European Journal of Clinical Nutrition (2015), 1–5 © 2015 Macmillan Publishers Limited All rights reserved 0954-3007/15 www.nature.com/ejcn
ORIGINAL ARTICLE
Coffee but not green tea consumption is associated with prevalence and severity of hepatic steatosis: the impact on leptin level T Imatoh1, S Kamimura2 and M Miyazaki3 BACKGROUND/OBJECTIVES: Most of the studies that have investigated the association between coffee consumption and hepatic steatosis have been experimental and small-scale clinical studies. As a result, epidemiological studies are scarce. To clear the association, we conducted a cross-sectional study and investigated the effects of coffee consumption with those of green tea consumption. SUBJECTS/METHODS: We analyzed 1024 Japanese male workers. The diagnosis of hepatic steatosis was based on ultrasonography. We divided coffee and green tea consumption into the following three categories: non-drinker; 1–2 cups/day and ⩾ 3 cups/day. To investigate the association between hepatic steatosis and coffee or green tea consumption, we calculated the odds ratio (OR) and adjusted the means of leptin levels on each severity of hepatic steatosis. RESULTS: A total of 265 of our subjects (25.9%) were diagnosed with hepatic steatosis. The ORs of the group of subjects who drank 43 cups of coffee/day was significantly lower compared with that of the noncoffee drinker group (OR 0.59, 95% confidence intervals 0.38–0.90, P = 0.03). Although there was a significant difference between coffee consumption and leptin level only in the asymptomatic group, we found a decreasing trend in the asymptomatic and moderate–severe hepatic steatosis group. We did not find the same relationships in green tea consumption. CONCLUSIONS: Although we did not find an association between hepatic steatosis and green tea consumption, coffee may have beneficial effects on hepatic steatosis. In addition, we produced one possible hypothesis that coffee consumption negatively associates with leptin levels in hepatic steatosis. European Journal of Clinical Nutrition advance online publication, 25 March 2015; doi:10.1038/ejcn.2015.23
INTRODUCTION Coffee is one of the most widely consumed beverages in the world. Various potential health effects of coffee have been reported. Habitual coffee consumption is associated with a substantially lower risk of type 2 diabetes mellitus. Recently, a large prospective study showed that coffee consumption was inversely associated with total and cause-specific mortality.1 Nevertheless, the majority of studies that have investigated the association between coffee consumption and hepatic steatosis have been experimental small-scale clinical studies. Epidemiological data on the association between coffee consumption and hepatic steatosis are sparse. Gutiérrez-Grobe et al.2 performed a case-control study and indicated that a high intake of coffee has a protective effect against nonalcoholic fatty liver disease (NAFLD). Molloy et al.3 have reported that coffee caffeine consumption is associated with a significant reduction in the risk for fibrosis among nonalcoholic steatohepatitis (NASH) patients. Although several studies have reported that regular coffee intake has beneficial effects on various liver diseases, it is not clear which component of coffee is responsible for these effects. The biological mechanism responsible for this beneficial effect of coffee remains largely unknown. Green tea is also one of the world’s most popular beverages and has been shown to possess anticancer, antiobesity and antiviral
properties.4 Many studies have reported that green tea extract has a protective effect against many diseases, such as type 2 diabetes mellitus,5 cardiovascular disease6 and some kinds of cancer.7 Recently, it has been demonstrated that green tea cathechins have a beneficial effect on liver disease.8,9 As in the case of coffee, most published studies are experimental. There have been no epidemiological studies that have investigated the association between green tea consumption and hepatic steatosis. NAFLD, including hepatic steatosis, is a major cause of liver disease worldwide. Recently, NAFLD was found to be associated with the metabolic syndrome and could evolve into NASH. NASH is a serious risk factor for disabling and deadly liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanism underlying the progress of NAFLD is not completely understood. Transformation from NAFLD to NASH could have been thought to be based on the so-called ‘two-hit hypothesis’.10 Nowadays, this hypothesis is being modified by the ‘multiple parallel hits’ hypothesis. Many hits such as lipotoxicity, adipocytokine and so on may act.11 Obesity-related cytokines such as adipocytokine and tumor necrosis factor-α influence the inflammatory state in obesity. Leptin is an adipocytokine and considered to be a mediator of inflammation.12 Some findings were reported to associate with inflammation and oxidative stress in liver disease. Therefore, leptin
1 Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; 2Division of Preventive Medicine, Department of Internal Medicine, Tenjin Clinic, Fukuoka, Japan and 3Saitama City Institute of Health Science and Research, Saitama, Japan. Correspondence: Dr T Imatoh, Division of Medical Safety Science, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. E-mail: [email protected] Received 28 January 2014; revised 2 December 2014; accepted 8 January 2015
Coffee consumption and hepatic steatosis T Imatoh et al
2 has been suggested to have an important role in the development of liver disease. We first investigated the association between the prevalence of hepatic steatosis and coffee or green tea consumption in an epidemiological study. Then, we evaluated the effects of coffee and green tea against leptin levels in hepatic steatosis. SUBJECTS AND METHODS Study subjects The study comprised 1059 male workers who had received annual health checkups at a clinic located in the center of Fukuoka city. We recruited from March 2010 to November 2010 at the clinic. Sixteen of the study subjects did not participate in the study, giving a participation rate of 98.4%. Twelve hepatitis B surface antibody-positive subjects and seven hepatitis C virus antibody-positive subjects were excluded. Twelve subjects had no coffee consumption data. Similarly, 61 subjects had no green tea consumption data. Therefore, we excluded these subjects, who had no coffee or green tea data, from each analysis. We obtained informed consent from all subjects. The subjects who agreed to participate in this study filled out a self-reported questionnaire regarding lifestyle. The diagnosis of hepatic steatosis was based on the brightness of the liver in ultrasonography in comparison with the kidney, vascular blurring of the hepatic vein trunk and deep attenuation in the right hepatic lobe. Severity of steatosis was classified as no, mild or moderate-to-severe hepatic steatosis using a 0–3 scale based on echogenicity and visualization of vasculature, parenchyma and diaphragm. This study was approved by the ethics committee of Fukuoka University.
Measurements Each subject completed a questionnaire covering his clinical history in addition to coffee and green tea consumption, smoking status and drinking status. We asked the participants to provide data on the number of cups of coffee or green tea they drink in case they used 150–200 ml cups. We divided coffee and green tea consumption into the following three categories each: nonregular drinker, o2 cups/day and 43 cups/day. Systolic blood pressure and diastolic blood pressure were measured twice using a standard mercury sphygmomanometer with the cuff on the right arm and the subjects in a sitting position. Body mass index was calculated by the following formula: weight (kg)/height (m)2. Waist circumference (in cm) was measured at the midpoint between the lower costal edge and the upper iliac crest following normal expiration. A fasting blood sample was drawn from a peripheral vein into a siliconized disposable plastic tube. Serum leptin level was determined by means of the RIA2 antibody assay. Aspartate aminotransferase, alanine aminotransferase and γ-glutamyltranspeptidase were measured using the Japan Society of Clinical Chemistry consensus method.
