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Classification of PAH

Pulmonary arterial hypertension (PAH) represents Group 1 within the Pulmonary Hypertension World Health Organisation (WHO) clinical classification system (Dana Point 2008) and is one of five such groups. The groups are divided based on aetiology.1

The table below shows the classifications of pulmonary hypertension:

Group 1.

Pulmonary arterial hypertension (PAH)

 
  • Idiopathic (IPAH)
  • Heritable (HPAH)
    • Bone morphogenetic protein receptor type 2 (BMPR2)
    • Activin receptor-like kinase 1 gene (ALK1), endoglin (with or without haemorrhagic telangiectasia)
    • Unknown
  • Drug- and toxin-induced
  • Associated with (APAH):
    • Connective tissue diseases
    • Human immunodeficiency virus (HIV) infection
    • Portal hypertension
    • Congenital heart disease (CHD)
    • Schistosomiasis
    • Chronic haemolytic anaemia
  • Persistent pulmonary hypertension of the newborn (PPHN)

Group 1'.

Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary haemangiomatosis (PCH)

Group 2.

Pulmonary hypertension due to left heart diseases

  • Systolic dysfunction
  • Diastolic dysfunction
  • Valvular disease

Group 3.

Pulmonary hypertension due to lung diseases and/or hypoxemia

  • Chronic obstructive pulmonary disease (COPD)
  • Interstitial lung disease (ILD)
  • Other pulmonary diseases with mixed restrictive and obstructive pattern
  • Sleep-disordered breathing
  • Alveolar hypoventilation disorders
  • Chronic exposure to high altitude
  • Developmental abnormalities

Group 4.

Chronic thromboembolic pulmonary hypertension (CTEPH)

Group 5.

PH with unclear multifactorial mechanisms

 

One of the more common forms of PAH is idiopathic PAH (IPAH), which corresponds to sporadic disease in which there is neither a family history of PAH nor an identified risk factor.1 Heritable PAH (HPAH) accounts for at least 6% of cases of PAH2 and mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in the majority of cases.3

PAH is also a rare side effect of certain anorexigenic agents, such as fenfluramine.1,4 However, the incidence of drug-induced PAH related to fenfluramine is decreasing as these agents are no longer available.

PAH can also be associated with a number of other conditions (associated PAH, APAH), which together account for most other cases. These conditions include:1

Connective tissue diseases

  • including systemic sclerosis (scleroderma, SSc) and systemic lupus erythematosus (SLE)

HIV

Portal hypertension

Congenital heart disease

  • Eisenmenger's syndrome
  • PAH associated with systemic-to-pulmonary shunts
  • PAH with small defects
  • PAH after corrective cardiac surgery

Schistosomiasis

Chronic haemolytic anaemia (e.g. sickle cell disease)

PAH associated with connective tissue disease

  • Connective tissue diseases are systemic autoimmune diseases that commonly cause the formation of scar tissue (fibrosis) within the connective tissue that surrounds, supports, and protects organs, including vascular tissue. PAH is a well-recognised complication of connective tissue diseases, such as systemic sclerosis (SSc) and SLE
  • The prevalence of PAH in patients with connective tissue diseases has been well established only for patients with SSc.1 In recent studies the prevalence of right heart catheterisation-confirmed PAH in patients with SSc was between 7% and 12%, 5,6 and pulmonary complications, such as interstitial lung disease and PAH, are now the leading causes of death in these patients 7
  • Patients with PAH associated with systemic sclerosis have a particularly poor prognosis compared to those patients with systemic sclerosis without PAH8, and markedly worse outcome that that of patients with IPAH1
  • Patients with SSc associated PAH have been shown to have the highest brain-type natriuretic peptide (BNP) levels, lowest diffusing capacity of carbon monoxide (DLCO), and poorest survival when compared to all other CTD associated PAH subgroups9

