Lab Studies:
 

• Serum AAT levels

• To identify disease, determine serum AAT levels.

• Testing is readily available in most clinical laboratories and is underutilized.

• Clinical features that suggest the possibility of AAT deficiency and the need for serum testing include emphysema at an early age, emphysema in a nonsmoker (or light smoker), a family history of emphysema, emphysema of the lower lungs (as determined by chest radiograph), adult-onset asthma, and recurrent bronchitis.

• Serum testing is a screening procedure. Test most patients with chronic or recurrent respiratory symptoms (dyspnea, cough, wheezing) at least once.

• Most hospital laboratories report serum AAT levels in mg/mL, with a reference range of approximately 100-300 mg/mL. Levels less than 80 mg/mL suggest a significant risk for lung disease.

• Reference laboratories usually report the serum levels in micromolar concentration, with a reference range of 20-60 mmol/L and a threshold level for emphysema at 11 mmol/L.

• Phenotyping

• Test patients with low or borderline serum levels with phenotyping. Use an experienced reference laboratory for this test.

• Phenotyping is required to confirm the presence of AAT deficiency. Do not initiate AAT replacement therapy without testing.

• More than 100 different phenotypic variants of AAT deficiency have been identified, but 1 phenotype, PiZZ, is responsible for nearly all cases of AAT emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 mmol/L, about 10-20% of the reference range levels.

• Functional assay of alpha1 antiprotease

• In rare circumstances, a third test is utilized to evaluate a patient with clinical features that are highly suggestive of AAT deficiency but whose serum levels are within the reference range.

• Specialized laboratories can perform a functional assay of alpha1 antiprotease, which measures the ability of the patient's serum to inhibit human leukocyte elastase. Such a defect is rare.

• Evaluate hepatic function in patients with low or borderline levels of AAT. Measure serum transaminases, bilirubin, albumin, and routine clotting function (activated partial thromboplastin time and international normalized ratio).

Imaging Studies:
 

• Chest radiograph

• AAT deficiency emphysema produces a hyperlucent appearance because healthy tissue has been destroyed.

• The process is not uniform; certain areas are affected more than others.

• Affected regions also are described as oligemic because they lack the normal rich pattern of branching blood vessels.

• An unusual characteristic in AAT emphysema is the basilar distribution of abnormalities found in approximately 75% of PiZZ patients; however, cigarette smoking is associated with more severe apical disease.

• High-resolution CT scan

• High-resolution CT (HRCT) scan of the chest demonstrates widespread abnormally low attenuation areas resulting from a lack of lung tissue. As in smoking-related emphysema, the appearance has been described as a simplification of lung architecture. As tissue is lost, pulmonary vessels appear smaller, fewer in number, and farther spread apart.

• Mild forms of AAT disease can be missed by HRCT scan, but, when the disease is moderate, discerning the panlobular nature of the process and the characteristic lower zone predominance is possible.

• Very severe forms may be indistinguishable from severe centrilobular emphysema.

Other Tests:
 

• The severity of emphysema is best documented with standard pulmonary function tests. Spirometric determination of forced vital capacity (FVC) and forced expired volume in 1 second (FEV₁) are essential. Determining lung volume (preferably by plethysmography) and measuring diffusing capacity provide additional valuable information.

• Patients who are symptomatic at the time of diagnosis usually demonstrate moderate-to-severe airflow obstruction with an FEV₁ in the range of 30-40% of the predicted value. Also, reduced vital capacity and increased lung volumes secondary to air trapping (residual volume >120% of predicted value) usually are present. Diffusing capacity values are reduced substantially (<50% of predicted value) in most symptomatic patients. AAT-deficient individuals who are identified by screening programs or because a relative has been diagnosed with the disease may have few or no abnormalities.

