Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings

Abstract

The diagnosis of nonalcoholic steatohepatitis (NASH) is defined by the presence and pattern of specific histological abnormalities on liver biopsy. A separate system of scoring the features of nonalcoholic fatty liver disease (NAFLD) called the NAFLD Activity Score (NAS) was developed as a tool to measure changes in NAFLD during therapeutic trials. However, some studies have used threshold values of the NAS, specifically NAS ≥5, as a surrogate for the histologic diagnosis of NASH. To evaluate whether this unintended use of the NAS is valid, biopsy and clinical data from the 976 adults in NASH Clinical Research Network (CRN) studies were reviewed. Biopsies were evaluated centrally by the NASH CRN Pathology Committee. Definite steatohepatitis (SH) was diagnosed in 58.1%, borderline SH in 19.5% and "not SH" in 22%. The NAS was ≥5 in 50% and ≤4 in 49%; in this cohort only 75% of biopsies with definite SH had an NAS ≥5, whereas 28% of borderline SH and 7% of "not SH" biopsies had NAS ≥5. Of biopsies with an NAS ≥5, 86% had SH and 3% "not SH". NAS ≤4 did not indicate benign histology; 29% had SH and only 42% had "not SH." Higher values of the NAS were associated with higher levels of alanine aminotransferase and aspartate aminotransferase, whereas the diagnosis of SH was associated with features of the metabolic syndrome.

Conclusion: The diagnosis of definite SH or the absence of SH based on evaluation of patterns as well as individual lesions on liver biopsies does not always correlate with threshold values of the semiquantitative NAS. Clinical trials and observational studies should take these different performance characteristics into account.

Figure 1

shows the percentages of biopsies with diagnoses of definite steatohepatitis (closed triangle), borderline (probable) steatohepatitis (open circle) and definitely not steatohepatitis (closed square). As can be noted, the majority of definite SH are > 5 and the majority of not SH are <3, however, the scores and diagnostic categories are not as easily separated in the NAS 3–5 ranges.

Figure 2

Figure 2a is an example of high NAS (steatosis, grade 3; lobular inflammation grade 2; ballooning grade 0, NAS = 5), but not SH by diagnosis. (20X, Hematoxylin and Eosin) Figure 2b is an example of low NAS (steatosis, lobular inflammation and ballooning all grade 1, NAS = 3), but diagnosed as definite SH. (20X, Hematoxylin and Eosin)

Figure 2

Figure 2a is an example of high NAS (steatosis, grade 3; lobular inflammation grade 2; ballooning grade 0, NAS = 5), but not SH by diagnosis. (20X, Hematoxylin and Eosin) Figure 2b is an example of low NAS (steatosis, lobular inflammation and ballooning all grade 1, NAS = 3), but diagnosed as definite SH. (20X, Hematoxylin and Eosin)