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PubMedDate not supplied

Prevalence of metabolic syndrome in non-diabetic and non-cirrhotic patients with non-alcoholic steatohepatitis.

Recently, insulin resistance (IR) was proposed as a primary pathogenic mechanism in non-alcoholic steatohepatitis (NASH). The prevalence of IR and metabolic syndrome remains largely unstudied in patients with NASH and without diabetes and cirrhosis, both being conditions associated with IR. During a 1-year period, all non-diabetic and noncirrhotic patients seen in our institute with a diagnosis of NASH were subjected to anthropometric measurements, clinical examination, lipid profile and glucose tolerance test to define metabolic syndrome. All the patients underwent test for fasting glucose and insulin levels to define the insulin resistance by HOMA-R (homeostasis model assessment) method. Of the 25 patients with NASH, the metabolic syndrome was present in 17 (68%) and at least one criterion for the metabolic syndrome was present in all the patients. IR was present in 20 patients (80%). All the patients were either overweight (8%) or obese (92%). Because of the high prevalence of the metabolic syndrome and IR in patients with NASH, it is pertinent to test for IR and metabolic abnormalities in all patients with NASH. Also, all patients with metabolic syndrome should undergo liver function tests and, in the presence of abnormal transaminases, a liver biopsy to define NASH.

Adult↗

PubMed2005

Non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) represents only a part of a wide spectrum of non-alcoholic fatty liver disease (NAFLD) and its prevalence is only 2 - 3% in the general population. Obesity, diabetes, hyperlipidemia and female sex are important risk factors for NASH. Two hit theory describes very well the pathogenesis of NASH wherein hepatic steatosis, the first hit is followed up by the second hit, one of which may be reactive oxygen species. Mitochondria is the main source of reactive oxygen species which may trigger steatohepatitis by lipid peroxidation, cytokine induction or induction of fas-ligand. Insulin resistance syndrome is the only metabolic syndrome that has been consistently associated with NASH. The diagnosis rests on the hallmark histological features and rigorous exclusion of significant alcohol consumption. Most patients are asymptomatic, have mild-to-moderate elevations of serum aminotransferase levels, clinical hepatomegaly and features of fatty liver on imaging. Liver biopsy is essential for positive diagnosis and prognostication of NASH. Histologically, fat deposition is typically macrovesicular and inflammation of steatohepatitis is predominantly lobular. Neutrophilic cells in lobular inflammatory infilterate are a distinguishing feature of steatohepatitis and differentiate it from other chronic hepatitis. The pattern of collagen deposition is perivenular & peri-sinusoidal spaces in zone 3. NASH is a progressive disease in more than one in four and has spontaneous regression in less than one in six. Therapy options include weight reduction in obese, good control in diabetics and exercise. Ursodeoxycholic acid has membrane stabilizing, cytoprotective and immunological effect and normalizes raised transaminases. Liver transplantation has been done in NASH but transplanted liver shows re-development in more than two thirds. Many more therapies are in the pipeline and show promise for the future.

Adult↗

PubMed2006

[Fatty hepatosis. Non-alcoholic steatohepatitis (evolution of the knowledge about clinico-morphological features, prognosis, treatment)].

AIM: To study histological, clinical features and prognosis in patients with fatty hepatosis (FH) and non-alcoholic steatohepatitis (NASH). MATERIAL AND METHODS: Clinical and laboratory data on 74 patients with FH of non-alcoholic origin were studied. All the patients have undergone puncture biopsy of the liver (a total of 91 biopsies). Patients with fatty dystrophy of the first, second and third degree and fibrosis of the first and second degree entered the group of fatty hepatosis without inflammation (group 1, n = 54), patients with fatty dystrophy of the second and third degree and fibrosis of the third degree were assigned to group 2 (n = 20), i.e. to the group of FH with inflammation. The latter group by modern histological characteristics belongs to NASH. RESULTS: Functional disorders of the liver were insignificant, urobilinogenuria, delayed retention of bromsulphalein, hypertriglyceridemia were observed. AlAT activity was insignificantly elevated in FH patients. It was elevated 1.5-2.5-fold in NASH, the activity of AsAT, gamma-GTP was high in half of the patients. NASH has no specific clinico-biochemical signs and its diagnosis is based on the data of puncture biopsy of the liver. Long-term follow-up of 42 patients with FH and NASH discovered stabilization of the process in 34 patients. Cirrhosis of the liver occurred in 5 patients. Repeated biopsies established association of fatty dystrophy with developing micronodular cirrhosis. CONCLUSION: NASH is an independent disease. This should be taken into consideration in differential diagnosis in patients with a stable rise of serum activity of AlAT and AsAT, especially in obesity, diabetes, hyperlipidemia. The diagnosis is verified at biopsy of the liver. In spite of scare symptoms, long-term follow-up detects progression of the disease in more than 1/3 of the patients. Cirrhosis arose in 1/6 of the patients. Standard NASH treatment is absent, though elimination of the provoking factors, therapy with antioxidant drugs and ursodesoxycholic acid produce a favourable effect.

Antioxidants↗

PubMed2006

Cisapride decreasing orocecal transit time in patients with nonalcoholic steatohepatitis.

BACKGROUND: Altered small-intestine motility, lengthening of orocecal transit time (OCTT), and small-intestinal bacterial overgrowth (SIBO) have been detected in patients with nonalcoholic steatohepatitis (NASH). These changes might be related to the progressive course and poor prognosis of the disease. This study was undertaken to investigate the effect of 4-week treatment with cisapride on OCTT. METHODS: Ten NASH patients without diabetes were included. Ten healthy individuals served as controls. OCTT was measured by lactulose breath test (LBT). Anti-endotoxin core antibodies (EndoCAb) IgG were also examined. The effect of cisapride (10 mg TID during 4 weeks) on LBT and serum EndoCAb IgG levels in NASH patients was investigated. RESULTS: The NASH patients had more significantly prolonged OCTT (95 +/- 17 min) than the controls (59 +/- 18 min, P=0.00032). Cisapride administration decreased OCTT (from 95 +/- 17 min to 83 +/- 19 min, P=0.037), basal breathed H2 (from 9.87 +/- 1.60 ppm to 8.61 +/- 1.63 ppm, P=0.046) and EndoCAb IgG titers (from 5.24 +/- 0.68 GMU/ml to 4.20 +/- 0.72 GMU/ml, P=0.013) in NASH patients. CONCLUSIONS: The present data suggest the existence of deranged intestinal motility and endotoxemia in NASH patients. Cisapride administration during 4 weeks possibly restore intestinal motility and ameliorate endotoxemia in NASH patients.

Cisapride↗

PubMed2004

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis.

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.

Adult↗

PubMed2004

Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis.

Nonalcoholic fatty liver disease, frequently associated with obesity, can lead to nonalcoholic steatohepatitis (NASH) and cirrhosis. The pathophysiology of NASH is poorly understood, and no effective treatment is available. In view of a potential deleterious role for reactive oxygen species (ROS), we investigated the origin of ROS overproduction in NASH. Mitochondrial production of ROS and its alterations in the presence of antioxidant molecules were studied in livers from ob/ob mice that bear a mutation of the leptin gene and develop experimental NASH. N-acetyl-cysteine and the superoxide dismutase (SOD) mimics ambroxol, manganese [III] tetrakis (5,10,15,20 benzoic acid) (MnTBAP), and copper [II] diisopropyl salicylate (CuDIPS) were used to target different checkpoints of the oxidative cascade to determine the pathways involved in ROS production. Liver mitochondria from ob/ob mice generated more O(2)*- than those of lean littermates (P <.01). Ex vivo, all three SOD mimics decreased O(2)*- generation (P <.001) and totally inhibited lipid peroxidation (P <.001) versus untreated ob/ob mice. Those modifications were associated with in vivo improvements: MnTBAP and CuDIPS reduced weight (P <.02) and limited the extension of histological liver steatosis by 30% and 52%, respectively, versus untreated ob/ob mice. In conclusion, these data demonstrate deleterious effects of superoxide anions in NASH and point at the potential interest of nonpeptidyl mimics of SOD in the treatment of NASH in humans.

Animals↗

PubMed2005

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy.

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206-->226 mg/dL, P = .002), glucose (220-->144 mg/dL, P = .02), insulin (46.4-->24.8 muIU/mL, P = .004), ALT (54-->24 U/L, P = .02), AST (47-->22 U/L, P = .046), liver volume (3209-->2391 cm(3), P = .007), and liver fat content (31-->11%, P = .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH.

Adolescent↗

PubMed2006

Nonalcoholic fatty liver disease: from steatosis to cirrhosis.

