Emphysema and Diseases of Large Airways

Introduction

The disorders included in this chapter are grouped under the heading “obstructive lung diseases.” These diseases share the characteristic of increased resistance to airflow, which can be caused by either an increase in the resistance of the conducting airways or an increase in lung compliance due to emphysematous lung destruction, or both. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs. Obstructive lung diseases include emphysema, chronic bronchitis, asthma, and bronchiectasis. Although these diseases have distinctive clinical and pathologic features, patients can show features of more than one of these disorders. The combination of emphysema and chronic bronchitis is particularly frequent, due to the strong linkages of these diseases to a common etiologic factor: tobacco smoking. The term chronic obstructive pulmonary disease (COPD) is commonly used to refer to both processes and is defined physiologically by airflow limitation measured during forced expiration. A component of asthma may also contribute to COPD in some patients. Small-airway abnormalities also form part of the constellation of changes contributing to airflow limitation in smokers and are discussed in more depth in Chapter 21 . COPD is now the third leading cause of death in the United States and is projected to be the third leading cause of death worldwide by 2020. The current clinical consensus definition of COPD emphasizes that it is a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The risk factor of exposure to cigarette smoke and other noxious particles or gases is well known in COPD. More recent research has focused on the modulating role of individual genetic variations and its implications for disease classification, disease severity, and treatment.

Emphysema

Emphysema is a disorder characterized by abnormal permanent enlargement of airspaces distal to the terminal bronchiole, with destruction of their walls and without obvious fibrosis. It is often associated with chronic bronchitis and produces physiologic airflow obstruction. There are four described variants that affect different regions of the pulmonary lobule: (1) centriacinar or centrilobular, (2) panacinar or panlobular, (3) paraseptal, and (4) irregular. Centriacinar emphysema is the most common form of emphysema and is most closely associated with long-standing tobacco use. Panacinar emphysema is characteristic of α-1-antitrypsin (A1AT) deficiency. Paraseptal emphysema may coexist with other types of emphysema, but paraseptal blebs/bullae are also considered to be a cause of pneumothorax in young, otherwise healthy, and predominantly male adults. Irregular emphysema occurs at the periphery of large scars or other focal lesions. Patients may have more than one type; mixtures of centriacinar and paraseptal emphysema are common in smokers, and centriacinar emphysema can progress in smokers to involve whole acini. Large bullae can also develop, compress adjacent lung tissue, and further compromise ventilation, or these structures may spontaneously rupture, leading to a pneumothorax.

The pathogenesis of emphysema has received extensive study and remains a subject of continued investigation. The protease-antiprotease theory suggests that emphysema results from an imbalance between activities of proteases (especially elastase) and antiproteases. Supporting this theory is the association between human A1AT deficiency and emphysema, and the observation that exposure of the lungs of experimental animals to certain proteolytic enzymes can reproduce lesions of emphysema. The inflammatory response triggered by smoking may play an important role in pathogenesis; smokers with severe emphysema appear to accumulate substantially increased numbers of neutrophils, macrophages, T-lymphocytes, and eosinophils compared with smokers with normal lung function. Neutrophil and macrophage activation is believed to occur with release of proteases, especially elastase. Inactivation of antiproteases by reactive oxygen species introduced via tobacco smoke and activated neutrophils has also been described, further promoting tissue injury.

A1AT is a serine protease inhibitor synthesized by the liver and secreted into the blood. Its major function is the inhibition of neutrophil proteases, and it represents the most important inhibitor of protease activity in the lung. The A1AT protein is encoded by the protease inhibitor (PI) locus gene on chromosome 14q32.1 and manifests an autosomal codominant pattern of allelic expression. The PI locus is highly polymorphic, and about 100 variants have been identified to date. The PiMM phenotype is the most common phenotype, occurring in 90% of the general population. Individuals homozygous for PiZ (PiZZ) have markedly reduced A1AT activity and are the most commonly affected by symptomatic emphysema, with 80% to 90% eventually developing emphysema. Heterozygous PiSZ individuals have 30% to 35% of normal activity and are at a higher risk as well. Tobacco smoking accelerates the progression of emphysema in patients with A1AT deficiency.

Radiologic Features

Chest radiographs reveal hyperinflation with hyperlucency, rapidly tapering vascular shadows, “pushed down” diaphragms, and a long, narrow heart shadow. High-resolution computed tomography (HRCT) is a more sensitive and specific test for emphysema ( Fig. 20.1 ) and will reveal bullae that may be less apparent on routine x-rays. However, HRCT is not part of routine evaluation and is usually done in instances when lung volume reduction surgery is planned or if another abnormality (eg, a lung cancer) is suspected.

Pathologic Features

Gross Findings

The lungs usually appear enlarged and hyperinflated and have less than normal weight. Blebs or large, air-filled bullae ( Fig. 20.2 ) may be present, particularly in the apices. In centriacinar emphysema, enlarged airspaces are visible in the centers of the lobules and are surrounded by normal-appearing parenchyma ( Fig. 20.3 ). This type of emphysema is usually most pronounced in the central regions of the upper lobes. The walls of the enlarged airspaces often have a blackened appearance. In A1AT deficiency, panacinar emphysema is usually most severe in the lung bases and involves the entire lobule. Paraseptal emphysema appears as enlarged airspaces along interlobular septa and pleura. In irregular emphysema, the abnormal airspaces lie adjacent to focal lesions such as scars. Combinations of more than one type of emphysema are common, and bullae (emphysematous airspaces measuring more than 1.0 cm in diameter) may develop in any type.

Microscopic Findings

Histologically, there is alveolar wall destruction with isolated, or “free-floating,” portions of septae that appear to be disconnected from other parenchymal structures ( Fig. 20.4 , [CR] ). Enlargement of alveolar sacs without airway destruction can occur secondary to subtotal airway obstruction or as an artifact caused by overinflation with formalin and should not be overdiagnosed as emphysema. In centriacinar emphysema, airspace enlargement occurs in the proximal portion of the acinus/lobule (primarily at the level of the respiratory bronchiole), and distal alveoli are relatively spared. A small artery is often seen adjacent to the enlarged airspace and represents a clue to the centriacinar location of the emphysema. Groups of pigment-containing macrophages are also frequently seen in peribronchiolar regions. Panacinar emphysema results in diffuse acinar destruction and airspace enlargement, involving all portions of the acinus/lobule ( [CR] ). In paraseptal emphysema, the centriacinar structures are preserved, and the site of emphysematous airspace enlargement lies adjacent to an interlobular septum or the pleura. In irregular emphysema, the emphysematous airspaces lie adjacent to a focal lesion, usually a scar.

Chronic Bronchitis