Clinic will offer patients a full spectrum of liver care.

Robert Gish (left) and Alan Hemming, UC San Diego

Patients in Nevada seeking care for liver disease may now access the university-level expertise of UC San Diego Health System’s Center for Hepatobiliary Disease and Abdominal Transplantation (CHAT). Led by Robert Gish, M.D., world-renowned hepatologist, patients may benefit by having access to a full spectrum of liver care, from diagnostics and testing to novel therapies and clinical trials not found anywhere else in the state. Located at 3033 W. Horizon Ridge Parkway, Suite 101, in the city of Henderson, patients may make appointments by calling toll free 1-855-LV LIVER (1-855-585-4837) or 1-702-331-6303.

“I am so grateful to be able to return to the Las Vegas community to practice advanced liver care and to provide local and regional tertiary care for the patients in this region,” said Gish. “Even if you have been told that your liver disease is untreatable, there is hope for you through UC San Diego Health System experts who will come here to care for you.”

Gish will be joined by Lisa Richards, N.P., and Anthony Martinez, M.D., in the Las Vegas-based liver practice, and treat and manage patients with liver disease, in conjunction with each patient’s local health care provider. Patients who need specialized consultative care for liver transplantation or the surgical care of liver cancer will be seamlessly referred to UC San Diego Health System in San Diego.

For more than two decades, Gish has lead an extensive hepatology practice specializing in the care of liver failure, transplantation, viral hepatitis and cancer. He has served more than 22,000 patients in California and Nevada treating challenging types of liver disease in diverse populations. Gish is recognized in Southeast Asia for establishing a roadmap to improve screening, treatment for, and prevention of liver disease and Hepatitis B.

Gish is a NIH-funded researcher whose work focuses on the epidemiology of liver disease, biomarkers for liver disease and multi-targeted therapies for liver cancer, such as protein kinase inhibitors, fibroblast growth factors and iRNA technologies to prevent liver graft rejection. Novel therapies also include bio-artificial liver devices (BAL) as a bridge to transplant for patients suffering from acute liver failure.

Gish received his undergraduate training in pharmaceutical sciences at the University of Kansas in Lawrence and his medical degree from the University of Kansas in Kansas City. After graduation, he completed his internship and residency in internal medicine at UC San Diego School of Medicine and a fellowship in Gastroenterology and Hepatology at UCLA in Los Angeles. He is board certified in Internal Medicine and Gastroenterology, has the advance Certificate of Added Qualification (CAQ) in Liver Transplantation, and was formerly director of liver transplant at California Pacific Medical Center (CPMC) in San Francisco.

He is a member of the American Association for the Study of the Liver, the American Gastroenterological Association, the American Society of Transplant Physicians, and the International Liver Transplant Society, among others. Gish is fluent in Spanish and Vietnamese.

Center renamed the Oppenheimer Family Center for Neurobiology of Stress.

Investigators at UCLA’s Center for Neurobiology of Stress have been studying the links between the brain and digestive system in the development and treatment of common chronic digestive disorders in adults and children.

Now, with the support of the Gerald Oppenheimer Family Foundation, the center will expand its activities to include research into brain-body interactions in other chronic medical disorders and the biology underlying mind-based therapies. In recognition of this support, the center has been renamed the Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress.

The center’s new 5,500-square-foot facility on the UCLA campus features labs and clinic areas and houses 30 faculty and staff.

Supported by $4 million in annual federal grants, the center will receive additional support from the Oppenheimer family’s 2002 gift of $9.6 million, directed to underwrite both the center and the UCLA Center for East–West Medicine. Half of the gift has been established as an endowment to meet these programs’ long-term objectives.

The endowment will help investigators at the Oppenheimer Family Center for Neurobiology of Stress explore mind-brain-body interactions in several stress-sensitive conditions, including persistent pain disorders, such as irritable bowel syndrome and interstitial cystitis; obesity; inflammatory diseases of the liver and intestine; and chronic cardiovascular disorders. It also will support studies of the biological mechanisms underlying the effectiveness of various mind-body therapies.

