Alpha-1 Antitrypsin Deficiency (AATD)

Liver Treatments

Development of treatments targeting the hepatocytes that have accumulated in the alpha-1 antitrypsin (AAT) protein include: 

• AAT polymerization blockage using small molecules and peptides^1,2 
• stabilization of AAT proteins using chaperones to improve hepatic secretions^3,4
• and use of pharmaceuticals that support autophagy to destroy pathological inclusions⁵ 

Lung Treatments

Usual medical treatment for COPD pertains to individuals with COPD due to AATD. Primary goals for treatment are to prevent and treat respiratory infections, reduce hypoxemia, and provide access to pulmonary rehabilitation programs that improve lung function and capacity. Treatment typically includes:

• use of inhaled bronchodilators and corticosteroids
• supplemental oxygen therapy if required
• anticholinergics
• antibiotics or phosphodiesterase 5 inhibitors for frequent respiratory infections^6,7 

Prospective treatments are in development to target and slow progression of the lung disease associated with AATD. These include:

• inhalation delivery of AAT 
• inhibition of neutrophil elastase protease activity
• prolongation of the serum half-life of AAT using lipid polymers (PEG)
• gene therapy which injects an adenovirus carrying the human AAT gene
• and use of recombinant AAT⁵ 

Preventative Medical Care For AATD

Smoking cessation and avoidance of second hand smoke is a very important aspect of medical care as smoking expedites the lung disease process in individuals with AATD.^6,7 Avoidance of non-medical aerosols, certain household cleaning chemicals, and work environments with inhaled particulates is also critical to prevent further damage to the lung tissue.^6,7 Excessive alcohol consumption should be avoided as this may accelerate liver damage due to AATD.⁸

Preventive annual influenza vaccinations and pneumococcal vaccinations every 5 years are highly recommended to prevent further damage to the lungs from recurrent respiratory infections.^6,7,8

Intravenous augmentation therapy is a specific, AATD-targeted treatment that infuses purified pooled human plasma AAT. This intervention’s objective is to raise the serum concentration of AAT above the protective threshold to prevent alveolar lung tissue destruction by neutrophil elastase protease enzymes.⁵ 

There are 6 identified preparations of purified AAT pooled human plasma available in the US, including Prolastin, Prolastin-C, Aralast, Aralast NP, Zemaira, and Glassia.^5,6 This is an intervention that is recommended in individuals with AATD related lung disease who do not smoke, as well as AATD cases with necrotizing panniculitis.⁹ Augmentation therapy is not recommended for individuals with AATD who continue to smoke, who have undergone liver transplantation,  have bronchiectasis or emphysema without airflow obstruction, and  have the MZ genotype of AATD. It is not meant to treat liver disease associated with AATD.⁹ 

Currently, studies using biochemical markers show that intravenous augmentation therapy infusing 60 mg/kg once weekly successfully raises the serum concentration of AAT in recipients for a week,¹⁰ but any longer than 1 week between treatments is not as effective.^11,12,13 Analysis of 2 randomized controlled trials to assess the clinical efficacy of augmentation therapy shows that while augmentation therapy slows the rate of loss of lung density (-2.74 vs -1.73 g/l/yr; p=0.006), it does not have any statistically significant impact on forced expiratory volume in the first second (FEV₁) of spirometry testing (13 ml/yr; p=0.321).¹⁴ 

A meta-analysis of 5 studies comprising 1509 individuals receiving augmentation therapy reported a 23% slower rate of FEV₁ decline (13.4 ml/yr difference; 95% CI, 1.5-25.3 ml/yr) compared with non-augmentation.¹⁵ In 2003, the American Thoracic Society and the European Respiratory Society published a standard of care for AATD, which concludes that augmentation therapy shows the most beneficial impact including decreased mortality and slower FEV₁ rate of decline in individuals with moderate airflow obstruction (FEV₁ 35%-60% predicted). Less evidence supports augmentation use in individuals with mild or severe airflow obstruction.¹⁶  

Surgical Care for AATD

Large volume paracentesis (LVP) may be performed for individuals with AATD and liver disease who have ascites.⁷ 

To decrease bleeding risk in the esophagus, veins may be treated with banding (use of rubber bands to halt blood flow) or sclerotherapy (use of chemical irritants to shunt blood from a diseased vein to a healthy vein).^6,7 

Portal vein decompression uses shunts to reduce pressure in the blood vessels entering the liver from multiple digestive organs. This reduces the risk of bleeding in advanced liver disease.^6,7  

In AATD individuals with advanced liver disease,  transplantation may be necessary. Individuals receiving a donor liver will begin to produce normal levels of serum AAT following transplantation.^6,7 In some individuals with Pi*ZZ and Pi*SZ genotypes of AATD, FEV₁ may continue to decline even following liver transplantation.⁸ 

Lung volume reduction surgery (LVRS) involves the surgical excision of large regions (up to 20-35% of each lung) of emphysema, called bullae, that have formed. It is usually not recommended for individuals with AATD related COPD due to less evidence of benefit compared with other individuals with emphysema not due to genetic causes.^6,8 

Lung transplantation (single or double lung) has been performed on individuals who have AATD with advanced stage lung disease.⁶ Many transplant programs utilize a BODE index score of 5 or 6 to identify patients with emphysema or COPD that may optimally benefit from lung transplantation or select patients who have had episodes of respiratory failure.⁸ 

Consultations

Possible consultations for AATD include:

• a pulmonologist who can monitor lung function and chronic obstructive pulmonary decline via spirometry and treat appropriately
• a nutritionist who can recommend foods to eat and to avoid⁷
• an exercise specialist or pulmonary rehabilitation programs for the recommendation of safe, effective ways to exercise to improve lung capacity, endurance, and muscular strength^7,8
• a hepatologist who can monitor and treat liver disease if present
• a genetic counselor who can perform genetic testing to ascertain if other family members and spouses are carriers of or have AATD as well as provide advice on the risk of having children with AATD⁷
• a Clinic Resource Center (CRC) that has Alpha-1 treatment specialization and may perform research studies that may be beneficial to individuals with AATD¹⁷
• patient education, resource, and support groups sponsored by multiple organizations including Alpha-1 National Association, Alpha-1 Association, Alpha-1 Foundation, AlphaNet, and Alpha-1 Advocacy Alliance.¹⁸ 

Long-Term Monitoring for AATD

Annual pulmonary function tests (PFTs) via spirometry are important to optimize treatment, counsel the patient on disease progression, and initiate early planning for lung transplantation.^8,9 

Monitoring for liver disease associated with AATD, especially in those with the Pi*ZZ genotype, at annual intervals should include blood work for albumin, bilirubin, INR, the liver enzymes AST, ALT, GGT, and platelets. Ultrasound imaging studies should be performed every 6-12 months to detect early fibrotic changes and hepatocellular carcinoma.^8,9 

Nutrition and Diet for AATD

Consultation with a nutritionist may be beneficial for those with AATD. For individuals with liver complications due to AATD, it is suggested to reduce sodium intake as this may aggravate abdominal fluid retention.⁷ AATD may impact the ability of the liver to digest fatty foods properly, so a low-fat diet may be recommended for those with liver disease.⁷ Conversely, fat-based non-protein calories may assist individuals with AATD who are receiving mechanical ventilation for respiratory failure.⁸ 

Alcohol, certain vitamins, supplements, some over-the-counter and prescribed medications including acetaminophen and those containing alcohol may cause further injury to the liver, so a nutritionist may suggest avoidance of these substances. In infants with liver disease who have failure to thrive and poor growth, a special formula is recommended with a possible necessity of total parenteral nutrition (TPN).

The total daily caloric intake may be adjusted for individuals with lung disease related to AATD as research indicates these individuals consume more calories just to breathe.⁷ Protein-calorie supplementation is important for individuals with AATD-related lung disease who experience a loss of muscle mass, termed pulmonary cachexia, but protein can also be harmful for those with liver disease, so depending on the type of AATD present, recommendations for protein intake may differ.^7,8 Maintaining a healthy body weight and well-rounded diet is important for individuals with COPD to prevent pulmonary cachexia.¹⁹

References

1. Parfrey H, Dafforn TR, Belorgey D, Lomas DA, Mahadeva R. Inhibiting polymerization: new therapeutic strategies for Z alpha1-antitrypsin-related emphysema. Am J Respir Cell Mol Biol. 2004; 31(2):133-139. doi:10.1165/rcmb.2003-0276OC
2. Zhou A, Stein PE, Huntington JA, Sivasothy P, Lomas DA, Carrell RW. How small peptides block and reverse serpin polymerisation. J Mol Biol. 2004; 342(3):931-941. doi:10.1016/j.jmb.2004.07.078 
3. Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci U S A. 2000; 97(4):1796-1801. doi:10.1073/pnas.97.4.1796
4. Marcus NY, Perlmutter DH. Glucosidase and mannosidase inhibitors mediate increased secretion of mutant alpha1 antitrypsin Z. J Biol Chem. 2000; 275(3):1987-1992. doi:10.1074/jbc.275.3.1987
5. Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012; 185(3):246-259. doi:10.1164/rccm.201108-1428CI
6. Alpha-1 antitrypsin deficiency. National Organization for Rare Disorders (NORD). Accessed June 7, 2021.  
7. Alpha-1 antitrypsin deficiency: a guide for the recently diagnosed. Alpha-1 Foundation. Accessed June 7, 2021. 
8. Anariba, DEI. Alpha1 antitrypsin treatment and management: medical care, surgical care, consultations, diet, activity, prevention, and long-term monitoring. Medscape. Accessed June 9, 2021. 
9. Robert A. Sandhaus MD, Gerard Turino MD, Mark L. Brantly MD, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation. 2016; 3(3):668-682.
10.  Wewers MD, Casolaro MA, Sellers SE, et al. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med. 1987; 316(17):1055-1062. doi:10.1056/NEJM198704233161704
11. Dirksen A, Dijkman JH, Madsen F, et al. A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy. Am J Respir Crit Care Med. 1999; 160(5 Pt 1):1468-1472. doi:10.1164/ajrccm.160.5.9901055
12. Barker AF, Iwata-Morgan I, Oveson L, Roussel R. Pharmacokinetic study of alpha1-antitrypsin infusion in alpha1-antitrypsin deficiency. Chest. 1997; 112(3):607-613. doi:10.1378/chest.112.3.607
13. Hubbard RC, Sellers S, Czerski D, Stephens L, Crystal RG. Biochemical efficacy and safety of monthly augmentation therapy for alpha 1-antitrypsin deficiency. JAMA. 1988; 260(9):1259-1264.
14. Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A.  Therapeutic efficacy of α-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res. 2010; 11:136. doi:10.1186/1465-9921-11-136
15. Chapman KR, Stockley RA, Dawkins C, Wilkes MM, Navickis RJ. Augmentation therapy for alpha1 antitrypsin deficiency: a meta-analysis. COPD. 2009; 6(3):177-184. doi:10.1080/15412550902905961
16. American Thoracic Society, European Respiratory Society. American thoracic society/european respiratory society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003; 168(7):818-900. doi:10.1164/rccm.168.7.818
17. Find an alpha-1 specialist. Alpha-1 Foundation. Accessed June 9, 2021.
18. Anariba, DEI. Which specialist consultations are recommended for the treatment of alpha1-antitrypsin deficiency (AATD)? Medscape. Accessed June 9, 2021.
19. Schols AM, Ferreira IM, Franssen FM, et al. Nutritional assessment and therapy in COPD: a european respiratory society statement. Eur Respir J. 2014; 44(6):1504-1520. doi:10.1183/09031936.00070914

Article reviewed by Harshi Dhingra, MD on July 1, 2021.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.