Alpha-1-antitrypsin deficiency is an autosomal recessive disorder. The most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, ... Alpha-1-antitrypsin deficiency is an autosomal recessive disorder. The most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age (Crystal, 1990).
Kidd et al. (1983) used a chemically synthesized specific oligonucleotide probe (19-mer) as a sensitive and direct test for the presence or absence of the Z allele (E342K; 107400.0011). Kidd et al. (1984) reported the use of such ... Kidd et al. (1983) used a chemically synthesized specific oligonucleotide probe (19-mer) as a sensitive and direct test for the presence or absence of the Z allele (E342K; 107400.0011). Kidd et al. (1984) reported the use of such probes in the prenatal diagnosis of the deficiency syndrome. Hejtmancik et al. (1986) compared prenatal diagnosis by RFLP analysis with prenatal diagnosis by oligonucleotide probe analysis. They concluded that although it seems reasonable to use oligonucleotide analysis in families in which no sibs are available for comparison, in all other situations RFLP analysis is preferable because it is as accurate and reliable as oligonucleotide analysis and is technically easier. Abbott et al. (1988) used the PCR for prenatal diagnosis of alpha-1-antitrypsin deficiency associated with the ZZ genotype. To identify accurately the SZ phenotype at the DNA level, Nukiwa et al. (1986) prepared 19-mer synthetic oligonucleotide probes: 2 to show the M/S difference in exon 3, and 2 to show the M/Z difference in exon 5. Harrison et al. (1990) described an improved method for detecting what they termed 'low Z expressor' phenotype in MZ heterozygotes. An obligate carrier mother who was being typed as part of a family study appeared to be a PI(M)/PI(null) heterozygote. By routine isoelectric focusing, she was typed as M, her affected child as Z, and her husband as MZ. Atypically low concentrations of circulating Z peptides were demonstrated by the improved method. Dry (1991) described a method for detecting the single-base substitution in PiZ useful for same-day diagnosis of AAT deficiency in chorion villus samples.
Laurell and Eriksson (1963) described absence of alpha-1-antitrypsin from the plasma in patients with degenerative lung disease leading to death in middle life. Emphysematous changes involve primarily the lower lung fields (Bell, 1970).
Gans et al. ... Laurell and Eriksson (1963) described absence of alpha-1-antitrypsin from the plasma in patients with degenerative lung disease leading to death in middle life. Emphysematous changes involve primarily the lower lung fields (Bell, 1970). Gans et al. (1969) described familial infantile liver cirrhosis in presumed homozygotes for alpha-1-antitrypsin deficiency. An adult with antitrypsin deficiency and combined liver and lung disease was reported by Gherardi (1971). See the study of 12 cases of combined disease by Berg and Eriksson (1972). Aagenaes et al. (1972) described the clinical picture in children with severe AAT deficiency (ZZ genotype) as neonatal cholestasis. Five such cases were described. Fargion et al. (1981) found an increased frequency of non-M phenotypes in patients with hepatocellular carcinoma. Furthermore, patients with liver cancer and a non-M phenotype had a lower average age than those with an M phenotype. Cox and Smyth (1983) found a relatively high risk for liver disease in men between 51 and 60 years who had AAT deficiency. A low concentration of serum prealbumin was a sensitive indicator of impaired liver function. Eriksson et al. (1986) concluded that the risk of cirrhosis and liver cancer is increased for males homozygous for alpha-1-antitrypsin deficiency but not for females. The finding suggested additive effects of exogenous factors. Wiebicke et al. (1996) confirmed the absence of pulmonary function abnormalities in the vast majority of children with severe (homozygous ZZ) AAT deficiency. Rodriguez-Cintron et al. (1995) suggested that bronchiectasis should be considered part of the spectrum of pulmonary pathology that may be encountered in individuals with AAT deficiency. They described a 21-year-old man with massive hemoptysis and severe (homozygous ZZ) AAT deficiency. Neither panlobular emphysema nor cirrhosis of the liver was present.
Deficiency of protease inhibitor activity is associated with several of the electrophoretic variants of serum alpha-1-antitrypsin; Axelsson and Laurell (1965) first suggested that the genes for electrophoretic variants are allelic with the deficiency gene.
- 'Normal' ... Deficiency of protease inhibitor activity is associated with several of the electrophoretic variants of serum alpha-1-antitrypsin; Axelsson and Laurell (1965) first suggested that the genes for electrophoretic variants are allelic with the deficiency gene. - 'Normal' Alleles Crystal (1989) listed 10 normal AAT alleles that had been sequenced (107400.0001-107400.0010). Nukiwa et al. (1988) stated that the most common alleles are the 2 forms of M1, that with valine at position 213 (M1V; 107400.0002) and that with alanine at position 213 (M1A; 107400.0001). - 'Risk' Alleles Crystal (1989) divided AAT 'at risk' alleles into 'deficiency' alleles and 'null' alleles. He stated that except for the rare Pittsburgh allele (107400.0026), which is associated with a bleeding disorder, only those phenotypes comprising 2 'at risk' alleles place the individual at risk for development of disease. Alleles in the 'at risk' class are found almost exclusively among Caucasians of European descent, with the highest frequency in northern Europe. Blacks and Asians are rarely affected. The most common AAT deficiency allele is the Z allele (glu342 to lys; 107400.0011), which occurs on an M1A (ala213; 107400.0001) haplotype background (Nukiwa et al., 1986). The homozygous ZZ phenotype is associated with a high risk of both emphysema and liver disease. The Z allele reaches polymorphic frequencies in Caucasians and is rare or absent in Asians and blacks (DeCroo et al., 1991; Hutchison, 1998). Another common AAT deficiency allele is the S allele (glu264-to-val; 107400.0013), which occurs on an M1V (val213; 107400.0002) haplotype background. Pi*S homozygotes are at no risk of emphysema, but compound heterozygotes with a Z or a null allele have a mildly increased risk (Curiel et al., 1989). The S allele reaches polymorphic frequencies in Caucasians and is rare or absent in Asians and blacks. It is not associated with liver disease. Other rare deficiency AAT alleles may result in increased risk for both liver and lung disease (e.g., Pi M(Malton); 107400.0012) or only emphysema (e.g., Pi M(Procida); 107400.0016). Some of the rare deficiency alleles have been found in Japanese (e.g., Pi S(Iiyama); 107400.0039). By means of isoelectric focusing, Weber and Weidinger (1988) found a PI variant that they called PI S (Cologne). A father and daughter were heterozygous. Alpha-1-antitrypsin concentrations were within the normal range. Null AAT alleles are rare but have been found in all populations. Garver et al. (1986) investigated the molecular basis of the Pi null-null AAT phenotype. The gene appeared to be intact without discernible deletion or other structural abnormality, yet there was no detectable mRNA produced. The 5-prime promoter region also appeared to be normal. No evidence of hypermethylation of cytosine nucleotides in the promoter region was detected. The defect may be comparable to that in some forms of thalassemia in which a change, at a splicing site, for example, may lead to greatly reduced mRNA production. The null-null phenotype is accompanied by emphysema as is the ZZ and SZ phenotypes but an important difference is that cirrhosis and liver disease do not occur with the null-null phenotype; there is no abnormal antitrypsin produced that is excreted with difficulty from the cells of synthesis. Nukiwa et al. (1987) identified a null form of alpha-1-antitrypsin resulting from a frameshift causing a stop codon to be formed approximately 44% from the N terminus of the precursor protein (Null(Granite Falls); 107040.0020). Although the molecular basis of antitrypsin deficiency was quite different from that in the Z haplotype, the phenotypic consequences were similar: severe deficiency associated with high risk of emphysema. Bamforth and Kalsheker (1988) discussed a rare Pi null allele that in homozygous state leads to pulmonary emphysema at an early age. In 3 families, all the affected individuals presented in early childhood with recurrent chest infections and wheezing, presumably related to passive smoking. Even though there was no detectable AAT, no partial or complete deletion of the gene could be identified. Seixas et al. (2002) reported 2 null alleles of the PI gene in Portuguese patients with emphysema. These alleles were associated with total lack of circulating protein as indicated by the absence of isoelectric focusing banding patterns. One of the alleles, designated Q0(Ourem), was identical to Q0(Mattawa) on an M3 normal background (107400.0022). The second allele, Q0(Porto), had a novel mutation which restricted mononuclear phagocyte transcripts to mRNA species resulting from the direct splice of exon IA to exon II. The absence of this normal splice alternative in the liver, where PI is primarily synthesized, provided a basis for the pathogenic effects of this mutation. - PI Pittsburgh The PI Pittsburgh allele (M358R; 107400.0026), which occurs at the AAT active site, is an example of a mutation leading to altered function of the gene product. AAT becomes a potent inhibitor of thrombin and factor XI rather than of elastase and results in a bleeding disorder (Lewis et al., 1978; Owen et al., 1983). - SERPINA1 Haplotypes Associated with Chronic Obstructive Pulmonary Disease The most widely recognized candidate gene in COPD (see 606963) is SERPINA1, although it has been suggested that SERPINA3 (107280) may also play a role. Chappell et al. (2006) identified 15 single-nucleotide polymorphism (SNP) haplotype tags from high-density SNP maps of the 2 genes and evaluated these SNPs in the largest case-control genetic study of COPD conducted to that time. For SERPINA1, 6 newly identified haplotypes with a common backbone of 5 SNPs were found to increase the risk of disease by 6- to 50-fold, the highest risk of COPD that had been reported. In contrast, no haplotype associations for SERPINA3 were identified. - Reviews Crystal (1990) gave a comprehensive review of the pathogenetic relationship between AAT deficiency and emphysema and liver disease, including a detailed listing of the various mutations that have been identified and a discussion of the possibilities for therapy.
Roychoudhury and Nei (1988) tabulated worldwide gene frequencies for allelic variants M (M1, M2, M3, M4), S, Z, F, I, and V. Cox (1989) and Crystal (1989) reviewed the variants, 'normal' and pathologic, of the PI gene. ... Roychoudhury and Nei (1988) tabulated worldwide gene frequencies for allelic variants M (M1, M2, M3, M4), S, Z, F, I, and V. Cox (1989) and Crystal (1989) reviewed the variants, 'normal' and pathologic, of the PI gene. Alpha-1-antitrypsin deficiency is said to be rare among Japanese. Kawakami et al. (1981) cited 2 studies in which no Pi Z was found among 965 healthy Japanese and 183 Japanese with pulmonary diseases. This is to be compared with a frequency of 1.6% for Pi Z among Norwegians. DeCroo et al. (1991) studied the frequency of alpha-1-antitrypsin alleles in US whites, US blacks, and African blacks (living in Nigeria). While the PI*S allele was present at a polymorphic level in US whites, it was present only sporadically in US blacks and completely absent in African blacks. The PI*Z allele was not detected in the black populations tested. DeCroo et al. (1991) used the PI allele frequency data to calculate white admixture in US blacks. The average white admixture estimate in US blacks, based on all PI alleles, was about 13%. This value was about 24% when only the S and Z alleles were used. Studies of the distribution of the S and Z in Europe demonstrated that they occur mainly among those of European stock. Hutchison (1998) found that the frequency of the gene for PiZ is highest on the northwestern seaboard of the continent and that the mutation seems to have arisen in southern Scandinavia. The distribution of PiS is quite different: the gene frequency is highest in the Iberian peninsula and the mutation is likely to have arisen in that region. By means of a metaanalysis of 43 studies, Blanco et al. (2001) analyzed the distribution of the PI*S and PI*Z alleles in countries outside Europe and compared them with data from Europe. On the basis of data from previously published genetic epidemiologic studies, de Serres et al. (2003) estimated the frequency of AAT deficiency in France, Italy, Portugal, and Spain. In another report, de Serres et al. (2003) focused on the distribution of the PiS and PiZ deficiency alleles in Australia, Canada, New Zealand, and the United States. Among 15,484 ethnically diverse individuals screened for alpha-1 antitrypsin deficiency carrier status, Lazarin et al. (2013) identified 1,178 carriers (7.6%), for an estimated carrier frequency of approximately 1 in 13. Forty-seven 'carrier couples' were identified. Thirty-eight individuals were identified as homozygotes or compound heterozygotes. Among 8,570 individuals of northern European origin, Lazarin et al. (2013) identified a carrier frequency of 1 in 10. Among 747 individuals of east Asian origin, the carrier frequency was 1 in 249.
Alpha1-antitrypsin deficiency (α1ATD, AATD) is suspected in individuals with evidence of pulmonary disease (i.e., emphysema, asthma, persistent airflow obstruction, and/or chronic bronchitis) and/or evidence of liver disease at any age, including obstructive jaundice in infancy. AATD is also observed rarely in individuals with Wegener granulomatosis and necrotizing panniculitis....
DiagnosisClinical DiagnosisAlpha1-antitrypsin deficiency (α1ATD, AATD) is suspected in individuals with evidence of pulmonary disease (i.e., emphysema, asthma, persistent airflow obstruction, and/or chronic bronchitis) and/or evidence of liver disease at any age, including obstructive jaundice in infancy. AATD is also observed rarely in individuals with Wegener granulomatosis and necrotizing panniculitis.The diagnosis of AATD relies on the following:Demonstration of low plasma concentration of alpha1-antitrypsin (AAT) ANDObservation of a deficient variant of the protein AAT by protease inhibitor (PI) typing ORDetection by molecular genetic testing of mutations in both copies of SERPINA1, the gene encoding AATTestingPlasma Concentration of AATNormal. Range is 80%-120% of normal. Mean is 1.3 g/L (range: 1.06-1.58 g/L) [Cox et al 1991, Whicher et al 1994].Adults with the PI SS genotype. The range is usually 12%-24% of normal (mean: 18%±5% of normal, or 0.23 g/L).Children with the PI ZZ genotype and liver disease. The plasma concentration can be as high as 40% of normal [Moroz et al 1976].Note: (1) The PI type should be determined in all samples in which the plasma concentration of AAT is below 50% of normal. (2) Other conditions associated with low plasma concentration of AAT include: respiratory distress syndrome in newborns, severe protein loss, terminal liver failure, and cystic fibrosis. (3) Because AAT is an acute-phase reactant, its plasma concentration can be elevated into the normal range in PI MZ heterozygotes. Up to fourfold increases are observed in inflammatory conditions, cancer, and liver disease. Pregnancy and estrogen therapy produce modest increases.Testing for PI TypePI type is determined by polyacrylamide isoelectric focusing (PIEF) of serum using a narrow pH range.Note: Letters were originally used to designate the protein, anode to cathode, in isoelectric focusing [Fagerhol & Braend 1965]. PI alleles can also be designated as amino acid changes.PI allelesPI*M (standard allele nomenclature) is the most common allele in all populations described to date. Common subtypes of the M allele are designated M1, M2, M3, and so on.PI*Z (p.Glu342Lys) is the most common deficiency allele.PI*S (p.Glu264Val):Reaches polymorphic frequencies in some populations, particularly in ItalyIs usually of clinical interest only when associated with a deficiency variant that decreases the plasma concentration of AAT to less than 40% of normal [Jeppsson & Franzen 1982]Usually occurs with M allele as PI MS (~8% among persons of northern European heritage).Other deficiency alleles include PI*Mmalton (p.Phe52del), PI*Siiyama (p.Ser53Phe). Those of the other deficiency alleles that are "null" alleles do not produce a detectable AAT protein. Note: At least 20 rare deficiency alleles comprise approximately 5% of all deficiency alleles, the majority being PI*Z. A large number of AAT protein variants that are not clinically significant have also been identified.PI typesPI MM. Observed in normal individuals with normal plasma concentration of AAT who are homozygous for the M allelePI MZ. Slightly increased risk for decreased lung function among heterozygotesPI SZ. Not usually associated with a high risk for liver or lung disease; higher risk of developing chronic obstructive pulmonary disease (COPD) among smokersPI ZZ. Observed in individuals homozygous for the Z allele who have clinical disease and plasma concentration of AAT approximately 18% of normalMolecular Genetic TestingGene. SERPINA1, encoding alpha1-antitrypsin (AAT), is the only gene in which mutations are known to cause alpha1-antitrypsin deficiency (α1ATD, AATD).Clinical testingTargeted mutation analysis. Ninety-five percent of AATD is caused by the presence of two Z alleles. PCR-based approaches have been developed for detection of Z and S mutations.Sequence analysis. Sequence analysis detects rare and null alleles in SERPINA1 that are not detected by targeted mutation analysis.Table 1. Summary of Molecular Genetic Testing Used in Alpha1-Antitrypsin DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySERPINA1Targeted mutation analysisPI*Z, PI*S95% 2ClinicalSequence analysisSequence variants 3Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 95% of AATD results from presence of these variants. Targeted mutation analysis that is specific for detecting PI Z and S does not detect any of the rare deficiency alleles.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. The diagnosis of AATD is based on: (1) the presence of abnormally low AAT plasma concentration and (2) determination of PI type by: (a) polyacrylamide isoelectric focusing (IEF) or (b) molecular genetic testing.IEF is less costly than molecular genetic testing and uses serum both for measuring the serum concentration and for PI typing. A range of variants from normal to deficient (though not "null") can be observed in a single IEF assay, testing many samples in a single gel. Molecular genetic testing using targeted mutation analysis for PI*Z and PI*S does not detect any of the rare deficiency variants.Molecular genetic testing may be performed if the results of the PI typing are ambiguous; e.g., when a rare deficiency allele is suspected but cannot be observed on IEF.Sequence analysis is useful if targeted mutation analysis reveals only one disease-associated allele in an individual who meets diagnostic criteria for AATD; however, identification of both disease-associated alleles is not required for diagnosis.Molecular genetic testing is useful for prenatal diagnosis when the specific deficiency allele is known.Note: Liver biopsy is not specific and is not required for diagnosis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder. Clinical disease is infrequent in heterozygotes, except in some smokers.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotype other than AATD is currently known to be associated with mutations in SERPINA1.
Alpha1-antitrypsin deficiency (α1ATD, AATD) can present with hepatic dysfunction in individuals from infancy to over age 50 years and with pulmonary disorders in individuals over age 20 years. Phenotypic expression varies within and between families....
Natural HistoryAlpha1-antitrypsin deficiency (α1ATD, AATD) can present with hepatic dysfunction in individuals from infancy to over age 50 years and with pulmonary disorders in individuals over age 20 years. Phenotypic expression varies within and between families.Lung DiseaseAdult-onset lung disease. Chronic obstructive pulmonary disease (COPD), specifically emphysema, is the most common clinical manifestation of AATD. In adults, smoking is the major factor influencing the course of COPD. The onset of respiratory disease in smokers with AATD is between age 40 and 50 years. In non-smokers, the onset can be delayed to the sixth decade and is often associated with a normal life span.Obstructive pulmonary disease typically presents with dyspnea, cough, and wheezing for an average of five years before the diagnosis is established. In individuals with emphysema, chest CT shows a symmetric decrease in peripheral vasculature that is most prominent in the lower lungs [Fujimoto et al 2002, Ley et al 2004]. In individuals with emphysema, changes in lung mechanics are observed, with apparent increase in lung volumes and expiratory flow rates, which can be attributed in part to loss of elastic recoil.Some individuals present with symptoms of bronchial asthma or chronic bronchitis. Features of asthma are common in individuals with severe AATD and are important factors in the accelerated FEV1 decline seen in young smokers with AATD [Eden et al 2003].Clinically asymptomatic individuals with AATD may have abnormalities in closing volume, nitrogen washout volume, and lung mechanics [Gadek & Crystal 1983, Burdon et al 1996, Cheung et al 1997].Childhood-onset lung disease. Although reported, emphysema in children with AATD is extremely rare and may result from the coexistence of other unidentified genetic disorders affecting the lung [Cox & Talamo 1979].Risk for lung disease in heterozygotes. PI MZ heterozygotes constitute 2%-5% of most populations:Non-smokers with the PI MZ type may show slight differences in lung function from individuals with the PI MM type, but they rarely express clinical symptoms.Smokers with the PI MZ type show impairment in lung function, reflecting a loss of elastic recoil; some may show clinical symptoms [Hersh et al 2004]. In general, loss in elastic recoil for a smoker with the PI MZ type is similar to that of a non-smoker with the PI ZZ type.Slight abnormalities of lung function can be present without clinical symptoms.PI MZ or PI MS heterozygotes do not have an increased risk of developing asthma.Liver DiseaseChildhood-onset liver disease. The most common manifestation of AATD-associated liver disease is jaundice, with increased bilirubinemia and raised serum aminotransferase levels in the early days and months of life. Histopathologic features include intrahepatic cholestasis, varying degrees of hepatocellular injury, and moderate fibrosis with inflammatory cells in portal areas.Liver abnormalities develop in only a portion of children with AATD. In a study of 200,000 Swedish children who were followed up after newborn screening for AATD, 18% of those with the PI ZZ type developed clinically recognized liver abnormalities and 2.4% developed liver cirrhosis with death in childhood [Sveger 1976, Sveger 1988]. Liver damage may progress slowly [Volpert et al 2000].In a follow-up study of 44 children with AATD-associated liver disease initially manifest as cirrhosis or portal hypertension, outcomes ranged from liver transplantation in two, to relatively healthy lives up to 23 years after diagnosis in seven [Migliazza et al 2000].The overall risk to an individual with PI ZZ of developing severe liver disease in childhood is generally low (~2%); the risk is higher among sibs of a child with the PI ZZ type and liver disease. When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PI ZZ type is approximately 13%. When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PI ZZ type may be approximately 40% [Cox 2004].It is not known why only a small proportion of children with early hyperbilirubinemia have continued liver destruction leading to cirrhosis.PI MZ and PI SZ types are not associated with an increased risk for childhood liver disease, although elevated levels of liver enzymes that resolve have sometimes been observed. In a study of 58 heterozygous children showing signs of liver involvement during the first six months of life, follow-up indicated that almost all children had normal values of liver enzymes at age 12 months, five years, and ten years [Pittschieler 2002].Adult-onset liver disease. Liver disease in adults, manifest as cirrhosis and fibrosis, is not necessarily associated with a history of neonatal hepatitis. The incidence of liver disease apparently increases with age and is higher in males. Liver inclusions may be responsible for the liver disease in adults. Destruction of the liver is rapid when onset occurs in adults.Between 15% and 19% of individuals over age 50 years with the PI ZZ type develop cirrhosis. The risk of liver disease at age 20-40 years is approximately 2%; at age 41-50 years, it is approximately 4% [Cox & Smyth 1983].Hepatocellular carcinoma (HCC) has been reported. Significantly elevated risk of developing HCC was observed only in males with PI ZZ, and was unrelated to the presence of hepatitis B or C infection [Elzouki & Eriksson 1996].Liver pathology. Aggregation/polymerization of Z-type AAT, first recognized during protein purification and observed within the hepatic inclusions [Carrell & Lomas 2002], is thought to be the cause of the liver disease. AATD liver inclusions are visualized as bright pink globules of various sizes, using periodic acid-Schiff (PAS) stain following diastase treatment (PAS-D). The extent of inclusion formation varies considerably; the number and size of liver inclusions increases with age. Inclusions are not observed before age 12 weeks. In infants with AATD, inclusions may be fine and granular and difficult to identify in percutaneous liver biopsy specimens. They are also observed in bile duct epithelium [Cutz & Cox 1979] and now studied as a model.Because liver inclusions indicate the presence of at least one PI Z allele, histologic examination of the liver cannot distinguish between heterozygotes and homozygotes for AATD.Persons who do not produce any AAT (i.e., null allele homozygotes) have not been reported to have liver inclusions or liver disease, although the number of reported null allele homozygotes is small.Risk for liver disease in heterozygotes seems to be low. Among individuals presenting with chronic liver failure, a greater number of PI type MZ heterozygotes (8.4%) were observed than were reported in the general population (2%-4%) [Graziadei et al 1998]. Another study found a slightly increased risk of chronic liver disease in PI MZ heterozygotes, based on the presence of Z deposits in liver biopsy samples [Fischer et al 2000].Kidney DiseaseMembranoproliferative glomerulonephritis (MPGN) may occur in individuals with AATD with liver disease, although the overall probability of an individual of PI type ZZ developing severe renal disease appears to be low. All of the children in whom MPGN was identified had severe liver disease, suggesting that the kidney abnormality was a consequence of liver disease [Strife et al 1983].Rheumatoid Arthritis (RA)Increased tendency to severe RA in PI MZ heterozygotes can be explained as a consequence of a low amount of circulating protease inhibitor in the joint fluid to prevent leukocyte elastase, cathepsin G, and collagenase from attacking the structural proteins of joint cartilages [Cox & Huber 1980]. Several subsequent studies produced conflicting results, probably because of varying disease severity among the different series under study. Of 246 Swedish persons who are PI ZZ, 4.4% had rheumatoid arthritis and an additional 3% had significant joint pain [Larsson 1978].Other FindingsThe following are rarely associated with AATD:Vascular disease can present as intracranial aneurysms, arterial fibromuscular dysplasia, and severe bleeding disorders [Cox 1994]. One study reported decreased rates of hypertension in PI ZZ homozygotes [Cox 1994, Dahl et al 2003].Panniculitis, occurring rarely in PI ZZ homozygotes, can present as erythematous tender nodules mainly on the trunk and proximal extremities, with characteristic ulceration [McBean et al 2003].Anterior uveitis, an immunologic inflammatory eye disease, has been reported to be associated with an increased frequency of Z heterozygotes [Fearnley et al 1988].Systemic necrotizing vasculitis in 14 PI ZZ homozygotes, all of whom had skin involvement and either renal or joint involvement, was associated with high prevalence of emphysema and hepatic abnormalities [Mazodier et al 1996].Wegener granulomatosis can involve respiratory tract or multiple organs and presents with the inflammation of small to medium vessels with associated granulomas [Barnett et al 1999, Lonardo et al 2002].
Individuals with the PI ZZ genotype have highly variable phenotypes (see Other Findings); thus, additional genetic and environmental factors must be involved....
Genotype-Phenotype CorrelationsIndividuals with the PI ZZ genotype have highly variable phenotypes (see Other Findings); thus, additional genetic and environmental factors must be involved.Liver involvement is associated mainly with PI ZZ genotype [DeMeo & Silverman 2004].Other rare deficiency variants are also characterized by highly variable phenotypes (see Testing for PI Type, Other deficiency alleles).
Lung disease. Signs of airflow limitation in alpha1-antitrypsin deficiency (α1ATD, AATD) can be similar to features of asthma or allergy. In a study of 1,052 individuals with AATD, features of asthma were present in 21% and attacks of wheezing in 66% [Eden et al 2003]. The prevalence of AATD in persons with asthma or pulmonary emphysema does not differ from that found in the general population [Wencker et al 2002, Miravitlles et al 2003]....
Differential DiagnosisLung disease. Signs of airflow limitation in alpha1-antitrypsin deficiency (α1ATD, AATD) can be similar to features of asthma or allergy. In a study of 1,052 individuals with AATD, features of asthma were present in 21% and attacks of wheezing in 66% [Eden et al 2003]. The prevalence of AATD in persons with asthma or pulmonary emphysema does not differ from that found in the general population [Wencker et al 2002, Miravitlles et al 2003].Liver disease. Other liver diseases that need to be considered are: chronic viral hepatitis, hereditary hemochromatosis (see HFE-Associated Hereditary Hemochromatosis, Juvenile Hereditary Hemochromatosis), Wilson disease, non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis.In a study of 85 children with neonatal cholestasis, AATD was among the most common diagnoses (11/85); others were extrahepatic biliary atresia (30/85) and progressive familial intrahepatic cholestasis (11/85) (see Low Gamma-GT Familial Intrahepatic Cholestasis) [Fischler et al 2001a, Fischler et al 2001b].Z allele frequency was also high (12%) in a group of 29 individuals with cholestatic jaundice and cirrhosis, when compared with controls (0.5%) [Lima et al 2001].The presence of Z or S mutations in persons with cystic fibrosis confers a three- to sevenfold increased risk for CF-associated severe liver disease [Friedman et al 2001].A deficiency of the related serpin alpha1-antichymotrypsin (SERPINA3) is reported to be associated with liver disease [Lindmark & Eriksson 1991].
To establish the extent of disease in an individual diagnosed with alpha1-antitrypsin deficiency (α1ATD, AATD), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with alpha1-antitrypsin deficiency (α1ATD, AATD), the following evaluations are recommended:Liver assessment. In individuals with manifestations of liver disease, liver biopsy for light microscopy and histochemistry is useful initially to determine the extent of liver disease and liver inclusions. However, liver function tests are usually adequate for subsequent monitoring of liver status.Pulmonary assessment. Lung function measurements including spirometry, lung volumes, and diffusing capacity. In alpha1-antitrypsin deficiency (α1ATD, AATD), lung density is a more sensitive indicator of lung disease progression than lung function measurements [Shaker et al 2004]. Lung density measurements by CT scan appear to show excellent sensitivity for early detection of pulmonary abnormalities [Stolk et al 2003].Treatment of ManifestationsLung transplantation may be an appropriate option for individuals younger than age 60 years with end-stage lung disease (i.e., FEV1 below 30%) [Seersholm et al 1994, Trulock 1998]. However, despite apparent clinical improvement, five-year survival is no greater than for individuals who have not undergone lung transplantation.Liver transplantation, the preferred surgical treatment for advanced liver disease, can provide a cure because the donor liver produces AAT [Francavilla et al 2000].Panniculitis, a rarely associated disorder, has been alleviated with intravenous AAT. The lesions usually resolve spontaneously or after oral steroid therapy [Yesudian et al 2004]. In a severe case, immediate reduction of inflammation was achieved after administering human purified ATT [Chowdhury et al 2002].Prevention of Primary ManifestationsTherapies to prevent FEV1 decline in individuals with AATD with pulmonary symptoms are the following:Intravenous augmentation therapy. Regular infusion of purified AAT to augment deficient serum levels is used in some individuals; however, appropriately controlled trials have not been carried out [Gildea et al 2003]. Studies have demonstrated possible clinical efficacy for those with moderate lung damage. Recipients of augmentation therapy, particularly those with moderate degrees of airflow obstruction, have a somewhat slower rate of FEV1 decline. Guidelines for its use have been reported [Abboud et al 2001, American Thoracic Society & European Respiratory Society 2003, Abboud et al 2005, Stoller et al 2005]. Augmentation therapy has been recommended by the Canadian Thoracic Society for individuals with AATD whose FEV1 is 35%-50% of predicted, who have quit smoking, and who continue to show rapid decline in FEV1 despite optimal medical therapy [Abboud et al 2001].Lifestyle. Expression of the disorder can be modified in asymptomatic individuals by lifestyle changes, including avoidance of smoking and occupations with exposure to environmental pollutants. Regular exercise and good nutrition are expected to be beneficial in maintaining lung health.Vitamin E therapy improves liver function in infants with PI MZ and in children with cholestasis [Sokol et al 1986, Pittschieler 1991], and could be predicted to help prevent oxidative damage to the lungs.Breast-feeding. The risk of childhood-onset liver disease in infants with PI ZZ who are breast-fed during the first month of life was reported to be reduced, but breast-feeding does not offer absolute protection against the development of severe liver disease [Sveger 1985].SurveillanceLiver function should be evaluated periodically in all individuals with PI ZZ, including those who did not manifest childhood liver disease.Agents/Circumstances to AvoidSmoking (both active and passive) is a risk factor for AATD.Occupational hazards including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes are an independent risk factor for impairment of lung function in older non-smoking PI ZZ individuals.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationInhaled administration of purified AAT can reconstitute the lower respiratory tract antitrypsin screen and potentially reduce inflammation [Hubbard & Crystal 1990]. Although several products have been developed for this therapy, the approach has not been evaluated in randomized, blinded efficacy trials [Sandhaus 2004, Abusriwil & Stockley 2006].Synthetic inhibitors of human neutrophil elastase, administered intravenously and orally, could theoretically replace purified AAT in its function. Synthetic inhibitors of human neutrophil elastase have been used to treat cystic fibrosis, chronic bronchitis, and COPD without promising results. Trials in individuals with AATD have not been done [Sandhaus 2004].Antioxidant therapy. Vitamins A, C, and E have been suggested in the treatment of AATD-related emphysema. The efficacy of such treatment has not been evaluated [Sandhaus 2004].Synthetic chaperones and polymerization could potentially prevent intracellular polymerization of AAT leading to liver inclusions. Modest improvement in liver retention and increase in plasma concentrations of AAT was suggested after administration of 4-phenyl-butyric acid [Burrows et al 2000]. However, further studies have so far failed to demonstrate improvement [Teckman 2004]. Biochemical data on a peptide that specifically binds to Z AAT and inhibits polymerization are promising, but future cellular and animal studies are necessary [Mahadeva et al 2002, Parfrey et al 2004].Gene therapy is aimed at introducing a normal gene into the cells and turning off production of the endogenous abnormal gene product. While cell culture and animal studies have been promising, the effectiveness of this approach in humans is still theoretic [Stecenko & Brigham 2003].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherLung volume reduction surgery (LVRS) performed for persons with advanced non-AATD emphysema can improve lung function; individuals with higher preoperative FEV1 have a survival benefit [Fujimoto et al 2002]. However, in AATD-associated emphysema, the physiologic improvement is modest and offers only short-term benefits [Gelb et al 1999]. In a study of 12 individuals with AATD-related emphysema, lung function returned to baseline six to 12 months postoperatively but showed further deterioration 24 months postoperatively [Cassina et al 1998]. LVRS is therefore not recommended for individuals with AATD.Transgenic/recombinant production of human AAT protein could solve the potential problems of limited supply of AAT purified from human plasma and transmission of infectious agents. However, clinical trials of transgenic/recombinant production of AAT in sheep and goats [Casolaro et al 1987, Wright et al 1991, Ziomek 1998] have been discontinued because of serious immunologic reactions in the lungs of recipients.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Alpha1-Antitrypsin Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSERPINA114q32.13Alpha-1-antitrypsinA1-antitrypsin database CCHMC - Human Genetics Mutation DatabaseSERPINA1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Alpha1-Antitrypsin Deficiency (View All in OMIM) View in own window 107400SERPIN PEPTIDASE INHIBITOR, CLADE A, MEMBER 1; SERPINA1 613490ALPHA-1-ANTITRYPSIN DEFICIENCYMolecular Genetic PathogenesisThe basis for pulmonary disease in alpha1-antitrypsin deficiency (AATD) is a reduced inhibition of leukocyte elastase in the lung, resulting in excessive destruction of the elastin in the alveolae. Decades of research support this mechanism as causative. The adult-onset liver disease seen in individuals with AATD may result from damage caused by the accumulation of aggregated AAT in hepatocytes and bile ducts. The cause of progressive liver disease in infants and children with AATD is less clear. Early damage to bile ducts may be a destructive factor. Liver abnormalities in infants are noted in early weeks when deposits of AAT are minimal. Liver destruction proceeds, in a minority of infants, to cirrhosis, but the genetic and/or environmental factors have not been defined. Ineffective clearance by protein chaperones has been suggested as a factor [Kopito & Ron 2000, Perlmutter 2002].Normal allelic variants. SERPINA1 has five exons and a total length of 12.2 kb. There are two promoters, with one controlling expression in macrophaqes. More than 100 genetic variants of AAT, most of which have no disease associations, have been described.Pathologic allelic variants. Ninety-five percent of AATD results from the presence of two Z alleles. At least 14 null alleles and at least 20 rare deficiency alleles, found in many populations, comprise the remaining 5% of all deficiency variants. PI*Mmalton, like the Z variant, aggregates in the liver and is one of the more prevalent variants of the 5%.Normal gene product. Alpha1-antitrypsin (AAT) is a major serum protease inhibitor (PI), particularly important in inhibiting tissue elastase.Abnormal gene product. The Z variant self-aggregates, other variants are more easily degraded, and others are not produced because of unstable mRNA. The null variants produce less than 2% of normal AAT [Brantly et al 1988, Cox & Billingsley 1989, Faber et al 1994].