Impact of steatosis and inflammation definitions on the performance of NASH tests

Thierry Poynard, Mona Munteanu, Frederic Charlotte, Hugo Perazzo, Yen Ngo, Olivier Deckmyn, Raluca Pais, Philippe Mathurin, Vlad Ratziu, FLIP consortium, the FibroFrance-CPAM group, FibroFrance-Obese group, Thierry Poynard, Mona Munteanu, Frederic Charlotte, Hugo Perazzo, Yen Ngo, Olivier Deckmyn, Raluca Pais, Philippe Mathurin, Vlad Ratziu, FLIP consortium, the FibroFrance-CPAM group, FibroFrance-Obese group

Abstract

Background and aim: One of the unmet needs in subjects with metabolic risks is the prediction of metabolic liver disease by noninvasive tests. The construction of performant tests is dependent on the appropriateness of the histological reference definition. The aim of this study was to analyze the limitations of similar European (Fatty Liver Inhibition of Progression) and USA (Clinical-Research-Network) standard definitions and their impact on the construction of tests.

Methods: We hypothesized that a simpler histological definition of non-alcoholo steato-hepatitis (NASH), which does not require the presence of steatosis and the presence of both lobular inflammation and ballooning, should improve the concordance rates with previously validated blood tests. We reviewed the landmark studies in metabolic liver disease, sources of the standard definitions, and we compared the adequacy of these standards to other possible definitions in 1081 subjects with biopsies, by concordance and accuracy rates.

Results: The limitations of standard definitions included the presence of appropriate controls in only 6.6% of landmark studies, an arbitrary definition of steatosis and NASH covering only four (15%) out of 27 possible combinations of features, compared with 18 (67%) for a simplified NASH definition, which did not require steatosis. A total of 39/1081 (3.6%) cases were not identified by standard definition, but were identified by the simplified definition as significant active disease, including 15 cases with significant fibrosis. The simplified definition increased the κ concordance (P<0.0001) between test prediction and histological reference.

Conclusion: A simplified definition of NASH could help in the construction of biomarkers with higher performances.

Trial registration: ClinicalTrials.gov NCT01927133.

Figures

Fig. 1
Fig. 1
Flow charts of methodology and the corresponding populations used in the analyses. The context of use population is cases at risk of metabolic liver disease (MLD), preferred to the acronym nonalcoholic fatty liver disease (NAFLD), as requirement of steatosis is not mandatory in the absence of other causes of liver disease. Steatosis could be absent because of sampling error or temporal variability. SAF referred to steatosis, activity and fibrosis elementary histological features. Scores referred to NASH Clinical Research Network (NASH-CRN) and fatty liver inhibition of progression (FLIP) scoring systems. NASHs referred to the proposed simplified histological definition of NASH, being at least a grade 2 in the SAF scoring system not requiring both ballooning and lobular inflammation, and not requiring presence of steatosis (1 or 5%), in the presence of metabolic risk factors and in the absence of all other causes of liver disease. NITs is the acronym of noninvasive tests.

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