161 Nonalcoholic steatohepatitis (NASH) in patients with morbid obesity is commonly associated with normal liver enzymes

HEPATOLOGY, Vol. 38, No. 4, Suppl. 1, 2003

AASLD ABSTRACTS

160

DESIGN AND VALIDATION OF A HISTOLOGIC SCORING SYSTEM FOR NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND NON-ALCOHOLIC STEATOHEPATITIS (NASH). David ~ Kleiner, NCI, Bethesda, MD; ~ lizabeth M Brunt,

Sant Louis University, SL Louis, MO; Mark L Van Natta, Johns Hopkins University, Baltimore, MD; Cynthia Behling, University of California San Diego, San Diego, CA; Melissa J Contos, Virginia Commonwealth University, Richmond, VA; Oscar W Cummings, Indiana University, Indianapolis, IN; Linda D Ferrell, University of California San Francisco, San Francisco, CA; Yao-Chang Liu, MetroHealth Medical Center, Cleveland, OH; Michael S Torbenson, Johns Hopkins University, Baltimore, MD; Matthew Yeh, University of Washington Medical Center, Seattle, WA; Arthur J McCullough, MetroHealth Medical Center, Cleveland, OH; Arun J Sanyal, Virginia Commonwealth University, Richmond, VA BACKGROUND:NAFLD is defined by hepatic steatosis in the absence of known chronic liver disease (CLD) or significant alcohol use. NASH is a subset of NAFLD defined histologically by steatosis, spotty lobular inflammation and distinctive pattern of zone 3 injury with ballooning degeneration; Mallory's hyaline and perisinusoidal fibrosis (PSF) may also be present. A poorly defined fraction of patients progress to cirrhosis and hepatocellular carcinoma. The NASH Clinical Research Network (NASH CRN) is a multicenter consortium sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to study the natural history and initiate clinical therapeutic trials for NAFLD and NASH in adult and pediatric patients. AIMS: To design and validate a histologic scoring system for the spectrum of NAFLD useful for relating histologic features to clinical and physiologic measurements and for following histologic changes over time in natural history studies and clinical trials. METHODS: Pathologists from the 8 participating centers and from NIH agreed on scoring criteria. Each pathologist contributed cases of adult (n-32) and pediatric liver bxs (n-18) to create an anonymized study set. The cases were chosen from those referred for consideration of NASH, had been diagnosed histologically (diagnostic, borderline, or not NASH), and had no confounding CLD. The set was circulated twice. Weighted group and pair-wise kappa statistics were used to evaluate inter- and intra-rater agreement. Cochran's chi-square test for trend and logistic regression with robust variance estimation were used to analyze univariate and multivariate relationships between feature scores and the diagnosis of NASH. Adult and pediatric cases were analyzed separately. RESULTS: 14 features of NAFLD were evaluated. 4 features were evaluated semi-quantitatively: steatosis percent (0-3), modified Brunt criteria for fibrosis (0-4; zone 3 PSF l a or lb; portal fibrosis only lc), lobular inflammatory foci/20x (0-3), and ballooning (0-2). Zonality of steatosis was recorded but not scaled. Another 9 features were recorded (present/absent). Weighted group kappa statistics for the inter-rater agreement on adult cases were: fibrosis 0.84; steatosis 0.79; ballooning 0.56; lobular inflammation 0.45. Kappa agreement on the diagnosis of NASH was 0.61. Kappa values for intra-rater agreement were higher for all features while inter-rater agreement on pediatric cases was generally lower. By multivariate analysis 5 features were independently associated with the diagnosis of NASH in adults: ballooning (p <0.0001), fibrosis (p-0.0009), lobular inflammation (p-0.002), steatosis (p-0.004) and acidophil bodies (p-0.02). CONCLUSION: We have devised and validated a scoring system for NAFLD and NASH that has inter and intra-rater agreement similar to other semiquantitative systems for CLD. The pediatric NAFLD features were not as reproducible as those of adult, possibly due to varied patterns of injury. Since NASH is a pattern of injury comprised of several features, this system demonstrates that a firm diagnosis of NASH correlates with the degree of steatosis, lobular inflammation, ballooning and a characteristic pattern of fibrosis. Based on these evaluations, the NASH CRN will be using this system for the planned studies. Disclosures: Cynthia Behling - No relationships to disclose Elizabeth M Brunt - No relationships to disclose Melissa J Contos - No relationships to disclose

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Oscar W Cummings - No relationships to disclose Linda D Ferrell - No relationships to disclose David E Kleiner - No relationships to disclose Yao-Chang Liu - No relationships to disclose Arthur J McCullough - No relationships to disclose NASH-Clinical Research Network - No relationships to disclose Arun J Sanyal - No relationships to disclose Michael S Torbenson - No relationships to disclose Mark L Van Natta - No relationships to disclose Matthew Yeh - No relationships to disclose

161

NONALCOHOLIC STEATOHEPATITIS (NASH) IN PATIENTS WITH MORBID OBESITY IS COMMONLY ASSOCIATED WITH NORMAL LIVER ENZYMES. Patricia S Latham, Marie L

Borum, ~ phraim ~ Nsien, George Washington School of Medicine, Washington, DC; Joseph D Afram, Center for Obesity Surgery, Washington, DC Background: Several studies have found a correlation between elevations of liver enzymes and the finding of NASH on liver biopsy in patients with steatosis and Nonalcoholic Fatty Liver Disease (NAFLD). Patients with morbid obesity have b e e n found to have a very high prevalence of NAFLD on liver biopsy. This study explores the spectrum of liver pathology and specifically NASH in patients with morbid obesity undergoing Roux-en Y Gastric Bypass (RYGB) and correlates the findings with clinical data and the results of liver enzymes at the time of surgery. Methods: This study is a retrospective review of all patients with morbid obesity who underwent RYGB and wedge liver biopsy during Y2002 at our Hospital. All biopsies were reviewed and scored for the characteristic features of NAFLD and NASH by one pathologist (PL), using the scoring system described by Brunt, et al. Hospital charts on these patients were reviewed for demographic, clinical, and biochemical data. Patients totaled 155 in number, predominately female (90% of cases), with a mean age of 38 yrs (range 17 to 61). Results: Characteristic features of NASH were found in 20 of the cases (13%), 78% were female, mean age was 43yrs (range 18-58), and mean BMI was 50, similar to that seen in other patients undergoing RYGB. A clinical diagnosis of Diabetes was noted in 7 patients (35% of the NASH cases). Alcohol abuse was denied in all cases. Histological features in all cases included included centrilobular steatosis, lobular inflammation, and balloon degeneration a n d / o r perisinusoidal fibrosis. Steatosis was present in all cases, 65% were scored 3-4+ (on a scale of 0-4). The activity of the steatohepatitis cases was judged to be mild in 9 (45% of NASH cases), moderate in 10 (50% of NASH cases), and severe in 1 (5% of NASH cases). The extent of fibrosis of the steatohepatitis was judged to be absent (stage 0) in I (5% of NASH cases), mild (stage 1) in 7 (35% of NASH cases), moderate (stage 2-3) in 10 (50% of NASH cases, with bridges of fibrosis in 2), and cirrhotic (stage 4) in 2 (10% of NASH cases). Routine liver tests were entirely normal in 15_patients found to have steatohepatitis on biopsy (75% of NASH cases), and < 1.5X elevated in the remainder. There was no correlation between grade of activity and serum levels of AST or ALT. In 7 cases, liver enzymes were normal even w h e n grade 2-3 activity was seen on liver biopsy. Conclusions: NASH is present on liver biopsy in approximately 13% of patients with morbid obesity. The histological activity of disease in these cases is usually mild, but moderate fibrosis and even cirrhosis may be present. Liver enzymes in patients with morbid obesity and NASH can be entirely normal in up to 75% of cases. Although elevations of liver enzymes have been found to correlate with the presence of NASH in other studies of Nonalcoholic fatty liver disease (NAFLD), NASH can be present in a substantial number of cases w h e n liver enzymes are normal. Disclosures: Joseph D Afram - No relationships to disclose Marie L Borum - No relationships to disclose Patricia S Latham - No relationships to disclose Ephraim E Nsien - No relationships to disclose