“Traditionally, doctors believed that the mind and the brain had very little role or impact on chronic medical disorders, including those of the digestive system,” said Dr. Emeran Mayer, the center’s director and a professor of medicine, physiology and psychiatry at the David Geffen School of Medicine at UCLA. ”This is changing as the field grows. We are very excited to be expanding our research and clinical programs through this generous funding.”

Mayer and his team are pioneers in the characterization of brain-gut interactions in chronic abdominal pain syndromes such as irritable bowel syndrome. Recent research supports the concept that irritable bowel syndrome patients, like other chronic-pain patients, have alterations in their brain structure, characterized by a remodeling of the connections among different brain regions that play a role in pain modulation.

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New treatments form part of “triple therapy” with improved outcomes for many patients.

Lorenzo Rossaro, UC Davis

Hepatitis C, the viral liver disease afflicting more than 3.2 million people nationwide, may no longer be a painfully slow death sentence for many of those infected, thanks to two newly approved drugs tested at sites around the country, including UC Davis Medical Center.

Victor Garcia is one of the California success stories. The 59-year-old Sacramento resident recently completed a clinical trial at the medical center using Victrelis (boceprevir), the drug approved in early May by the Food and Drug Administration for general use against the disease. The other drug physicians are hailing as a cure, Incivek (telaprevir), was approved by the FDA on May 23.

“It’s extended my life,” said Garcia, a father of five. “My doctor originally told me I didn’t have that long to live, so I was really fortunate to get into the study. Now it’s amazing to think that I don’t have hepatitis C at all anymore.”

Garcia, who says he doesn’t know how he contracted the disease, took part in two clinical trials at UC Davis, one of the top five enrolling sites for testing the safety and effectiveness of the two drugs against the chronic virus. Victrelis was evaluated as part of a phase 3 clinical trial involving 1,500 adult patients around the nation. A protease inhibitor that prevents viral replication, Victrelis was tested on Garcia and other hepatitis C patients who had previously been treated with other drugs, but were unable to be cured.

Victrelis, like Incivek, is part of a “triple therapy.” The drug is added to the current standard of care for hepatitis C — a combination of the drugs peginterferon alfa and ribavirin, which among Latino and African-American patients had a low success and cure rate. In Garcia’s case, the addition of Victrelis made all the difference.

“This is an exciting time,” said Lorenzo Rossaro, professor of internal medicine and chief of the Division of Gastroenterology and Hepatology at UC Davis, who directed the clinical trials at the medical center. “To realize that a majority of my patients can be cured of devastating disease is one of the most wonderful experiences imaginable for a physician.”

Rossaro co-authored recent studies published in the New England Journal of Medicine and Lancet about the impressive and sustained virologic responses hepatitis C patients had with boceprevir. He estimates that the success rates for triple therapy will be between 70 to 80 percent. The treatment, which lasts from 24 to 48 weeks, is determined by each patient’s response to the rigorous drug regimen, which consists of once-a-week injections and multiple daily pills. How well patients tolerate the drugs, and how quickly the virus is eliminated from their bloodstream, determines the length of treatment.

While the new drugs have a significantly higher cure rate, they are not 100 percent effective in all cases. Both Vitrelis and Incivek can have significant side effects — including rashes, low red-blood cell counts (anemia), nausea, fatigue, headache and diarrhea, which force one out of seven patients to halt treatment.

“Because the new hepatitis drug cocktail is so powerful, this triple therapy requires providers to closely monitor their patients,” said Rossaro. “With all the cases that now can be treated and probably cured, specialists and primary-care providers will be playing very important roles in this effort.”

Rossaro noted that using telemedicine (medical consultations using videoconferencing equipment) will be an important way to reach patients in smaller, more rural communities, as well as train more providers to help manage the disease. With an estimated 650,000 hepatitis C cases in California, he and other specialists are working with the UC Davis Center for Health and Technology to provide telemedicine consultation services, education and training for primary-care providers who can help dispense and monitor the triple-therapy drugs.

“At $1,100 a week, the new drug therapy might appear to be a very expensive,” said Rossaro. “But compared to years of clinic visits, hospitalizations, liver transplantation and the costs arising from the complications of the infection, this is extremely cost effective because it offers a complete cure. It’s going to be worth every penny.”

