- Email: [email protected]
Sleep and gastrointestinal disease: A new horizon in sleep medicine
Sleep Medicine 10 (2009) 595–596
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Editorial
Sleep and gastrointestinal disease: A new horizon in sleep medicine Much has been written of late concerning the hazards of restricted or fragmented sleep. Americans now sleep about two hours less per night than 100 years ago, and poor sleep has been linked to the dramatic rise in obesity, metabolic syndrome and immune responses to include susceptibility to the flu virus. It is difficult to establish, however, a direct causal relationship between poor sleep and disease manifestation in a specific individual. In gastroenterology it is now well established that patients with gastroesophageal reflux disease (GERD) often manifest sleep complaints as well as complaints of nighttime heartburn [1,2]. However, it is not clear in a specific individual to what extent GERD may be causing a sleep disturbance and to what extent the sleep disturbance may be contributing to the manifestations of GERD. It has, however, been shown that sleep related reflux results in marked alterations in esophageal acid mucosal contact which predispose to the development of esophagitis and other complications of GERD [3]. More direct relationships between sleep and GERD have been noted in studies which have documented that sleep quality is related to the severity of reflux during sleep and that patients with nighttime heartburn and sleep complaints have greater acid contact time [4,5]. Of particular relevance is the fact that disturbed sleep alone results in a lower threshold for esophageal perception of acid contact [6]. However, the precise mechanism which causes sleep disturbance in GERD patients remains unclear. In a most interesting study in this issue of Sleep Medicine, Tang et al. show that in a murine model either acute (ASD) or chronic intermittent sleep deprivation (CISD) exacerbates the colonic mucosal response to the infusion of a pro-inflammatory solution used as a model of inflammatory bowel disease (IBD) [7]. The authors have shown what they describe as a ‘‘dose response effect” of sleep deprivation in that ASD produced evidence only of mucosal inflammation, while the CISD produced worsening of histologic and macroscopic (i.e., shortening of colonic length) changes. This significant ‘‘dose response” finding lends credence to the reliability of these findings. Although these results do not suggest that sleep deprivation can ‘‘trigger” symptom exacerbation in patients with IBD, they do provide evidence that, if generalizable to humans, sleep deprivation in patients with IBD may result in a worsening of the inflammatory response. These results have a number of potential clinical implications. However, the design of the study, and the inherent problems in doing sleep deprivation studies in animals, make any conclusions about human disease difficult. It is prudent to discuss some of these issues. In any sleep deprivation study involving animals the question arises whether the mechanism of sleep deprivation itself may cause the physiologic response which may be observed. In this study, the authors used a wheel rotation method, but several animals were also sleep deprived by ‘‘gentle handling,” and no difference was observed between the sleep deprivation methods. The 1389-9457/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2009.03.001
question of the role of stress in sleep deprivation results may never be resolved, but some measure of a physiologic stress response would be useful. For example, in the very elegant design of this study the authors included a group of animals who had sleep deprivation, but no infusion of the pro-inflammatory solution. It would seem that if cortisol levels were no different between these two groups one could conclude at least that the addition of the proinflammatory drug alone did not add to the ‘‘stress” experienced by the animals in the experimental group. Perhaps the major flaw in this study, however, is the very small number of observations. Only 4 animals were in the control group and 8 were in the experimental groups (ASD and CISD). This begs the question of a type II error, especially when the data show a dose response in the symptom data without statistical significance. The authors note that sleep disruption can cause alterations in the immune system and that studies from their group have also shown that IBD patients have significant subjective sleep complaints as measure by validated questionnaires [8]. This was noted both during periods of exacerbation and remission of disease state, and the sleep disturbance was correlated with the IBD disease severity score. This would suggest that there is an underlying sleep disturbance in these patients, but the etiology is unclear. Might this simply be a conditioned response induced by the years of pain, discomfort and worry associated with a chronic, debilitating disease? This same group has also documented objective sleep alterations, but in both studies results were significantly different from normal controls, but not from a control group of patients with irritable bowel syndrome (IBS) [8,9]. Thus, there appears to be nothing unique about sleep complaints and sleep disturbances in patients with a clinical syndrome which involves chronic relapsing and exacerbations of abdominal pain. IBS patients have intermittent abdominal pain (many with bouts of diarrhea as well) and their sleep patterns appear to be indistinguishable