• To define the course of AATD-associated liver disease.

• To use the obtained samples for biomedical research which includes:

  1. Search for serum-based disease biomarkers and the associated molecular pathways.
  2. Multi-omic spatial analysis of human AATD-LD.

AATD is one of the most common, potentially lethal genetic conditions and results from mutations in alpha-1 antitrypsin (AAT), an abundant serine protease inhibitor (SERPIN) produced primarily in hepatocytes. The majority of severe AATD cases result from a homozygous PiZ mutation termed PiZZ that leads to a rapid polymerization of the mutated protein and its retention in the endoplasmic reticulum (ER) of hepatocytes. The consecutive lack of AAT in circulation increases proteolytic digestion of lung tissue and predisposes to chronic obstructive pulmonary disease and lung emphysema. The hepatic AAT misfolding confers a proteotoxic stress and may lead to both pediatric and adult liver disease (pAATD-LD/aAATD-LD). The former becomes apparent as neonatal jaundice and constitutes one of the most common causes of pediatric liver transplantation while the latter emerges mostly at >40 years of age as significant liver fibrosis and occurs more frequently in subjects with metabolic risk factors such as obesity and diabetes mellitus.

Much less is known about pAATD-LD that is considered a more cholestatic condition with less obvious AAT accumulation. Moreover, the exact relationship between AAT accumulation and development of AATD-LD remains unclear.

A major obstacle when studying AATD-LD is the lack of a suitable experimental model system. While transgenic animals overexpressing PiZ have been widely used, they have several disadvantages such as presence of multiple PiZ copies as well as inability to reproduce pAATD-LD. To circumvent that, analyses of human specimen as well as human induced pluripotent stem cells (iPSC) derived hepatocyte like cells (HLCs) are essential. Therefore, our research aims to obtain further insights into the process of AAT accumulation as well as to delineate the mechanistic differences between pediatric and adult AATD-LD.

Inclusion Criteria:

• Adult patients (≥18 years) with genetically confirmed alpha-1 antitrypsin deficiency (Pi*ZZ genotype).
• Availability of longitudinal clinical follow-up data (minimum 5 years) within the AATD consortium.
• At least one documented liver assessment including liver stiffness measurement (LSM) and serum-based fibrosis markers.
• Availability of stored serum samples for proteomic analysis.
• For translational analyses: availability of liver tissue samples (pediatric or adult) and/or induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells.

Exclusion Criteria:

• Presence of other chronic liver diseases (e.g., viral hepatitis, autoimmune hepatitis) that may confound fibrosis assessment.
• History of liver transplantation prior to study inclusion.
• Incomplete clinical, laboratory, or follow-up data.
• Poor-quality or insufficient biological samples for proteomic or molecular analyses.
• Patients lost to follow-up or with unreliable longitudinal data

• Adult patients (≥18 years) with genetically confirmed alpha-1 antitrypsin deficiency (Pi*ZZ genotype).
• Availability of longitudinal clinical follow-up data (minimum 5 years) within the AATD consortium.
• At least one documented liver assessment including liver stiffness measurement (LSM) and serum-based fibrosis markers.
• Availability of stored serum samples for proteomic analysis.
• For translational analyses: availability of liver tissue samples (pediatric or adult) and/or induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells.