The diagnosis of nonalcoholic steatohepatitis (NASH) is established by the presence of a characteristic pattern of steatosis, inflammation, and hepatocellular ballooning on liver biopsies in the absence of significant alcohol consumption. The value of establishing a diagnosis of NASH is that it identifies individuals who are at risk for progressive liver disease to the point of cirrhosis and death from chronic liver disease. However, the dichotomous assessment of liver biopsies as either having steatohepatitis (SH) or not is less helpful in treatment trials of therapeutic agents to improve NASH because it cannot identify patients in whom NASH significantly lessened in severity with treatment but continued to fulfill diagnostic criteria for NASH. For this reason, a scoring system was needed that included the full spectrum of nonalcoholic fatty liver disease and would be sensitive to changes in the underlying disease process independent of the diagnosis of NASH.
To meet this need, a scoring system for nonalcoholic fatty liver disease (NAFLD) was developed and validated by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Pathology Committee.1 The methodology proposed for feature-based scoring of histologic lesions of NAFLD has been widely utilized, as evidenced by its application in numerous clinical and experimental settings in NAFLD-related studies. The recognized strengths of the method include the relative ease of understanding and, therefore, application of the system; division of lesions of active and potentially reversible injury (“grade”) in the NAFLD Activity Score (NAS) and those potentially less reversible and characterized by collagen deposition and architectural alterations that may evolve toward more permanent parenchymal remodeling (“stage”). The proposed NAS also clearly separates the three lesions that comprise grade: steatosis, lobular inflammation, and ballooning. This allows detailed analysis of histologic changes for comparative and correlative studies in therapeutic intervention trials.
The histologically based NAS was derived from 10 pathologists' blinded and individual readings of biopsies from 32 adults and 18 children with clinically presumed NAFLD. The adult biopsies were read twice, and the pediatric biopsies once by each pathologist. It was noted in the publication of the validation study that the numeric scores correlated closely but not perfectly with separately derived diagnoses of “definite SH,” “not SH,” and “borderline SH.”
It is, however, increasingly apparent from ongoing and published studies that the numeric value of the composite NAS is considered by some investigators to be either “synonymous” with, or actually a replacement for, a microscopic diagnosis that is based on overall pattern of injury as well as the presence of additional lesions such as zonality of lesions, portal inflammation, and fibrosis.2 The validity of this unintended use of the NAS has not been formally evaluated.
In order to objectively assess the relationships of the NAS, the diagnosis of SH, and important clinical characteristics of NAFLD, we availed ourselves of the large, well-characterized dataset from the NASH CRN. We demonstrate that the NAS and the diagnostic category of definite SH are closely correlated, but also have distinct clinicopathologic relationships. The study further highlights that not all biopsies with NAS ≥5 have findings that meet diagnostic criteria of definite SH, and that some cases of NAS ≤4 do, indicating that the a threshold value of an NAS > 5 cannot be used reliably to establish the presence or absence of NASH.