The liver produces a protein called alpha-1 antitrypsin (AAT). AAT is normally released into the bloodstream. In some people, the liver makes an abnormal version of AAT, called Z-AAT. Z-AAT builds up in liver cells and also leads to low blood levels of AAT (called Alpha-1 Antitrypsin Deficiency or AATD). Over time, this build up leads to different stages of liver problems, if not treated. This is called natural history of AATD.
The main aim of this study is to learn about liver problems caused by AATD in adults when not treated over 4 to 8 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 care, and describe how the AATD also affects an 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 complete questionnaires (called patient-reported outcomes or PROs).
Eligibility
Sex
ALL
Min age
18 Years
Max age
—
Healthy volunteers
No
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 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.
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), FibroScan (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 (i.e., index date +90 days).
4. Participants with prior participation in an interventional clinical trial evaluating liver or lung disease, or who have received an investigational AATD-directed therapy under a compassionate use program, will be excluded if they do not present one of the following:
* A minimum washout period of 6 months has elapsed since the last dose of the investigational product.
* A history of having received placebo in prior interventional trials (to be evaluated on a case-by-case basis).
Primary outcome measure(s)
Number of Participants With Liver Disease Progression — Baseline up to 8 years Liver disease progression will be defined as advancement in greater than or equal to (\>=)1 fibrosis stage: example any progression from fibrosis stage F0/F1 to F2, F1 to F2, F2 to F3 etc. and/or occurrence of any of these composite events: a) advancement in \>=1 fibrosis stage, b) development of a liver disease-related clinical event, c) model for end-stage liver disease (MELD) score increase, d) newly added on liver transplant list, e) receipt of a liver transplant. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis. The MELD score ranges from 6 to 40 with higher scores indicating more severe liver disease and a worse outcome.
Time to Liver Disease Progression — Baseline up to 8 years Time to liver disease progression is defined as time to advancement in \>=1 fibrosis stage (example F0/F1 to F2, F2 to F3 etc.) and/or time to the earliest of: Advancement in \>=1 fibrosis stage, or development of a liver disease-related clinical event, or MELD score increase or receipt/newly added to transplant list of a liver transplant. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis. The MELD score ranges from 6 to 40 with higher scores indicating more severe liver disease and a worse outcome.
Time to Liver Disease Trajectory — Baseline up to 8 years Time to liver disease trajectory is defined as time of transition from F0/F1 to F2, F2 to F3, F3 to F4, F4 to the first decompensating event or liver transplant/listing and first to second decompensating event and all subsequent decompensating events or liver transplant/listing. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.
Probability of Transition in Liver Disease Trajectory — Baseline up to 8 years Probability of liver disease trajectory is defined as probability of transition from F0/F1 to F2, F2 to F3, F3 to F4, F4 to the first decompensating event or liver transplant/listing and first to second decompensating event and all subsequent decompensating events or liver transplant/listing. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.
Percentage of Participants With Disease Regression — Baseline up to 8 years Disease regression is defined as decrease in \>=1 fibrosis staging. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.
Time to Liver Disease Regression — Baseline up to 8 years Time to liver disease regression is defined as time to decrease in \>=1 fibrosis stage. The fibrosis stages range from F0 to F4, with F0 indicating no fibrosis and F4 indicating cirrhosis.
Percentage of Participants With All-cause Mortality and Cause-specific Mortality — Baseline up to 8 years Cause-specific mortality is defined as mortality due to liver failure or complications of cirrhosis/portal hypertension or hepatocellular carcinoma, or infections secondary to liver failure.
Time to Death (All-causes) and Cause-specific Death (Liver Disease-specific Causes) — Baseline up to 8 years Cause-specific mortality is defined as mortality due to liver failure or complications of cirrhosis/portal hypertension or hepatocellular carcinoma, or infections secondary to liver failure.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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