Emphysema

Definition

Types of Emphysema

1. Centriacinar (Centrilobular) Emphysema

• Most common form - constitutes >95% of clinically significant cases
• The central/proximal parts of the acinus (respiratory bronchioles) are affected; distal alveoli are spared
• Both emphysematous and normal airspaces coexist within the same acinus and lobule
• Distribution: upper lobes, particularly apical segments
• Etiology: almost exclusively in heavy smokers; often accompanied by chronic bronchitis
• In severe cases, the distal acinus is also affected, making differentiation from panacinar emphysema difficult

2. Panacinar (Panlobular) Emphysema

• The entire acinus is uniformly enlarged - from respiratory bronchiole to terminal alveoli
• Distribution: lower lung zones and anterior margins; most severe at the bases
• Etiology: strongly associated with α1-antitrypsin (AAT) deficiency; exacerbated by smoking
• About 1% of emphysema patients have this defect; >80% of homozygous ZZ individuals develop symptomatic panacinar emphysema, at an earlier age if they smoke

3. Distal Acinar (Paraseptal) Emphysema

• The proximal acinus is normal; the distal portion (alveolar ducts and sacs) is predominantly involved
• More striking adjacent to the pleura, along lobular connective tissue septa, and at the margins of lobules
• Characteristic: multiple enlarged airspaces, 0.5 mm to >2.0 cm in diameter, sometimes forming cystic structures and bullae
• Usually more severe in the upper half of the lungs
• Cause is unknown; typically presents in young adults with spontaneous pneumothorax
• Not significantly associated with airflow obstruction

4. Irregular (Paracicatricial) Emphysema

• Acinus is irregularly involved, almost invariably associated with scarring
• Occurs in small foci adjacent to areas of fibrosis, scarring, or atelectasis
• Clinically insignificant in most cases

Additional Descriptive Forms (not primary anatomical types)

• Bullous emphysema: Large subpleural blebs or bullae (>1 cm diameter) occurring in any form of emphysema, often near the apex; rupture can cause pneumothorax
• Compensatory hyperinflation: Alveolar dilation in response to lung tissue loss elsewhere (e.g., post-lobectomy); not true emphysema as there is no wall destruction
• Obstructive overinflation: Air trapping from subtotal airway obstruction (tumor, foreign body, congenital lobar overinflation); not true emphysema
• Interstitial emphysema: Air entry into connective tissue stroma, mediastinum, or subcutaneous tissue; usually from alveolar tears caused by sudden increases in intraalveolar pressure

Etiopathogenesis

1. Toxic Injury and Inflammation

• Inhaled cigarette smoke and noxious particles damage respiratory epithelium, triggering inflammation
• Inflammatory mediators released include leukotriene B4 (LTB4), IL-8, TNF, and others
• Released by resident epithelial cells and macrophages, these mediators:
  • Recruit neutrophils, macrophages, CD4+, and CD8+ T cells from the circulation
  • Amplify inflammation via proinflammatory cytokines
  • Induce structural changes via growth factors
• Bacterial/viral infections do not initiate disease but acutely exacerbate existing disease

2. Protease-Antiprotease Imbalance

• Central mechanism in emphysema pathogenesis
• Proteases (particularly elastase) released from neutrophils and macrophages degrade elastin and other connective tissue components
• In susceptible individuals, there is a relative deficiency of protective antiproteases
• α1-antitrypsin (AAT): the major inhibitor of neutrophil elastase; encoded at the Pi locus on chromosome 14; the ZZ genotype (0.01% of US population) causes markedly decreased serum AAT levels
• Smoking further compounds AAT deficiency by:
  • Stimulating recruitment of more neutrophils and macrophages to the lung
  • Inactivating AAT via oxidation by cigarette smoke oxidants
• Loss of elastin in alveolar walls removes the radial traction that keeps small airways open, causing respiratory bronchiole collapse during expiration - producing functional airflow obstruction without mechanical obstruction

3. Oxidative Stress

• Tobacco smoke, alveolar damage, and inflammatory cells generate reactive oxygen species (ROS)
• ROS cause tissue damage, endothelial dysfunction, and inflammation
• NRF2 (encoded by NFE2L2) is a transcription factor that senses intracellular oxidants and upregulates cytoprotective genes; mice lacking NRF2 are significantly more sensitive to tobacco smoke
• Genetic variants in NRF2, its regulators, and target genes are linked to smoking-related lung disease in humans
• Oxidants promote apoptosis and cellular senescence of alveolar cells

4. Other Genetic Factors

• Variants of the nicotinic acetylcholine receptor are linked to tobacco addiction behavior, and to both lung cancer and emphysema risk - emphasizing that smoking is the dominant driver

Morphology

Gross Appearance

• Advanced emphysema produces voluminous, pale lungs that often overlap the heart anteriorly and flatten the diaphragm
• In smoking-related disease, the upper two-thirds of the lung are more severely affected
• Large alveoli are easily visible on cut sections of fixed lung
• Apical blebs or bullae may be present in advanced disease

• Panacinar emphysema produces the most impressive gross appearance: paler and more voluminous lungs; lower lobes predominate
• Centriacinar emphysema: lungs are a deeper pink and less voluminous until late stages; upper two-thirds more affected

Microscopic Appearance

• Abnormally large alveoli separated by thin septa with focal centriacinar fibrosis
• Loss of attachments between alveoli and small airway walls
• Pores of Kohn become so enlarged that septa appear to "float" or protrude blindly into airspaces with club-shaped ends
• Decrease in capillary bed area due to alveolar wall destruction
• In advanced disease: larger abnormal airspaces, blebs, bullae; deformation and compression of respiratory bronchioles and vasculature
• No significant fibrosis (the key distinguishing histological feature)
• Superimposed inflammatory changes in small airways (related to chronic bronchitis) are common
• Vascular changes of pulmonary hypertension from local hypoxemia and capillary loss

Clinical Course

Presentation

• Most affected patients have a smoking history of ≥40 pack-years
• Onset is insidious: slowly increasing dyspnea on exertion, chronic cough with sputum
• May present with acute exacerbations from superimposed infection
• Key diagnostic test: spirometry showing FEV1/FVC < 0.7

Classic Clinical Phenotypes

Mechanisms of Dyspnea and Airflow Obstruction

1. Loss of elastic recoil - destruction of elastic tissue in alveolar walls reduces radial traction on surrounding small airways, causing expiratory collapse
2. Air trapping - expiratory airway collapse leads to hyperinflation (barrel chest, flattened diaphragm)
3. Reduced gas exchange surface - capillary bed destruction lowers diffusion capacity (DLCO)
4. Pulmonary hypertension - from hypoxic vasoconstriction and loss of capillary beds; leads to cor pulmonale (right heart failure)

Complications and Prognosis

• Cor pulmonale and right heart failure in advanced disease
• Respiratory failure precipitated by superimposed infection
• Pneumothorax (especially from ruptured bullae in paraseptal emphysema)
• Often fatal from heart failure or respiratory failure from superimposed infection
• Prognosis is significantly worsened by continued smoking
• In AAT-deficient patients, disease occurs earlier, is more severe, and progresses faster, especially in smokers