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‘Metabolic NAFLD’ and the MetS share common pathophysiology
MetS and NAFLD share a common pathophysiology but also differ in many respects [2]. The liver is
the site of production of two of the key components of the MetS, fasting serum glucose and VLDL,
which contains most of the triglycerides present in serum. In subjects with NAFLD, the ability of
insulin to normally suppress production of glucose and VLDL is impaired resulting in hyperglycemia,
hyperinsulinemia and hypertriglyceridemia combined with low HDL cholesterol. The liver, once fatty,
also overproduces many other markers of cardiovascular risk, such as C-reactive protein, fibrinogen,
coagulation factors, and plasminogen activator inhibitor-1 [2] (Fig. 2).
Figure 2. NAFLD and T2DM.
‘Metabolic NAFLD’ may even be a better predictor of CVD as it measures more directly
abnormal metabolism than MetS
Increases in features of IR and markers of cardiovascular risk in NAFLD are associated with endothelial
vascular dysfunction and could, in part, explain why NAFLD predicts CVD, also when adjusted for
obesity [3]. On the other hand, some prospective studies have suggested that NAFLD may an even be a
better predictor of the risk of CVD than MetS [3]. Whether this is because the measurement of liver fat
content provides a more direct estimate of the risk of CVD than the MetS (diagnosed using ten different
combinations of its five components) [1] or other mechanisms is unclear.
Dissociation between steatosis and IR
In 2008, a genome-wide association study in Hispanic, African-American, and European-American
individuals showed genetic variation in PNPLA3 confers susceptibility to NAFLD. An allele in PNPLA3
(rs738409[G], encoding Ile148Met) was associated with increased liver fat, hepatic inflammation and
fibrosis. This finding has subsequently been reproduced. For example, in a meta-analysis comprising
16 studies, compared with non-carriers, homozygous carriers of the variant had a 73% higher liver
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 57
MetS and NAFLD share a common pathophysiology but also differ in many respects [2]. The liver is
the site of production of two of the key components of the MetS, fasting serum glucose and VLDL,
which contains most of the triglycerides present in serum. In subjects with NAFLD, the ability of
insulin to normally suppress production of glucose and VLDL is impaired resulting in hyperglycemia,
hyperinsulinemia and hypertriglyceridemia combined with low HDL cholesterol. The liver, once fatty,
also overproduces many other markers of cardiovascular risk, such as C-reactive protein, fibrinogen,
coagulation factors, and plasminogen activator inhibitor-1 [2] (Fig. 2).
Figure 2. NAFLD and T2DM.
‘Metabolic NAFLD’ may even be a better predictor of CVD as it measures more directly
abnormal metabolism than MetS
Increases in features of IR and markers of cardiovascular risk in NAFLD are associated with endothelial
vascular dysfunction and could, in part, explain why NAFLD predicts CVD, also when adjusted for
obesity [3]. On the other hand, some prospective studies have suggested that NAFLD may an even be a
better predictor of the risk of CVD than MetS [3]. Whether this is because the measurement of liver fat
content provides a more direct estimate of the risk of CVD than the MetS (diagnosed using ten different
combinations of its five components) [1] or other mechanisms is unclear.
Dissociation between steatosis and IR
In 2008, a genome-wide association study in Hispanic, African-American, and European-American
individuals showed genetic variation in PNPLA3 confers susceptibility to NAFLD. An allele in PNPLA3
(rs738409[G], encoding Ile148Met) was associated with increased liver fat, hepatic inflammation and
fibrosis. This finding has subsequently been reproduced. For example, in a meta-analysis comprising
16 studies, compared with non-carriers, homozygous carriers of the variant had a 73% higher liver
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 57
