The main aim of this study is to learn about liver problems caused by the lack of alpha-1 antitrypsin (called Alpha-1 Antitrypsin Deficiency or AATD) in adults when not treated (this is called the natural history of a condition) over 5 years. Other aims are to learn what can predict the AATD-liver condition starting and getting better or worse, describe how this condition is currently being diagnosed and watched in normal hospital care, and describe how the AATD also affects and adult's lung function.

Data in this study will be collected to include medical history of a participant, including the date AATD was first identified and/or the date on which the first AATD-related liver or lung problems were diagnosed. At study start and then every year until study end, participants will be asked to completed questionnaires (called patient-reported outcomes or PRO).

Inclusion Criteria:

Participants who meet all the following criteria will be included in the study.

Cohorts 1 and 2:

1. Willing to provide written informed consent or currently enrolled in an ongoing participating AATD patient registry that does not require reconsenting to participate in the study.

2. >=18 years of age at enrollment in this study.

3. Participants with documented diagnosis of AATD, meeting the following criteria:

   1. Cohort 1 (AATD-Pi*ZZ genotype/phenotype).

      • Pi*ZZ genotype as documented from rapid genetic assay, sequencing, or polymerase chain reaction (PCR), or Pi*ZZ phenotype as documented from iso-electric focusing (IEF) electrophoresis.

   2. Cohort 2 (AATD-Pi*SZ genotype/phenotype with liver disease manifestation).

      • Pi*SZ genotype as documented from rapid genetic assay, sequencing, or PCR, or Pi*SZ phenotype as documented from IEF electrophoresis, and

      • Moderate-advanced or severe liver disease manifestation as defined by either liver biopsy or surrogate laboratory or imaging measures, as determined through:

        • Lab and imaging measures to define liver disease manifestation

Exclusion Criteria:

Participants who meet any following criteria will be excluded from the study.

1. Documented AATD genotype/phenotype other than Pi*ZZ or Pi*SZ.
2. History of liver transplant.
3. No results for either biopsies, magnetic resonance elastography (MRE), fibro scan (vibration controlled transient elastography [VCTE]), or Aspartate aminotransferase to platelet ratio index (APRI) in the 24 months prior to the index/enrollment date and has none of these tests ordered during the index period.
4. Participants who had previously been treated or in an active participation in an interventional trial studying liver or lung disease.
5. Treatment with liver directed AATD investigational therapy as part of a compassionate use request.

Participants who have already been diagnosed with AATD of genotype/phenotype Pi*ZZ, with mild or without liver disease manifestation, or with genotype/phenotype of Pi*SZ with moderate-advanced or severe liver disease manifestation.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.