November 11, 2013

Journal of Gastroenterology and Hepatology

Accepted Articles, Accepted manuscript online: 7 NOV 2013

Article type: Review Article

Received date: 12-Aug-2013 Accepted date: 12-Sep-2013

1 Shaohua Chen *1,2 , Narci C Teoh *2 , Shiv Chitturi 2 , Geoffrey C. Farrell 2

1.Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79, QingChun Road, Hangzhou,310003 P.R.China.

2. Liver Research Group, ANU Medical School at the Canberra Hospital, Level 5 Bldg10, Yamba Drive, Garran, ACT, 2605 Australia.
*Equal first author: Shaohua Chen and Narci C Teoh

Corresponding author: Geoffrey C. Farrell
Address: Liver Research Group, ANU Medical School at the Canberra
Hospital, Level 5 Bldg10, Yamba Drive, Garran, ACT, 2605 Australia.
Email: geoff.farrell@anu.edu.au  
Ph: 61 2 6244 2473  Fx: 61 2 6244 3235

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12422

Abstract: Coffee is one of the most popular beverages in the world. Several studies consistently show that coffee drinkers with chronic liver disease have a reduced risk of cirrhosis and a lower incidence of hepatocellular carcinoma (HCC) regardless of primary etiology. With the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide, there is renewed interest in the effect of coffee intake on NAFLD severity and positive clinical outcomes. This review gives an overview of growing epidemiological and clinical evidence which indicate that coffee consumption reduces severity of NAFLD. The possible mechanisms underlying coffee’s hepatoprotective effects in NAFLD are also discussed. Key words: coffee, nonal

Key words: coffee, nonalcoholic fatty liver disease, hepatocellular carcinoma, fibrotic severity, liver inflammation

Introduction Coffee is a brewed beverage with a distinct aroma and flavor, prepared from the roasted seeds of the coffee plant. It has been part of the human diet since the 15th century. In its various forms (including decaffeinated coffee), coffee is one of the most consumed drinks in the world, partly for its mild mood-enhancing and stimulatory effects on the central nervous system. Caffeine, one of the main constituents of coffee, has been shown to have a wide spectrum of biological activities. The effects of coffee on chronic liver disease, especially in lowering the risk of developing hepatocellular carcinoma (HCC) has recently attracted considerable attention.

The first reported association between caffeine accumulation and liver disease can be attributed to Statland and colleagues in 1976[1]. They found a prolonged caffeine half-time in a case with alcoholic liver disease, reflecting impaired caffeine metabolism in cirrhosis which has subsequently been well documented. During the last 20 years, several investigators have focused more specifically on coffee and its beneficial health effects, especially against liver disease. In 1992, Klatsky and Armstrong reported an inverse relationship between coffee drinking and the risk of cirrhosis in a 10-year follow-up study of a large number of subjects drawn from a North American general population[2]. Their results show that coffee drinkers (at least 3 cups/day), had significantly lower levels of gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), serum alkaline phosphatase (SAP) and bilirubin concentration compared with non-coffee-drinking subjects, or those consuming less than 3 cups daily [3]. Coffee consumption has also been associated with decreased blood GGT levels in humans, and reported to confer possible hepatoprotection against alcoholic liver disease [21, 22].

Coffee consumption may reduce the risk of HCC [4-8]. A consistent inverse relationship between coffee and HCC risk has been found in 3 meta-analyses [9-12]. Further, the relationship between coffee intake and severity of different etiological types of chronic liver disease has been extensively studied. Hepatitis B virus (HBV) infection is the most common cause of HCC worldwide. In those with chronic HBV infection, moderate coffee consumption (drinking coffee ≥4 times/week) reduced the risk of HCC by half (OR=0.54, 95% CI: 0.30 - 0.97) with a significant dose-response effect (χ²=5.41, df=1, p=0.02) [13]. In another hospital-based case-control study, it was found that a high lifetime coffee consumption (≥20,000 cups) was an independent protective factor against HCC in all subjects. However, high levels of coffee consumption did not significantly affect HCC risk in patients with HBV (OR=0.64, 95% CI:0.36-1.14) after adjustment for HBeAg status, serum HBV DNA level and antiviral therapy[14]. In addition, others have reported that caffeine intake did not appear to affect liver stiffness (detected by transient elastography) in patients with chronic HBV [15]. A preliminary conclusion from these observations is that the protective effect of coffee against cirrhosis is not likely to be as significant as the viral determinants of chronic liver disease.

