Biomarkers of Liver Fibrosis
Biomarkers of Liver Fibrosis
Chronic liver injury leads to the accumulation of proteins in the liver that form dense
 scars. Liver scar formation is typically a slow process that leads to major organ damage and
 loss of function over the course of many years. During scar formation the extracellular
 matrix in the liver changes. The type and quantity of extracellular collagen and other
 proteins change during tissue remodeling. Some of these changes can be detected by analyzing
 factors present in blood. Because of the lengthy time course, changes in the rate of liver
 scar formation and regression are very difficult measure; however, accurate measurements are
 needed in order to conduct trials of interventions aimed at preventing scar formation and/or
 promotion scar regression. Current methods have sub-optimal specificity and selectivity. The
 long term objective of the study is to identify serum proteins that can be used to accurately
 estimate rates of liver fibrosis progression and regression. The project focusses on a novel
 methodology that uses stable isotope labeling with deuterated water, D2O, to tag
 newly-synthesized proteins. Mass spectroscopy is used to identify individual proteins and to
 quantify the ratio of labeled protein to total protein. This ratio provides information about
 the rate of synthesis of the protein of interest. This method will be applied to specimens
 from patients with hepatitis C virus (HCV) infection who are about to begin HCV treatment.
 Treatment is known to reduce liver inflammation and collagen content.
Chronic liver injury leads to the accumulation of proteins in the liver that form dense
 scars. Liver scar formation is typically a slow process that leads to major organ damage and
 loss of function over the course of many years. During scar formation the extracellular
 matrix in the liver changes. The type and quantity of extracellular collagen and other
 proteins change during tissue remodeling. Some of these changes can be detected by analyzing
 factors present in blood. Because of the lengthy time course, changes in the rate of liver
 scar formation and regression are very difficult measure; however, accurate measurements are
 needed in order to conduct trials of interventions aimed at preventing scar formation and/or
 promotion scar regression. Current methods have sub-optimal specificity and selectivity. The
 long term objective of the study is to identify serum proteins that can be used to accurately
 estimate rates of liver fibrosis progression and regression. The project focusses on a novel
 methodology that uses stable isotope labeling with deuterated water, D2O, to tag
 newly-synthesized proteins. Mass spectroscopy is used to identify individual proteins and to
 quantify the ratio of labeled protein to total protein. This ratio provides information about
 the rate of synthesis of the protein of interest. This method will be applied to specimens
 from patients with hepatitis C virus (HCV) infection who are about to begin HCV treatment.
 Treatment is known to reduce liver inflammation and collagen content.

 The main questions being addressed are whether the regression of scar in the liver can be
 predicted based on the half-life of serum proteins and what is the identity of the proteins
 that are the best indicators of liver scar formation and regression.

 The long term goal of the study is to develop a non-invasive test that can be used to
 estimate the extent of liver fibrosis and the rate of liver fibrosis generation and
 regression. Such a marker could be used to test drugs that promote fibrosis regression and/or
 prevent fibrogenesis and it could also be used to provide patients and healthcare providers
 with information about the extent of liver scarring.

 Research is being done around the globe to determine develop innovative methods to accurately
 determine liver status. A metabolic labeling method will be tested in this project. This
 approach is based on the concept that liver status can be determined by measuring the ratio
 of newly-synthesized/pre-existing proteins. Patients will be given "heavy water" to drink.
 Heavy water contains D20. Deuterium is a stable isotope of hydrogen. Deuterium is not
 radioactive. It has been given to many patients and is considered to be entirely safe when
 administered according to the protocol that will be used in this study. Proteins that are
 synthesized during D20 labeling contain D20. Mass spectrometry is used to determine the
 percentages of scar proteins (and other indicator proteins) that are newly-synthesized. The
 analysis can be performed on a variety of tissues and bodily fluids. In this study,
 measurements will be made on blood, saliva, and urine samples from all the participants.
 Study subjects will be given the option of undergoing liver biopsy. The D20 content of biopsy
 tissue will be determined for the patients who elect this option.

 The study group for this investigation is comprised of patients with chronic hepatitis C
 virus (HCV) infection who are about to begin HCV treatment. It is well established that HCV
 treatment reduces the amount of inflammation and scar in the liver. New treatments for HCV
 are far more effective and less toxic than earlier treatments. The treatment-induced changes
 in inflammation and hepatic scarring will impact the ratio of proteins in the metabolic
 labeling study. The rate of synthesis of scar proteins will go down and the ratio of
 new/pre-existing protein will change. Metabolic labeling data will be compared to other data
 about liver status, such as values of serum markers, liver stiffness measurements, and liver
 histopathology (when available).

 Research will be performed at the Mount Sinai Medical Center, with coded, but de-identified
 specimens analyzed at Kinemed Patients initiating treatment for HCV infection are the source
 of potential subjects.

 The final study group is expected to include 40 subjects. We expect about 2/3 of subjects who
 are approached to agree to participate and to sign the consent document. We expect 90% of the
 40 subjects to complete the first 6 months of the study and we expect 80% to complete the
 entire study.

 This is a single center study The duration of an individual subject's participation in the
 study: 36 months (including all follow up) The duration anticipated to enroll all study
 subjects: 6 months
Inclusion Criteria:

 -  Adult (18 years of age or older)

 -  Positive test for HCV RNA

 -  Planning to initiate treatment for HCV in the near future

 -  Not diagnosed with any additional liver diseases, such as autoimmune hepatitis,
 hepatitis B, alcoholic liver disease, or HIV

 -  Able to travel to Mount Sinai

 -  Must understand and speak English

 -  Willing to sign informed consent and participate

 Exclusion Criteria:

 -  Pregnancy

 -  Incarcerated Person