Robert M. Centor, MD; Angelo L. Gaffo, MD, MSPH
Disclosures: Dr. Centor has disclosed the following: Honoraria: Medscape. Dr. Gaffo has disclosed the following: Research grants/contracts: Amgen.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Proctor & Gamble, Pfizer, and Johnson & Johnson.
Audio. Annals On Call - Understanding Gout Pathophysiology: Dr. Centor discusses the pathophysiology of gout and the prevention and treatment of gout attacks with Dr. Angelo Gaffo, Rheumatology Section Chief at University of Alabama at Birmingham.
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February 2, 2019
Connecting gout with sleep apnea
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 gout whether symptomatic or not.Many gout flares are a direct result of sleep apnea, and overcoming the sleep apnea can cure the gout. Four epidemiologic studies have been reported that show gout to be significantly more prevalent in people diagnosed with sleep apnea than it is in people never diagnosed with sleep apnea [2,3,4,5]. Here are the physiological reasons for those results. Although Kelley's Textbook of Rheumatology lists respiratory insufficiency as a cause of acidosis leading to hyperuricemia , the chronic intermittent hypoxemia of sleep apnea actually has three effects which can lead to an overnight gout flare in short order. Effect #1 is intermittent cellular catabolism in which adenosine triphosphate degradation is accelerated, leading to nucleotide turnover which culminates irreversibly in the intermittent cellular generation of excess uric acid fed into the blood [7,8], faster than any food would cause. Effect #2 is concurrent intermittent hypercapnia and acidosis, so that the blood can hold less uric acid in solution. Effect #3 is a long term deterioration of the kidneys' glomerular filtration rate  so that removal of uric acid from the blood is slowed. Thus, with sleep apnea there are repeated abrupt increases in the influx of uric acid in the blood along with abruptly reduced storage capacity, plus slowed efflux -- perfect storm conditions for monosodium urate precipitation. Furthermore, after awakening and normal breathing is restored, the first two effects 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.Gout has been reported to have so many of the same comorbidities already known to be consequences of long-term untreated sleep apnea (eg., cardiovascular diseases, diabetes, kidney disease, hypertension) [10,11]. A recent study has found that increasing the dosage of allopurinol had no benefit for reducing the risk of major cardiovascular events or all-cause mortality in gout patients , and another study found that febuxostat increased the risk . One of the first steps for treating gout should be diagnostic testing for sleep apnea, followed by treatment of the sleep apnea where indicated. I know from my own experience and the experiences of others that overcoming sleep apnea can prevent additional inflammatory gout flares immediately and completely. Effects #1 and #2 don't occur, and Effect #3 may reverse following effective treatment for sleep apnea [14,15]. More importantly, gout is an early warning of sleep apnea, which when heeded can lead to the early treatment of sleep apnea, thereby greatly reducing the risk for the later development of sleep apnea's life-threatening consequences . Overcoming the sleep apnea can save lives as well as save joints. References1. Choi HK, Niu J, Neogi T, et al. Nocturnal risk of gout attacks. Arthritis Rheumatol. 2015 Feb; 67(2):555-62.2. Roddy E, Muller S, Hayward R, Mallen CD. The association of gout with sleep disorders: a cross-sectional study in primary care. BMC Musculoskelet Disord. 2013 Apr; 14:119.3. Zhang Y, Peloquin CE, Dubreuil M, et al. Sleep apnea and the risk of incident gout: a population-based, body mass index-matched cohort study. Arthritis Rheumatol. 2015 Dec; 67(12):3298-302.4. Singh JA, Cleveland JD. Gout and the risk of incident obstructive sleep apnea in adults 65 years or older: an observational study. J Clin Sleep Med. 2018 Sep. 14(9):1521-1527.5. Blagojevic-Bucknall M, Mallen C, Muller S, et al. The risk of gout among patients with sleep apnea: a matched cohort study. Arthritis Rheumatol. 2019 Jan. 71(1):154-160.6. Firestein GS, Budd RC, Gabriel SE, et al. Kelley’s Textbook of Rheumatology 9th edition. Elsevier Saunders 2013.7. Hasday JD, Grum CM. Nocturnal increase of urinary uric acid:creatinine ratio. A biochemical correlate of sleep-associated hypoxemia. Am Rev Respir Dis. 1987 Mar; 135(3):534-8.8. Grum CM. Cells in crisis. Cellular bioenergetics and inadequate oxygenation in the intensive care unit. Chest. 1992 Aug; 102(2):329-30.9. Ahmed SB, Ronksley PE, Hemmelgarn BR, et al. Nocturnal hypoxia and loss of kidney function. PLoS One. 2011 Apr; 6(4):e19029.10. Huang CF, Liu JC, Huang HC, et al. Longitudinal transition trajectory of gouty arthritis and its comorbidities: a population-based study. Rheumatol Int. 2017 Feb; 37(2):313-22.11. Chiang CL, Chen YT, Wang KL, et al. Comorbidities and Risk of Mortality in Patients with Sleep Apnea. Ann Med. 2017 Aug; 49(5): 377-83.12. Coburn BW, Michaud K, Bergman DA, Mikuls TR. Allopurinol dose escalation and mortality among patients with gout:a national propensity-matched cohort study. Arthritis Rheumatol. 2018 Aug; 70(8): 1298-1307.13. White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018 Mar; 378(13):1200-1210. 14. Kinebuchi S, Kazama JJ, Satoh M, et al. Short-term use of continuous positive airway pressure ameliorates glomerular hyperfiltration in patients with obstructive sleep apneoa syndrome. Clin Sci (Lond). 2002 Sep; 107(3):317-22.15. Koga S, Ikeda S, Yasunaga T, et al. Effects of nasal continuous positive airway pressure on the glomerular filtration rate in patients with obstructive sleep apnea syndrome. Intern Med. 2013 Mar; 52(3):345-9. 16. Huang QR, Qin Z, Zhang S, Chow CM. Clinical patterns of obstructive sleep apnea and its comorbid conditions: a data mining approach. J Clin Sleep Med. 2008 Dec; 4(6):543-550.
Centor RM, Gaffo AL. Annals On Call - Understanding Gout Pathophysiology. Ann Intern Med. 2019;170:OC1. doi: https://doi.org/10.7326/A18-0012
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Published: Ann Intern Med. 2019;170(2):OC1.
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