RxPG News : Liver

Increased mortality risk in later years in obese children following Liver transplantation

Thu, 28 Oct 2010 18:27:35 PST

( from http://www.rxpgnews.com ) A new study from the University of Washington reported obese children are at increased mortality risk in later years following primary liver transplantation (LT). Pediatric patients who are thin or severely thin, experience an early mortality risk—within the first year post-LT. Details of the ten-year survival analysis are published in the November issue of Liver Transplantation, a peer-reviewed journal of the American Association for the Study of Liver Diseases (AASLD).

Childhood obesity is a serious public health concern worldwide. According to the World Health Organization (WHO), the prevalence of obesity has been increasing at an alarming rate, with 22 million children under the age of five worldwide who are overweight. In the U.S., the National Center for Health Statistics estimates that 17% of children between the ages of 2 and 19 years old are overweight or obese.

"Controversies exist regarding the mortality of patients undergoing liver transplantation at the extremes of body mass index (BMI), and in pediatric patients weight is typically the only factor considered in survival analysis," explained lead study author André Dick, M.D., from Seattle Children's Hospital and the University of Washington. "Our study is the largest thus far to report on the impact of pre-transplant BMI on post liver transplant survival in the pediatric population." Prior studies in adult populations have shown there to be a negative impact on post transplantation survival for LT patients with extreme BMIs.

For the present study, researchers reviewed data from the Organ Procurement and Transplantation Network (OPTN) and found that 7,942 patients less than 18 years of age (who had full BMI data) underwent primary liver transplantation between 1987 and 2007. Using the WHO BMI criteria, the authors categorized patients as severely thin, thin, normal weight, overweight, or obese. During the study period 61% of patients were at normal weight.

Results indicate that children who were thin or severely thin had a significantly lower survival (84%) at one year compared to the survival (89%) of children in the normal and overweight groups. Researchers found no significant difference in survival during the first year after transplantation for obese pediatric patients. However, by the twelfth year following LT, those in the obese group had significantly lower survival (72%) than the survival (77%) of normal weight or overweight pediatric patients.

The authors observed that obesity had a significantly negative impact on pediatric patient survival more than five years after LT. They speculate post metabolic syndrome (PTMS) could contribute to the late morbidity and mortality due to the time it takes to develop long-term obesity-related conditions such as diabetes, hypertension, and hyperlipidemia. Moreover, long-term use of immunosuppressive therapy following transplantation, which while improving patient survival, can exacerbate the effects of PTMS. "Further research is needed to determine the optimal immunosuppressive regimen that will lessen the effects of PTMS," concluded Dr. Dick. "Pre- and post-transplant identification of malnourished or obese pediatric patients, along with optimization of their modifiable risk factors will help to best use scarce donor organs and maximize patient survival."

Some patients with hepatitis B faring better after liver transplant

Tue, 04 May 2010 04:00:00 PST

( from http://www.rxpgnews.com ) ROCHESTER, Minn. -- Treatment to reduce recurrence of hepatitis B appears to improve liver transplant outcomes for some patients, according to a Mayo Clinic study presented at the American Transplant Congress under way May 1-5 in San Diego.

We found that in patients with hepatitis B, the number of patients who were listed for a second transplant within three years decreased by 50 percent between 1996 and 2005, says Ray Kim, M.D., the senior investigator of the research team.

Hepatitis B infection is a major cause of liver damage that can eventually lead to end-stage liver disease and the need for a liver transplant. In the past, hepatitis B recurred in some transplant patients, causing liver damage and the need for a second transplant.

In the past 10 years, new medications have improved our ability to control hepatitis B, says Dr. Kim. Today, transplant recipients routinely are treated with antiviral therapy and hepatitis B immune globulin to reduce the risk of recurrence. We wanted to know if the medication protocols were making a difference in patient outcomes, he says.

Researchers reviewed data provided by the Organ Procurement and Transplantation Network of 31,242 liver transplants in the United States. The underlying reasons for transplantation were categorized as hepatitis B, hepatitis C or other.

From 1996 to 1998, 6.5 percent of liver transplant patients with hepatitis B were listed for a second transplant. For 2003 to 2005, the number of liver transplant patients with hepatitis B listed for a second transplant was 3.3 percent -- roughly a 50 percent reduction.

For patients with hepatitis C or other underlying liver disease, there were smaller declines in relisting numbers. Preventing recurrence of hepatitis C has proved to be more challenging than preventing recurrence of hepatitis B, says Dr. Kim.

Over the same periods, mortality rates increased for all three groups. For patients with hepatitis B, the death rate was 10.8 percent from 1996 to 1998. The rate increased to 12.8 percent for 2003 to 2005.

Our results show that transplant outcome is consistently improving for patients with hepatitis B with a significant decrease in need for second transplants, says Dr. Kim. The increases in mortality rates are concerning. The incidence of liver cancer has increased and it may explain some of the mortality. However, more work needs to be done to understand the reasons.

Dr. Kim says the study results are significant because an estimated 800,000 Americans have hepatitis B. That number is likely an under-representation, he says. In some U.S. immigrant communities, which often are excluded in disease tracking national surveys, the hepatitis B infection rate is 5 to 15 percent.

Those high numbers portend a continued high demand for liver transplants. In the United States, nearly 16,000 people are waiting for liver transplants.

Study shows liver transplant center impacts patient outcomes

Sun, 02 May 2010 04:00:00 PST

( from http://www.rxpgnews.com ) ROCHESTER, Minn. -- For patients in need of a liver transplant, their choice of a transplant center can make a noteworthy difference in their outcomes, according to a Mayo Clinic study presented at the American Transplant Congress under way May 1-5 in San Diego.

We did find significant variation between centers in patient outcomes in the first year after transplant, says Ray Kim, M.D., one of the lead investigators on the study. Previous studies have looked at outcomes based on factors about the recipients and donors involved, but no known previous study has focused on what effect the transplant center could have on patient outcomes.

Researchers documented an average 30 percent difference in risk for failed transplant between centers. Between centers with the best and worst outcomes, there may be as much as a fourfold difference in risk. Failed transplant was defined as either patient death or the need for a subsequent liver transplant within a year. Though one intuitively expects a certain amount of difference between centers, this effect seems larger than previously thought. The bottom line for patients: do your homework before selecting a transplant center, he says.

But transplant center size alone, measured in patient volume, didn't account for the difference in outcomes. Results showed that the number of transplants performed didn't materially affect outcomes, says Dr. Kim. This implies the largest center won't necessarily have the best results. Similarly, a smaller center may deliver similar outcomes.

Using data from the Organ Procurement and Transplantation Network, Mayo Clinic researchers reviewed data from 12,233 patients who received liver transplants to treat chronic liver disease. The data included transplants performed at more than 100 U.S. hospitals that performed at least one liver transplantation surgery from 2005 to 2008.

Of those transplants, 15 percent failed within a year. The outcome differences between transplant centers were greatest during the first three months post-transplant.

Data used in the study was combined and analyzed without naming the transplant centers. The goal of the research is not to point fingers, says Dr. Kim. The study was undertaken with the hope of finding ways for the transplant community to make the best use of a very limited resource, namely the donated organs. The data clearly showed that where the transplantation is done makes a difference whether the outcome of a transplant will be successful. In the United States, nearly 16,000 people are waiting for liver transplants.

Dr. Kim notes that there may be several ways transplant center factors can affect transplant outcomes. The most immediate factor is quality of care provided at the center, including surgical, medical and nursing expertise. In addition, how patients and donor organs are selected for transplantation also contributes to the outcome. And last, where the center is located geographically has a substantial impact on availability and quality of donated organs.

Extracorporeal liver support therapy shows promise for severely ill patients

Sun, 18 Apr 2010 12:49:40 PST

( from http://www.rxpgnews.com ) Vienna, Austria: Results from two studies presented on 16th April 2010 at the International Liver Congress 2010 have shown that treatment with extracorporeal devices may not confer a survival advantage for severe liver failure patients, despite positive dialysis effects. However, results among a small sub-group of patients show promise.

Extracorporeal liver support therapy is in its infancy but is valued as a detoxification treatment option for patients with cirrhosis who have rapid worsening of their liver function. The objectives of these two studies were to better understand the potential of two new devices (Molecular Adsorbent Recirculating System – MARS - and Prometheus®) in terms of survival benefits for patients who suffer from cirrhosis.

Commenting on the studies, Professor Burroughs from the Royal Free Hospital NHS Trust, London UK, said: "The accepted prognosis for these patients is generally poor and current treatment strategies involve supportive therapy, with the hope that liver function will recover if sufficient time is allowed. Extracorporeal support systems such as the two included in these studies are very useful bridges, but the overall data on survival is disappointing. The positive data for severely ill patients with hepatorenal syndrome I or a MELD score over 30, though, does offer some encouragement".

In the first study , 145 patients with cirrhosis and rapid deterioration of their liver function were recruited across seven European countries. This study is the first large prospective randomized controlled trial on the survival of patients with the condition (HELIOS study). Prometheus® is a new extracorporeal liver support system allowing the removal of protein bound and water soluble toxins by fractionated plasma separation and absorption (FPSA). Patients were randomized to standard medical therapy or standard medical therapy plus FPSA and the primary endpoints of the study were survival at 28 and 90 days regardless of liver transplantation.

The results show that difference in the overall survival was not statistically different overall (66% vs. 63% p=0.7 at day 28 and 47% vs. 38% p=0.35 at day 90). Only in pre-defined patient sub-groups with hepatorenal syndrome type I* and MELD** score >30 was a significant survival benefit with treatment with FPSA observed (p=0.04 and p=0.02 respectively).

*Hepatorenal syndrome type I is a common type of rapidly progressive kidney failure that affects individuals with liver cirrhosis, with a doubling of serum creatinine to a level greater than 2.5 mg/dL or a halving of the creatinine clearance to less than 20 mL/min over a period of less than two weeks.

**The Model for End-Stage Liver Disease, or MELD, is a scoring system for assessing the severity of chronic liver disease. MELD uses the patient's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to predict survival.

In the second study , 189 patients with acute-on-chronic liver failure across six European countries were randomized either to treatment with the Molecular Adsorbent Recirculating System (MARS) or to standard therapy. Treatment with MARS was scheduled at low dose (up to ten sessions of 6-8 hours during 21 days) and the main endpoint was survival at 28 days.

Results showed a significant decrease in serum creatinine (20.0 ±33.1% vs. 6.4 ±33.5% p=0.02) and bilirubin (26.4 ±26.1% vs. 8.9 ±22.3% p=0.001) as well as higher improvement in the hepatic encephalopathy (estimated by the percentage of evaluations in which HE decreased from II-IV at inclusion to 0-I during therapy, 56% vs. 39% p=0.06) in the MARS group. The primary endpoint was not met however, with the proportion of patients dying within 28 days almost identical in both groups (40.8% vs 40.0%). Findings show that MARS at low dosage is a safe procedure which has significant dialysis effect and improves severe hepatic encephalopathy in patients with cirrhosis and rapid deterioration of their liver function; however a significant beneficial effect on survival could not be demonstrated.

Putting a name to the fluke

Wed, 11 Feb 2009 05:00:00 PST

( from http://www.rxpgnews.com ) In a world first, a UQ researcher has developed a non-invasive screening method for potentially fatal liver and intestinal flukes plaguing the lives of an estimated 9 million people throughout southeast Asia.

The PCR test is already being used by Thai researchers to screen people for the presence of three species of liver and intestinal flukes which range in length from a few millimetres to one centimetre.

The highly accurate test can identify the species involved from one gene from an egg of a fluke among billions of other genes in a single faecal sample.

Dr Rebecca Traub and Dr Julie Macaranas, from UQ's School of Veterinary Science, developed the test after field work in Thailand, testing samples from more than 300 people in a remote village, 150km east of Bangkok.

Other researchers involved with the project included Dr Mathurit Mungthin from Phramongkutklao College of Medicine in Bangkok, Professor Darwin Murrell from the Danish Centre for Experimental Parasitology and Professor Andrew Thompson from Murdoch University.

To develop the molecular-based test, Dr Traub also called on the parasite identification expertise of UQ's Associate Professor Tom Cribb, from the Centre of Marine Studies, once back in the labs at the St Lucia campus.

The breakthrough test is a vast improvement existing testing methods to identify the flukes, involving a painful process of inducing people to purge the fully grown flukes.

The test also allows authorities to more effectively handle infestations once they know the particular species, its life cycle and host animals if any.

Dr Traub's research was funded by a three-year, Australian Research Council Linkage grant with Bayer Animal Health GmbH as the industry partner.

The leaf-shaped flukes enter the human digestive tract though consumption of raw fish, an important cultural practice which continues despite authorities warning against it.

The creatures' life cycle involve marine snails and even dogs and cats depending on the species of fluke.

In extreme cases, the flukes can cause cancer of the bile duct and/or painful stones in the bile duct, leading to liver disease and even death.

Dr Traub said her research was important because 70 percent of the world's emerging infectious diseases involved an animal source or host. Examples include Hendra Virus, SARS, Avian Flu and Hydatid Disease.

Multi-disciplinary research teams engaged in public health research are increasingly adopting a 'One Medicine' approach involving medical doctors, veterinarians and biologists. This is the most effective way of tackling the understanding and control of such diseases, Dr Traub said. She said she would seek further ARC or Wellcome Trust funding for the next stage of her research.

Factors for developing IPF in Hepatitis C patients

Thu, 23 Oct 2008 14:12:44 PST

( from http://www.rxpgnews.com ) Hepatitis C virus (HCV) is one of the more common causes of chronic liver disease in world with a variety of extrahepatic complications such as essential mixed cryoglobulinemia, membranoproliferative glomerulonep hritis, autoimmune thyroiditis, sialadenitis, and cardiomyopathy. IPF is present in patients with chronic HCV infection. However, there is little or no information on the yearly cumulative incidence and risk factors on the development rate of IPF in patients with HCV.

A research team led by Yasuji Arase from Toranomon Hospital of Japan addresses this question and this will be published on October 14, 2008 in the World Journal of Gastroenterology. In this study, they studied 6150 HCV infected patients who were between 40-70 years old (HCV-group). Another 2050 patients with hepatitis B virus (HBV) were selected as control (HBV-group). The mean observation period was 8.0 ± 5.9 years in HCV-group and 6.3 ± 5.5 years in HBV-group.

They found that fifteen patients in HCV-group developed IPF. On the other hand, none of the patients developed IPF in HBV-group. In HCV-group, the cumulative rates of IPF development were 0.3% at 10th year and 0.9% at 20th year. The IPF development rate in HCV-group was higher than that in HBV-group (P = 0.021). The IPF development rate in patients with HCV or HBV was high with statistical significance in the following cases: (1) patients ≥ 55 years (P < 0.001); (2) patients who had smoking index (package per day × year) of ≥ 20 (P = 0.002); (3) patients with liver cirrhosis (P = 0.042). This result indicated that age, liver cirrhosis and smoking enhance the development of IPF in patients with chronic hepatitis C infection.

Children's Hospital of Pittsburgh of UPMC scientific director elected to Institute of Medicine

Mon, 13 Oct 2008 04:00:00 PST

( from http://www.rxpgnews.com ) David H. Perlmutter, MD, scientific director and physician-in-chief at Children's Hospital of Pittsburgh of UPMC, has been elected to the prestigious Institute of Medicine (IOM).

The IOM was established in 1970 by the National Academy of Sciences as a national resource for independent, scientifically informed analysis and recommendations on health issues. The institute provides unbiased, evidence-based, authoritative information and advice concerning health and science policy to policy-makers, professionals, leaders in every sector of society and the public at large. Election to the IOM is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.

Dr. Perlmutter, the Vira I. Heinz Professor and Chair of the Department of Pediatrics at the University of Pittsburgh School of Medicine, is one of only 65 new members and five foreign associates who are being announced at the IOM's annual meeting Monday, Oct. 13, 2008. Current active members elect new members from among candidates nominated for their professional achievement and commitment to service.

Since joining Children's Hospital in 2001, Dr. Perlmutter has led an effort to expand the hospital's basic and clinical research program so that it is ideally poised to investigate the molecular basis of pediatric disease and to develop innovative new therapies for childhood illnesses. Under his leadership, Children's Hospital has become among the fastest growing pediatric research program in the country in terms of National Institutes of Health (NIH) funding from 2000.

It's a tremendous honor to be elected to the Institute of Medicine. I view this recognition as a testament to the great people with whom I have had the opportunity to work in my clinical and research lives at several wonderful institutions, Dr. Perlmutter said. As a physician-scientist, I've dedicated my career to improving children's health, through my basic research and clinical care of young patients, and by fostering the development of new generations of physician-scientists and clinicians who are dedicated to child health issues.

Dr. Perlmutter has carried out basic research on alpha-1-antitrypsin deficiency, the most common genetic liver disease of childhood, for more than 20 years. His work has led to many new concepts about the pathobiology of liver disease in this deficiency and has suggested several new concepts for chemoprophylaxis of chronic liver injury, hepatocellular carcinoma and emphysema in this genetic disease. He is the principal investigator on three NIH grants in this area and also now holds four other NIH grants, including the Child Health Research Center of Excellence Award for training pediatric physician-scientists in the molecular basis of pediatric disease.

Election to the Institute of Medicine is a unique and particularly noteworthy recognition of an individual's professional achievements and contributions to the medical sciences and health care. I can think of no one more deserving of such an honor than Dr. Perlmutter, whose basic research has elucidated the fundamental etiology of pediatric liver disease and whose translation of that knowledge into clinical practice has improved the health of countless children, said Arthur S. Levine, MD, senior vice chancellor for the health sciences and dean of the School of Medicine at the University of Pittsburgh. However, it is his mentorship of an emerging cadre of young physician-scientists and his transformation of the University of Pittsburgh Department of Pediatrics into one of the nation's strongest pediatric research enterprises that secure his enduring legacy in medicine and science.

Dr. Perlmutter's research has been recognized by numerous awards including the E. Mead Johnson Award for Research in Pediatrics. He is a member of the American Society for Clinical Investigation and the Association of American Physicians. He has served as the president of the Society of Pediatric Research and is now a member of the Advisory Council of the National Institute for Diabetes, Digestive and Kidney Diseases.

Dr. Perlmutter earned his bachelor's degree from the University of Rochester and his medical degree from St. Louis University School of Medicine. He completed his residency in pediatrics at The Children's Hospital of Philadelphia and his fellowship in pediatric gastroenterology and nutrition at Children's Hospital Boston.

After several years on the faculty of Harvard Medical School, Dr. Perlmutter joined the faculty at Washington University School of Medicine and St. Louis Children's Hospital. From 1992, he was the director of the Division of Gastroenterology and Nutrition at St. Louis Children's, and in 1996 he became the first to hold the Donald Strominger Endowed Professorship of Washington University School of Medicine. In 2001 he left St. Louis to take his current position in Pittsburgh.

How to prevent liver damage induced by anti-tuberculosis treatment?

Fri, 19 Sep 2008 04:00:00 PST

( from http://www.rxpgnews.com ) About one third of the world's population has latent tuberculosis and roughly 9 million cases of active tuberculosis emerge annually resulting in 2-3million deaths. Most new cases occur in the most populated nations like India and China. Combination chemotherapy containing Isoniazid (INH), Rifampicin (RMP), Pyrazinamide (PZA) with or without ethambutol for initial 2 months followed by a continuation phase of 4-6 months of Isoniazid and Rifampicin is the preferred regimen for successful treatment and for preventing acquired resistance. Drug induced hepatotoxicity is a potentially serious adverse effect of antituberculosis (ATT) regimen. A higher risk of hepatotoxicity has been reported in Indian patients (up to 11.5%) than in their western counterpart (up to 4.3%). The only measure available for managing hepatotoxicity is stopping the offending agents, once there is an evidence of liver damage and reintroducing the same after normalization of liver enzymes. Preventive therapy of contacts causes severe hepatotoxicity more often than curative treatment of clinical tuberculosis. Search for non-toxic and highly effective new compounds for treating tuberculosis or an effective vaccine conferring sustained protective immunity have yet not seen the face of success.

A research article to be published on August 14, 2008 in the World Journal of Gastroenterology addresses this question. The research team led by Dr. Meghna Adhvaryu of Bapalal Vaidya Botanical research center, Departrment of Biosciences, Veer Narmad South Gujarat University Surat, India in joint effort with Dr. Bhasker Vakharia running a charitable mobile clinic in tribal belt of district surat, conducted a clinical trial of two Ayurvedic herbs in a modified form used as an adjuvant to conventional ATT to evaluate their ability to prevent hepatotoxicity.

The pathogenesis of hepatotoxicity is not entirely clear but INH and RMP induced damage may involve oxidative stress, lipid peroxidation, choline deficiency leading to lowering of phospholipids protein synthesis with alteration in cell wall configuration, reduced glutathione level and activation of CYP2E1. It is well known that some non toxic herbs are having opposite activities in the form of membrane stabilizing, anti-oxidative and CYP2E1 inhibitory effects. A review of available literature suggests that reduction in lipid peroxide content in tissue and increase in superoxide dismutase, catalase, glutathione, glutathione-s-transferase and glutathione peroxidase activities should help to maintain liver cell integrity and control the increase in level of liver enzymes.

Initially four potential candidate herbs were tested in a guinea pig model of ATT induced hepato-toxicity and marked hepato-protective ability was demonstrated. The research article was published on 21st June 2007 in the

small intestinal bacteria overgrowthplays a role in nonalcoholic fatty liver disease?

Fri, 22 Feb 2008 07:09:07 PST

( from http://www.rxpgnews.com ) An article recently published in the January 14 issue of the World Journal of Gastroenterology has great significance for NASH. This article will undoubtedly bring about new pathogenesis and treatment of NASH.

Small intestinal bacterial overgrowth has been reported to play a role in the pathogenesis of NASH, endotoxin and TNF-¦Á being the possible mediators. Contrary to this hypothesis, in another study, antibiotic treatment did not normalize aminotransferase levels in NASH patients. This article describes an animal experiment of NASH by Dr. Wan-Chun Wu et al.

A research article to be published on January 14, 2008 in the World Journal of Gastroenterology addresses this question. Dr. Wan-Chun Wu et al established a NASH animal model by a high fat diet for 12 wks successfully, and treated with cidomycin after 8 wks of the high fat diet. A semi-solid colored marker was used for monitoring small intestinal transit. The proximal small intestine was harvested under sterile condition and processed for quantitation for aerobes (E. coli) and anaerobes (Lactobacilli). Liver pathologic score was calculated to qualify the severity of hepatitis. Serum ALT and AST levels were detected to evaluate the severity of hepatitis.

