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

hepatitis, poor growth, and hepatomegaly (or splenomegaly). As people with AATD age, more genotypes are at risk of even more severe symptoms. The PiZZ genotype is still at the most risk; however, the PiMZ and PiSZ genotypes can expect some complications if little to no care is taken in regards to liver and lung health. Older individuals with AATD can experience both liver and lung complications. However, lung issues are far more common symptom. Overall, individuals with genotypes other than PiZZ can expect to live a normal lifespan; however, those with the PiZZ genotype are likely to have a shortened lifespan as a result of severe liver and lung complications1 .

Lung Disease in Individuals With AATD

The most frequent complication with AATD in general is Chronic Obstructive Pulmonary Disease (COPD). Individuals with AATD experience a 50% increased risk of developing COPD especially in cases of smokers and those with the PiZZ genotype1 . Additionally, there is a 50% increased risk of hospitalization from COPD for those with AATD.1 In individuals with COPD caused by AATD, their symptoms are generally exacerbated drastically, and then hold steady from some time before being exacerbated again. Higher levels of elastase have been observed before and after these exacerbations, leading researchers to believe that elastase is the cause of these exacerbations.1 As it relates to emphysema, the same trend was observed. Individuals with homozygous null mutations for AATD (PiSS or PiZZ) were shown to experience more severe forms of emphysema. A study conducted by L. Fregonese, J. Stolk, R. Frants, and B. Veldhuisen5 displayed a clear link between homozygous AATD null mutations and the severity of emphysema. This increased severity correlated directly with both age and smoking history. Older subjects experienced significantly worsened emphysema as well as those who were either smokers or ex-smokers. As a result, the study concludes that patients with AATD homozygous null/null mutations “should be considered a subgroup at particularly high risk of emphysema within AATD.”5 The specific mechanism by which AATD increases the risk of COPD and emphysema is not yet fully understood6 . Patients with AATD experience higher levels of three enzymes believed to be linked to the increased risk of disease: macrophage elastase, interstitial collagenase, and cysteine proteases. Most research seeking to further the understanding of the effects AATD has on lung disease has been conducted in genetically altered mice. Thus, while researchers believe these studies give insight into the mechanism by which AATD causes and worsens lung disease in humans, it is worth noting that there are likely discrepancies in how this deficiency affects mice and humans. The most thoroughly understood of these enzymes is elastase. It appears that the macrophage elastase causes airway neutrophil to obstruct the airways in the lungs (see figure 2).1

Figure 2. shows the current model for the mechanism by which AATD leads to emphysema. 1

Overtime this buildup leads to conditions like COPD and emphysema as the elastase is not regulated properly by alpha-1 antitrypsin7 .

Liver Disease in Individuals with AATD

Liver disease in individuals with AATD is far less common but still a significant risk factor associated with the condition. The two most common liver diseases associated with AATD are cirrhosis and fibrosis, with 31% of AATD patients dying with cirrhosis (although not necessarily from cirrhosis.) in extreme cases of AATD (mostly affecting those with the PiZZ genotype) where individuals can expect liver failure later in life.2 In the US approximately 60-90 liver transplants are conducted annually for individuals with PiZZ AATD2. These are not only conducted after liver failure, but in some cases, transplants are used as a curative measure in younger people with the PiZZ genotype and severely low levels of alpha-1 antitrypsin.2 Finally, there has been a suggested link between AATD and hepatocellular carcinoma. Problematically, however, there is a lack of population-based controls, making it hard to definitively state the magnitude of the risk increase. The mechanism by which AATD increases the risk of liver disease is much better understood than its effects on lung disease. Liver disease is caused not by a lack of alpha-1 antitrypsin, but by the buildup of the Z polymer of antitrypsin. As the Z polymer builds up in the endoplasmic reticulum of hepatocytes, liver cells die (see figure 3).

1 Teckman, Jeffrey H., and Nisha Mangalat. "Alpha-1 antitrypsin and liver disease: mechanisms of injury and novel interventions." Expert Rev. Gastroenterol. Hepatol., pp. 1-6. 2 Stolk, Jan. "Alpha-1-antitrypsin deficiency." Dept of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands., pp. 1+. 3 Serres, F., and I. de Blanco. "Role of alpha-1 antitrypsin in human health and disease." Journal of Internal Medicine, pp. 1-9. 4 Fairbanks, Kyrsten D., and Anthony S. Tavill. "Liver Disease in Alpha 1-Antitrypsin Deficiency: A Figure 3. shows the buildup of Z polymer antitrypsin in the hepatocytes, leading to cellular death and liver disease. (Z polymer is stained pink)2

Treatment for liver disease caused by AATD is not specific. Most doctors utilize standard treatments for liver disease. The focus of treatment is primarily on mitigating symptoms. The symptoms include but are not limited to: portal hypertension, bleeding, ascites, pruritus, malnutrition, fat soluble vitamin deficiency, hepatocellular carcinoma, and growth disturbances (in younger children). 2

Conclusions

Alpha-1 antitrypsin deficiency leads to an increased risk for long term complications in both the liver and lungs. Because the general understanding of how AATD impacts lung disease is limited, further research should be conducted, especially as it relates to treatment. As a final note, research into the ability to undo the improper folding of the Z antitrypsin using a single peptide is currently underway and could solve problems associated with the disorder1. However, in the meantime symptom mitigation will likely remain the focus of scientific inquiry.

Review." American Journal of Gastroenterology, 2008, pp. 1-5. 5 Fregonese, Laura, et al. "Alpha-1 antitrypsin Null mutations and severity of emphysema." Respiratory Medicine, pp. 1-8. 6"Emphysema." Mayo Clinic, www.mayoclinic.org/diseasesconditions/emphysema/symptomscauses/syc-20355555. Accessed 1 May 2022. 7 "Chronic Obstructive Pulmonary Disease (COPD)." Centers for Disease Control and Prevention