New Guidelines for Alpha-1 Antitrypsin Deficiency
News Author: Laurie Barclay, MD
Oct. 10, 2003 — Much has changed since the last revision of guidelines for
diagnosis and management of alpha-1 antitrypsin (AAT) deficiency, according to
a summary of latest recommendations published by the recently created AAT task
force in the October issue of the American Journal of Respiratory
and Critical Care Medicine.
"Since the first American Thoracic Society statement regarding the
diagnosis and management of severe AAT deficiency in 1989...significant
advances in understanding the cell and molecular biology of AAT and the
diagnosis, natural history, and treatment of individuals with AAT deficiency
have occurred," write James K. Stoller, MD, MS, from the Cleveland Clinic
Foundation in Ohio, and colleagues from the Task Force. "AAT is frequently
underrecognized or misdiagnosed by clinicians."
Features suggesting the diagnosis include emphysema with onset at age 45
years or younger; emphysema occurring in the absence of smoking, occupational
dust exposure, or other recognized risk factors; or emphysema with prominent
basilar hyperlucency. Other features that should raise the index of suspicion
for AAT include otherwise unexplained liver disease, necrotizing panniculitis,
antiproteinase 3-positive vasculitis, bronchiectasis without evident etiology,
and family history of emphysema, bronchiectasis, liver disease, or
Based on the presence or absence of these features, the Task Force issued
specific recommendations for diagnostic genetic testing in different clinical
The authors review the prevalence of AAT deficiency in newborns estimated
from several large population studies. This figure ranges from 1 in 1,600 in
Sweden from 1972 to 1974 to 1 in 5,097 in Oregon. In the Swedish cohort, lung
function remained normal during the first two decades of life, and most
studies of the natural history concur that emphysema leading to early death
usually begins during the third or fourth decade of life.
Pulmonary emphysema is the major cause of disability and death, whereas
liver cirrhosis and carcinoma affect about 30% to 40% of those with AAT
deficiency older than 50 years.
Liver transplantation is the only therapy currently available for advanced
AAT-deficiency liver disease.
For obstructive lung disease associated with AAT deficiency, general
management should include inhaled bronchodilators, preventive vaccination
against influenza and pneumococcus, supplemental oxygen as needed, pulmonary
rehabilitation for functional impairment, lung transplantation in selected
patients, brief courses of systemic corticosteroids for acute exacerbations,
and ventilatory support and early antibiotic therapy when needed.
Although lung volume reduction surgery may improve symptoms and functional
status, the authors note that "well-studied, robust selection criteria for
ideal candidates remain elusive and the duration of lung volume reduction
surgery benefit appears shorter than in individuals with AAT-replete COPD."
The American Thoracic Society, the European Respiratory Society, and the
Alpha-1 Foundation sponsored this task force.
Am J Respir Crit Care Med. 2003;168: 818-900
ATT deficiency, a hereditary condition, has an estimated prevalence of 1 in
1,600 newborns according to European reports. Studies in Oregon, New York, and
St. Louis, Missouri, have yielded a prevalence of 1 in 5,097; 1 in 3,694; and
1 in 2,857 respectively. The associated PI*ZZ deficiency is an autosomal
codominant gene, with the risk of a homozygous offspring being 1 in 4 if both
parents are carriers of the Z allele. If one parent is PI*ZZ and the other
heterozygous, then all offspring are either carriers or affected. There is
currently no effective prenatal diagnostic tool, and there is no cure.
Clinically, the disease tends to present with obstructive lung disease
between age 32 and 41 years. It rarely presents before age 25 years. The most
common misdiagnosis is asthma. With fewer than 60% of affected individuals
developing severe airflow obstruction, the decision to screen asymptomatic
individuals becomes ethically challenging when insurability and employment are
considered. Smoking is the strongest predictor of disease severity and
progression. The majority of deaths (72%) are due to emphysema. In a registry
cohort of the National Heart, Lung, and Blood Institute (NHLBI), 30% of
sufferers were medically disabled at 46 years and 68% reported at least one
serious disabling respiratory condition within three years. Panacinar
emphysema with basal predominance is seen at autopsy in all adults with severe
ATT deficiency. Liver cirrhosis and carcinoma may affect up to 30% to 40% of
patients with ATT deficiency older than 50 years.
