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REVIEW

Coffee and non-alcoholic fatty liver disease:Brewing evidence for hepatoprotection?Shaohua Chen,*,† Narci C Teoh,† Shiv Chitturi† and Geoffrey C Farrell†

*Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; and †Liver ResearchGroup, ANU Medical School at the Canberra Hospital, Garran, Australian Capital Territory, Australia

Key words

coffee, fibrotic severity, hepatocellularcarcinoma, liver inflammation, non-alcoholicfatty liver disease.

Accepted for publication 12 September 2013.

Correspondence

Professor Geoffrey C Farrell, Liver ResearchGroup, ANU Medical School at the CanberraHospital, Level 5 Building 10, Yamba Drive,Garran, ACT 2605, Australia.Email: [email protected]

Equal first author: Shaohua Chen and Narci CTeoh.

AbstractCoffee is one of the most popular beverages in the world. Several studies consistently showthat coffee drinkers with chronic liver disease have a reduced risk of cirrhosis and a lowerincidence of hepatocellular carcinoma regardless of primary etiology. With the increasingprevalence of non-alcoholic fatty liver disease (NAFLD) worldwide, there is renewedinterest in the effect of coffee intake on NAFLD severity and positive clinical outcomes.This review gives an overview of growing epidemiological and clinical evidence whichindicate that coffee consumption reduces severity of NAFLD. These studies vary inmethodology, and potential confounding factors have not always been completelyexcluded. However, it does appear that coffee, and particular components other thancaffeine, reduce NAFLD prevalence and inflammation of non-alcoholic steatohepatitis.Several possible mechanisms underlying coffee’s hepatoprotective effects in NAFLDinclude antioxidative, anti-inflammatory, and antifibrotic effects, while a chemopreventiveeffect against hepatocarcinogenesis seems likely. The so-far limited data supporting sucheffects will be discussed, and the need for further study is highlighted.

IntroductionCoffee is a brewed beverage with a distinct aroma and flavor,prepared from the roasted seeds of the coffee plant. It has been partof the human diet since the 15th century. In its various forms(including decaffeinated coffee), coffee is one of the most con-sumed drinks in the world, partly for its mild mood-enhancing andstimulatory effects on the central nervous system. Caffeine, one ofthe main constituents of coffee, has been shown to have a widespectrum of biological activities. The effects of coffee on chronicliver disease, especially in lowering the risk of developing hepa-tocellular carcinoma (HCC) has recently attracted considerableattention.

During the last 20 years, several investigators have focused onthe potential beneficial health effects of coffee, especially againstliver disease. In 1992, Klatsky and Armstrong reported an inverserelationship between coffee drinking and the risk of cirrhosis in a10-year follow-up study of a large number of subjects using mul-tivariate analysis by Cox proportional hazards model.1 Coffeedrinking also decreased the risk of clinically significant chronicliver disease.2 Other studies show that coffee drinkers (at least3 cups/day) had significantly lower levels of gamma-glutamyltranspeptidase (GGT), alanine aminotransferase (ALT), serumalkaline phosphatase, and bilirubin concentration compared withnon-coffee-drinking subjects or those consuming less than threecups daily.3 Coffee consumption has also been associated with

decreased blood GGT levels in humans, and reported to conferpossible hepatoprotection against alcoholic liver disease.4,5

On the other hand, authors found caffeine intake did not appearto affect liver stiffness (detected by transient elastography) inpatients with chronic hepatitis B virus (HBV).6 A preliminaryconclusion from these observations is that if coffee has a protectiveeffect against cirrhosis in HBV infection, this is not as significantas the viral determinants of chronic liver disease.

More than 180 million people worldwide are chronicallyinfected with the hepatitis C virus (HCV), and approximately350 000 people die every year from HCV-related liver disease,such as decompensated cirrhosis and/or HCC. Some case–controlstudies have shown that coffee consumption is associated withreduced risk of HCC among HCV-infected patients.7,8 Costentinet al. found that caffeine consumption of > 408 mg/day (≥ 3 cupscoffee) was associated with reduced histological activity inpatients with chronic HCV infection.9 However, there was norelationship between coffee consumption and fibrosis severity.9

Finally, coffee consumption may improve virological response topegylated-interferon and ribavirin antiviral treatment.10,11

Coffee consumption may be associated with a reduced risk ofHCC.12–16 This relationship appears to be very consistent, and theeffect is a powerful one. Thus, four meta-analyses found thatinverse relationship between coffee and HCC risk.17–20 Further,the relationship between coffee intake and decreased risk of HCChas been observed for several etiological types of chronic liver

doi:10.1111/jgh.12422

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435Journal of Gastroenterology and Hepatology 29 (2014) 435–441

