Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver‐related mortality

Since the initial description of nonalcoholic steatohepatitis (NASH), several sets of pathologic criteria for its diagnosis have been proposed. However, their interprotocol agreement and ability to predict long‐term liver‐related mortality (LRM) have not been demonstrated. In this study, we examined patients with biopsy‐proven nonalcoholic fatty liver disease (NAFLD) for whom liver biopsy slides and clinical and mortality data were available. Liver biopsy samples were evaluated for a number of pathologic features and were classified according to the presence or absence of NASH by (1) the original criteria for NAFLD subtypes, (2) the nonalcoholic fatty liver disease activity score (NAS), (3) the Brunt criteria, and (4) the current study's criteria. All NASH diagnostic criteria and individual pathologic features were tested for agreement and for their independent associations with LRM, which were determined with a Cox proportional hazards model. Two hundred fifty‐seven NAFLD patients with complete data were included. The diagnoses of NASH by the original NAFLD subtypes and by the current study's definition of NASH were in almost perfect agreement (κ = 0.896). However, their agreement was moderate with NAS (κ = 0.470 and κ = 0.511, respectively) and only fair to moderate with the Brunt criteria (κ = 0.365 and κ = 0.441, respectively). Furthermore, the agreement of the Brunt criteria with NAS was relatively poor (κ = 0.178). During the follow‐up (median = 146 months), 31% of the patients died (9% were LRM). After we controlled for confounders, a diagnosis of NASH by the original criteria for NAFLD subtypes [adjusted hazard ratio = 9.94 (95% confidence interval = 1.28‐77.08)] demonstrated the best independent association with LRM. Among the individual pathologic features, advanced fibrosis showed the best independent association with LRM [adjusted hazard ratio = 5.68 (95% confidence interval = 1.50‐21.45)]. Conclusion: The original criteria for NAFLD subtypes and the current study's criteria for NASH were in almost perfect agreement, but their level of agreement with the NAS and Brunt criteria was lower. A diagnosis of NASH by the original criteria for NAFLD subtypes demonstrated the best predictability for LRM in NAFLD patients. (HEPATOLOGY 2011;)

[1]  J. Marrero,et al.  NAFLD may be a common underlying liver disease in patients with hepatocellular Carcinoma in the United States , 2002, Hepatology.

[2]  S. Harrison,et al.  Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection , 2010, Hepatology.

[3]  J. Goldblum,et al.  Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[4]  Z. Younossi,et al.  Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. , 2008, Journal of hepatology.

[5]  I. Wanless,et al.  Fatty liver hepatitis (steatohepatitis) and obesity: An autopsy study with analysis of risk factors , 1990, Hepatology.

[6]  M. Bennett,et al.  The natural history of nonalcoholic fatty liver: A follow‐up study , 1995, Hepatology.

[7]  Z. Goodman,et al.  Predictors of Nonalcoholic Steatohepatitis and Advanced Fibrosis in Morbidly Obese Patients , 2005, Obesity surgery.

[8]  G. Zoppini,et al.  Risk of all-cause and cardiovascular mortality in patients with chronic liver disease , 2010, Gut.

[9]  J. R. Landis,et al.  The measurement of observer agreement for categorical data. , 1977, Biometrics.

[10]  Z. Younossi,et al.  6 NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ASSOCIATED WITH HIGHER OVERALL MORTALITY AND LIVER RELATED MORTALITY , 2008 .

[11]  Z. Younossi,et al.  Erratum: Nonalcoholic fatty liver disease in patients with type 2 diabetes (Clinical Gastroenterology and Hepatology (2004) 2 (262-265)) , 2004 .

[12]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions , 1999, American Journal of Gastroenterology.

[13]  J. Ludwig,et al.  Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. , 1980, Mayo Clinic proceedings.

[14]  Z. Younossi,et al.  Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. , 1999, Gastroenterology.

[15]  G. Marchesini,et al.  Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon? , 2008, Diabetologia.

[16]  Z. Younossi,et al.  Epidemiology and natural history of NAFLD and NASH. , 2007, Clinics in liver disease.

[17]  Z. Goodman,et al.  Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. , 2009, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[18]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[19]  G. Targher,et al.  Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. , 2007, Atherosclerosis.

[20]  M. Stepanova,et al.  Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study , 2010, Gut.

[21]  Z. Younossi,et al.  Nonalcoholic fatty liver disease in patients with type 2 diabetes. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[22]  Z. Younossi,et al.  Nonalcoholic fatty liver disease: a practical approach to evaluation and management. , 2009, Clinics in liver disease.

[23]  G. Musso,et al.  Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity , 2011, Annals of medicine.

[24]  K. Tokushige,et al.  Prevalence, gender, ethnic variations, and prognosis of NASH , 2011, Journal of Gastroenterology.

[25]  R. Xu,et al.  Suspected Nonalcoholic Fatty Liver Disease and Mortality Risk in a Population-Based Cohort Study , 2008, The American Journal of Gastroenterology.

[26]  Greger Lindberg,et al.  Decreased survival of subjects with elevated liver function tests during a 28‐year follow‐up , 2010, Hepatology.

[27]  B. Neuschwander‐Tetri,et al.  Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings , 2011, Hepatology.

[28]  Chunhong Bai,et al.  Long-term follow-up of patients with nonalcoholic fatty liver. , 2009, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[29]  S. Sanderson,et al.  The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. , 2005, Journal of hepatology.

[30]  M. Holmqvist,et al.  Long‐term follow‐up of patients with NAFLD and elevated liver enzymes , 2006, Hepatology.

[31]  B. Neuschwander‐Tetri,et al.  Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease , 2010, Hepatology.