Emphysema

Emphysema
H&E (haematoxylin and eosin) stained lung tissue sample from an end-stage emphysema patient. RBCs are red, nuclei are blue-purple, other cellular and extracellular material is pink, and air spaces are white.
ICD-10	J43
ICD-9	492
DiseasesDB	4190
MedlinePlus	000136
eMedicine	med/654

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For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Emphysema is a form of lung disease that is frequently associated with exposure to toxic chemicals or long-term exposure to tobacco smoke.

Pathophysiology

Emphysema is caused by loss of elasticity (increased compliance) of the lung tissue, from destruction of structures supporting the alveoli, and destruction of capillaries feeding the alveoli. The result is that the small airways collapse during exhalation (although alveolar collapsability has increased), leading to an obstructive form of lung disease (airflow is impeded and air is generally "trapped" in the lungs in obstructive lung diseases).

Pathology of lung showing centrilobular emphysema characteristic of smoking. Closeup of fixed, cut surface shows multiple cavities lined by heavy black carbon deposits. (CDC/Dr. Edwin P. Ewing, Jr., 1973)

In normal breathing, air is drawn in through the bronchial passages and down into the increasingly fine network of tubing in the lungs called the alveoli, which are many millions of tiny sacs surrounded by capillaries. These absorb the oxygen and transfer it into the blood. When toxins such as smoke are breathed into the lungs, the particles are trapped and cause a localized inflammatory response. Chemicals released during the inflammatory response (e.g., elastase) can break down the walls of alveoli (alveolar septum). This leads to fewer but larger alveoli, with a decreased surface area and a decreased ability to absorb oxygen and exude carbon dioxide by diffusion. The activity of another molecule called alpha 1-antitrypsin normally neutralizes the destructive action of one of these damaging molecules.

After a prolonged period, hyperventilation becomes inadequate to maintain high enough oxygen levels in the blood. The body compensates by vasoconstricting appropriate vessels. This leads to pulmonary hypertension, which places increased strain on the right side of the heart, the one that pumps unoxygenated blood to the lungs, fails. The failure causes the heart muscle to thicken to pump more blood. Eventually, as the heart continues to fail, it becomes larger and blood backs up in the liver.

Emphysema occurs in a higher proportion in patients with decreased alpha 1-antitrypsin (A1AT) levels (alpha 1-antitrypsin deficiency, A1AD). In A1AD, inflammatory enzymes (such as elastase) are able to destroy the alveolar tissue (the elastin fibre, for example). Most A1AD patients do not develop clinically significant emphysema, but smoking and severely decreased A1AT levels (10-15%) can cause emphysema at a young age. In all, A1AD causes about 2% of all emphysema. However, smokers with A1AD are in the highest risk category for emphysema.

While A1AD provides some insight into the pathogenesis of the disease, hereditary A1AT deficiency only accounts for a small proportion of the disease. Studies for the better part of the past century have focused mainly upon the putative role of leukocyte elastase (also neutrophil elastase), a serine protease found in neutrophils, as a primary contributor to the connective tissue damage seen in the disease. This hypothesis, a result of the observation that NE is the primary substrate for A1AT, and A1AT is the primary inhibitor of NE, together have been known as the "protease-antiprotease" theory, implicating neutrophils as an important mediator of the disease. However, more recent studies have brought into light the possibility that one of the many other numerous proteases, especially matrix metalloproteases might be equally or more relevant than NE in the development of non-hereditary emphysema.

The better part of the past few decades of research into the pathogenesis of emphysema involved animal experiments where various proteases were instilled into the trachea of various species of animals. These animals developed connective tissue damage, which was taken as support for the protease-antiprotease theory. However, just because these substances can destroy connective tissue in the lung, as anyone would be able to predict, doesn't establish causality. More recent experiments have focused on more technologically advanced approaches, such as ones involving genetic manipulation. Perhaps the most interesting development with respect to our understanding of the disease involves the production of protease "knock-out" animals, which are genetically deficient in one or more proteases, and the assessment of whether they would be less susceptible to the development of the disease.

Diagnosis

Differential Diagnosis of Associated Conditions

Emphysema is commonly associated with bronchitis and chronic bronchitis. It is often difficult to delineate "pure" cases of emphysema or chronic bronchitis.

Emphysema is associated with alpha 1-antitrypsin deficiency. Severe cases of A1AD may also develop cirrhosis of the liver, where the accumulated A1AT leads to a fibrotic reaction.

Symptoms

Symptoms include shortness of breath on exertion (typically when climbing stairs or inclines, and later at rest), hyperventilation, and an expanded chest.

Signs

Emphysema patients are sometimes referred to as "pink puffers". This is because emphysema sufferers may hyperventilate to maintain adequate blood oxygen levels. Hyperventilation explains why mild emphysema patients do not appear cyanotic as chronic bronchitis (another COPD disorder) sufferers often do; hence they are "pink puffers" (able to maintain almost normal blood gases through hyperventilation) and not "blue bloaters" (cyanosis; inadequate oxygen in the blood). However, any severely chronically obstructed (COPD) respiratory disease will result in hypoxia (decreased blood partial pressure of oxygen) and hypercapnia (increased blood partial pressure of Carbon Dioxide); so called Blue Bloaters. Blue Bloaters are so named as they have almost normal ventilatory drive (due to decreased sensitivity to carbon dioxide secondary to chronic hypercapnia), are plethoric (red face/cheeks due to a polycythemia secondary to chronic hypoxia) and cyanotic (due to decreased hemoglobin saturation).

Physical Examination

Ear, nose and throat

Examination of the face resveals a plethoric complexion (if there is a secondary polycythemia), pursed-lipped breathing, and central cyanosis.

Lungs

Examination of the chest reveals increased percussion notes (particularly over the liver) and a difficult to palpate apex beat (all due to hyperinflation), decreased breath sounds, audible expiratory wheeze. Classically,clinical examination of an emphysematic patient reveals no overt crackles, however, in some patients the fine opening of airway 'popping' (dissimilar to the fine crackles of pulmonary fibrosis or coarse crackles of mucinous or oedematous fluid) can be auscultated. This is known as "Barclay's sign".

Extremities

Clinical signs on at the fingers include cigarette stains (although actually tar) and asterixis (metabolic flap) at the wrist if they are carbon dioxide retainers (NOTE: Finger clubbing is NOT a general feature of emphysema). Fluid overload can be seen in advanced disease, with pitting peripheral edema.

Laboratory Studies

Spirometry

Diagnosis is by spirometry (lung function testing), including diffusion testing. Findings will often demonstrate a decrease in FEV1 but an increase in Total Lung Capacity (TLC). Diffusion tests such as DLCO will show a decreased diffusion capacity. Other investigations might include X-rays, high resolution spiral chest CT-scan, bronchoscopy (when other lung disease is suspected, including malignancy).

Prognosis and treatment

Emphysema is an irreversible degenerative condition. The most important measure that can be taken to slow the progression of emphysema is for the patient to stop smoking and avoid all exposure to cigarette smoke and lung irritants. Pulmonary rehabilitation can be very helpful to optimize the patient's quality of life and teach the patient how to actively manage his or her care. Emphysema is also treated by supporting the breathing with anticholinergics, bronchodilators and (inhaled or oral) steroid medication, and supplemental oxygen as required. Treating the patient's other conditions including gastric reflux and allergies may also improve lung function. Supplemental oxygen used as prescribed (20+ hours/day) is the only non-surgical treatment which has been shown to prolong life in emphysema patients. Other medications are being researched. There are lightweight portable oxygen systems which allow patients increased mobility. Patients fly, cruise, and work while using supplemental oxygen.

Lung volume reduction surgery (LVRS) can improve the quality of life for certain carefully selected patients. It can be done by several different methods, some of which are minimally invasive. In July of 2006 a new treatment, placing tiny valves in passages leading to diseased lung areas, was announced to have good results- but 7% of patients suffered from partial lung collapse. The only known "cure" for emphysema is a lung transplant, although few patients are strong enough physically to survive the surgery. The combination of a patient's age, oxygen deprivation and the side-effects of the medications used to treat emphysema cause damage to the kidneys, heart and other organs. Transplants also require the patient to take an anti-rejection drug regimen which suppresses the immune system and creates other medical problems.

A study published by the European Respiratory Journal suggests that tretinoin (commercially available as Accutane, an anti-acne drug) derived from vitamin A can reverse the effects of emphysema in mice by returning elasticity (and regenerating lung tissue through gene mediation) to the alveoli. While vitamin A consumption is not known to be an effective treatment or prevention for the disease, this research could in the future lead to a cure. A newer follow-up study done in 2006 found inconclusive results ("no definitive clinical benefits") using Vitamin A (retinoic acid) in treatment of emphysema in humans and stated that further research is needed to reach conclusions on this treatment.

External links

• NIH/Medline

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