The interaction of cigarette smoke solution with alpha 1-antitrypsin: effect on inhibitory capacity, electrophoretic mobility and immunological measurement

1. The effects of an aqueous solution of cigarette smoke upon the functional, immunological and electrophoretic assessment of alpha 1-antitrypsin have been studied. 2. The addition of cigarette smoke reduced the inhibitory capacity of the alpha 1-antitrypsin and this was associated with at least a 22% underestimation of the protein concentration by immunological measurement. 3. Furthermore the cigarette-smoke-damaged alpha 1-antitrypsin had an increased electrophoretic mobility in plain agarose compared with the pure protein and was more susceptible to proteolytic damage by elastase. 4. Comparison with results obtained in vivo suggests that oxidative damage to alpha 1-antitrypsin is not the only mechanism involved in the reduction of its inhibitory capacity in secretions, even in non-smokers     

Alpha1-antitrypsin deficiency: incidence and implications.

Alpha1-antitrypsin (AAT) deficiency is an underrecognized inherited disorder with pulmonary and hepatic implications for both adults and neonates. Clinical expressions of AAT deficiency are seen in the lung, liver, and the skin, with considerable variability in the severity of clinical disease. AAT deficiency accounts for nearly 3% of all cases of chronic obstructive pulmonary disease and is responsible for early-onset emphysema in nonsmokers. Ten to twenty percent of affected neonates develop significant liver disease. Panniculitis, a rare skin complication of AAT deficiency, is characterized by acute inflammatory infiltrate and fat necrosis. While we concentrate on the pulmonary aspect of AAT deficiency, we have included discussion of liver disease and panniculitis. Critical care and advanced practice nurses will benefit from gaining a better understanding of the causes, pathophysiology, diagnosis, and treatment of this disorder.     

Alpha1-antitrypsin deficiency and inflammatory bowel diseases

OBJECTIVE: To evaluate a possible etiologic role of alpha1-antitrypsin deficiency (alpha1AD), most frequently caused by a Z allele mutation, in ulcerative colitis (UC) and Crohn disease (CD). PATIENTS AND METHODS: This retrospective study included 10 patients diagnosed with and/or treated for inflammatory bowel disease (IBD) between 1976 and 1997 and identified from the Mayo Clinic Medical Index System. All 10 patients had either alpha1AD and CD or alpha1AD and UC. The alpha1-antitrypsin (alpha1AT) types and levels were determined with isoelectric focusing testing. The allele types, representing genotypes, were designated PiZZ (or ZZ) for homozygotes and PiMZ (or MZ) for heterozygotes. RESULTS: Seven patients had UC: 4 were genotype ZZ and 3 MZ. Four of these 7 patients had emphysema, 2 had asthma, and 1 had chronic bronchitis. Five were cigarette smokers, but only 1 had smoked coincident with activity of her UC. Two of the UC patients never smoked, and 1 of these 2 had asthma. Three of the 10 patients had CD, 2 genotype ZZ and 1 MZ. Two of the 3 patients were long-term cigarette smokers, and both had emphysema. Nine of the 10 patients with UC and alpha1AD required surgery. CONCLUSIONS: The need for surgery in patients with UC and alpha1-AD may point to a unique phenotypic subgroup of patients with alpha1AD and severe UC. Further studies are required to substantiate the etiologic role of alpha1AD in IBD. Our observations, if confirmed by future studies, suggest that in patients with both IBD and chronic obstructive pulmonary disease, alpha1AD testing should be considered.     

Alpha 1-antitrypsin granules in the liver--always important?

We have studied the clinical histories and liver biopsy findings in 1951 consecutive adult patients with suspected chronic liver disease, and in four known PiZ-homozygous alpha 1-antitrypsin-deficient patients with emphysema (candidates for lung transplant) and no known liver disease, in order to assess the importance of periportal alpha 1-antitrypsin granules in the liver and their possible causal role in liver disease, and to assess the value of possible screening tests. Periportal granules were found in 30 (1.5 per cent) of the 1951 liver biopsies and in all four known PiZ-homozygous subjects. They were the sole putative aetiological agent in eight of 85 patients (9.4 per cent) with otherwise cryptogenic cirrhosis and present in 2.5 per cent of patients with cirrhosis of known aetiology (alcohol, autoimmune etc.). All but one were Z phenotype (seven homozygotes, 22 heterozygotes). alpha 1-Antitrypsin granules were seen in 12 patients (including three of four lung transplant candidates) with no histological chronic liver disease. Determination of serum alpha 1-antitrypsin levels was quite unhelpful in identifying these patients. This study does not support the concept that periportal alpha 1-antitrypsin granules are necessarily pathogenic, but in some cases they may be causally related to otherwise cryptogenic liver disease. The presence of granules gave no important diagnostic, therapeutic or prognostic information.     

Alpha 1-antitrypsin deficiency and liver cirrhosis in adults

Although cirrhosis of the liver caused by alpha 1-antitrypsin deficiency is not uncommon in children, only a few cases have been described in adults. We have seen three such patients--one man and two women, ranging in age from 57 to 66 years. These cases show the wide spectrum of this genetically influenced disease.     

Alpha 1-antitrypsin phenotypes of healthy persons and chronic bronchitis patients

The paper is concerned with phenotyping of alpha 1-antitrypsin using a method of isoelectric focusing in the polyacrylamide gel with ampholine (pH-4-6) in 1000 healthy persons and 583 patients with chronic bronchitis. Phenotype M was registered in 96 and 95.71% of the cases, respectively. The occurrence of heterozygous phenotypes was practically similar among the healthy persons as well as among the patients (4.0 and 4.29%, respectively). It was concluded that the heterozygous carrying of an alpha 1-antitrypsin deficit gene was of no particular importance in the development of chronic bronchitis.     

The effect of tamoxifen in intermediate alpha 1-antitrypsin deficiency associated with the phenotype PiSZ

Three patients, one with lung disease and two with liver disease, with intermediate alpha 1-antitrypsin (AAT) deficiency phenotype PiSZ, (plasma AAT concentration approximately 1/3 of normal) were treated with the anti-oestrogen drug, tamoxifen, for 2-24 months. Patients responded with 50-70% increases in plasma AAT concentrations. Progress of emphysema appeared to be retarded in one case but no improvement in liver function was recorded in the other two patients.     

Alpha 1-antitrypsin deficiency and status asthmaticus in a black teen-ager.

The rare occurrence of alpha 1-antitrypsin deficiency in black Americans has led to the suggestion that routine screening of such subjects in needless. Our report of a black teen-ager with deficiency of this protease inhibitor in association with status asthmaticus suggests that at least relatively young black patients with otherwise unexplained chronic pulmonary disease should be tested for this defect.     

Alpha1-antitrypsin phenotypes in chronic active liver disease and primary biliary cirrhosis.

Alpha1-antitrypsin concentrations and phenotypes were determined in groups of patients with chronic active liver disease and primary biliary cirrhosis. The concentrations of alpha1-antitrypsin were above normal values in both groups; the patients with primary biliary cirrhosis had higher concentrations than those with chronic active liver disease. The prevalence of common phenotypes in these two groups did not differ from that in a sample of healthy blood donors from this institution of from a large Norwegian sample. We interpret our data as disputing the view that alpha1-antitrypsin phenotypes, other than Z. significantly predispose adults to hepatic cirrhosis.     

Automated assay for alpha 1-antitrypsin with N-alpha-benzoyl-DL-arginine-p-nitroanilide as trypsin substrate and standardized with p-nitrophenyl-p'-guanidinobenzoate as titrant for trypsin active sites

alpha 1-Antitrypsin is the most abundant of several serum protease inhibitors. Its deficiency is associated with an increased incidence of emphysema in adults, jaundice in newborns, and childhood cirrhosis. We describe an automated functional assay for the Instrumentation Laboratory's Multistat III Microcentrifugal Analyzer with N-alpha-benzoyl-DL-arginine-p-nitroanilide as trypsin substrate. The assay is standardized in terms of moles of trypsin active sites inhibited per liter of serum, by use of a chromogenic titrant for trypsin active sites, p-nitrophenyl-p'-guanidinobenzoate. The method is rapid, precise, and independent of trypsin supplier, and results correlate well with those by a manual chromogenic and a nephelometric assay.