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Metabolic aspects of adult patients with nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2016年第31期22卷 7006-7016页

作者： Ludovico Abenavoli Natasa Milic Laura Di Renzo Tomislav Preveden Milica Medi?-Stojanoska Antonino De Lorenzo Department of Health Sciences University Magna Graecia Campus Germaneto Department of Pharmacy Faculty of Medicine University of Novi Sad Division of Clinical Nutrition and Nutrigenomic Department of Biomedicine and Prevention University of Tor Vergata Clinic for Infectious Diseases Clinical Centre of Vojvodina Faculty of Medicine University of Novi Sad Faculty of Medicine Clinical Centre of Vojvodina Clinic for Endocrinology Diabetes and Metabolic Diseases University of Novi Sad

nonalcoholic fatty liver disease(NAFLD) is a major cause of chronic liver disease and it encompasses a spectrum from simple steatosis to steatohepatitis, fibrosis, or cirrhosis. The mechanisms involved in the occurrence of NAFLD and its progression are probably due to a metabolic profile expressed within the context of a genetic predisposition and is associated with a higher energy intake. The metabolic syndrome(MS) is a cluster of metabolic alterations associated with an increased risk for the development of cardiovascular diseases and diabetes. NAFLD patients have more than one feature of the MS, and now they are considered the hepatic components of the MS. Several scientific advances in understanding the association between NAFLD and MS have identified insulin resistance(IR) as the key aspect in the pathophysiology of both diseases. In the multi parallel hits theory of NAFLD pathogenesis, IR was described to be central in the predisposition of hepatocytes to be susceptible to other multiple pathogenetic factors. The recent knowledge gained from these advances can be applied clinically in the prevention and management of NAFLD and its associated metabolic changes. The present review analyses the current literature and highlights the new evidence on the metabolic aspects in the adult patients with NAFLD.

关键词： nonalcoholic fatty liver disease nonalcoholic steatohepatitis Insulin resistance obesity Metabolic syndrome

phosphatase and tensin homolog is a differential diagnostic marker between nonalcoholic and alcoholic fatty liver disease

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World Journal of Gastroenterology 2016年第14期22卷 3735-3745页

作者： Andrea Sanchez-Pareja Sophie Clément Marion Peyrou Laurent Spahr Francesco Negro Laura Rubbia-Brandt Michelangelo Foti Division of Clinical Pathology University Hospital of Geneva Department of Cellular Physiology and Metabolism Faculty of Medicine University of Geneva Diabetes Center Faculty of Medicine University of Geneva Division of Gastroenterology and Hepatology University Hospital of Geneva

AIM: To investigate the protein expression of phosphatase and tensin homolog(PTEN) in human liver biopsies of patients with alcoholic and non-alcoholic liver disease.METHODS: PTEN protein expression was assessed by immunohistochemistry in formalin-fixed, paraffinembedded liver sections of patients with non-alcoholic fatty liver disease(NAFLD)(n = 44) or alcoholic liver disease(ALD)(n = 25). Liver resections obtained from 3 healthy subjects candidate for partial liver donation served as controls. Histological evaluations were performed by two experienced pathologists, and diagnoses established based on international criteria. The intensity of the PTEN staining in nuclei was compared between steatotic and non-steatotic areas of each liver fragment analyzed. For each liver specimen, the antibody-stained sections were examined and scored blindly by three independent observers, who were unaware of the patients' clinical history.RESULTS: In healthy individuals, PTEN immunostaining was intense in both the cytoplasm and nuclei of all hepatocytes. However, PTEN was strongly downregulated in both the nucleus and the cytoplasm of hepatocytes from steatotic areas in patients with NAFLD, independently of the disease stage. In contrast, no changes in PTEN protein expression were observed in patients with ALD, regardless of the presence of steatosis or the stage of the disease. The degree of PTEN downregulation in hepatocytes of patients with NAFLD correlated with the percentage of steatosis(r = 0.3061, P = 0.0459) and the BMI(r = 0.4268, P = 0.0043). Hovewer, in patients with ALD, PTEN expression was not correlated with the percentage of steatosis with or without obesity as a confounding factor(P = 0.5574). Finally, PTEN expression level in steatotic areas of ALD patients was significantly different from that seen in steatotic areas of NAFLD patients(P < 0.0001).CONCLUSION: PTEN protein expression is downregulated early in NAFLD, but not in ALD. PTEN immunohistochemical detection could help in the differential diagnosis of NAF

关键词： Fibrosis Phosphatase and tensin homolog Steatosis Non-alcoholic fatty liver disease nonalcoholic ste

Simple scoring system for predicting cirrhosis in nonalcoholic fatty liver disease

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World Journal of Gastroenterology 2014年第29期20卷 10108-10114页

作者： Takaomi Kessoku Yuji Ogawa Masato Yoneda Kento Imajo Yoshio Sumida Yuichiro Eguchi Hideki Fujii Hideyuki Hyogo Masafumi Ono Yasuaki Suzuki Takumi Kawaguchi Kazuaki Chayama Saiyu Tanaka Kazuma Fujimoto Keizo Anzai Toshiji Saibara Michio Sata Yoshito Itoh Atsushi Nakajima Takeshi Okanoue Japan Study Group of NAFLD(JSG-NAFLD)[] Department of Gastroenterology Hepatology Yokohama City University Graduate School of MedicineYokohama 236-0004Japan Department of Molecular Gastroenterology Hepatology Kyoto Prefectural University of Medicine Kyoto 602-0841Japan Department of General Medicine Saga Medical School Saga 849-8501Japan Department of Hepatology Osaka City University Osaka 558-8585Japan Department of Medicine Molecular Science Graduate School of Biomedical Sciences Hiroshima University Hiroshima 730-0053 Japan Department of Gastroenterology and Hepatology Kochi Medical School Kochi 783-8505 Japan Department of Gastroenterology Nayoro City General Hospital Hokkaido 096-8511 Japan Department of Gastroenterology Kurume University School of Medicine Kurume 830-0011 Japan Department of Internal Medicine University Hospital Saga 849-8577 Japan Department of Gastroenterology Hepatology Saiseikai Suita Hospital Osaka 565-0862 Japan

AIM:To investigate a simple noninvasive scoring system for predicting liver cirrhosis in nonalcoholic fatty liver disease(NAFLD)patients.METHODS:A total of 1048 patients with liver-biopsyconfirmed NAFLD were enrolled from nine hepatology centers in Japan(stage 0,216;stage 1,334;stage 2,270;stage 3,190;stage 4,38).The weight and height of the patients were measured using a calibrated scale after requesting the patients to remove their shoes and any heavy clothing.Venous blood samples were obtained in the morning after the patients had fasted overnight for 12 h.Laboratory evaluation was performed in all patients.Statistical analysis was conducted using SPSS version 12.0.Continuous variables were expressed as mean±SD.RESULTS:The optimal cutoff value of platelet count,serum albumin,and aminotransferase/alanine aminotransferase ratio(AAR)was set at0.9,respectively,by the receiver operating characteristic curve.These three variables were combined in an unweighted sum(platelet count=1 point,serum albumin=1 point,AAR=1 point)to form an easily calculated composite score for predicting cirrhosis in NAFLD patients,called the PLALA(platelet,albumin,AAR)score.The diagnosis of PLALA≥2 had sufficient accuracy for detecting liver cirrhosis in NAFLD patients.CONCLUSION:The PLALA score may be an ideal scoring system for detecting cirrhosis in NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.

关键词： nonalcoholic fatty liver disease Cirrhosis Fibrosi

Central obesity and nonalcoholic fatty liver disease risk after adjusting for body mass index

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World Journal of Gastroenterology 2015年第5期21卷 1650-1662页

作者： Qing Pang Jing-Yao Zhang Si-Dong Song Kai Qu Xin-Sen Xu Su-Shun Liu Chang Liu Department of Hepatobiliary Surgery the First Affiliated Hospital of Medical CollegeXi’an Jiaotong University

