Alpha1-Antitrypsin Deficiency

Background

Alpha1-antitrypsin deficiency (AATD) was first described by Laurell and Eriksson in 1963.^{[1, 2]} Laurell noted the absence of the band of alpha1- protein in 5 of 1500 serum protein electrophoreses (SPEP) submitted to his laboratory in Sweden.^[1] Laurell and Eriksson found that 3 of the 5 of these patients had emphysema at a young age, and that one had a family history of emphysema. Hence, the cardinal clinical features of AATD were established: absence of a protein in the alpha1 region of the SPEP, emphysema with early onset, and a genetic predisposition.^[1]

AATD is a relatively common genetic condition, which often goes undiagnosed. People with AATD are predisposed to obstructive pulmonary disease and liver disease (eg, cirrhosis and hepatocellular carcinoma in children and adults).^{[1, 2, 3]} AATD is one of the most common inherited disorders among white persons. Its primary manifestation is early-onset panacinar emphysema. About 1-5% of patients with diagnosed chronic obstructive pulmonary disease (COPD) are estimated to have alpha1-antitrypsin deficiency.^[4] Although extremely rare, emphysema in children with AATD has been reported.^[3] The incidence of liver disease increases with age.^[3]

Slowly progressive dyspnea is the primary symptom, though many patients initially have symptoms of cough, sputum production, or wheezing. Treatment involves smoking cessation, preventive vaccinations, bronchodilators, supplemental oxygen when indicated, and physical rehabilitation in a program similar to that designed for patients with smoking-related COPD. In addition, intravenous (IV) augmentation therapy with alpha1-antitrypsin benefits some patients.

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Pathophysiology

Alpha1-antitrypsin deficiency (AATD) is a genetically inherited autosomal-codominant condition with more than 120 alleles identified.^{[1, 2]} Alpha1-antitrypsin is the prototype member of the serine protease inhibitor (serpin) superfamily of proteins. AATD is caused by mutations in the SERPINA1 gene located in the long arm of chromosome 14.^{[1, 2, 5]}  This genetic defect alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. As a result, serum levels of alpha1-antitrypsin are decreased, leading to low alveolar concentrations, where the alpha1-antitrypsin molecule normally would serve as protection against proteases such as neutrophil elastase. The resulting protease excess in alveoli destroys alveolar walls and causes emphysema. Likewise, the accumulation of excess alpha1-antitrypsin in hepatocytes can also lead to destruction of these cells and ultimately, clinical liver disease.

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Etiology

Alpha1-antitrypsin deficiency (AATD) is an uncommon but not rare disease. It is underdiagnosed.^{[1, 2]} 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 AATD develops clinically significant disease.^[2]

The major biochemical activity of the alpha1-antitrypsin molecule is inhibition of several neutrophil-derived proteases (eg, trypsin, elastase, proteinase 3, cathepsin G). Therefore, the protein is more accurately termed alpha1-antiprotease. However, most physicians, and virtually all patients, refer to the disease as alpha1-antitrypsin deficiency, and doctors and patients often refer to those who are affected as "alphas."

Hepatocytes synthesize alpha1-antiprotease. After its release from the liver, alpha1-antiprotease circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principal function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particles in the alveoli.

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 patients with the Z allele, the alpha1-antitrypsin produced has a lysine substituted for glutamate. This results in spontaneous polymerization within the endoplasmic reticulum of the hepatocyte, which leads to decreased serum levels of alpha1-antitrypsin and thus a deficiency of peripheral alpha1-antitrypsin.

Additionally, the accumulation of intrahepatic alpha1-antitrypsin is thought to result in apoptosis of hepatocytes. This initially can manifest as laboratory abnormalities, but also can progress to hepatitis, followed by fibrosis and cirrhosis.^[6]

In healthy persons, alpha1-antiprotease serves as a protective screen that prevents alveolar wall destruction. The lungs have a large surface area and are continuously exposed to a high burden of airborne pathogens, which results in a cellular immune response. This is characterized by local release of oxidants and proteases. The presence of alpha1-antiprotease serves to keep these proteases in check and protect the lungs from unregulated protease activity. Individuals with the alpha1-antitrypsin genetic defect do not release alpha1-antiprotease from the liver, and serum and alveolar levels of the protein are low. Consequently, alveoli lack antiprotease protection. The imbalance of proteases-antiproteases in the alveoli leads to unopposed neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema.

