Association between circulating alpha-1 antitrypsin polymers and lung and liver disease

Abstract

Background Alpha-1 antitrypsin deficiency (AATD) is considered one of the most common genetic diseases and is characterised by the misfolding and polymerisation of the alpha-1 antitrypsin (AAT) protein within hepatocytes. The relevance of circulating polymers (CP) of AAT in the pathogenesis of lung and liver disease is not completely understood. Therefore, the main objective of our study was to determine whether there is an association between the levels of CP of AAT and the severity of lung and liver disease. Method This was a cross-sectional study in patients with different phenotypes of AATD and controls. To quantify CP, a sandwich ELISA was performed using the 2C1 monoclonal antibody against AAT polymers. Sociodemographic data, clinical characteristics, and liver and lung parameters were collected. Results A cohort of 70 patients was recruited: 32 Pi*ZZ (11 on augmentation therapy); 29 Z-heterozygous; 9 with other genotypes. CP were compared with a control group of 47 individuals (35 Pi*MM and 12 Pi*MS). ZZ patients had the highest concentrations of CP (p < 0.001) followed by Z heterozygous. The control group and patients with Pi*SS and Pi*SI had the lowest CP concentrations. Pi*ZZ also had higher levels of liver stiffness measurements (LSM) than the remaining AATD patients. Among patients with one or two Z alleles, two patients with lung and liver impairment showed the highest concentrations of CP (47.5 µg/mL), followed by those with only liver abnormality (n = 6, CP = 34 µg/mL), only lung (n = 18, CP = 26.5 µg/mL) and no abnormalities (n = 23, CP = 14.3 µg/mL). Differences were highly significant (p = 0.004). Conclusions Non-augmented Pi*ZZ and Z-patients with impaired lung function and increased liver stiffness presented higher levels of CP than other clinical phenotypes. Therefore, CP may help to identify patients more at risk of developing lung and liver disease and may provide some insight into the mechanisms of disease.

Tracing genetic diversity captures the molecular basis of misfolding disease

“…Consistent with the clinical observations that serum polymer level can be used as a biomarker for liver disease 71,72 , the measured secreted polymer is strongly correlated with intracellular polymer for all the variants in both vehicle DMSO control (Supplementary Fig. 8b, left panel; Pearson's r = 0.92, P = 4.3 × 10 −31 ) and PU-WS13 treatment condition (Supplementary Fig.…”

“…8a). These results suggest that PU-WS13 has a broad impact on the AAT fold to decrease the polymer pools for around a half of the polymerogenic AAT variants, a metric highly relevant to monitoring liver disease in the patient population 32,[70][71][72] .…”

“…These results further suggest that GRP94 ATPase inhibition increases the tolerance of the ER for AAT folding in a manner that can differentially impact the monomer secretion and the NE inhibitory activity on a residue-by-residue basis. We next explored the impact of these changes on intracellular polymer accumulation-the hallmark of liver disease 32,[70][71][72] .…”

Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry

“…f p < 0.05 for comparison between the groups "Impaired FEV1(%) and normal PFTs" with healthy controls [35]. Some studies have suggested that there is a relationship between increased markers of systemic inflammation and the severity of lung and liver disease [36][37][38]. In our PI*ZZ patients, markers of systemic inflammation, such as increased neutrophils and platelets, were associated with more impaired FEV1(%), but this association was not observed in augmented patients.…”

Profiling Genetic Diversity Reveals the Molecular Basis for Balancing Function with Misfolding in Alpha-1 Antitrypsin

“…A deficiency of functional AAT disrupts the protease-antiprotease balance in the lung, triggering emphysema and COPD 14 . Polymers of AAT are also found to be secreted from liver and lung cells [15][16][17][18][19][20][21] that potentially contribute to inflammation and lung damage [22][23][24] . Compared with efforts focused on Z-AAT, the impact of the many other variants are poorly studied or completely unknown 3,5,7 .…”