Statistical methods All statistical analyses were conducted using R 2.15 software (R Foundation for Statistical Computing, Vienna, Austria). For continuous variables, results are presented as means ± s.d. or median (minimum and maximum), and differences between the two groups were evaluated with the unpaired t-test. Because the distribution of leptin, aspartate aminotransferase, alanine aminotransferase and γ-glutamyltranspeptidase levels was skewed, log transformation was used, which yielded more normally distributed data. Categorical variables were presented as frequency counts, and intergroup comparisons were tested for statistical significance using a χ2test. The associations between hepatic steatosis and coffee consumption or green tea consumption were analyzed by logistic regression analysis. The results are presented as odds ratios (ORs) together with their 95% confidence intervals. We obtained the least-squares means of leptin levels by coffee consumption and severity of steatosis via the function ‘lsmeans’ in the ‘Lsmeans’ R 2.15 package.13 Levels of leptin were logarithmically transformed before statistical analysis, as they did not follow a normal distribution. The pairwise comparison among these least-squares means is conducted by the Tukey honestly significance difference (HSD) method. We used polynomial contrasts (linear and quadratic) to test three leastsquares means of leptin levels. Statistical significance was considered as a P-value o 0.05. European Journal of Clinical Nutrition (2015) 1 – 5
RESULTS Basic characteristics and leptin levels of our study subjects by the presence of hepatic steatosis are summarized in Table 1. A total of 265 subjects (25.9%) showed hepatic steatosis in the ultrasonic examination. There were significant differences between the two groups with respect to body mass index, waist circumference, blood pressure, liver markers, alcohol drinking status, the prevalence of hypertension or diabetes mellitus and leptin levels. We calculated ORs by means of logistic regression analysis to estimate associations between hepatic steatosis and coffee or green tea consumption (Table 2). We divided coffee and green tea consumption into the following three categories: non-drinker, 1–2 cups/day and ⩾ 3 cups/day. Compared with nonregular coffee drinkers, subjects who drink 43 cups of coffee/day have a lower OR compared with noncoffee drinkers (OR 0.67, 95%CI 0.47–0.96). When we adjusted for body mass index, age, smoking status, alcohol drinking status and green tea consumption, the association became significant (OR 0.59, 95% confidence intervals 0.38–0.90). Moreover, a dose–response relationship was observed (P for trend o0.05). On the other hand, there were no significant associations between hepatic steatosis and green tea consumption. We calculated the means of leptin level adjusted with age, body mass index, smoking status and alcohol drinking status to investigate the effects of coffee and green tea consumption against leptin levels. In addition, the severity of hepatic steatosis was divided into the following three categories: nonsymptomatic, Table 1. Basic characteristics and leptin level of our study subjects by the presence of hepatic steatosis Variables Number of subjects Age (years), mean (s.d.) Median (min–max) BMI (kg/m2), mean (s.d.) Waist circumference (cm), mean (s.d.) SBP (mm Hg), mean (s.d.) DBP (mm Hg), mean (s.d.) GGT (IU/l), meana (s.d.) ALT (IU/l), meana (s.d.) AST (IU/l), meana (s.d.)
Non-steatosis 270 48.4 47 23.1 83.6 120.0 77.1 34.6 21.7 20.8
(26.4) (10.0) (25-76) (3.3) (7.2) (12.4) (9.2) (2.0) (1.5) (1.3)
Steatosis 754 48.7 48 26.3 92.2 124.4 80.7 52.4 35.6 25.9
P
(73.6) (9.3) 0.66 (28-79) (2.5) o0.001 (8.2) o0.001 (11.6) (9.1) (2.0) (1.7) (1.5)
o0.001 o0.001 o0.001 o0.001 o0.001 o0.01
Alcohol drinking status, n (%) Everyday Sometimes Non
368 (48.8) 276 (36.6) 110 (14.6)
98 (36.3) 117 (43.3) 55 (20.4)
Smoking status, n (%) Regular smoker Nonsmoker
271 (35.9) 483 (64.0)
100 (37.2) 169 (62.8)
Coffee consumption, n (%) Non 1–2 Cups/day ⩾ 3 Cups/day
271 (36.5) 262 (35.3) 210 (28.3)
88 (32.7) 84 (31.2) 97 (36.1)
Green tea consumption, n (%) Non 1–2 Cups/day ⩾ 3 Cups/day
156 (22.0) 194 (27.3) 360 (50.7)
59 (23.3) 75 (29.6) 119 (47.0)
Hypertension, n (%) Diabetes mellitus, n (%) Leptin (ng/ml), meana (s.d.)
140 (18.6) 26 (3.4) 4.3 (1.6)
95 (35.2) 32 (11.9) 6.8 (1.5)
0.77
0.06
0.60
o0.001 o0.001 o0.001
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; GGT, γ-glutamyltranspeptidase; SBP, systolic blood pressure. aThe geometric mean was used.
© 2015 Macmillan Publishers Limited
Coffee consumption and hepatic steatosis T Imatoh et al
3 Table 2.
The crude and adjusted odds ratios by coffee and green tea consumption on hepatic steatosis Non-steatosis
Steatosis
Crude
Adjusted
n
(%)
n
(%)
Coffee Non 1–2 Cups/ day ⩾ 3 Cups/day
214 277 269
(68.8) (75.7) (76.2)
97 89 84
(31.2) (24.4) (23.8)
1.00 (reference) 0.68 (0.48–0.97) 0.67 (0.47–0.96) P for trend o 0.05
0.05 0.03
1.00 (reference) 0.67 (0.44–1.01) 0.59 (0.38–0.90) P for trend o0.05
0.05 0.03
Green teab Non 1–2 Cups/ day ⩾ 3 Cups/day
372 158 195
(75.6) (72.8) (72.2)
120 59 75
(24.4) (27.2) (27.8)
1.00 (reference) 1.16 (0.80–1,66) 1.19 (0.85–1.67) P for trend = 0.28
0.43 0.31
1.00 (reference) 1.40 (0.91–2.14) 1.16 (0.77–1.74) P for trend = 0.39
0.11 0.31
OR
95% CI
P
OR
95% CI
P
a
Abbreviations: BMI, body mass index; CI, confidence intervals; OR, odds ratio. aAdjusted with BMI (continuous), age (continuous), smoking status (categorical), alcohol drinking status (categorical) and green tea consumption (categorical). bAdjusted with BMI (continuous), age (continuous), smoking status (categorical), alcohol drinking status (categorical) and coffee consumption (categorical). Bold text indicates a statistically significant difference with a P-value less than 0.05.