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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disease. In those with chronic HBV infection, moderate coffeeconsumption (drinking coffee ≥ 4 times/week) was associatedwith a reduced risk of HCC by half (odds ratio [OR] = 0.54,95% confidence interval [CI]: 0.30–0.97) with a significantdose–response effect (χ2 = 5.41, df = 1, P = 0.02).21 In anotherhospital-based case–control study, it was found that a high life-time coffee consumption (≥ 20 000 cups) was an independentprotective factor against HCC in all subjects. However, highlevels of coffee consumption did not significantly affect HCCrisk in patients with HBV (OR = 0.64, 95% CI: 0.36–1.14)after adjustment for HBeAg status, serum HBV DNA level, andantiviral therapy.22

The prevalence of non-alcoholic fatty liver disease (NAFLD)is escalating rapidly worldwide in association with such metabolicdisorders as type 2 diabetes mellitus (T2DM), obesity, hyperten-sion, and hyperlipidemia (metabolic syndrome). NAFLD com-prises a pathological spectrum characterized by fat accumulationwithin the liver known as simple steatosis, or “non-NASHNAFLD,” and/or in combination with varying degrees of hepato-cellular injury manifested by ballooning, inflammation, liver fibro-sis, cirrhosis, and HCC. In NAFLD-related cirrhosis, liverhistology may no longer show inflammation or even steatosis, andthis likely represents the largest proportion of cases often referredto as “cryptogenic cirrhosis.” The diagnosis of NAFLD is usuallymade by abnormal liver tests and hepatic imaging showing fea-tures of fatty infiltration (“bright liver”) in the context of obesity, afamily history of diabetes, and/or features of metabolic syndrome;as well, other causes of liver disease and significant alcohol intakemust be excluded.

Several studies of hepatic lipid metabolism, insulin resistance,mitochondrial dysfunction, oxidative stress, as well as geneticpredisposition to altered cell metabolism and injury have contrib-uted to current understanding of NAFLD.23 Lifestyle measuresdirected at increasing physical activity (which counters insulinresistance) and weight loss remain the cornerstone of manage-ment. Notably, the effects of pharmacotherapy are still conten-tious; most agents studied are either modest in their effects, such asvitamin E, pioglitazone, ezetimibe, or pentoxifyllne, or have nobeneficial long-term hepatoprotective effects (e.g. metformin,ursodeoxycholic acid). In general, moderate energy and simplecarbohydrate restriction, reduction of total and saturated fat intake,along with increasing physical activity are beneficial and highlyrecommended. Interestingly, recent studies have shown that coffeedrinking may be protective against NAFLD-related chronic liverdisease and possibly, HCC.

Sources of informationThis systematic review is the first that we are aware of to focus onthe epidemiology, magnitude, and mechanisms of possible benefi-cial effects of coffee consumption in patients with NAFLD. Using“liver disease” and “coffee” as search terms in the PubMed data-base, 240 articles were returned. The abstracts of all these articleswere reviewed, and 12 studies that evaluated relationship betweenNAFLD and coffee were examined in detail. Specific questionspertaining to this area of research were evaluated, as indicatedbelow. The number of articles published about coffee and liverdisease has increased steadily since 2003 (Fig. 1).

Relationship between coffeeconsumption and NAFLD in communitystudiesFour continuous cycles of the National Health and NutritionExamination Surveys (NHANES, USA 2001–2008) were used toinvestigate the effects of dietary behavior in NAFLD patients.Dietary intake was evaluated by questionnaires that includednutrition components. Multivariate analyses were conducted ofvariables that included demographics, clinical parameters, andnutritional components in relation to presence of NAFLD (definedin this study by elevated aminotransferase, without ultrasonogra-phy). Five factors were independently associated with NAFLD:African American race, male gender, obesity, caffeine intake, aswell as plain water consumption. These findings show a strongassociation between coffee consumption and protection against thedevelopment of NAFLD24 (see Table 1). The limitation of theNHANES data analysis is the restricted define of NAFLD; caseswith cirrhosis may not have shown elevated ALT.

In an Italian study, 137 NAFLD cases and 108 controls wereenrolled, and coffee intake determined by the absolute number ofcups 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 analyzed by homoeostasis modelassessment-insulin resistance (HOMA-IR) index. When comparedwith non-coffee drinkers, those who consumed coffee had lesssevere fatty liver evaluated by ultrasound “bright liver score”(BLS). Further, obesity, insulin resistance, lower high-densitylipoprotein (HDL) cholesterol, older age, and arterial hypertensionwere 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 associ-ated with the degree of “bright liver,” while insulin resistance andobesity were directly associated with increased likelihood andseverity of BLS on ultrasound.25 A case–control study fromMexico also found similar protective effects of coffee consump-tion against NAFLD as assessed by ultrasonography26 (Table 1).The limitations of these studies are the insensitivity of ultrasoundfor minor grade of steatosis and possibly for established cirrhosiswhen steatosis may be resolved.

