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A Comprehensive Overview of the Risks and Benefits of Coffee Consumption 1

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Authors: L. Kirsty Pourshahidi*1, Luciano Navarini2, Marino Petracco2 & JJ Strain1 3

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Affiliations: 1Northern Ireland Centre for Food and Health (NICHE), University of Ulster, 5

Coleraine, BT52 1SA, UK 6

2illycaffè s.p.a, Trieste, Italy 7

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*Corresponding author: Dr Kirsty Pourshahidi, Room W2038, Northern Ireland Centre for 9

Food and Health (NICHE), University of Ulster, Coleraine, BT52 1SA, UK 10

Tel: +44 (0) 28 7012 4030; Fax: +44 (0) 28 7012 4965; Email: k.pourshahidi@ulster.ac.uk 11

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Short title: Coffee consumption and human health 14

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Keywords: Coffee; human; health; risk; benefit 16

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Manuscript number: CRF3-2015-1797.R1 20

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Word count (including abstract & references, but excluding tables & figures): 11,657 25

Number of tables: 10 26

Number of figures: 1 27

Supplementary documents: 1 (pdf file) 28

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Contents: 29

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ABSTRACT 31

1. Introduction 32

2. Methods 33

3. Results 34

3.1. Cancer 35

3.2. Cardiovascular disease (CVD) 36

3.3. Metabolic health 37

3.4. Neurological disorders 38

3.5. Gastrointestinal conditions 39

3.6. Liver disorders 40

3.7. Mortality 41

3.8. Other conditions/health outcomes 42

3.9. Additional risks 43

4. Conclusions 44

5. Future work 45

6. Acknowledgements 46

7. Author contributions 47

8. References 48

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ABSTRACT 49

Findings on both the health benefits and the potentially harmful effects of coffee consumption 50

have been contradictory. However, the general scientific consensus is that moderate, regular 51

coffee drinking by healthy individuals is either essentially benign or mildly beneficial. Results 52

and generalizations are complicated by a number of factors, including differences in age, 53

gender, health status, type of coffee preparation, serving size, source of coffee. Coffee may 54

have potential health benefits as well as risks, but causality cannot be established for either 55

with the research currently available as these are largely based on observational data. This 56

review aimed to provide a comprehensive overview of the risks and benefits of coffee 57

consumption on health outcomes. A systematic search [search terms: ‘coffee’ OR ‘coffee adj3 58

(consum* or intake* or drink*)] of the literature (from 1970; humans; in English) using the 59

electronic databases ‘OVID’, ‘CINAHL’, and ‘Web of Knowledge’ returned 12,405 results. 60

Duplicates were removed, studies were screened (based on inclusion/exclusion criteria) and 61

the remaining eligible studies (n=1,277) were used to collate an exhaustive list of the potential 62

health benefits and risks of coffee consumption, which were grouped and are discussed with 63

regard to major diseases/conditions (mortality, CVD, cancer and metabolic/liver/neurological 64

disorders), at-risk/vulnerable groups, and specific coffee constituents. This qualitative 65

assessment has shown that the health benefits (or null effects) clearly outweigh the risks of 66

moderate coffee consumption in adult consumers for the majority of health outcomes 67

considered. Results from this research may aid further qualitative and quantitative 68

deterministic risk-benefit assessments of coffee consumption. 69

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250 words 71

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1. Introduction 72

Coffee is a widely consumed beverage worldwide and extensive scientific research has 73

been conducted to examine the relationship between coffee consumption and a wide range of 74

chronic diseases and health outcomes, including total mortality, many cancers, 75

cardiometabolic risk, liver disorders, and neurological conditions. Such effects have been 76

attributed to many different bioactive constituents of coffee, including caffeine 77

(methylxanthine), chlorogenic acids (polyphenol), diterpenes, and other phenolics, some of 78

which may also potentially have additive or synergistic effects. 79

Although both findings on the potential health benefits and harmful effects of coffee 80

consumption have historically been reported, the general consensus is that moderate, regular 81

coffee drinking by healthy individuals is either essentially benign or mildly beneficial (George 82

and others 2008; Cano-Marquina and others 2013; O'Keefe and others 2013; Fardet and 83

Boirie 2014). Findings to-date are largely based on observational data, albeit from large 84

prospective cohort studies as well as case-control and cross-sectional data. However, 85

heterogeneity between study populations and designs, and also lack of control for many other 86

confounding factors, add limitations to the existing literature. Moreover, studies or meta-87

analyses to-date typically focus on single disease outcomes or endpoints and few (if any) 88

weigh up the benefits and risks on multiple health outcomes. 89

Therefore, the aim of this review was to provide a comprehensive overview of the risks and 90

benefits of coffee consumption on health outcomes. 91

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2. Methods 93

A systematic search for the appropriate literature (from 1970, limited to humans and 94

available in English) was conducted using the online electronic databases ‘OVID’ (AMED, 95

FSTA, EMBASE, MEDLINE (PubMED), PSYCinfo), ‘CINAHL’ (academic journals only), and 96

