COFFEE AND ALZHEIMER’S DISEASE

Interest in the possibility that the consumption of coffee or caffeine might protect against the development of Alzheimer’s disease is growing. A retrospective Portuguese study of 54 cases of Alzheimer’s disease and 54 controls recently demonstrated that caffeine intake over the preceding 20 years was inversely and significantly associated with risk of Alzheimer&'s disease (1). A prospective Canadian cohort study of 4,615 elderly subjects diagnosed 194 cases of Alzheimer's disease and showed that coffee consumption was inversely associated with disease risk (2).

In 2007 researchers reviewed all observational studies that evaluated the association between Alzheimer’s disease risk and coffee consumption. (3)Four studies were identified: two case-control studies and two cohorts. These studies were carried out between 1990 and 2002. There was an obvious protective effect of coffee consumption in the pooled estimate. The authors concluded that ‘Although our pooled estimates show that coffee consumption is inversely associated with the risk of Alzheimer's disease, the four studies had heterogenous methodologies and results.

In 2009 Swedish and Finnish researchers published the results of thier work which looked at midlife coffee and tea drinking and the risk of late-life dementia. In a cohort of 1409 individuals after an average follow-up of 21 years, a total of 61 cases were identified as demented, 48 with Alzheimer's disease. In this study coffee drinkers at midlife had a lower risk of dementia and Alzheimer's disease later in life compared with those drinking none or only little coffee. The lowest risk was found in people who drank 3 to 5 cups of coffee per day. Tea drinking was relatively uncommon in this cohort and was not associated with dementia or Alzhiemer's disease (4).

Whilst research has continued into this area, further prospective studies evaluating the association between coffee consumption and Alzheimer’s disease are needed before any firm conclusions can be arrived at.

References:

1. Maia, L. and De Mendonca, A. European Journal of Neurology, 9, 377-382, 2002.

2. Lindsay, J. et al. American Journal of Epidemiology, 156, 445-453, 2002.

3. Barraco Quintana, J L et al, Neurological Research, Volume 29, 2007

4. Eskelinen, M H et al, Journal of Alzheimer's Disease, Volume 16, 2009

COFFEE, CAFFEINE AND ASTHMA

Two large cross-sectional studies have examined the relationship between the intake of coffee and tea and the prevalence of asthma. A study of 72,284 Italians showed that there was an inverse association between intake of coffee and prevalence of asthma (1). Risk of asthma fell by 28% when three or more cups of coffee were drunk every day. The Second National Health and Nutrition Examination Survey (NHANES II) studied 20,322 Americans and found that risk of current asthma fell significantly by 29% and risk of wheeze fell insignificantly by 13% when regular coffee drinkers were compared with non-coffee drinkers (2). There was also a significant dose response relationship with current asthma.

Intervention trials of effects of caffeine intake on asthma have recently been critically reviewed (3). Nine intervention trials of effects of caffeine on pulmonary function were identified although three of them were excluded from the analysis due to a variety of design faults (4, 5, 6). A randomised controlled trial on 7 adult asthmatics was unable to show any difference between 6 mg caffeine/kg body weight and placebo on airway responsiveness to methacholine (7). By contrast, a double-blind randomised crossover study of 9 adult asthmatics using four doses of caffeine up to 7.2 mg/kg body weight showed a dose response effect of caffeine on forced expiratory volume (FEV), forced expiratory flow (FEF) and specific airway conductance (Gaw/VL) (8). This suggests that caffeine is an effective bronchodilator. The effect of caffeine on FEV was confirmed in a second trial on 8 adult asthmatics using a dose of 5 mg/kg body weight (9). However, in 10 mild asthmatics 5 mg caffeine/kg body weight had little if any effect on histamine provoked bronchoconstriction (10). By contrast, the higher of two doses of caffeine (3.5 and 7 mg/kg body weight) prevented exercise- induced bronchoconstriction in 10 asthmatics (11). In a subsequent double-blind, placebo controlled randomised crossover trial, it was shown that 10 but not 5 mg caffeine/kg body weight reduced bronchoconstriction induced by eucapnic voluntary hyperventilation in 11 asthmatics (12).

The beneficial effects of caffeine on asthma have been appreciated for over 100 years. In Scotland, caffeine has been used to treat asthma since at least 1859 (13). Marcel Proust, an asthmatic, wrote in A l’Ombre de Jeunes Filles en Fleur that he used caffeine as a child which “was prescribed to help me breathe”. He was born in 1871. As reviewed above, modern research has confirmed that caffeine and hence caffeine-containing beverages have a role to play in the management of asthma.

References:

1. Pagano, R et al. Chest, 94, 386-389, 1988.

2. Schwartz, J. and Weiss, S.T. Annals of Epidemiology, 2, 627-635, 1992.

3. Bara, A.I. and Barley, E.A. Caffeine for asthma (Cochrane Review). In: The Cochrane Library, Issue 2, 2003. Oxford: Update Software.

4. Becker, A.B. et al. New England Journal of Medicine, 310, 743-746, 1984.

5. Henderson, J.C. et al. Thorax, 48, 824-826, 1993.

6. Simmons, M. et al. Chest, 84, 332, 1983.

7. Crivelli, M. et al. Respiration, 50, 258-264, 1986.

8. Gong, H. et al. Chest, 89, 335-342, 1986.

9. Bukowskj, M. and Nakatsu, K. American Review of Respiratory Disease, 135, 173-175, 1987.

10. Colacone, A. et al. Thorax, 45, 630-632, 1990.

11. Kivity, S. et al. Chest, 97, 1083-1085, 1990.

12. Duffy, P. et al. Chest, 99, 1374-1377, 1991.

13. Salter, H. Edinburgh Medical Journal, 4, 1109-1115, 1859.

ANTIOXIDANTS IN COFFEE

Plant phenols are a large and diverse group of compounds including cinnamic acids, benzoic acids, flavonoids, proanthocyanidins, stilbenes, coumarins, lignans and lignins. It has been shown that plant phenols have strong antioxidant activity in vitro (1). As a result it has been hypothesised that plant phenols might protect cellular DNA, lipids and proteins from free radical- mediated damage in vivo. Since free radicals are believed to play a role in the development of chronic diseases such as cardiovascular disease and cancer then the consumption of plant phenols may protect against these diseases. As reviewed recently, five out of seven published observational epidemiological studies have shown that flavonols protect against cardiovascular disease but only one out of four studies showed that they protect against cancer (2). Hence the available evidence for a protective effect of flavonols against cardiovascular disease and cancer is far from conclusive and other categories of plant phenols have yet to be investigated.

Chlorogenic acids are a family of esters formed between trans-cinnamic acids and quinic acid. The commonest individual chlorogenic acid is formed between caffeic acid and quinic acid. It has been shown that both chlorogenic acid and caffeic acid are strong antioxidants in vitro (1). Coffee beans are one of the richest dietary sources of chlorogenic acid and for many consumers this will be their major dietary source (3). It has been reported that a 200 ml cup of arabica coffee contains between 70 and 200 mg chlorogenic acid whereas a cup of robusta coffee contains between 70 and 350 mg (3). It has been estimated that coffee drinkers might ingest as much as 1 g per day cinnamate esters (mostly chlorogenic acid) and 500 mg per day cinnamates (mostly caffeic acid). Coffee could supply as much as 70% of the total making it far and away the most important dietary source of this group of antioxidants (3).

The amount of chlorogenic acid or caffeic acid available to act as an antioxidant in vivo will depend on absorption from the gut which may be incomplete and any subsequent metabolism which may be extensive. It has recently been demonstrated that humans absorb about 33% of ingested chlorogenic acid and about 95% of ingested caffeic acid (4). A study of human chlorogenic acid metabolism showed that the unabsorbed chlorogenic acid which reaches the colon is hydrolysed to caffeic acid and quinic acid by the colonic microflora (5). Following dehydroxylation by the colonic microflora, absorption and further metabolism in the liver and kidney, benzoic acid is formed and conjugated to glycine to form hippuric acid. About half the ingested chlorogenic acid appears as urinary hippuric acid (5). This metabolism can be expected to considerably diminish the antioxidant activity of chlorogenic acid in vivo as hippuric acid has no antioxidant activity.

The roasting of coffee beans dramatically increases their total antioxidant activity. A roasting time of 10 minutes (medium-dark roast) was found to produce coffee with optimal oxygen scavenging and chain breaking activities in vitro (6). A study of robusta and arabica coffees from six different countries showed that robusta samples contained significantly more reducing substances than arabica samples and that protective activity measured ex vivo was significantly greater in roasted samples than in green coffee (7). Using the ABTS•+ method (the gold standard), it was confirmed that light roast or medium roast coffee has a significantly higher antioxidant activity in vitro than green coffee (8). This difference was observed despite a 19% and 45% decrease in the chlorogenic acid content of light and medium roast coffee respectively implying that other compounds make significant contributions to the total antioxidant activity of roasted coffee. Melanoidins are brown polymers formed by the Maillard reaction during the roasting of coffee beans and account for up to 25% of the dry matter. It has recently been shown by the ABTS•+ method that coffee melanoidins have significant antioxidant activity in vitro (9). 

The total antioxidant activities of different plant phenol- containing beverages have been compared. Using a method based on the ex vivo oxidation of low density lipoprotein (LDL), it has been shown that coffee has significantly more total antioxidant activity than either cocoa, green tea, black tea or herbal tea (10). Using the ABTS•+ method, it has been confirmed that coffee has a significantly greater total antioxidant activity in vitro than cola, beer, a variety of fruit juices, lemon ice tea or black tea (11). A study conducted in 2004 looked at dietary sources of antioxidants and found that the single greatest contributor to total antioxidant intake was coffee (12). A further study in 2006 (13) set out to determine the content of phenolic acids in the most consumed fruits and beverages. Coffee, as wel as black and green teas were the best source among beverages with coffee containing 97mg/100 g whilst teas contained 30-36 mg/100 g

It can be concluded that coffee possesses greater in-vitro antioxidant activity than other beverages, due in part to intrinsic compounds such as chlorogenic acid, in part to compounds formed during roasting such as melanoidins and in part to as yet unidentified compounds. Authors of a study published in 2002 (14) suggested that uric acid was the main component responsible for plasma antioxidant capacity increase after tea drinking, whereas molecules other than uric acid (probably phenolic compounds) are likely to be responsible for the increase in plasma antioxidant capacity after coffee drinking. Whether the antioxidants characteristic of coffee are protective against chronic diseases such as cardiovascular disease and cancer remains to be determined. Research continues, and the conclusion of a study published in 2006 (15) consisting of a cohort of 41,836 postmenopausal women, was that 'Consumption of coffee, a major source of dietary antioxidants, may inhibit inflammation and thereby reduce the risk of cardiovascular disease and other inflammatory diseases in postmenopausal women'.
It should be noted that these results of course refer to a specific sub group and it would not, at this stage, be appropriate to extrapolate them across to the general population before further research clarifies these conclusions.

References:

1. Rice-Evans, C.A. et al. Free Radical Biology and Medicine, 20, 933-956, 1996.

2. Hollman, P.C.H. Journal of the Science of Food and Agriculture, 81, 842-852, 2001.

3. Clifford, M.N. et al. Journal of the Science of Food and Agriculture, 79, 362-372, 1999.

4. Olthof, M.R. et al. Journal of Nutrition, 131, 66-71, 2001. 

5. Olthof, M.R. et al. Journal of Nutrition, 133, 1806-1814, 2003.

6. Nicoli, M.C. et al. Lebensmittel, Wissenschaft und Technologie, 30, 292-297, 1997.

7. Daglia, M. et al. Journal of Agricultural and Food Chemistry, 48, 1449-1454, 2000.

8. Del Castillo, M.D. et al. Journal of Agricultural and Food Chemistry, 50, 3698-3703, 2002.

9. Borrelli, R.C. et al. Journal of Agricultural and Food Chemistry, 50, 6527-6533, 2002.

10. Richelle, M. et al. Journal of Agricultural and Food Chemistry, 49, 3438-3442, 2001. 

11. Pellegrini, N. et al. Journal of Agricultural and Food Chemistry,51, 260-264,2003.

12. Svilaas, A. et al. Journal of Nutrition, 134, 562-567, 2004.

13.Mattila P et al,

14. Natelle, F. et al. Journal of Agricultural and Food Chemistry, 50, 6211-6216, 2002.


15. Frost Andersen, L. et al. American Journal of Clinical Nutrition, 83, 2006.

COFFEE, CAFFEINE, CALCIUM BALANCE ANDBONE HEALTH

GENERAL

A 2002 review of the scientific literature by Professor Heaney concluded that “There is no evidence that caffeine has any harmful effect on bone status or on the calcium economy in individuals who ingest the currently recommended daily allowances of calcium" (1).

CALCIUM BALANCE

It is generally assumed that a decrease in the supply of calcium, an essential mineral for bone formation, would be likely to decrease bone mass and hence increase the risk of fracture. A number of intervention trials have focused on the effects of coffee, tea or caffeine on calcium balance. Although such studies can show cause effect relationships they cannot establish whether the magnitude of the effects on calcium balance observed are large enough to influence bone health.

A careful study of calcium balance in 170 healthy middle-aged women examined the effects of tea and coffee consumption (2). Multiple regression analysis showed that caffeine consumption in the form of tea or coffee was significantly associated with a small negative calcium balance. It was calculated that for every cup of coffee consumed less than 5 mg calcium was lost, probably due to increased urinary or faecal excretion.

This trial was followed by a series of studies (3, 4, 5) from a second laboratory showing that caffeine induced a loss of calcium in the urine. For example, it was shown that when 37 healthy women consumed 6 mg caffeine/kg body weight the urinary calcium loss increased in the two hour period following caffeine consumption (5). However, it should be noted that these caffeine intakes were unrealistically high and that the two-hour study period was too short. A further study from the same laboratory (6) looked at the effects of 6 mg caffeine/kg body weight in 17 healthy males and females on calcium excretion over a longer time period. They found that caffeine significantly increased urinary calcium excretion for six hours after intake, had no effect in the subsequent nine hours and significantly decreased urinary calcium excretion in the following three hours. Although there was an overall net increase in urinary calcium excretion in response to high intakes of caffeine it is clear that two-hour study periods seriously overestimate calcium loss in response to caffeine.

Two studies were unable to reveal any effects of more moderate doses of caffeine on 24-hour calcium loss (7, 8, 9). A double-blind placebo controlled crossover study with a 37-day washout compared the effects of 400 mg caffeine/day for 19 days with placebo in 16 healthy pre-menopausal women (7). There were no significant effects of caffeine on calcium absorption, urinary calcium excretion or faecal calcium excretion. This is an important study as it looks at the effects of caffeine consumption over the longer-term i.e. 19 days. Most other studies have only looked at the effects of caffeine over periods ranging from two hours to twenty-four hours.

The original calcium balance study (2) has since been expanded by examining 191 healthy perimenopausal women on two or three occasions over a 15-year period, generating a total of 518 balance studies (8, 9). There were no significant effects of caffeine-containing beverages on either urinary calcium loss (8) or faecal calcium loss (9). However, the negative calcium balance observed in the original study (2) persisted in the expanded study (8,9). It was estimated that 4 mg calcium were lost for every cup of coffee consumed and multivariate analysis suggested that this was due to a small but significant decrease in calcium absorption efficiency. However, calcium intakes in the study population were only 660 mg/day or about half the recommended intake in the USA so the effects of caffeine observed on calcium balance may only be relevant to women with inadequate calcium intakes.

Three other studies of effects of caffeine on 24-hour urinary calcium excretion have given mixed results (10,11,12). In eight pre-menopausal women given 1.4 l diet cola per day (equivalent to approximately four and a half cans) as the sole source of caffeine for two weeks, there were no effects on 24-hour calcium excretion (10). In twenty-five pre- and postmenopausal women normally consuming at least 5.8 mg caffeine/kg body weight, abstinence for 2 weeks had no effect on urinary calcium excretion (11). By contrast, in eighty-five postmenopausal women suffering from osteoporosis, multiple regression analysis showed that coffee intake was inversely associated with calcium balance (12). It was calculated that for every 100 ml coffee consumed 6 mg calcium/day was lost. 

It can be concluded that the consumption of caffeine is associated with a small negative calcium balance probably arising from reduced calcium absorption efficiency. The negative balance has been variously estimated as between 4 and 6 mg calcium/day. However, this effect is seen only in women with inadequate calcium intakes. In addition, it has been estimated that this small calcium deficit can be compensated for by the addition of only 1-2 tablespoons of milk to a caffeine-containing beverage such as coffee (8).

BONE HEALTH

Osteoporosis has been defined as “a disease characterised by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk”. Like many chronic diseases it is multifactorial. Risk factors for osteoporosis include age, cigarette smoking, alcohol consumption, level of physical activity and calcium intake.

As reviewed recently (13), there are at least 31 cross-sectional, case control and cohort studies of associations between caffeine intake and bone health involving many thousands of subjects. The aspects of bone health measured include bone mineral density, change in bone mineral density, fracture rate and osteoporosis. Although these studies have the advantage of measuring aspects of bone health directly, such observational epidemiological studies can only demonstrate associations and not cause effect relationships. All such studies are subject to confounding.

Twenty-two studies have looked at associations between bone mineral density or change in bone mineral density and caffeine intake. Four cross-sectional studies have shown inverse associations between bone mineral density and caffeine intake which were weak (14), present at one skeletal site but not at others (15) or present in the hip but not in the spine (16, 17). By contrast, a further ten cross-sectional studies were unable to find any associations between caffeine intake and bone mineral density at any skeletal site (18-27). A fifteenth cross-sectional study was able to show a negative association between caffeine intake and bone mineral density but only in subjects consuming inadequate amounts of calcium (28). This finding is supported by the results of a cohort study which found a negative association between change in bone mineral density and caffeine intake (29). By contrast, four other cohort studies failed to find any associations between caffeine intake and change in bone mineral density (30, 31, 32,33) and two other cohort studies failed to find any associations between caffeine intake and bone mineral density (34,35).

Eight studies have looked at associations between risk of fracture and intake of caffeine. Four case control studies were unable to find any associations between risk of fracture and caffeine intake (36, 37, 38,39). A fifth case control study used osteoporosis as an endpoint but was unable to find any association with caffeine intake (40). By contrast, four cohort studies reported a significant association between caffeine intake and risk of fracture. In a subset of the Framingham cohort, there was an incremental increase in fracture risk for coffee consumption above two cups per day (41). In the Nurses Health Study, the risk of hip fracture increased three-fold with caffeine intake but only in women younger than 65 years old (42). In the Study of Fractures cohort, the investigators identified 17 independent risk factors and found that caffeine intake was one of the weakest (43). In a Norwegian study, fracture risk increased with caffeine intake but only when coffee consumption was greater than nine cups per day .

Out of the 31 studies cited above, 10 showed an inverse association between consumption of caffeine- containing beverages and some aspect of bone health and 21 found no association. Although the available evidence is contradictory, the weight of evidence does not support the idea that caffeine-containing beverages adversely affect bone health. One reason for the contradictory results is confounding. Taking one study as an example, the inverse association observed before adjustment for confounders between intake of caffeine containing beverages and bone mass disappeared after adjustment for other risk factors (20). It is also possible that intake of caffeine- containing beverages is acting as a marker for a true causal factor. It is known that there is an inverse relationship between the intake of milk and consumption of caffeine-containing beverages (8). It is possible, therefore, that a low intake of milk rather than a high intake of caffeine-containing beverages is a true cause of impaired bone health. This positon was supported by Hallstrom et al (44) who examined the relationship between consumption of coffee and tea and total caffeine intake associated with osteoporotic fracture risk. They found that a daily intake of 330 mg caffeine, or more, may be associated with a modestly increased risk of osteoporotic fractures, especially in those women with a low calcium intake.

References:

1. Heaney, R.P. Food and Chemical Toxicology, 40, 1263-1270, 2002

2. Heaney, R.P. and Recker, R.R. Journal of Laboratory and Clinical Medicine, 99, 46-55, 1982.

3. Massey, L.K. and Wise, K.J. Nutrition Research, 4, 43-50, 1984. 

4. Massey, L.K. and Hollingberry, P.W. Nutrition Research, 8, 1005-1012, 1988.

5. Bergman, E.A. et al. Life Sciences, 47, 557-564, 1990.

6. Kynast-Gales, S.A. and Massey, L.K. Journal of the American College of Nutrition, 13, 467-472, 1994.

7. Barger-Lux, M.J. et al. American Journal of Clinical Nutrition, 52, 722-725, 1990.

8. Barger-Lux, M.J. and Heaney, R.P. Osteoporosis International, 5, 97-102, 1995.

9. Heaney, R.P. and Recker, R.R. Journal of Bone and Mineral Research, 9, 1621-1627, 1994.

10. Smith, S. et al. Archives of Internal Medicine, 149, 2517-2519, 1989.

11. Massey, L.K. et al. Journal of the American College of Nutrition, 13, 592-596, 1994.

12. Hasling, C. et al. Journal of Nutrition, 122, 1119-1126, 1992.

13. Heaney, R.P. Food and Chemical Toxicology,  40, 1263-1270, 2002.

14. Bauer, D.C. et al. Annals of Internal Medicine, 118, 657-665, 1993.

15. Hernandez-Avila, M. et al. Epidemiology, 4, 128-134, 1993.

16. Krahe, C. et al. Brazilian Journal of Medical and Biological Research, 30, 1061-1066, 1997.

17. Rubin, L.A. et al. Journal of Bone and Mineral Research, 14, 633-643, 1999.

18. Lacey, J.M. et al. Journal of Bone and Mineral Research, 6, 651-659, 1991.

19. Cooper, C. et al. Journal of Bone and Mineral Research, 7, 465-471, 1992.

20. Johansson, C. et al. Age and Ageing, 21, 20-26, 1992.

21.Glynn, N.W. et al. Journal of Bone and Mineral Research, 10, 1769-1777, 1995.

22. Hansen, M.A. Osteoporosis International, 5, 283, 1995.

23. Travers-Gustafson, D. et al. Calcified Tissue International, 57, 267-271, 1995.

24. Lloyd, T. et al. American Journal of Clinical Nutrition, 65, 1826-1830, 1997.

25. Grainge, M.J. et al. Osteoporosis International, 8, 355-363, 1998.

26. Maini, M. et al. Minerva Medicine, 87, 385-399, 1996.

27. Picard, D. et al. Bone Minerals, 4, 299-309, 1988.

28. Barrett-Connor, E. et al. Journal of the American Medical Association, 271, 280-283, 1994.

29. Harris, S.S. and Dawson-Hughes, B. American Journal of Clinical Nutrition, 60, 573-578, 1994.

30. Reid, I.R. et al. Journal of Clinical Endocrinology and Metabolism, 79, 950-954, 1994.

31. Lloyd, T. et al. Journal of the American College of Nutrition, 17, 454-457, 1998.

32. Hannan, M.T. et al. Journal of Bone and Mineral Research, 15, 710-720, 2000.

33. Lloyd, T. et al. Journal of the American College of Nutrition, 19, 256-261, 2000.

34. Hansen, M.A. et al. Osteoporosis International, 1, 95-102, 1991.

35. Packard, P.T. and Recker, R.R. Osteoporosis International, 6, 149-152, 1996.

36. Nieves, J.W. et al. Osteoporosis International, 2, 122-127, 1992.

37. Cummings, R.G. and Klineberg, R.J. American Journal of Epidemiology, 139, 493-503, 1994.

38. Tavani, A. et al. Preventive Medicine, 24, 396-400, 1995.

39. Kanis, J. et al. Osteoporosis International, 9, 45-54, 1999.

40. Blaauw, R. et al. South African Medical Journal, 84, 328-332, 1994.

41. Hernandez-Avila, M. et al. American Journal of Clinical Nutrition, 54, 157-163. 1991.

42. Cummings, R.R. et al. New England Journal of Medicine, 332, 767-773. 1995

43. Meyer,H.E. et al. American Journal of Epidemiology, Volume 145, 117-123. 1997

44. Hallstrom et al, Osteoporosis International, Online Edition, May 2006

COFFEE AND CANCER

GENERAL

There are no intervention trials of effects of coffee consumption on risk of cancer at any site and consequently there is no cause effect evidence. By contrast, there are numerous case control and cohort studies of associations between coffee consumption and risk of cancer at various sites particularly the bladder, breast, colon, ovary, pancreas and kidney. Such studies of associations cannot prove cause effect relationships and are subject to confounding by other risk factors and to bias. In addition, coffee consumption might be a marker for some other aspect of lifestyle such as smoking which is a true cause of cancer.

Associations between coffee consumption and cancer risk have been reviewed at regular intervals. In 1997 the World Cancer Research Fund in association with the American Institute for Cancer Research concluded that “Most evidence on coffee suggests that coffee drinking has no relationship with cancer risk” (1). The authors of a 2000 scientific review wrote that “This updated and comprehensive overview of coffee and cancer epidemiology provides further reassuring information on the absence of any appreciable association between coffee intake and most common cancers, including cancer of the genital tract, digestive tract and of the breast” (4).

Accordingly there is no scientific reason for believing that moderate consumption of coffee increases the risk of developing cancer at any site.

BLADDER AND LOWER URINARY TRACT CANCER

A 1991 review of associations between bladder cancer and coffee consumption identified 26 studies and analysed 22 of them (3). Sixteen studies demonstrated a higher risk of bladder cancer in coffee consumers. In 7 of these 16 studies the association was significant and in 3 there was evidence of a dose response relationship. There were no associations in the other 6 studies. When non-smokers were considered separately in 7 of these studies, the association weakened but persisted, suggesting that confounding by smoking is not the only explanation for the association. It was concluded that there was a weak positive association between risk of bladder cancer and coffee consumption but the possibility that this was due to bias or confounding could not be excluded.

A 2000 review of all types of study published since 1991 identified an additional 3 cohort studies and 12 case control studies (4). The authors stated in their abstract “Thus, a strong association between coffee drinking and bladder cancer can be excluded, although it is still unclear whether the weak association is causal or non-specific and due to some bias or confounding”. A 2001 review and meta-analysis identified 34 case control studies and 3 cohort studies (5). In agreement with previous studies, it was found that coffee consumption increased the risk of urinary tract cancer by approximately 20%.

Two meta-analyses of case control studies have been published. In 1993 thirty-five case control studies published between 1971 and 1992 were identified and 7 core studies selected for meta-analysis according to strict methodological criteria (6). The authors concluded that “the best available data do not suggest a clinically important association between the regular use of coffee and development of cancer of the lower urinary tract in men or women”. In 2000 a pooled analysis of 10 European case control studies attempted to eliminate confounding by cigarette smoking by considering non-smokers only (7). It was found that the risk of bladder cancer in coffee drinkers was no greater than in non-coffee drinkers unless consumption was ten cups or more per day. This is considerably greater than the average consumption in the United Kingdom of between 3 and 4 cups per day.

Although cohort studies have more robust designs than case control studies they have never been separately analysed. In the Californian Seventh Day Adventist Study, 52 cases of bladder cancer were identified in a study population of 34,198 but there was no significant association between coffee consumption and risk of disease (8). In a study of 7,995 Japanese American men living in Hawaii, 96 cases of bladder cancer were diagnosed and although coffee consumption was associated with an increase in bladder cancer risk this was not significant (9). In a study of almost 43,000 Norwegian men and women, 53 cases of bladder cancer were identified, but no significant associations between a coffee consumption greater than or equal to 7 cups per day and disease risk emerged either in men or women (10). The most recently published study of a subcohort of the Netherlands Cohort Study identified 569 bladder cancer cases in a study population of 3,123 men and women (11). After adjustment for all confounders, a non-significant association between bladder cancer risk and coffee consumption was observed in men but a significant inverse association in women. Hence there is no evidence from cohort studies that coffee consumption increases the risk of bladder cancer. 

In 2007, the World Cancer Research Fund Report brought further clarity to the debate surrounding coffee drinking and bladder cancer. In this report they state that 'The judgements of the previous report on coffee were practically the same as in this report, except that the previous report judged that drinking more than 5 cups per day was a possible cause of bladder cancer. The evidence now indicates that coffee is unlikely to have a substantial effect on risk of this cancer'.

BREAST CANCER

A 1991 review of the literature identified 7 case control studies none of which showed any association between coffee consumption and risk of breast cancer (3). By 2000, a further three cohort studies and four case control studies had been published (4). The three cohort studies and three of the four case control studies were also unable to show any association between the risk of breast cancer and coffee consumption. By contrast, the fourth case control study from Finland demonstrated an inverse association between coffee consumption and risk of breast cancer in postmenopausal women (12). The authors concluded that “there is no appreciable relation between coffee and cancer of the breast”.

At least seven cohort studies of associations between coffee consumption and breast cancer risk have been published. Studies of 23,912 male and female Californian Seventh-day Adventists (13), 2,891 Norwegian women (14), 14,593 Norwegian women (15), 89,494 female nurses from the USA (16), 18,586 postmenopausal women living in New York State (17), 34,388 postmenopausal women living in Iowa (18) and 59,036 Swedish women (19) found no significant associations between risk of breast cancer and coffee consumption.

Male breast cancer also exists although it is a much rarer disease. A recent population-based case control study from Canada which compared 81 cases with 1905 controls found an inverse and statistically significant association between coffee consumption and risk of male breast cancer both before and after correction for confounders (20). The possibility that coffee consumption protects against male breast cancer awaits confirmation by other studies.

There is no evidence whatever for an association between female breast cancer and coffee consumption.

COLORECTAL CANCER

Case control studies and cohort studies give different messages about associations between coffee consumption and risk of colorectal cancer. Out of the 12 informative case control studies identified in a 1991 review, 11 showed an inverse association between coffee consumption and the risk of colorectal cancer (3). In 5 of these case control studies the association was statistically significant and a significant dose response relationship was demonstrated in one of them. By contrast, none of the four cohort studies reviewed showed any evidence of an inverse association between coffee consumption and risk of colorectal cancer. 

A 2000 review identified 2 new cohort studies and 11 new case control studies published since 1991 (4). In their abstract the authors wrote that “Overall evidence on the coffee-colorectal cancer relation suggests an inverse association, since most case control studies found odds ratios below unity, particularly for colon cancer. The pattern of risk is less clear for cohort studies”. A population based case control study published since the 2000 review was published also reported an inverse association between coffee consumption and risk of colon cancer with evidence of a significant dose response relationship (21).

A similar conclusion was arrived at in a meta-analysis published in 1998 of the 12 case control studies and 5 cohort studies which met the selection criteria of the study (22). When the case control studies were analysed separately, then coffee consumption lowered the risk of colorectal cancer by 28%. However, when the 5 cohort studies were analysed separately, then coffee consumption lowered the risk of colorectal cancer by only 3%. When both types of study were combined the reduction in risk was 24% due to the larger number of case control studies. The lower risk of colorectal cancer in heavy coffee drinkers was observed in studies from Asia, Northern and Southern Europe and North America. The author suggested that ongoing cohort studies might help resolve the discrepancy between the results of case control studies and cohort studies.

Cohort studies have a stronger experimental design than case control studies. In a study of nearly 43,000 Norwegian men and women where 130 cases of colon cancer and 79 cases of rectal cancer were diagnosed, there were no significant associations between coffee consumption and disease risk (10). When 27,111 male Finnish smokers were studied, 106 cases of colon cancer and 79 cases of rectal cancer were identified but no associations between coffee consumption and disease risk were reported (23). In the most recently published study, 460 new cases of colorectal cancer were diagnosed in a cohort of 61,463 Swedish women but no association between risk of colorectal cancer and coffee consumption was shown (24).

The disagreement between the results of case control studies and cohort studies remains to be resolved. On the one hand, the results of prospective cohort studies showing no protective effect of coffee against colorectal cancer are more reliable than the results of retrospective case control studies showing a protective effect. On the other hand, there is a remarkable degree of consistency in the results of case control studies. It is hard to imagine how a methodological artefact could account for this consistency.

OVARIAN CANCER

Twelve case control studies of associations between consumption of coffee and risk of ovarian cancer have been published (25-36). Nine of these studies were unable to show any consistent or significant associations (25-33). However, two of these studies indicated a consistent and significant association between coffee consumption and risk of ovarian cancer was demonstrated (34, 35). A population-based case control study from the USA of 549 cases of ovarian cancer and 516 controls showed no significant association between coffee or caffeine consumption and risk of ovarian cancer (36).

However, when pre-menopausal and postmenopausal women were analysed separately, the consumption of coffee or caffeine was significantly associated with risk of ovarian cancer in pre-menopausal but not in postmenopausal women.

Two cohort studies have also examined associations between coffee consumption and ovarian cancer risk. A study of 23,912 Californian Seventh-day Adventists found no association between coffee consumption and fatal ovarian cancer (13). A study of 21,238 Norwegian women found 93 cases of ovarian cancer but no significant associations with coffee consumption (10).

It can be concluded that there is no consistent evidence for a link between coffee or caffeine consumption and the risk of developing ovarian cancer.

PANCREATIC CANCER

A case control study from the USA published in 1981 suggesting a two to three fold increase in risk of pancreatic cancer associated with drinking three or more cups of coffee per day stimulated an enormous amount of research in this area (37). In 1987 a pooled analysis of nine epidemiological studies gave a relative risk of 1.3 for moderate coffee drinkers and 1.6 for heavy coffee drinkers when the original study was included in the analysis but only 1.2 and 1.4 when it was excluded (38). By 1990 when thirty epidemiological studies were reviewed it was concluded that the evidence did not support the hypothesis that coffee consumption increases the risk of pancreatic cancer (39). In 1991 twenty-six case control studies were reviewed and it was concluded that “the data are suggestive of a weak relationship between high levels of coffee consumption and the occurrence of pancreatic cancer, but the possibility that this is due to bias or confounding is tenable” (3). In addition none of the six cohort studies reviewed reported a significant association between pancreatic cancer risk and coffee consumption. By 2000 an additional twelve case control studies and four cohort studies had been published (4). Nine of these case control studies reported no association, one reported an inverse association and two reported a positive association. None of the four cohort studies reported any significant associations. It was concluded that “a strong association between coffee and pancreatic cancer can now be excluded; however, the presence of some moderate and inconsistent association may deserve further investigations”.

As has recently been pointed out, there is a particular reason for distrusting the results of case control studies on pancreatic cancer as poor survival leads to reduced participation rates by cases in interviews and consequently more interviews with surrogates (40). A clearer picture of the relationship between coffee consumption and pancreatic cancer is likely to emerge from a consideration of cohort studies only.

At least thirteen cohort studies of associations between coffee consumption and pancreatic cancer risk have been published and the vast majority of these found no significant associations. Thus studies of 23,912 Californian Seventh-day Adventists (13), 50,000 USA college alumni (41), 7,355 Japanese men living in Hawaii (42), nearly 43,000 Norwegian men and women (10), 34,000 Californian Seventh-day Adventists (43), 122,894 men and women living in California (44), 17,633 American men (45), 13,979 elderly Americans (46), 175,000 Americans (47), 47,794 American men and 88,799 American women (40) and 12,204 Swedish women and 9,608 Swedish men (48) were all unable to show significant associations between coffee consumption and risk of pancreatic cancer. By contrast, a study of 265,118 Japanese men (49) and 33,976 postmenopausal women from Iowa (50) reported a significant positive association between pancreatic cancer risk and coffee consumption. Nevertheless the weight of cohort evidence remains firmly against the concept that coffee drinking increases the risk of developing pancreatic cancer.

It can be concluded that while some case control studies, particularly the earlier ones, suggest that coffee drinking is associated with an increase in the risk of pancreatic cancer, the vast majority of cohort studies do not support the idea. Since there are no intervention trials published on the effect of coffee drinking on the risk of pancreatic cancer then there is no evidence for a cause effect relationship.

RENAL CANCER

As noted on a 1991 review (3), out of four case control studies, three showed that coffee consumption was associated with a slight increase in risk of transitional cell cancers of the renal pelvis and ureter but none of the associations was significant. In addition, six case control studies and one cohort study failed to provide consistent evidence of an association between coffee drinking and adenocarcinoma of the kidney.

Subsequent studies have also failed to provide any consistent evidence for an association between coffee consumption and renal cancer. No significant associations were shown between coffee consumption and renal cancer in case control studies of 203 cases from the USA (51), 240 cases from Italy (52), 196 cases from France (53) and 518 cases from Canada (54). A cohort study from Norway was also unable to demonstrate any significant associations between renal cancer and coffee consumption (10). Finally, a case control study carried out in Australia, Denmark, Sweden and the United States which analysed 1,185 cases of renal cancer was also unable to show any consistent or significant associations nor any evidence for a dose response relationship (55). A 2000 review of these data concluded that “epidemiological data on the relation between coffee consumption and kidney cancer risk are reassuring” (4).

OCHRATOXIN A

Ochratoxin A is one of a family of mycotoxins produced by  the mould Penicillium verrucosum and by several species of Aspergillus including A. ochraceus, A. carbonarius and A. niger. Chemically it consists of a chlorinated isocoumarin moiety linked through a carboxyl group to L-phenylalanine via an amide bond. The major food contaminated by ochratoxin A is cereals but much lower levels of contamination may be found in grape juice and red wine, coffee, cocoa, nuts, spices and dried fruits, and other agricultural products subjected to conditions that result in mould growth. Ochratoxin A is an accepted nephrotoxin  and in animals is a carcinogen and is also teratogenic and immunotoxic. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has set a provisional tolerable weekly intake (PTWI) of 100 ng/kg body weight although the Canadian authorities have set a lower tolerable daily intake (TDI) of 1.5 to 5.7 ng/kg body weight and the European Commission a TDI of not more than 5 ng/kg body weight (56). 

Ochratoxin A production by Penicillium verrucosum is characteristic of cereals. By contrast, a recent study of 408 Brazilian coffee samples identified Aspergillus ochraceus as the major source of ochratoxin A followed by Aspergillus carbonarius (57). Aspergillus niger was an unimportant source. It was also found that there was little infection of coffee cherries while on the tree but infection occurred postharvest, the most likely sources being soil, equipment and drying yard surfaces. Improvements in good agricultural practices have reduced ochratoxin A contamination of coffee.

Processing also lowers the ochratoxin A content of coffee. Roasting dramatically lowers the ochratoxin A content of coffee by 50-90% (58), 30-90% (59) or 81% (60). It has also been reported that decaffeination lowers the ochratoxin A content of coffee by 92% (61).

It has recently been estimated that mean total intakes of ochratoxin A are 45 ng/kg body weight per week assuming a body weight of 60 kg (62). Cereals and wine contribute about 25 and 10 ng/kg body weight per week respectively whereas grape juice and coffee each contribute only 2-3 ng/kg body weight per week. Other foods such as dried fruits, beer, tea, milk, cocoa, poultry and pulses contributed less than 1 ng/kg body weight per week. These estimates underline the conclusion of the Ministry of Agriculture, Fisheries and Food that coffee is not a major source of ochratoxin A in the normal diet (63).

LIVER CANCER

In recent years studies have suggested that coffee drinking may be protective against the development of hepatocellular carcinoma independently of its aetiology. Coffee has been studied extensively in relation to other conditions affecting the liver and this is reported elsewhere on this site. In 2005 Japanese researchers (64) published their findings after conducting a large-scale population-based cohort study that confirmed a statistically significant inverse association between habitual coffee drinking and hepatocellular carcinoma. A further hospital based case-control study conducted in Italy (65) with 250 cases and 500 controls reached similar conclusions. Finally, the findings of these studies were further endorsed by Shimazu et al (66) who, using pooled analysis consisting of over 60,000 people, found a significant inverse association between coffee consumption and the risk of liver cancer.
Research has continued to investigate the inverse association between coffee consumption and liver cancer, with three large studies published in 2007. One of these, an Italian case-control study (67) explored the relationship between coffee drinking and hepatocellular carcinoma risk in a population whose coffee consumption is highly variable. The results support the hypothesis of a favourable effect of coffee on hepatocellular canrcinoma risk. A meta-analysis of four cohort and five case-control studies, involving 2260 cases and 239,146 controls, suggested that an increase in coffee consumption may reduce the risk of liver cancer. The authors point out that the mechanisms involved and the substances in coffee responsible for the relation remain to be elucidated (68). A further meta-analysis (69) of 10 studies covering both European and Japanese populations provided quantitave evidence of an inverse association between coffee drinking and liver cancer.These authors also point out that the mechanisms of action ivolved remain unclear at this time.

References:

1. World Cancer Research Fund. Food, Nutrition and the Prevention of Cancer: a Global Perspective, 1997.

2. Department of Health, Committee on Medical Aspects of Food Policy. Report on Health and Social Subjects, 48, p 130. HMSO: London, 1998. 

3. IARC. IARCMonographs: Evaluation of Carcinogenic Risks to Humans, Vol. 51, Coffee, Tea, Maté, Methylxanthines and Methylglyoxal. International Agency for Research on Cancer, Lyon, 1991.

4. Tavani, A. and La Vecchia, C. European Journal of Cancer Prevention, 9, 241-256, 2000. 

5. Zeegers, M.P.A. et al. International Journal of Epidemiology, 30, 353-362, 2001.

6. Viscoli, C.M. et al. Lancet, 341, 1432-1437, 1993.

7. Sala, M. et al. Cancer Causes and Control, 11, 925-931, 2000.

8. Mills, P.K. et al. American Journal of Epidemiology, 133, 230-239, 1991.

9. Chyou, P-H. et al. Annals of Epidemiology, 3, 211-216, 1993.

10. Stensvold, I. and Jacobsen, B.K. Cancer Causes and Control, 5, 401-408, 1994.

11. Zeegers, M.P.A. et al. Cancer Causes and Control, 12, 231-238, 2001.

12. Mannisto, S. et al. Journal of Clinical Epidemiology, 52, 429-439, 1999.

13. Snowden, D.A. and Phillips, R.L. American Journal of Public Health, 74, 820-823, 1984.

14. Jacobsen, B.K. et al. Journal of the National Cancer Institute, 76, 823-831, 1986.

15. Vatten, L.J. et al. British Journal of Cancer, 62, 267-270, 1990.

16. Hunter, D.J. et al. American Journal of Epidemiology, 136, 1000-1001, 1992.

17. Graham, S. et al. American Journal of Epidemiology, 136, 1327-1337, 1992.

18. Folsom, A.R. et al. American Journal of Epidemiology, 138, 380-383, 1993.

19. Michels, K.B. et al. Annals of Epidemiology, 12, 21-26, 2002.

20. Johnson, K.C. et al. European Journal of Cancer Prevention, 11, 253-263, 2002.

21. Woolcott, C.G. et al. European Journal of Cancer Prevention, 11, 137-145, 2002.

22. Giovannucci, E. American Journal of Epidemiology, 147, 1043-1052, 1998.

23. Hartmann, T.J. et al. Nutrition and Cancer, 31, 41-48, 1998.

24. Terry, P. et al. Gut, 49, 87-90, 2001.

25. Hartge, P. et al. International Journal of Cancer, 30, 531-532, 1982.

26. Byers, T. et al. Journal of the National Cancer Institute, 71, 681-686, 1983.

27. Miller, D.R. et al. Ovarian cancer and coffee drinking In MacMahon B. and Sugimura, T. (eds) Coffee and Health (Banbury Report 17), Cold Spring Harbor, NY, CSH press, 1984. 

28. Miller, D.R. et al. International Journal of Epidemiology, 16, 13-17, 1987.

29. Trichopoulos, D. et al. International Journal of Cancer, 28, 691-693, 1981. 

30. Trichopoulos, D. et al. International Journal of Cancer, 36, 291-297, 1986.

31. Tzonou, A. et al. European Journal of Cancer and Clinical Oncology, 20, 1045-1052, 1984.

32. Cramer, D.W. et al. Obstetrics and Gynaecology, 63, 833-838, 1984.

33. Polychronopoulou, A. et al. International Journal of Cancer, 55, 402-407, 1993.

34. La Vecchia, C. et al. International Journal of Cancer, 33, 559-562, 1984.

35. Whittemore, A.S. et al. American Journal of Epidemiology, 128, 1228-1240, 1988.

36. Kuper, H. et al. International Journal of Cancer, 88, 313-318, 2000.

37. MacMahon, B. et al. New England Journal of Medicine, 304, 630-633, 1981.

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39. Gordis, L. Cancer Letters, 52, 1-12, 1990.

40. Michaud, D.S. et al. Cancer Epidemiology Biomarkers and Prevention, 10, 429-437, 2001.

41. Whittemore, A.S. et al. Journal of Chronic Disease, 36, 251-256, 1985.

42. Nomura, A. et al. Journal of the National Cancer Institute, 76, 587-590, 1986.

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47. Friedman, G.D. and van den Eeden, S.K. International Journal of Epidemiology, 22, 30-37, 1993. 

48. Isaksson, B. et al. International Journal of Cancer, 98, 480-482, 2002.

49. Hirayama, T. et al. Japanese Journal of Clinical Oncology, 19, 208-215, 1989.

50. Harnack, L.J. et al. Cancer Epidemiology Biomarkers Prevention, 6, 1081-1086, 1997.

51. Maclure, M. and Willett, W. Epidemiology, 1, 430-440, 1990.

52. Talamini, R. et al. Cancer Causes and Control, 1, 125-131, 1990.

53. Benhamou, S. et al. International Journal of Cancer, 55, 32-36, 1993.

54. Kreiger, N. et al. Cancer Causes and Control, 4, 101-110, 1993.

55. Wolk, A. et al. International Journal of Cancer, 65, 67-73, 1996.

56. Walker, R. Advances in Experimental Medicine and Biology, 504, 249-255, 2002.

57. Taniwaki, M.H. et al. International Journal of Food Microbiology, 82, 173-179, 2003.

58. Micco, C. et al. Food Additives and Contaminants, 6, 333-339, 1989.

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63. Ministry of Agriculture, Fisheries and Food, Surveillance of Ochratoxin A in Retail Coffee Products (Food Surveillance Information Sheet No. 73), London: Joint Food Safety and Standard Group, 1995.

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68. Larsson, S & Wolk, A. Gastroenterology, 132, 2007.

69. Bravi, F. et al. Hepatology, Online/In Press, 2007.

COFFEE AND GASTROINTESTINAL FUNCTION

The scientific evidence for effects of coffee consumption on the gastrointestinal system was last reviewed in 1999 (1). The authors of this review critically evaluated the evidence for effects of coffee on upper gastrointestinal symptoms such as dyspepsia and heartburn and aspects of gastrointestinal function such as gastric motor function, small intestinal secretion and transit, gallbladder contractility and colonic motor activity. They concluded that “Coffee promotes gastro-oesophageal reflux, but is not associated with dyspepsia. Coffee stimulates gallbladder contraction and colonic motor activity”.

The vast majority of cases of dyspepsia or indigestion have no obvious explanation and are referred to as non-ulcer (or functional) dyspepsia. A few cases of dyspepsia are caused by ulcers of the stomach or duodenum. In a study from the USA, there was no difference between the habitual consumption of coffee in duodenal ulcer patients, functional dyspepsia patients or controls (2). Surprisingly, dyspepsia symptoms were more prevalent in the 55 functional dyspepsia patients than in the 58 patients with duodenal ulcers. A cross-sectional study of 592 Australian blood donors which excluded peptic ulcer patients was unable to find any significant association between coffee consumption and dyspepsia (3). Similarly, a large cross-sectional study of 8,407 adults in the United Kingdom found no association between coffee consumption and dyspepsia (4). There are few data on the relationship between caffeine intake and dyspepsia although one study was unable to show any association between caffeine intake and indigestion in 4,558 Australians after adjusting for confounders (5). The anecdotal observation that conduction roasting by comparison with conventional roasting of coffee beans reduces dyspeptic symptoms in coffee sensitive individuals was not confirmed by a recent intervention trial (6). It can be concluded that coffee has no effects on dyspepsia in most individuals.

Gastro-oesophageal reflux (GOR) refers to the backward flow of acid from the stomach up into the oesophagus. People experience heartburn, also known as acid indigestion, when excessive amounts of acid reflux into the oesophagus. Gastro-oesophageal reflux disease (GORD) is the name given to this condition. In GORD patients oesophageal sensitivities to coffee, orange juice, and tomato drink are all significantly increased suggesting that the effects of these beverages are not specific to coffee (7). In 394 patients with heartburn, neither the acidity nor the osmotic strength of coffee was associated with reported heartburn (8). In 16 healthy subjects, ambulatory oesophageal pH-monitoring was used to show that coffee provokes more GOR than water (9). This effect was reduced but not eliminated by decaffeinated coffee suggesting that other components of coffee are involved. Improvement of GOR symptoms in 17 GORD patients by decaffeinated coffee was confirmed by a second study (10). A study of 20 subjects with coffee sensitivity looked at the effects of three different coffees on GOR and found that a European coffee provoked more GOR than a USA coffee (11). A more recent study compared the effects of coffee and water on GOR by ambulatory oesophageal pH-monitoring in 7 GORD patients and 8 healthy controls but no effects were found (12). The authors concluded that “The results of this study, therefore, do not support a general advice to patients with reflux symptoms to refrain from drinking coffee or to favour decaffeinated coffee”. Although this advice would seem to contradict the conclusions of the review (1) and the results of the above studies, it was pointed out that the effects of coffee on GOR observed were not large enough to be clinically significant.

There are several recent studies on effects of coffee on gastrointestinal function. The suggestion that changes in gastric motor and sensory function might mediate any effects of coffee on dyspepsia is not supported by the findings that coffee has no effects on the function of the proximal stomach (13) or gastric emptying (14). The belief that coffee promotes diarrhoea is not consistent with the observation that coffee has no effect on oro-caecal transit time (14). By contrast, the finding that regular or decaffeinated coffee increase cholecystokinin levels and decrease gallbladder volume may explain why gallstone patients claim that coffee provokes biliary pain (15).      

Two studies on associations between coffee consumption and risk of peptic ulcer disease in the pre-Helicobacter pylori era failed to show any statistically significant associations (16, 17). A recent cohort study of 2,416 Danish adults showed that the major risk factors for peptic ulcer disease are tobacco smoking and Helicobacter pylori infection but coffee consumption was not a risk factor (18). A large USA cohort study of 47,806 men identified 138 new cases of duodenal ulcer in six years (19). There were no significant associations between duodenal ulcer risk and consumption of caffeine, caffeine- containing beverages or decaffeinated coffee.

Hence, there is no evidence that coffee consumption increases the risk of developing peptic (gastric plus duodenal) ulcer or duodenal ulcer alone.


The debate into whether coffee has any significant impact on gastroesophageal reflux disease continues. In 2006 a review paper was published that evaluated several lifestyle factors, including diet, to provide more clarity on this subject (20) . With regard to coffee and caffeine consumption, the authors still found the reported data to be conflicting with the relationship between caffeine or coffee and gastroesophageal reflux disease remaining unclear. However, they do state that 'There is insufficient evidence to support the routine recommendation that patients with gastroesophageal reflux disease avoid such beverages.   

References:

1. Boekema, P.J. et al. Scandinavian Journal of Gastroenterology, 34 Suppl 230, 35-39, 1999.

2. Elta, G.H. et al. American Journal of Gastroenterology, 85, 1339-1342, 1990.

3. Nandurkar, S. et al. Archives of Internal Medicine, 158, 1427-1433, 1998.

4. Moayyedi, P. et al. American Journal of Gastroenterology, 95, 1448-1455, 2000.

5. Shirlow, M.J. and Mathers, C.D. International Journal of Epidemiology, 14, 239-248, 1985.

6. DiBaise, J.K. Digestive Diseases and Sciences, 48, 652-656, 2003.

7. Price, S.F. et al. Gastroenterology, 75, 240-243, 1978.

8. Feldman, M. and Barnett, C. Gastroenterology, 108, 125-131, 1995.

9. Wendl, B. et al. Alimentary Pharmacology and Therapeutics, 8, 283-287, 1994.

10. Brazer, S.R. et al. Physiology and Behavior, 57, 563-567, 1995.

11. Pehl, C. et al. Alimentary Pharmacology and Therapeutics, 11, 483-486, 1997.

12. Boekema, P.J. et al. European Journal of Gastroenterology, 11, 1271-1276, 1999.

13. Boekema, P.J. et al. Digestive Diseases and Sciences, 46, 945-951, 2001

14. Boekema, P.J. et al. European Journal of Clinical Investigation, 30, 129-134, 2000.

15. Douglas, B.R. et al. American Journal of Clinical Nutrition, 52, 553-556, 1990.

16. Friedman, G.D. et al. New England Journal, 290, 469-473, 1974.

17. Ostensen, H. et al. Scandinavian Journal of Gastroenterology, 20, 1227-1235, 1985. 

18. Rosenstock, S. et al. Gut, 52, 186-193, 2003.

19. Aldoori, W.H. et al. Epidemiology, 8, 420-424, 1997.


20. Kaltenbach,T. et al, Archives of Internal Medicine, 166, 2006.

COFFEE AND DIABETES

The only cell in the body able to synthesise and secrete insulin is the β cell of the endocrine pancreas. In type 1 diabetes, sometimes known as insulin -dependent diabetes (IDDM) or juvenile onset diabetes, this cell has been selectively destroyed by the immune system. Although type 1 diabetes is an inherited disease an environmental factor is required to trigger it. Environmental factors hypothesised to trigger the disease include viral infections, cow’s milk protein and coffee. The evidence for a role for coffee in triggering type 1 diabetes is weak and comes from a single ecological study showing a correlation between the incidence of type 1 diabetes and the annual consumption of coffee in 13 countries (1).

In type 2 diabetes, also known as non-insulin dependent diabetes (NIDDM) or maturity onset diabetes, the target tissues for insulin (muscle, liver and adipose tissue) become insensitive or resistant to the action of insulin. This means that more insulin is needed to obtain the same response from the target tissues. A Dutch cohort study of 17,111 adults identified 306 new cases of type 2 diabetes and showed that those subjects drinking at least 7 cups of coffee per day were half as likely to develop the disease (2). This association was statistically significant. By contrast, a cohort study of 2,680 Pima Indians in Arizona identified 824 new cases of type 2 diabetes but found no significant association between coffee consumption and disease risk (3). An intervention trial has also reported that a single dose of 3 mg caffeine/kg body weight significantly decreased ). An intervention trial has also reported that a single dose of 3 mg caffeine/kg body weight significantly decreased insulin sensitivity in 12 healthy subjects (4). Clearly available data on the relationship between type 2 diabetes incidence and coffee or caffeine consumption are contradictory.

Both types of diabetes are characterised by glucose intolerance that is a higher than normal blood glucose concentration after a meal. One study reported that coffee consumption improved glucose tolerance (5) whereas two other studies reported that coffee consumption resulted in a deterioration in glucose tolerance (6, 7). In addition, a single dose of 200 mg caffeine has been shown to impair glucose tolerance in 30 healthy subjects (8). The available results on effects of coffee or caffeine intake on glucose tolerance are also contradictory.

Hypoglycaemia is a characteristic short-term metabolic complication of diabetes. Any agent that improves the perception of hypoglycaemic symptoms or increases the effectiveness of the counter-regulatory hormonal responses designed to raise the blood glucose concentration would be valuable in the management of diabetes. After 72 hours abstinence, ingestion of 250-400 mg caffeine improved the perception of hypoglycaemic symptoms and the counter-regulatory responses in non-diabetics and type 1 diabetics (9, 10). However, the longer-term effects of caffeine are more complex. When the effects of abstinence were compared with ingestion of 400 mg caffeine/day for 7 days it was found that counter-regulatory responses were unaffected. At onset the perception of hypoglycaemic symptoms was greater after caffeine abstinence but as the symptoms continued perception was greater in response to caffeine (11).  Researchers of a study conducted in Sweden and published in 2004 (12) also found a reduced risk of type 2 diabetes and impaired glucose tolerance with increased coffee consumption.  

Research into the relationship between coffee drinking and the development of type 2 diabetes continues with three studies being published in the early months of 2006. A prospective cohort study (13)including 88,529 women as part of the US Nurses Health Study found that moderate consumption of both caffeinated and decaffeinated coffee may lower the risk of type 2 diabetes in younger and middle aged women. The authors suggest, as have others before them, that coffee constituents other than caffeine may be responsible for the observed effect. Van Dam, who was one of the authors of this study, conducted an extensive review (14) of 71 published studies and recommended further research to establish the constituent responsible for the observed effect, and to identify the exact mechanism of action. Another study (15) evaluated the effects of coffee consumption on glucose tolerance, and on serum glucose and insulin levels. After adjustment for potential confounding factors (age, body mass index, systolic blood pressure, occupational, commuting and leisure time physical activity, alcohol intake, tea drinking, and smoking), coffee consumption was significantly inversely associated with fasting glucose, two-hour plasma glucose, and fasting insulin in men and women. These authors concluded that in this cross sectional analysis, coffee showed positive effects on several glycaemic markers. 

Throughout 2006 several studies have been conducted, and published, in different populations, all of which suggest a strong inverse association between coffee consumption and the onset of type 2 diabetes. Iso et al (16) in thier study of a Japanese population consisting on 17,413 participants found an inverse association of green tea and coffee consumption with the risk of type 2 diabetes in women and over-weight men. Gruber (17) in the Netherlands evaluated various lifestyle factors in relation to diabetes prevention, and found that individuals who drank 4 to 7 cups of coffee per day had the smallest risk. A study on a Finnish population set (18) of over 21,000 men and women examined the joint associations of coffee consumption and other lifestyle factors, including physical activity, obesity and alcohol consumption with the risk of type 2 diabetes. Coffee drinking was associated with a reduced risk of type 2 diabetes in both men and women, and this association was observed regardless of levels of physical activity, body mass index and alcohol consumption. Pereira et al (19) as part of the IOWA Womens Health Study in the USA consisiting of over 28,000 women, examined the association between total, caffeinated and decaffeinated coffee consumption, and risk of incident type 2 diabetes. In this cohort, coffee intake, especially decaffeinated, was inversely associated with the risk of type 2 diabetes. A further US study (20) analysed data from a prospective, community-based cohort to assess the risk of incident type 2 diabetes associated with coffee and sweetened beverage consumption. Both men and women who drank more than 4 cups of coffee per day had a risk of developing type 2 diabetes that was about 67% less than that of their counterparts who drank no coffee. Finally, Smith et al (21) investigated the association between coffee drinking and incident type 2 diabetes based on an oral glucose test and examined coffee drinking habits in those with impaired glucose separately from those with normal glucose at baseline. These authors found a 'striking protective effect of caffeinated coffee against incident type 2 diabetes'.

Research continues to suggest that coffee drinking lowers the risk of developing type 2 diabetes. 

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19. Pereira,M.A. et al, Archives of Internal Medicine, 166, 2006.
20. Paynter, N.P. et al, American Journal of Epidemiology, IN PRESS/Online 2006
21. Smith, B. et al, Diabetes Care, Volume 29, 2006

COFFEE AND GALLSTONE DISEASE 

The gallbladder stores bile which is a fluid released into the small intestine where it emulsifies fats thus assisting their digestion. Almost 90 percent of gallstones are composed of solid cholesterol and the remainder consist of solid bilirubin, a pigment. Patients with symptomatic gallstones experience severe abdominal pain. However, about 80 percent of people who have gallstones have no symptoms. Gallstones are usually diagnosed by ultrasound but other procedures such as x-rays may also be used. Risk factors for gallstones include age and obesity.

Three cross sectional studies using ultrasound documented gallbladder disease as an endpoint were unable to show any significant associations with coffee consumption in a Danish population (1), pregnant Irish women (2) or German blood donors (3). Although a fourth cross sectional study from the USA could not show any significant associations between coffee consumption and total or previously undiagnosed gallbladder disease, there was a significant inverse association with previously diagnosed gallbladder disease in women although not in men (4).  

Two small hospital- based case control studies from Greece (5) and Italy (6) were unable to demonstrate any significant associations between coffee consumption and symptomatic gallbladder disease. By contrast, a large population- based case- control study from Italy showed a significant inverse association between coffee consumption and ultrasound-documented gallstones (7).

Two out of the three published prospective cohort studies showed a protective effect of coffee against the development of gallstones. A large study of college alumni in the USA was unable to show any significant association between coffee consumption and clinical gallbladder disease (8). By contrast, a publication from the Health Professionals Follow-up Study on 46,008 men diagnosed 1,081 new cases of ultrasound documented gallbladder disease and found that men who drank 4 or more cups of coffee per day were 45% less likely to develop the disease (9). Similarly, a publication from the Nurses Health Study on 80,898 women identified 7,811 cholecystectomies and found that women who drank 4 or more cups of caffeinated coffee per day were 28% less likely to have their gallbladder removed (10). The associations were statistically significant in both cohorts.

It can be concluded that the results of the better quality prospective cohort studies suggest that coffee consumption protects against gallstone disease in men and women although the degree of protection may be less in women.        

References:

1. Jorgensen, T. et al. Gut, 30, 528-534, 1989.

2. Basso, L. et al. European Journal of Epidemiology, 8, 629-633, 1992.

3. Kratzer, W. et al. Scandinavian Journal of Gastroenterology, 32, 953-958, 1997.

4. Ruhl, C.E. and Everhart, J.E. American Journal of Epidemiology, 152, 1034-1038, 2000.

5. Pastides, H. et al. Archives of Internal Medicine, 150, 1409-1412, 1990.

6. La Vecchia, C. et al. International Journal of Epidemiology, 20, 209-215, 1991. 

7. Misciagna, G. et al. European Journal of Gastroenterology and Hepatology, 8, 585-593, 1996.

8. Sahi, T. et al. American Journal of Epidemiology, 147, 644-651, 1998.

9. Leitzmann, M.F. et al. Journal of the American Medical Association, 281, 2106-2112, 1999. 

10. Leitzmann, M.F. et al. Gastroenterology, 123, 1823-1830, 2002.

COFFEE AND HEART DISEASE

MYOCARDIAL INFARCTION AND OVERALL CORONARY HEART DISEASE

The scientific evidence for a link between coffee drinking or caffeine intake and coronary heart disease risk is entirely derived from observational epidemiological studies. Such studies can only show associations and not cause effect relationships. There are no intervention trials on the relationship between coffee drinking or caffeine intake and coronary heart disease risk and hence no cause effect studies although there are intervention trials on risk factors for disease such as blood pressure, blood lipids and blood homocysteine. Two types of observational epidemiological study have been published. The case control study has the weakest design as exposure, in this case to caffeine or coffee, is measured at the same time as coronary heart disease risk making it impossible to decide which is cause and which effect. The cohort study has a stronger design as exposure is measured prospectively in a group of initially healthy subjects and the appearance of coronary heart disease over time monitored.

Case control studies and cohort studies are subject to confounding and the best studies adjust the data for other known risk factors for coronary heart disease. However, even after adjustment it is still possible that coffee drinking or caffeine intake are acting as markers for some other aspect of lifestyle which is the true cause of the disease. A good example of this is the finding of the Olivetti Heart Study that after multivariate adjustment coffee consumption was significantly associated with cigarette smoking, a well-established risk factor for heart disease (1). The idea that coffee drinking is a marker for a lifestyle characterised by known risk factors for heart disease including smoking, lack of physical activity and consumption of saturated fat is supported by data from three other cohort studies (2, 3, 4).

Observational epidemiological studies of associations between coffee consumption and risk of cardiovascular disease were reviewed in the early 1990s (5, 6, 7). Greenland (6), for example, published a meta-analysis of 8 case control studies and 14 cohort studies and noted a fairly homogeneous increased risk in case control studies and a very heterogeneous and much smaller increased risk in cohort studies. It was concluded that the evidence thus remains ambiguous regarding both the existence and size of a coffee effect.

A number of case control studies have been published since the early 1990s. An Italian case control study carried out within the framework of the GISSI-2 trial on therapy for heart attack survivors found that after adjustment for other risk factors coffee consumption may indicate an increase in the risk of heart attack (8). A second Italian case control study indicated that the consumption of decaffeinated coffee was significantly associated with risk of heart attack in women although this association was no longer significant after adjustment for diabetes, hypertension and hyperlipidaemia. However, a case control study from the USA was unable to find any significant associations between consumption of either caffeinated or decaffeinated coffee and risk of heart attack. By contrast, a third Italian case control study found a significant association between the consumption of 6 or more cups of coffee per day and risk of heart attack after adjustment for confounders (19). Finally, a Swedish case control study showed that consumption of boiled coffee rather than filtered coffee was associated with increased risk of a first nonfatal heart attack. However, this result could be interpreted as suggesting that boiled coffee consumption helps people survive a heart attack.

A number of cohort studies have also been published since the early 1990s. In a cross-sectional study of 10,359 subjects in the Scottish Heart Health Study, it was found that non coffee drinkers had a significantly higher risk of coronary heart disease than the three categories of coffee drinkers. After 7.7 years of follow-up of this cohort, coffee consumption was associated with reduced risk of coronary morbidity and mortality although the statistical significance of these associations was marginal.

By contrast, a recent publication from the John Hopkins Precursors Study found that most categories of coffee consumption were significantly associated with increased risk of coronary heart disease, particularly heart attack, in smokers and non-smokers. However, in an editorial Willett argued that the author's conclusions were not supported by their data and concluded that the results must have been due to chance.

Four subsequent cohort studies have not established any strong associations between coffee drinking and risk of coronary heart disease. A Norwegian cohort study of 38,500 subjects over 12 years found that coffee consumption was associated with increased risk of death from coronary heart disease but only when nine or more cups of strong Scandinavian coffee were drunk. In addition, if the first six years of follow-up were excluded, the association disappeared. A publication from the Nurses Health Study in the USA in which 712 cases of coronary heart disease were diagnosed in a cohort of 85,747 women over a period of ten years were unable to find any associations between coffee consumption or caffeine intake and risk of coronary heart disease. In a cohort of 5,766 Scottish men followed up for 21 years there were no associations between coffee consumption and coronary heart disease mortality. In a Finnish cohort of 20,179 subjects followed up for 10 years, there were no significant associations between coffee consumption and the risk of nonfatal heart attack, coronary heart disease mortality or total mortality in men or women. Although not significant, the highest risks were found in the non-coffee drinkers.

The strongest evidence for the idea that coffee consumption is associated with increased risk of coronary heart disease comes from the case control studies. Such studies have a weaker design than cohort studies and suffer from bias introduced by the choice of controls and differential recall of food and beverage consumption over extended periods by cases and controls. By contrast, the results of cohort studies do not support the idea that coffee consumption increases risk of coronary heart disease and one study even suggests that coffee consumption might protect against coronary heart disease. The single study showing an increased risk of coronary heart disease with coffee consumption was dismissed by the editor of the journal it was published in who is himself a well known epidemiologist.

Overall the evidence does not support the proposition that coffee consumption causes heart disease.

CARDIAC ARRHYTHMIAS

There is little experimental evidence for the idea that caffeine causes cardiac arrhythmias. In intervention trials neither 300 nor 450 mg doses of caffeine increased the occurrence or severity of ventricular arrhythmias in patients recovering from a heart attack. In addition 200 mg caffeine had no effect on patients with malignant ventricular arrhythmia and 275 mg caffeine had no effect on patients with clinical ventricular tachycardia. Caffeine restriction had no effect on patients with symptomatic idiopathic ventricular beats. In a prospective cohort study of 128,934 adults over 8 years there was no association between consumption of coffee and risk of death attributed to cardiac arrhythmia without specified cause. A review of intervention trials and epidemiological studies concluded that “moderate ingestion of caffeine does not increase the frequency or severity of cardiac arrhythmia’s in normal persons, patients with ischaemic heart disease, or those with pre-existing serious ventricular ectopy.

BLOOD PRESSURE

Confusion surrounding caffeine effect on blood pressure is long-standing. It was originally thought to lower blood pressure but subsequently believed to raise it. In 1988 Myers reviewed seventeen intervention trials and cross-sectional studies (1). He concluded that caffeine does not produce a persistent increase in blood pressure. Individuals who do not regularly consume caffeine may experience a slight increase in blood pressure when they are exposed to caffeine, but tolerance develops rapidly and blood pressure returns to baseline.

The results of studies on subjects with normal blood pressure published since this review confirm its conclusions. An intervention trial in moderate coffee drinkers showed that moderate daily consumption of coffee does not elevate blood pressure measured in an outpatient clinic. A second intervention trial in habitual coffee drinkers showed that caffeine supplements produced a small increase in ambulatory blood pressure which returned to normal after three days. A third intervention trial in habitual coffee drinkers showed that abstaining from caffeine for 9 weeks had no effect on blood pressure.

Similar effects of caffeine have been observed in hypertensive subjects. In an intervention trial, caffeine administration to hypertensive subjects raised systolic blood pressure but this effect was no longer observed after the first 24 hours. In a second intervention trial there were no effects on blood pressure of drinking caffeinated coffee or abstaining in patients with borderline or mild hypertension. In a cohort study of hypertensive subjects, there were no associations between caffeine consumption and all-cause or cardiovascular disease mortality. Hence there is no evidence in hypertensive subjects of a sustained effect of caffeine consumption on blood pressure nor increased death rates from cardiovascular disease.

However, some studies have demonstrated potential negative effects of caffeine on blood pressure. It has been shown that intake of caffeine during behavioural stress in subjects with borderline hypertension elevates blood pressure. Subjects with hypertension and subjects with normal blood pressure may respond differently to caffeine. Thus diastolic blood pressure returned to normal more quickly in subjects with normal blood pressure than in subjects with hypertension after caffeine ingestion. It has also been claimed that 24 hour monitoring of blood pressure is necessary to reveal all the effects of caffeine on blood pressure.

Prospective epidemiological studies have given contradictory results. Results from the Multiple Risk Factor Intervention Trial (MRFIT) on 11,000 men for 6 years indicated a statistically significant inverse association between caffeine consumption and systolic or diastolic blood pressure. By contrast, a study of 1017 men for 33 years demonstrated an increased risk of hypertension associated with drinking 5 or more cups of coffee per day. However, this association was not significant.

In the light of the results of subsequent studies, the conclusions of Myers in his 1988 review are still valid. A more recent critical review of over 100 published studies concluded that coffee or caffeine may only be harmful to hypertension prone subjects and then only in large doses although the authors did not specify these doses.

Research into the effects of coffee drinking on blood pressure has continued and it can be concluded that coffee drinking is generally not considered to be an important risk factor for hypertension. The effect of caffeine from all drinks, including coffee, on blood pressure was found to be in the range of 2.0 - 2.4 mm Hg for systolic blood pressure and 0.73 - 0.80 for diastolic blood pressure (15,16,17). Blood pressure levels return to baseline/control levels within a few hours following ingestion, with a fading of the mild hypertensive effect of caffeine taking place over a few days or weeks. A recently published meta-analysis of 16 studies reported that blood pressure elevations are larger with caffeine (systolic 4.16 mm Hg, diastolic 2.41 mm Hg) than with coffee (systolic 1.22 mm Hg, diastolic 0.49 mm Hg). This reflects that when ingested from coffee, caffeine has a small effect on blood pressure. Further, Geliejnse et al in 2004 reported that hypertension, the prevalence of which is increasing in Western societies, is mainly caused by being overweight, physical inactivity, high sodium intake, and low potassium intake with the impact of coffee being quite small by comparison. It is also relevant to point out that the slight increase in blood pressure levels attributable to coffee is not larger than that experienced during common activities such as taking part in a conversation. A recent study examined the association between caffeine intake and incident hypertension in a cohort of 155,594 women in the United States. Caffeine intake and possible confounders were ascertained from regularly administered questionnaires. In this large cohort habitual coffee consumption WAS NOT associated with an increased risk of hypertension, but consumption of sugared or diet cola was associated with it. On thier website, the UK based Blood Pressure Association, in answer to a question 'Does drinking too much coffee raise your blood pressure?' state that 'Drinking coffee only has a small effect on blood pressure and therefore cutting down or stopping will not lower it. Other parts of your diet, such as the amount of salt or fruit and vegetables you eat are much more likely to have an effect on your blood pressure, so concentrate on getting these right'. Further, in 2008, and extensive review of both cross-sectional and prospective studies concluded that 'Although the precise nature of the relation between coffee and blood pressure is still unclear, most evidence suggests that regular inrtake of caffeinated coffee does not increase the risk of hypertension'. (21)

BLOOD CHOLESTEROL

The effects of drinking different types of coffee on blood lipid levels including total, low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol have been reviewed (1). The authors summarised the evidence that the diterpenes cafestol and kahweol are the cholesterol-raising factors in coffee and classified coffee brews as containing low, moderate or high levels of diterpenes.

Filtered coffee and instant coffee contain low levels of diterpenes. In some intervention trials, neither filtered coffee (2) nor instant coffee (3) had any effect on blood lipid levels. In one intervention trial, however, filtered coffee elevated both LDL- and HDL-cholesterol levels so that the ratio of LDL to HDL and hence the risk of cardiovascular disease did not change (4). Mocha coffee, common in Italy and Spain, and Espresso coffee contain moderate levels of diterpenes. Intervention trials have demonstrated that neither Mocha coffee (5) nor Espresso coffee (6) had any effect on total, LDL or HDL cholesterol levels. Boiled coffee and cafetiere coffee contain high levels of diterpenes. Intervention trials have demonstrated that both boiled coffee (2) and cafetiere coffee (7) raise total and LDL-cholesterol levels. However, the second of these studies has been criticised (8, 9) because the effect was small and within the normal diurnal and seasonal variation in cholesterol levels, the effect was of marginal statistical significance and there was evidence at the end of the 24-week study that cholesterol levels were falling again implying adaptation to coffee intake.

The caffeine content of coffee does not appear to have any influence on blood lipid levels. An intervention trial has shown that consumption of decaffeinated coffee did not lower total or LDL-cholesterol levels and a cross-sectional study was unable to show any association between caffeine intake and total, LDL- or HDL-cholesterol

A meta-analysis of intervention trials published prior to December 1998 on the effects of coffee on blood lipid levels was published in 2001 (12). The authors identified twenty- three papers but excluded nine from their analysis due to design faults. A significant dose response relationship between consumption of all types of coffee and total or LDL cholesterol levels was shown. They observed greater effects in subjects with hyperlipidaemia or when either caffeinated and decaffeinated coffee or boiled and filtered coffee were compared.&

It can be concluded that heavy consumption of boiled coffee but not filtered coffee elevates blood total and LDL cholesterol levels. This effect is more obvious in hyperlipidaemic subjects. However, the clinical, statistical and long-term significance of the effects of boiled coffee on blood lipid levels has been questioned.  Although more common in Scandinavia and the Middle East, drinking boiled coffee is comparatively rare in most countries

BLOOD HOMOCYSTEINE

Homocysteine is a naturally occurring amino acid found in the blood and tissues. However, it is not among the twenty amino acids which are the building blocks of proteins and hence is not found in dietary protein. Homocysteine is formed from the amino acid methionine which is a constituent of dietary protein. Homocysteine can also be converted back to methionine by two pathways. One of these pathways requires cobalamin (vitamin B₁₂) and tetrahydrofolate (derived from dietary folic acid) as cofactors. An alternative route for the metabolism of homocysteine is conversion to cystathionine and then to the amino acid cysteine. This conversion requires pyridoxal phosphate (derived from vitamin B₆) as a cofactor. Hence, efficient disposal of homocysteine requires three dietary vitamins namely folic acid, vitamin B₁₂ and vitamin B₆. Green vegetables and citrus fruits are excellent sources of folic acid, and vitamins B₆ and B₁₂ are found in a wide range of plant and animal foods including whole grain products, bananas, fatty fish, nuts, poultry and red meats. A balanced diet will, therefore, provide adequate intakes of all three vitamins and hence ensure efficient disposal of homocysteine.

Over thirty years have gone by since it was first suggested that elevated levels of homocysteine in the blood are associated with a high risk of cardiovascular disease (1). However, not all studies have been able to demonstrate this association. After correction for other risk factors, a study of cases and controls from the Atherosclerosis Risk in Communities (ARIC) study was unable to find any association between blood homocysteine levels and risk of coronary heart disease (2). Similarly, after correction for other risk factors, a study of cases and controls from the Caerphilly cohort was unable to show that coronary heart disease risk was associated with serum homocysteine levels (3). 

The crucial question is whether the elevated blood homocysteine level causes cardiovascular disease or whether cardiovascular disease causes the elevated blood homocysteine level. A review of 43 studies found that most cross-sectional and case control studies were able to find an association between blood homocysteine levels and cardiovascular disease risk whereas most prospective studies were not (4). The authors noted that the few prospective studies showing an association included subjects with pre-existing cardiovascular disease. They concluded that elevated homocysteine levels were a consequence of cardiovascular disease and not a cause of it. By contrast, a more recent meta-analysis of 72 studies of subjects with a genetically determined elevated homocysteine level and 20 prospective studies of normal subjects concluded that there was & strong evidence that the association between homocysteine and cardiovascular disease is causal& (5). The authors concluded that lowering homocysteine levels by 3 &mol/l would reduce the risk of heart disease by 16%.

It has been suggested that coffee consumption elevates homocysteine levels and that abstention from coffee lowers them. While seven cross-sectional studies (6, 7, 8, 9, 10, 11, 12) have shown that coffee consumption is positively associated with plasma total homocysteine concentrations in both men and women, three other cross-sectional studies (13, 14, 15) failed to show any association.

Although these associations do not prove that coffee consumption raises the blood level of homocysteine they are supported by the results of four out of five intervention trials. Plasma total levels of homocysteine were elevated by 1.2 & mol/l by drinking a litre of unfiltered coffee per day for 2 weeks (16) or increased by 1.5 & mol/l by drinking a litre of paper-filtered coffee per day for 4 weeks (17). It has also been shown that abstention from filtered coffee for 6 weeks is associated with a decrease in total homocysteine levels of 1.08 &;mol/l (18). Plasma levels of homocysteine were elevated by 0.4 & mol/l by 870 mg caffeine per day and by 0.9 mol/l by 0.9 l filtered coffee (containing 870 mg caffeine) per day for two weeks suggesting that caffeine is partly responsible for the homocysteine raising effect of coffee (19). By contrast, a fifth intervention trial was unable to demonstrate any effect of five cups of coffee per day for 1 week on plasma homocysteine levels although this study was not well controlled (20).

It has been suggested that caffeine might be the factor in coffee that elevates plasma total levels of homocysteine because it may inhibit the conversion of homocysteine to cysteine by acting as a vitamin B₆ antagonist (6, 11, 16). However, direct evidence for this proposal is lacking. Chlorogenic acid may also be partly responsible for this effect as an intake of 2 g per day for a week increased plasma total homocysteine (21).

Hence there is still disagreement over whether the blood homocysteine level is a risk factor for cardiovascular disease. In addition, it is not clear whether even high intakes of coffee are sufficient to raise blood homocysteine levels enough to influence cardiovascular disease risk nor is it clear whether abstention from coffee will lower levels enough to reduce risk. An effect of coffee consumption on cardiovascular disease risk mediated by homocysteine levels is unlikely. 

References:

COFFEE AND HEART DISEASE

1. Jossa, F. et al. Annals of Epidemiology, 3, 250-255, 1993.

2. Puccio, M. et al. American Journal of Public Health, 80, 1310-1313, 1990.

3. Jacobsen, B.K. and Thelle, D.S. Acta Medica Scandinavica, 222, 215-221, 1987. 

4. Gyntelberg, F. et al. Journal of Internal Medicine, 236, 1-7, 1994.

5. Myers, M.G. and Basinski, A. Archives of Internal Medicine, 152, 1767-1772, 1992.

6. Greenland, S. Epidemiology, 4, 366-374, 1993.

7. Kawachi, I. et al. British Heart Journal, 72, 269-275, 1994. 

8. D’Avanzo, B. et al. Annals of Epidemiology, 3, 595-600, 1993. 

9. La Vecchia, C. et al. Annals of Epidemiology, 3, 601-604, 1993.

10. Sesso, H.D. et al. American Journal of Epidemiology, 149, 162-167, 1999.

11. Brown, C.A. et al.Journal of Epidemiology & Community Health, 47, 171-175, 1993.

12. Woodward, M. and Tunstall-Pedoe, H. Journal of Epidemiology & Community Health, 53, 481-487, 1999.

13. Klag, M.J. et al. Annals of Epidemiology, 4, 425-433, 1994.

14. Willett, W.C. Annals of Epidemiology, 4, 497-498, 1994.

15. Stensvold, I. et al. British Medical Journal, 312, 544-545, 1996.

16. Willett, W.C. et al. Journal of the American Medical Association, 275, 458-462, 1996.

17. Hart, C. and Davey Smith, G. Journal of Epidemiology and Community Health, 51, 461-462, 1997.

18. Kleemola, P et al. Archives of Internal Medicine, 160, 3393-3400, 2000.

19. Tavani, A. et al. European Journal of Epidemiology, 17, 1131-1137, 2001.

20. Hammar, N. et al. Journal of Internal Medicine, 253, 653-659, 2003.

COFFEE AND CARDIAC ARRHYTHMIAS

1. Myers, M.G. et al. American Journal of Cardiology, 59, 1024-1028, 1987.

2. Myers, M.G. et al. Canadian Journal of Cardiology, 6, 95-98, 1990.

3. Graboys, T.B. et al. Archives of Internal Medicine, 149, 637-639, 1989.

4. Chelsky, L.B. et al. Journal of the American Medical Association, 264, 2236-2240, 1990.

5. Newby, D.E. et al. Heart, 76, 355-357, 1996.

6. Klatsky, A.L. et al. Annals of Epidemiology, 3, 375-381, 1993. 

7. Myers, M.G. et al. Annals of Internal Medicine, 114, 147-150, 1991. 

COFFEE AND BLOOD PRESSURE

1. Myers, M.G. et al. Archives of Internal Medicine, 148, 1189-1193, 1988. 

2. Rosmarin, P.C. et al. Journal of General Internal Medicine, 5, 211-213, 1990.

3. Myers, M.G. et al. American Journal of Hypertension, 4, 427-431, 1991.

4. Bak, A. and Grobbee, D. American Journal of Clinical Nutrition, 53, 971-975, 1991. 

5. Robertson, D. et al. American Journal of Medicine, 77, 54-60, 1984.

6. MacDonald, T.M. et al. British Medical Journal, 303, 1235-1238, 1991.

7. Martin, J.B. et al. Café, Cacao, Thé, 30, 281-287, 1986.

8. Martin, J.B. et al Preventive Medicine, 17, 310-320, 1988.

9. Lavallo, W.R. et al. Health Psychology, 15, 11-17, 1996.

10. Sung, B.H. et al. American Journal of Hypertension, 8, 1184-1188, 1995. 

11. Green, P.J. and Suls, J. Journal of Behavioural Medicine, 19, 111-128, 1996.

12. Stamler, J. et al. American Journal of Clinical Nutrition, 65 (Suppl) 338S-365S,1997.

13. Klag, M. et al. Archives of Internal Medicine, 162, 657-662, 2002.

14. Nurminen, N.L. et al. European Journal of Clinical Nutrition, 53, 831-839, 1999.

15. Jee, S.H. et al. Hypertension, 33, (2) 647-652, 1999.

16. Lovallo, W.R. et al. Hypertension, 43, (4) 760-765, 2004.

17. Noordzij, M. et al. Journal of Hypertension, 23, (5) 921-928, 2005.

18. Geleijnse, J.M. et al, European Journal of Public Health, 14, (3) 235-239, 2004.

19. Myers, M.G. International Life Sciences Institute, North American Edition,
1998.

20. Winkelmayer,W.C. et al, JAMA, 294, 2330-2335, 2005

21. J M Geleijnse, Vascular Health & Risk Management, Volume 4, 2008

COFFEE AND BLOOD CHOLESTEROL

1. Urgert, R. and Katan, M.B. Annual Review of Nutrition, 17, 305-324, 1997.

2. Bak, A.A.A. et al. New England Journal of Medicine, 321, 1432-1437, 1989.

3. Rosmarin, P.C. et al. American Journal of Medicine, 88, 349-356, 1990.

4. Fried, R.E. et al. Journal of the American Medical Association, 267, 811-815, 1992.

5. Sanguigni, V. et al. European Journal of Epidemiology, 11, 75-78, 1995.

6. D’Amicis, A. et al. International Journal of Epidemiology, 25, 513-520, 1996.

7. Urgert, R. et al. British Medical Journal, 313, 1362-1366, 1996.

8. Gurr, M.I. British Medical Journal, 314, 680, 1996.

9. Gurr, M.I. British Journal of Cardiology, 4, 51-53, 1997.

10. Wahrburg, U. et al. European Journal of Clinical Nutrition, 48, 172-179, 1994.

11. Carson, C.A. et al. American Journal of Epidemiology, 138, 94-100, 1993.

12. Jee, S.H. et al. American Journal of Epidemiology, 153, 353-362, 2001.

COFFEE AND BLOOD HOMOCYSTEINE

1. Hankey, G. J. and Eikelboom, J.W. Lancet, 354, 407-413, 1999.

2. Folsom, A.R. et al. Circulation, 98, 1-7, 1998.

3. Fallon, U.B. et al. Heart, 85, 153-158, 2001.

4. Christen, W.G. et al. Archives of Internal Medicine, 160, 422-434, 2000.

5. Wald, D.S. et al. British Medical Journal, 325, 1202-1206, 2002.

6. Nygard, O. et al. American Journal of Clinical Nutrition, 65, 136-143, 1997.

7. Oshaug, A. et al. European Journal of Clinical Nutrition, 52, 7-11, 1998.

8. Nygard, O. et al. American Journal of Clinical Nutrition, 67, 263-270, 1998.

9. Stolzenberg-Solomon, R.Z. et al. American Journal of Clinical Nutrition, 69, 467-475, 1999.

10. De Bree, A. et al. American Journal of Epidemiology, 154, 150-154, 2001.

11. Jacques, P.F. et al. American Journal of Clinical Nutrition, 73, 613-621, 2001. 

12. Koehler, K.M. et al. American Journal of Clinical Nutrition, 73, 628-637, 2001. 

13. Nieto, F.J. et al. American Journal of Clinical Nutrition, 66, 1475-1476, 1997.

14. Rasmussen, L.B. et al. American Journal of Clinical Nutrition, 72, 1156-1163, 2000.

15. Saw, S.M. et al. American Journal of Clinical Nutrition, 73, 232-239, 2001.

16. Grubben, M.J. et al. American Journal of Clinical Nutrition, 71, 480-484, 2000.

17. Urgert, R. et al. American Journal of Clinical Nutrition, 72, 1107-1110, 2000.

18. Christensen, B. et al. American Journal of Clinical Nutrition, 74, 302-307, 2001.

19. Verhoef, P. et al. American Journal of Clinical Nutrition, 76, 1244-1248, 2002.

20. Esposito, F. et al. Alimentary Pharmacology and Therapeutics, 17, 595-601, 2003. 

21. Olthof, M.R. et al. American Journal of Clinical Nutrition, 73, 532-538, 2001.

COFFEE AND KIDNEY FUNCTION/FLUID BALANCE

The effects of coffee or caffeine consumption on several aspects of kidney function have been studied including diuresis, detrusor instability and kidney stones.

Increased urine output over a 24 hour period was observed with high coffee intake (aprroximately 6 cups equating to 642mg caffeine) though such effects have not been confirmed at levels below 300mg (1).

Athletes and physically active people are often recommended to abstain from consuming caffeinated beverages. It is assumed that caffeine, which is a mild diuretic, will exaggerate the dehydration and electrolyte loss caused by exercise and lead to impaired athletic performance or health although no scientific evidence is offered in support of this assumption. Nine studies, which have looked at the effects of caffeine consumption on the volume of urine, have recently been reviewed (2). The author wrote in his abstract that the scientific literature suggests that athletes and recreational enthusiasts will not incur detrimental fluid-electrolyte imbalances if they consume caffeinated beverages in moderation and eat a typical U.S. diet&.

Two of these nine studies are particularly informative. The first study was one to collect urine over a 24-hour period (3). It was found that there were no significant differences in the volume of urine produced in response to water, 114 mg caffeine or 253 mg caffeine. The second study was the only one to measure urine production during exercise (4). It was observed that a single dose of 8.7 mg caffeine per kg body weight led to a significant increase in urine production vs. placebo at rest but a non-significant reduction in urine production by comparison with placebo both at rest and during cycling exercise.

A recently published large cross sectional study of 27,936 Norwegian women found that coffee consumption was not significantly associated with urinary incontinence (5). This confirms the results of three earlier but smaller studies (6,7,8). Patients with symptoms of urgency and frequency due to detrusor muscle instability often complain that their symptoms are exacerbated by drinking coffee or tea. It has been shown that a single dose of 200 mg caffeine significantly increased detrusor pressure in 20 women with confirmed detrusor instability but not in 10 asymptomatic women (9). Although a study of 41 elderly women found that a decrease in the amount of caffeine consumed was associated with fewer episodes of involuntary urine loss, this association was not significant (10). In a case control study of 131 women with detrusor instability and 128 controls, caffeine intake was significantly higher in cases than in controls (11). Cohort studies and intervention trials are required to confirm these results.     

A high fluid intake is the oldest existing treatment for kidney stones. However, recent research suggests that the composition of the fluid may also exert a beneficial influence. An early case control study was the first to show an inverse association between coffee consumption and a history of kidney stones (12). In a subsequent cohort study of 45,289 men in the USA, 753 new cases of kidney stones were diagnosed and the risk of developing a stone fell by 10% in response to 240 ml/day of caffeinated or decaffeinated coffee (13). In a cohort study of 81,093 women in the USA, 719 new cases of kidney stones were identified and the risk of developing a stone fell by 10% in response to 240 ml caffeinated and 9% in response to 240 ml decaffeinated coffee (14). The available evidence consistently demonstrates that coffee consumption lowers the risk of developing a kidney stone.

Caffeine has long been recognised as a mild diuretic, however, current science does not support the idea that the consumption of caffeine containing beverages promotes dehydration. In fact, it is now increasingly being acknowledged that caffeine containing beverages, consumed in moderation, can be an important source of fluid in the diet. A 2007 study was published that offered a fresh perspective on topics related to fluid balance, hydration and exercise in the heat. In respect of caffeine , the authors state that 'Acute ingestion of moderate to low levels of caffeine (<300mg) does not promote dehydration at rest or during exercise. Long term ingestion of low to high levels of caffeine does not compromise hydration status and thermoregulation at rest or during exercise'. Further, they also point out that either increasing or decreasing ones level of caffeine ingestion does not seem to change hydration status. They conclude that there is no evidence to support caffeine restriction on the basis of impaired thermoregulation or changes of hydration status at levels less that 300 to 400mg per day. (15) Further an extensive review paper, also published in 2007, concluded that caffeinated fluids contribute to the daily human water requirement in a manner that is similar to pure water. Scientific evidence does not support the claim that caffeine containing beverages promote dehydration. (16)   

References:

1.Neuhauser-Berthold, M. et al. Annals of Nutrition & Metabolism,41, 29-36, 1997.

2. Armstrong, L.E. International Journal of Sport Nutrition and Exercise Metabolism, 12, 189-206, 2002.

3. Grandjean, A.C. et al. Journal of the American Collegeof Nutrition, 19, 591-600, 2000.

4. Wemple, R.D. et al. International Journal of Sports Medicine, 18, 40-46, 1997.

5. Hannestad, Y.S. et al. British Journal of Obstetrics and Gynaecology, 110, 247-254, 2003. 

6. Burgio, K.L. et al. Journal of Urology, 146, 1255-1259, 1991.

7. Brown, J.S. et al. Obstetrics and Gynecology, 87, 715-721, 1996.

8. Roe, B. and Doll, H. Journal of Wound, Ostomy and Continence Nursing, 26, 312-319, 1999.

9. Creighton, S.M. and Stanton, S.L. British Journal of Urology, 66, 613-614, 1990.

10. Tomlinson, B.U. et al. International Urogynecology Journal, 10, 22-28, 1999.

11. Arya, L.A. et al. Obstetrics and Gynecology, 96, 85-89, 2000.

12. Shuster, J. et al. Journal of Chronic Disease, 38, 907-914, 1985. 

13. Curhan, G.C. et al. American Journal of Epidemiology, 143, 240-247, 1996.

14. Curhan, G.C. et al. Annals of Internal Medicine, 128, 534-540, 1998.

15. Ganio, M.S. et al. Clinical Sports Medicine, 26, 1-16, 2007.

16. Armstrong, L.E. et al. Exercise and Sports Science Reviews, 35, 135-140, 2007.

COFFEE AND LIVER CIRRHOSIS

Two studies, each on the Kaiser Permanente Medical Care Program cohort in California, originally demonstrated that coffee drinking might protect against liver cirrhosis. In the first study, 59 cases of liver cirrhosis were diagnosed and it was shown that subjects who drank four or more cups of coffee per day had 80% less chance of developing liver cirrhosis than non-coffee drinkers (1). In the second study, it was reported that coffee drinkers had 23% less chance of dying from liver cirrhosis than non-coffee drinkers (2). A third cohort study of 51,306 Norwegian adults which diagnosed 53 case of liver cirrhosis showed inverse associations between total and alcoholic liver cirrhosis mortality and coffee consumption (3).

The results of these two prospective cohort studies have since been confirmed by the results of three retrospective case control studies. An Italian study of 115 cases of liver cirrhosis showed an inverse association between coffee consumption and disease risk as well as an inverse association of coffee consumption with alcohol-related cirrhosis risk (4). A larger Italian study of 274 cases and 458 controls reported an 84% lower risk of developing liver cirrhosis in subjects who drank four or more cups of coffee per day (5). Finally, a third Italian study of 101 cases and 1538 controls showed a 71% lower risk of developing liver cirrhosis in subjects drinking three or more cups of coffee (6).

The two striking features of the results of these six studies are their consistency and the very large reductions in disease risk observed.

A study of over 125,000 people (7) published in 2006 found a robust inverse relation of coffee drinking to risk of alcoholic cirrhosis, independent of sveral confounders. In contrast, this study found no statistically significant relation of coffee drinking and non-alcoholic cirrhosis.

References:

1. Klatsky, A.L. and Armstrong, M.A. American Journal of Epidemiology, 136, 1248-1257, 1992.

2. Klatsky, A.L. et al. Annals of Epidemiology, 3, 375-381, 1993.

3. Tverdal, A. and Skurtveit, S. Annals of Epidemiology, 13, 419-423, 2003.

4. Corrao, G. et al. European Journal of Epidemiology, 10, 657-664, 1994.

5. Corrao, G. et al. Annals of Epidemiology, 11, 458-465, 2001.

6. Gallus, S. et al. Annals of Epidemiology, 12, 202-205, 2002.

7. Klastsky,A.L. et al. Archives of Internal Medicine, Volume 166, 2006.

COFFEE AND PARKINSON’S DISEASE

A review of the scientific literature up to 1 January, 2002 identified 8 case control studies and 5 cohort studies on the relationship between coffee consumption and risk of Parkinson's disease which met the criteria for inclusion in a meta-analysis (1). This analysis demonstrated that coffee drinkers had 31% less chance of developing Parkinson's disease than non-coffee drinkers. Hence, the available evidence consistently demonstrates that coffee consumption lowers the risk of Parkinson's disease.

However, the authors of the review identified a gender difference. When the two cohorts consisting solely of men were considered (2, 3), a strong inverse linear association between cups of coffee consumed and risk of Parkinson's disease was evident corresponding to a reduction in risk of 49% for every three additional cups of coffee drunk per day. By contrast, the single cohort study consisting solely of women (2) found no association at all. However, a more recent study of 77,713 women, which identified 154 cases of Parkinson’s disease, found that while coffee or caffeine consumption lowered disease risk in women who did not use postmenopausal hormones, they raised disease risk in women who used postmenopausal hormones (4). More studies are needed to decide whether the combined use of oestrogen and coffee or caffeine increases Parkinson's disease risk.

Research into this debilitating condition continues, with recently published studies supporting the hypothesis that coffee consumption may reduce the risk. A large prospective study consisting of 29,335 Finnish subjects found a reduced risk of Parkinson's disease among habitual coffee drinkers(5). A further study consisting of 6710 men and women, also conducted in Finland, reported similar findings and concluded that 'The results support the hypothesis that coffee consumption reduces the risk of Parkinson's disease, but that the protective effect of coffee may varyby exposure to other factors' (6).

While the available results are encouraging, more research is needed to define the mechanism of action of coffee in protecting against Parkinson’s disease.

References: 

1. Hernan, M.A. et al. Annals of Neurology, 52, 276-284, 2002.

2. Ascherio, A. et al. Annals of Neurology, 50, 56-63, 2001.

3. Ross, G.W. et al. Journal of the American Medical Association, 283, 2674-2679, 2000.

4. Ascherio, A. et al. Neurology, 60, 790-795, 2003.

5. Hu, G. et al. Movement Disorders, Online/In Press, August 2007.

6. Saaksjarvi, K. et al. European Journal of Clinical Nutrition, 2007.

COFFEE, CAFFEINE AND PREGNANCY 

GENERAL

There is a degree of confusion surrounding the safe level of caffeine intake during pregnancy with different organisations providing different advice. In the UK, the Food Standards Agency suggest 200 mg of caffeine per day from all sources and this level is the same as that recommended by the March of Dimes in the USA. However, also in the USA, the American Dietetic Association, in thier 2008 Position Paper, suggest 300mg per day as a safe upper limit and this is in line with the advice given by the EU Scientific Committee on Foodstuffs who state that 'While intakes (of caffeine) up to 300 mg/day appear to be safe, the possible question of effects on pregnancy and the offspring at regular intakes above 300mg/day remains open'.

DELAYED CONCEPTION

Eleven studies on effects of caffeine consumption on conception were reviewed recently (1) although not all published studies were included (6). The hypothesis that caffeine delays conception was originally suggested by a study of 104 women which showed that those who consumed an amount of caffeine equivalent to one cup of coffee were less likely to conceive than those who consumed smaller amounts (2). The design of this study has been questioned (1) and some of the design faults have been acknowledged by the authors (3). Criticisms include recruitment of women who did not have an equal probability of conceiving, elimination of 117 women who conceived in the first three months of the study, use of caffeine consumption estimated during the fourth month of trying to conceive as representative of consumption during the entire period and the possibility that caffeine intake might be a marker for anxiety, a known inhibitor of fertility.

Subsequent studies do not support the hypothesis that caffeine consumption delays conception. In a study of 2817 women, the average time to conception was no different in women who consumed more than 7 g caffeine per month and women who consumed 0.5 g per month and caffeine consumption was no higher in 1818 women with primary infertility than in 1765 controls (4). In a study of 11,888 pregnant Danish women there was no association between consumption of caffeine containing beverages and time to conception (5). A prospective study of 210 women found no significant association between delayed conception and consumption of coffee (6).

Studies reporting an association between caffeine consumption and delayed conception are frequently badly designed or wrongly interpreted. For example, the authors of a study of 1909 women reported odds ratios of 1.39 for consumption of 1-150 mg caffeine/day, 1.88 for consumption of 151-300 mg/day and 2.24 for consumption of over 300 mg/day after correction for last method of birth control, parity and cigarette smoking (7). In this study, delayed conception was defined as greater than 12 cycles. The last of these associations was statistically significant. However, it has been pointed out that correction for cigarette smoking, a known risk factor for delayed conception, actually increased risk of delayed conception when it should have decreased it (1). A second example is a study of 1430 women which indicated an increased risk of delayed conception associated with the consumption of more than 300 mg caffeine/day for one year in non-smokers but not in the entire study population (8). The dangers of concluding that a treatment effect exists in a subgroup of subjects when there is no evidence for the same effect in all subjects are well known (1). Cigarette smoking is an important risk factor for delayed conception. A study of 1341 pregnant women showed that conception was delayed by more than 12 cycles in all smokers irrespective of whether or not they drank coffee but not among non-smoking coffee drinkers (9). 

A recent although not quite complete review of the scientific literature concluded that the claim that caffeine consumption by women delays conception has not been followed by convincing support. Some studies finding an association between caffeine consumption and delayed conception found it only in a subgroup whereas others failed to correct for confounders. Cigarette smoking emerges from these studies as a far more likely explanation for delayed conception.   

MISCARRIAGE/SPONTANEOUS ABORTION

Sixteen studies on association between caffeine consumption and spontaneous abortion were reviewed recently (1) but none of these studies addressed the issue raised by Stein and Susser (10). According to these authors, a healthy placenta produces a surge of one or more hormones, which in some women results in a reduced desire for aromatic and strongly flavoured beverages. Hence a high caffeine consumption in the first trimester of pregnancy would be a marker for a low rate of hormone production. A vulnerable implantation would be the result of a low rate of hormone production.

The first suggestion of an association between caffeine consumption and miscarriage came from a survey of 600 households (11). Out of 16 women who consumed more than 600 mg caffeine/day, only one had an uncomplicated delivery. Eight had a miscarriage, five stillbirths and two premature births. This study has been criticised on the grounds that the response rate was only 61%, data on caffeine-containing beverage consumption were collected a long time after the birth suggesting recall bias and there was no correction for confounders such as cigarette smoking, alcohol consumption or socio-economic status (12).

Several retrospective case control studies have examined the relationship between caffeine intake and spontaneous abortion. A case control study of 927 women is the only one to have classified spontaneous abortions as chromosomally normal or according to the type of chromosomal abnormality (13). Caffeine intake was estimated immediately before and after conception and during pregnancy. Caffeine intake around conception was associated with an increased risk of a monosomy X abortion, although there was no evidence for a dose response effect, but not with any other chromosomal abnormality or with chromosomally normal abortions. Caffeine consumption during pregnancy was reported to increase the risk of both chromosomally normal and chromosomally abnormal spontaneous abortions. A second case control study of 591 spontaneous abortions and 2558 controls measured serum paraxanthine (a metabolite of caffeine) levels (14). Spontaneous abortion was associated with very high levels of paraxanthine only. A third population-based case control study of 562 spontaneous abortions and 953 controls showed that women who consumed the most caffeine were at an increased risk of spontaneous abortion (15). However, the possibility that caffeine consumption is a marker for a vulnerable implantation was suggested by two of the authors of the first case control study (10) and could explain the results of all three. An alternative explanation would be confounding by other risk factors which is highly likely in case control studies.

Two prospective cohort studies did not find any significant associations between caffeine intake and risk of spontaneous abortion. The first of these recruited 431 pregnant women and identified all spontaneous abortions after day 21 of gestation and made 7 prospective assessments of caffeine intake (16). In women consuming more than 300 mg caffeine/day, risk of spontaneous abortion increased by 20% but this association was not significant. The second recruited 5144 pregnant women, 499 of which had a spontaneous abortion before week 20 of gestation (17). Odds ratios were 1.3 for consumption of 300 mg caffeine/day, 0.8 for consumption of 3 or more cups of caffeinated coffee/day, 1.5 for consumption of 3 or more cans of soda/day containing caffeine and 2.4 for consumption of 3 or more cups of decaffeinated coffee/day. Only the last of these associations was significant.

A recent review of the scientific literature concluded that the association between caffeine consumption and spontaneous abortion may well reflect the Stein-Susser epiphenomenon (women with prominent nausea tend to reduce caffeine consumption and nausea appears to be a marker of good implantation, perhaps reflecting a favourable balance of hormones produced by a healthy placenta (1).  

Research continues in this emotive area and in early 2008 there were 2 studies published which caused some confusion, one suggesting no association between caffeine intake and miscarriage (D A Savitz et al, Epidemiology, Vol 19,2008) and one suggesting an increase in risk at levels of consumption above 200 mg per day. (X Weng et al, Am J Obs & Gyn, January 2008). Savitz et al examined the relationship of coffee and caffeine intake and pregnancy loss prior to 20 weeks gestation in a cohort of 2407 women. They found little indication of a harmful effect of caffeine on miscarriage risk within the range of coffee and caffeine consumption reported (up to 300 mg per day). However, Weng et al found that high dooses of caffeine intake during pregnancy increase the risk of miscarriage. Weng classified 'high doeses' as being 200 mg per day.

LOW BIRTH WEIGHT AND PREMATURITY

Caffeine intake and low birth weight has been the subject of at least 29 published studies and caffeine intake and prematurity of at least 18 published studies (1).

In a comparison of 175 women who delivered before week 37 of gestation and 313 women who delivered after, there was no effect of drinking four or more cups of coffee per day during pregnancy on the risk of preterm delivery (18). A much larger study of 12,205 women published the same year found no significant association between coffee consumption and risk of low birth weight, short gestation or congenital malformations after correction for confounders (19). 

One of the best designed and executed studies published in this area recruited 1513 women out of 1860 women who consecutively attended a London district hospital (20). Data were prospectively collected at three time points during gestation on coffee, tea and caffeine intake and on a wide variety of confounders. After adjustment for most of the confounders, coffee, tea or caffeine consumption were significantly associated with reduced birth weight. However, when the data were also corrected for smoking, these associations were no longer significant. In a prospective cohort study which recruited 431 pregnant women and identified all spontaneous abortions after day 21 of gestation and made 7 prospective assessments of caffeine intake, there was no association between caffeine intake and early foetal growth as assessed by crown-rump length on ultrasonic examination (16). In a second prospective study of 2291 mothers, an inverse association between caffeine intake and birth weight was observed after correction for confounders although there was no association with consumption of decaffeinated coffee (21). However, the authors noted that the small decrease in birth weight observed was unlikely to be clinically important unless six or more cups of coffee were consumed every day.  

As observed in a recent review (1), “the larger the sample and the better the analyses, the more likely no association is seen between coffee/caffeine consumption and reduced birth weight”. The authors also pointed out that studies executed before smoking was socially undesirable tended to find no association between coffee/caffeine consumption and low birth weight. They suggested that “This raises the possibility that residual confounding really does plague this field since women have been admonished not to smoke if they are pregnant”.

In November 2008, the UK Food Standards Agency on the advice of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (an independent scientific committee that provides advice to the Food Standards Agency, the Department of Health and other Governmental Departments and Agencies on matters concerning the toxicity of chemical) revised thier guidelines to pregant women on caffeine intake during pregancy. The revised figure is 200mg per day from all dietary sources of caffeine.It is suggested that consumption of more than 200mg per day may result in a low birthweight baby, which in turn may have health implications later in life. (36)

FOETAL ANOMALIES

According to a recent review (1), there are at least 7 studies of caffeine intake and foetal anomalies. As observed in the review, poorly designed studies (22, 23, 24) tend to be the ones that show associations between caffeine/coffee consumption and foetal anomalies whereas the better studies (13, 19, 25, 26) show no such associations.

One of the better-designed and executed studies in this field is a hospital based

case-control study which looked at all children born in Finland between January 1980 and April 1982 with defects of the central nervous system (n = 112), orofacial clefts (n = 241), structural defects of the skeleton (n = 210) or cardiovascular malformations (n = 143) (26). After adjustment for confounders, there were no associations between coffee drinking during pregnancy and the risk of any of the anomalies studied. In addition no significant dose response relationship was observed.  

The authors of a recent review (1) concluded that no paper has been published on this topic during the last 12 years. Perhaps investigators of the antecedents of anomalies feel the matter is closed&.

BREAST FEEDING 

The American Academy of Pediatrics Committee on Drugs has recently published a statement on the transfer of drugs and other chemicals into human milk (27). Caffeine was placed in Table 6 of this statement entitled maternal medication usually compatible with breast feeding. It was noted that when adverse effects of caffeine on the infant are reported they tend to include irritability and a poor sleeping pattern. However, such effects were not found in infants whose mothers had a moderate intake of caffeinated beverages corresponding to 2 to 3 cups of coffee per day. Six studies of caffeine secretion into human breast milk have been published (28, 29, 30, 31, 32, 33). Although caffeine has been found in breast milk the concentrations were not great enough to have pharmacological effects (30).

SUDDEN INFANT DEATH SYNDROME (SIDS)

It is highly unlikely that the consumption of caffeine-containing beverages is a risk factor for SIDS sometimes known as cot death. A case control study from New Zealand found that the consumption of 400 mg caffeine/day during the third trimester of pregnancy was associated with an increased risk of SIDS months after birth (34). However, no dose response relationship was found. As pointed out recently (1) this study is probably flawed due to residual confounding by smoking which was inadequately measured. This suggestion is supported by the results of a more recent study from Scandinavia on 244 SIDS cases and 869 controls which was unable to show associations between caffeine intake during or after pregnancy and the risk of SIDS after correction for confounders including smoking, maternal age, education and parity (35).  However, case-control studies have inherently weak designs.

References:

1. Leviton, A. and Cowan, L. Food and Chemical Toxicology, 40, 1271-1310, 2002.

2. Wilcox, A. et al. Lancet, 2, 1453-1455, 1988.

3. Weinberg, C.R. and Wilcox, A.J. Lancet, 335, 792, 1990.

4. Joesoef, M.R. et al. Lancet, 335, 136-137, 1990.

5. Olsen, J. American Journal of Epidemiology, 133, 734-739, 1991.

6. Caan, B. et al. American Journal of Public Health, 88, 270-274, 1998. 

7. Hatch, E.E. and Bracken, M.B. American Journal of Epidemiology, 138, 1082-1092, 1993.

8. Stanton, C.K. and Gray, R.H. American Journal of Epidemiology, 142, 1322-1329, 1995.

9. Alderette, E. et al. Epidemiology, 6, 403-408, 1995.

10. Stein, Z. and Susser, M. Epidemiology, 2, 163-167, 1991.

11. Weathersbee, P.S. et al. Postgraduate Medicine, 62, 64-69, 1977.

12. FDA, 1980. Caffeine: deletion of GRAS status, proposed declaration that no prior sanction exists, and use on an interim basis pending additional study. Federal Register 45/205, 69817-69838.

13. Kline, J et al. Epidemiology, 2, 409-417, 1991. 

14. Klebanoff, M.A. et al. New England Journal of Medicine, 341, 1639-1644, 1999.

15. Cnattingius, S. et al. New England Journal of Medicine, 343, 1839-1845, 2000.

16. Mills, J.L. et al. Journal of the American Medical Association, 269, 593-597, 1993.

17. Fenster, L. et al. Epidemiology, 8, 515-523, 1997.

18. Berkowitz, G.S. et al. Early Human Development, 7, 239-250, 1982.

19. Linn, S. et al. New England Journal of Medicine, 306, 141-145, 1982.

20. Brooke, O.G. et al. British Medical Journal, 298, 795-801, 1989.

21. Bracken, M.B. et al. American Journal of Epidemiology, 157, 456-466, 2003. 

22. Borlee, I. et al. LouvainMedical, 97, 284-297, 1978.

23. Furuhashi, N. et al. Gynecologic and Obstetric Investigation, 19, 187-191, 1985.

24. McDonald, A.D. et al. American Journal of Public Health, 82, 91-93, 1992.

25. Rosenberg, L. et al. Journal of the American Medical Association, 247, 1429-1432, 1982.

26. Kurppa, K. et al. American Journal of Public Health, 73, 1397-1399, 1983. 

27. American Academy of Pediatrics. Committee on Drugs. Pediatrics, 108, 776-789, 2001.

28. Berlin, C.M. Seminars in Perinatology, 5, 389-394, 1981.

29. Tyrala, E.E. and Dodson, W.E. Archives of Diseases in Childhood, 54, 787-800, 1979.

30. Hildebrandt, R. and Gundert-Remy, U. Pediatric Pharmacology, 3, 237-244, 1983.

31. Berlin, C.M. et al. Pediatrics, 73, 59-63, 1984.

32. Ryu, J.E. Developmental Pharmacology and Therapeutics, 8, 329-337, 1985. 

33. Ryu, J.E. Developmental Pharmacology and Therapeutics, 8, 355-363, 1985.

34. Ford, R.P.K. et al. Archives of Diseases in Childhood, 78, 9-13, 1998.

35. Helweg-Larsen, K. et al. Acta Paediatrica, 88, 521-527, 1999.

36. Care Study Group, British Medical Journal, In Press, November 2008

COFFEE AND HEALTH-UNSUBSTANTIATED LINKS 

This information covers only those medical conditions for which there are published scientific data available. It does not comment on unsubstantiated links between coffee and health for which there have been no properly conducted and published trials, nor where it is a question of individual sensitivity to caffeine, which varies considerably.

SUMMARY

Coffee is enjoyed as a drink by millions of people world-wide and has been for at least a thousand years. It contains caffeine, which is a mild stimulant, and in many people coffee drinking enhances alertness, concentration and mental and physical performance. Although it contains a wide variety of substances, it is generally accepted that caffeine is responsible for many of coffee's physiological effects. Because caffeine influences the central nervous system in a number of ways and because a small number of people may be particularly sensitive to these effects, some people have attributed all sorts of health problems to coffee. Caffeine is not recognised as a drug of abuse and there is no evidence for caffeine dependence. Some particularly sensitive people may suffer mild symptoms of withdrawal after sudden abstention from coffee drinking. A 150 ml cup of instant coffee contains about 60mg caffeine and filter coffee contains about 85 mg. For those who like coffee but are sensitive to caffeine, the decaffeinated beverage contains only 3 mg per cup.

There is no sound evidence that modest consumption of coffee has any effects on the outcomes of pregnancy or on the wellbeing of the infant. In the UK, the Food Standards Agency issued guidelines for caffeine intake during pregnancy with an upper limit of 300mg/day. This figure is in line with that stated in 1999 by the EU Scientific Committee on Food who said that 'While intakes up to 300mg/day appear to be safe, the question of possible effects on pregnancy and the offspring at regular intakes above 300mg/day remains open. Despite a small negative effect on calcium balance which can easily be made up from other dietary sources there is no evidence that this is translated into any effect on bone health. It has been known for over 100 years that coffee drinking can help asthma sufferers by improving ventilatory function.

There is no evidence that coffee increases the risk of cancer of the female breast, ovary, pancreas or kidney. It is now accepted that the small increased risk of bladder cancer sometimes associated with coffee drinking is primarily caused by cigarette smoking. There is also evidence that coffee protects against colon cancer and preliminary evidence that it protects against male breast cancer.

There is no evidence that coffee increases the risk of heart disease. Moderate consumption of coffee does not increase cardiac arrhythmias. In some sensitive individuals, ingestion of coffee after a period of abstinence may cause a temporary rise in blood pressure but there is no persistent hypertensive effect in the long term. Coffee made by the Scandinavian method of boiling or by the cafetiere method may cause mild elevation of plasma cholesterol concentration in some people but instant and filter coffee have no such effects. Although coffee elevates plasma homocysteine levels this effect is not large enough to have a significant effect on the risk of heart disease.

There is no evidence that coffee promotes indigestion in the majority of people. Although coffee is known to increase heartburn this effect is not large enough to justify advising people with gastro-oesophageal reflux disease to abstain from drinking coffee. There is no evidence that coffee increases the risk of developing peptic ulcer disease. There is some evidence that coffee may protect against gallstone disease.

Caffeine is a mild diuretic but scientific studies do not support the idea that caffeinated beverages exaggerate dehydration and electrolyte loss caused by exercise. There is some evidence that coffee may protect against the development of kidney stones.

Evidence is growing that coffee might protect against the development of Parkinson's disease and a few studies suggest that it might also protect against Alzheimer's disease. The relationship between coffee consumption and diabetes is an area of active investigation but no clear picture has emerged so far. Available evidence suggests that coffee might also protect against liver cirrhosis.

Coffee has a much higher total in-vitro antioxidant activity than other commonly consumed beverages. This is due in part to intrinsic compounds of coffee such as chlorogenic acid, in part to compounds formed during coffee bean roasting such as melanoidins and in part to as yet unidentified compounds. It is widely believed that antioxidants protect against the development of chronic diseases including heart disease and cancer but whether the antioxidants characteristic of coffee have such effects remains to be determined