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1-Antitrypsin Deficiency Therapy
Dr. Sandhaus is Clinical Professor of Medicine at the University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, CO. He is also Medical Director of the Alpha One Foundation, Miami, FL, and co-director of the University of Colorado Center for Genetic Lung Disease.
Correspondence to: Robert A. Sandhaus, MD, PhD, FCCP, Division of Pulmonary and Critical Care Medicine, UCHSC, Mail drop C272, 4200 E. Ninth Ave, Denver, CO 80262
The article by Marion Wencker et al in this issue of
CHEST (see page 737) fits another piece within the
yet-unfinished jigsaw puzzle of the pathophysiology and treatment of
1-antitrypsin (AAT) deficiency. The molecular
and cellular mechanisms leading to this deficiency are among the best
understood of the genetic conditions leading to an increased risk for
organ dysfunction. The single amino-acid substitution seen in the most
common form of AAT deficiency leads to an altered conformation of this
protein as it is translated in the hepatocyte.1
This
provokes insertion of the reactive loop of one Z mutation AAT
molecule into the A-sheet of another Z mutation AAT molecule, resulting
in polymerization and accumulation of AAT within the hepatocyte
cytoplasm.2
This, in turn, leads to the characteristic
periodic acid-Schiff–positive, diastase-resistant hepatocyte
granules and a low serum level of this important serine proteinase
inhibitor. Lowered levels of AAT bathing the lungs leads to the
possibility of connective tissue degradation by phagocyte proteinases,
normally inhibited by physiologic concentrations of AAT.3
The insights gained from studying AAT deficiency have provided the
basis for our growing comprehension of the mechanisms leading to COPD
in general.
Despite this understanding of the basic pathophysiologic mechanisms, it has been difficult to design studies testing the treatment of this disorder. While the prevalence of AAT deficiency in US and European communities is relatively high (as many as 100,000 individuals on each continent), only approximately 6% of affected individuals have been identified to date. Thus, large randomized trials become difficult to enroll. IV augmentation therapy using pooled human plasma AAT (Prolastin; Bayer Biologics; Research Triangle Park, NC) was approved in the United States and several European countries approximately 10 years ago. This approval was based on "biochemical efficacy": the replacement of a deficient serum protein. The presence of a well-accepted therapeutic option makes the implementation of placebo-controlled trials of clinical efficacy problematic.
The article by Wencker at al attempts to evaluate the clinical efficacy
of pooled human plasma AAT therapy using a multicenter, retrospective
trial design, evaluating the same patients both before and after
initiation of therapy. Previous studies from this group and from the
United States National Institutes of Health
1-Antitrypsin Deficiency Registry had detected
a decrease in the rate of decline of FEV1 and
improved mortality in treated individuals whose lung function was
moderately impaired. The current study of 96 patients showed a
statistically significant lower rate of decline of
FEV1 in the whole group during augmentation
therapy compared with the pretreatment period. The mean difference in
rate of decline was 14.9 mL/yr. Interestingly, there was not a
significant difference in the pretreatment-posttreatment rate of
decline (-3.7 mL/yr) in 25 patients with FEV1
< 30% predicted. The difference in pretreatment-posttreatment rate
of decline was larger (11.6 mL/yr) but not statistically significant in
60 patients with FEV1 30 to 65% predicted. The
pretreatment-posttreatment rate of decline was greatest (73.6 mL/yr)
and statistically significant in 11 patients with
FEV1 > 65% predicted. Seven patients with a
rapid decline of FEV1 during the pretreatment
period within the last group had a pretreatment-posttreatment
augmentation therapy difference in FEV1 rate of
decline of 203 mL/yr; four slow decliners showed a difference of
- 26.4 mL/yr.
One study4 has suggested that the rapid decline in lung function seen in AAT-deficient individuals does not follow a straight line or smooth curve but, rather, proceeds in a stepwise fashion with each drop associated with a lung infection or other inflammatory process. Using the pooled information of available studies1 5 6 leads to a potential profile of the appropriate AAT-deficient patient to treat with augmentation therapy: one with moderately severe obstructive lung disease, or one with well-preserved lung function but early evidence of a rapid decline. The utility of treating AAT-deficient patients with advanced COPD remains unproven; the results of the current study in 25 patients with initial FEV1 values < 30% predicted suggest that augmentation therapy is not worthwhile. However, this is a retrospective study, and the results may therefore be biased.
As recently as 1 year ago, pooled human plasma AAT was in short supply in the United States, with individuals with newly diagnosed conditions precluded from initiating therapy; those already receiving therapy were forced to reduce their doses to amounts likely to be ineffective. As these patients changed location, physician, or insurance, they would find themselves unable to receive the drug. These problems have been largely eliminated since November 1, 1999, by an important and unique drug distribution method: direct patient allocation (Bayer Direct). Under this system, the drug is distributed directly to each patient and the allocation follows the patient regardless of changes in insurance or location.
Another clinical problem of growing magnitude, and which bears
importantly on developing screening programs for
1-antitrypsin deficiency, is the concern
regarding potential genetic discrimination in hiring and insurance.
While the gene frequency of AAT-deficient alleles is approximately 21
million individuals in the United States, this condition is still
considered quite rare by the practicing physician. Just as large-scale
detection efforts were being developed, an appreciation of genetic
discrimination issues led to a tabling of these efforts. Until
legislative and regulatory proscriptions against such discrimination
are in place, the efforts to increase detection of this genetic
condition will be thwarted. Regardless, it is anticipated that even the
current, relatively meager detection efforts will lead to a worldwide
shortage of augmentation therapy in the near future.
In the late 1980s, we congratulated ourselves for having "solved" the riddle of AAT deficiency and its treatment in a mere 25 years. Now, in this new millennium, we see that our celebrations may have been a bit premature.
References
1-antitrypsin deficiency. Respir Med 94,S3-S6
1-antitrypsin deficiency. Ann Allergy 72,105-120[ISI][Medline]
1-antitrypsin: the 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 1998; 158:49–59
1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary 1-antitrypsin deficiency? Eur Respir J 10,2260-2263[Abstract]
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