Obstructive Sleep Apnea as a Cause of Gout

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 acid^19-21. This pathway tends to protect against hypoxia by reducing mitochondrial function while stimulating glycolysis, thereby reducing oxygen needs^22,23. 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 OSA^36,37. 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 cases^36,37,42.

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.