Alpha 1-antitrypsin deficiency pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Overview
Alpha-1 antitrypsin (AAT) is a type of protein called a "protease inhibitor." It is made in the liver and it works to protect the lungs and liver. AAT deficiency means there is not enough of this protein in the body. It is caused by a genetic defect in the formation of the 14th chromosome. Additional environmental factors such as smoking may influence the pathophysiologic outcome.
Pathophysiology
- Alpha 1-antitrypsin (A1AT) is synthesized and secreted mainly by hepatocytes.
- However, other sources of the enzyme include macrophages and bronchial epithelial cells. and one of its functions is to protect the lungs from proteases like the neutrophil elastase enzyme.
- Alpha1-antitrypsin enzyme is a member of the serine protease inhibitor (serpin) family of proteins. Functions of alpha1-antitrypsin include inhibition of pancreatic trypsin, and other proteinases including neutrophil elastase, cathepsin G54 and proteinase 3.
- Genetic mutation in the SERPINA1 gene results in decreased levels of alveolar alpha1 antitrypsin. Proteases accumulate in the alveoli causing a destruction of alveolar walls and resultant emphysema. Excess alpha1-antitrypsin in hepatocytes results in chronic liver disease.
Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 gm/l. In individuals with PiSS, PiMZ and PiSZ phenotypes, blood levels of A1AT are reduced to between 40 and 60 % of normal levels. This is sufficient to protect the lungs from the effects of elastase in people who do not smoke. However, in individuals with the PiZZ phenotype, A1AT levels are less than 15 % of normal, and patients are likely to develop emphysema at a young age; 50 % of these patients will develop liver cirrhosis, because the A1AT is not secreted properly and instead accumulates in the liver. A liver biopsy in such cases will reveal Periodic acid-Shiff (PAS)-positive, diastase-negative granules.
Cigarette smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammatory reaction in the airways, cigarette smoke directly inactivates alpha 1-antitrypsin by oxidizing essential methionine residues to sulfoxide forms, decreasing the enzyme activity by a rate of 2000.
Genetics
Alpha1-antitrypsin deficiency (AATD) is inherited in an autosomally-codominant pattern caused by mutations in the SERPINA1 gene.The alpha-1 AT gene has been located on the long arm of chromosome 14 and has been successfully been sequenced and cloned. There have been 120 different alleles for alpha-1 AT variants that have been described, but only 10-15 are associated with severe alpha-1 deficiency. Each allele has been given a letter code based upon electrophoretic mobility. SERPINA1 gene mutation alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule. This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency. The 75 alleles can basically be divided into four groups:
- Normal – M alleles (normal phenotype is MM), found in 90% of the U.S. population, patients have normal lung function.
- Deficient – Z allele (carried by 2-3% of the U.S. Caucasian population), have plasma levels of alpha-1 AT that is < 35% of normal.
- Null – No detectable alpha-1 AT. Least common and most severe form of the disease.
- Dysfunctional – Patients have a normal alpha-1 AT level, but the enzyme does not function properly.
Molecular Biology
- Crystal structure of alpha1-antitrypsin enzyme is composed of three β sheets (A, B, C) and an exposed mobile reactive loop with a peptide sequence as a pseudosubstrate for the target proteinase enzyme. This loop consists of amino acids within this loop are the PI–PI′ residues, methionine serine, as these are binding sites for neutrophil elastase.
- The Alpha-1 AT molecule is an acute phase glycoprotein
- Alpha-1 AT is the protease inhibitor in highest concentration in human plasma, and although it is a good inhibitor of trypsin, its primary physiologic target is neutrophil elastase. Alpha-1 AT belongs to the serpin class of serine protease inhibitors, and is synthesized and secreted primarily by hepatocytes, but also the mononuclear phagocytes. Other examples of the serpin class of protease inhibitors include antithrombin, C1-inhibitor, and the many inhibitors of plasminogen. The serine protease inhibitors have a unique ability to undergo a conformational change. An advantage of this molecular mobility is that it enables the inhibitor to snare its target protease and tightly entrap it, forming a complex that can remain stable for hours. A potential disadvantage, however, is that it makes the serpins more than usually vulnerable to dysfunctional mutations.
Associated Conditions
α1-antitrypsin deficiency has been associated with a number of diseases:
- COPD
- Asthma
- Wegener's granulomatosis
- Pancreatitis
- Gallstones
- Bronchiectasis (possibly)
- Prolapse[3]
- Primary sclerosing cholangitis
- Autoimmune hepatitis
- Emphysema
- Cancer