Heterozygous Alpha 1-antitrypsin Deficiency Research Articles

Occurrence of Emphysema in Individuals With Williams-Beuren Syndrome: A Narrative Review

BackgroundWilliams-Beuren syndrome (WBS) is a multisystem genetic condition characterized by a submicroscopic deletion on the 7th chromosome (7q11.23), which usually includes the elastin gene. Research QuestionThough the elastin deficiency in WBS can predispose to emphysema, the prevalence of emphysema in WBS is unknown. This narrative review aims to address this gap by estimating the frequency of emphysema (or suggestive features thereof) in patients with WBS, with a special focus on concomitant alpha-1 antitrypsin deficiency. MethodsLiterature was reviewed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ResultsOf 419 studies identified by the search strategy, 19 eligible studies reported 393 adult patients with WBS. The criteria by which emphysema was assessed varied greatly among the relatively few reports addressing this issue. Chest CT evidence of emphysema was reported in 3 of 26 (11.5%) patients. Physiologic evidence of airflow obstruction, though not definitive for emphysema (i.e., with asthma not excluded) was present in as many as 38.6%. Considering studies that reported multi-organ clinical manifestations of WBS, irrespective of whether chest CT imaging and/or pulmonary function testing was reported, the frequency of spirometric and imaging signs suggestive of emphysema was 4.3%. Emphysema was not reported in any of the 11 patients with concomitant PI*MZ heterozygous alpha-1 antitrypsin deficiency. InterpretationIn the context that only few adults with WBS have been fully characterized regarding the occurrence of emphysema, confidently estimating the prevalence of emphysema is difficult. This review shows that the frequency of imaging and PFT abnormalities suggestive of emphysema seems relatively low in the context that the elastin deficiency of WBS clearly can predispose to emphysema, and that other manifestations of elastin deficiency are present early in life. Acknowledging the challenges of studying uncommon diseases or syndromes, more systematic study of adults with WBS is needed.

Clinical, histological, and biochemical liver phenotype of European adults with heterozygous alpha-1 antitrypsin deficiency (Pi*MZ genotype)

Clinical, histological, and biochemical liver phenotype of European adults with heterozygous alpha-1 antitrypsin deficiency (Pi*MZ genotype)

The Alpha-1 Antitrypsin Polymer Load Correlates With Hepatocyte Senescence, Fibrosis Stage and Liver-Related Mortality.

Alpha-1 antitrypsin deficiency (AATD) is an important, inherited cause of chronic liver disease. Marked variation in fibrosis stages in patients with homozygous deficiency and those factors that determine whether heterozygous carriers develop liver fibrosis, remain unexplained. Murine studies implicate polymerized alpha-1 antitrypsin (AAT) within hepatocytes as pathogenic. The relationship between the quantity of polymerized AAT within hepatocytes (polymer load), stage of hepatic fibrosis and liver-related clinical outcomes (death, evolution to hepatocellular carcinoma, or need for liver transplantation) were investigated using liver tissue from 92 patients at first presentation with either homozygous or heterozygous AATD. Further tissue-based studies were undertaken to determine if polymerized AAT was associated with failure of cell cycle progression, accelerated aging or hepatocyte senescence by immunohistochemical analysis. The AAT polymer load correlated closely with hepatic fibrosis stage and long-term clinical outcome, independent of homozygous or heterozygous status. AAT polymers within hepatocytes correlated closely with failure of cell cycle progression assessed using cell cycle phase markers, accelerated aging manifest as shortened telomeres and other markers consistent with hepatocyte senescence manifest as the presence of nuclear p21 expression and enlarged nuclei. The proportion of p21 positive hepatocytes or hepatocytes with enlarged nuclei correlated with hepatic fibrosis stage and the long-term clinical outcome. These data suggest that accumulation of AAT polymers within hepatocytes drives senescence. Quantitation of both the AAT polymer load or hepatocyte senescence markers correlated with hepatic fibrosis stage and the long-term clinical outcome. Either or both could be considered markers of disease severity and treatment response in clinical trials.

