α1-Antitrypsin deficiency

Abstract

α1-Antitrypsin deficiency (A1ATD) is an inherited disorder caused by mutations in SERPINA1, leading to liver and lung disease. It is not a rare disorder but frequently goes underdiagnosed or misdiagnosed as asthma, chronic obstructive pulmonary disease (COPD) or cryptogenic liver disease. The most frequent disease-associated mutations include the S allele and the Z allele of SERPINA1, which lead to the accumulation of misfolded α1-antitrypsin in hepatocytes, endoplasmic reticulum stress, low circulating levels of α1-antitrypsin and liver disease. Currently, there is no cure for severe liver disease and the only management option is liver transplantation when liver failure is life-threatening. A1ATD-associated lung disease predominately occurs in adults and is caused principally by inadequate protease inhibition. Treatment of A1ATD-associated lung disease includes standard therapies that are also used for the treatment of COPD, in addition to the use of augmentation therapy (that is, infusions of human plasma-derived, purified α1-antitrypsin). New therapies that target the misfolded α1-antitrypsin or attempt to correct the underlying genetic mutation are currently under development.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

“…For this approach, mutations in alpha1-antitrypsin (AAT; SERPINA1 gene) are attractive candidates. AAT is one of the most abundant serum proteins and is produced predominantly within hepatocytes 7. The presence of AAT variants typically lead to decreased serum AAT concentrations giving rise to the systemic disease alpha1-antitrypsin deficiency (AATD).…”

“…The most relevant variant is termed ‘Pi*Z’ (rs28929474), which has a prevalence of up to 8% in Northern Europe 7 9. The somewhat less severe variant, termed ‘Pi*S’ (rs17580), is more common in Southern Europe, with a prevalence of up to 20% 7. In total, approximately 120 million people worldwide carry at least one Pi*Z or Pi*S allele and up to 10% of Caucasians carry an AAT variant 7 9.…”

ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency

“…One such protein is the normally soluble luminal protein Alpha 1-Antitrypsin (1AT). As a member of the serine protease inhibitor (serpin) family, 1AT is also the most abundant antiprotease in the serum [2]. This protein is mainly produced by hepatocytes in the liver to act as a general inhibitor of serine proteases [3].…”

Genetics Association and Epigenetic Changes in COPD

“…SERPINA1 is the gene encoding alpha-1 antitrypsin (AAT) and systemic deficiency in AAT (AATD) due to genetic mutations can result in liver failure and chronic lung disease such as emphysema (4). AAT is the most abundant circulating serine protease inhibitor (serpin) and an acute phase reactant.…”

“…Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder and its role in lung emphysema was established by studying the phenotype of the patients [4]. The single candidate gene provides association for a gene in host physiology, whereas Genome-wide association studies (GWAS) identifies genome-wide set of genetic variants to a complex disease.…”