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Obstructive Sleep Apnea as a Cause of Gout

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22 February 2023

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24 February 2023

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Abstract
Gout is not only associated with obstructive sleep apnea (OSA), but the intermittent episodes of hypoxia that occur with OSA may also have a role in causing gout. Epidemiological studies have documented a higher incidence and prevalence of gout in individuals diagnosed with OSA than in individuals never diagnosed with OSA. The pathophysiology of OSA’s chronic episodes of hypoxia leading to hyperuricemia and gout involves boththe overproduction and underexcretion of uric acid. Treating OSA may be an additional way to control gout and its life-threatening comorbidities. Clinicians are urged to evaluate their patients with hyperuricemia/gout for OSA as it may lead to alternative ways to control gout with superior outcomes that simply pharmacologic treatment alone.
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Subject: Medicine and Pharmacology  -   Immunology and Allergy

1. Introduction

Gout, while once thought to be a self-limited arthritis, is now recognized as being an important systemic disease that warrants aggressive treatment1. There are classically four commonly recognized causes of gout that are discussed in the literature, namely, genetics2, diet (especially from fructose-containing sugars, animal purine foods, or alcohol)3-5, impaired kidney function6, and insulin resistance7. While hyperuricemia commonly precedes and predicts insulin resistance8, there is evidence that chronically elevated insulin may stimulate the reabsorption of uric acid (along with sodium) in the proximal tubule. Here we would like to emphasize that there is a fifth common cause, which is obstructive sleep apnea (OSA). In fact, it is common enough that the presence of OSA should encourage the physician to measure uric acid and inquire about gout, and also that the physician who diagnoses gout should consider evaluating the individual for OSA.

2. Epidemiological Association of OSA with Gout

Epidemiological studies have documented a strong association of OSA with gout (Table 1)9-14. The relative risk for gout among subjects with OSA is exceeds 2-fold, on average. Not only are both hyperuricemia and gout associated with OSA, but those subjects with higher uric acid levels tend to have worse hypoxia and poorer cardiovascular outcomes14.
The frequency of OSA in subjects with gout may be higher than assumed from epidemiological data base studies. In one clinical study conducted by rheumatologists, 89% of 54 gout patients were diagnosed by polysomnography with OSA15, a percentage which is about as high as the sensitivity for OSA of one night of polysomnography16

3. How is OSA Connected with Gout?: Understanding the Pathophysiology

Sleep apnea is not simply associated with hyperuricemia and gout, it also has a causal role17. Sleep apnea is classically associated with intermittent hypoxic spells that can activate hypoxia-mediated pathways. One of the most important hypoxic pathways is driven by activation of the nuclear transcription factor, HIF-1α, and levels of HIF-1α are elevated in the plasma of patients with OSA18. In turn, HIF-1α is known to activate a survival pathway known as the polyol-fructokinase-xanthine oxidase pathway that can generate uric acid19-21. This pathway tends to protect against hypoxia by reducing mitochondrial function while stimulating glycolysis, thereby reducing oxygen needs22,23. However, chronic activation can lead to worsening feature of metabolic syndrome and chronic inflammation.
Moreover, in chondrocytes hypoxia induces GLUT1 and HIF-1alpha expression and a glycolytic shift that favors the Warburg effect, which causes the accumulation of lactate and the increased acidity of the extracellular microenvironment 24. The acidification of the microenvironment causes the release of calcium ions which has been shown to nucleate the crystallization of monosodium urate (MSU). This, along with the release of IL-1beta, attracts resident macrophages that are activated by the MSU crystals leading downstream to a gout flare 25,26. A similar metabolic mechanism has been shown to exist in MSU stimulated macrophages 26.
Other mechanisms are also involved in the rise of uric acid that occurs with hypoxia. Figure 1 depicts those hyperuricemic mechanisms, with overproduction shown in the leftmost pathway of the figure, and underexcretion shown in the other two pathways. The hypoxic episodes lead to nucleotide turnover from ATP degradation culminating in irreversible cellular generation of excess uric acid17. The hypoxic episodes also are associated with both a respiratory acidosis from hypoventilation27 as well as a lactic acidosis from tissue ischemia28, which both act to reduce serum pH and that might increase the risk for urate crystallization in the synovial joint and elsewhere. In addition, the lactate can act on the renal tubule to increase urate reabsorption29. The hypercapnia can also induce an increase in renal vascular resistance30 that might also reduce urate excretion. The net effect is both an increase in urate production with a reduction in excretion, resulting in hyperuricemia with MSU precipitation, and a gout flare in an individual genetically predisposed to gout.
It is of interest that most gout attacks occur during the night31. While this is often thought to be due to dietary indiscretion, as a high purine load can increase serum uric acid three to four hours after ingestion32, it may also relate to the presence of sleep apnea and the acute effects of hypoxia on urate metabolism.

4. Does Treating OSA Provide Another Means for Controlling Gout and Its Comorbidities?

Gout has been reported to have so many of the same life-threatening metabolic syndrome comorbidities already known to be consequences of long-term untreated OSA (eg., cardiovascular diseases, diabetes, kidney disease, hypertension)33,34, some of which are reversible just by resolving the OSA35.
Following effective OSA treatment, the OSA-induced gout flares cease because OSA’s episodic effects no longer occur, and the reduced glomerular filtration rate may improve and potentially reverse within three months of effective treatment for OSA36,37. The slow dissolution of MSU stores after OSA has been resolved is likely to be assisted by ULT.
OSA been shown to elevate the risk for cardiovascular disease38. The rate of cardiovascular events has been shown to be the same in those with OSA resolved by controlled positive airway pressure (CPAP) vs. healthy individuals39. CPAP has been shown to reduce the recurrence of atrial fibrillation40, and to restore cardiac mechanical function41. CPAP also has been shown to ameliorate the progression of chronic kidney disease, and to reverse it in some cases36,37,42.

5. Summary

In summary, OSA is not only common in gout, but likely is a causal risk factor, similar to the role of genetics, diet, and kidney function. Subjects presenting with gout should be questioned for signs and symptoms of OSA with a low threshold for testing. Likewise, subjects presenting with OSA should be screened for hyperuricemia and gout and treated appropriately. The treatment of OSA appears to be beneficial for preventing gout flares, and may also have some effect on reducing uric acid levels. Treating OSA provides an additional approach for controlling hyperuricemia besides diet and medications.

Author Contributions

Conceptualization, all authors; writing—original draft preparation, RJ, BA, PD; writing—review and editing- RJ, BA. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Not applicable

Conflicts of Interest

The authors declare no conflict of interest.

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Preprints 69017 g001
Figure 1. Pathophysiology of OSA Leading to a GOUT FLARE.
Figure 1. Pathophysiology of OSA Leading to a GOUT FLARE.
Preprints 69017 g001
Table 1. Synopses of Epidemological Studies Connecting Gout with OSA.
Table 1. Synopses of Epidemological Studies Connecting Gout with OSA.
Ref
#		 Description of Study Number of Participants Results Risk
Ratio
9 Data from UK Clinical Practice Research
Datalink. Comparison of gout incidence
rate in cohort diagnosed with OSA vs.
cohort (matched by age, sex, practice)
never diagnosed with OSA.
5.8 yrs. median follow-up.		 15,878 diagnosed
with OSA.

63,296 never
diagnosed with OSA* 		OSA: 4.9% with gout.
Incidence rate
7.83/KPyr
No OSA: 2.6% with
gout.
Incidence rate
4.03/KPyr		 1.9
10 Data from UK general practice data base.
Comparison of gout prevalence in those
diagnosed with OSA vs. those never
diagnosed with OSA.		 1,689 diagnosed
with OSA.
6,756 never
diagnosed with OSA*		 OSA: 0.7%

No OSA: 0.3%		 2.3
11 Internet questioning about sleep
disorders of people with
physician-diagnosed gout who
visited a gout education website.		 454 320 with gout.
77 with diagnosed OSA.		 N/A
12 Data from 5% US Medicare beneficiary
sample 2006-2012. Selected entries
with new diagnosis of OSA.		 1.74 M, follow-up of
10,448,472
person-years* 		Incidence rates with
OSA: 14.3/KPyr
No OSA: 3.9/KPyr		 3.7
13 Data from UK Health Improvement Network.Comparison of gout incidence
rate with first SA diagnosis vs.
cohort (matched by age, sex, BMI)
never diagnosed with SA.		 9,865 with first SA diagnosis.
43,598 never
diagnosed with SA* 		Incidence rates with
SA: 8.4/KPyr
No SA: 4.8/KPyr		 1.75
14 All participants tested for OSA, and
questioned about history of
cardiovascular disease.		 72 controls (AHI<5)
47 mild (5<AHI<15)
75 moderate OSA
(15<AHI<30)
192 severe (AHI>30)		 Serum uric acid data show
monotonic increase with
AHI in those who had a
cardiovascular event.		 N/A
* Not all subjects were tested for OSA so the numbers are likely to underrepresent the true number of subjects with OSA. Key: AHI = apnea-hypopnea index; KPyr = kiloperson-years; N/A = not applicable; OSA = obstructive sleep apnea; SA = sleep apnea.
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