March 28, 2015
Alpha-1-antitrypsin (AAt) is a serine protease inhibitor produced primarily in the liver. AAt deficiency, which affects males and females equally, is inherited in an autosomal codominant fashion and primarily results in liver disease, lung disease or both.
The skin is rarely affected, resulting in panniculitis. During the first two to three decades of life, AAt deficiency is primarily a liver disorder that can present as neonatal cholestasis, hepatitis and cirrhosis. Lung disease presents typically after the third decade of life with accelerated panacinar emphysema predominantly affecting the lung bases. Bronchiectasis and asthma also have been linked to AAt deficiency.
AAt deficiency occurs when a single point mutation in the AAt gene results in misfolding and polymerization of the mutated AAt protein within the hepatocytes, according to an article published by Michael J. Krowka, M.D., and others in the Journal of Hepatology in 2013. About 80 to 90 percent of this misfolded-polymerized AAt protein is retained within the rough endoplasmic reticulum of the hepatocyte, resulting in two problems:
- Cellular injury (hepatitis) and eventual cirrhosis due to the toxic effects of the retained AAt protein
- Significantly reduced AAt serum levels due to this hepatocyte retention and lack of secretion
This circulating serum AAt deficiency results in unopposed neutrophil elastase activity, progressive lung destruction and emphysema. Such lung destruction is dramatically accelerated in individuals with AAt deficiency who are smokers. Normal AAt levels can be achieved by exogenous AAt supplementation and can maintain the delicate balance between protease (neutrophil elastase) and anti-protease (AAt) activity in the lung.
Mayo Clinic is recognized as a Clinical Resource Center by the Alpha-1 Foundation. Patients suspected of having AAt deficiency should be referred to such centers for evaluation and management recommendations. Such patients would include those individuals with liver dysfunction and early-stage chronic obstructive lung disease or asthma that does not respond to treatment. Family members also may request consultation to check on their AAt status and to assess end-organ disease.
The laboratory evaluation includes serum alpha-1-antitrypsin level measurement (normal 100 to 190 mg/dL). It is thought that levels less than 57 mg/dL predispose to accelerated lung damage. Routine Mayo testing includes state-of-the-art AAt proteotype assessment by liquid chromatography-tandem mass spectrometry to discern normal protein variants (M variant) from specific AAt disease variants such as Z and S variants.
Same-day consultation, state-of-the-art pulmonary function testing and imaging studies (chest CT scan with 3-D reconstruction), liver ultrasound, and a noninvasive MRI-based technique to detect liver fibrosis (MR elastography) are available to guide clinical management decisions and recommendations.
AAt-related treatment options
The lung manifestations may be slowed by correcting the serum deficiency with intravenous replacement of the AAt protein from human pooled plasma (augmentation therapy). Currently, there are four commercial Food and Drug Administration-approved products available. The infusions are accomplished weekly or biweekly and conducted either at infusion centers or at the patient's home. Specific guidelines exist as to which patients should receive and will benefit most from these expensive therapies (over $75,000 a year).
Severe AAt deficiency may lead to advanced emphysema, causing hyperinflation and severe expiratory flow obstruction with or without airway hyperreactivity. In selected individuals, bullectomy or lung volume reduction surgery may be recommended. For others, bronchoscopically placed one-way endobronchial valves are designed to decrease air trapping and emphysema.
Some patients may be candidates for lung transplantation, which can more than double survival rates in those with the ZZ genotype, as published by Hanan A. Tanash, M.D., and others in The Journal of Heart and Lung Transplantation in 2011.
The liver manifestations of AAt accumulation (and abnormal degradation) in hepatocytes may lead to cirrhosis and the need for liver transplantation. These individuals may or may not have coexisting lung manifestations of AAt deficiency.
Mayo investigators recently published the largest series to date describing outcomes following liver transplantation in 73 patients with severe AAt deficiency and cirrhosis. The one-, three- and 10-year post-transplant survivals were 91 percent, 86 percent and 79 percent, respectively. Of interest, a subgroup of patients continued to experience accelerated lung function decline even after liver transplantation.
Prospective studies are being planned to better understand the impact of liver transplantation (with resulting normalization of serum AAt levels) and subsequent lung function outcomes, according to an article published by Elizabeth J. Carey, M.D., of Mayo Clinic's campus in Arizona, and others in Liver Transplantation in 2013.
Basic science and clinical research in AAt deficiency is ongoing and described on the Alpha-1 Foundation website at www.alpha1portal.org. In addition, The Alpha-1 Project (TAP), which is a subsidiary owned by the foundation, is designed to fund and facilitate the commercialization of lung- and liver-related therapeutic discoveries. Mayo Clinic is active in screening studies and participating in multicenter treatment trials conducted for patients with AAt-related lung disease, liver disease or both. Mayo is currently facilitating participation in a multicenter inhaled alpha-1 protein research study.
Regarding AAt-related liver disease, Mayo is participating in a multicenter trial using carbamazepine as a medication to facilitate unfolding of the accumulated AAt protein within the hepatocytes, thus increasing the serum levels.
For more information
Krowka MJ, et al. Pulmonary contraindications, indications and MELD exceptions for liver transplantation: A contemporary view and look forward. Journal of Hepatology. 2013;59:367.
Tanash HA, et al. Survival benefit of lung transplantation in individuals with severe alpha-1-anti-trypsin deficiency (PiZZ) and emphysema. The Journal of Heart and Lung Transplantation. 2011;30:1342.
Carey EJ, et al. Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency-related cirrhosis. Liver Transplantation. 2013;19:1370.
Kamada Ltd. Phase II, Safety and ELF Study of "Kamada-API for Inhalation." ClinicalTrials.gov.