SAN DIEGO, CA (May 20, 2008) - Researchers have made great strides in identifying the mechanisms and associations involved in liver diseases to devise better treatments. Results showing that liver cells can be created from embryonic stem cells; that innate immunity influences the response of patients to treatment for chronic hepatitis C; and a potential link between recurrent urinary tract infections and primary biliary cirrhosis (PBC); and will be presented today at Digestive Disease Week® 2008 (DDW®). DDW is the largest international gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
"Each of these studies enhances our understanding of the liver, provides clues to mechanisms causing liver diseases and increases our ability to diagnose and refine therapeutic strategies for patients with liver diseases." said John M. Vierling, MD, FACP, professor of medicine and surgery, chief of hepatology, Baylor College of Medicine in Houston, TX.
Highly Efficient Differentiation of Human Embryonic Stem Cells to Metabolically Active Hepatocytes In Vitro and In Vivo (Abstract #688)
Scientists have efficiently generated human liver cells from embryonic stem cells that could be used to screen potentially harmful side-effects of drugs before they are tested in patients, according to new research which focuses on certain enzymes within the liver cells that play a key role in processing drugs.
"While people have investigated the toxicity of drugs relating to the liver, we have generated a unique model that allows us to focus on key enzymes, which are important in drug metabolism," said David Hay, MD, senior fellow at the University MRC Centre for Regenerative Medicine at the University of Edinburgh. "This has the potential to revolutionize drug toxicity studies by testing in a laboratory setting before trials in animals and humans."
Previously, these assays were not possible as scientists were hampered by poor cell yields and impure cultures. "In our study, we have overcome these problems and demonstrated that we can scale-up the production of liver cells which are very pure (~90 percent) and demonstrate high levels of function in high through-put assays," said Dr. Hay.
Hay added that the findings also have a major clinical application: the liver cells generated in vitro could be used in bioartificial devices, a strategy comparable to kidney dialysis, helping to maintain normal bodily function. As a long term strategy, the liver cells could be transplanted into patients with compromised liver function. These include cirrhosis and cystic fibrosis in which patients suffer from an error in their liver metabolism resulting in too few enzymes.
Combination Antiviral Therapy Differentially Affects Dendritic Cell Chemokine Receptor and Maturation Marker Expression in Chronic Hepatitis C Infection (Abstract #461)
Researchers have found that current therapy for hepatitis C virus (HCV) differentially affects dendritic cells - the most potent stimulator of T cells. Treatment for HCV, a viral infection affecting the liver, typically involves 48 weeks of combination antiviral therapy. This therapy, which induces flu-like symptoms for patients, successfully combats HCV in only half of the cases.
Working with participants in the Virahep-C study, researchers examined 64 patients with genotype 1 HCV, the most common and hardest to treat strain of the virus. Blood samples were studied from each patient prior to and 24 weeks after undergoing HCV therapy. Investigators studied the frequency of plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) and measured the median fluorescence intensities (MFIs) of chemokine receptors and maturation markers.
Researchers found that pretreatment frequencies of pDC and mDC were significantly lower in HCV patients than normal controls. They also found that some, but not all, inflammatory chemokine receptors and maturation markers were elevated at baseline, in patients compared to normal controls, suggesting incomplete maturation.
In addition, they found that the levels of pDC cells in those who responded to therapy normalized, while non-responders did not. Levels of maturation markers and chemokine receptors also normalized in patients who responded to therapy. Patients with increased pre-treatment pDC migration to chemokines were less likely to respond to therapy.
"If we are able to use DC cells studies to predetermine who will respond to therapy and who will not, we can spare some patients from a long and painful 48 week regimen that is ultimately ineffective. Further, this research tells us that the DC cells may hold the key to finding improved therapy for chronic HCV patients," said John A. Mengshol, MD, PHD, fellow at the department of gastroenterology and hepatology at the University of Colorado Denver School of Medicine.
