Development of a Novel Biomarker for Liver Fibrosis

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.

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.