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The SAF score has been prospectively designed by the FLIP Pathology Consortium and its use, in
association with the FLIP algorithm, increases agreement for the overall diagnosis between observers
[4]. It defines precisely, in a didactic and easy-to-understand form, the 3 main, cardinal histological
features (Steatosis, Activity and Fibrosis) (Table 3). Activity is a composite score adding hepatocellular
ballooning and lobular inflammation, two lesions that, in association, are supposed to sustain the
development of fibrosis (each being graded from 0 to 2). Furthermore, it serves as a backbone for the
diagnosis of NASH according to the FLIP algorithm. The SAF score has not yet been tested within
therapeutic trials.
Staging of fibrosis relies on the Kleiner fibrosis stage [5]. Unfortunately, this system under scores
perisinusoidal (pericellular) fibrosis within the lobule, which is a common pattern, particularly in
patients with diabetes (Fig. 1). Furthermore, it does not allow the distinction between biopsies with rare
or short septa from biopsies where septa are numerous (the contrary of what is done by distinguishing
F2 from F3 with the METAVIR score in chronic hepatitis). This is a significant limitation since there
is no clear-cut border to define what differentiates biopsies with significant fibrosis from those with
advanced fibrosis. Morphometry that assesses the amount of fibrous tissue quantitatively (or collagen
proportional area, CPA) might be a useful adjunct, as it is done in most clinical trials.
Figure 1. Typical pattern of NASH with clarification and ballooning of hepatocyte with
perisinusoidal fibrosis (Sirius Red stain, x 40).
A key issue is which histological features of NAFLD predict liver disease progression and liver-related
events or mortality,as these could be acceptable surrogates for therapeutic trials.Studies with large cohorts,
defined histologically by a central pathologist and with long follow-up for clinical events, are necessary
to answer this question. Such studies have shown that both the diagnosis of steatohepatitis and the stage
of fibrosis (bridging fibrosis or cirrhosis) predict liver-related mortality [8, 9]. Because steatohepatitis
most likely drives fibrogenesis, the demonstration of an independent effect of steatohepatitis from that
of fibrosis can be difficult to delineate statistically because of co-linearity between the two variables.
22 Postgraduate Course Syllabus • Metabolic Liver Disease
association with the FLIP algorithm, increases agreement for the overall diagnosis between observers
[4]. It defines precisely, in a didactic and easy-to-understand form, the 3 main, cardinal histological
features (Steatosis, Activity and Fibrosis) (Table 3). Activity is a composite score adding hepatocellular
ballooning and lobular inflammation, two lesions that, in association, are supposed to sustain the
development of fibrosis (each being graded from 0 to 2). Furthermore, it serves as a backbone for the
diagnosis of NASH according to the FLIP algorithm. The SAF score has not yet been tested within
therapeutic trials.
Staging of fibrosis relies on the Kleiner fibrosis stage [5]. Unfortunately, this system under scores
perisinusoidal (pericellular) fibrosis within the lobule, which is a common pattern, particularly in
patients with diabetes (Fig. 1). Furthermore, it does not allow the distinction between biopsies with rare
or short septa from biopsies where septa are numerous (the contrary of what is done by distinguishing
F2 from F3 with the METAVIR score in chronic hepatitis). This is a significant limitation since there
is no clear-cut border to define what differentiates biopsies with significant fibrosis from those with
advanced fibrosis. Morphometry that assesses the amount of fibrous tissue quantitatively (or collagen
proportional area, CPA) might be a useful adjunct, as it is done in most clinical trials.
Figure 1. Typical pattern of NASH with clarification and ballooning of hepatocyte with
perisinusoidal fibrosis (Sirius Red stain, x 40).
A key issue is which histological features of NAFLD predict liver disease progression and liver-related
events or mortality,as these could be acceptable surrogates for therapeutic trials.Studies with large cohorts,
defined histologically by a central pathologist and with long follow-up for clinical events, are necessary
to answer this question. Such studies have shown that both the diagnosis of steatohepatitis and the stage
of fibrosis (bridging fibrosis or cirrhosis) predict liver-related mortality [8, 9]. Because steatohepatitis
most likely drives fibrogenesis, the demonstration of an independent effect of steatohepatitis from that
of fibrosis can be difficult to delineate statistically because of co-linearity between the two variables.
22 Postgraduate Course Syllabus • Metabolic Liver Disease