The association of caffeine consumption with both the preva-lence and severity of NAFLD was further established in anotherstudy where a validated questionnaire of caffeine consumptionwas utilized to determine if there was a relationship betweencaffeine intake and NAFLD severity, this time established by

Figure 1 Number of publications related to coffee intake and liverdisease in the past decade.

Coffee and fatty liver S Chen et al.

436 Journal of Gastroenterology and Hepatology 29 (2014) 435–441


histological examination of liver biopsies. In this study, the authorsreported a strong inverse relationship between caffeine consump-tion and hepatic fibrosis27 (Table 1).

Mechanisms by which coffee mayreduce severity of NAFLDDespite the persuasive epidemiological data, particularly for ultra-sound and histological studies, the cellular and molecular mecha-nisms underlying the effects of coffee consumption in patientswith NAFLD remain undefined. Antioxidant, anti-inflammatory,antifibrotic, and altered energy metabolism have been potentiallyimplicated.

Prior to examining these possible effects of coffee on NAFLD,a consideration of coffee constituents is important. The basicchemical composition of coffee depends on its species and physi-ological aspects. The main bioactive compounds and their effectson liver disease are listed in Table 2 and have been reviewed.24,27–35

Coffee and T2DM. Individuals with T2DM have higher inci-dence of NAFLD, while NAFLD exacerbates hepatic insulin resis-tance and increases the risk of developing T2DM.36,37 To date,systematic reviews and meta-analysis have indicated that highercoffee consumption is consistently associated with a lower risk ofT2DM. This association does not depend on race, gender, geo-graphic distribution of the study populations, or the type of coffeeconsumed.38–41 The mechanism(s) for this strong protective effectof coffee on T2DM is still needed to be elucidated. High coffeeconsumption was associated with greater insulin sensitivity inseveral but not all cross-sectional studies.40 Increased plasmaadiponectin, antioxidation, anti-inflammation, and thermogeniceffect of coffee may contribute to the lower risk of T2DM.41,42

Coffee and oxidative injury. Of interest, there have beenseveral studies which indicate that coffee consumption is inverselyrelated to the incidence of diseases in which reactive oxygenspecies (ROS) are involved. It is postulated that the antioxidantproperties of coffee may account for this phenomenon. Vitaglioneet al.34 established a high-fat-diet (HFD)-induced non-alcoholicsteatohepatitis (NASH) model in male Wistar rats to study theprotective mechanisms of coffee, or its component polyphenols ormelanoidins against NAFLD. Biomarkers of antioxidant statusmeasured in both serum and liver samples show that HFD-fed ratshad significantly higher concentrations of oxidized glutathione(GSSG) than control rats. Coffee, polyphenols, or melanoidinsreduced GSSG concentrations in HFD-fed rats supplementedwith coffee in their drinking water compared with those givenwater only. Likewise, serum malondialdehyde concentrationwas significantly higher in rats in the HFD group than in controlrats (2.03 ± 0.14 μM vs 1.47 ± 0.12 μM). Coffee consumption(1.50 ± 0.09 μM) or polyphenols (1.62 ± 0.08 μM) returned theselevels to control values. Further, there was a significant increasein antioxidant capacity in rats treated with polyphenols in drink-ing water compared with controls (0.36 ± 0.02 mM Trolox®equivalent [TE] vs 0.32 ± 0.01 mM TE).34

Goya L et al. investigated the potential protective effect ofcoffee melanoidins, in particular, a water-soluble high-molecularweight fraction, on the redox status of cultured human HCC,HepG2 cells. The results show that coffee melanoidins conferredsignificant protection against oxidative insults.35

To establish whether coffee consumption protects humansagainst oxidative DNA damage, a cross-over intervention studywas conducted. In this trial, 38 participants consumed 800 mLcoffee (or water in controls) daily over 5 days. DNA damagewas measured in peripheral lymphocytes. The extent of DNA

Table 1 Relationship between coffee consumption and non-alcoholic fatty liver disease (NAFLD) in community studies

Authors(Reference)

Subjects Design Results Comments

Birerdinc Aet al.24

2012; USA

1 782 NAFLD; 16 768controls from 4continuous cycles ofNHANES

NAFLD defined byALT/AST exclusive ofother liver disease

Caffeine intake in NAFLD 165 ± 6.55 mg, controls188 ± 4.90 mg (P = 0.0006). MVA showed caffeineintake an independent predictor of NAFLD(OR = 0.999, 95% CI: 0.999–1.00, P = 0.0003)

Minor effect inloweringprevalence ofNAFLD

Catalano Det al.25

2010; Italy

137 NAFLD; 108controls.

Assessed by ultrasoundBLS, with exclusioncriteria

BLS less in coffee drinkers than in non-coffeedrinkers. Coffee consumption as cups/day(0/< 3/≥ 3) per groups by BLS:

severe: 9/7/0; moderate: 12/37/33;light: 9/21/29 (P < 0.0001)

Inverse associationbetween coffeeintake and degreeof BLS

Gutierrez-Grobe,Y et al.26

2012;Mexico

57 NAFLD73 controls.

Case control studyAssessed by

ultrasonographyDietary history

questionnaire.

