Marlyn J. Mayo, M.D.
Assistant Professor of Internal Medicine
Division of Digestive and Liver Diseases

CLINICAL STUDIES IN PRIMARY BILIARY CIRRHOSIS

Primary Biliary Cirrhosis (PBC) is an autoimmune liver disease in which the intrahepatic bile ducts are gradually destroyed by chronic inflammation. The typical patient with PBC is a middle-aged female who presents with fatigue and pruritus. As the disease progresses, patients may develop liver failure. Currently, 9% of liver transplants in the U.S. are done for PBC. Roughly two out of every million persons in the US die from PBC each year, which is more than die from chronic hepatitis B or acute hepatitis A. The etiology of the disease is unknown, and current treatments are inadequate. UTSW serves as a national referral center for patients with PBC. Drs Mayo and Combes have initiated and carried out multi-center clinical trials of ursodeoxycholic acid and methotrexate for the treatment of PBC. They maintain a clinical trials program in conjunction with the General Clinical Research Center at UTSW and also a basic laboratory for translational research in the field of autoimmune liver diseases.

Project I. USE OF SEROTONIN REUPTAKE INHIBITORS TO CONTROL CHOLESTATIC PRURITUS. Patients with cholestatic liver disease often suffer from disabling pruritus. Current treatments are not always effective, and liver transplantation is sometimes necessary to alleviate the pruritus. The hypothesis of this project, which is based on the previous observation that some patients with PBC have experienced resolution of their pruritus when given sertraline, is that sertraline therapy will improve the symptom of cholestatic pruritus. The specific aims are: 1) to determine the optimal dose and time to response of sertraline treatment for cholestatic pruritus 2) to determine the tolerability of sertraline in patients with reduced liver function. The secondary aims of this project are to evaluate the effect of sertraline on cholestatic pruritus and to determine how changes in pruritus are related to changes in depressive symptoms or plasma sertraline/desmethylsertraline levels. This is a NIH-funded, double-blind, randomized, placebo-controlled, crossover study. Investigators from gastroenterology, dermatology, and psychiatry are collaborating to identify a novel treatment for cholestatic pruritus and also to better understand the mechanistic role of serotonin in itch perception.

Project II. SERUM MARKERS OF FIBROSIS IN PRIMARY BILIARY CIRRHOSIS.
Establishing a clinical diagnosis of PBC without histological confirmation is becoming more widely accepted. However, clinical investigators need accurate biomarkers of disease progression in order to evaluate new potential therapies. Currently available biochemical and clinical markers are excellent predictors of death. However, they are not sensitive to disease progression earlier in the course of PBC. Liver biopsy is risky and prone to significant sampling error. The NIH 2004 Action Plan in Liver Disease has therefore established the development of better serum markers of disease severity as a high priority. This study aims to develop a novel combination of serum markers of fibrosis and clinical variables that can be used as an alternative to liver biopsy and predictor of clinical outcome. This project utilizes the UTSW PBC repository, which contains clinical data matched with 2,084 serial serum specimens and 972 liver biopsies obtained from 265 subjects over a 10-year period. Subjects continue to be monitored for signs of disease progression through clinical trial office visits every 6 months. They are screened for development of varices and/or ascites with endoscopy and abdominal ultrasound. Serum markers of fibrosis, such as hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP-1), amino terminal procollagen peptide III (PCPIII), collagen IV, tenascin, undulin (collagen XIV), laminin P1, matrix metalloproteinase-2 (MMP-2), procollagen I carboxyterminal propeptide (PICP), collagen VI will be assayed and entered into regression models with traditional clinical variables (e.g. bilirubin, prothrombin time) in order to derive the best predictor of disease progression.

Project III: RELLAXIN IN HEPATIC FIBROSIS

Relaxin is a polypeptide hormone, first described many years ago as the key hormone that facilitates remodeling of the matrix of the pregnant uterus.Recently, relaxin has been re-discovered as the key regulator of fibrosis in other diseases characterized by progressive scarring and remodeling of specific organs, such as idiopathic pulmonary fibrosis, cardiomyopathies, and systemic sclerosis. In these diseases, relaxin production increases over time, as the body attempts to regulate the process of fibrosis. Exogenous relaxin is safe and has been administered successfully as therapy to retard fibrosis in systemic sclerosis. Receptors for relaxin have recently been identified on hepatic stellate cells, the main producers of hepatic fibrosis. Thus, it is highly likely that liver fibrosis is also regulated by relaxin. The hypothesis of this project is that relaxin is a key inhibitor of hepatic fibrosis. Serum relaxin levels will be measured by ELISA in a large cohort of subjects with varying stages of liver disease and correlated with histological fibrosis. Production of relaxin in the liver will be assayed by real time PCR and relaxin receptors identified by immunihistochemistry.