AIM:To investigate whether central obesity is associated with nonalcoholic fatty liver disease(NAFLD) formation after adjusting for general obesity.METHODS:The online databases Pub Med,EMBASE,and ISI Web of Science were searched for studies estimating the influence of central obesity on NAFLD occurrence published through April 2014.Studies that did not adjust for body mass index(BMI) were excluded.In addition,the independent effect of BMI was also assessed with the included studies.The pooled effect sizes and 95% confidence intervals(CIs) were calculated using random- or fixed-effects models based on the degree of heterogeneity.Furthermore,subgroup analyses,meta-regression,sensitivity analyses,and publication bias were performed.RESULTS:Twenty eligible studies were identified.The summary odds ratio(OR) values per-unit increase in waist circumference(WC) and BMI for NAFLD formation were 1.07(95%CI:1.03-1.10,I2 = 73.9%,n = 11 studies) and 1.25(95%CI:1.13-1.38,I2 = 88.7%,n = 11 studies),respectively.When the indices were expressed as binary variables(with the non-obesity group as reference),the pooled OR in WC,waist-tohip ratio,and BMI were 2.34(95%CI:1.83-3.00,I2 = 41.8%,n = 7 studies),4.06(95%CI:1.53-10.79,I2 = 65.7%,n = 3 studies),and 2.85(95%CI:1.60-5.08,I2 = 57.8%,n = 5 studies),respectively.Using the same studies as the latter(n = 5),pooled OR in WC was 3.14(95%CI:2.07-4.77),which is greater than that in BMI.CONCLUSION:Central obesity may pose a greater threat to national health than general obesity,although both are independently associated with increased risk of NAFLD.

关键词： Central obesity General obesity nonalcoholic fatty

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice

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World Journal of Gastroenterology 2016年第8期22卷 2512-2523页

作者： Takaya Yamamoto Yukiomi Nakade Taeko Yamauchi Yuji Kobayashi Norimitsu Ishii Tomohiko Ohashi Kiyoaki Ito Ken Sato Yoshitaka Fukuzawa Masashi Yoneda Division of Hepatology and Pancreatology Department of Internal Medicine Aichi Medical University

AIM: To investigate whether a glucagon-like peptide-1(GLP-1) analogue inhibits nonalcoholic steatohepatitis(NASH), which is being increasingly recognized in Asia, in non-obese mice. METHODS: A methionine-choline-deficient diet(MCD) along with exendin-4(20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice(non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride(TG) and free fatty acid(FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry.RESULTS: Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fattyacid transport protein 4(FATP4), a hepatic FFA influxrelated gene; macrophage recruitment; and the level of malondialdehyde(MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c(SREBP-1c) m RNA(lipogenesis-related gene) and acyl-coenzyme A oxidase 1(ACOX1) m RNA(β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein m RNA(a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 m RNA level. CONCLUSION: These results suggest that GLP-1 inhibits hepatic steatosis and inflammation through the inhibition

关键词： Glucagon like peptide-1 nonalcoholic steatohepatitis Kupffer cells Free fatty acid Oxidative stress

Hepatocellular carcinoma in nonalcoholic fatty liver: Role of environmental and genetic factors

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World Journal of Gastroenterology 2014年第36期20卷 12945-12955页

作者： Paola Dongiovanni Stefano Romeo Luca Valenti Internal Medicine 1B Fondazione IRCCS Ca’ Granda Ospedale Policlinico 20122 Milano Italy Department of Pathophysiology and Transplantation Università degli Studi di Milano 20122 Milano Italy Wallenberg Laboratory Department of Molecular and Clinical Medicine University of Gothenburg 40530 Gothenburg Sweden Clinical Nutrition Unit Department of Medical and Surgical Sciences University Magna Graecia 88100 Catan-zaro Italy

Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.

