Page 68 - EASL POSTGRADUATE COURSE
P. 68
each other. A current model for the pathogenesis of NASH is centred on lipotoxicity [3], and states that
the influx of fatty acids and their derivatives through the liver induces apoptosis, oxidative stress, ER
stress, activation of proinflammatory pathways and ultimately liver cell injury (Fig. 1).The main source
of free fatty acids reaching the liver is an uncontrolled release from insulin-resistant adipose tissue.
Therefore, correcting IR, in particular at the adipose level, is a relevant aim and most therapeutic trials
have focused on insulin sensitizers.
Metformin
Metformin is an oral biguanide approved for use in T2DM where it acts as an insulin-sensitizing agent
with reduction of hepatic glucose production and increased peripheral glucose utilization [4]. Signalling
is via AMP-activated protein kinase. The biguanides alter cellular bioenergetics without inducing
weight gain. While initial pre-clinical (genetic models of hyper-feeding) and clinical data suggested that
metformin might be an ideal treatment for NAFLD that reduces liver steatosis, inflammatory mediators
and hepatic inflammation [5], subsequent small studies provided inconsistent results. In a small,
randomized, 6-month trial, metformin improved glucose and lipid parameters but not hepatic histology
and aminotransferases [6]. The benefit of metformin in NASH, if any, seems to be related primarily to
the weight loss induced by the drug in a fraction of treated patients. The inefficacy of metformin could
be explained by its very weak antisteatogenic effect and the lack of induction of circulating adiponectin
compared to glitazones, although this has only been tested with medium term exposure (4 months) and
not longer-term [7]. Although metformin is a safe antidiabetic drug, it is not recommended for treating
NASH, as no effect on liver histology has been demonstrated. Recent data has emerged showing that
metformin inhibits hepatocyte proliferation and induces cell-cycle arrest in hepatoma cell lines and also
inhibits chemically-induced liver tumorigenesis in vivo. It was inferred from these observations that
metformin might decrease the risk of HCC; unfortunately, the data available so far are retrospective,
and the analyses do not take into account important confounders related to treatment assignment bias.
No firm conclusion can be drawn regarding a putative protective effect of metformin against NASH-
associated carcinogenesis.
Figure 1.The lipotoxicity model of NASH. Reproduced from Neuschwander-Tetri [3] with permission.
68 Postgraduate Course Syllabus • Metabolic Liver Disease
the influx of fatty acids and their derivatives through the liver induces apoptosis, oxidative stress, ER
stress, activation of proinflammatory pathways and ultimately liver cell injury (Fig. 1).The main source
of free fatty acids reaching the liver is an uncontrolled release from insulin-resistant adipose tissue.
Therefore, correcting IR, in particular at the adipose level, is a relevant aim and most therapeutic trials
have focused on insulin sensitizers.
Metformin
Metformin is an oral biguanide approved for use in T2DM where it acts as an insulin-sensitizing agent
with reduction of hepatic glucose production and increased peripheral glucose utilization [4]. Signalling
is via AMP-activated protein kinase. The biguanides alter cellular bioenergetics without inducing
weight gain. While initial pre-clinical (genetic models of hyper-feeding) and clinical data suggested that
metformin might be an ideal treatment for NAFLD that reduces liver steatosis, inflammatory mediators
and hepatic inflammation [5], subsequent small studies provided inconsistent results. In a small,
randomized, 6-month trial, metformin improved glucose and lipid parameters but not hepatic histology
and aminotransferases [6]. The benefit of metformin in NASH, if any, seems to be related primarily to
the weight loss induced by the drug in a fraction of treated patients. The inefficacy of metformin could
be explained by its very weak antisteatogenic effect and the lack of induction of circulating adiponectin
compared to glitazones, although this has only been tested with medium term exposure (4 months) and
not longer-term [7]. Although metformin is a safe antidiabetic drug, it is not recommended for treating
NASH, as no effect on liver histology has been demonstrated. Recent data has emerged showing that
metformin inhibits hepatocyte proliferation and induces cell-cycle arrest in hepatoma cell lines and also
inhibits chemically-induced liver tumorigenesis in vivo. It was inferred from these observations that
metformin might decrease the risk of HCC; unfortunately, the data available so far are retrospective,
and the analyses do not take into account important confounders related to treatment assignment bias.
No firm conclusion can be drawn regarding a putative protective effect of metformin against NASH-
associated carcinogenesis.
Figure 1.The lipotoxicity model of NASH. Reproduced from Neuschwander-Tetri [3] with permission.
68 Postgraduate Course Syllabus • Metabolic Liver Disease
