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patients had stage 0 or 1 fibrosis and 10% stage 2, 21% of the NASH patients had stage 2 fibrosis and
18% stage 3 and 4.This is consistent with the notion that the higher liver-related mortality in NASH vs.
steatosis observed in some, although not all, studies reflects the higher degree of fibrosis in the NASH
patients.
This analysis is supported by a more recent single centre study with 108 NAFLD patients undergoing
repeat liver biopsy at a median interval of 6.6 years (range 1.3-22.6 years) [7]. The mean annual rate
of fibrosis progression was 0.08 ± 0.25 stages. No difference in the proportion exhibiting fibrosis
progression was found between patients with steatosis or NASH at index biopsy (37% vs. 43%) although
all steatosis patients developing fibrosis had also developed NASH on follow-up biopsy. The NASH
patients had more fibrosis at baseline than the steatosis patients, as was the case in the studies included
in the meta-analysis. Interestingly, similar to an observation reported from a recent systematic review
[8], steatosis patients with mild inflammation were more likely to have fibrosis progression than those
with bland steatosis (60% vs. 24%, P=0.07). This finding was consistent with two of the four previous
studies to have examined it [2, 9]. What’s more, the bland steatosis patients who progressed had higher
steatosis scores than those who didn’t (2, range 2-3, vs. 1, range 1-2, respectively, P=0.01). Given these
two observations, steatosis patients developing fibrosis unsurprisingly had significantly higher baseline
NAS than those who did not progress (2.5, range 2-3, vs. 1, range 1-4, respectively, P=0.007).
Considering these studies together, it appears that fibrosis progression in NAFLD is generally slow,
taking around eight years to progress from stage 0 to stage 1 fibrosis, although, as in other liver diseases,
there is a subgroup of ‘rapid progressors’ who can progress 3-4 stages within 2-6 years. There appears
to be no great difference in the risk of progression according to the presence or absence of NASH on
baseline histology. Some evidence suggests that the lowest risk of progression is seen in patients with
mild/moderate steatosis in the absence of inflammation. Given the evidence of similar rates of fibrosis
progression in NASH and steatosis, it seems likely that the higher stages of fibrosis seen in patients
with NASH compared to those with steatosis reflect a longer disease duration. Supporting this is the
most recent study [7] where patients with NASH were nine years older than those with steatosis. In this
study, 44% of the steatosis patients developed NASH after a median eight years follow-up, suggesting
that NASH usually develops after steatosis. Age is a well-recognized risk factor for advanced fibrosis in
multiple cross-sectional studies. These data also suggest that mechanisms related to the development
of, or resulting from, the classical NASH lesions of ballooning degeneration and lobular inflammation
may not be that important for fibrogenesis in NAFLD, questioning the current focus of clinical trials on
resolving NASH rather than reducing fibrosis.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 95
18% stage 3 and 4.This is consistent with the notion that the higher liver-related mortality in NASH vs.
steatosis observed in some, although not all, studies reflects the higher degree of fibrosis in the NASH
patients.
This analysis is supported by a more recent single centre study with 108 NAFLD patients undergoing
repeat liver biopsy at a median interval of 6.6 years (range 1.3-22.6 years) [7]. The mean annual rate
of fibrosis progression was 0.08 ± 0.25 stages. No difference in the proportion exhibiting fibrosis
progression was found between patients with steatosis or NASH at index biopsy (37% vs. 43%) although
all steatosis patients developing fibrosis had also developed NASH on follow-up biopsy. The NASH
patients had more fibrosis at baseline than the steatosis patients, as was the case in the studies included
in the meta-analysis. Interestingly, similar to an observation reported from a recent systematic review
[8], steatosis patients with mild inflammation were more likely to have fibrosis progression than those
with bland steatosis (60% vs. 24%, P=0.07). This finding was consistent with two of the four previous
studies to have examined it [2, 9]. What’s more, the bland steatosis patients who progressed had higher
steatosis scores than those who didn’t (2, range 2-3, vs. 1, range 1-2, respectively, P=0.01). Given these
two observations, steatosis patients developing fibrosis unsurprisingly had significantly higher baseline
NAS than those who did not progress (2.5, range 2-3, vs. 1, range 1-4, respectively, P=0.007).
Considering these studies together, it appears that fibrosis progression in NAFLD is generally slow,
taking around eight years to progress from stage 0 to stage 1 fibrosis, although, as in other liver diseases,
there is a subgroup of ‘rapid progressors’ who can progress 3-4 stages within 2-6 years. There appears
to be no great difference in the risk of progression according to the presence or absence of NASH on
baseline histology. Some evidence suggests that the lowest risk of progression is seen in patients with
mild/moderate steatosis in the absence of inflammation. Given the evidence of similar rates of fibrosis
progression in NASH and steatosis, it seems likely that the higher stages of fibrosis seen in patients
with NASH compared to those with steatosis reflect a longer disease duration. Supporting this is the
most recent study [7] where patients with NASH were nine years older than those with steatosis. In this
study, 44% of the steatosis patients developed NASH after a median eight years follow-up, suggesting
that NASH usually develops after steatosis. Age is a well-recognized risk factor for advanced fibrosis in
multiple cross-sectional studies. These data also suggest that mechanisms related to the development
of, or resulting from, the classical NASH lesions of ballooning degeneration and lobular inflammation
may not be that important for fibrogenesis in NAFLD, questioning the current focus of clinical trials on
resolving NASH rather than reducing fibrosis.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 95