Nonalcoholic steatohepatitis (NASH), the lynchpin between steatosis and cirrhosis in the spectrum of nonalcoholic fatty liver disorders (NAFLD), was barely recognized in 1981. NAFLD is now present in 17% to 33% of Americans, has a worldwide distribution, and parallels the frequency of central adiposity, obesity, insulin resistance, metabolic syndrome and type 2 diabetes. NASH could be present in one third of NAFLD cases. Age, activity of steatohepatitis, and established fibrosis predispose to cirrhosis, which has a 7- to 10-year liver-related mortality of 12% to 25%. Many cases of cryptogenic cirrhosis are likely endstage NASH. While endstage NAFLD currently accounts for 4% to 10% of liver transplants, this may soon rise. Pathogenic concepts for NAFLD/NASH must account for the strong links with overnutrition and underactivity, insulin resistance, and genetic factors. Lipotoxicity, oxidative stress, cytokines, and other proinflammatory mediators may each play a role in transition of steatosis to NASH. The present "gold standard" management of NASH is modest weight reduction, particularly correction of central obesity achieved by combining dietary measures with increased physical activity. Whether achieved by "lifestyle adjustment" or anti-obesity surgery, this improves insulin resistance and reverses steatosis, hepatocellular injury, inflammation, and fibrosis. The same potential for "unwinding" fibrotic NASH is indicated by studies of the peroxisome proliferation activator receptor (PPAR)-gamma agonist "glitazones," but these agents may improve liver disease at the expense of worsening obesity. Future challenges are to approach NAFLD as a preventive public health initiative and to motivate affected persons to adopt a healthier lifestyle.

Animals↗

PubMed2001

[Alcoholic and nonalcoholic steatohepatitis. Histopathologic and pathogenetic considerations].

Alcoholic (ASH) and nonalcoholic (NASH) steatohepatitis show an almost identical morphology. Since the clinical picture is not characteristic, liver biopsy is still the diagnostic gold standard. ASH and NASH are morphologically characterized by a combination of steatosis, hepatocellular injury (ballooning degeneration, apoptosis, necrosis), perivenular and pericellular fibrosis, and inflammation (mostly neutrophils). A definitive differentiation of ASH and NASH is only possible by exclusion of alcohol abuse. Although NASH comprises a syndrome with a multifactorial etiology, adipositas seems to be the most constant associated causal factor. The pathogenesis of both diseases is still unclear. Clinical evidence and experimental studies suggest an important toxic role of reactive oxygen species (oxidative stress). According to our experience, ballooning of hepatocytes is a constant morphologic feature of ASH and NASH and already present in the early stages of disease. Ballooned cells often (but not always) contain Mallory bodies (alcoholic hyalin), which are irregular cytoplasmic inclusions consisting of keratins and nonkeratin components, including ubiquitin. Ballooning is associated with a disturbance and finally almost disappearance of the keratin-intermediate filament cytoskeleton. In our studies on the pathogenesis of ASH and NASH, we concentrated on these cytoskeletal alterations and Mallory body formation. It could be shown that in the early stages overexpression and hyperphosphorylation of keratins take place. Moreover, the 1:1 ratio of keratin type I (keratin 18) and type II (keratin 8) necessary for the assembly of intermediate filaments is disturbed and the equilibrium shifted toward keratin 8. Thus, the pool of soluble keratin 8 increases. The resulting keratin monomers are sensitive to misfolding and either degraded or aggregated as inclusion bodies. If the proteolytic capacity is impaired (e.g., by inhibition of the proteasomal system) in the chronically stressed cell aggregation prevails,finally leading to Mallory body formation. Convincing evidence exists on the basis of clinical and experimental studies that keratins exert a nonskeletal protective function in simple epithelia (e.g., liver cells). Disturbance of the keratin system may thus significantly contribute to cell damage.

Biopsy↗

PubMed2004

Clinical characteristics and prevalence of GB virus C, SEN virus, and HFE gene mutation in Japanese patients with nonalcoholic steatohepatitis.

