UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults

Author
Elizabeth S Klings, MD
Section Editors
Jess Mandel, MD
Talmadge E King, Jr, MD
Deputy Editor
Geraldine Finlay, MD

INTRODUCTION

Patients with pulmonary hypertension (PH) due to diffuse lung disease (eg, chronic obstructive pulmonary disease, interstitial lung disease, or overlap syndromes) or conditions that cause hypoxemia (eg, obstructive sleep apnea, alveolar hypoventilation disorders) are classified as having group 3 PH (table 1).

The prevalence, pathogenesis, and diagnosis of PH due to lung disease and/or hypoxemia are presented here. The treatment and prognosis of patients with group 3 PH are reviewed separately. (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis".)

CLASSIFICATION AND DEFINITIONS

The classification and definitions of PH and cor pulmonale are discussed below:

Classification – The World Health Organization (WHO) classifies patients with PH into five groups based upon etiology [1]. Patients in group 1 are considered to have pulmonary arterial hypertension (PAH; also sometimes referred to as pre-capillary pulmonary hypertension), whereas patients in group 2 (due to left-sided heart disease), group 3 (due to chronic lung disorders and hypoxemia), group 4 (due to chronic thromboembolic disease), and group 5 (due to unidentified mechanisms) are considered to have PH (table 1). When all five groups are discussed collectively, the term PH is used. (See "Classification and prognosis of pulmonary hypertension in adults", section on 'Classification'.)

Pulmonary hypertension – PH is defined as a mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterization [2]. PH is considered severe if mPAP is ≥35 mmHg or the mPAP is ≥25 mmHg with an elevated right atrial pressure and/or the cardiac index is <2 L/min/m2 [3]. (See "Clinical features and diagnosis of pulmonary hypertension in adults", section on 'Diagnostic criteria'.)

                   
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Mar 07, 2017.
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 ©2017 UpToDate, Inc.
References
Top
  1. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62:D34.
  2. Badesch DB, Champion HC, Sanchez MA, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:S55.
  3. Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013; 62:D109.
  4. Budev MM, Arroliga AC, Wiedemann HP, Matthay RA. Cor pulmonale: an overview. Semin Respir Crit Care Med 2003; 24:233.
  5. Pugh ME, Sivarajan L, Wang L, et al. Causes of pulmonary hypertension in the elderly. Chest 2014; 146:159.
  6. Chatila WM, Thomashow BM, Minai OA, et al. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008; 5:549.
  7. Falk JA, Kadiev S, Criner GJ, et al. Cardiac disease in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008; 5:543.
  8. Arcasoy SM, Christie JD, Ferrari VA, et al. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003; 167:735.
  9. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J 2008; 32:1371.
  10. Vizza CD, Lynch JP, Ochoa LL, et al. Right and left ventricular dysfunction in patients with severe pulmonary disease. Chest 1998; 113:576.
  11. Thabut G, Dauriat G, Stern JB, et al. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest 2005; 127:1531.
  12. Scharf SM, Iqbal M, Keller C, et al. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med 2002; 166:314.
  13. Cuttica MJ, Kalhan R, Shlobin OA, et al. Categorization and impact of pulmonary hypertension in patients with advanced COPD. Respir Med 2010; 104:1877.
  14. Burrows B, Kettel LJ, Niden AH, et al. Patterns of cardiovascular dysfunction in chronic obstructive lung disease. N Engl J Med 1972; 286:912.
  15. Weitzenblum E, Hirth C, Ducolone A, et al. Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax 1981; 36:752.
  16. Doi M, Nakano K, Hiramoto T, Kohno N. Significance of pulmonary artery pressure in emphysema patients with mild-to-moderate hypoxemia. Respir Med 2003; 97:915.
  17. Higham MA, Dawson D, Joshi J, et al. Utility of echocardiography in assessment of pulmonary hypertension secondary to COPD. Eur Respir J 2001; 17:350.
  18. Fayngersh V, Drakopanagiotakis F, Dennis McCool F, Klinger JR. Pulmonary hypertension in a stable community-based COPD population. Lung 2011; 189:377.
  19. Oswald-Mammosser M, Apprill M, Bachez P, et al. Pulmonary hemodynamics in chronic obstructive pulmonary disease of the emphysematous type. Respiration 1991; 58:304.
  20. Christensen CC, Ryg MS, Edvardsen A, Skjønsberg OH. Relationship between exercise desaturation and pulmonary haemodynamics in COPD patients. Eur Respir J 2004; 24:580.
  21. Kessler R, Faller M, Weitzenblum E, et al. "Natural history" of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med 2001; 164:219.
  22. Raghu G, Nathan SD, Behr J, et al. Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction. Eur Respir J 2015; 46:1370.
  23. Lettieri CJ, Nathan SD, Barnett SD, et al. Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 2006; 129:746.
  24. Shorr AF, Wainright JL, Cors CS, et al. Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J 2007; 30:715.
  25. Nathan SD, Shlobin OA, Ahmad S, et al. Pulmonary hypertension and pulmonary function testing in idiopathic pulmonary fibrosis. Chest 2007; 131:657.
  26. Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128:2393.
  27. Harari S, Simonneau G, De Juli E, et al. Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation. J Heart Lung Transplant 1997; 16:460.
  28. Leuchte HH, Neurohr C, Baumgartner R, et al. Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2004; 170:360.
  29. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126:14S.
  30. Hoeper MM. Pulmonary hypertension in collagen vascular disease. Eur Respir J 2002; 19:571.
  31. Rayner CF, Grubnic S. Pulmonary manifestations of systemic autoimmune disease. Best Pract Res Clin Rheumatol 2004; 18:381.
  32. Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest 1996; 110:1515.
  33. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132:425.
  34. MacGregor AJ, Canavan R, Knight C, et al. Pulmonary hypertension in systemic sclerosis: risk factors for progression and consequences for survival. Rheumatology (Oxford) 2001; 40:453.
  35. Fagan KA, Badesch DB. Pulmonary hypertension associated with connective tissue disease. Prog Cardiovasc Dis 2002; 45:225.
  36. Hesselstrand R, Ekman R, Eskilsson J, et al. Screening for pulmonary hypertension in systemic sclerosis: the longitudinal development of tricuspid gradient in 227 consecutive patients, 1992-2001. Rheumatology (Oxford) 2005; 44:366.
  37. Chang B, Wigley FM, White B, Wise RA. Scleroderma patients with combined pulmonary hypertension and interstitial lung disease. J Rheumatol 2003; 30:2398.
  38. Rhee RL, Gabler NB, Sangani S, et al. Comparison of Treatment Response in Idiopathic and Connective Tissue Disease-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2015; 192:1111.
  39. Wigley FM, Lima JA, Mayes M, et al. The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 2005; 52:2125.
  40. Rosenman KD, Zhu Z. Pneumoconiosis and associated medical conditions. Am J Ind Med 1995; 27:107.
  41. Tomasini M, Chiappino G. Hemodynamics of pulmonary circulation in asbestosis: study of 16 cases. Am J Ind Med 1981; 2:167.
  42. Scano G, Garcia-Herreros P, Stendardi D, et al. Cardiopulmonary adaptation to exercise in coal miners. Arch Environ Health 1980; 35:360.
  43. Jankowich MD, Rounds SI. Combined pulmonary fibrosis and emphysema syndrome: a review. Chest 2012; 141:222.
  44. Mejía M, Carrillo G, Rojas-Serrano J, et al. Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with severe pulmonary arterial hypertension. Chest 2009; 136:10.
  45. Cottin V, Le Pavec J, Prévot G, et al. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome. Eur Respir J 2010; 35:105.
  46. Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung transplantation. Chest 2002; 122:233.
  47. Handa T, Nagai S, Miki S, et al. Incidence of pulmonary hypertension and its clinical relevance in patients with sarcoidosis. Chest 2006; 129:1246.
  48. Shorr AF, Helman DL, Davies DB, Nathan SD. Pulmonary hypertension in advanced sarcoidosis: epidemiology and clinical characteristics. Eur Respir J 2005; 25:783.
  49. Dobarro D, Schreiber BE, Handler C, et al. Clinical characteristics, haemodynamics and treatment of pulmonary hypertension in sarcoidosis in a single centre, and meta-analysis of the published data. Am J Cardiol 2013; 111:278.
  50. Rapti A, Kouranos V, Gialafos E, et al. Elevated pulmonary arterial systolic pressure in patients with sarcoidosis: prevalence and risk factors. Lung 2013; 191:61.
  51. Alhamad EH, Idrees MM, Alanezi MO, et al. Sarcoidosis-associated pulmonary hypertension: Clinical features and outcomes in Arab patients. Ann Thorac Med 2010; 5:86.
  52. Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and clinical characteristics of pulmonary hypertension complicating pulmonary Langerhans cell histiocytosis. Mayo Clin Proc 2004; 79:1269.
  53. Ismail K, Roberts K, Manning P, et al. OSA and pulmonary hypertension: time for a new look. Chest 2015; 147:847.
  54. Minai OA, Ricaurte B, Kaw R, et al. Frequency and impact of pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am J Cardiol 2009; 104:1300.
  55. Chaouat A, Weitzenblum E, Krieger J, et al. Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest 1996; 109:380.
  56. Kessler R, Chaouat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases. Chest 2001; 120:369.
  57. Weissmann N, Ebert N, Ahrens M, et al. Effects of mitochondrial inhibitors and uncouplers on hypoxic vasoconstriction in rabbit lungs. Am J Respir Cell Mol Biol 2003; 29:721.
  58. Mauban JR, Remillard CV, Yuan JX. Hypoxic pulmonary vasoconstriction: role of ion channels. J Appl Physiol (1985) 2005; 98:415.
  59. Klinger JR. Group III Pulmonary Hypertension: Pulmonary Hypertension Associated with Lung Disease: Epidemiology, Pathophysiology, and Treatments. Cardiol Clin 2016; 34:413.
  60. Eddahibi S, Hanoun N, Lanfumey L, et al. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 2000; 105:1555.
  61. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995; 92:5510.
  62. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med 1980; 93:391.
  63. McQuillan LP, Leung GK, Marsden PA, et al. Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 1994; 267:H1921.
  64. Defouilloy C, Teiger E, Sediame S, et al. Polycythemia impairs vasodilator response to acetylcholine in patients with chronic hypoxemic lung disease. Am J Respir Crit Care Med 1998; 157:1452.
  65. Wang J, Juhaszova M, Rubin LJ, Yuan XJ. Hypoxia inhibits gene expression of voltage-gated K+ channel alpha subunits in pulmonary artery smooth muscle cells. J Clin Invest 1997; 100:2347.
  66. Gelband CH, Gelband H. Ca2+ release from intracellular stores is an initial step in hypoxic pulmonary vasoconstriction of rat pulmonary artery resistance vessels. Circulation 1997; 96:3647.
  67. Post JM, Hume JR, Archer SL, Weir EK. Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction. Am J Physiol 1992; 262:C882.
  68. Simonneau G, Escourrou P, Duroux P, Lockhart A. Inhibition of hypoxic pulmonary vasoconstriction by nifedipine. N Engl J Med 1981; 304:1582.
  69. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328:1732.
  70. Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis? J Anat 2002; 201:335.
  71. MacLean MR. Endothelin-1 and serotonin: mediators of primary and secondary pulmonary hypertension? J Lab Clin Med 1999; 134:105.
  72. Tuder RM, Cool CD, Yeager M, et al. The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 2001; 22:405.
  73. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004; 109:159.
  74. Kirchengast M, Luz M. Endothelin receptor antagonists: clinical realities and future directions. J Cardiovasc Pharmacol 2005; 45:182.
  75. Braun-Moscovici Y, Nahir AM, Balbir-Gurman A. Endothelin and pulmonary arterial hypertension. Semin Arthritis Rheum 2004; 34:442.
  76. Trakada G, Nikolaou E, Pouli A, et al. Endothelin-1 levels in interstitial lung disease patients during sleep. Sleep Breath 2003; 7:111.
