Nonalcoholic Fatty Liver Disease (nonalcoholic + fatty_liver_disease)

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Selected Abstracts

Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression,

HEPATOLOGY, Issue 6 2009
Kimberley D. Bruce
Nonalcoholic fatty liver disease (NAFLD) describes an increasingly prevalent spectrum of liver disorders associated with obesity and metabolic syndrome. It is uncertain why steatosis occurs in some individuals, whereas nonalcoholic steatohepatitis (NASH) occurs in others. We have generated a novel mouse model to test our hypothesis: that maternal fat intake contributes to the development of NAFLD in adult offspring. Female mice were fed either a high-fat (HF) or control chow (C) diet before and during gestation and lactation. Resulting offspring were fed either a C or a HF diet after weaning, to generate four offspring groups; HF/HF, HF/C, C/HF, C/C. At 15 weeks of age, liver histology was normal in both the C/C and HF/C offspring. Kleiner scoring showed that although the C/HF offspring developed nonalcoholic fatty liver, the HF/HF offspring developed NASH. At 30 weeks, histological analysis and Kleiner scoring showed that both the HF/C and C/HF groups had NAFLD, whereas the HF/HF had a more severe form of NASH. Therefore, exposure to a HF diet in utero and during lactation contributes toward NAFLD progression. We investigated the mechanisms by which this developmental priming is mediated. At 15 weeks of age, hepatic mitochondrial electron transport chain (ETC) enzyme complex activity (I, II/III, and IV) was reduced in both groups of offspring from HF-fed mothers (HF/C and HF/HF). In addition, measurement of hepatic gene expression indicated that lipogenesis, oxidative stress, and inflammatory pathways were up-regulated in the 15-week-old HF/C and HF/HF offspring. Conclusion: Maternal fat intake contributes toward the NAFLD progression in adult offspring, which is mediated through impaired hepatic mitochondrial metabolism and up-regulated hepatic lipogenesis. (HEPATOLOGY 2009.) [source]

Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice,

HEPATOLOGY, Issue 5 2009
Nora Bijl
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. The hyperinsulinemia that occurs as a consequence of insulin resistance is thought to be an important contributor to the development of fatty liver. We have shown that the iminosugar N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase, is a potent enhancer of insulin signaling in rodent models for insulin resistance and type 2 diabetes. The present study was designed to assess the impact of AMP-DNM on insulin levels, liver triglyceride synthesis, and gene expression profile. Treatment of ob/ob mice with AMP-DNM restored insulin signaling in the liver, corrected blood glucose values to levels found in lean mice, and decreased insulin concentration. The expression of sterol regulatory element-binding protein 1c target genes involved in fatty acid synthesis normalized. AMP-DNM treatment significantly reduced liver to body weight ratio and reversed hepatic steatosis, comprising fat as well as inflammatory markers. In addition, AMP-DNM treatment corrected to a large extent the gene expression profile of ob/ob mice livers toward the profile of lean mice. Conclusion: Pharmacological lowering of glycosphingolipids with the iminosugar AMP-DNM is a promising approach to restore insulin signaling and improve glucose homeostasis as well as hepatic steatosis. (HEPATOLOGY 2009.) [source]

Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids,

HEPATOLOGY, Issue 2 2009
Claudio J. Villanueva
Nonalcoholic fatty liver disease, characterized by the accumulation of triacylglycerols (TGs) and other lipids in the liver, often accompanies obesity and is a risk factor for nonalcoholic steatohepatitis and fibrosis. To treat or prevent fatty liver, a thorough understanding of hepatic fatty acid and TG metabolism is crucial. To investigate the role of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), a key enzyme of TG synthesis, in fatty liver development, we studied mice with global and liver-specific knockout of Dgat1. DGAT1 was required for hepatic steatosis induced by a high-fat diet and prolonged fasting, which are both characterized by delivery of exogenous fatty acids to the liver. Studies in primary hepatocytes showed that DGAT1 deficiency protected against hepatic steatosis by reducing synthesis and increasing the oxidation of fatty acids. In contrast, lipodystrophy (aP2-SREBP-1c436) and liver X receptor activation (T0901317), which increase de novo fatty acid synthesis in liver, caused steatosis independently of DGAT1. Pharmacologic inhibition of Dgat1 with antisense oligonucleotides protected against fatty liver induced by a high-fat diet. Conclusion: Our findings identify a specific role for hepatic DGAT1 in esterification of exogenous fatty acids and indicate that DGAT1 contributes to hepatic steatosis induced by this mechanism. (HEPATOLOGY 2009.) [source]

Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management,

HEPATOLOGY, Issue 1 2009
Raj Vuppalanchi
Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease in the western world. It is now recognized that these patients have myriad of important co-morbidities (e.g., diabetes, hypothyroidism and metabolic syndrome). The workup of patients with suspected NAFLD should consist of excluding competing etiologies and systemic evaluation of metabolic comorbidities. NAFLD is histologically categorized into steatosis and steatohepatitis, two states with fairly dichotomous natural history. While significant progress has been made in terms of noninvasively predicting advanced fibrosis, insufficient progress has been made in predicting steatohepatitis. Currently, liver biopsy remains the gold standard for the histological stratification of NAFLD. While sustained weight loss can be effective to treat NASH, it is often difficult to achieve. Foregut bariatric surgery can be quite effective in improving hepatic histology in selected patients without liver failure or significant portal hypertension. Thiazolidinediones have shown promise and the results from the ongoing, large multicenter study should become available soon. Large multicenter studies of CB, receptor anatagonists are also underway but their results will not be available for several years. Several recent studies have highlighted that cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. Conclusion: Health care providers should not only focus on liver disease but also concentrate on aggressively modifying and treating their cardiovascular risk factors. (HEPATOLOGY 2009;49:306-317.) [source]

Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: Present and future,

HEPATOLOGY, Issue 2 2007
Anna Wieckowska
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, and its prevalence is increasing worldwide. It currently affects approximately 30% of adults and 10% of children in the United States. NAFLD represents a wide spectrum of conditions ranging from simple fatty liver which in general follows a benign nonprogressive clinical course, to nonalcoholic steatohepatitis (NASH), which is a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. At present, a liver biopsy remains the only reliable way to diagnose NASH and establish the presence of fibrosis. Current noninvasive clinically available tests lack accuracy and reliability. In light of the dramatic increase in the prevalence of NAFLD in conjunction with the significant research effort in developing novel therapies for patients with NASH, noninvasive, simple, reproducible, and reliable biomarkers are greatly needed. They will not only help in the diagnosis of NASH, but also be useful for assessment of treatment response and prognosis and remain a research priority in the NAFLD field. (HEPATOLOGY 2007;46:582,589.) [source]

Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis

Yumiko Anezaki
Aim:, Nonalcoholic fatty liver disease (NAFLD) is considered to be a public health problem worldwide. NAFLD is more prevalent in men than in women. Tamoxifen, a potent estrogen receptor antagonist, causes nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. Thus, there may be a sex difference that is dependent on estrogens in NAFLD and NASH. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to NASH and are considered to be a clinical model of NASH. We aimed to shed light on any sex differences in the hepatic lesions of Pten-deficient mice and the underlying mechanisms. Methods:, At 40 weeks, livers from male and female Pten-deficient mice were processed for measuring lipid content, genes expression analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Seventy-six-week-old mice were used in tumor burden experiments. Results:, Hepatic steatosis, inflammation, and even carcinogenesis in Pten-deficient mice were attenuated in females compared to males. Attenuated fatty liver in females was ascribed to inactivation of sterol regulatory element binding protein-1c. Hepatic inflammation in females was suppressed via decreased ROS with increased antioxidant gene expression and decreased proinflammatory cytokine production. Anti-cancer effect in female mice was, at least in part, due to the significantly lower ratio of oleic to stearic acid in the liver. Conclusions:, Hepatic lesions in Pten-deficient mice were attenuated in females compared to males, as were human NAFLD and NASH. Some of the underlying mechanisms in sex difference appeared to be due to the change of gene expression, dependent on estrogens. [source]

Nonalcoholic steatohepatitis and hepatocellular carcinoma in galectin-3 knockout mice

Yuko Nakanishi
Aim:, Nonalcoholic fatty liver disease (NAFLD) represents a growing health concern due to its rapidly increasing prevalence worldwide. Nonalcoholic steatohepatitis (NASH) is a progressing form of NAFLD, and recently many studies have reported that it could eventually develop into hepatocellular carcinoma (HCC). We previously reported that 6-month-old male galectin-3 knockout (gal3,/,) mice developed clinicopathological features similar to those of NAFLD in humans. Our aim was to investigate the changes in liver histology in gal3,/, mice by long-term observation. Methods:, We initially investigated three 15-month-old gal3,/, mice, of which two developed multiple liver nodules with dysplastic changes. Then, we histopathologically examined the liver specimens of the 15-, 20- and 25-month-old gal3,/, mice and attempted to evaluate the liver morphology by contrast enhanced computed tomography (CT) before sacrifice. Results:, At the age of 15 months or later, gal3,/, mice developed liver nodules with varying degrees of architectural and nuclear atypia based on mild to moderate delicate zone 3 fibrosis. In addition, we successfully confirmed the presence of some of the liver nodules by CT. We report herein that gal3,/, mice develop dysplastic liver nodules and HCC. Conclusions:, We believe that it would be interesting to use this murine model to investigate liver carcinogenesis based on a natural history of NAFLD. Furthermore, CT scanning might be a useful tool for longitudinal evaluation of morphological changes in vivo. [source]

Nonalcoholic fatty liver disease: is all the fat bad?

A. D. Clouston
Abstract Nonalcoholic fatty liver disease is now a major cause of liver disease in developed countries, largely as a result of an epidemic of obesity, diabetes and sedentary lifestyles. This has resulted in raised clinical awareness and diagnostic refinement. The entity encompasses several histologic patterns from benign steatosis to nonalcoholic steatohepatitis, the latter having a significant risk of progressive fibrosis and the development of cirrhosis. Labor­atory tests and imaging are not able to distinguish steatosis from steatohepatitis, which requires liver biopsy. However following an assessment of several risk factors, patients can be stratified for the potential risk of fibrosis, allowing the rational use of liver biopsy. This review will describe the various patterns of nonalcoholic fatty liver disease and relate this to disease pathogenesis and progression. Strategies for management, including experimental interventions, will be discussed. (Intern Med J 2004; 34: 187,191) [source]

Nonalcoholic fatty liver disease: Quantitative assessment of liver fat content by computed tomography, magnetic resonance imaging and proton magnetic resonance spectroscopy

OBJECTIVE: The purpose of this study was to evaluate the clinical application of imaging technology in the quantitative assessment of fatty liver with magnetic resonance imaging (MRI) and proton MR spectroscopy. METHODS: Overall 36 patients with diffuse fatty liver who had undertaken the computed tomography (CT) scan, MRI and proton MR spectroscopy (1H MRS) were analyzed. Their body mass index (BMI) was measured and their liver to spleen CT ratio (L/S) calculated on the plain CT scan. MR T1-weighted imaging (T1WI) was obtained with in-phase (IP) and out-of-phase (OP) images. T2-weighted imaging (T2WI) was acquired with or without the fat-suppression technique. The liver fat content (LFC) was quantified as the percentage of relative signal intensity loss on T1WI or T2WI images. The intrahepatic content of lipid (IHCL) was expressed as the percentage of peak value ratio of lipid to water by 1H MRS. RESULTS: The results of BMI measurement, CT L/S ratio, LFC calculated from MR T1WI and T2WI images, as well as IHCL measured by 1H MRS were 27.26 ± 3.01 kg/m2, 0.88 ± 0.26, 13.80 ± 9.92%, 40.67 ± 16.04% and 30.98 ± 20.43%, respectively. The LFC calculated from MR T1WI, T2WI images and IHCL measured by 1H MRS correlated significantly with the CT L/S ratio (r=,0.830, P= 0.000; r=,0.736, P= 0.000; r=,0.461, P= 0.005, respectively). BMI correlated significantly only with the liver fat contents measured by T1WI IP/OP and 1H MRS (r=,0.347, P= 0.038; r=,0.374, P= 0.025, respectively). CONCLUSION: CT, MR imaging and 1H MRS were effective methods for the quantitative assessment of LFC. The MR imaging, especially 1H MRS, would be used more frequently in the clinical evaluation of fatty liver and 1H MRS could more accurately reflect the severity of fatty liver. [source]

Bile acids and insulin resistance: implications for treating nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease is characterized by an accumulation of excess triglycerides in hepatocytes, and insulin resistance is now considered the fundamental operative mechanism throughout the prevalence and progression of the disease. Besides their role in dietary lipid absorption and cholesterol homeostasis, evidence has accumulated that bile acids are also signaling molecules that play two important roles in glucose and lipid metabolism: in the nuclear hormone receptors as farnesoid X receptors (FXR), as well as ligands for G-protein-coupled receptors TGR5. The activated FXR-SHP pathway regulates the enterohepatic recycling and biosynthesis of bile acids and underlies the down-regulation of hepatic fatty acid and triglyceride biosynthesis and very low density lipoprotein production mediated by sterol-regulatory element-binding protein-1c. The bile acid-TGR5-cAMP-D2 signaling pathway in human skeletal muscle in the fasting,feeding cycle increases energy expenditure and prevents obesity. Therefore, a molecular basis has been provided for a link between bile acids, lipid metabolism and glucose homeostasis, which can open novel pharmacological approaches against insulin resistance and nonalcoholic fatty liver disease. [source]

Non-alcoholic fatty liver disease in Malaysia: A demographic, anthropometric, metabolic and histological study

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is increasing rapidly in the Asia,Pacific region. There has been a paucity of studies from the region. The aims of this study were to define the demographic, anthropometric, metabolic and histological characteristics of patients with NAFLD in our local population and to determine independent predictors of severe liver fibrosis. METHODS: Patients with persistently raised liver enzymes and/or fatty liver detected on ultrasonography with exclusion of other liver disorders were prospectively recruited. Their insulin resistance was assessed using the homeostasis model assessment of insulin resistance score. A liver biopsy was performed in all cases for grading (for steatohepatitis) and staging (for fibrosis) of NAFLD. Independent risk factors for fibrosis were determined using multiple logistic regression analysis. RESULTS: Seventy-five patients were recruited: 39 men (52%) and 36 women (48%). The mean age of the patients was 47.0 ± 12.2 years. Of these, 58 patients (77.3%) were centrally obese, 29 patients (38.7%) were diabetic and 15 patients (20.0%) had impaired glucose tolerance. Insulin resistance was diagnosed in 62 out of 64 (96.9%) patients. Benign steatosis, nonalcoholic steatohepatitis and cirrhosis were diagnosed in three (4.3%), 59 (84.3%) and eight (11.4%) of 70 patients, respectively. Significant independent predictors of liver fibrosis were; male sex (P = 0.019, OR = 5.55, CI = 1.33,23.18) and Indian race (P = 0.013, OR = 8.21, CI = 1.56,43.16). CONCLUSIONS: The full histological spectrum of NAFLD was seen in our patients. The majority of patients were insulin resistant, centrally obese and either diabetic or had impaired glucose tolerance. The predictors of severe liver fibrosis were male sex and Indian race. [source]