关键词： nonalcoholic fatty liver disease Steatosis Hepatoc

Hepatic fat quantification magnetic resonance for monitoring treatment response in pediatric nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2015年第33期21卷 9741-9748页

作者： Hong Koh Seung Kim Myung-Joon Kim Hyun Gi Kim Hyun Joo Shin Mi-Jung Lee Department of Pediatrics Severance Pediatric Liver Disease Research GroupSeverance Children’s HospitalYonsei University College of Medicine Department of Radiology and Research Institute of Radiological Science Severance Pediatric Liver Disease Research GroupSeverance Children’s HospitalYonsei University College of Medicine

AIM: To evaluate the possibility of treatment effect monitoring using hepatic fat quantification magnetic resonance(MR) in pediatric nonalcoholic steatohepatitis(NASH).METHODS: We retrospectively reviewed the medical records of patients who received educational recommendations and vitamin E for NASH and underwent hepatic fat quantification MR from 2011 to 2013.Hepatic fat fraction(%) was measured using dual- and triple-echo gradient-recalled-echo sequences at 3T.The compliant and non-compliant groups were compared clinically,biochemically,and radiologically.RESULTS: Twenty seven patients(M:F = 24:3; mean age: 12 ± 2.3 years) were included(compliant group = 22,non-compliant = 5).None of the baseline findings differed between the 2 groups,except for triglyceride level(compliant vs non-compliant,167.7 mg/d L vs 74.2 mg/d L,P = 0.001).In the compliant group,high-density lipoprotein increased and all other parameters decreased after 1-year follow-up.However,there were various changes in the non-compliant group.Dualecho fat fraction(-19.2% vs 4.6,P < 0.001),tripleecho fat fraction(-13.4% vs 3.5,P < 0.001),alanine aminotransferase(-110.7 IU/L vs-10.6 IU/L,P = 0.047),total cholesterol(-18.1 mg/d L vs 3.8 mg/d L,P = 0.016),and triglyceride levels(-61.3 mg/d L vs 11.2 mg/d L,P = 0.013) were significantly decreased only in the compliant group.The change in body mass index and dual-echo fat fraction showed a positive correlation(ρ = 0.418,P = 0.030).CONCLUSION: Hepatic fat quantification MR can be a non-invasive,quantitative and useful tool for monitoring treatment effects in pediatric NASH.

关键词： nonalcoholic fatty liver disease Steatohepatitis H

Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2014年第2期20卷 475-485页

作者： Yoshio Sumida Atsushi Nakajima Yoshito Itoh Department of Gastroenterology and Hepatology Kyoto Prefectural University of MedicineKyoto 602-8566Japan Division of Gastroenterology Yokohama City University Graduate School of MedicineYokohama 236-0004Japan

It is estimated that 30%of the adult population in Japan is affected by nonalcoholic fatty liver disease(NAFLD).Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography(US)and computed tomography(CT),but the sensitivity of these imaging techniques is low in cases of mild steatosis.Alanine aminotransferase levels may be normal in some of these patients,warranting the necessity to establish a set of parameters useful for detecting NAFLD,and the more severe form of the disease,nonalcoholic steatohepatitis(NASH).Although liver biopsy is currently the gold standard for diagnosing progressive NASH,it has many drawbacks,such as sampling error,cost,and risk of complications.Furthermore,it is not realistic to perform liver biopsies on all NAFLD patients.Diagnosis of NASH using various biomarkers,scoring systems and imaging methods,such as elastography,has recently been attempted.The NAFIC score,calculated from the levels of ferritin,fasting insulin,and typeⅣcollagen 7S,is useful for the diagnosis of NASH,while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis.This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH.

关键词： nonalcoholic fatty liver disease Liver biopsy Stea

Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

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World Journal of Gastroenterology 2015年第13期21卷 3777-3785页

作者： Yoshihisa Takahashi Keiichiro Sugimoto Hiroshi Inui Toshio Fukusato Department of Pathology Teikyo University School of MedicineTokyo 173-8605Japan Research and Development Center Nagaoka Perfumery Co. Ltd.IbarakiOsaka 567-0005Japan Center for Research and Development of Bioresources Osaka Prefecture UniversitySakaiOsaka 599-8570Japan Department of Clinical Nutrition College of Health and Human SciencesOsaka Prefecture UniversityHabikinoOsaka 583-8555Japan

nonalcoholic fatty liver disease(NAFLD)/nonalcoholic steatohepatitis(NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers(thiazolidinediones) and antioxidants(vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.

关键词： Pharmacological therapy nonalcoholic fatty liver d