimmune hepatitis which worsened after switching from a brand name to a generic version of prednisolone].

We recently encountered a case of autoimmune hepatitis whose symptoms worsened after switching from a brand name to a generic version of prednisolone. The patient was a 46-year-old woman. She was admitted because of elevation of alanine aminotransferase (ALT) levels during follow-up sessions. We diagnosed worsening of autoimmune hepatitis and increased the medication dose of prednisolone, which resulted in a quick normalization of serum ALT levels. When the prednisolone medication was switched from a brand name to a generic version, the serum ALT levels again increased. We concluded that switching from a brand name to generic version of the drug was one of reasons for the elevation in the serum ALT levels. Although most generic drugs are considered to be useful, it is important to carefully observe patients to confirm that an equivalent effect is obtained after switching from a brand name to a generic drug.

Hepatocyte growth factor protects against Fas-mediated liver apoptosis in transgenic mice.

BACKGROUND: Apoptosis via the Fas/Fas ligand signalling system plays an important role in the development of various liver diseases. The administration of an agonistic anti-Fas antibody to mice causes massive hepatic apoptosis and fulminant hepatic failure. Several growth factors including hepatocyte growth factor (HGF) have been found to prevent apoptosis. METHODS: In this study, we demonstrated the overexpression of HGF to have a protective effect on Fas-mediated hepatic apoptosis using a transgenic mice (Tg mice) model. RESULTS: In HGF Tg mice, the elevation of alanine aminotransferase was dramatically inhibited at 12 and 24 h after the administration of 0.15 mg/kg anti-Fas antibody. HGF Tg mice showed a significantly lower number of apoptotic hepatocytes at 12 h compared with wild-type (WT) mice. Furthermore, 85% (six of seven) HGF Tg mice were able to survive after the administration of 0.3 mg/kg anti-Fas antibody, while none of the WT mice survived. The Bcl-xL expression was increased in HGF Tg mice, while there was no difference in the expression of Bax, Bid, Mcl-1 and bcl-2 between WT mice and HGF Tg mice. In addition, the HGF Tg mice showed more Akt phosphorylation than the WT mice both before and after the anti-Fas antibody injection. CONCLUSIONS: Taken together, our findings suggest that HGF protects against Fas-mediated liver apoptosis in vivo, and the upregulation of Bcl-xL via Akt activation may also play a role in the protective effects of HGF.

Marked eosinophilia as the first manifestation of sclerosing cholangitis.

We encountered a 45-year-old man who presented with marked eosinophilia as the first manifestation of sclerosing cholangitis. He was found to have a liver dysfunction during a regular physical check up and thereafter consulted our hospital. The laboratory data on admission indicated an elevation of AST (96 IU/L), ALT (136 IU/L) and ALP (1,025 IU/L). Furthermore, the leukocyte count was 18,190/mm(3) and he also showed marked eosinophilia (54.5%, 9,914/mm(3)). There were no atypical findings in the eosinophils. Other diseases causing eosinophilia, including parasite infection, allergic disorders, hypereosinophilic syndromes, drug-induced eosinophilia, malignancies, etc. were all investigated and ruled out. A liver biopsy revealed marked eosinophilic infiltration in the portal area and interlobular bile duct injury. Magnetic resonance cholangiopancreatography (MRCP) demonstrated a slight dilatation of the left intrahepatic bile ducts, but no clear diagnosis could be made at that time. A follow-up liver biopsy and endoscopic retrograde cholangiopancreatography (ERCP) finally revealed a diagnosis of secondary sclerosing cholangitis due to eosinophilic cholangiopathy. According to previous Japanese reports, eosinophilia of more than 5% was reported in 39 of 142 (27.0%) primary sclerosing cholangitis (PSC) patients. Eosinophilic cholangiopathy could cause a condition mimicking PSC and it might be confused as PSC with eosinophilia. The literature contains only about 40 case reports on eosinophilic cholangiopathy, and therefore, to date little attention has been paid to this condition. We should therefore pay attention to this condition when making a differential diagnosis of either PSC or IgG4-related sclerosing cholangitis.