Development of Kinetic Biomarkers of Liver Fibrosis Measuring NAFLD



Status:Not yet recruiting
Conditions:Gastrointestinal, Gastrointestinal, Gastrointestinal
Therapuetic Areas:Gastroenterology
Healthy:No
Age Range:18 - Any
Updated:4/2/2016
Start Date:May 2014
End Date:May 2019
Contact:Leander A Lazaro
Email:llazaro@ucsd.edu
Phone:619-471-3915

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Development of Kinetic Biomarkers of Liver Fibrosis Based on Stable Isotope Mass Spectrometry Techniques for Measuring Nonalcoholic Fatty Liver Disease NAFLD)

This is a small preliminary study conducted to explore new methods for the potential of
aiding in diagnosis of liver fibrotic disease as well as predicting disease progression.
There will be a total of 4 visits spread out over approximately 8 weeks. You will be asked
to drink "heavy water" during most of that time. "Heavy Water" also known as deuterated
water, is physically and chemically very similar to ordinary drinking water. It tastes and
feels exactly like regular water. It is odorless and has no known harmful effects at the
doses given here. Heavy water occurs naturally, and is a minor component of the water we all
ingest daily.

Management of NASH and NAFLD remain a significant unmet medical challenge that is growing in
importance as part of the obesity epidemic. Minimally invasive tools for monitoring disease
progression and evaluating therapeutic interventions in NASH would be extremely valuable.
Utilizing in vivo heavy water labeling, multiple pathways related to protein metabolism
(fibrogenesis) and lipid metabolism can be quantified in human subjects. We have recently
discovered that plasma lumicam synthesis represents a non-invasive kinetic biomarker of
tissue fibrogenesis in patients with viral hepatitis. In addition, synthesis of fatty acids
in plasma VLDL-triglycerides provide a window into hepatic lipid metabolism.

Stable isotopes have a long history as a safe, effective tracer for measuring synthesis of
molecules in humans (1). Recently, new developments in stable isotope labeling techniques
and advances in mass spectrometry have made in vivo kinetic measurement of slow metabolic
processes possible. Through the use of 2H2O as the source of labeling, we and others have
measured T-cell proliferation (2), mammary epithelial cell proliferation (3), prostate
epithelial cell proliferation (4), triglyceride synthesis (5) and protein synthesis (6) in
humans. We have recently evaluated this approach for the measurement of fibrogenesis
patients with fibrotic liver disease.

Excess accumulation of collagen in the liver is termed fibrosis. Fibrosis is a common
pathological feature of several chronic liver diseases (e.g. Hepatitis C, alcoholic liver
disease, primary biliary sclerosis, drug/toxin induced liver disease, etc.). Currently, the
standard method for detection of fibrosis is liver biopsy and histochemical analyses of
tissue collagen content (8, 9). Although effective in diagnosing existing, advanced
fibrosis, a single biopsy cannot measure current disease activity or predict rate of
progression. To determine whether disease is progressing using current methods, a second
biopsy is required. If significant additional collagen has accumulated since the first
biopsy, this suggests that the disease is progressing. However, this measurement represents
the history of the disease, not the current disease activity at the time of the second
biopsy. There are also significant limitations in current methods, since changes in collagen
pool size measurable by histochemistry cannot measure small changes in collagen content and
intra-laboratory variability inherent in histochemical assays reduce their sensitivity (10,
11).

This stable isotope / mass spectrometry based method will be applied here for the
quantification of fibrogenesis in vivo (from a bone marrow biopsy) and the identification of
novel biomarkers of fibrogenesis in plasma in patients receiving investigational therapies.

If successful, this research will identify plasma proteins which can be easily measured by
tandem mass spectrometry (LC/MS/MS) methods and whose synthesis rate reflects disease
activity in the heart. Ideally, a set of markers related to NASH/ NAFLD will be developed
that can detect and differentiate among multiple disease phenotypes, based on the kinetic
signature measured in a single blood draw from a patient labeled with deuterated water.

The role of de novo lipogenesis (DNL) has been suggested by several clinical studies
(Donnelly JCI 2005, Puri Hepatology 2009). DNL contributes significantly to the accumulation
of lipid in NASH (Donnelly JCI 2005). Moreover DNL is elevated in many other inflammatory
states and may be a useful marker of hepatic inflammation. DNL as well as hepatic TG
assembly and cholesterogenesis are easily measured in plasma or dried blood spot samples
from patients consuming 2H2O, after several days of labeling the plasma DNL reaches a steady
state and reflects hepatic DNL rates.

Inclusion Criteria:

1. Adults (≥ 18 years of age)

2. Adult male and female subjects, all races, ethnic groups, social and economic
backgrounds and health status who are scheduled to undergo a liver biopsy as part of
routine medical care will be included in the research.

3. Willingness to follow-up for 8 weeks

4. Written inform consent.

Exclusion Criteria:

1. Children younger than 18 will be excluded, since growth of liver tissue may confound
measurements of collagen synthesis and cell proliferation due to normal turnover or
disease.

2. The eligibility of patients will be determined by Dr. Rohit Loomba, MD or a referring
physician at the time the potential subject is recommended to undergo a liver biopsy
procedure as part of their medical treatment.
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