page_title: Alpha-1 antitrypsin
section_title: Role in disease
hierarchical_section_title: Alpha-1 antitrypsin / Role in disease
caption_attribution_description: English: Alpha 1-antitrypsin (white) with highlighted 'reactive centre loop' (blue) and A-sheet (light blue). (PDB: 1QLP)
context_page_description: Alpha-1 antitrypsin or α₁-antitrypsin is a protein belonging to the serpin superfamily. It is encoded in humans by the SERPINA1 gene. A protease inhibitor, it is also known as alpha₁–proteinase inhibitor or alpha₁-antiproteinase because it inhibits various proteases. In older biomedical literature it was sometimes called serum trypsin inhibitor, because its capability as a trypsin inhibitor was a salient feature of its early study. As a type of enzyme inhibitor, it protects tissues from enzymes of inflammatory cells, especially neutrophil elastase, and has a reference range in blood of 0.9–2.3 g/L, but the concentration can rise manyfold upon acute inflammation. When the blood contains inadequate amounts of A1AT or functionally defective A1AT, neutrophil elastase is excessively free to break down elastin, degrading the elasticity of the lungs, which results in respiratory complications, such as chronic obstructive pulmonary disease, in adults. Normally, A1AT leaves its site of origin, the liver, and joins the systemic circulation; defective A1AT can fail to do so, building up in the liver, which results in cirrhosis in either adults or children.
context_section_description: Disorders of this protein include alpha-1 antitrypsin deficiency, an autosomal codominant hereditary disorder in which a deficiency of alpha-1 antitrypsin leads to a chronic uninhibited tissue breakdown. This causes the degradation especially of lung tissue and eventually leads to characteristic manifestations of pulmonary emphysema.  Evidence has shown that cigarette smoke can result in oxidation of methionine 358 of α₁-antitrypsin (382 in the pre-processed form containing the 24 amino acid signal peptide), a residue essential for binding elastase; this is thought to be one of the primary mechanisms by which cigarette smoking (or second-hand smoke) can lead to emphysema. Because A1AT is expressed in the liver, certain mutations in the gene encoding the protein can cause misfolding and impaired secretion, which can lead to liver cirrhosis.
  An extremely rare form of Pᵢ, termed PᵢPittsburgh, functions as an antithrombin (a related serpin), due to a mutation (Met358Arg). One person with this mutation has been reported to have died of a bleeding diathesis.
  A liver biopsy will show abundant PAS-positive globules within periportal hepatocytes.
  Patients with rheumatoid arthritis (RA) have been found to make autoantibodies toward the carbamylated form of A1AT in the synovial fluid. This suggests that A1AT may play an anti-inflammatory or tissue-protecting role outside the lungs. These antibodies are associated with a more severe disease course, can be observed years before disease onset, and may predict the development of RA in arthralgia patients. Consequently, carbamylated A1AT is currently being developed as an antigenic biomarker for RA.
caption: Alpha-1 antitrypsin (white) with highlighted 'reactive centre loop' (blue) and A-sheet (light blue). (PDB: 1QLP)
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