Development of a Novel Biomarker for Liver Fibrosis

The overall aim of this study is to validate a quantitative digital tool for staging liver fibrosis in biopsies from chronic human liver diseases and then evaluate it prospectively in patients.

Study Overview

• Status: Completed
• Conditions: Liver Fibrosis

Detailed Description

Preliminary data suggest that cholesterol and retinoid metabolism are tightly linked in these cells, prompting us to examine this relationship in the setting of obesity and diabetes. Specific aims have been developed to test the following hypotheses: 1) Quantifying liver fibrosis as a continuous variable will predict clinically significant outcomes in fatty liver disease related to metabolic syndrome; and 2) In a prospective cohort of patients, quantified liver fibrosis will correlate more strongly with tissue and circulating retinoid metabolites than with other, commonly measured serum markers.

This study offers a major innovation by performing accurate fibrosis quantification without any human intervention or post-analysis correction. In addition, we can test whether subtle differences in quantified fibrosis impact outcome for a given clinical stage of disease severity, possible because we are measuring fibrosis as a continuous variable, not a categorical one. We are using a disease-independent approach to evaluate anti-fibrotic agents in clinical trials and for evaluating other diagnostic markers.

We are also testing whether a novel diagnostic marker, retinoid storage, correlates with liver disease progression in humans. We propose to extend the study to address fatty liver disease, NAFLD/NASH, in the context of adult patients with abnormal liver tests, fatty liver identified on imaging, physical obesity, and diabetes. Clinical variables and outcomes to be recorded and analyzed include: morphology (age, gender, ethnicity, height, weight/BMI, waist circumference and steatosis on imaging studies); biochemistry (glucose intolerance or diabetes, complete blood counts, metabolic panels, liver function tests, cholesterol panels, insulin, and vitamin D levels); clinical outcomes (date of liver disease diagnosis and estimated duration of disease, listing on liver transplant list, occurrence of liver transplant or re-transplant, presence of cancer, and death); medications (current or previous prescribed, herbals, supplements taken for diabetes, dyslipidemia, hypertension, cardiovascular disease, or stroke); and disease exacerbation/modifying factors (presence of other chronic liver diseases such as NASH + HIV, liver toxins such as alcohol consumption, weight gain, or worsening diabetes).

Data will be collected from subjects who complete eight visits over a 24-month period. Assessments will include morphometric measurements, blood collection for laboratory analysis and completion of dietary history report.

• Study Type: Observational
• Enrollment (Actual): 25

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Clinical and Translational Research Center (CTRC)

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: Non-Probability Sample

Study Population

Adult subjects 18 years and older with at least one liver function test abnormality and body mass index > 20.

Description

Inclusion Criteria:

• Age >/= 18 years
• At least one liver function test abnormality (AST/SGOT, ALT/SOT, alkaline phosphatase, or bilirubin) defined as a value outside of the normal range at UCLA clinical labs. This must be present on at least two occasions within a 24 month consecutive period
• Any body mass index > 20
• One of the following:
• Clinical indication, according to standard of care assessment, for undergoing image-guided percutaneous (or transjugular) liver biopsy
• Eligible for weight loss (bariatric) surgery with fatty liver disease
• NAFLD/NASH patient who meets the above criteria and has already undergone a liver biopsy for diagnosis and disease staging
• NAFLD/NASH patient who meets above criteria but chooses not to participate in the liver biopsy, extra blood draws or the dietary assessment for the study.

Exclusion Criteria:

• Age < 18 years
• Current pregnancy
• Significant clinical co-morbidities that would preclude getting either a percutaneous or transjugular liver biopsy (i.e. platelets < 50, 000 or International Normalized Ratio (INR) > 1.5 or Hemoglobin < 8)
• Unwilling or unable to participate or consent.

Study Plan

How is the study designed?

Number of groups / cohorts

8

Cohorts and Interventions

Group / Cohort
normal weight; BMI 20-25
overweight; BMI 25-30
obese; BMI 30-35
morbidly obese; BMI > 35
non-diabetic; HgbA1c (<5.7%) and blood glucose (65-99 mg/dL) within normal range as defined at UCLA Clinical Lab
diabetic; HgbA1c (>6.5%) and blood glucose (>100 mg/dL) as defined at UCLA Clinical Lab
non-cirrhotic; Normal liver function tests (AST/SGOT, ALT, SGPT, alkaline phosphatase, bilirubin) as defined at UCLA Clinical Lab
dyslipidemic; Abnormal lipid profile (Total cholesterol >170 mg/dL, LDL >100 mg/dL, HDL >130 mg/dL, triglycerides >150 mg/dL) as defined at UCLA Clinical Lab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Clinical Outcomes-change over time	Date of liver disease diagnosis and estimated duration of disease, listing on liver transplant list, occurrence of liver transplant or re-transplant, presence of cancer (liver-related or otherwise), and death	Participants will be followed up to 24 months; measured outcomes at 8 timepoints

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Morphometric Outcomes-change over time	height, weight (BMI), waist circumference, and steatosis (fat) on imaging studies	Participants will be followed up to 24 months; measured outcomes at 8 timepoints

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Biochemical Outcomes-change over time	presence of glucose intolerance or diabetes, complete blood counts with differential, complete metabolic panels with liver function tests, cholesterol panels, insulin, C-reactive protein, vitamin D levels, and hepatocellular carcinoma or other solid tumor cancer markers	Participants will be followed up to 24 months; measured outcomes at 8 timepoints

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Investigators: Principal Investigator: Simon Beaven, MD/PhD, UCLA Dept of Medicine, Division of Digestive Diseases

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): January 26, 2019
• Study Completion (Actual): February 26, 2019

Study Registration Dates

• First Submitted: January 14, 2015
• First Submitted That Met QC Criteria: January 22, 2015
• First Posted (Estimate): January 28, 2015

Study Record Updates

• Last Update Posted (Actual): April 17, 2019
• Last Update Submitted That Met QC Criteria: April 15, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: NAFLD, NASH
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: UL1TR000124-2016; UL1TR000124 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO