Alpha1-Antitrypsin Deficiency: A Review for Physicians

Alpha1Center
Edward J. Campbell, MD, Laboratory Director

The purpose of this review of alpha1-antitrypsin (AAT) deficiency is twofold. First, it will present some of the features of this condition; and second, it will provide a current list of references for those who wish to read more than this space will permit. In part, the motivation for this review is that medical and even subspecialty textbooks are not current and are often not accurate in their descriptions of the deficiency. The American Thoracic Society and European Respiratory Society have published a joint statement regarding evidence-based standards for the diagnosis and management of AAT deficiency in 2003.1 While useful for reference, this comprehensive document is too lengthy for casual reading, and newer information is available.

Many individuals with AAT deficiency remain clinically healthy or have minimal disease. Thus, people who have recently discovered that they have AAT deficiency should neither be unduly alarmed nor inappropriately unconcerned about their diagnoses.

AAT deficiency is the most prevalent potentially lethal hereditary disease of Caucasians. Individuals with severe AAT deficiency have an increased risk of early-onset severe pulmonary emphysema2 and of liver disease.3

Discovery of AAT deficiency by Laurell and Eriksson in 19634 provided a foundation for current thinking about the pathogenesis of pulmonary emphysema. Although AAT deficiency has become one of the best-understood genetic disorders at a molecular and protein level, many questions about the clinical disease remain unanswered. Current American and international research projects are providing answers to some of these questions.

Biochemistry of AAT

Serum was shown to inhibit trypsin nearly a century ago. A specific trypsin-inhibitory protein was isolated from the alpha1-globulin region of human serum in 1962, and was named alpha1-antitrypsin. Following the recognition that this protein inhibits a number of other proteinases, it has also been named alpha1-proteinase inhibitor. When used in a clinical context, the original terms "alpha1-antitrypsin" and "alpha1-antitrypsin deficiency" are used most often, to respect the investigators who discovered the protein and its deficiency. Details about the biochemistry of AAT have been reviewed.5

AAT is synthesized by hepatocytes, and to a lesser extent by monocytes and other cells. Most of the circulating AAT is synthesized by the liver.

Function: It is now thought that inhibition of human leukocyte elastase is the major function of AAT. Leukocyte elastase is a serine proteinase found within granules of neutrophils and monocytes. This enzyme has a number of biologically important activities; for example, it is probably very important in killing bacteria,6 in digesting injured tissue during wound healing, and in allowing neutrophils and monocytes to exit from the vasculature and penetrate tissues to reach sites of inflammation. However, if its activity is uncontrolled, it can injure a variety of structural components of normal tissues, and uncontrolled leukocyte elastase may be proinflammatory.7,8 Deficiency of AAT removes a major control mechanism for leukocyte elastase, and this deficiency can allow leukocyte elastase to injure the delicate gas-exchanging region of the lung, eventually leading to pulmonary emphysema. Uncontrolled leukocyte elastase also has the potential for inactivating tissue inhibitors of metalloproteinases,9,10 and thus promoting uncontrolled, injurious activity of metalloproteinases.

AAT Deficiency

The synthesis of AAT is controlled by a pair of genes at the proteinase inhibitor (Pi) locus. The genes are inherited as codominant alleles (products of both genes can be found in the circulation). Many abnormal variants have been very well characterized; most of them result from point mutations in the gene, and they most commonly have one or two amino acid substitutions when compared to the normal protein. Some of these changes result in little (or rarely, no) AAT in the circulation.

Variant types of AAT: More than 500 different genetic variants of AAT are now recognized,11 but many of them are quite rare. The AAT protein in the plasma that results from these genetic variants can be characterized by phenotyping, which is accomplished by isoelectric focusing of serum. The DNA for AAT (most often in white blood cells) can also be analyzed by genotyping, which is accomplished by allele-specific amplification. The identity of rare alleles can only be learned with certainty by nucleotide sequencing. The most common variants of AAT will be discussed below.

Nomenclature for phenotypes and genotypes: The names of phenotypes and genotypes begin with the name of the locus (Pi), followed by the letter names that have been given to the AAT alleles. Historically, alleles have been named with letters of the alphabet, corresponding in order to their migration in a test system. By convention,12 genotypes are printed in italics, with the alleles in superscript. For example, the most common type of heterozygote for AAT deficiency (see below) is phenotype Pi MZ and genotype Pi MZ. With continued scientific progress and with the advent of large-scale genomic sequencing operations, the number of described genetic variants of AAT has outgrown the historical naming convention. New variants are now described only by their molecular sequence abnormalities, while the more common abnormal AAT alleles have retained their letter designations for convenience.

Genetic transmission: Individuals with severe AAT deficiency have two deficient alleles for the protein. Heterozygotes and individuals with unusual AAT alleles have variable clinical phenotypes (see below), and can transmit their abnormal alleles to their children. Brothers and sisters of severely deficient individuals have a 25% chance of also having the condition. Children of severely deficient individuals can usually be expected to be heterozygotes (having one normal and one abnormal AAT allele). Such children have only a small risk of being severely AAT deficient themselves, and this risk is present only if they receive an abnormal AAT gene from the partner of the deficient individual. Phenotyping or genotyping is necessary to reliably detect heterozygotes, since AAT levels of normals and heterozygotes overlap significantly.

The normal M alleles: The normal M alleles represent by far the largest group of AAT alleles. They result in normal amounts, and normal functionality, of AAT in the blood. The M1, M2, and M3 alleles differ only subtly from one another, and the differences are not clinically important. Usually, no distinction is made among the M alleles in clinical laboratory testing. In normals, only the M variant is seen on phenotyping. By convention, the phenotype of these individuals is Pi M (not Pi MM), because a small fraction of individuals with apparently normal phenotype results will have a null (nonexpressing) AAT deficiency allele that of course is not detected when plasma proteins are phenotyped. Genotyping detects specific abnormal nucleotide sequences, so it cannot be used to identify the normal M alleles. Normal plasma levels of AAT, in combination with Pi M phenotype, provide some assurance that two normal M alleles are present, but only family studies or exon sequencing can identify Pi MM genotype with certainty.

The Z variant: The most prevalent type of severe AAT deficiency by far is classified as phenotype Pi Z. In these individuals, isoelectric focusing reveals only an abnormally migrating Z type AAT. These individuals may be either Pi ZZ homozygotes or Pi Znull heterozygotes, since no AAT attributable to the null genes can be found in the circulation. Genotyping is necessary to distinguish between these two possibilities, although family studies of the pattern of inheritance of low AAT levels may also be helpful.

The Z variant has two amino acid substitutions when compared to the most prevalent normal type of AAT. It is subtly abnormal as an inhibitor of leukocyte elastase.13 However, the most striking abnormality in affected individuals is that circulating levels of the protein are only 10%-15% of normal. When livers of these individuals are examined, the hepatocytes contain an abnormal accumulation of AAT.14 The Pi Z type of AAT is secreted in decreased amounts and abnormally slowly by both hepatocytes and monocytes, and this abnormality is thought to cause the deficiency. One of the amino acid substitutions (Glu342→Lys342) results in misfolding of the AAT, leading to intracellular accumulation and intracellular degradation of the abnormal protein.15 The structural alteration in the Z variant allows "loop-sheet polymerization" of the molecule, during which the reactive center loop of one molecule becomes inserted into an opening in the A sheet of another molecule.16-19 Chains of these AAT polymers become tangled within the endoplasmic reticulum of hepatocytes, and most (~85%) are degraded before they reach the circulation.

The S variant: The S variant has a single amino acid substitution (Glu264→Val264) when compared with the most prevalent normal type of AAT. The S mutation is not associated with intracellular accumulation of the protein, and the S protein inhibits elastase nearly normally. The amounts of the S protein that reach the circulation are typically somewhat lower than normal, because of intracellular degradation of the AAT before it is secreted.20 The S allele is slightly more prevalent than the Z allele among US Caucasians, and it is much more prevalent in the Iberian Peninsula and neighboring countries. There is no mechanistic reason to suspect that individuals who have an S allele would have an excess risk of liver disease.

Other less common and rare AAT variants causing severe deficiency: A large number of molecular abnormalities, in addition to the Z variant, have been shown to result in severely reduced secretion of AAT into the plasma. The most prevalent of these are Mmalton, Mheerlen, Mprocida, and Plowell. Besides these, a large number of rarer variants, called null variants, produce no secretion of AAT into plasma. These variants can be generally categorized as are nonsense mutations ( premature stop codons), insertions/deletions, and translocations. Regardless of the molecular mechanism, the phenotypic result (absence of a contribution to AAT in the plasma) and clinical significance (severe AAT deficiency allele) are the same.

Common Heterozygotes and Pi SS Homozygotes

PI MZ heterozygotes: Pi MZ individuals have one normal allele and one allele for the Z variant. AAT that has been synthesized under the direction of each of these alleles appears in the plasma. Pi MZ individuals usually have decreased levels of AAT in their circulation; however, since they are capable of mounting an acute phase response, their levels can fall within the normal range (particularly if they are ill or are taking oral contraceptives).

Whether or not Pi MZ individuals have a significantly increased risk of lung disease, and the magnitude of that risk (if any) has been debated for decades. It has been known for more than 50 years (since the original report of AAT deficiency) that most Pi MZ heterozygotes have somewhat reduced concentrations of AAT in plasma. Examples of early explorations of lung disease risk included an initial small case-control study of heterozygotes that found no effect of heterozygosity on lung function21 included Pi MS and Pi SS individuals (see below) and studied only subjects who were less than 40 years old; these results were immediately challenged.22 In 1984, a study of respiratory symptoms and lung function tests showed no difference between 143 Pi MZ individuals and matched controls.23 Pi MZ individuals appeared to be more prevalent in lung disease populations than in the general population in some24-26 but not other27 studies. In 2002, a longitudinal study of the Danish general population showed that Pi MZ individuals demonstrated a slightly greater annual decrease in lung function, greater prevalence of airway obstruction, and greater hospitalization and mortality from COPD when compared with Pi M individuals.28 In 2004, a meta-analysis of published studies of Pi MZ risk showed increased odds of COPD in Pi MZ individuals in case-control studies but not in cross-sectional studies.29 The most definitive historical study compared airflow obstruction, and quantified emphysema by CT scanning, in two large subject populations with phenotype Pi MZ. This analysis found a lower FEV1/VC ratio in both cohorts, and 3.7% more emphysema in the case-control study.30

In February, 2014, Molloy et al. published a definitive and comprehensive assessment of the risk for lung disease among Pi MZ heterozygotes.31 The research design was a family-based study, which eliminated the effects of selection bias between the Pi M and Pi MZ subjects, and was robust against the effects of population stratification. Starting with 51 index Pi MZ individuals who had a diagnosis of GOLD stage II-IV chronic obstructive pulmonary disease (COPD), they identified 99 Pi MM and 89 Pi MZ relatives of the index cases. These 188 subjects, all of whom were over 30 years of age, comprised the study population. Note that 34/89 (38%) of the Pi MZ subjects were children of the index cases, and that the mean age of the Pi MZ index cases was 53.4 years. By inference, many of the Pi MZ subjects who were studied were considerably younger than 50 years of age. The results of the analyses were conclusive. Among the Pi MZ subjects who had ever smoked, the authors found a strongly significantly reduced FEV1/FVC ratio, and FEF25-75. Most dramatically, Pi MZ heteozygosity in ever-smokers was associated with an adjusted odds radio for COPD of 10.7 (p = 0.004). In the sample size of lifelong non-smokers studied, there was no difference in lung function or COPD risk between Pi M and Pi MZ subjects. Important conclusions about Pi MZ individuals can be drawn from this well-designed and well-executed study, as follows: 1) Among Pi MZ individuals who have ever smoked, there is a significantly increased risk of airway obstruction and COPD; 2) The amount of exposure of Pi MZ individuals to cigarette smoke is important; 3) The risk of lung disease in Pi MZ individuals might have been even higher if older subjects were studied; and 4) Although lifelong non-smoking Pi MZ individuals did not show an increased lung disease risk, the relatively small population size of Pi MZ nonsmokers (47 subjects) may not have been sufficient to allow detection of an increased Pi MZ risk in this subset. Because the index cases in Molloy’s study all had COPD, it is possible that the family members studied were enriched for a predisposition to the development of COPD. However, this possibility does not diminish the power or the validity of the study.

In summary, the decades-long debate about the existence of an excess lung disease risk among Pi MZ heterozygotes32 has now been resolved. Pi MZ individuals who have ever smoked definitely have an increased risk of lung disease, and their risk increases with the amount of smoke exposure. Among lifelong non-smoking Pi MZ individuals, an excess risk of lung disease has not been proven, but a larger clinical study might do so. It must be concluded that it identification of Pi MZ individuals has now assumed an importance of its own. Early identification of Pi MZ heterozygotes, followed by intensive smoking cessation interventions, can be expected to result in a considerable reduction of their lung disease morbidity. Additionally, Pi MZ heterozygotes should be counseled about the chances of genetic transmission of their Z allele, and they should encourage their family members to be tested.

The livers of Pi MZ heterozygotes show mild intracellular accumulation of the protein. A slight excess risk of liver disease among Pi MZ heterozygotes seems to be demonstrated by the excess prevalence of Pi MZ individuals among subjects with end-stage liver disease.33,34

Pi SZ compound heterozygotes: These individuals have one allele for the S variant and one for the Z variant (the classical deficiency variant). They have AAT levels that range from approximately 1/3 to 1/2 of normal. Pi SZ heterozygotes are slightly more common than Pi Z (AAT deficient) individuals in American populations. The livers of Pi SZ heterozygotes show mild accumulation of AAT. The risk of liver disease in this group should be related to the Z allele, and thus should be the same as that in the Pi MZ population discussed above.33,34

Studies of the risk of lung disease in Pi SZ heterozygotes have reached variable conclusions in the past,35,36 and this issue was discussed in Hutchison's review.37 Some of these Pi SZ individuals have AAT levels that are slightly less than the 11 μM plasma concentration that is arbitrarily used to define severe AAT deficiency; however, the available data appear to show no excess risk of lung disease in these individuals when compared with that of the remainder of the Pi SZ population.36 The best information about the risk of lung disease among Pi SZ heterozygotes, comes to us from a meta-analysis published by Dahl and colleagues in 2005.38 After aggregating data from six earlier studies, they concluded that Pi SZ individuals, when compared with Pi M controls, had a significantly increased odds ratio (3.26) for development of COPD. Certainly, in light of the results of the Molloy study detailed above, Pi SZ heterozygotes would be expected to have an excess risk of lung disease that was at least as great as Pi MZ individuals, and presumably greater.

In summary, Pi SZ individuals have an excess risk of development of both lung and liver disease. The same cautions and recommendations regarding cigarette smoking and its cessation apply to both Pi SZ and Pi MZ individuals. As with Pi MZ heterozygotes discussed above, it is advisable to counsel Pi SZ heterozygotes regarding the risk of transmission of the Z allele, and to encourage testing of available family members.

Pi FZ heterozygotes: Pi FZ individuals have one unusual (F) allele and one Z allele (the most common severe deficiency allele). They have levels of AAT in plasma that, on average, fall between the levels seen in Pi MZ and Pi SZ individuals. They can be expected to have at least the same lung disease risk profile as Pi MZ individuals (see the discussion above). Moreover, there has been a report that the F variant is a poor (meaning slow) inhibitor of leukocyte elastase.39 The one report of this observation was immediately challenged on minor technical grounds, and the research has not been repeated. Nevertheless, there is reason for concern that the risk of lung disease in these individuals may be higher than would be expected for Pi MZ individuals (and possibly even higher than would be expected from consideration of the plasma AAT concentration alone in Pi FZ heterozygotes). Unfortunately, not enough cases have been studied to allow a determination of the specific excess risk for lung disease among Pi FZ individuals. Clinical judgment must apply to the management of their lung disease, if present. It is advisable to encourage testing of available family members. Intensive counseling and smoking intervention activities are prudent. The risk of liver disease in this group should be related to the Z allele, and thus should be the same as that in the Pi MZ population as discussed above.

Pi FM heterozygotes: Pi FM individuals have one normal (M) allele and one unusual (F) allele. These individuals have normal or nearly normal levels of AAT in plasma. However, the cautions described above regarding the probably abnormal biologic function of the F variant also apply to Pi FM heterozygotes, who could have a greater risk of lung disease than would be expected from their plasma AAT levels alone. There have been no clinical studies of excess risk of lung disease in Pi FM heterozygotes, and clinical judgment must apply to their management. It is advisable to encourage testing of available family members. Intensive counseling and smoking intervention activities are prudent. There is no reason to expect that these individuals would have an excess risk of liver disease.

Pi MS heterozygotes: Pi MS individuals have one normal (M) allele and one S allele. They have nearly normal, and often normal, levels of AAT in their plasma. There is no reason to suspect that Pi MS individuals have an excess risk of liver disease. The best information about their risk of lung disease is derived from the study by Dahl and associates that has been described above.38 In their meta-analysis, Pi MS individuals had a minimally increased odds ratio for development of COPD (1.19), but there was no associated excess risk after correction for smoking. There was no effect of Pi MS status, as opposed to Pi M controls, on FEV1. In summary, although there appears to be minimal if any excess risk of lung disease among Pi MS heterozygotes, it is prudent to caution them strongly about cigarette smoking and to encourage smoking cessation. As with the heterozygotes discussed above, it is advisable to encourage testing of available family members.

Pi SS homozygotes: Pi SS individuals have two S alleles. They have mildly reduced, and occasionally normal, levels of AAT in plasma. There is no reason to suspect that they would have an increased risk of liver disease. Not enough cases have been studied to allow a determination of their risk for lung disease. Clinical judgment must apply to the management of these individuals. It is advisable to encourage testing of available family members.

Rare heterozygotes: A large number of other genetic variations in the AAT gene have been described. These mutations are well beyond the scope of this review. For the rare deficiency alleles (see above), their associated clinical phenotype is presumed to be similar to the phenotype produced by the Z variant. For example, individuals with Pi MmaltonZ should have a similar risk of lung and liver disease as those with Pi ZZ (see below). The other variants that are not associated with severe AAT deficiency are rare, and there is little or no information available about their clinical consequences. Alpha1 Center can provide information about these rare alleles by telephone. However, the same cautions and recommendations regarding cigarette smoking and its cessation apply to these affected individuals. Clinical judgment must apply to their management. It is advisable to encourage testing of family members.

Lung and Liver Disease in Severe AAT Deficiency

Pulmonary emphysema: As noted above, AAT normally provides an important defense against attack on the normal structural components of the lung parenchyma by leukocyte elastase. Thus, deficiency of this inhibitor increases the risk that leukocyte elastase will injure alveolar walls when it is released from inflammatory cells in the lower respiratory tract. Over many years, the cumulative effect of this injury is alveolar septal destruction and airspace enlargement, which presents clinically as pulmonary emphysema. As lung disease develops, additional mechanisms may accelerate or contribute to lung function impairment. Pulmonary emphysema was described as a complication of AAT deficiency by Eriksson in 1964.2 In the classical description of AAT deficiency,40 patients have: 1) insidious onset of progressive shortness of breath between ages 25 and 40; 2) increasing dyspnea and increasing evidence of airflow obstruction as the disease progresses; 3) chest radiographic abnormalities including hyperinflation and symmetrical loss of parenchymal vascularity; and 4) chest radiographic abnormalities most marked in the lung bases, and commonly associated with bullae. About half of the patients have chronic or episodic productive cough.

Interestingly, however, only a very small fraction (probably less than 10% in the United States) of all individuals with AAT deficiency have been diagnosed, and there is reason to believe that many of those who have escaped diagnosis have either: 1) no lung disease; or 2) mild or atypical disease. This most interesting "hidden" population of individuals with AAT deficiency is further discussed below.

When lung disease becomes established, lung function impairment tends to be progressive in severity. In British and American studies, the range of decline in FEV1 tends to be between 51 and 100 mL/year (with a large variability) in the absence of intervention.40 This rate is in the range of 1.5 to 3 times the normal rate of lung function decline.

Liver disease: Ten to 20% of infants with AAT deficiency have neonatal hepatitis with cholestatic jaundice; others may have abnormal liver enzymes, hepatomegaly, or both.41 A very small proportion (1%-2%) of children with AAT deficiency develop end-stage liver disease in childhood. Despite these small numbers, AAT deficiency is the most common genetic cause of neonatal liver disease and the most frequent diagnosis necessitating liver transplantation.42 In the remainder of affected children, liver abnormalities tend to diminish or disappear,43 although mild hepatomegaly or mild elevations in liver enzymes may persist in a few.

Adults with AAT deficiency have a significant risk of cirrhosis and hepatoma in middle to late life.3 The exact risk for individual patients is difficult to determine, however, and this risk probably should be given little emphasis when counseling patients who currently have no clinically detectable liver abnormalities.

The liver disease appears to be related to chronic stress on hepatocytes resulting from the burdens of accumulated intracellular AAT and the increased requirement for intracellular protein degradation.14,15

Variability in Severity of Clinical Disease

The extent of lung and liver disease in AAT deficiency varies strikingly. An interesting paradox is that adults with severe lung disease often do not have liver disease, and vice versa.

While some patients with AAT deficiency develop end-stage lung disease in the third to fifth decades of life, many others escape clinically important lung disease into mid to late life.44-46 Many individuals ascertained through non-standard means may escape significant lung disease.

Cigarette smoking clearly has an adverse effect on the course of lung disease. This has been shown to be true early in life for a Swedish cohort of individuals who were identified at birth and studied at an average age of 22.47 and it has been repeatedly shown in adult populations, such as a Swedish cohort.48 Asthma, repeated pulmonary infections, and as-yet unidentified additional familial factors also are associated with a more severe course of lung disease.44

The prognosis for newly identified individuals with little or no lung disease is not known. However, many may escape significant lung disease, especially if they do not smoke.44-46 It is prudent to follow such individuals with periodic lung function testing, at least until continued research clarifies their prognosis. Ongoing research may provide further information about the natural history of lung disease in these individuals.

Liver disease: The severity of clinically apparent liver disease is highly variable. A minority of infants and children are affected, as noted above.42,43,49 Only 1%-2% of children have a severe course, with death from cirrhosis (or requirement for liver transplantation) in childhood. Only some adults with AAT deficiency eventually develop cirrhosis and/or hepatocellular carcinoma.3,50 The risk for adult liver disease increases with age. The reason for the variability in severity of liver disease is the subject of ongoing research.51,52

Treatment of AAT Deficiency

A major goal in the management of patients with AAT deficiency is the prevention of lung disease, or reduction in the rate of progression of any lung function impairment that is already present. It is important to realize that few inflammatory cells are found within the normal lung parenchyma. Therefore, the potential for lung injury in AAT deficiency may be small in the absence of other proinflammatory stimuli (smoking, asthma, respiratory infections, etc). A mainstay of management is to reduce the number of inflammatory cells in the lung. A specific treatment, "augmentation" therapy, is also available to increase circulating levels of AAT.

Smoking cessation: This should be the first priority in management of AAT deficiency. Lifelong nonsmokers can be told that if they continue to refrain from smoking they will have a good chance of avoiding serious lung disease. Once they have been informed about their diagnosis and about the very serious consequences of continuing to smoke, most current smokers are successful in quitting.

Aggressive treatment of asthma: Asthma is now recognized as an inflammatory disease of the airways. Inflammatory cells (particularly neutrophils) accumulate in and around the airways, and increase the burden of leukocyte elastase in the lower respiratory tract. There is evidence that asthma can lead to permanent lung injury in patients with AAT deficiency. Thus, aggressive treatment of asthma, with an emphasis on controller medications, may reduce the long-term impact of AAT deficiency on lung function.

It is prudent to treat even mild asthma in patients with AAT deficiency with inhaled corticosteroids. In patients with AAT deficiency, inhaled corticosteroids may be especially appropriate to suppress the increase in airway inflammation and the consequential increase in elastase burden (as well as to relieve symptoms).

Early and aggressive treatment of respiratory infections: AAT-deficient patients with severe lung disease often have a history of repeated respiratory infections.44 Even minor respiratory infections probably warrant antibiotic coverage for common respiratory pathogens. A brief course of systemic corticosteroids is often helpful to reduce the severity and duration of lower respiratory illnesses.

General supportive care: When lung disease is severe, patients may require supplemental oxygen and home healthcare. Motorized carts may help in allowing patients to retain mobility. Pulmonary rehabilitation programs and support groups have been very helpful for many patients.

Augmentation therapy: Concentrated preparations of human α1-proteinase inhibitor are available for intravenous administration to AAT-deficient patients. These preparations, when infused weekly at a dose of 60 mg/kg body weight, increase circulating levels of AAT to concentrations (>11 μM) that are thought to lessen the risk of continued lung injury. Each of the available products is purified from large lots of pooled human plasma.

In Pi Z individuals, once-weekly intravenous infusion of each of these products, at a dose of 60 mg/kg body weight, maintains circulating levels of AAT that are thought to be adequate for protection of the lung parenchyma.53-58 Infusions increase levels of AAT in broncho-alveolar lavage fluid, and the AAT recovered from the broncho-alveolar lavage is functionally active. These intravenous infusions appear to at least partially correct the biochemical deficiency in Pi Z individuals.

Data from a large North American registry of patients with AAT deficiency showed that augmentation was associated with a statistically significant diminution in the rate of decline of lung function among individuals with moderately impaired lung function, and with a lower mortality.59 While encouraging, this study suffered from the flaw that treatment was not randomized. Thus, true treatment effects could have been confounded by other variables in the study population, such as socioeconomic status or access to medical care. A European study, also not randomized, compared German with Danish patients (the latter not augmented) and showed a similar effect of augmentation therapy on slowing the rate of decline of lung function.60 A Danish-Dutch randomized, controlled trial showed a strong trend toward a lowering of the rate of decline of lung function in the augmented group, but the difference did not quite reach statistical significance at the 0.05 level in the modest number of subjects studied.61 A meta-analysis of five trials, with 1509 total patients analyzed, found that the decline in FEV1 was 23% slower in the group that was receiving augmentation therapy. This analysis supported the conclusion that augmentation can slow the rate of decline of lung function, particularly in those with moderate airway obstruction.62 Preliminary analyses of an ongoing double-blind, placebo controlled study of augmentation, using change in lung density over time as the clinical endpoint, has shown promising results, but the results of the completed trial are yet to be published.

In summary, intravenous augmentation is a logical approach to specific treatment of AAT deficiency, and clinical studies have shown promise for the treatment.

Some risks of infusion reactions to any biological product should be expected, and these products are not exceptions. However, there appear to be no mechanism-specific reactions to the augmentation products, and they are all well tolerated. The available products are dosed based upon their content of active AAT, which minimizes the clinical importance of any lot-to-lot and/or purification-related differences in the relative activity of the AAT they contain. The biological product suppliers use diligence to detect and eliminate donors with infectious diseases from the plasma pools, and they take pains to eliminate and/or inactivate viral and other pathogens. There has been no documented transmission of infection with augmentation products.

Augmentation has been approved for once-weekly intravenous infusion of 60 mg of active product per kilogram of body weight. A once-monthly infusion of larger amounts has also been shown to be safe, but to be associated with AAT levels less than the goal levels in the fourth week.63 A more prolonged monthly infusion regimen might be more convenient than a more brief weekly regimen, and may offer some cost savings for disposable IV supplies. This convenience must be balanced against the suboptimal circulating AAT levels in the week prior to the succeeding dose. Other dosing schedules have been used in clinical practice; however, weekly administration is the only schedule that has been approved by the FDA. Full prescribing information can be found in the package inserts for the products.

The augmentation products can be administered in a physician's office or in a facility where intravenous infusions are routinely given for other indications. However, home administration is the option chosen by the majority of patients.

Further guidelines can be found in a statement by The American Thoracic Society regarding the approach to individuals with AAT deficiency, and in the ATS/ERS Standards.1

Lung transplantation: Lung transplantation is increasingly becoming a viable option for patients with advanced disease. Lung volume reduction surgery may be beneficial for highly selected individuals.

Liver transplantation: Successful liver transplantation can obviously be lifesaving. This may be an option for carefully selected individuals with end-stage liver disease.

 

 

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