Elastase binding capacity of alpha 2-macroglobulin in plasma of patients with asthma or chronic obstructive pulmonary disease, without alpha 1-protease inhibitor deficiency

The amidolytic activity of alpha 2-macroglobulin complexed with porcine pancreatic elastase (EC 3.4.21.11) was assayed using succinyl-trialanyl-p-nitroanilide. The levels of activity were compared in chronic obstructive pulmonary disease patients, asthma patients, and in healthy subjects with no record of lung disease. Levels of alpha 1-protease inhibitor were also determined and only those cases within the normal range for alpha 1-protease inhibitor were selected. Both the asthma cases and those with chronic obstructive pulmonary disease had levels of elastase-binding capacity related to alpha 2-macroglobulin which were significantly higher than the control groups.     

Diagnosing alpha 1-antitrypsin deficiency

Alpha 1-antitrypsin deficiency is a genetically transmitted disorder associated with an increased risk of emphysema and liver disease. The highest incidence occurs in whites of Northern European descent; the disorder affects between 70,000 and 100,000 individuals in the United States. Most persons with alpha 1-antitrypsin deficiency are misdiagnosed or undiagnosed. The laboratory tests used to screen for and diagnose the disorder are simple, inexpensive, and provide an opportunity to prevent the development of clinical disease through education about cofactor avoidance. This article provides a review of the epidemiology, genetics, and clinical presentation of this disorder.     

Cyclophosphamide therapy for Weber-Christian disease associated with alpha 1-antitrypsin deficiency

Weber-Christian disease is an uncommon disorder of unclear etiology whose unifying feature is fatty tissue inflammation. Its association with alpha 1-antitrypsin deficiency produces severe clinical manifestations. Although many agents have been used to treat Weber-Christian disease, current therapy is based on the poorly documented use of corticosteroids. We have reported the case of a young man with life-threatening Weber-Christian disease associated with alpha 1-antitrypsin deficiency unresponsive to corticosteroids who responded to cyclophosphamide.     

DNA polymorphisms of the alpha 1-antitrypsin gene region in patients with chronic obstructive pulmonary disease

Alpha 1-antitrypsin (AAT) is an important part of the defence mechanism of the lung against proteolytic attack. The Z and Null mutants of the AAT gene are associated with very low or missing serum concentrations of AAT, so that for individuals with genotypes ZZ or Null there is a very high risk of developing chronic obstructive pulmonary disease (COPD). In more than 90% of the patients suffering from COPD, however, the common MM phenotype of AAT is expressed at normal AAT serum levels. The MM phenotype has a heterogeneous constitution and the alleles M1, M2 and M3 are distinguished by isoelectric focusing. At the DNA level many mutants of the AAT gene may exist that cannot be recognized by IEF. In this paper we report DNA sequence heterogeneity of the AAT gene region among 137 patients with COPD and 130 healthy control subjects. All 267 individuals studied were MM phenotype. Several restriction fragment length polymorphisms (RFLPs) were observed using genomic probes of the AAT gene. One allele (T2) of a Taq I RFLP located 1 kb downstream of the AAT gene was significantly more frequent in patients (15.3%) than in controls (5.4%) (P less than 0.005). The relative incidence of COPD was 3.3 times higher for subjects carrying at least one T2 allele than for the common T1T1 genotype. The T2 allele may be in linkage disequilibrium with a functionally deficient variant of AAT or some gene in close neighbourhood, e.g. the alpha 1-antichymotrypsin gene. A deletion of 1.8 kb in the alpha 1-antichymotrypsin-like gene (PIL gene) occurs at a frequency of 0.26 in patients and in control subjects as well.     

Spontaneous pneumothorax and alpha 1-antitrypsin deficiency

Spontaneous pneumothorax has been observed in patients with abnormal levels of alpha 1-antitrypsin. We report the case of a young woman with a low level of alpha 1-antitrypsin who presented with recurrent episodes of spontaneous pneumothorax and who required pleuroscopy, apical lung resection, and pleurodesis.     

Inherited chronic obstructive pulmonary disease: new selective-sequencing workup for alpha1-antitrypsin deficiency identifies 2 previously unidentified null alleles

BACKGROUND: alpha(1)-Antitrypsin (alpha(1)AT) deficiency predisposes individuals to chronic obstructive pulmonary disease (COPD) and/or liver disease. Phenotyping of the protein by isoelectric focusing is often used to characterize alpha(1)AT deficiency, but this method may lead to misdiagnosis (e.g., by missing null alleles). We evaluated a workup that included direct sequencing of the relevant parts of the gene encoding alpha(1)AT, SERPINA1 [serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1], for patients with alpha(1)AT concentrations < or =1.0 g/L. METHODS: During a 5-year period, we identified 66 patients with alpha(1)AT concentrations < or =1.0 g/L and amplified and sequenced exons 2, 3, and 5 of the alpha(1)AT gene in these patients. To ensure that no relevant genotypes were missed, we sequenced the same exons in 48 individuals with alpha(1)AT concentrations between 1.0 and 1.5 g/L. RESULTS: Sequence analysis revealed 18 patients with combinations of disease-associated alpha(1)AT alleles: 8 homozygous for the deficient Z allele and 10 compound heterozygotes for various deficient or null alleles. We identified and named 2 new null alleles, Q0(soest) (Thr(102)-->delA, which produces a TGA stop signal at codon 112) and Q0(amersfoort) (Tyr(160)-->stop). No relevant disease-associated allele combinations were missed at a 1.0-g/L threshold. CONCLUSIONS: Up to 22% of the alleles in disease-associated alpha(1)AT allele combinations may be missed by conventional methods. Genotyping by direct sequencing of samples from patients with alpha(1)AT concentrations < or =1.0 g/L detected these alleles and identified 2 new null alleles.     

Molecular mousetraps, alpha1-antitrypsin deficiency and the serpinopathies

Point mutations in members of the serine proteinase inhibitor or serpin superfamily cause them to change shape, polymerise and be deposited in the tissues. This process is best seen in mutants of alpha1-antitrypsin within hepatocytes to cause periodic acid-Schiff (PAS) positive inclusions and cirrhosis. An identical process underlies the PAS positive inclusions of mutants of neuroserpin within neurones to cause a dementia that we have called familial encephalopathy with neuroserpin inclusion bodies (FENIB). In both cases, there is a direct correlation between the molecular instability, the rate of intracellular polymer formation and the severity of disease. This process of polymerisation also explains the failure to secrete mutants of other members of the serpin superfamily--antithrombin, C1 inhibitor and alpha1-antichymotrypsin--to cause thrombosis, angio-oedema and emphysema, respectively. In view of the common mechanism underlying these conditions, we have grouped them together as the serpinopathies.     

Principles and clinical management of alpha 1-antitrypsin deficiency

Alpha 1-antitrypsin (alpha 1-AT) deficiency can cause a lung disease that, until a few years ago, has proved fatal to all patients diagnosed with this disease. This deficiency can now be treated with alpha 1-proteinase inhibitor, a protein derived from human plasma and delivered via intravenous infusion. Infusion therapy for alpha 1-AT deficiency can be delivered in the hospital or home environments. This article discusses the pathophysiology of alpha 1-AT deficiency and outlines nursing considerations for the intravenous clinician who is administering this therapy.     

Systemic necrotizing vasculitides in severe alpha1-antitrypsin deficiency

We describe the clinical presentation and outcome in a series of eight patients with systemic necrotizing vasculitis and severe alpha1-antitrypsin (AAT) deficiency followed up at three Swedish hospitals during 1968-92. We also review six other cases reported in the literature during the same period. Diagnosis of severe AAT deficiency was based on the presence of the PiZZ phenotype, or low plasma total trypsin inhibitory capacity, or a low plasma AAT concentration (10-40% of the normal mean value) and presence of the PiSZ or PiFZ phenotype. The diagnosis of systemic vasculitis was biopsy-verified in all eight patients. Pretreatment laboratory findings, treatment protocol, and outcome were reviewed in each of the 14 patients. Of the eight patients in the Swedish series, six had systemic vasculitis of the microscopic polyangiitis form, one had Wegener's granulomatosis, and another had Henoch-Schonlein purpura. In the series as a whole (n=14), median age at diagnosis was 48 years (range 44-84), the median number of affected organs was eight, and all 14 patients had skin involvement, and either renal or joint involvement (in most cases both); 71% (10/14) had emphysema; 57% (8/14) had hepatic abnormalities (two having cirrhosis, two fibrosis, and one multiple aneurysms in hepatic arteries); one patient who presented with acute ulcerative colitis developed manifest vasculitic syndrome three years later; and 64% (9/14) died, the major cause of death being renal failure. This syndrome, characterized by multiple organ involvement and fatal outcome, has been underdiagnosed. Physicians should be alert to the presence of the PiZ AAT deficiency gene in patients with systemic vasculitis, especially when the course is progressive or when the patient also has emphysema or cirrhosis. Awareness of those features may aid prompt recognition and enable early treatment.      

Molecular diagnosis of intermediate and severe alpha(1)-antitrypsin deficiency: MZ individuals with chronic obstructive pulmonary disease may have lower lung function than MM individuals

BACKGROUND: We tested whether intermediate (MZ, SZ) and severe (ZZ) alpha(1)-antitrypsin deficiency affects lung function in the population at large. METHODS: We performed spirometry [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)] and genotyping of 9187 individuals from the adult general population of Copenhagen, Denmark. RESULTS: As expected, the frequencies of individuals with MM, MS, SS, MZ, SZ, and ZZ genotypes were 0.891, 0.054, 0.001, 0.052, 0.001, and 0.001, respectively. Genotype interacted with clinically established chronic obstructive pulmonary disease (COPD) on the percentage of the predicted FEV(1) (P = 0. 004): the percentage of the predicted FEV(1) was reduced in MZ compared with MM individuals among those with clinically established COPD, but not among those without COPD. Furthermore, SZ compound heterozygotes had lower FEV(1)/FVC ratios than MM individuals (P <0.05), and ZZ homozygotes had lower percentages of the predicted FEV(1) and FEV(1)/FVC ratios than MM, MS, SS, and MZ individuals (all Ps <0.01). Reduced lung function in SZ and ZZ vs MM individuals could be demonstrated in current and ex-smokers, but not in nonsmokers. Compared with MM individuals in the same groups, FEV(1) was reduced 655 mL in MZ individuals with clinically established COPD, 364 mL in SZ current smokers, and 791 mL in ZZ current smokers. CONCLUSIONS: In the population at large, MZ was associated with reduced pulmonary function in individuals with clinically established COPD, whereas SZ and ZZ were associated with reduced pulmonary function in smokers. The presence of the alpha(1)-antitrypsin MZ genotype may in certain circumstances produce marked aggravation of airway obstruction in individuals prone to develop COPD.