- Email: [email protected]
The paradox of gout
Joint Bone Spine 70 (2003) 95–96 www.elsevier.com/locate/bonsoi
Editorial
The paradox of gout Gout is probably the first properly identified disease, not only in the field of rheumatology but also in general. When I use the word “identified” here, I do not refer to diagnosis in recent times by examination of skeletal remains but to clinical descriptions written by the ancients. Hippocrates (460-377 BC) cursorily described a joint disease that did not occur in eunuchs, women before the cessation of menses, or boys with no sexual experience [1,2]. Two centuries later, Soranos of Ephesus (117-161 BC) wrote a detailed description of acute gout in the great toe. Aretaeus of Cappadocia (120-200 BC) emphasized the intermittent course of the symptoms, specifying that “a patient afflicted with gout won the race in Olympus between two attacks”. The abrupt nocturnal onset and subsidence in the early hours of the morning were illustrated by the Greek playwright Lucian of Samosata (125-192 BC), particularly in “the Tragedy of Podagra”, written 15 centuries before the classical description by Sydenham (1624-1689). In the XVIth century, Ambroise Paré noted that gout often runs in families. From the Renaissance to the XVIIIth century, most medical authors wrote about “gout”, using the term indiscriminately for any form of joint disease, despite the introduction by Guillaume de Baillou of the term “rheumatism”. A.J. Landré Beauvais used the term “primary asthenic gout” in his seminal description of rheumatoid arthritis. The link between gout and uric acid was recognized in the XIXth century, first by Garrod then by Charcot. Nevertheless, although the joint fluid crystals were identified by these authors, their responsibility in the disease was established only in 1960, by McCarthy, who gracefully drew attention to the forgotten work done by Freudweiller at the beginning of the XXth century. Colchicum extracts were suggested as a treatment for gout in ancient times but did not become widely used until the XIXth century. Prophylaxis of acute gouty attacks by uricosuric agents, of which the earliest was probenicid, then by uric acid synthesis inhibitors, was introduced in the second half of the XXth century. Nonsteroidal antiinflammatory drugs gained acceptance in gout during the same period. Opinion remains sharply divided regarding the use of glucocorticoid therapy for gout. Now, at the beginning of the XXIth century, with proper treatment, the vast majority of gout sufferers remain free of the incapacitating lesions, renal dysfunction, and other organ involvement that used to be typical of the disease. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. DOI: 1 0 . 1 0 1 6 / S 1 2 9 7 - 3 1 9 X ( 0 3 ) 0 0 0 0 3 - 4
This brief historical overview leads me to the nature of the gout paradox. Whereas the pathophysiology of hyperuricemia-related acute gouty attacks and urate deposition has been elucidated, the cause of the hyperuricemia remains undetermined in most cases. Only a minority of patients has detectable causes of hyperuricemia, which include genetic abnormalities, exposure to toxic agents or cytolytic medications, and congenital or acquired deficiencies in renal excretion of uric acid [3]. The most striking example of hyperuricemia related to a known cause is LeschNyhan disease, in which an enzymatic abnormality results in increased de novo synthesis of purines [4]. Degradation of an excessive amount of purines present in food (gout was virtually nonexistent in occupied France during World War II) or released by cells (during the treatment of leukemia) is another cause of gout. However, the mechanism that results in hyperuricemia remains unknown in most patients with apparently primary gout of a familial nature. The genetic basis for this form of gout has not been investigated, as pointed out in two recent review articles [5,6]. This is what I call the “gout paradox”. In these early years of the XXIth century, most metabolic diseases have been characterized as either monogenic or plurigenic, and many causative mutations associated with the production of defective proteins have been identified. Gout stands apart. To my knowledge, no well-designed controlled studies quantitating the role of a familial predisposition have been published. A very recent report [7] merely notes that disease onset usually occurs at an earlier age in patients with familial forms of gout. Interestingly, a number of anecdotal features of primary gout that have been known for centuries are being rediscovered or remain unexplained. For instance, the preferential occurrence of gouty attacks in early winter or early spring has been reported as an original finding by several authors, including Schlesinger and Schumacher [8], who failed to cite the many authors who described this feature in centuries long past. Another oddity is the physical appearance of gout patients, with a round head, sanguine complexion, and tendency to overweight. This habitus has been known for many centuries and represented in etchings and paintings (e.g. those of Stendahl and Louis XVIII). The fondness of these patients for good food went unnoticed. In 1976, I conducted a controlled study [9] comparing the eating behaviors of overweight patients with and without primary gout. The results showed that the patients with gout
96
Editorial / Joint Bone Spine 70 (2003) 95–96
were gourmets, whereas the patients without gout simply ate to excess.
