HPE Alpha 1 Antitrypsin Deficiency | Page 3

INTRODUCTION Alpha 1 Antitrypsin Deficiency: A special type of COPD Alpha 1 Antitrypsin Deficiency increases the risk of developing a variety of diseases including pulmonary emphysema and cirrhosis of the liver, and is caused by mutations in the gene coding for the 52 kDa glycoprotein, Alpha 1 Antitrypsin Kenneth R Chapman MD MSc FRCPC FACP FCCP FERS Professor of Medicine, University of Toronto; Director, Asthma & Airway Centre, University Health Network, Toronto, Canada In medical school curricula, emphysema caused by Alpha 1 Antitrypsin Deficiency (AATD) is characterised as a special type of COPD. Students are taught that this deficiency is associated with early-onset emphysema often in patients with little or no exposure to tobacco smoke. Moreover, the pattern of emphysema is distinctive; the most typical pulmonary abnormality in AATD is an unusual panlobular form of emphysema seen primarily at the lung bases. 1 This is in contrast to more tobacco-induced emphysema, which is typically centrilobular and is most prominent at the apices. Even the comorbidities of AATD are distinctive: cirrhosis, panniculitis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. 1 Finally, the disorder is detected by screening with a simple blood test and can be verified with well-established genetic techniques. Despite this distinctive set of characteristics, it is unwise to regard AATD as an abnormality far-removed from commonplace tobacco-induced COPD. Both clinically and conceptually, AATD has much in common with non-alpha forms of the disease. A seminal discovery In 1963, Laurell and Eriksson published their seminal paper describing an unusual pattern on serum protein electrophoresis studies. 2 In five individuals, they found little or no Alpha 1 Antitrypsin (AAT) in the serum and noted that what little of the glycoprotein present tended to move sluggishly in the electrophoresis gel. This suggested to them that the deficiency was associated with an abnormality of the protein. Furthermore, they noted that in three of the five individuals, early-onset emphysema was present, hinting at a relationship between the glycoprotein and some protection of lung structure. Finally, they found that one of the individuals with low serum levels of AAT and pulmonary disease had a sister who was similarly affected and they postulated that the abnormality was genetic. With this one paper, they established the fundamentals of the disorder as we now understand it. Subsequent study has shown that common base pair DNA mutations lead to the production of an abnormal AAT protein that fails to conform or fold after it is produced in the liver. The result is sluggish excretion into the serum and accumulation of abnormal protein in the liver. This leads to the two fundamental characteristics of the disorder. The lungs are relatively unprotected from elastases leading to premature emphysema while engorgement of the endoplasmic reticulum in the liver can lead to hepatic injury. These and other manifestations of AATD are highly variable. Some of this variability is explained easily; those deficient in AAT who smoke are more likely to develop emphysema than non-smokers, for example. Much of this variability remains unexplained; however, it is thought to relate to other as yet to be determined genetic factors. Such textbook descriptions of AATD are deceptive. Busy clinicians grow accustomed to the routine of tobacco-induced COPD and regard AATD as a rare disorder that will declare itself by its distinctive presentation. However, individuals with emphysema caused by AATD are typically middle-aged at presentation and most have a smoking history, albeit typically with fewer pack years of exposure than other forms of COPD. The clinician who expects that AATD will present as a dramatically younger individual will reserve screening for only a handful of younger patients. Such selective screening no doubt contributes to low detection rates of AATD. It is estimated that in most Western nations no more than 10% of affected individuals are diagnosed. For this reason, contemporary guidelines recommend routine screening of all patients with COPD to rule out the presence of AATD as a contributing factor. 3 In this sense, the ‘special’ nature of AATD has been counterproductive and has led to underdetection. Definition and description of AATD AATD is commonly described as ‘the genetic form of emphysema’ but this description is misleading. Although it’s true that no other form of emphysema is associated with a single gene mutation, it is clear that the development of non-alpha COPD is also the consequence of a genetic predisposition. It has long been known that only about one in six regular tobacco smokers develops some form of COPD. Presumably those who do develop an obstructive airways problem are those with genes that fail to protect the lungs from tobacco injury or that respond to such exposure with inappropriate inflammatory or obliterative injury. Indeed, genetic research has now established several gene associations for non-alpha COPD and work is underway to unravel the consequent pathophysiology. 4 The description of AATD and its association with emphysema profiled a small subgroup of individuals with a distinctive and ‘special’ form of a common disease, COPD. However, in many ways, AATD is similar to the more common category of pulmonary disorders. Pathophysiology and the potential of therapy The discovery of AATD emphysema also led hospitalpharmacyeurope.com | 2019 | 3