‘Web of Knowledge: Web of Science with Conference Proceedings’, together with manual 97

searches of reference lists. 98

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Searches were conducted using coffee as a broad search term, or within 3 words of 99

consumption/consume(r), intake(s) or drink(s) [‘coffee’ OR ‘coffee adj3 (consum* or intake* or 100

drink*)]. Duplicates were then removed, and remaining studies were screened for eligibility 101

based on set inclusion and exclusion criteria (Table 1). To be eligible for inclusion, studies 102

must have been conducted in humans and have reported original data linking the effect of 103

coffee consumption on a specified health outcome(s). All types of coffee were included as 104

relevant (such as instant, filtered, cafetiere, or boiled), although those studies concerned with 105

the effect of caffeine per se, were excluded. 106

Eligible studies were then qualitatively evaluated and were used to collate an exhaustive 107

list of the potential health benefits and harmful effects of coffee consumption. Health benefits 108

and risks were grouped and discussed with regard to: 109

total mortality; 110

cardiovascular disease (CVD); 111

cancers; 112

metabolic health (for example, diabetes, metabolic syndrome, insulin resistance, 113

weight gain); 114

liver disorders (for example, non-alcoholic fatty liver disease, cirrhosis); 115

gastrointestinal conditions (for example, peptic/gastric ulcers, dyspepsia, bowel 116

function); 117

neurological disorders (for example, Alzheimer’s disease, dementia, cognitive 118

function/decline, mental health); 119

other miscellaneous health outcomes/conditions. 120

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Additional risks of coffee consumption were also discussed according to at-risk/vulnerable 122

groups (for example, pregnancy, elderly) and specific ‘bioactive’ constituents identified during 123

the literature search (such as, caffeine, diterpenes, acrylamide, furan, mycotoxins). 124

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3. Results 126

The study selection and screening process is illustrated in Figure 1. Initially, 12,329 results 127

were returned following the literature searches. An additional 76 studies were identified by 128

email alerts updating the searches within the Web of Knowledge database (total, n=12,405 129

studies). 130

After screening to remove duplicate citations (n=6,047) and exclusion of the studies 131

deemed unsuitable for inclusion (n=5,081) based on the pre-determined inclusion/exclusion 132

criteria, a total of 1,277 studies were included in the review. This represented approximately 133

10% of those studies identified by the original search strategy. 134

For each category of the health conditions/outcome discussed below, example citations 135

are included to highlight the key points. A complete bibliography list of all studies reviewed is 136

included as Supplementary Material. 137

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3.1. Cancer 139

Coffee consumption has been linked to cancer risk or incidence in virtually every tissue 140

type in the body, with the most commonly reported sub-sites being colorectal, bladder/urinary 141

tract, pancreatic, and female-specific and breast cancers. A total of 352 (27.6%) studies have 142

reported links between coffee consumption and cancer, and these are typically observational 143

(Table 2). Only the more mechanistic studies are tested using an intervention study design. 144

Observational findings have for the majority reported a beneficial or null effect of coffee 145

consumption on cancer, with the exception of bladder/urinary tract cancers where the risks of 146

coffee consumption are more commonly reported. An increased risk of bladder/urinary 147

cancer, however, was typically only reported in males, not females (Hartge and others 1983; 148

Marrett and others 1983; Clavel and Cordier 1991; Zeegers and others 2001) and non-149

smokers compared to smokers (Pujolar and others 1993). Negative interactions with alcohol 150

(Donato and others 1997) were also evident, together with an influence of certain genetic 151

polymorphisms (such as CYP1A2) (Pavanello and others 2010). Moreover, other studies only 152

reported an increased risk of cancer of the urinary system to be evident in consumers of 153

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Turkish coffee (Akdas and others 1990), high coffee consumers (40+ cups per week) (Slattery 154

and others 1988) or have failed to demonstrate a dose-response (Simon and others 1975; 155

D'Avanzo and others 1992) which suggested that such associations are noncausal. 156

Similar modifiers of risk are also noted in the observational evidence for other types of 157

cancer. Coffee drinking appears to increase the risk of gastric (Galanis and others 1998) and 158

colorectal cancer in men (Slattery and others 1990; Boutron-Ruault and others 1999; Yamada 159

and others 2014) but not in women (Lee and others 2007), although the authors queried if the 160

former was just a chance finding (Galanis and others 1998). The risk of pancreatic cancer 161

also appears to be higher in smokers (Gorham and others 1988; Harnack and others 1997) 162

and non consumers of alcohol (Clavel and others 1989), whilst genetic polymorphisms 163

(CYP1A2 and GSTM1/GSTT1) can modify the relationship between coffee consumption and 164

risk of breast (Kotsopoulos and others 2007; Bageman and others 2008; Ayari and others 165

2013), ovarian (Goodman and others 2003) and skin (Fortes and others 2009, 2013) cancer. 166

In some instances, only caffeinated coffee appears to be protective when compared with 167

decaffeinated coffee (for example, in skin, endometrial and some gastric cancers) (Abel and 168

others 2007; Bhoo-Pathy and others 2015; Sanikini and others 2015) but in other studies, the 169

opposite is true (for example, for ovarian, rectal and lung cancers) (Michels and others 2005; 170

Baker and others 2005; Baker and others 2007). Comparisons between other types of coffee 171

preparations also produce equivocal results within the literature, for example for boiled (not 172

filtered) versus filtered coffee (Nilsson and others 2010; Tverdal 2015) or hot versus iced 173

coffee (Green and others 2014), and risks are also typically associated with heavy coffee 174

consumption (Gullo and others 1995; Efird and others 2004; Luo and others 2007; Lueth and 175

others 2008; Bissonauth and others 2009) or coffee abuse (Uzcudun and others 2002) 176

compared to light/moderate coffee consumption. Finally, for some cancers, risks also appear 177

to be more apparent in younger adults (<60 years) (Gallus and others 2007), with a null or 178

beneficial (inverse) effect of coffee consumption on cancer risk becoming apparent only in 179

older adults after more than 35 years coffee consumption (Kokic and others 1996), or in post- 180

compared to pre-menopausal females (Kuper and others 2000; Koizumi and others 2008). 181

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More consistently, positive or beneficial associations between coffee consumption and 182

cancer risk are evident in the mechanistic studies, and as alluded to above, this evidence more 183

often than not comes from intervention studies. Such research reports a protective or 184

beneficial effect of coffee consumption on antioxidant status (Bakuradze and others 2011), 185

oxidative DNA damage (Steinkellner and others 2005; Hoelzl and others 2010; Misik and 186

others 2010; Bakuradze and others 2011; Hori and others 2014), urine mutagenicity 187

(Aeschbacher and Chappuis 1981) and DNA strand breaks/integrity (Bakuradze and others 188

2014, 2015). Overall, these data from intervention studies would suggest that coffee can have 189

a beneficial role in terms of reducing the risk of some cancers. 190

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3.2. Cardiovascular disease (CVD) 192

A total of 273 (21.4%) studies have reported links between coffee consumption and CVD, 193

and they are mainly observational, although some evidence from intervention studies is 194

reported, particularly for hyperlipidemias, hypercholesterolemia, and blood pressure (Table 3). 195

Such studies have reported on a number of different outcomes or disease endpoints, ranging 196

from mechanistic studies focusing on individual risk factors (or causes of such) to those 197

reporting adverse events such as myocardial infarction, heart failure, or stroke. 198

Within CVD, the majority of evidence has reported negative (or null) associations between 199

coffee consumption and blood cholesterol (that is, an increased risk of hypercholesterolemia). 200

Such inverse associations though are mainly caused by the consumption of cafetiere (Urgert 201

and others 1995, 1996), French-press (De Roos and others 2000), Arabic (el Shabrawy Ali 202

and Felimban 1993) or boiled coffee (Bonaa and others 1988; Bak and Grobbee 1989; 203

Pietinen and others 1990; Lindahl and others 1991; Van Dusseldorp and others 1991; Ahola 204

and others 1991; Fried and others 1992), as compared to filtered coffee preparations. A direct 205

dose-dependent effect is also evident (Aro and others 1990; D'Avanzo and others 1993) and 206

another study has quantified a 1.66 and 1.58 mg/dL increase in LDL-cholesterol per daily cup 207

of coffee consumed by men and women, respectively (Berndt and others 1993). Moreover, 208

abstinence from coffee for at least 6 weeks will lower cholesterol concentrations in the general 209

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population (Christensen and others 2001) as well as in hypercholesterolemic patients (Forde 210

and others 1985). This negative effect of coffee on cholesterol concentrations, particularly 211

from boiled coffee, is owing to higher concentrations of diterpenes (kahweol and cafestol) in 212

such coffee preparations (deGroot and others 1996; Gross and others 1997; Naidoo and 213

others 2011). On the other hand, 4 randomized controlled trials have shown that diterpenes 214

have lipoprotein(a)-reducing potential, but the authors concluded that their well-known 215

adverse side effects on LDL cholesterol preclude their use as such (Urgert and others 1997). 216

Of interest, an inverse relationship has been reported between coffee consumption and 217

triglyceride concentrations (Carson and others 1994; Lancaster and others 1994; Miyake and 218

others 1999) which requires further investigation. 219

Risks of raised blood pressure/hypertension in coffee consumers are also apparent within 220

the literature, and this pressor effect may be caused by a coffee-induced increase in 221

adrenaline concentrations (Smits and others 1986a; Smits and others 1986b; Palatini and 222

others 2009). The pressor effect, however, was observed more often than not in coffee naïve 223

individuals, with no effect seen in habitual drinkers (Corti and others 2002) or those who have 224

adapted to heavy coffee consumption (8 cups per day for 4 weeks) (Ammon and others 1983). 225

Furthermore, whilst abstinence from coffee for 9 weeks was able to decrease blood pressure 226

in normotensives (Bak and Grobbee 1990), others have shown no effect on ambulatory blood 227

pressure measurements (Eggertsen and others 1993), nor on the prospective risk of 228

developing hypertension over 33 years (Basile 2002). Indeed, benefits of coffee consumption 229

on blood pressure have also been reported in human intervention studies conducted in both 230

normotensive and mildly hypertensive adults (Awaad and others 2011), as well as in coffee 231

drinkers with the rapid *1A/*1A genotype, compared to the increased risk observed in those 232

with the slow CYP1A2*1F genotype (rapid versus slow caffeine metabolizers, respectively) 233

(Palatini and others 2009). 234

Coffee consumers also appear to be at an increased risk of higher homocysteine 235

concentrations, an independent risk factor for CVD (Strandhagen and others 2003; 236

Strandhagen and others 2004; Slow and others 2004). This relationship may be driven by the 237

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chlorogenic acid (Piters and others 1985) rather than the trigonelline content of coffee (Slow 238

and others 2004), but, can be modified by folic acid (Strandhagen and others 2003), 239

particularly in those with the TT polymorphism of the methylenetetrahydrofolate reductase 240

(MTHFR) gene which codes for the MTHFR enzyme. 241

For some outcomes (such as myocardial infarction), the increased risk seen in coffee 242

drinkers is dependent on family history (Azevedo and Barros 2006), CYP1A2 genotype 243

(Cornelis and others 2006) and type of coffee preparation (boiled versus filtered) (Hammar 244

and others 2003), thus highlighting the importance of adequately controlling for these and 245

other confounders in such studies. Although, coffee polyphenols (extracted from green coffee 246

beans and given as a single oral ingestion) have been reported to have a beneficial effect on 247

endothelial function (Ochiai and others 2014), the opposite or at least a null effect is seen 248

when either caffeinated or decaffeinated coffee, respectively, is consumed as a beverage 249

(Buscemi and others 2010). For other outcomes, U- or J-shaped risks of coffee consumption 250

have been reported (Panagiotakos and others 2003; Enga and others 2011). Although such 251

a relationship would suggest that the cardiovascular benefits are achieved by moderate 252

(compared to null/little or heavy/high) coffee consumption, differences in the definition of 253

‘moderate consumption’ make it difficult to compare and draw adequate conclusions between 254

the studies. 255

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3.3. Metabolic health 257

The vast majority of evidence investigating coffee consumption and metabolic health (Table 258

4) consistently shows a beneficial (inverse) association with the risk of type 2 diabetes (n=126; 259

9.9% studies). These associations are at least in part mediated by a decreased insulin 260

resistance (or improved insulin sensitivity) and/or improved glucose tolerance. Direct effects 261

on glucose tolerance appear to be caused by the antagonistic effect of chlorogenic acid 262

(with/without caffeine) on glucose transport, shifting glucose absorption to more distal parts of 263

the intestine (Johnston and others 2003), rather than acting through the incretin hormones. 264

Other mechanisms of action suggested include associations with low-grade systematic 265

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inflammation (C-reactive protein and sCD163) (Arsenault and others 2009; Chacon 2014), 266

oxidative stress (Bakuradze and others 2011) and sex-hormone binding globulin (Goto and 267

others 2011, 2014). Results may also be different depending on the range of body mass index 268

(BMI) categories included within the study (Arsenault and others 2009; Otake and others 269

2014), as well as the use of hormone replacement therapy (HRT) (Catalano and others 2008; 270

Arsenault and others 2009), again highlighting these as important confounders. 271

Coffee intake (3 x 250 mL/day for 4 weeks) can also decrease energy intake, by improving 272

satiety hormones (ghrelin and serotonin) and therefore decreasing levels of body fat 273

(Bakuradze and others 2014). Moreover, others have shown that either the 274

mannooligosaccharides (Kumao and Fujii 2006) or polyphenols (chlorogenic acid) (Soga and 275

others 2013) in coffee can increase or stimulate postprandial fat utilization, thus promoting 276

excretion of fat in the feces. 277

Although some studies have shown an adverse effect on the risk of metabolic syndrome, 278

this has only been shown, for example, for higher coffee consumption (>3 cups/day), 279

particularly of instant coffees with excess sugar and powdered creamer (Kim and others 2014), 280

and therefore these results must be interpreted with caution. 281

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3.4. Neurological disorders 283

Coffee consumption has been positively linked to improvements in (or a decreased risk of) 284

a number of neurological disorders, with the most commonly reported being Parkinson’s 285

disease, cognitive decline/function and mental health. A total of 94 (7.4%) studies have 286

reported links between coffee consumption and neurological outcomes, and they are typically 287

observational (Table 5). 288

Overall, coffee has been shown to be beneficially associated with the risk of Parkinson’s 289

disease (Ross and others 2000; Tan and others 2003; Hosseini Tabatabaei and others 2013; 290

van der Mark and others 2014), with a dose-response protective relationship apparent (Tan 291

and others 2003), but possibly only in males (Savica and others 2013; Ascherio and others 292

2001) and female non-HRT users (Ascherio and others 2004; Ascherio and others Mar 2003). 293

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Additive effects were also apparent with preceding diabetes (D'Amelio and others 2009) and 294

smoking (Grandinetti and others 1994; Powers and others 2008). Whilst some studies 295

reported an effect of certain genetic polymorphisms (for example, adenosine A2A receptor, 296

CYP1A2, and AP06) (Tan and others 2006; McCulloch and others 2008; Popat and others 297

2011), others have shown no such generic-environmental interactions (Facheris and others 298

2008; Chung and others 2013). The protective effect of coffee on the risk of Parkinson’s 299

disease is at least in part due to certain alkaloid compounds within coffee acting as 300

monoamine oxidase (MAO) inhibitors (Herraiz and Chaparro 2006). 301

The protective effect of coffee on cognitive decline/function may be more apparent in 302

females compared to males (Johnson-Kozlow and others 2002; Arab and others 2011) and 303

such effects on psychomotor/cognitive performance (Natu and Agarwal 1997) are more likely 304

to be due to caffeine consumption (Johnson-Kozlow and others 2002), rather than the 305

chlorogenic acids within coffee (Camfield and others 2013). Furthermore, it has been 306

postulated that antioxidants in coffee capable of decreasing reactive oxygen species may give 307

rise to a reduction in the risk of Alzheimer’s disease (Kotyczka and others 2011). 308

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3.5. Gastrointestinal (GI) conditions 310

GI complaints have been traditionally linked in the literature with coffee consumption, with 311

null/adverse associations with reflux, ulcers, heartburn and dyspepsia most commonly 312

reported. A total of 73 (5.7%) studies have reported links between coffee consumption and 313

GI conditions, the majority being observational studies (Table 6). 314

While negative findings are apparent, suggesting an increased risk of GI complaints in 315

coffee consumers, such negative associations are weak at best, and are only reported in 316

univariate, not multivariate analyses (Bhatia and others 2011); for (unusually) high coffee 317

consumption (Schlemper and others 1996); they are perceived side effects by the consumer 318

or patient rather than being tested/diagnosed (Ostensen and others 1985; Eisig and others 319

1989; Sihvo and Hemminki 1999); or they are only reported in coffee-sensitive/susceptible 320

individuals (Cohen 1980; DiBaise 2003). Moreover, some of the adverse effects are from 321

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acute feeding studies where coffee is either directly instilled into the stomach or given intra- 322

or orogastrically (Cohen 1980; Coffey and others 1986; Boekema and others 2001) so results 323

are not comparable to normal habitual coffee consumption. Others have suggested that 324

variability in coffee-induced gastric responses may be caused by differences in bean 325

processing (Van Deventer and others 1992; DiBaise 2003; Rubach and others 2014), such as 326

dark or light roasting. 327

Lastly, beneficial effects of moderate coffee consumption on gut health offer some promise 328

for additional benefits of coffee drinking among the general population. Such effects have 329

been reported by 4 intervention studies to-date and include improvements in the fecal 330

microbiota (Umemura and others 2004; Jaquet and others 2009; Walton and others 2010), as 331

well as improved colonic fermentation (Scazzina and others 2011). These positive findings 332

warrant confirmation in larger, and longer-term studies. 333

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3.6. Liver disorders 335

A total number of 72 (5.6%) studies have investigated the effect of coffee consumption 336

on liver disorders, namely, liver function/enzymes in general and gallstones/gallstone disease 337

(Table 7). Overall, this evidence, largely from observational studies, is showing coffee to have 338

a protective effect on the liver. In general, coffee may offer protection against alcohol-induced 339

liver damage/impairment (Corrao and others 1994; Tanaka and others 1998; Honjo and others 340

2001; Klatsky and others 2006; Ikeda and others 2010; Marotta and others 2013) and alcohol-341

induced hepatic inflammation (Maki and others 2010), which does not appear to be related to 342

the caffeine content (Corrao and others 2001; Xiao and others 2014), or antioxidant activity 343

(Gutierrez-Grobe and others 2012). In some studies, such beneficial effects are more evident 344

in males (Pintus and Mascia 1996; Danielsson and others 2013) and smokers (Kono and 345

others 1994), compared to females and non smokers respectively. Strong cafetiere (versus 346

filtered) coffee, however, may show the opposite effect. Drinking 5-6 cups per day negatively 347

affected the integrity of liver cells in a 24-week randomized-controlled intervention study 348

(Urgert and others 1996). There is debate in the literature, however, if the compounds which 349

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might be responsible for such effects are the diterpenes, e.g. kahweol within coffee oil (Urgert 350

and others 1996; Boekschoten and others 2004). 351

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3.7. Mortality 353

Overall, coffee consumption has been associated with a reduced risk of total/all-cause 354

and cause-specific mortality, particularly for CVD and coronary heart disease (CHD) (n=62; 355

4.9% studies) (Table 8). In contrast, in some of the earlier studies conducted 20+ years ago, 356

CHD or ischemic heart disease (IHD) mortality was inversely associated with coffee 357

consumption (Heyden and others 1976; Hennekens and others 1976; Hemminki and Pesonen 358

1977; LeGrady and others 1987; Tverdal and others 1990; Klatsky and others 1993). In these 359

studies, however, risks were related to sale of coffee, not consumption (Hemminki and 360

Pesonen 1977), none/very low (0-1 cups) or very high (6-9+ cups) daily consumption (LeGrady 361

and others 1987; Tverdal and others 1990), or associated risks were minimal (Hennekens and 362

others 1976) and therefore results should be interpreted with caution. Similar to the discussion 363

previously for other conditions, the link between coffee consumption and mortality seems to 364

vary inconsistently by gender (Tverdal and others 1990; Jazbec and others 2003; Leurs and 365

others 2010; Liu and others 2013), HRT users versus non-users (Ascherio and others 2004), 366

and smoking status (Rosengren and Wilhelmsen 1991; Odegaard and others 2015), but 367

remains beneficial in the majority of evidence, when populations are considered as a whole. 368

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3.8. Other conditions/health outcomes 370

In addition to all of the health relationships outlined above, a number of other conditions or 371

health outcomes have also been linked to coffee consumption. A total of 155 (12.1%) studies 372

are listed in Table 9 and corresponding conditions within each category are listed in Table 10. 373

Overall, the other most frequently reported condition associated with coffee consumption 374

is poor bone health. Although approximately half of the studies included in the current review 375

have shown a null effect on bone outcomes (22 out of 43), a similar proportion has also 376

reported adverse effects (18 out of 43). These adverse effects are reported only in lean 377

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compared to overweight/obese individuals (Korpelainen and others 2003), and in females, not 378

males (Meyer and others 1997), with high daily coffee consumption (Meyer and others 1997; 379

El Maghraoui and others 2010). Nevertheless, others have shown that the adverse effects on 380

bone mineral density can be offset by milk, typically consumed with coffee (Barrett-Connor 381

and others 1994), and are only evident in those with the rapid CYP1A2 CC genotype 382

(Hallstrom and others 2010), and may not translate into an increase in fracture risk in the 383

longer-term (Trimpou and others 2010; Hallstrom and others 2013). Additional research is 384

clearly warranted to elucidate the effect of coffee consumption on bone health. 385

Finally, for all other categories of health outcomes identified, results are equivocal and 386

therefore conclusions on the benefit, risk, or null effect of coffee consumption cannot be 387

determined based on the current literature. 388

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3.9. Additional risks 390

Additional risks of coffee consumption were apparent for pregnant women (for example 391

relative to pregnancy complications, birth outcomes, or the health of the infant). Although 392

these risks were noted in 26 out of the 50 studies, many were linked with higher coffee 393

consumption (Olsen and others 1991; Armstrong and others 1992; Parazzini and others 1998; 394

Bech and others 2005; Parazzini and others 2005; Werler and others 2015) and approximately 395

the same number of studies (22 out of 50) also reported null (no) effects on such adverse 396

events of pregnancy (Borlee and others 1978; Zhang and others 2010; Conde and others 397

2011; Alonso and others 2012; Conde and others 2010). Indeed, some studies did report 398

positive (beneficial) effects on certain pregnancy/infant health outcomes, such as the risk of 399

pre-term delivery (Petridou and others 1996) or childhood acute leukemia (Clavel and others 400

2005). Many of these studies state caffeine as responsible for the adverse events noted. 401

However, in support of those that have shown null effects, the European Food Safety Authority 402

(EFSA) recently concluded that habitual caffeine consumption (200 mg/d) does not give rise 403

to safety concerns for the fetus (EFSA 2015). 404

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Finally, a number of other studies (n=45) were identified by the literature search that 405

highlighted coffee as a potential source of certain unwanted/toxic constituents, such as 406

ochratoxin A (StuderRohr and others 1994, 1995), furan (Crews and others 2009; Altaki and 407

others 2011), heavy metals (Taylor and others 2013; Nedzarek and others 2013) and 408

acrylamide (Bjellaas and others 2007; Eerola and others 2007). For the most part, however, 409

such studies did report that measured/estimated intake levels were well below estimated daily 410

acceptable intakes or that coffee was not a major source, therefore deemed safe (Perez de 411

Obanos and others 2005; Akdemir and others 2010; Guenther and others 2010; Ates and 412

others 2011; Coronel and others 2012). Moreover, the beneficial effects of other ‘bioactive’ 413

components, such as chlorogenic acids, phenolic acids and melanoids, add further support to 414

the beneficial effect of coffee as a beverage (Olthof and others 2001; Borrelli and others 2002; 415

Monteiro and others 2007; Rufian-Henares and de la Cueva 2009; Fumeaux and others 2010; 416

Fogliano and Morales 2011; Farrell and others 2012; Lardeau and Poquet 2013). 417

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4. Conclusions 419

Overall, results of this comprehensive review show that the health benefits (or null effects) 420

clearly outweigh the risks of moderate coffee consumption in adult consumers for the majority 421

of health outcomes considered. This finding is largely based on observational data and, 422

moreover, major interactions were noted between coffee consumption and other lifestyle 423

habits (such as smoking/alcohol/HRT). 424

Additional randomized clinical trials are warranted, particularly in relation to cardiovascular 425

risk factors or endpoints and gastrointestinal disorders. This research should distinguish 426

effects of coffee consumption as a beverage, rather than quantify effects of caffeine intake per 427

se, adequately quantify/define coffee consumption and take account of all potential 428

confounding factors. Consideration should also be given to the type of coffee preparation or 429

brewing method, any potential influences of relevant genetic polymorphisms (for example, 430

CYP2A1), as well as the population group of interest (for example, healthy individuals vs. 431

patient groups and habitual vs. non habitual coffee drinkers). 432

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5. Future work 434

Results from this research may aid further qualitative and quantitative risk-benefit 435

assessments of coffee consumption, using published approaches (Hoekstra and others 2012; 436

Verhagen and others 2012; Boobis and others 2013; Vidry and others 2013; Hart and others 437

2013) and further activities emphasizing the potential benefits should be pursued. As such, 438

the potential benefits for public health of consuming coffee or not consuming coffee could be 439

calculated for the most convincing benefits (for example, type 2 diabetes and neurological 440

and/or hepatic disorders). The potential public health benefits can be quantified in terms of 441

more Quality Adjusted Life Years (QALYs) or less Disability Adjusted Life Years (DALYs) (Hart 442

and others 2013) for countries and population groups of interest, depending on the availability 443

of population level dietary consumption data. 444

445

6. Acknowledgements 446

Professor Hans Verhagen is acknowledged for his introduction to risk-benefit assessment. 447

Thanks also go to illycaffè s.p.a. for funding this research. Disclosure statement: Even though 448

some financial support for this study was provided by the company (illycaffè s.p.a.), the 449

authors declare no conflict of interest regarding this objective search and summary of the 450

published literature. 451

452

7. Author contributions 453

LKP was responsible for study design, searching the literature, interpreting, results and 454

preparing the manuscript; LN, MP, and JJS were responsible for study design and drafting the 455

final manuscript. All authors reviewed the final manuscript before submission. 456

457

458

459

460

18

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consumption associated with urinary tract cancer risk? A systematic review and meta-1072

analysis. Int J Epidemiol 30:353-62. 1073

Zhang B, Wei Y, Niu J, Li Y, Miao Z, Wang Z. 2010. Risk factors for unexplained recurrent 1074

spontaneous abortion in a population from southern China. Int J Gyn Obst 108:135-8. 1075

41

Table 1 Study inclusion/exclusion criteria 1076

INCLUSION CRITERIA EXCLUSION CRITERIA

Human observational and intervention original

research studies

Examined coffee consumption and reported

health outcome(s)

English

Published 1970 - 30th June 2015

In vitro or animal studies, systematic reviews or

meta-analyses

No health outcome

No original data (e.g. letters/editorials)

Not available in English

Published before 1970

1077

1078

42

Table 2 Number of studies investigating cancer and coffee consumption by outcome and type of study1

Type of cancer Benefit Null effect Risk

Observational2 Intervention3 Observational2 Intervention3 Observational2 Intervention3

Colorectal 28 30 11

Bladder/Urinary Tract 3 33 33

Pancreas 5 35 7

Female-specific (ovarian, endometrial, vulva)

15 17 8

Breast 15 18 5

Prostate 8 14 4

Oral/Upper Aerodigestive Tract 13 5 5

Gastric 6 9 7

Mechanisms (DNA damage, DNA integrity, oxidative damage)

5 9 2 4

Carcinomas (hepatocellular, squamous/basal cell, soft tissue)

14 5

Renal/Kidney 2 11 3

Skin 9 3

Lung/Respiratory Tract 2 4 4

All types (or tobacco-related) 2 4

Lymphoma's 2 2 1

Leukemia 2 1 1

Liver 4

Brain/Glioma 1 1 2

Thyroid 1 1

Gallbaldder/Bile Ducts 1

TOTAL 138 9 195 0 95 0

1Total number of studies, n=352 2Including cross-sectional, case-control, retrospective, prospective and longitudinal studies 3Including controlled/non-controlled, randomised/non-randomised parallel and crossover studies

1079

43

Table 3 Number of studies investigating cardiovascular disease (CVD) and coffee consumption by outcome and type of study1

Type of CVD/CV outcome Benefit Null effect Risk

Observational2 Intervention3 Observational2 Intervention3 Observational2 Intervention3

Hypercholesterolaemia/lipidaemia 6 4 29 13 37 14

Blood Pressure/Hypertension 9 5 11 7 15 11

Myocardial Infarction 1 10 1 13 2

CVD 5 9 7 4

Homocysteine 2 4 3 10 6

CHD 2 8 12

Stroke/Blood Clot/Clotting 7 3 2 6 1

Coronary Events 2 1 4 7

Endothelial Function 4 1 1 1 2 1

Haemodynamic Effects/Haemostasis

1 3 2

Gout/Uric Acid 3 1 2

Heart Rate 1 2 1 1 1

CAD 1 1 3

Heart Failure 1 2 1

Atherosclerosis 1 1 1 1

IHD 3

CRP (inflammation) 2 1

Aortic/Coronary Calcification 2 1

Peripheral Arterial Occlusive Disease

2

Haptoglobin Levels 1

Myelodysplastic Syndromes 1

TOTAL 48 20 88 30 119 42

1Total number of studies, n=273 2Including cross-sectional, case-control, retrospective, prospective and longitudinal studies 3Including controlled/non-controlled, randomised/non-randomised parallel and crossover studies

CVD, cardiovascular disease; CHD, coronary heart disease; CAD, coronary artery disease; IHD, ischemic heart disease; CRP, C-reactive protein

1080

44

Table 4 Number of studies investigating metabolic health and coffee consumption by outcome and type of study1

Metabolic outcome Benefit Null effect Risk

Observational2 Intervention3 Observational2 Intervention3 Observational2 Intervention3

Type 2 Diabetes 33 1 4 1

Obesity/Body Weight/Fat 8 10 8 1 3

IGT 9 5 1 3 2 4

Insulin Resistance/Sensitivity

6 3 4

Metabolic Syndrome 6 3 2

Diabetes (all) 7

Inflammation/Oxidative Stress

2 2 1

Metabolic Health 2 1 1 1

Type 1 Diabetes 3

Satiety Regulation 1 2

Exercise Performance/fitness

1 1

Gestational Diabetes 1

TOTAL 72 24 22 10 10 5

1Total number of studies, n=126

2Including cross-sectional, case-control, retrospective, prospective and longitudinal studies

3Including controlled/non-controlled, randomised/non-randomised parallel and crossover studies

1081

1082

45

Table 5 Number of studies investigating neurological disorders and coffee consumption by outcome and type of study1

Type of neurological outcome

Benefit Null effect Risk

Observational2 Intervention3 Observational2 Intervention3 Observational2 Intervention3

Parkinson's disease 23 9 1

Cognitive Function/Decline 12 3 7

Depression/Anxiety 6 3 1

Headache/Migraine 3 6

Sucide 2 3

Pain 1 1 2

Mental Health/Disease 2 2

Restless Leg Syndrome 3

Mood 1 2

Stress 1 2

Blepharospasm 2

Sympathetic Nerve Activity 1 1

Multiple Sclerosis 1

Amyotrophic Lateral Sclerosis 1

Multiple System Atrophy 1

TOTAL 51 5 22 1 23 1

1Total number of studies, n=94

2Including cross-sectional, case-control, retrospective, prospective and longitudinal studies

3Including controlled/non-controlled, randomised/non-randomised parallel and crossover studies

1083

46

Table 6 Number of studies investigating gastrointestinal (GI) conditions and coffee consumption by outcome and type of study1

Type of GI outcome Benefit Null effect Risk

Observational2 Intervention3 Observational2 Intervention3 Observational2 Intervention3

Reflux 1 9 6

Peptic Ulcer Disease 8 1 1

Bowel/Colon Symptoms 1 1 4 2 1 1

Duodenal Ulcer 5 1

Dyspepsia 4 2

Helicobacter Pylori 4 1

Gastric Acid Secretion 1 1 2

Gastric Emptying 2 2

Gut Microbiotia/Colonic Fermentation

4

Inflammatroy Conditions (gastritis, duodenitis, ulcerative colitis, IBD)

2 1

Pancreatic Function 1 1 1

Heartburn 3

Proximal Stomach Function 1 2

Gastric Ulcer 1 1

Anal Fisure 1 1

Intraoesophageal Tempature 1

Post-operative Ileus 1

TOTAL 4 10 40 7 14 8

1Total number of studies, n=73 2Including cross-sectional, case-control, retrospective, prospective and longitudinal studies 3Including controlled/non-controlled, randomised/non-randomised parallel and crossover studies

GI, gastrointestinal; IBD, inflammatory bowel disease

1084

47

Table 7 Number of studies investigating liver disorders and coffee consumption by outcome and type of study1

Liver outcome Benefit Null effect Risk

Observational2 Intervention3 Observational2 Intervention3 Observational2 Intervention3

Liver Enzymes/Function 25 1 3 1 3

Gallstones/Gallstone disease 8 1 10 3

Cirrhosis 6

Fibrosis 4 1

NAFLD/Fatty Liver Disease 4 1

Hepatitis C 2 2

Liver disease 1 1

Cholangitis 1

Choledocholithiasis 1

Hepatic Drug Metabolism 1

Hepatic Inflammation 1

TOTAL 52 4 17 2 3 3

1Total number of studies, n=72

2Including cross-sectional, case-control, retrospective, prospective and longitudinal studies

3Including controlled/non-controlled, randomised/non-randomised parallel and crossover studies

1085

1086

48

Table 8 Number of studies investigating mortality and coffee consumption by outcome and type of study1

Mortality outcome Benefit Null effect Risk

Observational2 Intervention3 Observational2 Intervention3 Observational2 Intervention3

Total/All-Cause 14 13 3

CVD/CHD 10 10 6

Cirrhosis 6 1

Cancer (all types) 5 1

Pancreatic Cancer 3 3

Prostate Cancer 3

Breast/Overian Cancer 2 1

Respiratory Disease 2

Infection/Inflammatory disease

2

Parkinson's disease 1 1

Hepatocellular Carcinoma 2

Urinary Bladder Cancer 1 1

Diatetes 1

Injuries/Accidents 1

Oral/Pharyngeal Cancer 1

Suicide 1

Colon Cancer 1

TOTAL 41 0 39 0 16 0

1Total number of studies, n=62 2Including cross-sectional, case-control, retrospective, prospective and longitudinal studies 3Including controlled/non-controlled, randomised/non-randomised parallel and crossover studies

CVD, cardiovascular disease; CHD, coronary heart disease

1087

49

Table 9 Number of studies investigating other conditions and coffee consumption by outcome and type of study1

Health condition/outcome

Benefit Null effect Risk

Observational2 Intervention3 Observational2 Intervention3 Observational2 Intervention3

Bone Health 3 22 18

Renal (Kidney/Urinary) 7 1 9 1 6

Hormonal Conditions/Disturbance

5 4 2 3

Nutritional Status 3 2 1 7 1

Fertility 1 6 6

Eye Health/Vision 1 2 2 2

Sleep Conditions 2 1 1 3

Respiratory Health 3 2 1

Prostate Conditions 1 5

Skin Conditions 1 3 1

Ageing 1 2 1

Pancreatic Health 1 2 1

Female Health 3 1

Other 8 1 4 4

TOTAL 37 2 67 5 54 3

1Total number of studies, n=155

2Including cross-sectional, case-control, retrospective, prospective and longitudinal studies

3Including controlled/non-controlled, randomised/non-randomised parallel and crossover studies

1088

50

Table 10 Details of other conditions related to coffee consumption within the literature

Category List of conditions

Bone health

Risk for osteoporosis; bone mineral density; bone fragility; bone loss; hip fracture; fracture risk; fracture prevalence;

perimenopausal fractures; markers of bone metabolism; T-Score variability; risk of rheumatoid arthritis; musculoskeletal

pain

Renal (kidney/urinary)

Interstitial cystitis; urinary incontinence; urinary/kidney stones; nephrolithiasis; chronic kidney disease; nocturia;

dehydration; estimated glomerular filtration rate; glomerular function (urinary hydrogen peroxide); hypokalemia; bladder

pain syndrome; IgA nephropathy;

Hormonal

Menstrual disturbances; premenstrual syndrome; menstrual function (menstrual pattern, dysmenorrhea);

menopausal/climacteric symptoms (hot flashes and night sweats); onset of menopause; salivary cortisol; sex hormone

and other hormone levels (estradiol, testosterone); erectile dysfunction; anterior pituitary hormones

Nutritional status

Iron status/stores; prenatal zinc deficiency; total antioxidant capacity; iron deficiency anemia; B-vitamin status;

tocopherol (adipose tissue content); selenium levels (toenail); serum beta-carotene and alpha-tocopherol; dietary

/nutritional behaviours

Fertility

Sperm progressive motility; semen quality; male infertility (azoospermia or oligospermia); sperm aneuploidy; fecundity;

time to pregnancy

Eye health/vision

Intraocular pressure; exfoliation glaucoma/glaucoma suspect; macular edema; cataract; age-related maculopathy;

choroidal thickness

Sleep conditions Insomnia; drowsiness; sleep problems; alertness, sleep onset and sleep quality; alertness and performance

Respiratory health MRSA nasal carriage; pulmonary function; bronchial asthma;

Prostate conditions Benign prostatic hyperplasia; prostatic hypertrophy

Skin conditions Psoriasis; dermatoses; skin photoprotection

Aging Skin aging; frailty; health-related quality of life; reaching 90 years of age

Pancreatic health Pancreatitis; chronic calcific pancreatitis of the tropics; pancreatic ductal adenocarcinoma

Female health Fibrocystic breasts; benign breast disease; endometriosis

Other

Thyroid disease; serum uric acid/hyperuricemia; acute hyperammonemia; urinary vanilmandelic acid levels; tinnitus;

hearing function; periodontal health/disease; oral clefts

1089

51

Figure 1 Study selection and screening