Running for gout research

H. Gunawardena, P. Churn and D. R. Blake

Royal National Hospital for Rheumatic Diseases, Rheumatology, Bath, UK

Correspondence to: H. Gunawardena. E-mail: harsha1mail{at}aol.com

SIR, The differential diagnosis of a swollen red forefoot includes acute gouty arthritis of the first metatarsophalangeal joint (MTPJ). This is confirmed following demonstration of sodium monourate crystals in synovial fluid or tissues. Classic risk factors include obesity, family history, diuretic use and historically high alcohol- and purine-containing diets.

We describe a case of acute podagra in a young, athletic man. Our case reinforces important risk factors and we feel provides support for associated aetiology.

A 28-yr-old rheumatology Senior House Officer ran the 2003 London Marathon. Following completion of the 26.2 mile course he unsurprisingly complained of widespread myalgia and arthralgia. Despite this, his euphoria and thirst led him to a public house where he drank two pints of beer. He then returned home and continued his pre-marathon diet of foods rich in purine including nuts, crab and sardine sandwiches.

Over the next 2 days his right first MTPJ became increasingly painful. Unable to ignore his symptoms he asked his Specialist Registrar to investigate.

Blood results were normal except for creatinine kinase of 248 IU/l and C-reactive protein of 7 mg/l. Serum urate concentration was normal at 0.4 mmol/l and 24-h urine collection showed a normal renal output of urate. Plain X-ray confirmed soft tissue swelling around the first MTPJ. Joint aspiration yielded 2 ml of turbid synovial fluid. Polarized light microscopy confirmed negatively birefringent needles. The diagnosis of acute gout was confirmed and treated with non-steroidal anti-inflammatory drugs.

When investigating the causes of acute forefoot pain, one would not be immediately suspicious of gout in a young man. However, our case displayed a number of risks in that he was male and perhaps more significantly he was exposed to recognized predisposing factors including a high-purine diet and dehydration exacerbated by alcohol intake [1, 2].

Alcohol is associated with reduced renal excretion of urate by lactic acid production. It can also promote degradation of adenosine triphosphate (ATP) leading to increased formation of urate.

Choi et al. [2] have shown an increased risk of gout associated with seafood intake in men with a normal or low body mass index as opposed to those who are overweight. It is suggested this is related to differences in metabolism and excretion of urate.

Despite this, gout remains relatively rare in males under the age of 30. It is well recognized that acute gout occurs in the presence of normal plasma uric acid in approximately 30% of cases. In our case urate was not measured at the time of onset of symptoms. The 24-h urine urate measurement excluded the possibility of under-excretion.

This led us to examine the possible role of severe physical exertion leading to muscle fatigue, tissue hypoxia and reperfusion injury. Case reports of gout precipitated by marathon running are rare. Moore and Anderson [3] reported a 33-yr-old male runner with knee and ankle pain complicated by an aortic valve nodule secondary to gout and visceral tophi. Studies have shown elevated plasma hypoxanthine and uric acid levels following prolonged exercise. The mechanism involves activation of adenylate kinase in muscle cells leading to degradation of adenosine nucleotides. This has been demonstrated consistently in anaerobic but also aerobic exercise, both conditions induced in distance running [4, 5]. A case study by Hellsten Westing et al. [6] confirmed high plasma hypoxanthine and urate levels and this correlated with increased running distance. Sutton et al. [7] demonstrated elevated plasma uric acid concentration in 11 subjects following a marathon run.

We feel that the additional factor of tissue hypoxia affecting the distal extremity of the first MTPJ triggered the cascade of ischaemia and reperfusion thus contributing to urate production. This mechanism may be exacerbated by foot stance. Our case has a high medial arch and ‘toe strikes’ when running thus potentiating the ischaemic insult directly onto the joint.

Hypoxia causes reduced ATP levels and inhibits fatty acid desaturation. This increases degradation of phospholipids and changes cellular permeability with calcium influx from extracellular and intracellular stores. In response calcium-dependent proteases are activated and this initiates the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO). Xanthine is catalysed to urate by XO [8]. Reperfusion increases oxygen concentration, leading to XO generating production of free radicals including superoxide, nitric oxide and hydroxide. These free radicals attack cell integrity by damaging DNA leading to cell death and this promotes the inflammatory process [8, 9].

In summary we feel our case illustrates multifactorial triggers including classic risk factors combined with hypoxic reperfusion injury which led to an episode of acute gout in a healthy young individual.

Finally our case may provide evidence for a ‘class seniority’ effect. Our SHO finished the marathon in 3 h; his SpR paced himself to 3 h 50 min in order to remain free of crystal arthropathy. Their consultant Professor of Rheumatology decided it best not to run at all.

The authors have declared no conflicts of interest.

References

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  8. Meneshian A, Bulkley GB. The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction [review]. Microcirculation 2002;9:161–75.[CrossRef][ISI][Medline]
  9. Millar TM, Kanczler JM, Bodamyali T, Blake DR, Stevens CR. Xanthine oxidase is a peroxynitrite synthase—newly identified roles for a very old enzyme. Redox Rep 2002;7:65–7.[CrossRef][ISI][Medline]
Accepted 15 March 2005





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