BACKGROUND: This study was carried out to clarify differences in clinical characteristics between fatty liver and nonalcoholic steatohepatitis in a Japanese population, and to assess the significance of GB virus C (GBV-C) infection, SEN virus (SENV) infection, and HFE gene mutation in the pathophysiology of these conditions. METHODS: Twenty patients with nonalcoholic steatohepatitis and 18 patients with simple steatosis were enrolled, and their clinical characteristics and histological findings were compared. Detection of GBV-C RNA and SENV DNA was performed by polymerase chain reaction (PCR). Mutational analysis of the HFE gene was performed by PCR-restriction fragment length polymorphism (RFLP). RESULTS: Serum aspartate aminotransferase (AST) and ferritin were significantly higher ( P < 0.05, for both) in NASH than in simple steatosis, and serum total cholesterol (T-Chol) was significantly lower ( P < 0.05) in NASH than in simple steatosis. While GBV-C was detectable in the serum of only one patient with NASH, SENV was detected in 50% (15/30) of the patients whose sera were tested for this virus, but the prevalence was not significantly different between the two groups (42% [8/19] in simple steatosis and 64% [7/11] in NASH). The sex ratio, body mass index (BMI), and age were not significantly different between the two groups, and mutation in the HFE gene was not detected in any patient. CONCLUSIONS: Higher serum AST and ferritin, and lower serum T-Chol are distinctive features in NASH when compared with simple steatosis. GBV-C infection, SENV infection, and HFE gene mutation were not considered to influence the development of NASH from simple fatty liver.

Adult↗

PubMed2001

Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients.

Nonalcoholic steatohepatitis (NASH) is a syndrome frequently associated with obesity, diabetes mellitus, and dyslipidemia. Increased fasting insulinemia and blood glucose levels may trigger a reduced catabolism of lipoproteins rich in triglycerides by lipoprotein lipase (LPL) and an increase in their fasting and postprandial levels. An association between postprandial lipemia and coronary heart disease has been observed, and many studies now support this concept. The most important result of our study is the increase in triglyceride-rich lipoproteins response after a fat load in NASH patients, the increase of incremental area under the postprandial curve, and the duration of the hypertriglyceridemic peaks. The persisting postprandial plasma triglyceride elevation in NASH patients was mostly due to the elevated plasma level of large triglyceride-rich particles. These data are coupled with lower plasma HDL2-cholesterol levels. As for lipoprotein analyses, the number of apolipoprotein B100 (ApoB100) particles is not significantly different between the two groups, and the higher content of triglycerides in NASH very low density lipoproteins (VLDL) increases the triglyceride-to-ApoB ratio and the particle size. A decreased enzymatic activity of LPL or a defective assembly and secretion of VLDL from hepatocytes due to a moderate reduction in microsomal triglyceride transfer protein could be involved in the overloading of VLDL. Moreover, the undetectable levels of ApoB48 in triglyceride-rich lipoproteins fraction A could be related to the synthesis of smaller and denser chylomicrons. NASH patients not only are insulin resistant but also tend to present alterations in fatty meal delivery, suggesting that an increase in fasting plasma insulin and glucose, with insulin resistance, joins with depressed metabolism of triglyceride-rich lipoproteins. An increase in postprandial triglyceride levels with production of large VLDL suggests an atherogenic behavior of lipid metabolism, in accordance with the high prevalence of the metabolic syndrome in NASH patients. This paper suggests that a fat load may be useful in early detection of atherogenic risk in the presence of otherwise normal fasting plasma lipids.

Adult↗

PubMed2002

Evolving pathophysiologic concepts in nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is increasingly recognized as a relatively prevalent disorder (ie, occurring in 3% of adults) that may progress to cirrhosis in 15% to 40% of those who are afflicted. NASH is a subset of a broader diagnostic category, nonalcoholic fatty liver disease, a term applied to a condition involving the presence of excess fat in the liver with or without inflammation and cellular injury. A diagnosis of NASH is established by the presence of morphologic changes on liver biopsy similar to those seen in alcoholic hepatitis, including hepatocellular fat accumulation, evidence of lobular inflammation and cell injury, and in some cases, progressive fibrosis. Obesity and type 2 diabetes, two conditions associated with insulin resistance, are major risk factors for the development of NASH. Accumulating evidence suggests that the hyperinsulinemia associated with insulin resistance may be important in the pathogenesis of NASH. Clinical trials will now determine whether treatment of insulin resistance is an effective therapy for NASH.

Diabetes Mellitus, Type 2↗

PubMed2006

Microinjection of the L-type calcium channel antagonist diltiazem into the ventral nucleus accumbens shell facilitates cocaine-induced conditioned place preferences.