After 12 wks, they had significant findings. Small intestinal transit was inhibited in NASH group. Rats treated with cidomycin had higher small intestine transit rate than rats in NASH group. The high fat diet resulted in quantitative alterations in the aerobes (E. coli) but not in the anaerobics (Lactobacill). There was an increase in the number of E. coli in the proximal small intestinal flora in NASH group than in control group. TNF-¦Áconcentration was significantly higher in NASH group than in control group. TNF-¦Áconcentration was lower in cidomycin group than in NASH group. Treatment with cidomycin showed its effect by significantly lowering serum ALT, AST and TNF-¦Álevels of NASH rats. SIBO may decrease small intestinal movement in NASH rats. SIBO may be an important pathogenesis of Nash and treatment with cidomycin by mouth can alleviate the severity of NASH.

The results of this study suggest a promising future for many NASH patients. Due to the high disease incidence of NAFLD around the world and no effective treatment at present, this case reported by Dr. Wan-Chun Wu is surely worth the attention of both doctors and the public at large.

Scientists using laser light to detect potential diseases via breath samples, says new study

Mon, 18 Feb 2008 05:00:00 PST

( from http://www.rxpgnews.com ) By blasting a person's breath with laser light, scientists from the National Institute of Standards and Technology and the University of Colorado at Boulder have shown that they can detect molecules that may be markers for diseases like asthma or cancer.

While the new technique has yet to be tested in clinical trials, it may someday allow doctors to screen people for certain diseases simply by sampling their breath, according to the research team from JILA, a joint institute of NIST and CU-Boulder. This technique can give a broad picture of many different molecules in the breath all at once, said Jun Ye, a fellow of JILA and NIST who led the research.

CU-Boulder graduate research assistant Michael Thorpe, Ye, CU-Boulder doctoral student Matthew Kirchner and former CU graduate student David Balslev-Clausen describe the research in a paper that appeared in the Feb. 18 online edition of Optics Express, the free, open-access journal published by the Optical Society of America. Known as optical frequency comb spectroscopy, the technique is powerful enough to sort through all the molecules in human breath and sensitive enough to distinguish rare molecules that may be biomarkers for specific diseases, said Ye.

When breathing, people inhale a complex mixture of gases, including nitrogen, oxygen, carbon dioxide, water vapor and traces of other gases like carbon monoxide, nitrous oxide and methane, said Ye, an adjoint professor of physics at CU-Boulder. Exhaled breath contains less oxygen, more carbon dioxide and a rich collection of more than a thousand types of other molecules, most of which are present only in trace amounts.

Just as bad breath can indicate dental problems, excess methylamine may signal liver and kidney disease, ammonia may be a sign of renal failure, elevated acetone levels can indicate diabetes and nitric oxide levels can be used to diagnose asthma, Ye said.

When many breath molecules are detected simultaneously, highly reliable, disease-specific information can be collected, said Ye. Asthma, for example, can be detected much more reliably when carbonyl sulfide, carbon monoxide and hydrogen peroxide are all detected simultaneously with nitric oxide.

While current breath analysis using biomarkers is a noninvasive and low-cost procedure, approaches are limited because the equipment is either not selective enough to detect a diverse set of rare biomarkers or not sensitive enough to detect particular trace amounts of molecules exhaled in human breath, Ye said.

The new technique has the potential to be low-cost, rapid and reliable, and is sensitive enough to detect a much wider array of biomarkers all at once for a diverse set of diseases, he said.

The optical frequency comb is a very precise laser for measuring different colors, or frequencies, of light, said Ye. Each comb line, or tooth, is tuned to a distinct frequency of a particular molecule's vibration or rotation, and the entire comb covers a broad spectral range -- much like a rainbow of colors -- that can identify thousands of different molecules.

Laser light can detect and distinguish specific molecules because different molecules vibrate and rotate at certain distinct resonant frequencies that depend on their composition and structure, he said. He likened the concept to different radio stations broadcasting on separate radio frequencies.

Europe's most common genetic disease is a liver disorder

Wed, 06 Feb 2008 20:55:00 PST

( from http://www.rxpgnews.com ) Much less widely known than the dangerous consequences of iron deficiencies is the fact that too much iron can also cause problems. The exact origin of the genetic iron overload disorder hereditary hemochromatosis (HH) has remained elusive. In a joint effort, researchers from the European Molecular Biology Laboratory (EMBL) and the University of Heidelberg, Germany, have now discovered that HH is a liver disease. They report in the current issue of Cell Metabolism that the disorder develops when a crucial gene is lacking in liver cells.

Iron is essential for our body, because it is a central component of red blood cells. Too little iron can lead to dangerous anemias, but also too much iron can be detrimental as it promotes the formation of toxic radicals that lead to tissue damage. Hereditary hemochromatosis is an iron overload disorder that, affecting about one in 300 people, is probably the most common genetic disorder in Europe. Scientists have identified a gene, called HFE, that when mutated causes hemochromatosis in mice and humans. But as yet it is unknown in which tissue or organ the gene is acting to prevent iron overload.

A group of researchers around Matthias Hentze at EMBL and Martina Muckenthaler and Wolfgang Stremmel at the University of Heidelberg have now found that mice that are genetically engineered to lack HFE only in liver cells show all central features of the disease.

“For a long time scientists thought of HH as a disease of the intestine, because this is where iron uptake actually takes place,” says Matthias Hentze, Associate Director of EMBL. “Our research now reveals the crucial point is actually the liver and explains why HH patients suffer from increased iron absorption.”

HFE encodes a protein that is likely involved in transmitting signals about the current iron contents of the body to liver cells. In response to these signals, the liver cells make a special iron hormone, hepcidin that is released into the blood stream and reduces iron uptake in the intestine.

“HFE influences hepcidin expression through a series of intermediate molecules, but when the HFE gene is mutated the result is that less hepcidin is produced. This in turn means iron uptake in the intestine cannot be limited as effectively and an overload develops,” says Martina Muckenthaler, professor at the University of Heidelberg.

Ginsenosaide Rb1 (R1)- chinese medicine ingredient found to protect liver

Wed, 16 Jan 2008 13:48:31 PST

( from http://www.rxpgnews.com ) Many patients worldwide are going to receive major abdomen surgery or intestine transplantation every year and expect to be afflicted with liver injury afterwards. The finding of a research group headed by Professor Han Jing-Yan in China and reported in January 7, 2008 of the World Journal of Gastroenterology (volume 14, issue 1) may prove good news for them.

The study by Han Jing-Yan et al discovered Ginsenosaide Rb1 (R1) is able to prevent hepatic microcirculatory disturbance and subsequent liver injury in mice induced by intestine ischemia and reperfusion (I/R). R1 is one of the major effective ingredients of Panax notoginseng (PN), a traditional Chinese herb medicine frequently included in various compound Chinese medicines for treatment of liver injury and numerous other diseases in China and other Asian countries.

In 2005, Dr. Han was working on the effect and underlying mechanism of cardiotonic pills (CP) in cooperation with Prof. Toshifumi Hibi and Dr Yoshinori Horie in the Department of Internal Medicine, School of Medicine, Keio University, Japan. They revealed the beneficial effect of CP for improving gut I/R induced liver injury (Horie Y, Han JY, Mori S, Konishi M, Kajihara M, Kaneko T, Yamagishi Y, Kato S, Ishii H, Toshifumi Hibi. Herbal cardiotonic pills prevent gut ischemia/reperfusion-induced hepatic microvascular dysfunction in rats fed ethanol chronically. World J Gastroenterol 2005; 11(4): 511-515). However, CP is a compound Chinese medicine preparation that contains PN, and salvia miltiorrhiza and Borneol additionally. It was not clear at that time which one among the three ingredients is actually responsible for this action. The present report of Dr. Han¡¯s group shows R1, one of the major compounds of PN, protects against the gut I/R induced liver injury impressively.

In this study, the animal model is established by ligation of the superior mesenteric artery (SMA) in C57/BL mice for 15 min followed by 30 min reperfusion. The researchers apply several techniques to address the issue concerned. First, they take advantage of an inverted intravital microscope assisted by a 3CCD color camera and high speed video camera and laser confocal microscope. This enables a dynamic examination of the hepatic microcirculatory parameters under investigation in mouse subjected to gut I/R and observes the gut I/R imposed impairment in vascular diameter, red blood cell velocity, sinusoid perfusion and leukocyte rolling and adhesion is obviously alleviated or completely abolished by pretreatment with R1.

Secondly, immunofluorescent staining is used to examine the endothelial adhesion molecules E-selectin and ICAM-1. Finally, blood is collected for detecting the expression of adhesion molecules in leukocyte and the activity of hepatic enzymes, including LDH, ALT, and AST, and the concentration of pro-inflammatory mediators such as TNF-¦Á, IL-6 and monocyte chemotactic protein-1 (MCP-1). After careful evaluation, the researchers concluded R1 prevents I/R-induced hepatic microcirculation disturbance and hepatocyte injury by inhibition of leukocyte rolling and adhesion, through depressing the expression of E-selectin in endothelium and CD18 in neutrophils. This result is of significance not only for better understanding the mechanism of the effect of PN and PN containing preparations, but also for R1 to be used to prevent liver injury originated from gut I/R.

Research reveals secrets of alcohol's effect on brain cells

Fri, 07 Dec 2007 05:00:00 PST

( from http://www.rxpgnews.com ) NEW YORK (Dec. 7, 2007) -- Alcohol triggers the activation of a variety of genes that can influence the health and activity of brain cells, and new research from Weill Cornell Medical College in New York City sheds light on how that process occurs.

The findings, published in the Nov. 21 issue of The Journal of Neuroscience, may also edge scientists closer to understanding alcohol-linked disorders such as the brain damage associated with chronic alcoholism, and the abnormal brain development seen in the fetal alcohol syndrome (FAS).

If you are going to understand the biological effects of alcohol on genes within cells, you have to understand the molecular machinery driving the transcription, or activation, of the genes in question. That's what we believe we have done here, says the study's senior author Dr. Neil L. Harrison, professor of pharmacology and pharmacology in anesthesiology at Weill Cornell.

In research conducted in cell cultures and in mouse neurons in vivo, his team found that alcohol stimulates a ubiquitous, stress-linked biochemical cascade -- called the heat shock pathway -- to send a molecule called heat shock factor 1 (HSF1) into the neuron's nucleus. HSF1 then stimulates the transcription of many of the genes known to be activated by alcohol.

The fact that alcohol triggers the activation of genes in the brain is not new and has long been the subject of intense research.

One gene in particular, called Gabra4, is closely linked to the function (or dysfunction) of receptors for GABA, an important neurotransmitter.

We knew that levels of expression of Gabra4 fluctuated rapidly in the presence of alcohol, and so we wondered if we could find out how this happens, says lead author Dr. Leonardo Pignataro, instructor in pharmacology in anesthesiology at Weill Cornell.

At the same time, research in Korea with the C. elegans worm (a common tool for genomics research) had discovered that alcohol worked on a particular bit of DNA to trigger activity in the heat shock pathway, finding the same piece of DNA in the Gabra4 gene of mice and humans. This was all very intriguing, because the heat shock pathway is a biochemical mechanism found in almost all cells and all organisms, says Dr. Harrison. Scientists believe it helps cells deal with stressors -- including excessive heat or environmental toxins -- substances such as alcohol.

Working with mouse cells in the lab, the researchers used microarray technologies to search for genes other than Gabra4 that might be activated when the heat shock pathway was exposed to alcohol. They found many others.

The big question that remains is how does this activation occur The current theory holds that, under conditions of stress, heat shock proteins break away from a key molecule, HSF1. HSF1 then makes its way to the cell nucleus, where it helps stimulate the transcription and activation of a variety of genes that enable the cell to survive stress. We think this may happen with alcohol exposure, Dr. Harrison explains.

This finding, observed in vitro in the cell cultures, was replicated in in vivo experiments in mice, conducted in the lab of Dr. Daniel Herrera, assistant professor of psychiatry at Weill Cornell and an attending psychiatrist at NewYork-Presbyterian/Weill Cornell.

It was really exciting to see this mechanism work itself out in an animal model, suggesting that this same pathway may mediate at least some of the effects of alcohol on human brain cells, Dr. Herrera says.

Exactly what those effects might mean clinically remains in the realm of speculation for now, the researchers stress.

Alcohol can have bad effects -- the well-known effects of alcoholism, such as liver or brain damage, for example -- but moderate alcohol use also has more benign effects, such as the improvement in cardiovascular health observed in drinkers of red wine compared with tee-totallers, Dr. Pignataro points out.

One theory holds that alcohol-mediated stimulation of the heat shock pathway might trigger genes that help mop up mis-folded proteins that can damage cells. This would be a beneficial effect.

But it might also be possible that inappropriate activity of this pathway -- either during fetal brain development or in the adult brain -- is harmful. We just don't know, Dr. Harrison says. We'd certainly like to explore these issues going forward, and this research will give us some tools to answer these questions.

Hepatitis C treatment reduces the virus but serious liver problems may progress

Tue, 06 Nov 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Patients with chronic hepatitis C and advanced liver disease who did not respond to previous standard therapy experienced significant decreases in their liver enzymes, viral levels, and liver inflammation following treatment with long-term pegylated interferon. However, the treatment did not slow or prevent the progression of serious liver disease. These findings come from the clinical trial, Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) and were reported at the annual meeting of the American Association for the Study of Liver Disease in Boston on November 5, 2007. HALT-C is funded by the National Institutes of Health (NIH) with additional support from Hoffmann-La Roche Inc.

The HALT-C trial unequivocally demonstrated that maintenance therapy with peginterferon does not prevent progression of liver disease among patients who have failed prior treatments, said James Everhart, M.D., project scientist for HALT-C and a program director for the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the principal sponsor of HALT-C at NIH. These results add to the incentive to develop more effective drugs that will benefit patients with severe liver disease due to hepatitis C.

HALT-C, a randomized multicenter trial of 1,050 patients with chronic hepatitis C who had failed prior treatment to eradicate the infection, assessed whether long-term treatment with peginterferon alfa-2a reduced the development of cirrhosis, liver failure, or liver cancer. The 517 patients randomized to the treatment arm received 90 micrograms of peginterferon in weekly injections for 3.5 years. The 533 patients in the control arm underwent the same follow-up and care as the treated patients including liver biopsies, quarterly clinic visits, and blood tests. All patients had advanced liver fibrosis, a gradual scarring of the liver that puts patients at risk for progressive liver disease.

The outcomes assessed in HALT-C were death, liver cancer, ascites (excess fluid in the abdomen), or encephalopathy (brain and nervous system damage), and for those who did not have cirrhosis initially, the development of cirrhosis. At the end of the study, 34.1 percent of the patients in the treated group and 33.8 percent of the patients in the control group had experienced at least one outcome. Patients in the treated group had significantly lower blood levels of the hepatitis C virus and less liver inflammation. However, there was no major difference in rates of any of the primary outcomes between groups.

Among treated patients, 17 percent stopped peginterferon by one year and six months and 30 percent stopped the drug two years later. Adverse events such as infections, musculoskeletal or digestive problems were the most common reasons patients stopped taking the drug.

Viral hepatitis C infects more than 100 million persons worldwide and as many as 4 million persons in the United States. Hepatitis C ranks with alcohol abuse as the most common cause of chronic liver disease and leads to about 1,000 liver transplants in the United States each year. The best current antiviral therapy consists of pegylated interferon given by injection in combination with oral ribavirin prescribed for about 6 months to a year. This therapy eliminates the virus in about 50 percent of infected patients.

Portal vein thrombosis is common in extraportal vein obstruction

Fri, 12 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Among the 118 patients with portal vein thrombosis, noncirrhotic and nontumoral extrahepatic portal vein obstruction are young and present with well tolerated bleed. Cirrhosis and tumor related portal vein thrombosis patients are older and have grim prognoses. Hypercoagulable state as a cause of portal vein thrombosis is less common. The idiopathic group comprises the second largest number of patients.

A research article to be published on October 21 in the World Journal of Gastroenterology addresses the etiology and clinical outcome of portal vein thrombosis. The research team led by Dr. Pankaj Jain and Dr. Sandeep Nijhawan from Sawai Man Singh Hospital, Jaipur worked on patients with portal vein thrombosis for two years. The researchers had observed that patients with portal vein thrombosis in the two groups behaved differently in etiology, presentation and prognosis. Therefore, they collected data from their centre to verify the differences.

The researchers included cirrhosis and tumor-related AND non-cirrhotic non-tumoral extrahepatic portal venous obstruction. The large sample size allowed them to obtain significant results and draw very reliable conclusions.

Factor V Leiden mutation was present in 2% of cases and is uncommon in India. Umbilical sepsis in childhood or catheterization of umbilical veins in the neonatal period may be responsible for extrahepatic portal vein obstruction in the developing countries.

Extrahepatic portal vein obstruction (EHPVO) patients were young and commonly presented with features of hematemesis, hypersplenism, pain abdomen and abdominal distension. Ten patients had acute PVT and two had presentation as acute Budd-Chiari syndrome. Cirrhosis and tumor-related portal vein thrombosis presented with abdominal distension, abdominal pain and jaundice. On follow-up of a mean period of 7 months (range 1-24 months), 48% patients had died. The role of JAK2mutation in the early diagnosis of overt or silent myeloproliferative disease cannot be undermined but requires standardization.

Therefore, portal vein thrombosis is common in cirrhotic, tumor and non-tumoral, non-cirrhotic extraportal vein obstruction. EHPVO is a benign disease whereas cirrhotic and tumoral-related portal vein obstruction has a grim prognosis. Any patient with portal vein obstruction, in whom secondary cause is not known, should have hypercoagulable work up done to find out a treatable cause. Furthermore, as a primary prevention antenatal care has to be more meticulously planned and carried out.

Dr. Pankaj Jain (doing a fellowship in gastroenterology) and Dr. Sandeep Nijhawan (Professor of Gastroenterology) are working in the Department of Gastroenterology at Sawai Man Singh College and Hospital, Jaipur.

The experts opined that this research presents a large series of patients with portal vein thrombosis which they believed will be useful to the practitioners.

Can liver cirrhosis be partially cured?

Wed, 10 Oct 2007 04:00:00 PST

( from http://www.rxpgnews.com ) The diffusion of hepatitis C virus infection worldwide is astonishing. Liver cirrhosis is present in at least 10-20% of these infected patients, with highly increasing health care and emotional costs. In patients with compensated (early stage) hepatitis C virus-related cirrhosis, antiviral combined therapy offers an interesting rate of response, ending in viral clearance. Unfortunately post-therapy data on different aspects of the illness, such as the residual liver function, measured as Total Overnight Salivary Caffeine Assessment (TOSCA, a liver test of microsomal function), and hepatic hemodynamics to indirectly evaluate the portal hypertension, measured as the Resistive Index of Splenic Artery (SARI) at Ultra Sound Doppler are still lacking, because to date only the survival rate and hepato-carcinoma appearance have been studied in depth.

Thirty five cirrhotic patients (24 grade A5 and 11 grade A6 of the Child-Pugh classification system, used to assess illness severity), with active virus replication and treated for a mean period of three years with moderate doses of Interferon-alpha and Ribavirin were compared to a cohort of 36 patients with similar characteristics and without antiviral treatment. TOSCA was determined at the starting point and three times throughout the course of therapy after a mean period of one year. Meanwhile, the SARI was only measured at the beginning and end of the study.

The more notable findings are as follows. Thirteen treated patients showed a significant TOSCA improvement. A reduction greater than 20% on the Resistive Index of Splenic Artery was obtained in eight of the patients with improved liver function. This previously abnormal Doppler parameter showed a clear total decreasing tendency at the end of therapy. Hepatitis C virus clearance was achieved in four patients at a median period of eight months of combined therapy. In the cohort of non-treated cirrhotic patients, not only the considered parameters remained unchanged, but three patients ended with a worse Child-Pugh score.

Dr. Tarantino and his team from the Federico II University Medical School believes that moderate-dosed, prolonged antiviral therapy can make stable or ameliorate residual liver function, the entity of portal hypertension and the compensation status, all at acceptable costs. In this way, more severe liver cirrhosis complications, such as variceal hemorrhage, the appearance of refractory ascites and advanced encephalopathy, are can be delayed, thereby prolonging the survival period of many patients. His team, however, still emphasises the need to evaluate individuals affected by liver cirrhosis using alternative, non-invasive, and easily repeatable parameters of outcome to better understand the progression of this illness.

Immune system modulation can halt liver failure in animals

Tue, 25 Sep 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Massachusetts General Hospital (MGH) researchers have a developed a totally new approach to treating liver failure � manipulating the immune response. If the results of the animal study can be applied in human patients, the approach may be able to keep patients alive until donor organs become available or to support liver function until the organ can regenerate itself, eliminating the need for a transplant. The findings are being reported in the journal PLOS One.

�We have identified a non-hepatic source of cells that can easily be expanded to the scale required for clinical application,� says Martin Yarmush, MD, PhD, director of the Center for Engineering in Medicine at MGH, the paper�s senior author. He also is the Helen Andrus Benedict Professor of Surgery and Bioengineering in the Harvard-MIT Division of Health Science and Technology (HST) and a senior scientific staff member at the Boston Shriners Burns Hospital.

The liver is one of the few major organs that is able to regenerate itself. But when the organ is damaged by diseases like chronic hepatitis, long-term alcohol consumption, or other causes, ongoing inflammation can increase cell death and suppress the natural regenerative process. The only current treatment for end-stage liver failure is transplantation, which is limited by the organ supply and requires long-term immunosuppressive treatment. While external liver assist devices have successfully supported some patients, such machines require a supply of preferably human liver cells, which have been difficult to acquire and expand.

For their investigation, the MGH research team used mesenchymal stem cells (MSCs) � cells from the bone marrow that develop into tissues supporting blood cell development in the marrow cavity. Previous research has shown that MSCs are able to inhibit several immune system activities. A supply of MSCs can be extracted from a patient�s own marrow and expanded to levels that could be therapeutically useful. To evaluate the ability of human MSCs to treat organ failure involving inflammatory activity, the investigators tested several ways of using the cells to treat rats in which liver failure had been induced.

Several approaches to administering MSCs reduced the biological signs of liver failure and improved the animals� survival. Although simply transplanting MSCs was not effective, two methods of delivering molecules secreted by the cells lessened inflammation within the liver and halted cell death. Cycling the blood of rats with liver failure through an external bioreactor containing MSCs also greatly reduced the metabolic signs of liver failure in the animals. Even more significantly, 71 percent of the rats treated with the MSC-seeded bioreactor survived, while only 14 percent of those in a control group were alive one week later.