Coffee intake(log caffeine) between differentseverity of NAFLD:

severe steatosis: 0.15 ± 0.05;moderate steatosis: 1.58 ± 0.72;mild steatosis: 1.61 ± 0.79;no steatosis: 1.75 ± 0.70(P ≤ 0.05)

High coffee intakeassociated withlower gradeNAFLD

Molloy JWet al.27

2012; USA

36 NASH stage 2–4;61 NASH stage 0–1;83 bland steatosis;126 controls

Biopsied NAFLD cases.Validated caffeinequestionnaire

Coffee caffeine intake (mg/day):NASH stage 2–4: 153;NASH stage 0–1: 256;bland steatosis: 160;controls: 228. (r = −0.215, P = 0.035).

Negative correlationbetween caffeineintake and stageof fibrosis

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BLS, bright liver score; MVA, multivariate analysis; NASH, non-alcoholic steato-hepatitis; NHANES, National Health and Nutrition Examination Surveys.

S Chen et al. Coffee and fatty liver



migration attributable to formation of oxidized purines (alsoknown as formamidopyrimidine glycosylase sensitive sites) wasdecreased by 12% after coffee intake (P = 0.006). These findingssuggest that coffee consumption prevents endogenous formationof oxidative DNA damage in humans. While this observationmay 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, glutathioneconcentrations in blood, intracellular ROS levels, and the activitiesof superoxide dismutase and glutathione peroxidase in lympho-cytes were not markedly altered at the end of the trial.43

Investigators have observed different levels of oxidative DNAdamage and DNA repair in the livers of coffee-fed mice.44 Inone study, lean male mice were fed 0.1% (w/v) instant coffeesolution prepared weekly with 60°C tap water. At 2, 4, and8 months, there was no difference in the hepatic levels of 8-hydroxydeoxyguanosine (8-OH-dG, a marker of oxidative DNAdamage) and 8-OH-dG repair-associated genes, redox system-associated genes, and hepatic lipoperoxide levels between thecoffee-fed and control groups of mice. These results suggest that

instant coffee consumption has little, if any, effect on hepaticoxidative stress in lean mice. Similarly, others report little or nosignificant 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 ± 3.4 U/mL),or thiobarbituric acid-reactive substances (3.9 ± 1.5 vs 4.0 ±1.8 μM/mL) between NAFLD and controls. Hence, while coffeeintake has a protective effect against severity of NAFLD, theweight of evidence (albeit, currently incomplete) is that coffee’spositive effects are unlikely to be attributable to any differencesin antioxidant variables.26

Coffee and liver inflammation. Coffee intake has beenassociated with reduced levels of abnormalities in serum aspartateaminotransferase (AST), ALT,45–47 and GGT.48 Fukushima Yet al.49 conducted a study where mice were fed HFD to induceNAFLD, then treated with or without coffee (1.1% decaffeinated/caffeine-containing instant coffee). Mesenteric fat weight waslower in the HFD+coffee group than those fed a HFD withoutcoffee (P < 0.05). Further, serum AST and ALT levels weresignificantly lower in the HFD+coffee group than in mice fed aHFD only (P < 0.05). Pro-inflammatory interleukin-1beta (IL-1β)gene expression in murine liver was upregulated in the HFDgroup and was significantly downregulated by coffee consumption(P < 0.01). Expression of monocyte chemoattractant protein-1 inliver and adipose was also suppressed in the HFD+coffee group.Hence, coffee consumption appears to significantly reduce hepaticpro-inflammatory response.

In a separate study, co-administration of coffee with a HFD inrodents 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 ofadiponectin receptor and peroxisome proliferator-activated recep-tor α. Coffee also lowered hepatic concentrations of TNF-α,interferon-γ and increased anti-inflammatory cytokines, IL-4,and IL-10.34

Coffee and hepatic fibrosis. Few studies have discussedthe influence of coffee on liver fibrosis in NAFLD. In a recentEuropean study, 195 morbidly obese patients referred for bariatricsurgery were assessed.50 Liver biopsies showed NASH in 19%,and significant fibrosis in 35%. By logistic regression analysis,regular coffee intake was an independent factor negatively associ-ated 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 indepen-dently protective against fibrosis.50 Sucrose, which is composed ofglucose and fructose, is often added by espresso consumers to theircoffee and the authors noted that this may have potentially coun-tered coffee’s positive effects in this study, particularly by thepotential detrimental effect of fructose on NAFLD. Thus, fructoseconsumption has been noted to aggravate the severity of liverfibrosis in North American patients who have NASH.51,52

Few studies have addressed the mechanism for the possibleanti-fibrotic effects of coffee on liver fibrosis in NAFLD. InNASH-associated fibrosis, the principal cell type responsible forextracellular matrix production is the hepatic stellate cell.53 Themechanisms of fibrogenesis in the liver are dependent on an inter-play of many pro-fibrotic and anti-fibrotic cytokines and growth

Table 2 List of chemical composition of coffee proposed biologicaleffects

Constituents Effects References

Carbohydrates andfiber

SucroseReducing sugars

Most non-digestible, thedigestible carbohydratefraction is negligible.