This is the first consensus evidence-based guideline for ATT management
since the 1989 (American Thoracic Society) and 1992 (Canadian Thoracic
Society) standard statements. It is copublished by the American Thoracic
Society, the European Respiratory Society, and the Alpha-1 Foundation. A
multidisciplinary Task Force prepared the findings from 1997 to 2002. The
current report includes updated research findings for the cell and molecular
biology, diagnosis, natural history, and treatment of individuals at risk for,
and those suffering from, ATT deficiency.
Diagnostic testing is recommended for patients with early-onset
emphysema or in the absence of recognized risk factors for emphysema
(smoking and occupational dust exposure), emphysema with prominent basilar
hyperlucency, unexplained liver disease, necrotizing panniculitis,
antiproteinase 3-positive vasculitis (C-ANCA), or family history of the
above, and bronchiectasis without unexplained etiology.
Predispositional testing is recommended for siblings of a patient with
ATT deficiency, relatives of those with homozygous or heterozygous ATT
deficiency, and those with a family history of unexplained chronic
obstructive pulmonary disease (COPD) or liver disease.
Population, prenatal, and postnatal screening are not generally
The NHLBI cohort study suggests that the most common presenting symptoms
are dypsnea on exertion (84%), wheezing (74%), cough (42%), and chronic
Risk factors for disease presentation include male sex, age older than
50 years, active and passive smoking, kerosene heaters, employment in
agriculture, and exposure to environmental respiratory irritants.
Diagnostic testing includes both quantitative tests for plasma ATT
levels and qualitative blood tests for identifying ATT genetic variants.
Initial assessment should include a chest x-ray; computed tomography
(CT), including thin slices for morphology and thick slices for
densitometry; spirometry pre- and postbronchodilator (usually only
moderately reversible); arterial blood gas analysis; lung volume measurement
by body plethysmography or helium dilution; and single-breath CO-diffusion
capacity. Ventilation-perfusion scan may be a useful tool.
Disease progression should be monitored by rate of decline of forced
expiratory volume in 1 second (FEV1),
CT lung density histograms and spirometry annually.
The life expectancy is 40 years for smokers and 65 years for nonsmokers.
rate of decline is the most important predictor of survival, with a median
survival of 6.3 years for those with 25% or less of predicted FEV1,
increasing to 10.5 and 14.2 years for those with FEV1
above 25% and 50% predicted, respectively. Bronchial hyperreactivity is a
strong prognostic indicator of FEV1
Treatment includes (a) preventive therapies such as smoking cessation,
influenza and pneumococcal vaccination, and hepatitis immunization for those
with overt liver disease; (b) symptomatic treatment including
bronchodilators, inhaled and oral steroids (to be used with caution due to
risk of bone loss resulting in loss of lung volume), antibiotics for
infectious exacerbations, oxygen for patients who desaturate during
exercise, pulmonary rehabilitation, and detection and treatment of comorbid
depression; and (c) augmentation with aerosol, recombinant, or intravenous
human plasma-derived ATT therapy for those with FEV1
of 35%-65% of predicted, although double-blind, randomized controlled trials
have not been conducted for this recommendation.
Lung transplantation produces a 5-year actuarial survival rate of 50% in
severely affected patients with lung disease, with better results achieved
with double lung transplantation. Bronchiolitis obliterans is the major
cause of death after lung transplantation. Lung volume reduction surgery
involving resection of 20%-30% of the most severely affected lung offers
only short-term improvement, has not been shown to improve survival, and is
not currently recommended.
Future research needs to focus on identifying pathophysiological
correlates, especially for bronchiectasis, risk factors other than smoking,
and randomized controlled trials for aerosol and intravenous augmentation