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PubMed2026

p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.

Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Livers from PiZ transgenic mice expressing the human Z-AAT and AATD patients who are homozygotes for the allele expressing Z-AAT were found to have increased p62/SQSTM1, a multifunctional protein involved in protein homeostasis. The goal of this study was to elucidate the involvement of p62/SQSTM1 in the formation of Z-AAT globules that are responsible for liver injury in AATD. In the present study, we found that p62/SQSTM1 decorated ubiquitin-positive, Periodic-Acid Shiff-diastase-resistant Z-AAT globules and interacted with Z-AAT at the ER-cytosol interface. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ;p62-/-) led to marked reduction in hepatic Z-AAT globules and polymers, and decreased serum Z-AAT, highlighting a central role for p62/SQSTM1 in disease pathogenesis. Moreover, hepatocyte-specific somatic deletion of the ubiquitin-association (UBA) domain of p62/SQSTM1 reduced Z-AAT aggregation. Furthermore, KEAP1 was identified as a binding partner of p62/SQSTM1-Z-AAT complex, leading to nuclear translocation and activation of NRF2. Inhibition of KEAP1-p62/SQSTM1 interaction reduced the abundance of p62 and phosphorylated p62, decreased intracellular Z-AAT, and redistributed NRF2 to the cytoplasm. In conclusion, this study identifies p62/SQSTM1 as a regulator of Z-AAT proteostasis and link Z-AAT/p62 accumulation to KEAP1 sequestration and NRF2 pathway activation in liver disease due to Z-AAT.

AATD↗

PubMed1979

Alpha 1-antitrypsin screening of 18-year-old men.

In 11 128 apparently healthy 18-year-old men screened for alpha 1-antitrypsin deficiency (AATD) 44 had an alpha 1-antitrypsin (AAT) level of 50% or less of the transferrin reference. In 42 of the 44 the Pi types were: five Pi Z, 10 Pi SZ, three Pi MZ, one presumptive Pi M-, one Pi FM, and 22 Pi M. Probably all Pi Z and most of the Pi SZ subjects were identified. The transferrin reference, however, is probably less reliable for the study of this age group, and alpha 1-antichymotrypsin may provide a more valid reference for the AAT screening procedure. In the clinical investigation the additive risk factor of smoking was discovered in eight of 15 individuals with AATD Pi Z or Pi SZ. We believe screening for Pi Z and probably also Pi SZ AATD should be done before young people start smoking or train for jobs in polluted environments.

Adolescent↗

PubMed1989

Pressure-volume curves in smokers. Comparison with alpha-1-antitrypsin deficiency.

The diagnosis of emphysema has been associated with changes in the appearance of the pressure-volume (P-V) curve: reduced maximal recoil pressure, increased lung volume, and a shift in the position of the curve to the left. In our clinical practice, we have observed that patients with chronic obstructive lung disease (COPD) commonly had P-V curves with reduced maximal elastic recoil that are difficult to classify according to the classic description of the P-V curve in emphysema. In order to study the variability of P-V curves, we studied 39 cigarette smokers attending a pulmonary clinic (age, 61 +/- 1 yr; smoking history, 45 +/- 3 pack-years; mean +/- SEM) and compared them with 20 patients with alpha-1-antitrypsin deficiency (AATD) (age, 41 +/- 2 yr; 13 smokers with a smoking history of 17 +/- 2 pack-years, and seven nonsmokers). Subjects underwent spirometry, lung volume, and diffusing capacity measurements as well as static deflation P-V curves. To characterize the P-V curves, we used transpulmonary pressure at 90% of TLC (PL90) as a measure of overall recoil and specific compliance (Csp) as a measure of the slope of the initial part of the P-V curve. The curves of non-AATD smokers were classified into three groups: 13 had PL90 greater than or equal to 80% predicted (Group I), 13 had PL90 less than 80% predicted and Csp greater than or equal to 0.08 (Group II), and 13 had PL90 less than 80% predicted and Csp less than 0.08 (Group III).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2026

Advances in Precision Editing Therapies for Alpha-1 Antitrypsin Deficiency.

Genome and RNA editing modalities have revolutionized precision gene therapy, offering a safer alternative to traditional gene replacement approaches. Alpha-1 antitrypsin deficiency (AATD) is a compelling model for precision medicine because the disease mechanism is well defined-mutations in a single gene are responsible for both liver and lung pathology. In this review, we summarize the current preclinical and clinical efforts for AATD, with an emphasis on genome and RNA editing strategies.

Humans↗

PubMed1975

Liver pathology in alpha1-antitrypsin deficiency. A review.

Alpha1-antitrypsin deficiency (AATD), in addition to its association with chronic pulmonary disease, is reported with liver disease. Twenty per cent of Pi-type ZZ AATD infants present with a cholestatic type of neonatal hepatitis and develop a slowly progressive cirrhosis, and most die before adult life. Ten per cent of Pi-type ZZ adults develop cirrhosis. They have an increased frequency of primary liver carcinoma. In Z homozygotes and heterozygotes specific globules, due to accumulation of a type of alpha1-antitrypsin, are seen in liver cells. They are thought not to be hepatotoxic but to render the liver cell more susceptible to damage by an additional factor.

Adult↗

PubMed1975

Alpha1-antitrypsin deficiency--an association with hepatic malignancy.

