Uric Acid and Diet — Insights into the Epidemic of Cardiovascular Disease
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《新英格兰医药杂志》
Gout is the only enemy that I do not wish to have at my feet.
— Reverend Sydney Smith, 1841
Gout, a disease that has been known since antiquity, is an acute, often recurrent arthritis mediated by the crystallization of uric acid within the joints and typically associated with hyperuricemia. Described by Hippocrates during the Golden Age of Greece, gout was originally a disease of the affluent, primarily observed in middle-aged men of the wealthy upper class ("the Patrician malady"). A "disease of kings and king of diseases," gout has often kept good company, afflicting kings (including Alexander the Great, Charlemagne, and Henry VIII), statesmen (including Benjamin Franklin and Alexander Hamilton), artists (including Tennyson, Coleridge, and Voltaire), and scientists (including Isaac Newton, Charles Darwin, and Leonardo da Vinci). Gout was associated with the wealthy and the educated, and it had a penchant for those who not only could afford the comforts of life, but also enjoyed its excesses, with habits that bordered on overindulgence, gluttony, and intemperance. During the days of the Roman Empire, Seneca (4 B.C. to 65 A.D.) commented that even women were getting gout, for they now "rival men in every kind of lasciviousness." Although gout was observed throughout the ages, it became epidemic in the 17th to 19th centuries in England, where it was a favorite subject of artists (see Figure).
Figure. The Gout, by James Gillray, 1799.
Courtesy of the Wellcome Library, London.
Humans are the only mammals in which gout develops spontaneously, probably because humans are the only mammalian species in which hyperuricemia (serum uric acid levels >6.5 to 7.0 mg per deciliter) commonly develops. Most mammals have a low serum uric acid level (0.5 to 1.0 mg per deciliter), owing to the presence of the enzyme uricase, which converts uric acid to allantoin. However, during the Miocene Epoch, several parallel mutations occurred in the uricase gene of our hominoid ancestors, initially involving the promoter region but eventually silencing the whole gene.1 As a consequence of these mutations, humans and the great apes have higher serum uric acid levels than other mammals.
Among humans, serum uric acid levels vary markedly. Premenopausal women, for example, have lower serum uric acid levels than men or postmenopausal women, since estrogen stimulates urinary urate excretion. Genetic differences in the regulation of uric acid synthesis, renal uric acid excretion, or both are also likely to be important, and these factors may account for some of the racial differences in the susceptibility to gout. Chronic lead intoxication from contamination of wine and food has also been implicated in the epidemics of gout that affected both the Roman Empire and Victorian England, since lead toxicity impairs the ability of the kidney to excrete uric acid. However, it has been postulated that a major mechanism underlying the development of gout is the excess ingestion of purine-rich foods and alcohol. Indeed, a diet low in meat and high in dairy products was proposed as a means to prevent gout by the philosopher John Locke (1632–1704), who encouraged milk drinking and "eating very little flesh but abundance of herbs"; similar diets were proposed by George Cheyne in the 1700s and by Alexander Haig in the late 1800s.
In a study reported in this issue of the Journal, Choi et al. (pages 1093–1103) examined potential dietary risk factors for gout in 47,150 men over a 12-year period as part of the Health Professionals Follow-up Study. The authors found that the risk of gout was increased by diets that were high in meats (particularly red meats) and seafood and low in low-fat dairy products. Neither the total protein intake nor the intake of purine-rich vegetables was correlated with the development of gout. The study thus provides scientific verification of the long-standing view that gout is most common among people whose diet is rich in meats and low in dairy products.
The marked risk of gout associated with diet, which in the current study amounted to an increase in risk of 21 percent per additional portion of meat per day and an increase of 7 percent per additional portion of seafood per week, is most likely a consequence of the loss of uricase. Uricase is a potent regulator of uric acid levels. It is difficult, for example, to increase uric acid levels in rats by administering uric acid unless an inhibitor of uricase is also given. In contrast, the administration of an oral purine load to humans can increase the serum uric acid level by 1 to 2 mg per deciliter within 24 hours.2 Birds and many reptiles also lack uricase, and providing meat in the diet in these species can cause a marked increase in serum uric acid. Indeed, gout is easily induced in turkeys through the administration of raw horse meat in their feed.
The ability of dietary changes to modulate the uric acid levels in species that lack uricase may explain why the serum uric acid levels in the great apes (1.5 to 3.0 mg per deciliter) are lower than those in the general human population of the United States (mean, 4.0 mg per deciliter among women and 5.5 mg per deciliter among men): the diet of the great apes consists of fruits and vegetation, with only small amounts of animal protein. It is likely that people in some indigenous human hunting and gathering societies who subsist on traditional diets primarily derived from fruits and vegetables with sporadic additions of fish and game have serum uric acid levels approaching those of the great apes. Some indigenous peoples, however, such as the Polynesians of Pukapuka in the Cook Islands, have relatively high serum uric acid levels despite a traditional diet that is low in red meats; this finding suggests that genetic or other influences are also important modulators of serum uric acid levels.
The effect of diet on serum uric acid levels is relevant to the changing worldwide epidemiology of hyperuricemia and gout. Gout has become epidemic among some native peoples, such as the Maori of New Zealand, since the introduction of Western culture and dietary habits. In the 19th century, the lean and strong Maori ate a diet of sweet potato, taro, fern root, birds, and fish. Gout was unknown. After the introduction of a diet low in dairy products and high in fatty meats and carbohydrates in the early 1900s, an epidemic of obesity and gout developed.3 The immigration of certain non-Western peoples to Western countries — for example, that of the Filipino and Japanese to North America — has also been associated with increases in serum uric acid levels, the incidence of gout, or both, in parallel with a shift to a diet containing greater amounts of meat and saturated fat.4 Gout was rare among blacks in the United States until the 1940s and 1950s, when changes in diet led to the rapid development of obesity, diabetes, and hypertension; now gout is more common among blacks in this country than among whites. Gout was also rare among blacks in Africa, especially in rural areas where traditional agricultural and dairy-based diets were common, but the frequency is now increasing, particularly in urban communities, in association with an increasing frequency of hypertension and cardiovascular disease.5
Gout is thus no longer a disease of the wealthy; rather, its appearance reflects an increase in access to fatty meats and a decrease in the intake of dairy products worldwide associated with Westernization. Gout should thus be considered part of the current global epidemic of obesity, hypertension, and diabetes. Diets that are rich in fruits, vegetables, and low-fat dairy foods, such as Dietary Approaches to Stop Hypertension (DASH), may reduce not only blood pressure but also the frequency of gout. Such interventions may be of particular importance if clinical studies confirm the experimental evidence that uric acid has a role in the pathogenesis of hypertension.6
Supported by grants from the National Institutes of Health (HL-68607 and DK-64233, to Dr. Johnson).
Source Information
From the Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville (R.J.J.); and the Center for Reproduction of Endangered Species, Zoological Society of San Diego, San Diego, Calif. (B.A.R.).
References
Oda M, Satta Y, Takenaka O, Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol 2002;19:640-653.
Clifford AJ, Riumallo JA, Young VR, Scrimshaw NS. Effect of oral purines on serum and urinary uric acid of normal, hyperuricemic and gouty humans. J Nutr 1976;106:428-450.
Lennane GAQ, Rose BS, Isdale IC. Gout in the Maori. Ann Rheum Dis 1960;19:120-125.
Kagan A, Harris BR, Winkelstein W Jr, et al. Epidemiologic studies on coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: demographic, physical, dietary and biochemical characteristics. J Chronic Dis 1974;27:345-364.
Cassim B, Mody GM, Deenadayalu VK, Hammond MG. Gout in black South Africans: a clinical and genetic study. Ann Rheum Dis 1994;53:759-762.
Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183-1190.(Richard J. Johnson, M.D.,)
— Reverend Sydney Smith, 1841
Gout, a disease that has been known since antiquity, is an acute, often recurrent arthritis mediated by the crystallization of uric acid within the joints and typically associated with hyperuricemia. Described by Hippocrates during the Golden Age of Greece, gout was originally a disease of the affluent, primarily observed in middle-aged men of the wealthy upper class ("the Patrician malady"). A "disease of kings and king of diseases," gout has often kept good company, afflicting kings (including Alexander the Great, Charlemagne, and Henry VIII), statesmen (including Benjamin Franklin and Alexander Hamilton), artists (including Tennyson, Coleridge, and Voltaire), and scientists (including Isaac Newton, Charles Darwin, and Leonardo da Vinci). Gout was associated with the wealthy and the educated, and it had a penchant for those who not only could afford the comforts of life, but also enjoyed its excesses, with habits that bordered on overindulgence, gluttony, and intemperance. During the days of the Roman Empire, Seneca (4 B.C. to 65 A.D.) commented that even women were getting gout, for they now "rival men in every kind of lasciviousness." Although gout was observed throughout the ages, it became epidemic in the 17th to 19th centuries in England, where it was a favorite subject of artists (see Figure).
Figure. The Gout, by James Gillray, 1799.
Courtesy of the Wellcome Library, London.
Humans are the only mammals in which gout develops spontaneously, probably because humans are the only mammalian species in which hyperuricemia (serum uric acid levels >6.5 to 7.0 mg per deciliter) commonly develops. Most mammals have a low serum uric acid level (0.5 to 1.0 mg per deciliter), owing to the presence of the enzyme uricase, which converts uric acid to allantoin. However, during the Miocene Epoch, several parallel mutations occurred in the uricase gene of our hominoid ancestors, initially involving the promoter region but eventually silencing the whole gene.1 As a consequence of these mutations, humans and the great apes have higher serum uric acid levels than other mammals.
Among humans, serum uric acid levels vary markedly. Premenopausal women, for example, have lower serum uric acid levels than men or postmenopausal women, since estrogen stimulates urinary urate excretion. Genetic differences in the regulation of uric acid synthesis, renal uric acid excretion, or both are also likely to be important, and these factors may account for some of the racial differences in the susceptibility to gout. Chronic lead intoxication from contamination of wine and food has also been implicated in the epidemics of gout that affected both the Roman Empire and Victorian England, since lead toxicity impairs the ability of the kidney to excrete uric acid. However, it has been postulated that a major mechanism underlying the development of gout is the excess ingestion of purine-rich foods and alcohol. Indeed, a diet low in meat and high in dairy products was proposed as a means to prevent gout by the philosopher John Locke (1632–1704), who encouraged milk drinking and "eating very little flesh but abundance of herbs"; similar diets were proposed by George Cheyne in the 1700s and by Alexander Haig in the late 1800s.
In a study reported in this issue of the Journal, Choi et al. (pages 1093–1103) examined potential dietary risk factors for gout in 47,150 men over a 12-year period as part of the Health Professionals Follow-up Study. The authors found that the risk of gout was increased by diets that were high in meats (particularly red meats) and seafood and low in low-fat dairy products. Neither the total protein intake nor the intake of purine-rich vegetables was correlated with the development of gout. The study thus provides scientific verification of the long-standing view that gout is most common among people whose diet is rich in meats and low in dairy products.
The marked risk of gout associated with diet, which in the current study amounted to an increase in risk of 21 percent per additional portion of meat per day and an increase of 7 percent per additional portion of seafood per week, is most likely a consequence of the loss of uricase. Uricase is a potent regulator of uric acid levels. It is difficult, for example, to increase uric acid levels in rats by administering uric acid unless an inhibitor of uricase is also given. In contrast, the administration of an oral purine load to humans can increase the serum uric acid level by 1 to 2 mg per deciliter within 24 hours.2 Birds and many reptiles also lack uricase, and providing meat in the diet in these species can cause a marked increase in serum uric acid. Indeed, gout is easily induced in turkeys through the administration of raw horse meat in their feed.
The ability of dietary changes to modulate the uric acid levels in species that lack uricase may explain why the serum uric acid levels in the great apes (1.5 to 3.0 mg per deciliter) are lower than those in the general human population of the United States (mean, 4.0 mg per deciliter among women and 5.5 mg per deciliter among men): the diet of the great apes consists of fruits and vegetation, with only small amounts of animal protein. It is likely that people in some indigenous human hunting and gathering societies who subsist on traditional diets primarily derived from fruits and vegetables with sporadic additions of fish and game have serum uric acid levels approaching those of the great apes. Some indigenous peoples, however, such as the Polynesians of Pukapuka in the Cook Islands, have relatively high serum uric acid levels despite a traditional diet that is low in red meats; this finding suggests that genetic or other influences are also important modulators of serum uric acid levels.
The effect of diet on serum uric acid levels is relevant to the changing worldwide epidemiology of hyperuricemia and gout. Gout has become epidemic among some native peoples, such as the Maori of New Zealand, since the introduction of Western culture and dietary habits. In the 19th century, the lean and strong Maori ate a diet of sweet potato, taro, fern root, birds, and fish. Gout was unknown. After the introduction of a diet low in dairy products and high in fatty meats and carbohydrates in the early 1900s, an epidemic of obesity and gout developed.3 The immigration of certain non-Western peoples to Western countries — for example, that of the Filipino and Japanese to North America — has also been associated with increases in serum uric acid levels, the incidence of gout, or both, in parallel with a shift to a diet containing greater amounts of meat and saturated fat.4 Gout was rare among blacks in the United States until the 1940s and 1950s, when changes in diet led to the rapid development of obesity, diabetes, and hypertension; now gout is more common among blacks in this country than among whites. Gout was also rare among blacks in Africa, especially in rural areas where traditional agricultural and dairy-based diets were common, but the frequency is now increasing, particularly in urban communities, in association with an increasing frequency of hypertension and cardiovascular disease.5
Gout is thus no longer a disease of the wealthy; rather, its appearance reflects an increase in access to fatty meats and a decrease in the intake of dairy products worldwide associated with Westernization. Gout should thus be considered part of the current global epidemic of obesity, hypertension, and diabetes. Diets that are rich in fruits, vegetables, and low-fat dairy foods, such as Dietary Approaches to Stop Hypertension (DASH), may reduce not only blood pressure but also the frequency of gout. Such interventions may be of particular importance if clinical studies confirm the experimental evidence that uric acid has a role in the pathogenesis of hypertension.6
Supported by grants from the National Institutes of Health (HL-68607 and DK-64233, to Dr. Johnson).
Source Information
From the Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville (R.J.J.); and the Center for Reproduction of Endangered Species, Zoological Society of San Diego, San Diego, Calif. (B.A.R.).
References
Oda M, Satta Y, Takenaka O, Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol 2002;19:640-653.
Clifford AJ, Riumallo JA, Young VR, Scrimshaw NS. Effect of oral purines on serum and urinary uric acid of normal, hyperuricemic and gouty humans. J Nutr 1976;106:428-450.
Lennane GAQ, Rose BS, Isdale IC. Gout in the Maori. Ann Rheum Dis 1960;19:120-125.
Kagan A, Harris BR, Winkelstein W Jr, et al. Epidemiologic studies on coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: demographic, physical, dietary and biochemical characteristics. J Chronic Dis 1974;27:345-364.
Cassim B, Mody GM, Deenadayalu VK, Hammond MG. Gout in black South Africans: a clinical and genetic study. Ann Rheum Dis 1994;53:759-762.
Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183-1190.(Richard J. Johnson, M.D.,)