References [1]
Current knowledge about the genetic differences underlying taste discrimination may suggest new lines of research, particularly as the differences were more marked for the familial forms of gout. In short, we have effective treatments for gout, yet we do not know what causes primary gout unrelated to renal abnormalities. Why does this oldest of known human diseases remain so unattractive to basic scientists that it has become an orphan disease? Probably because we know how to treat and to prevent gout, and here a parallel can be drawn with rheumatic fever. Furthermore, the available data suggest a heterogeneous group of complex genetic factors. The same is true, however, of chondrocalcinosis, another crystal deposition disease that was identified more than 2000 years after gout, yet has been the focus of numerous pathophysiological and genetic studies. Yet, experience teaches that the elucidation of pathophysiological mechanisms and genetic determinants of a disease can have beneficial consequences that extend far beyond the disease in question. May my ardent plea for an end to the gout paradox be heard!
[2] [3]
[4]
[5] [6] [7]
[8]
[9]
Delpeuch A. Histoire de la goutte et du rhumatisme. Paris: Carré et Naud; 1900. Guiraud G. la goutte. Bulletin du Centre d’Histoire de la Médecine (Toulouse). Histoire de 1999;29:6–18. Kamatani N, Moritani M, Yamanaka H, Takeuchi F, Hosoya T, Ikatura M. Localisation of a gene for familial hyperuricemic nephropathy causing underexcretion—type gout to 16p12 genome-wide linkage analysis of a large family. Arthritis Rheum 2000;43:925–9. Jinnah HA, de Gregorio L, Harris JC, Nyhan WL, O’Neill JP. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 2000;463:309–26. Terkeltaub RA. Gout: questions that still need to be answered. Ann Rheum Dis 1995;54:79–81. Agudelo CA, Wise CM. Gout. Diagnosis. Pathogenesis and clinical manifestations. Curr Opin Rhumatol 2001;13:234–9. Chen SY, Chen CL, Shen ML, Kamatani N. Clinical features of familial gout and effects of probable genetic association between gout and its related disorders. Metabolism 2001;50:1203–7. Schlesinger N, Gowin KM, Baker DG, Beutler AM, Hoffman BI, Schumacher HR. Acute gouty arthritis is seasonal. J Rhumatol 1998; 25:342–4. Kahn MF. Goutte, obésité et plaisirs de la table. Comparaison entre 40 goutteux et 40 témoins. Nouvelle Presse Med 1976;5:1897–8.
Marcel-Francis Kahn
Editorial
The paradox of gout Gout is probably the first properly identified disease, not only in the field of rheumatology but also in general. When I use the word “identified” here, I do not refer to diagnosis in recent times by examination of skeletal remains but to clinical descriptions written by the ancients. Hippocrates (460-377 BC) cursorily described a joint disease that did not occur in eunuchs, women before the cessation of menses, or boys with no sexual experience [1,2]. Two centuries later, Soranos of Ephesus (117-161 BC) wrote a detailed description of acute gout in the great toe. Aretaeus of Cappadocia (120-200 BC) emphasized the intermittent course of the symptoms, specifying that “a patient afflicted with gout won the race in Olympus between two attacks”. The abrupt nocturnal onset and subsidence in the early hours of the morning were illustrated by the Greek playwright Lucian of Samosata (125-192 BC), particularly in “the Tragedy of Podagra”, written 15 centuries before the classical description by Sydenham (1624-1689). In the XVIth century, Ambroise Paré noted that gout often runs in families. From the Renaissance to the XVIIIth century, most medical authors wrote about “gout”, using the term indiscriminately for any form of joint disease, despite the introduction by Guillaume de Baillou of the term “rheumatism”. A.J. Landré Beauvais used the term “primary asthenic gout” in his seminal description of rheumatoid arthritis. The link between gout and uric acid was recognized in the XIXth century, first by Garrod then by Charcot. Nevertheless, although the joint fluid crystals were identified by these authors, their responsibility in the disease was established only in 1960, by McCarthy, who gracefully drew attention to the forgotten work done by Freudweiller at the beginning of the XXth century. Colchicum extracts were suggested as a treatment for gout in ancient times but did not become widely used until the XIXth century. Prophylaxis of acute gouty attacks by uricosuric agents, of which the earliest was probenicid, then by uric acid synthesis inhibitors, was introduced in the second half of the XXth century. Nonsteroidal antiinflammatory drugs gained acceptance in gout during the same period. Opinion remains sharply divided regarding the use of glucocorticoid therapy for gout. Now, at the beginning of the XXIth century, with proper treatment, the vast majority of gout sufferers remain free of the incapacitating lesions, renal dysfunction, and other organ involvement that used to be typical of the disease. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. DOI: 1 0 . 1 0 1 6 / S 1 2 9 7 - 3 1 9 X ( 0 3 ) 0 0 0 0 3 - 4
