Nonalcoholic Steatohepatitis (nonalcoholic + steatohepatitis)

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Distribution within Medical Sciences

Selected Abstracts

Evaluation of Quantitative Portal Venous, Hepatic Arterial, and Total Hepatic Tissue Blood Flow Using Xenon CT in Alcoholic Liver Cirrhosis,Comparison With Liver Cirrhosis Related to Hepatitis C Virus and Nonalcoholic Steatohepatitis

ALCOHOLISM, Issue 2010
Hideaki Takahashi
Background/Aims:, Xenon computed tomography (Xe-CT) is a noninvasive method of quantifying and visualizing tissue blood flow (TBF). For the liver, Xe-CT allows separate measurement of hepatic arterial and portal venous TBF. The present study evaluated the usefulness of Xe-CT as a noninvasive diagnostic procedure for measuring hepatic TBF in alcoholic liver cirrhosis (AL-LC), compared with liver cirrhosis related to nonalcoholic steatohepatitis (NASH), (NASH-LC), and hepatitis C virus (HCV), (C-LC). Methods:, Xe-CT was performed on 22 patients with AL-LC, 7 patients with NASH-LC, and 24 patients with C-LC. Severity of LC was classified according to Child-Pugh classification. Correlations between hepatic TBF, Child-Pugh classification, and indocyanin green retention (ICG) rate after 15 minutes (ICG15R) were examined. Correlations of hepatic TBF in Child-Pugh class A to AL-LC, NASH-LC, and C-LC were also examined. Results:, Portal venous TBF (PVTBF) displayed a significant negative correlation with Child-Pugh score and ICG15R (r = ,0.432, p < 0.01, r = ,0.442, p < 0.01, respectively). Moreover, ICG15R displayed a significant positive correlation with Child-Pugh score (r = 0.661, p < 0.001). Meanwhile, mean PVTBF and total hepatic TBF (THTBF) was significantly lower in AL-LC than in C-LC (p < 0.05). Mean PVTBF was significantly lower in Child-Pugh class A to AL-LC and NASH-LC than in that to C-LC (p < 0.05). Similarly, mean THTBF was significantly lower in Child-Pugh class A to NASH-LC than in that to C-LC (p < 0.05). Conclusions:, Measurement of hepatic TBF using Xe-CT is useful as a noninvasive, objective method of assessing the state of the liver in chronic liver disease. [source]

Nitric Oxide Plays a Crucial Role in the Development/Progression of Nonalcoholic Steatohepatitis in the Choline-Deficient, l-Amino Acid-Defined Diet-Fed Rat Model

ALCOHOLISM, Issue 2010
Koji Fujita
Background:, The pathogenesis of nonalcoholic steatohepatitis (NASH) is still unclear. Recently, the 2-hit hypothesis was proposed, in which nitric oxide production, representing oxidative stress, was proposed as a very important candidate for the second hit. Methods:, The total study period was 10 weeks. A total of 20 rats were randomly divided into 2 groups. Group 1 was administered the Choline-Deficient, l-Amino Acid-Defined diet to produce a NASH model, and Group 2 as control received the Choline-Sufficient, l-Amino Acid-defined diet. The blood and tissue concentrations of nitrate + nitrite were measured using the Griess reagent and the expression levels of inducible nitric oxide synthase (iNOS) proteins and mRNA was determined by Western blotting. Results:, In regard to nitric oxide (NO) and NO metabolites, there were significant differences in the blood (especially portal venous blood) as well as tissue (liver and visceral fat) concentrations between the 2 animal groups; the amounts of NO metabolites in the tissues were much higher in the NASH models. The level of nitrotyrosine was much markedly higher in the NASH models than in the controls. In regard to the tissue expression of iNOS a significant difference between the 2 groups was found in the visceral fat, especially in the mesenterium. Conclusions:, Based on these results, we hypothesize that the iNOS expression and NO levels in the visceral fat increase, with increased diffusion of NO and its metabolites into the liver, resulting in increased nitrotyrosine formation in the liver; this, in turn, induces inflammation, apoptosis, and fibrosis in the liver, which are one of the characteristic features of NASH. [source]

Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis,

HEPATOLOGY, Issue 6 2007
Akira Hirose
Nonalcoholic steatohepatitis (NASH) is now the most frequent cause of chronic liver impairment in developed countries and is a suggested causative factor in the development of cryptogenic cirrhosis and hepatocellular carcinoma. At present there is no effective and accepted therapy for NASH. The renin-angiotensin system is involved in hepatic fibrosis through activation of hepatic stellate cells, major fibrogenic cells in the liver. Hepatic stellate cells are activated by liver injury to express excessive matrix proteins and profibrogenic cytokines such as transforming growth factor,beta 1. Medicines that inhibit this pathway may be of therapeutic potential in NASH. Using a methionine-choline,deficient rat model of NASH, we studied the potential utility of an angiotensin II type 1 receptor blocker (ARB), olmesartan, on biochemical, histologic, and antioxidant measures of disease activity. ARB significantly attenuated increases in aspartate aminotransferase, activation of hepatic stellate cells, oxidative stress, expression of transforming growth factor,beta 1, expression of collagen genes, and liver fibrosis. Conclusion: Our observations strongly suggest a potential preventive role for ARB in the progression of nonalcoholic steatohepatitis. (HEPATOLOGY 2007.) [source]

Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats,

HEPATOLOGY, Issue 4 2006
Mitsuteru Kitade
Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid,defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione- S -transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P,positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH. (HEPATOLOGY 2006;44:983,991.) [source]

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis,,

HEPATOLOGY, Issue 1 2004
Kittichai Promrat
Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsy-proven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study. (HEPATOLOGY 2004;39:188,196.) [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]

Effect of losartan on early liver fibrosis development in a rat model of nonalcoholic steatohepatitis

Patricio Ibañez
Abstract Background and Aim:, Nonalcoholic steatohepatitis (NASH) is a metabolic disorder of the liver that may evolve into fibrosis or cirrhosis. Recent studies have shown reduction of experimental liver fibrosis with the use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor antagonists. The aim of this study was to determine whether losartan can influence the early phase of fibrogenesis in an animal model of NASH. Methods:, To induce NASH, a choline-deficient diet (CDD) was given to Sprague-Dawley rats for 12 weeks. These animals were then compared with a control group receiving choline-supplemented diet (CSD) and a group fed a CDD plus losartan (10 mg/kg/day). Biochemical (serum levels of alanine aminotransferase and aspartate aminotransferase) and histological evaluation of fatty liver was performed by conventional techniques. Hydroxyproline content in liver tissue was assayed by spectrophotometry. In addition, mRNA levels of procollagen I and transforming growth factor (TGF)-, were assessed by semiquantitative RT-PCR and stellate cell activation by ,-actin immunofluorescence stain. Results:, After 12 weeks CDD induced a marked elevation of serum aminotranferases, a severe fatty liver infiltration with mild histological inflammation and fibrosis. These findings correlated with a significant increase in mRNA levels of both procollagen I and TGF-, and significant increased liver hydroxyproline content. No differences were seen between rats receiving CDD alone and rats receiving CDD plus losartan with regard to the biochemical, morphological or molecular alterations induced by the CDD. Conclusion:, Losartan does not seem to influence liver injury and fibrogenic events in the CDD model of NASH. [source]

Moderate Alcohol Consumption Aggravates High-Fat Diet Induced Steatohepatitis in Rats

ALCOHOLISM, Issue 3 2010
Yan Wang
Background:, Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition. Methods:, Sprague-Dawley rats were first fed ad libitum with Lieber-DeCarli high-fat diet (71% energy from fat) for 6 weeks to induce NASH, as demonstrated previously. Afterwards, these rats were continuously fed with high-fat diet (HFD, 55% total energy from fat) or high fat plus alcohol diet (HFA, 55% energy from fat and 16% energy from alcohol) for an additional 4 weeks. Pathological lesions including fat accumulation and inflammatory foci in liver were examined and graded. Lipid peroxidation and apoptotic hepatocytes in the liver were assessed. The mRNA expressions of tumor necrosis factor-, (TNF,) and TNF receptor 1 (TNF-R1), Fas death receptor (Fas) and Fas ligant (FasL), IL-1, and IL-12 were determined by real-time PCR. Protein levels of total and cleaved caspase-3, CYP2E1, Bax, and Bcl-2 were measured by western blotting. Results:, The number of hepatic inflammatory foci and apoptotic hepatocytes were significantly increased in rats fed with HFA as compared with those in HFD-fed rats. The aggravated inflammatory response and cellular apoptosis mediated by HFA were associated with elevated mRNA expression of Fas/FasL and cleaved caspase-3 protein. Although no significant differences were observed between HFD and HFA groups, the levels of lipid peroxidation, Bax and Bcl-2 protein concentration, and mRNA levels of other inflammatory cytokines were significantly higher in these 2 groups than those in the control group. Conclusions:, These data suggest that even moderate alcohol consumption can cause more hepatic inflammation and cellular apoptosis in a pre-existing NASH condition. [source]

Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease

Vishal Bhagat
Nonalcoholic steatohepatitis (NASH) is becoming a common cause of liver cirrhosis requiring liver transplantation (LT). Cardiovascular complications related to metabolic syndrome and NASH recurrence in the transplanted liver may affect the outcome of LT in these patients. We compared the outcomes of LT for NASH cirrhosis and alcoholic cirrhosis (ETOH) in a large transplant center. A retrospective chart review was performed for all patients who underwent LT for cryptogenic cirrhosis with the NASH phenotype (the NASH group) or ETOH (the ETOH group) at the University of Miami from January 1997 to January 2007. There was no significant difference in survival between the NASH and ETOH groups, despite a trend toward lower survival in the former (P = 0.1699). Sepsis was the leading cause of posttransplant death in both groups, and it was followed by cardiovascular causes in the NASH group (26% versus 7% in the ETOH group, P = 0.21) and malignancies in the ETOH group (29% versus 0% in the NASH group, P = 0.024). Recurrent steatohepatitis (33% versus 0%, P < 0.0001) and acute rejection (41% versus 23%, P < 0.023) were significantly more frequent in the NASH group than in the ETOH group. There was no difference in graft failure between the groups (24% in the NASH group versus 18% in the ETOH group, P = 0.3973). In conclusion, despite a numerical trend favoring the ETOH group, there were no statistically significant differences in posttransplant survival and cardiovascular mortality between the NASH and ETOH groups. Acute rejection and recurrent steatohepatitis were significantly more frequent in the NASH group but did not lead to higher rates of retransplantation. Liver Transpl 15:1814,1820, 2009. © 2009 AASLD. [source]

Obesity, hyperlipidemia, and metabolic syndrome

Michael Charlton
Key Points 1. Obesity is increasingly common among liver transplantation (LT) recipients and donors. Outcomes following LT for selected patients with class I-III obesity are similar to those for nonobese recipients. In patients who are otherwise satisfactory candidates for LT, a high body mass index, as long as it does not present a technical barrier, should not be considered to be an absolute contraindication to LT. 2. The most common causes of death beyond the first year of LT are, in descending order of frequency, graft failure (especially secondary to hepatitis C virus recurrence), malignancy, cardiovascular disease, infections, and renal failure. Metabolic syndrome is an important risk factor for each of these etiologies of posttransplant death. Posttransplant diabetes, posttransplant hypertension, and an original diagnosis of cryptogenic cirrhosis, which is commonly associated with metabolic syndrome, are all associated with an increased risk of post-LT mortality. Features of metabolic syndrome should be screened for and treated in LT recipients. 3. Because of the physiological mechanism of post-LT hypertension, which includes renal arteriolar constriction secondary to calcineurin inhibition, calcium channel blocking agents are a good pharmacological treatment modality and have been shown to be effective in renal protection in randomized controlled trials of posttransplant hypertension. 4. It is rare for dietary changes and weight reduction to result in normalization of the lipid profile. Statins should thus be initiated early in the course of management of post-LT dyslipidemia. Forty milligrams of simvastatin per day, 40 mg of atorvastatin per day, and 20 mg of pravastatin per day are reasonable starting doses for post-LT hypercholesterolemia. It is important to remember that the effects of statin therapy are additive to those of a controlled diet (eg, a Mediterranean diet rich in omega-3 fatty acids, fruits, vegetables, and dietary fiber). 5. Nonalcoholic steatohepatitis, an increasingly common etiology of cirrhosis and liver failure, recurs commonly after LT and may also arise de novo. Treatment should be directed at managing obesity and complications of metabolic syndrome. Optimal immunosuppression in patients with nonalcoholic steatohepatitis is still evolving but should include steroid minimization. Liver Transpl 15:S83,S89, 2009. © 2009 AASLD. [source]

Outcome After Liver Transplantation for NASH Cirrhosis

S. M. Malik
Nonalcoholic steatohepatitis (NASH) associated cirrhosis is an increasing indication for liver transplant (LT). The aim of this study was to determine outcome and poor predictive factors after LT for NASH cirrhosis. We analyzed patients undergoing LT from 1997 to 2008 at a single center. NASH was diagnosed on histopathology. LT recipients with hepatitis C, alcoholic or cholestatic liver disease and cryptogenic cirrhosis acted as matched controls. Ninety-eight LT recipients were identified with NASH cirrhosis. Compared to controls, NASH patients had a higher BMI (mean 32.3 kg/m2), and were more likely to be diabetic and hypertensive. Mortality after transplant was similar between NASH patients and controls but there was a tendency for higher earlier mortality in NASH patients (30-day mortality 6.1%, 1-year mortality 21.4%). Sepsis accounted for half of all deaths in NASH patients, significantly higher than controls. NASH patients ,60 years, BMI ,30 kg/m2 with diabetes and hypertension (HTN) had a 50% 1-year mortality. In conclusion, patients undergoing LT for NASH cirrhosis have a similar outcome to patients undergoing LT for other indications. The combination of older age, higher BMI, diabetes and HTN are associated with poor outcome after LT. Careful consideration is warranted before offering LT to these high-risk patients. [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]

Peroxisome proliferator-activated receptor-, as emerging target in liver disease

Bernd Schnabl
Abstract Liver fibrosis is characterized by an excessive deposition of extracellular matrix (ECM) proteins that occurs in chronic liver disease of any origin, including nonalcoholic steatohepatitis (NASH), alcohol abuse, and viral hepatitis. Cirrhosis occurs with the development of regenerating nodules of hepatocytes and is a major health burden worldwide. Patients with decompensated liver cirrhosis have a poor prognosis, with liver transplantation often being necessary. The current treatment paradigm for patients with hepatic fibrosis is to treat the underlying liver disease. However, if this cannot be achieved, there are currently no effective antifibrotic treatments for patients with chronic liver diseases. With the advent of basic molecular technology providing insight into the mechanisms of the development of hepatic fibrosis, there is now an opportunity to develop therapeutic interventions for human clinical use. In this review, the function of peroxisome proliferator-activated receptor-, (PPAR ,) will be summarized with a special emphasis on ligand activation as potential use in liver disease. Drug Dev Res 2009. © 2009 Wiley-Liss, Inc. [source]

Effects of ,-aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesity

Karima Begriche
Abstract ,-Aminoisobutyric acid (BAIBA) is a catabolite of thymine and antiretroviral thymine analogues AZT and d4T. We recently discovered that this ,-amino acid is able to enhance fatty acid oxidation and reduce body weight in mice through an increased production of leptin by the white adipose tissue (WAT). Furthermore, BAIBA could have favourable effects on nonalcoholic steatohepatitis in a leptin-independent manner. In the present review, we shall recall the circumstances that led us to discover the effects of BAIBA on body fat mass and lipid homeostasis. In addition, we put forward several hypothetical mechanisms whereby BAIBA could enhance leptin secretion by WAT and present some anti-inflammatory effects in the liver. We also discuss in this review (i) the deleterious impacts caused by the absence of, or low leptin expression on lipid homeostasis and body weight in humans and animals and (ii) recent data from other investigators suggesting that increasing leptin levels and/or responsiveness may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity, at least in some individuals. [source]

Smoking is associated with histological severity in nonalcoholic steatohepatitis,

HEPATOLOGY, Issue 4 2010
Emmanuel A. Tsochatzis M.D.
No abstract is available for this article. [source]

Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites,

HEPATOLOGY, Issue 2 2010
Brent A. Neuschwander-Tetri
First page of article [source]

Serum cytokeratin-18 fragment level: A noninvasive biomarker for not only nonalcoholic steatohepatitis, but also alcoholic steatohepatitis,

HEPATOLOGY, Issue 5 2010
M.D., Xiaohua Li Ph.D.
No abstract is available for this article. [source]

CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis,

HEPATOLOGY, Issue 4 2010
Mirko Moreno Zaldivar
Liver fibrosis is a major cause of morbidity and mortality worldwide. Platelets are involved in liver damage, but the underlying molecular mechanisms remain elusive. Here, we investigate the platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) as a molecular mediator of fibrotic liver damage. Serum concentrations and intrahepatic messenger RNA of CXCL4 were measured in patients with chronic liver diseases and mice after toxic liver injury. Platelet aggregation in early fibrosis was determined by electron microscopy in patients and by immunohistochemistry in mice. Cxcl4,/, and wild-type mice were subjected to two models of chronic liver injury (CCl4 and thioacetamide). The fibrotic phenotype was analyzed by histological, biochemical, and molecular analyses. Intrahepatic infiltration of immune cells was investigated by fluorescence-activated cell sorting, and stellate cells were stimulated with recombinant Cxcl4 in vitro. The results showed that patients with advanced hepatitis C virus,induced fibrosis or nonalcoholic steatohepatitis had increased serum levels and intrahepatic CXCL4 messenger RNA concentrations. Platelets were found directly adjacent to collagen fibrils. The CCl4 and thioacetamide treatment led to an increase of hepatic Cxcl4 levels, platelet activation, and aggregation in early fibrosis in mice. Accordingly, genetic deletion of Cxcl4 in mice significantly reduced histological and biochemical liver damage in vivo, which was accompanied by changes in the expression of fibrosis-related genes (Timp-1 [tissue inhibitor of matrix metalloproteinase 1], Mmp9 [matrix metalloproteinase 9], Tgf -, [transforming growth factor beta], IL10 [interleukin 10]). Functionally, Cxcl4,/, mice showed a strongly decreased infiltration of neutrophils (Ly6G) and CD8+ T cells into the liver. In vitro, recombinant murine Cxcl4 stimulated the proliferation, chemotaxis, and chemokine expression of hepatic stellate cells. Conclusion: The results underscore an important role of platelets in chronic liver damage and imply a new target for antifibrotic therapies. (HEPATOLOGY 2010.) [source]

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]

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]

Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis,,

HEPATOLOGY, Issue 3 2009
Koji Fujita
The specific mechanisms of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) pathogenesis remain unknown. In the present study we investigated the differences between NAFL and NASH in terms of liver lipid metabolites and serum lipoprotein. In all, 104 Japanese subjects (50 men and 54 postmenopausal women) with histologically verified NAFL disease (NAFLD) (51 with NAFL, 53 with NASH) were evaluated; all diagnoses were based on liver biopsy findings and the proposed diagnostic criteria. To investigate the differences between NAFL and NASH in humans, we carefully examined (1) lipid inflow in the liver, (2) lipid outflow from the liver, (3) very-low-density lipoprotein (VLDL) synthesis in the liver, (4) triglyceride (TG) metabolites in the liver, and (5) lipid changes and oxidative DNA damage. Most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, VLDL synthesis and lipid outflow from the liver were impaired, and surplus TGs might have been produced as a result of lipid oxidation and oxidative DNA damage in the NASH group. Conclusion: A growing body of literature suggests that a deterioration in fatty acid oxidation and VLDL secretion from the liver, caused by the impediment of VLDL synthesis, might induce serious lipid oxidation and DNA oxidative damage, impacting the degree of liver injury and thereby contributing to the progression of NASH. Therefore, dysfunctional VLDL synthesis and release may be a key factor in progression to NASH. (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]

