Yukiomi Nakade

Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: A meta-analysis of randomized controlled trials

OBJECTIVESnVitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH.nnnMETHODSnPubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis.nnnRESULTSnAccording to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment.nnnCONCLUSIONSnVitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH.

Diagnostic Accuracy of Real-Time Tissue Elastography for the Staging of Liver Fibrosis: A Meta-Analysis

ObjectiveTo evaluate the overall accuracy of real-time tissue elastography (RTE) for the staging of liver fibrosis.MethodsWe systematically reviewed 15 studies (1,626 subjects) in which sensitivity and specificity of RTE for liver fibrosis are available. For each cut-off stage of fibrosis, i.e., Fu2009≥u20091, Fu2009≥u20092, Fu2009≥u20093, and Fu2009≥u20094, summary sensitivity and specificity were estimated using a bivariate random-effects model. Publication bias was assessed using funnel plots and Egger’s test.ResultsSummary sensitivity and specificity were 0.79 and 0.76 for Fu2009≥u20092, 0.82 and 0.81 for Fu2009≥u20093, and 0.74 and 0.84 for Fu2009≥u20094, respectively. Meta-regressions revealed scoring methods of RTE and liver diseases in the samples might not influence sensitivity and specificity of RTE. However, the estimated accuracy of RTE might be overestimated due to publication bias (pu2009=u20090.004 for Fu2009≥u20092, pu2009<u20090.001 for Fu2009≥u20093, and pu2009=u20090.002 for Fu2009≥u20094).ConclusionsRTE is not highly accurate for any cut-off stage of fibrosis. Compared with findings of meta-analyses on Transient Elastography and Acoustic Radiation Force Impulse imaging, the overall accuracy of RTE seems to be nearly identical for the evaluation of significant liver fibrosis, but less accurate for the evaluation of cirrhosis.Key Points• Non-invasive methods for evaluating liver fibrosis are necessary to replace liver biopsy.• ARFI is as accurate as TE for evaluating liver fibrosis.• RTE may be as accurate as TE and ARFI for fibrosis.• RTE may be less accurate than TE and ARFI for cirrhosis.• The estimated accuracy of RTE may be overestimated by publication bias.

Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis

BackgroundAngiotensin II type 1 receptor blockers (ARBs) have been reported to attenuate hepatic fibrosis in non-alcoholic steatohepatitis (NASH). However, it is uncertain whether ARBs prevent hepatocarcinogenesis in NASH even after hepatic fibrosis has developed.MethodsMale Wistar rats were fed with a choline-deficient, l-amino acid-defined (CDAA) diet for 24xa0weeks, and then fed with the CDAA diet with telmisartan (2xa0mg/kg/day), a novel ARB, or vehicle for another 24xa0weeks. The liver histology and the expression of genes and proteins related to angiogenesis were investigated.ResultsThe 24-week CDAA diet induced liver cirrhosis. The 48-week CDAA diet exacerbated liver cirrhosis, and developed hepatocellular carcinoma (HCC) in 54.6xa0% of the rats concurrently with increases of hypoxia-inducible factor-1α (HIF-1α) protein and vascular endothelial growth factor (VEGF) mRNA, which are potent angiogenic factors in the liver. Telmisartan inhibited hepatic fibrosis and preneoplastic lesions and prevented the development of HCC along with inducing decreases in HIF-1α protein and VEGF mRNA.ConclusionsThese data indicated that telmisartan may prevent hepatocarcinogenesis through the inhibition of hepatic angiogenesis even after liver cirrhosis has been established.

Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels and liver fibrosis: A meta-analysis

A reliable, non‐invasive biomarker for diagnosis of liver fibrosis in chronic liver disease patients is needed. The aim of this study was to assess by meta‐analysis the efficacy of measuring serum levels of Wisteria floribunda agglutinin‐positive Mac‐2‐binding protein (WFA+‐M2BP), a novel and promising biomarker, for staging liver fibrosis and predicting the development of hepatocellular carcinoma and overall survival.

Ezetimibe for the treatment of non-alcoholic fatty liver disease: A meta-analysis.

