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(‘bland steatosis’), or with only mild inflammation or cellular injury, have no increase in overall or liver-
related mortality compared with the age and gender matched general population. In contrast, patients
with NASH exhibit a higher overall and liver-related mortality [2].This is perhaps best explained by the
greater propensity of patients with NASH either to have or to develop cirrhosis compared to those with
simple steatosis. Therefore, in the long-term follow-up studies reported thus far, only 1% of patients
with simple steatosis developed cirrhosis and died a liver-related death after a mean 15.6 years follow-
up, compared with 11% of those with NASH having or developing cirrhosis, and 7.3% of those with
NASH dying from a liver related cause after a similar period of follow-up.
Given these data, it would seem likely that the presence and severity of fibrosis on a NAFLD liver biopsy
would be the most important histological determinant of long-term prognosis, with the difference
between the prognosis of NASH and simple steatosis being due to the greater likelihood of fibrosis
being present in patients with NASH compared to steatosis, rather than any adverse effect of NASH,
per se, on prognosis. This concept is supported by a number of recent studies. A Swedish study of 118
patients with biopsy-confirmed NAFLD, followed for a median of 21 years [3], reported no difference
in overall or liver-related mortality between those with definitive NASH and non-NASH (classified
with the NASH CRN scoring system). In contrast, patients who died had a higher incidence of any
stage of fibrosis (89%) compared with survivors (70%, P<0.02) and a greater incidence of fibrosis stage
>2 (68% vs. 28%, P<0.001). A more recent study of 209 NAFLD patients with a median 12 years of
follow-up showed the presence of NASH only correlated with liver mortality when fibrosis was included
in its definition. Furthermore, when the individual histological features of NASH were analysed, only
grade 3 portal fibrosis (which would include all patients with bridging fibrosis and cirrhosis) was
independently associated with liver related mortality (HR 5.68, 95% CI 1.5-21.5) [4]. Further evidence
of the prognostic significance of fibrosis comes from recent studies demonstrating that non-invasive
scoring systems correlating with the degree of fibrosis are capable of predicting liver-related events,
transplantation and death in patients with NAFLD [5].
Accepting that the presence and severity of fibrosis is the key factor determining long-term, liver-related
mortality, the key question is which patients with NAFLD are most at risk of developing progressive
fibrosis so they can be identified and managed appropriately? This is distinct from identifying those
likely to have fibrosis at presentation, which is covered elsewhere, and starts with the premise that a
histological diagnosis of NAFLD has already been made.
Histological predictors of fibrosis progression in patients with NAFLD
The best way to determine the risk of fibrosis progression in patients with biopsy-proven NAFLD is
to perform repeat liver biopsies ideally after a long period of follow-up in the absence of treatment.
These studies have recently been subjected to systematic review and meta-analysis [6]. This analysis
identified 11 cohort studies including 411 patients with biopsy-proven NAFLD (150 with steatosis
and 261 with NASH). Over 2,145.5 person-years of follow-up, 33.6% had fibrosis progression, 43.1%
had stable fibrosis, and 22.3% had an improvement in fibrosis stage. The annual fibrosis progression
rate in patients with steatosis who had stage 0 fibrosis at baseline was 0.07 stages (95% CI 0.02–0.11
stages), compared with 0.14 stages in patients with NASH who had stage 0 fibrosis at baseline (95%
CI 0.07–0.21 stages).These findings correspond to one stage of progression over 14.3 years for patients
with NAFL (95% CI 9.1–50.0 y) and 7.1 years for patients with NASH (95% CI 4.8–14.3 y) (Figs.
1A and 1B). When patients with stages 0 and 1 fibrosis were grouped together there was no difference
between the annual progression rates in NAFL vs. NASH patients (0.09 stages, 95% CI 0.04–0.14, vs.
0.10 stages, 95% CI 0.03–0.17, respectively).
Interestingly, the proportion of fibrosis progressors who progressed from stage 0 to stage 3 or 4 fibrosis
(‘rapid progressors’) was identical in the two histological sub-groups (17% of steatosis patients and
18% of NASH patients). Moreover, there was no association between the severity of necroinflammation
and risk of progressive fibrosis in the four studies that examined it. The fibrosis progression rate did not
appear to depend on the initial stage of fibrosis. Importantly, in these studies, while 90% of the steatosis
94 Postgraduate Course Syllabus • Metabolic Liver Disease
related mortality compared with the age and gender matched general population. In contrast, patients
with NASH exhibit a higher overall and liver-related mortality [2].This is perhaps best explained by the
greater propensity of patients with NASH either to have or to develop cirrhosis compared to those with
simple steatosis. Therefore, in the long-term follow-up studies reported thus far, only 1% of patients
with simple steatosis developed cirrhosis and died a liver-related death after a mean 15.6 years follow-
up, compared with 11% of those with NASH having or developing cirrhosis, and 7.3% of those with
NASH dying from a liver related cause after a similar period of follow-up.
Given these data, it would seem likely that the presence and severity of fibrosis on a NAFLD liver biopsy
would be the most important histological determinant of long-term prognosis, with the difference
between the prognosis of NASH and simple steatosis being due to the greater likelihood of fibrosis
being present in patients with NASH compared to steatosis, rather than any adverse effect of NASH,
per se, on prognosis. This concept is supported by a number of recent studies. A Swedish study of 118
patients with biopsy-confirmed NAFLD, followed for a median of 21 years [3], reported no difference
in overall or liver-related mortality between those with definitive NASH and non-NASH (classified
with the NASH CRN scoring system). In contrast, patients who died had a higher incidence of any
stage of fibrosis (89%) compared with survivors (70%, P<0.02) and a greater incidence of fibrosis stage
>2 (68% vs. 28%, P<0.001). A more recent study of 209 NAFLD patients with a median 12 years of
follow-up showed the presence of NASH only correlated with liver mortality when fibrosis was included
in its definition. Furthermore, when the individual histological features of NASH were analysed, only
grade 3 portal fibrosis (which would include all patients with bridging fibrosis and cirrhosis) was
independently associated with liver related mortality (HR 5.68, 95% CI 1.5-21.5) [4]. Further evidence
of the prognostic significance of fibrosis comes from recent studies demonstrating that non-invasive
scoring systems correlating with the degree of fibrosis are capable of predicting liver-related events,
transplantation and death in patients with NAFLD [5].
Accepting that the presence and severity of fibrosis is the key factor determining long-term, liver-related
mortality, the key question is which patients with NAFLD are most at risk of developing progressive
fibrosis so they can be identified and managed appropriately? This is distinct from identifying those
likely to have fibrosis at presentation, which is covered elsewhere, and starts with the premise that a
histological diagnosis of NAFLD has already been made.
Histological predictors of fibrosis progression in patients with NAFLD
The best way to determine the risk of fibrosis progression in patients with biopsy-proven NAFLD is
to perform repeat liver biopsies ideally after a long period of follow-up in the absence of treatment.
These studies have recently been subjected to systematic review and meta-analysis [6]. This analysis
identified 11 cohort studies including 411 patients with biopsy-proven NAFLD (150 with steatosis
and 261 with NASH). Over 2,145.5 person-years of follow-up, 33.6% had fibrosis progression, 43.1%
had stable fibrosis, and 22.3% had an improvement in fibrosis stage. The annual fibrosis progression
rate in patients with steatosis who had stage 0 fibrosis at baseline was 0.07 stages (95% CI 0.02–0.11
stages), compared with 0.14 stages in patients with NASH who had stage 0 fibrosis at baseline (95%
CI 0.07–0.21 stages).These findings correspond to one stage of progression over 14.3 years for patients
with NAFL (95% CI 9.1–50.0 y) and 7.1 years for patients with NASH (95% CI 4.8–14.3 y) (Figs.
1A and 1B). When patients with stages 0 and 1 fibrosis were grouped together there was no difference
between the annual progression rates in NAFL vs. NASH patients (0.09 stages, 95% CI 0.04–0.14, vs.
0.10 stages, 95% CI 0.03–0.17, respectively).
Interestingly, the proportion of fibrosis progressors who progressed from stage 0 to stage 3 or 4 fibrosis
(‘rapid progressors’) was identical in the two histological sub-groups (17% of steatosis patients and
18% of NASH patients). Moreover, there was no association between the severity of necroinflammation
and risk of progressive fibrosis in the four studies that examined it. The fibrosis progression rate did not
appear to depend on the initial stage of fibrosis. Importantly, in these studies, while 90% of the steatosis
94 Postgraduate Course Syllabus • Metabolic Liver Disease