�One essential function of MSCs in the bone marrow is to secrete molecules that promote the growth and maturation of blood cells,� say co-lead author Biju Parekkadan, an HST graduate student working in Yarmush�s lab. �We are now finding that these same molecules can be used as potent immunotherapeutics and envision a multi-tiered treatment of liver failure based on this work. A patient presenting with liver failure could first be treated with an intravenous injection of an �off-the-shelf� drug containing MSC-produced factors in an effort to halt cell damage and allow the organ to regenerate. If that is not effective, an MSC-based support device could be used as a bridge to transplantation or even as a long-term treatment.�

The researchers note that exactly how MSC-produced molecules inhibit the movement of immune cells into a damaged organ is not yet known and is currently under investigation. They also hope to examine the possibility of combining both MSCs and liver cells in a potential support device and to test the potential of MSCs to treat other immunological diseases.

Inhaling nitric oxide helps transplant success

Wed, 29 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) BIRMINGHAM, Ala. � Administering inhaled nitric oxide (NO) during surgery helps protect liver transplant patients from organ failure, according to a new study from researchers at the University of Alabama at Birmingham (UAB).

The colorless gas improves post-surgical liver function by minimizing reperfusion injury, an unwanted side effect of restoring blood flow swiftly to a donor organ moments after transplantation into the recipient, the study authors said.

The findings on inhaled NO were published in the most recent issue of the Journal of Clinical Investigation. Results from this small study are preliminary and must be confirmed through larger clinical trials, said Rakesh Patel, Ph.D., an associate professor in the UAB Department of Pathology and a co-lead author on the study.

Exactly how the inhaled NO improves organ function at the cellular and molecular level is still unknown, Patel said. What is clear from post-surgical data are the benefits of inhaled NO for transplant patients: decreased hospital length-of-stays, and improved blood-clotting and liver-enzyme activity in post-transplant tests.Inhaled NO was administered to study subjects through an anesthesia mask by UAB anesthesiologists during transplant surgery.

The trial was designed to be �blinded� and placebo-controlled, which means some patients got inhaled NO and others did not, and neither patients nor their surgeons knew who was getting the gas.

�We were pleasantly surprised at how good the inhaled NO patients performed after the results were gathered,� Patel said. He said the results also showed inhaled NO protects transplanted livers from a rise in hepatic cell death.NO can be toxic to humans if breathed at high doses without medical supervision. Doses administered to the Journal of Clinical Investigation study participants were about 80 ppm, which did not cause toxicity and even proved beneficial, Patel said.

A larger clinical trial of inhaled NO involving more patients is about to start up at UAB in conjunction with Seattle-based University of Washington and the U.S. Department of Veterans Affairs Puget Sound Health Care System.Since reperfusion injury is possible in a wide range donated organs, the hope is that inhaled NO holds promise for improving �results to other solid organ transplants, such as heart, lung, kidney and pancreas,� said Devon Eckhoff, M.D., chief of UAB�s liver transplant program and a professor in the Department of Surgery.

Clearly if more donor organs end up healthier after transplantation, then donor-organ shortages may see some relief. �The more organs that are made suitable for transplantation will decrease the wait time for organ transplant recipients and subsequently save lives,� Eckhoff said.

New cancer fighter may help ICU patients beat infections

Mon, 27 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) HSP 90 inhibitors, which are finding favor in fighting cancer, may also help battle overwhelming infection in intensive care patients, researchers say.

Studies in an animal model of sepsis, a major cause of ICU patient death, indicate HSP 90 inhibitors help degrade proteins perpetuating inflammation, says Dr. John D. Catravas, director of the Medical College of Georgia Vascular Biology Center.

Results include restored lung function, reduced blood vessel leakage, which can lead to dangerous swelling in the lungs, and fewer byproducts of inflammation such as white blood cells, MCG researchers report in the American Journal of Respiratory and Critical Care Medicine, a journal of the American Thoracic Society.

They already have begun looking at the impact of HSP 90 inhibitors on the function of other organs, such as the liver and kidneys, also typically impacted by sepsis.

�We would die without an inflammatory response, but unreined inflammation is bad,� says Dr. Catravas. That�s just what happens with overwhelming infection; inflammation, which helps the body eliminate invaders, essentially keeps working after invaders are gone and the new target is the body.

�These are proteins that initially are useful in combating an invading bacteria but then, in some of us that develop sepsis for reasons that are poorly understood, the inflammatory response is amplified and stays much longer than it should,� says Dr. Catravas, the paper�s corresponding author.

Heat shock proteins carry proteins where they are needed and fold them up nicely so they do the correct job. Dr. Catravas compares their two-protein configuration to a lobster with its claws closed while tending to �client� proteins.

�The hypothesis we worked on is that these HSP 90 inhibitors take the heat shock protein and move it into a different conformation,� says Dr. Catravas. The published research indicates they were correct and that inhibitors, fortunately, readily target proteins that no longer have a useful function.

�The HSP 90 inhibitor binds to a little pocket in the dimer, the two identical proteins that make up HSP 90 complex, and forces the two claws open,� he says. �As soon as they open, as soon as the three-dimensional conformation of the HSP dimer and the client protein change, other proteins start attaching to the complex.� The client protein then becomes susceptible to degradation. It was their earlier finding that inducible nitric oxide synthase, a major mediator of sepsis, is a client protein of HSP 90 that led to the inhibitor study.

For the study, researchers used what would be considered lethal doses of endotoxin to create a worse-case infection and pretreated animals with smaller doses of HSP 90 than those currently under study for a wide range of cancers.

They have begun looking at more clinically relevant infection levels and identifying the best time after the insult to give the lowest dose. However, Dr. Catravas has not ruled out HSP 90 inhibitors� potential to preventively treat patients at risk because patients seem to tolerate it well in the cancer clinical trials.

He hopes to move ahead soon with clinical trials of HSP 90 inhibitors, used in conjunction with antibiotics, in intensive care patients.

These manmade HSP 90 inhibitors work by attaching where the protein pair�s energy source, called ATP, should be. The body appears to have an endogenous version, ADP, which has one less phosphate than ATP and binds at the same site, also opening the protein claws and sending the client protein toward degradation.

Age alone does not increase risk of death following liver transplant among selected septuagenarians

Mon, 20 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Advanced age alone does not appear to be associated with the risk of death following liver transplant, according to a report in the August issue of Archives of Surgery, one of the JAMA/Archives journals.

Life expectancy has increased in recent years, with individuals older than 70 representing a large and fast-growing segment of the general population, according to background information in the article. A healthy 70-year-old adult living in a developed country with a nutritious diet and good medical care can expect to live to age 80 or 90. �As longevity has increased, the burden of liver disease in patients of advancing age has also increased and is associated with a higher mortality than in younger adults,� the authors write. �In the 1980s, the death rate from chronic liver disease was highest in patients 65 to 74 years of age. This has led to more older patients undergoing liver transplantation.�

Gerald S. Lipshutz, M.D., M.S., and colleagues at the David Geffen School of Medicine at UCLA reviewed the records of patients who received their first liver transplant between 1988 and 2005. They compared 62 patients who were age 70 or older (average age 71.9) to 864 patients age age 50 to 59 (average age 54.3). Survival time was measured until death, the last known follow-up date or retransplantation.

Overall, 31 of 62 patients age 70 or older and 345 of 864 patients younger than 70 died during the study period. After one year, 73.3 percent of older patients and 79.4 percent of younger patients survived; after ten years, 39.7 percent of older patients and 45.2 percent of younger patients were still alive. �We found no statistically significant difference in survival in the first 10 years after transplantation for a group of 62 patients 70 years or older when compared with a younger cohort of 864 recipients aged 50 to 59 years with similar characteristics,� the authors write. �The longest-surviving patient was 88 years old at 15 years after transplantation. One-year unadjusted survival of septuagenarians in the most recent surgical period, 2001 to 2005, was 94.4 percent.�

The researchers also analyzed 26 variables related to the recipients, donors and transplant operations to see which predicted patient deaths. Of the 26, four were associated with death rates: preoperative hospitalization, prolonged period of cold storage between liver removal and transplantation, cirrhosis caused by hepatitis C and alcohol and an increasing model for end-stage liver disease (MELD) score, a measure of disease severity. An age of 70 years or older did not independently predict death in transplant patients.

�In conclusion, biological and physiological variables may play a more important role than advanced age in predicting poor survival after liver transplantation. Measures of physiological age and risk of complications should be used in the evaluation process of elderly transplant candidates,� the authors conclude. �Age by itself should not be used to limit liver transplantation.�

Metabolic study in mice could lead to 'good cholesterol' boosters

Tue, 07 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers have identified a new player in the control of so-called good cholesterol that circulates in the bloodstream and reduces heart attack risk, according to a report in the August issue of Cell Metabolism, a publication of Cell Press. Should the metabolic pathway uncovered in mice operate similarly in humans, the new discovery could point the way to therapies that protect against heart disease by boosting concentrations of the beneficial high-density lipoprotein cholesterol (HDL-C).

By and large, the medicines now available lower levels of the bad low-density lipoprotein cholesterol [LDL-C], said Weijun Jin of the University of Pennsylvania School of Medicine. There is a great need for methods to raise good cholesterol levels. Our findings suggest there may be multiple places to interrupt the metabolism of HDL-C.

LDL-C can build up in blood vessel walls, increasing the risk of heart disease or stroke. By contrast, HDL-C tends to carry cholesterol away from the arteries to the livera process known as reverse cholesterol transportwhere it is broken down and then eliminated from the body.

Existing LDL-C-lowering drugs such as statins can reduce the risk of heart attack by 20 to 35 percent, Jin said. However, treatment methods that would simultaneously lower bad cholesterol and increase good cholesterol have the potential to work even better. Indeed, researchers believe that increasing HDL-C while lowering LDL-C might cut heart attack risk by as much as 70 percent, he explained.

In the current study, the researchers found that treatments that partially block the activity of liver enzymes called proprotein convertases decreased plasma HDL-C levels in mice. They showed that the metabolic effect of the proprotein convertases depended on yet another factor, an enzyme called endothelial lipase (EL), which breaks down HDL-C. Proprotein convertases normally reduce EL function, they reported. Thus, the loss of proprotein convertase activity leads to an increase in EL and a decline in HDL-C.

Likewise, they showed that increased activity of proprotein convertases in the liver gives a significant boost to the protective HDL-C.

Proprotein convertases are an unexpected new player in HDL-C metabolism, Jin said. By manipulating levels of the enzyme in both directions, we were able to reduce HDL-C to almost nothing or double it. That wide range of effects suggests that it may be theoretically possible to manipulate good cholesterol levels to whatever point you like.

He emphasized, however, that the new findings represent basic research in animals. Further investigation will examine to what extent the pathway is preserved in humans, Jin said. The authors will also look for chemicals capable of modifying the pathway, which could hold promise as new good-cholesterol-boosting drugs.

Study shows radiofrequency ablation highly effective in treating kidney tumors

Wed, 01 Aug 2007 04:00:00 PST

( from http://www.rxpgnews.com ) The patients underwent CT-guided radiofrequency ablation (RFA) at Wake Forest Baptist for kidney tumors ranging in size from 0.6 cm to 8.8 cm. A total of 125 tumors in 104 patients were treated over the period 2000 to 2006. In all of the patients, a biopsy had confirmed the presence of renal cell carcinomas (RCC), a common type of renal malignancy.

Of 95 tumors that were smaller than 3.7 cm (about 1.5 in.), all were completely eradicated by a single treatment, along with 14 of the larger tumors. Seven more of the 16 remaining larger tumors were eradicated after a second treatment, for a total 93 percent success rate for all 125 tumors. The results, reported in the August issue of the American Journal of Roentgenology, were based on follow-up exams over an average of about 14 months.

This is the largest treatment group to date of patients with biopsy-proven renal malignancies, said Ronald J. Zagoria, M.D., a professor of radiology at Wake Forest Baptist, an associate in urologic surgery, and lead author on the study. The results a high cure rate and low complication rate establish that at institutions with experience doing this procedure, this is an alternative method for treating small renal malignancies in patients who are not good surgical candidates.

RFA uses a needle-like treatment probe, guided by computed tomography (CT) as it is inserted through the skin into the tumor. The probes high-frequency alternating current heats the tumor tissue and destroys it. The technique has been used successfully in liver tumors since the early 1990s and has more recently been adapted for treatment of RCC.

Renal cell carcinomas that are smaller than 3.7 cm in diameter can be reliably and safely eradicated with percutaneous RFA, Zagoria and his colleagues conclude in the report. This result is regardless of the location or position of the RCC in the kidney. Larger tumors can also be eradicated with percutaneous RFA, they say, but with the larger tumors the risk of incomplete tumor destruction increases substantially. The authors also note that larger tumors near the middle of the kidney may be more difficult to ablate, possibly because they are close to large blood vessels or the ureter.

RFA is an outpatient procedure in which the patient is sedated but conscious and a local anesthetic is used at the puncture site. In the study being reported, 101 of the 104 patients went home the same day, and three were hospitalized after the procedure one for a planned treatment, another for treatment of bruising around the puncture, and a third for treatment of exacerbation of a heart condition.

A total of eight patients experienced complications, including temporary air pockets in the chest cavity, mild to severe pain after the procedure, pneumonia, and problems with their ureters. Generally, the report says, this study shows that the procedure ... has a very low rate of complications. Standard treatment for RCC has been a removal of the affected kidney, along with adjoining blood vessels and lymph nodes, known as a radical nephrectomy, although newer minimally invasive techniques, such as laparoscopic surgery, have also been used successfully.

Zagoria cautioned that RFA is not recommended if patients are good surgical candidates who are healthy, younger, and have two normal kidneys, because long-term follow-up is lacking and therefore the durability of cure is not confirmed. (The average age of patients in the study was about 70, with a range of 30-89.) However, he said, I think this is a big advance in treating renal tumors. The best candidates for RFA, he said, are patients with increased risk of complications from surgery and those with an hereditary condition that makes it likely they will require repeated treatments because of continual development of RCCs.

Antibody retards growth and induces death in liver cancer cells

Wed, 11 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) PITTBURGH, July 11 Researchers from the University of Pittsburgh School of Medicine report a significant new advance in the search for an effective treatment for human liver cancer in the July issue of Molecular Cancer Therapeutics. Using a newly available monoclonal antibody, they demonstrated significant reductions in tumor cell proliferation and survival in human and mouse hepatocellular cancer (HCC) cell lines. According to the researchers, this finding has significant implications not only for the treatment of liver cancer but for a number of different types of cancer.

Most cases of HCC are secondary to either a viral hepatitis infection or cirrhosis of the liver. Despite recent advances, it remains a disease of grim prognosis due to the poorly understood mechanism of how the disease originates and spreads. Most patients live only a short time after diagnosis.

Based on previous studies showing that some pathways that were previously thought to be active only during fetal liver development, particularly the class III receptor tyrosine kinase (RTK) family pathway, became highly active again in the liver of HCC patients, Satdarshan P. Singh Monga, M.D., associate professor, division of cellular and molecular pathology and colleagues at the University of Pittsburgh School of Medicine, obtained rat and human liver cancer cell lines and analyzed them for level of expression of an RTK protein known as platelet-derived growth factor receptor-alpha, or PDGFRá. The investigators also analyzed the cells for their level of activation of the PDGFRá gene.

At an early fetal stage of liver development in the mouse, the investigators found that the level of expression of PDGFRá was 37 times higher compared to later stages of development in the adult mouse liver. They also found significantly higher levels of PDGFRá in rat and human liver cancer cell lines as compared to normal cells in culture.

Dr. Mongas group then treated human and mouse liver cancer cell lines with a monoclonal antibody targeted against PDGFRá. It resulted in a significant decrease in tumor cell proliferation and a marked increase in tumor cell death. In fact, all tumor cell lines experienced significant decreases in proliferation in response to the monoclonal antibody and there was a 4- to 18-fold increase in programmed cell death, or apoptosis, among the cancer cell lines compared to normal control cells.

According to Dr. Monga, these results suggest that PDGFRá offers an important new therapeutic target for the treatment of HCC.

We are very excited because this is the first targeted therapy for liver cancer. Other therapies have some modest benefits, but no one knows exactly how they work. We now have identified a pathway that appears to be overly active in more than 70 percent of the cancers we examined and, when targeted, leads to significant reduction in tumor cell proliferation and survival, said Dr. Monga.

More importantly, targeting the PDGFRá pathway in liver cancer cells does not appear to affect normal liver cells, making the treatment relatively non-toxic. Normally, regenerating liver cells are not exclusively dependent on this pathway, and it is not overly active in other types of cells. So this monoclonal antibody is a highly targeted treatment for this disease, he added.

Furthermore, because high expression of PDGFRá has been detected in a variety of tumors, such as skin cancer, brain tumors, gastrointestinal tumors, prostate tumors, ovarian cancer and leukemia, Dr. Monga believes these findings could have much broader applications.

Why liver cancer is more prevalent in males than in females

Thu, 05 Jul 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Production of a protein that promotes inflammation appears to be linked to the higher incidence of liver cancer in men than in women, researchers at the University of California, San Diego (UCSD) School of Medicine have determined in mouse studies. Their discovery that female mice produce far less of the protein called interleukin-6 (IL-6) in response to liver injury than males do, and that production of this protein is suppressed by estrogen, may point the way to therapies to reduce the incidence of liver cancer in males. IL-6 contributes to the chronic liver inflammation that leads to cancer.

The research team was led by Michael Karin, Ph.D., professor of pharmacology in UCSDs Laboratory of Gene Regulation and Signal Transduction. The findings will be published in the July 6 issue of the journal Science.

Males show a higher rate of inflammation than females in the same diseases, including cancer, said Willscott Naugler, M.D., clinical instructor in UCSDs Department of Medicine and first author of the paper. We wondered if increased inflammation was behind the higher incidence of liver cancer in males and, if so, how and why?

Heptocellular carcinoma (HCC) a devastating complication of chronic liver disease and inflammation caused by risk factors such as hepatitis B and C viruses, or alcoholic liver disease makes up the majority of liver cancers in humans. Overall, men are three to five times more likely to develop HCC than women; however, in individuals who are under 50, HCC is seen seven to 10 times more frequently in men. A similar or even more pronounced gender disparty is seen in mice.

In order to understand the mechanisms underlying gender disparity in HCC, the UCSD researchers used a chemical carcinogen, DEN, to induce cancer in mice. This resulted in HCC in 100 percent of male mice, but only in 10 to 20 percent of their female littermates.

The researchers discovered that normal female mice given DEN produced far less IL-6 than the males. Comparing the normal mice to knockout mice missing the IL-6 cytokine, the scientists found that when knockout mice were given DEN, both males and females developed liver cancer at the same, lower, rates.

By eliminating IL-6, we reduced the incidence of liver cancer in the males by close to 90%, Karin said. However, the missing IL-6 made no further difference in female mice.

The researchers then treated normal male mice with estrogen, and exposed them to DEN. The IL-6 level in those males was reduced to the same level as in female mice, as was the degree of liver injury. Experiments on specialized cells in the liver that produce IL-6 showed that estrogen acts on these cells to suppress IL-6 production.

A similar mechanism may account for the gender bias in liver cancer in humans, according to the researchers. Their discovery could lead to development of therapies to reduce development of liver cancer in males by either decreasing the levels IL-6 in males, interfering with IL-6 action or by administering estrogen-like compounds to males in order to inhibit production of IL-6.

While some organs, such as breasts, are clearly influenced by gender, others like the liver are not, said Naugler. So its quite interesting that liver inflammation is so markedly suppressed by estrogens. It raises the possibility that organs not usually associated with gender differences may be governed by the same principle. Bladder cancer, for example, occurs more frequently in males than females, and the differences may be a result of higher IL-6 levels and inflammation in male bladders.

Ablation procedure proves safe, effective and fast

Fri, 29 Jun 2007 17:02:00 PST

( from http://www.rxpgnews.com ) Multiple-electrode radiofrequency ablation is a safe and effective way of treating patients with liver cancer that can be completed in less time than current ablation techniques, according to a recent study conducted by researchers at the University of Wisconsin in Madison.

?One of the biggest limitations of current radiofrequency ablation techniques is the inability to effectively treat large tumors? said Paul Laeseke, PhD, lead author of the study. ?Current radiofrequency ablation systems can only power one electrode and create relatively small ablation zones,? Dr. Laeseke said. Large tumors are treated by sequentially overlapping the small ablation zones--a technique that is both complicated and time consuming,? he said.

The study consisted of 38 malignant liver tumors in 23 patients who underwent multiple-electrode radiofrequency ablation. Local control was achieved in 37 of 38 tumors, with 34 of these tumors treated during just one session. The total ablation time was reduced by approximately 54% compared to if the patients would have been treated using a single-electrode system, Dr. Laeseke said.

?A reduction in procedure time would make staff and imaging equipment available for other cases,? said Dr. Laeseke. ?The treatment success rates in this study are comparable to those reported in the literature for smaller tumors treated with single-electrode radiofrequency,? he said. ?In other words, the multiple-electrode system allowed us to effectively treat larger tumors in less time.?

Dr. Laeseke cautioned though that these are short-term results. ?While the short-term results are promising and demonstrate that multiple-electrode radiofrequency ablation is safe and effective, longer term follow-up is needed to determine the impact of multiple-electrode radiofrequency ablation on patient survival and tumor recurrence rates,? he said.

The full results of this study appear in the June issue of the American Journal of Roentgenology, published by the American Roentgen Ray Society.

Could statins be a new option for hepatitis C patients?

Tue, 22 May 2007 10:00:00 PST

( from http://www.rxpgnews.com ) WASHINGTON, D.C. (May 20, 2007) -- Research presented today at Digestive Disease Week? 2007 (DDW?) demonstrates the potential of statins, important cholesterol management therapies, for improving the management of hepatitis C ? a disease that affects nearly four million Americans. Although there have been no new treatments for hepatitis C since the introduction of pegylated interferon in 2001, the opportunity to develop a new generation of therapies that offer better outcomes may be imminent. DDW is the largest international gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

Studies such as these are designed to improve the effectiveness of antivirals ? the standard of care therapy for hepatitis C, said John Vierling, M.D., Baylor College of Medicine. The findings from these studies support the rationale and need for larger, controlled trials that may provide additional and more advantageous hepatitis C treatment options.

New Mayo Clinic MRI technology enables noninvasive liver diagnoses

Tue, 22 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) ROCHESTER, Minn. -- Two recent Mayo Clinic studies have found that magnetic resonance elastography (MRE), a new imaging technique invented at Mayo Clinic, is an accurate tool for non-invasive diagnosis of liver diseases. The findings will be presented this week at the International Society for Magnetic Resonance in Medicine Annual Meeting in Berlin, Germany, and Digestive Disease Week 2007 in Washington, D.C.

The liver responds to many diseases that damage its cells by developing scar tissue or fibrosis. MRE uses a modified form of magnetic resonance imaging (MRI) to accurately measure the hardness or elasticity of the liver. By applying vibrations to the liver, MRE obtains pictures of the mechanical waves passing through the organ. The wave pictures are then processed to generate a quantitative image of tissue stiffness.

Healthy liver tissue is very soft, while a liver with fibrosis is firmer, and a liver with cirrhosis is almost rock-hard, says Richard Ehman, M.D., lead researcher on the MRE project. If detected early, fibrosis of the liver can be treated, but once the disease has progressed to cirrhosis, the condition is irreversible.

Dr. Ehman and his imaging research team collaborated with Mayo Clinic gastroenterologists to study whether MRE could provide reliable and accurate diagnoses in patients with varying degrees of liver disease.

One study involved MRE examinations of 57 individuals with chronic liver disease and 20 healthy volunteers. The researchers confirmed that MRE accurately detects fibrosis with high sensitivity and specificity. Researchers also found that steatosis, which is deposits of fatty acids and triglycerides in liver cells and a common condition in patients with liver disease, did not interfere with detection of fibrosis with MRE.

Based on this research, we are now using MRE examinations in select patients to determine liver stiffness and assess the need for liver biopsies, says Jayant Talwalkar, M.D., a Mayo Clinic gastroenterologist and an investigator on the MRE studies. More than 170 million people in the world are known to have hepatitis C, and nearly one-fourth of those will develop severe liver fibrosis. MRE can help us noninvasively identify fibrosis in this large patient population.

A second study looked at whether MRE can accurately measure portal hypertension, or high blood pressure in the portal vein that carries blood from the digestive track to the liver, usually as a result of cirrhosis of the liver. This study involved 35 individuals with varying degrees of chronic liver disease and 12 healthy volunteers. Researchers studied MRE examinations of liver and spleen stiffness and found that a highly significant correlation exists between liver and spleen stiffness in patients with portal hypertension. However, the validity of spleen stiffness as a noninvasive measure of portal venous pressure requires further study.

According to Dr. Ehman, many diseases cause the properties of tissue to change and will be likely candidates for diagnosis using MRE in the future. His research team is exploring the use of MRE in detecting breast cancer and Alzheimers disease.

Mice, men make livers differently

Mon, 21 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) CAMBRIDGE, Mass. -- Scientists often study mice as a model for human biology and disease, because their basic biological processes are assumed to be essentially the same as those of humans.

But now, a team of MIT researchers has uncovered a surprising difference. In a study of gene regulation in mouse and human liver cells, they found that master regulatory proteins function in very different ways in mice and humans.

Evolution has discovered several different ways to make a liver from the same building blocks, said Ernest Fraenkel, MIT assistant professor of biological engineering and leader of the research team. Comparing these different ways of regulating genes may unlock some of nature's most closely guarded secrets.

The work, which will be published in the May 21 online edition of Nature Genetics, could help identify patterns in the extremely complicated control mechanisms involved in gene expression.

You can think of it as two different dialects of the same language. By exploring the human and mouse versions, we hope to find an underlying grammar, said Fraenkel.

Every cell in the human (or mouse) body has the same collection of genes, but the genome of each cell is carefully regulated so that only certain genes are expressed. Regulatory proteins known as transcription factors control this expression by binding to specific locations within the genome and turning nearby genes on or off.

The researchers and their colleagues had previously worked out many aspects of gene regulation in the human liver, which is one reason the researchers chose to study the liver. In the current study they compared 4,000 human genes with nearly identical counterparts, known as homologous genes, from mouse liver cells.

Given the similarity between the two species DNA sequences, the researchers expected that transcription factors would bind to the same sites in most pairs of homologous genes. To their surprise, they found that most of the binding sitesbetween 41 percent and 89 percent, depending on the transcription factorwere in different locations in humans and mice.

The number of genes with the identical regulation in both species was very, very small, Fraenkel said.

Before they began, the researchers expected to see some differences in gene regulation between mice and humans, because the human liver has evolved to process cooked food, said Fraenkel. However, the magnitude of change was much higher than they anticipated.

Fraenkel speculated that the changes accumulated without having much of an effect on gene expression. Unless the location of binding sites affects gene expression, it is not under any natural selection pressure.

All of that meaningless variation makes it harder to identify the small number of genes where binding site migrations do have an evolutionary impact, because they are being drowned out by all the insignificant changes, Fraenkel said. In future studies, the research team plans to investigate why some genes binding sites are conserved over time while others shift.

We want to understand whats special about those genes, Fraenkel said.

Fraenkel said the results should provide guidance for researchers who study mice to better understand human biology. To get the most out of mice for biomedical research we need to fully map out the regulation in both organisms, he said.

Cure for hepatitis C announced by VCU researcher

Mon, 21 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) RICHMOND, Va. (May 21, 2007) The use of peginterferon alone, or in combination with ribavirin, points to a cure for hepatitis C, the leading cause of cirrhosis, liver cancer and the need for liver transplant, a Virginia Commonwealth University researcher said today.

Mitchell Shiffman, M.D., professor in the VCU School of Medicine, and chief of hepatology and medical director of the Liver Transplant Program at the Virginia Commonwealth University Medical Center, is one of the lead investigators in the study, which was presented at the 38th annual Digestive Disease Week conference in Washington, D.C. VCU was among about 40 sites worldwide studying pegylated interferon alfa-2a, manufactured by Roche Inc.

Nearly all -- 99 percent of patients with hepatitis C who were treated successfully with peginterferon alone, or in combination with ribavirin, had no detectable virus up to seven years later. Researchers say this data validates the use of the word cure when describing hepatitis C treatment as successful treatment is defined as having undetectable hepatitis C virus in the blood six months following treatment.

We at VCU are encouraged by this data because it is rare in the treatment of life-threatening viral diseases that we can tell patients they may be cured, Shiffman said. In hepatitis C today, we are able to help some patients achieve an outcome that effectively enables them to put their disease behind them.

The results are based on a long-term follow-up study designed to determine if the virus re-emerges in patients who have achieved treatment success. The study reviewed 997 patients, either mono-infected with chronic HCV or co-infected HCV and HIV, who achieved a sustained viral response (SVR) following treatment with either Pegasys (peginterferon alfa-2a) monotherapy or combination therapy with Pegasys and ribavirin.

After successful treatment, researchers monitored serum levels of HCV once a year for an average of 4.1 years (range 0.4 to 7 years). Of the 997 patients, 989 maintained undetectable levels of HCV. The remaining eight patients tested positive for HCV at an average of two years following treatment completion. The study found that these eight patients exhibited no consistency in age, gender or HCV genotype, and it has not yet been determined if these patients experienced a relapse or if they were re-infected with HCV.

Hepatitis C is a blood-borne infectious disease of the liver and a leading cause of cirrhosis, liver cancer and the need for liver transplants. According to the Centers for Disease Control and Prevention, an estimated 4.1 million Americans have been infected with hepatitis C, and 3.2 million are chronically infected. The number of new infections per year declined from an average of 240,000 in the 1980s to about 26,000 in 2004, the latest year for which statistics are available. The CDC estimates the number of hepatitis C-related deaths could increase to 38,000 annually by the year 2010, surpassing annual HIV/AIDS deaths.

Hepatitis C increases risk of non-Hodgkin lymphoma

Tue, 08 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Hepatitis C infection is associated with an increased risk of non-Hodgkin lymphoma (malignancy involving lymphatic tissue) of 20 percent to 30 percent, and a three-fold increase in the risk of another type of lymphoma, according to a study in the May 9 issue of JAMA.

The prevalence of hepatitis C virus (HCV) is estimated at 1.6 percent of the U.S. population. It is more common among U.S. military veterans who use the Veterans Affairs (VA) medical system, in which approximately five percent of veterans are infected with HCV. HCV infection causes liver cancer and cirrhosis, and may also increase the risk of other tumors. Previous studies have been too small to adequately assess these risks, according to background information in the article.

Thomas P. Giordano, M.D., M.P.H., of Baylor College of Medicine and the Michael E. DeBakey Veterans Affairs Medical Center, Houston, and colleagues conducted a retrospective cohort study to test the hypothesis that HCV infection is associated with increased risk for malignancies of the blood and blood-forming tissues, related disorders, and thyroid cancer. The study involved patients from U.S. Veterans Affairs health care facilities from 1997-2004 and included 146,394 individuals infected with HCV, and 572,293 not infected with HCV. The research examined the risks of hematopoietic malignancies (relating to the formation of blood cellular components), related lymphoproliferative precursor diseases (referring to the proliferation of the bone marrow cells that give rise to lymphoid cells), and thyroid cancer.

There were 1,359 cases of non-Hodgkin lymphoma, 165 cases of Waldenström macroglobulinemia (a low grade lymphoma), 551 cases of cryoglobulinemia and 320 cases of thyroid cancer.

We found a small but significant 20 percent to 30 percent increase in the risk of NHL [non-Hodgkin lymphoma], including all subtypes, and an almost three-fold increased risk of the low-grade lymphoma subtype Waldenström macroglobulinemia in persons with HCV infection, the authors report. Low-grade lymphoma tends to grow and spread slowly.

HCV infection was also associated with an increased risk of nonmalignant plasma cell disorders.

We demonstrated that infection precedes development of these outcomes, and that the risk in individuals infected with HCV is consistently increased, with over five years of follow-up, the authors continue.

The study found no significantly increased risk for other hematological malignancies. The risk for thyroid cancer was not increased.

Although the clinical significance of these findings is unknown, it is possible that screening of individuals infected with HCV could identify early stage lymphoproliferative conditions suitable for early intervention strategies, including chemoprevention trials on premalignant disease. Future epidemiological and pathophysiological studies are needed to further explore the relationship between HCV and NHL, the authors conclude.

Risk of lymphoma increases with hepatitis C virus infection

Tue, 08 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) People infected with the hepatitis C virus (HCV) are at an increased risk of developing certain lymphomas (cancers of the lymphatic system), according to a study published in the May 8, 2007, issue of the Journal of the American Medical Association. Researchers from the National Cancer Institute (NCI), part of the National Institutes of Health, and Baylor College of Medicine, found that HCV infection increased the risk of developing non-Hodgkin's lymphoma by 20 percent to 30 percent. The risk of developing Waldenström's macroglobulinemia (a rare type of non-Hodgkin's lymphoma) went up by 300 percent and the risk for cryoglobulinemia, a condition marked by abnormal levels of certain antibodies in the blood, was also elevated for those with HCV infections.

The researchers looked at patient records collected from Veterans Affairs (VA) hospitals across the United States between 1996 and 2004. Researchers selected more than 700,000 records; 146,394 represented patients who were diagnosed with the hepatitis C virus, while 572,293 represented patients who were not. Based on that review, researchers determined, first, that the patients infected with HCV had a higher risk of developing lymphoma and, second, that HCV infection preceded development of the lymphoma. The risk of lymphomas in HCV-infected patients was charted across more than five years of follow-up.

This is one of the largest studies ever conducted to look at the relationship between hepatitis C virus infection and cancers of the lymphatic system, said NCI Director John E. Niederhuber, M.D. Since so much is still unknown about the causes of lymphoma, establishing which factors contribute to the disease is the first step in finding ways to reduce its incidence and lessen mortality.

HCV causes hepatitis, which is an inflammation of the liver. The HCV virus is carried through the blood and is passed from person to person through the exchange of bodily fluids -- via shared needles, open wounds, and sexual contact, among other means. HCV is also known to cause cirrhosis and liver cancer.

Although the risk of developing lymphomas is small, our research suggests that screening of HCV-infected individuals could identify conditions which may lead to cancer. It might then be possible to prevent progression to lymphoma, said investigator Eric A. Engels, M.D., from the Viral Epidemiology Branch of NCI's Division of Cancer Epidemiology and Genetics. More research is needed to further clarify the relationship between HCV infection and lymphoma.

In the United States, there are more than 4.1 million people living with hepatitis C virus infection -- about 1.6 percent of the population. In 2007, it is estimated that 71,380 Americans will be diagnosed with some type of lymphoma, which will take 19,730 lives.

The researchers note that this study was limited to military veterans who used the VA system, so the results may not be applicable to the overall U.S. population. The study population was mostly men (97 percent), the majority of patients were white, and the average age was 52 years. Patients in the HCV-infected group were more likely to have served during the Vietnam era (1964-1975) than were uninfected patients in the comparison group.

Previous studies found that the prevalence of HCV infection is much higher among U.S. veterans who use the VA medical system (5 percent) than in the general population, where only 1.6 percent carry the virus. Several factors have likely contributed to this higher prevalence, including demographics, socioeconomic status, and particularly a history of injection drug use or blood transfusions received before 1990, when screening for hepatitis C virus was started.

Keeping the immune system from starting a 'food fight'

Thu, 03 May 2007 04:00:00 PST

( from http://www.rxpgnews.com ) After every meal, the body must prevent the immune system from launching an all-out fight against food. Now, researchers report the identity of a nutrient floodgate that serves to protect against such an inflammatory immune response. Their findings appear in the May 4, 2007 issue of the journal Cell, a publication of Cell Press.

The researchers found that animals lacking a protein enriched in fat cells, called STAMP2, develop acute inflammation in deep pockets of visceral fat. The animals also showed symptoms of metabolic syndromeincluding insulin resistance and fatty liver diseaseeven while eating a regular diet.

In those who regularly consume an overload of nutrients, the flood control protein may become overwhelmed and give out, leading to the chronic, low-grade inflammation characteristic of obesity and other metabolic diseases, the researchers suggest. Treatments designed to reinforce that barrier may therefore provide the next frontier of therapies to combat the rising tide of chronic metabolic disease, they said.

Humans were not meant to deal with little to no exercise and a constant bombardment of nutrients, said Gökhan Hotamisligil of the Harvard School of Public Health of his teams findings. If we could find ways to strengthen STAMP2 or prevent its suppression, the body might retain control, effectively unlinking chronic overeating and obesity from other symptoms of metabolic disease. He cautioned, however, that the realization of such a treatment strategy remains uncertain and would require years of continued investigation.

Cells and organisms must strike an appropriate balance between nutrient sufficiency and surplus, the researchers explained. While adequate amounts of nutrients must be obtained to ensure health and survival, chronic overeating can lead to obesity and an array of associated metabolic disorders, including insulin resistance, fatty liver disease, type 2 diabetes, and cardiovascular disease. This cluster of chronic diseases now constitutes the largest global health threat, Hotamisligil said.

Their current findings pinpoint STAMP2 as a critical factor to prevent overt inflammatory responses during everyday nutrient fluctuations or conditions of nutrient excess. In fat cells, a lack of STAMP2 led to aberrant inflammatory responses to both nutrients and acute inflammatory stimuli, they reported.

Similarly, they showed that the visceral fat surrounding the internal organs of STAMP2-deficient mice became inflamed, and the animals developed spontaneous metabolic disease on a regular diet, manifesting insulin resistance, glucose intolerance, high blood sugar and lipid levels, and fatty liver disease. They also showed that the loss of STAMP2 exacerbated the metabolic symptoms of mice with a genetic predisposition to obesity due to other factors.

When food enters the system, STAMP2 normally keeps the immunity response button from getting pushed, Hotamisligil said.

We suggest that, over time, the accumulation of small cellular stresses due to daily changes and fluctuations in nutrients in STAMP2-deficient mice may lead to the activation of inflammatory pathways and inhibition of insulin action, resulting in systemic metabolic deterioration over the long term, he continued.

Mailman School of Public Health researchers report blood DNA can be early predictor of liver cancer

Sun, 15 Apr 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers at Columbia Universitys Mailman School of Public Health have discovered a means for early detection of liver cancer. Using DNA isolated from serum samples as a baseline biomarker, the scientists examined changes in certain tumor suppressor genes that have been associated with the development of liver carcinomas. This is the first study to prospectively examine potential biomarkers for early detection of liver cancer in high-risk populations, including those with chronic hepatitis B and C virus infections.

Since most hepatocellular or liver carcinomas (HCC) are diagnosed at an advanced and usually fatal stage, the development of screening methods for early detection is critical. HCC is one of the most common and rapidly fatal human malignancies. Worldwide, the almost 500,000 new cases and nearly equivalent number of fatalities illustrates the lack of effective therapeutic alternatives for this disease.

The Mailman School researchers and colleagues studied the blood of patients enrolled in a cancer screening program in Taiwan, who provided repeated blood samples prior to diagnosis. A total of 12,000 males and over 11,900 females recruited in 1991-2 are being followed. Screenings performed by the team of Mailman School scientists found changes associated with cancer in serum DNA, presumably released from the tumor, one to nine years before actual clinical diagnosis.

Certain clinical risk factors such as age and hepatitis B and C virus infections, are well documented risk factors for the development of HCC. According to the study findings, these factors coupled with smoking and alcohol status, and alterations found in this study in serum DNA, resulted in an overall predictive accuracy of 89% for detection of HCC.

These are extremely encouraging findings, says Regina Santella, PhD, professor of Environmental Health Sciences at the Mailman School of Public Health, director of the Columbias NIEHS Center for Environmental Health in Northern Manhattan, and principal investigator on the research. Having the tools to identify hepatocellular carcinoma at earlier stages, is truly a breakthrough for addressing the challenges that result from this highly lethal form of cancer.

Dr. Santella and the team of researchers previously found that several environmental factors including aflatoxin B1, a dietary mold contaminant sometimes found in peanuts and corn; polycyclic aromatic hydrocarbons, ubiquitous environmental contaminants; and 4-aminobiphenyl, a carcinogen found in cigarette smoke, are also associated with the development of HCC. While HCC incidence is highest in East Asia and Sub-Saharan Africa, it is also increasing in the U.S primarily as a result of HCV infection.

We are not only very excited about what this means in terms of early detection for hepatocellular cancer but optimistic about how it could also be applied to other cancers, observes Dr. Santella.

The full study findings are published in the April 15, 2007 issue of Clinical Cancer Research.

Blood sugar's manufacture limited by building blocks' supply

Tue, 03 Apr 2007 04:00:00 PST

( from http://www.rxpgnews.com ) Researchers have discovered a factor that controls blood sugar's manufacture in a novel way: by limiting the supply of its building blocks. The findings are reported in the April issue of the journal Cell Metabolism, published by Cell Press.

The study found that mice deficient for KLF15, a member of the so-called Krüppel-like family of transcription factors, become severely lacking in the blood sugar glucosea primary energy source for the body and the sole source for the brainafter a period of overnight fasting. The researchers traced that deficiency back to an inability to produce new glucose in the liver, a process known as gluconeogenesis, due to a defect in the processing of amino acids. Amino acids are the main ingredients of proteins and the source of a key substrate in blood sugar's production.

Gluconeogenesis is a complicated process, said Mukesh K. Jain of Case Western Reserve University. It fundamentally requires two big things: the building blocks and the [glucose-building] enzymes that make it all happen. A lot of previous work has focused on the enzymes.

We've found the first defect [in glucose production] due to a loss of substrate, added Susan Gray of Brigham and Women's Hospital.

During fasting, the supply of glucose derived from food dries up, Gray explained. In response, the body first breaks down liver glycogen, the principal storage form of glucose. However, the body goes through those stores overnight, she said.

Once the reserves are depleted, the body must rely on the synthesis of new glucose, primarily in the liver, to prevent a life-threatening shortage, a condition known as hypoglycemia. The de novo synthesis of glucose depends on the availability of a substrate molecule that comes from an amino acid.

The researchers found that mice with a targeted deletion of KLF15 display severe hypoglycemia after an overnight fast. They further found evidence that defective amino acid breakdown promotes the development of fasting hypoglycemia in the mutant animals by limiting the availability of a glucose substrate called pyruvate.

Indeed, the mice had markedly reduced activity of genes that encode amino acid-degrading enzymes, the researchers showed. The mice also had a deficiency in the activity of an enzyme that converts the critical amino acid, called alanine, into pyruvate. Consistent with this observation, injection of pyruvate, but not alanine, rescued the mice from their fasting hypoglycemia.

The findings point to a novel form of control over glucose levels, the researchers said. Ultimately, this window into glucose control might also have implications for diabetes treatmenta condition characterized by high glucose concentrations, Gray said.

Inhibiting KLF15 might prove beneficial in people with type II diabetes who have too much glucose, partly because the liver produces more than necessary, Jain said.

Their glucose sensor is off. If you attenuate KLF15 in the liver, you might limit glucose production.

Gray said she plans to further explore the underlying mechanisms involved in KLF15's glucose regulation and see how increasing KLF15 levels affects blood sugar production. Meanwhile, Jain plans to further examine the transcription factor's function in other parts of the body where it is active, namely in skeletal and heart muscle.

Survival rates after liver transplants

Fri, 02 Mar 2007 12:58:22 PST

( from http://www.rxpgnews.com ) Survival rates are similar among patients with hepatitis B who are listed for liver transplantation, whether or not they have hepatocellular carcinoma (HCC), according to a new study in the March 2007 issue of Liver Transplantation. An accompanying editorial suggests that these results affirm the current policy on the allocation of donor livers.

The study and the editorial appear in the March 2007 issue of Liver Transplantation, the official journal of the American Association for the Study of Liver Diseases (AASLD) and the International Liver Transplantation Society (ILTS). The journal is published on behalf of the societies by John Wiley & Sons, Inc. and is available online via Wiley InterScience athttp://www.interscience.wiley.com/journal/livertransplantation.

The United Network for Organ Sharing (UNOS) utilizes the Model for End-Stage Liver Disease (MELD) to determine allocation of available organs. Patients with hepatocellular carcinoma have higher MELD scores, and may be more likely to receive transplants quickly compared to patients with other types of liver disease. Without transplant, many HCC patients die or become unsuitable for transplantation because of tumor progression.

Led by Anna S. Lok, M.D. of the Division of Gastroenterology at the University of Michigan, researchers set out to compare clinical outcomes for hepatitis B patients awaiting a liver transplant, whether or not they had HCC. They enrolled 279 patients from the National Institutes of Health-sponsored HBV-OLT study between November 2001 and June 2005. Of these patients 183 had HBV with cirrhosis, and 96 had HBV with HCC. Most were receiving antiviral therapy. The researchers collected demographic and laboratory data for all participants, and computed a MELD score for each. They then followed the patients for a median of 30.2 months.

