What are the causes of pulmonary hypertension and how to assess it?

Causes and Assessment of Pulmonary Hypertension

Definition and Diagnostic Threshold

Pulmonary hypertension is defined as a mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest measured by right heart catheterization, which remains the gold standard for diagnosis. 1, 2 More recent guidelines have proposed lowering this threshold to >20 mmHg, though the 25 mmHg cutoff remains widely referenced in clinical practice 1, 3.

Clinical Classification: Five Major Groups

The causes of pulmonary hypertension are organized into five distinct clinical groups based on etiology, pathophysiology, and treatment approaches 1, 2, 4:

Group 1: Pulmonary Arterial Hypertension (PAH)

This is characterized by pre-capillary PH (mPAP ≥25 mmHg, pulmonary wedge pressure ≤15 mmHg, and pulmonary vascular resistance >3 Wood units) 1, 2. Specific causes include:

• Idiopathic PAH (approximately 50% of PAH cases) 1
• Heritable PAH (BMPR2 mutations and other genetic variants) 1
• Drug and toxin-induced (mitomycin-C, carfilzomib, methamphetamines, cocaine) 1, 3
• Associated conditions:
  • Connective tissue diseases (especially scleroderma) 1
  • HIV infection 1
  • Portal hypertension (portopulmonary hypertension) 1
  • Congenital heart disease 1
  • Schistosomiasis 1

Prevalence is 15-150 cases per million adults, making this a rare condition 1.

Group 2: PH Due to Left Heart Disease

This is the most common form of PH and includes 1, 4:

• Left ventricular systolic dysfunction 1
• Left ventricular diastolic dysfunction 1
• Valvular disease (present in up to 65% of symptomatic aortic stenosis patients) 1
• Congenital/acquired left heart inflow/outflow obstruction 1

Group 3: PH Due to Lung Diseases and/or Hypoxia

Common pulmonary causes include 1:

• Chronic obstructive pulmonary disease (COPD) 1
• Interstitial lung disease 1
• Combined pulmonary fibrosis and emphysema 1
• Sleep-disordered breathing 1
• Obesity hypoventilation syndrome (30-88% develop PH) 1
• Alveolar hypoventilation disorders 1

Group 4: Chronic Thromboembolic PH (CTEPH)

Results from persistent pulmonary artery obstruction following pulmonary embolism 1, 4, 5. This is a rare but potentially surgically curable form of PH.

Group 5: PH with Unclear/Multifactorial Mechanisms

Includes 1:

• Hematological disorders (chronic hemolytic anemia, myeloproliferative disorders) 1
• Systemic disorders (sarcoidosis, pulmonary histiocytosis) 1
• Metabolic disorders (glycogen storage disease, thyroid disorders) 1

Comprehensive Assessment Algorithm

Step 1: Clinical Evaluation

Screen for specific risk factors and associated conditions 1:

• Family history of PAH or sudden cardiac death 1
• Drug/toxin exposure (appetite suppressants, chemotherapy agents, illicit drugs) 1
• Connective tissue disease symptoms (Raynaud's phenomenon, digital ulceration, sclerodactyly, telangiectasia) 1
• HIV status 1
• Liver disease (spider nevi, palmar erythema, testicular atrophy suggesting portal hypertension) 1
• Thromboembolic history 1
• Congenital heart disease (childhood murmurs, cyanosis, clubbing) 1

Key symptoms (though nonspecific) include dyspnea on exertion, fatigue, weakness, angina, syncope, and dry cough 1. Physical examination findings include left parasternal lift, accentuated P2 heart sound, elevated jugular venous pressure, hepatomegaly, ascites, and peripheral edema 1.

