Page 62 - EASL POSTGRADUATE COURSE
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function. It also stimulates circulating angiogenic cells.
Inflammatory mediators can also contribute to the increased risk of CVD. NASH is associated with an
increased intrahepatic production of pro-inflammatory cytokines, which are also increased systemically.
Although all these mechanisms are plausible links between the liver affected by NAFLD and the
development of CVD, no studies to date have scientifically proven a cause-effect relationship. Most
probably, several mechanisms are concomitantly present, and might substantially differ between patients.
Further study is therefore needed to gain mechanistic insights into the pathophysiology of the NAFLD-
CVD axis, with an individualized preventive and therapeutic approach as the ultimate goal.
NAFLD and CVD: NAFL or NASH?
The question of whether the role of NAFLD in the development of CVD is confined to NASH or is
already present in NAFL is important. Only about 5-10% of NAFLD patients have NASH, so if the risk
would be confined to NASH, this would substantially reduce the CVD burden attributable to NAFLD.
This might be in contrast with the current data on the impact of NAFLD on CVD, which does not seem
to fit with the relatively small number of NASH patients within the NAFLD group. The answer to this
question has potential implications for the management of NAFLD patients. Indeed, if NAFL as well
as NASH is associated with an increased risk of CVD, one might argue that NAFLD should be treated
regardless of the presence of NASH. In this scenario, NAFL could no longer be considered as a benign
condition and guidelines for the treatment of NAFLD might have to consider the treatment of NAFL,
with CVD prevention as an indication.
The question, however, remains largely unanswered. The main reason is that most of the data comes
from studies where no distinction is made between NAFL and NASH [2, 3]. This distinction still
requires a biopsy. Series that include histology have smaller patient numbers and there is a potential to
over-represent those patients with more severe liver disease. Furthermore, most of these studies have
rather short mean follow-up times and methodological limitations hamper the general applicability of
their results.
Nevertheless, biochemical and histological data give an indication that the risk is confined to NASH, or
is at least higher in NASH patients compared to NAFL (Table 1). Matteoni et al. reported differences in
liver-related mortality but not all-cause or other cause mortality according to the histological subtype of
NAFLD [5]. Dam-Larsen et al. did not detect differences in mortality when comparing histologically-
proven patients with NAFL compared to the general population [6]. More recent studies, however,
consistently show CVD as more prevalent in NAFLD patients, with three out of four studies confining
this risk to patients with NASH [7-10].
Although these most recent data suggest that the risk is mainly associated with NASH, or is at least more
pronounced in patients with NASH compared to NAFLD, further methodologically stringent studies
with long follow-up are needed to answer this question.
Treatment of NAFLD: impact on CVD?
Currently there is no approved pharmacological treatment for NAFLD. Although it can be hypothesized
that improving NAFLD reduces the risk of CVD, there is currently limited data on potential changes
in the risk of CVD in relation to the success of NAFLD treatment. Interestingly, two recent studies on
the effects of statins on CV events demonstrated a significantly reduced CV event rate in those patients
with baseline elevation of liver tests (used as a surrogate marker for the presence of NAFLD) as well
as significantly improved liver tests in one of the studies [11, 12]. The cardio-protective effect of statins
was less pronounced in patients with normal liver tests at baseline. Glitazones also improve CV risk, but
it is unclear to what extent this can be attributed to their beneficial effect on NAFLD. Furthermore,
as outlined previously, it is not clear whether the risk of CVD is increased in all subtypes of NAFLD.
Therefore, no evidence-based recommendations can be formulated at present.
62 Postgraduate Course Syllabus • Metabolic Liver Disease
Inflammatory mediators can also contribute to the increased risk of CVD. NASH is associated with an
increased intrahepatic production of pro-inflammatory cytokines, which are also increased systemically.
Although all these mechanisms are plausible links between the liver affected by NAFLD and the
development of CVD, no studies to date have scientifically proven a cause-effect relationship. Most
probably, several mechanisms are concomitantly present, and might substantially differ between patients.
Further study is therefore needed to gain mechanistic insights into the pathophysiology of the NAFLD-
CVD axis, with an individualized preventive and therapeutic approach as the ultimate goal.
NAFLD and CVD: NAFL or NASH?
The question of whether the role of NAFLD in the development of CVD is confined to NASH or is
already present in NAFL is important. Only about 5-10% of NAFLD patients have NASH, so if the risk
would be confined to NASH, this would substantially reduce the CVD burden attributable to NAFLD.
This might be in contrast with the current data on the impact of NAFLD on CVD, which does not seem
to fit with the relatively small number of NASH patients within the NAFLD group. The answer to this
question has potential implications for the management of NAFLD patients. Indeed, if NAFL as well
as NASH is associated with an increased risk of CVD, one might argue that NAFLD should be treated
regardless of the presence of NASH. In this scenario, NAFL could no longer be considered as a benign
condition and guidelines for the treatment of NAFLD might have to consider the treatment of NAFL,
with CVD prevention as an indication.
The question, however, remains largely unanswered. The main reason is that most of the data comes
from studies where no distinction is made between NAFL and NASH [2, 3]. This distinction still
requires a biopsy. Series that include histology have smaller patient numbers and there is a potential to
over-represent those patients with more severe liver disease. Furthermore, most of these studies have
rather short mean follow-up times and methodological limitations hamper the general applicability of
their results.
Nevertheless, biochemical and histological data give an indication that the risk is confined to NASH, or
is at least higher in NASH patients compared to NAFL (Table 1). Matteoni et al. reported differences in
liver-related mortality but not all-cause or other cause mortality according to the histological subtype of
NAFLD [5]. Dam-Larsen et al. did not detect differences in mortality when comparing histologically-
proven patients with NAFL compared to the general population [6]. More recent studies, however,
consistently show CVD as more prevalent in NAFLD patients, with three out of four studies confining
this risk to patients with NASH [7-10].
Although these most recent data suggest that the risk is mainly associated with NASH, or is at least more
pronounced in patients with NASH compared to NAFLD, further methodologically stringent studies
with long follow-up are needed to answer this question.
Treatment of NAFLD: impact on CVD?
Currently there is no approved pharmacological treatment for NAFLD. Although it can be hypothesized
that improving NAFLD reduces the risk of CVD, there is currently limited data on potential changes
in the risk of CVD in relation to the success of NAFLD treatment. Interestingly, two recent studies on
the effects of statins on CV events demonstrated a significantly reduced CV event rate in those patients
with baseline elevation of liver tests (used as a surrogate marker for the presence of NAFLD) as well
as significantly improved liver tests in one of the studies [11, 12]. The cardio-protective effect of statins
was less pronounced in patients with normal liver tests at baseline. Glitazones also improve CV risk, but
it is unclear to what extent this can be attributed to their beneficial effect on NAFLD. Furthermore,
as outlined previously, it is not clear whether the risk of CVD is increased in all subtypes of NAFLD.
Therefore, no evidence-based recommendations can be formulated at present.
62 Postgraduate Course Syllabus • Metabolic Liver Disease
