eMedicine Specialties > Pulmonology > Obstructive Airways Diseases

Alpha1-Antitrypsin Deficiency: Follow-up

Author: Paul Fairman, MD, Director, Pulmonary Hypertension Service, Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University
Coauthor(s): Rajiv Malhotra, DO, Fellow, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University Health System
Contributor Information and Disclosures

Updated: Apr 16, 2009

Follow-up

Further Outpatient Care

• 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.

Transfer

• Alpha1-antitrypsin (AAT) deficiency 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.

Deterrence/Prevention

• 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 associated liver damage.

Complications

• Alpha1-antitrypsin – deficient patients are subject to all the complications characteristic of patients with chronic obstructive pulmonary disease from cigarette smoking.
• Complications may include pneumothorax, pneumonia, acute exacerbation of airflow obstruction, and respiratory failure.

Prognosis

• The major manifestation of alpha1-antitrypsin deficiency in the first 2 decades of life is liver disease; pulmonary manifestations appear later. Lung function appears to be normal among adolescents with PiZZ compared with a similarly matched group with alpha1-antiprotease levels in the reference range. FVC, FEV₁, residual volume, and total lung capacity measurements were not different between the 2 groups. Lung function begins to decline at some later point. FEV₁ decreases in adult PiZZ patients at 51-317 mL per year (estimated decline in healthy patients is 30 mL/y).
  • In the NIH registry, PiZZ individuals had a 16% likelihood of surviving to age 60 years in contrast to an 85% likelihood for the general US population. Emphysema was the most common cause of death (72%), and chronic liver disease was second (10%). In the NIH registry, of 1129 affected individuals, the mortality rate was approximately 3% per year and the excess mortality was ascribable entirely to lung and liver disease.⁹
  • In the Danish registry, the outlook was better, especially for nonindex cases involving nonsmokers. In this group, survival closely approximated that of the healthy Danish population. The Danish registry confirmed the poor outlook for index cases and the additional mortality risk among patients who smoked.
• Prognosis is dependent on how patients are identified. Patients found as a result of screening often have a prognosis near that of healthy people. Those identified because of their symptoms face a more limited future. Specific features that portend a poor prognosis include the following:
  • More severe degree of airflow obstruction (FEV₁ >50%, 5-y mortality rate is 4%; FEV₁ 35-49%, 5-y mortality rate is 12%; FEV₁ <35, 5-y mortality rate is 50%)
  • Significant bronchodilator response (>12% and >200 mL)
  • Smoking
  • Male sex

Patient Education

• Several organizations offer patients and family members education, support and opportunities to participate in research.
  • The Alpha-1 National Association offers a telephone hotline (1-800-4ALPHA-1), a national newsletter (Alpha-1 News), and local support groups that provide information and support for patients, their families, and their caregivers.
  • In addition, the AlphaNet and the Alpha 1 Foundation, organizations that provide services to patients and a research focus.
  • The Alpha-1 Advocacy Alliance information line is 1-866-For-A1AA.

Miscellaneous

Medicolegal Pitfalls

• Most patients with symptomatic alpha1-antitrypsin deficiency have seen several physicians over several years before their underlying problem is recognized and diagnosed. A patient could claim that (1) the physician failed to establish a diagnosis even though diagnostic testing was readily available and inexpensive, (2) that appropriate treatment was delayed, (3) that specific educational and counseling opportunities were missed, and (4) that all of these harmed the patient.

Special Concerns

• Direct population screening studies in Sweden and the United States identified 1 in 3000-5000 whites with the PiZZ phenotype. The findings suggest that about 70,000-100,000 individuals in the United States may have severe alpha1-antitrypsin deficiency, but fewer than 10,000 have been recognized, and fewer than 60% are receiving replacement therapy. Most of the 10,000 patients (approximately 80%) were identified because they were symptomatic; the remaining 20% are relatives of index cases. If the estimates are correct, an additional 60,000-90,000 alpha1-antitrypsin–deficient individuals remain unidentified in the country. This possibility suggests that physicians may be missing cases or that some affected individuals have not developed clinically significant disease. Evidence for both possibilities exists.
• Genetic screening of population groups poses several risks, including potential adverse psychological consequences and insurance or employment discrimination. However, it also offers the potential for care of patients with mild disease and the opportunity for family and individual counseling about the risks of cigarette smoking and for potential interventions to prevent smoking or to assist efforts to stop. Genetic counseling may be particularly helpful.
• Other potential therapies
  • 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 could be used 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, and 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 done in muscle and liver cells. Gene-repair technologies are also being studied, as are attempts to turn off production of the abnormal gene product.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Sarah Catherine Lyman Hellewell, MD, to the development and writing of this article.

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