Alveolar cell apoptosis may also play an important role in emphysema pathogenesis. Recent evidence suggests that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation.^[7]

Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years, by producing an increase in the number of neutrophils (and neutrophil elastase) in the alveolus and inactivating the remaining small amounts of antiprotease.^[1] Other factors that can accelerate the onset or worsen symptoms of disease include infections and exposures to dust and fumes, which can also cause the recruitment of neutrophils to the alveoli.

Other than cigarette smoking, the role of environmental exposures on spirometric decline in patients with alpha1-antitrypsin deficiency has been uncertain. Banauch et al investigated the possible interaction of alpha1-antitrypsin deficiency and short-term massive pollution in New York City Fire Department (FDNY) rescue workers responding to the World Trade Center (WTC) collapse. In the first 4 years after the event, they found significant accelerated declines in spirometry and increased respiratory symptoms. Declines were related to the degree of exposure at the disaster site and to the degree of AATD.^[8] These results support the theory that environmental factors other than cigarette smoke may play a role in the progression of lung disease in alpha1-antitrypsin-deficient patients. However, the size of the study was very small, and care should be taken in generalizing this theory given the unique nature of the WTC disaster. Further studies are needed.

The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. The SERPINA1 (formerly known as Pi) gene responsible for encoding alpha1-antitrypsin is located on chromosome 14 and is highly pleomorphic, with more than 100 allelic variants (denoted by letters).^[1] The variants are classified based on serum levels of alpha1-antitrypsin protein. M alleles are the most common and normal variants. Most patients with clinical disease are homozygous SS or ZZ or heterozygous MS, MZ, or SZ.

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 µmol/L or 150-350 mg/dL).

The most common form of alpha1-antitrypsin deficiency is associated with allele Z, or homozygous PiZ (ZZ). Serum levels of alpha1-antitrypsin in these patients are about 3.4-7 µmol/L, 10-15% of normal serum levels. Serum levels greater than 11 µmol/L appear to be protective.^{[1, 4]} Emphysema develops in most (but not all) individuals with serum levels less than 9 µmol/L.

Other genotypes associated with severe alpha1-antitrypsin deficiency include PiSZ, PiZ/Null, and PiNull. The S gene is more frequent among individuals of Spanish or Portuguese descent, whereas the frequency of the Z gene is highest in patients of Northern or Western European descent.

Patients with the PiSZ phenotype have a 20-50% increased likelihood of developing emphysema compared with MM homozygotes. Serum levels of patients with PiSZ alpha1-antitrypsin deficiency are 75-120 mg/dL.

Patients with the null gene for alpha1-antitrypsin do not produce any alpha1-antitrypsin and are at high risk for emphysema (100% by age 30 years). None with the null gene develops liver disease because of a lack of production, and thus accumulation, of alpha1-antitrypsin in the hepatocytes.

Carriers or heterozygotes (MZ, MS or M/Null) have levels approximately 35% of normal levels, but they do not develop disease.

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Epidemiology

Frequency

United States

Alpha1-antitrypsin deficiency (AATD) is 1 of the 3 most common lethal genetic diseases among adult white persons, affecting 1 per 3000-5000 individuals. Severe AATD affects an estimated 70,000-100,000 individuals, and approximately 25 million people carry of at least 1 deficient gene. However, less than 10% of severely deficient individuals are currently identified.^{[1, 2, 9, 10]}

International

AATD has been identified in all populations, but it is most common in individuals of Northern European (1 in 1600) and Iberian descent. Similar rates are found among white persons worldwide, with an estimated 117 million carriers and 3.4 million affected individuals.

Race

White persons constitute an estimated 117 million carriers and 3.4 million affected individuals. Racial groups other than whites are affected less frequently.

Sex

Women and men are affected in equal numbers.

Age

The enzyme deficiency is congenital and has a bimodal distribution with respect to symptoms. It can be seen in neonates as a cause of neonatal jaundice and hepatitis. It can present in infants as cholestatic jaundice and in children as hepatic cirrhosis or liver failure. AATD is also the leading underlying condition requiring liver transplantation in children.

In adults, AATD leads to chronic liver disease in the fifth decade of life. As a cause of emphysema, it is seen in nonsmokers in the fifth decade of life and during the fourth decade of life in smokers.

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Prognosis

The major manifestation of alpha1-antitrypsin deficiency (AATD) in the first two 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 two 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.^[11]

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

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 history of having symptoms for several years and being evaluated by multiple physicians before the diagnosis was made is common. At present, the median time between the observation of symptoms and diagnosis is approximately 8 years.^[10] The mortality rate is high in symptomatic patients.

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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.

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History

Not all the population with alpha1-antitrypsin deficiency (AATD) develops attributable disease.^[2] The presentation of disease depends on the type of mutation associated with AATD However, most of the symptoms secondary to AATD are limited to the respiratory system.^[1] Liver diseases such as cirrhosis and chronic hepatitis are the result of the abnormal accumulation of AAT within the hepatocytes and hepatoma, and emphysema due to loss of the proteolytic protection of the lung are the two major clinical presentations of AATD of the PiZZ type. Less common associations are panniculitis and an increase in the association of cytoplasmic antineutrophil cytoplasmic antibody‒positive vasculitis.^[5]

The initial symptoms of alpha1-antitrypsin deficiency include cough, sputum production, and wheezing. Symptoms are initially 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.

Dyspnea is the symptom that eventually dominates AATD (84%).^[1]

Similar to other forms of emphysema, the dyspnea of AATD is initially evident only with strenuous exertion. Over several years, it eventually limits even mild activities.

Patients with AATD frequently develop dyspnea 20-30 years earlier (at age 30-45 y) than do smokers with emphysema and normal alpha1-antitrypsin levels.

Cigarette smoking accelerates the progression of emphysema in patients with AATD. Symptoms develop about 10 years earlier in alpha1-antitrypsin-deficient individuals who smoke regularly.

By the time dyspnea becomes the dominant manifestation and a diagnosis is established, most patients will have seen several physicians over several years. Efforts to improve the interval between the onset of symptoms and the diagnosis of AATD have been disappointing. Between 1968 and 2003, a significant improvement has not been noted in the average interval (approximately 8.3 +/- 6.9 y) and the number of medical evaluations before an initial diagnosis is made.^{[2, 12]} It should be noted, however, that improvement has been shown in AATD detection in older individuals.^[12]

Based on a large clinical population study, Bornhorst et al suggested that early diagnosis of AATD is sporadic and average age of diagnosis is 45.5 ± 9.5 years, as noted in other surveys.^[10]

Often this diagnosis is missed, as it presents similarly to other more common illnesses such as asthma, COPD, or chronic cough. Thus, the healthcare provider must have a high level of suspicion and consider AATD in the differential diagnosis.

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Physical Examination

No single physical sign confirms a diagnosis of alpha1-antitrypsin deficiency (AATD) 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 paradoxus.

Hyperinflation results in barrel chest, increased percussion note, decreased breath sound intensity (see breath sound assessment video, below), and distant heart sounds.

View Video

Breath sound assessment. Video courtesy of Therese Canares, MD, and Jonathan Valente, MD, Rhode Island Hospital, Brown University.

Patients with mild emphysema generally have no abnormal findings on physical examination. Even moderate disease may be evident only when a complicating acute 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 easily missed if the physician relies solely on physical findings.

In those with unexplained liver disease with or without respiratory symptoms should be evaluated for AATD. Assessment for signs for stigmata of chronic liver disease, and panniculitis must be performed. Hepatomegaly can be seen, but is not specific for AATD.

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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.

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Approach Considerations

Despite being a relatively common disease, alpha1-antitrypsin deficiency (AATD) is frequently underrecognized, with only approximately 15% of the population with AATD having been diagnosed with this disease.^[5] Limited knowledge about the disease as well as lack of adherence to screening guidelines for those symptomatic patients presenting with fixed airflow obstruction are considered to have a negative impact in the early and opportune diagnosis of AATD.^[13]

Greulich et al in 2016 found an increase in the detection of AATD in patients with COPD, emphysema, and/or bronchiectasis by raising awareness on the availability of current diagnostic tests.^[14]

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Laboratory Studies

Alpha1-antitrypsin deficiency (AATD) should be suspected in any person who presents with early onset emphysema or COPD, regardless of his or her of smoking history.^[15] And, in those individuals with unexplained liver disease at any age, including obstructive jaundice of infancy.^[3] Definitive diagnosis of AATD is most frequently accomplished with use of a combination of biochemical and/or genetic tests.^[9] Therefore, AATD testing should be seen as a laboratory diagnosis and not as a clinical diagnosis,^[16] and the healthcare provider should maintain a low level of suspicion as the diagnosis is often missed.

Serum alpha1-antitrypsin levels

Serum alpha1-antitrypsin levels are used to identify disease and determine levels. The study is most commonly performed by nephelometry.

Testing is readily available in most clinical laboratories and is inexpensive and underutilized. The AAT Deficiency Task Force of the American Thoracic Society (ATS) and European Respiratory Society (ERS) had published standards guidelines aimed at improving clinical recognition of AATD and avoiding underrecognition or misdiagnosis.

Clinical features that suggest the possibility of AATD and the need for serum testing include emphysema at an early age (age 45 y or younger), emphysema in a patient with the absence of a recognized risk factor like smoking or occupational dust exposure, emphysema of the lower lungs, asthma with persistent airflow obstruction after treatment, unexplained liver disease, necrotizing panniculitis, antiproteinase 3-positive vasculitis (antineutrophil cytoplasmic antibody [C-ANCA]–positive vasculitis), bronchiectasis without a clear etiology, and a family history of emphysema, bronchiectasis, liver disease, or panniculitis.^[17]

Serum testing is used for diagnostic testing and predispositional testing as in those patients with family histories compatible with alpha1-antitrypsin deficiency or with siblings with known alpha1-antitrypsin deficiency. However, guidelines from the ATS/ERS AAT Deficiency Task Force do not recommend predispositional fetal testing or population screening unless the prevalence of AATD is high (>1 case per 1500 population), smoking is prevalent, and adequate counseling services are available.

Most hospital laboratories report serum alpha1-antitrypsin levels in milligrams per decimeter, with a reference range of approximately 100-300 mg/dL. Levels less than 80 mg/dL suggest a significant risk for lung disease. Reference laboratories usually report the serum levels in micromolar concentration, with a reference range of 20-60 µmol/L and a threshold level for emphysema at 11 µmol/L.

Serum alpha1-antitrypsin concentration alone has a low sensitivity for detecting AATD.^[9]

See the image below.

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Graph outlines alpha1-antitrypsin levels and risk of lung disease for the 5 most common phenotypes of alpha1-antitrypsin deficiency (AATD). Dashed lin....

Phenotyping

Test patients with low or borderline serum levels with phenotyping (serum levels < 100 mg/dL). Alpha1-antitrypsin phenotype determined by isoelectric focusing (IEF) is the most commonly used method to definitively detect the alpha1-antitrypsin phenotype that indicates a risk for AATD. It is considered the criterion standard test for identifying alpha1-antitrypsin variants, but involves complex interpretation.^{[3, 9, 15, 16]} Use an experienced reference laboratory for this test. Phenotyping with dried blood-spot samples, by using a blood drop absorbed on special paper, permits easier transport of samples and is suitable for screening purposes, but the identification of a deficient variant should be confirmed with serum or plasma samples.

Patients and healthcare providers can obtain a free Alpha-1 Test Kit (finger-stick test) from the Alpha-1 Research Registry at (877) 886-2383, which is associated with the Alpha-1 Association. The test sample can be submitted directly to the Registry at the Medical University of South Carolina. The test screens for the most common Z and S genotypes. If more extensive testing is needed to determine an alpha1-antitrypsin level, both patient and physician are notified. There is no charge for the Alpha-1 Screening Program.