This brief historical overview leads me to the nature of the gout paradox. Whereas the pathophysiology of hyperuricemia-related acute gouty attacks and urate deposition has been elucidated, the cause of the hyperuricemia remains undetermined in most cases. Only a minority of patients has detectable causes of hyperuricemia, which include genetic abnormalities, exposure to toxic agents or cytolytic medications, and congenital or acquired deficiencies in renal excretion of uric acid [3]. The most striking example of hyperuricemia related to a known cause is LeschNyhan disease, in which an enzymatic abnormality results in increased de novo synthesis of purines [4]. Degradation of an excessive amount of purines present in food (gout was virtually nonexistent in occupied France during World War II) or released by cells (during the treatment of leukemia) is another cause of gout. However, the mechanism that results in hyperuricemia remains unknown in most patients with apparently primary gout of a familial nature. The genetic basis for this form of gout has not been investigated, as pointed out in two recent review articles [5,6]. This is what I call the “gout paradox”. In these early years of the XXIth century, most metabolic diseases have been characterized as either monogenic or plurigenic, and many causative mutations associated with the production of defective proteins have been identified. Gout stands apart. To my knowledge, no well-designed controlled studies quantitating the role of a familial predisposition have been published. A very recent report [7] merely notes that disease onset usually occurs at an earlier age in patients with familial forms of gout. Interestingly, a number of anecdotal features of primary gout that have been known for centuries are being rediscovered or remain unexplained. For instance, the preferential occurrence of gouty attacks in early winter or early spring has been reported as an original finding by several authors, including Schlesinger and Schumacher [8], who failed to cite the many authors who described this feature in centuries long past. Another oddity is the physical appearance of gout patients, with a round head, sanguine complexion, and tendency to overweight. This habitus has been known for many centuries and represented in etchings and paintings (e.g. those of Stendahl and Louis XVIII). The fondness of these patients for good food went unnoticed. In 1976, I conducted a controlled study [9] comparing the eating behaviors of overweight patients with and without primary gout. The results showed that the patients with gout
96
Editorial / Joint Bone Spine 70 (2003) 95–96
were gourmets, whereas the patients without gout simply ate to excess.
References [1]
Current knowledge about the genetic differences underlying taste discrimination may suggest new lines of research, particularly as the differences were more marked for the familial forms of gout. In short, we have effective treatments for gout, yet we do not know what causes primary gout unrelated to renal abnormalities. Why does this oldest of known human diseases remain so unattractive to basic scientists that it has become an orphan disease? Probably because we know how to treat and to prevent gout, and here a parallel can be drawn with rheumatic fever. Furthermore, the available data suggest a heterogeneous group of complex genetic factors. The same is true, however, of chondrocalcinosis, another crystal deposition disease that was identified more than 2000 years after gout, yet has been the focus of numerous pathophysiological and genetic studies. Yet, experience teaches that the elucidation of pathophysiological mechanisms and genetic determinants of a disease can have beneficial consequences that extend far beyond the disease in question. May my ardent plea for an end to the gout paradox be heard!
[2] [3]
[4]
[5] [6] [7]
[8]
[9]
Delpeuch A. Histoire de la goutte et du rhumatisme. Paris: Carré et Naud; 1900. Guiraud G. la goutte. Bulletin du Centre d’Histoire de la Médecine (Toulouse). Histoire de 1999;29:6–18. Kamatani N, Moritani M, Yamanaka H, Takeuchi F, Hosoya T, Ikatura M. Localisation of a gene for familial hyperuricemic nephropathy causing underexcretion—type gout to 16p12 genome-wide linkage analysis of a large family. Arthritis Rheum 2000;43:925–9. Jinnah HA, de Gregorio L, Harris JC, Nyhan WL, O’Neill JP. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 2000;463:309–26. Terkeltaub RA. Gout: questions that still need to be answered. Ann Rheum Dis 1995;54:79–81. Agudelo CA, Wise CM. Gout. Diagnosis. Pathogenesis and clinical manifestations. Curr Opin Rhumatol 2001;13:234–9. Chen SY, Chen CL, Shen ML, Kamatani N. Clinical features of familial gout and effects of probable genetic association between gout and its related disorders. Metabolism 2001;50:1203–7. Schlesinger N, Gowin KM, Baker DG, Beutler AM, Hoffman BI, Schumacher HR. Acute gouty arthritis is seasonal. J Rhumatol 1998; 25:342–4. Kahn MF. Goutte, obésité et plaisirs de la table. Comparaison entre 40 goutteux et 40 témoins. Nouvelle Presse Med 1976;5:1897–8.
Marcel-Francis Kahn