eMedicine World Medical Library

Alpha1-Antitrypsin Deficiency

Last Updated: March 7, 2004
Synonyms and related keywords: alpha-1 antiprotease deficiency, alpha1 antiprotease deficiency, alpha-1 antitrypsin deficiency, AAT, early-onset panacinar emphysema, hepatic cirrhosis

 

  AUTHOR INFORMATION  

Author: Paul Fairman, MD, Medical Director of Lung Transplant Service, Professor, Department of Internal Medicine, Divisions of Pulmonary and Critical Care Medicine, Medical College of Virginia

 

Paul Fairman, MD, is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Thoracic Society, and International Society for Heart and Lung Transplantation

 

Editor(s): Ryland P Byrd, Jr, MD, Chief of Pulmonary Medicine, Medical Director of Respiratory Therapy, Quillen VA Medical Center; Professor, Department of Internal Medicine, Division of Pulmonary Diseases and Critical Care Medicine, Quillen College of Medicine, East Tennessee State University; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Om Prakash Sharma, MD, Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Southern California; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; and Zab Mohsenifar, MD, Director, Division of Pulmonary/Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center; Professor, Department of Internal Medicine, University of California at Los Angeles School of Medicine
  INTRODUCTION  

Background: Alpha1-antitrypsin (AAT) deficiency is one of the most common inherited disorders among whites. Its primary manifestation is early-onset panacinar emphysema. A minority of patients develops hepatic cirrhosis. Slowly progressive dyspnea is the primary symptom, although many patients initially have symptoms of cough, sputum production, or wheezing.

 

Pathophysiology: The genetic defect in AAT deficiency results in a molecule that cannot be released from its production site in hepatocytes. Low serum levels of the protein result in low alveolar concentrations, where the AAT molecule normally would serve as protection against antiproteases. The resulting protease excess destroys alveolar walls and causes emphysema.

 

Frequency:
 

  • In the US: This genetic defect affects 1 per 3000-5000 individuals. AAT is 1 of the 3 most common lethal genetic diseases among whites. The other 2 common fatal genetic defects are cystic fibrosis and Down syndrome.
  • Internationally: Similar rates are found among whites worldwide.

Mortality/Morbidity: Specific morbidity and mortality rates are unknown. Not all patients with homozygous deficiency develop symptomatic emphysema or cirrhosis; however, among those who develop symptomatic disease, the mortality rate is very high.

Race: Racial groups other than whites are affected rarely.

Sex: Women and men are affected in equal numbers.

Age: The enzyme deficiency is present from birth and can be an unusual cause of neonatal jaundice. Symptomatic emphysema develops in the fourth decade of life in smokers and a decade later in nonsmokers.

  CLINICAL  

History: Symptoms of AAT deficiency emphysema are limited to the respiratory system.

  • Dyspnea is the symptom that characterizes and eventually dominates AAT deficiency.
    • Similar to other forms of emphysema, the dyspnea of AAT deficiency initially is evident only with strenuous exertion. Over several years, it eventually limits even mild activities.
    • Patients with AAT deficiency frequently develop dyspnea 20-30 years earlier (age 30-45 y) than smokers with emphysema and without AAT deficiency.
    • Cigarette smoking accelerates the progression of emphysema in patients with AAT deficiency; symptoms develop about 10 years earlier in AAT-deficient individuals who smoke regularly.
  • Other symptoms, including cough, sputum production, and wheezing, may predominate in the early stages of disease.
  • Symptoms initially are intermittent, and, if wheezing is the predominant symptom, patients often are told they have asthma.
  • If recurrent episodes of cough are most prominent, patients may be treated with multiple courses of antibiotics and evaluated for sinusitis, postnasal drip, or gastroesophageal reflux.
  • By the time dyspnea becomes the dominant manifestation and a diagnosis is established, most patients will have seen several physicians over several years.

Physical: No single physical sign confirms a diagnosis of AAT deficiency emphysema. Signs characteristic of increased respiratory work, airflow obstruction, and hyperinflation eventually develop but are dependent on the severity of emphysema at the time of diagnosis.

  • Increased respiratory work is evident as tachypnea, scalene and intercostal muscle retraction, and tripod position.
  • Airflow obstruction manifests as pursed-lip breathing, wheezing, and pulsus paradox.
  • Hyperinflation results in barrel chest, increased percussion note, decreased breath sound intensity, and distant heart sounds.
  • Patients with mild emphysema generally have no abnormal findings on physical examination. Even moderate disease may be evident only when a complicating acute intercurrent infection occurs. Most of the signs generally considered a part of emphysema (from any cause) are signs of moderate-to-severe disease; mild-to-moderate disease is missed easily if the physician relies solely on the physical examination findings.

