Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pathogenesis of obesity hypoventilation syndrome

Amanda Piper, PhD
Brendon Yee, MBChB, PhD
Section Editor
M Safwan Badr, MD
Deputy Editor
Geraldine Finlay, MD


Obesity hypoventilation syndrome (OHS) is defined as obesity (body mass index [BMI] ≥30 kg/m2) and chronic alveolar hypoventilation (arterial carbon dioxide tension [PaCO2] >45 mmHg) during wakefulness occurring in the absence of other conditions that would better explain hypoventilation [1]. When first described, this was referred to as Pickwickian syndrome after a character in Charles Dickens' book, The Posthumous Papers of the Pickwick Club [2].

The pathogenesis of OHS and factors that contribute to it are reviewed here. Clinical manifestations, diagnosis, and treatment are discussed separately. (See "Clinical manifestations and diagnosis of obesity hypoventilation syndrome" and "Treatment of the obesity hypoventilation syndrome" and "Noninvasive positive pressure therapy of the obesity hypoventilation syndrome".)


Alveolar hypoventilation in patients with obesity occurs when the normal compensatory ventilatory mechanisms that maintain adequate ventilation fail [3]. The main physiologic abnormalities of obesity hypoventilation syndrome (OHS) are obesity, sleep disordered breathing (obstructive sleep apnea [OSA] and/or sleep hypoventilation), altered pulmonary mechanics, and impaired ventilatory control, with a complex interaction between each of these factors (figure 1 and table 1 and algorithm 1) [3].

Obesity — In patients with OSA, increasing body mass index (BMI) increases the likelihood of OHS being present [4,5]. This is due, in part, to excess carbon dioxide (CO2) production associated with increased body surface area [6]. The distribution of excess weight is important, with OHS individuals being more centrally obese than individuals with eucapnic obesity, even at the same BMI [7]. The important role obesity plays in the pathogenesis of this disorder is supported by the observation that weight loss alone decreases the partial pressure of carbon dioxide (PaCO2) during wakefulness in patients with OHS [8]. Nevertheless, obesity cannot be the only mechanism accounting for hypoventilation, as the majority of morbidly obese individuals are able to compensate for the increased load on the respiratory system and maintain daytime eucapnia. Hence, OHS develops when the usual compensatory mechanisms necessary to maintain ventilation in the presence of obesity fail.

