In the past, a distinction was made between primary (idiopathic) pulmonary hypertension of unknown cause and a secondary form resulting from underlying diseases. However, this concept was dropped at the WHO 3rd Symposium on Pulmonary Hypertension in 2003 in Venice as a result of new scientific findings about the pathophysiology, molecular biology and clinical symptoms. The “Venice classification” distinguishes between 5 major groups, with primary PH (PPH) today being described as idiopathic PAH (iPAH). During the 4th World Symposium on PH, in 2008 in Dana Point, California, an international conference of experts decided to retain the general philosophy and organisation of this “Venice Classification” (Table 1). However, on the basis of recent publications, slight modifications were made, affecting Group 1 of the Venice Classification, pulmonary arterial hypertension, in particular.
An accurate diagnosis assigning patients affected to one of the PH groups is important because of the different therapy strategies. While patients assigned to Group 1 of the Dana Point Classification are given specific vasodilatory therapies, the main focus of treatment in Groups 2, 3 and 5 is geared to treating the underlying cardiac or pulmonary disease. The differential diagnosis of chronic, thromboembolic pulmonary hypertension (CTEPH) (Group 4 of the Dana Point Classification) is of particular importance because this is the only form of pulmonary hypertension that is curable by means of pulmonary endarterectomy (PEA) and lifetime oral anticoagulation.
1. Pulmonary arterial hypertension
1.1. Idiopathic pulmonary arterial hypertension (iPAH)
iPAH is a sporadic disease with neither a family predisposition nor definite risk factors. However, mutations were found in the BMPR II gene in between 11 and 40% of supposedly idiopathic forms with no family background, so that a clear distinction between idiopathic and family BMPR II mutations is problematic and would appear to be artificial [6].
1.2. Heritable pulmonary arterial hypertension
A hereditary disease is involved in all patients with BMPR II mutations, regardless of whether the mutation is occurring for the first time (de novo mutation) or has already been present in family members. For this reason, the new classification should no longer refer to “familial PAH” but to a “heritable” form. Genetic testing as a result of the new category of “heritable PAH” is, however, not generally necessary for all patients with iPAH or familial cases of PAH. The gene has very low penetration so that manifestation of the disease occurs in only 20% of all carriers of the mutation. If genetic testing is desired, this should be undertaken only after a detailed discussion of the risks, possibilities and consequences of this testing.
1.3. PAH associated with drugs and toxins
An epidemic occurrence of PAH was seen in Austria, Germany and Switzerland in the 1960s in connection with patients taking aminorex. Thirty years later, fenfluramine and dexfenfluramine, two appetite suppressants authorised in the USA, were taken off the market as a result of increased numbers of cases of PAH. Chronic cocaine or amphetamine abuse also increases the risk of developing PAH. According to a recent case-control study, selective serotonin receptor inhibitors taken by pregnant women increase the risk of persistent PH in the neonate (1.5 in the Dana Point classification) [7].
1.4. Pulmonary arterial hypertension secondary to diseases such as:
1.4.1. Connective tissue diseases
Pulmonary hypertension may develop as a complication of various connective tissue diseases. Patients with progressive systemic sclerosis are particularly frequently affected, prospective studies having demonstrated a prevalence of about 12% [8]. It is interesting to note that PAH is not the only form of PH found with systemic sclerosis. Interstitial lung disease (PH with interstitial lung disease, 3.2.) and diastolic dysfunction (2.2. of the Dana Point classification) in the context of systemic sclerosis may also result in increased pressure in the small circulatory system [9]. If pulmonary hypertension is suspected, these patients should therefore be assessed precisely so as to allow for accurate classification and hence the relevant treatment. Several studies have shown that the prognosis for PAH secondary to systemic sclerosis is less good, despite modern treatment, than in patients with iPAH.
1.4.2. HIV infection
In cases of HIV infection with unclear dyspnoea on exertion, the possibility of pulmonary hypertension should always be considered after ruling out typical secondary disorders. The incidence of pulmonary hypertension in the HIV population is some 1,000 times higher than in the general population (approximately 0.5% of all patients infected with HIV develop PAH). Here, again, the molecular mechanisms that lead to the disease have not been clarified but there appears to be an unequivocal correlation between the number of CD4-positive lymphocytes and disease activity. Because neither the virus itself nor viral DNA has been found in endothelial cells of the pulmonary vessels, secondary messengers, such as cytokines, growth factors, endothelin and viral proteins have been discussed.
1.4.3. Portal hypertension (= portopulmonary hypertension = PPHT)
Between 2 and 6% of all patients with portal hypertension develop PAH, and far greater numbers must be assumed for patients with advanced cirrhosis of the liver and ascites [10]. The underlying pathomechanisms are speculative. It is possible that increased pulmonary blood flow and microthrombi are involved. The severity of the liver disease does not correlate with the prevalence of PPHT, whereas female gender and autoimmune diseases are linked to increased prevalence [11].
1.4.4. Congenital heart diseases
Between 5 and 10% of all patients with congenital shunts develop PAH. Morbidity and mortality in these patients depend on the heart defect involved. Increased pressure / volume load and shear stress on pulmonary endothelial cells are potential mechanisms, as is a genetic susceptibility. A shunt reversal (Eisenmenger syndrome) may develop as a result of the increased pulmonary vascular resistance.
1.4.5. Schistosomiasis
One major change in the new classification involves PH secondary to schistosomiasis. This form was previously considered one of the thromboembolic and/or embolic diseases based on an assumption of the pulmonary arteries being obstructed by Schistosoma eggs. However, recent publications show that both the clinical symptoms and the histopathology (plexiform lesions) exhibit major similarities to iPAH. Local inflammation triggered by parasitic antigens is being discussed as the pathomechanism. Migration of the parasites causes portopulmonary hypertension, a common complication of the disease that further encourages the development of pulmonary hypertension [12]. Over 200 million people globally are infected with schistosomiasis, about 1% of the chronically ill patients developing PH. PAH secondary to schistosomiasis is thus probably the most common form of PH, but clinical trials rarely include this group. Unfortunately, those affected seldom have access to specific treatments.
1.4.6. Chronic haemolytic anaemia
PAH may occur as a complication of chronic hereditary and acquired haemolytic anaemia, including sickle cell anaemia, thalassaemia, hereditary spherocytosis, acquired spherocytosis and microangiopathic haemolytic anaemia. The pathomechanism under discussion is increased NO consumption by free haemoglobin but chronic inflammatory processes and microthromboses are probably also involved in the development of the disease.
1.5. Persistent pulmonary hypertension of the newborn
Absent or delayed postnatal adaptation of the pulmonary vascular system causes the development of PPHN. PPHN has an incidence of 0.43 to 6.8 cases per 1,000 live births and has a mortality rate of between 10 and 20%. In the event of response to therapy, PPHN has a favourable prognosis and generally results in complete recovery.
1. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary haemangiomatosis (PCH)
These very rare diseases have been classed in PH Group I since the Venice Classification (2003). Previously they were assigned to Group II, pulmonary venous hypertension. The initial categorisation in Group II was made on the basis of detection of fibrous intimal lesions in the region of the pulmonary venous vascular bed as an indication of pulmonary occlusive venopathy. But, in addition to the venous intimal fibrosis, PVOD also involves capillary and arterial damage to the pulmonary vasculature. In clinical terms, patients with PVOD/PCH often present with very similar symptoms to those of patients with iPAH. “Drumstick fingers” and bilateral basal crackles on auscultation of the lungs may be indications of the presence of PVOD. The detection, in high-resolution computed tomography of the lung, of accentuated septal lines, mediastinal adenopathy and ground-glass opacity of the parenchyma of the lung, particularly in a centrilobular position, should arouse suspicion of the existence of PVOD in cases of PH of unclear origin. Aggressive progress with poor therapeutic response is typical of these forms of the disease. Administering prostacyclins may cause potentially fatal pulmonary oedema.
2. Pulmonary hypertension secondary to left heart diseases
PH with left heart disease is one of the most important differential diagnoses for PAH. In contrast to PAH, the increased pulmonary pressure is not the result of pathology of the precapillary pulmonary circulation but develops as a result of left atrial or left ventricular pressure increase. Pulmonary vascular resistance is normal or only slightly increased (<3.0 Wood units) and there is no gradient between mean PAP and wedge pressure (trans-pulmonary gradient <12 mmHg). A number of valvular and/or myocardial diseases, such as mitral and aortic valve pathologies or cardiomyopathies, for example, may be responsible. The new classification distinguishes between 3 sub-groups (systolic and diastolic left ventricular dysfunction and left heart valve diseases).
3. Pulmonary hypertension secondary to lung diseases and/or hypoxaemia
Patients with chronic lung diseases and/or hypoxaemia may develop increased pulmonary vascular resistance as a result of hypoxic vasoconstriction of the pulmonary arteries. The mean pulmonary arterial pressure is usually only slightly raised (mPAP <35 mmHg). In the case of higher pressure values and only minor damage to the lung parenchyma, reference is made again here to “out-of-proportion PH”. The prevalence of PH with lung diseases is unclear. A retrospective study diagnosed PH on right heart catheterisation in only 1% of just under 1,000 patients with COPD [13]. The survival of the patients is determined not by the pulmonary vessel disease but by the severity of the lung disease.
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
Chronic thromboembolic pulmonary hypertension develops as a reaction to single or recurrent pulmonary embolisms if thrombi lead to fibrotic remodelling processes in the vascular walls and obstruction of the pulmonary blood vessels. Any resulting increase in pulmonary vessel resistance causes chronic right heart stress. It is estimated that up to 4% of all patients with acute pulmonary embolism develop CTEPH [14]. An early pulmonary embolism, young age, major perfusion defect and idiopathic presentation are linked to an increased probability of developing CTEPH in this context. The true incidence of CTEPH might even be higher since no history of a thromboembolic event can be ascertained in one third of those affected [15]. Factors linked to an increased risk of developing CTEPH are status post-splenectomy, ventriculo-atrial (VA) shunt for the treatment of hydrocephalus, osteomyelitis, chronic inflammatory bowel diseases, malignancies and thyroid replacement therapy [16]. Antiphospholipid antibodies were diagnosed in 10 to 20% of all patients and increased plasma factor VIII in 25% [17].
A positive segmental ventilation/perfusion scan is diagnostic for CTEPH. Computed tomography and pulmonary angiography can be used to determine the anatomical position of the blood clots within the pulmonary vascular tree, which is an essential criterion for operability.
The treatment of choice is surgical endarterectomy of the pulmonary obstructions, which results in a functional cure for 80 per cent of patients. The surgical risk depends not only on the experience of the surgical team but also on the selection of patients. Thus, patients with no CTEPH risk disease have a surgical mortality rate of about 4%; patients with splenectomy, VA shunt, osteomyelitis or chronic inflammatory bowel disease, on the other hand, have a 20% of dying during surgery [18].
In inoperable cases or cases of persistent PAH, it may be possible to improve symptoms and long-term survival with drug therapy. Lifetime oral anticoagulation is indicated for patients with CTEPH even after successful surgery.
5. Pulmonary hypertension with other diseases
This category includes diseases that may cause pulmonary hypertension as a result of inflammatory processes or mechanical obstruction (haematological diseases, sarcoidosis, storage diseases, tumours, etc.). Treatment is restricted to treatment of the underlying disease.