For many centuries, "gout" was a nonspecific term. The differentiation of the disease was begun in the late seventeenth century by Thomas Sydenham; his contemporary, Anton van Leeuwenhoek, described crystals from a tophus. In 1776, Swedish pharmacist Karl W. Scheele discovered an organic acid in urinary concretions - he called it "lithic acid." In 1797 at Cambridge, William H. Wollaston found that tophi contained lithic acid. In 1798, lithic acid was renamed acide ourique ("uric acid") by French chemist Antoine F. de Fourcroy because he found it was present in urine.
A half century passed. In 1847 and in 1854, London physician Alfred B. Garrod devised two tests whereby uric acid could be detected in hyperuricemic states such as gout. He demonstrated urate in subcutaneous tissue and cartilage in cases of gout. Garrod hypothesized that gout resulted from either loss of excretory capacity or increased formation of uric acid. A century after his 1859 monograph on gout, both concepts were proved correct. In 1876 Garrod postulated that gout results from precipitation of sodium urate in or near a joint, and this was proven in 1962.
Beginning in 1871 numerous assays of uric acid were devised, but none was sensitive enough. Lack of understanding of uric acid metabolism cast doubt on the relationship of uric acid to gout, and two effects resulted. One was that the old belief in a "gouty poison" - that caused a wide variety of symptoms or diseases -gained new adherents. The other was that clinicians virtually ceased diagnosing gout.
The first practical technique sensitive enough to detect normal concentrations of uric acid was devised by Otto Folin at Harvard in 1912. Its sensitivity was improved so that in 1938, uric acid content was shown to be greater in men than in women, thereby correlating with the rarity of gout in women. However, physicians continued to be poorly aware of true gout. Specificity in uric acid determination was achieved in 1953 with a technique employing the enzyme uricase. Nevertheless, most laboratories use less specific methods that give somewhat higher than "true" values.
Therapy of gout has two components: treatment of the acute attack and prophylaxis to decrease uric acid content. Colchicum in various alcoholic or aqueous extracts from the meadow saffron came into use in the nineteenth century in France and England. It was included in an American "Dispensatory" in 1836, although its use was advocated somewhat earlier. Colchicum was toxic, however, causing se vere diarrhea, which was believed to constitute its therapeutic effect. Its active component, colchicine, was isolated in 1820 and available in pill form by 1900, but crude tinctures were still in use in the 1950s.
Until about 1910, when cinchophen was introduced, colchicine was the only remedy for gout. Cinchophen not only was effective against gouty attacks but also was an analgesic. However, by the 1930s it became evident that cinchophen may cause severe, even fatal, liver damage. Its use faded, and colchicine again became the standard treatment.
Two pharmaceutical breakthroughs occurred in 1951. Probenecid, a drug developed to retard excretion of penicillin, was found to accelerate the excretion of uric acid and was well tolerated and convenient to take. The other discovery was phenylbutazone, which proved to have effects similar to cinchophen. Like probenecid, it increased excretion of uric acid, and like colchicine, it counteracted attacks. However, it proved to be toxic and has fallen into disfavor.
Another pair of pharmaceutical products was introduced in 1963. Indomethacin counteracts gouty attacks, and it gradually superseded phenylbutazone. Allopurinol lowers uric acid like probenecid but by a different mechanism. Like probenecid, allopurinol lacks value against gouty attack, but it is effective during renal failure and is convenient.
Dietetic attempts to treat gout are ancient and based on belief in the virtue of moderation. Gout was thought to be caused largely by excessive consumption of food and alcohol, but in 1924 it was shown that starvation results in increased uric acid concentration. Since the 1960s, it has been found that certain circumstances may operate to block excretion of uric acid and thereby increase the possibility of gouty attack. Starvation, alcohol ingestion (especially without eating), and uncontrolled diabetes mellitus are among such conditions.
Uric acid is synthesized from foodstuffs, particularly those rich in nucleoproteins. A low-fat, largely vegetarian diet reduces uric acid concentration, but the effect such diets have on reducing gouty attacks is equivocal. Since the advent of urate-depleting drugs, dietetic therapy has become irrelevant except for the advantages of weight reduction for obese patients.
Gout is rarely a direct cause of death, although it is commonly associated with hypertension or arteriosclerosis, and untreated hypertension with normal renal function is frequently associated with hyperuricemia. Hyper-lipidemia appears not to correlate with hyperuricemia; rather, both are associated with hypertension and obesity. Angina pectoris is twice as frequent among gouty men, and one study found that causes of death among 427 gout patients were cardiovascular in 66 percent of cases.
Although a rough correlation does exist between hyperuricemia and the likelihood of a gouty attack, its predictive value is poor. The most important measurable factors affecting uric acid concentration are the protein content of the diet and overweight. Weight and rate of uric acid metabolism are to some extent genetically predetermined. However, the immediate cause of a gouty attack remains unknown.
