Continuing Education Activity

Alpha-1 antitrypsin is a protease inhibitor produced primarily in the liver. It inhibits the neutrophil elastase activity in the lung and protects it from proteolytic damage. It is responsible for approximately 90% of the protection against elastolytic activity in the lower airways caused by elastase released from neutrophils. If the neutrophils' elastases are not opposed, panacinar lung tissue is damaged, increasing the risk of developing chronic obstructive pulmonary disease (COPD). On the other hand, the retention and accumulation of mutated polymers in the endoplasmic reticulum of hepatocytes renders individuals with this disease at risk of "a gain of toxic function," leading to liver disease. This activity reviews the evaluation and management of alpha-1 antitrypsin mutation. It highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes in caring for patients with this rare condition.

Objectives:

• Identify the etiology and epidemiology of alpha 1 antitrypsin deficiency.

• Assess the evaluation of alpha-1 antitrypsin deficiency.

• Differentiate the treatment and management options available for alpha-1 antitrypsin deficiency.

• Communicate the interprofessional team strategies for improving care coordination and communication to advance alpha-1 antitrypsin deficiency management and improve outcomes.

Introduction

Alpha-1 antitrypsin is a protease inhibitor (PI) produced primarily in the liver. It inhibits the neutrophil elastase activity in the lung and protects it from proteolytic damage. It is responsible for approximately 90% of the protection against elastolytic activity in the lower airways caused by elastase released from neutrophils. If the neutrophils' elastases are not opposed, panacinar lung tissue is damaged, increasing the risk of developing chronic obstructive pulmonary disease (COPD). On the other hand, the retention and accumulation of mutated polymers in the endoplasmic reticulum of hepatocytes renders individuals with this disease at risk of "a gain of toxic function," leading to liver disease.[1][2][3]

Etiology

Genetic mutations, also known as serpinopathies, in the serpin superfamily cause alpha-1 antitrypsin deficiency. The condition is autosomal codominant, which causes the affected individuals to have a homozygous or heterozygous mutation in the SERPINA1 gene located on the long arm of chromosome 14. The standard nomenclature to describe alpha-1 antitrypsin deficiency uses an acronym for PI along with the alleles that have been identified. The most common allele is associated with the normal function of alpha-1 antitrypsin and is labeled M. PI*MM, the most common homozygous allele. The most common deficiency alleles are Z and S. Uncommon deficiency alleles include I,  M, M, and null, as well as other rare ones. Polymerase chain reaction techniques detect specific DNA sequences that identify AAT alleles. The PI*Z allele, characterized by a single amino acid substitution of lysine for glutamic acid at position 342 on the 394 amino acid AAT molecule, is involved in approximately 95% to 96% of known clinical cases of severe AATD. Such amino acid substitution leads to the polymerization of the abnormally formed protein in the hepatocyte and lowers inhibitory function to neutrophil elastases in the lungs. The PI*S allele, which involves the substitution of valine for glutamic acid at position 264, is associated with accelerated degradation in hepatocytes but not an increased risk for liver disease. The homozygous condition PI*SS is not associated with clinical lung disease. Yet, approximately 10% of double heterozygous PI*SZ can be at risk of COPD if the AAT levels are below the reference range or if they are smokers.[4][5]

Epidemiology

Studies have shown that the most commonly found deficiency allele in alpha-1 antitrypsin deficiency is the PI*Z allele, which is more prevalent in northern and western Europe. In comparison, PI*S allele variants have a higher prevalence in southern Europe. The prevalence of the PI*ZZ deficiency allele accounts for 0.1% of the world population, while PI*SZ heterozygous allele deficiency represents about 0.7% of deficiency genotypes worldwide. Despite the relatively common appearance of these deficiency alleles, AATD is highly underdiagnosed, with fewer than 10% of the expected number of cases reported in the United States. The mean age when the disease was diagnosed was 41.3 years. As with other rare diseases, it often takes several doctors and many years before a diagnosis is made.[6][7]

History and Physical

Alpha-1 antitrypsin deficiency leads to COPD, liver disease, and panniculitis. Other studies have linked it to conditions such as glomerulonephritis and certain cancers. Other associations include celiac disease, fibromuscular dysplasia, and pancreatitis. Approximately 15% of patients with granulomatosis with polyangiitis are found to have a ZZ genotype.

Pulmonary Disease

Pulmonary clinical manifestations are similar to the COPD of other etiologies; however, it has some certain characteristics, such as early onset of symptoms, usually in the third or fourth decade, and on CT, the emphysematous involvement is mainly in the lung base. However, symptoms may not present until later, and the basilar changes may occur along with apical changes, thus making the symptoms or signs of ATTD similar to COPD unrelated to ATTD. Symptoms include dyspnea, cough, wheezing, and upper respiratory tract infections. Some risk factors, like cigarette smoking, exposure to burning biomass materials, and respiratory infections, can aggravate pulmonary symptoms. Such factors increase the unopposed elastase activity of neutrophils, leading to the destruction of lung tissue and, eventually, COPD.

Extrapulmonary Manifestations

The accumulation of the ZZ protein and the development of polymers leads to hepatitis in children, liver cirrhosis in adults, and an increase in the risk for hepatocellular carcinoma. Early in life, infants may develop clinical hepatitis, and AATD is the second most common cause of liver transplant in children. As childhood continues, liver inflammation subsides only to be replaced by smoldering inflammation in adults, leading to cirrhosis in some, which in the majority of cases is subclinical. A small fraction of adults progress to liver failure and need a liver transplant. Panniculitis is a rare presentation of the ZZ genotype and occurs in 1 per 1000 cases.

Evaluation

The American Thoracic Society and the European Respiratory Society have proposed that all patients with COPD, nonresponsive asthmatic adults, and adolescents, cryptogenic cirrhosis or liver disease without obvious etiology should be screened for alpha-1 antitrypsin deficiency using quantitative testing. Initial testing is done by determining alpha-1 antitrypsin serum levels. If serum levels are low, genotyping may be pursued. If the genotype and serum level are discordant, then phenotyping or genetic analysis can confirm the diagnosis. Chest radiographs and chest CT scans demonstrate emphysematous lung changes. Pulmonary function tests are also necessary to detect the expected decline in FEV1.[8][9]

Treatment / Management

Individuals with alpha-1 antitrypsin deficiency should avoid triggers that stimulate the unopposed neutrophil elastase activity, such as smoking and infections. Available vaccines that are important to prevent patient infections are pneumococcal polysaccharide vaccine, yearly influenza vaccine, protein conjugate pneumococcal vaccine, and tetanus-diphtheria-pertussis vaccine. Inhalers typically used for COPD should be prescribed and initially should include long-acting beta-agonists and or anticholinergics. Because of the increased risk of pneumonia, inhaled corticosteroids should be reserved for patients who develop frequent exacerbations despite the other two inhalers. Pulmonary rehabilitation, oxygen, and, in some circumstances, lung transplants should be prescribed as indicated. Transplant is usually reserved for those that fall below an FEV1 of 30% despite maximum therapy.

Augmentation Therapy

Augmentation therapy should not displace typical COPD therapies but instead should be used to preserve lung function. Augmentation includes an infusion of purified pooled human plasma alpha antitrypsin, which is infused IV weekly to increase and maintain serum alpha-1 antitrypsin levels near the threshold values but definitely above the critical threshold of 11 micrometers or 57 mg/dl that is thought to be essential to preserve lung function. Augmentation therapy is only indicated for patients who have severe alpha-1 antitrypsin serum deficiency and COPD. Augmentation therapy is infused to elevate alpha-1 antitrypsin levels in plasma to oppose the elastase activity of the neutrophils in the lungs, which protects the lung tissue from damage. The benefit of augmentation seems to be best in patients with FEV1 below 70% and an FEV1 above 30%, and because of these data, guidelines suggest using augmentation between these 2 FEV1 values. The Food and Drug Administration in the United States only approves augmentation therapy at 60 mg/kg weekly doses. Adverse effects of augmentation therapy are rare and include headache, nausea, dizziness, and very rarely anaphylaxis. Augmentation does not affect liver disease.

Surgery

The role of lung transplantation and its efficacy in alpha-1 antitrypsin deficiency patients is not yet established due to insufficient data. However, in 2013, the International Society for Heart and Lung Transplantation reported that COPD related to alpha-1 antitrypsin deficiency accounted for the fourth-highest percentage of lung transplants in the adult population between January 1995 and June 2012. A retrospective cohort study has shown that patients with alpha-1 antitrypsin deficiency who had bilateral lung transplantation have a faster rate of FEV1 decline than non-alpha-1 antitrypsin deficiency transplantation ones. Yet, both groups had a wide degree of similarity, including post-transplant FEV1 slope, the severity of acute cellular rejection, and survival rate. On the other hand, survival times were shown to be significantly longer in those who had the transplant compared to those who did not believe in very severe COPD (FEV1 below 30%). The limited data on lung volume reduction surgery have not been promising, and thus, this procedure is not recommended for alpha-1 antitrypsin deficiency patients.  Following the liver transplant, it has not been established whether the new liver secreting normal alpha-1-protein prevents the progression of lung disease. Unfortunately, for this reason, there is no consensus on whether alpha-1-protein augmentation should be administered to patients after lung transplant.

Future of Alpha-1 Antitrypsin

Treatment

Inhaled augmentation therapy

Inhalation offers an opportunity to target the treatment of the organ of interest, hence reducing the required dose of alpha-1-protein necessary to preserve lung function. Inhaled therapy reduces the amount of alpha-1 protein needed, reducing the cost. Also, inhaled therapy reduces the need for intravenous therapy and multiple injections per month, as well as associated adverse events. Data supporting this route of therapy are lacking, and until further studies are available, intravenous therapy should be the preferred route of augmentation.

Gene therapy

The problem with augmentation therapy is that it is costly and requires weekly to monthly IV infusions, which carry a risk of allergic reactions and infections. On the contrary, gene therapy offers the advantage of a single administration and, if successful, produces constant levels of alpha-1 antitrypsin. The gene therapy strategy is to deliver the normal human M-type alpha-1 antitrypsin complementary DNA under the control of a constitutive promoter using a gene transfer vector. Consequently, the transduced cells can secrete the deficient protein into the blood after a single administration. The parameters to be considered in gene therapy are the vector, the organ to be modified genetically, and where the gene is expressed. For these reasons, different approaches have been used.

Recombinant alpha-1 antitrypsin

Studies are underway to determine the effectiveness and safety of recombinant products to replace human plasma-derived alpha-1 protein. Progress thus far has been limited, but a humanized protein with 2 elastase inactivating sites is being studied.

Differential Diagnosis

The differential diagnosis for alpha-1 antitrypsin mutation includes the following:

• Autoimmune hepatitis
• Bronchiectasis
• Bronchitis
• COPD
• Cystic fibrosis
• Emphysema
• Kartagener syndrome
• Viral hepatitis

Enhancing Healthcare Team Outcomes

Alpha-1 antitrypsin deficiency is a systemic disorder that affects many organs. Thus, it is best managed by an interprofessional team. Alpha-1 antitrypsin deficiency leads to COPD, liver disease, and panniculitis. Other studies have linked it to conditions such as glomerulonephritis and certain cancers. Other associations include celiac disease, fibromuscular dysplasia, and pancreatitis. Approximately 15% of patients with granulomatosis with polyangiitis are found to have a ZZ genotype. The primary care provider should educate the patient on avoidance of triggers that stimulate the unopposed neutrophil elastase activity, such as smoking and infections. Patients should be encouraged to get the yearly influenza, protein conjugate pneumococcal, and tetanus-diphtheria-pertussis vaccine. Inhalers typically used for COPD should be prescribed and initially should include long-acting beta-agonists and or anticholinergics. Because of the increased risk of pneumonia, inhaled corticosteroids should be reserved for patients who develop frequent exacerbations despite the other two inhalers. Pulmonary rehabilitation, oxygen, and, in some circumstances, lung transplants should be prescribed as indicated. Transplant is usually reserved for those that fall below an FEV1 of 30% despite maximum therapy.