Clinical trial NCT01810458: Liver Fibrosis in Alpha-1 Antitrypsin Deficiency (Liver AATD)
Official title: Clinical Predictors and Epigenetic Markers for Liver Fibrosis in Alpha-1 Antitrypsin Deficiency
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Liver Fibrosis
Alpha-1 Antitrypsin Deficiency
AAT Deficiency
AATD
Keywords: Liver
Fibrosis
Alpha-1
AAT
AATD
Lead sponsor: University of Florida
Sponsor class: OTHER
First posted: 2013-03-13
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Pulmonary clinic, hepatology clinic, and the Alpha-1 Antitrypsin Tissue and Data Bank.

Brief summary: We hypothesize that individuals with Alpha-1 Antitrypsin (AAT) deficiency have ongoing liver injury which is not detected by the usual blood tests used to look at liver function. This ongoing liver injury leads to cirrhosis in a significant number of adults with AAT deficiency.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: To estimate the prevalence and histologic spectrum of liver injury in an adult with Alpha-1 Antitrypsin deficiency having a ZZ genotype or other rare allele.
timeFrame: up to 30 days
Secondary outcomes:
measure: To identify environmental and host risk factors for clinically significant liver fibrosis.
timeFrame: At each study visit including screening, first liver biopsy, year 1, year 2, and year 3 visits.
measure: To define the diagnostic accuracy of non-invasive markers of fibrosis in AAT liver disease.
timeFrame: At the screening and year 3 visits.
measure: To explore epigenetic markers for the development of liver fibrosis.
timeFrame: Starting with the first liver biopsy and ending with the second liver biopsy done at year 3.
measure: To quantify liver fibrosis progression.
timeFrame: At each study visit including screening, first liver biopsy, year 1, year 2, and year 3 visits.
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: Shands at the University of Florida
state: Florida
Study officials:
affiliation: University of Florida
name: Mark Brantly, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Clark VC, Marek G, Liu C, Collinsworth A, Shuster J, Kurtz T, Nolte J, Brantly M. Clinical and histologic features of adults with alpha-1 antitrypsin deficiency in a non-cirrhotic cohort. J Hepatol. 2018 Dec;69(6):1357-1364. doi: 10.1016/j.jhep.2018.08.005. Epub 2018 Aug 21.