Association of coffee consumption, sleeping and smoking status
with CAP and LSM
Coffee consumption was associated
with lower CAP in all of the multivariate models (CAP unadjusted and
model 1,2 and 3), with largest effect in most frequent coffee consumers
(≥3, model 3). Also, most frequent coffee consumers were associated with
lower LSM in unadjusted model, model 1 and 2, while this was not the
case for model 3 and those who consumed 1-2 cups of coffee per day.
Reduced sleeping was confirmed as
risk factor for elevated CAP in most of the models (unadjusted and model
1 and 2). Also, negative association of LSM was also confirmed in
unadjusted model and model 2. Patients which slept 6-8 hours per day
were mostly associated with lower CAP and LSM. Smoking did not affect
CAP or LSM values.
DISCUSSION
Nowadays, we know that T2DM, obesity, hypertension, and dyslipidemia as
the MetS components are the main risk factors for NAFLD. On the other
hand, NAFLD development is also influenced by multiple features, such as
demographic, genetic, and environmental determinants (23). Therefore,
the investigation of the possible influence of other putative factors is
becoming in interest of clinicians who manage NAFLD patients. To the
best of our knowledge, there are limited data about the association
among coffee consumption and sleep duration with elastographic
parameters of liver steatosis and fibrosis; CAP and LSM in population of
patients with NAFLD. In this large cohort of NAFLD patients we have
investigated the association between coffee consumption, sleep duration
and smoking status with the CAP and LSM as a surrogate marker of
steatosis and fibrosis.
According to the epidemiological study by Nordestgaard AT, et al (24)
that had included 93.179 individuals, high coffee intake was associated
with lower risk of T2DM, obesity and MetS. Similar data were reported by
the meta-analysis from 2016. that had analyzed 11 reports including 13
studies with a total of 159.805 participants. Coffee consumption was
associated with a low risk of MetS (25). Furthermore, Xie C, et al (26)
in their meta-analysis that was published two years ago had reported
that consumption of coffee was inversely associated with the risk of
hypertension in a dose-response manner. In the line with this data, in
our study frequent coffee consumers (3≥caps per day) had the lowest
incidence of all MetS components; dyslipidemia, obesity, T2DM and
hypertension. Interestingly, female patients consumed coffee more
frequent. In multivariate analysis moderate and frequent coffee
consumption showed significant negative association with obesity, and
this effect was and more pronounced for frequent coffee consumption.
Additionally, earlier data have been reported that coffee consumption
has been associated with lower liver enzyme levels; ALT, GGT, AST. A
first report about the beneficial effect of coffee consumption on GGT
was published in 1986 (27). Until then, many authors have demonstrated a
similar effect on AST, ALT as well as GGT levels (28-31). Accordingly,
based on our results, all three liver enzymes (AST, ALT, GGT) were the
lowest in the subgroup of frequent coffee consumers. In multivariate
analysis, moderate coffee consumption did not to have a significant
effect on liver enzymes, while frequent coffee consumption was
significant predictor of lower ALT and GGT. These results suggest that
the beneficial effect of coffee consumption on liver enzymes is dose
dependent. Regarding the earlier data about beneficial effect of coffee
consumption on MetS and its individual components and regarding the fact
that NAFLD is strongly associated with MetS it is not surprising that
many authors had also showed beneficial effect of coffee in the context
of NAFLD. For example, study by Birerdinc A, et al (32) has shown that
caffeine intake is independently associated with a lower risk for NAFLD.
In this study NAFLD was defined by elevated serum aminotransferases.
Similar results were reported by the study that was published 10 years
ago and, in this study, NAFLD was detected based on the US (33). More
convincing data about this association comes from the Molloy JW, et al
(34). However, in their study NAFLD was defined by liver biopsy. In
Rotterdam study from 2017, liver steatosis was defined by US while
fibrosis was defined by LSM (35). According to their results, frequent
coffee consumption was inversely related with liver stiffness but not
steatosis (35). On the contrary, Veronese N, et al (6) reported that the
consumption of coffee or an increased consumption of coffee were not
associated with the presence of mild, moderate or severe liver steatosis
in NAFD patients in a large study of 2819 participants from the
Mediterranean Area. NAFLD was defined by the US. Hodge A, et al (36)
have investigated the association between coffee intake and liver
stiffness in patients with NAFLD (n=155), hepatitis B (n=485) and C
(n=378). They have found that LSM was lower in those patients who drank
2 or more cups of coffee per day (36). Only in 105 NAFLD patients a CAP
measurement was performed (36). Authors did not find any correlation
between the coffee consumption and CAP values (36). According to our
best knowledge, this is only study that was investigated the influence
of coffee consumption in relation to the CAP measurements. In our study
we had performed LSM and CAP measurements in relatively large population
of NAFLD patients. According to our results, coffee non-consumers had
highest values of CAP and LSM. Moreover, in multivariate analysis,
moderate and frequent coffee consumption showed a significant negative
effect on CAP values, but none on the LSM measurements. The more
convincing data in our study come from the results that coffee
consumption was associated with lower CAP in all of the multivariate
models, with largest effect in most frequent coffee consumers (≥3, model
3). Also, most frequent coffee consumers were associated with lower LSM
in most of the models while this was not the case for those who consumed
1-2 cups of coffee per day. These results are in the line with some
clinical studies and some pre-clinical study. According to the
preclinical studies, caffeine has a few beneficial effects in the
context of NAFLD. Firstly, caffeine has antioxidant properties.
Secondly, it seems to be able to promote the blockade of transforming
growth factor β expression and of its downstream inductor connective
tissue growth factor. Thirdly, caffeine can inhibit hepatic stellate
cells and subsequently counteracted fibrogenesis and finally as it was
mentioned earlier it has beneficial effect on MetS development which is
closely related to NAFLD. Furthermore, coffee contain and polyphenols.
It has been suggested that polyphenols have hepatoprotective effects
independent of caffeine. Preclinical studies showed that
coffee-polyphenols attenuate obesity-related lipid accumulation in the
liver additionally with their antioxidant properties
(6,35,31,37,38,39,40).
In the second part of our study we had investigated the association
among sleep duration and CAP and LSM values. Patients who slept 6-8
hours per day had lowest values of CAP and LSM, while those who slept
< 6 hours per day had the highest values of CAP, and those
with > 8 hours highest LSM values. In multivariate
analysis, sleeping duration less than 6 hours per day was associated
with higher CAP values. Reduced sleeping was confirmed as risk factor
for elevated CAP in most of the models, while it has been show that
short sleep duration could have beneficial effect in the context of LSM,
in unadjusted model and model adjusted for age, gender and BMI. This
effect is weak, and moreover, there are still several sleeping factors
that could be taken into to achieve unbiased results such as sleep
disturbance, efficiency, quality etc. Further studies are needed
regarding sleeping factors and LSM. Additionally, patients which slept
6-8 hours per day were mostly associated with lower CAP and LSM values
independent of a variety of relevant confounders including age, gender,
BMI. We can explain these findings by some earlier data. Obesity, T2DM
and insulin resistance, all of which are of importance in the
development of NAFLD were more frequent in those who slept less than 6
hours per day, and their incidence was the lowest in those who slept 6-8
hours per day. In multivariate analysis, those who slept 6-8 hours per
day had significantly lower incidence of T2DM. Interestingly, patients
who slept 6-8 hours per day had the highest values of vitamin D, and we
know that vitamin D is also involved in pathogenesis of NAFLD. In
multivariate analysis vitamin D was positively associated with sleeping
duration of 6-8 hours per day and with sleep duration of less than 6
hours per day, although this effect was low, thus further studies
regarding the association among vitamin D and sleeping duration,
especially in the context of NAFLD are needing. According to other
studies, patients with a short sleep duration have higher levels of
tumor necrosis factor-alpha and interleukin-6, an inflammatory cytokine
that are involved in the pathogenesis of NAFLD (11,41,42). Sleep
deprivation could influence the hypothalamo-pituitary-adrenal axis
activity. That is important because some data showed that this could
cause subclinical hypercortisolism and exacerbate NAFLD. Also, it has
been showed that lifestyle is associated with sleep duration and earlier