Pathogenesis of nonalcoholic steatohepatitis (NASH)

Xiong MA
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases that range from hepatic steatosis at the most clinically benign end of the spectrum, through an intermediate lesion, nonalcoholic steatohepatitis (NASH), to cirrhosis at the opposite extreme. Epidemiology studies have estimated that about 20,30% of adults in the United States and other Western countries have NAFLD, and of these about 10% (2,3% of adults) meet the diagnostic criteria of NASH. Studies of animals and humans with obesity-related fatty liver disease have revealed much about the mechanisms that mediate this common pathology. The pathogenesis of NASH is multifactorial and includes insulin resistance, excessive intracellular fatty acids, oxidant stress, mitochondrial dysfunction and the role of innate immunity. This review will briefly discuss the epidemiology of NAFLD and focus on current understanding of the pathogenesis of NASH. [source]

Effects of nonalcoholic fatty liver disease on the development of metabolic disorders

Jian-Gao Fan
Abstract Background and Aim:, Nonalcoholic fatty liver disease (NAFLD) is considered to be the liver component of metabolic syndrome. However, the impact of NAFLD on metabolic syndrome is unclear. The aim of this study was to explore the influence of NAFLD on the development of metabolic disorders. Methods:, Patients with NAFLD and an age, sex, and occupation-matched control group were recruited from employees of Bao-Steel Group (Shanghai, China) who had received medical check-ups biennially between 1995 and 2002. Anthropometric and laboratory data, and incidence of metabolic disorders were assessed at baseline and at follow-up of at least 4 years. SPSS 11.5 was used for statistical analysis. Results:, The study consisted of 358 patients (326 men and 32 women) and 788 matched controls (711 men and 77 women) with a similar mean age of 39.0 years and median follow-up of 6 years. At the end of follow-up, incidence of obesity (47.6% vs 19.5%), hypertension (69.6% vs 16.3%), hypertriglyceridemia (39.1% vs 16.3%), hypercholesterolemia (24.5% vs 17.3%), impaired fasting glucose (IFG) (25.1% vs 11.6%), diabetes mellitus (20.3% vs 5.2%) and multiple metabolic disorders (MMD) (56.3% vs 16.3%) were significantly higher in the fatty liver group than the control group. Interestingly, the mean alanine aminotransferase (ALT) level in patients with fatty liver significantly decreased at follow-up compared with baseline (28.56 ± 18.86 vs 31.51 ± 18.34 U/L, P < 0.05). To separate the effects of obesity from fatty liver, the subjects were re-classified according to the presence of obesity and fatty liver at baseline. The incidence of hypertension (61.1% vs 41.3%), hypertriglyceridemia (38.1% vs 15.0%), hypercholesterolemia (29.9% vs 16.6%), IFG (21.3% vs 10.0%) and diabetes (11.1% vs 4.3%) were significantly higher in the fatty liver group without obesity (n = 84) than in the group with without fatty liver or obesity (n = 614). In addition, the incidence of hypertension (72.9% vs 57.4%), hypertriglyceridemia (39.4% vs 22.7%) and diabetes (23.2% vs 8.4%) was higher in the group with fatty liver and obesity (n = 274) than in the group with obesity alone (n = 174). Conclusions:, The presence of NAFLD might predict the development of metabolic disorders due to insulin resistance, rather than obesity itself. ALT levels decreased over time in patients with fatty liver. [source]

Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats

Min Pan
Abstract:, Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized condition that may progress to end-stage liver disease, which ranges from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. Oxidative stress and lipid peroxidation are key pathophysiological mechanisms in NAFLD. We investigate the preventive effects of intraperitoneal administration of melatonin (2.5, 5, 10 mg/kg, daily, respectively) in NAFLD rats induced by high-fat diets for 12 wk. Liver damage was evaluated by serological analysis, serum and hepatic lipid assay as well as hematoxylin,eosin staining in liver sections. Oxidative stress and lipid peroxidation were assessed by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in liver. The results showed that high-fat diet induced oxidative stress with extensive liver steatosis in rats. Melatonin (5 or 10 mg/kg) was effective in reducing hepatic steatosis and inflammation with lowering serum alanine aminotransferase, aspartate aminotransferase, and levels liver total cholesterol and triglycerides in high-fat diet rats. Moreover, melatonin (2.5, 5, 10 mg/kg) increased SOD and GSH-Px activities and the 10 mg/kg dose of melatonin reduced MDA levels in liver. This study shows that melatonin exerts protective effects against fatty liver in rats induced by high-fat diet possibly through its antioxidant actions. [source]