28

Nitrogenouscompounds

Protein/peptidesFree amino acidsCaffeineTrigonelline

Caffeine: stimulation of hepaticlipid metabolism, induction ofthermogenesis, anti-oxidativestress, anti-fibrosis

24,27,28

LipidsCoffee oilDiterpenes (Cafestol

and Kahweol)

Cafestol and Kahweol:cholesterol raising,anti-carcinogenesis

29,30

Minerals Potassium: reducinghypertension but in minimalamount

28

Acids and esters/polyphenol

Chlorogenic acidsAliphatic acidsQuinic acid

CPP: enhancing energymetabolism, reducinglipogenesis, downregulatingSREBP-1c

Chlorogenic acids: thepredominant antioxidant incoffee; reducing hepaticglucose output, loweringcholesterol, attenuating fattyliver and upregulating PPAR-α

28,31,32,33

Melanoidins Anti-oxidation, anti-inflammation, and increaseexpression of adiponectinreceptor and PPAR-α

34,35

CPP, coffee polyphenol; PPAR-α, peroxisome proliferator activatedreceptor α; SREBP-1c, sterol regulatory element-binding protein-1c.




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 factorsin NAFLD, and which can also mediate matrix production.54

Caffeine inhibits CTGF synthesis in hepatocytes and liver non-parenchymal cells, primarily by inducing degradation of Smad2,thereby interrupting TGF-β signaling.55

Coffee and hepatic metabolism. The liver plays diverseand crucial roles in lipogenesis, gluconeogenesis, and cholesterolmetabolism.37 In a rodent model that develops metabolic syndromeand NAFLD when fed a high-carbohydrate, HFD, supplementa-tion with Colombian coffee extract improved glucose tolerance,decreased hypertension, induced cardiovascular remodeling, andattenuated NAFLD severity. Of note, these changes were notassociated with weight loss or reduction of serum lipids in theanimals.56 Interestingly, one study reported that some coffeebrewing techniques raise serum total and low-density-lipoproteincholesterol concentrations in humans.29 The diterpene lipids,cafestol, and kahweol (also main constituents of coffee) wereconsidered to be the responsible lipid-altering factors. In contrast,filtered coffee does not appear to affect serum cholesterol, and thisis thought to be related to the removal of diterpenes by the filtra-tion process (filter paper).29

Adiponectin is an adipokine that governs insulin sensitivity andhas potent anti-inflammatory effects. Plasma adiponectin levelsare often lower in patients with NAFLD, and correlate inverselywith the severity of steatosis and NASH. In a cross-sectionalstudy 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 thatcoffee consumption was associated with higher serum adiponectinand lower serum leptin levels.57

Coffee is also enriched with polyphenols (coffee polyphenols,CPP). The effects of CPP on diet-induced body fat accumulationwas investigated, and C57BL/6J mice were fed either a controldiet, HFD, or HFD supplemented with 0.5–1.0% CPP for 2–15

weeks. Supplementation of a HFD with CPP significantly reducedbody weight gain, abdominal and liver fat accumulation, aswell macrophage infiltration into adipose. Energy expenditure,evaluated by indirect calorimetry, was significantly increased inCPP-fed mice. The hepatic transcript levels of sterol regulatoryelement-binding protein (SREBP)-1c, acetyl-CoA carboxylase-1and -2, stearoyl-CoA desaturase-1, and pyruvate dehydrogenasekinase-4 were also significantly reduced in CPP-fed mice com-pared with HFD mice. CPP has also been shown to suppress theexpression of SREBP-1c in Hepa 1–6 cells, with a concomitantincrease in microRNA (miR)-122. Structure–activity relationshipstudies of nine quinic acid derivatives isolated from CPP in Hepa1–6 cells also suggest that mono- or di-caffeoylquinic acids mayhave potent and potentially beneficial effects.33 Thus, it appearsthat CPP enhances energy metabolism, reduces lipogenesis bydownregulating SREBP-1c and related signaling pathways,thereby suppressing the accumulation of body fat and newlysynthesized (saturated) fatty acids in the liver.33

