Alpha-1 antitrypsin deficiency leads to COPD, liver disease, and panniculitis. Other studies have linked it to several other conditions such as glomerulonephritis and certain cancers. Other associations like celiac disease, fibromuscular dysplasia, and pancreatitis. There is also approximately 15% of patients with granulomatosis with polyangiitis who 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 characters 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 are mainly: dyspnea, cough, wheezing, and upper respiratory tract infections. The pulmonary symptoms can be aggravated by some risk factors like cigarette smoking, exposure to burning biomass materials, and respiratory infections. 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 development of polymers leads to hepatitis in children, liver cirrhosis in adults, and increase the risk for hepatocellular carcinoma. Early in life infants may develop clinical hepatitis and AATD is the second most 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 ZZ genotype and occurs in 1 per 1000 cases.

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 through determining alpha one antitrypsin serum levels. If serum levels are low, genotyping may be pursued. If the genotype and serum level are discordant than phenotyping or genetic analysis can confirm the diagnosis. Chest radiographs and chest CT scan demonstrate emphysematous lung changes. Pulmonary function tests are necessary as well to detect the expected decline in FEV1.[8][9]

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 infections in patients 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 (LABA) and or anticholinergics (LAMA). Because of the increased risk of pneumonia inhaled corticosteroids (ICS) should be reserved for when patients develop frequent exacerbations despite the other two inhalers. Pulmonary rehabilitation, oxygen, and in some circumstances, lung transplant, should be prescribed as indicated. Transplant is usually reserved for those that fall below an FEV-1 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 one 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 one antitrypsin serum deficiency and COPD. Augmentation therapy is infused to elevate alpha one 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 FEV-1 below 70%, and an FEV-1 above 30% and because of these data guidelines suggest using augmentation between these 2 FEV-1 values. Currently, the Food and Drug Administration (FDA) in the United States only approves augmentation therapy at doses of 60 mg/kg weekly. Adverse effects of augmentation therapy are rare and include a headache, nausea and 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 has 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 compared to non-alpha-1 antitrypsin deficiency transplantation ones, yet there was a wide degree of similarity between both groups 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 (FEV-1 below 30%). The limited data on lung volume reduction surgery have not been promising, and thus this procedure is not recommended for alpha one antitrypsin deficiency patients.   Following the liver transplant, it has not been established whether the new liver secreting normal alpha-1-protein will prevent the progression of lung disease. Unfortunately, for this reason, there is not a consensus if alpha-1-protein augmentation should be administered to patients after lung transplant.

Future of Alpha-1 Antitrypsin

Treatment

Inhaled augmentation therapy

By inhalation, there is an opportunity to target treatment to the organ of interest, and hence reducing the required dose of alpha-1-protein necessary to preserve lung function. Inhaled therapy reduces the amount of alpha-1 protein needed, and this reduces 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. Contrary, gene therapy offers the advantage of a single administration and if successful produces constant levels of alpha one antitrypsin. The strategy of gene therapy is to delivery the normal human M-type alpha one antitrypsin complementary DNA under control of a constitutive promoter using a gene transfer vector, and consequently, the transduced cells can secrete the deficient protein to the blood after a single administration. The parameters to be considered in gene therapy are the vector and the organ to be modified genetically and in which the gene will be expressed, and 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. The progress thus far has been limited, but presently a humanized protein with 2 elastase inactivating sites is being studied.

• Autoimmune hepatitis

• Bronchiectasis

• Bronchitis

• Chronic obstructive pulmonary disease

• Cystic fibrosis

• Emphysema

• Kartagener Syndrome

• Viral hepatitis

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 several other conditions such as glomerulonephritis and certain cancers. Other associations like celiac disease, fibromuscular dysplasia, and pancreatitis. There is also approximately 15% of patients with granulomatosis with polyangiitis who are found to have a ZZ genotype. The primary care provider and nurse practitioner 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 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 (LABA) and or anticholinergics (LAMA). Because of the increased risk of pneumonia inhaled corticosteroids (ICS) should be reserved for when patients develop frequent exacerbations despite the other two inhalers. Pulmonary rehabilitation, oxygen, and in some circumstances, lung transplant, should be prescribed as indicated. Transplant is usually reserved for those that fall below an FEV-1 of 30% despite maximum therapy.