The patients with HBV-HCC were older, more likely to be Asian and had less severe liver impairment than patients with HBV-cirrhosis; 78 percent underwent liver transplantation, compared to 51 percent of patients with HBV-cirrhosis. Despite this difference, 5-year survival rates were similar: 73 percent of the HBV-HCC group, compared to 78 percent of the HBV-cirrhosis group. The 5-year survival rates for patients who did not receive a transplant were also very similar: 82 percent of the HBV-HCC group versus 79 percent of the HBV-cirrhosis group. It should be noted that 71% of the patients in the HBV-HCC group who had not been transplanted had received some form of HCC treatment including surgical resection and the number of patients alive without transplant 5 years after listing was very small (n=6).

"Despite more advanced liver disease and a lower rate of transplantation, intention-to-treat survival of patients listed for HBV-cirrhosis was comparable to those with HBV-HCC, possibly related to beneficial effects of antiviral therapy. However, these data may not apply to patients with liver disease due to other etiologies for which safe and effective therapies that can improve or stabilize liver disease in those with decompensated cirrhosis are not available" the authors conclude.

In an accompanying editorial, Myron Schwartz and colleagues from the Mount Sinai Liver Cancer Program at the Mount Sinai School of Medicine in New York say the study vindicates UNOS policy while reporting a surprising finding: survival without transplantation was excellent and equal between the two groups, with 5-year survival in patients not transplanted actually better than the survival for the entire cohort.

"This figure calls into question the basis for placing these patients on the waiting list in the first place," the authors write. Furthermore, since previous studies have shown that 5-year survival for HCC patients without treatment is unusual, "the accuracy of the diagnosis of HCC in these is questionable," they say.

The Wong study does show that UNOS policy helps patients with high MELD scores get a liver transplant, and that their prioritization does not affect outcomes for non-HCC patients with HBV. "The refinement of the UNOS algorithm to optimally balance the risks for HCC and non-HCC liver transplant candidates remains a work in progress," conclude the authors.

Putting an old drug to a new use

Mon, 12 Feb 2007 05:00:00 PST

( from http://www.rxpgnews.com ) We all know that iron deficiencies are dangerous, but also too much iron is bad for our health. Our body stores excess iron in various tissues, where it can lead to organ failure and even death if not treated before irreversible damage has occurred. Researchers from the Innsbruck Medical University, the University of Heidelberg, Germany, and the European Molecular Biology Laboratory (EMBL) now made a surprising discovery that may lead to new therapeutic approaches to treating such disorders. In this week's online issue of the journal Nature Medicine they report that a compound that was frequently used to treat high blood pressure can reverse iron overload in mouse models and has the potential to treat similar conditions in humans.

Our body needs most of its iron to make red blood cells. A lack of the metal can lead to dangerous anemias, but also too much iron can be detrimental as iron promotes the formation of toxic radicals leading to tissue damage. Iron overload is the consequence of one of the most common genetic disorders in Europe, hereditary hemochromatosis, which affects about one in 300 Europeans. Excess iron also accumulates after repeated blood transfusions and can cause organ failure over time. Günter Weiss, a clinician from the Innsbruck Medical University, and his collaborators from the University of Heidelberg and EMBL now found out that nifedipine, a substance commonly used to control blood pressure, helps the body deal with too much iron.

We observed in mice with iron overload that nifedipine helps mobilise iron from stores in the liver and enhances its excretion into the urine, says Weiss, an EMBL alumnus who now heads a lab at the Department for General Internal Medicine at the University of Innsbruck. These effects make nifedipine a promising candidate for a new drug to treat hereditary hemochromatosis and other iron overload disorders.

Combining electrophysiology, cell biology and molecular investigations, Weiss and his collaborators found out that nifedipine exerts its effect on iron metabolism by acting on a molecule called DMT-1. DMT-1 transports iron across cell membranes. This transport is increased ten to 100-fold by nifedipine, but how exactly the compound brings about its effect is still unknown. Nifedipine is known to block membrane channels that control Ca2+ influx into cells, but if it exerts its effect on iron transport indirectly by changing Ca2+ levels in the cell or by binding directly to DMT-1 in liver and kidney still needs to be determined.

Understanding the exact molecular mechanism underlying nifedipine's effect on iron transport would be a big step towards developing it into an effective therapy that can be used on patients, says Martina Muckenthaler, an EMBL alumna who is now at the University of Heidelberg. Taking nifedipine from bench to bedside could be quicker than for other substances, because it has already been used for years to treat patients with high blood pressure. From this we know the drug and its side-effects.

An important step on the way from laboratory to clinic will be targeted pharmacological modifications of the compound to separate nifedipine's effect on iron metabolism from its established action on blood pressure.

Our discovery is an excellent example of how the combination of basic research and the expertise of clinicians can yield results that are relevant to medicine and could ultimately benefit patients, says Matthias Hentze, Associate Director of EMBL and co-author of the study. In the Molecular Medicine Partnership Unit (MMPU) between EMBL and the Medical Faculty of Heidelberg University we integrate molecular biology and clinical medicine to gain an understanding of the basis of human diseases. It is very gratifying to see how the collaboration with EMBL alumni and the MMPU yields exciting progress in medicine.

New culture method for hepatitis C virus uses primary hepatocytes and patient serum

Tue, 23 Jan 2007 05:00:00 PST

( from http://www.rxpgnews.com ) Seattle, WA -- Researchers open the way for improved study of hepatitis C virus by devising a novel virus culture system that allows replication of patient-isolated virus in nontransformed hepatocytes, instead of culture-adapted virus strains in transformed cell lines. The related report by Lázaro et al, Hepatitis C virus replication in transfected and serum-infected cultured human fetal hepatocytes, appears in the February issue of The American Journal of Pathology.

Hepatitis C virus (HCV) infection affects approximately 170,000,000 people worldwide. HCV liver disease, which may induce liver inflammation, cirrhosis, and/or hepatocellular carcinoma, represents the foremost reason for liver transplantation in much of the U.S.

Study of HCV replication within liver cells, or hepatocytes, has been hampered by a lack of adequate virus culture systems. Some systems allow the virus to infect cells but do not permit prolonged replication and production of virus, while other systems rely on derivatives of permissive virus isolates for efficient replication in transformed (mutated) cell lines. Still lacking has been a system to sustain replication of novel virus isolates from patients using nontransformed hepatocytes.

Nelson Fausto of the University of Washington School of Medicine has crossed this hurdle using a human fetal hepatocyte culture system that was previously developed in his lab. Using this system, his group has demonstrated sustained replication and production of virus particles for at least 2 months, with these virus particles able to infect new cells.

In their first experiments, Fausto and colleagues transfected hepatocyte cultures with HCV genomic RNA and found replication of HCV RNA genomes and production of core protein (for virus particle formation). Release of infectious virus particles was confirmed, as media from these cells were able to infect naive hepatocytes. Finally, virus particles were examined by electron microscopy and shown to possess the expected size and shape of HCV virus particles.

Once the system was established, the group examined whether sera from patients carrying HCV could infect the human fetal hepatocytes. When sera from patients infected with different HCV strains were added to the hepatocyte culture system, viral replication occurred and new virus particles were produced.

In both transfection and infection models, virus particles were released in a cyclical manner, with bursts of virus produced every 10-14 days. This is similar to what has been reported during clinical HCV infection, possibly due to the host's natural defenses. Interestingly, cultured hepatocytes responded to viral replication by displaying signs of distress and cell death and by expressing interferon-beta, a cellular antiviral, in an effort to control the infection.

This culture system provides a breakthrough in studying HCV replication in nontransformed hepatocytes, the natural target of the virus. By allowing infection by patient serum containing a wide array of virus strains, this system may allow better understanding of the differences between different strains, further improving treatment strategies.

Gene chip discovery may lead to individualized treatment for 5 hereditary liver diseases

Thu, 21 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) CINCINNATI -- Researchers at Cincinnati Children's Hospital Medical Center have developed the first gene chip to use in the early diagnosis of at least five hereditary liver diseases, to detect genetic causes of jaundice in children and adults, and potentially to lead to personalized treatment options.

The chip, termed the jaundice chip, is nearly 100 percent effective in the detection of the most common mutations in children with inherited causes of jaundice, according to a new Cincinnati Children's study in the January issue of the journal Gastroenterology.

Other chips have been developed to assess drug metabolism, said Jorge Bezerra, MD, a pediatric gastroenterologist at Cincinnati Children's and the study's lead investigator. This is the first chip in the world that has been customized to diagnose genetic mutations in patients with inherited types of liver diseases.

The chip uses a new technology that rapidly and accurately discloses the composition of several genes known to cause liver disease in children and adults. The jaundice chip may also help us to discover whether subtle changes in these five genes that can cause devastating diseases in children may also modify the clinical course of other common liver diseases in adults,said Mitchell Cohen, M.D., director of the division of gastroenterology hepatology and nutrition at Cincinnati Children's.

Jaundice is a yellowing of the eyes and skin caused by impairment in bile flow from the liver to the intestine. Impaired bile flow, or cholestasis, commonly known as jaundice, can lead to severe liver disease. In children, jaundice and cirrhosis are responsible for more than half of the need for liver transplantation.

Previous research on humans identified five genes responsible for inherited forms of jaundice, Until now, the broad array of causes of cholestasis including genetic, metabolic, inflammatory and drug- or toxin-induced disorders, created a challenge for physicians to diagnose a specific disease. Therefore, the treatment of affected children was not disease-specific and aimed at optimizing care to help reduce liver transplantation. With the jaundice chip, however, diagnosis can be simplified by surveying the genetic code for mutations in specific diseases.

The jaundice chip was designed as a five-in-one gene chip to screen mutations (a permanent change in the DNA sequence that makes up a gene) in five genes using only one milliliter, or less than a half of a teaspoon, of blood. Gene chips contain several thousand small fragments of DNA on a small piece of glass. Incubation of these chips with the patient's DNA sample produce chemical signals that glow and allow for the detection of the normal gene sequence, or of mutations if they are present in the patient.

The jaundice chip is an extraordinary advance for our patients with liver diseases. It will improve diagnostic accuracy for perplexing diseases in infants and children, potentially decrease the need for invasive and costly studies, and allow us to develop specific treatment plans based on the correct genetic diagnosis, said Dr. Cohen.

With further genetic testing of liver disease, there is the potential that medications can be tailored to meet the needs of individual patients taking into account the patient's genetic make-up, adds Dr. Bezerra. For now, the use of the gene chip gives families piece of mind, knowing what their child is living with. The next focus of advances will be the development of medication that may block progression of their disease.

Today, detection of liver diseases with the jaundice chip is continuing, using samples from children worldwide through a research protocol in the division of gastroenterology, hepatology and nutrition at Cincinnati Children's. Once approved by the Food and Drug Administration, the potential for wider use is limitless, according to Dr. Bezerra.

Phototherapy for neonatal jaundice associated with increased risk of skin moles in childhood

Mon, 18 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Children who received light therapy (phototherapy) for jaundice as infants appear to have an increased risk of developing skin moles in childhood, according to a report in the December issue of Archives of Dermatology, one of the JAMA/Archives journals. Some types of moles are risk factors for developing the skin cancer melanoma.

Jaundice or hyperbilirubinemia occurs when bilirubin, a yellow pigment created as a byproduct of the normal breakdown of red blood cells, cannot yet be processed by a newborns liver and builds up in the blood, turning the skin, whites of the eyes and mucous membranes yellow. The condition affects between 45 percent and 60 percent of healthy babies and as many as 80 percent of infants born prematurely, according to background information in the article. During phototherapy, the treatment of choice for jaundice, babies are placed under blue lights (bili lights) that convert the bilirubin into compounds that can be eliminated from the body. Studies have been performed to assess the safety of this therapy, but many have not focused on its effects on the skin, the authors write.

Emmanuelle Matichard, M.D., Bichat-Claude Bernard Hospital, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris, and colleagues assessed the presence of melanocytic nevi (moles) in 58 French children who were 8 or 9 years old at the time of the study. Eighteen children had phototherapy as newborns; 40 who were the same age but did not have phototherapy were recruited from a public school and served as controls. All the children and their parents were interviewed about the use of phototherapy, history of sun exposure and sunscreen use. A dermatologist performed physical examinations on the children and recorded their skin color, eye color, hair color, skin type and the number and size of moles.

Thirty-seven children (63 percent) had moles that were 2 millimeters or larger, and there was an average of 2.09 moles per child. Those who were exposed to phototherapy had significantly more moles of this size than those who did notan average of 3.5 vs. 1.45 per child. When the analysis was limited to moles between 2 millimeters and 5 millimeters, the association was stronger. Lentigo simplex [moles smaller than 2 millimeters in diameter] may represent more recent nevi, whereas those nevi due to early events should be larger, the authors write. Nevi larger than 5 millimeters probably are congenital nevi and are most probably associated with genetic predisposition. These associations did not change when other risk factors for the frequency of moles, including skin type and light hair, were considered. Sun exposure, particularly during vacations, was also associated with the number of moles of all sizes, and light hair color was correlated with the number of moles smaller than 2 millimeters.

The study did not examine whether phototherapy increases the risk for melanoma in adults, and it is possible that the small difference in the number of moles between the two groups would not change their risk of developing cancer. However, further study could help illuminate the association. Higher numbers of acquired benign nevi are associated with increased risk of melanoma, they conclude. A detailed evaluation of the factors responsible for the development of nevi in children would be useful to identify high-risk groups to be targeted for prevention. The link between melanoma and phototherapy should be the focus of such a study.

Study highlights new and cheaper way to treat heroin addiction

Thu, 07 Dec 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Costly methadone treatment for heroin addicts could be replaced by a substitute painkiller that is half the price, safer and less toxic.

In a study spanning three and a half years, researchers found that the prescription painkiller dihydrocodeine is equally as effective as methadone to help drug users kick the habit.

The research by the Universities of Edinburgh, Napier and Adelaide could have major implications for treatment programmes for drug users, which have proved controversial not least because of the high costs involved.

In contrast to methadone which comes in liquid not tablet form dihydrocodeine is much easier to store and comes under less stringent regulations because it is not as toxic and less likely to cause a fatal overdose. It is estimated that whereas methadone treatment can cost almost £1,500 annually per patient, the cost of dihydrocodeine is £713.

Dihydrocodeine has been used by GPs and specialists for many years to treat drug users . It is often preferred in situations where methadone is seen as hazardous, such as police custody or prison. Its effectiveness has, however, never been tested before.

Dr Roy Robertson, a Reader at the University of Edinburgh, who is the studys main author, said: Heroin addiction is a chronic condition requiring long-term medication. Just as with other chronic conditions, such as diabetes or arthritis, there should be a number of treatments available so that doctors and nurses can tailor medication to the needs of each patient.

Methadone should still be used to treat the majority of patients withdrawing from heroin and requiring maintenance treatment, but dihydrocodeine offers an alternative treatment for those who cant tolerate methadone, or find it hard to deal with the stigma of having to take their dose sometimes every day in a pharmacy. It is also much cheaper.

The study, the first of its kind in the world, assessed 235 people requiring treatment for opiate dependency in Edinburgh and found that dihydrocodeine was just as effective as methadone.

Dr Roberston, who also works as a GP, added that while there were less restrictions attached to prescribing dihydrocodeine tablets, it is still essential that treatment regimes are controlled and tailored to the individual.

We want to engage young people in a treatment programme which stops them from injecting drugs and running the risk of infection, he said.

Apart from the danger of contracting AIDS, drug users run the real risk of exposure to the potentially fatal liver disease, Hepatitis C. We face an epidemic of Hepatitis C in Scotland, with 40% of young people who have been injecting drugs for more than two years being infected with this serious illness.

New drug helps hepatitis C patients start antiviral therapy

Mon, 30 Oct 2006 05:00:00 PST

( from http://www.rxpgnews.com ) DURHAM, N.C. -- A new drug that stimulates the production of blood platelets can enable patients infected with hepatitis C virus to take other antiviral medications they previously could not take to fight the disease, according to the results of a clinical trial led by a Duke University Medical Center researcher.

Hepatitis C attacks the liver. An estimated 20 percent of patients go on to develop cirrhosis, a condition that involves destruction of liver cells.

Patients with hepatitis C who have cirrhosis and abnormally low platelet levels, a disorder known as thrombocytopenia, cannot take the standard drugs for fighting the infection, because these drugs also act to lower platelet counts further. Patients with low platelet counts are also at risk for spontaneous bruising; bleeding in mucosal linings, such as in nose, gums and the gastrointestinal tract; and in severe cases, bleeding in the brain. They are also at greater risk of bleeding at the time of medical procedures.

The new drug, called eltrombopag, works by stimulating cells in the bone marrow to produce more platelets, according to Duke liver specialist John McHutchison, M.D., professor of medicine and the principal investigator for the clinical trial. The trial was of a type called Phase II, which tests the safety and effectiveness of a drug in a small population.

McHutchison presented the results of the trial on Monday, Oct. 30, 2006, at the annual meeting of the American Association for the Study of Liver Disease, in Boston. The trial was supported by GlaxoSmithKline, which developed eltrombopag. McHutchison has received research support from GSK.

To date, physicians have been reluctant to prescribe the standard antihepatitis C drugs called pegylated interferon and ribavirin to patients with advanced liver disease due to hepatitis C and thrombocytopenia because of pegylated interferon's known effect on lowering platelet counts in the blood, McHutchison said.

When we give these antiviral agents to patients with normal platelet counts, we can cure approximately half of them, McHutchison said. Eltrombopag increases platelet levels to the point where patients with thrombocytopenia can then be effectively treated with the antiviral therapies. If the promising results we've seen so far in these early clinical trials are borne out in future larger scale registration trials, we will be able to potentially treat many more patients for whom there are currently no options.

The trial enrolled 74 hepatitis C patients with thrombocytopenia. They were randomized to one of four groups: three groups received eltrombopag at doses of 30 milligrams, 50 milligrams or 75 milligrams, and one group received an inactive placebo. All of the patients took the drug daily for four weeks. Patients whose platelet counts rose to a predefined level after four weeks were then started on the standard antiviral treatment.

We found that 95 percent of the patients who received the highest dose of the new drug responded with increased levels of platelets, and 91 percent of those patients were then able to start antiviral therapy with pegylated interferon and ribavirin, McHutchison said. After 12 weeks, 61 percent of these patients were still able to maintain antiviral therapy.

The patients receiving the lower doses of the drug also had better responses than those receiving placebo. Three-quarters of the patients taking either 30 milligrams or 50 milligrams of the drug demonstrated increased platelet levels enough to initiate antiviral therapy. In the placebo group, no patients saw this improvement. Fifty-three percent of patients taking the 50 milligram dose were able to complete the 12-week course of antivirals, and 36 percent of those taking 30 milligrams completed the course.

Side effects of the drug -- headache, dry mouth, nausea and diarrhea -- were not clinically worrisome, McHutchison said.

The new drug also may benefit patients who have low platelet counts caused by other liver diseases, particularly those who need to undergo surgery or other invasive procedures that carry a significant risk of bleeding, he said.

McHutchison and other investigators are currently involved in planning larger Phase III clinical trials of eltrombopag to further refine the optimal dosing for the drug and to determine which patients would benefit most from receiving the drug. Phase III trials usually are the final stage before a new drug is introduced to the marketplace.

It is estimated that about 3.9 million Americans are infected with the hepatitis C virus. The virus is most commonly transmitted by injected drug use.

Genetic disorder linked to rapid lung function decline in some World Trade Center rescue workers

Mon, 23 Oct 2006 04:00:00 PST

( from http://www.rxpgnews.com ) A rare genetic disorder known as alpha-1 antitrypsin (A1AT) deficiency may predispose patients to developing lung conditions, but a new rapid-response test could help identify patients with the deficiency before significant lung damage has occurred.

New research presented at CHEST 2006, the 72nd annual international scientific assembly of the American College of Chest Physicians (ACCP), shows that World Trade Center rescue workers deficient in the A1AT protein who were exposed to environmental irritants had more rapid decline in lung function compared with exposed workers with normal levels of protein. A1AT deficiency alters the ability of the lungs and liver to control the naturally-occurring healing process, thereby leading to unchecked inflammation in these areas. Individuals with low levels of A1AT are at an increased risk for chronic lung and liver disorders.

A1AT deficiency is a genetic defect with variable penetrance, said the study's lead researcher Gisela Banauch, MD, Montefiore Medical Center, New York, NY. Some with the defect will develop emphysema early, even without cigarette smoking. Others, with less penetrance, may need to be exposed to additional environmental irritants in order to develop emphysema and other forms of obstructive airway disease.

Dr. Banauch and colleagues followed 90 World Trade Center (WTC) rescue workers from October 2001 through 2005. Patients underwent annual lung function testing and, in September 2005, all patients were offered A1AT testing. Of the patients, 11 were categorized as either severely or moderately A1AT deficient, while the remaining patients showed normal A1AT levels. Results showed that severely deficient patients had significantly faster post-WTC lung function declines than all other subjects, while moderately deficient patients experienced faster lung function declines than normal patients. Prior to the WTC disaster, A1AT-deficient patients showed no accelerated lung function decline.

If further research in larger numbers of patients confirms these preliminary findings, then early screening in patients may help minimize lung damage in patients with this condition.

A1AT deficiency is underrecognized and underdiagnosed, said the study's coauthor David J. Prezant, MD, FCCP, Montefiore Medical Center. But we can overcome this challenge by a simple blood test that should be performed in all persons with family members having A1AT deficiency and in all persons who have no risk factors for early onset of COPD but are showing symptoms of disease.

An estimated 150,000 people in North America have A1AT deficiency, but only about 5 percent of these people have been diagnosed, reinforcing the need for effective awareness and screening programs that lead to diagnosis and treatment.

Current guidelines recommend screening all symptomatic individuals with lung disease with no known risk factors or who have a family history of the deficiency. However, some experts believe screening programs have not been completely effective because of slow data analysis, cost, and other logistical problems. A new test for A1AT deficiency, currently in development in Great Britain, may make screening for the deficiency easier and more accessible.

In a separate study presented at CHEST 2006, researchers from the United States and Great Britain introduced preliminary data on a point-of-care test for A1AT deficiency that uses as little as one drop of blood from a finger-stick test to deliver rapid results. Using plasma samples, the test demonstrated specificity by delivering a negative result with normal samples and a positive result with samples that were abnormally low in A1AT. Although the test is still in development, researchers are hopeful that the new screening tool will enable physicians to screen patients for A1AT deficiency in their offices and obtain accurate test results within minutes.

