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α1-Antitrypsin: A Guardian of Vascular Tissue

  • Diane Wilson Cox
    Correspondence
    Address reprint requests to Dr. D. W. Cox, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8
    Affiliations
    The Research Institute, The Hospital for Sick Children, University of Toronto Toronto, Ontario, Canada
    Departments of Paediatrics and Molecular and Medical Genetics, University of Toronto Toronto, Ontario, Canada
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      α1-Antitrypsin (α1-AT) is the most abundant proteinase inhibitor (PI) in human plasma. This inhibitor is important in protecting tissue from damage inflicted by proteinases, particularly neutrophil elastase. A recessively inherited deficiency of α1-AT was found to be associated with early-onset emphysema.
      • Laurell C-B
      • Eriksson S
      The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency.
      (Details and related references are available elsewhere.
      • Cox DW
      α1-Antitrypsin deficiency.
      ) The reduced concentration of α1-AT is inadequate to control the action of proteinases such as elastase, and lung elastin is slowly destroyed. Childhood liver disease has also been found to be associated with α1-AT deficiency.
      • Sharp HL
      • Bridges RA
      • Krivit W
      • Freier EF
      Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder.
      Severe and fatal liver disease occurs in a few percentage of persons born with the deficiency.
      • Sveger T
      Prospective study of children with α1-antitrypsin deficiency: eight-year-old follow-up.
      In those families at risk, prenatal diagnosis can be performed,
      • Cox DW
      • Mansfield T
      Prenatal diagnosis of α1 antitrypsin deficiency and estimates of fetal risk for disease.
      and the deficiency can be diagnosed by molecular methods with use of the polymerase chain reaction on a very small amount of fetal tissue.
      • Schwartz M
      • Bruun Petersen K
      • Gregersen N
      • Hinkel K
      • Newton CR
      Prenatal diagnosis of alpha-1-antitrypsin deficiency using polymerase chain reaction (PCR): comparison of conventional RFLP methods with PCR used in combination with allele specific oligonucleotides or RFLP analysis.
      Adults with α1-AT deficiency also have an increased risk for liver disease, and the risk increases with advancing age.
      • Cox DW
      • Smyth S
      Risk for liver disease in adults with alpha1-antitrypsin deficiency.

      Genetic Defect.

      Usually, α1-AT deficiency is due to the production of a mutant form (called Z) of α1-AT. Persons with α1-AT deficiency (PI*ZZ phenotype) have approximately 18% of the normal plasma concentration of α1-AT, and heterozygotes (PI*MZ phenotype) have approximately 60%. The PI*ZZ phenotype can be identified by a simple immunologic measurement of the protein, which, if low, must be confirmed by PI typing (isoelectric focusing in a narrow-range pH gradient). The abnormal Z protein has a tendency to self-aggregate
      • Cox DW
      • Billingsley GD
      • Callahan JW
      Aggregation of plasma Z type α1-antitrypsin suggests basic defect for the deficiency.
      • Lomas DA
      • Evans DL
      • Finch JT
      • Carrell RW
      The mechanism of Z α1-antitrypsin accumulation in the liver.
      and thereby produce molecular complexes or inclusions, which accumulate in the liver
      • Sharp HL
      Alpha-1-antitrypsin deficiency.
      (where α1-AT is produced).

      Associated Clinical Disorders.

      In addition to susceptibility to lung and liver destruction, α1-AT deficiency seems to contribute to susceptibility to, or severity of, other disorders, particularly those with inflammatory or immune components (or both). In 1980, an increased frequency of PI*MZ heterozygotes was reported among patients with severe erosive rheumatoid arthritis,
      • Cox DW
      • Huber O
      Association of severe rheumatoid arthritis with heterozygosity for α1-antitrypsin deficiency.
      a pattern subsequently confirmed in several studies. Asthma is probably more severe in patients with the PI*MZ phenotype
      • Gaillard MC
      • Kilroe-Smith TA
      • Nogueira C
      • Dunn D
      • Jenkins T
      • Fine B
      • et al.
      Alpha-1-protease inhibitor in bronchial asthma: phenotypes and biochemical characteristics.
      than in other patients. Panniculitis
      • Edmonds BK
      • Hodge JA
      • Rietschel RL
      Alpha1-antitrypsin deficiency-associated panniculitis: case report and review of the literature.
      and membranoproliferative glomerulonephritis
      • Davis ID
      • Burke B
      • Freese D
      • Sharp HL
      • Kim Y
      The pathologic spectrum of the nephropathy associated with α1-antitrypsin deficiency.
      have occurred in association with the PI*ZZ phenotype. Evidence for increased susceptibility to other diseases, including anterior uveitis and asthma, is less secure.

      Mechanisms of Action.

      At least two mechanisms can lead to disease in patients with α1-AT deficiency. The presence of hepatic inclusions is probably the cause of the liver damage in adults with this deficiency and may have a role in childhood liver disease as well. Susceptibility to other disorders, including obstructive lung disease, seems to be due to the inadequate plasma levels of α1-AT. An imbalance of PI (particularly against leukocyte elastase) allows tissue destruction to occur. This imbalance can explain the tendency for severe rheumatoid arthritis and extensive lung damage in patients with asthma when the PI*MZ phenotype is present; those with the PI*ZZ phenotype apparently are at risk for panniculitis. Recently, my colleagues and I
      • Byth BC
      • Billingsley GD
      • Cox DW
      Physical and genetic mapping of the serpin gene cluster at 14q32.1: allelic association and a unique haplotype associated with α1-antitrypsin deficiency.
      have shown that genes for corticosteroid-binding globulin, which is involved in control of inflammation through delivery of cortisol to tissues, and for α1-AT are physically close (approximately within 80 kb) on chromosome 14. These genes lie so close that variants of one could act as markers for variant forms of the other. Therefore, disease associations noted for α1-AT could be due to genetic variation in cortisol-binding globulin that inefficiently controls the inflammatory response.
      Cumulative evidence suggests that α1-AT may have an important role in the protection of blood vessels. The plasma concentration of α1-AT has been found to be considerably lower in patients with aneurysms than in those with occlusive aortic disease. This finding could be attributable to formation and removal of α1-AT as an elastase and α1-AT complex. Neutrophils release proteinases, such as elastin and cathepsin G, onto the endothelium at the time of occlusion. Both plasma α1-AT and α1-antichymotrypsin (cathepsin G inhibitor) are bound to the surface of endothelium.
      • Forsyth KD
      • Talbot V
      • Beckman I
      Endothelial serpins—protectors of the vasculature?.
      If the amount of these inhibitors is inadequate, tissue damage could potentially ensue.

      Previous Investigations.

      In a study of 47 patients with infrarenal abdominal aortic aneurysms, 5 (11%) were of PI*MZ phenotype.
      • Cohen JR
      • Sarfati I
      • Ratner L
      • Tilson D
      α1-Antitrypsin phenotypes in patients with abdominal aortic aneurysms.
      No control population was tested, but 1 in 47 (2%) would have been expected. A male patient with emphysema and α1-AT deficiency (PI*ZZ) reportedly had a ruptured colic artery aneurysm and multiple other small aneurysms of the middle colic artery.
      • Mitchell MB
      • McAnena OJ
      • Rutherford RB
      Ruptured mesenteric artery aneurysm in a patient with alpha1-antitrypsin deficiency: etiologic implications.
      In addition to abdominal aneurysms, intracranial aneurysms have been noted. On examination of medical records for 362 patients with α1-AT deficiency, apparently including both partial (PI*MZ) and homozygous (PI*ZZ) deficiency,
      • Schievink WI
      • Prakash UBS
      • Piepgras DG
      • Mokri B
      α1-Antitrypsin deficiency in intracranial aneurysms and cervical artery dissection.
      a ruptured intracranial aneurysm was found in 1 patient with the PI*ZZ and 2 with the PI*MZ (or PI*GZ) phenotype. An additional PI*MZ heterozygote had spontaneous dissection of the cervical internal carotid artery. These findings can be considered suggestive but not yet definitive.

      Mayo Study.

      Further evidence of arteriopathy associated with α1-AT deficiency is reported by Schievink and associates in the current issue of the Mayo Clinic Proceedings (pages 1040 to 1043). Of 6,696 patients in whom postmortem examination was done, 6 were recorded as having α1-AT deficiency (4 ZZ, 1 MZ, and 1 not tested). Arterial fibromuscular dysplasia (FMD) was found in two of these six patients, both with the PP*ZZ phenotype and with hepatic or pulmonary failure. This observation is important because FMD is found in approximately 12% of patients with spontaneous cervical artery dissection and up to 20% of those with ruptured intracranial aneurysms and thus may indicate an underlying arteriopathy. FMD may represent the response to damage of the vascular extracellular matrix, in some patients due to inadequate inhibition of proteinases.

      Conclusion.

      Several lines of evidence suggest that α1-AT is an important guardian of vascular tissue. Further studies need to be conducted. PI typing of series of patients with various types of aneurysms, and suitable control subjects, should be done. A history of smoking should especially be elicited because smoking can inactivate α1-AT through reduction of a crucial methionine at the active site.
      • Johnson D
      • Travis J
      The oxidative inactivation of human α-1-proteinase inhibitor: further evidence for methionine at the reactive center.
      The incidence of FMD, or overt arterial disease, is not easily determined because of the need for autopsy, but the presence of FMD should be considered whenever autopsy is possible. Whether the extra stress of liver and lung disease have substantially contributed to vascular injury remains to be determined. The extent of capacity of α1-AT response to inflammation may well be a factor that precipitates severe arterial damage in at least some persons with the PI*MZ or PI*ZZ phenotype.

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