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α‎1-Antitrypsin deficiency and the serpinopathies 

α‎1-Antitrypsin deficiency and the serpinopathies
Chapter:
α‎1-Antitrypsin deficiency and the serpinopathies
Author(s):

David A. Lomas

DOI:
10.1093/med/9780199204854.003.1213_update_001

July 30, 2015: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

Update:

New and emerging treatments—discussion of use of carbamazepine, genomically corrected fibroblasts, and strategies to ‘knock down’ the expression of mutant Z α‎1-antitrypsin within hepatocytes.

Updated on 28 Nov 2012. The previous version of this content can be found here.
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Essentials

α‎1-Antitrypsin is an acute phase glycoprotein synthesized by the liver that functions as an inhibitor of a range of proteolytic enzymes, most importantly neutrophil elastase. Severe plasma deficiency of α‎1-antitrypsin results from homozygocity for the Z allele, which causes the protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes as PAS-positive inclusions.

Clinical features—(1) Liver—all adults with the Z allele of α‎1-antitrypsin have slowly progressive hepatic damage that is often subclinical and only evident as a minor degree of portal fibrosis, but up to 50% of Z homozygotes present with clinically evident cirrhosis and occasionally with hepatocellular carcinoma. (2) Lung—patients with Z α‎1-antitrypsin deficiency develop panlobular emphysema that tends to affect the bases rather than the apices of the lungs and is greatly exacerbated by smoking; cor pulmonale and polycythaemia are late features.

Diagnosis and management—severe genetic deficiency of α‎1-antitrypsin is readily diagnosed by low plasma levels and the virtual absence of the α‎1-band on protein electrophoresis. Patients should be very strongly advised to abstain from smoking, and to avoid agents that cause hepatic injury (such as excessive alcohol and obesity). Treatment otherwise involves conventional trials of bronchodilators and inhaled corticosteroids, pulmonary rehabilitation and—where appropriate—assessment for long-term oxygen therapy and lung transplantation. α‎1-Antitrypsin replacement therapy is widely used in North America, but its value is uncertain.

Other serpinopathies—the polymerization that underlies α‎1-antitrypsin deficiency is found in other members of the serine protease inhibitor (or serpin) superfamily to cause diseases as diverse as thrombosis (antithrombin), angioedema (C1 inhibitor), and dementia (neuroserpin).

Introduction

α‎1-Antitrypsin deficiency was first described by Carl-Bertil Laurell and Sten Eriksson in 1963 when they reported five individuals in whom there was a deficiency of the α‎1 band on serum protein electrophoresis. Three of the individuals had emphysema and one had a family history of emphysema. α‎1-Antitrypsin is a 394 amino acid, 52-kDa acute phase glycoprotein synthesized by the liver and macrophages and by intestinal and bronchial epithelial cells. It is present in the plasma at a concentration of between 0.9 and 1.8 g/litre and functions as an inhibitor of a range of proteolytic enzymes of which the most important is neutrophil elastase. α‎1-Antitrypsin deficiency results from point mutations that cause the protein to misfold and be retained within hepatocytes which in turn causes liver disease. The lack of circulating α‎1-antitrypsin causes uncontrolled tissue digestion within the lung and hence emphysema.

Genetics and pathogenesis of disease

Genetics

α‎1-Antitrypsin is subject to genetic variation resulting from mutations in the 12.2-kb, 7-exon SERPINA1 gene on the long arm of chromosome 14 (14q32.1) (OMIM 107400). Over 100 allelic variants have been reported and classified using the PI (protease inhibitor) nomenclature that assesses α‎1-antitrypsin mobility in isoelectric focusing analysis. Normal α‎1-antitrypsin migrates in the middle (M) and variants are designated A (anodal) to L if they migrate faster than M, and N to Z if they migrate more slowly. Many of these variants have been sequenced at the DNA level and shown to result from point mutations in the α‎1-antitrypsin gene (Table 12.13.1). For example, the Z allele results from the substitution of a positively charged lysine for a negative glutamic acid at position 342. The S allele results from the substitution of a neutral valine for a glutamic acid at position 264. Point mutations are inherited by simple mendelian trait; the normal genotype is designated PI MM or PI M, a heterozygote for the Z gene is PI MZ, and a homozygote is PI ZZ or PI Z. α‎1-Antitrypsin alleles are codominantly expressed, with each allele contributing to the plasma level of protein. Therefore each of the deficiency alleles results in a characteristic decrease in the plasma concentration of α‎1-antitrypsin; the S variant forms 60% of the normal M concentration and the Z variant 10 to 15%. Null alleles produce no α‎1-antitrypsin. Thus combinations of alleles have predictable effects, the MZ heterozygote has an α‎1-antitrypsin plasma level of 60% (50% from the normal M allele and 10% from the Z allele), the MS heterozygote 80% and the SZ heterozygote 40%. Very rarely point mutations can result in dysfunctional α‎1-antitrypsin that no longer inhibits neutrophil elastase or which can inhibit other serine proteases. The most striking example is the Pittsburgh mutant (Met358Arg) which converted α‎1-antitrypsin into an inhibitor of thrombin, thereby causing a fatal bleeding diathesis.

Table 12.13.1 Some alleles of SERPINA1. The letter denotes the migration on isoelectric focusing (PI) and the name denotes the origin of the mutation

Mutation

Normal alleles

M1

Val213Ala

M2

Arg101His

M3

Glu376Asp

Xchristchurch

Glu363Lys

Deficiency alleles

F

Arg223Cys

I

Arg39Cys

King’s

His334Asp

Mheerlen

Pro369Leu

Mmalton

Phe52del or Phe51del

Mmineral springs

Gly67Glu

Mprocida

Leu41Pro

Plowell

Asp256Val

S

Glu264Val

Siiyama

Ser53Phe

Z

Glu342Lys

Null alleles

QObellingham

Lys217X

QObolton

Pro362X

QOgranite falls

Tyr160X

QOhongkong-1

Leu318 deletion of 2 bp and premature stop codon at 334

QOludwigshafen

Ile92Asn

Dysfunctional alleles

Pittsburgh*

Met358Arg

* Antithrombin activity that results in a bleeding diathesis.

The molecular basis of α‎1-antitrypsin deficiency

Liver disease

α‎1-Antitrypsin functions by presenting its reactive-centre methionine residue on an exposed loop of the molecule such that it forms an ideal substrate for the enzyme neutrophil elastase (Fig. 12.13.1). The conformational transition that ensues results in the formation of a stable complex that inhibits the enzyme and allows it to be eliminated from sites of inflammation. The Z mutation (Glu342Lys) results in normal translation of the gene, but 85% of the Z α‎1-antitrypsin is retained within the endoplasmic reticulum with only 10 to 15% entering the circulation. The Z mutation distorts the relationship between the loop and the A β‎-pleated sheet that forms the major feature of the molecule. The consequent perturbation in structure allows the reactive-centre loop of one α‎1-molecule to lock into the A sheet of a second to form a dimer which then extends to form chains of loop-sheet polymers (Fig. 12.13.1). The formation of these polymers is temperature and concentration dependent and is localized to the endoplasmic reticulum of the hepatocyte (Fig. 12.13.2). These chains of polymers become interwoven to form the insoluble aggregates that are the hallmark of α‎1-antitrypsin liver disease. The process of intrahepatic polymerization also underlies the severe plasma deficiency of the rare Siiyama (Ser53Phe), Mmalton (deletion of residue 52) and King’s (His334Asp) deficiency alleles and the mild plasma deficiency of the S (Glu264Val) and I (Arg39Cys) variants. There is a strong genotype–phenotype correlation that can be explained by the molecular instability caused by the mutation and in particular the rate at which the mutant forms polymers. Those mutants that cause the most rapid polymerization cause the most retention of α‎1-antitrypsin within the liver. This in turn correlates with the greatest risk of liver damage and cirrhosis, and the most severe plasma deficiency. Misfolded Z α‎1-antitrypsin within hepatocytes is cleared by the proteosome but the ordered polymers are not detected by the unfolded protein response and are handled by less well understood pathways including autophagy.

Fig. 12.13.1 Mutant Z α‎1-antitrypsin is retained within hepatocytes as polymers. The structure of α‎1-antitrypsin is centred on β‎-sheet A (green) and the mobile reactive centre loop (red). Polymer formation results from the Z variant of α‎1-antitrypsin (Glu342Lys at P17; arrowed) or mutations in the shutter domain (blue circle) that open β‎-sheet A to favour partial loop insertion and the formation of an unstable intermediate (M*). The patent β‎-sheet A can either accept the loop of another molecule to form a dimer (D) which then extends into polymers (P). The individual molecules of α‎1-antitrypsin within the polymer are coloured red, yellow and blue.

Fig. 12.13.1
Mutant Z α‎1-antitrypsin is retained within hepatocytes as polymers. The structure of α‎1-antitrypsin is centred on β‎-sheet A (green) and the mobile reactive centre loop (red). Polymer formation results from the Z variant of α‎1-antitrypsin (Glu342Lys at P17; arrowed) or mutations in the shutter domain (blue circle) that open β‎-sheet A to favour partial loop insertion and the formation of an unstable intermediate (M*). The patent β‎-sheet A can either accept the loop of another molecule to form a dimer (D) which then extends into polymers (P). The individual molecules of α‎1-antitrypsin within the polymer are coloured red, yellow and blue.

(From Gooptu, B., Hazes, B., Chang, W.-S.W., Dafforn, T.R., Carrell, R.W., Read, R. & Lomas, D.A. (2000). Inactive conformation of the serpin a1-antichymotrypsin indicates two stage insertion of the reactive loop; implications for inhibitory function and conformational disease. Proc. Natl. Acad. Sci (USA), 97, 67–72. with permission.)

Fig. 12.13.2 Z α‎1-antitrypsin is retained within hepatocytes as intracellular inclusions. These inclusions are PAS positive and diastase resistant (a) and are associated with neonatal hepatitis and hepatocellular carcinoma. (b) Electron micrograph of an hepatocyte from the liver of a patient with Z α‎1-antitrypsin deficiency shows the accumulation of α‎1-antitrypsin within the rough endoplasmic reticulum (arrow). These inclusions are composed of chains of α‎1-antitrypsin polymers (c).

Fig. 12.13.2
Z α‎1-antitrypsin is retained within hepatocytes as intracellular inclusions. These inclusions are PAS positive and diastase resistant (a) and are associated with neonatal hepatitis and hepatocellular carcinoma. (b) Electron micrograph of an hepatocyte from the liver of a patient with Z α‎1-antitrypsin deficiency shows the accumulation of α‎1-antitrypsin within the rough endoplasmic reticulum (arrow). These inclusions are composed of chains of α‎1-antitrypsin polymers (c).

((b) and (c) reproduced from (i) Lomas, D.A., Evans, D.L., Finch, J.T. & Carrell, R.W. (1992). The mechanism of Z α‎1-antitrypsin accumulation in the liver. Nature, 357, 605–607. (ii) Lomas, D.A., Finch, J.T., Seyama, K., Nukiwa, T. & Carrell, R.W. (1993). α‎1-antitrypsin Siiyama (Ser53→Phe); further evidence for intracellular loop-sheet polymerisation. J. Biol. Chem., 268, 15333–15335, with permission.)

Lung disease

The development of emphysema associated with α‎1-antitrypsin deficiency is greatly accelerated by tobacco smoking. Emphysema results from uncontrolled enzymatic activity within the lung with those individuals with plasma α‎1-antitrypsin levels of <40% of normal being most at risk. This is compounded by a fivefold reduction in association rate kinetics with neutrophil elastase caused by the Z mutation and the polymerization of secreted Z α‎1-antitrypsin within the airways and alveoli. The formation of polymers inactivates α‎1-antitrypsin (thereby further reducing the protein available to inhibit neutrophil elastase) and the polymers themselves may drive some of the excessive inflammation that characterizes this condition.

Epidemiology

Two point mutations have been shown to explain the vast majority of cases of α‎1-antitrypsin deficiency. The Z allele causes the most severe plasma deficiency and is most prevalent in southern Scandinavia and the north-western European seaboard where 4% of the population are MZ heterozygotes and 1 in 1700 are PI Z homozygotes. The gene frequency of the Z allele reduces towards the south and east of Europe. In contrast, the S allele causes only mild plasma deficiency and is most common in southern Europe where up to 28% of the population are MS heterozygotes. The S allele becomes less frequent as one moves north-east. The frequencies of the Z allele in the United States of America are similar to the lowest frequencies in Europe but the S allele is more common than in northern Europeans. α‎1-Antitrypsin deficiency is infrequent in Asian, African, and Middle Eastern populations. It is also rare in Japan, but when present it is usually due to the Siiyama mutation (Ser53Phe). In the genetically isolated island of Sardinia the commonest cause of severe α‎1-antitrypsin deficiency is the Mmalton mutation (deletion of residue 52).

The Z allele is believed to have arisen from a single origin 66 generations or 2000 years ago. The high frequency in southern Scandinavia suggests that the mutation arose in the Viking population. The date of origin implies that the allele arose when the Vikings populated mid/northern Europe and before their migration to Scandinavia. It is likely that the Z allele of α‎1-antitrypsin was then distributed across northern Europe by the Viking raiders between 800 and 1100 ad, and then to the United States and the rest of the world during migration over the past 200 years. The S allele appears to have arisen in the north of the Iberian peninsula, but the date of origin is uncertain. This mutation was similarly introduced into North America by mass migration.

Clinical features

α‎1-Antitrypsin deficiency and liver disease

The accumulation of abnormal protein starts in utero and is characterized by diastase-resistant, periodic acid–Schiff (PAS) positive inclusions of α‎1-antitrypsin in the periportal cells (Fig. 12.13.2). Seventy-three per cent of Z α‎1-antitrypsin homozygote infants have a raised serum alanine aminotransferase in the first year of life but in only 15% of people is it still abnormal by 12 years of age. Similarly serum bilirubin is raised in 11% of PI Z infants in the first 2–4 months but falls to normal by 6 months of age. One in 10 infants develops cholestatic jaundice and 6% develop clinical evidence of liver disease without jaundice. These symptoms usually resolve by the second year of life but approximately 15% of patients with cholestatic jaundice progress to juvenile cirrhosis. The overall risk of death from liver disease in PI Z children during childhood is 2 to 3%, with boys being at more risk than girls. All adults with the Z allele of α‎1-antitrypsin have slowly progressive hepatic damage that is often subclinical and only evident as a minor degree of portal fibrosis. However, up to 50% of Z α‎1-antitrypsin homozygotes present with clinically evident cirrhosis and occasionally with hepatocellular carcinoma.

α‎1-Antitrypsin deficiency and emphysema

Patients with emphysema related to α‎1-antitrypsin deficiency usually present with increasing dyspnoea with cor pulmonale and polycythaemia occurring late in the course of the disease. Emphysema associated with Z α‎1-antitrypsin deficiency differs from ‘usual chronic obstructive pulmonary disease (COPD)’ with normal levels of M α‎1-antitrypsin in that it affects predominantly the bases rather than the apices of the lungs, it is associated with panlobular rather than centrilobular disease, and it results from the expression of different genes when assessed by microarray analysis. However in many cases the distribution of disease is indistinguishable from ‘usual COPD’. High-resolution CT scans are the most accurate method of assessing the distribution of panlobular emphysema and for monitoring the progress of the pulmonary disease, although this currently has little value outside clinical trials. Lung function tests are typical for emphysema with a reduced FEV1/FVC ratio (forced expiratory volume in 1 s/forced vital capacity) and FEV1, gas trapping (raised residual volume/total lung capacity ratio), and a low gas-transfer factor. As in many individuals with COPD, partial reversibility of airflow obstruction (as defined by an increase of 12% and 200 ml in FEV1) is common in individuals with COPD secondary to α‎1-antitrypsin deficiency. The most important factor in the development and progression of emphysema in α‎1-antitrypsin deficiency is tobacco smoking.

