Alpha1-Antitrypsin (AAT) Deficiency Treatment & Management

Preventing or slowing the progression of lung disease is the major goal of AAT deficiency (AATD) management. Decreasing any proinflammatory stimuli in the alveolus, including smoking, asthma, or respiratory infection, facilitates this goal. Alternatively, augmenting or replacing the deficient enzyme, and thereby moderating inflammatory stimuli, is also important. Most patients are identified only after they develop lung disease, and the goals of treating AATD emphysema are similar to those for treating all forms of emphysema.

To decrease the risk of liver disease, vaccination against hepatitis A and B is recommended.

Smoking cessation

No treatment for emphysema has a greater effect on survival than quitting smoking.

Make a concerted effort to inform patients about the serious consequences of smoking on AATD and provide them with one of the many aids to help them quit.

Remember the 4 steps in the process of helping patients become nonsmokers: (1) ask about smoking habits; (2) advise about health effects; (3) assist the patient with encouragement, education, and nicotine replacement; and (4) arrange follow-up.

Improving lung function in AAT deficiency

Provide similar efforts to improve lung function in patients with AATD emphysema as those provided to patients with emphysema from the usual causes.

Administer short-acting beta-adrenergic agents and ipratropium bromide bronchodilators to maximize lung function. Metered-dose inhalers are the preferred method of administration because they have a lower incidence of adverse effects than other routes. No matter how they are administered, no evidence indicates that these drugs have any long-term effect on disease progression.

Inhaled corticosteroids have not been studied in patients with AATD emphysema, but many patients have significant bronchoreactivity. In this group, inhaled steroids probably help control symptoms. Patients with frequent exacerbations may also benefit. Evidence of infection can be an adverse effect.

Long-acting inhaled beta-adrenergic drugs and anticholinergics provide improved bronchodilation and symptoms for patients with COPD. They have not been studied in a population with AATD, but they are likely to provide the same benefits.

Reserve oral corticosteroids for acute exacerbations with increased cough and sputum. Long-term administration of corticosteroids does not protect the lung from progressive emphysema, but it is associated with many detrimental adverse effects. Limit oral steroid use to brief courses of 1-2 weeks. Start therapy to prevent osteoporosis when long courses are administered.

Theophylline may lessen the degree of dyspnea in some individuals, and a therapeutic trial may be indicated for selected patients. The therapeutic range of theophylline is relatively small, and its metabolism frequently is altered by other drugs or illness, which can lead to frequent episodes of drug toxicity or the need for frequent monitoring of serum levels. It also should be noted that theophylline is metabolized by the liver. Likewise, when smoking, metabolism is actually increased; thus, smoking cessation may effect levels.

Preventing respiratory infections

Pneumonia and annual influenza vaccines will help prevent respiratory infections.

The ATS/ERS AAT Deficiency Task Force recommends early antibiotic therapy for all exacerbations with purulent sputum. Aggressively treatment of infections may help decrease the potential for additional lung injury from an influx of neutrophils into the alveolus.

Providing pulmonary rehabilitation

According to a National Institutes of Health (NIH) workshop, pulmonary rehabilitation is defined as "a multi-disciplinary continuum of services directed to persons with pulmonary disease and their families, usually by an interdisciplinary team of specialists, with the goal of achieving and maintaining the individual's maximum level of independence and function in the community."

Most programs combine education, exercise conditioning, breathing training, chest physical therapy, and respiratory muscle training with nutritional counseling and psychological support.

Therapy does not improve pulmonary function test results, but well-controlled studies document significant improvement in exercise endurance, exercise work capacity, level of dyspnea, quality of life, and reduction of health-related expenses.

Reducing hypoxemia

Hypoxemia accelerates mortality in patients with severe airflow obstruction, and oxygen supplementation prolongs survival for this group.

Oxygen also increases exercise capacity, improves mental performance, decreases dyspnea with exercise, and improves sleep quality.