More than 180 million people worldwide are chronically infected with the hepatitis C virus (HCV), and approximately 350,000 people die every year from HCV-related liver disease such as decompensated cirrhosis, and/or HCC. Some case-control studies have shown that coffee consumption can reduce the risk of HCC amongst HCV-infected patients [16, 17]. Costentin et al found that caffeine consumption of >408 mg/day (≥3 cups coffee) was associated with reduced histological activity in patients with chronic HCV infection [18]. Coffee consumption also appeared to slow disease progression. Finally, coffee consumption may improve virologic response to pegylated-interferon and ribavirin antiviral treatment [19] [20] .

The prevalence of NAFLD is escalating rapidly worldwide in association with such metabolic disorders as type 2 diabetes, obesity, hypertension and hyperlipidemia (metabolic syndrome). NAFLD comprises a pathological spectrum characterized by fat accumulation within the liver known as simple steatosis, or “non-NASH NAFLD”, and/or in combination with varying degrees of hepatocellular injury manifest by ballooning, inflammation, liver fibrosis, cirrhosis and HCC. In NAFLD-related cirrhosis, liver histology may no longer show inflammation or even steatosis, and likely represent the largest proportion of cases often referred to as “cryptogenic cirrhosis”. The diagnosis of NAFLD is usually made by abnormal liver tests and hepatic imaging showing features of fatty infiltration (‘bright liver’) in the context of obesity, a family history of diabetes and/or features of metabolic syndrome; as well, other causes of liver disease and significant alcohol intake must be excluded.

Several studies of hepatic lipid metabolism, insulin resistance, mitochondrial dysfunction, oxidative stress as well as genetic predisposition to altered cell metabolism and injury have contributed to current understanding of NAFLD[23]. Lifestyle measures directed at increasing physical activity (which counters insulin resistance) and weight loss remain the cornerstone of management. Notably, the effects of pharmacotherapy are still contentious; most agents studied are either modest in their effects, such as vitamin E, pioglitazone, ezetimibe or pentoxiphyllne, or have no beneficial long term hepatoprotective effects (eg. metformin, ursodeoxycholic acid). In general, moderate energy and simple carbohydrate restriction, reduction of total and saturated fat intake, along with increasing physical activity are beneficial and highly recommended. Interestingly, recent studies have shown that coffee drinking may be protective against NAFLD-related chronic liver disease and possibly, HCC

Sources of information

This systematic review is the first that we are aware of to focus on the epidemiology, magnitude and mechanisms of possible beneficial effects of coffee consumption in patients with NAFLD. Using ‘Liver disease’ and ‘coffee’ as search terms in the PubMed database, 240 articles were returned. The abstracts of all these articles were reviewed, and 12 studies that evaluated relationship between NAFLD and coffee were examined in detail. Specific questions pertaining to this area of research were evaluated, as indicated below. The number of articles published about coffee and liver disease has increased steadily since 2003 (Figure 1).

Relationship between coffee consumption and NAFLD in community studies

Four continuous cycles of the National Health and Nutrition Examination Surveys (NHANES, USA 2001-2008) were used to investigate the effects of dietary behavior in NAFLD patients. Dietary intake was evaluated by questionnaires that included nutrition components. Multivariate analyses were conducted of variables that included demographics, clinical parameters and nutritional components in relation to presence of NAFLD (defined by ultrasonography). Five factors were independently associated with NAFLD: African American race, male gender, obesity, caffeine intake as well as plain water consumption. These findings show a strong association between coffee consumption and protection against the development of NAFLD [24].(See Table 1) The association of caffeine consumption with both the prevalence and severity of NAFLD was further established in another study where a validated questionnaire of caffeine consumption was utilized to determine if there was a relationship between caffeine intake and NAFLD severity as established by histological examination of liver biopsies. In this study, the authors reported an inverse relationship between caffeine consumption and hepatic fibrosis[25] . (See Table 1)

In an Italian study from Europe, 137 NAFLD cases and 108 controls were enrolled, and coffee intake determined by the absolute number of cups of coffee consumed. This was graded as 1 (0 cups of coffee/day), 2 (1-2 cups of coffee/day) and 3 (≥3 cups of coffee/day). Insulin resistance was assessed by homoeostasis model-insulin resistance index (HOMA). When compared with non-coffee drinkers, those who consumed coffee had less severe fatty liver evaluated by ultrasound “bright liver score” (BLS). Further, obesity, insulin resistance, lower HDL cholesterol, older age and arterial hypertension were associated with a greater risk of more severe grades of BLS, while coffee intake was associated with a lower risk of severe BLS. By multiple regression analysis, coffee use was inversely associated with the degree of “bright liver”, while insulin resistance and obesity were directly associated with increased likelihood and severity of BLS on ultrasound[26]. A case-control study from Mexico also found similar protective effects of coffee consumption against NAFLD as assessed by ultrasound [27]. (See Table 1)

Mechanisms by which coffee may reduce severity of NAFLD

Despite firm epidemiological data, the cellular and molecular mechanisms underlying the effects of coffee consumption in patients with NAFLD remain undefined. Antioxidant, anti-inflammatory, antifibrotic and altered energy metabolism have been potentially implicated.

Coffee and oxidative injury

Of interest, there have been several studies which indicate that coffee consumption is inversely related to the incidence of diseases in which reactive oxygen species (ROS) are involved. It is postulated that the antioxidant properties of coffee may account for this phenomenon. Vitaglione et al [28] established a high-fat-diet (HFD)-induced NASH model in male Wistar rats to study the protective mechanisms of coffee, or its component polyphenols or melanoidins against NAFLD. Biomarkers of antioxidant status measured in both serum and liver samples show that HFD-fed rats had significantly higher concentrations of oxidized glutathione (GSSG) than control rats. Coffee, polyphenols, or melanoidins reduced GSSG concentrations in HFD-fed rats supplemented with coffee in their drinking water compared with those given water only. Likewise, serum malondialdehyde concentration was significantly higher in rats in the HFD-water group than in control rats (2.03±0.14 μM vs 1.47±0.12 μM). Coffee consumption (1.50±0.09 μM) or polyphenolss (1.62±0.08 μM) returned these levels to control values. Further, there was a significant increase in antioxidant capacity in rats treated with polyphenols in drinking water compared with controls [0.36±0.02 mM Trolox® equivalent(TE) vs 0.32±0.01 mM TE] [28]

Goya L et al. investigated the potential protective effect of coffee melanoidins, in particular, a water-soluble high-molecular weight fraction, on the redox status of cultured human hepatocellular carcinoma, HepG2 cells. The results show that coffee melanoidins conferred significant protection against oxidative insults [29].

To establish whether coffee consumption protects humans against oxidative DNA-damage, a cross-over intervention study was conducted. In this trial, 38 participants consumed 800 mL coffee (or water in controls) daily over 5 days. DNA-damage was measured in peripheral lymphocytes. The extent of DNA-migration attributable to formation of oxidized purines (also known as formamidopyrimidine glycosylase sensitive sites) was decreased by 12% after coffee intake (p=0.006). These findings suggest that coffee consumption prevents endogenous formation of oxidative DNA-damage in humans. While this observation may be causally related to the beneficial health effects of coffee, biochemical indices of redox status such as malondialdehyde, 3-nitrotyrosine and total antioxidant levels in plasma, glutathione concentrations in blood, intracellular ROS levels and the activities of superoxide dismutase and glutathione peroxidase in lymphocytes, were not markedly altered at the end of the trial[30].

Investigators have observed different levels of oxidative DNA damage and DNA repair in the livers of coffee-fed mice [31]. In one study, lean male mice were fed 0.1% (w/v) instant coffee solution prepared weekly with 60℃ tap water. At 2, 4, and 8 months, there was no difference in the hepatic levels of 8-hydroxydeoxyguanosine (8 Accepted -OH-dG)(a marker of oxidative DNA damage) and 8-OH-dG repair-associated genes, redox system-associated genes and hepatic lipoperoxide levels between the coffee-fed and control groups of mice. These results suggest that instant coffee consumption has little, if any, effect on hepatic oxidative stress in lean mice. Similarly, others report little or no significant difference in catalase (0.2 ± 0.7 vs. 0.3 ± 0.7 nM/min/mL) levels, superoxide dismutase (4.7 ± 2.1 vs. 5.4 ± 3.4U/mL) or thiobarbituric acid-reactive substances (3.9 ± 1.5 vs. 4.0 ± 1.8 µM/mL) between NAFLD and controls. Hence, while coffee intake has a protective effect against severity of NAFLD, the weight of evidence (albeit, currently incomplete) is that coffee’s positive effects are unlikely to be attributable to any differences in antioxidant variables [27].

Coffee and liver Inflammation

Coffee intake has been associated with reduced levels of abnormalities in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) [32-34] and GGT [35]. Fukushima Y et al [36] conducted a study where mice were fed HFD to induce NAFLD, then treated with or without coffee (1.1% decaffeinated/caffeine-containing instant coffee). Mesenteric fat weight was lower in the HFD+coffee group than those fed a HFD without coffee (p<0.05). Further, serum AST and ALT levels were significantly lower in the HFD+coffee group than in mice fed a HFD only (p < 0.05). Proinflammatory interleukin -1beta(IL-1β) gene expression in murine liver was upregulated in the HFD group and was significantly downregulated by coffee consumption (p<0.01). Expression of monocyte chemoattractant protein-1 (MCP-1) in liver and adipose was also suppressed in the HFD+coffee group. Hence, coffee consumption appears to significantly reduce hepatic pro-inflammatory response.

In a separate study, co-administration of coffee with a HFD in rodents appeared to reduce tumor necrosis factor α (TNF-α), tissue transglutaminase, and transforming growth factor β(TGF-β) expression in the liver, and increased expression of adiponectin receptor and peroxisome proliferator-activated receptor α(PPARα). Coffee also lowered hepatic concentrations of TNF-α, interferon-γ and increased anti-inflammatory cytokines, IL-4 and IL-10.[28]

Coffee and hepatic fibrosis

Few studies have discussed the influence of coffee on liver fibrosis in NAFLD. In a recent European study, 195 morbidly obese patients referred for bariatric surgery were assessed [37]. Liver biopsies showed NASH in 19%, and significant fibrosis in 35%. By logistic regression analysis, regular coffee intake was an independent factor negatively associated with significant fibrosis in a model that included AST, HOMA-IR, presence of the metabolic syndrome, and NASH. Interestingly, the consumption of regular coffee (but not espresso) was associated with an earlier stage of fibrosis and was independently protective against fibrosis [37]. Sucrose, which is composed of glucose and fructose, is often added by espresso consumers to their coffee and may have potentially countered coffee’s positive effects in this study. Fructose consumption has been noted to aggravate the severity of liver fibrosis in North American patients who have NASH [38, 39].

Few studies have addressed the mechanism for the possible anti-fibrotic effects of coffee on liver fibrosis in NAFLD. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is the hepatic stellate cell[40]. The mechanisms of fibrogenesis in the liver are dependent on an interplay of many pro-fibrotic and anti-fibrotic cytokines and growth factors. TGF-β is one such pro-fibrogenic growth factor. In turn TGF-β can activate connective tissue growth factor(CTGF) which is also responsive to insulin and other metabolic factors in NAFLD, and which can also mediate matrix production[41]. Caffeine inhibits CTGF synthesis in hepatocytes and liver non-parenchymal cells, primarily by inducing degradation of Smad2, thereby interrupting TGF-β signaling[42] .

