Despite advances in alpha-1 antitrypsin (AAT) augmentation therapy for individuals with emphysema secondary to alpha-1 antitrypsin deficiency (AATD), lung transplantation remains the only definitive treatment option available for patients who have progressed to end-stage lung disease. Similarly, liver transplantation may also be indicated in advanced forms of AATD causing liver failure due to the accumulation of mutant forms of AAT within the liver.
A review published earlier this year in Therapeutic Advances in Chronic Disease summarized the outcomes associated with lung and liver transplantation in individuals with advanced AATD. According to the review authors, AATD treatment guidelines tend to focus on augmentation therapy and disease monitoring up to the point of lung transplantation but often fail to adequately discuss transplantation as a viable treatment option for advanced disease.
According to the review authors, “It is important to be aware of outcomes in AATD post-lung and liver transplantation so that patients can be provided with all the necessary information before deciding whether to go ahead with these treatment options.”
Transplantation and the Burden of Disease
Primarily a disease affecting the lungs and liver, AATD is a genetic disorder that results in considerable morbidity and mortality. Although extrapulmonary manifestations do occur in patients with AATD, respiratory failure continues to be the leading cause of death followed by liver failure. According to the review authors, hepatic manifestations can be much more insidious in nature and are often only detected once the disease has progressed to the point of cirrhosis or hepatocellular carcinoma.
The review notes that the burden of lung and liver transplantation for advanced cases of AATD is disproportionate to what is otherwise considered to be a relatively rare disease. In individuals with AATD, end-stage lung disease requiring transplantation occurs in only about 5% of patients. Interestingly, AATD remains the fourth most common indication for lung transplantation globally behind non-AATD chronic obstructive pulmonary disorder (COPD), idiopathic pulmonary fibrosis, and cystic fibrosis.
Read more about AATD therapies
On average, patients with AATD requiring lung transplantation tend to be about 10 years younger than individuals undergoing lung transplantation for other indications. Patients also tend to have less exposure to tobacco products, potentially making them better surgical candidates. In cases of advanced disease complicated by cirrhosis, liver transplantation may be indicated as a stand-alone intervention or combined with lung transplantation in patients who would not be expected to survive liver transplantation alone.
According to the review authors, a substantial proportion of lung transplants performed globally are related to AATD. Between 1995 and 2015, over 2500 lung transplants were performed in the United States in patients with AATD-related COPD.
Outcomes for individuals with AATD undergoing lung transplantation are encouraging. A registry performed in the United Kingdom between 1996 and 2011 showed favorable post-lung transplant survival rates for patients with AATD of 81.3%, 74.2%, 52.9%, and 45.2% at 90 days, 1 year, 5 years, and 10 years, respectively. A Swedish retrospective study conducted in 2014 found that the average survival time for AATD lung transplant recipients was approximately 12 years compared to 6 years for non-AATD recipients (95% CI, 9.6-13.5, P =.000).
Interestingly, initial studies demonstrated worse short-term survival but improved long-term survival rates for individuals with AATD undergoing lung transplantation compared to non-AATD COPD patients who had lung transplants. According to the review authors, this difference in survival has not been observed in more recent data obtained in the United States and may be secondary to the implementation of the lung allocation score (LAS) adopted in 2005, which prioritizes patients for lung transplantation based on disease severity rather than time spent on a transplant waiting list. Another theory for this discrepancy includes the increasing use of AAT augmentation, which may delay the need for lung transplantation in patients with AATD.
As the review authors note, “There are, therefore, conflicting reports on the overall value of lung transplantation in AATD, with early studies suggesting longer survival in patients with AATD, but with worse short-term survival. These differences are less apparent in recent studies in the US, which may be attributed to the more widespread use of AAT augmentation and the LAS.” They added, “Further studies could investigate whether patients with AATD today have significantly worse clinical state than those with non-AATD COPD at the time of lung transplantation.”
End-stage liver disease is also a significant contributor of morbidity and mortality in patients with AATD. Often undetectable until sequelae of cirrhosis or hepatocellular carcinoma are evident, liver transplantation is the only available curative treatment for liver failure due to AATD.
The review notes that liver transplantation is also associated with favorable survival rates in patients with AATD. Studies have demonstrated a 5-year survival rate of 72.9% for patients with AATD undergoing liver transplantation, slightly higher than the 69.2% overall 5-year survival rate for all-cause liver transplantation. The review authors note that survival in children with AATD is even higher, with studies demonstrating a 90% 5-year survival rate for pediatric liver recipients with AATD.
In severe cases of AATD, a combined transplant may be indicated for patients with both end-stage lung and liver diseases. Due to the complexities associated with this procedure, it is rarely performed and the review notes that outcome data is limited. Outcomes derived from patients with cystic fibrosis undergoing dual transplantation, however, seem to suggest that the procedure can likely be performed with favorable outcomes in carefully selected patients with AADT.
The review concludes by acknowledging that “Lung and liver transplantation are viable treatment options for end-stage lung and liver disease in patients with AATD, and data shows that post-lung and liver transplant survival is favorable.”
Zamora MR, Ataya A. Lung and liver transplantation in patients with alpha-1 antitrypsin deficiency. Ther Adv Chronic Dis. 2021;12_suppl:20406223211002988. doi:10.1177/20406223211002988
Tanash HA, Riise GC, Ekström MP, Hansson L, Piitulainen E. Survival benefit of lung transplantation for chronic obstructive pulmonary disease in Sweden. Ann Thorac Surg. 2014;98(6):1930-1935. doi:10.1016/j.athoracsur.2014.07.030