Early and proper diagnosis of A1AT deficiency is vital to managing and treating this chronic lung and liver disorder. However, the most important issue associated with timely screening for A1AT is increased awareness among primary care physicians and pulmonologists, said the study's lead author Jim Carney, PhD, British Biocell International (BBI), Cardiff, UK. An inexpensive, sensitive, and specific screening tool applied at the point of care, combined with effective A1AT deficiency awareness programs, will move us closer to the goal of quickly recognizing and confirming symptoms of A1AT deficiency. The test is being developed by Talecris Biotherapeutics, Research Triangle Park, NC, in partnership with BBI.

A1AT deficiency can greatly affect the health and well being of patients, particularly in those who remain undiagnosed, said Mark J. Rosen, MD, FCCP, President of the American College of Chest Physicians. It is important for pulmonologists and other clinicians to understand screening guidelines for A1AT deficiency and recommend appropriate testing for patients accordingly.

Children's Hospital of Pittsburgh and UPMC surgeons save two lives with domino transplant

Mon, 02 Oct 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Transplant surgeons at Children's Hospital of Pittsburgh and UPMC have saved two patients with life-threatening liver conditions utilizing a technique known as a domino transplant. It is only the nation's second domino transplant involving a patient with maple syrup urine disease (MSUD).

Domino transplants are so named for the sequential nature of the transplants an organ from a deceased donor is transplanted into the first recipient. The first recipient's organ then is transplanted into a second recipient. Domino transplants are a rare but effective way of overcoming the shortage of organs available for transplant.

In this case, a liver from a cadaveric donor was transplanted into Nickolai Rudd, an adult patient at Children's with MSUD, a rare and potentially life-threatening genetic disease. Mr. Rudd's liver was transplanted into James Paulshock, an adult suffering from liver failure caused by primary sclerosing cholangitis. The MSUD that afflicted Mr. Rudd was not passed onto Mr. Paulshock through his donated liver, while Mr. Rudd's new liver metabolically cured his MSUD. Because MSUD does not originate in the liver, and is caused by a lack of enzymes, the second patient will not inherit the disease. Both patients' new livers are now functioning normally.

Mr. Rudd's transplant was led by George V. Mazariegos, MD, director of Pediatric Transplantation at Children's Hillman Center for Pediatric Transplantation and an associate professor of surgery at the University of Pittsburgh School of Medicine. Mr. Paulshock's transplant surgery was led by Amadeo Marcos, MD, clinical director of transplantation at the Thomas E. Starzl Transplantation Institute and a professor of surgery at the University of Pittsburgh School of Medicine. The transplants were performed May 30, 2006, and both patients have since been discharged.

Domino transplants are rare because there are a very limited number of diseases in which the organ of a sick patient can be transplanted into another individual without passing on the disease. MSUD is one such disease, Dr. Mazariegos said. Because Children's and UPMC are the leading transplant centers in the world for patients with MSUD, we foresee the opportunity to continue performing domino transplants in appropriate situations. We have performed more than 20 liver transplants in patients with MSUD, and in each and every patient, liver function has returned to normal, metabolically curing these patients. Domino transplants are an extremely resourceful approach to overcome the scarcity of organs available for transplant.

Only 109 domino transplants have been performed in the United States, all involving heart or liver transplants, according to the United Network for Organ Sharing.

Our novel immunosuppression therapies have enabled our live donor liver transplant recipients to recover more quickly without dependency on heavy anti-rejection medications, commented Amadeo Marcos, M.D., professor of surgery, chief, division of transplantation and clinical director of the Starzl Transplantation Institute. Furthermore, through our exceptional partnership with surgeons at Children's Hospital, we have been able to expand the donor pool to adult recipients who can benefit by receiving an MSUD liver, since the disease is not transferred to the recipient.

Transfusion-free surgical program reduced use of blood products for all liver transplant patients

Mon, 18 Sep 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Development of a transfusion-free surgical program for Jehovah's Witness patients undergoing liver transplantation also has helped reduce the overall use of blood products for non-Jehovah's Witnesses undergoing the procedure, according to a study in the September issue of Archives of Surgery, one of the JAMA/Archives journals.

Orthotopic liver transplantation [in which a patient's diseased liver is removed and a donor liver transplanted into the same place] is typically associated with a large volume of blood loss, resulting in multiple transfusions and related complications, the authors describe in background information in the article. Transfusion-free surgery is rapidly gaining much-needed attention primarily because of the concerns surrounding transmission of diseases such as human immunodeficiency virus, hepatitis C and other viral infections. Additionally, long-term shortage of blood products and a paucity of alternatives put the system under duress, resulting in cancellation or postponement of elective cases.

Nicolas Jabbour, M.D., from the INTEGRIS Baptist Medical Center, Oklahoma City, and colleagues analyzed the medical records of 365 adult and pediatric orthotopic liver transplants performed from January 1997 through December 2004 at the University of Southern California-University Hospital in Los Angeles. The investigators evaluated the impact of the initiation of a transfusion-free program for Jehovah's Witnesses undergoing liver transplantation on the overall use of blood products in non-Jehovah's Witnesses undergoing the procedure. The pediatric and Jehovah's Witness transplant recipients were eliminated from the study, leaving only adult non-Jehovah's Witness patients who either received a liver transplant from a deceased donor or a living donor (n=272). These patients were categorized into two groups based on the initiation of the Transfusion-Free Medicine and Surgery Program at USC (for Jehovah's Witnesses) in January 2000. Group 1 consisted of recipients who received the liver transplant before January 2000 and group 2 included all patients who underwent transplantation after January 2000.

Recipients in group 1 underwent orthotopic liver transplants without intraoperative blood-saving or salvaging techniques, whereas all transplant recipients in group 2 underwent intraoperative cell salvage (ICS) and acute normovolemic hemodilution (ANH) whenever feasible, the authors report. ANH indicates a therapeutic initiative that involves simultaneously removing the patient's blood and replacing it with nonblood products

In comparing group 2 with group 1, the mean (average) MELD [model of end-stage liver disease] score was statistically significantly higher, whereas the mean number of intraoperative PRBC (packed red blood cells) and FFP (fresh frozen plasma) transfusions were significantly lower, the authors report. The MELD score describes the survival probability of a patient with end-stage liver disease, with higher scores indicating sicker patients. The number of preoperative and postoperative PRBC, FFP and platelet transfusions between the two groups was not statistically different.

The development of a transfusion-free surgical program for Jehovah's Witness patients has had a positive impact on reducing the overall blood use in non-Jehovah's Witness patients, the authors note. According to the authors, autotransfusion decreases some of the complications of transfusions, such as transmission of unknown pathogens, and also helps to preserve blood bank resources, which consequently reduces the overall procedure cost. Surgeons are the leading consumers of blood products, and it is important that we are leaders in promoting transfusion-free techniques. In conclusion, we propose that the recognized need to minimize the use of blood products be elevated to the same level as antibiotic and deep venous thrombosis prophylaxis (prevention).

MR Elastography may help in early diagnosis of liver fibrosis

Fri, 08 Sep 2006 17:11:00 PST

( from http://www.rxpgnews.com ) Mayo Clinic researchers have developed a new technique for using magnetic resonance imaging (MRI) to accurately measure the hardness or elasticity of the liver. First tests show this technology -- called MR Elastography (MRE) -- holds great promise for detecting liver fibrosis, a common condition that can lead to incurable cirrhosis if not treated in time. Traditionally, liver fibrosis is usually diagnosed using needle biopsies, which can involve complications and may be inaccurate due to sampling errors. The new technology promises to provide an accurate, painless, and lower risk alternative to liver biopsy and may have implications for diagnosing cancer. These research findings appeared in the journal Radiology.

"This is potentially an important diagnostic advance, since conventional imaging techniques, such as CT, MRI and ultrasound are not capable of identifying liver fibrosis prior to the onset of cirrhosis," says Richard Ehman, M.D., Mayo researcher and lead investigator on the study.

"The Elastogram"

The healthy liver is very soft compared to most other tissues and especially compared to a liver with cirrhosis, which is rock hard. The development by Dr. Ehman and his colleagues applies vibrations to the liver and then utilizes a modified form of MRI to obtain pictures of the mechanical waves passing through the organ. The imaging can be accomplished in as little as 20 seconds. The wave pictures are then processed to generate a quantitative image of tissue stiffness -- called an elastogram.

Researchers compared results of the process on 12 patients with biopsy-proven liver fibrosis with those of 12 healthy participants. This pilot trial of MRE showed strikingly elevated stiffness in patients with fibrosis and that the stiffness increased with the progression of the condition.

Impact of the Research

The availability of a reliable, non-invasive method for detecting liver fibrosis could lead to early diagnosis -- in patients considered at risk for liver disease -- and increase their chances for successful treatment. For example, 170 million people worldwide are infected with chronic hepatitis C and a significant number will develop cirrhosis, which is untreatable. Even if some risk factors are identified, there is no way to predict which patients will develop fibrosis, and successive liver biopsies in all these patients aren't possible. Non-invasive monitoring with MRE of those at risk would detect the problem early and help assess the effect of treatments.

Combined liver-kidney transplant beneficial for patients with dual organ disease

Mon, 21 Aug 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Combined liver and kidney transplant appears to benefit patients with diseases in both organs, including those with a condition known as hepatorenal syndrome who have been receiving dialysis for more than two months, according to an article in the August issue of Archives of Surgery, one of the JAMA/Archives journals.

A combined liver and kidney transplant is the procedure of choice for patients with both end-stage liver disease and end-stage renal (kidney) disease, according to background information in the article. However, the decision is more complicated in cases when kidney dysfunction may be temporary. Currently, hepatorenal syndrome--potentially reversible kidney failure combined with cirrhosis or another liver disease--is often treated with liver transplant alone and not a combined procedure. As waiting times for organs increase, more patients with hepatorenal syndrome will likely develop a chronic, irreversible condition that may require a combination transplant.

Richard Ruiz, M.D., and colleagues at the University of California, Los Angeles, reviewed data from 98 patients who underwent 99 combined liver and kidney transplants at one academic medical facility during a 16-year period, from 1988 to 2004. The patients had an average age of 46 years; 76 had primary kidney diseases and 22 had hepatorenal syndrome. For comparison, the researchers also reviewed data from 148 patients with hepatorenal syndrome who underwent a liver transplant alone between 1998 and 2002 and 743 patients who received kidney transplants alone.

Of the 99 combined transplant patients, 31 had died at the end of the analysis. One-, three-, and five-year survival rates were 76, 72 and 70 percent. None of the risk factors analyzed by the researchers, including characteristics of the donor, age of the recipient or previous transplants affected whether or not the patients would die after surgery. In dual transplant patients, 70 percent of the transplanted livers and 76 percent of the transplanted kidneys survived after one year; after three years, 65 percent of the livers and 72 percent of the kidneys; and after five years, 65 percent of the livers and 70 percent of the kidneys. Among those who underwent kidney transplants only, 23 percent of the kidneys were rejected by the recipient's body after one year, compared with 14 percent of those who had liver-kidney transplants.

When compared with hepatorenal syndrome patients who received only liver transplants, those who were undergoing dialysis--use of a machine to perform the blood filtration normally handled by the kidneys--for longer than eight weeks before surgery did better after the combined transplant. Before this analysis, we recommended combined liver and kidney transplantation when patients receive hemodialysis for longer than one month before transplantation, the authors write. However, on the basis of current findings, we find that the acuteness of renal failure subsides after two months of hemodialysis and that combined liver and kidney transplantation after this time will not only offer improvement in patient survival but also reduce hospital expenditures for patient care.

Combined kidney and liver transplantation offers the best option for patients with simultaneous chronic liver and kidney failure when it is performed at a high-volume academic transplant center, they conclude.

Genes linked to daily flux in drug toxicity

Wed, 05 Jul 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Those so-called PAR-domain basic leucine zipper transcription factors (PAR bZip) are known to accumulate in body tissues, including the liver and kidneys, in a highly circadian manner, the researchers said. Circadian refers to biological variations within a roughly 24 hour period.

The findings in mice underscore the crucial role of the body's daily timekeeping system in modulating drug toxicity, the researchers said, and suggest that patients might benefit from treatment regimens that are scheduled accordingly.

The findings also highlight the general importance of circadian clocks to many body functions, said Ueli Schibler of the University of Geneva.

I think it's fair to say that nearly all physiology has some circadian component, Schibler said. People think of jet lag as a sleep disturbance, when that may be the least of the problem, he added. All of your organs--from the gastrointestinal system to liver enzymes, for example--depend on clocks.

Circadian rhythms control rest-activity cycles, heartbeat frequency, body temperature, blood pressure, hormones, and metabolism, among other behavioral and physiological processes.

The circadian timing system of mammals has a hierarchical structure, in that a master pacemaker in the brain synchronizes self-sustaining and cell-autonomous circadian clocks present in virtually all tissues, the researchers said. Drivers of circadian rhythms in peripheral cells--such as the three PAR bZip proteins: DBP, TEF, and HLF--mediate rhythmic physiology by regulating the activity of still other genes.

Earlier studies by Schibler's group found that mice lacking one or two of the PAR bZip proteins exhibit only mild symptoms. Half of those animals lacking all three genes, however, died as a result of epileptic seizures in the first three months of life. Those that survived began to show signs of early aging by the time they reached nine months of age.

To further elucidate the genes' roles in the current study, Schibler's team looked to the liver and kidneys, the two organs in which all three transcription factors are known to have high activity.

By scanning the liver and kidneys of normal mice and PAR bZip-deficient mice for global gene activity patterns, the researchers found differences in many genes known to be involved in defense against chemical compounds and oxidative stress--an indication that the circadian transcription factors normally control the activity of those other detoxifying genes.

Without the normal complement of detox genes, the mice showed evidence of liver damage. Normal mice showed pronounced circadian rhythms in response to the sedative pentobarbitol, they found, clearing the drug faster at night than in the day. In contrast, the mutant mice had severe deficits in sedative clearance at all times and therefore slept much longer following injection. The mutants also suffered much greater harm than normal mice did from two of four chemotherapy drugs.

The inability to handle chemicals properly might explain the animals' rapid aging, the researchers suggest.

The results provide an important example of the fundamental role that circadian clocks play at the cellular and metabolic level and highlight their dire consequences when disrupted, wrote Carla Green and Joseph Takahashi in an accompanying commentary. A deeper understanding of circadian detoxification mechanisms provides a rational basis for optimizing the efficacy of pharmaceutical agents whose toxicity and side effects should be reduced by delivery at optimal times of day.

The findings reemphasize a principle that scientists had long recognized: sensitivities to chemotherapies and other drugs vary over the course of a day, Schibler agreed. Although rigorous clinical study is needed, patient outcomes might therefore be improved in some cases by delivering chemotherapies, or perhaps other drugs, in accordance with the circadian rhythm.

Even if patients were made less sick when given chemotherapy at a particular time of day, that could be very important for their well-being, he said.

Why does prolonged IV feeding damage the liver?

Mon, 03 Jul 2006 23:20:00 PST

( from http://www.rxpgnews.com ) Children who cannot eat on their own because of intestinal failure must rely on parenteral nutrition (PN), an intravenous method of feeding. Unfortunately, long-term PN can cause life-threatening liver disease, especially in infants, for reasons that have been unknown. Many infants who develop this complication die within a year of diagnosis, unless they can be weaned off PN or receive a liver/small intestine transplant. In the July issue of Pediatrics, researchers at Children's Hospital Boston report saving two babies' lives with one able to come off a liver-transplant list simply by changing the type of fat used in the PN solution.

The story began in 2001 when, seeking to understand why PN was causing liver disease, surgeon Mark Puder, MD, surgical resident Jenna Garza, MD, and pharmacist Kathy Gura, PharmD, decided to conduct studies in mice. They found evidence that the fat used in standard PN solutions, called Intralipid®, was contributing to liver disease by causing fat to accumulate in the liver.

Made largely of soybean oil, Intralipid is high in omega-6 fatty acids that are known to have an inflammatory effect. Puder's team decided to substitute OmegavenTM, an IV fat mixture made from fish oil. Fish oil contains omega-3 fatty acids, which have been shown to prevent fat accumulation and have anti-inflammatory properties. As hoped, PN using Omegaven as the fat prevented fat accumulation and liver injury in the mice.

Surgeon Rusty Jennings, MD, who directs Children's Advanced Fetal Care Center, had heard of Puder's research and wanted to try Omegaven in one of his patients, a 5-month-old patient born with gastroschisis, a life-threatening congenital defect in which the intestines develop outside the body. The surgeons had only been able to save a small portion of the boy's bowel, so he was unable to feed normally and was put on standard PN. He soon developed such serious liver damage that Jennings placed him on a transplant list for a liver and small bowel. But his small size made the chances of finding a donor slim, so Jennings appealed to Puder to "save his baby."

Since Omegaven isn't approved for use in the U.S., Puder had to receive special permission, under a compassionate-use protocol, to use Omegaven rather than Intralipid in his PN solution. Within 8 weeks, the baby's laboratory tests normalized, and his liver function improved so much that he was removed from the liver transplant list. Puder later treated a second child, a premature baby whose bowel had ruptured; he too had complete resolution of liver disease.

To date, 21 patients at Children's have received Omegaven as the fat portion of their PN under FDA compassionate-use guidelines, and most have done well; 2 have died from unrelated causes. Now, Puder and colleagues plan a formal clinical trial aimed at preventing liver disease in PN recipients, and have received funding from the March of Dimes.

"Using a fat emulsion consisting solely of fish oils may enable liver toxicity to be treated or prevented entirely in children and adults who are dependent on parenteral nutrition," Puder says.

Speeding discovery of the 'human cancer genome'

Wed, 28 Jun 2006 04:00:00 PST

( from http://www.rxpgnews.com ) As a demonstration of the value of such strategic comparisons between species, the researchers report promising finds: one of the research teams identified two genes that can--in some circumstances--conspire to produce liver cancer, while the second uncovered a gene important to the spread of melanoma, the most serious form of skin cancer. Such functionally important genes, and the larger genetic pathways of which they are a part, are also those with the most promise as potential targets for cancer drugs, according to the researchers.

With improvements in genome technology, we've found that human cancer is noisy, said Howard Hughes Medical Institute investigator Scott Lowe of Cold Spring Harbor Laboratory. There are lots of alterations, only some of which causally contribute to the disease.

Genetically engineered mice, by definition, develop more defined cancers than humans, he said. Mice can therefore be used as a filter to help reduce that noise, and as a tool to determine, in areas of chromosomal alteration, what changes are functionally relevant.

The difficulty stems from the fact that studies that scan the genomes of human tumors for differences typically find hundreds to thousands of genes that distinguish cancer and noncancer.

Some of those differences are at the root of the cancer, while others are what Lowe refers to as evolutionary byproducts. In other words, they are genes that simply came along for the ride with those that actually contribute to the cancerous cells' ability for unchecked proliferation or spread.

Simply sorting through those differences one by one takes time and money, said Lynda Chin of the Dana-Farber Cancer Institute and Harvard Medical School.

There has to be a way to prioritize the effort, she said.

Chin's and Lowe's groups already relied on large-scale structural changes to chromosomes as a way of identifying areas of the genome with potential importance for cancer. Such chromosomal rearrangements often lead to the amplification of cancer-causing genes or the loss of genes that normally suppress tumor formation.

But as genome technology continues to improve, providing ever-increasing resolution, researchers have found more than they had expected, Chin said.

In human melanoma, for example, more than 100 genomic regions exhibit recurring structural changes, not all of which appear to be important, she said. One way to narrow down the number of regions is to look for chromosomal alterations found in both humans and in the complementary, or syntenic, regions of the mouse genome.

If you are seeing the same event in different species, it becomes more likely that a common biological pressure is responsible--more likely that it is an important event, Chin said.

Using that strategy in the current study, Chin's group examined genetically engineered mice with melanoma that had developed an increased potential to spread, a process known as metastasis. Metastasis is a multistep process that requires and selects for tumor cells capable of escaping their normal microenvironment, traversing into and out of lymphatic or blood vessels, and proliferating in new soil, the researchers said.

Metastasis is particularly important in skin cancer, Chin added, as the primary tumor is almost always curable. Once the cancer spreads from the skin to other parts of the body, however, it can be difficult to treat and deadly.

The metastatic cancers of mice developed a chromosomal amplification--a region of the genome expressed in an unusually large number of copies--that corresponded to a much larger amplified region in the metastatic human melanomas, they found. Further study of that common region in mouse melanomas that independently developed their invasive ability revealed just one consistently elevated protein, called Nedd9.

To find out whether Nedd9 could play a role in skin cancer's spread, the researchers blocked the protein in both mouse and human metastatic melanoma cells. Cancer cells without active Nedd9 lost their ability to invade. Similarly, primary melanomas, when made to express too much Nedd9, became invasive, identifying Nedd9 as a bona fide melanoma metastasis gene. Nedd9's role appears to result from its interaction with another enzyme known to be important for cell's ability to migrate and take root.

As further evidence, they also found that the Nedd9 gene was frequently expressed at higher levels in metastatic human melanomas compared to primary melanomas.

Drugs aimed at Nedd9 might therefore prevent the skin cancer's spread, Chin said. Measurement of Nedd9 levels in primary melanomas might also provide an indication of the cancer's likelihood of spreading, although any prognostic significance would require rigorous investigation and validation in appropriately designed prospective clinical trials.

Taking a similar approach, Lowe's team identified two genes that can work together to encourage one form of liver cancer, called hepatocellular carcinoma.

Hepatocellular carcinoma is the fifth most frequent form of cancer worldwide but, owing to the lack of effective treatment options, represents the third leading cause of death, Lowe said. The only curative treatments involve surgery or transplantation as chemotherapies are ineffective, and no existing drug regimen prolongs survival.

While a handful of genes have been linked to liver cancer, how specific lesions interact to produce its aggressive characteristics remains poorly understood.

Lowe's team relied on mice with specific pathological changes known to play a role in some liver cancers. They then searched for other spontaneous mutations in the animals' tumors and compared them to recurrent alterations observed in the human disease.

That comparison narrowed the field to two genes that appear to drive liver tumors in both species: a gene called cIAP1, known to inhibit cell death, and a transcription factor called Yap. Both are required to sustain rapid growth of the tumors, they showed.

As the chromosomal region under study is found in five to ten percent of human tumor types, including lung, ovarian, esophageal, and liver carcinomas, the findings suggest the overall contribution of cIAP1 and Yap to human cancer may be substantial, the researchers said.

Their new mouse model now offers an excellent setting for preclinical tests of the potential of cIAP1 and Yap as targets for new cancer therapies, they added.

Taken together, the papers demonstrate a general principle with real importance for cancer patients, Chin said.

Robust, stringent and biologically relevant systems for filtering, annotating, and prioritizing the efforts of cancer geneticists and biologists will be essential to facilitate and accelerate the translation of our genomic knowledge into cancer drugs that will impact patient survival, she wrote.

Coffee may reduce risk of alcoholic cirrhosis

Tue, 13 Jun 2006 13:33:00 PST

( from http://www.rxpgnews.com ) Drinking coffee may be related to a reduced risk of developing the liver disease alcoholic cirrhosis, according to a report in the June 12 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Cirrhosis progressively destroys healthy liver tissue and replaces it with scar tissue. Viruses such as hepatitis C can cause cirrhosis, but long-term, heavy alcohol use is the most common cause of the disease in developed countries, according to background information in the article. Most alcohol drinkers, however, never develop cirrhosis; other factors that may play a role include genetics, diet and nutrition, smoking and the interaction of alcohol with other toxins that damage the liver.

Arthur L. Klatsky, M.D., and colleagues at the Kaiser Permanente Medical Care Program, Oakland, Calif., analyzed data from 125,580 individuals (55,247 men and 70,333 women) who did not report liver disease when they had baseline examinations, between 1978 and 1985. Participants filled out a questionnaire to provide information about how much alcohol, coffee and tea they drank per day during the past year. Some of the individuals also had their blood tested for levels of certain liver enzymes; the enzymes are released into the bloodstream when the liver is diseased or damaged.

By the end of 2001, 330 participants had been diagnosed with cirrhosis, including 199 with alcoholic cirrhosis. For each cup of coffee they drank per day, participants were 22 percent less likely to develop alcoholic cirrhosis. Drinking coffee was also associated with a slight reduction in risk for other types of cirrhosis. Among those who had their blood drawn, liver enzyme levels were higher among individuals who drank more alcohol, indicating liver disease or damage; however, those who drank both alcohol and coffee had lower levels than those who drank alcohol but did not drink coffee, with the strongest link among the heaviest drinkers.

Tea drinking was not related to reduced risk in the study, suggesting that it is not caffeine that is responsible for the relationship between coffee and reduced cirrhosis risk. "Previous reports are disparate with respect to whether the apparently protective coffee ingredient is caffeine; in our opinion this issue is quite unresolved," the authors write.

The findings do not suggest that physicians prescribe coffee to prevent alcoholic cirrhosis, the authors continue. "Even if coffee is protective, the primary approach to reduction of alcoholic cirrhosis is avoidance or cessation of heavy alcohol drinking," they conclude. "Assuming causality, the data do suggest that coffee intake may partly explain the variability of cirrhosis risk in alcohol consumers. Basic research about hepatic coffee-ethanol interactions is warranted, but we should keep in mind that coffee might represent only one of a number of potential cirrhosis risk modulators."

Coffee drinking associated with lower risk for alcohol-related liver disease

Mon, 12 Jun 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Cirrhosis progressively destroys healthy liver tissue and replaces it with scar tissue. Viruses such as hepatitis C can cause cirrhosis, but long-term, heavy alcohol use is the most common cause of the disease in developed countries, according to background information in the article. Most alcohol drinkers, however, never develop cirrhosis; other factors that may play a role include genetics, diet and nutrition, smoking and the interaction of alcohol with other toxins that damage the liver.

Arthur L. Klatsky, M.D., and colleagues at the Kaiser Permanente Medical Care Program, Oakland, Calif., analyzed data from 125,580 individuals (55,247 men and 70,333 women) who did not report liver disease when they had baseline examinations, between 1978 and 1985. Participants filled out a questionnaire to provide information about how much alcohol, coffee and tea they drank per day during the past year. Some of the individuals also had their blood tested for levels of certain liver enzymes; the enzymes are released into the bloodstream when the liver is diseased or damaged.

By the end of 2001, 330 participants had been diagnosed with cirrhosis, including 199 with alcoholic cirrhosis. For each cup of coffee they drank per day, participants were 22 percent less likely to develop alcoholic cirrhosis. Drinking coffee was also associated with a slight reduction in risk for other types of cirrhosis. Among those who had their blood drawn, liver enzyme levels were higher among individuals who drank more alcohol, indicating liver disease or damage; however, those who drank both alcohol and coffee had lower levels than those who drank alcohol but did not drink coffee, with the strongest link among the heaviest drinkers.

Tea drinking was not related to reduced risk in the study, suggesting that it is not caffeine that is responsible for the relationship between coffee and reduced cirrhosis risk. Previous reports are disparate with respect to whether the apparently protective coffee ingredient is caffeine; in our opinion this issue is quite unresolved, the authors write.

The findings do not suggest that physicians prescribe coffee to prevent alcoholic cirrhosis, the authors continue. Even if coffee is protective, the primary approach to reduction of alcoholic cirrhosis is avoidance or cessation of heavy alcohol drinking, they conclude. Assuming causality, the data do suggest that coffee intake may partly explain the variability of cirrhosis risk in alcohol consumers. Basic research about hepatic coffee-ethanol interactions is warranted, but we should keep in mind that coffee might represent only one of a number of potential cirrhosis risk modulators.

(Arch Intern Med. 2006;166:1190-1195. Available pre-embargo to the media at

MUHC announces a transplant first in Quebec

Thu, 08 Jun 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Combined heart/liver transplants are so rare that the best technique for a combined implantation has not yet been elucidated, says Dr. Kevin Lachapelle, a Cardiac Surgeon at the MUHC, who performed the combined procedure with Dr. Peter Metrakos (Liver Surgeon). Historically these procedures are done separately, but because both organs were procured from Quebec City at the same time by MUHC Drs. Ergina and Paraskevas and because sequential transplants can have a profound negative effect on the heart, we decided a simultaneous implantation offered the best hope of success.

The patient, Patrice Dionne, who was referred to the Institut de cardiologie de Quebec for medical evaluation for a possible heart transplant, was transferred to the MUHC after liver complications necessitated a complex multi-organ transplant. The patient had waited three years for a heart transplant, during which time his liver began to deteriorate, says Dr. Bernard Cantin, Director of Heart Transplantation at the Institut de cardiologie de Quebec. At this point we knew the MUHC was the only hospital where we could transfer our patient for this lifesaving surgery. The speed and ease at which this patient transfer occurred demonstrates the level of collaboration and teamwork that exists between hospitals within Quebec.

The patient made a rapid recovery after surgery, and was discharged after only 10 days, says Dr. Nadia Gianetti, Medical Director the Heart Failure and Heart Transplant Program at the MUHC. The seamless collaboration between the cardiac and liver transplant teams at the MUHC is one of many reasons why the planning, surgery, and follow-up care of Mr. Dionne was so straightforward and uncomplicated. The patient has now fully recovered and is again living a full and rich life. I am extremely impressed with the doctors at the MUHC; from the onset I had unquestioned confidence in their ability to perform this complex surgery, says Patrice Dionne. I'm so thankful that I will now be able to enjoy this fathers day with my three sons.

As a comprehensive Multi-Organ Transplant Program, we are accustomed to collaborating with other institutions across Quebec and other provinces for this form of highly specialized patient care, says Dr. Renzo Cecere, Surgical Director of Heart Failure and Heart Transplantation at the MUHC. We are particularly pleased to have specialists from every discipline with a strong interest in transplantation, allowing us to successfully offer combined organ transplants within one institution.

The world's first heart transplant was conducted less than forty years ago; complex combined transplants have only been conducted since the 1980's. Multi-organ transplants, such as the combined heart-liver transplant conducted at the MUHC require a multi-specialized team, consisting of cardiologists, hepatologists, intensive care specialists, anesthesiologists, nurses, physiotherapists and Transplant Quebec coordinators. Combined heart-liver transplants are rare--only a few successful procedures have been performed in Canada, and this is the first in Quebec.

Gene first linked to rare disease may trigger skin cancer, other tumors

Thu, 18 May 2006 04:00:00 PST

( from http://www.rxpgnews.com ) The disease familial cylindromatosis results from the loss of a gene called CYLD, causing tumors known as cylindromas to develop in hair-follicle cells. Earlier studies indicated a role for CYLD in inflammation, but the mechanism behind the gene's control over tumor growth had remained uncertain.

A team led by Reinhard Fässler of the Max Planck Institute of Biochemistry in Germany and his colleagues has now found that CYLD has a second role that explains its ability to keep tumors at bay.

The enzyme chemically modifies the cancer-promoting protein Bcl-3, first identified in connection with some forms of leukemia. That modification bars the oncogenic protein's entry into the cell nucleus, the central command center and storehouse for DNA, where it would otherwise drive the uncontrolled increase in cell numbers characteristic of tumor growth.

The researchers first showed that mice lacking CYLD were highly sensitive to developing skin tumors. Mutant mice exposed to particular chemicals all developed skin tumors compared to half of normal mice experiencing the same exposures. Moreover, the CYLD-deficient mice developed 7-fold more and significantly larger tumors than their control littermates.

Further examination of tumors taken from the mutant mice suggested that the defect stemmed from an increase in cell proliferation rather than cell survival. Isolated CYLD-deficient skin cells, when treated with the tumor-inducing chemicals, began to proliferate due to an accumulation of Bcl-3 in the nucleus, they found. Treatment with a single dose of ultraviolet light--thought to be a trigger of cylindromas--sparked the same reaction in the mutant cells, they found.

In the absence of CYLD, it is the accumulation of Bcl-3 that is the problem, Fässler said. Bcl-3 is normally under tight regulation; it is primarily found out in the cytoplasm, with very little in the nucleus. Cytoplasm is the clear, jelly-like material in which all the cell's components are suspended.

In animals deficient for CYLD, much too much Bcl-3 makes it into the nucleus where it activates genes leading to the growth of tumors.

In normal skin cells, chemical treatment or UV light prompts the transport of CYLD out into the cytoplasm, they reported. Once there, the protein binds and modifies the cancer promoter Bcl-3 to prevent its nuclear accumulation.

In addition to elucidating the cause of cylindromas, the findings might have important implications for understanding the events underlying skin cancer, and perhaps also tumors in other body tissues, the researchers said.

Indeed, the group noticed an intriguing trend--most of the tumors found in the mutant mice developed from cells of the epidermis rather than the hair-follicle cells thought to be involved in cylindromatosis. They therefore conducted a preliminary analysis of CYLD levels in human skin cancers originating from the epidermis, including basal cell carcinomas (BCC) and squamous cell carcinomas (SCC).

BCC and SCC represent the two most common forms of skin cancer, which together affect an estimated one million Americans each year.

Interestingly, we observed reduced or absent expression of CYLD in more than ten samples of BCC and SCC, respectively, the researchers wrote. This strongly suggests that CYLD plays a general role as a tumor suppressor, which is in agreement with its ubiquitous expression pattern and with a recent observation showing that CYLD levels are downregulated in several other tumors such as kidney, liver, and uterine cervix.

The researchers are now further examining their CYLD-deficient mice to find out whether the animals also show an increased prevalence of colon tumors. Early indications suggest that they do, according to Fässler.

We think the CYLD tumor suppressor involved in cylindromas is likely to be important to many, many other tumors, he said.

Chronic hepatitis in pediatric liver transplant patients

Wed, 03 May 2006 01:22:00 PST

( from http://www.rxpgnews.com ) A new study on the long-term outcome of children undergoing liver transplants found that chronic hepatitis (CH) was common and that it was not detectible using standard blood tests. The presence of autoantibodies (antibodies that attack the body's own tissues) in these patients indicates that although not fully understood, CH may be related to the immune response.

The results of this study appear in the May 2006 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). Published by John Wiley & Sons, Inc., Hepatology is available online via Wiley InterScience.

Children normally undergo liver transplants for diseases that do not recur and are potentially curable by the procedure. Although their long-term survival rates are over 80 percent, little is known about tissue changes that occur over time in these young patients. "An important question within the field of paediatriac liver transplantation is whether children who have undergone successful transplantation can expect a normal life expectancy or whether there will be a gradual decline in liver function and eventual graft loss," the authors write.

Led by Helen M. Evans of the Birmingham Children's Hospital in Birmingham, United Kingdom, the study involved children who received liver transplants at the hospital's Liver Unit between 1983 and 1996. Patients underwent standard liver function tests, sonograms and liver biopsies at approximately 1, 5 and 10 years following transplant, and autoantibodies were measured at 5 and 10 years. A total of 113 children had liver biopsies at the one year mark, 135 had biopsies after 5 years, and 64 underwent biopsies at 10 years.

The results showed that there was a decrease over time in the proportion of biopsies considered to be normal, with chronic hepatitis being the most common abnormality (22 percent at 1 year, 43 percent at 5 years, 64 percent at 10 years). While liver function tests at 5 years were not significantly different in children who had CH, the presence of autoantibodies was significantly higher at 5 and 10 years in children with CH (72 percent and 80 percent respectively). In addition, there was a strong association between the presence of CH and the development of progressive fibrosis (the formation of scar-like tissue). The authors note that "the finding of increasing fibrosis in children with chronic hepatitis has not been reported before and has potentially important implications for long term graft function."

The authors note that transient autoantibody production following transplant sometimes occurs during episodes of rejection. In addition, late rejection may be associated with tissue changes that are different to those normally seen in acute rejection but more closely resemble those seen in chronic viral or autoimmune hepatitis. "It is therefore possible that some cases of otherwise unexplained chronic hepatitis in the liver allograft may represent a form of late cellular rejection," the authors suggest.

The results of the present study indicate that important tissue abnormalities can be detected in biopsies obtained from children who are clinically well and have normal liver function tests, the authors state. "Screening for chronic allograft hepatitis using liver biochemistry is therefore not possible and may instead require regular measurement of autoantibodies," they conclude.

Bile acids, receptor key in regenerating livers

Thu, 13 Apr 2006 04:00:00 PST

( from http://www.rxpgnews.com ) Studies by researchers from Baylor College of Medicine in a report that appears in today's issue of the journal Science suggest that they may have been on the right track.

In fact, regenerating liver tissue may depend on signals sent out when there is an imbalance in bile, said Dr. David Moore, BCM professor of molecular and cellular biology. He and colleagues at BCM identified an imbalance of bile, specifically bile acids, as a major signal for this process.

Liver is an unusual organ because it can regrow when injured.

Understanding how this happens could help physicians seeking to treat liver disease.

Bile acids are made in the liver and are the detergents of fat metabolism, said Moore. However, they are also signaling molecules that provide the body with key information about the state of the liver.

They are released into the gut as part of digestion, reabsorbed and then back to the liver. More than 90 percent are cycled, he said. You do not get rid of the bile acids when you lose a piece of liver, said Moore Instead, you expose the remaining portion to a higher relative amount of bile acids, sending a signal through a specific receptor called FXR to activate liver regeneration.

Animals bred to lack FXR have difficulty regenerating liver, he said. And when he and his colleagues fed animals a diet that contains bile acids, the liver regenerated faster.

Those who receive drugs that sequester bile acids (such as drugs used to lower cholesterol) cannot regenerate liver.

Drugs could be developed to take advantage of this finding, promoting the growth of liver in some instances.

People are interested in this, said Moore. Can you promote the growth of liver cells to restore liver function? People are also interested in treating liver with disease with hepatocytes or liver cells.

The experiments carried out in his laboratory indicate that equilibrium in liver growth and function is maintained by FXR and possibly other receptors.

FXR and perhaps others as-yet unidentified receptors sense the ability of the liver to function. When it does not function well, one or more receptors are activated to protect the liver cells and enable the organ to grow. In this view, the liver grows until its function is restored and the signal for regeneration is lost.

In Greek legend, Prometheus, who gave man fire, was punished by Zeus. Each day, Zeus' eagle would eat his flesh and his liver. Overnight, the liver would regenerate and heal. With the dawn, the dreadful process began again.

In a way, said Moore, these studies are a scientific way to explain the regenerative process told in that legend.

Others who participated in the research include: Drs. Wendong Huang, Ke Ma, Jun Zhang, Mohammed Qatanani, James Cuvillier, Jun Liu, Bingning Dong and Xiongfei Huang. Dr. Wendong Huang and Dr. Xiongfei Huang are now at City of Hope in Duarte, California, and Dr. Jun Zhang is at Stanford University.

Pennsylvania researchers find liver transplants provide metabolic cure for rare genetic disease

Mon, 10 Apr 2006 04:00:00 PST

( from http://www.rxpgnews.com ) All patients from the study (ranging in age from 1-20) are alive and well with normal liver function, according to the researchers. Amino acid levels in the study patients stabilized within 6-12 hours of transplant and remained stable since transplant despite unrestricted intake of protein.

MSUD is a metabolic disease which causes amino acids from proteins to accumulate in the body. The disease gets its names from the sweet smell of the urine. The accumulation of amino acids in the blood can cause metabolic crisis at any age, which can lead to brain swelling, stroke and even sudden death. Over a patient's lifetime, chronic instability of blood amino acids can result in serious learning disabilities and mental illness.

Before transplant, the only treatment was strict adherence to a diet almost devoid of protein. Despite adherence to this diet, patients were still at risk of metabolic crisis from something as simple as a common cold, which can disrupt the body's metabolism and cause rapid neurological deterioration.

In 1997, an MSUD patient at another hospital received a liver transplant due to an unrelated medical condition and physicians noticed the symptoms of her MSUD were alleviated.

Based on this serendipitous result, physicians from Children's and the Clinic for Special Children, located in Strasburg, Pa., began working collaboratively to develop a liver transplant protocol for MSUD which optimized patient safety. With a comprehensive, multidisciplinary protocol established, Children's transplant surgeons began performing liver transplants on MSUD patients in May 2004. Children's has performed 18 MSUD liver transplants since then.

The study by Children's and the Clinic for Special Children involved 11 of these MSUD patients, including the original patient. Results of the study are published in the March issue of the American Journal of Transplantation.

The development of liver transplantation as a treatment for MSUD has dramatically improved our patients' quality of life, said George V. Mazariegos, director of Pediatric Transplantation at Children's and one of the study authors. Our MSUD patients and their families had lived in fear of everything from a chicken nugget to a common cold. Liver transplantation is not without risks, but for some patients, it is the best option and it has allowed these recipients and their families to live without fear of simple things most people take for granted.

Kevin A. Strauss, MD, a pediatrician at the Clinic for Special Children and a co-author of the study, said that over the past 15-20 years, early diagnosis of MSUD followed by careful nutritional therapy have improved the health and developmental outcome of affected individuals.

Nevertheless, the risk for metabolic crisis and acute neurological injury is always present, and many older individuals with MSUD suffer from depression, anxiety, and impaired concentration and learning, Dr. Strauss said. Liver transplantation protects patients from these acute and chronic neurological complications. It is a reasonable alternative to nutritional therapy, particularly for patients with poor access to specialized medical care. However, liver transplantation is not without serious risks, and decisions about the best course of therapy will vary on an individual basis.

Possible brain hormone may unlock mystery of hibernation

Thu, 06 Apr 2006 04:00:00 PST

( from http://www.rxpgnews.com ) If the findings in chipmunks are confirmed, the hormone would represent the first essential brain signal governing the seasonal adaptation, according to the researchers.

As hibernation factors endow animals with an incredible ability to cope under otherwise lethal conditions--ratcheting down their metabolic rate to survive on limited energy reserves and withstanding extreme cardiovascular and oxygen stresses--the candidate hormone might also pave the way toward clinical therapies that lend humans the same kind of protection, they added.

The researchers earlier found that concentrations of hibernation-specific protein complex (HPc) decline in the blood of hibernating chipmunks. The team now reports evidence that the level of HPc in the brain increases at the onset of hibernation independently of changes in body temperature. Moreover, treatments that block HP activity in the animals' brains cuts hibernation short.

One of the most curious biological phenomena in mammals is theirability to hibernate circannually, which allows them to survive unusuallylow body temperatures at or near freezing, said study author Noriaki Kondoof Mitsubishi Kagaku Institute of Life Sciences in Japan.

Although the functions of HP remain to be clarified, thecurrent observations lead us to propose the involvement of the proteincomplex in the regulation of energy metabolism and/or biological defensesduring hibernation--crucial events for adapting to the severe physiologicalstate, Kondo said.

In the current study, the researchers first demonstrated that hibernation in chipmunks is strictly controlled by an individual's internal circannual rhythm even under conditions of constant cold. In 20 hibernators examined throughout their lives, concentrations of HPc in the blood started to decrease prior to hibernation and remained low throughout the inactive state. Hibernation ended after blood HPc levels rose.

Further study revealed an inverse relationship between HPc levels in the blood and brain. While HPc levels dipped in blood, the putative hormone rose dramatically in cerebral spinal fluid, they reported. Likewise, HPc levels decreased abruptly in spinal fluid when hibernation terminated.

The researchers also found that blocking the activity of one of the HP complex proteins in the brain with antibody greatly decreased the hibernation time during which the chipmunks maintained a lowered body temperature, suggesting its critical role in the brain's capacity for dormancy.

The researchers propose that HPc in the blood is actively transported into the spinal fluid in response to the animals' natural rhythm. The hibernation complex might also play a role in the seasonal behavior changes of animal species that do not hibernate, the researchers suggested.

For example, the complex could moderate physiological events suchas reproduction in seasonally breeding mammals and migration in birds, theysaid. Even humans can maintain seasonal rhythms as exhibited by seasonalaffective disorder, a recurrent depression characterized by increased sleep,overeating, and weight gain--behaviors similar to those seen in hibernators,Kondo noted.

Hibernation is an extreme response to a seasonal environment, yet we knew almost nothing about how it is timed, nor how vital cellular functions are sustained in the face of plummeting body temperature, wrote Michael Hastings in a preview. The researchers now identify a liver-derived protein complex as an essential coordinator of this adaptation to the depredations of winter.

The finding has more than passing biological interest because understanding how tissues cope with the cardiovascular and oxidative stresses associated with hibernation or torpor may have direct clinical relevance, he added.

For example, he wrote, such a protective program might be exploited in transplant and vascular surgery. Scientists have suggested that hibernation therapy might effectively preserve donor organs for weeks or months.

Hibernation has also been found to protect animals from a wide range of potential threats, from muscle disuse to cancer, the study authors said. Therefore, hibernation therapy might confer protective effects in other clinical arenas as well.

The new findings could lead to potential pharmacological applications in humans to the prevention of lethal diseases, such as hypothermia, ischemia, muscle atrophy, bacterial infection, and tumorigenesis, which has been observed during hibernation in hibernators, the researchers said.

These studies may further stimulate the exploration of new techniques for cryosurgery of the heart and brain, as well as the development of hypothermia treatment that is effective for preventing brain ischemic damage. In cryosurgery, physicians use extreme cold to destroy abnormal tissue, such as cancerous tumors.

Nanoparticles may pose threat to hepatocytes

Wed, 05 Apr 2006 14:08:00 PST

( from http://www.rxpgnews.com ) Researchers at the University of Edinburgh are to study the effects of nanoparticles on the liver. In a UK first, the scientists will assess whether nanoparticles already found in pollution from traffic exhaust, but also used in making household goods such as paint, sunblock, food, cosmetics and clothes can cause damage to the cells of the liver.

Nanoparticles are atoms and molecules 80,000 times smaller than the width of a human hair, with various properties according to their composition, which explains their widespread usage. Airborne nanoparticles present in traffic exhaust are already known to enter the lungs and affect human health.

Scientist Dr Celine Filippi explains: "In experiments carried out elsewhere to mimic environmental exposure, nanoparticles delivered into the lungs crossed the lung barrier and entered the blood. Particles in the blood can reach the liver, amongst other organs. We also know that nanoparticles directly injected into the blood for medical purposes are also likely to end up in the liver.

"We don't yet know if the nanoparticles are safely eliminated from the liver by specialised cells or whether these extremely small particles can enter the liver cells and disrupt their normal functioning. Our research will try to establish whether nanoparticles, which are set to be used increasingly in industry and the manufacture of household goods, can damage the cells of the liver."

Professor Ken Donaldson, Professor of Respiratory Toxicology at the University of Edinburgh said: "We are looking at the new idea that the liver is a target for nanoparticles, and a lot more work needs to be done to assess the levels and impact of nanoparticles reaching the liver."

Vaccinating Infants of Hepatitis B Mothers Prevents Infection - Systematic Review

Tue, 31 Jan 2006 19:00:00 PST

( from http://www.rxpgnews.com ) Immunising newborn infants of mothers with hepatitis B prevents infection being transmitted from mother to child, finds a study published online by the BMJ.

There are around 350 million hepatitis B carriers worldwide. The virus is transmitted by contact with blood or body fluids of an infected person. Mother to child transmission around the time of birth is common and accounts for up to half of all carriers.

Researchers analysed randomised trials to assess the beneficial and harmful effects of hepatitis B vaccines (active production of antibodies) and hepatitis B immunoglobulin (passive transfer of antibodies) in newborn infants of mothers positive for hepatitis B surface antigen.

They found that hepatitis B vaccine, hepatitis B immunoglobulin, or the combination of vaccine plus immunoglobulin given to the newborn infants of mothers positive for hepatitis B surface antigen prevents the occurrence of hepatitis B. Furthermore, the combination of vaccine plus immunoglobulin was superior to vaccine alone.

There was no difference between the two types of vaccine currently available.

Although this study confirms that vaccines and immunoglobulin are effective, more research is needed to identify the optimal dose and treatment schedule of hepatitis B immunisation, conclude the authors.

U of S researchers develop new vaccine candidate against hepatitis C

Tue, 10 Jan 2006 05:00:00 PST

( from http://www.rxpgnews.com ) VIDO is the first in Canada to show that this vaccination technique may be effective against HCV. The study was published in this month's Journal of General Virology.

The team, funded by the Canadian Institutes of Health Research (CIHR) and the Canadian Network for Vaccines and Immunotherapeutics (CANVAC), produced a vaccine candidate that decreased the amount of a carrier virus expressing hepatitis C virus (HCV) protein in mice by 100,000 times compared to the control.

This technique uses the body's own cells, called dendritic cells, to vaccinate against hepatitis C, said Dr. Bhagirath Singh, Scientific Director of the CIHR Institute of Infection and Immunity.

Dendritic cells are key components of the immune system, activating and shaping the immune response. The vaccine reduced the amount of hepatitis C protein in a highly significant manner, he said. This offers a very promising approach to prevent liver disease caused by the virus and to ultimately eliminate it from the body.

About 20 per cent of people who contract HCV overcome the virus on their own. For those who develop chronic hepatitis, the immune system cannot clear the infection.

In patients with chronic hepatitis C, there is evidence that the function of their dendritic cells is altered, said Sylvia van den Hurk, senior VIDO scientist and member of the research team that developed the vaccine candidate.

We thought that if we could 'teach' the dendritic cells how to properly activate the immune response and deliver them back to the patient as a vaccine, the patients would clear or at least control the infection.

HCV is the leading cause for liver transplants in the western world, and its annual death toll is expected to triple in the next 10 years. Worldwide, there are about five times more people infected by HCV than with the HIV virus. Treatment of hepatitis C, which like HIV is spread by blood-to-blood contact, is costly and ineffective in about half the patients.

Researchers working in this field have a tough job, says van den Hurk. The hepatitis C virus is always mutating. For example, one patient can be infected with a strain that spawns sub-strains with different sequences. They are all present at the same time, in the same patient.

The VIDO vaccine uses a viral protein that is common among different strains, ensuring that the vaccine will be effective against them.

The researchers exposed dendritic cells in vitro to a HCV protein. The cells were also exposed to a strong immune stimulator to increase the immune response and then injected into mice as a vaccine. Because HCV does not infect mice, mice were challenged with a carrier virus containing the hepatitis C protein. The levels of HCV protein in immunized mice using this model were five orders of magnitude lower than the control.

Need for treatment modification in older hepatitis C patients

Fri, 06 Jan 2006 03:35:00 PST

( from http://www.rxpgnews.com ) A new study in Japan examining the effects of combination therapy on older patients with hepatitis C found more adverse effects necessitating discontinuation of treatment, lowering of dosages, and lower long-term benefits in this age group.
The results of this study appear in the January 2006 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). (published by John Wiley & Sons, Inc)

Chronic hepatitis C virus (HCV), the most common cause of liver disease, affects approximately 300 million people worldwide. The virus was seen in the Japanese population decades before the U.S., with the result that HCV patients in Japan are 10 to 15 years older than patients in western countries. The standard treatment is combination therapy with interferon or pegylated interferon (a newer form of the drug that is thought to be more effective) and the antiviral drug ribavirin. However, this treatment tends to be associated with adverse effects that lead to either a dose reduction or discontinuation of therapy in up to 28 percent of patients.

Researchers led by Yoshiaki Iwasaki of the Department of Gastroenterology and Hepatology at Okayama University in Okayama, Japan conducted a study involving 208 HCV patients between December 2001 and July 2003. They classified the patients into three groups: younger than 50 years of age, 50 to 59 years old, and 60 years of age or older and scheduled them for 24 weeks of combination therapy with interferon and ribavirin. Of the 208 patients, 56 percent had to discontinue therapy or reduce their dosage due to adverse effects such as decreased appetite, retinal hemorrhage, and low white blood cell count and the older the patient, the more likely it was that this was the case. In addition, there was a tendency toward a lower sustained virological response (SVR, the absence of HCV for more than 6 months after completing therapy) in the older patient group.

The dose reductions and discontinuation of therapy in this study were much more frequent than in previous studies, which the researchers attribute to the more advanced age of the patients. The fact that older patients had higher rates of impaired kidney function and high blood pressure may have led to more frequent adverse effects. In addition, they note that patients were given high-dose induction therapy of standard interferon, which may render them more susceptible to adverse effects than HCV patients in western countries, where lower doses of interferon or pegylated interferon are the norm.

The results also indicated that for more than 70 percent of the patients, dose reduction and discontinuation of therapy was necessary within the first 12 weeks of therapy, which had a negative impact on SVR, especially in older patients and in cases where the doses of both drugs were reduced. Of the two drugs, reducing ribavirin during the first 12 weeks of therapy seemed to have a greater impact on SVR than reducing interferon.

"The present data demonstrated the importance of considering patient age when treating hepatitis C via combination therapy, especially for patients more than 60 years old," the authors state. "The treatment schedule should be modified, or other therapeutic modalities should be considered for older patients with chronic hepatitis C." They stress the importance of patient education and support to maximize patient compliance in completing the treatment regimen. Although the study involved only Japanese patients, it should be noted that approximately 35,000 new HCV infections occur each year in the U.S.; the proper treatment of older patients with chronic hepatitis C may therefore become an emerging problem in this country.

Increase in death rates from liver cirrhosis in Britain largest in western Europe

Thu, 05 Jan 2006 05:00:00 PST

( from http://www.rxpgnews.com ) Rates of mortality due to liver cirrhosis can indicate the extent of alcohol harm occurring in a population. David Leon (London School of Hygiene and Tropical Medicine, UK) and Jim McCambridge (King's College London, UK) calculated the mortality rates for liver cirrhosis using data from the World Health Organization Mortality Database. They calculated rates for all ages and specific age groups in Scotland, England and Wales and compared these to rates in 12 other western European countries Austria, Finland, Germany, Ireland, Italy, Netherlands, Norway, Portugal, Spain, Sweden, and Denmark.

The investigators found that mortality rates for liver cirrhosis increased steeply in Scotland, England and Wales during the 1990s. Steady increases took place until the end of the 1970s, and accelerated in the 1980s and again from 1990 to 1994 onwards. In comparison, mortality rates for both men and women in the other European countries declined by 20-30% from the early 1970s. Between the periods 1987-1991, and 1997-2001, cirrhosis mortality in men in Scotland more than doubled, and in England and Wales it rose by over two-thirds. For women, rates increased by a half in the same period. Across both age-groups and sexes, the liver cirrhosis mortality rates in Scotland are now about double that of the European comparison group.

The authors blame increases in alcohol consumption, particularly wine and spirits, as the main reason for the rise in liver cirrhosis mortality. Total recorded alcohol consumption doubled between 1960 and 2002. They add that increases in the rates of heavy drinking, obesity, and hepatitis C may have also contributed. In western Europe, the reduction in mortality rates from liver cirrhosis has been driven by a decline in overall alcohol consumption in the mainly wine-drinking countries of Southern Europe, state the authors.

Professor Leon states: Current alcohol policies in Britain should be assessed by the extent to which they can successfully halt the adverse trends in liver cirrhosis mortality. The situation in Scotland warrants particular attention.

In an accompanying comment Robin Room (Stockholm University, Sweden) states: The UK used to be known to alcohol researchers for its relatively low rate of liver cirrhosis deaths. But Leon and McCambridge show that Great Britain has recorded the steepest rise in rates in western EuropeWhile beverage type, as mentioned in the paper, and pattern of drinking might both affect the risk of developing cirrhosis, there is no doubt that the cumulative amount of alcohol consumed has a primary role. But the UK Government has turned a determined blind eye to the problem and has failed to make the reduction of the population's alcohol intake a policy goal. Through the new alcohol licensing law and the official guidance on it, the national government has also done its best to tie the hands of local government on this issue.

Obese mice are more susceptible to liver abnormalities

Tue, 04 Oct 2005 00:34:00 PST

( from http://www.rxpgnews.com ) Mice that were fed diets high in fat and sugar developed immune system abnormalities in their livers, including reduced numbers of natural killer T (NKT) cells. These diet-related changes may contribute to obesity-related liver disease, according to a new study. The study is published in the October 2005 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD).

NKT cells originate in the thymus but accumulate in the liver where they regulate the production of cytokines (cell proteins). A previous study of leptin-deficient obese mice noted depleted levels of NKT cells. However, since obese humans have increased leptin levels, the researchers were not sure if their findings in mice were relevant to human fatty liver disease. To address this question, they studied a new diet-induced model of non-alcoholic fatty liver disease.

The researchers, led by Zhiping Li of Johns Hopkins University in Baltimore, obtained wild-type mice and fed them commercial diets with different nutritional contents for four to twelve weeks. The mice were then sacrificed to obtain liver and serum tissue. The researchers isolated hepatic mononuclear cells, which they then incubated and evaluated by flow cytometry. They also isolated total hepatic RNA for analysis. Finally, they measured levels of serum alanine aminotransferases (ALT), a marker of liver injury.

The mice on high fat diets gained significantly more weight than the mice on normal diets, and they also developed fatty livers. Their hepatic mononuclear cells revealed significantly fewer hepatic CD4+ NKT cells. Subsequent tests revealed doubled production of IL-12, a cytokine that reduces NKT cell viability, as well as increased NKT cell death.

"Preliminary studies suggest that hepatic NKT cell numbers remain constant before high fat-fed mice develop significant steatosis after consuming the high fat diet for one week," the authors report. "However, more studies are needed to better understand the temporal relationship between development of steatosis and NKT cell depletion."

The results also showed that high fat diets increased the production of hepatic pro-inflammatory cytokine. When the researchers induced liver injury in mice on the varying diets, they found that high fat-diet mice experienced more inflammation and necrosis than normal-diet mice.

This study shows that high-fat diets correlate to a chronic inflammatory state in the liver, which promotes chronic liver disease. The researchers suggest a potential mechanism for this outcome: diet-induced depletion of the hepatic NKT cells that balance local production of pro- and anti-inflammatory cytokines.

"Further evaluation of other mouse strains, different age groups and genders will be necessary to clarify if any of these factors modulate susceptibility to diet-related changes in hepatic NKT cells," the authors say.

"Nevertheless," they conclude, "our findings are important because they clearly demonstrate significant dietary effects on 'classic' NKT cells and cytokine production by other liver mononuclear cells."

TWEAK Induces Liver Progenitor Cell Proliferation

Fri, 19 Aug 2005 13:51:00 PST

( from http://www.rxpgnews.com ) Liver injury can occur as a result of alcohol toxicity, necrosis, or a host of other factors. When the liver is injured, it responds with progenitor cell (oval cell) proliferation in the remaining parts of the organ. The oval cells can become either liver cells or epithelial cells, and are vital for recovery from liver injury. But the regulation of oval cell expansion is not well understood.

In a study appearing online on August 18 in advance of print publication of the September 1 issue of the Journal of Clinical Investigation, Aniela Jakubowski and colleagues from Biogen report the discovery of a novel role for the TNF family member, TWEAK, as an inducer of oval cell proliferation in the liver. This is the first demonstration of a role for this cytokine in the regulation of liver progenitor cells.

Unlike other factors that can modulate the proliferation of oval cells, the researchers show that TWEAK acts selectively on oval cells with no effect on mature liver cells. They use three independent approaches: animals overexpressing TWEAK, adenoviral delivery of TWEAK, and TWEAK blocking antibodies in a model of oval cell hyperplasia.

The potential role for the TWEAK pathway in chronic human liver diseases that are accompanied by oval cell proliferation is suggested by data showing increased expression of the receptor for TWEAK in alcoholic cirrhosis and viral hepatitis. A better understanding of the molecular pathways regulating the progenitor cell response may lead to specific therapies for liver diseases.

Therapy may not be necessary for asymptomatic autoimmune hepatitis

Mon, 15 Aug 2005 21:08:00 PST

( from http://www.rxpgnews.com ) It is not uncommon for patients with autoimmune hepatitis (AIH), a disease in which the patient's own immune system attacks the liver, to have no symptoms. Such cases are being diagnosed more frequently due to the increased practice of administering routine liver enzyme and antibody tests. Whether or not to treat asymptomatic AIH remains unclear--therapy with immunosuppressants could potentially slow progress of the disease but involves side effects that are sometimes toxic.

In order to determine if immunosuppressive therapy is indicated when no symptoms are present, researchers led by Jordan J. Feld, M.D. of the Departments of Medicine and Pathology at the University Health Network of the University of Toronto, compared the natural course of asymptomatic AIH with symptomatic AIH.

The study included 124 patients diagnosed with AIH at the Toronto Western Hospital Liver Clinic between 1970 and 2002 31 of whom were asymptomatic. Researchers reviewed the patients' clinical records to document the presence or absence of symptoms. Patients were considered asymptomatic if they were free of all symptoms, even non-specific ones such as fatigue or abdominal pain. Immunosuppressive therapy was recommended for all symptomatic patients, while asymptomatic patients were not treated, unless treatment had already been initiated. Patients who developed symptoms during the study period were started on immunosuppressive therapy. If they remained in remission for two years with no relapse the therapy was discontinued, but it was restarted if the disease recurred off treatment.

The results of the study indicated that asymptomatic patients had lower liver enzyme and IgG antibody levels, as well as lower scores on the hepatic activity index (HAI), which measures liver inflammation, but otherwise did not differ from patients with symptoms. Half of the asymptomatic patients ended up receiving treatment either because it was already started by their physicians or because they eventually developed symptoms. "Our data suggest that it may be safe to follow asymptomatic patients with a strategy to institute immunosuppressive treatment if symptoms develop over time," the authors state, although they note that patients with no symptoms were less likely to respond to treatment than those that had symptoms.

Notably, the current study also showed that patients who had cirrhosis when diagnosed had a worse outcome than those that did not, with a higher incidence of complications or death. Treatment is normally initiated in asymptomatic patients because it is thought to prevent the development of cirrhosis, but whether this is the case remains unclear. Other studies have been inconclusive in this area and based on the current study the authors conclude: "Most [asymptomatic] patients will not develop symptoms during follow-up and they appear to do well without immunosuppressive therapy at least for as long as they remain asymptomatic."

Although the authors note that the results should be considered with caution due to the limited number of patients who underwent liver biopsy, they conclude that severe OSA, independent of being overweight, is a risk factor for liver disease. In addition, they postulate that OSA may contribute to insulin resistance and fatty liver disease, since insulin responsiveness improves after treating OSA. They suggest that the striking relationship between the severity of sleep apnea and liver damage indicates that OSA may play a role in how fatty liver disease develops.

In conclusion, the authors state, OSA is a risk factor for abnormal liver enzymes independently from BMI, and should be investigated in patients without other cause of liver disease. They conclude: Further studies are needed to assess the prevalence of OSA in patients with NASH [nonalcoholic steatohepatitis, or fatty liver disease with inflammation] and to evaluate whether treatment of OSA may improve liver injury.

PegInterferon-alfa-2b with Ribavirin Shows Promise

Tue, 03 May 2005 13:26:00 PST

( from http://www.rxpgnews.com ) More than half of 61 children infected with chronic hepatitis C achieved a sustained viral response after treatment with peginterferon-alfa-2b and ribavirin, report the authors of a new study published in the May 2005 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD).

The combined treatment regimen is considered the best available treatment for adults with chronic hepatitis C, but until now, no published studies have examined its value of for children. To address this lack of information, researchers, led by Stefan Wirth of HELIOS Children's Hospital Wuppertal, Germany sought to evaluate the efficacy and tolerability of the therapy in infected children based on HCV genotype, liver enzyme tests, and route of disease transmission.

The researchers recruited 62 children ranging in age from 2 to 17 years, of mixed genders and races, all with chronic hepatitis C. Researchers determined their HCV genotype, mode of infection, and liver enzyme levels, then initiated the therapy that included a weekly subcutaneous dose of peginterferon-alfa-2b and a daily oral dose of ribavirin. All 62 completed the therapy according to the study protocol, save one who dropped out after developing an allergic reaction at the injection site.

Twelve months later, 39 of the 61 patients (64 percent) had undetectable levels of HCV RNA. Three of these responders relapsed during the 6-month follow-up period, but 36 (59 percent) remained HCV-free. All of the children with HCV genotype 2 or 3 achieved a persistent sustained viral response, in contrast to the fewer than half of the patients with HCV genotype 1. The study also showed that children who had been infected via needle (for example, from a blood transfusion) responded better to treatment than those who were infected by their mothers at birth. Lastly, the researchers found that patients with normal liver enzyme levels before treatment responded better than those with elevated levels.

Most of the children experienced side effects from the treatment ranging from mild flu-like symptoms to weight loss to leucopenia (a decrease in white blood cell count). One girl developed diabetes mellitus, a rare but permanent side effect associated with interferon. She continued treatment and achieved sustained viral response. All other side effects resolved when the treatment protocol ended.

"The data of this uncontrolled study confirms that treatment with recombinant peginterferon-alfa-2b plus ribavirin in children and adolescents with chronic hepatitis C was well tolerated and yielded an encouraging result with 59 percent sustained viral response," the authors report. While the response rate was not significantly higher compared to studies using non-pegylated interferon-alfa-2b plus ribavirin, "it is particularly remarkable that all patients infected by genotype 2 and 3 showed permanent response."

The authors also emphasized the importance of the high viral response rate of children whose liver enzyme tests were normal before treatment began, which suggests that such children should not be excluded from treatment. The lower response rates among children with genotype 1 and in those who were infected by their mothers implies a need for additional research.

"Further studies with larger numbers of patients have to elucidate whether there is a different response rate in relation to mode of transmission," the authors conclude. Other studies "should focus on treatment duration for genotype 2 and 3 patients and particularly on vertically infected children with genotype 1."

Inhibiting NF kappa B protects against Liver Injury

Fri, 18 Mar 2005 23:06:00 PST

( from http://www.rxpgnews.com ) Liver damage after organ transplantation or hemorrhagic shock is due to a type of injury known as ischemia/reperfusion, occurring when blood flow is temporarily stopped and, upon restoration, leads to massive inflammation and death of liver cells.

Studies have shown that a protein called NF kappa B plays a role in this type of injury, but its precise function is unclear. In a study appearing online on March 17, in advance of the April 1 print edition of the Journal of Clinical Investigation, Christian Trautwein and colleagues from Hannover Medical School interfere with NF kappa B function in liver cells to examine its role in liver injury.

The researchers found that inhibiting NF kappa B protects against liver injury by decreasing expression of inflammatory proteins and may be a therapeutic target in liver disease.

Dual and divergent roles of macrophages during liver injury and repair

Tue, 04 Jan 2005 19:42:00 PST

( from http://www.rxpgnews.com ) Macrophages have been shown to perform both injury-inducing and reparative tasks during inflammation. In the January 3 issue of the Journal of Clinical Investigation, Jeremy Duffield and colleagues from the University of Edinburgh examined macrophage function in the injury and recovery phases of liver fibrosis in mice. They found that macrophages promote scarring during liver injury but enhance the breakdown of fibrotic tissue during recovery. The study is the first to demonstrate that functionally distinct populations of macrophages exists within the same tissue and that they play critical roles in both the injury and recovery phases of inflammatory scarring.

Scott Friedman from Mount Sinai School of Medicine discusses this important finding in an accompanying commentary.