Liver Fibrosis in Alpha-1 Antitrypsin Deficiency (Liver AATD)

Our overarching hypothesis is that liver disease in adults with AAT deficiency is the result
of the accumulation of the abnormally folded protein within the endoplasmic reticulum of the
hepatocyte. In some individuals, the intrinsic cellular mechanisms of the hepatocyte are
sufficient to clear adequate amounts of the abnormally folded protein such that liver disease
does not occur. In AAT deficient individuals who develop liver disease, environmental and
other genetic factors stress the hepatocyte, and the normal cellular mechanisms that maintain
homeostasis are disrupted, leading to liver disease.

For this proposal, our hypothesis is that the prevalence of liver disease in adults with AAT
is higher than previously reported because liver injury and fibrosis is not accurately
detected by available routine liver testing. Testing this hypothesis will require an initial
evaluation for liver disease with liver function testing and imaging, and then histologic
confirmation by liver biopsy.

Inclusion Criteria:

- Alpha-1 Antitrypsin deficiency confirmed to be PI*ZZ by both genotype or another
identified rare allele;

- Age range from 18-70;

- Willingness to consent to liver biopsy;

- Ability to travel to UF as necessary by protocol; and

- Platelet count greater than or equal to 50,000/mm3 and an INR less than or equal to
1.5.

Exclusion Criteria:

- Hemophilia, anticoagulant therapy that cannot be interrupted briefly, malignancy, or
any other condition that would compromise the safety of a liver biopsy;

- Any known pre-existing medical condition that might interfere with the patient's
participation in and completion of the study or any condition, which in the opinion of
the investigator would make the patient unsuitable for enrollment;

- Active substance abuse including, but not limited to, alcohol, intravenous or, inhaled
drugs;

- History of adverse reactions or allergy to the local anesthetic, sedative, or
pre-medication used for the percutaneous liver biopsy;

- Poor venous access making the subject unable to complete the required laboratory
testing schedule; and

- Females who are pregnant or lactating at time of enrollment. Should a female subject
become pregnant during the follow up period after the initial liver biopsy, continued
participation would be allowed if the following conditions are met: the subject
desires to continue; a discussion of risk and benefits of participation between the
principal investigator and the subject has occurred; and no liver biopsy would be
performed in the follow up period.