Causes: The name of this disease originated from a deficiency of the serum antiprotease, originally called AAT. The responsible genetic defect affects 1 in 3000-5000 individuals, making it 1 of the 3 most common lethal genetic diseases among whites. The other 2 common fatal genetic defects are cystic fibrosis and Down syndrome. Fortunately, not every individual with AAT deficiency develops clinically significant disease.

  • The major biochemical activity of the AAT molecule is inhibition of several neutrophil-derived proteases (eg, trypsin, elastase, proteinase 3, cathepsin G), and, therefore, the protein is more accurately termed alpha1 antiprotease. However, most physicians, and virtually all patients, refer to the disease as AAT deficiency.
  • The protein is synthesized predominantly by hepatocytes. After its release from the liver, it circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principle function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particulates in the alveolus. Alpha1 antiprotease constitutes about 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction.
  • In healthy persons, alpha1 antiprotease serves as a protective screen that prevents alveolar wall destruction. Individuals with the AAT genetic defect do not release alpha1 antiprotease from the liver, and the alveoli lack protection. The imbalance of proteases-antiproteases in the alveolus leads to unimpeded neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema.
  • Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years by increasing the number of neutrophils in the alveolus and inactivating the remaining small amounts of antiprotease.
  • The production of alpha1 antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. Nearly 24 variants of the alpha1 antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1 antiprotease (serum levels of 20-53 mmol/L). Deficient levels of alpha1 antiprotease are associated with allele Z (homozygous PiZ, serum level 3.4-7 mmol/L). Serum levels greater than 11 mmol/L appear to be protective. Emphysema develops in most (but not all) individuals with serum levels less than 9 mmol/L.
  DIFFERENTIALS  

Bronchiectasis
Bronchitis
Chronic Bronchitis
Chronic Obstructive Pulmonary Disease
Emphysema
Kartagener Syndrome
 


Other Problems to be Considered:

Immotile cilia syndrome
Cystic fibrosis


 
  WORKUP  

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.
Histologic Findings: All forms of emphysema destroy alveolar walls and leave permanent abnormal enlargement of the airspace distal to the terminal bronchiole. In AAT deficiency, the emphysematous areas are distributed uniformly throughout the acinus (lobule) and, for reasons that are not known, primarily in the basilar portions of the lung. This contrasts with centrilobular emphysema characteristic of cigarette smoking, which predominantly affects the respiratory bronchioles in the central portion of the lobule, usually initially at the apex of the lung.

 

  TREATMENT  

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.

  MEDICATION  

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.

Drug Name
 
Alpha1 protease inhibitor (Prolastin) -- Sterile, stable, lyophilized preparation of purified human alpha1 antiprotease inhibitor prepared from pooled human plasma. Indicated as replacement (or augmentation) for normal serum alpha1 antiprotease to prevent progression of emphysema. Each unit of plasma is tested for HIV, hepatitis B, and hepatitis C before inclusion in the product. Product is heat-treated to reduce potential risk of infectious agent transmission. To date, no cases of viral infections have been attributed to the product.
Adult Dose 60 mg/kg IV qwk
Pediatric Dose Not recommended
Contraindications Documented hypersensitivity; selective IgA deficiency; known anti-IgA antibody
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Administer within 3h of reconstitution; do not mix with other drugs; caution in patients at risk for circulatory overload; recipients should be immunized against hepatitis B using a licensed hepatitis B vaccine
  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.

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.
  MISCELLANEOUS  

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/).
  PICTURES  

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.
Click to see larger picture
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.
Click to see larger picture
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.
Click to see larger picture
Picture Type: Graph
  BIBLIOGRAPHY  

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  • American Thoracic Society: Guidelines for the approach to the patient with severe hereditary alpha- 1-antitrypsin deficiency. American Thoracic Society. Am Rev Respir Dis 1989 Nov; 140(5): 1494-7.
  • Brantly ML, Paul LD, Miller BH: Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis 1988 Aug; 138(2): 327-36.
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  • Seersholm N, Kok-Jensen A, Dirksen A: Survival of patients with severe alpha 1-antitrypsin deficiency with special reference to non-index cases [published errata appear in Thorax 1994 Nov;49(11):1184 and 1998 Jan;53(1):78]. Thorax 1994 Jul; 49(7): 695-8.
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