The Association of Gout With Sleep Disorders
The Association of Gout With Sleep Disorders
To our knowledge, apart from one previous case report, this is the first empirical epidemiological study to explore an association between gout and obstructive sleep apnoea syndrome. We examined the association between gout and firstly all sleep problems combined ("any sleep problem") and secondly sleep problems re-categorised as sleep apnoea and sleep problems other than sleep apnoea. There were small but significant associations between gout and both any sleep problem and sleep problems other than sleep apnoea which remained largely unchanged after adjusting for associated co-morbid conditions. Although we found a two-fold increased risk of sleep apnoea in those with gout on univariable analysis, this was no longer statistically significant after adjustment for multiple confounding variables.
The strengths of the study are its primary care setting and the rigorous quality assurance processes undertaken to ensure the robustness of computerized morbidity coding in the participating practices. Limitations of our study are worthy of acknowledgement. First, the cross-sectional study design merely informs about association and does not allow for any inferences concerning causality or direction of association. Second, use of primary care consultation data relies upon a primary care diagnosis which may introduce misdiagnosis and hence misclassification bias. In primary care, the diagnosis of gout is most frequently made on clinical grounds whereas definitive diagnosis requires crystal identification. It has previously been suggested that gout is frequently over-diagnosed in primary care. However, primary care consultation records have been widely used in gout research and, although not undertaken during the current analysis, in a previous study undertaken using consultation data from the CiPCA database, scrutiny of consultation free text recorded by general practitioners confirmed features of inflammation and distribution of affected joints generally consistent with a diagnosis of gout. Diagnosis in primary care is also an important consideration for obstructive sleep apnoea syndrome which is frequently unrecognized. Indeed, the prevalence of obstructive sleep apnoea syndrome is lower in our study than in previous general population studies which have employed more definitive diagnostic methods. It seems likely therefore that some patients with obstructive sleep apnoea syndrome will have gone unrecognised altogether although it is also possible that some may have been misdiagnosed as having another sleep problem, in which case they would have been classified firstly as "any sleep problem" and then as a "sleep problems other than sleep apnoea" in this study. However, previous studies indicate that a diagnosis of obstructive sleep apnoea made by a general practitioner is usually correct. A further limitation is that obesity and alcohol which are risk factors for both gout and obstructive sleep apnoea syndrome are infrequently coded in primary care databases and hence we were unable to adjust for either of these important potential confounding variables. We acknowledge also that our analysis is likely to have been under-powered to detect a significant association between gout and obstructive sleep apnoea syndrome. However, we believe that this is a novel and interesting potential association which has not been previously studied and for which there is a biologically credible underlying mechanism, namely enhanced degradation of adenosine triphosphate in the presence of hypoxia leading to increased substrate provision for the purine metabolic pathway of which uric acid is the end-product in humans and prevalent hyperuricaemia in obstructive sleep apnoea syndrome. These preliminary findings provide justification for a larger prospective epidemiological study to examine in more detail the possibility that obstructive sleep apnoea syndrome is a risk factor for gout.
We found a significant association between gout and sleep problems other than sleep apnoea. These disorders consisted of a heterogeneous group of conditions, most commonly insomnia and non-specific sleep disorders (data not shown). To our knowledge, associations between these conditions and either gout or hyperuricaemia have not been studied previously and we are not aware of biological mechanisms to link them with either hyperuricaemia or crystal formation. More detailed study of this association, which specific sleep disorders are associated with gout, and the mechanisms underlying this association is warranted.
Notwithstanding the lack of association between gout and obstructive sleep apnoea syndrome after adjustment for confounding factors, our univariate analysis suggests that gout and obstructive sleep apnoea syndrome can co-exist and hence clinicians should be aware of gout as a potential cause of painful joints in patients with obstructive sleep apnoea syndrome and also of the latter as a significant cause of excessive sleepiness in patients with gout. Prompt and accurate recognition of obstructive sleep apnoea syndrome is particularly important because of the associated risk of motor vehicle accidents and legal requirements not to drive unless treated. Furthermore, treatment of obstructive sleep apnoea syndrome with continuous positive airways pressure (CPAP) has been shown to improve certain parameters of the metabolic syndrome such as hypertension and hyperlipidaemia. It is plausible that lowering of uric acid levels with CPAP treatment would theoretically lead to better control of gout although to our knowledge the effect of CPAP on uric acid levels has not been studied and further research is required. Further large prospective epidemiological studies are required to explore this association and establish causality in more detail.
Discussion
To our knowledge, apart from one previous case report, this is the first empirical epidemiological study to explore an association between gout and obstructive sleep apnoea syndrome. We examined the association between gout and firstly all sleep problems combined ("any sleep problem") and secondly sleep problems re-categorised as sleep apnoea and sleep problems other than sleep apnoea. There were small but significant associations between gout and both any sleep problem and sleep problems other than sleep apnoea which remained largely unchanged after adjusting for associated co-morbid conditions. Although we found a two-fold increased risk of sleep apnoea in those with gout on univariable analysis, this was no longer statistically significant after adjustment for multiple confounding variables.
The strengths of the study are its primary care setting and the rigorous quality assurance processes undertaken to ensure the robustness of computerized morbidity coding in the participating practices. Limitations of our study are worthy of acknowledgement. First, the cross-sectional study design merely informs about association and does not allow for any inferences concerning causality or direction of association. Second, use of primary care consultation data relies upon a primary care diagnosis which may introduce misdiagnosis and hence misclassification bias. In primary care, the diagnosis of gout is most frequently made on clinical grounds whereas definitive diagnosis requires crystal identification. It has previously been suggested that gout is frequently over-diagnosed in primary care. However, primary care consultation records have been widely used in gout research and, although not undertaken during the current analysis, in a previous study undertaken using consultation data from the CiPCA database, scrutiny of consultation free text recorded by general practitioners confirmed features of inflammation and distribution of affected joints generally consistent with a diagnosis of gout. Diagnosis in primary care is also an important consideration for obstructive sleep apnoea syndrome which is frequently unrecognized. Indeed, the prevalence of obstructive sleep apnoea syndrome is lower in our study than in previous general population studies which have employed more definitive diagnostic methods. It seems likely therefore that some patients with obstructive sleep apnoea syndrome will have gone unrecognised altogether although it is also possible that some may have been misdiagnosed as having another sleep problem, in which case they would have been classified firstly as "any sleep problem" and then as a "sleep problems other than sleep apnoea" in this study. However, previous studies indicate that a diagnosis of obstructive sleep apnoea made by a general practitioner is usually correct. A further limitation is that obesity and alcohol which are risk factors for both gout and obstructive sleep apnoea syndrome are infrequently coded in primary care databases and hence we were unable to adjust for either of these important potential confounding variables. We acknowledge also that our analysis is likely to have been under-powered to detect a significant association between gout and obstructive sleep apnoea syndrome. However, we believe that this is a novel and interesting potential association which has not been previously studied and for which there is a biologically credible underlying mechanism, namely enhanced degradation of adenosine triphosphate in the presence of hypoxia leading to increased substrate provision for the purine metabolic pathway of which uric acid is the end-product in humans and prevalent hyperuricaemia in obstructive sleep apnoea syndrome. These preliminary findings provide justification for a larger prospective epidemiological study to examine in more detail the possibility that obstructive sleep apnoea syndrome is a risk factor for gout.
We found a significant association between gout and sleep problems other than sleep apnoea. These disorders consisted of a heterogeneous group of conditions, most commonly insomnia and non-specific sleep disorders (data not shown). To our knowledge, associations between these conditions and either gout or hyperuricaemia have not been studied previously and we are not aware of biological mechanisms to link them with either hyperuricaemia or crystal formation. More detailed study of this association, which specific sleep disorders are associated with gout, and the mechanisms underlying this association is warranted.
Notwithstanding the lack of association between gout and obstructive sleep apnoea syndrome after adjustment for confounding factors, our univariate analysis suggests that gout and obstructive sleep apnoea syndrome can co-exist and hence clinicians should be aware of gout as a potential cause of painful joints in patients with obstructive sleep apnoea syndrome and also of the latter as a significant cause of excessive sleepiness in patients with gout. Prompt and accurate recognition of obstructive sleep apnoea syndrome is particularly important because of the associated risk of motor vehicle accidents and legal requirements not to drive unless treated. Furthermore, treatment of obstructive sleep apnoea syndrome with continuous positive airways pressure (CPAP) has been shown to improve certain parameters of the metabolic syndrome such as hypertension and hyperlipidaemia. It is plausible that lowering of uric acid levels with CPAP treatment would theoretically lead to better control of gout although to our knowledge the effect of CPAP on uric acid levels has not been studied and further research is required. Further large prospective epidemiological studies are required to explore this association and establish causality in more detail.
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