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

Pathophysiology

• Alpha 1-antitrypsin (A1AT) is synthesized and secreted mainly by hepatocytes. However, other sources of the enzyme include macrophages and bronchial epithelial cells.
• 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 G and proteinase 3. Alpha 1-antitrypsin (A1AT) protects the lungs from proteases like the neutrophil elastase enzyme.
• 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.
• The Z mutation results in a conformational change in the alpha 1 antitrypsin molecule. The β sheet opens leaving it susceptible to interaction with another alpha 1 antitrypsin molecules to form a dimer or a polymer. These polymers get trapped in the endoplasmic reticulum.The Z mutation causes most of the unstable protein to form polymers.
• Cigarette smoking is an important risk factor in the development of the lung disease associated with AAT deficiency. The protease-antiprotease imbalance in the lung has a major consequenc, 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.
• The protease-antiprotease imbalance in the lung has a major effect. In Z-variant of AAT deficiency, there is less AAT in the lung. The AAT that is present is 5 times less effective than normal AAT. The residual AAT is susceptible to inactivation by oxidation of the P1 methionine residue by free radicals from leukocytes or direct oxidation by cigarette smoke. The Z AAT also favors the formation of polymers in the lung. ZAAT-deficient patients have excess neutrophils in lavage fluid and in tissue sections of the lung possibly related to the chemoattractant effect of an excess of leukotriene B4 (LTB4) and interleukin (IL)-8 and the polymers themselves. These circumstances of unopposed proteolytic enzyme activity and an increase in inflammatory conditions cause the trademark emphysema of this disease.

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 (gene locus:14q32.1) and has been successfully been sequenced and cloned. The SERPINA1 gene has six introns, seven axons and 12.2kb in length. 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 that varies according to protein charge from amino acid alterations on gel electrophoresis that is used to identify the PI phenotype. 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.

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.

Differences in speed of migration of different protein variants on gel electrophoresis have been used to identify the PI phenotype, and these differences in migration relate to variations in protein charge resulting from amino acid alterations (Fig. 1).43 The M allele results in a protein with a medium rate of migration; the Z form of the protein has the slowest rate of migration. Some individuals inherit null alleles that result in protein levels that are not detectable. Individuals with a Z pattern on serum isoelectric focusing are referred to as phenotype PIZ (encompassing both PIZZ and PIZnull genotype variants). The S variant occurs at a frequency of 0.02–0.03 and is associated with mild reductions in serum AAT levels. The Z variant is associated with a severe reduction in serum AAT levels. The most common alleles are the M variants with allele frequencies of greater than 0.95 and normal AAT levels

Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 gm/l.

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
  • Hepatocellular carcinoma (liver)
  • Bladder carcinoma
  • Gallbladder cancer
  • Lymphoma
  • Lung cancer

Gross Pathology

Microscopic Pathology

References

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