Virologic Responses to PegIFNa-2a/Ribavirin in Treatment-Naïve Latino vs Non-Latino Caucasians Infected with HCV Genotype 1: The Latino Study (Abstract #161)
Despite the high prevalence of hepatitis C (HCV) and the severity of the disease in the Latino population, Latinos have been historically underrepresented in HCV trials and under-treated in clinical practice. Therefore, until now, the efficacy of treatment of HCV in the Latino population was unknown.
Researchers hypothesized that Latino patients with HCV would achieve sustained virologic response (SVR), meaning that when tested six months after treatment they are shown to have cleared the virus, at a rate 15 percent lower than Caucasians. To test for the effects of ethnicity, investigators enrolled in the study only Spanish-speaking Latinos whose parents and grandparents were all Latino (269) and only Caucasians in the comparison group (300).
All patients in the multi-center study received the same therapy, Pegasys 180 mcg weekly and Ribavirin 1000/1200mg daily, based upon their weight. Researchers found dramatic differences in their response to therapy from the beginning of treatment, with higher rates of Caucasians showing rapid virologic response (RVR), which is a predictor of a patient's ability to reach SVR, or clearing the virus.
Using multiple logistic regression analysis to control for all other characteristics, investigators found that ethnicity predicted a patient's response to therapy. Their study found that 49.3 percent of Caucasians reached SVR compared with 33.5 percent of Latinos, a 15 percent difference that matched researchers' hypothesis.
"The results of this study demonstrate the need to treat Latinos infected with hepatitis C as a special population," said Maribel Rodriguez-Torres, MD, chief medical officer, Fundacion de Investigacion de Diego, San Juan, PR. "Without culturally targeted education and treatment plans, we will have many, many Latinos dying of liver disease in the next decades."
Recurrent Urinary Tract Infection in Mice Results in Immune-Mediated Cholangiopathy Similar to Human Primary Biliary Cirrhosis (Abstract #W1846)
Investigators have discovered a possible link between urinary tract infection (UTI) and primary biliary cirrhosis (PBC), a progressive liver disease that is responsible for 10 percent of adult liver transplants, yet whose cause remains largely unknown. PBC disproportionately affects middle-aged women and is characterized by inflammation and destruction of bile ducts, which carry bile from the liver into the gallbladder and the upper part of the small intestine. A history of UTI puts women at increased risk for developing PBC, and women with PBC also have an increased incidence of bacteriuria, bacteria in the urine.
Previous research identified certain antibodies, proteins found in the blood that are present in women with PBC and also can occur in women with UTIs. This finding suggests that some women with UTIs are more likely to develop PBC, which could allow doctors to identify patients at risk for PBC and intervene earlier. The hope is that "if you can get rid of the bacteria, you can stop liver injury or prevent it from worsening," said Joe Palermo, MD, PhD, instructor of pediatric gastroenterology at Washington University in St. Louis.
Investigators studied mice and found that female mice with chronic UTIs developed specific antibodies as well as lesions in the liver that were similar to early PBC. Using catheters, investigators gave mice UTIs and looked at their livers and blood. As early as four to eight weeks following an infection, there was a chance the mice would develop antibodies. While in the six to eight month timeframe, mice showed fairly significant evidence of liver injury.
By studying this animal model, they plan to identify the specific triggers that lead to liver injury. Also, by looking at patients with PBC and comparing bacteria from their urine to bacteria from patients who do not have PBC, they hope to determine which bacterial factors are more likely to be associated with liver injury. They also will be able to follow women with recurring UTIs with an eye toward identifying their risk for developing PBC in the future.
Dr. Palermo said that while thus far, all the different breeds of mice examined have developed liver injury; the research is still at its early stages. "The possible link between UTI and PBC might lead to newer diagnostic and therapeutic strategies," he said. "But we still have to look at these findings in conjunction with what clinical observations in human patients suggest."
Digestive Disease Week® 2008 (DDW®) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 17-22, 2008 in San Diego, Calif. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.