Other conditions associated with α‎1-antitrypsin deficiency

α‎1-Antitrypsin deficiency is associated with an increased prevalence of asthma, panniculitis, Wegener’s granulomatosis and possibly pancreatitis, gallstones, bronchiectasis, and intracranial and intra-abdominal aneurysms. There appears to be a reduced risk of cerebrovascular disease.

Clinical investigation

The severe genetic deficiency of α‎1-antitrypsin is readily diagnosed by low plasma levels and the virtual absence of the α‎1-band on protein electrophoresis. As α‎1-antitrypsin is an acute phase protein, most laboratories will report levels with another acute-phase reactant, such as α‎1-antitchymotrypsin, which allows the clinician to assess the likelihood of deficiency in the context of the inflammatory response. The acute phase response raises the plasma level of α‎1-antitrypsin, but the plasma level of the PI Z homozygote can never reach the normal range. The deficiency variant is then assigned a PI phenotype according to the migration of the protein on an isoelectric focusing gel. The mutation underlying the deficiency can be determined by sequencing the SERPINA1 gene. Commercial kits permit detection of the Z and S alleles but will not detect null or other rare alleles.

Treatment

The treatment of α‎1-antitrypsin deficiency depends largely on the avoidance of stimuli causing repeated pulmonary inflammation—primarily smoking. Patients with α‎1-antitrypsin deficiency-related emphysema should receive conventional therapy with trials of bronchodilators and inhaled corticosteroids, pulmonary rehabilitation and, where appropriate, assessment for long-term oxygen therapy and lung transplantation. The role of lung volume-reduction surgery in this group is unclear as the disease is basal rather than apical and resections of this region are technically more difficult. Mixed results have been reported in uncontrolled trials.

The lung disease results from a deficiency in the antielastase screen. This may be rectified biochemically by intravenous infusions of α‎1-antitrypsin. Registry data suggest that individuals with α‎1-antitrypsin deficiency and an FEV1 of 35 to 49% predicted may derive benefit from replacement therapy. The only controlled trial showed a nonsignificant trend towards reduced progression of emphysema in individuals receiving intravenous α‎1-antitrypsin. α‎1-Antitrypsin replacement therapy is not currently available in many European countries, including the United Kingdom, but it is widely used in North America.

All Z homozygotes have some liver damage and, as such, would be wise to avoid alcohol abuse and obesity. PI Z homozygotes should be monitored for the persistence of hyperbilirubinaemia as this, along with deteriorating results of coagulation studies, indicates the need for liver transplantation. Parents with a child with severe Z α‎1-antitrypsin liver disease may require genetic counselling. The likelihood of similar severe liver damage in a subsequent Z homozygote sibling is approximately 20%.

The uncommon α‎1-antitrypsin deficiency-associated panniculitis usually responds to dapsone, 100 to 150 mg daily, for 2 to 4 weeks, but occasionally it necessitates the administration of intravenous α‎1-antitrypsin replacement therapy.

Prognosis

Estimates of the annual rate of decline in FEV1 range from 41 to 109 ml in individuals with α‎1-antitrypsin deficiency although one study reported a rate of decline of 316 ml/year in current smokers. The fastest rate of decline is in current smokers (and to a lesser extent ex-smokers), men, individuals aged 30–44 years, those with FEV1 values between 35 and 79% predicted and those with a bronchodilator response. Respiratory failure accounts for 50 to 72% of deaths in individuals with α‎1-antitrypsin deficiency with the second most common cause of death being liver cirrhosis (10–13%). Most children avoid significant liver damage in childhood but are still at risk of disease in adult life. The factors that predict progressive liver disease are unclear but males and the obese appear to be most at risk. The only significant cohort study has followed 184 individuals with α‎1-antitrypsin deficiency (127 PI Z, 2 PI Z–, 54 PI SZ, and 1 PI S–) from birth to 26 years of age. One PI SZ and 5 PI Z children died in early childhood (2 of liver disease and 2 of other causes but were found to have histological signs of cirrhosis or fibrosis at post-mortem) and 12% and 6% of PI Z subjects had abnormal liver function tests at 18 and 26 years respectively but no clinical evidence of liver disease. All the 26-year-olds had normal lung function (including the 17% of individuals who were current or ex-smokers).

A logical follow-on from the association of α‎1-antitrypsin antitrypsin deficiency with emphysema is an assessment of the risk of COPD in heterozygotes who carry an abnormal Z allele and a normal M allele. These individuals have plasma α‎1-antitrypsin levels that are approximately 60% of normal. A population-based study demonstrated that PI MZ heterozygotes do not have a clearly increased risk of lung damage. However if groups of patients are collected who already have COPD, then the prevalence of PI MZ individuals appears to be elevated. In addition, a longitudinal study has demonstrated that among COPD patients, the PI MZ heterozygotes have a more rapid decline in lung function. These data suggest that either all PI MZ individuals are at slightly increased risk for the development of COPD, or that a subset of the PI MZ subjects are at substantially increased risk of pulmonary damage if they smoke.

Other ‘serpinopathies’

α‎1-Antitrypsin is the archetypal member of a superfamily of proteins termed the serine protease inhibitors, or serpins, that have closely related structures and functions. These inhibitors control various inflammatory cascades, including coagulation (antithrombin), complement activation (C1-inhibitor), and fibrinolysis (α‎2-antiplasmin). Pathological processes that underlie the deficiency of one member may account for deficiency of others. Indeed the process of polymer formation has also been reported in deficiency-mutants of antithrombin, C1-inhibitor, α‎1-antichymotrypsin, and heparin co-factor II. These polymers are inactive as proteinase inhibitors and so predispose the individual to thrombosis (antithrombin) and angio-oedema (C1-inhibitor). The plasma deficiency that results from the polymerization of mutants of α‎1-antichymotrypsin has been associated with COPD in some (but not all) association studies, but the plasma deficiency of heparin cofactor II has yet to be associated with a clinical phenotype. Perhaps the most striking serpinopathy results from the polymerization of mutants of a neuron-specific serpin, neuroserpin, to cause the novel inclusion-body dementia known as familial encephalopathy with neuroserpin inclusion bodies (FENIB; OMIM 604218). This is inherited as an autosomal dominant trait with the inclusions of neuroserpin in the brain being PAS-positive and diastase-resistant, identical to those of Z α‎1-antitrypsin in the liver. The six mutations that have been described show a striking inverse correlation between the rate that the protein forms polymers and the age of onset/severity of the dementia.

α1-Antitrypsin deficiency and the serpinopathiesNew and emerging treatments

Other treatments at earlier stages of development include gene and stem cell therapy, the administration of retinoic acid, and chemical chaperones. Vectors carrying the α‎1-antitrypsin gene have been targeted to liver, lung, and muscle in animals. There is good expression of α‎1-antitrypsin but further data are required to assess whether this can be achieved in humans. In particular it is important to determine the length of time of protein expression and whether the levels of α‎1-antitrypsin in the epithelial lining fluid of the lung are sufficient to prevent ongoing proteolytic damage. Genomic correction of fibroblast-derived induced pleuripotential stem cells provides a novel strategy to generate ‘corrected hepatocytes’ from individuals with α‎1-antitrypsin deficiency, but further development is required before these can be used as ‘hepatocyte-replacement therapy’ in humans. The antiepileptic drug carbamazepine increases autophagy and so promotes the degradation of Z α‎1-antitrypsin in cell lines and mouse models of disease. Clinical trials are being established to evaluate the efficacy of this agent in α‎1-antitrypsin deficiency related liver disease in man. Retinoic acid stimulates alveolar regeneration in the rat but was ineffective in patients with emphysema. More promising is the strategy to ‘knock down’ the expression of mutant Z α‎1-antitrypsin within hepatocytes to prevent the protein overload that causes liver disease: trials are expected to start in 2012. The long-term aim is to exploit of our understanding of the pathogenesis of α‎1-antitrypsin deficiency to develop small molecules to block polymerization and so treat the associated liver and lung disease.

Further reading

Davis RL, et al. (2002). Association between conformational mutations in neuroserpin and onset and severity of dementia. Lancet, 359, 2242–7. [Description of families with mutations in the serpin, neuroserpin, that form polymers in vivo and an inclusion-body dementia.]Find this resource:

Eriksson S, Carlson J, Velez R (1986). Risk of cirrhosis and primary liver cancer in alpha1-antitrypsin deficiency. N Engl J Med, 314, 736–9. [Post-mortem study demonstrating a high prevalence of liver disease in adults with PiZ α‎1-antitrypsin deficiency.]Find this resource:

Gooptu B, Lomas DA (2009). Conformational pathology of the serpins - themes, variations and therapeutic strategies. Ann Rev Biochem, 78, 147–176.Find this resource:

Hidvegi T, et al. (2010). An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science, 329, 229–32. [The antiepileptic drug carbamazepine increases autophagy and so promotes the degradation of Z α‎1-antitrypsin in cell lines and mouse models of disease.]Find this resource:

Laurell C-B, Eriksson S (1963). The electrophoretic α‎1-globulin pattern of serum in α‎1-antitrypsin deficiency. Scand J Clin Lab Invest, 15: 132–40. [The first report of α‎1-antitrypsin deficiency in five individuals of whom three had emphysema and one had a family history of emphysema.]Find this resource:

    Lomas DA (2006). The selective advantage of α‎1-antitrypsin deficiency. Am J Resp Crit Care Med, 173, 1072–7. [Discussion of the reason for the high prevalence of the Z allele of α‎1-antitrypsin in the white population.]Find this resource:

    Mahadeva R, et al. (2005). Polymers of Z α‎1-antitrypsin co-localise with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am J Pathol, 166, 377–86. [Demonstration that polymers co-localise with neutrophils in lungs from individuals with α‎1-antitrypsin deficiency and that they are chemotactic when instilled into the lungs of mice.]Find this resource:

    Owen MC, et al. (1983). Mutation of antitrypsin to antithrombin.α‎1-antitrypsin Pittsburgh (358 Met to Arg), a fatal bleeding disorder. N Engl J Med, 309, 694–8 [Description of a point mutation inα‎1-antitrypsin that converted it to an inhibitor of thrombin and so caused an episodic bleeding disorder in a 14 year-old-boy.]Find this resource:

    Piitulainen E, Eriksson S (1999). Decline in FEV1 related to smoking status in individuals with severe alpha1-antitrypsin deficiency. Eur Resp J, 13, 247–51. [Report of rate of decline in lung function of 608 patients followed for 1–31 years. Current smokers have an accelerated rate of decline in lung function but ex-smokers have the same rate as non-smokers. The values are likely to be more representative than other reports as many subjects were ascertained from screening and family studies.]Find this resource:

    Piitulainen E, et al. (2005). Alpha1-antitrypsin deficiency in 26-year-old subjects: lung, liver, and protease/protease inhibitor studies. Chest, 128, 2076–81. [Report on the follow up of individuals with α‎1-antitrypsin deficiency from birth to 26 years. This is the only long-term prospective study of patients with α‎1-antitrypsin deficiency and therefore the only study that is free from selection bias.]Find this resource:

    Stoller JK, Aboussouan LS (2005). Alpha-1-antitrypsin deficiency. Lancet, 365, 2225–36 [A review of the pathophysiology, clinical features and management of α‎1-antitrypsin deficiency.]Find this resource:

    Sveger T (1976). Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med, 294, 1316–21. [Prospective study of liver disease in 120 Pi Z, 48 Pi SZ, two PI Z-and one Pi S-infants in the first 6 months of life.]Find this resource:

    Yusa K (2011). Targeted gene correction of α‎1-antitrypsin deficiency in induced pluripotent stem cells. Nature, 478, 391–4. [Genomic correction of fibroblast-derived induced pleuripotential stem cells provides a novel strategy to generate ‘corrected hepatocytes’ from individuals with α‎1-antitrypsin deficiency.]Find this resource: