Liver Injury In Nonalcoholic Fatty Liver Disease Research Articles

Apoptosis in Nonalcoholic Steatohepatitis With Normal Aminotransferase Values: Zooming in on Cytokeratin 18 Fragments

Recent years have witnessed an increasing inter­ est in the relationship between alanine amino­ transferase (ALT) and nonalcoholic fatty liver disease (NAFLD) [1]. Traditionally, increased ALT concentrations are believed to be a conse­ quence of liver injury in NAFLD and are, thus, widely used as a surrogate marker of this condi­ tion [2]. However, studies assessing the specificity and sensitivity of ALT as a marker of NAFLD have been limited and efforts to identify reliable cut­off values for this enzyme, in order to facili­ tate the identification of subjects with NAFLD, have generated conflicting results [3]. Another issue inherent to the use of ALT as a biomarker of NAFLD is the possible confounding factors that might cause ALT elevation [4]. For example, small amounts of alcohol consumption, as well as hepatotoxic medications, may act as confounding factors in the association between increased ALT concentrations and NAFLD. These caveats not­ withstanding, ALT can be considered an accept­ able marker for NAFLD in epidemio logical studies. By contrast, caution should exercised regarding the use of ALT for diagnostic and mon­ itoring purposes in the clinical care of NAFLD patients [5]. Another problem with the use of ALT as a diagnostic or monitoring biomarker of NAFLD is the existence of two isoforms of this enzyme, termed ALT1 and ­2 [6]. Jadhao and colleagues have previously demon strated that murine ALT2 gene expression is induced two­ fold in fatty livers of obese mice [7]. By contrast, the expression of murine ALT1 was unchanged. This raises a question regarding which ALT form is actually measured in serum in the settings of standard clinical chemistry. It is now widely accepted that the full histo­ logical spectrum of NAFLD may be found in patients with normal ALT. Francanzani and coworkers have convincingly demonstrated that

Nonalcoholic Fatty Liver Disease: Pathology and Pathogenesis

Nonalcoholic fatty liver disease (NAFLD) is recognized as the leading cause of chronic liver disease in adults and children. NAFLD encompasses a spectrum of liver injuries ranging from steatosis to steatohepatitis with or without fibrosis. Fibrosis may progress to cirrhosis and complications including hepatocellular carcinoma. Histologic findings represent the complexity of pathophysiology. NAFLD is closely associated with obesity and is most closely linked with insulin resistance; the current Western diet, high in saturated fats and fructose, plays a significant role. There are several mechanisms by which excess triglycerides are acquired and accumulate in hepatocytes. Formation of steatotic droplets may be disordered in NAFLD. Visceral adipose tissue dysfunction in obesity and insulin resistance results in aberrant cytokine expression; many cytokines have a role in liver injury in NAFLD. Cellular stress and immune reactions, as well as the endocannabinoid system, have been implicated in animal models and in some human studies.

Leptin in nonalcoholic fatty liver disease: Original Article

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition associated with obesity and insulin resistance (IR). Leptin plays a key role in the control of energy balance, and insulin sensitivity. In this study, we aimed to examine whether serum leptin levels correlate with insulin resistance, oxidative stress parameters and the severity of histological changes in NAFLD. Methods: Fifty-two patients (M/F: 28/24) with no alcohol intake and biopsy-proven diagnosis of NAFLD were studied. Serum leptin levels were measured by radioimmunoassay. HOMA (homeostasis model assessment) IR index was calculated. Comparisons between the patients with NAFLD and non-alcoholic steatohepatitis (NASH) were performed using the Student’s t test. Multivariate regression analysis and the area under the receiver operating characteristic (ROC) curve were used to identify the independent predictors for NASH. Results: We found no association between serum leptin, fasting insulin levels, and oxidative stress parameters. ROC curve and multiple regression analysis revealed no association between the severity of histological changes and serum leptin levels. During six months followed-up period only NASH group with elevated leptin levels had significant reductions of ALT and AST values (p = 0.03, and 0.005, respectively). Conclusion: Our findings show a preventive effect of leptin against progressive liver injury in NAFLD.

In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease

In patients with nonalcoholic fatty liver disease (NAFLD), a liver biopsy remains the only reliable way to differentiate simple steatosis from nonalcoholic steatohepatitis (NASH). Noninvasive methods are urgently needed. Increasing evidence suggests hepatocyte apoptosis is a key mediator of liver injury in NAFLD. The aim of this study was to quantify hepatocyte apoptosis in plasma from patients with NAFLD and correlate it with histological severity. Plasma was obtained from 44 consecutive patients with suspected NAFLD at the time of liver biopsy. Histology was assessed blindly. Caspase-3-generated cytokeratin-18 fragments were measured in situ via immunohistochemistry and in vivo using a novel enzyme-linked immunosorbent assay. Plasma cytokeratin-18 fragments were markedly increased in patients with NASH compared with patients with simple steatosis or normal biopsies (median [interquartile range]: 765.7 U/L [479.6-991.1], 202.4 U/L [160.4-258.2], 215.5 U/L [150.2-296.2], respectively; P < .001). Cytokeratin-18 fragment levels independently predicted NASH (OR 1.95; 95% CI 1.18-3.22; P = .009 for every 50 U/L increase). A cutoff value of 395 U/L calculated using the receiver operating characteristic curve approach showed a specificity of 99.9%, a sensitivity of 85.7%, and positive and negative predictive values of 99.9% and 85.7%, respectively, for the diagnosis of NASH. In conclusion, these findings strongly suggest that determination of hepatocyte caspase activation in the blood is a strong and independent predictor of NASH in human subjects. These data highlight the potential usefulness of this test as a noninvasive diagnostic means of determining histological disease severity in patients with NAFLD.

Relationship between in vivo chlorzoxazone hydroxylation, hepatic cytochrome P450 2E1 content and liver injury in obese non-alcoholic fatty liver disease patients

The aim of the present study was to test the hypothesis that induction of cytochrome P450 2E1 (CYP2E1) in the liver of patients with non-alcoholic fatty liver disease (NAFLD) is correlated both with the in vivo activity of the cytochrome and with the development of liver injury. For this purpose, the liver content of CYP2E1 was determined by Western blot and the CYP2E1 activity by the in vivo hydroxylation of chlorzoxazone (CLZ). The study groups were obese women with an average body mass index (BMI) of 40.3kg/m(2), who underwent therapeutic gastroplasty or gastrectomy with a gastro-jejunal anastomosis. Further, the hepatic histology was determined to establish the pathological score grouping the subjects into three categories: control, steatosis and steatohepatitis. The liver CYP2E1 content and the CLZ hydroxylation of obese patients with steatosis and, particularly, with steatohepatitis were significantly higher than controls and correlated positively with both the severity of the liver damage. These data provide evidence that CYP2E1 would be involved in the mechanism of liver injury found in obese NAFLD patients. Also, the correlation between liver CYP2E1 content and in vivo CLZ hydroxylation would validate the latter as a reliable indicator of liver injury in NAFLD, thus providing a simple and not invasive method to study these patients.