To the Editor:

We wish to comment on the article entitled “Pathologic Criteria for Nonalcoholic Steatohepatitis: Interprotocol Agreement and Ability to Predict Liver-Related Mortality” by Younossi et al.,1 which was recently published in HEPATOLOGY. The stated goals of the study were 2-fold: (1) to compare the results of biopsy interpretations made according to three previously published histological scoring systems2-4 and a previously unpublished system1 for the histopathological diagnosis of nonalcoholic steatohepatitis (NASH) and (2) to compare the use of these systems for the prediction of long-term mortality. The study cohort consisted of patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) who had at least 5 years of follow-up.

Details of the utilization of the previously described histological scoring systems provide insight into our concerns. Matteoni et al.2 described a system for the categorization of the spectrum of diseases in NAFLD and classified cases into four types: (1) steatosis, (2) steatosis plus inflammation, (3) steatosis plus ballooning, and (4) steatosis plus Mallory-Denk bodies or fibrosis. This classification system was not used to identify the presence or absence of NASH in the original study according to Younossi et al. The degree of inflammation and its location (portal or lobular) were not specified in the system, nor was the degree of fibrosis or its zonality (perisinusoidal or portal). On the other hand, the Brunt proposal3 for grading and staging NASH was just that: a proposal, published in the same year as the Matteoni classification system, that followed the same paradigm used in chronic hepatitis for separating grading (activity) and staging (fibrosis). This proposal was, however, not intended for establishing a diagnosis of NASH. This system was applied to liver biopsy samples only after NASH had been diagnosed and not to cases with steatosis only or steatosis and inflammation. Thus, the use of “fat plus lobular inflammation” for a “Brunt” diagnosis of “NASH” by Younossi et al. is the result of a misunderstanding, and this misapplication of the proposal has led to their conclusion that the system results in the overdiagnosis of NASH.

The National Institutes of Health–sponsored NASH Clinical Research Network system, which is called the Kleiner scoring system,4 also separates the activity [nonalcoholic fatty liver disease activity score (NAS)] and the stage (fibrosis). The NAS comprises steatosis, inflammation and ballooning only, and no fibrosis, as implied by Younossi et al.1 Importantly, the NAS scoring system was not intended to be used as a surrogate for a diagnostic determination of NASH versus NAFLD without NASH. Although, as noted by Younossi et al., other authors have used the NAS as a surrogate for establishing a diagnosis of NASH, neither the NASH Clinical Research Network nor we as the participating pathologists have ever supported the use of the system for diagnosis in writing or presentations. Furthermore, as we have recently demonstrated, although higher NAS scores correlate with a diagnosis of NASH statistically, they have separate and distinct clinical meanings, and the NAS cannot replace the histological diagnosis.5

Unfortunately, Younossi et al.1 also assessed both the Brunt and Kleiner scoring systems for another purpose for which they were not designed: the prediction of liver-related mortality. Interestingly, they tested these systems against the Matteoni system, which was developed specifically for this purpose. Several statistical analyses were performed and led to a final conclusion confirming what has been shown in many studies of NASH over the past decades: hepatic fibrosis is a predictor of long-term morbidity/mortality.

In conclusion, the comparison of histological grading and staging systems and the validation of their elements against clinical outcomes are important goals in clinical investigation. Of utmost importance in these types of studies, however, is careful attention to the details of the methods that are used. The “Brunt” and “NAS” systems, as applied in this article,1 have not been appropriately used in this context, and we emphasize this to the editor and the readers of this article to dispel any potential misunderstandings about the usefulness of these grading systems when they are applied in the appropriate way.


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  • 1
    Younossi Z, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. HEPATOLOGY 2011.
  • 2
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116: 1413-1419.
  • 3
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999; 94: 2467-2474.
  • 4
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. HEPATOLOGY 2005; 41: 1313-1321.
  • 5
    Brunt EM, Kleiner DE, Wilson L, Belt P, Neuschwander-Tetri BA, for the NASH Clinical Research Network. The NAS and the histopatholoic diagnosis of NASH: distinct clinicopathologic meanings. HEPATOLOGY 2011; 53: 810-820.

Elizabeth M. Brunt M.D.*, David E. Kleiner M.D., Ph.D.†, Cynthia Behling M.D., Ph.D.‡, Melissa J. Contos M.D.§, Oscar W. Cummings M.D.¶, Linda D. Ferrell M.D.**, Michael S. Torbenson M.D.††, Matthew Yeh M.D., Ph.D.‡‡, * Department of Pathology and Immunology, Washington University, St. Louis, MO, † Department of Laboratories, National Cancer Institute, National Institutes of Health, Bethesda, MD, ‡ Sharp Memorial Hospital, San Diego, CA, § Department of Pathology, Virginia Commonwealth University, Richmond, VA, ¶ Department of Pathology, Indiana University, Indianapolis, IN, ** Department of Pathology, University of California San Francisco, San Francisco, CA, †† Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, ‡‡ Department of Pathology, University of Washington Medical Center, Seattle, WA.