data reported that participants with a short sleep duration had dinner
at late-night which was a risk of hyperglycemia or obesity. It is
believed that short sleep duration is a risk factor for T2DM, obesity,
insulin resistance and MetS development, that are all risk factors for
NAFLD development (11,43,44,45). Taking together all this data, short
sleep duration could be a risk factor for NAFLD development. Our results
are in line with some other clinical studies. For example, Okamura T, et
al (11) had showed that short sleep duration was a risk factor for
incident NAFLD. Similar results were reported by Peng K, et al (46). In
their study, short sleep duration and longer daytime napping were
associated with an increased risk of prevalent NAFLD. In both studies
NAFLD was diagnosed with US. However, abdominal US is good method for
those NAFLD patients who have a percentage of liver steatosis of more
than 30%. It is known that US has a low sensitivity for the detection
of mild steatosis and is more operator dependent. In contrast to US, TE
with CAP can detect a mild steatosis when approximately 10% of
hepatocytes have fatty infiltration. Thus, studies using US are more
likely to underestimate the true prevalence of NAFLD (19,47). According
to our best knowledge, there are no studies that were using CAP for
steatosis detection in relation to the sleep duration. In the study by
Marin-Alejandre BA, et al (15) NAFLD was diagnosed by transaminases and
liver stiffness was determined by Acoustic Radiation Force Impulse
elastography (ARFI). In this study, the authors had found the
association of sleep characteristics with the development and
progression of NAFLD (15). In our study we did not analyzed other sleep
characteristics such as sleep disturbance, sleep efficiency and sleep
quality, thus further studies should analyze more comprehensively the
association between sleep characteristics and NAFLD are needed.
Finally, the relationship between smoking status and NAFLD remains
controversial. Recent study had reported that current smoking,
pack-years, and urinary cotinine levels were associated with the risk of
incident NAFLD (48). Ou H,et al (49) analyzed 225 NAFLD patients. NAFLD
was diagnosed by TE. Authors showed that smoking was associated with
liver fibrosis (defined by LSM) among the patients with NAFLD. The
sample size of this study is relatively small. In our study with a
relatively large population of patients with TE defined NAFLD we did not
find any association among smoking status and CAP and LSM values as a
surrogate marker of steatosis and fibrosis. Further studies are
warranted.
This study has some limitations. Firstly, NAFLD was defined by TE with
CAP, and we did not use liver biopsy for detection of it. Although liver
biopsy is the gold standard for NAFLD diagnosis, CAP and LSM are the
best validated noninvasive marker for steatosis and fibrosis detection.
And according to recent study, CAP and LSM have good correlation with
liver histology (50). Secondly, this was a prospective, cross-sectional
study, therefore, we are not able to draw conclusions regarding the
cause-effect relationship of coffee consumption, sleep duration and
smoking status in relation to the CAP and LSM. Thirdly, in our study we
investigated the sleep duration and we did not analyzed other sleep
characteristics such as sleep disturbance, sleep efficiency and sleep
quality, thus further studies should analyze more comprehensively the
association between sleep characteristics and CAP and LSM are needed.
Thirdly, short sleep duration is possible associated with increased
energy intake which is a risk factor for NAFLD. In this study, we did
not have the information’s regarding the dietary intake and thus we did
not investigate the association between sleep duration and dietary
intake.
However, the current study has the strength of a relatively large sample
size and the use of one of the best non-invasive methods for liver
steatosis and fibrosis detection and quantification. According to our
best knowledge, there are limited data about the association of coffee
consumption and sleep duration in relation to the CAP and LSM.
We have shown that coffee
consumption has beneficial effect on CAP and LSM and that effect is dose
dependent since the positive effect of coffee consumption was the most
pronounced in the frequent users. This effect was independent of a
variety of relevant confounders. Additionally, we have shown that
optimal sleep duration (6-8 hours per day) has also beneficial effect on
CAP and LSM. Since sleep insufficiency is a common problem today and
since coffee is a widely accessible and relatively low-cost beverage,
present study can have considerable public health implications for the
relationships between lifestyle factors and NAFLD epidemic. This is
important regarding the fact that as our population ages, the prevalence
of NAFLD will increase and due to growing epidemic of obesity, T2DM and
MetS. Because of absence of prospective data, we can only conclude that
there is positive association between better liver health and coffee
consuming as well as between better liver health and sleep duration
between 6-8 hours. Otherwise speaking, more prospective studies needs to
be done before we can conclude that coffee consuming, and sleep duration
are responsible for prevention and better outcome in patients with
NAFLD.
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Table 1. Demographic and laboratory characteristics of study subjects by
coffee consumption, sleeping hours and smoking status