Comparison of Heterozygous Alpha-1 Antitrypsin Deficiency in Patients with Liver Cirrhosis and Transplant Recipients with the General Population and Liver Donors

Comparison of Heterozygous Alpha-1 Antitrypsin Deficiency in Patients with Liver Cirrhosis and Transplant Recipients with the General Population and Liver Donors

Genotyping diagnosis of alpha-1 antitrypsin deficiency in Saudi adults with liver cirrhosis.

The acute phase protein alpha-1 antitrypsin (AAT) is mainly produced in liver cells. AAT deficiency affects the lungs and liver. We conducted a case-control study to define a valuable method for the proper diagnosis of alpha-1 antitrypsin deficiency (AATD), as well as the association of liver cirrhosis with AATD in Saudi adults.Blood samples from 300 liver cirrhosis patients and 400 controls were analyzed according to serum AAT concentration, phenotyping, and genotyping. Nephelometry was used for AAT quantification, isoelectric focusing electrophoresis was used for phenotyping detection, and real-time PCR was used for genotyping to determine the Z and S deficiency alleles.This study highlights the accuracy of using genotyping in addition to AAT quantification, since this technique has proven to be successful in the diagnosis of AATD for 100% of our cases. A significant deviation in AAT genotypes frequencies from the Hardy–Weinberg equilibrium in the adult cirrhosis group occurred due to a higher observed frequency than expected for the Pi ZZ homozygous genotype.Pi ZZ in adults may be considered as the risk factor for liver cirrhosis. However, we could not establish this relationship for heterozygous AATD genotypes (such as Pi MZ and Pi SZ).

THU-037 - Comparison of heterozygous alpha-1 antitrypsin deficiency in unselected patients with liver cirrhosis and transplant recipients with the general population and liver donors

THU-037 - Comparison of heterozygous alpha-1 antitrypsin deficiency in unselected patients with liver cirrhosis and transplant recipients with the general population and liver donors

Lung function of school children with low levels of alpha1-antitrypsin and tobacco smoke exposure.

Exposure to environmental tobacco smoke (ETS) and other air pollutants has been associated with small decrements in lung function. The susceptibility to pollution exposure may, however, vary substantially between individuals. Children with an impaired protease-antiprotease balance may be particularly vulnerable. Therefore this study aimed to investigate the effects of ETS exposure on children with reduced levels of alpha1-antitrypsin (alpha1-AT). Random samples of school children (aged 9-11 yrs) (n=3,526) were studied according to the International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol, including parental questionnaires, pulmonary function and allergy testing. Blood samples were obtained to measure plasma levels of alpha1-AT and to genotype for pleomorphic protein inhibitor (Pi)Z and PiS alleles. Children with low levels of alpha1-AT (< or = 116 mg x dL(-1)) showed significant, albeit small decrements in baseline lung function. When exposed to ETS, pronounced decrements of pulmonary function, particularly in measures of mid- to end-expiratory flow rates, were seen in these children as compared to exposed children with normal levels of alpha1-AT. The mean levels of % predicted+/-SE in both groups were: maximum expiratory flow at 50% of vital capacity 79.4+/-7.2 versus 99.0+/-1.5, maximum expiratory flow at 25% of vital capacity 67.4+/-10.0 versus 100.3+/-2.1, maximal midexpiratory flow 73.7+/-8.6 versus 99.9+/-1.7. These findings suggest that school children with low levels of alpha1-antitrypsin are at risk of developing pronounced decrements in pulmonary function, particularly if they are exposed to environmental tobacco smoke. Parents of children with heterozygous alpha1-antitrypsin deficiency resulting in significantly reduced blood concentrations should be advised to prevent their children from being exposed to environmental tobacco smoke and dissuade them from taking up smoking.

Fibromuscular dysplasia of the internal carotid artery associated with alpha1-antitrypsin deficiency.

A deficiency of alpha1-antitrypsin has been implicated in the development of various disorders affecting medium-sized arteries, including intracranial aneurysms, cervicocephalic arterial dissections, and fibromuscular dysplasia (FMD). We performed alpha1-antitrypsin phenotyping in three consecutive patients who underwent bypass surgery for FMD of the extracranial internal carotid artery to test the hypothesis that alpha1-antitrypsin deficiency is a genetic risk factor for the development of FMD. The study population consisted of three women (aged 37, 49, and 53 years, respectively) who had bilateral internal carotid artery stenosis caused by FMD. The indications for surgery included ocular or cerebral ischemic symptoms in two patients and progressive stenosis in one patient. The diagnosis of FMD was confirmed by histological examination of the resected segment of artery. The alpha1-antitrypsin phenotype was determined by isoelectric focusing in polyacrylamide gels. Two of the three patients had a heterozygous alpha1-antitrypsin deficiency (PiMZ phenotype). Pathological examination of the resected arterial segment showed typical medial FMD with focal intimal fibroplasia in both patients with the PiMZ phenotype. These findings suggest that a heterozygous alpha1-antitrypsin deficiency may be a genetic risk factor for the development of FMD of the internal carotid artery.

Risk factors for cirrhosis in patients with chronic hepatitis C virus infection: Results of a case-control study

The role of the viral genotype, especially genotype 1b, in the severity of liver injury induced by chronic hepatitis C virus (HCV) infection is unclear, probably because of confounding factors such as the date and mode of contamination. Host genetic or environmental factors such as heterozygous MZ alpha1-antitrypsin deficiency or alcoholism, could also be potential risk factors for the development of cirrhosis. The aim of this study was to compare the prevalence of genotypes, alpha1-antitrypsin phenotype, past hepatitis B virus infection, and alcohol consumption in cirrhotic and noncirrhotic patients with chronic hepatitis C. We conducted a case-control study comparing 84 consecutive cirrhotic patients with chronic hepatitis C (cases) with 84 noncirrhotic patients with chronic hepatitis C (controls) selected from a cohort of 464 patients hospitalized during the same period. Controls were paired with cases according to age, sex, risk factors, and date of infection. HCV genotypes were determined using the InnoLiPA technique (Innogenetics, Zwijnaarde, Belgium) and classified according to the method of Simmonds. Patients were divided in three groups according to alcohol consumption: <30 g/d (light), 30 to 80 g/d (moderate), and >80 g/d (heavy). Cirrhotic and noncirrhotic patients were not significantly different in terms of genotype distribution (1a/1b/2a/3a/others/undetermined: 10/48/7/17/0/2 versus 11/43/10/10/5/5), alpha1-antitrypsin phenotype distribution (MM/MS/MZ: 84%/14%/2% vs. 87%/11%/2%, respectively), and prevalence of antibody to hepatitis B core antigen positivity (29% vs. 23%). Alcohol consumption was significantly different between cases and controls (L/M/H: 58%/27%/16% vs. 76%/15%/9%, respectively; P < .05). Two conclusions regarding patients with chronic hepatitis C virus infection can be drawn from this study: 1) viral genotype, especially 1b, past hepatitis B virus infection, and heterozygous MZ alpha1-antitrypsin deficiency are not risk factors for cirrhosis; and 2) alcohol consumption, even moderate, is a risk factor for cirrhosis. (Hepatology 1997 Sep;26(3):776-9)

Heterozygous α1-Antitrypsin Deficiency (PiSZ) in an Adolescent With Asthma

Although alpha 1-antitrypsin deficiency has been associated with obstructive lung disease in individuals possessing a homozygous phenotype (PiZZ), this association has not been as clearly documented in heterozygous individuals (PiMZ, PiMS, and PiSZ phenotypes). Information regarding the heterozygous adolescent population is particularly lacking, making the evaluation and treatment of such patients difficult. We present the case of an adolescent with a history of asthma and heterozygous (PiSZ) alpha 1-antitrypsin deficiency and outline our management with reference to appropriate literature.

Alpha-1-antitrypsin phenotypes among patients with intracranial aneurysms.

A deficiency of alpha 1-antitrypsin has been implicated in the development of arterial aneurysms, including intracranial aneurysms. The authors determined the prevalence of alpha 1-antitrypsin deficiency of different phenotypes in 100 consecutive patients with intracranial aneurysms and compared the distribution of alpha 1-antitrypsin phenotypes to that in the general population (904 people). The study population consisted of 44 men and 56 women with a mean age of 52 years (range 15-81 years). The heterozygous alpha 1-antitrypsin deficiency states (PiMS and PiMZ) were more common in patients (16%) than in the general population (7%), providing an odds ratio of 2.56 (95% confidence interval (CI) 1.32-4.75; p = 0.005). In addition, one patient (1%) was homozygous for the deficient allele (PiZZ) compared to an expected number of 0.015, providing an odds ratio of 67.0 (95% CI 2.0-363.3; p = 0.015). These findings lead the authors to suggest that the heterozygous and homozygous alpha 1-antitrypsin deficiency states are genetic risk factors for the development of intracranial aneurysms.

Causes of liver disease in an adult population with heterozygous and homozygous alpha1‐antitrypsin deficiency

Acta PaediatricaVolume 83, Issue s393 p. 24-26 Causes of liver disease in an adult population with heterozygous and homozygous alpha1-antitrypsin deficiency W Vogel, Corresponding Author W Vogel Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaW Vogel, Department of Internal Medicine, Innsbruck University, Anichstr. 35, A-6020 Innsbruck, AustriaSearch for more papers by this authorT Propst, T Propst Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaSearch for more papers by this authorA Propst, A Propst Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaSearch for more papers by this authorO Dietze, O Dietze Department of Pathology, Innsbruck University, Innsbruck, AustriaSearch for more papers by this authorG Judmaier, G Judmaier Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaSearch for more papers by this authorH Braunsteiner, H Braunsteiner Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaSearch for more papers by this author W Vogel, Corresponding Author W Vogel Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaW Vogel, Department of Internal Medicine, Innsbruck University, Anichstr. 35, A-6020 Innsbruck, AustriaSearch for more papers by this authorT Propst, T Propst Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaSearch for more papers by this authorA Propst, A Propst Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaSearch for more papers by this authorO Dietze, O Dietze Department of Pathology, Innsbruck University, Innsbruck, AustriaSearch for more papers by this authorG Judmaier, G Judmaier Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaSearch for more papers by this authorH Braunsteiner, H Braunsteiner Department of Internal Medicine, Innsbruck University, Innsbruck, AustriaSearch for more papers by this author First published: February 1994 https://doi.org/10.1111/j.1651-2227.1994.tb13203.xCitations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume83, Issues393February 1994Pages 24-26 RelatedInformation

Prevalence of hepatocellular carcinoma in alpha-1-antitrypsin deficiency

The aim of the present study was to determine the prevalence of hepatocellular carcinoma in adults with heterozygous alpha 1-antitrypsin deficiency and to assess the presence of possible co-risk factors for the development of hepatocellular carcinoma. Two hundred and forty patients with cirrhosis of different aetiologies and 130 patients with alpha 1-antitrypsin deficiency without evidence of chronic liver disease were investigated. Out of the 240 patients with cirrhosis, 61 patients (25%) were found to have alpha 1-antitrypsin deficiency, 36 patients (15%) had chronic hepatitis C infection, 50 (21%) had chronic hepatitis B and 24 (10%) had hepatitis C and hepatitis B infection. Thirty patients (12%) had cryptogenic cirrhosis and 39 (16%) alcoholic cirrhosis. The prevalence of hepatocellular carcinoma in patients with alpha 1-antitrypsin deficiency-associated cirrhosis was comparable to that of hepatocellular carcinoma in patients with cirrhosis of other aetiologies. Positive viral markers were found in 67% of the patients with alpha 1-antitrypsin deficiency-associated cirrhosis with hepatocellular carcinoma. In contrast, in the group of 130 patients with alpha 1-antitrypsin deficiency but without clinical and laboratory signs of chronic liver disease, none was found to have hepatocellular carcinoma (p = 0.001). Our results indicate that heterozygous alpha 1-antitrypsin deficiency-associated cirrhosis is a risk factor for hepatocellular carcinoma, but this is due to chronic liver disease and not due to the metabolic disorder itself.

