Deciphering the Mechanisms Involved in Microbial Translocation Across the Spectrum of HCV Associated Liver Fibrosis

Cirrhosis

Chronic Hepatitis C, Cirrhosis, Liver Biopsy, Microbiome, Natural History

Background: \- Hepatitis C infection (HCV) is a leading cause of liver disease. Normal bacteria from the intestines may spread to the liver and blood during liver disease. This is called bacterial translocation (BT). Researchers think BT may cause liver disease to worsen. Objectives: \- To study the mechanisms involved in BT in early and advanced liver disease. To find out whether BT causes liver disease to worsen. Eligibility: \- People over age 18 with HCV and clinically stable liver disease. Design: * Participants will be screened with medical history and physical exam. They will have blood tests and imaging studies. * Participants will have 2 outpatient visits and a 3-day stay at the clinic. * At visit 1, participants will have urine and blood tests. They will have a magnetic resonance imaging (MRI) scan. A solution will be injected into a vein. The MRI scanner is a metal cylinder surrounded by a magnetic field. The participant will lie on a table that slides in and out of the cylinder. * At visit 2, a substance will be injected into a vein and swallowed. Participants will then have blood drawn 5 times over 90 minutes. * During the inpatient stay, serial blood tests will be drawn. * Participants will give 2 stool samples and have another MRI. * A needle will be inserted through the chest wall into a vein inside the liver, guided by ultrasound. The blood pressure inside this vein will be measured and blood will be drawn from it. About 1 inch of liver tissue will be removed. * A study investigator will call participants to discuss all test results.

Hepatitis C (HCV) is a leading cause of cirrhosis worldwide. Most complications associated with cirrhosis are driven by an altered portal circulation and the development of portal hypertension. Bacterial translocation (BT) from the gut to the systemic circulation is considered a pivotal mechanism contributing to the development of life-threatening complications in end stage cirrhosis. Recent evidence suggests that the liver and systemic circulation may be exposed to gut derived microbial products at earlier stages of liver disease. This early exposure may trigger hepatic inflammation, modify immune host response and accelerate hepatic fibrogenesis; which, in turn, impairs portal inflow, alters the portal circulation, and leads to development of portal hypertension. The mechanisms resulting in systemic exposure to gut derived microbial products, and the subsequent host response to BT has not been studied in patients with early liver disease nor fully compensated cirrhosis. We therefore intend to enroll 30 chronic HCV patients with either cirrhosis (20) or minimal liver fibrosis (10). Study participants will undergo extensive evaluation with portal vein sampling and pressure measurements, dual cholate clearances, liver biopsy, serologic, immunologic, fecal microbiome and imaging studies. This will be followed by an optional second percutaneous liver biopsy and portal vein sampling 9-15 months after HCV treatment. The treatment protocol is a separate independent protocol, 15-DK- 0143 utilizing Sofosbuvir and GS-5816. The goals of our study are to characterize the extent of BT in early stages of cirrhotic and non-cirrhotic liver disease, explore the mechanisms contributing to its occurrence and identify potential serological, immunological and hemodynamic biomarkers associated with chronic infection. This, in turn, can aid in establishing a possible link between BT, subsequent host responses and severity of liver disease.

United States