Classification of PAH

Pulmonary arterial hypertension (PAH) represents Group 1 within the Pulmonary Hypertension (PH) WHO clinical classification system (Venice 2003 revision) and is one of five such groups. The groups are divided based on aetiology.¹

Idiopathic Pulmonary Arterial Hypertension (PAH) (IPAH), which by definition has no identifiable underlying cause, is one of the more common types of Pulmonary Arterial Hypertension (PAH). Familial PAH (FPAH) accounts for at least 6% of cases of IPAH and mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in the majority of cases of FPAH.^2,3

Pulmonary Arterial Hypertension (PAH) can also be associated with a number of conditions (Associated Pulmonary Arterial Hypertension - APAH), which together account for most other cases of Pulmonary Arterial Hypertension (PAH).  These conditions include;

Pulmonary Arterial Hypertension (PAH) is also a rare side effect of certain anorexigenic agents, such as fenfluramine and dexfenfluramine. However, the incidence of drug-induced Pulmonary Arterial Hypertension (PAH) is decreasing as these agents are no longer available.

1. Pulmonary Arterial Hypertension (PAH) associated with connective tissue disease
Pulmonary Arterial Hypertension (PAH) is a well-recognised complication of connective tissue diseases such as systemic sclerosis and SLE and in affected patients may also occur in association with Interstitial lung disease. The prevalence of Pulmonary Arterial Hypertension (PAH) in patients with systemic sclerosis has been reported to be up to 16%⁴ and in systemic sclerosis patients, pulmonary complications, such as interstitial lung disease and Pulmonary Arterial Hypertension (PAH), are now the leading causes of death. Patients with Pulmonary Arterial Hypertension (PAH) associated with systemic sclerosis have a particularly poor prognosis compared to those with systemic sclerosis without Pulmonary Arterial Hypertension (PAH).⁵

2. Pulmonary Arterial Hypertension (PAH) associated with congenital heart disease
Congenital heart disease is relatively common, affecting around 1% of the population. Within this population 15% will go on to develop Pulmonary Arterial Hypertension (PAH).⁶ As determined by the level of pulmonary vascular resistance, the most severe form of Pulmonary Arterial Hypertension (PAH) is Eisenmenger's Physiology, which is associated with the reversal of an initial left to right shunt causing Cyanosis and limited exercise capacity.⁷ 

3. Pulmonary Arterial Hypertension (PAH) associated with HIV infection
Pulmonary Arterial Hypertension (PAH) is a rare (estimated prevalence in patients with HIV: 0.5%)⁸ but relatively well-documented complication of HIV infection. With the advent of highly active anti-retroviral therapy (HAART) and markedly improved survival, Pulmonary Arterial Hypertension (PAH) and other non-infectious manifestations of HIV infection are increasingly responsible for HIV-associated morbidity and poor prognosis. In patients with HIV, the HIV-1 envelope glycoprotein GP120 may stimulate the production of endothelin by macrophages.⁹ HIV-associated Pulmonary Arterial Hypertension (PAH) shows a similar clinical picture to IPAH and seems to be independent of the degree of immunosuppression.

4. Pulmonary Arterial Hypertension (PAH) associated sickle cell disease
The prevalence of Pulmonary Arterial Hypertension (PAH) in patients with sickle cell disease is 20%-40%.¹⁰

References
1. Simonneau G, Galiè N, Rubin LJ et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:Suppl S: 5S−12S
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(1):81-4.
3. Deng Z, Morse JH, Slager SL et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000 ;67(3):737-44
4. 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(1 Suppl): 14S−34S.
5. Koh ET, Lee P, Gladman DD, Abu-Shakra M. Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 1996;35(10):989-993
6. Beghetti M. Pulmonary arterial hypertension related to congenital heart disease. Elsevier 2006.
7. Diller GP, Dimopoulos K, Okonko D etal. Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication. Circulation 2005; 112(6): 828-35.
8. Sitbon et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. AJRCCM 2008; 177:108-113
9. 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(11): 1212-7.
10. Lin EE, Rodgers GP, Gladwin MT. Hemolytic anemia-associated pulmonary hypertension in sickle cell disease. Curr Hematol Rep. 2005; 4(2):117-25