BACKGROUND: Calcium (Ca2+) influx within the nucleus accumbens shell (NASh) can influence brain reward processes. We found previously that rats self-administer NMDA receptor antagonists (which block Ca2+ influx through NMDA receptors) into the NASh. We also found that manipulations which increase expression of Ca2+-permeable AMPA receptors within this region make cocaine aversive. Here we examined if Ca2+ influx via L-type Ca2+ channels within the NASh would influence cocaine reward. METHODS: Rats received bilateral microinjections of the L-type Ca2+ channel antagonist diltiazem into the ventral NASh prior to place conditioning with systemic cocaine. RESULTS: Microinjections of diltiazem (10 nmol/hemisphere) into the ventral NASh facilitated the ability of a sub-threshold dose of cocaine (5.0 mg/kg) to establish place preferences, but did not affect place conditioning on their own (5.0-40 nmol/hemisphere). Microinjections into more dorsal regions had no effects. CONCLUSIONS: Blockade of Ca2+ influx through L-type channels Ca2+ within the ventral NASh increases cocaine reward.

Anesthetics, Local↗

PubMed2005

Pathology of nonalcoholic steatohepatitis.

To date, histologic evaluation, most commonly in the form of liver biopsy, remains the gold standard in evaluation of nonalcoholic fatty liver disease (NAFLD). Histologic evaluation was fundamental to the initial studies that introduced and defined the concept of fatty liver as a liver disease. Currently, liver biopsy in NAFLD serves multiple roles: confirmation (or exclusion) of the diagnosis; distinction of steatohepatitis from "simple steatosis"; assessment of extent of necroinflammatory activity, fibrosis, and architectural alterations. Histopathologic studies have underscored the fact that not all obese and/or diabetic individuals with elevated liver tests have fatty liver disease; for example, hepatic glycogenosis and hepatosclerosis have been described in diabetics, and other significant liver diseases have been documented. Likewise biopsy studies have documented lesions of steatosis or steatohepatitis in unusual patient groups or clinical settings, such as lean individuals, individuals with normal liver tests, patients taking certain medications, patients with co-existent serologically-diagnosed liver disease, and pediatric patients. Biopsy studies have shown that the lesions of NASH may or may not persist in cirrhosis; prior evidence of NASH on liver biopsy serves as a benchmark for the concept that many cases of otherwise cryptogenic cirrhosis developed from NAFLD/NASH. Liver biopsy remains a significant feature of studies delineating long-term outcome of NAFLD, some of which have shown that "simple steatosis" is not always non-progressive and benign. Finally, investigators have noted correlations of proposed pathophysiologic processes in NASH with particular histologic features. Therapeutic trials for NASH rely on histologic evaluation as the most sensitive analysis to document effects of treatment. Treatment trials afford an opportunity to evaluate histologic features of resolution, and these trials have also provided an opportunity for correlations of particular histologic lesions with clinical and laboratory features in well-characterized patient populations. These kinds of studies are currently relatively few, but results of a recent study have reinforced the concept of necessary criteria for diagnosis. Current discussions in pathology include identification of lesions of concern for progression, reproducible methods of diagnosis and semiquantification of lesions, and appropriate nomenclature. Matteoni et al. proposed NAFLD types 1-4 based on long-term outcome studies; Brunt et al. proposed a system of grading and staging for NASH that follows methods of separate assessment for necroinflammatory lesions (grade) and fibrosis (stage) accepted in other forms of non-biliary chronic liver disease. Recently, the Pathology Committee of the NIDDK NASH Clinical Research Network has proposed a system of evaluation that encompasses the entire spectrum of NAFLD from steatosis to steatohepatitis with fibrosis for use in upcoming treatment trials. And, just as the clinician cannot distinguish steatosis and steatohepatitis, the pathologist cannot discern if alcohol abuse may be an underlying cause of the lesions. Proposed nomenclature to align with either extant terminology in other forms of chronic liver disease, or to align with our knowledge of underlying cause(s) (such as metabolic syndrome) will be discussed.

Journal Article↗

PubMed2005

Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates.

BACKGROUND/AIMS: The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study aimed to elucidate the relation between steatosis and inflammation in NASH in a human-like hyperlipidemic mouse model. METHODS: Liver phenotype and gene expression were assessed in APOE2 knock-in mice that were fed a western-type high fat diet with or without co-administration of fenofibrate. RESULTS: In response to a western diet, APOE2 knock-in mice developed NASH characterized by steatosis and inflammation. Strikingly, macrophage accumulation in the liver preceded the steatosis during progression of the disease. This phenotype was in line with gene expression patterns, which showed regulation of two major groups of genes, i.e. inflammatory and lipid genes. Fenofibrate treatment decreased hepatic macrophage accumulation and abolished steatosis. Moreover, a marked reduction in the expression of inflammatory genes occurred immediately after fenofibrate treatment. CONCLUSIONS: These data indicate that inflammation might play an instrumental role during the development of NASH in this mouse model. Inhibition of NASH by fenofibrate may be due, at least in part, to its inhibitory effect on pro-inflammatory genes.

