Alpha-1-antitrypsin phenotypes in adult liver disease patients

The maintenance of proteome homeostasis, or proteostasis, is crucial for preserving cellular functions and for cellular adaptation to environmental challenges and changes in physiological conditions. The capacity of cells to maintain proteostasis requires precise control and coordination of protein synthesis, folding, conformational maintenance, and clearance. Thus, protein degradation by the ubiquitin–proteasome system (UPS) or the autophagy–lysosomal system plays an essential role in cellular functions. However, failure of the UPS or the autophagic process can lead to the development of various diseases (aging-associated diseases, cancer), thus both these pathways have become attractive targets in the treatment of protein conformational diseases, such as alpha 1-antitrypsin deficiency (AATD). The Z alpha 1-antitrypsin (Z-AAT) misfolded variant of the serine protease alpha 1-antitrypsin (AAT) is caused by a structural change that predisposes it to protein aggregation and dramatic accumulation in the form of inclusion bodies within liver hepatocytes. This can lead to clinically significant liver disease requiring liver transplantation in childhood or adulthood. Treatment of mice with autophagy enhancers was found to reduce hepatic Z-AAT aggregate levels and protect them from AATD hepatotoxicity. To date, liver transplantation is the only curative therapeutic option for patients with AATD-mediated liver disease. Therefore, the development and discovery of new therapeutic approaches to delay or overcome disease progression is a top priority. Herein, we review AATD-mediated liver disease and the overall process of autophagy. We highlight the role of this system in the regulation of Z-variant degradation and its implication in AATD-medicated liver disease, including some open questions that remain challenges in the field and require further elucidation. Finally, we discuss how manipulation of autophagy could provide multiple routes of therapeutic benefit in AATD-mediated liver disease.

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Alpha-1-antitrypsin deficiency and juvenile liver disease Ultrastructural observations compared with light microscopy and routine liver tests

Virchows Archiv B Cell Pathology Including Molecular Pathology ◽

10.1007/bf02890156 ◽

1983 ◽

Vol 44 (1) ◽

pp. 15-33 ◽

Cited By ~ 14

Author(s):

Antal Németh ◽

Birgitta Strandvik ◽

Hans Glaumann

Keyword(s):

Liver Disease ◽

Light Microscopy ◽

Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin ◽

Liver Tests

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Advances in Alpha-1-Antitrypsin Deficiency Liver Disease

Current Gastroenterology Reports ◽

10.1007/s11894-013-0367-8 ◽

2013 ◽

Vol 16 (1) ◽

Cited By ~ 26

Author(s):

Jeffrey H. Teckman ◽

Ajay Jain

Keyword(s):

Liver Disease ◽

Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin

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Motion – All Patients with NASH Need to Have a Liver Biopsy: Arguments against the Motion

Canadian Journal of Gastroenterology ◽

10.1155/2002/614302 ◽

2002 ◽

Vol 16 (10) ◽

pp. 722-726 ◽

Cited By ~ 20

Author(s):

Jacqueline Laurin

Keyword(s):

Liver Disease ◽

Liver Biopsy ◽

Chronic Liver Disease ◽

Chronic Liver ◽

Nonalcoholic Fatty Liver ◽

Histological Assessment ◽

Clinical Benefits ◽

Liver Biopsies ◽

Alpha 1 Antitrypsin ◽

Iron Profile

Most cases of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are suspected on the basis of the exclusion of viral, autoimmune, metabolic and genetic causes of chronic liver disease in patients with chronic elevation of aminotransferase enzymes. However, the definitive diagnosis of NASH requires liver biopsy. Valuable blood tests include hepatitis B and C serology, iron profile, alpha 1-antitrypsin phenotype, ceruloplasmin, antinuclear antibody and antismooth muscle antibody, and serum protein electrophoresis. If these tests are negative or normal, and if there are no symptoms or signs of chronic liver disease, it is unlikely that a specifically treatable liver disease would be discovered at biopsy. The prevalence of NAFLD in the general population appears to be approximately 20%, and 2% to 3% of people have NASH. There is no proven specific therapy for the spectrum of nonalcoholic liver disease; therefore, the management of the patient with NASH is not likely to be changed after histological assessment. Bleeding, sometimes fatal, and other complications requiring hospitalization can occur, and liver biopsies should not be undertaken without clear clinical indications. The high cost of undertaking histological assessment of all persons with asymptomatic elevations of liver enzymes cannot be justified in view of the risks and limited clinical benefits.

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

Respiratory Research ◽

10.1186/s12931-021-01842-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Alexa Núñez ◽

Irene Belmonte ◽

Elena Miranda ◽

Miriam Barrecheguren ◽

Georgina Farago ◽

...

Keyword(s):

Liver Disease ◽

Genetic Diseases ◽

Sandwich Elisa ◽

Liver Stiffness ◽

Cross Sectional Study ◽

Control Group ◽

Cross Sectional ◽

Impaired Lung Function ◽

Alpha 1 Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin

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.

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