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 panniculitis.

Based on the presence or absence of these features, the Task Force issued specific recommendations for diagnostic genetic testing in different clinical settings.

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

Clinical Context

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.

Highlights

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 recommended.

The NHLBI cohort study suggests that the most common presenting symptoms are dypsnea on exertion (84%), wheezing (74%), cough (42%), and chronic bronchitis (8%-40%).

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. FEV₁ 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 loss.

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 therapy.