In the first chapter of his seminal work, A Brief History of Time, Stephen Hawking charts the historical developments leading to our understanding of the universe. He juxtaposes current scientific theory with more apocryphal, but nonetheless fascinating, theories from the past, such as the infinite tower of tortoises on which the flat plate of the Earth was purportedly supported.1 Medical history similarly plumbs a rich vein of the apocryphal and the factual. However, in rheumatology few conditions have captured the imagination of people from all walks of life as gout. Although lacking the epic scale of the Big Bang and its impact on the universe, gout is nonetheless one of the small but significant number of medical conditions which has dramatically affected the composition of the world today.
Evidence of uric acid deposition in joints has been found in mummified Egyptian remains in Philae dating from approximately 4000 years ago. However, Hippocrates was thought to be the first person to accurately describe it c. 400 BCE. At the time, the prevailing orthodoxy sought to ascribe physical manifestations of disease to an imbalance, or dyscrasy, in the four main humours of the body – black bile, yellow bile, blood and phlegm. Hippocrates felt that gout resulted from an abnormal accumulation of one of the humours in the joints. He was in no doubt about its severity, writing,
Persons affected with the gout who are aged, have tophi in their joints, who have led a hard life, and whose bowels are constipated are beyond the power of medicine to cure.2
At the time, and for many centuries thence, gout was thought to be the result of an intemperate, bacchanalian lifestyle. A popular Greek legend at the time had it that the goddess Podagre was born through the seduction of Aphrodite by Dionysius (the Greek god of wine); Homer's Iliad tells the story of the Trojan Anchises, who began to limp after having been struck by a thunderbolt from Zeus.3,4 The Romans, by all accounts, felt similarly. Galen, the celebrated Roman physician of Greek origin, wrote prolifically on all matters medical. He is said to have opined: ‘Gout is the daughter of Bacchus and Venus.’5 Seneca, Nero's tutor in the 1st century AD, purportedly saw gout in women as a particularly vituperous consequence of the depravity generally practised by the populace, and questioned ‘. . . why need we be surprised at seeing so many of the female sex afflicted with the gout?’6 Roman literature is littered with descriptions of gouty epidemics among the aristocracy. However, it seems that such attacks may have carried with them a darker subtext, and contributed to the demise of the Roman empire.
Roman wine was preserved using a grape syrup simmered slowly in a lead-lined vessel and then mixed with the wine. This was known as sapa. Evidence suggests that the conflation of the two resulted in very high concentrations of lead. Sapa was frequently used as a sugar substitute, and lead was also prevalent in the lining of water pipes. Wine consumption in ancient Rome varied widely – from a plebian 1 litre per day to the rapacious appetite of the emperor Elgabalus, whose contemporaries believed consumed his wine from a swimming pool.7 Conservative estimates therefore place the Roman intake of lead at many times those required to cause lead poisoning, and the pleasure-loving aristocracy would certainly have been disproportionately exposed.7
Among the many effects of lead poisoning, neuro-psychiatric effects including impaired mentation and, by extension, decision-making, are prominent. Moreover, plumbism is strongly associated with hyper-uricaemia and gout by virtue of chronic kidney disease and effects on the renin-angiotensin-aldosterone axis. Claudius, Nero, Caligula and Tiberius were but a few of the prominent Romans thought not only with gouty symptoms, but also with many oddities of speech and behaviour. Important decisions taken by them, and quite possibly many of their contemporaries, may therefore have been made through lead-lined glasses – with unpredictable consequences for the empire.7
Subsequent empires fared no better. Charles V, whose 40-year reign occurred during the transition from the Middle Ages to modern times, presided over a global empire spanning Europe, Africa, Asia and parts of South America. However, he was crippled by intense arthritic pain and swelling, which his physicians diagnosed clinically as gout.8 Charles V had a renowned proclivity for meat, beer and wine – he reportedly ordered a specially designed 4-handled drinking mug built to satisfy his thirst. Running thus unchecked, his attacks became so severe and frequent that he found himself ‘. . . not able to write long because of the gout . . .’ in his later life. The nation-altering ramifications of his disease are amply illustrated by the battle of Metz. In the mid-1500s, a severe attack of gout forced Charles V to postpone his attempt to recapture the city of Metz from the French. As with the Russians in World War II Stalingrad, the arrival of winter allowed the French to resist and inflict defeat on the emperor's army. Charles V was said to be so guilt-ridden at the defeat, which he ascribed to his disease, that he promptly abdicated.8
However, in 2006 historical speculation was turned into medical fact by an intrepid team of Spanish researchers, who uncovered an histological diagnosis using an innovative approach. Charles’ body was interred from the Royal Monastery of San Lorenzo de El Escorial in Spain. The terminal phalanx of one of his fingers was separately enshrined in a velvet box, presumably as a religious relic. The Spanish team obtained permission to analyse the phalanx histologically, chemically and using scanning electron microscopy.8 Their aggregate analysis conclusively demonstrated the existence of an enormous gouty tophus almost completely eroding the royal digit, and thereby lending objective confirmation to the rapacity of his illness.