Stable patients with resting hypoxia benefit most if they wear their oxygen mask continuously. The benefits for patients with hypoxemia only during exercise or sleep are not as clear, and oxygen may be prescribed for those intervals when the oxygen saturation is likely to be low.

Replacing enzymes

Alpha1-antitrypsin-deficient individuals who have or show signs of developing significant emphysema can be treated with Prolastin, a pooled, purified, human plasma protein concentrate replacement for the missing enzyme that has been screened for HIV and hepatitis viruses, although practitioners should immunize patients against hepatitis regardless. It also is heat-treated as an additional precaution against transmission of infection. The US Food and Drug Administration (FDA) has approved 2 other alpha1-antitrypsin protein concentrates, Aralast and Zemaira, for augmentation therapy.

Weekly IV infusions of alpha1-antitrypsin protein concentrates restore serum and alveolar alpha1-antitrypsin concentrations to protective levels. Although other dosing regimens have been used, only the weekly infusion schedule has US FDA approval.

No controlled studies have proven that IV augmentation therapy improves survival or slows the rate of emphysema progression. Results from the NIH patient registry and a comparison of Danish and German registries have been published, and both suggest that augmentation therapy has beneficial effects. Although they were not controlled treatment trials, the similarity of the results suggests that the findings are significant.

The NIH report described an overall death rate 1.5 times higher for those who did not receive augmentation therapy and a rate of FEV₁ decline (54 mL/y) in alpha1-antitrypsin-deficient individuals, about twice that of healthy nonsmokers but about 50% that of smokers (108 mL/y). While Prolastin augmentation therapy did not improve the average FEV₁ decline (54 mL/y) in the group as a whole, participants with moderate airflow obstruction (FEV₁ 35-60% of predicted value) had a slower rate of decline (mean difference 27 mL/y).

These findings bolster the long-held belief that augmentation therapy provides clinical benefit. Studies of Aralast and Zemaira have shown equivalency with Prolastin in achieving and maintaining alpha1-antitrypsin serum levels and alveolar epithelial levels above the target level. No studies of Aralast or Zemaira have been performed to show effects on FEV₁, rate of decline of FEV₁, or survival.

Current guidelines recommend augmentation therapy for individuals with abnormal alpha1-antitrypsin genotypes who have alpha1-antitrypsin levels below 11 μM and documented evidence of airflow obstruction in pulmonary function tests. ^{[16, 17]}

While no firm guidelines have been developed for initiating or continuing augmentation therapy, most pulmonary physicians require the serum level to be below the threshold protective value and that the patient have one or more of the following: signs of significant lung disease: chronic productive cough or unusual frequency of lower respiratory infection, airflow obstruction, accelerated decline of FEV₁, or chest radiographic or CT evidence of emphysema.

The ATS recommends starting treatment when the FEV₁ is less than 80% of the patient's predicted value, though the benefits of augmentation therapy for individuals with severe (FEV₁< 35%) or mild (FEV₁ >60%) airflow obstruction are less, as shown in studies with Prolastin.

Evidence for the use of alpha1-antitrypsin augmentation in patients after lung transplantation for alpha1-antitrypsin deficiency is insufficient. However, observational studies do show that inflammation from acute rejection or infection allows for free elastase activity in the epithelial lining fluid of individuals who have undergone lung transplantation. Therefore, the ATS/ERS Task Force favors the use of augmentation therapy for lung transplant recipients during episodes that provoke inflammation.

A 2008 commentary by the authors of the Medical and Scientific Advisory Committee of the Alpha-1 Foundation regarding the use of augmentation therapy for PI*MZ heterozygotes states that currently, until supportive data in the subset of heterozygotes becomes available, the only approved use for augmentation therapy is for PiZZ individuals. ^[19]

The Canadian Thoracic Society recommends the use of augmentation therapy in nonsmoking or smoking individuals with COPD attributable to emphysema and documented AATD who are receiving optimal and pharmacological and nonpharmacological therapy.