High prevalence of viral infection in adults with homozygous and heterozygous alpha 1-antitrypsin deficiency and chronic liver disease.

To determine the prevalence of chronic liver disease in adults with homozygous (Pi ZZ) and heterozygous (Pi Z) alpha 1-antitrypsin deficiency and to assess the presence of other possible risk factors for the development of chronic active hepatitis and cirrhosis of the liver in these patients. Cross-sectional study. A referral-based university hospital. Consecutive patients (164) with the Pi ZZ and Pi Z phenotype with and without chronic liver disease. The presence of antibody to hepatitis C virus (anti-HCV) was determined using an assay incorporating synthetic peptide antigen from capsid protein (United Biomedical [UBI] assay) and a second-generation enzyme immunoassay (Abbott test); the presence of antibody to hepatitis B virus (anti-HBV) was determined using radioimmunoassays incorporating hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg); assays for antinuclear antibody and antimitochondrial antibody (M2 subtype) were also done, and alcohol abuse was assessed by history. Among patients with cirrhosis (32%), 62% were anti-HCV positive by the Abbott test (P = 0.006), and 41% were anti-HCV positive by the UBI assay (P = 0.007). Thirty-three percent of patients with cirrhosis had hepatitis B virus (HBV) infection (P = 0.01); 41% had a history of alcoholism; and 12% had features of autoimmune liver disease. Only five patients (9%) with cirrhosis had no other risk factor for chronic liver disease. Among patients with chronic active hepatitis (7%), 80% were anti-HCV positive by the Abbott test (P = 0.002), and 75% were anti-HCV positive by the UBI assay (P less than 0.001). Thirty percent of patients with chronic active hepatitis had HBV infection (P = 0.023); 18% had autoimmune hepatitis; and 8% abused alcohol. Only two patients (17%) had no additional risk factor for the development of chronic active hepatitis. Among patients with steatosis of the liver (48%), 5% were anti-HCV positive by the Abbott test, and none were anti-HCV positive by the UBI assay; 18% had serologic evidence of past HBV infection, and 28% abused alcohol. Among patients without chronic liver disease (13%), no viral infection could be found; 9% were alcoholics. Chronic liver disease in patients with alpha 1-antitrypsin deficiency is associated with a high prevalence of viral infection; this infection, rather than alpha 1-antitrypsin deficiency alone, may be the cause of the liver disease in such patients.

Lack of increase in heterozygous alpha 1-antitrypsin deficiency phenotypes among patients with hepatocellular and bile duct carcinoma.

Homozygous alpha 1-antitrypsin deficiency (PiZZ phenotype) is known to be associated with increased risk of cirrhosis and primary liver cancer. Although a relationship between heterozygous alpha 1-antitrypsin deficiency and chronic liver disease was suggested recently, it is still a matter of controversy whether such patients are at increased risk of liver cancer. The goal of this study was to determine the prevalence of heterozygous alpha 1-antitrypsin deficiency of different phenotypes among patients with primary hepatobiliary cancers. We studied 82 patients with primary hepatobiliary cancer; 59 had hepatocellular carcinoma and 23 had bile duct carcinoma. alpha 1-Antitrypsin quantitation and phenotyping were performed in each patient using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds-ratio and chi 2 tests were used to measure the relative risk and the significance of association, respectively, between primary hepatobiliary cancers and heterozygous alpha 1-antitrypsin deficiency. Four patients in each of the cancer groups were heterozygous. Among the hepatocellular carcinoma patients, three had the PiMS phenotype and one had the PiMZ phenotype. Of these four heterozygous patients, only two had cirrhosis; one had cryptogenic cirrhosis and the other had hepatitis B virus-related cirrhosis. One noncirrhotic patient with a PiMZ phenotype had a fibrolamellar carcinoma. Of the four patients with bile duct carcinoma, three had the PiMS phenotype and one had the PiMZ phenotype. Of the four heterozygous patients, two had primary sclerosing cholangitis without associated inflammatory bowel disease and one patient had had previous biliary operations.(ABSTRACT TRUNCATED AT 250 WORDS)

Partial Deficiency of α1-Antichymotrypsin Is Associated with Chronic Cryptogenic Liver Disease

alpha 1-Antichymotrypsin (ACT) and alpha 1-antitrypsin (AAT) are two closely related antineutrophil proteinase inhibitors. Whereas AAT deficiency is clearly linked to liver disease, an association between liver disease and partial ACT deficiency has not been established. In a previous study we noted an increased prevalence of liver abnormalities among subjects with heterozygous ACT deficiency. To study a possible association between partial ACT deficiency and liver disease, we screened 316 consecutive patients with biopsy-verified liver disease for partial ACT deficiency and compared the prevalence with that of an unselected adult population in a case-control study. In all, 9 of 316 patients had partial ACT deficiency, which is more than expected (prevalence ratio (PR), 2.46 (1.15-5.27), P less than 0.05). The prevalence of partial ACT deficiency was highest in the chronic active hepatitis (5 of 40; PR, 12.0 (5.33-27.0] and the cryptogenic cirrhosis (3 of 24; PR, 12.0 (4.38-32.9] subgroups. In the chronic active hepatitis subgroup two patients (PR, 8.16 (2.25-29.5] were ACT deficiency heterozygotes, thus partly explaining the high prevalence of partial ACT deficiency among patients with chronic liver disease. The majority (6 of 9) of the patients with partial ACT deficiency lacked autoimmune and viral markers and were thus cryptogenic. The present findings show that partial ACT deficiency and chronic cryptogenic liver disease are associated. To some extent (the true magnitude of which is at present unknown) partial ACT deficiency is caused by a rare trait, heterozygous ACT deficiency, which in parallel with heterozygous alpha 1-antitrypsin deficiency (PiMZ) also seems to be associated with chronic cryptogenic liver disease.

Inherited Risk Factors for Chronic Lung Disease

Laurel and Ericksson's 1 Laurel CB Eriksson S The electrophoretic A1-globulin pattern of serum in A1-antitrypsin deficiency. Scand J Clin Lab Invest. 1963; 15: 132-140 Crossref Scopus (1271) Google Scholar serendipitous discovery that severe antitrypsin deficiency is a risk factor for chronic obstructive pulmonary disease (COPD) has been well validated. Approximately ten years ago, Lieberman, 2 Lieberman J Frequency of heterozygous and homozygous alpha1-antitrypsin deficiencies in patients with pulmonary emphysema. Clin Res. 1969; 17: 165 Google Scholar Lieberman and Mittman, 3 Lieberman J Mittman C Schneider AS Screening for homozygous and heterozygous alpha1-antitrypsin deficiency. JAMA. 1969; 210: 2055 Crossref PubMed Scopus (41) Google Scholar Kueppers 4 Kueppers F Fallat R Larson RK Obstructive lung disease and alpha1-antitrypsin deficiency gene heterozygosity. Science. 1969; : 165-899 Google Scholar and others suggested that intermediate antitrypsin deficiency (PiMZ) might also be a significant risk factor for developing COPD. This factor is of great potential significance since it is found in approximately 3 percent of some populations. It is now well established that the PiMZ type occurs more often than expected in groups of patients with obstructive lung disease. 5 Mittman C The PiMZ phenotype: Is it a significant risk factor for the development of chronic obstructive lung disease?. Am Rev Respir Dis. 1978; 118: 649-652 Crossref PubMed Scopus (28) Google Scholar However, the question remains controversial since some investigators, such as Lebowitz and associates, 6 Lebowitz MD Knudsen RJ Morse JO et al. Closing volume and flow abnormalities in alpha 1-antitrypsin phenotype groups in a community population. Am Rev Respir Dis. 1978; 117: 179 PubMed Google Scholar Webb and associates 7 Webb DR Hyde RW Schwartz RH et al. Serum alpha1-antitrypsin variants: Prevalence and clinical spirometry. Am Rev Respir Dis. 1973; 108: 918 PubMed Google Scholar and others have reported that lung function tests in community populations show no differences between subjects with the PiM (normals) and variant phenotypes. Others, such as Klayton et al, 8 Klayton R Fallat R Cokes AB Determinants of chronic obstructive pulmonary disease in patients with intermediate levels of alpha1-antitrypsin. Am Rev Respir Dis. 1975; 112: 71 PubMed Google Scholar Cox and associates, 9 Cox DW Hoeppner VH Levison H Protease inhibitors in patients with chronic obstructive pulmonary disease: The alpha1-antitrypsin heterozygote controversy. Am Rev Respir Dis. 1976; 113: 601 PubMed Google Scholar and Cooper and colleagues,10 who performed studies in selected and healthy volunteers, have supported our earlier hypothesis.

Relation of Protease Inhibitor Phenotypes to Obstructive Lung Diseases in a Community

To examine the relative risk for the development of obstructive lung disease in persons heterozygous for alpha1-antitrypsin deficiency, we determined protease inhibitor phenotypes in 2944 subjects in a general community population. Phenotype M was found in 89.5 per cent, MS in 7.1 per cent, and MZ in 3.0 per cent of the population. There were two persons of phenotype Z and six of phenotype SZ. The study also included respiratory questionnaires and spirometry. There were no statistically significant differences in the prevalence of respiratory symptoms and diagnoses or of ventilatory impairment among the three major phenotype groups (M, MS and MZ), nor were there differences in the rates of deterioration of function with age or smoking. Consequently, we do not consider population screening for heterozygous alpha1-antitrypsin deficiency to be worthwhile.

Alpha-1-antitrypsin bodies in the liver.

The cytoplasmic bodies in hepatocytes thought to indicate possession of the Z allele for alpha 1-antitrypsin deficiency were found in necropsy in 10 of 64 adults with cirrhosis, four of nine with hepatic fibrosis, and four of 15 with hepatocellular carcinoma. They were also found in six of 76 adults with severe panacinar emphysema, and in four of a control series of 110 adults with neither emphysema nor liver disease. The association of the bodies with each of the three liver diseases was statistically significant, but the association of the bodies with emphysema was not. It is considered probable that heterozygous (PiMZ) alpha 1-antitrypsin deficiency is associated with an increased incidence of cirrhosis, hepatic fibrosis, and hepatocellular carcinoma.

Obstructive airway disease associated with heterozygous alpha-1 antitrypsin deficiency

Twenty-eight members of one family were investigated for the presence of pulmonary disease concurrent with variable (ZZ, MZ, or MS) degrees of alpha-1 antitrypsin deficiency. Three symptomatic siblings (2, ZZ; 1, MZ) had abnormal pulmonary scans and abnormal routine pulmonary function studies. Five asymptomatic heterozygotes, three of whom had never smoked and were the youngest studied, had distinctly abnormal closing volumes. Three of the five patients also had abnormal perfusion dynamics when scanning was done in the upright position. Pulmonary dysfunction occurs in asymptomatic heterozygotes but requires the use of sensitive techniques for its appreciation.