Clinical trial: a nutritional supplement Viusid, in combination with diet and exercise, in patients with nonalcoholic fatty liver disease

Summary Background, Nonalcoholic fatty liver disease (NAFLD) is a significant health problem for which there is no universally accepted pharmacological treatment. The combination of weight loss and antioxidant drugs to ameliorate insulin resistance and improve steatosis, inflammation and fibrosis provides the rational for therapeutic trials. Aim, To evaluate the efficacy and safety of a nutritional supplement Viusid in association with diet and exercise for NAFLD. Methods, A randomized, controlled and parallel-group trial was conducted at a tertiary care academic centre (National Institute of Gastroenterology, Havana, Cuba). We randomly assigned 60 patients with liver biopsy-proven NAFLD to 6 months of treatment with a hypocaloric diet plus aerobic exercise daily and three Viusid sachets daily or a hypocaloric diet and exercise. Endpoints were improvement in the NAFLD activity score (NAS), fibrosis and normalization of serum aminotransferase levels. Results, A significant improvement in steatosis, necroinflammation and fibrosis was seen in each group of treatment (P < 0.01 for each feature). The Viusid group, as compared with the control group, significantly reduced the mean of NAS [from 4.18 to 0.54 points in the Viusid group vs. 4.45 to 2.2 points in the control group (P < 0.001)]. On between-group comparison, Viusid was found to be associated with a significantly greater improvement in steatosis (P < 0.001), ballooning (P = 0.002) and lobular inflammation (P = 0.025), but not in fibrosis (P = 0.07). Viusid was well tolerated. Conclusions, Our results indicate that treatment with diet and exercise leads to a notable improvement in the histological features of NAFLD; however, the administration of Viusid intensifies the improvements of histological findings, especially of steatosis and inflammation. [source]

Treating nonalcoholic fatty liver disease

Nahum Méndez-Sánchez
Abstract Nonalcoholic fatty liver disease (NAFLD) is a chronic illness with multiple consequences. The spectrum of disease ranges from simple steatosis, with benign prognosis, to a potentially progressive form, nonalcoholic steatohepatitis, which may lead to liver fibrosis and cirrhosis, leading to an increase in morbidity and mortality. Furthermore, hepatocellular carcinoma incidence in NAFLD is comparable with that observed in hepatitis C-infected patients once cirrhosis is established. Current therapy is limited to lifestyle changes and control of associated metabolic disorders; however, new treatments are on the way from basic research to bedside. A review of the current literature on treatment of nonalcoholic fatty liver disease is presented in this article. [source]

Current concepts in the pathogenesis of nonalcoholic fatty liver disease

Nahum Méndez-Sánchez
Abstract Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of chronic liver disease, representing the leading cause of hepatology referral in some centres. However, its pathophysiology is not completely understood. Insulin resistance is one of the major mechanisms involved in disease prevalence and progression. Owing to the lack of an effective pharmacological therapy, recommendations on treatment are scarce and are based mainly on lifestyle changes, including diet and exercise. A review of the current literature on pathogenesis of NAFLD is presented in this article. [source]

Prevalence and clinical associations of posttransplant fatty liver disease

Lee Guan Lim
Abstract Background and Aims: Nonalcoholic fatty liver disease (NAFLD) could recur after liver transplant in patients with preexisting NAFLD, and has recently been reported to occur after transplant in patients transplanted without preexisting NAFLD. The literature on posttransplant NAFLD is limited. We aimed to study the prevalence of posttransplant NAFLD in patients transplanted for non-NAFLD-related liver diseases. Methods: Thirty liver transplant recipients: 18 with chronic hepatitis B (CHB), seven with chronic hepatitis C (CHC), five others, were recruited. Liver biopsies were performed in all CHB and CHC patients annually as per protocol, or when clinically indicated. All biopsies were reviewed by one hepato-histopathologist blindly to assess and stage for steatosis and steatohepatitis. Results: After a mean follow-up of 44±4 months, 12 (40%) and four (13%) developed posttransplant steatosis and steatohepatitis, respectively. None developed steatosis-related fibrosis or cirrhosis. Posttransplant steatohepatitis was associated with higher pretransplant body mass index (BMI) (32.3±3.9 vs 23.1±0.8, P=0.02) and higher BMI at last biopsy (32.5±4.3 vs 22.9±0.7, P=0.01). Conclusion: Posttransplant steatosis is common after liver transplant even in patients transplanted for non-NAFLD-related liver diseases. However, it is mostly benign during our follow-up, with only 13% developing steatohepatitis and none with fibrosis or cirrhosis. [source]

Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease

Nicole A. Palekar
Abstract: Nonalcoholic fatty liver disease (NAFLD) encompasses both simple steatosis and nonalcoholic steatohepatitis (NASH). Differentiation of these two entities requires histopathologic evaluation. The aim of this study was to establish a reliable diagnostic model for differentiating steatosis from steatohepatitis utilizing both clinical characteristics and a panel of biochemical markers of lipid peroxidation and fibrosis. Eighty subjects with biopsy proven NAFLD were enrolled, 39 with simple steatosis and 41 with histopathologic evidence of NASH. Demographic and laboratory data to include serologic testing for 8-epi-PGF2,, transforming growth factor-, (TGF-,), adiponectin, and hyaluronic acid (HA) were obtained and compared between the two groups. There were significant differences between the two groups with respect to age (P=0.004), female gender (P=0.024), aspartate aminotransferase (AST) (P=0.028), body mass index (BMI) (P=0.003), fasting insulin (0.018), AST/alanine aminotransferase (ALT) ratio (AAR) (P=0.017), quantitative insulin sensitivity check index (QUICKI) (P=0.002), and HA (P=0.029). A composite index for distinguishing steatosis from NASH was calculated by summing the risk factors of age ,50 years, female gender, AST,45 IU/l, BMI ,30 mg/kg2, AAR,0.80, and HA,55 mcg/l, and its accuracy was determined by receiver operating characteristic (ROC) analysis to be 0.763 (95% CI: 0.650,0.876). The presence of three or more risk factors had a sensitivity, specificity, PPV, and NPV of 73.7%, 65.7%, 68.2%, and 71.4%, respectively. In addition, HA at a cutoff of 45.3 mcg/l was a good predictor of advanced fibrosis. In conclusion, we propose a noninvasive screening model for distinguishing simple steatosis from NASH. Identifying patients at risk for NASH will allow clinicians to more accurately determine who may benefit from liver biopsy. [source]

Markers of the Hepatic Component of the Metabolic Syndrome as Predictors of Mortality in Renal Transplant Recipients

D. M. Zelle
Cardiovascular disease (CVD) is a leading cause of mortality in renal transplant recipients (RTRs). Metabolic syndrome (MS) is highly prevalent in RTRs. Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of MS. We investigated associations of NAFLD markers with MS and mortality. RTRs were investigated between 2001 and 2003. NAFLD markers, alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and alkaline phosphatase (AP) were measured. Bone and nonbone fractions of AP were also determined. Death was recorded until August 2007. Six hundred and two RTRs were studied (age 52 ± 12 years, 55% men). At baseline 388 RTRs had MS. Prevalence of MS was positively associated with liver enzymes. During follow-up for 5.3[4.5,5.7] years, 95 recipients died (49 cardiovascular). In univariate Cox regression analyses, GGT (HR = 1.43[1.21,1.69], p < 0.001) and AP (HR = 1.34[1.11,1.63], p = 0.003) were associated with mortality, whereas ALT was not. Similar associations were found for cardiovascular mortality. Adjustment for potential confounders, including MS, diabetes and traditional risk factors did not materially change these associations. Results for nonbone AP mirrored that for total AP. ALT, GGT and AP are associated with MS. Of these three enzymes, GGT and AP are associated with mortality, independent of MS. These findings suggest that GGT and AP are independently related to mortality in RTRs. [source]

Methylenetetrahydrofolate reductase gene polymorphisms in patients with nonalcoholic steatohepatitis (NASH)

Ali Sazci
Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of a history of alcohol use. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms result in hyperhomocysteinemia. To examine whether the C677T and A1298C polymorphisms of the MTHFR gene were associated with NASH, we analysed the allele and genotype distribution of the MTHFR C677T and A1298C polymorphisms in 57 well-diagnosed NASH patients, 324 healthy controls in a case-control study of Turkish subjects of Caucasian origin. The diagnosis of the NASH patients was based on liver biopsy. The method used in the analysis of genotypes was PCR-RFLP. The MTHFR A1298C polymorphism was significantly associated with NASH (,2,=,8.439; p,=,0.015) in the total NASH patients compared with healthy controls. The MTHFR 1298C allele (odds ratio (OR),=,2.480; 95%CI,=,1.286,4.782; ,2,=,7.703; df,=,1; p,=,0.006) was significantly associated with NASH in the total NASH patients. The MTHFR C677C/A1298C compound genotype (OR,=,2.218; 95%CI,=,1.003,4.906; ,2,=,3.998; df,=,1; p,=,0.046) in men patients was also significantly associated with NASH. Likewise the MTHFR C1298C genotype was significantly associated with NASH in women patients with NASH (OR,=,2.979; 95%CI,=,1.027,8.641; ,2,=,4.343; df,=,1; p,=,0.037). In conclusion, the MTHFR 1298C allele in all NASH patients, C1298C genotype, C677C/C1298C compound genotype in women NASH patients and C677C/A1298C compound genotype in men NASH patients were genetic risk factors for NASH. Copyright © 2007 John Wiley & Sons, Ltd. [source]

A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents,,

HEPATOLOGY, Issue 4 2010
Nicola Santoro
The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPAR,2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). Conclusion: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size. (HEPATOLOGY 2010.) [source]

Emerging genes associated with the progression of nonalcoholic fatty liver disease,,

HEPATOLOGY, Issue 3 2010
Christina Koutsari
First page of article [source]

Fitness versus fatness: Moving beyond weight loss in nonalcoholic fatty liver disease,,

HEPATOLOGY, Issue 1 2010
Nathan A. Johnson
The rapid emergence of nonalcoholic fatty liver disease (NAFLD) as a cause of both liver-related morbidity and mortality and cardiometabolic risk has led to the search for effective lifestyle strategies to reduce liver fat. Lifestyle intervention comprising dietary restriction in conjunction with increased physical activity has shown clear hepatic benefits when weight loss approximating 3%-10% of body weight is achieved. Yet, the poor sustainability of weight loss challenges the current therapeutic focus on body weight and highlights the need for alternative strategies for NAFLD management. Epidemiologic data show an independent relationship between liver fat, physical activity, and fitness, and a growing body of longitudinal research demonstrates that increased physical activity participation per se significantly reduces hepatic steatosis and serum aminotransferases in individuals with NAFLD, independent of weight loss. Mechanistic insights to explain this interaction are outlined, and recommendations for the implementation of lifestyle intervention involving physical activity are discussed. In light of the often poor sustainability of weight loss strategies, and the viability of physical activity therapy, clinicians should assess physical fitness and physical activity habits, educate patients on the benefits of fitness outside of weight loss, and focus on behavior change which promotes physical activity adoption. (HEPATOLOGY 2010) [source]

Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway,

HEPATOLOGY, Issue 5 2010
Nitika Arora Gupta
Glucagon-like peptide 1 (GLP-1) is a naturally occurring peptide secreted by the L cells of the small intestine. GLP-1 functions as an incretin and stimulates glucose-mediated insulin production by pancreatic , cells. In this study, we demonstrate that exendin-4/GLP-1 has a cognate receptor on human hepatocytes and that exendin-4 has a direct effect on the reduction of hepatic steatosis in the absence of insulin. Both glucagon-like peptide 1 receptor (GLP/R) messenger RNA and protein were detected on primary human hepatocytes, and receptor was internalized in the presence of GLP-1. Exendin-4 increased the phosphorylation of 3-phosphoinositide-dependent kinase-1 (PDK-1), AKT, and protein kinase C , (PKC-,) in HepG2 and Huh7 cells. Small interfering RNA against GLP-1R abolished the effects on PDK-1 and PKC-,. Treatment with exendin-4 quantitatively reduced triglyceride stores compared with control-treated cells. Conclusion: This is the first report that the G protein,coupled receptor GLP-1R is present on human hepatocytes. Furthermore, it appears that exendin-4 has the same beneficial effects in vitro as those seen in our previously published in vivo study in ob/ob mice, directly reducing hepatocyte steatosis. Future use for human nonalcoholic fatty liver disease, either in combination with dietary manipulation or other pharmacotherapy, may be a significant advance in treatment of this common form of liver disease. (HEPATOLOGY 2010) [source]

Molecular signatures of nonalcoholic fatty liver disease: The present and future,

HEPATOLOGY, Issue 5 2010
Yusuf Yilmaz M.D.
No abstract is available for this article. [source]

Activation of the complement system in human nonalcoholic fatty liver disease,

HEPATOLOGY, Issue 6 2009
Sander S. Rensen
Activation of the innate immune system plays a major role in nonalcoholic fatty liver disease (NAFLD). The complement system is an important component of innate immunity that recognizes danger signals such as tissue injury. We aimed to determine whether activation of the complement system occurs in NAFLD, to identify initiating pathways, and to assess the relation between complement activation, NAFLD severity, apoptosis, and inflammatory parameters. Liver biopsies of 43 obese subjects with various degrees of NAFLD and of 10 healthy controls were analyzed for deposition of complement factors C1q, mannose-binding lectin (MBL), C4d, activated C3, and membrane attack complex (MAC)-associated C9. Furthermore, hepatic neutrophil infiltration, apoptosis, and pro-inflammatory cytokine expression were quantified. Whereas complement activation was undetectable in the liver of healthy subjects, 74% of the NAFLD patients showed hepatic deposition of activated C3 and C4d. C1q as well as MBL accumulation was found in most activated C3-positive patients. Strikingly, 50% of activated C3-positive patients also displayed MAC-associated C9 deposition. Deposition of complement factors was predominantly seen around hepatocytes with macrovesicular steatosis. Subjects showing accumulation of activated C3 displayed increased numbers of apoptotic cells. Importantly, hepatic neutrophil infiltration as well as interleukin (IL)-8 and IL-6 expression was significantly higher in patients showing activated C3 deposition, whereas patients with C9 deposition additionally had increased IL-1, expression. Moreover, nonalcoholic steatohepatitis (NASH) was more prevalent in patients showing hepatic C9 or activated C3 deposition. Conclusion: There is widespread activation of the complement system in NAFLD, which is associated with disease severity. This may have important implications for the pathogenesis and progression of NAFLD given the function of complement factors in clearance of apoptotic cells, hepatic fibrosis, and liver regeneration. (HEPATOLOGY 2009.) [source]

Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss,

HEPATOLOGY, Issue 4 2009
Nathan A. Johnson
Weight loss remains the most common therapy advocated for reducing hepatic lipid in obesity and nonalcoholic fatty liver disease. Yet, reduction of body weight by lifestyle intervention is often modest, and thus, therapies which effectively modulate the burden of fatty liver but are not contingent upon weight loss are of the highest practical significance. However, the effect of aerobic exercise on liver fat independent of weight loss has not been clarified. We assessed the effect of aerobic exercise training on hepatic, blood, abdominal and muscle lipids in 19 sedentary obese men and women using magnetic resonance imaging and proton magnetic resonance spectroscopy (1H-MRS). Four weeks of aerobic cycling exercise, in accordance with current physical activity guidelines, significantly reduced visceral adipose tissue volume by 12% (P < 0.01) and hepatic triglyceride concentration by 21% (P < 0.05). This was associated with a significant (14%) reduction in plasma free fatty acids (P < 0.05). Exercise training did not alter body weight, vastus lateralis intramyocellular triglyceride concentration, abdominal subcutaneous adipose tissue volume, 1H-MRS,measured hepatic lipid saturation, or HOMA-IR (homeostasis model assessment of insulin resistance; P > 0.05). Conclusion: These data provide the first direct experimental evidence demonstrating that regular aerobic exercise reduces hepatic lipids in obesity even in the absence of body weight reduction. Physical activity should be strongly promoted for the management of fatty liver, the benefits of which are not exclusively contingent upon weight loss. (HEPATOLOGY 2009.) [source]

Adipokines in liver diseases,

HEPATOLOGY, Issue 3 2009
Fabio Marra
Adipokines are polypeptides secreted in the adipose tissue in a regulated manner. While some of these molecules are expressed only by adipocytes, resident and infiltrating macrophages and components of the vascular stroma markedly contribute to expression of other adipokines. As a result, adipose tissue inflammation is associated with a modification in the pattern of adipokine secretion. Leptin, adiponectin, and resistin are the best-studied molecules in this class, but cytokines such as tumor necrosis factor or interleukin-6 are also secreted at high levels by the adipose tissue. Several other molecules have been recently identified and are actively investigated. Adipokines interfere with hepatic injury associated with fatty infiltration, differentially modulating steatosis, inflammation, and fibrosis. Several studies have investigated plasma levels of adiponectin in patients with nonalcoholic fatty liver disease, to establish correlations with the underlying state of insulin resistance and with the type and severity of hepatic damage. Hepatitis C is another disease where adipokines may represent a link between viral infection, steatosis, and metabolic disturbances. Identification of the mediators secreted by expanded adipose tissue and their pathogenic role is pivotal in consideration of the alarming increase in the prevalence of obesity and of the detrimental role that this condition exerts on the course of liver diseases. (HEPATOLOGY 2009.) [source]

Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease,

HEPATOLOGY, Issue 6 2009
Luca Miele
The role played by the gut in nonalcoholic fatty liver disease (NAFLD) is still a matter of debate, although animal and human studies suggest that gut-derived endotoxin may be important. We investigated intestinal permeability in patients with NAFLD and evaluated the correlations between this phenomenon and the stage of the disease, the integrity of tight junctions within the small intestine, and prevalence of small intestinal bacterial overgrowth (SIBO). We examined 35 consecutive patients with biopsy-proven NAFLD, 27 with untreated celiac disease (as a model of intestinal hyperpermeability) and 24 healthy volunteers. We assessed the presence of SIBO by glucose breath testing (GBT), intestinal permeability by means of urinary excretion of 51Cr-ethylene diamine tetraacetate (51Cr-EDTA) test, and the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 (ZO-1) expression in duodenal biopsy specimens. Patients with NAFLD had significantly increased gut permeability (compared with healthy subjects; P < 0.001) and a higher prevalence of SIBO, although both were lower than in the untreated celiac patients. In patients with NAFLD, both gut permeability and the prevalence of SIBO correlated with the severity of steatosis but not with presence of NASH. Conclusions: Our results provide the first evidence that NAFLD in humans is associated with increased gut permeability and that this abnormality is related to the increased prevalence of SIBO in these patients. The increased permeability appears to be caused by disruption of intercellular tight junctions in the intestine, and it may play an important role in the pathogenesis of hepatic fat deposition. (HEPATOLOGY 2009.) [source]