Other potential therapies for AAT deficiency

Several manufacturers are testing alternative routes of administration of current augmentation medications. Although IV replacement therapy shows promise in delaying progression the disease, it has the disadvantage that only 2% of the administered drug reaches the lungs. In addition, IV replacement requires weekly visits for treatment. Testing is now underway to investigate direct application of Prolastin in the lungs by inhalation. With commercial inhalation devices and deep slow inhalation, peripheral deposition of approximately 60% of aerosolized drug can be achieved. Further randomized, blinded, controlled efficacy studies are needed, though the small doses and ease of administration make inhalation therapy an attractive option.

Some manufacturers are investigating alternative sources of augmentation therapy particularly given concerns related to the limited supply of the pooled human plasma and the potential for transmission of infectious agents. Transgenic production of human alpha1-antitrypsin protein has been accomplished in sheep and goats. Recombinant technology has also been used to produce human alpha1-antitrypsin in yeast. Unfortunately, because of differences in the glycosylation of the alpha1-antitrypsin protein in the different species, these proteins are cleared rapidly from human circulation; therefore, IV administration is difficult. However, such transgenic or recombinant sources may prove useful in inhalation devices.

Other investigations have targeted the emphysematous changes in the lungs. Studies with elastase induced emphysema in rats suggested that administration of all-trans retinoic acid (ATRA) caused reversal of the emphysematous changes due to stimulation of growth of new alveoli by ATRA. Other trials are testing hyaluronic acid as individuals with emphysema have been noted to have reduced levels of hyaluronic acid in their lungs. Last, investigators are considering antioxidants, such as vitamins A, C and/or E, as potential treatments for emphysema.

The most common alpha1-antitrypsin genetic defects prevent release of the protein from hepatocytes because of inappropriate polymerization and folding. Some investigators are testing processes or medications that could promote release from the liver cells. Synthetic chaperones, such a 4-phenyl-butyric acid (4-PBA), have been used in cystic fibrosis and are being studied in alpha1-antitrypsin deficiency. Initial results show modest increases in serum alpha1-antitrypsin levels, but GI adverse effects can be dose limiting. Work is being done on molecular interventions, such as the introduction of small peptides that fit into the abnormal alpha1-antitrypsin molecule at the site where abnormal folding begins. Other approaches are to replace specific amino-acid targets in the folding site to prevent abnormal folding.

Insertion of a normal human alpha1-antitrypsin gene has been performed in muscle and liver cells. Gene-repair technologies are also being studied, as are attempts to turn off production of the abnormal gene product.

Transfer of care

AATD is a rare problem, yet it demands substantial expertise for appropriate management and counseling.

Physicians without specific training in the management of this disease or without the time to obtain the necessary expertise should not hesitate to transfer the care of patients to a physician or center with the necessary experience.

The Alpha-1 National Association, 1-800-4-ALPHA-1, can help in identifying physicians with experience in the management of this disorder.

Two surgical approaches may help selected patients with emphysema due to alpha1-antitrypsin deficiency (AATD).

Volume-reduction surgery in AAT deficiency

Volume-reduction surgery has generated nationwide interest and hope for patients with all types of emphysema. ^[20]

Selected patients with severe emphysema and significant air trapping have experienced symptomatic improvement by removing the most severely affected 20-35% of each lung. Spirometry and exercise tolerance generally improve following postoperative recovery. Dyspnea generally is diminished. The effects on blood gas values are variable.

Some of the enthusiasm for the procedure has waned, even as surgical mortality rates have diminished, because the duration of improvement seems to be brief; an accelerated rate of FEV₁ decline appears to occur after the surgery.

The randomized controlled National Emphysema Treatment Trial showed benefit to only those with poor exercise tolerance and predominantly upper lobe disease. Others with diffuse disease, basilar disease, and/or good exercise tolerance did not benefit from lung-volume reduction. In some instances, mortality was increased. This study included patients with emphysema of all etiologies.