Step 2: Initial Diagnostic Testing

Laboratory studies 1:

• Complete blood count, comprehensive metabolic panel 1
• Thyroid function tests (thyroid disorders associated with PH) 1
• NT-proBNP (elevated in right ventricular dysfunction) 1
• Hepatitis serologies and HIV testing 1
• Autoimmune panel if screening ANA positive (anti-Scl-70, anti-centromere, anti-RNP, anti-SSA, anti-SSB) 1
• Hypercoagulable panel when indicated 1

Electrocardiogram: Look for right axis deviation, RV hypertrophy, RV strain pattern, right bundle branch block, QTc prolongation 1. While RV hypertrophy has only 55% sensitivity and 70% specificity, RV strain is more sensitive for significant PH 1.

Chest radiography: May show enlarged pulmonary arteries, but can be normal in early disease 1.

Step 3: Pulmonary Function Testing and Arterial Blood Gas

Complete pulmonary function tests with DLCO are essential 1. Key indicators of PH in lung disease patients include:

• Disproportionately low DLCO relative to spirometry 1
• Low pCO2 1
• Symptoms more severe than expected based on PFT results 1

Step 4: Echocardiography

Transthoracic echocardiography is the primary screening tool 1, 5. An RVSP >45 mmHg should trigger comprehensive PH workup 1.

Critical caveat: Echocardiography accuracy is significantly reduced in patients with advanced lung disease 1. The test estimates probability of PH but cannot definitively diagnose it 5.

Echocardiography should assess 1:

• Estimated pulmonary artery systolic pressure
• Right ventricular size and function
• Left ventricular function and valvular disease
• Bubble study if shunt suspected 1

Step 5: Ventilation-Perfusion (V/Q) Scan

All patients with suspected or confirmed PH without established left heart or lung disease MUST undergo V/Q scanning to exclude CTEPH 5. V/Q scan is more sensitive than CT angiography for detecting chronic thromboembolic disease 1, 5. If CTEPH remains suspected despite negative V/Q, proceed to pulmonary angiography 1.

Step 6: Chest CT Imaging

High-resolution CT or CT angiography evaluates 1:

• Parenchymal lung disease (essential since some patients with substantial disease have pseudo-normalized PFTs) 1
• Pulmonary artery enlargement
• Thromboembolic disease (though V/Q remains superior for CTEPH) 1

Step 7: Right Heart Catheterization

Right heart catheterization is mandatory for definitive diagnosis and must be performed before initiating PAH-specific therapy 1, 5. This should only be done after completing the full diagnostic workup 1.

Hemodynamic criteria 1, 2:

• Pre-capillary PH: mPAP ≥25 mmHg, PAWP ≤15 mmHg, PVR >3 Wood units (Groups 1,3,4,5)
• Isolated post-capillary PH: mPAP ≥25 mmHg, PAWP >15 mmHg, PVR ≤3 Wood units (Group 2)
• Combined pre- and post-capillary PH: mPAP ≥25 mmHg, PAWP >15 mmHg, PVR >3 Wood units (Group 2)

Critical consideration: Perform invasive assessment on optimized volume status 1.

Step 8: Additional Testing for Specific Scenarios

• Sleep study if obesity hypoventilation syndrome or obstructive sleep apnea suspected 1
• Genetic testing for heritable PAH if family history or young age at presentation 1
• Vasoreactivity testing during right heart catheterization for idiopathic, heritable, or drug-induced PAH to identify calcium channel blocker responders 1

Referral to Expert Centers

Patients requiring specialist referral 1:

• All confirmed PAH (Group 1) patients 5
• All CTEPH (Group 4) patients 5
• PH with severe pre-capillary component (high diastolic pressure gradient and/or high PVR) in left heart disease 1
• NYHA functional class ≥III with intermediate to high-risk surgery planned 1
• Clinical or echocardiographic signs of severe PH and/or severe RV dysfunction 1
• Patients with mild lung disease but severe PH (possible dual pathology) 1

Common pitfall: Delaying referral until after attempting empiric therapy. PAH-specific medications should never be initiated without right heart catheterization confirmation and expert center involvement 1.