Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease in the United States. It is commonly associated with the components of the metabolic syndrome including obesity. From the spectrum of NAFLD, only patients with nonalcoholic steatohepatitis (NASH) have been convincingly shown to have a potential for progression to cirrhosis. We report the prevalence of NAFLD and NASH as well as predictors of NASH and advanced fibrosis in morbidly obese patients. METHODS: 212 consecutive patients who underwent bariatric surgery were enrolled in the study. A liver biopsy was performed at the time of the surgery. Causes of chronic liver disease other than NAFLD were excluded by clinical and laboratory evaluation. RESULTS: The prevalence of NAFLD was 93%. Of those with NAFLD, 26% had NASH. 17 patients (9%) had advanced fibrosis (i.e., bridging fibrosis or cirrhosis). Male gender, AST, and type 2 diabetes mellitus were independently associated with NASH. Waistto-hip ratio, AST, and focal hepatocyte necrosis on liver biopsy were independently associated with advanced fibrosis. Interestingly, while AST was associated with NASH and advanced fibrosis, the majority of the patients with either NASH or advanced fibrosis had normal AST. CONCLUSIONS: NAFLD and NASH are very common in morbidly obese patients undergoing bariatric surgery. Features associated with the metabolic syndrome and liver cell injury are independently associated with either NASH or advanced fibrosis.

Obesity-related differential gene expression in the visceral adipose tissue.

BACKGROUND: This study investigates the expression patterns in human adipose tissue, and identifies genes that may be involved in the abnormal energy homeostasis. METHODS: Subjects were prospectively recruited from morbidly obese patients undergoing bariatric surgery and from non-obese organ donors. Extensive clinical data and visceral fat specimens were obtained from each subject at the time of surgery. A group of 50 obese patients and 9 non-obese controls were selected for further study. Two custom two-color cDNA microarrays were produced with 40,173 human individual cDNA clones. Microarray experiments were performed for each sample, and a selected group of gene expression values were confirmed with real-time RT-PCR. RESULTS: A comparison of gene expression profiles from obese and non-obese patients identified 1,208 genes with statistically significant differential expression between the 2 groups. Most prominent among these genes are multiple glycolysis enzyme encoding genes; others are involved in oxysterol biosynthesis and signaling, or are ATP-binding transporters and solute carriers. CONCLUSION: Differential gene expression in the adipose tissue of morbidly obese patients includes genes related to lipid and glucose metabolism, membrane transport, and genes promoting the cell cycle. These findings are a first step toward clarifying the molecular pathogenesis of obesity and identifying potential targets for therapeutic intervention.

Hepatic gene expression in patients with obesity-related non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease. NAFLD includes a spectrum of clinicopathologic syndromes that includes non-alcoholic steatohepatitis (NASH) that has potential for progression. The pathogenesis of NASH is poorly characterized. AIM: This study was designed to identify differences in hepatic gene expression in patients with NASH and to relate such differences to their clinical characteristics. DESIGN: Consecutive patients undergoing bariatric surgery were prospectively recruited. Extensive clinical data and two liver biopsy specimens were obtained at the time of enrollment. A single hepatopathologist reviewed and classified the liver biopsies. Patients with excessive alcohol use and other causes of liver disease were excluded. A group of 29 NASH patients, 12 with steatosis alone, seven obese controls and six non-obese controls were selected for further investigation. Customized cDNA microarrays containing 5220 relevant genes were designed specifically for this study. Microarray experiments were run in triplicate for each sample and a selected group of genes were confirmed using real-time PCR. OUTCOME MEASURE: Differential hepatic gene expressions in patients with NASH as compared with controls. RESULTS: Thirty-four genes with significant differential expression were identified in patients with NASH when compared with non-obese controls. Moreover, 19 of these genes showed no significant expression differences in obese vs. non-obese controls, suggesting a stronger association of these genes to NASH. CONCLUSIONS: Several differentially expressed genes in patients with NASH are related to lipid metabolism and extracellular matrix remodeling. Additionally, genes related to liver regeneration, apoptosis, and the detoxification process were differentially expressed. These findings may help clarify the molecular pathogenesis of NASH and identify potential targets for therapeutic intervention.

A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and some of its forms are progressive. This study describes the profiling of hepatic gene expression and serum protein content in patients with different subtypes of NAFLD. Liver biopsy specimens from 98 bariatric surgery patients were classified as normal, steatosis alone, steatosis with nonspecific inflammation, and nonalcoholic steatohepatitis (NASH). Microarray hybridizations were performed in triplicate and the microarray expression levels of a selected group of genes were confirmed using real-time quantitative reverse-transcriptase polymerase chain reaction. Serum protein profiles of the same patients were determined by SELDI-TOF mass spectrometry. Of 98 obese patients, 91 were diagnosed with NAFLD (12 steatosis alone, 52 steatosis with nonspecific inflammation, and 27 NASH), and 7 patients without NAFLD served as obese controls. Each group of NAFLD patients was compared with the obese controls, and 22 genes with more than twofold differences in expression levels were revealed. Proteomics analyses were performed for the same group comparisons and revealed twelve significantly different protein peaks. In conclusion, this genomic/proteomic analysis suggests differential expression of several genes and protein peaks in patients within and across the forms of NAFLD. These findings may help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic intervention.

Risk factors for hepatocellular carcinoma in patients with cirrhosis.

Recent research suggests an increase in the incidence of hepatocellular carcinoma (HCC) in the United States, which may be related to an upsurge in the sequelae of chronic liver disease from hepatitis C virus. In addition to factors related to the underlying etiology of liver disease, a number of host factors such as age, gender, and ethnic background may be associated with this increased risk. The aim of this study was to evaluate a number of potential risk factors for HCC in patients with cirrhosis. Patients with biopsy proven HCC were identified from our pathology and cancer registry databases. All those without histologic or clinical cirrhosis and non-HCC hepatic malignancies were excluded. Cirrhotic patients without HCC were also selected from the Cleveland Clinic unified transplant database and were designated controls. Extensive clinicodemographic data were obtained from the databases and chart reviews. When available, paraffin-embedded liver biopsy blocks were obtained for HFE gene analysis. Univariate comparisons were made with chi-square and Fisher's exact test and multivariate analysis was carried out with logistic regression. A total of 760 patients were included in this study, 244 documented cases of HCC and 516 cirrhotic controls without HCC. Patients' age (RR = 3.1 [2.6-3.8]; P < 0.0001), male gender (RR = 3.4 [2.3-5.1]; P < 0.0001), African-American ethnicity (RR = 3.1 [1.6-5.8]; P = 0.0005), and other non-Caucasian ethnicity (RR = 6.9 [3.2-14.4]; P < 0.0001) were independently associated with HCC. Restricting the analysis to HCV-related cirrhosis, the same risk factors remained independently associated with HCC: age (decade; RR = 2.3 [1.6-3.4]; P < 0.0001), male gender (RR = 2.9 [1.2-7.0]; P = 0.02), African-American ethnicity (RR = 3.1 [1.3-7.4]; P = 0.009), and other non-Caucasian ethnicity (RR = 15.8 [1.9-134]; P = 0.01). Iron studies did not reveal an increased risk for iron overload or HFE mutation. Male gender, advancing age, and non-Caucasian ethnic background are independently associated with HCC.