Conclusions and future perspectivesTaken together, these studies provide reasonably strong evidencefor a protective effect of coffee consumption on development ofNAFLD, and on reducing its severity in NASH. Since the mostconvincing effect of coffee consumption on other forms of liverdisease is its association with a substantially reduced rate of HCC,future studies on HCC in NAFLD examining coffee consumptionwith other potential environmental factors (fructose, vegetables,smoking, vitamin D, and selenium, etc.) are keenly awaited.Meanwhile, it does appear that possible hepatoprotective effects ofcoffee are related more to polyphenols not caffeine. The possibleprotective effects of coffee bean polyphenols may be related toa diverse range of mechanisms, including anti-oxidant, anti-inflammatory, anti-fibrotic pathways as well as modulation inenergy metabolism, reduced insulin resistance, and reduced sever-ity of diabetes (Fig. 2). However, studies to date have been explor-atory and confined to a limited range of experimental systems,only a small subset of which have utilized clinically relevant

Figure 2 Schematic diagram illustrating themechanisms underlying coffee’s potentialhepatoprotective effects in non-alcoholicfatty liver disease. CTGF, connective tissuegrowth factor; GSSG, oxidized glutathione;IFN-γ, interferon-γ; IL-10, interleukin-10; IL-1β,interleukin-1β; IL-4, interleukin-4; MCP-1,monocyte chemoattractant protein-1; NASH,non-alcoholic steatohepatitis; PPAR-α, peroxi-some proliferator-activated receptor α; ROS,reactive oxygen species; Smad2, Mothersagainst decapentaplegic homolog 2, SMADfamily member 2; SREBP-1C, sterol regulatoryelement-binding protein-1C; TGF-β, transform-ing growth factor β; TNF-α, tumor necrosisfactor α.




experimental models of NASH. It is clear that some components ofcoffee other than caffeine may be involved, and specific identifi-cation of these compounds require more rigorous study to eluci-date the mechanisms underlying coffee’s hepatoprotective effectsin patients with NAFLD.

References1 Klatsky AL, Armstrong MA. Alcohol, smoking, coffee, and

cirrhosis. Am. J. Epidemiol. 1992; 136: 1248–57.2 Ruhl CE, Everhart JE. Coffee and tea consumption are associated

with a lower incidence of chronic liver disease in the United States.Gastroenterology 2005; 129: 1928–36.

3 Casiglia E, Spolaore P, Ginocchio G, Ambrosio GB. Unexpectedeffects of coffee consumption on liver enzymes. Eur. J. Epidemiol.1993; 9: 293–7.

4 Danielsson J, Kangastupa P, Laatikainen T, Aalto M, Niemela O.Dose- and gender-dependent interactions between coffeeconsumption and serum GGT activity in alcohol consumers. AlcoholAlcohol. 2013; 48: 303–7.

5 Ikeda M, Maki T, Yin G et al. Relation of coffee consumption andserum liver enzymes in Japanese men and women with reference toeffect modification of alcohol use and body mass index. Scand. J.Clin. Lab. Invest. 2010; 70: 171–9.

6 Ong A, Wong VW, Wong GL, Chan HL. The effect of caffeine andalcohol consumption on liver fibrosis—a study of 1045 Asianhepatitis B patients using transient elastography. Liver Int. 2011; 31:1047–53.

7 Ohfuji S, Fukushima W, Tanaka T et al. Coffee consumption andreduced risk of hepatocellular carcinoma among patients withchronic type C liver disease: a case-control study. Hepatol. Res.2006; 36: 201–8.

8 Wakai K, Kurozawa Y, Shibata A et al. Liver cancer risk, coffee,and hepatitis C virus infection: a nested case-control study in Japan.Br. J. Cancer 2007; 97: 426–8.

9 Costentin CE, Roudot-Thoraval F, Zafrani ES et al. Association ofcaffeine intake and histological features of chronic hepatitis C.J. Hepatol. 2011; 54: 1123–9.

10 Freedman ND, Curto TM, Lindsay KL, Wright EC, Sinha R,Everhart JE. Coffee consumption is associated with response topeginterferon and ribavirin therapy in patients with chronic hepatitisC. Gastroenterology 2011; 140: 1961–9.

11 Freedman ND, Everhart JE, Lindsay KL et al. Coffee intake isassociated with lower rates of liver disease progression in chronichepatitis C. Hepatology 2009; 50: 1360–9.

12 Tanaka K, Hara M, Sakamoto T et al. Inverse association betweencoffee drinking and the risk of hepatocellular carcinoma: acase-control study in Japan. Cancer Sci. 2007; 98: 214–18.

13 Kurozawa Y, Ogimoto I, Shibata A et al. Coffee and risk of deathfrom hepatocellular carcinoma in a large cohort study in Japan.Br. J. Cancer 2005; 93: 607–10.

14 Gelatti U, Covolo L, Franceschini M et al. Coffee consumptionreduces the risk of hepatocellular carcinoma independently of itsaetiology: a case-control study. J. Hepatol. 2005; 42: 528–34.