Intramitochondrial crystalline inclusions in nonalcoholic steatohepatitis,

HEPATOLOGY, Issue 6 2009
Stephen H. Caldwell
Mitochondrial dysfunction is an important element in the pathogenesis of nonalcoholic steatohepatitis (NASH). Intramitochondrial crystals (IMCs) are a well-documented morphological abnormality seen on transmission electron microscopy in this disease. It has been suggested that IMCs consist of phospholipids, but their exact composition remain uncertain many years after their discovery. Micellar phase transitions of phospholipid bilayers is a well-known but little-studied phenomenon in living systems. Its presence in the mitochondria of NASH would offer significant insight into the disease with possible therapeutic implications. We postulated that intramitochondrial disturbances in NASH are sufficient to produce such transitions and that their detection in fresh biopsies would therefore be a dynamic process. To test this, we performed a blinded, prospective analysis of fresh liver biopsy samples immediately fixed under different conditions. Quantitative transmission electron microscopy morphometry, performed by systematically counting total mitochondria and IMCs within areas of uniform dimension, showed a stepwise decline in IMCs with cooler fixation temperature in each subject studied. Randomization testing (Monte Carlo resampling) confirmed that the detection of IMCs was strongly dependent on fixation temperature (P < 0.0001). Conclusion: These results indicate that the intramitochondrial crystals characteristic of NASH are highly dynamic and unstable structures. The findings offer the strongest support yet for their origin in micellar phase transitions. We speculate that such transitions result from microenvironmental changes within the mitochondria and carry therapeutic implications, especially in regard to dietary manipulations of mitochondrial lipid composition. (HEPATOLOGY 2009.) [source]

Transcription factor 7,like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH,

HEPATOLOGY, Issue 2 2009
Giovanni Musso
Genetic factors underlying the association of NAFLD with diabetes and atherosclerosis are unknown. Recent human studies suggest transcription factor 7,like 2 (TCF7L2) polymorphism predisposes to diabetes through modulation of ,-cell function and modulates lipid levels in familial dyslipidemia. Emerging experimental evidence connects TCF7L2 to adipocyte metabolism and lipid homeostasis, as well. We tested if TCF7L2 polymorphism is a risk factor for nonalcoholic fatty liver disease (NAFLD) and if it modulates liver injury, glucose homeostasis, lipoprotein, and adipokine profiles in NASH. TCF7L2 genotype and dietary habits of 78 nondiabetic normolipidemic NAFLD subjects and 156 age-, body mass index,, sex-matched healthy controls were assessed. In 39 biopsy-proven nonalcoholic steatohepatitis (NASH) and matched controls TCF7L2 polymorphism was correlated to liver histology and oral glucose tolerance test,derived parameters of glucose homeostasis. Patients with NASH and controls consumed a high-fat meal and TCF7L2 genotype was correlated to postprandial circulating lipoproteins, adipokines, and cytokeratin-18 fragments. The TCF7L2 CT/TT genotype was more frequent in NAFLD and predicted the presence and severity of liver disease, of ,-cell dysfunction, of reduced incretin effect and hepatic insulin resistance in NASH; it also modulated postprandial hepatocyte apoptosis, lipoproteins, and adipokine profiles in both groups. Conclusion: TCF7L2 polymorphism predisposes to NAFLD and significantly impacts liver injury, glucose homeostasis, and postprandial lipoprotein and adipokine responses to fat ingestion. This polymorphism also modulates a fat-induced increase in circulating markers of hepatocyte apoptosis in NASH. Targeting postprandial lipemia, at least in at-risk TCF7L2 genotypes, may improve liver disease and glucose dysmetabolism in these patients. (HEPATOLOGY 2008.) [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]

Hemochromatosis genotypes and risk of 31 disease endpoints: Meta-analyses including 66,000 cases and 226,000 controls,

HEPATOLOGY, Issue 4 2007
Christina Ellervik
Hemochromatosis genotypes have been associated with liver disease, diabetes mellitus, heart disease, arthritis, porphyria cutanea tarda, stroke, neurodegenerative disorders, cancer, and venous disease. We performed meta-analyses including 202 studies with 66,263 cases and 226,515 controls to examine associations between hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, C282Y/wild type, H63D/H63D, and H63D/wild type versus wild type/wild type and 9 overall endpoints and 22 endpoint subgroups. We also explored potential sources of heterogeneity. For liver disease, the odds ratio for C282Y/C282Y versus wild type/wild type was 3.9 (99% confidence interval: 1.9,8.1) overall, 11 (3.7,34) for hepatocellular carcinoma, 4.1 (1.2,14) for hepatitis C, and 10 (2.1,53) for nonalcoholic steatohepatitis. For porphyria cutanea tarda, the odds ratios were 48 (24,95) for C282Y/C282Y, 8.1 (3.9,17) for C282Y/H63D, 3.6 (1.8,7.3) for C282Y/wild type, 3.0 (1.6,5.6) for H63D/H63D, and 1.7 (1.0,3.1) for H63D/wild type versus wild type/wild type. Finally, for amyotrophic lateral sclerosis, the odds ratio was 3.9 (1.2,13) for H63D/H63D versus wild type/wild type. These findings were consistent across individual studies. The hemochromatosis genotypes were not associated with risk for diabetes mellitus, heart disease, arthritis, stroke, cancer, or venous disease in the overall analyses; however, the odds ratio for C282Y/C282Y versus wild type/wild type was 3.4 (1.1,11) for diabetes mellitus among North Europeans. Conclusion: In aggregate, clinically ascertained cases who are homozygous for the C282Y mutation are associated with a 4,11,fold risk of liver disease, whereas all 5 hemochromatosis genotypes are associated with a 2,48,fold risk of porphyria cutanea tarda, and H63D/H63D is associated with a 4-fold risk of amyotrophic lateral sclerosis. These results, mainly from case-control studies, cannot necessarily be extrapolated to the general population. (HEPATOLOGY 2007.) [source]