A small prospective study of 21 patients with alpha1-antitrypsin deficiency showed improvement in the mean dyspnea score at 3 months after surgery. This finding persisted for as long as 3.5 years. Improvements were also noted in mean FEV₁, vital capacity, and the ratio of residual volume to total lung capacity; these results persisted for 1-2 years. Patients with heterogeneous emphysema with little or no inflammatory airway disease appeared to benefit most. Overall, changes in patients with advanced emphysema from alpha1-antitrypsin deficiency were inferior to those changes in patients with smoking-related emphysema, as they were decreased in magnitude and duration.

Lung transplantation in AAT deficiency

If patients are at substantial risk of early mortality and are otherwise healthy, they may be candidates for lung transplantation.

Contact a local transplant center before patients become too ill (cachexia, inactivity, frequent infections). With a recent change in the system for allocation of lungs for transplantation, patients with emphysema are being more carefully evaluated for listing. Many transplant programs have adopted the BODE index to identify patients with emphysema who are most likely to benefit from transplantation. The uncertainties of emphysema exacerbations and complications that might prevent transplantation make it imperative that patients be referred when their BODE index is 5-6 or if they have experienced an episode of acute hypercapnic respiratory failure. ^[21]

Liver transplantation in AAT deficiency

Liver transplantation is the definitive treatment for advanced liver disease. ^[3] Despite the normalization of AAT levels after liver transplantation, the FEV₁ continues to decline unexpectedly after liver transplantation in some ZZ or SZ phenotype patients. ^[22]

The diagnosis of alpha1-antitrypsin deficiency (AATD) emphysema is not difficult, but most physicians have no experience treating a patient, in determining the need for enzyme replacement, in providing counseling, or in answering the questions that this uncommon hereditary disorder generates. Consultation with a specialist offers answers to these and other needs.

The Alpha-1 National Association, 1-800-4ALPHA-1, can help in locating physicians with interest and experience in caring for these patients.

Several organizations have been created to provide support, education, advocacy, and links to ongoing research.

• Alpha-1-Association, phone 800-521-3025, fax 410-216-6983

• AlphaNet, phone 800-577-2638

• Alpha-1-Foundation, phone 877-2CUREA1 or 877-228-7321, fax 305-567-1317

• Alpha-1 Advocacy Alliance, phone 866-FOR-A1AA or 866-367-2122

Patients with advanced COPD are characterized by a significant reduction in fat-free muscle mass. This pulmonary cachexia is common in patients with alpha1-antitrypsin deficiency (AATD) and is associated with a decline in clinical status and a harbinger of mortality in emphysema. The syndrome is a result of multiple factors, including hypermetabolism, drug therapy, inactivity, and aging. Prolonged glucocorticoid administration accelerates the process.

Protein-calorie supplementation, as one component of a comprehensive treatment program, may reverse the loss of muscle mass, and dietary counseling may aid patients at high nutritional risk. Adding fat-based nonprotein calories may benefit patients with respiratory failure who are receiving mechanical ventilation. However, other than this special circumstance, little evidence exists to suggest that this dietary manipulation aids ambulatory patients.

Dyspnea limits activity, which results in deconditioning and further reductions in activity levels. Encourage all patients with lung disease to maintain activity levels. Pulmonary rehabilitation programs and patient support groups are particularly helpful.

Instruct patients with homozygous deficiency to avoid exposure to cigarette smoke.

Chemical exposures might also have detrimental effects on pulmonary function, but no studies have been conducted to show a relationship between employment and progression of airflow obstruction.

Excessive alcohol consumption should be avoided as it may hasten alpha1-antitrypsin deficiency (AATD)‒associated liver damage.

Measuring pulmonary function yearly permits better counseling and planning for interventions such as initiating replacement therapy (if not already started) or transplantation preparation.

Repeat influenza vaccination yearly.

Repeat pneumococcal vaccination every 5 years.

For all individuals with the PiZZ genotype, periodic evaluations of liver function are recommended.

For all persons with established liver disease, ultrasound monitoring every 6-12 months is recommended in order to detect early fibrotic changes and hepatocellular carcinoma.