Differentials

Pulmonary arterial hypertension (PAH) associated with left-sided heart disease (pulmonary venous hypertension)

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Older patients, male preponderance, usual cardiovascular risk factors (diabetes, hypertension, smoking). Left ventricular gallops and mitral valve murmurs.

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Transthoracic echo: left atrial enlargement, left ventricular systolic and/or diastolic dysfunction, mitral valve disease.[3]​​

Right heart catheterization: elevated pulmonary arterial wedge pressure, transpulmonary gradient <12 mmHg.

Left heart catheterization: coronary disease, elevated left ventricular end-diastolic pressure.

PAH associated with respiratory diseases and/or hypoxia

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COPD: older than 40-50 years, history of smoking, chronic cough and sputum production, decreased breath sounds, wheezing.

Interstitial lung disease: history of occupational exposures, drug use, smoking, or connective tissue disease; chronic nonproductive cough, bibasilar inspiratory crackles, digital clubbing.

Sleep-disordered breathing (e.g., obstructive sleep apnea): loud snoring, excessive daytime sleepiness, morning headaches, obesity, mild elevations in pulmonary artery pressure.[48]

Alveolar hypoventilation disorders: obesity-hypoventilation syndrome, neuromuscular disease.

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Pulmonary function tests: obstructive or restrictive defects (obstructive: FEV₁ <60%; restrictive: forced vital capacity (FVC) <70%).

ABG: hypoxemia, hypercapnia.

Overnight oximetry: desaturation, screening for sleep apnea.

Polysomnography: obstructive sleep apnea.

High-resolution chest CT scan: emphysema, interstitial lung disease.

PAH due to chronic thrombotic and/or embolic disease

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History of pulmonary embolism; bruits over the lung fields (pulmonary flow murmurs) are present in 30% of cases but are not present in IPAH.[49]

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Ventilation-perfusion lung scintigraphy: one or more segmental-sized or larger unmatched perfusion defects.[3][36]​​

Pulmonary angiography: vascular webs or band-like narrowings, intimal irregularities, pouch defects, abrupt and angular narrowing, proximal obstruction.[49]

PAH associated with connective tissue disease

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Multisystem organ involvement: skin lesions, arthralgias/arthritis, GERD, Raynaud phenomenon, oral ulcers, serositis, renal disease, hematologic abnormalities, etc.

Scleroderma: especially the limited form (CREST syndrome: calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasis) in the absence of interstitial lung disease.

Less common in systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis.

INVESTIGATIONS

Antinuclear antibodies >1:80 titer.[3][36]

Anticentromere antibodies in limited scleroderma.[39]

Anti-U3-ribonucleoprotein (RNP) antibodies in diffuse scleroderma and mixed connective tissue diseases.

Anticardiolipin antibodies in lupus.

Rheumatoid factor.

PAH associated with congenital systemic-to-pulmonary shunts

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Simple shunts (more common than complex): ventricular septal defect (highest risk, especially if >1 cm), atrial septal defect (especially if >2 cm and sinus venosus type), patent ductus arteriosus, anomalous pulmonary venous return.

Complex shunts: truncus arteriosus (almost all patients develop PAH), atrioventricular septal defects.

For all defects, risk of PAH is highest if unrepaired.

Eisenmenger physiology: secondary erythrocytosis, iron deficiency, hemoptysis, "paradoxical" embolization, brain abscesses.[50]

INVESTIGATIONS

Contrast echocardiography with agitated saline ("bubble"): best for shunt reversal (right-to-left).[51]​​

Transesophageal Doppler echocardiography and/or cardiac MRI: anatomic definition.[50]

Right and left heart catheterization with oxygen saturation measurement.[3]​​

PAH associated with portal hypertension (portopulmonary hypertension)

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Mean age of presentation is the fifth decade of life, male-to-female ratio of 1.1:1.[52]

Signs of underlying liver disease: jaundice, spider telangiectasia lower extremity edema, ascites.

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LFTs: abnormal.

Abdominal ultrasound with color Doppler: liver cirrhosis, increase in the transhepatic venous gradient.

Right heart catheterization: increased gradient between free and occluded (wedged) hepatic vein pressure.

PAH associated with HIV infection

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HIV risk factors.

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Positive HIV serology.

PAH associated with drugs and toxins

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History of appetite-suppressant use: aminorex, fenfluramine derivatives, use of methamphetamine.[33][40]

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Abnormal toxicology.

PAH associated with other medical disorders

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History of thyroid disease, hemoglobinopathies, myeloproliferative disorders, splenectomy.[3]​​​

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Abnormal thyroid function tests, abnormal CBC with platelet count.[3]​​

Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis

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Digital clubbing and/or basilar rales on exam.[3]

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More severe hypoxemia and decreased in diffusing capacity of the lung for carbon monoxide.

CT chest: ground-glass opacities with a centrilobular distribution, septal lines, and adenopathy.

Elevated numbers of hemosiderin-laden macrophages in bronchoalveolar lavage fluid.

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