A 70-year-old man with homozygous alpha1-antitrypsin deficiency (AATD) (Pi-ZZ phenotype) at tutopsy was found to have a hepatocellular carcinoma and hepatic fibrosis, pulmonary emphysema, and cor pulmonale. Characteristic cytoplasmic inclusion bodies, with identical histochemical and ultrastructural features, were detected in both normal and malignant liver cells. It is suggested that AATD may precede malignancy, since this is the eleventh case report of this association.

Aged↗

PubMed1991

Alpha 1-antitrypsin deficiency.

alpha 1-Antitrypsin (AAT) is a polymorphic protein with many variants collectively known as the Pi system. The most common alleles are the M, S and Z, which are co-dominantly inherited. Infants with PiZZ have approximately 16% of the normal AAT serum concentration. alpha 1-Antitrypsin deficiency (AATD) is an inborn error of metabolism which is principally associated with liver disease in children and emphysema in young adulthood. Individuals with AATD produce an abnormal protein which accumulates in the liver, resulting in decreased serum levels. Affected individuals cannot protect their lungs from digestion by elastase. Smoking is a significant risk factor for the early development of emphysema. Prolastin, human alpha 1-protease inhibitor, is now available as replacement therapy. Weekly intravenous administration, with the goal of maintaining the serum AAT greater than 80 mg/dl, appears to arrest pulmonary damage. Its effect on liver disease is unknown at this time. A recombinant alpha 1-protease inhibitor is being tested in aerosol form with promising early results.

Humans↗

PubMed2026

Exploring Professional Experiences in Caring for Vulnerable Migrants in an Italian Rural Reception Centre: A Qualitative Study Using Multidimensional Textual Analysis-Professional Experiences in Rural Migrant Care.

AIM: This study aims to explore the experiences, strengths, challenges, and potential improvements for professionals in managing the complex needs of vulnerable migrants (VM) in an Italian rural reception centre. METHODS: A qualitative study using semi-structured interviews was conducted in April 2024. Data were analysed using the Automatic Analysis of Textual Data, based on Fraire's seven-step model for Exploratory Multidimensional Data Analysis. DATA SOURCES: Data were collected from 16 professionals working in a rural reception centre in southern Italy. Interviews were conducted and analysed using AATD in April 2024. FINDINGS: The analysis identified two main dimensions of professionals' roles: balancing systemic responsibilities with personal engagement and managing immediate needs versus long-term integration goals. Professionals face significant challenges, such as resource scarcity, bureaucratic inefficiencies, and emotional fatigue, which impact their well-being and the quality of care provided to migrants. Resilience, adaptability, and multidisciplinary collaboration were identified as key strengths. CONCLUSION: The study highlights the dual nature of professionals' work in reception centres, requiring them to balance operational tasks with emotional involvement in migrant care. Targeted interventions and systemic reforms are necessary to support professionals and enhance the quality of care for vulnerable migrants, particularly in resource-constrained rural settings. IMPLICATIONS FOR PRACTICE AND/OR PATIENT CARE: This study underscores the importance of providing targeted support to professionals working in reception centres, including training in intercultural competence, stress management, and coping strategies. Policies should address systemic challenges and provide resources to enhance healthcare delivery and social integration programs. REPORTING METHOD: This study adhered to the EQUATOR guidelines for reporting qualitative research (COREQ). The findings were reported in compliance with these guidelines, ensuring methodological rigour and transparency. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study highlights the critical need for targeted support and training for professionals working in reception centres, particularly in rural settings. To improve care for vulnerable migrants, professionals should receive training in intercultural competence, stress management, and coping strategies to better navigate the complex challenges they face. Furthermore, systemic changes are necessary to alleviate the pressures on reception centres, such as streamlining bureaucratic processes and enhancing healthcare infrastructure, particularly in rural areas where resources are limited. By addressing these needs, we can improve the well-being of both the professionals and the migrants they serve, fostering more effective support systems and better care outcomes. Additionally, fostering multidisciplinary collaboration and community engagement can contribute to more comprehensive and sustainable care models. PROTOCOL REGISTRATION: The Ethics Committee of the University of Rome Tor Vergata approved this study on 07/07/2021 (protocol registration number 160.21).

Humans↗

PubMed2024

Editing Approaches to Treat Alpha-1 Antitrypsin Deficiency.

TOPIC IMPORTANCE: Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder most commonly due to a single G to A point mutation (E342K), leading to debilitating lung and/or liver disorders and is associated with increased mortality. The E342K point mutation causes a conformational change of the AAT protein resulting in its retention in liver hepatocytes. This reduces AAT secretion into the serum resulting in higher protease activities due to the lack of inhibition from AAT, causing damage to healthy lung tissue. The current standard of care for lung manifestations involves weekly IV augmentation therapy and is considered suboptimal for these patients. Furthermore, there is currently no approved treatment for liver manifestations. The unmet medical need for patients with AAT deficiency remains high, and new treatment options are needed to treat the underlying disease etiology. REVIEW FINDINGS: Advances in genomic medicines may enable treatment by editing the DNA or RNA sequence to produce wild-type AAT instead of the mutated AAT caused by the E342K mutation. One approach can be achieved by directing endogenous adenosine deaminases that act on RNA to the E342K RNA site, where they catalyze adenosine to inosine conversion through a process known as RNA editing. The A-I RNA change will be read as a G during protein translation, resulting in an altered amino acid and restoration of wild-type AAT secretion and function. SUMMARY: In this review, we will discuss the pathophysiology of AAT deficiency and emerging treatment options with particular focus on RNA editing as a disease-modifying treatment for both liver and lung disease.

alpha 1-Antitrypsin Deficiency↗