Development of Kinetic Biomarkers of Liver Fibrosis Measuring NAFLD

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.

Study Overview

• Status: Recruiting
• Conditions: Non-alcoholic Fatty Liver Disease

Detailed 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.

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

• Study Contact: Name: Leander A Lazaro; Phone Number: 619-471-3915; Email: llazaro@ucsd.edu
• Study Contact Backup: Name: Phirum Nguyen; Phone Number: 619-471-0774; Email: psnguyen@ucsd.edu

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • Recruiting
      • University of California, San Diego
      • Contact: Leander A Lazaro; Phone Number: 619-471-3915
      • Contact: Phirum S. Nguyen; Phone Number: 619-471-0774; Email: psnguyen@ucsd.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Adults, age 18 or above, may have NAFLD or NASH-related cirrhosis or may serve as a control participant without this condition.

Description

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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
evaluate stable isotope/mass spectrometric methods	Our primary aim is to evaluate stable isotope/mass spectrometric methods for measuring in vivo liver collagen synthesis (fibrogenesis) and liver lipogenesis rates using liver biopsy specimens from patients with Non-Alcoholic Steatohepatitis (NASH)/ Nonalcoholic fatty liver disease (NAFLD).	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
serum or urine markers of liver fibrogenesis that can be measured by the same stable isotope/mass spectrometric approach	Our secondary aim is to look for new serum or urine markers of liver fibrogenesis that can be measured by the same stable isotope/mass spectrometric approach in the same subjects. Subjects will drink the safe, non-toxic stable isotope heavy water (2H2O, deuterated water) prior to having a liver biopsy and providing urine and blood samples.	Baseline

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: KineMed
• Investigators: Principal Investigator: Rohit Loomba, MD, University of California, San Diego

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Anticipated): May 1, 2021
• Study Completion (Anticipated): May 1, 2021

Study Registration Dates

• First Submitted: April 24, 2014
• First Submitted That Met QC Criteria: April 24, 2014
• First Posted (Estimate): April 28, 2014

Study Record Updates

• Last Update Posted (Actual): May 6, 2021
• Last Update Submitted That Met QC Criteria: May 3, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Fibrosis; Liver Diseases; Fatty Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: 140338