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PubMedDate not supplied

A new approach to drug therapy in non-alcoholic steatohepatitis (NASH).

Liver steatosis is a common human disease, most often caused by long-term alcohol consumption. Non-alcoholic steatohepatitis (NASH) is characterized by similar histopathological features to those observed in alcoholic liver disease, but occurs in the absence of significant alcohol consumption. Several aetiological factors contribute to NASH: obesity, type 2 diabetes mellitus, hyperlipidaemia, pregnancy, different chemical intoxications, parenteral nutrition, jejeuno-ileal bypass, chronic inflammatory bowel disease, nutritional protein deficiency and congenital metabolic disorders. Biochemically, oxidative stress and lipid peroxidation and their ensuing damage are implicated in the pathogenesis of NASH and alcoholic steatohepatitis (probably resulting from free fatty acids in the mitochondria, and induction of the cytochrome P450 isoform CYP2E1 in hepatocytes and Kupffer's cells). This paper deals with the pathomechanisms, clinical findings and currently available therapies for NASH. The potential use of metadoxine in the treatment of NASH is also discussed.

Antioxidants↗

PubMedDate not supplied

Nonalcoholic steatohepatitis (NASH) with diabetes: predictors of liver fibrosis.

INTRODUCTION: Nonalcoholic steatohepatitis (NASH) is common cause of chronic liver disease strongly associated with insulin resistance leading to fibrosis. No factors that determine increasing fibrosis have been well recognized. Liver biopsy is considered as gold standard for diagnosis and prognosis of this disease. AIM: To identify independent predictive factors of liver fibrosis in patients of NASH with diabetes. MATERIAL AND METHODS: During the year 2001 and 2002 total 36 patients of NASH associated with diabetes were included in the study. The diagnosis of NASH was based on 1) presence of steatosis, inflammation and ballooning on liver biopsy 2) Intake of alcohol < 20 gm of ethanol per week 3) Exclusion of other liver diseases. Patients were labeled as diabetic if random glucose was > 200 mg/dL or fasting glucose more than 140 mg/dL on 2 occasion or having documented use of oral hypoglycemic medications or insulin. Clinical and biochemical variables such as age, sex, obesity, hypercholesterolemia, AST, ALT and AST: ALT were examined for predictors of fibrosis using univariate and multiple regression statistical analysis. Obesity was defined as BMI > 30 for both males and females. Hypercholesterolemia was considered when fasting cholesterol level was above 95th percentile of normal on at least 2 occasions. Fibrosis was noted as present or absent on histology. RESULTS: Of 36 patients 17 were females and 19 males with age range of 25 to 75 years, mean age 50.8 years. Fibrosis was present in 11 (30.5%) and absent in 25 (69.4%) patients. Univariate and multiple correlations co-efficient failed to detect significant association of fibrosis with above mentioned variables. However multiple regression and logistic regression analysis (MLR) detected statistical significance for AST, ALT levels and AST: ALT ratio between fibrosis and no fibrosis in 80.6% patients. CONCLUSION: There is no definite noninvasive test that helps to predict liver fibrosis however AST, ALT levels and AST: ALT ratio may help to determine the fibrosis in patients of NASH with diabetes in majority of cases.

Adult↗

PubMed2006

[Role of liver biopsy in the diagnosis of NASH].

Liver biopsy interpretation remains the gold standard for diagnosis of NASH. It also permits determination of disease severity and may provide insight into prognosis. The histopathologic criteria for NASH generally include the presence of hepatic steatosis, lobular inflammation, and hepatocyte ballooning degeneration. The system proposed by Brunt remains the best known and most frequently used method for the grading and staging of NASH. Recently a histologic scoring system (NAFLD activity score (NAS)) has been proposed that can assist in diagnosis of NAFLD and may be useful for assessing the response to therapy. In our hospital, informed consent about liver biopsy was obtained from 65(56%) of 116 consecutive NAFLD patients with elevated ALT levels: 35% (23/65) had NASH, 59% (38/65) had simple steatosis, and 6% (4/65) had normal liver histology. Sampling variability continues to be a limitation of liver biopsy in staging NASH.

Biomarkers↗

PubMed2006

[High-sensitivity C-reactive protein (hs-CRP): a promising biomarker for the screening of non-alcoholic steatohepatitis (NASH)].

Nonalcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) that may progress eventually to cirrhosis. Any clinically useful serum biomarkers have never been reported to distinguish patients with NASH from those with simple steatosis. The serum CRP concentration, formerly used as a marker of acute-phase reaction, has been revealed to be a strong predictor of coronary event after the introduction of the high-sensitivity assay method. Patients with metabolic syndrome also have been reported to have higher high-sensitivity CRP(hs-CRP) concentration. We showed patients with more active form of NASH (grade2-3) have higher concentration of hs-CRP than those with quiescent form of NASH (grade1) or simple steatosis. hs-CRP may be a promising biomarker for screening of NASH, a hepatic manifestation of metabolic syndrome.

Biomarkers↗

PubMed2000

Nash equilibria for an evolutionary language game.

We study an evolutionary language game that describes how signals become associated with meaning. In our context, a language, L, is described by two matrices: the P matrix contains the probabilities that for a speaker certain objects are associated with certain signals, while the Q matrix contains the probabilities that for a listener certain signals are associated with certain objects. We define the payoff in our evolutionary language game as the total amount of information exchanged between two individuals. We give a formal classification of all languages, L(P, Q), describing the conditions for Nash equilibria and evolutionarily stable strategies (ESS). We describe an algorithm for generating all languages that are Nash equilibria. Finally, we show that starting from any random language, there exists an evolutionary trajectory using selection and neutral drift that ends up with a strategy that is a strict Nash equilibrium (or very close to a strict Nash equilibrium).

Algorithms↗

PubMed2006

[Non-alcoholic liver disease (NASH)].

NASH, an increasingly recognized condition resembles alcohol-induced liver disease, but occurs in patients who do not abuse alcohol. Obesity, insulin resistance and oxidative stress have critical roles in the pathogenesis of NASH. Liver biopsy remains the only modality that can reliably distinguish steatosis from steatohepatitis. Simple steatosis may have the best prognosis. In patients with NASH liver enzymes are insensitive and can not be used reliably to confirm the diagnosis or stage the extent of fibrosis. Currently no effective medical therapy is available. Weight reduction may improve the disease. Liver-transplantation in end-stage liver disease is a potential therapeutic option also in patients with NASH.

Biopsy↗

PubMed2004

Association of non-alcoholic steatohepatitis (NASH) with chronic neutrophilic leukemia.

A 54-yr-old female having chronic neutrophilic leukemia (CNL) associated with severe liver injury is presented. Physical examination on admission showed severe jaundice, hepatosplenomegaly, massive ascites, and pretibial edema. Complete blood count showed a hemoglobin level of 9.1 g/dL, platelet count of 25.8 x 10(4)/microL, and white blood cell count of 36.6 x 10(3)/microL with 89.7% neutrophils. Blood chemistry showed hyperbilirubinemia (21.9 mg/dL) with normal transaminase levels. There was no abnormality in serum cholesterol, triglyceride, or glucose levels. Neutrophil alkaline phosphatase activity was significantly elevated. Bone marrow aspiration showed myeloid hyperplasia with normal karyotype. Rearrangement of the bcr/abl was not detected by either polymerase chain reaction or fluorescence in situ hybridization. Human androgen receptor gene assay (HUMARA) of the bone marrow cells showed clonal proliferation of neutrophils. The patient was diagnosed as having CNL. To evaluate the pathogenesis of the liver injury, a needle biopsy was performed, which showed steatohepatitis with infiltration of neutrophils. As the patient had no history of alcohol abuse, a diagnosis of non-alcoholic steatohepatitis (NASH) was made. Assuming that the infiltration of abnormal neutrophils into the liver contributed to the development of NASH, she was treated with cytoreductive chemotherapy (cytosine arabinoside: 100 mg/d, 1-3 doses/wk). With decreases in white blood cell counts, serum bilirubin levels decreased gradually to 1.5 mg/mL. A postchemotherapy liver biopsy specimen showed marked improvement of the fatty degenerative change. To our knowledge, this is the first report describing the development of NASH in a myeloproliferative disorder. We believe that the infiltration of leukemic cells contributed to the development of NASH in this patient.

Antimetabolites, Antineoplastic↗

PubMed2004

The Nash equilibrium: a perspective.

In 1950, John Nash contributed a remarkable one-page PNAS article that defined and characterized a notion of equilibrium for n- person games. This notion, now called the "Nash equilibrium," has been widely applied and adapted in economics and other behavioral sciences. Indeed, game theory, with the Nash equilibrium as its centerpiece, is becoming the most prominent unifying theory of social science. In this perspective, we summarize the historical context and subsequent impact of Nash's contribution.

Economics↗

PubMed2006

Pathogenesis of nonalcoholic steatohepatitis (NASH).

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.

