Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02124577 |
| Other study ID # |
140338 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 2014 |
| Est. completion date |
May 2021 |
Study information
| Verified date |
May 2021 |
| Source |
University of California, San Diego |
| Contact |
Leander A Lazaro |
| Phone |
619-471-3915 |
| Email |
llazaro[@]ucsd.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
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.
Description:
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.
