Howard Kenney MD, WRA Vice President
One aspect of gout which is too often overlooked in guidelines and in practice is that most gout flares are initiated during sleep. The sleep connection has been known at least since Dr. Thomas Sydenham, himself a gout sufferer, wrote about it in 1683. A recent study  confirms Dr. Sydenham’s observation. It is a very important clue to the pathogenesis of hyperuricemia and gout.
Many gout flares are a direct result of hyperuricemic episodes from obstructive sleep apnea (OSA) in individuals who are genetically predisposed to gout, and resolving the OSA can prevent any additional flares. A number of epidemiologic studies have been reported that show gout to be significantly more prevalent in people diagnosed with OSA than it is in people never diagnosed with OSA [2,3,4,5,6], despite the fact that an overwhelming percentage of people with OSA have never been diagnosed with it so they are misplaced in the noOSA category.
Here are the physiological reasons for those results. OSA’s chronic intermittent episodes of hypoxemia lead to concurrent catabolic episodes in every oxygen-starved cell of the body in which adenosine triphosphate decomposes, leading to nucleotide turnover which culminates irreversibly in the generation of excess uric acid to be fed into the blood [7,8]. These episodes are accompanied with episodes of reduced serum pH , which reduces the solubility of serum uric acid, and an increase in serum lactate , which leads to URAT1 reducing renal reabsorption of uric acid thereby slowing removal of serum uric acid. OSA also leads to gradual deterioration of the kidneys’ glomerular filtration rate  so that removal of uric acid from the blood is slowed even further. Thus, with OSA there are repeated abrupt increases in the influx of uric acid in the blood along with its abruptly reduced solubility, plus slowed efflux — perfect storm conditions for monosodium urate precipitation (MSU). When the MSU crystals are deposited in a joint, they cause a gout flare. Furthermore, after awakening and normal breathing is restored, the three episodic effects of OSA dissipate so that a blood test taken during waking hours misses their peaks. And if monosodium urate has precipitated recently, then the measurement of serum uric acid is greatly undervalued.
A clinical study conducted by rheumatologists reported that 89% of 54 gout patients were diagnosed by polysomnography with OSA , a percentage which is as high as the sensitivity for OSA of one night of polysomnography. Gout has been reported to have so many of the same comorbidities already known to be consequences of long-term untreated OSA (eg., cardiovascular diseases, diabetes, kidney disease, hypertension) [13,14], some of which are reversible just by resolving the OSA .
Use of urate lowering therapy (ULT) has questionable benefit for preventing these comorbidities. Increasing the dosage of allopurinol was found to have no benefit for reducing the risk of major cardiovascular events or all-cause mortality in gout patients [16,17], a meta-analysis found no difference in all-cause mortality between gout patients using allopurinol and those not , and those who are hypersensitive to it often have serious reactions with high mortality . Febuxostat was found to increase the risk of major cardiac events and mortality .
One of the first steps for treating gout should be diagnostic testing for OSA, followed by treatment of the OSA where indicated. I know from my own experience and the experiences of others that resolving OSA can prevent future gout flares immediately and completely. OSA’s episodic effects no longer occur, and the reduced glomerular filtration rate may reverse within three months of effective treatment for OSA [21,22]. (The slow dissolution of MSU stores after OSA has been resolved can be accelerated by ULT.) More importantly, the onset of gout is usually an early warning of OSA, which when heeded can lead to OSA’s prompt treatment, thereby greatly reducing the risk for later development of OSA’s irreversible and life-threatening consequences . Resolving OSA early enough can improve the length and quality of life.
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