Intermediate Alpha1-antitrypsin Deficiency Research Articles

Transplant with MZ genotype liver: what is theclinical pulmonarypicture after 30years? a case report and review of the literature.

Alpha-1 antitrypsin, also known as alpha1 proteinase inhibitor, is a protein 90% synthesized by hepatocytes. Alpha-1 antitrypsin deficiency should be suspected if patients have unexplained emphysema or liver disease in the absence of others recognized causes. The diagnosis is based on tests that measure the amount of the enzyme in the blood and confirm by molecular analysis. We present the case of a man of Caucasian ethnicity, who started experiencing difficulty in breathing 20years after liver transplantation. After about 30years since transplantation, an intermediate alpha-1 antitrypsin deficiency is diagnosed with evidence of air trapping, pulmonary emphysema and bronchiectasis. The presence of a Z-variant synthesized from the donor liver may have contribute to the onset of respiratory disease.

Intermediate Alpha-1 Antitrypsin Deficiency Can Play a Role in Pulmonary Exacerbation?

Background: Alpha-1 antitrypsin deficiency is generally suspected in young patients with pulmonary emphysema or chronic obstructive pulmonary disease (COPD). Patients often suffer from diagnostic delays or are misdiagnosed, for example, with COPD, asthma, or airway hyperresponsiveness because of the nonspecific nature of respiratory symptoms recognised with Alpha-1 antitrypsin deficiency (AATD). These pathologies develop in homozygous patients (both compromised alleles) with severely deficient protein; however, they are also frequently observed in heterozygous patients (only one compromised allele) for the gene mutation with a more or less deficient protein and functional anatomical damage of varying severity depending on the type of mutation and the exposure to environmental risk factors and/or professional that can trigger the repeated injurious inflammatory process. Case Description: We describe two cases of late diagnosis of alpha-1 antitrypsin deficiency, with many exacerbations and intermediate level of alpha-1 antitrypsin. Due to the peculiar clinical history, and the PLowell rare mutation, although intermediate AATD, the patients were subjected to replacement therapy and they obtained clinical improvement. Discussion: Both the cases carried a heterozygous PLowell mutation representing two interesting and rare examples of clinical cases with double heterozygosity. The presence in the other AAT allele of the S-mutation in the first case and a concomitant presence of another mutation in the cystic fibrosis gene in the second case contributed to the protease-antiprotease imbalance and, despite intermediate AATD, was the probable cause of the numerous exacerbations. Conclusion: Alpha-1 antitrypsin deficiency should always be suspected in patients with respiratory disease and an unclear or complex clinical history. It may be useful to recognize and evaluate treatment even outside the established parameters, in selected cases.

Diagnostic biochimique et moléculaire du déficit en alpha 1 antitrypsine dans une famille tunisienne

Our study investigated alpha 1 antitrypsin deficiency (AATD) diagnosis in a family originated from central Tunisia and showing a familial history of asthma. Biochemical and genetic diagnosis for AATD was performed according to current diagnostic standards. AAT level quantification in affected individuals showed plasma AAT levels consistent with intermediate AATD (ranged from 0.91 to 1.04 g/L). The molecular analysis was assessed using the genotyping of the most prevalent PI*S and PI*Z SERPINA1 mutations and the sequencing of AAT coding exons for rare AATD variants detection. No PI*S or PI*Z deficient variants were seen in this family. Sequencing results showed the inheritance of the deficient rare variant PI*M(wurzburg) (P369S) at the heterozygous state in the mother and two affected siblings. However, AATD status remains unexplained in the third affected case, with no mutations detected in the AAT coding exons.

Alpha1-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.

Changes of volume of trapped gas after bronchodilation in subjects with suspected subclinical emphysema.