Figure 1. Note the adjusted means on severity of hepatic steatosis by coffee consumption (a) and green tea consumption (b). The adjusted means of leptin levels of subjects with moderate and severe hepatic steatosis have been combined. Means were adjusted for age (continuous), body mass index (continuous), smoking status (categorical) and alcohol drinking status (categorical).
mild and moderate–severe. As shown in Figure 1a, as the severity of liver steatosis increased, leptin levels increased. There was a significant difference between coffee consumption and leptin level only in the asymptomatic group. We found significant trends in the asymptomatic and moderate–severe groups. The trends were quadratic but not linear (no symptoms: linear P = 0.389, quadratic P = 0.001; moderate–severe: linear P = 0.569 and quadratic P = 0.035). Regarding green tea consumption, we did not find a relationship similar to the relationship between coffee consumption and leptin levels, as shown Figure 1b. DISCUSSION We conducted a cross-sectional study to explore whether coffee consumption is associated with the prevalence of hepatic steatosis. First of all, the prevalence of hepatic steatosis was 25.9% in this study. Another Japanese cross-sectional study has reported that 32.2% (n = 1874 of 5811) of Japanese men, 18–83 years of age, have NAFLD.14 Another Japanese study indicated that 639 of 2545 (25.1%) male participants were diagnosed with hepatic steatosis by ultrasonography.15 Approximately 20–30% of the Japanese population is estimated to have NAFLD. It is thought that the prevalence in this study does not deviate extremely compared with previous Japanese studies. Most of the epidemiological and experimental studies have shown beneficial effects of regular coffee drinking on the © 2015 Macmillan Publishers Limited
development of various diseases, such as type 2 diabetes mellitus, obesity, Alzheimer’s and Parkinson’s disease. Most of the epidemiological studies, carried out in different countries, have clearly associated coffee consumption with a lower prevalence of chronic liver disease and have found an inverse association of coffee intake (42 cups/day) with the risk of elevated γ-glutamyltranspeptidase or alanine aminotransferase levels. Moreover, coffee has been reported to reduce the risk of advanced liver disease and its complications,16 as well as hepatocellular carcinoma.17 However, the epidemiological studies that examined an association between coffee consumption and hepatic steatosis have been few. In our study, the prevalence of hepatic steatosis in subjects drinking three cups of coffee a day was 42% lower compared with those of nonregular coffee drinkers. The association was doseresponsive. In addition, we carried out the same analysis to estimate the association between green tea consumption and hepatic steatosis. However, we did not find a significant association between green tea consumption and prevalence of hepatic steatosis. As with coffee, it is supposed that green tea has beneficial effects on health. Green tea contains epigallocatechin 3-gallate. Many of the biological effects of green tea are mediated by epigallocatechin 3-gallate. In animal studies, it has been reported that green tea polyphenol and ECGC reduce the severity of liver injury and that they may be useful supplements in the prevention of NAFLD.18 European Journal of Clinical Nutrition (2015) 1 – 5
Coffee consumption and hepatic steatosis T Imatoh et al
4
In a meta-analysis, Jin X et al.19 reported that eight out of ten qualified studies showed a significant protective role of green tea against various liver diseases. Therefore, they concluded that increased green tea consumption may reduce the risk of liver disease. However, we did not observe any beneficial effect of green tea. We focused only on hepatic steatosis as the outcome. As hepatic steatosis is considered to be relatively less severe compared with other liver disease, it is supposed that the effects of green tea become negligible. In addition, studies that compare the effects of coffee consumption with that of green tea consumption are scarce. In the past, although we have shown that coffee consumption positively associated with adiponectin levels in Japanese workers, we did not find any beneficial effect on adiponectin levels by green tea consumption.20 Coffee contains numerous bioactive compounds. Chlorogenic acid is an important component of coffee. It has been reported that chlorogenic acid has many health benefits.21 Coffee polyphenol including chlorogenic acid may have effects stronger compared with those of green tea. A two-hit hypothesis for the pathogenesis of NASH was proposed nearly two decades ago. Recently, it was found reasonable to assume that adipokine, bacterial endotoxin, mitochondrial dysfunction and so on multiply contribute the progression from NAFLD to NASH. Therefore, the initial two-hit hypothesis is now being modified by the ‘multiple parallel hit hypothesis’.11 Adipocytokines have been reported to have, an important role in the development of liver disease. Leptin is considered to be an essential mediator of liver fibrosis, as well as one of the inflammatory status.22 Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and tumor necrosis factor-α levels.23 In the human study, hyperleptinemia has been reported to be one of the major factors of proinflammatory status.12 Therefore, leptin may contribute as one of the many hits on the development of NASH. We demonstrated whether coffee consumption affects the leptin level. Leptin levels were higher with increasing severity of hepatic steatosis. As coffee consumption increased, those levels were lowered. Moreover, we examined the association between coffee consumption and leptin levels by severity of hepatic steatosis. We found a significant decrease in the leptin level only in the asymptomatic group. We found a significant decreasing trend. In the non-hepatic steatosis and moderate–severe hepatic steatosis groups, significantly decreasing trends were found. Regarding drinkers of 43 cups of coffee a day, leptin levels of subjects with moderate–severe hepatic steatosis were about the same as those of subjects with non-hepatic steatosis. Liver marker levels of subjects with moderate and severe hepatic steatosis who consumed three cups of coffee a day were significantly lower compared with those of subjects with non-hepatic steatosis (data are not shown). We did not observe the same trend with green tea consumption. Most studies have indicated that coffee has beneficial effects on human health. Katayama et al.24 evaluated the efficacy of coffee consumption with one of the experimental animal models for hepatitis and liver cancer. Their findings indicated that coffee drinking prevents hepatitis and liver carcinogenesis through its anti-inflammation effects.24 Yamashita et al.25 concluded that coffee consumption was associated with low leptin level and adipocytokines may explain the association between coffee consumption and high-sensitivity C-reactive proteins. Several mechanisms have been conceived. Coffee might protect against liver disease and help retard liver damage progression via several mechanisms, such as suppression of fat accumulation and antioxidative and anti-inflammatory properties. A recent animal study identified that coffee activates autophagy26 and enhances the expression of chaperones and antioxidant proteins.27 However, the underlying mechanisms have not been understood completely. There is a possibility that coffee European Journal of Clinical Nutrition (2015) 1 – 5
suppressed fat accumulation, with the result that decreases in leptin levels were induced. Several studies indicated that coffee or coffee components suppress fat accumulation.21,28 Second, coffee may suppress leptin levels directly. Recently, Meli et al.29 indicated that a high-fat diet induces expression of leptin mRNA and serum leptin levels in rats. To clear the beneficial effect of coffee on health, elaborate longitudinal studies are required. Our study has some limitations. First, our study was crosssectional; such studies cannot establish causality as both the exposure and the outcomes are being measured at the same time. Second, many factors, such as inflammation, antioxidative property and so on, are involved in liver diseases. However, we did not measure any other maker, such as high-sensitivity C-reactive protein, thiobarbituric acid reactive substances levels and so on. Third, we could not carry out liver biopsy. Liver ultrasonography is the most commonly used imaging diagnostic mode. Although it can provide a good estimate of the degree, or the extent of hepatic steatosis, it cannot rule out the presence of steatohepatitis or fibrosis completely. We tried to reduce the influence of fibrosis by excluding the carriers of hepatitis B surface or hepatitis C virus. Fourth, we did not collect information on the types of coffee consumed. Coffee composition varies depending on the preparation method. In general, Japanese people drink regular coffee. The associations between the types of coffee and the health benefits of coffee have been studied, but those results have not been consistent. Unfiltered coffee, such as espresso, contains diterpenes. These components are likely to have adverse effects rather than beneficial effects.30 In summary, we observed that high coffee consumption is associated with lower prevalence of hepatic steatosis and leptin levels. Conversely, we did not find that green tea has the same beneficial effects as coffee. In addition, we produced one possible theory that coffee consumption negatively associates with leptin levels on hepatic steatosis. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This work was supported by Grant of The Clinical Research Promotion Foundation (2010, 2014). We thank public health nurse Yuko Shibata for her invaluable help.
