Clinical considerations in individuals with α₁-antitrypsin PI*SZ genotype

Abstract

α1-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α1-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Intravenous AAT therapy, the only specific treatment for patients with AATD, has been shown to slow disease progression in PI*ZZ individuals; however, there is no specific evidence for AAT therapy in PI*SZ individuals, and it remains unclear whether AAT therapy should be considered in these patients. This narrative review evaluates the available data on the PI*SZ genotype, including genetic prevalence, the age of diagnosis and development of respiratory symptoms compared with PI*ZZ individuals, and the impact of factors such as index versus non-index identification and smoking history. In addition, the relevance of the putative 11 µM “protective threshold” for AAT therapy and the risk of liver disease in PI*SZ individuals is explored. The purpose of this review is to identify open research questions in this area, with the aim of optimising the future identification and management of PI*SZ individuals.

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

“…53,54 Indeed, this phenomenon of heteropolymerization affords a better understanding of the incidence of hepatic disease among SZ subjects, particularly when there is a second hit caused by other risk factors, such as infection, fat liver or alcoholism. 53,55 Oddly, the risk of lung disease among SZ individuals is not yet fully elucidated. This results from some contradictory studies concerning the association of the SZ genotype with pulmonary emphysema and COPD, but also from the small numbers of individuals analyzed so far.…”

“… 53 , 54 Indeed, this phenomenon of heteropolymerization affords a better understanding of the incidence of hepatic disease among SZ subjects, particularly when there is a second hit caused by other risk factors, such as infection, fat liver or alcoholism. 53 , 55 …”

Alpha-1 antitrypsin deficiency: an update on clinical aspects of diagnosis and management

“…Smoking cessation is the most important protective measure in AATD, even though there are studies reporting a minor effect when comparing PiSZ with PiZZ. Nevertheless, a faster rate of decline in lung function has been observed in both genotypes, which indicates that tobacco cessation must be a priority 25 , 26 . PiSZ patients exhibit a lower risk of lung disease and are less susceptible to smoking effects when compared with PiZZ patients 10 ; however, because of their higher AAT levels, they may have less concern that their genotype presents a risk of disease, prompting them to unhealthy behaviors 5 , 8 .…”

The Probable, Possible, and Novel Functions of ERp29

“…Type two diabetes (T2D) Smeekens et al, 1992;Nishigori et al, 1996;Viviano et al, 2020 Thyroglobulin (Tg) Thyroid hormone (T 3 and T 4 ) precursor Goiter, hypothyroidism Sargsyan et al, 2002a;Baryshev et al, 2006;Citterio et al, 2013 Alpha-1 antitrypsin (A1AT) Serpin protein protects tissues from proteases Liver failure, cirrhosis, chronic obstructive pulmonary disease (COPD) Sifers et al, 1988;Davis et al, 1990;McElvaney et al, 2020 Alpha-1 type 1 collagen (Collagen-I)…”

“…In the liver, aggregation and polymerization of the PiZ mutant in the hepatocyte ER may culminate in hepatocyte death, liver failure and cirrhosis as early as the newborn period (Patel and Teckman, 2018). Lack of protection from neutrophil elastase in the lung with A1AT deficiency increases lung susceptibility to injury, often manifesting clinically as emphysema or chronic obstructive pulmonary disease (COPD) (McElvaney et al, 2020).…”