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PubMed1978

[Pulmonary emphysema and hepatic involvement by alpha-1 antitrypsin deficiency in two adults with a PiZ phenotype (author's transl)].

Two unreleated adult males were found to be suffering from an association of pan-lobular severe emphysema and hepatomegally of unknown origin which led to the discovery of a marked deficit in alpha-1 antitrypsin (A1-AT) in relation to a PiZ phenotype. Liver biopsy revealed cirrhosis with portal fibrosis in one case and in both cases fatty infiltration with the accumulation of a glycoprotein antigenically identical to A1-AT. Electron microscopy showed this protein to be situated within the dilated lumina of the endoplasmic reticulum of the hepatocytes. A1-AT deficiency is usually associated with pulmonary involvement only in the adult and liver involvement only in the child. The association of the two remains rare--hence the interest of the two cases reported.

Adult↗
PubMed1990

Discovery of alpha 1-antitrypsin deficiency.

The author reviews the early history of alpha 1-antitrypsin (AAT) deficiency; the biochemical characterization of this inborn error of metabolism, its pattern of inheritance, frequency and predisposition to early, panacinar emphysema. The importance of the destructive element in emphysema and the gradual focusing on neutrophil elastase as a key enzyme in the pathogenesis of emphysema in alpha 1-antitrypsin deficiency is emphasized. The deficiency state as a prototype of an endoplasmic reticulum storage disease is discussed.

Humans↗
PubMed1974

Chronic obstructive pulmonary disease and alpha-1-antitrypsin (Pi) variation: a family study.

A kindred of a white male proband with alpha1-antitrypsin deficiency, ZZ phenotype, and a severe obstructive ventilatory defect secondary to pulmonary emphysema was studied with regard to alpha1-antitrypsin phenotype, serum trypsin inhibitory capacity (T.I.C.), and pulmonary function. T.I.C.'s and alpha1-antitrypsin phenotypes were consistent with autosomal codominant inheritance. While MZ relatives as well as the proband had pulmonary function abnormalities, the pattern varied within the kindred and abnormalities were observed in some MM relatives also.

Adolescent↗
PubMed1986

Alpha 1-antitrypsin Pi-types in 965 COPD patients.

To study further the role of intermediate alpha 1-antitrypsin (AAT) deficiency in chronic obstructive pulmonary disease (COPD), AAT Pi-types and serum-trypsin-inhibitory-capacity (STIC) were measured in 965 patients with COPD. Heterozygosity of the Z variant was the major cause of intermediate AAT deficiency (primarily the MZ phenotype), accounting for 8.0 percent of the patients compared to 2.9 percent of control subjects (p less than .0005). ZZ homozygosity was detected in 1.9 percent of the patients, compared to 0.04 percent of control studies performed by others (none was present in our own control group of 1,380 subjects). The mean age for MS or MZ patients did not differ from that of the COPD patients as a whole, whereas the ZZ homozygotes were younger (55.9 +/- 9.8 vs 65.3 +/- 7.5 years). These results resemble those of a previous study in 66 male veterans with pulmonary emphysema suggesting that the MZ phenotype, or intermediate AAT deficiency in general, probably does predispose to the development of COPD. However, the prevalence of AAT deficiency in COPD patients is small (approximately 10 percent). The number with an MS phenotype was not increased in this group of COPD patients.

Adult↗
PubMed1996

Alpha 1-antitrypsin deficiency: evaluation of bronchiectasis with CT.

PURPOSE: To assess bronchiectasis depicted with computed tomography (CT) in patients with alpha 1-antitrypsin deficiency and to examine associated clinical correlates. MATERIALS AND METHODS: CT scans in 14 patients with alpha 1-antitrypsin deficiency were evaluated by two thoracic radiologists for the presence and extent of bronchiectasis and emphysema. The findings were correlated with numeric infection scores on the basis of symptoms of sputum production and respiratory infection and with a history of conditions that may predispose to development of bronchiectasis. RESULTS: Six (43%) of 14 patients had CT evidence of bronchiectasis. Patients with bronchiectasis had significantly higher infection scores than did patients without bronchiectasis (P < .005). Two patients had diffuse cystic bronchiectasis, and neither reported a history of illness that may have predisposed them to this condition. CONCLUSION: Bronchiectasis may be more common in patients with alpha 1-antitrypsin deficiency than has been previously recognized. The diagnosis of alpha 1-antitrypsin deficiency should be considered in patients with emphysema and diffuse cystic bronchiectasis.

Bronchiectasis↗
PubMed1975

Alpha-1-antitrypsin deficiency in New Zealand.

A severe deficiency of the serum protein alpha-1-antitrypsin can be expected to occur in 1 in 750 European New Zealanders. It can usually be identified by a faint or absent alpha-1 band on serum protein electrophoresis. Forty-seven cases are presented. 31 phenotype ZZ and 16 phenotype SZ. Eighteen have developed emphysema usually by age 40 years, two show childhood liver disease. One adult died of liver disease and three of the emphysema patients had liver abnormalities at post mortem. The remainder, mainly aged less than 30 years, are as yet asymptomatic. Individuals at risk should be protected from respiratory irritants (cigarettes, dusty environments and chest infections) and liver toxins (e.g., alcohol). The partial deficiency state (MZ) which occurs in 4 percent of the population also predisposes to respiratory and perhaps liver disease.

Adolescent↗
PubMed1977

[Alpha 1 antitrypsin deficiency].

Alpha-1-antitrypsin (alpha-1-AT) is a potent protease inhibitor. Its deficiency predisposes to serious diseases such as "neonatal hepatitis" and "obstructive pulmonary emphysema". Due to the existence of multiple codominant alleles at one single locus, there are several genetic variants from alpha-1-AT. In homozygous persons the protease inhibitor type (Pi type) MM is prevailing, in heterozygous persons the Pi types MZ and MS. So far one knows at least 24 different alleles. Their phenotypes differ as well in their electrophoretic position as in the protein concentration of the serum. Pi type MM guarantees a normal concentration of alpha-1-AT in the serum, whereas Pi type ZZ causes of serious alpha-1-AT deficiency which bears a particularly high risk of disease.

Adolescent↗
PubMed2002

Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer.

Transforming growth factor-betas (TGF-betas) are multifunctional growth factors that are secreted as inactive (latent) precursors in large protein complexes. These complexes include the latency-associated propeptide (LAP) and a latent transforming growth factor-beta binding protein (LTBP). Four isoforms of LTBPs (LTBP-1-LTBP-4) have been cloned and are believed to be structural components of connective tissue microfibrils and local regulators of TGF-beta tissue deposition and signaling. By using a gene trap strategy that selects for integrations into genes induced transiently during early mouse development, we have disrupted the mouse homolog of the human LTBP-4 gene. Mice homozygous for the disrupted allele develop severe pulmonary emphysema, cardiomyopathy, and colorectal cancer. These highly tissue-specific abnormalities are associated with profound defects in the elastic fiber structure and with a reduced deposition of TGF-beta in the extracellular space. As a consequence, epithelial cells have reduced levels of phosphorylated Smad2 proteins, overexpress c-myc, and undergo uncontrolled proliferation. This phenotype supports the predicted dual role of LTBP-4 as a structural component of the extracellular matrix and as a local regulator of TGF-beta tissue deposition and signaling.

Adaptor Proteins, Signal Transducing↗
PubMed1982

Structure and variation of human alpha 1-antitrypsin.

The sequence of alpha 1-antitrypsin is in keeping with its role as a tissue scavenger of leukocyte elastase. Two abnormal variants commonly present in Europeans cause a deficiency that predisposes them to a progressive loss of lung elasticity. The nature of the reactive centre helps explain why cigarette smoking greatly accelerates the onset and severity of this degenerative process to give the disease emphysema.

Amino Acid Sequence↗
PubMed1999

Quantum proteolysis by neutrophils: implications for pulmonary emphysema in alpha 1-antitrypsin deficiency.

Traditional enzyme kinetics provide a poor explanation for the increased risk of lung injury in alpha 1-antitrypsin (AAT) deficiency. Millimolar concentrations of leukocyte elastase, when released from single azurophil granules of activated neutrophils, lead to evanescent quantum bursts of proteolytic activity before catalysis is quenched by pericellular inhibitors. Herein, we tested the possibility that quantum proteolytic events are abnormal in AAT deficiency. We incubated neutrophils on opsonized fluoresceinated fibronectin in serum from individuals with various AAT phenotypes, and then measured and modeled quantum proteolytic events. The mean areas of the events in serum from heterozygous individuals (Pi MZ and Pi SZ) were slightly, but significantly, larger than those in serum from normal patients (Pi M). In marked contrast, mean areas of events in serum from AAT-deficient individuals were 10-fold larger than those in serum from normal patients. Diffusion modeling predicted that local elastase concentrations exceed AAT concentrations for less than 20 milliseconds and for more than 80 milliseconds in Pi M and Pi Z individuals, respectively. Thus, quantum proteolytic events are abnormally large and prolonged in AAT deficiency, leading directly to an increased risk of tissue injury in the immediate vicinity of activated neutrophils. These results have potentially important implications for the pathogenesis and prevention of lung disease in AAT deficiency.

Cytoplasmic Granules↗
PubMed1996

A 30-year perspective on alpha 1-antitrypsin deficiency.

The early history of alpha 1-antitrypsin deficiency, in the years between 1962 and 1965, and its impact on the understanding of emphysema abnormalities were reviewed by me in 1989. This report discusses the disease spectrum (including emphysema, liver, and vasculitic diseases) and focuses on the variable clinical expression of the deficiency state. Some new findings that may be relevant to the function of alpha 1-antitrypsin are also considered.

Humans↗
PubMed1978

Selective IgA deficiency and Pi ZZ-antitrypsin deficiency. Association with recurrent sinopulmonary infections, emphysema, and bronchiectasis.

We describe a patient in whom selective IgA deficiency and homozygous alpha1-antitrypsin deficiency were discovered. Clinically, the patient suffered from chronic sinopulmonary infections, destructive emphysema, and bronchiectasis. The interrelation of IgA and alpha1-antitrypsin was studied. Twenty-three alpha1-antitrypsin-deficient sera were screened for IgA deficiency. None of these sera were deficient in IgA. Fifteen IgA-deficient sera were screened for alpha1-antitrypsin deficiency. In this group, three patients were found to have variant alpha1-antitrypsin phenotypes. Respiratory infections were a prominent complaint in all three of these patients, with bronchiectasis in two patients. We believe that the combination of IgA and alpha1-antitrypsin deficiencies should be considered in the evaluation of any patient with idiopathic bronchiectasis.

Bronchiectasis↗
PubMed2006

[Klotho gene and endothelial function].

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g. arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, skin atrophy). We have demonstrated that mice deficient for the klotho gene show endothelial dysfunction as manifested by an attenuated response of aortic relaxation in response to acetylcholine stimulation. Systemic nitric oxide production was also significantly reduced in klotho deficient mice. Oxidative stress was increased in klotho deficient mice. The klotho gene delivery improves multiple aging phenotypes. Our findings establish the basis for the therapeutic potential of klotho gene delivery in age-related diseases.

Aging↗
PubMed1989

Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates.

STUDY OBJECTIVE: To determine the range of pulmonary function variability in alpha-1-antitrypsin-deficient persons and to identify epidemiologic factors and pulmonary symptoms and conditions associated with this variability. DESIGN: Case series ascertained through investigation of extant obstructive lung disease (index cases, 22 subjects) or by other means (non-index cases, 30 subjects). SETTING: Referral-based pulmonary division at a tertiary care medical center. PARTICIPANTS: Fifty-two alpha-1-antitrypsin-deficient persons of type Pi Z ascertained by: extant chronic obstructive pulmonary disease (22 cases), family studies (20 cases), liver disease (4 cases), population screening (4 cases), and other pulmonary problems (2 cases). MEASUREMENTS AND MAIN RESULTS: Pulmonary function tests and a version of the American Thoracic Society 1978 standard respiratory epidemiology questionnaire were used. Persons of type Pi Z who were not specifically ascertained with chronic obstructive pulmonary disease had values of forced expiratory volume in 1 second over 65% of predicted in 20 out of 30 cases and frequently had normal lung function. Univariate and multivariate analyses of possible causes of lung disease showed that the following factors were significant (P less than 0.05): pulmonary symptoms (effects associated with chronic obstructive pulmonary disease), including dyspnea and chronic cough; age and pack-years of smoking (epidemiologic correlates); and other pulmonary conditions (potential causes or effects) including asthma, pneumonia, and episodes of increased cough and phlegm. Finally, we found a striking excess of questionnaire-reported parental emphysema in families of type Pi Z persons with chronic obstructive pulmonary disease compared with families of type Pi Z persons without disease. CONCLUSIONS: Many persons with alpha-1-antitrypsin deficiency do not have clinically significant lung function impairment: the perceived natural history of antitrypsin deficiency has been distorted by ascertainment bias. In addition to cigarette smoking, it appears that asthma, lower respiratory infections, and possibly some familial factors contribute to a severe clinical course. Follow-up of our cohort with widely varying lung function will provide insights into the natural history of the emphysema associated with alpha-1-antitrypsin deficiency.

Adolescent↗