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Patients, caregivers and experts gather for Sacramento event targeting PSC.

Emily Spannagel was a college freshman 12 years ago when she first learned that she had a rare liver disease that could lead to liver failure and eventually require a transplant. Her illness, primary sclerosing cholangitis (PSC), results in inflammation that progressively scars and narrows the liver’s bile ducts. The disease has dictated nearly every aspect of her life since.”When I was given the diagnosis, I was in a complete state of denial,” said Spannagel, now a stay-at-home mother with an energetic 4-year-old, who has grappled with tough decisions about career and family and suffers from severe fatigue on a daily basis. “It was extremely difficult to hear that I was going to need a liver transplant in my lifetime.”

Spannagel will be among several hundred people expected to attend the seventh annual “PSC Partners Seeking a Cure” conference, which brings together patients and caregivers, and features presentations by international health experts, including Spannagel’s physician, Christopher Bowlus, an associate professor of internal medicine. The event begins on Friday, April 29, and continues through May 1 at the Sheraton Grand Hotel in Sacramento, 1230 J St., Sacramento.

Conference attendees will learn about the latest research and treatments into the incurable disease, which is estimated to affect about 6-in-100,000 people. There is no known cause for PSC, but it is thought to be related to an autoimmune disorder. Current treatments help control PSC symptoms, which include fatigue, itching and severe jaundice.

“Most patients with early PSC have no symptoms, and its presence is recognized only because of abnormally elevated blood levels of liver enzymes that often are analyzed as part of routine blood tests for physicals,” said Bowlus, who specializes in liver diseases.  “It’s a disease that is much more common among men than women, but it has equally challenging impacts on physical health.”

In addition to Bowlus, the conference includes UC Davis Health System experts Eric Gershwin, distinguished professor of medicine and the Jack and Donald Chia Professor of Medicine, Division of Rheumatology, Allergy and Clinical Immunology; John McVicar, professor of surgery and a liver transplant expert; Natalie Torok, associate clinical professor, Division of Gastroenterology and Hepatology; and Carlo Selmi, assistant professor of medicine.

PSC sufferer Spannagel has undergone a procedure to widen the strictures in the bile ducts and takes antibiotics to fight infections there. Both are temporary measures and do not stop the progression of the disease. For the Sacramento resident, the worst thing about PSC is the uncertainty of when or how the disease might develop. She noted that patients often wait with a laundry list of symptoms that show the disease’s progression, such as fevers, hypertension, esophageal varices (dilated veins), and other problems. They also must endure the wait for the day when their MELD (Model for End-stage Liver Disease) scores are high enough that they can be put on the liver transplant list.

“Being positive is key,” said Spannagel, who is looking forward to the conference and anxious to learn more about the ongoing research and any potential treatments on the horizon. “Because there are still so many unanswered questions about PSC, any new information is important. It will be truly uplifting to be in a room full of PSCers and know that we are in this fight together.”

About PCS Partners Seeking a Cure
PSC Partners Seeking a Cure is a volunteer organization formed in 2005 to provide primary sclerosing cholangitis (PSC) patients and their caregivers with education and support as well as raise funds for research into the origins of the disease and finding a cure for it.

About UC Davis Medical Center
UC Davis Medical Center is a comprehensive academic medical center where clinical practice, teaching and research converge to advance human health. Centers of excellence include the National Cancer Institute-designated UC Davis Cancer Center; the region’s only level 1 pediatric and adult trauma centers; the UC Davis MIND Institute, devoted to finding treatments and cures for neurodevelopmental disorders; and the UC Davis Children’s Hospital. The medical center serves a 33-county, 65,000-square-mile area that stretches north to the Oregon border and east to Nevada. It further extends its reach through the award-winning telemedicine program, which gives remote, medically underserved communities throughout California unprecedented access to specialty and subspecialty care. For more information, visit medicalcenter.ucdavis.edu.

UCLA researchers find that liver X receptors dampen the cirrhosis-causing actions of stellate cells.

UCLA researchers have demonstrated that a key regulator of cholesterol and fat metabolism in the liver also plays an important role in the development of liver fibrosis — the build-up of collagen scar tissue that can develop into cirrhosis. Cirrhosis, in turn, is a major cause of premature death and is incurable without a liver transplant.

Published in the March issue of the journal Gastroenterology, the study shows that liver X receptors (LXRs), master regulators of cholesterol, fat and inflammatory gene expression, also control the fibrosis-making cells of the liver, known as hepatic stellate cells.

In the face of chronic liver injury — due to excess fat, chronic viral hepatitis or alcohol abuse, for example — stellate cells become activated and launch an inflammatory and fibrotic cascade that eventually results in the build-up of collagen scar tissue in the liver.

LXRs, when stimulated, “turn on” several hundred genes that hold instructions to create proteins for carrying out bodily processes in cells, from transporting and excreting cholesterol to synthesizing fat in the liver. They have also been shown to suppress inflammatory processes in several contexts.

“Our work sets the stage for looking at new ways to modulate cholesterol and/or fat metabolism in order to have therapeutic potential for the treatment of fibrosing liver diseases,” said lead author Dr. Simon Beaven, an assistant professor of digestive diseases at the David Geffen School of Medicine at UCLA.

The research was done in the laboratory of senior author Dr. Peter Tontonoz, a professor of pathology and laboratory medicine at the Geffen School of Medicine and a Howard Hughes Medical Institute investigator.

Beaven noted that the recent rise in obesity has resulted in a surge in the prevalence of a condition known as fatty liver, which can be a precursor to fibrosis and chronic liver disease. Simple fatty liver, also known as non-alcoholic fatty liver disease, or NAFLD, is one of the most common reasons patients consult a liver doctor in the United States. Cirrhosis due to fatty liver is skyrocketing and within a decade may become the most common indication for liver transplantation.

Beaven said the need to find better treatments for liver disease is crucial.

“A ‘holy grail’ for liver researchers is to develop anti-fibrotic treatments that target activated stellate cells in order to slow or prevent the development of cirrhosis,” Beaven said. “Our study offers the first detailed look at how LXRs specifically impact the activation of hepatic stellate cells and the subsequent development of liver fibrosis in animal models.”

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UCSF researchers uncover hormone pathway to fatty liver disease.

Ethan Weiss, UC San Francisco

Scientists at the UCSF Cardiovascular Research Institute have discovered how a change in growth hormone activity in mice leads to fatty liver disease, a condition whose human counterpart is of rising concern worldwide.

Disruption of a key protein in the pathway that responds to growth hormone could explain how fatty liver disease develops, the researchers said, but may also offer insights into how our bodies regulate fat in general.

The team’s findings and the first reports of a mouse model to study the pathway will appear in the April issue of the Journal of Clinical Investigation and online March 1 at http://www.jci.org/articles/view/42894.

Until recently, the growth of fat deposits in the liver that characterizes fatty-liver disease was mainly considered a result of alcoholism. Over the last decade, though, scientists have been baffled by the rising incidence of the non-alcoholic version of the disease, which now affects as many as one in four people worldwide, according to UCSF cardiologist Ethan Weiss, MD, senior author of the paper.

Known risk factors for the condition include obesity, diabetes and malnutrition, among many others, but its precise mechanism had eluded researchers.

“Fatty liver disease is an increasingly prevalent condition that is poorly understood,” Weiss said. “We knew that growth hormone had been linked to fatty liver, but previous reports showed that it both causes and cures the condition. We set out to figure out why that happens.”

The team focused on a protein in the liver known as JAK2. While better known as being linked to cancers such as blood cancers, this protein is also a key player in an important chemical pathway in the liver.

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UC Davis study holds promise for creating organs to treat liver disease.

UC Davis researchers have announced that they have used a novel technique to transplant human liver cells into an animal model that enabled the cells to function well for a considerably longer period of time than methods used in previous studies.

The technique has the potential to one day create a working liver for transplantation into people with severe liver disease, or be used as an interim measure for a patient who must wait until a conventional donor organ becomes available.