Several studies on the efficacy of ezetimibe, a potent inhibitor of cholesterol absorption, in treating non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) have been published; however, the results are inconsistent. We undertook a meta‐analysis to evaluate the efficacy of ezetimibe in treating NAFLD and NASH.

Δ40p53α suppresses tumor cell proliferation and induces cellular senescence in hepatocellular carcinoma cells.

ABSTRACT Splice variants of certain genes impact on genetic biodiversity in mammals. The tumor suppressor TP53 gene (encoding p53) plays an important role in the regulation of tumorigenesis in hepatocellular carcinoma (HCC). Δ40p53α is a naturally occurring p53 isoform that lacks the N-terminal transactivation domain, yet little is known about the role of Δ40p53α in the development of HCC. Here, we first report on the role of Δ40p53α in HCC cell lines. In the TP53+/Δ40 cell clones, clonogenic activity and cell survival dramatically decreased, whereas the percentage of senescence-associated β-galactosidase (SA-β-gal)-positive cells and p21 (also known as WAF1, CIP1 and CDKN1A) expression significantly increased. These observations were clearly attenuated in the TP53+/Δ40 cell clones after Δ40p53α knockdown. In addition, exogenous Δ40p53 expression significantly suppressed cell growth in HCC cells with wild-type TP53, and in those that were mutant or null for TP53. Notably, Δ40p53α-induced tumor suppressor activity was markedly attenuated in cells expressing the hot-spot mutant Δ40p53α-R175H, which lacks the transcription factor activity of p53. Moreover, Δ40p53α expression was associated with increased full-length p53 protein expression. These findings enhance the understanding of the molecular pathogenesis of HCC and show that Δ40p53α acts as an important tumor suppressor in HCC cells. Summary: Δ40p53 exerts tumor suppressor activity that is associated with upregulation of p53-target gene expression and induces senescence in hepatocellular carcinoma cell lines.

Conophylline inhibits non-alcoholic steatohepatitis in mice

Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Ervatamia microphylla, attenuates hepatic fibrosis in mice. However, little is known about whether CnP inhibits steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH) in mice. A methionine-choline-deficient (MCD) diet was administered to male db/db mice as a NASH model, and CnP (1 μg/kg/d) was co-administered. Eight weeks after the commencement of the MCD diet, hepatic steatosis, inflammation, and fibrosis, and hepatic fat metabolism-, inflammation-, and fibrosis-related markers were examined. Feeding on an MCD for 8 weeks induced hepatic steatosis, inflammation, and fibrosis. CnP significantly attenuated the MCD-induced increases in hepatic steatosis, as well as hepatic inflammation and fibrosis. The MCD diet increased hepatic transforming growth factor-β (TGF-β) mRNA levels, which are correlated with hepatic steatosis, inflammation, and fibrosis. The diet also attenuated acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1 (CPT1) mRNA levels, which are involved in β-oxidation. The putative mechanism of the CnP effect involves reduced hepatic TGF-β mRNA levels, and increased mRNA levels of hepatic peroxisome proliferator-activated receptor (PPAR) α and its target genes ACOX1 and CPT1. The results of this study indicate that CnP inhibits steatohepatitis, possibly through the inhibition of hepatic TGF-β mRNA levels, and induces an increase in PPARα mRNA levels, resulting in the attenuation of hepatic steatosis, inflammation, and fibrosis in mice. CnP might accordingly be a suitable therapeutic option for NASH.

Simultaneous Versus Sequential Side-by-Side Bilateral Metal Stent Placement for Malignant Hilar Biliary Obstructions