Coffee and hepatic metabolism

The liver plays diverse and crucial roles in lipogenesis, gluconeogenesis and cholesterol metabolism[43]. In a rodent model which develops metabolic syndrome and NAFLD when fed a high-carbohydrate, HFD, supplementation with Colombian coffee extract improved glucose tolerance, decreased hypertension, induced cardiovascular remodeling and attenuated NAFLD severity. Of note, these changes were not associated with weight loss or reduction of serum lipids in the animals [44]. Interestingly, one study reports that some coffee brewing techniques raise serum total and low-density-lipoprotein cholesterol concentrations in humans[45]. The diterpene lipids, cafestol and kahweol (also main constituents of coffee) were considered to be the responsible lipid-altering factors. In contrast, filtered coffee does not appear to affect serum cholesterol and this is thought to be related to the removal of diterpenes by the filtration process (filter paper) [45] .

Adiponectin is an adipokine which governs insulin sensitivity and has potent anti-inflammatory effects. Plasma adiponectin levels are often lower in patients with NAFLD, and correlate inversely with the severity of steatosis and NASH. In a cross-sectional study comprised of 2554 male and 763 female Japanese workers, associations between coffee consumption and adiponectin, leptin, markers for subclinical inflammation, glucose metabolism, lipids and liver enzymes were ascertained. The findings revealed that coffee consumption was associated with higher serum adiponectin and lower serum leptin levels[46].

Coffee is also enriched with polyphenols (coffee polyphenols, CPP). The effects of CPP on diet-induced body fat accumulation was investigated and C57BL/6J mice were fed either a control diet, HFD, or HFD supplemented with 0.5 to 1.0% CPP for 2-15 wk. Supplementation of a HFD with CPP significantly reduced body weight gain, abdominal and liver fat accumulation, as well macrophage infiltration into adipose. Energy expenditure, evaluated by indirect calorimetry, was significantly increased in CPP-fed mice. The hepatic transcript levels of sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase-1 and -2, stearoyl-CoA desaturase-1, and pyruvate dehydrogenase kinase-4 were also significantly reduced in CPP-fed mice compared with controls, reflecting the increased biological activity of adiponectin and leptin. CPP has also been shown to suppress the expression of SREBP-1c in Hepa 1-6 cells, with a concomitant increase in microRNA (miR)-122. Structure-activity relationship studies of nine quinic acid derivatives isolated from CPP in Hepa 1-6 cells also suggest that mono- or di-caffeoyl quinic acids (CQA) may have potent and potentially beneficial effects[47]. Thus, it appears that CPP enhances energy metabolism, reduces lipogenesis by down-regulating SREBP-1c and related signaling pathways, thereby suppressing the accumulation of body fat and newly-synthesized (saturated) fatty acids in the liver[47] .

Conclusions and future perspectives

Taken together, these studies provide reasonable evidence for a protective effect of coffee consumption on NAFLD. The protective effects may be related to a diverse range of mechanisms, including anti-oxidant, anti-inflammatory, anti-fibrotic pathways as well as modulations in energy metabolism (Figure 2). Most studies to date have been exploratory and confined to a limited range of experimental systems, only a small subset of which have utilized clinically relevant experimental models of NASH. It is clear that some components of coffee, other than caffeine may be involved, and specific identification of these compounds require more rigorous study to elucidate the mechanisms underlying coffee’s hepatoprotective effects in patients with NAFLD.

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Figure 1: Number of publications related to coffee intake and liver disease in the past decade

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Figure 2: Schematic diagram illustrating the mechanisms underlying coffee’s potential hepatoprotective effects in NAFLD

Key: NASH: non alcoholic steatohepatitis; GSSG: oxidized glutathione; ROS: reactive oxygen species; SREBP-1C: sterol regulatory element-binding protein -1C; IL-1β: interleukin-8; IL-4: interleukin-4; IL-10: interleukin-10; MCP-1: monocyte chemoattractant protein-1; TNF-α: tumor necrosis factor α; IFN-γ: interferon-γ; PPAR-α: peroxisome proliferator-activated receptor α; TGF-β: transforming growth factor β; CTGF: connective tissue growth factor; Smad2: Mothers against decapentaplegic homolog 2, SMAD family member 2

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