Sleep disordered breathing — Patients with OHS may present OSA syndrome with hypercapnia, sleep hypoventilation, or a combination of the two [1,9]. OSA is a syndrome characterized by episodic hypopnea or apnea due to recurrent partial or complete upper airway obstruction during sleep. (See "Overview of obstructive sleep apnea in adults".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Nov 23, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Olson AL, Zwillich C. The obesity hypoventilation syndrome. Am J Med 2005; 118:948.
  2. BICKELMANN AG, BURWELL CS, ROBIN ED, WHALEY RD. Extreme obesity associated with alveolar hypoventilation; a Pickwickian syndrome. Am J Med 1956; 21:811.
  3. Piper AJ. Obesity hypoventilation syndrome--the big and the breathless. Sleep Med Rev 2011; 15:79.
  4. Kaw R, Hernandez AV, Walker E, et al. Determinants of hypercapnia in obese patients with obstructive sleep apnea: a systematic review and metaanalysis of cohort studies. Chest 2009; 136:787.
  5. Mokhlesi B. Obesity hypoventilation syndrome: a state-of-the-art review. Respir Care 2010; 55:1347.
  6. Javaheri S, Simbartl LA. Respiratory determinants of diurnal hypercapnia in obesity hypoventilation syndrome. What does weight have to do with it? Ann Am Thorac Soc 2014; 11:945.
  7. Resta O, Foschino-Barbaro MP, Bonfitto P, et al. Prevalence and mechanisms of diurnal hypercapnia in a sample of morbidly obese subjects with obstructive sleep apnoea. Respir Med 2000; 94:240.
  8. Rochester DF, Enson Y. Current concepts in the pathogenesis of the obesity-hypoventilation syndrome. Mechanical and circulatory factors. Am J Med 1974; 57:402.
  9. Berger KI, Ayappa I, Chatr-Amontri B, et al. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest 2001; 120:1231.
  10. Rapoport DM, Garay SM, Epstein H, Goldring RM. Hypercapnia in the obstructive sleep apnea syndrome. A reevaluation of the "Pickwickian syndrome". Chest 1986; 89:627.
  11. Kawata N, Tatsumi K, Terada J, et al. Daytime hypercapnia in obstructive sleep apnea syndrome. Chest 2007; 132:1832.
  12. Piper AJ, Wang D, Yee BJ, et al. Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation. Thorax 2008; 63:395.
  13. Kessler R, Chaouat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest 2001; 120:369.
  14. Pérez de Llano LA, Golpe R, Ortiz Piquer M, et al. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 2005; 128:587.
  15. De Miguel Díez J, De Lucas Ramos P, Pérez Parra JJ, et al. [Analysis of withdrawal from noninvasive mechanical ventilation in patients with obesity-hypoventilation syndrome. Medium term results]. Arch Bronconeumol 2003; 39:292.
  16. Berger KI, Ayappa I, Sorkin IB, et al. Postevent ventilation as a function of CO(2) load during respiratory events in obstructive sleep apnea. J Appl Physiol (1985) 2002; 93:917.
  17. Ayappa I, Berger KI, Norman RG, et al. Hypercapnia and ventilatory periodicity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002; 166:1112.
  18. Norman RG, Goldring RM, Clain JM, et al. Transition from acute to chronic hypercapnia in patients with periodic breathing: predictions from a computer model. J Appl Physiol (1985) 2006; 100:1733.
  19. Berger KI, Goldring RM, Rapoport DM. Obesity hypoventilation syndrome. Semin Respir Crit Care Med 2009; 30:253.
  20. Goldring RM, Turino GM, Heinemann HO. Respiratory-renal adjustments in chronic hypercapnia in man. Extracellular bicarbonate concentration and the regulation of ventilation. Am J Med 1971; 51:772.
  21. Hlavac MC, Catcheside PG, McDonald R, et al. Hypoxia impairs the arousal response to external resistive loading and airway occlusion during sleep. Sleep 2006; 29:624.
  22. Lopata M, Onal E. Mass loading, sleep apnea, and the pathogenesis of obesity hypoventilation. Am Rev Respir Dis 1982; 126:640.
  23. Piper AJ, Grunstein RR. Big breathing: the complex interaction of obesity, hypoventilation, weight loss, and respiratory function. J Appl Physiol (1985) 2010; 108:199.
  24. Zerah F, Harf A, Perlemuter L, et al. Effects of obesity on respiratory resistance. Chest 1993; 103:1470.
  25. Behazin N, Jones SB, Cohen RI, Loring SH. Respiratory restriction and elevated pleural and esophageal pressures in morbid obesity. J Appl Physiol (1985) 2010; 108:212.
  26. Pelosi P, Croci M, Ravagnan I, et al. Respiratory system mechanics in sedated, paralyzed, morbidly obese patients. J Appl Physiol (1985) 1997; 82:811.
  28. Rochester DF, Arora NS. Respiratory failure from obesity. In: Medical Complications of obesity, Mancini M, Lewis B, Contaldo F (Eds), Academic Press, London 1980. p.183.
  29. Pankow W, Hijjeh N, Schüttler F, et al. Influence of noninvasive positive pressure ventilation on inspiratory muscle activity in obese subjects. Eur Respir J 1997; 10:2847.
  30. Sharp JT, Druz WS, Kondragunta VR. Diaphragmatic responses to body position changes in obese patients with obstructive sleep apnea. Am Rev Respir Dis 1986; 133:32.
  31. Lee MY, Lin CC, Shen SY, et al. Work of breathing in eucapnic and hypercapnic sleep apnea syndrome. Respiration 2009; 77:146.
  32. Javaheri S, Colangelo G, Lacey W, Gartside PS. Chronic hypercapnia in obstructive sleep apnea-hypopnea syndrome. Sleep 1994; 17:416.
  33. Steier J, Jolley CJ, Seymour J, Roughton M, Polkey MI, Moxham J. Neural respiratory drive in obesity. Thorax. 2009 Aug;64(8):719-25.
  34. Budweiser S, Jörres RA, Criée CP, et al. Prognostic value of mouth occlusion pressure in patients with chronic ventilatory failure. Respir Med 2007; 101:2343.
  35. Chouri-Pontarollo N, Borel JC, Tamisier R, et al. Impaired objective daytime vigilance in obesity-hypoventilation syndrome: impact of noninvasive ventilation. Chest 2007; 131:148.
  36. Monneret D, Borel JC, Pepin JL, et al. Pleiotropic role of IGF-I in obesity hypoventilation syndrome. Growth Horm IGF Res 2010; 20:127.
  37. Zwillich CW, Sutton FD, Pierson DJ, et al. Decreased hypoxic ventilatory drive in the obesity-hypoventilation syndrome. Am J Med 1975; 59:343.
  38. Jokic R, Zintel T, Sridhar G, et al. Ventilatory responses to hypercapnia and hypoxia in relatives of patients with the obesity hypoventilation syndrome. Thorax. 2000 Nov;55(11):940-5.
  39. Han F, Chen E, Wei H, et al. Treatment effects on carbon dioxide retention in patients with obstructive sleep apnea-hypopnea syndrome. Chest. 2001 June 1, 2001;119(6):1814-9.
  40. Kalra SP. Central leptin insufficiency syndrome: an interactive etiology for obesity, metabolic and neural diseases and for designing new therapeutic interventions. Peptides 2008; 29:127.
  41. O'Donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med. 1999 May;159:1477-84.
  42. Phipps PR, Starritt E, Caterson I, Grunstein RR. Association of serum leptin with hypoventilation in human obesity. Thorax 2002; 57:75.
  43. Yee BJ, Cheung J, Phipps P, et al. Treatment of obesity hypoventilation syndrome and serum leptin. Respiration 2006; 73:209.
  44. Borel JC, Tamisier R, Gonzalez-Bermejo J, et al. Noninvasive ventilation in mild obesity hypoventilation syndrome: a randomized controlled trial. Chest 2012; 141:692.
  45. Redolfi S, Corda L, La Piana G, et al. Long-term non-invasive ventilation increases chemosensitivity and leptin in obesity-hypoventilation syndrome. Respir Med 2007; 101:1191.