Alpha-1 Antitrypsin Deficiency Adult Liver Study

Alpha-1 Antitrypsin Deficiency (AATD) is a genetic disorder resulting in a low level of a
protein called alpha-1 antitrypsin (AAT). This deficiency can cause life-threatening liver
disease and/or lung disease at various ages. Some patients experience life-threatening liver
disease in childhood or liver cancer as adults. There is no specific treatment for AAT
related liver disease. Some patients develop emphysema as young adults, while some patients
remain healthy throughout their lives. Differences in the environment or in other genes may
explain such inconsistency in the disease.

The primary objective of this multi-center study is to assess the natural history of
individuals with Pi-ZZ AAT deficiency, identify biomarkers for the progression of liver
disease and construct a database capable of linking cohort data with repository biospecimens.
The secondary objective is to analyze components of the demographic, social, and family
history associated with more severe liver disease.

This study will examine the natural history of liver disease by recording participant's
family history, medical history, current health, laboratory test results, and medical
treatment(s). Participants may complete brief research questionnaires about their physical
and mental health, diet, alcohol intake, and smoke, environmental and occupational (work)
exposures.

At least 120 Pi-ZZ AAT deficient adults with no previous history of liver disease,
moderate-severe liver disease, or post liver transplant, will be enrolled at one of three
sites. Eligible subjects will participate in one of the following study arms:

1. Liver Biopsy

2. Known Severe Liver Disease - subjects not meeting Biopsy Group eligibility due to the
presence of advanced liver disease

3. Post Liver Transplant - subjects who have previously undergone a liver transplant

At the time of enrollment, each participant will be assigned a unique study identification
(ID) number. All participant information recorded and samples collected for the study will be
saved by this unique number. All blood, tissue and genetic samples collected will be sent to
a secured repository for future retrieval and study. The process of coding data and samples
lessens the chances of a breach in confidentiality.

The length of study participation, tests and activities performed specifically for research
will be determined by the enrollment group. Subjects in the Biopsy and Known Severe Liver
Disease groups participate in the study for 5 years (enrollment and four annual follow-up
visits). Both groups undergo a physical exam, diagnostic abdominal ultrasound, pulmonary
function testing and the collection of serum, plasma and blood for routine laboratory and
genetic testing (Induced Pluripotent Stem Cells (iPS cells), microRNA and DNA). However, only
the Biopsy Group participants undergo a liver biopsy and FibroScan at enrollment, and again
in Year 5. The liver tissue samples will help the researchers learn what causes liver disease
in some patients and how the liver disease progresses.

Subjects in the Post Liver Transplant group have a single study visit to record their
history, complete questionnaires and perform pulmonary function testing. In addition, whole
blood for DNA analysis will be collected from these participants.

Based on their study arm assignment, participants will receive copies of their diagnostic
abdominal ultrasound, pulmonary function test, routine laboratory test and liver biopsy
pathology results, to share with their primary care physician.

Liver Biopsy Group:

Inclusion Criteria

- Adults (≥ 18 years of age), with Alpha-1 Antitrypsin Deficiency

- Documented evidence Pi-ZZ phenotype or genotype

- Both genders, all races and ethnic groups

- Willingness to be followed for up to 5 years

Exclusion Criteria:

- Evidence of advanced liver disease defined by Child-Pugh Class B or C (score ≥ 7)

- Known advanced lung disease defined as forced expiratory volume at one second (FEV1) <
40 % of Predicted

- History of Organ Transplantation

- Known congenital or metabolic liver disease (e.g.: Wilson's, glycogen storage, cystic
fibrosis)or iron overload as evidenced by ≥ Grade 3 iron staining on a previous liver
biopsy

- Evidence of chronic hepatitis B (marked by the presence of HBsAg in serum) or
Hepatitis C (marked by the presence of anti-hepatitis C virus (HCV) or HCV RNA in
serum)

- Vascular disorders of the liver (e.g.: cardiac sclerosis, acute or chronic
Budd-Chiari, hepatoportal sclerosis, peliosis)

- Known HIV positivity

- Diagnosis of malignancy within the last 5 years

- Active substance abuse, that in the opinion of the study investigator, would interfere
with adherence to study requirements

- Concomitant severe underlying systemic illness or medical condition which in the
opinion of the investigator, would make the patient unsuitable for the study or would
interfere with completion of follow-up

- Inability to comply with the longitudinal follow-up as outlined in the protocol

- Failure of the participant to sign informed consent or Health Insurance Portability
and Accountability Act (HIPAA) documents

Known Severe Liver Disease Group:

Inclusion Criteria

- Adults (≥ 18 years of age), with alpha-1-antitrypsin deficiency

- Documented evidence PI-ZZ phenotype or genotype

- Documented evidence of portal hypertension or evidence of advanced liver disease
defined by Child-Pugh Class B or C (score ≥ 7), or previous liver biopsy with an Ishak
Fibrosis Score ≥ 4

- Both genders, all races and ethnic groups

- Willingness to be followed for up to 5 years

Exclusion Criteria

- History of Organ Transplantation

- Known congenital or metabolic liver disease (e.g.: Wilson's, glycogen storage, cystic
fibrosis) and iron overload as evidenced by ≥ Grade 3 iron staining on a previous
liver biopsy

- Evidence of chronic hepatitis B (marked by the presence of HBsAg in serum) or
Hepatitis C (marked by the presence of anti-HCV or HCV RNA in serum)

- Vascular disorders of the liver (e.g.: cardiac sclerosis, acute or chronic
Budd-Chiari, hepatoportal sclerosis, peliosis)

- Known HIV positivity

- Diagnosis of malignancy within the last 5 years which in the opinion of the
investigator, would make the patient's follow-up problematic or the results
uninterpretable.

- Active substance abuse, that in the opinion of the study investigator, would interfere
with adherence to study requirements

- Concomitant severe underlying systemic illness or medical condition which in the
opinion of the investigator, would make the patient unsuitable for the study or would
interfere with completion of follow-up

- Inability to comply with the longitudinal follow-up as outlined in the protocol

- Failure of the participant to sign informed consent or HIPAA documents.

Post Liver Transplant Group

Inclusion Criteria

- Adults (≥ 18 years of age), with alpha-1-antitrypsin deficiency

- Pre-transplant documented evidence of PI-ZZ phenotype or genotype

- Documented evidence of liver transplantation

- Both genders, all races and ethnic groups

Exclusion Criteria

- Active substance abuse, that in the opinion of the study investigator, would interfere
with adherence to study requirements

- Concomitant severe underlying systemic illness or medical condition which in the
opinion of the investigator, would make the patient unsuitable for the study or would
interfere with completion of study requirements

- Failure of the participant to sign informed consent or HIPAA documents.