Updated: 2/10/2020

Pulmonary Hypertension

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  • A 37-year-old woman is referred to the pulmonologist’s office from her PCP for worsening shortness of breath. She reports that she has had increasing dyspnea on exertion and fatigue for the past 3 years, but it has gotten much worse in the last 2 months. She used to walk around the neighborhood with her friends but now gets short of breath with occasional chest pain just walking around the house. Her past medical history is otherwise completely negative. On physical exam, she has a JVP of 13 cm H
    O, a loud P2, an S3, a right-sided heave, a liver palpable 3 cm below the costal margin, and bilateral leg edema. She is sent for a trans-thoracic echocardiogram which estimates a high pulmonary artery systolic pressure and shows right ventricular hypertrophy and right heart failure. The diagnosis is confirmed with a right heart catheterization and she is started on epoprostenol.
  •  Clinical definition
    • mean pulmonary artery pressure ≥ 20 mmHg
      • normal = 8-20 mmHg
      • gold standard for measurement is right heart catheterization
  • Epidemiology
    • incidence
      • varies by etiology; affects all ages, races, and genders
      • can be very rare (~4 cases per million for idiopathic pulmonary hypertension (IPAH))
      • or relatively common 10-40% of patients with at-risk associated diseases (below)
    • demographics
      • females > males
        • up to 9:1 (for IPAH)
  • Etiologies

    Etiologies of Pulmonary Hypertension
    Primary Etiologies
    Etiology Key Points
    Idiopathic pulmonary arterial hypertension (IPAH)
    • By definition, the cause is unknown
    Hereditary pulmonary arterial hypertension (HPAH)
    • Mutation in the BMPR-2 gene
      • acts normally to inhibit smooth muscle growth
    • Mnemonic: Blocker of Muscle PRoliferation
    • More common in women (9:1)
    • Poor prognosis
    Secondary Etiologies 
    Etiology (secondary to)
    Key Points
    Autoimmune disease
    • Systemic sclerosis > SLE >> RA
    • Inflammation of vessel wall leads to scarring and stiff vessels
    • Direct pulmonary vasoconstriction
      • e.g., cocaine or methamphetamine
    • Schistosomiasis
      • leading cause of pulmonary hypertension in endemic areas
    • HIV
    Left-to-right shunt
    • Increased flow to pulmonary system
      • e.g., from congenital heart defects
    Left heart disease
    • Decreased cardiac output backs blood into pulmonary circuit
      • e.g., left heart failure or mitral valvular disease
    Lung disease/hypoxia
    • Decreased oxygen delivery leads to hypoxemic pulmonary vasoconstriction
      • e.g., COPD, obstructive sleep apnea, obesity hypoventilation syndrome, or high altitudes
    Thromboembolic disease
    • Chronic, recurrent micro-emboli decrease the cross-sectional area of pulmonary vessels
    • e.g., carcinoid syndrome, sarcoidosis, vasculitis, or metabolic disorders 
  • Pathogenesis
    • common final pathway for all etiologies
      • luminal injury from increased pulmonary pressure
      • smooth muscle proliferation of the media and intima
      • fibrosis resulting in plexiform lesions on pathology  
    • fibrosis leads to stiff vessels
    • increased pulmonary vascular resistance (PVR)
    • right ventricle has to pump harder to overcome resistance
    • right ventricular hypertrophy
    • right heart failure
  • Associated conditions
    • schistosomiasis
    • systemic sclerosis
    • SLE
    • HIV 
    • persistent pulmonary hypertension of the newborn
  • Prognosis
    • progressive and fatal if untreated
    • incurable
      • treatment focuses on slowing the disease progression
    • rate of progression is variable
    • for IPAH and HPAH, 5-year survival is approximately 50%
  • Symptoms
    • dyspnea on exertion
    • fatigue
    • if subsequent right heart failure
      • exertional chest pain (angina)
      • exertional syncope
      • swelling
      • RUQ pain (from hepatic congestion)
      • anorexia (from hepatic congestion)
  • Physical examination
    • loud P2 on auscultation
    • right-sided heave
      • from right ventricular hypertrophy
    • if subsequent right heart failure
      • elevated JVP
      • hepatomegaly
      • S3 heart sound

  • Echocardiogram  
    • usually first step in the workup
    • right ventricular hypertrophy
    • enlarged pulmonary arteries
    • estimated pulmonary arterial systolic pressure
      • estimated from flow rate across the tricuspid valve
  • Chest radiograph
    • enlarged pulmonary arteries
    • pruning of peripheral vessels
  • CT angiography  
    • enlarged pulmonary trunk and pulmonary arteries
  • Labs
    • BNP
      • non-specific
  • Diagnostic procedures
    • right heart catheterization
      • allows measurement of pulmonary arterial pressures
      • gold standard for diagnosis
  • Diagnosis
    • clinical diagnosis by appropriate history, physical exam, and imaging/lab findings
    • very likely if echocardiogram estimates high pressures
    • if few or ambiguous clinical findings, may need to confirm with right heart cath (early IPAH and HPAH)
  • Congestive heart failure (without PH)
    • clinically very similar
    • distinguishing factors
      • typically, a long history of heart attacks, coronary artery disease, hypertension, and/or other risk factors for heart failure
      • can be distinguished by echo and/or cath
  • Coronary artery disease
    • can also present with exertional chest pain, shortness of breath, and fatigue
    • distinguishing factors
      • positive stress testing
      • coronary vessel occlusion and normal pulmonary pressures upon catheterization
  • Liver disease
    • can present with lower extremity swelling and RUQ pain
    • distinguishing factors
      • lack of respiratory symptoms
      • normal JVP
  • Management approach
    • as PH is incurable, management is focused on slowing disease progression and alleviating symptoms
    • for PH secondary to other disease (heart, lung, etc…), treat the underlying cause
  • Medical
    • for symptoms
      • oxygen
      • diuretics
      • exercise therapy
    • PH-specific therapies
      • prostacyclin (PGI2)
        • epoprostenol (IV) and iloprost (inhaled)
        • mechanism
          • vasodilation
        • side effects
          • jaw pain and flushing
      • endothelin receptor antagonists (bosentan) 
        • endothelin-1 (ET-1) is a potent vasoconstrictor in the lungs
        • mechanism
          • blocks the ET-1 receptor to decrease vasoconstriction
        • side effects
          • hepatotoxic
      • PDE-5 inhibitors (sildenafil)
        • nitric oxide is a vasodilator
          • PDE-5 helps to break down nitric oxide
        • mechanism
          • blocks PDE-5, increasing NO, and thus vasodilation
        • side effects
          • headache
  • Cor pulmonale 
    • right-sided congestive heart failure secondary to pulmonary disease
  • Chronic hypoxemic respiratory failure

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Questions (6)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2

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