AbstractBackgroundEndoscopic bilateral self-expandable metallic stent (SEMS) placement for malignant hilar biliary obstructions (MHBOs) is technically demanding, and a second SEMS insertion is particularly challenging. A simultaneous side-by-side (SBS) placement technique using a thinner delivery system may mitigate these issues.AimsnWe aimed to examine the feasibility and efficacy of simultaneous SBS SEMS placement for treating MHBOs using a novel SEMS that has a 5.7-Fr ultra-thin delivery system.MethodsThirty-four patients with MHBOs underwent SBS SEMS placement between 2010 and 2016. We divided the patient cohort into those who underwent sequential (conventional) SBS placement between 2010 and 2014 (sequential group) and those who underwent simultaneous SBS placement between 2015 and 2016 (simultaneous group), and compared the groups with respect to the clinical outcomes.ResultsThe technical success rates were 71% (12/17) and 100% (17/17) in the sequential and simultaneous groups, respectively, a difference that was significant (Pxa0=xa0.045). The median procedure time was significantly shorter in the simultaneous group (22xa0min) than in the sequential group (52xa0min) (Pxa0=xa0.017). There were no significant group differences in the time to recurrent biliary obstruction (sequential group: 113xa0days; simultaneous group: 140xa0days) or other adverse event rates (sequential group: 12%; simultaneous group: 12%).ConclusionsSimultaneous SBS placement using the novel 5.7-Fr SEMS delivery system may be more straightforward and have a higher success rate compared to that with sequential SBS placement. This new method may be useful for bilateral stenting to treat MHBOs.

Relationship between Non-alcoholic Fatty Liver Disease and Thyroid Dysfunction

Non-alcoholic fatty liver disease (NAFLD) has been recognized as the most common liver disease and leading cause of cryptogenic cirrhosis worldwide (1, 2). It includes a spectrum of hepatic dysfunctions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which causes liver cirrhosis (2). Although the pathogenesis of NASH remains to be elucidated, NASH is thought to progress to liver cirrhosis and made potentially lead to hepatocellular carcinoma (3). Because the mechanism underlying the development of NAFLD has been linked to insulin resistance and an impairment of energy homeostasis, NAFLD is considered to be the hepatic manifestation of metabolic syndrome, which is reported to be a cluster of cardiovascular risk factors (2, 4, 5). Thyroid hormone plays an important role in energy homeostasis and influences body weight and lipid metabolism (6). Hypothyroidism may cause of an impairment of energy homeostasis and induce hypercholesterolemia (7, 8). Subclinical hypothyroidism, which refers to an elevated thyroid-stimulating hormone level and a normal free thyroxine (T4) level, has been associated with metabolic syndrome, cardiovascular disease and mortality (9, 10). The relationship between NAFLD and hypothyroidism has also been reported. The prevalence of NAFLD is negatively correlated with free T4 levels, and decreased free T4 levels contribute to the risk of NAFLD (11). Subclinical hypothyroidism has been found in NAFLD, and it has been reported that hypothyroidism is closely associated with NAFLD (12). On the other hand, little is known regarding the relationship between hyperthyroidism and NAFLD. In this issue of the journal, Miyake et al. reported a case of NASH with hyperthyroidism (13). They showed the relationship between serum free T4 levels and serum alanine aminotransferase (ALT) levels in a patient with NASH complicated with Graves’ disease. Three months after the commencement of thiamazole treatment, the patient’s serum ALT levels and body weight increased concurrently with an improvement of abnormal thyroid hormone levels. The patient’s body weight was 64.5 kg and body mass index (BMI) was 25.2 kg/m at the commencement of thiamazole treatment. Eighteen months after the initial admission, the patient’s body weight decreased to 53 kg and BMI to 20.7 kg, and the free T4 levels were increased and serum ALT levels fell to within normal levels. After the patient was diagnosed with reactivation of Graves’ disease, thiamazole was resumed. As the thyroid hormone level decreased, the patient’s serum ALT levels and body weight increased. Interestingly, in this case, the patient’s body weight and serum ALT levels appeared to have an inverse correlation with the serum free T4 levels. However, it remains unclear whether the serum free T4 levels are correlated with pathological staging and grading of NASH. A recent report indicated that the serum ALT level was not a candidate biomarker for NASH (14). In particular, hepatic fibrosis progressed even in NASH patients with normal ALT levels (15). Because the aspartate aminotransferase (AST)/ALT ratio is reported to be associated with hepatic fibrosis staging, the serum AST/ALT ratio is preferable as a potential hepatic fibrosis marker. This manuscript presented that an anti-thyroid agent increased the serum ALT levels in a NASH patient with Graves’ disease. An accumulation of case reports of NASH complicated with hyperthyroidism is expected, and it is of particular interest to examine whether thyroid hormone or its analogue improves NASH as a new strategy for the regulation of steatohepatitis.

Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models

Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson’s, and Huntington’s diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson’s and Huntington’s diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases.