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Impacts Of liver Disease Examined

May 22, 2012

New research being presented at Digestive Disease Week® (DDW) offers key insights into the progression of diseases leading to liver damage, which affect diverse populations, including young people. Studies show that the increasing rates of obesity are putting teens at risk for developing nonalcoholic fatty liver disease and are decreasing the availability of healthy livers for organ donations, which are urgently needed as people continue to experience complications from diseases, such as hepatitis C and drug-induced liver toxicity.

“Liver disease often leads to lifelong problems and serious consequences,” said Donald M. Jensen, MD, professor of medicine, and director, Center for Liver Diseases, University of Chicago Medical Center, IL. “With increasing incidence, it is more important than ever to investigate the causes, prevention and treatment for conditions like nonalcoholic fatty liver diseases and chronic hepatitis C, as well as to identify obstacles to liver transplantation.” DDW is the largest international gathering of physicians and researchers in the field of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

Prevalence of Suspected NAFLD Is Increasing Among U.S. Adolescents (Abstract #705)

Suspected non-alcoholic fatty liver disease (NAFLD) is increasing in teens, affecting approximately 10 percent of the age group, leading to a host of conditions, including liver damage, diabetes, hypertension and cancer. While the common perception has been that there are an increasing number of children identified with NAFLD, previous studies have not demonstrated the rate of that increase nor whether the increase actually exists. Investigators led by Miriam Vos, MD, assistant professor of pediatrics at Emory University and Children’s Healthcare of Atlanta, GA, sought to determine whether rates seem high because people are studying them more closely or whether there really are more cases of teenagers with NAFLD.

Investigators determined that the increase in NAFLD was not defined by the number of overweight children. When comparing the rate of increase in children with fatty liver disease to the rate of increase in overweight children, research showed that the increase in children with fatty liver was much greater than the increase in overweight children. This finding demonstrates that just having overweight kids does not explain the increase in fatty liver. Investigators also looked at cross-sectional data to explain the increase and found a link to increased NAFLD and waist circumference (the measure of the distance around the abdomen half way between the inferior margin in the last rib and the crest of the hip bone).

“We know that if a child is overweight, they are more likely to be overweight as an adult, and we know from national data that teens with fatty liver disease become adults with fatty liver disease, unless they improve their diet and lose a significant amount of weight,” said Dr. Vos. She added that adolescents may have an easier time losing weight compared to adults because they have been overweight for a shorter period of time.

To increase the likelihood of weight loss success, Dr. Vos supports a multi-sector approach, including community programs and school programs that steadily support healthy food and exercise. These types of programs are increasing around the country, but need to be uniformly available so that entire communities and children are not excluded from their benefits. She also recommends instituting these supportive programs while children are young so that their parents can help them develop good habits at an early age. Dr. Vos added that she is hopeful that, in the future, we will have medications for the most severe cases of NAFLD to help complement a healthy regimen. This summer, the National Institutes of Health (NIH)-sponsored NASH Clinical Research Network will start a new clinical trial to research the treatment of fatty liver.

Dr. Vos and colleagues are also studying the connection between diet and fat in the liver and increased cardiovascular risk. Data show that cardiovascular disease is very high in adults with NAFLD, and multiple studies have shown that adolescents with NAFLD have markers that show increased risk for cardiovascular disease.

In this study, investigators reviewed nationally representative data of more than 10,000 12- to 18-year-olds from the National Health and Examination Survey datasets, spanning from 1988 to 2008, excluding subjects with missing data and known liver disease. Suspected NAFLD was defined as overweight/obese (those with a body mass index greater than the 85th percentile) with elevated alanine aminotransferase (ALT) levels greater than 25.8 for boys or 22.1 for girls, and also as overweight/obese with ALT levels greater than 30 to allow for comparison with previous studies. ALT is a blood test that is typically used to detect liver injury.

Funding for this study was provided by the NIH.

Dr. Vos will present these data on Monday, May 21 at 11:15 a.m. PT in Room 2 of the San Diego Convention Center.

Current and Future Disease Progression of HCV-Infected Patients Among Different Age Cohorts (Abstract# Sa1084)

Several hundred thousand Americans with chronic hepatitis C virus infection (HCV) are predicted to develop potentially life-threatening liver complications within the next few years, according to a new study from Vertex Pharmaceuticals. Risk was found to be dramatically higher among baby boomers, a segment of the population that accounts for 82 percent of all Americans with HCV.

To assess the future health needs of HCV patients, researchers evaluated medical insurance claims data to determine how many individuals with HCV already have advanced liver disease and how many more will develop complications in time. Researchers found that more than 200,000 HCV patients were suffering from advanced liver disease in 2008 and a projected 300,000 additional patients – mostly baby boomers – are on track to develop advanced liver disease by 2015. Without treatment, the number of patients with advanced liver disease is expected to triple by 2015.

“This alarming finding places additional stress on an already overburdened health-care system, which will need to prepare for an increase in patients suffering from advanced liver disease,” said Ann Kwong, PhD, vice president and HCV franchise lead at Vertex. “It is critical to treat HCV patients before they develop costly and irreversible liver complications.”

Dr. Kwong recommends that one important course of action is a focus on HCV diagnoses. By screening patients for HCV infection, there is a greater opportunity to identify and potentially cure infection before liver complications occur. Currently approved HCV therapies are most effective in patients without advanced liver disease, so diagnosing the virus earlier offers patients the best chance to be cured.

Researchers stressed that not all patients developing liver complications can be accurately identified with insurance claims data. Individuals with existing liver disease may not be diagnosed and therefore cannot be accounted for in this study. In the future, universal screenings for HCV infection are expected to help diagnose not only more cases of HCV, but also lead to more testing for liver complications.

Up to five million U.S. adults have HCV, and 75 percent of them are unaware of their infection. HCV is commonly called a “silent killer” because it often has no symptoms and can go decades without being detected. Chronic HCV is the leading cause of liver cancer and the most common reason for liver transplantation in the U.S.

This study was funded by Vertex Pharmaceuticals.

Dr. Kwong will present these data on Saturday, May 19 at noon PT in Halls C-G of the San Diego Convention Center.

The Number of Grafts Available for Liver Transplantation is Decreasing as a Result of Increasing Donor Age, Metabolic Syndrome and Donation After Cardiac Death (Abstract #841)

The number of liver transplants has declined in the U.S. since 2006, so investigators led by Eric S. Orman, MD, gastroenterology fellow, the University of North Carolina, Chapel Hill, looked at various donor factors to determine why. By studying the United Network for Organ Sharing (UNOS) database for all donor information, researchers assessed which factors prompted physicians to discard an organ.

With standard donation, a patient is declared brain dead and kept on cardiovascular support so the organs can continue to receive oxygen and blood before being removed for transplant. In recent years, surgeons have also increasingly used the method known as donation after cardiac death, which occurs when patients die and the heart stops on its own. Cardiac death donation is considered an alternative way to donate organs and has been promoted as a way to increase the total number of organ donors. An increasingly large percentage of organ donors are in the donation after cardiac death category; less than 10 years ago, it was fewer than 2 percent, but currently, the rate has increased to more than 12 percent.

However, there is a widespread pattern of health-care professionals becoming increasingly reluctant to use organs donated after cardiac death. In reviewing the UNOS database, researchers found that the total number of donors who have at least one organ recovered for transplant has stopped increasing over the past few years, despite an increasing proportion of donation after cardiac death donors.

Investigators looked at the group of organ donors who had at least one organ recovered for transplant to determine whether the donor liver was a fatty liver. By reviewing donor characteristics that are strongly associated with having a fatty liver, such as diabetes, obesity, older age and high blood pressure, researchers found that these factors were all associated with discarding a liver. “Cardiac death donation is negatively impacting the overall number of liver transplants that we can do,” said Dr. Orman.

The next step of the research is to look more closely at why more livers are being discarded, how large of a role donation after cardiac death is playing in those organs discarded, and what is driving the increase in donation after cardiac death.

No pharmaceutical funding was provided for this study.

Dr. Orman will present these data on Monday, May 21 at 4 p.m. PT in Halls C-G of the San Diego Convention Center.

Patterns of Usage of Acetaminophen in Excess of Four Grams Daily in a Hospitalized Population at a Tertiary Care Center (Abstract #743)

Hospitalized patients who receive multiple orders of medication containing acetaminophen are likely to receive a higher than intended dose of the drug, even when provided by physicians, according to new research from Thomas Jefferson University Hospital, Philadelphia, PA.

Reviewing 46,000 hospital admissions over a two-year period, investigators led by Jesse Civan, MD, GI fellow, division of gastroenterology, Thomas Jefferson University Hospital, found that about 1,100 individuals received more than 4 grams of acetaminophen on at least one day. In other words, about 2.5 percent of all patients admitted to the hospital received more than what is currently considered the safe cumulative daily dose on at least one calendar day.

Investigators sought to determine exactly how much acetaminophen was being dispensed in a large tertiary-care hospital and how it compared to the generally accepted safe maximum dose. They reviewed a computer database tracking every patient admitted to their hospital and every dose of medicine prescribed and received. This allowed them to calculate exactly how much medication patients were exposed to, including any medication containing acetaminophen, such as Tylenol®, Percocet® and other similar medicines, and to generate a list of all patients who received more than 4 grams of acetaminophen on at least one calendar day.

Researchers also reviewed liver function and injury, which are reported in the same database, to determine potential detrimental effects of acetaminophen use on patients. By reviewing a specific blood test – the alanine amino-transferase (ALT) test, which is generally used to screen for liver injury possibly related to acetaminophen – Dr. Civan and his colleagues found that only a small minority of patients were administered an ALT test. They attribute this finding to the fact that the blood test is only usually checked when a physician is particularly concerned about a possible liver problem.

In the small minority of patients who did have an ALT checked, there was insufficient data to do a “formal cause analysis” to determine whether an abnormal ALT could be blamed on the acetaminophen exposure. Because of the paucity of ALT monitoring, no conclusion could be reached about whether the acetaminophen exposure might have had any detectable detrimental consequences.

Dr. Civan added that these findings could have implications on public health and the need to improve patient education regarding safe dosages at home, since many patients will likely attempt to emulate the medications provided at the hospital once they get home. He concluded that further study in this closely monitored population in which every dose of acetaminophen-containing medication administered is recorded might shed light on the ongoing discussion at the U.S. Food and Drug Administration and elsewhere regarding new recommendations for maximum safe daily dosing. Dr Civan stressed that although it remains unclear whether blood test abnormalities may have resulted from acetaminophen use, he did not find any evidence of any cases of serious liver injury.

Acetaminophen has been under increasing scrutiny in the U.S. – it is the leading cause of acute liver failure and emergent liver transplant, and previous studies have suggested that unintentional overdose is a significant problem. There has also been debate in the medical literature about whether a less severe form of acetaminophen-induced liver injury due to unintentional overdose may be important.

This study received no pharmaceutical funding.

Dr. Civan will present these data on Monday, May 21 at 2:15 p.m. in 6e, San Diego Convention Center.

Herbal and Dietary Supplement Hepatoxicity in the U.S.A. (Abstract #167)

Dietary supplements used for body building and weight loss are the most common of any supplements to cause liver injury, according to new research from the U.S. Drug Induced Liver Injury Network (DILIN). Dietary supplements include herbal remedies, bodybuilding supplements, health food supplements, or anything that people can buy over the counter or online that is not prescribed by a physician.

Liver injury from medication is the main reason why drugs are taken off the market. While estimates suggest that herbal/dietary supplement products are used by up to 40 percent of the U.S. population, their side effects, including potential toxicity, is not well defined. Researchers led by Victor J. Navarro, MD, an investigator funded by the National Institutes of Health-sponsored DILIN, and professor of medicine, pharmacology and experimental therapeutics, Thomas Jefferson University, Philadelphia, PA, sought to explore liver injury from herbal/dietary supplements by examining the types of products taken, and the severity and outcomes associated with liver injury due to them.

Investigators looked at 109 cases of patients in the DILIN who appeared to have liver damage due to dietary supplements; most were male, white and overweight. They found that the supplements most likely to be the cause of liver injury were those reported for body building and for weight loss.

“There is so little regulation of the many products on the market; we couldn’t possibly begin to figure out which products to target first without doing this research,” said Dr. Navarro. He added that now that they know that bodybuilding and weight loss supplements are the most common causes of dietary supplement-induced injury among the products, they can focus their efforts accordingly.

Investigators are also looking at targeted components of herbal/dietary supplements. For example, previous studies have shown that green tea extract, which can be added to herbal/dietary supplements in high concentrations in pill form, can potentially cause damage to the liver. So DILIN investigators have also sought to determine how common the ingredients of green tea are in dietary supplements when the manufacturer has not identified it as such.

They hypothesized that green tea extract is prevalent in many products but is not specifically identified – in fact, their research has shown that it is present in up to 40 percent of products in which it was not listed on the label. For this reason, investigators will always have difficulty linking liver injuries to green tea extract unless they do a careful analysis of each product.

Dr. Navarro cautioned that because it is not well known how common liver injury is due to dietary supplements, it is difficult to suggest how likely it is that someone would suffer liver damage, but that this is another area where investigators are looking to do more research.

Investigators now have many more cases to study and their next step is to understand how the supplements cause injury and why. They are working with the Food and Drug Administration to identify various contaminants and determine which of the products on the market are the most harmful, especially since herbal/dietary supplement are not tightly regulated. They are also studying possible factors that may predispose a consumer of herbal/dietary supplement to liver injury, such as genetic makeup.

Dr. Navarro will present the DILIN’s research data on Saturday, May 19 at 2:15 p.m. PT in Halls C-G of the San Diego Convention Center.

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