The study, “Decellularized liver matrix as a carrier for transplantation of human fetal and primary hepatocytes in mice,” has been accepted by the journal Liver Transplantation and is now online.

The innovative technique devised by the UC Davis scientists working in Sacramento involved “decellularizing” a mouse liver – stripping all cells out of the organ while preserving its protein structure and blood supply framework. Using the decellularized liver as a scaffold, the researchers inserted human liver cells into the structure, prompting the cells to survive longer and function better in this native liver scaffold. The scaffold with liver cells was then implanted into the fatty tissue of a mouse abdomen, where it functioned well for two months after transplantation. Researchers say that having the cells function for at least 60 days is an important milestone in the research work now under way to create new organs and tissues from stem cells.

“We have demonstrated the best results to date for the efficacy of transplanting cells into an animal model using a decellularized liver matrix,” said Jian Wu, an adjunct professor of internal medicine and senior author of the study. “This is an important step in the pathway to providing people suffering from liver failure with more hope and a much better chance of survival.”

New approaches to treating liver failure are critically needed, according to Mark Zern, a senior member of the research team, professor of internal medicine and director of the UC Davis Transplant Research Program. “There are not enough organs available for transplant, and many patients die waiting for one,” said Zern.

About 25,000 people are on waiting lists around the country for liver transplants, but only 6,000 to 7,000 organs become available each year. The liver is essential for life and has many complex functions: It stores glucose, as well as many vitamins and minerals; makes blood-clotting factors and the building blocks of proteins; and detoxifies impurities that enter the bloodstream.

The method of decellularizing an organ and transplanting new working cells into animals using this scaffold has been used experimentally in research to regenerate other organs such as the heart, trachea, lungs and kidneys. Until now, other studies to create a functioning liver have been rudimentary and have only resulted in hours or days of activity rather than months.

Ping Zhou, the first author of the study, along with Wu and their UC Davis colleagues, are continuing their research, with a focus on regenerating livers that will function well over an extended period.

“We are very excited about the clinical applications of this research,” said Jan A. Nolta, another senior member of the research team and a professor of cell biology and human anatomy, as well as the director of the UC Davis stem cell program and its Institute for Regenerative Cures. “Our ultimate goal is to ‘scale it up’ to help humans in the future.”

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Protein long thought to indicate fibrosis may not be to blame — entire area of research now may be questioned.

David Brenner, UC San Diego

In the latest of a series of related papers, researchers at the UC San Diego School of Medicine, with colleagues in Austria and elsewhere, present a new and more definitive explanation of how fibrotic cells form, multiply and eventually destroy the human liver, resulting in cirrhosis. In doing so, the findings upend the standing of a long-presumed marker for multiple fibrotic diseases and reveal the existence of a previously unknown kind of inflammatory white blood cell.

The results are published in this week’s (Dec. 20) early online edition of the Proceedings of the National Academy of Sciences.

In all types of chronic diseases, healthy, functioning tissues are progressively replaced by fibrous scarring, which renders the tissues or larger organ increasingly dysfunctional until, eventually, it fails. The process is called fibrosis. In the human liver, the end result is cirrhosis, the 12th leading cause of death by disease in the United States with roughly 27,000 deaths annually. Fibrosis occurs in other organs as well, such as the heart, kidneys and lungs, with comparable deadly effect.

Scientists do not fully understand the process of fibrosis, particularly how problematic fibroblast cells are created. For years, conventional wisdom has posited that fibroblasts are likely to be transformed epithelial cells, a conversion called “epithelial to mesenchymal transition” or EMT. A protein called fibroblast-specific protein 1 (FSP1) has long been considered to be a reliable indicator of fibroblasts in injured organs undergoing tissue remodeling and has been broadly used to identify the presence of fibrotic disease.

The new research undermines the validity of prevailing assumptions about EMT and FSP1, but also opens the door to new avenues of investigation that could ultimately lead to improved detection and treatment of cirrhosis and similar conditions.