from those of patients with IBD. These facts seem to argue that the sleep disorders noted in these patient groups are the result of the disease itself, and most likely have little to do with the cause of the disease. The consequences of altered immune responses and lowered visceral pain thresholds secondary to sleep disturbances clearly may play a role in the inflammatory and clinical reaction to exacerbations of disease in both IBD and IBS groups. The study by Tang and colleagues adds to the accumulating body of evidence that sleep plays an important role in both the physiologic and clinical manifestation of gastrointestinal disease. Although their study clearly needs replication due to the very small numbers, their data are provocative and potentially clinically very significant in the management of patients with IBD. For example, might it be appropriate to administer hypnotic drugs to treat the underlying sleep disturbance in patients with IBD? Thus, gastroenterologists, like pulmonary specialists dealing with occult
596
Editorial / Sleep Medicine 10 (2009) 595–596
respiratory disorders, need to be aware that sleep and sleep habits can profoundly affect symptom manifestation and disease progression. It is appropriate to recall the words of Eugene Robin who said over 50 years ago: ‘‘The sleeping patient is still a patient, his disease goes on not only while he sleeps, but indeed may progress in an entirely different fashion than in the waking state.” References [1] Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med 2001;161:45–52. [2] Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an underappreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487–93. [3] Orr W. Night-time gastro-oesophageal reflux disease: prevalence, hazards, and management. Eur J Gastroenterol Hepatol 2005;17:113–20. [4] Dickman R, Green C, Fass S, et al. Relationships between sleep quality and pH monitoring findings in persons with gastroesophageal reflux disease. J Clin Sleep Med 2007;3:505–13.
[5] Chen CL, Robert JT, Orr WC. Sleep symptoms and gastroesophageal reflux. J Clin Gastroenterol 2008;42:13–7. [6] Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133: 1787–95. [7] Tang Y, Preuss F, Turek F, et al. Sleep deprivation worsens the inflammation and delays recovery in a mouse model of colitis. Sleep Med 2009;10:597–603. [8] Ranjbaran Z, Keefer L, Farhadi A, et al. Impact of sleep disturbances in inflammatory bowel disease. J Gastro Hep 2007;22:1748–53. [9] Keefer L, Stepanski E, Ranjbaran Z, et al. An initial report of sleep disturbance in inactive inflammatory bowel disease. J Clin Sleep Med 2006;2:409–16.
William C. Orr Lynn Health Science Institute, 3555 NW 58th St., Oklahoma City, OK 73112, USA Clinical Professor of Medicine, University of Oklahoma Health Sciences Center, USA E-mail address: [email protected]
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Editorial
Sleep and gastrointestinal disease: A new horizon in sleep medicine Much has been written of late concerning the hazards of restricted or fragmented sleep. Americans now sleep about two hours less per night than 100 years ago, and poor sleep has been linked to the dramatic rise in obesity, metabolic syndrome and immune responses to include susceptibility to the flu virus. It is difficult to establish, however, a direct causal relationship between poor sleep and disease manifestation in a specific individual. In gastroenterology it is now well established that patients with gastroesophageal reflux disease (GERD) often manifest sleep complaints as well as complaints of nighttime heartburn [1,2]. However, it is not clear in a specific individual to what extent GERD may be causing a sleep disturbance and to what extent the sleep disturbance may be contributing to the manifestations of GERD. It has, however, been shown that sleep related reflux results in marked alterations in esophageal acid mucosal contact which predispose to the development of esophagitis and other complications of GERD [3]. More direct relationships between sleep and GERD have been noted in studies which have documented that sleep quality is related to the severity of reflux during sleep and that patients with nighttime heartburn and sleep complaints have greater acid contact time [4,5]. Of particular relevance is the fact that disturbed sleep alone results in a lower threshold for esophageal perception of acid contact [6]. However, the precise mechanism which causes sleep disturbance in GERD patients remains unclear. In a most interesting study in this issue of Sleep Medicine, Tang et al. show that in a murine model either acute (ASD) or chronic intermittent sleep deprivation (CISD) exacerbates the colonic mucosal response to the infusion of a pro-inflammatory solution used as a model of inflammatory bowel disease (IBD) [7]. The authors have shown what they describe as a ‘‘dose response effect” of sleep deprivation in that ASD produced evidence only of mucosal inflammation, while the CISD produced worsening of histologic and macroscopic (i.e., shortening of colonic length) changes. This significant ‘‘dose response” finding lends credence to the reliability of these findings. Although these results do not suggest that sleep deprivation can ‘‘trigger” symptom exacerbation in patients with IBD, they do provide evidence that, if generalizable to humans, sleep deprivation in patients with IBD may result in a worsening of the inflammatory response. These results have a number of potential clinical implications. However, the design of the study, and the inherent problems in doing sleep deprivation studies in animals, make any conclusions about human disease difficult. It is prudent to discuss some of these issues. In any sleep deprivation study involving animals the question arises whether the mechanism of sleep deprivation itself may cause the physiologic response which may be observed. In this study, the authors used a wheel rotation method, but several animals were also sleep deprived by ‘‘gentle handling,” and no difference was observed between the sleep deprivation methods. The 1389-9457/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2009.03.001
question of the role of stress in sleep deprivation results may never be resolved, but some measure of a physiologic stress response would be useful. For example, in the very elegant design of this study the authors included a group of animals who had sleep deprivation, but no infusion of the pro-inflammatory solution. It would seem that if cortisol levels were no different between these two groups one could conclude at least that the addition of the proinflammatory drug alone did not add to the ‘‘stress” experienced by the animals in the experimental group. Perhaps the major flaw in this study, however, is the very small number of observations. Only 4 animals were in the control group and 8 were in the experimental groups (ASD and CISD). This begs the question of a type II error, especially when the data show a dose response in the symptom data without statistical significance. The authors note that sleep disruption can cause alterations in the immune system and that studies from their group have also shown that IBD patients have significant subjective sleep complaints as measure by validated questionnaires [8]. This was noted both during periods of exacerbation and remission of disease state, and the sleep disturbance was correlated with the IBD disease severity score. This would suggest that there is an underlying sleep disturbance in these patients, but the etiology is unclear. Might this simply be a conditioned response induced by the years of pain, discomfort and worry associated with a chronic, debilitating disease? This same group has also documented objective sleep alterations, but in both studies results were significantly different from normal controls, but not from a control group of patients with irritable bowel syndrome (IBS) [8,9]. Thus, there appears to be nothing unique about sleep complaints and sleep disturbances in patients with a clinical syndrome which involves chronic relapsing and exacerbations of abdominal pain. IBS patients have intermittent abdominal pain (many with bouts of diarrhea as well) and their sleep patterns appear to be indistinguishable from those of patients with IBD. These facts seem to argue that the sleep disorders noted in these patient groups are the result of the disease itself, and most likely have little to do with the cause of the disease. The consequences of altered immune responses and lowered visceral pain thresholds secondary to sleep disturbances clearly may play a role in the inflammatory and clinical reaction to exacerbations of disease in both IBD and IBS groups. The study by Tang and colleagues adds to the accumulating body of evidence that sleep plays an important role in both the physiologic and clinical manifestation of gastrointestinal disease. Although their study clearly needs replication due to the very small numbers, their data are provocative and potentially clinically very significant in the management of patients with IBD. For example, might it be appropriate to administer hypnotic drugs to treat the underlying sleep disturbance in patients with IBD? Thus, gastroenterologists, like pulmonary specialists dealing with occult
596
Editorial / Sleep Medicine 10 (2009) 595–596
respiratory disorders, need to be aware that sleep and sleep habits can profoundly affect symptom manifestation and disease progression. It is appropriate to recall the words of Eugene Robin who said over 50 years ago: ‘‘The sleeping patient is still a patient, his disease goes on not only while he sleeps, but indeed may progress in an entirely different fashion than in the waking state.” References [1] Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med 2001;161:45–52. [2] Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an underappreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487–93. [3] Orr W. Night-time gastro-oesophageal reflux disease: prevalence, hazards, and management. Eur J Gastroenterol Hepatol 2005;17:113–20. [4] Dickman R, Green C, Fass S, et al. Relationships between sleep quality and pH monitoring findings in persons with gastroesophageal reflux disease. J Clin Sleep Med 2007;3:505–13.
[5] Chen CL, Robert JT, Orr WC. Sleep symptoms and gastroesophageal reflux. J Clin Gastroenterol 2008;42:13–7. [6] Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133: 1787–95. [7] Tang Y, Preuss F, Turek F, et al. Sleep deprivation worsens the inflammation and delays recovery in a mouse model of colitis. Sleep Med 2009;10:597–603. [8] Ranjbaran Z, Keefer L, Farhadi A, et al. Impact of sleep disturbances in inflammatory bowel disease. J Gastro Hep 2007;22:1748–53. [9] Keefer L, Stepanski E, Ranjbaran Z, et al. An initial report of sleep disturbance in inactive inflammatory bowel disease. J Clin Sleep Med 2006;2:409–16.
William C. Orr Lynn Health Science Institute, 3555 NW 58th St., Oklahoma City, OK 73112, USA Clinical Professor of Medicine, University of Oklahoma Health Sciences Center, USA E-mail address: [email protected]