Can sarcoidosis cause primary pulmonary hypertension?

Sarcoidosis and Pulmonary Hypertension: Classification and Relationship

Sarcoidosis does not cause primary pulmonary hypertension, but rather can lead to pulmonary hypertension classified as Group 5 (pulmonary hypertension with unclear and/or multifactorial mechanisms) according to current guidelines. 1

Classification of Pulmonary Hypertension in Sarcoidosis

Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure ≥25 mmHg at rest measured by right heart catheterization. The relationship between sarcoidosis and PH is specifically addressed in current classification systems:

• According to the 2015 ESC/ERS guidelines, sarcoidosis-associated PH is classified under Group 5: "Pulmonary hypertension with unclear and/or multifactorial mechanisms" 1
• This represents a change from earlier classifications, as in the 2004 Venice classification, sarcoidosis was listed under the "Miscellaneous" category (Group 5) 1

Pathophysiological Mechanisms

Sarcoidosis can lead to pulmonary hypertension through multiple mechanisms:

1. Multifactorial pathophysiology:

   • Destruction of the distal capillary bed
   • Hypoxemia from parenchymal lung involvement
   • Specific granulomatous vasculopathy
   • Extrinsic compression of pulmonary vessels
   • Fibrotic changes in advanced disease 2

2. Disproportionate PH:

   • Some patients develop "out of proportion" PH, where the severity exceeds what would be expected from their functional impairment (mean PAP >35-40 mmHg) 2
   • This suggests direct vascular involvement beyond the effects of parenchymal disease

3. Venous involvement:

   • Sarcoidosis vasculopathy often affects the venous side of circulation
   • Can cause pulmonary veno-occlusive disease in some cases 2

Clinical Significance and Outcomes

Sarcoidosis-associated pulmonary hypertension (SAPH) is a significant complication with important implications:

• Prevalence: Approximately 6% of unselected sarcoidosis patients develop PH 2
• Higher prevalence in advanced disease, particularly stage IV (fibrotic) sarcoidosis 3
• Associated with significantly increased mortality and decreased functional capacity 4
• Median survival without transplantation is approximately 5.3 years 5
• Poor prognostic factors include:
  • Moderate to severe lung fibrosis
  • Right ventricular dysfunction
  • Lower body surface area
  • WHO functional class IV 5

Diagnostic Approach

For sarcoidosis patients with unexplained dyspnea or exercise limitation:

1. Initial screening:

   • Echocardiography as first-line screening test 6
   • Pulmonary function tests with DLCO (often severely reduced in SAPH) 7
   • 6-minute walk test to assess functional capacity

2. Definitive diagnosis:

   • Right heart catheterization is mandatory to confirm diagnosis 6
   • Hemodynamic criteria: mean PAP ≥25 mmHg
   • For pre-capillary PH: pulmonary wedge pressure ≤15 mmHg 6

3. Correlation with disease parameters:

   • DLCO percent predicted shows significant negative correlation with mean PAP and PVR 3
   • PVR is significantly higher in stage 4 disease than in stage 0 or 1 disease 3

Treatment Considerations

Management of sarcoidosis-associated PH requires a targeted approach:

• Treatment of underlying sarcoidosis with immunosuppression is typically insufficient to adequately treat SAPH 4

• Supportive therapy includes supplemental oxygen and diuretics as needed 2

• Pulmonary vasodilator therapy may be considered in selected cases:

  • Can improve hemodynamics and functional parameters in some patients 5
  • Meta-analysis shows improvement in 6-minute walk distance (average 30.64m) and hemodynamic parameters after treatment 5
  • Treatment response varies and should be monitored closely

• Lung transplantation should be considered early for eligible patients with refractory disease 2

Key Clinical Pearls

• The severity of pulmonary vascular disease in SAPH often occurs out of proportion to lung function abnormalities 7
• SAPH should be suspected in sarcoidosis patients with unexplained dyspnea, especially with disproportionate reduction in DLCO compared to spirometric values
• Right heart catheterization is essential to distinguish between pre-capillary and post-capillary PH, as left heart dysfunction may be underestimated by echocardiography 2
• Management by clinicians experienced in PH is advised, with early referral for transplantation evaluation in refractory cases 4