Worldwide, the prevalence of gout has changed since the 1940s. In developed countries, the disease is now rarely disabling. Elsewhere, however, it has become more prevalent, predominantly because of "improved" diets. Hypotheses about whether ethnic differences are genetic or the result of environmental changes are weakened by a lack of data.
Several American surveys have compared the uric acid levels of executives and either lower-level employees or age-matched population samples. The executives have consistently been found to have higher urate concentrations and a larger proportion of cases of hyperuricemia. This finding, which has been inconsistently confirmed in Europe, has not been explained by differences in physiognomy, blood pressure, or medications.
Most reports of gout in non-Caucasian populations are relatively recent. The first case was a 31-year-old African servant who died in 1807 in
Edinburgh, where he had often suffered severe pains that occurred in his great toes. A medical missionary in Hawaii in the early 1830s reported that rheumatism frequently occurred there, and although gout might also be expected to be common, the mild quality of the food suggested otherwise. Similarly, a military surgeon in New Zealand in the 1850s found that although "rheumatic affections" were much more frequent among New Zealanders than among the English, gout was unknown. A leading expert wrote in 1948 that gout "is common in England and France, less common but increasing in North America. Hebrews are affected, prosperous American Negroes occasionally." Another specialist stated in 1952 that gout "is unknown in China, Japan, and the tropics [and] is rare in Negroes."
Such statements may have reflected either ignorance or changing circumstances but clearly are incorrect now Probably the most ubiquitous factor underlying an increased prevalence of gout is the increased proportion of proteins in many diets, which increases the amount of uric acid. Comparisons of uric acid values of most adequately nourished populations give similar values. The exceptions remind us that there are unidentified (presumably genetic) factors that result in differences among groups that would be assumed not to differ empirically.
Generally, the ability of gouty individuals to excrete uric acid is normal, but differences in excretory capacity can be identified. One hypothesis suggests that some ethnic groups may include a large proportion of persons who have a (genetically determined) relatively low limit to their renal excretory capacity. As long as such individuals consume a low-protein diet, such as the Asian rice-based diets, or diets based on yams, their excretory mechanism is not saturated, urate remains in the normal range, and gout rarely occurs. When the protein consumption of such persons increases - as their diet becomes "Westernized" - the excretory capacity is overwhelmed, urate accumulates, and gout becomes more frequent.
There is a marked difference in the prevalence of hyperuricemia between Caucasian and various Pacific island populations. Less than 10 percent of most unselected Caucasian populations, but more than 40 percent of many Pacific populations, exceed "normal upper limits." Many surveys have been conducted since the 1960s. The hyperuricemia cannot be attributed entirely to dietary changes, nor is alcohol consumption necessarily a factor. The highest prevalence of hyperuricemia has been found on the Micronesian island of Nauru. The diet there had largely become Westernized by the time these surveys were conducted. However, some groups were hyperuricemic on their traditional diets. The complexity of the uricemia - gout relationship is illustrated by the unexplained observation that although the New Zealand Maoris, Tokelauans, and Raroton-gans have the same high prevalence of hype-ruricemia, a fourfold difference exists in the prevalence of gout.
Surveys in the early 1960s in the Osaka district of Japan showed an extremely low prevalence of hyperuricemia. With continued Westernization of the diet, however, an anticipated increase in the prevalence of gout is occurring. The clinical characteristics of gout are the same and occur in similar frequencies as in Caucasian populations.
A Chinese author claimed that the first case of gout to be described in China occurred in 1948, and that by 1959 he could collect only 12 cases, 10 with tophi. This almost certainly reflects socioeconomic rather than biological circumstances. The prevalence of gout may indeed have been low because of the widespread, inadequately low protein diet, but this would have pertained particularly to the large segment of the population that lacked medical care. In regard to the well-nourished upper classes, a lack of diagnostic acumen may have been at least partially responsible.
Aside from South Africa, there is little relevant information from the African continent. The effect on uricemia of the urbanization of primitive people has been well illustrated by studies in South Africa that showed the lowest values in a tribal population, higher values in a village, and the highest levels, equal to those of urban whites, in urban blacks. The combined three black populations contained no cases of gout. A survey in Ethiopia similarly showed the lowest values among rural Ethiopians, intermediate values among urban Ethiopians, and the normal, highest value among Caucasian and Indian urban professionals.
Data from Israel are analogous. Desert Bedouins were found to have lower uric acid values than villagers of the same Arabic stock, and the latter results were the same as those that were obtained from a nearby Jewish population in Haifa. These variations are presumed to be related to changes in nutrition associated with changes in life style.
Thomas G. Benedek
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