PAH associated with HIV infection

  • PAH is a rare but relatively well-documented complication of HIV infection (estimated prevalence in patients with HIV being 0.5%)10
  • Following the advent of highly active anti-retroviral therapy (HAART) and markedly improved survival rates in HIV patients, PAH and other non-infectious manifestations are increasingly responsible for HIV-associated morbidity and poor prognosis 11,12
  • Although the reasons for the development of PAH in patients with HIV infection are not yet fully understood, the HIV-1 envelope glycoprotein gp120 may stimulate the production of endothelin, a vasoactive mediator associated with the development of PAH, by macrophages 13
  • HIV-associated PAH shows a similar clinical picture to idiopathic PAH and seems to be independent of the degree of immunosuppression 4
  • Although rarely seen in IPAH, normalisation of pulmonary vascular haemodynamics has been seen in a substantial number of patients with HIV-associated PAH following therapy indicated for PAH1

PAH associated with portal hypertension

  • PAH is a well-recognised complication of chronic liver diseases that develop as a result of portal hypertension. PAH associated with portal hypertension (also called portopulmonary hypertension) represents around 10% of the PAH population 14,15

PAH associated with congenital heart disease

  • Congenital heart disease (CHD) is relatively common and affects around 1% of the population
  • Approximately 5-10% of adults with CHD will go on to develop PAH 16
  • The most severe form is Eisenmenger's syndrome, which is associated with the complete or partial reversal of an initial left-to-right shunt to a right-to-left shunt, causing cyanosis (a blue colouration of the skin due to low oxygen in the blood) and limited exercise capacity 1,17
  • Patients with PAH associated with CHD also include those with mild to moderate systemic-to-pulmonary shunts with no cyanosis at rest, patients with small defects, and those with residual PAH following corrective cardiac surgery 1,4

PAH associated with schistosomiasis

  • Schistosomiasis is a parasitic disease caused by trematode flatworms of the genus Schistosoma
  • Patients with schistosomiasis and PAH can have the required specific clinical and pathological characteristics to be included in the APAH group. The prevalence of PAH in patients with schistosomiasis is around 4.6%18

PAH associated with sickle cell disease

  • The prevalence of PAH in patients with sickle cell disease is around 2-3.75%19,20

 

References

  1. Simonneau G, Robbins I, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-S54.
  2. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 2000;26:81-4.
  3. Morrell NW. Genetics of pulmonary arterial hypertension: do the molecular findings have translational value? F1000 Biol Rep 2010;2.pii:22.
  4. Galiè N, Hoeper M, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2009;30:2493-537.
  5. Hachulla E, Gressin V, Guillevin L et al. Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 2005;52:3792-800.
  6. Mukerjee D, St George D, Coleiro B, et al. Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 2003;62:1088–93.
  7. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis 2007;66:940-4.
  8. Hachulla E, Carpentier P, Gressin V, et al. Risk factors for death and the 3-year survival of patients with systemic sclerosis: the French ItinérAIR-Sclérodermie study. Rheumatology (Oxford). 2009 Mar;48(3):304–8.
  9. Chung L, Liu J, Parsons L, et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest 2010;138:1383–94.
  10. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008;177:108–13.
  11. Sitbon O. HIV-related pulmonary arterial hypertension: clinical presentation and management. AIDS 2008;22 Suppl 3:S55–62.
  12. Kanmogne GD. Noninfectious pulmonary complications of HIV/AIDS. Curr Opin Pulm Med 2005;11:208–12.
  13. Sitbon O, Gressin V, Speich R, et al. Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;170:1212–7.
  14. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023–30.
  15. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010;137:376–87.
  16. Diller GP, Gatzoulis MA. Pulmonary vascular disease in adults with congenital heart disease. Circulation 2007;115:1039–50.
  17. Diller GP, Dimopoulos K, Okonko D, et al. Model of chronic adaptation: right ventricular function in Eisenmenger syndrome. European Heart Journal Supplements 2007;9(Suppl H):H54–H60.
  18. Lapa M, Dias B, Jardim C, et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 2009;119:1518–23.
  19. Machado RF, Gladw in MT. Pulmonary hypertension in hemolytic disorders: pulmonary vascular disease: the global perspective. Chest 2010;137:30S–38S.
  20. Fonseca GH, Souza R, Salemi VM, et al. Pulmonary hypertension diagnosed by right heart catheterization in sickle cell disease. Eur Respir J 2011 Sep 8. [Epub ahead of print].