What are the etiologies of emphysema?

Causes of Emphysema

Cigarette smoking is the predominant cause of emphysema, accounting for the vast majority of cases, with tobacco smoke inducing chronic inflammatory responses and oxidative stress that lead to permanent destructive enlargement of air spaces distal to the terminal bronchioles. 1

Primary Etiologies

Tobacco Smoke Exposure

• Cigarette smoking is the major risk factor for emphysema worldwide, causing chronic inflammatory responses and oxidative stress in susceptible individuals 1
• Smokers develop centriacinar emphysema where respiratory bronchioles, alveolar ducts, and alveoli at the center of the acinus are destroyed 1
• Some smokers also develop panacinar emphysema where the entire acinus is destroyed 1
• The oxidants in cigarette smoke directly inactivate proteinase inhibitors and trigger inflammatory cells to release additional proteases 2

Alpha-1 Antitrypsin Deficiency

• Severe alpha-1 antitrypsin (AAT) deficiency is the most important genetic cause of emphysema, leading to development of panacinar emphysema at a relatively young age 3
• The protease-antiprotease imbalance occurs when smoking-induced neutrophil elastase release is inadequately inhibited by deficient AAT levels 3
• Most AAT-deficient patients become disabled in their forties if they smoke 3
• Screening for AAT deficiency is recommended in patients with early onset disease (disability in their forties or fifties) or positive family history 3

Secondary Risk Factors

Occupational and Environmental Exposures

• Other inhaled noxious particles and gases beyond tobacco smoke contribute to emphysema development 1
• Occupational exposure to dust, fumes, and gases independently increases risk for respiratory symptoms and airflow limitation 1
• High mineral dust exposure significantly reduces FEV1 compared to no exposure 1
• Indoor kerosene heating and agricultural occupations accelerate emphysema development in males over 50 years 1
• Passive smoking exposure is detrimental to lung health 1

Pathobiological Mechanisms

Inflammatory and Oxidative Pathways

• Inhalation of noxious substances causes chronic inflammatory response and oxidative stress in the lungs 1
• The disease continues progressing in many patients even after cessation of exposure to the offending agent 1
• Inflammatory cells (neutrophils, alveolar macrophages, T-lymphocytes) accumulate in lung parenchyma and produce proteases that cannot be adequately regulated by antiproteases 4
• The extent of lung destruction correlates directly with numbers of alveolar macrophages and T-lymphocytes per cubic millimeter 4

Additional Contributing Mechanisms

• Genetic and epigenetically determined responses influence individual susceptibility 1
• Proteinase-antiproteinase imbalance leads to proteolytic damage to lung connective tissue, primarily elastic fibers 1, 3
• Abnormal interaction between environment and microbiome 1
• Chronic immune response dysregulation 1
• Inappropriate control of programmed cell death (apoptosis) 1, 5
• Accelerated lung aging 1
• Pulmonary endothelial cell dysfunction 1
• Cellular senescence and failed lung tissue repair 5

Clinical Pitfalls

Do not overlook AAT deficiency in younger patients (those disabled in their forties or fifties) or those with atypical features such as basilar-predominant emphysema on imaging 3. The familial clustering of COPD, particularly in siblings of index cases, should prompt consideration of genetic factors 1. Remember that occupational exposures act independently of smoking status and should be specifically queried in the history 1.