REFERENCES 1 Freedman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med 2012; 366: 1891–1904. 2 Gutierrez-Grobe Y, Chavez-Tapia N, Sanchez-Valle V, Gavilanes-Espinar JG, Ponciano-Rodriguez G, Uribe M et al. High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity. Ann Hepatol 2012; 11: 350–355. 3 Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology 2012; 55: 429–436. 4 Suzuki Y, Miyoshi N, Isemura M.. Health-promoting effects of green tea. Proc Jpn Acad Ser B Phys Biol Sci 2012; 88: 88–101. 5 Bae KC, Park JH, Na AY, Kim SJ, Ahn S, Kim SP et al. Effect of green tea extract/ poly-gamma-glutamic acid complex in obese type 2 diabetic mice. Diabetes Metab J 2013; 37: 196–206. 6 Bhardwaj P, Khanna D. Green tea catechins: defensive role in cardiovascular disorders. Chin J Nat Med 2013; 11: 345–353. 7 Yuan JM, Sun C, Butler LM. Tea and cancer prevention: epidemiological studies. Pharmacol Res 2011; 64: 123–135. 8 Fiorini RN, Donovan JL, Rodwell D, Evans Z, Cheng G, May HD et al. Short-term administration of (-)-epigallocatechin gallate reduces hepatic steatosis and protects against warm hepatic ischemia/reperfusion injury in steatotic mice. Liver Transpl 2005; 11: 298–308.
© 2015 Macmillan Publishers Limited
Coffee consumption and hepatic steatosis T Imatoh et al
5 9 Imai K, Nakachi K. Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases. BMJ 1995; 310: 693–696. 10 Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998; 114: 842–845. 11 Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52: 1836–1846. 12 Dos Santos Moraes A, Pisani LP, Corgosinho FC, Testa Carvalho LO, Masquio DC, Jamar G et al. The role of leptinemia state as a mediator of inflammation in obese adults. Horm Metab Res 2013; 45: 605–610. 13 Russell VL (2014) lsmeans: Least-Squares Means. R package version 2.12. http://CRAN.R-project.org/package=lsmeans. 14 Imamura Y, Uto H, Hiramine Y, Hosoyamada K, Ijuin S, Yoshifuku S et al. Increasing prevalence of diabetes mellitus in association with fatty liver in a Japanese population. J Gastroenterol 2013; 49: 1406–1413. 15 Omagari K1, Kadokawa Y, Masuda J, Egawa I, Sawa T, Hazama H et al. Fatty liver in non-alcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol 2002; 17: 1098–1105. 16 Bravi F, Bosetti C, Tavani A, Gallus S, La Vecchia C. Coffee Reduces Risk for Hepatocellular Carcinoma: An Updated Meta-Analysis. Clin Gastroenterol Hepatol 2013; 11: 1413–1421. 17 Bravi F, Bosetti C, Tavani A, Bagnardi V, Gallus S, Negri E et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 2007; 46: 430–435. 18 Xiao J, Ho CT, Liong EC, Nanji AA, Leung TM, Lau TY et al. Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways. Eur J Nutr 2014; 53: 187–199. 19 Jin X, Zheng RH, Li YM. Green tea consumption and liver disease: a systematic review. Liver Int 2008; 28: 990–996. 20 Imatoh T, Tanihara S, Miyazaki M, Momose Y, Uryu Y, Une H. Coffee consumption but not green tea consumption is associated with adiponectin levels in Japanese males. Eur J Nutr 2011; 50: 279–284.
© 2015 Macmillan Publishers Limited
21 Murase T, Misawa K, Minegishi Y, Aoki M, Ominami H, Suzuki Y et al. Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice. Am J Physiol Endocrinol Metab 2011; 300: E122–E133. 22 Tsochatzis EA, Papatheodoridis GV, Archimandritis AJ. Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm 2009; 2009: 831670. 23 Das S, Kumar A, Seth RK, Tokar EJ, Kadiiska MB, Waalkes MP et al. Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity. Toxicol Appl Pharmacol 2013; 269: 297–306. 24 Katayama M, Donai K, Sakakibara H, Ohtomo Y, Miyagawa M, Kuroda K et al. Coffee consumption delays the hepatitis and suppresses the inflammation related gene expression in the Long-Evans Cinnamon rat. Clin Nutr 2014; 33: 302–310. 25 Yamashita K, Yatsuya H, Muramatsu T, Toyoshima H, Murohara T, Tamakoshi K. Association of coffee consumption with serum adiponectin, leptin, inflammation and metabolic markers in Japanese workers: a cross-sectional study. Nutr Diabetes 2012; 2: e33. 26 Sinha RA, Farah BL, Singh BK, Siddique MM, Li Y, Wu Y et al. Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology 2014; 59: 1366–1380. 27 Salomone F, Li Volti G, Vitaglione P, Morisco F, Fogliano V, Zappalà A et al. Coffee enhances the expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease. Transl Res 2014; 163: 593–602. 28 Mubarak A, Hodgson JM, Considine MJ, Croft KD, Matthews VB. Supplementation of a high-fat diet with chlorogenic acid is associated with insulin resistance and hepatic lipid accumulation in mice. J Agric Food Chem 2013; 61: 4371–4378. 29 Meli R, Mattace Raso G, Irace C, Simeoli R, Di Pascale A, Paciello O et al. High fat diet induces liver steatosis and early dysregulation of iron metabolism in rats. PLoS One 2013; 8: e66570. 30 Cornelis MC, El-Sohemy A. Coffee, caffeine, and coronary heart disease. Curr Opin Clin Nutr Metab Care 2007; 10: 745–751.