Phenotyping is required to confirm AATD. Do not initiate alpha1-antitrypsin replacement therapy without testing.

More than 100 phenotypic variants of AATD have been identified, but one phenotype, PiZZ, is responsible for nearly all cases of AATD emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 µmol/L, about 10-20% of the reference range levels. Other phenotypes associated with alpha1-antitrypsin emphysema and liver disease include PiSZ and PiZ/Null. PiNull/Null is not associated with liver disease but is associated with alpha1-antitrypsin deficiency emphysema.

Functional assay of alpha1-antiprotease

In rare circumstances, a third test is used to evaluate a patient with clinical features that are highly suggestive of alpha1-antitrypsin 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 extremely rare.

Diagnosis at a molecular level (ie, genotyping) uses DNA extracted from circulating mononuclear blood cells. This genotyping is accomplished using DNA amplification techniques with melt-curve analysis.^[9] Greene et al. established a reference compendium of known AAT phenotypes that can be used as a resource for interpreting AAT phenotypes. Test kits capable of detecting S and Z alleles on samples from mouth swabs have made genetic testing easier. The presence of rare null alleles can be inferred by genotyping, because null alleles do not produce protein that can be identified by a band of isoelectric focusing field. These tests will, however, miss the rare null alleles.

Evaluate hepatic function in patients with low or borderline levels of alpha1-antitrypsin. Measure serum transaminases, bilirubin, albumin, and routine clotting function (activated partial thromboplastin time and international normalized ratio).

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Imaging Studies

Chest radiography

Alpha1-antitrypsin deficiency (AATD) emphysema produces a hyperlucent appearance because healthy tissue has been destroyed.

The process is not uniform, with certain areas being more affected than others.

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

An unusual characteristic in alpha1-antitrypsin deficiency is found in about two thirds of PiZZ patients; the emphysema has a striking basilar distribution. In contrast, cigarette smoking is associated with more severe apical disease.

See the image below.

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Close-up chest radiograph of the right lower zone of a 39-year-old woman with alpha1-antitrypsin deficiency (AATD). Normal lung markings are absent in....

High-resolution CT scanning

High-resolution CT (HRCT) scanning of the chest demonstrates widespread abnormally hypoattenuating 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 spread farther apart.

Mild forms of alpha1-antitrypsin disease can be missed on HRCT scanning. However, when the disease is moderate, discerning the panlobular nature of the process and the characteristic lower zone predominance is possible.

Severe forms may be indistinguishable from severe centrilobular emphysema.

See the image below.

View Image

CT scan of the right middle and right lower lobes in a 38-year-old patient with alpha1-antitrypsin deficiency (AATD). Entire middle lobe and much of t....

CT of abdomen may show hepatomegaly or changes associated with cirrhosis or hepatocellular carcinoma.^[15]

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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 have moderate-to-severe airflow obstruction with an FEV₁ in the range of 30-40% of the predicted value. Reduced vital capacity and increased lung volumes secondary to air trapping (residual volume >120% of predicted value) are usually present. Diffusing capacity values are reduced substantially (< 50% of predicted value) in most symptomatic patients.

Alpha1-antitrypsin-deficient individuals who are identified by screening programs or because a relative has been diagnosed with the disease may have few or no abnormalities.

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Histologic Findings

All forms of emphysema destroy alveolar walls and leave permanent abnormal enlargement of the airspace distal to the terminal bronchiole. In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are distributed uniformly throughout the acinus (lobule) and, for reasons that are not known, more commonly 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, initially at the apex of the lung.

Pathologic features from liver biopsies have shown to be nonspecific and variable depending on the classification and staging of the disease. The presence of PAS-positive globules may suggest AATD, and further investigation it is recommended.

Biopsy findings cannot replace IEF as a mode of diagnosis.

