AATD: What Happens When the Healthy Liver-Lung Connection is Under Siege?

If the body were a castle, then the alpha-1 antitrypsin (AAT) protein would be one of its drawbridges. AAT is synthesized by the liver and connects that organ with the lungs. AAT also protects lung tissue against attack by the proteolytic enzyme neutrophil elastase.

But a failure of the drawbridge can happen in the form of AAT deficiency (AATD), allowing diseases of the liver and/or lungs—cirrhosis, fibrosis, hepatocellular carcinoma (HCC), emphysema, chronic obstructive pulmonary disease (COPD)—to capture the castle.

In the pediatric population, AATD "can present insidiously with liver disease," they noted, explaining that for neonates, liver disease is generally cholestatic and can include symptoms of prolonged cholestatic jaundice, pruritus, and poor feeding and weight gain. While most children with AATD can recover clinically, about 5% will ultimately require liver transplantation, usually by age 4 years, they said.

In the lungs, the enzyme neutrophil elastase "can cleave many of the structural proteins…as well as innate immune proteins," explained David Lomas, ScD, of the Rayne Institute/University College London, and co-authors in The New England Journal of Medicine. "In the classic loss-of-function concept, the Z form of AAT fails to reach the lung in sufficient quantities and takes longer to inhibit neutrophil elastase."

While children can certainly experience AATD-related lung conditions, "[l]ung disease due to AAT deficiency may become apparent at any age in adulthood," Quiros’ group said. In smokers, the oxidants in cigarette smoke can further hobble Z AAT, "by oxidizing its active-site methionines and increasing polymerization, both of which render it unable to inhibit neutrophil elastase. This illustrates the pivotal role of smoking in AAT deficiency, which contributes to earlier and more severe lung disease," they noted. Not surprisingly, AATD is strongly linked with COPD and emphysema in smokers.

Smoking habits aside, AATD is an inherited disorder, and in these cases, the "clinical manifestations of lung disease associated with [AATD] are mainly indistinguishable from those of nonhereditary emphysema," Lomas’ group explained. "This is partly why severe [AATD] remains undiagnosed in approximately 90% of cases, with an interval of 5 to 7 years from the onset of symptoms to diagnosis." They noted that even in in young people with COPD, AATD "is often diagnosed late, at a point when the lung disease has become irreversible".

While lung disease generally does not present clinically until adulthood, pediatric patients with AATD should be counseled about the danger of cigarette smoking, second-hand smoke exposure, and heavy air pollution. They also "should be referred to a pulmonologist by 18 years of age to establish baseline pulmonary function," advised Amy Feldman, MD and Ronald J. Sokol, MD, both of Children’s Hospital Colorado in Aurora in Lung Health Prof Mag.

AATD has two primary genotypes: mild or moderate PI*MZ and more severe PI*ZZ. On a global level, it’s been estimated that more people have the PI*MZ genotype versus the PI*ZZ genotype. Management for individuals with the PI*MZ genotype is less clear than management of those with the PI*ZZ, pointed out Marc Miravitlles, MD, of the Hospital Universitari Vall D’Hebron in Barcelona, and Igor Barjaktarevic, MD, PhD, of the University of California Los Angeles in a pro/con "debate" published in BMC Pulmonary Medicine

Guidelines

Guidelines for diagnosis and management of AATD come from the COPD Foundation/Alpha-1 Foundation (COPD/Alpha-1) and the American Thoracic Society/ERS (ATS/ERS). People who produce normal levels of alpha1-PI are PI*MM (M allele), so it needs to be established if the AATD is PI*ZZ (Z allele for insufficient alpha1-PI) or PI*MZ (a combination of M and Z alleles).

ATS/ERS cautions that PI*ZZ AATD can be "underrecognized or misdiagnosed by clinicians." That group called for assessing patient symptoms or disorders—for example, emphysema at ages ≤45 or unexplained liver disease—and then following up with genetic testing and, when appropriate, pulmonary function testing, CT imaging, and/or testing for liver disease.

COPD/Alpha-1 warns that "[s]ome individuals with AATD have normal pulmonary function at the time of diagnosis," so "[h]igh value is placed on detecting the accelerated rate of lung function loss early in the disease process. Low value is placed on the cost of lung function testing."

For AATD management, COPD/Alpha-1 states that intravenous (IV) AAT augmentation therapy for patients with AATD and a forced expiratory volume in 1 second (FEV₁) in the range of 30%-65% predicted is strongly recommended. ATS/ERS points out that augmentation therapy is not currently the best treatment path for patients with AATD who do not have emphysema. In addition, the value of augmentation therapy in those with FEV₁ 35% predicted or FEV₁ 50%-60% predicted is uncertain, and "physicians are advised to discuss the cost of the therapy with potential AATD individuals with FEV₁ >65%" according to a guideline review in Rare Disease Advisor.

Guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) highlight that adverse events (AEs) in the various trials of augmentation therapy were generally mild and manageable, but they add that in one observational study, patients who received weekly IV AAT reported a higher rate of total adverse events (AEs) versus those who received treatment every two to three weeks, or even monthly. However, GOLD supports a steady weekly dosing schedule, as "[t]hese biweekly and monthly dosing intervals have been shown to result in trough serum AAT concentrations slightly below the 11 μM target threshold for augmentation therapy, and therefore, fixed weekly dosing should be recommended unless other dosing scenarios are absolutely necessary."

Robert A. Sandhaus, MD, PhD, of National Jewish Health in Denver, and co-authors writing in COPD, added that "[s]hort-term lifestyle considerations may prompt alternate dosing regimens, such as allowing an individual to enjoy a two-week vacation at a distant location by administering a double dose just before departure." However, they also warned that there "have been no dose-ranging studies completed to establish the appropriate dose based on clinical endpoints."

Canadian Thoracic Society guidelines warn that there "is ongoing debate regarding clinically meaningful end points in assessing the response to…augmentation therapy," although one cross-sectional study indicated that CT scan lung density correlated with FEV₁, airway conductance, gas-trapping, transfer factor, and health status. The authors said that CT scan lung density may be a better predictor of mortality versus lung function parameters in this patient population.

There’s more certainty about who most likely will not benefit from IV augmentation therapy, such as AATD patients undergoing active treatment for liver disease; non-smoking patients with the PI*MZ phenotype who generally have a lower risk for lung disease; and some patients with diagnosed bronchiectasis, although it may depend on if AATD is the reason for the condition or other etiologies, such as allergic bronchopulmonary aspergillosis.

Other Therapies

In patients with AATD, the management of symptomatic lung disease is generally similar to that for COPD without AATD, and that can include inhalers, pulmonary rehabilitation, and smoking cessation. Barjaktarevic and Michael Campos, PhD, also of UCLA, emphasized that, "[r]adiologically, augmentation therapy reduces lung density loss over time, thus delaying disease progression. The effect of augmentation therapy on other lung-related outcomes, such as exacerbation frequency/length, quality of life, lung function decline, and mortality, are less clear and questions regarding dose optimization or route of administration are still debatable."

Lung volume reduction surgery (LVRS) or lung transplant are possible in patients who develop advanced or end-stage lung disease. Martin R. Zamora, MD, of the University of Colorado in Aurora, and Ali Ataya, MD, of UFHealth in Gainesville, Florida, explained that "data suggest that survival rates for lung transplantation are significantly higher for patients with AATD-related [COPD] compared with non-AATD-related COPD, but, conversely, there is a higher risk of common post-lung transplant complications in patients with AATD versus non-AATD COPD." For LVRS, an ERS statement pointed out that endobronchial valves (EBV) and endobronchial coils are the "best evaluated devices" in patients with "specific patterns of emphysema," but that patient selection should be done by a multidisciplinary team.

Augmentation Therapy

In their BMC Pulmonary Medicine paper, Miravitlles and Barjaktarevic explained that the "only specific treatment for lung disease associated with severe AATD is the IV infusion of AAT augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals." But they also emphasized that there was no targeted "evidence for the clinical benefit of AAT therapy in PI*MZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PI*MZ individuals."

In augmentation therapy, AAT is purified from human plasma and delivered via IV to raise the serum and alveolar epithelial lining fluid levels and keep them at >11 μM and >1.2 μM, respectively, for about five days. "These levels were defined as protective thresholds by the FDA and the European regulatory agencies," explained David T. Curiel, MD, PhD, and Reka Lorincz, PhD, both of Washington University in St. Louis, in the American Journal of Respiratory Cell and Molecular Biology (AJRCMB).

An IV alpha1-proteinase inhibitor was FDA approved for augmentation therapy in 2002 and works by increasing "antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of Alpha1-PI," according to the package insert.

Since that approval, several additional augmentation therapies have hit the market and been vetted in various studies—EXACTLE, RAPID, a 2002 Chest study, a 2014 COPD study—noted the 2017 ERS statement.

Those authors pointed out that "there is the unusual situation where augmentation has been advocated (and given) for some time on the basis of biochemical effect (namely raising AAT level) and hence has become established as treatment in many areas of the world, without the level of evidence now expected for respiratory outcomes such as FEV1, quality of life, and mortality." Still, they acknowledged that "the fact that CT density has been shown in cross-sectional and longitudinal studies to relate well to other clinical outcomes, such as mortality and quality of life indicates that it is a clinically relevant measure," for patients getting augmentation.

Turner and co-authors looked at 52 trials (n=5,632 participants) with studies grouped into "four management themes: COPD medical, COPD surgical, AATD specific, and other treatments," and ultimately reported that IV augmentation therapy "slows decline in emphysema determined by CT density…augmentation remains the primary disease-specific therapy." They added that dosing regimens in the studies they reviewed ranged from weekly to monthly with most using 60 mg/kg/week.

Also under investigation is mesenchymal stem cell and recombinant AAT fused with Fc (AAT-Fc) to repair damaged lung tissue in experimental emphysema or to generate normal serum AAT.

Curiel and Lorincz wrote in AJRCMB that "pulmonary endothelium-targeted adenovirus vector could be a key technical mandate to achieve local augmentation of AAT within the lower respiratory tract, with the potential benefit of circumventing liver toxicities." They noted that the incorporation of the CRISPR-associated protein 9 (CRISPR/Cas9) nuclease system into gene-delivery technologies "has provided adjunctive technologies that could fully realize a one-time treatment for sustained, lifelong expression of AAT in patients with AATD."

Sandhaus reported support from, and/or relationships with, CSL Behring, Alpha-1 Foundation, AlphaNet, and the COPD Foundation. Co-authors reported support from, and/or relationships with multiple entities.

The Canadian Thoracic Society reported support from the Canadian Institutes of Health Research, AstraZeneca Canada, Boehringer Ingelheim Canada, GSK, Pfizer, and Talecris.

Sandhaus RA, et al "The diagnosis and management of alpha-1 antitrypsin deficiency in the adult" Chronic Obstr Pulm Dis 2016; 3(3): 668-682. DOI: 10.15326/jcopdf.3.3.2015.0182.

ATS/ERS "American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency" Am J Resp Crit Care 2003; DOI: 10.1164/rccm.168.7.818.

Miravitlles M, et al "European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α₁-antitrypsin deficiency" Eur Respir J 2017; 50: 1700610. DOI: 10.1183/13993003.00610-2017.

Marciniuk DD, et al "Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: A Canadian Thoracic Society clinical practice guideline" Can Respir J 2012; 19(2): 109-116.