JFS R: Concise Reviews/Hypotheses in Food Science Raynaud’s Phenomenon and the Possible Use of Foods CHRIS I. WRIGHT, CHRISTINE I. KRONER, AND RICHARD DRAIJER R: Concise Reviews in Food Science ABSTRACT: In this article we focus on the possible use of foods to alleviate Raynaud’s phenomenon (RP). RP is evoked, predominately, by cold and results in a potent vascular constriction of the microvascular blood vessels in the hands, thus leading to reduced hand blood flow and the elevation of pain sensation. To alleviate RP by diet, food components need to be able to promote hand skin blood flow, which may be achieved using fish oil, garlic, ginkgo biloba, L-carnitine, or inositol nicotinate, or to increase hand skin temperature, using evening primrose oil, ginkgo biloba, or inositol nicotinate. Although there are a number of studies documenting such improvements with these ingredients, they often are poorly designed. Hence, there is a need for more controlled studies to substantiate their use, but also to test alternative foods or target new ones. Therefore, we also discuss some alternate food options and briefly outline clinical drugs for the treatment of RP, as their mechanisms of action may also be possible targets for food. It is the intention of this article to address the research needs of this field and to provide a better understanding of alternative options for those with RP. Keywords: Raynaud’s, vascular constriction, dietary intervention, nutraceutical, functional foods Introduction Mahoney 1999; Generini and others 2003; Herrick 2003); however, lit- here are a growing number of studies focusing on the con- tle work has been published on the use of foods as a complementary Tceivable health benefits of foods, botanicals, and supplements treatment for RP patients or as a safeguard for those at high or future (Boelsma and others 2001; Green and others 2003). Some studies risk of developing it. Indeed, women are known to have a higher risk have reported beneficial effects in patients with Raynaud’s phenom- of developing RP than men. Others at risk include members of fam- enon (RP), which is perhaps the best-known cold-related circulatory ilies in which RP is already prevalent and people living in cold cli- disorder (Raynaud 1888), estimated to affect about 10% of the popu- mates (Belch and others 1996). For those affected by the primary lation (Belch 1997). RP is defined as episodic “attacks” of vasoconstric- condition, treatment is obviously based on its proper diagnosis and tion of the microvessels in the hand to cold or emotional stimuli this can entail a period of some 2 y (Coffman 1989; Turton and oth- (Bounameaux and others 1986; Coffman 1989; Darton and others ers 1998; Mahoney 1999). In those who do not seek treatment, the 1991; Belch 1997; Turton and others 1998). During such attacks, pe- condition worsens, but if treatment is sought, significant improve- ripheral sympathetic efferent activity is increased (Bongard and others ments occur in most cases. Hence, food components may help those 1993; Allen and others 2002; Malpas 2004), blood vessels narrow, and people at future risk as well as those already suffering. this leads to a reduction in the volume of blood flowing through the In this review, we discuss the prevalence and risk of RP, outline hands and fingers (and even the ears, nose, tongue, and lips). This the clinical strategies used to treat RP, detail the scientific findings leads to discoloration of the skin of the hands, which can turn white as of food intervention trials, and discuss possible future directions a result of vascular narrowing or collapse, or blue due to insufficient ox- for foods in this area. ygen delivery to tissue, or red, which is indicative of blood flow resto- ration after an attack of RP (Mahoney 1999). Raynaud’s Phenomenon Vasospasms, which are characteristic of RP, can occur several times each day, which means repeated attacks of ischemia fol- Primary and secondary RP lowed by periods of tissue reperfusion (Cerinic and others 1997). Cold is the main trigger for sporadic vasospasms in both primary Both stages can have serious consequences. Indeed, repeated and secondary RP, although emotional stress and excitement, par- bouts of ischemia lead to tissue damage, swelling, and ulceration, ticularly in the primary condition, also trigger events (Coffman whereas repeatedly exposing the endothelium to free-radical–in- 1989; Belch and others 1996; Landry and others 1996; Belch 1997; duced oxidative stress can result in connective tissue diseases such Turton and others 1998; Mahoney 1999; Generini and others 2003; as systemic sclerosis (Block and others 2001). To make things worse, Herrick 2003). The differentiation of these 2 conditions is based on vasospasm of the fingers may be a component of more widespread the presence or absence of an underlying vascular disorder. The vasospasm and so digital pain may be accompanied by other prob- primary form is thus not associated with any other condition, lems such as headaches and migraine, or even atypical angina or whereas the secondary form is. Also, the secondary condition has pulmonary hypertension (Block and others 2001). been associated with impaired endothelial function and flow and RP has received a lot of research interest (Landry and others 1996; changes in blood rheology (Mahoney 1999). Still, the mechanisms explaining the secondary condition are not fully understood. MS 20040728 Submitted 11/5/04, Revised 1/28/05, Accepted 2/22/05. The authors are with Unilever Health Inst., Olivier van Noortlaan 120, 3133 AT Vlaardingen, The Netherlands. Direct inquiries to author Draijer (E-mail: Diagnosing RP [email protected]). The diagnosis of primary RP is based on the criteria suggested by © 2005 Institute of Food Technologists Vol. 70, Nr. 4, 2005—JOURNAL OF FOOD SCIENCE R67 Further reproduction without permission is prohibited Published on Web 4/28/2005 R: Concise Reviews in Food Science Raynaud’s phenomenon and foods . Allen and Brown (Allen and others 1932; Coffman 1989): cold and/ cases (Mahoney 1999). RP attacks can also be alleviated, in part, by or stress elicit at least 2 of the 3 color changes (white, blue, or red); avoiding conditions in which sympathetic activity is elevated, such episodes occur periodically over the course of at least a 2-y period; as stress and smoking (Generini and others 2003). Other approaches attacks occur in the hands as well as the feet; there are strong and may be to wear heated gloves or more layers of clothing (Belch and symmetrical pulses; there is no evidence of digital pitting, ulcer- others 1996) or apply topical skin creams containing nitrous oxide, ations, or gangrene; nailfold capillaries appear normal; subjects which will promote skin blood flow (Tucker and others 1999). have a negative antinuclear antibody test (a titer of less than 1:100); and Westegren erythrocyte sedimentation rate is normal (<20 mm/ Pharmacological approaches h) (LeRoy and others 1992). Those falling outside these criteria fall Clinically, drugs promoting a generalized peripheral vasodilata- under the criteria for secondary RP but may also include a number tion and an increased flow of blood would be of benefit to those with of abnormalities relating to the esophagus, small intestines, colon, RP (Cerinic and others 1997; Tucker and others 1999; Herrick 2003). lungs heart, and kidneys (LeRoy and others 1992). Indeed, a wide range of compounds has been used to try and achieve such effects. Examples including niacin, calcium channel Prevalence of RP blockers (Gasser 1991), angiotensin-converting enzyme inhibitors In the general public, RP is estimated to be prevalent in some (Cerinic and others 1997; Herrick 2003), sympathetic alpha-1 (Ma- 4% to 15% of people and is obviously higher in colder environments honey 1999) and alpha-2 antagonists (Herrick 2003), prostaglandins (Coffman 1989; Landry and others 1996; Leppert and others 1997). (Murai and others 1989; Lau and others 1991; Saito and others 1994; It is estimated that between 50% and 90% of all RP cases are related Belch and others 1995) and calcitonin gene-related peptide (Bunker to the primary condition and that women are some 5 to 7 times more and others 1993; Szallasi and others 2000; Herrick 2003). Other drugs likely to develop the primary form that are men (Belch 1997). The may be of benefit, but instead of evoking a vasodilatation, they work average age at which RP is diagnosed is between 20 and 40 y, with to block the vascular actions of vasoconstrictors (such as serotonin symptoms being worse if the age of onset is younger than 30 y [Mahoney 1999] and endothelin-1 [Herrick 2003]). Other drugs may (Belch 1997). In such cases, associated symptoms worsen with age be of benefit as they afford additional benefits such as a reduction and there is a strong likelihood of developing associated vascular in the frequency of RP attacks or their severity (for example, antiox- disease (Belch and others 1996; Turton and others 1998; Mahoney idants [Herrick and others 2000] and serotonin and endothelin-1 1999). The age of onset for RP is known to be lower in females than receptor antagonists). For other drugs (for example, nicotine [Usuki males, and lower in those females in colder climates (Leppert and and others 1998]), further substantiation is required before they can others 1997; Maricq and others 1997). Once diagnosed, about 3 of be considered treatment options for RP. And finally, a number of the 10 people with primary RP go on to develop its secondary form. RP previously mentioned compounds can be associated with unwanted attacks are related to geographical location, but this has no bearing adverse effects (for example, headaches, dizziness, diarrhea, aggra- on their severity (Maricq and others 1997). Finally, studies assess- vation, sleep disorders, postural hypotension, and itching), which ing the familial predisposition of primary RP (Freedman and others can restrict their use in some subjects.