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Results for “alpha 1-Antitrypsin Deficiency”

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At least 19 recordsLinked to original sources
PubMed1975

Heterozygous alpha 1-antitrypsin deficiency and cirrhosis in adults, a fortuitous association.

Pi (protease inhibitor) genotype was determined in 394 healthy blood-donors, 132 adult patients with alcoholic cirrhosis, and 37 adult patients with cryptogenic cirrhosis. The frequency of the heterozygous genotype with a single allele Pi Z (heterozygous alpha 1-antitrypsin deficiency) was not different in blood-donors and in patients with cirrhosis. This finding suggests that the association of this heterozygous genotype with cirrhosis is not causal but fortuitous and that this heterozygous genotype does not increase susceptibility to cirrhosis due to other causes, in particular alcoholism.

Adult↗
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↗
PubMed2026

Loss of the Mechanistic Target of Rapamycin Complex 1 Causes a Lethal Alpha-1 Antitrypsin Deficiency-Associated Liver Disease.

BACKGROUND & AIMS: SERPINA1 mutations cause retention of the otherwise secreted alpha-1 antitrypsin and lead to the proteotoxic alpha-1 antitrypsin deficiency-related liver disease. As mechanistic target of rapamycin is a key coordinator of proteostasis, we studied its role in alpha-1 antitrypsin deficiency-related liver disease. METHODS: PiZ mice overexpressing the characteristic SERPINA1 mutation were mated with rodents harboring a hepatocyte specific-ablation of the interaction partners regulatory-associated protein of mechanistic target of rapamycin or rapamycin-insensitive companion of mammalian target of rapamycin, corresponding to mechanistic target of rapamycin complexes 1 or 2, or with mice lacking mechanistic target of rapamycin. Serum proteomics, liver bulk proteomics, spatial proteomics, and metabolomics were applied to characterize molecular and metabolic alterations. RESULTS: At 2 months of age, PiZ-mTORΔhep and PiZ-RaptorΔhep but not PiZ-RictorΔhep mice showed signs of increased liver injury and mortality despite diminished hepatic alpha-1 antitrypsin accumulation. PiZ-RaptorΔhep animals displayed increased levels of the proapoptotic protein C/EBP homologous protein, but C/EBP homologous protein ablation did not rescue the phenotype. Serum proteomics revealed no signs of advanced synthetic liver failure but immature hepatocellular products. Liver bulk proteomics and small metabolite measurement demonstrated a metabolic reprogramming of PiZ-RaptorΔhep mice. Spatial proteomics revealed alterations in liver zonation with increased ammonia levels as the likely cause of death in PiZ-RaptorΔhep animals. CONCLUSIONS: In summary, in alpha-1 antitrypsin deficiency-related proteotoxic liver injury, regulatory-associated protein of mechanistic target of rapamycin preserves a liver zonation, thereby protecting from lethal metabolic dysregulation.

Animals↗
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↗
PubMed2026

ALPHA-1 antitrypsin genotype, sex, and lung cancer: Clinical and molecular characterisation.

INTRODUCTION AND OBJECTIVES: Alpha-1 antitrypsin deficiency is associated with lung and liver disease, but its role in lung carcinogenesis remains unclear. This study aimed to compare the clinical, functional, and molecular characteristics of lung cancer according to alpha-1 antitrypsin (AAT) genotype and, additionally, to explore differences by sex and the possible influence of environmental exposures. PATIENTS AND METHODS: We conducted a cross-sectional, single-centre study including 407 patients with incident lung cancer diagnosed between 2020 and 2023. Clinical, functional, radiological, molecular, and environmental variables were collected. Comparisons were performed between carriers and non-carriers of altered AAT alleles and between women and men. RESULTS: Of the 394 patients with available genotyping, 24.4% carried at least one altered allele. No significant differences were observed by genotype in smoking status, radon exposure, comorbidities, lung function, or histological subtype. Carriers showed significantly lower serum AAT levels and a higher frequency of values&#x2009;<&#x2009;116&#x2009;mg/dL (p&#x2009;<&#x2009;0.001). PD-L1 expression&#x2009;&#x2265;&#x2009;50% was more common in carriers (28.1% vs. 19.4%; p&#x2009;=&#x2009;0.036). In the multivariable analysis, the altered AAT genotype remained independently associated with a higher probability of PD-L1 expression&#x2009;&#x2265;&#x2009;50% (aOR&#x2009;=&#x2009;2.04; 95% CI: 1.09-3.80; p&#x2009;=&#x2009;0.026). Women had lower cumulative tobacco exposure, lower prevalence of emphysema and COPD, greater biomass exposure, higher frequency of adenocarcinoma, and more EGFR mutations (p&#x2009;<&#x2009;0.001). CONCLUSIONS: Patients carrying altered AAT alleles did not exhibit a distinctly different clinical profile, although they showed higher PD-L1 expression (&#x2265;50%). Furthermore, significant differences were observed between women and men in terms of exposure, histology and molecular alterations.

Humans↗
PubMed1975

Chronic pancreatitis and alpha-1-antitrypsin.

110 patients with proven chronic pancreatitis have been studied to assess the prevalence of the various Pi phenotypes of alpha1-antitrypsin in this disease compared with a control group of 116 blood-donors. The phenotype PiMZ (including Mweak) was significantly more prevalent and PiMM significantly less so in the patients with pancreatitis. It is possible that a heterozygous deficiency of this protease inhibitor renders the pancreas more vulnerable to aetiological agents (e.g., alcohol).

Blood Donors↗
PubMed1975

Physiological studies in a large sibship with antitrypsin deficiency.

A large sibship demonstrated the severe consequences of alpha-1 antitrypsin deficiency. Of II living sibs 6 were homozygous deficient (Pi type ZZ) and 5 heterozygous (Pi type MZ). The homozygous group showed severe obstructive ventilatory impairment by spirometry, marked abnormality of airway resistance and specific conductance with striking pulmonary hyperinflation. The heterozygous deficient group demonstrated a less severe obstructive defect by ventilation measurements with only marginal abnormality of airway resistance, specific conductance, and normal lung volumes. The evidence suggests that both the heterozygous and the homozygous states of alpha-1 antitrypsin deficiency are lung damaging.

Adolescent↗
PubMed1979

Polypoid gastric heterotopy of the small intestine in a patient with primary hyperparathyroidism and alpha-1-antitrypsin deficiency belonging to a MEA-family. With particular reference to the ultrastructure of the epithelial cells.

A patient with a solitary polypoid gastric heterotopy in the jejunum and severe bleeding as a complication is described. Previous reports on this rare disorder and the conditions of its development are discussed. The patient belongs to a family with multiple endocrine adenomatosis (MEA), some members of which had an alpha-1-antitrypsin deficiency. The association between the familial disease and the gastric heterotopy in this case might be another argument for the assumed congenital nature of the latter. The polyp was studied by means of light and electron microscopy. It was mostly lined by fundic mucosa and only partially by antral mucosa. Focal foveolar hyperplasia, cysts and lymphoplasmacellular infiltration of the mucosa are regarded as secondary tissue alteration. Parietal cells, chief and endocrine cells were identified. The parietal cells were in the nonsecreting state and appeared in two distinct forms which are described in detail.

Adult↗
PubMed2025

&#x3b1;1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization.

BACKGROUND: &#x3b1;1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. OBJECTIVE: To characterize the influence of SERPINA1 variation on asthma severity. METHODS: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and &#x3b1;1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. RESULTS: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by-ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, &#x3b1;1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in &#x3b1;1-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). CONCLUSIONS: SERPINA1 variation and &#x3b1;1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

Adult↗
PubMed1976

Serological investigations in 15 cases of bird fanciers disease.

Serological studies in 15 patients with bird fanciers disease are reported. Quantitative analysis of serum proteins showed elevation of IgG in almost every case. High IgE was observed in three patients with isolated asthmatic reactions. In four patients alpha1-antitrypsin was transiently diminished. Two of these had heterozygous deficiency of this protein (genotype MS and MZ). Precipitins against avian sera and avian droppings were found in all patients, but also in some exposed and nonexposed controls. Cross-reactions to avian antigens from different species were observed quite regularly in patients but not in controls. One case is presented suggesting that these cross-reactions may be of clinical importance. Precipitins against other inhaled antigens such as Aspergillus fumigatus, cereals or Micropolyspora faeni were observed significantly more frequently in patients than in controls. These precipitins showed no cross-reactions with those against avian antigens.

Adult↗