15 Shimazu T, Tsubono Y, Kuriyama S et al. Coffee consumption andthe risk of primary liver cancer: pooled analysis of two prospectivestudies in Japan. Int. J. Cancer 2005; 116: 150–4.

16 Inoue M, Yoshimi I, Sobue T, Tsugane S, Group JS. Influence ofcoffee drinking on subsequent risk of hepatocellular carcinoma:a prospective study in Japan. J. Natl Cancer Inst. 2005; 97:293–300.

17 Bravi F, Bosetti C, Tavani A, Gallus S, La Vecchia C. Coffeereduces risk for hepatocellular carcinoma: an updated

meta-analysis. Clin. Gastroenterol. Hepatol. 2013; 11: 1413–21.doi: 10.1016/j.cgh.2013.04.039.

18 Sang LX, Chang B, Li XH, Jiang M. Consumption of coffeeassociated with reduced risk of liver cancer: a meta-analysis.BMC Gastroenterol. 2013; 13: 34.

19 Bravi F, Bosetti C, Tavani A et al. Coffee drinking andhepatocellular carcinoma risk: a meta-analysis. Hepatology 2007; 46:430–5.

20 Larsson SC, Wolk A. Coffee consumption and risk of liver cancer:a meta-analysis. Gastroenterology 2007; 132: 1740–5.

21 Leung WW, Ho SC, Chan HL, Wong V, Yeo W, Mok TS. Moderatecoffee consumption reduces the risk of hepatocellular carcinoma inhepatitis B chronic carriers: a case-control study. J. Epidemiol.Community Health 2011; 65: 556–8.

22 Jang ES, Jeong SH, Lee SH et al. The effect of coffee consumptionon the development of hepatocellular carcinoma in hepatitis B virusendemic area. Liver Int. 2013; 33: 1092–9.

23 Cheung O, Sanyal AJ. Recent advances in nonalcoholic fatty liverdisease. Curr. Opin. Gastroenterol. 2010; 26: 202–8.

24 Birerdinc A, Stepanova M, Pawloski L, Younossi ZM. Caffeineis protective in patients with non-alcoholic fatty liver disease.Aliment. Pharmacol. Ther. 2012; 35: 76–82.

25 Catalano D, Martines GF, Tonzuso A, Pirri C, Trovato FM, TrovatoGM. Protective role of coffee in non-alcoholic fatty liver disease(NAFLD). Dig. Dis. Sci. 2010; 55: 3200–6.

26 Gutierrez-Grobe Y, Chavez-Tapia N, Sanchez-Valle V et al. Highcoffee intake is associated with lower grade nonalcoholic fatty liverdisease: the role of peripheral antioxidant activity. Ann. Hepatol.2012; 11: 350–5.

27 Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM,Harrison SA. Association of coffee and caffeine consumption withfatty liver disease, nonalcoholic steatohepatitis, and degree of hepaticfibrosis. Hepatology 2012; 55: 429–36.

28 Tunnicliffe JM, Shearer J. Coffee, glucose homeostasis, and insulinresistance: physiological mechanisms and mediators. Appl. Physiol.Nutr. Metab. 2008; 33: 1290–300.

29 Urgert R, Katan MB. The cholesterol-raising factor from coffeebeans. Annu. Rev. Nutr. 1997; 17: 305–24.

30 Cavin C, Holzhaeuser D, Scharf G, Constable A, Huber WW,Schilter B. Cafestol and kahweol, two coffee specific diterpeneswith anticarcinogenic activity. Food Chem. Toxicol. 2002; 40:1155–63.

31 Wan CW, Wong CN, Pin WK et al. Chlorogenic acid exhibitscholesterol lowering and fatty liver attenuating properties byup-regulating the gene expression of PPAR-alpha inhypercholesterolemic rats induced with a high-cholesterol diet.Phytother. Res. 2013; 27: 545–51.

32 Herling AW, Burger HJ, Schwab D, Hemmerle H, Below P,Schubert G. Pharmacodynamic profile of a novel inhibitor of thehepatic glucose-6-phosphatase system. Am. J. Physiol. 1998; 274:G1087–1093.

33 Murase T, Misawa K, Minegishi Y et al. Coffee polyphenolssuppress diet-induced body fat accumulation by downregulatingSREBP-1c and related molecules in C57BL/6J mice. Am. J. Physiol.Endocrinol. Metab. 2011; 300: E122–133.

34 Vitaglione P, Morisco F, Mazzone G et al. Coffee reduces liverdamage in a rat model of steatohepatitis: the underlying mechanismsand the role of polyphenols and melanoidins. Hepatology 2010; 52:1652–61.

35 Goya L, Delgado-Andrade C, Rufian-Henares JA, Bravo L,Morales FJ. Effect of coffee melanoidin on human hepatomaHepG2 cells. Protection against oxidative stress induced bytert-butylhydroperoxide. Mol. Nutr. Food Res. 2007; 51:536–45.




36 Masuoka HC, Chalasani N. Nonalcoholic fatty liver disease: anemerging threat to obese and diabetic individuals. Ann. N. Y. Acad.Sci. 2013; 1281: 106–22.

37 Targher G, Byrne CD. Clinical review: nonalcoholic fatty liverdisease: a novel cardiometabolic risk factor for type 2 diabetes andits complications. J. Clin. Endocrinol. Metab. 2013; 98: 483–95.

38 van Dam RM. Coffee consumption and risk of type 2 diabetes,cardiovascular diseases, and cancer. Appl. Physiol. Nutr. Metab.2008; 33: 1269–83.

39 Huxley R, Lee CM, Barzi F et al. Coffee, decaffeinated coffee, andtea consumption in relation to incident type 2 diabetes mellitus: asystematic review with meta-analysis. Arch. Intern. Med. 2009; 169:2053–63.

40 van Dam RM, Hu FB. Coffee consumption and risk of type 2diabetes: a systematic review. JAMA 2005; 294: 97–104.

41 Natella F, Scaccini C. Role of coffee in modulation of diabetes risk.Nutr. Rev. 2012; 70: 207–17.

42 Williams CJ, Fargnoli JL, Hwang JJ et al. Coffee consumption isassociated with higher plasma adiponectin concentrations in womenwith or without type 2 diabetes: a prospective cohort study. DiabetesCare 2008; 31: 504–7.

43 Misik M, Hoelzl C, Wagner KH et al. Impact of paper filtered coffeeon oxidative DNA-damage: results of a clinical trial. Mutat. Res.2010; 692: 42–8.

44 Morii H, Kuboyama A, Nakashima T et al. Effects of instant coffeeconsumption on oxidative DNA damage, DNA repair, and redoxsystem in mouse liver. J. Food Sci. 2009; 74: H155–161.

45 Ruhl CE, Everhart JE. Coffee and caffeine consumption reduce therisk of elevated serum alanine aminotransferase activity in the UnitedStates. Gastroenterology 2005; 128: 24–32.

46 Honjo S, Kono S, Coleman MP et al. Coffee consumption and serumaminotransferases in middle-aged Japanese men. J. Clin. Epidemiol.2001; 54: 823–9.

47 Nakanishi N, Nakamura K, Suzuki K, Tatara K. Effects of coffeeconsumption against the development of liver dysfunction: a 4-year

follow-up study of middle-aged Japanese male office workers. Ind.Health 2000; 38: 99–102.

48 Nakanishi N, Nakamura K, Nakajima K, Suzuki K, Tatara K. Coffeeconsumption and decreased serum gamma-glutamyltransferase: astudy of middle-aged Japanese men. Eur. J. Epidemiol. 2000; 16:419–23.

49 Fukushima Y, Kasuga M, Nakao K, Shimomura I, Matsuzawa Y.Effects of coffee on inflammatory cytokine gene expression in micefed high-fat diets. J. Agric. Food Chem. 2009; 57: 11100–5.

50 Anty R, Marjoux S, Iannelli A et al. Regular coffee but not espressodrinking is protective against fibrosis in a cohort mainly composedof morbidly obese European women with NAFLD undergoingbariatric surgery. J. Hepatol. 2012; 57: 1090–6.

51 Ouyang X, Cirillo P, Sautin Y et al. Fructose consumption as a riskfactor for non-alcoholic fatty liver disease. J. Hepatol. 2008; 48:993–9.

52 Abdelmalek MF, Suzuki A, Guy C et al. Increased fructoseconsumption is associated with fibrosis severity in patients withnonalcoholic fatty liver disease. Hepatology 2010; 51: 1961–71.

53 Fujii H, Kawada N. Inflammation and fibrogenesis in steatohepatitis.J. Gastroenterol. 2012; 47: 215–25.

54 Gressner OA, Gressner AM. Connective tissue growth factor: afibrogenic master switch in fibrotic liver diseases. Liver Int. 2008;28: 1065–79.

55 Gressner OA. Less Smad2 is good for you! A scientific update oncoffee’s liver benefits. Hepatology 2009; 50: 970–8.

56 Panchal SK, Poudyal H, Waanders J, Brown L. Coffee extractattenuates changes in cardiovascular and hepatic structure andfunction without decreasing obesity in high-carbohydrate, high-fatdiet-fed male rats. J. Nutr. 2012; 142: 690–7.

57 Yamashita K, Yatsuya H, Muramatsu T, Toyoshima H, Murohara T,Tamakoshi K. Association of coffee consumption with serumadiponectin, leptin, inflammation and metabolic markers inJapanese workers: a cross-sectional study. Nutr. Diabetes 2012;2: e33.




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