Alpha-1 Antitrypsin deficiency (AATD) is a rare, autosomal codominant, genetic disorder characterized by mutations in the SERPINA1 gene, which predispose individuals to the development of multiple pulmonary and hepatic diseases. To date, more than 500 mutations have been identified, with the Pi*Z and Pi*S mutations being the most prevalent. Despite the growing understanding of these common variants, the knowledge regarding rare AATD mutations remains limited. Consequently, the objective of our study was to comprehensively compare the clinical phenotypes of patients with severe AATD caused by rare mutations with those with Pi*ZZ and Pi*SZ genotypes, as well as analyse their lung disease progression over time. In our investigation, we enrolled a total of 281 AATD patients from the Italian Registry for Alpha-1 Antitrypsin Deficiency (RIDA1) based on specific inclusion criteria. These criteria included a confirmed diagnosis of severe AATD, age above 18 years, voluntary consent to participate in the study, and the availability of comprehensive clinical data at the time of diagnosis as well as a three-year follow-up of respiratory function. We categorized them into three distinct cohorts based on their genotypes: Pi*ZZ genotype (n=160), Pi*SZ genotype (n=54), and rare genotypes Pi*R (n=67). Notably, we observed no statistically significant differences pertaining to gender, smoking habits, professional exposure, or age at the time of diagnosis within these sampled cohorts. Regarding the median alpha-1 antitrypsin (AAT) concentration in plasma, we found that Pi*R individuals exhibited a value of 30.5 mg/dL, Pi*SZ individuals displayed 62.0 mg/dL, and Pi*ZZ individuals exhibited 26.0 mg/dL. Statistical analysis revealed a significant disparity between the Pi*R and Pi*SZ cohorts (p-value=0.00017), as well as between the Pi*ZZ and Pi*SZ cohorts (p-value<0.00001). Moreover, our study revealed that Pi*R individuals exhibited clinical phenotypes and respiratory profiles that were akin to those of Pi*ZZ patients. Lung function tests, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio, indicated comparable results between Pi*R and Pi*ZZ patients at both T0 (initial assessment) and T1 (follow-up assessment). Although no statistically significant differences were observed among the three cohorts in terms of annual decline in lung function, it is worth noting that both Pi*R and Pi*ZZ populations exhibited a similar decline when compared to the Pi*SZ cohort. These findings underscore the critical importance of promptly diagnosing rare AATD variants to ensure effective clinical management and appropriate follow-up for affected patients. Moreover, individuals with Pi*R mutations should have equitable access to all available therapeutic options afforded to individuals with severe AATD. However, further comprehensive investigations are warranted to elucidate the diverse nature of rare variants and their associated clinical phenotypes. In conclusion, our study contributes valuable insights into the clinical presentation and disease progression of rare AATD mutations. By shedding light on the similarities and differences compared to more common mutations, this research emphasizes the necessity of tailored clinical approaches for patients with rare variants. Continued efforts in understanding the diverse landscape of AATD mutations will ultimately enhance patient care and lead to improved therapeutic strategies in the future.
Il deficit di alfa-1 antitripsina (AATD) è una malattia genetica rara, autosomica codominante, caratterizzata da mutazioni nel gene SERPINA1, che predispongono gli individui allo sviluppo di malattie polmonari e epatiche multiple. Fino ad oggi, sono state identificate più di 500 mutazioni, con le mutazioni Pi*Z e Pi*S che sono le più diffuse. Nonostante la crescente comprensione di queste varianti comuni, le conoscenze riguardanti le mutazioni rare di AATD sono ancora limitate. Di conseguenza, l'obiettivo del nostro studio era confrontare in modo esaustivo i fenotipi clinici dei pazienti con AATD severo causata da mutazioni rare con quelli con genotipi Pi*ZZ e Pi*SZ, nonché analizzare la progressione della malattia polmonare nel tempo. Nella nostra indagine, abbiamo reclutato un totale di 281 pazienti con AATD dal Registro Italiano per il deficit di Alfa-1 Antitripsina (RIDA1) sulla base di criteri di inclusione specifici. Questi criteri includevano una diagnosi confermata di AATD severo, età superiore ai 18 anni, consenso volontario a partecipare allo studio e disponibilità di dati clinici completi al momento della diagnosi e di un follow-up di tre anni sulla funzione respiratoria. Li abbiamo suddivisi in tre gruppi distinti in base ai loro genotipi: genotipo Pi*ZZ (n=160), genotipo Pi*SZ (n=54) e genotipi rari Pi*R (n=67). Va notato che non sono state osservate differenze statisticamente significative riguardo al sesso, alle abitudini tabagiche, all'esposizione professionale o all'età al momento della diagnosi all'interno di questi gruppi campionati. Per quanto riguarda la concentrazione mediana di alfa-1 antitripsina (AAT) nel plasma, abbiamo scoperto che gli individui Pi*R presentavano un valore di 30,5 mg/dL, gli individui Pi*SZ mostravano 62,0 mg/dL e gli individui Pi*ZZ presentavano 26,0 mg/dL. L'analisi statistica ha rivelato una disparità significativa tra i gruppi Pi*R e Pi*SZ (valore di p=0,00017), così come tra i gruppi Pi*ZZ e Pi*SZ (valore di