Claim flavonoids in citrus fruits 'cut stroke risk'

Grapefruit and oranges “appear to protect against having a ‘brain attack’”, the Daily Mail has reported. The Mail says that these and other citrus fruits can protect the brain from stroke due to their antioxidant content.

The research behind this story involved almost 70,000 women taking part in the Nurses’ Health Study in the US. They were asked to complete food frequency questionnaires (which asked them to recall how frequently certain foods were consumed during a specified period of time) every four years and over around 14 years of follow-up the researchers documented the numbers of strokes that occurred, overall and by type.

The researchers found that women who had the highest intake of flavanone (a crystalline compound found in citrus fruit) had a reduced risk of ischaemic stroke. However, they found no association between consuming actual citrus fruits and juices and being at risk of ischaemic stroke, and no association between consumption of flavonoids overall and risk of stroke.

This makes these findings far from conclusive. Whether citrus fruits and the chemicals they contain have any association with stroke risk needs more investigation. But on the basis of this study alone, there is no evidence that women who eat citrus fruits will reduce their risk of stroke. However, a balanced diet high in fruit and vegetables is known to be beneficial to health and can reduce the risk of several diseases, including cardiovascular disease.

Where did the story come from?

The study was carried out by researchers from the University of East Anglia and other institutions in the US and Italy, and was funded by the National Institutes of Health, Department of Health and Human Services. It was published in the peer-reviewed medical journal Stroke.

The Daily Mail does not accurately represent the findings of the study. Its headline, “How eating oranges and grapefruit can cut the risk of a stroke”, contradicts the finding that there was no significant association between intake of citrus fruits and juices and risk of stroke.

What kind of research was this?

This was an analysis of women enrolled in the ongoing Nurses’ Health Study in the US. The researchers aimed to use data from this cohort study to examine associations between subclasses of flavonoids and risk of stroke. Flavonoids are plant chemicals believed to have antioxidant properties, and are found in several food groups, including citrus fruits, berries, onions, certain pulses, tea and wine.

Cohort studies such as this aren't ideal for showing cause and effect. In this study, researchers circulated regular food frequency questionnaires at the same time as looking at clinical outcomes. It is difficult to guarantee that food intake patterns preceded the development of cardiovascular disease. Furthermore, because food frequency questionnaires are self-completed, they are also likely to contain inaccuracies and may not represent the pattern of food intake over a lifetime. Finally, it may be difficult to ensure that other things that could be associated with both diet and risk of stroke (confounding factors) have been taken into account.

What did the research involve?

The Nurses’ Health Study started in 1976 and enrolled 121,700 female nurses aged 30 to 55. Participants completed follow-up questionnaires on diseases and lifestyle factors every two years, as well as food frequency questionnaires every four years. In this study, researchers looked at food questionnaires completed from 1990 onwards (the time when the questionnaires covered sufficient fruit and vegetables to assess flavonoid intake). This study included the 69,622 women who had sufficient information on food intake and who did not report a stroke before 1990.

The researchers constructed a database to assess intake of the different flavonoid subclasses. Intake of individual subclasses was calculated as the total consumption frequency of each food, multiplied by the content of the specific flavonoid for the specified portion size. The six flavonoid subclasses were reported to be those commonly consumed in the US diet:

• flavanones (eriodictyol, hesperetin, naringenin)
• anthocyanins (cyanidin, delphinidin, malvidin, pelargonidin, petunidin, peonidin)
• flavan-3-ols (catechins, epicatachins)
• flavonols (quercetin, kaempferol, myricetin, isohamnetin)
• flavones (luteolin, apigenin)
• polymers (including proanthocyanidins, theaflavins, and thearubigins)

The outcome of stroke was self-reported, with reports verified by review of medical records.

What were the basic results?

Over 14 years of follow-up there were 1,803 strokes among the 69,622 participants (52% ischaemic strokes – caused by a blood clot, 14% haemorrhagic – caused by a bleed in the brain, and the rest – of unknown type).

The average intake of total flavonoids was 232mg per day. Tea was reported to be the main contributor to total flavonoid intake, followed by apples and oranges or orange juice. Women who ate more flavonoids tended to:

• exercise more
• have a greater intake of fibre, folate, fruits and vegetables
• have a lower intake of caffeine and alcohol
• be less likely to smoke

The researchers found that women who consumed the highest quantity of the flavanone subclass had reduced risk of ischaemic stroke compared with those who consumed the lowest quantity of flavanone (relative risk 0.81, 95% confidence interval 0.66 to 0.99). The relationship between flavanones and stroke overall was not reported.

As 95% of flavanones are reported to be derived from citrus (in this study, oranges and orange juice were the highest contributors), they looked for a relationship between intake of citrus fruit/juice and risk of ischaemic stroke but found no significant association (relative risk 0.90, 95% confidence interval 0.77 to 1.05).

How did the researchers interpret the results?

The researchers concluded that flavonoid intake was not associated with risk of stroke, but that increased intake of the flavanone subclass reduced the risk of ischaemic stroke. They said that because experimental data suggests that the flavanone content of citrus fruits may protect the heart, there may be an association between citrus fruit consumption and stroke risk, but this has not yet been proven.

Conclusion

Despite the news headlines, this study provides no evidence that women who eat citrus will reduce their risk of stroke.

The researchers found a link between higher intake of flavanones and reduced risk of ischaemic stroke, but:

• no association between the actual consumption of citrus fruits and juices and risk of ischaemic stroke
• no association between total flavonoid intake and risk of stroke

The researchers didn’t report on any association between flavanone, flavonoid or citrus consumption and risk of stroke overall. There was no association with haemorrhagic stroke and presumably there was none found for stroke overall.

Further problems with making the conclusions stated in the headlines include:

• The design of this cohort study cannot easily imply cause and effect. The researchers excluded women who had experienced a stroke prior to 1990, but assessed both food consumption and stroke outcomes over the following 14 years. This makes it difficult to ensure that food-intake patterns preceded the development of cardiovascular disease. 

• Food frequency questionnaires are self-completed and often contain inherent inaccuracies, and may not represent a lifelong food-intake pattern. 

• The researchers used the most recent US Department of Agriculture databases to categorise individual foods according to their content of flavonoid chemicals. However, they did not further describe how they did this in their report. As the researchers acknowledged, there is potential for the misclassification of flavonoids using this method as there is wide variation in flavonoid content of foods. Flavonoid content of fruit depends on their geographical origin, growing season, different cultivars, agricultural methods and processing. It is also difficult to say how flavonoids are processed in the body. 

• The researchers did adjust their analyses for multiple potential dietary, lifestyle and medical factors, but it is possible that some confounding factors that could be associated with both diet and risk of stroke have not been taken into account.

Whether or not citrus fruits and the chemicals they contain have any association with stroke risk may be a topic for further research. However, on the basis of this study alone, there is no evidence that women who eat grapefruit, oranges or any other citrus fruit will reduce their risk of stroke.

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