An overview of the clinical classification of pulmonary hypertension (PH), with associated conditions and important investigations to consider

Group 1 Pulmonary arterial hypertension (PAH)
1.1 Idiopathic PAH
  1.1.1 Non-responders at vasoreactivity testingImportant to exclude alternative causes of PAH before assigning this diagnosis
  1.1.2 Acute responders at vasoreactivity testingDiagnosed during vasoreactivity testing at RHC:
• mPAP reduction of ≥10 mmHg (to <40 mmHg)
• Cardiac output is increased/maintained
1.2 Heritable PAHEnquire regarding family history of PAH
• Offer genetic counselling and consider gene panel
e.g. gene mutations in BMPR2, EIF2AK4, TBX4, ACVRL1, ENG [6]
1.3 Associated with drugs and toxinsEnquire regarding specific drug and toxin exposure at home and at work (e.g. aminorex, fenfluramine, methamphetamines)
1.4 Associated with:
  1.4.1 Connective tissue disease (CTD)CTDs associated with PAH include SSc-PAH, SLE, mixed CTD, rheumatoid arthritis, dermatomyositis, Sjögren syndrome [3]
Considerations for subjects with SSc and suspected PAH:
• Ask regarding symptoms of Raynaud's, GORD, etc.
• Examine for features such as digital ulcers, sclerodactyly, calcinosis, telangiectasia, microstomia; consider nailfold capillaroscopy
• Request serum ANA and CTD panel
• Exclude comorbid LHD, and ILD in suspected SSc-PAH
  1.4.2 HIV infectionAssess for infection with HIV
  1.4.3 Portal hypertensionPortal hypertension with or without cirrhosis is associated with PAH
Investigate with:
• Liver screen including autoimmune serology, viral hepatitis screen and HIV
• Doppler ultrasound of liver and portal system
• A hepatic venous pressure gradient >5 mmHg during invasive catheterisation (may be normal in subjects with extrahepatic portal hypertension)
  1.4.4 Congenital heart diseaseEisenmenger syndrome; PAH associated with prevalent systemic-to-pulmonary shunts, PAH-with small/coincidental defects, PAH after defect correction [3, 7]
Consider investigation with:
• Doppler and contrast echocardiography
• Cardiac MRI
• Stepwise assessment of oxygen saturations at RHC if left-to-right shunt suspected
  1.4.5 SchistosomiasisPresent in 5% of patients with hepatosplenic schistosomiasis infection
Consider investigation with:
• Confirm infection, e.g. through the detection of parasite eggs in the stool or urine
• Doppler ultrasound of liver and portal system to assess for portal hypertension
1.5 PAH with features of venous/capillary (PVOD/PCH) involvementConsider family history, medical history (e.g. prior chemotherapy), occupational exposures (e.g. organic solvents)
Consider genetic screening for EIF2AK4
Suspect if:
• Often accompanied by severe hypoxia and marked reductions in DLCO (<50%)
• Treatment with PAH specific therapy may be complicated by pulmonary oedema
• CT thorax: septal lines, centrilobular ground-glass opacities, mediastinal adenopathy
1.6 Persistent PH of the newbornFailed circulatory adaptation at birth with sustained elevation in PVR; diagnosed in neonates and often resolves
Group 2 PH associated with left heart disease
Consider the pre-test probability of LHD and ensure adequate imaging of left heart, such as echocardiography, cardiac MRI. If suspected, consider fluid challenge at RHC [2, 8].
2.1 Heart failure:
  2.1.1 With preserved ejection fraction
  2.1.2 With reduced or mildly reduced ejection fraction
2.2 Valvular heart disease
2.3 Congenital/acquired cardiovascular conditions leading to post-capillary PH
Group 3 PH associated with lung diseases and/or hypoxia
Investigate with ABG, PFTs, chest imaging such as high-resolution CT thorax, polysomnography.
3.1 Obstructive lung disease or emphysema
3.2 Restrictive lung disease
3.3 Lung disease with mixed restrictive/obstructive pattern
3.4 Hypoventilation syndromes
3.5 Hypoxia without lung disease (e.g. high altitude)
3.6 Developmental lung disorders
Group 4 PH associated with pulmonary artery obstructions
CTPA and Vʹ/Qʹ imaging are important investigations. Consider invasive pulmonary angiogram if Group 4 PH suspected.
4.1 Chronic thromboembolic PH
4.2 Other pulmonary artery obstructions
Group 5 PH with unclear and/or multifactorial mechanisms
Guided by individual history and assessment.
5.1 Haematological disorders
5.2 Systemic disorders
5.3 Metabolic disorders
5.4 Chronic renal failure with or without haemodialysis
5.5 Pulmonary tumour thrombotic microangiopathy
5.6 Fibrosing mediastinitis

RHC: right heart catheterisation; mPAP: mean pulmonary artery pressure; BMPR2: bone morphogenetic protein receptor type 2; EIF2AK4: eukaryotic translation initiation factor 2 alpha kinase 4; TBX4: T-box 4; ACVRL1: activin receptor-like kinase 1 (ALK1); ENG: endoglin; SSc: systemic sclerosis; SLE: systemic lupus erythematosus; GORD: gastro-oesophageal reflux disease; ANA: antinuclear antibody; LHD: left heart disease; ILD: interstitial lung disease; MRI: magnetic resonance imaging; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillary haemangiomatosis; DLCO: diffusion capacity of the lung for carbon monoxide; CT: computed tomography; PVR: pulmonary vascular resistance; ABG: arterial blood gas; PFTs: pulmonary function tests; CTPA: computed tomography pulmonary angiogram; Vʹ/Qʹ: ventilation/perfusion. Reproduced and modified from [2], with permission.