ATP-Binding Cassette Transporters↗

PubMed2006

Hepatic histology in obese patients undergoing bariatric surgery.

BACKGROUND/AIMS: Obesity is one of the most important clinical associations with non-alcoholic steatohepatitis (NASH). Our aim was to assess the prevalence of non-alcoholic fatty liver disease (NAFLD)/NASH in morbidly obese patients and the risk factors to more aggressive liver disease in this population. METHODS: Review of available studies on prevalence of NAFLD/NASH in severely obese patients submitted to bariatric surgery. RESULTS: Twelve observational and transversal studies were included, with consecutive recruitment, and prospective evaluation of data, summing 1620 patients with severe obesity. Prevalence of steatosis and NASH was 91% (range: 85-98%) and 37% (24-98%), respectively, with unexpected cirrhosis in 1.7% (1-7%). NASH was not related with age or body mass index, but there was an association between male sex and NASH/hepatic fibrosis. Diabetes mellitus and insulin resistance were the conditions most frequently associated with NASH, and hypertension with advanced hepatic fibrosis. CONCLUSIONS: There is a very high prevalence of NAFLD in asymptomatic morbidly obese patients, more than one-third presenting histological criteria for NASH. This review underscores the large variations in prevalence of NASH between studies, calling for the need for a better agreement in the use of the histological criteria.

Adult↗

PubMed2003

Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis.

BACKGROUND/AIMS: Hyperinsulinemia may cause hepatic steatosis and non-alcoholic steatohepatitis (NASH). The aims of this pilot study were to examine the safety of using the insulin-sensitizing peroxisomal proliferator activated receptor (PPAR) gamma ligand rosiglitazone in patients with NASH and determine whether improved insulin sensitivity correlates with improved fatty liver. METHODS: Thirty subjects with NASH and elevated alanine aminotransferase (ALT) levels received rosiglitazone, 4 mg twice daily for 48 weeks; the preliminary results presented here were obtained at 24 weeks. Insulin sensitivity was measured using fasting insulin and glucose levels and liver fat content was estimated by CT imaging. RESULTS: By 24 weeks, rosiglitazone improved insulin sensitivity and reduced liver fat content. The mean ALT decreased from 86 to 37 U/l (P<0.01). Four subjects (13%) withdrew, one because of a rise in ALT from 59 to 277 U/l that coincided with concomitant prednisone use. Subjects experienced a mean weight gain of 3.5% and hemoglobin drop of 1.1 g/dl. CONCLUSIONS: Treatment of NASH with rosiglitazone for 24 weeks improved insulin sensitivity, reduced liver fat content and improved biochemical evidence of hepatocellular injury. These preliminary data provide evidence that hyperinsulinemia may be a cause of NASH. Strategies to improve insulin sensitivity as a treatment of NASH deserve further investigation.

Adult↗

PubMed2001

Fatty liver and nonalcoholic steatohepatitis.

Fatty liver is a relatively common incidental finding on imaging studies. Although generally a benign condition, fat in the liver can be troubling for clinicians because it can cause persistently elevated liver enzyme levels. The finding of fatty liver may also indicate the presence of nonalcoholic steatohepatitis (NASH). NASH is a histologic diagnosis applied to a constellation of liver biopsy findings that appear similar to alcoholic liver disease but are found in the absence of alcohol abuse. NASH is typically identified during the evaluation of elevated aminotransferase levels after exclusion of viral, metabolic, and other causes of liver disease. Obesity is a major risk factor; the role of diabetes is less certain, although evidence is accumulating that hyperinsulinism may play an important pathophysiologic role. About 15% to 40% of NASH patients develop hepatic fibrosis, a precursor to cirrhosis. Exactly how many patients with NASH progress to cirrhosis is unknown, but 1% to 2% of liver transplants are now performed because of a pretransplant diagnosis of NASH. Specific and effective treatments are needed but until the pathogenesis of this common liver disease is better understood, weight loss will remain the mainstay of treatment for obese patients.

Diabetes Complications↗