Liver and Lung Disease as a Result of Alpha-1 Antitrypsin Deficiency Dylan Luchsinger
Abstract: Alpha-1 Antitrypsin Deficiency is a generally underdiagnosed condition where there is a lack of the alpha-1 antitrypsin protein in the bloodstream1. This is caused by multiple genetic mutations, the most common of which being the Z and S mutations of the 14th chromosome.2 The deficiency leads to complications in both the lungs and liver, generally manifesting themselves in older individuals with the homozygous PiZZ mutation. This review will cover the function of alpha-1 antitrypsin as well as its effects on lung and liver disease. The Role of Alpha-1 Antitrypsin in the Body: Alpha-1 antitrypsin is a glycoprotein synthesized in the liver. Its function is to protect organ tissue from damage caused by neutrophil elastase. Neutrophil elastase is released into the lungs when inflamed or undergoing phagocytosis. Elastase that is released non-specifically poses a threat to the tissue of the lungs by causing lung blockages.2 In response, Alpha-1 Antitrypsin attaches to and is split by elastase, which deactivates the elastase by altering the active site, preventing it from causing blockages in the lungs2. Alpha-1 Antitrypsin Deficiency (AATD) Alpha-1 antitrypsin deficiency is the product of a number of mutations of chromosome 142. The two most prevalent genes related to AATD are delineated as the “Z” and “S” mutations. The Z mutation is the mutation primarily responsible for both liver and lung disease, specifically the homozygous PiZZ genotype. The normal manifestation of this gene is the PiMM genotype.3 AATD is most
common amongst Caucasians, affecting around one in 3,000-5,000 people. The mechanism behind AATD varies depending upon the specific genetic mutation. Rarer mutations have been found that completely inhibit the production of alpha-1 antitrypsin, causing greater harm to individuals with this mutation2. The standard Z and S mutations, however, cause the improper folding of alpha-1 antitrypsin which prevents its export from the endoplasmic reticulum. The newly formed alpha-1 antitrypsin undergoes a rapid reaction which bonds the center loop of one antitrypsin molecule to the beta sheet of another. This forms a long polymer of Zalpha-1 antitrypsin which builds up in the endoplasmic reticulum of hepatocytes.4 This decreases the levels of alpha-1 antitrypsin both by reacting the molecule into the Z polymer, which is unusable, and by clogging affected hepatocytes and preventing the release of usable alpha-1 antitrypsins.4
Figure 1. The structure of the Z polymer is formed with two alpha-1 antitrypsin molecules. 1 Diagnosis and Symptoms AATD is difficult to spot in young children as the complications associated with the disorder do not manifest themselves until later in life. Young children with AATD can expect a completely normal life. However, in extreme cases, inhibited growth can occur. In older children with the most severe PiZZ genotype, symptoms include chronic 13
