What is the differential diagnosis and treatment approach for pulmonary hypertension?

Differential Diagnosis for Pulmonary Hypertension

Pulmonary hypertension is classified into five distinct groups based on underlying etiology and hemodynamic characteristics, with Group 1 (pulmonary arterial hypertension) and Group 4 (chronic thromboembolic PH) requiring specialized treatment, while Groups 2,3, and 5 primarily require management of the underlying condition. 1, 2

Hemodynamic Definition

Pulmonary hypertension is defined as mean pulmonary arterial pressure ≥25 mmHg at rest on right heart catheterization, though recent guidelines suggest >20 mmHg as the threshold. 1, 3 The hemodynamic profile further distinguishes:

• Pre-capillary PH: PAWP ≤15 mmHg with PVR >3 Wood units (or >2 WU in newer definitions) 1, 3
• Post-capillary PH: PAWP >15 mmHg 1, 3
• Combined pre- and post-capillary PH: PAWP >15 mmHg with PVR >2 WU 3

Clinical Classification: Five Groups

Group 1: Pulmonary Arterial Hypertension (PAH)

This is pre-capillary PH with elevated PVR in the absence of other causes. 1, 2

Subtypes include:

• Idiopathic PAH: No identifiable cause; includes long-term responders to calcium channel blockers as a distinct subgroup 1, 3
• Heritable PAH: BMPR2 mutations and other genetic variants 1, 2
• Drug and toxin-induced: Definite associations include mitomycin-C and carfilzomib (recently added), with likely associations for drugs with similar mechanisms 1, 3
• Associated PAH includes:
  • Connective tissue disease (25% of PAH cases in clinical trials) 1, 4
  • HIV infection 1, 2
  • Portal hypertension 1, 2
  • Congenital heart disease 1, 2
  • Schistosomiasis 1, 2

Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis are distinct entities within Group 1, characterized by EIF2AK4 mutations in heritable forms. 1, 2

Group 2: PH Due to Left Heart Disease

This is the most common form of PH, affecting up to 60% of patients with severe LV systolic dysfunction and up to 70% with heart failure with preserved ejection fraction. 1 It is defined hemodynamically by PAWP >15 mmHg. 2

Causes include:

• Left ventricular systolic dysfunction 1, 2
• Left ventricular diastolic dysfunction 1, 2
• Valvular disease: Nearly 100% of patients with severe symptomatic mitral valve disease and up to 65% with symptomatic aortic stenosis develop PH 1
• Congenital/acquired left heart inflow/outflow tract obstruction 1, 2
• Congenital/acquired pulmonary vein stenosis 1

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

This group is now differentiated based on specific pulmonary diseases rather than functional abnormalities. 3

Causes include:

• Chronic obstructive pulmonary disease 1, 2
• Interstitial lung disease 1, 2
• Mixed restrictive and obstructive patterns 1
• Sleep-disordered breathing 1, 2
• Alveolar hypoventilation disorders 1, 2
• Chronic exposure to high altitude 1, 2
• Developmental lung diseases 1

Group 4: Chronic Thromboembolic PH (CTEPH) and Other Pulmonary Artery Obstructions

CTEPH results from organized thrombi obstructing pulmonary arteries and is the only potentially curable form of PH through pulmonary endarterectomy. 2, 5, 6

Other pulmonary artery obstructions include:

• Angiosarcoma and other intravascular tumors 1, 2
• Arteritis 1, 2
• Congenital pulmonary artery stenoses 1, 2
• Parasites (hydatidosis) 1, 2

Group 5: PH with Unclear and/or Multifactorial Mechanisms

Hematological disorders:

• Chronic hemolytic anemia (including sickle cell disease, affecting ~10% of adults) 1, 7
• Myeloproliferative disorders 1, 7
• Post-splenectomy state 1, 7

Systemic disorders:

• Sarcoidosis (granulomatous infiltration of pulmonary vasculature) 1, 7
• Pulmonary histiocytosis 1, 7
• Lymphangioleiomyomatosis 1, 7
• Neurofibromatosis 1, 7

Metabolic disorders:

• Glycogen storage disease 1, 7
• Gaucher disease 1, 7
• Thyroid disorders 1, 7

Other conditions:

• Pulmonary tumoral thrombotic microangiopathy 1, 7
• Fibrosing mediastinitis 1, 7
• Chronic renal failure (with or without dialysis) 1, 7
• Segmental pulmonary hypertension 1

Diagnostic Approach Algorithm

Step 1: Clinical suspicion based on unexplained dyspnea, exercise intolerance, or signs of right heart strain. 8, 9

Step 2: Initial screening with transthoracic echocardiography to estimate pulmonary artery pressure and assess right ventricular function. 8, 3

Step 3: If PH is suspected, obtain:

• Electrocardiogram (right ventricular hypertrophy, right axis deviation) 8
• Chest radiograph 8
• Pulmonary function tests with DLCO 10, 8
• Ventilation-perfusion scan (to exclude CTEPH) 8, 6
• Complete blood count, liver panel, thyroid function tests 8
• Serum albumin and urinalysis (to identify nephrotic syndrome) 10
• NT-proBNP or BNP (for prognostic value and right ventricular strain assessment) 10

Step 4: Fast-track referral to a PH center if there is high probability of severe pulmonary vascular disease or signs of right heart failure. 3

Step 5: Right heart catheterization is mandatory to confirm PH diagnosis, determine hemodynamic subtype, and guide treatment. 1, 7, 10, 3

Treatment Approach by Group

Group 1 (PAH) Treatment

Ten drugs from five substance classes are available, targeting three dysfunctional endothelial pathways: nitric oxide pathway, endothelin-1 pathway, and prostacyclin pathway. 5, 6

• Low or intermediate risk patients: Initial monotherapy or initial oral combination therapy 6
• High risk patients: Initial combination therapy including intravenous prostacyclin analogues 6
• Inadequate response to triple therapy: Assess for lung transplantation 6

Sildenafil (phosphodiesterase-5 inhibitor) is FDA-approved for WHO Group I PAH to improve exercise ability and delay clinical worsening, particularly when added to background epoprostenol therapy. 4 However, chronic use is not recommended in children due to increased mortality with higher doses. 4

Group 2 Treatment

Treat the underlying left heart disease; PAH-specific therapies are generally not recommended and may be harmful. 5, 6 Consider PAH therapeutics only if there is severe right heart strain despite optimal management of left heart disease. 5

Group 3 Treatment

Treat the underlying lung disease; PAH-specific therapies are not recommended unless severe right heart strain is present. 5, 6

Group 4 (CTEPH) Treatment

Pulmonary endarterectomy is the preferred treatment for eligible patients. 5, 6 For inoperable patients, consider balloon pulmonary angioplasty and/or medical therapy with PAH-specific drugs. 6 Anticoagulation is essential. 10

Group 5 Treatment

Disease-specific therapy is paramount: enzyme replacement for Gaucher disease, thyroid hormone optimization, immunosuppression for sarcoidosis when indicated. 7 Optimize volume status in chronic renal failure, as elevated right-sided venous pressure worsens kidney function. 7 Right heart catheterization is mandatory to exclude other PH groups before attributing to Group 5. 7

Critical Pitfalls to Avoid

• Do not assume normal creatinine excludes significant renal pathology: Nephrotic syndrome can present with normal serum creatinine but massive proteinuria. 10
• Do not use PAH-specific therapies for Group 2 or Group 3 PH without clear evidence of severe right heart strain, as these may worsen outcomes. 5, 6
• Do not delay referral to a PH center for suspected Group 1 or Group 4 PH, as early diagnosis and treatment improve outcomes. 5, 3
• Do not overlook CTEPH: Always obtain ventilation-perfusion scanning, as CTEPH is potentially curable with surgery. 6