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Staging

No specific grading system exists for alpha1-antitrypsin deficiency (AATD), but the severity of the emphysema that it creates can be staged using the body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index.^[18] This 4-step evaluation of patients with chronic obstructive lung disease appears to identify a population with limited survival who might benefit from intensified therapy. The index has not been evaluated in a population of individuals with AATD.

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Medical Care

Preventing or slowing the progression of lung disease is the major goal of alpha1-antitrypsin 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 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.

Improving lung function

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). Prolastin augmentation therapy did not improve the average FEV₁ decline (54 mL/y) in the group as a whole; however, 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

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 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.

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.

• References

Surgical Care

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

Volume-reduction surgery

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

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

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]

• References

Consultations

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

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Diet

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.

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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.

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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 (AATD)‒associated liver damage.

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Long-Term Monitoring

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.

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Guidelines Summary

Indications for diagnostic testing for alpha1-antitrypsin deficiency (AATD) as per the American Thoracic Society and the European Respiratory Society are as follows^{[5, 17]} :

• Symptomatic adults with emphysema, chronic obstructive pulmonary disease (COPD), or asthma with airflow obstruction that is incompletely controlled after aggressive treatment with bronchodilators
• Individuals with unexplained liver disease, including neonates, children, adults, and older adults
• Asymptomatic individuals with persistent obstruction on pulmonary function tests (PFTs) with identifiable risks factors (eg, smoking, occupational exposure)
• Adults with necrotizing panniculitis

Management recommendations are as follows:

• The use of intravenous augmentation therapy for individuals with established airflow obstruction from AATD

General management of obstructive lung disease are as follows:

• AAT repletion
• Inhaled bronchodilators
• Vaccinations against influenza and Pneumococcus to prevent infections
• Supplemental oxygen when indicated by conventional criteria
• Pulmonary rehabilitation for individuals with functional impairment
• Consideration of lung transplantation for selected individuals with severe functional impairment and airflow obstruction
• During acute exacerbations of COPD, AAT repletion should be included

The Spanish Society of Pneumology and Thoracic Surgery (SEPAR) recommends the following^[13] :

• All COPD patients should be screened for AATD at least once in their lifetime

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Medication Summary

The most important health intervention for a person with alpha1-antitrypsin deficiency (AATD) is avoiding cigarette smoking. Smoking clearly advances the progression of emphysema in severely deficient individuals by as much as 15 years over their nonsmoking counterparts.

Airflow obstruction and symptoms resulting from AATD can be treated 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. Likewise, corticosteroids may provide some short-term relief, but they have no proven long-term benefit in inhaled or oral preparations. Because of their long-term adverse effects, avoid oral steroids. For more information, see Emphysema.

Prescribe oxygen if patients are hypoxemic at rest, with activity, or during sleep.

Consider replacement (or augmentation) therapy to slow the progression of emphysema. At present, IV augmentation therapy is the only FDA-approved treatment specific for AATD. It is most clearly indicated for patients with moderate degrees of airflow obstruction (FEV₁ 35-65% of predicted). Three preparations are available. Although purifications and/or preparations differ, all are equivalent, and none have been a cause of hepatitis or HIV infection. Each is approved at the same dose and administration, that is, 60 mg/kg/wk given IV. See the Treatment section for more detail.

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Alpha1-proteinase inhibitor (Prolastin-C, Aralast NP, Glassia, Zemara)

• Dosing, Interactions, etc.

Clinical Context:  This is a sterile, stable, lyophilized preparation of purified human alpha1-antiprotease inhibitor prepared from pooled human plasma by using a cold alcohol fractionation process followed by further purification steps. Each unit of plasma is tested for HIV, hepatitis B, and hepatitis C before inclusion in the product. The product is treated with a solvent detergent mixture to inactivate viral agents to reduce the potential risk of infectious-agent transmission. No cases of viral infections have been attributed to the product. It is indicated as replacement (or augmentation) for normal serum alpha1-antiprotease to prevent progression of emphysema in patients with congenital deficiency of AAT with clinically evident emphysema.

These drugs have been approved for use in the United States.

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Class Summary

These drugs are used for long-term replacement in individuals with clinically demonstrable panacinar emphysema.

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