p<0,00001). Inoltre, il nostro studio ha rivelato che gli individui Pi*R presentavano fenotipi clinici e profili respiratori simili a quelli dei pazienti Pi*ZZ. I test di funzione polmonare, tra cui il volume espiratorio forzato in un secondo (FEV1), la capacità vitale forzata (FVC) e il rapporto FEV1/FVC, hanno indicato risultati simili tra i pazienti Pi*R e Pi*ZZ sia al momento T0 (valutazione iniziale) che al momento T1 (valutazione di follow-up). Sebbene non siano state osservate differenze statisticamente significative tra i tre gruppi riguardo alla diminuzione annuale della funzione polmonare, è importante notare che sia la popolazione Pi*R che quella Pi*ZZ hanno mostrato una diminuzione simile rispetto al gruppo Pi*SZ. Questi risultati sottolineano l'importanza critica di diagnosticare tempestivamente le varianti rare di AATD per garantire una gestione clinica efficace e un adeguato follow-up per i pazienti affetti. Inoltre, gli individui con mutazioni Pi*R dovrebbero avere un accesso equo a tutte le opzioni terapeutiche disponibili per gli individui con AATD severo. Tuttavia, ulteriori approfondimenti sono necessari per chiarire la natura diversificata delle varianti rare e i loro fenotipi clinici associati. In conclusione, il nostro studio fornisce preziose informazioni sulla presentazione clinica e la progressione della malattia nelle mutazioni rare di AATD. Facendo luce sulle somiglianze e differenze rispetto alle mutazioni più comuni, questa ricerca sottolinea la necessità di approcci clinici personalizzati per i pazienti con varianti rare. Gli sforzi continui per comprendere il panorama diversificato delle mutazioni di AATD miglioreranno ulteriormente l'assistenza ai pazienti e porteranno a strategie terapeutiche migliorate in futuro.
Clinical Profile in Patients with Severe Alpha-1 Antitrypsin Deficiency due to Rare Genotypes
ARANGIO, ALESSANDRO
2022/2023
Abstract
Alpha-1 Antitrypsin deficiency (AATD) is a rare, autosomal codominant, genetic disorder characterized by mutations in the SERPINA1 gene, which predispose individuals to the development of multiple pulmonary and hepatic diseases. To date, more than 500 mutations have been identified, with the Pi*Z and Pi*S mutations being the most prevalent. Despite the growing understanding of these common variants, the knowledge regarding rare AATD mutations remains limited. Consequently, the objective of our study was to comprehensively compare the clinical phenotypes of patients with severe AATD caused by rare mutations with those with Pi*ZZ and Pi*SZ genotypes, as well as analyse their lung disease progression over time. In our investigation, we enrolled a total of 281 AATD patients from the Italian Registry for Alpha-1 Antitrypsin Deficiency (RIDA1) based on specific inclusion criteria. These criteria included a confirmed diagnosis of severe AATD, age above 18 years, voluntary consent to participate in the study, and the availability of comprehensive clinical data at the time of diagnosis as well as a three-year follow-up of respiratory function. We categorized them into three distinct cohorts based on their genotypes: Pi*ZZ genotype (n=160), Pi*SZ genotype (n=54), and rare genotypes Pi*R (n=67). Notably, we observed no statistically significant differences pertaining to gender, smoking habits, professional exposure, or age at the time of diagnosis within these sampled cohorts. Regarding the median alpha-1 antitrypsin (AAT) concentration in plasma, we found that Pi*R individuals exhibited a value of 30.5 mg/dL, Pi*SZ individuals displayed 62.0 mg/dL, and Pi*ZZ individuals exhibited 26.0 mg/dL. Statistical analysis revealed a significant disparity between the Pi*R and Pi*SZ cohorts (p-value=0.00017), as well as between the Pi*ZZ and Pi*SZ cohorts (p-value<0.00001). Moreover, our study revealed that Pi*R individuals exhibited clinical phenotypes and respiratory profiles that were akin to those of Pi*ZZ patients. Lung function tests, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and the FEV1/FVC ratio, indicated comparable results between Pi*R and Pi*ZZ patients at both T0 (initial assessment) and T1 (follow-up assessment). Although no statistically significant differences were observed among the three cohorts in terms of annual decline in lung function, it is worth noting that both Pi*R and Pi*ZZ populations exhibited a similar decline when compared to the Pi*SZ cohort. These findings underscore the critical importance of promptly diagnosing rare AATD variants to ensure effective clinical management and appropriate follow-up for affected patients. Moreover, individuals with Pi*R mutations should have equitable access to all available therapeutic options afforded to individuals with severe AATD. However, further comprehensive investigations are warranted to elucidate the diverse nature of rare variants and their associated clinical phenotypes. In conclusion, our study contributes valuable insights into the clinical presentation and disease progression of rare AATD mutations. By shedding light on the similarities and differences compared to more common mutations, this research emphasizes the necessity of tailored clinical approaches for patients with rare variants. Continued efforts in understanding the diverse landscape of AATD mutations will ultimately enhance patient care and lead to improved therapeutic strategies in the future.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/16043