Divergent effects of peroxisome proliferator,activated receptor-, ligands in human and mouse nonalcoholic steatohepatitis,,

HEPATOLOGY, Issue 2 2007
Stephen H. Caldwell M.D.
No abstract is available for this article. [source]

The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis,

HEPATOLOGY, Issue 2 2007
Glen Lutchman
A pilot study of a 48-week course of pioglitazone demonstrated significant improvements in the biochemical and histological features of nonalcoholic steatohepatitis (NASH). The aim of the study was to assess the effects of stopping pioglitazone. Twenty-one patients with NASH were treated with pioglitazone (30 mg/day) for 48 weeks and underwent baseline and end-of-treatment evaluation including liver biopsy. Thirteen patients were followed for at least 48 weeks after stopping therapy and 9 underwent repeat liver biopsy. Statistical comparisons were made to evaluate whether discontinuation of pioglitazone resulted in a reversal of improvements seen on therapy. Stopping pioglitazone was associated with subsequent elevation in serum alanine aminotransferase levels (from 34 ± 13 to 70 ± 39 IU/l), decrease in adiponectin (from 9.7 ± 9.1 to 5.1 ± 4.5 ,g/ml), worsening insulin sensitivity (HOMA Index: from 2.9 ± 1.8 to 5.5 ± 5.4), and increase in total hepatic fat (from 30% ± 32% to 71% ± 33%) despite no change in average body weight compared to the end of treatment. Repeat liver biopsy in 9 patients revealed significant worsening of parenchymal inflammation (from 1.2 ± 0.7 to 2.9 ± 1.1) and steatosis (from 0.9 ± 0.6 to 2.1 ± 1.3) but no change in fibrosis (from 1.1 ± 1.2 to 1.2 ± 1.3). NASH was again present on liver biopsy in 7 patients. Conclusion: These findings suggest that long-term therapy with pioglitazone may be necessary to maintain improvements in disease activity in patients with NASH, although weight gain during treatment may ultimately limit its beneficial effects. (HEPATOLOGY 2007.) [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]

Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis,

HEPATOLOGY, Issue 6 2007
Akira Hirose
Nonalcoholic steatohepatitis (NASH) is now the most frequent cause of chronic liver impairment in developed countries and is a suggested causative factor in the development of cryptogenic cirrhosis and hepatocellular carcinoma. At present there is no effective and accepted therapy for NASH. The renin-angiotensin system is involved in hepatic fibrosis through activation of hepatic stellate cells, major fibrogenic cells in the liver. Hepatic stellate cells are activated by liver injury to express excessive matrix proteins and profibrogenic cytokines such as transforming growth factor,beta 1. Medicines that inhibit this pathway may be of therapeutic potential in NASH. Using a methionine-choline,deficient rat model of NASH, we studied the potential utility of an angiotensin II type 1 receptor blocker (ARB), olmesartan, on biochemical, histologic, and antioxidant measures of disease activity. ARB significantly attenuated increases in aspartate aminotransferase, activation of hepatic stellate cells, oxidative stress, expression of transforming growth factor,beta 1, expression of collagen genes, and liver fibrosis. Conclusion: Our observations strongly suggest a potential preventive role for ARB in the progression of nonalcoholic steatohepatitis. (HEPATOLOGY 2007.) [source]