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
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