Antitrypsin deficiency
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《胸》
Correspondence to:
J K Stoller
Division of Medicine, Cleveland Clinic Lerner College of Medicine, Section of Respiratory Therapy, Department of Pulmonary/Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Av, Cleveland OH 44195, USA; stollej@ccf.org
A new series focusing on this important and under-recognised illness
Keywords: 1-antitrypsin deficiency
Alpha1-antitrypsin (AAT) deficiency is a common but under-recognised clinical entity.1–3 The editors of Thorax have therefore commissioned a series of papers by internationally recognised experts on the key clinical and investigative concepts in this important disease, which will offer the reader an up to date summary of AAT deficiency. Topics to be addressed include:
* the epidemiology of AAT deficiency;
* genetic aspects of AAT deficiency: phenotypes and genetic modifiers of emphysema;
* clinical manifestations and natural history of AAT deficiency;
* molecular pathophysiology of AAT deficiency;
* pathogenesis of lung disease in AAT deficiency;
* intravenous augmentation therapy for AAT deficiency: current understanding;
* new and emerging therapies for AAT deficiency; and
* CT imaging in AAT deficiency.
Why this attention to AAT deficiency now? As mentioned above, despite the fact that it affects up to one in 1600 newborn infants,2 AAT deficiency is both under-recognised and "under-understood".3 As evidence of this under-recognition, in a survey of 300 PI*ZZ individuals the mean interval between the appearance of the first attributable symptom (almost invariably dyspnoea due to fixed airflow obstruction) and the diagnosis of AAT deficiency in a group of mean age 49 years was 7.2 years.3 Furthermore, 44% of the respondents reported seeing at least three physicians before the diagnosis of AAT deficiency was made. In the United States, of the expected 80 000–100 000 with severe AAT deficiency (PI*ZZ), fewer than 10% have been clinically recognised.4
Since establishing the diagnosis is both easy (a simple blood test for a serum level and, if low, a phenotype to secure the diagnosis) and relatively inexpensive (less than $US200 for a serum level or a phenotype in most commercial laboratories and widespread availability of free testing services), there are ample opportunities to increase recognition of the condition by enhancing clinicians’ diagnostic suspicion of AAT deficiency.
What clinical features should clinicians look for? As discussed in this series5 and in a recently published evidence-based standards document on the diagnosis and management of individuals with AAT deficiency,6 AAT deficiency should be suspected in patients with fixed airflow obstruction (especially in the absence of cigarette smoking or predisposing occupational exposures), in individuals whose family history suggests emphysema and/or liver disease, and in those with suggestive clinical characteristics—for example, basilar hyperlucency on the chest radiograph, bronchiectasis that is otherwise unexplained, panniculitis, or cirrhosis for which a known aetiology such as viral hepatitis, haemochromatosis, or Wilson’s disease is not evident.
Why make the diagnosis of AAT deficiency? As with all diseases, the impetus to diagnose is the desire to ameliorate the adverse effects of the illness, to prolong life, to improve the quality of life of affected individuals and, in the case of a genetic disease like AAT deficiency, to counsel at risk family members in order to encourage health attentive behaviour and treatment that will lessen the likelihood of disease and/or forestall its progression. Indeed, it is important to establish the diagnosis of AAT deficiency as a number of interventions are available that can produce a beneficial outcome.7–11 For example, population screening studies suggest that individuals identified as having PI*ZZ AAT deficiency at birth are less likely to start smoking or to continue smoking than age matched adolescent peers.12,13 Furthermore, although no definitive randomised clinical trial has established the clinical efficacy of augmentation therapy14—currently the intravenous infusion of purified pooled human plasma 1-antitrypsin—the results of many observational studies strongly suggest its clinical efficacy.9,10,15 Indeed, a recent standards document from the Canadian Thoracic Society16 and the aformentioned evidence-based standards document which is supported and endorsed by the European Respiratory Society, the American Thoracic Society, the American College of Chest Physicians, the American Respiratory Care Foundation, and the Alpha-1 Foundation6 both conclude that augmentation therapy has clinical efficacy.17 As reviewed in this series of articles, new and emerging therapies offer the prospect of even more effective treatments that can be made available to individuals known to have severe AAT deficiency.18
It is hoped that this comprehensive review will enhance the recognition of individuals with AAT deficiency by clinicians and foster optimal medical management.
REFERENCES
1. O’Brien ML, Buist NRM, Murphy WH. Neonatal screening for alpha 1-antitrypsin deficiency. J Pediatr 1978;92:1006–10.
2. Sveger T. Liver disease in alpha 1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294:1316–21.
3. Stoller JK, Smith P, Yang P, et al. Physical and social impact of alpha 1-antitrypsin deficiency: results of a survey. Cleve Clin J Med 1994;61:461–7.
4. Silverman EK, Miletich JP, Pierce JA, et al. Alpha 1-antitrypsin deficiency: high prevalence in the St Louis area determined by direct population screening. Am Rev Respir Dis 1989;140:961–6.
5. Needham M, Stockley RA. Clinical manifestations and natural history of alpha 1-antitrypsin deficiency. Thorax 2004;59 (in press).
6. American Thoracic Society/European Respiratory Society. Standards for the diagnosis and management of patients with alpha 1-antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818–900.
7. Wewers MD, Casolaro MA, Sellers SE, et al. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987;316:1055–62.
8. Stoller JK, Rouhani F, Brantly M, et al. Biochemical efficacy and safety of a new pooled human plasma alpha(1)-antitrypsin, Respitin. Chest 2002;122:66–74.
9. Seersholm N, Wencker M, Banik N, et al. Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group. Eur Respir J 1997;10:2260–3.
10. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. Am J Respir Crit Care Med 1998;158:49–59.
11. Wencker M, Fuhrmann B, Banik N, et al. Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor. Chest 2001;119:737–44.
12. Sveger T, Piitulainen E, Arborelius M Jr. Lung function in adolescents with alpha 1-antitrypsin deficiency. Acta Paediatr 1994;83:1170–3.
13. Wall M, Moe E, Eisenberg J, et al. Long-term follow-up of a cohort of children with alpha 1-antitrypsin deficiency. J Pediatr 1990;116:248–51.
14. Dirksen A, Dijkman JH, Madsen F, et al. A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999;160 (5 Pt1) :1468–72.
15. Minai OA, Stoller JK. Therapy for alpha 1-antitrypsin deficiency: pharmacology and clinical recommendations. BioDrugs 2000;13:135–47.
16. Abboud RT, Ford GT, Chapman KR, and the Standards Committee of the Canadian Thoracic Society. Alpha1-antitrypsin deficiency: a position statement of the Canadian Thoracic Society. Can Respir J 2001;8:81–8.
17. Stoller JK. Augmentation therapy for severe alpha 1-antitrypsin deficiency: is the jury still out on a trial? Thorax 1998;53:1007–9.
18. Sandhaus RA. New and emerging therapies for AAT deficiency. Thorax 2004 (in press)(J K Stoller)
J K Stoller
Division of Medicine, Cleveland Clinic Lerner College of Medicine, Section of Respiratory Therapy, Department of Pulmonary/Critical Care Medicine, Cleveland Clinic Foundation, 9500 Euclid Av, Cleveland OH 44195, USA; stollej@ccf.org
A new series focusing on this important and under-recognised illness
Keywords: 1-antitrypsin deficiency
Alpha1-antitrypsin (AAT) deficiency is a common but under-recognised clinical entity.1–3 The editors of Thorax have therefore commissioned a series of papers by internationally recognised experts on the key clinical and investigative concepts in this important disease, which will offer the reader an up to date summary of AAT deficiency. Topics to be addressed include:
* the epidemiology of AAT deficiency;
* genetic aspects of AAT deficiency: phenotypes and genetic modifiers of emphysema;
* clinical manifestations and natural history of AAT deficiency;
* molecular pathophysiology of AAT deficiency;
* pathogenesis of lung disease in AAT deficiency;
* intravenous augmentation therapy for AAT deficiency: current understanding;
* new and emerging therapies for AAT deficiency; and
* CT imaging in AAT deficiency.
Why this attention to AAT deficiency now? As mentioned above, despite the fact that it affects up to one in 1600 newborn infants,2 AAT deficiency is both under-recognised and "under-understood".3 As evidence of this under-recognition, in a survey of 300 PI*ZZ individuals the mean interval between the appearance of the first attributable symptom (almost invariably dyspnoea due to fixed airflow obstruction) and the diagnosis of AAT deficiency in a group of mean age 49 years was 7.2 years.3 Furthermore, 44% of the respondents reported seeing at least three physicians before the diagnosis of AAT deficiency was made. In the United States, of the expected 80 000–100 000 with severe AAT deficiency (PI*ZZ), fewer than 10% have been clinically recognised.4
Since establishing the diagnosis is both easy (a simple blood test for a serum level and, if low, a phenotype to secure the diagnosis) and relatively inexpensive (less than $US200 for a serum level or a phenotype in most commercial laboratories and widespread availability of free testing services), there are ample opportunities to increase recognition of the condition by enhancing clinicians’ diagnostic suspicion of AAT deficiency.
What clinical features should clinicians look for? As discussed in this series5 and in a recently published evidence-based standards document on the diagnosis and management of individuals with AAT deficiency,6 AAT deficiency should be suspected in patients with fixed airflow obstruction (especially in the absence of cigarette smoking or predisposing occupational exposures), in individuals whose family history suggests emphysema and/or liver disease, and in those with suggestive clinical characteristics—for example, basilar hyperlucency on the chest radiograph, bronchiectasis that is otherwise unexplained, panniculitis, or cirrhosis for which a known aetiology such as viral hepatitis, haemochromatosis, or Wilson’s disease is not evident.
Why make the diagnosis of AAT deficiency? As with all diseases, the impetus to diagnose is the desire to ameliorate the adverse effects of the illness, to prolong life, to improve the quality of life of affected individuals and, in the case of a genetic disease like AAT deficiency, to counsel at risk family members in order to encourage health attentive behaviour and treatment that will lessen the likelihood of disease and/or forestall its progression. Indeed, it is important to establish the diagnosis of AAT deficiency as a number of interventions are available that can produce a beneficial outcome.7–11 For example, population screening studies suggest that individuals identified as having PI*ZZ AAT deficiency at birth are less likely to start smoking or to continue smoking than age matched adolescent peers.12,13 Furthermore, although no definitive randomised clinical trial has established the clinical efficacy of augmentation therapy14—currently the intravenous infusion of purified pooled human plasma 1-antitrypsin—the results of many observational studies strongly suggest its clinical efficacy.9,10,15 Indeed, a recent standards document from the Canadian Thoracic Society16 and the aformentioned evidence-based standards document which is supported and endorsed by the European Respiratory Society, the American Thoracic Society, the American College of Chest Physicians, the American Respiratory Care Foundation, and the Alpha-1 Foundation6 both conclude that augmentation therapy has clinical efficacy.17 As reviewed in this series of articles, new and emerging therapies offer the prospect of even more effective treatments that can be made available to individuals known to have severe AAT deficiency.18
It is hoped that this comprehensive review will enhance the recognition of individuals with AAT deficiency by clinicians and foster optimal medical management.
REFERENCES
1. O’Brien ML, Buist NRM, Murphy WH. Neonatal screening for alpha 1-antitrypsin deficiency. J Pediatr 1978;92:1006–10.
2. Sveger T. Liver disease in alpha 1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 1976;294:1316–21.
3. Stoller JK, Smith P, Yang P, et al. Physical and social impact of alpha 1-antitrypsin deficiency: results of a survey. Cleve Clin J Med 1994;61:461–7.
4. Silverman EK, Miletich JP, Pierce JA, et al. Alpha 1-antitrypsin deficiency: high prevalence in the St Louis area determined by direct population screening. Am Rev Respir Dis 1989;140:961–6.
5. Needham M, Stockley RA. Clinical manifestations and natural history of alpha 1-antitrypsin deficiency. Thorax 2004;59 (in press).
6. American Thoracic Society/European Respiratory Society. Standards for the diagnosis and management of patients with alpha 1-antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818–900.
7. Wewers MD, Casolaro MA, Sellers SE, et al. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987;316:1055–62.
8. Stoller JK, Rouhani F, Brantly M, et al. Biochemical efficacy and safety of a new pooled human plasma alpha(1)-antitrypsin, Respitin. Chest 2002;122:66–74.
9. Seersholm N, Wencker M, Banik N, et al. Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group. Eur Respir J 1997;10:2260–3.
10. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. Am J Respir Crit Care Med 1998;158:49–59.
11. Wencker M, Fuhrmann B, Banik N, et al. Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor. Chest 2001;119:737–44.
12. Sveger T, Piitulainen E, Arborelius M Jr. Lung function in adolescents with alpha 1-antitrypsin deficiency. Acta Paediatr 1994;83:1170–3.
13. Wall M, Moe E, Eisenberg J, et al. Long-term follow-up of a cohort of children with alpha 1-antitrypsin deficiency. J Pediatr 1990;116:248–51.
14. Dirksen A, Dijkman JH, Madsen F, et al. A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999;160 (5 Pt1) :1468–72.
15. Minai OA, Stoller JK. Therapy for alpha 1-antitrypsin deficiency: pharmacology and clinical recommendations. BioDrugs 2000;13:135–47.
16. Abboud RT, Ford GT, Chapman KR, and the Standards Committee of the Canadian Thoracic Society. Alpha1-antitrypsin deficiency: a position statement of the Canadian Thoracic Society. Can Respir J 2001;8:81–8.
17. Stoller JK. Augmentation therapy for severe alpha 1-antitrypsin deficiency: is the jury still out on a trial? Thorax 1998;53:1007–9.
18. Sandhaus RA. New and emerging therapies for AAT deficiency. Thorax 2004 (in press)(J K Stoller)