European Journal of Clinical Nutrition (2015) 1 – 5
ORIGINAL ARTICLE
Coffee but not green tea consumption is associated with prevalence and severity of hepatic steatosis: the impact on leptin level T Imatoh1, S Kamimura2 and M Miyazaki3 BACKGROUND/OBJECTIVES: Most of the studies that have investigated the association between coffee consumption and hepatic steatosis have been experimental and small-scale clinical studies. As a result, epidemiological studies are scarce. To clear the association, we conducted a cross-sectional study and investigated the effects of coffee consumption with those of green tea consumption. SUBJECTS/METHODS: We analyzed 1024 Japanese male workers. The diagnosis of hepatic steatosis was based on ultrasonography. We divided coffee and green tea consumption into the following three categories: non-drinker; 1–2 cups/day and ⩾ 3 cups/day. To investigate the association between hepatic steatosis and coffee or green tea consumption, we calculated the odds ratio (OR) and adjusted the means of leptin levels on each severity of hepatic steatosis. RESULTS: A total of 265 of our subjects (25.9%) were diagnosed with hepatic steatosis. The ORs of the group of subjects who drank 43 cups of coffee/day was significantly lower compared with that of the noncoffee drinker group (OR 0.59, 95% confidence intervals 0.38–0.90, P = 0.03). Although there was a significant difference between coffee consumption and leptin level only in the asymptomatic group, we found a decreasing trend in the asymptomatic and moderate–severe hepatic steatosis group. We did not find the same relationships in green tea consumption. CONCLUSIONS: Although we did not find an association between hepatic steatosis and green tea consumption, coffee may have beneficial effects on hepatic steatosis. In addition, we produced one possible hypothesis that coffee consumption negatively associates with leptin levels in hepatic steatosis. European Journal of Clinical Nutrition advance online publication, 25 March 2015; doi:10.1038/ejcn.2015.23
INTRODUCTION Coffee is one of the most widely consumed beverages in the world. Various potential health effects of coffee have been reported. Habitual coffee consumption is associated with a substantially lower risk of type 2 diabetes mellitus. Recently, a large prospective study showed that coffee consumption was inversely associated with total and cause-specific mortality.1 Nevertheless, the majority of studies that have investigated the association between coffee consumption and hepatic steatosis have been experimental small-scale clinical studies. Epidemiological data on the association between coffee consumption and hepatic steatosis are sparse. Gutiérrez-Grobe et al.2 performed a case-control study and indicated that a high intake of coffee has a protective effect against nonalcoholic fatty liver disease (NAFLD). Molloy et al.3 have reported that coffee caffeine consumption is associated with a significant reduction in the risk for fibrosis among nonalcoholic steatohepatitis (NASH) patients. Although several studies have reported that regular coffee intake has beneficial effects on various liver diseases, it is not clear which component of coffee is responsible for these effects. The biological mechanism responsible for this beneficial effect of coffee remains largely unknown. Green tea is also one of the world’s most popular beverages and has been shown to possess anticancer, antiobesity and antiviral
properties.4 Many studies have reported that green tea extract has a protective effect against many diseases, such as type 2 diabetes mellitus,5 cardiovascular disease6 and some kinds of cancer.7 Recently, it has been demonstrated that green tea cathechins have a beneficial effect on liver disease.8,9 As in the case of coffee, most published studies are experimental. There have been no epidemiological studies that have investigated the association between green tea consumption and hepatic steatosis. NAFLD, including hepatic steatosis, is a major cause of liver disease worldwide. Recently, NAFLD was found to be associated with the metabolic syndrome and could evolve into NASH. NASH is a serious risk factor for disabling and deadly liver disease such as cirrhosis and hepatocellular carcinoma. The molecular mechanism underlying the progress of NAFLD is not completely understood. Transformation from NAFLD to NASH could have been thought to be based on the so-called ‘two-hit hypothesis’.10 Nowadays, this hypothesis is being modified by the ‘multiple parallel hits’ hypothesis. Many hits such as lipotoxicity, adipocytokine and so on may act.11 Obesity-related cytokines such as adipocytokine and tumor necrosis factor-α influence the inflammatory state in obesity. Leptin is an adipocytokine and considered to be a mediator of inflammation.12 Some findings were reported to associate with inflammation and oxidative stress in liver disease. Therefore, leptin
1 Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; 2Division of Preventive Medicine, Department of Internal Medicine, Tenjin Clinic, Fukuoka, Japan and 3Saitama City Institute of Health Science and Research, Saitama, Japan. Correspondence: Dr T Imatoh, Division of Medical Safety Science, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. E-mail: [email protected] Received 28 January 2014; revised 2 December 2014; accepted 8 January 2015
Coffee consumption and hepatic steatosis T Imatoh et al
2 has been suggested to have an important role in the development of liver disease. We first investigated the association between the prevalence of hepatic steatosis and coffee or green tea consumption in an epidemiological study. Then, we evaluated the effects of coffee and green tea against leptin levels in hepatic steatosis. SUBJECTS AND METHODS Study subjects The study comprised 1059 male workers who had received annual health checkups at a clinic located in the center of Fukuoka city. We recruited from March 2010 to November 2010 at the clinic. Sixteen of the study subjects did not participate in the study, giving a participation rate of 98.4%. Twelve hepatitis B surface antibody-positive subjects and seven hepatitis C virus antibody-positive subjects were excluded. Twelve subjects had no coffee consumption data. Similarly, 61 subjects had no green tea consumption data. Therefore, we excluded these subjects, who had no coffee or green tea data, from each analysis. We obtained informed consent from all subjects. The subjects who agreed to participate in this study filled out a self-reported questionnaire regarding lifestyle. The diagnosis of hepatic steatosis was based on the brightness of the liver in ultrasonography in comparison with the kidney, vascular blurring of the hepatic vein trunk and deep attenuation in the right hepatic lobe. Severity of steatosis was classified as no, mild or moderate-to-severe hepatic steatosis using a 0–3 scale based on echogenicity and visualization of vasculature, parenchyma and diaphragm. This study was approved by the ethics committee of Fukuoka University.
Measurements Each subject completed a questionnaire covering his clinical history in addition to coffee and green tea consumption, smoking status and drinking status. We asked the participants to provide data on the number of cups of coffee or green tea they drink in case they used 150–200 ml cups. We divided coffee and green tea consumption into the following three categories each: nonregular drinker, o2 cups/day and 43 cups/day. Systolic blood pressure and diastolic blood pressure were measured twice using a standard mercury sphygmomanometer with the cuff on the right arm and the subjects in a sitting position. Body mass index was calculated by the following formula: weight (kg)/height (m)2. Waist circumference (in cm) was measured at the midpoint between the lower costal edge and the upper iliac crest following normal expiration. A fasting blood sample was drawn from a peripheral vein into a siliconized disposable plastic tube. Serum leptin level was determined by means of the RIA2 antibody assay. Aspartate aminotransferase, alanine aminotransferase and γ-glutamyltranspeptidase were measured using the Japan Society of Clinical Chemistry consensus method.
Statistical methods All statistical analyses were conducted using R 2.15 software (R Foundation for Statistical Computing, Vienna, Austria). For continuous variables, results are presented as means ± s.d. or median (minimum and maximum), and differences between the two groups were evaluated with the unpaired t-test. Because the distribution of leptin, aspartate aminotransferase, alanine aminotransferase and γ-glutamyltranspeptidase levels was skewed, log transformation was used, which yielded more normally distributed data. Categorical variables were presented as frequency counts, and intergroup comparisons were tested for statistical significance using a χ2test. The associations between hepatic steatosis and coffee consumption or green tea consumption were analyzed by logistic regression analysis. The results are presented as odds ratios (ORs) together with their 95% confidence intervals. We obtained the least-squares means of leptin levels by coffee consumption and severity of steatosis via the function ‘lsmeans’ in the ‘Lsmeans’ R 2.15 package.13 Levels of leptin were logarithmically transformed before statistical analysis, as they did not follow a normal distribution. The pairwise comparison among these least-squares means is conducted by the Tukey honestly significance difference (HSD) method. We used polynomial contrasts (linear and quadratic) to test three leastsquares means of leptin levels. Statistical significance was considered as a P-value o 0.05. European Journal of Clinical Nutrition (2015) 1 – 5
RESULTS Basic characteristics and leptin levels of our study subjects by the presence of hepatic steatosis are summarized in Table 1. A total of 265 subjects (25.9%) showed hepatic steatosis in the ultrasonic examination. There were significant differences between the two groups with respect to body mass index, waist circumference, blood pressure, liver markers, alcohol drinking status, the prevalence of hypertension or diabetes mellitus and leptin levels. We calculated ORs by means of logistic regression analysis to estimate associations between hepatic steatosis and coffee or green tea consumption (Table 2). We divided coffee and green tea consumption into the following three categories: non-drinker, 1–2 cups/day and ⩾ 3 cups/day. Compared with nonregular coffee drinkers, subjects who drink 43 cups of coffee/day have a lower OR compared with noncoffee drinkers (OR 0.67, 95%CI 0.47–0.96). When we adjusted for body mass index, age, smoking status, alcohol drinking status and green tea consumption, the association became significant (OR 0.59, 95% confidence intervals 0.38–0.90). Moreover, a dose–response relationship was observed (P for trend o0.05). On the other hand, there were no significant associations between hepatic steatosis and green tea consumption. We calculated the means of leptin level adjusted with age, body mass index, smoking status and alcohol drinking status to investigate the effects of coffee and green tea consumption against leptin levels. In addition, the severity of hepatic steatosis was divided into the following three categories: nonsymptomatic, Table 1. Basic characteristics and leptin level of our study subjects by the presence of hepatic steatosis Variables Number of subjects Age (years), mean (s.d.) Median (min–max) BMI (kg/m2), mean (s.d.) Waist circumference (cm), mean (s.d.) SBP (mm Hg), mean (s.d.) DBP (mm Hg), mean (s.d.) GGT (IU/l), meana (s.d.) ALT (IU/l), meana (s.d.) AST (IU/l), meana (s.d.)
Non-steatosis 270 48.4 47 23.1 83.6 120.0 77.1 34.6 21.7 20.8
(26.4) (10.0) (25-76) (3.3) (7.2) (12.4) (9.2) (2.0) (1.5) (1.3)
Steatosis 754 48.7 48 26.3 92.2 124.4 80.7 52.4 35.6 25.9
P
(73.6) (9.3) 0.66 (28-79) (2.5) o0.001 (8.2) o0.001 (11.6) (9.1) (2.0) (1.7) (1.5)
o0.001 o0.001 o0.001 o0.001 o0.001 o0.01
Alcohol drinking status, n (%) Everyday Sometimes Non
368 (48.8) 276 (36.6) 110 (14.6)
98 (36.3) 117 (43.3) 55 (20.4)
Smoking status, n (%) Regular smoker Nonsmoker
271 (35.9) 483 (64.0)
100 (37.2) 169 (62.8)
Coffee consumption, n (%) Non 1–2 Cups/day ⩾ 3 Cups/day
271 (36.5) 262 (35.3) 210 (28.3)
88 (32.7) 84 (31.2) 97 (36.1)
Green tea consumption, n (%) Non 1–2 Cups/day ⩾ 3 Cups/day
156 (22.0) 194 (27.3) 360 (50.7)
59 (23.3) 75 (29.6) 119 (47.0)
Hypertension, n (%) Diabetes mellitus, n (%) Leptin (ng/ml), meana (s.d.)
140 (18.6) 26 (3.4) 4.3 (1.6)
95 (35.2) 32 (11.9) 6.8 (1.5)
0.77
0.06
0.60
o0.001 o0.001 o0.001
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; GGT, γ-glutamyltranspeptidase; SBP, systolic blood pressure. aThe geometric mean was used.
© 2015 Macmillan Publishers Limited
Coffee consumption and hepatic steatosis T Imatoh et al
3 Table 2.
The crude and adjusted odds ratios by coffee and green tea consumption on hepatic steatosis Non-steatosis
Steatosis
Crude
Adjusted
n
(%)
n
(%)
Coffee Non 1–2 Cups/ day ⩾ 3 Cups/day
214 277 269
(68.8) (75.7) (76.2)
97 89 84
(31.2) (24.4) (23.8)
1.00 (reference) 0.68 (0.48–0.97) 0.67 (0.47–0.96) P for trend o 0.05
0.05 0.03
1.00 (reference) 0.67 (0.44–1.01) 0.59 (0.38–0.90) P for trend o0.05
0.05 0.03
Green teab Non 1–2 Cups/ day ⩾ 3 Cups/day
372 158 195
(75.6) (72.8) (72.2)
120 59 75
(24.4) (27.2) (27.8)
1.00 (reference) 1.16 (0.80–1,66) 1.19 (0.85–1.67) P for trend = 0.28
0.43 0.31
1.00 (reference) 1.40 (0.91–2.14) 1.16 (0.77–1.74) P for trend = 0.39
0.11 0.31
OR
95% CI
P
OR
95% CI
P
a
Abbreviations: BMI, body mass index; CI, confidence intervals; OR, odds ratio. aAdjusted with BMI (continuous), age (continuous), smoking status (categorical), alcohol drinking status (categorical) and green tea consumption (categorical). bAdjusted with BMI (continuous), age (continuous), smoking status (categorical), alcohol drinking status (categorical) and coffee consumption (categorical). Bold text indicates a statistically significant difference with a P-value less than 0.05.
Figure 1. Note the adjusted means on severity of hepatic steatosis by coffee consumption (a) and green tea consumption (b). The adjusted means of leptin levels of subjects with moderate and severe hepatic steatosis have been combined. Means were adjusted for age (continuous), body mass index (continuous), smoking status (categorical) and alcohol drinking status (categorical).
mild and moderate–severe. As shown in Figure 1a, as the severity of liver steatosis increased, leptin levels increased. There was a significant difference between coffee consumption and leptin level only in the asymptomatic group. We found significant trends in the asymptomatic and moderate–severe groups. The trends were quadratic but not linear (no symptoms: linear P = 0.389, quadratic P = 0.001; moderate–severe: linear P = 0.569 and quadratic P = 0.035). Regarding green tea consumption, we did not find a relationship similar to the relationship between coffee consumption and leptin levels, as shown Figure 1b. DISCUSSION We conducted a cross-sectional study to explore whether coffee consumption is associated with the prevalence of hepatic steatosis. First of all, the prevalence of hepatic steatosis was 25.9% in this study. Another Japanese cross-sectional study has reported that 32.2% (n = 1874 of 5811) of Japanese men, 18–83 years of age, have NAFLD.14 Another Japanese study indicated that 639 of 2545 (25.1%) male participants were diagnosed with hepatic steatosis by ultrasonography.15 Approximately 20–30% of the Japanese population is estimated to have NAFLD. It is thought that the prevalence in this study does not deviate extremely compared with previous Japanese studies. Most of the epidemiological and experimental studies have shown beneficial effects of regular coffee drinking on the © 2015 Macmillan Publishers Limited
development of various diseases, such as type 2 diabetes mellitus, obesity, Alzheimer’s and Parkinson’s disease. Most of the epidemiological studies, carried out in different countries, have clearly associated coffee consumption with a lower prevalence of chronic liver disease and have found an inverse association of coffee intake (42 cups/day) with the risk of elevated γ-glutamyltranspeptidase or alanine aminotransferase levels. Moreover, coffee has been reported to reduce the risk of advanced liver disease and its complications,16 as well as hepatocellular carcinoma.17 However, the epidemiological studies that examined an association between coffee consumption and hepatic steatosis have been few. In our study, the prevalence of hepatic steatosis in subjects drinking three cups of coffee a day was 42% lower compared with those of nonregular coffee drinkers. The association was doseresponsive. In addition, we carried out the same analysis to estimate the association between green tea consumption and hepatic steatosis. However, we did not find a significant association between green tea consumption and prevalence of hepatic steatosis. As with coffee, it is supposed that green tea has beneficial effects on health. Green tea contains epigallocatechin 3-gallate. Many of the biological effects of green tea are mediated by epigallocatechin 3-gallate. In animal studies, it has been reported that green tea polyphenol and ECGC reduce the severity of liver injury and that they may be useful supplements in the prevention of NAFLD.18 European Journal of Clinical Nutrition (2015) 1 – 5
Coffee consumption and hepatic steatosis T Imatoh et al
4
In a meta-analysis, Jin X et al.19 reported that eight out of ten qualified studies showed a significant protective role of green tea against various liver diseases. Therefore, they concluded that increased green tea consumption may reduce the risk of liver disease. However, we did not observe any beneficial effect of green tea. We focused only on hepatic steatosis as the outcome. As hepatic steatosis is considered to be relatively less severe compared with other liver disease, it is supposed that the effects of green tea become negligible. In addition, studies that compare the effects of coffee consumption with that of green tea consumption are scarce. In the past, although we have shown that coffee consumption positively associated with adiponectin levels in Japanese workers, we did not find any beneficial effect on adiponectin levels by green tea consumption.20 Coffee contains numerous bioactive compounds. Chlorogenic acid is an important component of coffee. It has been reported that chlorogenic acid has many health benefits.21 Coffee polyphenol including chlorogenic acid may have effects stronger compared with those of green tea. A two-hit hypothesis for the pathogenesis of NASH was proposed nearly two decades ago. Recently, it was found reasonable to assume that adipokine, bacterial endotoxin, mitochondrial dysfunction and so on multiply contribute the progression from NAFLD to NASH. Therefore, the initial two-hit hypothesis is now being modified by the ‘multiple parallel hit hypothesis’.11 Adipocytokines have been reported to have, an important role in the development of liver disease. Leptin is considered to be an essential mediator of liver fibrosis, as well as one of the inflammatory status.22 Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and tumor necrosis factor-α levels.23 In the human study, hyperleptinemia has been reported to be one of the major factors of proinflammatory status.12 Therefore, leptin may contribute as one of the many hits on the development of NASH. We demonstrated whether coffee consumption affects the leptin level. Leptin levels were higher with increasing severity of hepatic steatosis. As coffee consumption increased, those levels were lowered. Moreover, we examined the association between coffee consumption and leptin levels by severity of hepatic steatosis. We found a significant decrease in the leptin level only in the asymptomatic group. We found a significant decreasing trend. In the non-hepatic steatosis and moderate–severe hepatic steatosis groups, significantly decreasing trends were found. Regarding drinkers of 43 cups of coffee a day, leptin levels of subjects with moderate–severe hepatic steatosis were about the same as those of subjects with non-hepatic steatosis. Liver marker levels of subjects with moderate and severe hepatic steatosis who consumed three cups of coffee a day were significantly lower compared with those of subjects with non-hepatic steatosis (data are not shown). We did not observe the same trend with green tea consumption. Most studies have indicated that coffee has beneficial effects on human health. Katayama et al.24 evaluated the efficacy of coffee consumption with one of the experimental animal models for hepatitis and liver cancer. Their findings indicated that coffee drinking prevents hepatitis and liver carcinogenesis through its anti-inflammation effects.24 Yamashita et al.25 concluded that coffee consumption was associated with low leptin level and adipocytokines may explain the association between coffee consumption and high-sensitivity C-reactive proteins. Several mechanisms have been conceived. Coffee might protect against liver disease and help retard liver damage progression via several mechanisms, such as suppression of fat accumulation and antioxidative and anti-inflammatory properties. A recent animal study identified that coffee activates autophagy26 and enhances the expression of chaperones and antioxidant proteins.27 However, the underlying mechanisms have not been understood completely. There is a possibility that coffee European Journal of Clinical Nutrition (2015) 1 – 5
suppressed fat accumulation, with the result that decreases in leptin levels were induced. Several studies indicated that coffee or coffee components suppress fat accumulation.21,28 Second, coffee may suppress leptin levels directly. Recently, Meli et al.29 indicated that a high-fat diet induces expression of leptin mRNA and serum leptin levels in rats. To clear the beneficial effect of coffee on health, elaborate longitudinal studies are required. Our study has some limitations. First, our study was crosssectional; such studies cannot establish causality as both the exposure and the outcomes are being measured at the same time. Second, many factors, such as inflammation, antioxidative property and so on, are involved in liver diseases. However, we did not measure any other maker, such as high-sensitivity C-reactive protein, thiobarbituric acid reactive substances levels and so on. Third, we could not carry out liver biopsy. Liver ultrasonography is the most commonly used imaging diagnostic mode. Although it can provide a good estimate of the degree, or the extent of hepatic steatosis, it cannot rule out the presence of steatohepatitis or fibrosis completely. We tried to reduce the influence of fibrosis by excluding the carriers of hepatitis B surface or hepatitis C virus. Fourth, we did not collect information on the types of coffee consumed. Coffee composition varies depending on the preparation method. In general, Japanese people drink regular coffee. The associations between the types of coffee and the health benefits of coffee have been studied, but those results have not been consistent. Unfiltered coffee, such as espresso, contains diterpenes. These components are likely to have adverse effects rather than beneficial effects.30 In summary, we observed that high coffee consumption is associated with lower prevalence of hepatic steatosis and leptin levels. Conversely, we did not find that green tea has the same beneficial effects as coffee. In addition, we produced one possible theory that coffee consumption negatively associates with leptin levels on hepatic steatosis. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This work was supported by Grant of The Clinical Research Promotion Foundation (2010, 2014). We thank public health nurse Yuko Shibata for her invaluable help.