Clinical Trials as Topic↗

PubMed2004

Clinical and histopathological features of NASH in workers exposed to chemicals with or without associated metabolic conditions.

BACKGROUND/AIMS: Non-alcoholic steatohepatitis (NASH) has been associated with exposure to chemicals among workers from an industrial complex in Brazil. We investigated the NASH profile of these individuals associated or not with metabolic conditions. METHODS: Eighty-four patients with NASH were classified into three groups: G1, 31 patients exposed to chemicals (benzene, xylene, vinyl chloride and others); G2, 30 exposed patients who also presented with obesity, hyperlipidemia and diabetes; and G3, 23 non-exposed patients who presented with metabolic conditions. RESULTS: G1 and G2 were similar in terms of gender (97% and 100% males) and age (37+/-5.4 and 39+/-6.5 years). In G3, 74% were males and the age was 48+/-3.4 years (P<0.05). In G2, obesity was present in 26.6%, hyperlipidemia in 66.6% and diabetes in 6.6%. In G3, obesity was observed in 43.4%, hyperlipidemia in 30.4% and diabetes in 26%. Macro- and microsteatosis were observed in 100% of cases. Perisinusoidal fibrosis was observed in 71% patients in G1, 80% in G2 and 52% in G3 (P<0.05). Histological evidence of cholestasis was present in 53% of cases in G1, 50% in G2 and 13% in G3 (P<0.05). CONCLUSIONS: Exposure to chemicals appears to be an independent risk factor for NASH that presents a peculiar profile. It is more frequently seen in men younger than non-exposed ones. Steatosis, fibrosis and cholestasis were frequent histological findings. Co-existing metabolic factors did not seem to influence clinical or histopathological presentation.

Adult↗

PubMed2002

Non-alcoholic steatohepatitis (NASH): where are we now and where are we going?

Although non-alcoholic steatohepatitis (NASH) was considered relatively uncommon prior to the middle of the last decade, over the past three years there has been an explosion of studies on various aspects of NASH with one study reporting that after hepatitis C, NASH was the most common diagnosis in patients presenting largely with persistent abnormalities of liver function tests. The field of NASH has come a long way in a relatively short space of time. This article considers advances in knowledge that have arisen as a result of these studies and highlights areas for further work.

Fatty Liver↗

PubMed2002

Motion - all patients with NASH need to have a liver biopsy: arguments against the motion.

Most cases of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are suspected on the basis of the exclusion of viral, autoimmune, metabolic and genetic causes of chronic liver disease in patients with chronic elevation of aminotransferase enzymes. However, the definitive diagnosis of NASH requires liver biopsy. Valuable blood tests include hepatitis B and C serology, iron profile, alpha 1-antitrypsin phenotype, ceruloplasmin, antinuclear antibody and antismooth muscle antibody, and serum protein electrophoresis. If these tests are negative or normal, and if there are no symptoms or signs of chronic liver disease, it is unlikely that a specifically treatable liver disease would be discovered at biopsy. The prevalence of NAFLD in the general population appears to be approximately 20%, and 2% to 3% of people have NASH. There is no proven specific therapy for the spectrum of nonalcoholic liver disease; therefore, the management of the patient with NASH is not likely to be changed after histological assessment. Bleeding, sometimes fatal, and other complications requiring hospitalization can occur, and liver biopsies should not be undertaken without clear clinical indications. The high cost of undertaking histological assessment of all persons with asymptomatic elevations of liver enzymes cannot be justified in view of the risks and limited clinical benefits.

Biopsy, Needle↗

PubMed2002

Motion - all patients with NASH need to have a liver biopsy: arguments for the motion.

Previously regarded as an obscure disorder, nonalcoholic steatohepatitis (NASH) has recently emerged as an important chronic liver disease. NASH is within a spectrum of disorders characterized by excessive accumulation of fat in the liver, including simple hepatic steatosis (fatty liver), inflammation and necrosis (steatohepatitis), and fibrosis. Collectively, the disorders are called nonalcoholic fatty liver disease (NAFLD). Estimates of the prevalence of these individual conditions are suspect because liver biopsy is required for definitive diagnosis and is not generally performed. Although these conditions have traditionally been thought of as diseases of obese women, and are frequently associated with diabetes mellitus and hypertriglyceridemia, they have also been identified in lean men. Insulin resistance appears to be a common factor. These conditions are difficult to distinguish from each other clinically, and no biochemical or radiological test reliably establishes the diagnosis. A ratio of serum aspartate to alanine aminotransferase levels of less than one can distinguish NAFLD from alcoholic liver disease, but this is a nonspecific finding. Fatty infiltration imparts a diffuse echogenicity to the liver at ultrasonography, but this test cannot easily distinguish fat from fibrous tissue or identify cases of NASH. Only histological examination can establish the diagnosis of NASH, grade its severity, determine the prognosis and guide treatment.

Alanine Transaminase↗

PubMed2005

The emerging problem of nonalcoholic steatohepatitis (NASH).

Nonalcoholic steatohepatitis (NASH) is an increasing recognized form of chronic liver condition affecting both children and adults within the wide spectrum of fatty liver diseases. Recently NASH has been often associated with insulin resistance and has shown potential harmful evolution towards end-stage liver disease. Its incidence and prevalence is increasing, paralleling the rise in obesity and diabetes mellitus in Western Countries. Once all the other causes of persistent elevation of serum transaminase levels are excluded, the diagnosis of NASH can be only confirmed by liver histology. Non-invasive diagnostic tools, however, are awaited to allow the follow-up of patients at higher risk for major liver dysfunction. This article focus on current thoughts on the natural history and clinical presentation of NASH and describes current trends in the diagnosis and treatment of this emerging condition.

Diet↗

PubMed2006

[NASH and metabolic syndrome].

Visceral obesity and insulin resistance are typical clinical features of nonalcoholic steatohepatitis (NASH) characterized by zone 3-dominant hepatic steatosis with ballooned hepatocytes and Mallory bodies, zone 3 pericellular and perivenular fibrosis with or without bridging fibrosis, and lobular inflammatory cell infiltration. Indeed, 90% of NASH revealed to be complicated with visceral obesity, and two thirds of NASH patients fulfill the criteria of metabolic syndrome. Therefore, NASH could be regarded as the hepatic manifestation of metabolic syndrome, and a variety of life-style related diseases such as obesity, hypertension, hyperlipidemia and diabetes mellitus could be used for detecting

Fatty Liver↗

PubMed1982

Sensitive formaldehyde determination with Nash's reagent and a 'tryptophan reaction'.

The widely applied Nash-method and its modifications have unsatisfactory specificity and restricted sensitivity for the determination of small amounts of formaldehyde. A method using small volumes of reaction mixtures with low background absorbance is described; this method avoids dilution during the protein denaturation step by the use of trichloroacetic acid. Alternatively a 'tryptophan-sulfuric acid-iron' reaction takes advantage of high specificity for formaldehyde detection. A more economical and sensitive variant is described including trichloroacetic acid precipitation of protein. The sensitivity and specificity of the colour development reaction of the 'tryptophan-sulfuric acid-iron' reaction appears to be superior to the Nash-modification. However the detection of formaldehyde by the NASH method can also be amplified by subsequent extraction and concentration of the reaction product diacetyl-dihydrolutidine into n-amyl alcohol so that a formaldehyde amount of few nanomoles can be determined. The application of these methods is recommended in cases of formaldehyde formation in small amounts such as in cell cultures or when kinetic data at low substrate concentrations and slow turnover rates have to be measured.

Animals↗

PubMed2005

Histological study on comparison between NASH and ALD.

We examined the histological findings of non-alcoholic steatohepatitis (NASH) and ALD to study resemblance and difference of these two diseases. At a glance of H&E staining, they looked same, however, careful examination on silver impregnation histology, the fibrosis of NASH showed lattice fibrosis on the other hand ALD showed solid fibrosis. The appearance of fibrosis was different due to qualitative difference. More examination on the change of hepatocytes, there were some difference in incidence of the findings such as megamitochondria, bile stasis, hemosiderin deposition, vacuolic nuclei, and lipogranuroma. So we are able to differentiate NASH and ALD histologically.

Journal Article↗

PubMed1990

Nash equilibrium and evolutionary stability in large- and finite-population "playing the field" models.

This paper studies the correspondence between Nash equilibrium and evolutionary stability in large- and finite-population "playing the field" models. Whenever the fitness function is sufficiently continuous, any large-population ESS corresponds to a symmetric Nash equilibrium in the game that describes the simultaneous interaction of the individuals in the population, and any strict, symmetric Nash equilibrium in that game corresponds to a large-population ESS. This correspondence continues to hold, approximately, in finite populations; and it holds exactly for strict pure-strategy equilibria in sufficiently large finite populations. By contrast, a sequence of (mixed-strategy) finite-population ESSs can converge, as the population grows, to a limit that is not a large-population ESS, and a large-population ESS need not be the limit of any sequence of finite-population ESSs.

Animals↗