We studied the volume of trapped gas (VTG), using a nitrogen washout method, before and after bronchodilation in four groups with theoretically increasing risk of developing pulmonary emphysema: (1) nonsmoking healthy controls (PiMn), (2) nonsmoking subjects with an intermediate alpha 1-antitrypsin deficiency (PiMZn), (3) smoking subjects with normal concentration of alpha 1-antitrypsin, and (4) smoking PiMZ subjects. VTG was the only lung function variable that showed a significant difference between PiMZn and PiMn subjects but only after bronchodilation. Some conventional lung function tests also distinguished smokers from nonsmokers of both genotypes but VTG was the most sensitive test. VTG decreased after salbutamol inhalation in the control group but showed a consecutively larger increase with more risk factors of developing emphysema. An increase in VTG after bronchodilation may be a sign of alveolar abnormality preceding development of clinical lung emphysema.

Chronic 'cryptogenic' liver disease and malignant hepatoma in intermediate alpha 1-antitrypsin deficiency identified by a Pi Z-specific monoclonal antibody.

Using a monoclonal antibody against the Pi Z genetic variant of alpha 1-antitrypsin in an enzyme-linked immunosorbent assay, we have screened plasma samples from 857 consecutive patients with liver disease for the presence of Pi Z alpha 1-antitrypsin. Intermediate alpha 1-antitrypsin deficiency (Pi MZ and SZ) was found in 64 cases, or 7.6%, compared with an expected 4.8% (p less than 0.001). The plasma alpha 1-antitrypsin level was subnormal in only 50% of them. Forty-three of the 64 heterozygotes were men, compared with 494 of 857 (58%) in the total study population (p less than 0.001). At least 14 heterozygotes had cryptogenic liver disease, compared with 3 of 128 sex- and age-matched controls from the same study population (p less than 0.001). Malignant hepatoma occurred in 6 heterozygotes compared with 1 control (p less than 0.01), and in 13 of all 793 non-Pi Z patients (p less than 0.001).

Monoclonal antibody specific for the mutant PiZ alpha 1-antitrypsin and its application in an ELISA procedure for identification of PiZ gene carriers.

The PiZ genetic variant of alpha 1-antitrypsin in its homozygous form is associated with an increased risk for chronic lung and liver disease. About 5% of the population are carriers of one PiZ deficiency gene resulting in intermediate levels of plasma alpha 1-antitrypsin (PiMZ, PiSZ, PiPZ). We report the preparation of a hybridoma cell line, ATZ 11, produced by fusion of spleen cells from BALB/c mice immunized with a purified liver PiZ alpha 1-antitrypsin and Sp 2/0 Ag 14 mouse myeloma cells. ATZ 11 produces monoclonal antibodies (IgG1 kappa) specifically interacting with PiZ alpha 1-antitrypsin. These antibodies were used in an ELISA procedure permitting easy and accurate identification of PiZ gene carriers. The method is especially well-suited for studying large population samples concerning the putative relationship between intermediate alpha 1-antitrypsin deficiency and disease.

Interrelationships between Serum Chemotactic Factor Inactivator, Alpha1-Antitrypsin Deficiency, and Chronic Obstructive Lung Disease1–4

Serum chemotactic factor inactivator (CFI) activity was quantitated in 22 subjects with chronic airflow obstruction (CAO); 8 had normal antitrypsin levels (Pi M phenotype), 6 had intermediate antitrypsin deficiency (Pi MZ phenotype), and 8 had severe antitrypsin deficiency (Pi Z phenotype). We studied 19 healthy subjects with normal lung function as controls; 3 had Pi M and 6 had Pi MZ phenotypes. Subjects with CAO, irrespective of the alpha 1-antitrypsin (AAT) phenotype, had significantly lower CFI activity than the normal subjects; the lowest levels were found in those with CAO and Pi Z phenotype. Normal subjects with intermediate AAT deficiency and MZ phenotype had normal levels of CFI. The results suggest that deficiency of serum CFI may be important in the pathogenesis of chronic airflow obstruction, particularly in those with severe AAT deficiency.

Lung Distensibility and Airway Function in Intermediate Alpha1-Antitrypsin Deficiency (PiMZ)

In recent years, numerous, well-controlled studies have failed to show any difference in spirometry or in maximum expiratory flow-volume (MEFV) curves (breathing air) between subjects with normal serum alpha1-antitrypsin (α1AT) levels (Pi type M) and heterozygotes with intermediate α1AT deficiency (Pi type MZ). 1 Camara M Martin JP Le deficit en alpha1-antitrypsine et son retentissement en pathologie pulmonaire. Bull Europ Physiopath Resp. 1978; 14: 91-124 PubMed Google Scholar , 2 Tattersall SF Petrik R Pereira Hunter D et al. Lung distensibility and airway function in intermediate alpha1-antitrypsin deficiency (PiMZ). Thorax. 1979; 34: 637-646 Crossref PubMed Scopus (21) Google Scholar Nevertheless, the incidence of emphysema at post mortem examination is noted to be increased in the lungs of subjects with PiMZ compared to that in PiM subjects. 3 Eriksson S Moestrup T Hägerstrand I Liver, lung and malignant disease in heterozygous (Pi MZ) α1-antitrypsin deficiency. Acta Med Scand. 1975; 198: 243-247 Crossref PubMed Scopus (53) Google Scholar There have been several reports of abnormalities in the static pressure-volume (PV) curve of the lung, although the two best-controlled studies, from Malmö 4 Larsson C Eriksson S Dirksen H Smoking and intermediate alpha-1 antitrypsin deficiency and lung function in middle-aged men. Br Med J. 1977; 2: 922-925 Crossref PubMed Scopus (48) Google Scholar and Tucson, 5 McDonagh DJ Nathan SP Knudson RJ et al. Assessment of alpha-1-antitrypsin deficiency heterozygosity as a risk factor in the etiology of emphysema. J Clin Invest. 1979; 63: 299-309 Crossref PubMed Scopus (23) Google Scholar have produced divergent results.

Lung distensibility and airway function in intermediate alpha 1-antitrypsin deficiency (Pi MZ).

We examined the role of intermediate alpha 1-antitrypsin deficiency in predisposing to abnormalities of lung distensibility and airway function in 20 heterozygotes (Pi MZ) who were individually matched with a control Pi M subject of similar age, height, and smoking habits drawn from the same male, working population. There were no significant differences between the heterozygotes and their controls in the results of spirometry, maximum expiratory flow-volume curves (breathing air), single breath nitrogen test, arterialised capillary blood oxygen pressure, or single breath carbon monoxide transfer. Additional studies were made in 12 of the pairs of Pi MZ and Pi M subjects. Comparison of maximum expiratory flow-volume curves breathing air and 80% helium-20% oxygen showed no differences between the Pi MZ and Pi M subjects. Although airway function was similar in the two groups, four of 12 Pi MZ subjects showed abnormalities of the pressure-volume curve of the lung (reduction in lung recoil pressure, abnormal shape factor, increase in functional residual capacity). Abnormalities of washout of a helium-sulphur hexafluoride gas mixture, of a type previously described as characteristic of emphysema, were found in two of the men with abnormal pressure-volume curves. The results suggest that Pi MZ subjects have an increased susceptibility to alveolar abnormalities without increased abnormalities of airway function; this may explain the increased frequency of emphysema at necropsy despite many studies showing no predisposition to abnormal airway function in life. The functional changes we observed would be unlikely to cause symptoms. The risk of disablement from chronic lung disease appears to be only slightly enhanced by intermediate alpha 1-antitrypsin deficiency.

Neutrophil elastase and pulmonary function in subjects with intermediate alpha1-antitrypsin deficiency (MZ phenotype).

We studied the relationships among neutrophil elastase, smoking, and pulmonary function in 32 subjects with intermediate alpha1-antitrypsin deficiency (Pi MZ phenotype). Nineteen subjects were dete...

Intermediate alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease in Yugoslavia.

As part of a larger investigation of factors associated with chronic obstructive pulmonary disease among Yugoslavian men, an attempt was made to measure the role played by alpha1-antitrypsin deficiency in the causation of those diseases. Almost 3,000 men from Tuzla, an industrial and mining center in central Bosnia, were screened for alpha1-antitrypsin deficiency. Twenty-six men heterozygous for the Pi MZ phenotype were found in this population. The men with the Pi MZ phenotype were compared with a random sample from the total population. The analysis of the data showed that there is an apparent physiologic impairment associated with Pi Z heterozygosity that produces a shift in the relationships between the different lung volumes without over-all hyperinflation, namely, an increase in residual volume at the expense of vital capacity. However, because of the low prevalence of the Pi Z gene, it does not appear to account for much of the high rate of chronic obstructive pulmonary disease found in this population.

Smoking and intermediate alpha1-antitrypsin deficiency and lung function in middle-aged men.

Lung function was evaluated in a representative population sample of 50-year-0ld men living in one Swedish city. Twenty-four smoking and 15 non-smoking men heterozygous for alpha1-antitrypsin deficiency--that is, with the protease-inhibitor (Pi1 phenotype MZ--were carefully matched for weight and smoking habit with Pi M controls. The pulmonary function of non-smoking Pi MZ subjects did not differ from that of non-smoking Pi M controls. In contrast, smoking heterozygotes showed a significant loss of elastic recoil, enlarged residual volumes, and increased closing capacity but no signs of obstructive ventilatory impairment. Most smoking Pi MZ individuals reported mild exertional dyspnoea.

Alpha1-Antitrypsin Deficiency and Liver Disease in Children: Phenotypes, Manifestations, and Prognosis

Among 424 children with liver disease, 20 had alpha1-antitrypsin deficiency associated with protease inhibitor ZZ phenotype. This disorder manifested itself as cholestasis in early infancy in 19 children. Jaundice and pruritus cleared in 16 of these by 7 months of age, but hepatomegaly and laboratory evidence of mild hepatic dysfunction persisted in all. Biliary cirrhosis and portal hypertension eventually developed or was suspected in eight, and hypoplasia of intraheptic bile ducts was demonstrated in another four. Routine screening revealed intermediate alpha1-antitrypsin deficiency in 16 other children with various types of liver disease. The phenotype in these patients was MZ, MS, or SZ. PAS-positive granules were present in liver of all patients with the ZZ phenotype and in none with other phenotypes. The findings indicate that manifestations and prognosis of this inherited liver disease are extremely variable.

Smoking and Chronic Obstructive Lung Disease in Alpha1-Antitrypsin Deficiency

Similar spectra of chronic obstructive lung disease were observed in eight patients with severe and 21 with intermediate alpha1-antitrypsin deficiency, but patients with intermediate levels of protease inhibitor became ill when older and following greater cigarette exposure. In 61 presumably healthy relatives of these patients, almost one-half of those with intermediate antitrypsin deficiency who smoked had spirometric evidence of early airways obstruction. Relatives with normal antitrypsin activity did not show this change, nor were perfusion lung scan or diffusing capacity abnormalities as common in normal relatives as in deficient ones. The intermediate deficiency may predispose to lung disease by accentuating an individual's susceptibility to the harmful effects of external irritants. An interaction of genetic and environmental factors suggests that lung disease could be prevented by identifying asymptomatic, susceptible relatives and counseling them against contact with irritants. Since antitrypsin deficiency cannot be reliably recognized by any other means, we advocate that all patients with chronic obstructive lung disease undergo an antitrypsin assay.

Pathophysiology of hereditary emphysema.

Patients with decreased serum alpha1-antitrypsin were designated as severely deficient (7% to 15% of normal) or intermediately deficient (30% to 65% of normal) by quantitative radial immunodiffusion. All severely deficient patients were symptomatic and had severe emphysema. Among intermediately deficient patients emphysema was clinically evident only after age 50. Younger subjects had significant loss of lung elastic recoil and hyperinflation without expiratory flow obstruction. Older patients with an intermediate deficiency had abnormalities that were radiographically and physiologically identical to those of younger severely deficient patients. Postmortem examination of the lung of two patients with severe deficiency and one patient with intermediate deficiency showed extensive panlobular emphysema of the lower two thirds of the lungs, with relative sparing of the upper third. It is concluded that patients with intermediate alpha1-antitrypsin deficiency may develop emphysema identical to that found in severely deficient patients but at an older age.