REFERENCES 1 Freedman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R. Association of coffee drinking with total and cause-specific mortality. N Engl J Med 2012; 366: 1891–1904. 2 Gutierrez-Grobe Y, Chavez-Tapia N, Sanchez-Valle V, Gavilanes-Espinar JG, Ponciano-Rodriguez G, Uribe M et al. High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity. Ann Hepatol 2012; 11: 350–355. 3 Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology 2012; 55: 429–436. 4 Suzuki Y, Miyoshi N, Isemura M.. Health-promoting effects of green tea. Proc Jpn Acad Ser B Phys Biol Sci 2012; 88: 88–101. 5 Bae KC, Park JH, Na AY, Kim SJ, Ahn S, Kim SP et al. Effect of green tea extract/ poly-gamma-glutamic acid complex in obese type 2 diabetic mice. Diabetes Metab J 2013; 37: 196–206. 6 Bhardwaj P, Khanna D. Green tea catechins: defensive role in cardiovascular disorders. Chin J Nat Med 2013; 11: 345–353. 7 Yuan JM, Sun C, Butler LM. Tea and cancer prevention: epidemiological studies. Pharmacol Res 2011; 64: 123–135. 8 Fiorini RN, Donovan JL, Rodwell D, Evans Z, Cheng G, May HD et al. Short-term administration of (-)-epigallocatechin gallate reduces hepatic steatosis and protects against warm hepatic ischemia/reperfusion injury in steatotic mice. Liver Transpl 2005; 11: 298–308.
© 2015 Macmillan Publishers Limited
Coffee consumption and hepatic steatosis T Imatoh et al
5 9 Imai K, Nakachi K. Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases. BMJ 1995; 310: 693–696. 10 Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998; 114: 842–845. 11 Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52: 1836–1846. 12 Dos Santos Moraes A, Pisani LP, Corgosinho FC, Testa Carvalho LO, Masquio DC, Jamar G et al. The role of leptinemia state as a mediator of inflammation in obese adults. Horm Metab Res 2013; 45: 605–610. 13 Russell VL (2014) lsmeans: Least-Squares Means. R package version 2.12. http://CRAN.R-project.org/package=lsmeans. 14 Imamura Y, Uto H, Hiramine Y, Hosoyamada K, Ijuin S, Yoshifuku S et al. Increasing prevalence of diabetes mellitus in association with fatty liver in a Japanese population. J Gastroenterol 2013; 49: 1406–1413. 15 Omagari K1, Kadokawa Y, Masuda J, Egawa I, Sawa T, Hazama H et al. Fatty liver in non-alcoholic non-overweight Japanese adults: incidence and clinical characteristics. J Gastroenterol Hepatol 2002; 17: 1098–1105. 16 Bravi F, Bosetti C, Tavani A, Gallus S, La Vecchia C. Coffee Reduces Risk for Hepatocellular Carcinoma: An Updated Meta-Analysis. Clin Gastroenterol Hepatol 2013; 11: 1413–1421. 17 Bravi F, Bosetti C, Tavani A, Bagnardi V, Gallus S, Negri E et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 2007; 46: 430–435. 18 Xiao J, Ho CT, Liong EC, Nanji AA, Leung TM, Lau TY et al. Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways. Eur J Nutr 2014; 53: 187–199. 19 Jin X, Zheng RH, Li YM. Green tea consumption and liver disease: a systematic review. Liver Int 2008; 28: 990–996. 20 Imatoh T, Tanihara S, Miyazaki M, Momose Y, Uryu Y, Une H. Coffee consumption but not green tea consumption is associated with adiponectin levels in Japanese males. Eur J Nutr 2011; 50: 279–284.
© 2015 Macmillan Publishers Limited
21 Murase T, Misawa K, Minegishi Y, Aoki M, Ominami H, Suzuki Y et al. Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice. Am J Physiol Endocrinol Metab 2011; 300: E122–E133. 22 Tsochatzis EA, Papatheodoridis GV, Archimandritis AJ. Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm 2009; 2009: 831670. 23 Das S, Kumar A, Seth RK, Tokar EJ, Kadiiska MB, Waalkes MP et al. Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity. Toxicol Appl Pharmacol 2013; 269: 297–306. 24 Katayama M, Donai K, Sakakibara H, Ohtomo Y, Miyagawa M, Kuroda K et al. Coffee consumption delays the hepatitis and suppresses the inflammation related gene expression in the Long-Evans Cinnamon rat. Clin Nutr 2014; 33: 302–310. 25 Yamashita K, Yatsuya H, Muramatsu T, Toyoshima H, Murohara T, Tamakoshi K. Association of coffee consumption with serum adiponectin, leptin, inflammation and metabolic markers in Japanese workers: a cross-sectional study. Nutr Diabetes 2012; 2: e33. 26 Sinha RA, Farah BL, Singh BK, Siddique MM, Li Y, Wu Y et al. Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology 2014; 59: 1366–1380. 27 Salomone F, Li Volti G, Vitaglione P, Morisco F, Fogliano V, Zappalà A et al. Coffee enhances the expression of chaperones and antioxidant proteins in rats with nonalcoholic fatty liver disease. Transl Res 2014; 163: 593–602. 28 Mubarak A, Hodgson JM, Considine MJ, Croft KD, Matthews VB. Supplementation of a high-fat diet with chlorogenic acid is associated with insulin resistance and hepatic lipid accumulation in mice. J Agric Food Chem 2013; 61: 4371–4378. 29 Meli R, Mattace Raso G, Irace C, Simeoli R, Di Pascale A, Paciello O et al. High fat diet induces liver steatosis and early dysregulation of iron metabolism in rats. PLoS One 2013; 8: e66570. 30 Cornelis MC, El-Sohemy A. Coffee, caffeine, and coronary heart disease. Curr Opin Clin Nutr Metab Care 2007; 10: 745–751.
European Journal of Clinical Nutrition (2015) 1 – 5
