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