Medical Care: Preventing or slowing the progression of lung disease is the major goal of AAT deficiency management. Facilitate this goal by decreasing any proinflammatory stimuli in the alveolus, including smoking, asthma, or respiratory infection. Alternatively, augmenting or replacing the deficient enzyme, and thereby moderating inflammatory stimuli, is possible. Most patients are identified only after they develop lung disease, and the goals of treating AAT deficiency emphysema are similar to those for treating all forms of emphysema.

• Quitting smoking

   

  • 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 AAT deficiency and provide them with one of the many aids to help them quit.

  • Remember the 4 stages 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.

  • Most patients with AAT deficiency quit successfully.

• Improving lung function

   

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

  • Administer 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.

  • 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.

  • Inhaled corticosteroids have not been studied in patients with AAT deficiency emphysema, but many patients have significant broncho-reactivity and, in this group, inhaled steroids probably help control symptoms.

  • 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 a long list of detrimental adverse effects. Limit their use to brief courses lasting 1-2 weeks. Institute therapy to prevent osteoporosis when administering longer courses.

• Preventing respiratory infections

   

  • Pneumonia and annual influenza vaccines will help prevent respiratory infections.

  • Aggressively treating infections that occur despite prophylaxis may help decrease the potential for additional lung injury from an influx of neutrophils into the alveolus.

• 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 documented significant improvement in exercise endurance, exercise work capacity, level of dyspnea, quality of life, and reducing 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

   

  • AAT-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. It also is heat-treated as an additional precaution against transmission of infection. Immunize patients against hepatitis regardless.

  • Weekly intravenous infusions of Prolastin restore serum and alveolar AAT concentrations to protective levels. Although other regimens for administration have proven to provide similar serum levels, only the weekly infusion schedule has US Food and Drug Administration approval.

  • No controlled studies have proven that intravenous 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 AAT-deficient individuals approximately twice that of healthy nonsmokers but approximately 50% that of smokers (108 mL/y). Prolastin treatment did not improve the average FEV₁ decline (54 mL/y); however, participants with moderate airflow obstruction (FEV₁ 35-49% of predicted value) experienced a slower rate of decline (mean difference 27 mL/y). These findings bolster the long-held belief that augmentation therapy provides clinical benefit. 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 1 or more of the following: signs of significant lung disease such as chronic productive cough or unusual frequency of lower respiratory infection, airflow obstruction, accelerated decline of FEV₁, or chest radiograph or CT scan evidence of emphysema.

  • The American Thoracic Society recommends starting treatment when the FEV₁ is less than 80% of the patient's predicted value.

Surgical Care: Two surgical approaches may help selected patients with AAT deficiency.

• Volume reduction surgery

• This procedure has generated nationwide interest and hope for patients with all types of emphysema.

• 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.

• A randomized controlled trial (National Emphysema Treatment Trial) currently is recruiting patients at 17 medical centers around the country to clarify the benefits and risks associated with the surgery.

• Because experience is limited, whether AAT deficiency emphysema patients fare better or worse with this surgery is unknown.

• Lung transplantation

• Transplantation is the second surgical option for patients with severe AAT emphysema.

• 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). Unfortunately, the average waiting time for a transplant in the United States is 18-24 months, and the uncertainties of emphysema exacerbations and complications that might prevent transplantation make it imperative that patients be referred well in advance of need.

• Offer patients with an FEV₁ less than 35% of predicted value (5-y mortality rate of 50%), especially men or individuals with substantial broncho-reactivity, the opportunity to discuss the option with a transplant physician.

Consultations: The diagnosis of AAT deficiency emphysema is not difficult, but most physicians will have no experience treating a patient, providing counseling, or answering the questions that an uncommon hereditary disorder generates. Several visits with a specialist in the first year usually are enough to meet a patient's needs. The Alpha-1 National Association, 1-800-4ALPHA-1, http://www.alpha1.org/ can facilitate locating physicians with interest and experience in caring for these patients.

Diet: Patients with advanced chronic obstructive lung disease are characterized by a significant reduction in fat-free muscle mass. This pulmonary cachexia is common in patients with AAT deficiency and is associated with a decline in clinical status. 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. Providing more fat-based nonprotein calories may benefit patients with respiratory failure who are on mechanical ventilation, but, other than this special circumstance, little evidence exists to suggest that this dietary manipulation aids ambulatory patients.

Activity: 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.

Treat airflow obstruction and symptoms resulting from AAT deficiency in a manner similar to emphysema. Bronchodilators may provide relief of some symptoms. Use antibiotics to treat bacterial complications, including pneumonia or purulent bronchitis. Neither bronchodilators nor antibiotics demonstrate any effect on disease progression. Similarly, corticosteroids may provide some short-term relief but have no proven long-term benefit in inhaled or oral preparations. Because of their long-term adverse effects, avoid oral steroids. Prescribe oxygen if patients are hypoxemic. Consider replacement (or augmentation) therapy to slow the progression of emphysema.
 

Drug Category: Respiratory enzymes -- For chronic replacement in individuals with clinically demonstrable panacinar emphysema.

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.

Transfer:
 

• 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 or http://www.alpha1.org/ can help to identify physicians with experience in the management of this disorder.

Deterrence/Prevention:
 

• Instruct patients with homozygous deficiency to avoid exposure to cigarette smoke. Chemical exposures also might have detrimental effects on pulmonary function, but no studies have been conducted to show a relationship between employment and progression of airflow obstruction.

Complications:
 

• AAT-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 AAT deficiency in the first 2 decades of life is liver disease; pulmonary manifestations appear later. Lung function appears to be normal among PiZZ adolescents when compared to a similar matched group with alpha1 antiprotease levels within 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% chance of surviving to age 60 years in contrast to an 85% chance for the general US population. Emphysema was the most common cause of death (72%), and chronic liver disease was second (10%).

• 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 smoking patients.

• 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 poorer 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:
 

• Excellent educational resources are available through the Alpha-1 National Association. This patient advocacy group offers a telephone hotline (1-800-4ALPHA-1), a national newsletter (Alpha-1 News), an internet site (http://www.alpha1.org/), and local support groups that provide information and support for patients, their families, and care givers.

Medical/Legal Pitfalls:
 

• Most patients with symptomatic AAT 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. These studies suggest that about 70,000-100,000 individuals in the United States may have severe AAT deficiency, but fewer than 10,000 have been recognized, and fewer than 50% of these 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 estimates are correct, an additional 60,000-90,000 AAT-deficient individuals remain unidentified in the country. This suggests that physicians may be missing cases and that some affected individuals may have not yet developed significant disease. Evidence for both of these 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 option of earlier care for patients with mild forms of disease, the opportunity for family and individual counseling about the risks of cigarette smoking, and encouragement to not start the habit. Assist those patients who smoke with efforts to stop. Genetic counseling may be particularly helpful, but families and affected individuals derive substantial support through the Alpha-1 National Association (http://www.alpha1.org/).

Caption: Picture 1. Close-up chest radiographic view of right lower zone of a 39-year-old woman with alpha1-antitrypsin (AAT) deficiency. Normal lung markings are absent in the costophrenic angle. Some lung markings are present in the pericardiac region, but even these are diminished.

Picture Type: X-RAY

Caption: Picture 2. CT scan of the right middle and right lower lobes in a 38-year-old patient with alpha1-antitrypsin (AAT) deficiency. The entire middle lobe and much of the lower lobe are emphysematous; normal lung structures have been replaced by abnormal airspaces. Only the posterior portions of the right lower lobe maintain a normal architecture.

Picture Type: CT

Caption: Picture 3. This graph outlines alpha1-antitrypsin (AAT) levels and risk of lung disease for the 5 most common phenotypes of AAT deficiency. The dashed line at 11 mmol/L (80 mg/mL) represents the threshold level below which emphysema is common.

Picture Type: Graph

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