“This work, along with earlier papers, puts into question a whole area of research — at least in terms of the liver,” said Dr. David Brenner, vice chancellor for health sciences, dean of the UC San Diego School of Medicine and co-author of the paper. “The old evidence and assumptions about the source of fibroblasts and the role of FSP1 as a marker are not valid.”

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Dr. Robert G. Gish, world-renowned hepatologist, has been recruited to the UC San Diego School of Medicine to co-direct the Center for Hepatobiliary Disease and Abdominal Transplantation (CHAT) — a multidisciplinary program designed to offer adult and pediatric patients in the western United States a single destination for the diagnosis and treatment of liver disease from common to complex.

“Hepatitis B is a global problem with more than 400 million infected individuals and more than one million deaths occurring as a result of cirrhosis and liver cancer each year,” said Gish, the new co-director of CHAT, chief of clinical hepatology and professor of clinical medicine. “The UCSD team will not only focus on lifesaving therapies for liver disease but on promoting liver health locally and across continents through multi-lingual health education.”

For more than two decades, Gish has lead an extensive hepatology practice specializing in the care of liver failure, liver transplantation, viral hepatitis and liver cancer. He has served more than 22,000 patients in California and Nevada treating challenging types of liver disease in diverse populations. Gish is recognized in Southeast Asia for establishing a roadmap to improve screening and treatment for, and prevention of liver disease and Hepatitis B in Vietnam. He received the “Humanitarian of the Year” award from the San Francisco-Ho Chi Minh City Sister City Committee for this work.

Gish is a NIH-funded researcher whose work will focus on the epidemiology of liver disease, biomarkers for liver disease and multi-targeted therapies for liver cancer such as protein kinase inhibitors, fibroblast growth factors and iRNA technologies to prevent liver graft rejection. Novel therapies also include bio-artificial liver devices (BAL) as a bridge to transplant for patients suffering from acute liver failure.

“Gish’s international expertise in treating complex liver disease will further elevate UC San Diego as a world-class center for innovative liver care,” said Dr. Alan Hemming, professor of surgery, chief of transplantation and co-director of CHAT. “Our care is aligned around the patient experience integrating advanced diagnostics, state-of-the-art radiation, experimental medical therapies and novel surgical approaches for liver resection and transplantation.”

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New research led by physician-scientists at the UC San Diego School of Medicine shows that the test most commonly used to screen pediatric patients for chronic liver disease is often incorrectly interpreted in many children’s hospitals throughout the United States.

The SAFETY study (Screening ALT For Elevation in Today’s Youth) will be published in the April issue of Gastroenterology and is available online now.

Currently, screening for chronic liver disease is most commonly done using serum alanine aminotransferease (ALT) activity and is intended to determine which children:

• have liver disease associated with obesity
• should be treated if they have viral hepatitis
• take medications that are harming their livers
• should not participate in clinical trials because of their livers

However, the appropriate ALT threshold value to use for detecting liver disease in children is unknown.

“Our first step was to find out what value was being used in the nation’s children’s hospitals,” said Dr. Jeffrey Schwimmer, associate professor of pediatrics, UC San Diego School of Medicine and Director of the Fatty Liver Clinic at Rady Children’s Hospital, San Diego. “We found such a broad range between hospitals for ALT values that they could not possibly be biologically appropriate. This means that a child identified with liver disease at one hospital would go undetected in another.”

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Distinguished transplant and cancer surgeon, Alan Hemming, MD, has been recruited to the UC San Diego School of Medicine to launch a multidisciplinary center for the treatment of advanced liver disease at the UC San Diego Medical Center and Moores UCSD Cancer Center. This innovative program is designed to offer adult and pediatric patients in the western United States a single destination for the treatment of complex liver disease, from advanced diagnostics to experimental medical therapies and novel approaches for liver resection and transplantation.

“Whether you are suffering from liver failure, or primary or secondary liver malignancy, there are new combinations of treatment that can be delivered to you at UCSD Medical Center,” said Hemming, professor of surgery and Chief of Transplantation and Hepatobiliary Surgery. “If you have been told that you have untreatable liver disease, there is hope for you here. As a world-recognized academic medical center, UC San Diego has the expertise, resources and skill to take on the most difficult cases.”

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