  77. Yamakami T, Taguchi O, Gabazza EC, et al. Arterial endothelin-1 level in pulmonary emphysema and interstitial lung disease. Relation with pulmonary hypertension during exercise. Eur Respir J 1997; 10:2055.
  78. Vender RL. Chronic hypoxic pulmonary hypertension. Cell biology to pathophysiology. Chest 1994; 106:236.
  79. Tozzi CA, Poiani GJ, Harangozo AM, et al. Pressure-induced connective tissue synthesis in pulmonary artery segments is dependent on intact endothelium. J Clin Invest 1989; 84:1005.
  80. Weir EK, Tucker A, Reeves JT, et al. The genetic factor influencing pulmonary hypertension in cattle at high altitude. Cardiovasc Res 1974; 8:745.
  81. Nattie EE, Doble EA. Threshold of intermittent hypoxia-induced right ventricular hypertrophy in the rat. Respir Physiol 1984; 56:253.
  82. Klinger JR, Hill NS. Right ventricular dysfunction in chronic obstructive pulmonary disease. Evaluation and management. Chest 1991; 99:715.
  83. Ashutosh K, Mead G, Dunsky M. Early effects of oxygen administration and prognosis in chronic obstructive pulmonary disease and cor pulmonale. Am Rev Respir Dis 1983; 127:399.
  84. Weitzenblum E, Schrijen F, Mohan-Kumar T, et al. Variability of the pulmonary vascular response to acute hypoxia in chronic bronchitis. Chest 1988; 94:772.
  85. Eddahibi S, Chaouat A, Morrell N, et al. Polymorphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease. Circulation 2003; 108:1839.
  86. Joppa P, Petrasova D, Stancak B, Tkacova R. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest 2006; 130:326.
  87. Broekelmann TJ, Limper AH, Colby TV, McDonald JA. Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci U S A 1991; 88:6642.
  88. Morrell NW, Yang X, Upton PD, et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 2001; 104:790.
  89. Koyama S, Sato E, Haniuda M, et al. Decreased level of vascular endothelial growth factor in bronchoalveolar lavage fluid of normal smokers and patients with pulmonary fibrosis. Am J Respir Crit Care Med 2002; 166:382.
  90. Strange C, Highland KB. Pulmonary hypertension in interstitial lung disease. Curr Opin Pulm Med 2005; 11:452.
  91. Mura M, Anraku M, Yun Z, et al. Gene expression profiling in the lungs of patients with pulmonary hypertension associated with pulmonary fibrosis. Chest 2012; 141:661.
  92. Yousem SA. The pulmonary pathologic manifestations of the CREST syndrome. Hum Pathol 1990; 21:467.
  93. Gagermeier J, Dauber J, Yousem S, et al. Abnormal vascular phenotypes in patients with idiopathic pulmonary fibrosis and secondary pulmonary hypertension. Chest 2005; 128:601S.
  94. Toonkel RL, Borczuk AC, Pearson GD, et al. Sarcoidosis-associated fibrosing mediastinitis with resultant pulmonary hypertension: a case report and review of the literature. Respiration 2010; 79:341.
  95. Hamilton-Craig CR, Slaughter R, McNeil K, et al. Improvement after angioplasty and stenting of pulmonary arteries due to sarcoid mediastinal fibrosis. Heart Lung Circ 2009; 18:222.
  96. Takemura T, Matsui Y, Saiki S, Mikami R. Pulmonary vascular involvement in sarcoidosis: a report of 40 autopsy cases. Hum Pathol 1992; 23:1216.
  97. Rodman DM, Lindenfeld J. Successful treatment of sarcoidosis-associated pulmonary hypertension with corticosteroids. Chest 1990; 97:500.
  98. Gluskowski J, Hawrylkiewicz I, Zych D, Zieliński J. Effects of corticosteroid treatment on pulmonary haemodynamics in patients with sarcoidosis. Eur Respir J 1990; 3:403.
  99. Hoffstein V, Ranganathan N, Mullen JB. Sarcoidosis simulating pulmonary veno-occlusive disease. Am Rev Respir Dis 1986; 134:809.
  100. Baughman RP, Engel PJ, Taylor L, Lower EE. Survival in sarcoidosis-associated pulmonary hypertension: the importance of hemodynamic evaluation. Chest 2010; 138:1078.
  101. Angomachalelis N, Hourzamanis A, Vamvalis C, Gavrielides A. Doppler echocardiographic evaluation of left ventricular diastolic function in patients with systemic sarcoidosis. Postgrad Med J 1992; 68 Suppl 1:S52.
  102. Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary hypertension in histiocytosis X. Am J Respir Crit Care Med 2000; 161:216.
  103. Harari S, Brenot F, Barberis M, Simmoneau G. Advanced pulmonary histiocytosis X is associated with severe pulmonary hypertension. Chest 1997; 111:1142.
  104. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009; 119:2250.
  105. Bradley TD, Rutherford R, Grossman RF, et al. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985; 131:835.
  106. Hoeper MM, Barberà JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol 2009; 54:S85.
  107. Corson N, Armato SG 3rd, Labby ZE, et al. CT-based pulmonary artery measurements for the assessment of pulmonary hypertension. Acad Radiol 2014; 21:523.
  108. Shlobin OA, Brown AW, Nathan SD. Pulmonary Hypertension in Diffuse Parenchymal Lung Diseases. Chest 2017; 151:204.
  109. Benza R, Biederman R, Murali S, Gupta H. Role of cardiac magnetic resonance imaging in the management of patients with pulmonary arterial hypertension. J Am Coll Cardiol 2008; 52:1683.