Is severe progressive liver disease caused by alpha‐1‐antitrypsin deficiency more common in children or adults?

Abstract

The classical form of alpha-1-antitrypsin deficiency (A1ATD) is known to cause liver disease in children and adults, but there is relatively little information about the risk of severe, progressive liver disease and the need for liver transplantation. To better understand how newly evolving pharmacological, genetic, and cellular therapies may be targeted according to risk for progressive liver disease, we sought to determine the age distribution of A1ATD as a cause of severe liver disease, as defined by the need for liver transplantation. Using 3 US liver transplantation databases for the period 1991-2012, we found 77.2% of 1677 liver transplants with a reported diagnosis of A1ATD were adults. The peak age range was 50-64 years. Using 2 of the databases which included specific A1AT phenotypes, we found that many of these adults who undergo liver transplantation with A1ATD as the diagnosis are heterozygotes and have other potential causes of liver disease, most notably obesity and ethanol abuse. However, even when these cases are excluded and only ZZ and SZ phenotypes are considered, severe liver disease requiring transplantation is more than 2.5 times as likely in adults. The analysis also showed a markedly increased risk for males. In the pediatric group, almost all of the transplants are done in children less than 5 years of age. In conclusion, A1ATD causes progressive liver disease most commonly in adults with males in the highest risk category. In the pediatric group, children less than 5 years of age are highest in risk. These results suggest that A1ATD most commonly causes liver disease by mechanisms similar to age-dependent degenerative diseases and more rarely in children by powerful modifiers.Liver Transplantation 22 886-894 2016 AASLD.

Evolving Trends in Liver Transplant for Metabolic Liver Disease in the United States

“…The impact of sex on the indication for transplant has been previously reported, and we have confirmed the higher proportion of males undergoing transplantation for hemochromatosis, A1ATD, cystic fibrosis liver disease, and UCDs. The cause of this sex imbalance is unclear in cystic fibrosis liver disease and A1ATD . The improved survival in male children undergoing transplant for metabolic disease has not been previously described and is not easily explained.…”

“…The significant fall in transplantation for A1ATD in childhood is less easily explained because there has been no step change in the management of the disorder. This observation has previously been attributed to a cohort effect where ill patients accumulated prior to the widespread availability of pediatric transplantation and this “backlog” of patients caused A1ATD to be overrepresented in the early years of transplantation . Why this should be confined to A1ATD is unclear, and if it were the case, age at LT for A1ATD should fall once the backlog was cleared, which did not occur.…”

“…The cause of this sex imbalance is unclear in cystic fibrosis liver disease and A1ATD. (19) The improved survival in male children undergoing transplant for metabolic disease has not been previously described and is not easily explained. This does not appear to simply reflect better overall outcomes in those disorders where males are overrepresented because this effect occurred across a range of disorders.…”

“…This observation has previously been attributed to a cohort effect where ill patients accumulated prior to the widespread availability of pediatric transplantation and this "backlog" of patients caused A1ATD to be overrepresented in the early years of transplantation. (19) Why this should be confined to A1ATD is unclear, and if it were the case, age at LT for A1ATD should fall once the backlog was cleared, which did not occur. This suggests that the decrease in LT for A1ATD may reflect a change in practice due to the introduction of minimal clinical criteria for listing.…”

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

“…For instance, liver biopsy is the only method for assessing the extent of hepatic lesions and liver transplantation is the only therapeutic strategy currently available for AATD-mediated liver disease. Thus, this pathology is the most common genetic cause of pediatric liver disease and the most frequent inherited indication for liver transplantation in the pediatric population [10].…”