The British aristocracy of the 1600s were staunchly conservative when compared to their Roman counterparts; however, they too were not spared the tender ministrations of gout. Once again, lead may have been a contributing factor. In the late 1600s, the English Parliament sought to limit commercial competition by the Dutch fleet by banning the importation of French wines, a cargo not carried by the British, in favour of Spanish and Portuguese wines. Port was particularly popular, but also happened to be rich in lead.9,10 This may explain the large number of people suffering from gout seen in caricatures of the time.
Perhaps unsurprisingly, many of the detailed descriptions of gout come from this era onwards. Thomas Sydenham, himself a sufferer, chronicled his attacks in the late 1600s as being
‘. . . so exquisitely painful as not to endure the weight of the clothes nor the shaking of the room from a person's walking briskly therein . . .’11
The Reverend Sydney Smith, considered to be one of Britain's greatest wits of the 19th century, had a more economical but no less colourful description, likening attacks of gout to ‘. . . walking on eyeballs . . .’6 Nonetheless, the notion of gout as an affliction of the privileged, and therefore highly desired, had a strong foothold.
In the mid-1800s, Lord Stanhope unequivocally drew a line in the sand between gout –‘the distemper of a gentleman’– and rheumatism –‘the distemper of a hackney coachman’. The familial predilection for gout among the aristocracy served to strengthen this perception, with representation in the paternal line of King Louis IV of France and in the children of King George III of England. Indeed 20 of the 34 kings of France were said to have been afflicted. Ambrose Bierce applied his mordant wit to the issue, defining gout in his Devil's Dictionary as ‘. . . a physician's name for the rheumatism of a rich patient . . .’12 Walpole considered podagra to be a natural result of the body's attempt to expel ‘depraved humours’ to the extremities, and Sir Arthur Conan Doyle published an article in The Lancet in which he paid as much attention to non-arthritic gout as Sherlock Holmes would to the whorls on one's fingertips.13
Significant progress into the diagnosis and aetiology of gout followed not long after. The German-Swedish pharmaceutical chemist Karl Scheele isolated uric acid in the 1700s, and it was aspirated from a gouty tophus a half century or so later. However, it was Sir Alfred Garrod, in his early role as clinical assistant to the chemical department of University College Hospital, who made a decisive contribution to our understanding of gout. Between 1848 and 1859, he demonstrated serum hyper-uricaemia in patients with gout as opposed to those with rheumatism; developed the ‘thread test’ in which polarized light microscopy was used to view crystals of gout in dessicated, acetate-impregnated serum; and established gout as a completely separate entity from rheumatoid arthritis.14
The treatment of gout has run its own tortuous course. Colchicine was first used as a treatment for gout around 500 BC, but with cathartic rather than anti-inflammatory intent. The meadow saffron, Colchicum autumnale, originated in the town of Colchis on the Black Sea, and was renowned as a laxative. It was considered a poisonous agent, with its use being chronicled even in Greek mythology. Medea, daughter of the king of Colchis and wife of Jason (of the Argonauts), used it to kill her children upon being betrayed by her husband.15 It was not until 1763 that the Viennese physician Baron von Storck began to use colchicum extract specifically for terminating acute gouty attacks. Around the same time, a French military officer, Nicholas Husson, formulated a colchicum-based preparation innocuously known as ‘Eau Medicinale’. This was used to treat various ailments, including gout. Some 30 years later Pelletier and Caventou isolated the active alkaloid colchicine, at which point it became more widely used.16 The product is thought to have been introduced to America in the late 1700s by Benjamin Franklin, himself a sufferer of gout. In the late 1800s, it was discovered that high-dose salicylates were an efficacious remedy for acute gout. Fifty years later, the period from 1948 to 1963 saw the introduction, in rapid succession, of corticotropin (ACTH), prednis(ol)one and allopurinol.
Thus, as with many rheumatological maladies, gout offers a fascinating insight into the biological and psychosocial zeitgeist spanning many centuries. Very few diseases captured the attention of so many people from so many different walks of life. Like melancholy in the Renaissance era, or tuberculosis in the Romantic era, it even managed to acquire its own social cachet. It may have contributed to dramatic changes in world affairs dating back to Roman times. However, even today, with our considerable diagnostic and therapeutic armamentarium, a foolproof, widely applicable solution remains anything but crystal-clear.