alpha1-antitrypsin deficiency

Definition: Autosomal recessive disease dut to mutation in the gene PI coding for alpha1-antitrypsin.

Clinical synopsis

 Dyspnea, onset 35 years in smokers, 45 years in nonsmokers

Pathological synopsis

 alveolar wall destruction
 panlobar emphysema, especially at bases
 chronic obstructive pulmonary disease (COPD)
 bronchiectasis of larger airways (minor feature)
 mildly increased bronchial gland-to-wall ratio
 mild inflammation
 goblet cell hyperplasia
 dilatation of membranous bronchioles
 hepatic intracellular inclusions in ZZ homozygotes
 infantile liver abnormalities in < 20% with deficiency
 hepatic fibrosis
 cirrhosis (rare)
 increased hepatocellular carcinoma risk

Biological synopsis

 Serum alpha-1-antitrypsin (Pi) deficiency
 Abnormal liver function tests (SGOT, SGPT)
 Z allele most common, only in Caucasians

Localization

 hepatic A1AT deficiency
 pulmonary A1AT deficiency

Etiology

 germline mutations in the protease inhibitor 1 gene (PI )(MIM.107400)

Deficiency of alpha1-antitrypsin was clinically described for the first time in 1963 by Carl-Bertil Laurell and Sten Eriksson, who noted an absence of the alpha1-band on electrophoresis of the serum of some patients with lung disease.

More then 70 naturally occurring variants of alpha1-antitrypsin have been described and characterized by their migration on isolelectric focusing gels.

Pathogenesis

One in 2,000 individuals from northern Europe is homozygous for the severe Z mutation (a E342K substitution), with plasma levels that are 10-15% of those present in individuals with the normal M allele.

The Z mutation results in the accumulation of alpha1-antitrypsin as PAS-positive inclusions in the rough endoplasmic reticulum of the liver.

These inclusions cause transient juvenile hepatitis in 90% of homozygotes; 1-2% of these individuals will also develop cirrhosis and be at risk of developing hepatocellular carcinoma.

The main function of alpha1-antitrypsin is to protect the tissues, and especially the elastic tissue of the lungs, against the enzyme neutrophil elastase. The lack of circulating alpha1-antitrypsin results in an imbalance between enzymes and inhibitors in the lung, which causes early-onset panlobular emphysema.

 The Z mutation

The Z mutation in alpha1-antitrypsin is a glutamic acid to lysine substitution at residue P17 (17 residues proximal to the P1 residue of the reactive-centre loop) at the head of strand five of -sheet A and at the base of the mobile reactive loop. The mutation is in a crucial mobile domain of alpha1-antitrypsin - the hinge between beta-sheet A and the peptide loop that contains the reactive centre.

As a result of this mutation, beta-sheet A opens, so allowing the reactive loop to insert partially into the top of the central strand in beta-sheet A.

This insertion into the top of the sheet leaves the bottom-half open and therefore ready to accept the reactive loop of another alpha1-antitrypsin molecule.

Most of the newly synthesized misfolded form will be eliminated but the remainder proceeds through the endoplasmic pathway.

Here, sequential intermolecular loop-sheet linkages occur with the formation of long chain polymers. It is the entanglement of these polymers in the final stages of the endoplasmic pathway of the hepatocyte that results in the large inclusion bodies that are apparent on light microscopy.

Support for the occurrence of this polymerization comes from the demonstration that Z alpha1-antitrypsin forms chains of polymers when incubated under physiological conditions in vitro. The rate was accelerated by raising the temperature to 41 °C and could be blocked by peptides that compete with the loop to anneal to beta-sheet A.

The role of polymerization in vivo was clarified by the demonstration of alpha1-antitrypsin polymers in inclusion bodies from the liver of a Z alpha1-antitrypsin homozygote with cirrhosis and in hepatoma cell lines that express the Z variant.

Moreover, point mutations that block polymerization increased the secretion of mutants of alpha1-antitrypsin from a Xenopus oocyte expression system.

It seems likely that the rate at which Z alpha1-antitrypsin polymers are degraded in the endoplasmic reticulum will determine the degree of cytotoxicity and hence explain why children with the same point mutation have different risks of liver disease.

 Failure to inactivate

Failure to inactivate a tissue-damaging substrate is best exemplified by α1-antitrypsin (α1-AT) deficiency. Patients who have an inherited deficiency of serum α1-AT are unable to inactivate neutrophil elastase in their lungs. Unchecked activity of this protease leads to destruction of elastin in the walls of lung alveoli, leading eventually to pulmonary emphysema.

 A serpinopathies

The structure of the serpins and their requirement to accept the reactive loop as an additional beta-strand is central to their role as effective antiproteinases.

However, this also renders them liable to undergo conformational change that might lead to disease (the serpinopathies). Point mutations can destabilize beta-sheet A to allow incorporation of the reactive loop of another serpin molecule. Sequential reactive-loop insertion results in chains of polymers that are retained in the cell of synthesis. This process is best characterized by the common condition of alpha1-antitrypsin deficiency in humans, which arises from the retention of this serpin in hepatocytes and is associated with liver damage.

Deficiency of alpha1-antitrypsin was clinically described for the first time in 1963 by Carl-Bertil Laurell and Sten Eriksson, who noted an absence of the 1-band on electrophoresis of the serum of some patients with lung disease.

More then 70 naturally occurring variants of alpha1-antitrypsin have been described and characterized by their migration on isolelectric focusin gels.

One in 2,000 individuals from northern Europe is homozygous for the severe Z mutation (PiZ) (a E342K substitution), with plasma levels that are 10–15% of those present in individuals with the normal M allele.

The Z mutation results in the accumulation of alpha1-antitrypsin as PERIODIC ACID SCHIFF (PAS)-positive inclusions in the rough endoplasmic reticulum of the liver.

These inclusions cause transient juvenile hepatitis in 90% of homozygotes; 1–2% of these individuals will also develop cirrhosis and be at risk of developing hepatocellular carcinoma.

The main function of alpha1-antitrypsin is to protect the tissues, and especially the elastic tissue of the lungs, against the enzyme neutrophil elastase.

The lack of circulating alpha1-antitrypsin results in an imbalance between enzymes and inhibitors in the lung, which causes early-onset emphysema (therefore explaining why this deficiency was first recognized in individuals with lung disease).

The Z mutation in alpha1-antitrypsin is a glutamic acid to lysine substitution at residue P17 (17 residues proximal to the P1 residue of the reactive-centre loop) at the head of strand five of alpha-sheet A and at the base of the mobile reactive loop.

The mutation is in a crucial mobile domain of alpha1-antitrypsin: the hinge between alpha-sheet A and the peptide loop that contains the reactive centre.

As a result of this mutation, beta-sheet A opens, so allowing the reactive loop to insert partially into the top of the central strand in -sheet A.

This insertion into the top of the sheet leaves the bottom-half open and therefore ready to accept the reactive loop of another alpha1-antitrypsin molecule.

Most of the newly synthesized misfolded form will be eliminated but the remainder proceeds through the endoplasmic pathway. Here, sequential intermolecular loop–sheet linkages occur with the formation of long chain polymers.

It is the entanglement of these polymers in the final stages of the endoplasmic pathway of the hepatocyte that results in the large inclusion bodies that are apparent on light microscopy.

Support for the occurrence of this polymerization comes from the demonstration that Z alpha1-antitrypsin forms chains of polymers when incubated under physiological conditions in vitro.

The rate was accelerated by raising the temperature to 41 °C and could be blocked by peptides that compete with the loop to anneal to beta-sheet A.

The role of polymerization in vivo was clarified by the demonstration of alpha1-antitrypsin polymers in inclusion bodies from the liver of a Z alpha1-antitrypsin homozygote with cirrhosis and in hepatoma cell lines that express the Z variant.

Moreover, point mutations that block polymerization increased the secretion of mutants of alpha1-antitrypsin from a Xenopus oocyte expression system.

It seems likely that the rate at which Z alpha1-antitrypsin polymers are degraded in the endoplasmic reticulum will determine the degree of cytotoxicity and hence explain why children with the same point mutation have different risks of liver disease.

 In the liver

Z mutant alpha1-antitrypsin is retained in hepatocytes as intracellular inclusions. The inclusions caused by the Z form of 1-antitrypsin are periodic acid Schiff (PAS) positive and diastase resistant and are associated with neonatal hepatitis and hepatocellular carcinoma.

Electron micrograph of hepatocytes from the liver of a patient with Z 1-antitrypsin deficiency shows the accumulation of 1-antitrypsin in the rough endoplasmic reticulum.

Videos

 Histopathology of the liver in hepatic A1AT deficiency by Washington Deceit

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References

 Tomashefski JF Jr, Crystal RG, Wiedemann HP, Mascha E, Stoller JK; Alpha 1-Antitrypsin Deficiency Registry Study Group. The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with Severe Deficiency of Alpha-1 Antitrypsin. Hum Pathol. 2004 Dec;35(12):1452-61. PMID: 15619203

 Lomas DA. The selective advantage of alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2006 May 15;173(10):1072-7. PMID: 16439713

 Lomas DA. Molecular mousetraps, alpha1-antitrypsin deficiency and the serpinopathies. Clin Med. 2005 May-Jun;5(3):249-57. PMID: 16011217

 Lomas DA, Belorgey D, Mallya M, Onda M, Kinghorn KJ, Sharp LK, Phillips RL, Page R, Crowther DC, Miranda E. Polymerisation underlies alpha1-antitrypsin deficiency, dementia and other serpinopathies. Front Biosci. 2004 Sep 1;9:2873-91. PMID: 15353322

 Lomas DA, Parfrey H. Alpha1-antitrypsin deficiency. 4: Molecular pathophysiology.Thorax. 2004 Jun;59(6):529-35. PMID: 15170041

 Crowther DC, Belorgey D, Miranda E, Kinghorn KJ, Sharp LK, Lomas DA. Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. Eur J Hum Genet. 2004 Mar;12(3):167-72. PMID: 14694355

 Parfrey H, Mahadeva R, Lomas DA.Alpha(1)-antitrypsin deficiency, liver disease and emphysema. Int J Biochem Cell Biol. 2003 Jul;35(7):1009-14. PMID: 12672469

 Lomas DA, Mahadeva R. Alpha1-antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy. J Clin Invest. 2002 Dec;110(11):1585-90. PMID: 12464660

 Lomas DA, Lourbakos A, Cumming SA, Belorgey D. Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia. Biochem Soc Trans. 2002 Apr;30(2):89-92. Review. PMID: 12023831

 Carrell RW, Lomas DA. Alpha1-antitrypsin deficiency—a model for conformational diseases. N Engl J Med. 2002 Jan 3;346(1):45-53. PMID: 11778003

 Mahadeva R, Lomas DA. Genetics and respiratory disease. 2. Alpha 1-antitrypsin deficiency, cirrhosis and emphysema. Thorax. 1998 Jun;53(6):501-5. PMID: 9713452

 Carrell RW, Lomas DA, Sidhar S, Foreman R.Alpha 1-antitrypsin deficiency. A conformational disease.Chest. 1996 Dec;110(6 Suppl):243S-247S. PMID: 8989158

 Lomas DA. New insights into the structural basis of alpha 1-antitrypsin deficiency. QJM. 1996 Nov;89(11):807-12. PMID: 8977959