Liver function breath tests for differentiation of steatohepatitis from simple Fatty liver in patients with nonalcoholic Fatty liver disease

J Clin Gastroenterol. 2014 Jan;48(1):59-65. doi: 10.1097/MCG.0000000000000036.

Tribonias G, Margariti E, Tiniakos D, Pectasides D, Papatheodoridis GV.

Abstract

GOALS: We investigated the utility of liver function breath tests [C-Aminopyrine Breath Test (C-ABT), C-Galactose Breath Test (C-GBT)], for the diagnosis of nonalcoholic steatohepatitis (NASH) among nonalcoholic fatty liver disease (NAFLD) patients.

BACKGROUND: Liver biopsy is currently the gold standard for the differentiation between simple fatty liver (NAFL) and NASH in NAFLD patients.

MATERIALS AND METHODS: Thirty-six patients with histologically proven NAFLD (NAFL:16, NASH:20) underwent C-ABT and C-GBT. The results were expressed as the percentage of administered C dose recovered per hour (%dose/h) and as cumulative percentage of administered C dose recovered over time (%cumulative dose). Histologic lesions were scored according to Brunt and Kleiner's classifications.

RESULTS: C-ABT results correlated inversely with activity grade (r=-0.650, P=0.001), NAFLD activity score (r=-0.473, P=0.026), and fibrosisstage (r=-0.719, P=0.001). Compared with NAFL, NASH patients had significantly lower %dose/h and %cumulative dose at 60, 90, and 120 minutes (always P<0.04) by C-ABT. C-ABT %dose/h and %cumulative dose at 120 minutes could predict the presence of NASH (area under the receiver operating characteristic curve: 0.762 and 0.741, respectively). In contrast, there was no significant association between C-GBT results and any patient characteristic.

CONCLUSIONS: In the NAFLD patients, decreased and delayed liver microsomal function, as assessed by C-ABT, is associated with more severe necroinflammation and fibrosis, whereas C-ABT results at 120 minutes may be helpful for the diagnosis of NASH.

PMID: 24335903 [PubMed - in process]

Source

Published Preclinical Study Demonstrates Therapeutic Effect of Galectin Inhibitors in Fatty Liver Disease With Fibrosis

PRESS RELEASE

Dec. 19, 2013, 8:01 a.m. EST

NORCROSS, Ga., Dec 19, 2013 (GLOBE NEWSWIRE via COMTEX) -- Galectin Therapeutics Inc. GALT +4.65% , the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, today announced that new preclinical data show its leading galectin-inhibiting drugs - GR-MD-02 and GM-CT-01 - demonstrate positive therapeutic effects on nonalcoholic steatohepatitis (NASH, or fatty liver disease) with fibrosis. Results were published in an article titled "Therapy of Experimental NASH and Fibrosis with Galectin Inhibitors" in the peer-reviewed, open-access journal PLOS ONE.

In the study, NASH-induced mice were treated with GM-CT-01 and GR-MD-02 at two different points - early fibrosis and later more severe fibrosis. The studies evaluated twice-weekly, dose escalation of once weekly by intravenous administration, as well as evaluated different routes of administration including intravenous, subcutaneous and oral.

Results revealed that treatment with GR-MD-02 significantly improved NASH activity and reduced fibrosis including prevention of accumulation of collagen and/or reduced accumulated collagen in the liver. Similar effects were seen with GM-CT-01 but with approximately four-fold lower potency than GR-MD-02. The data also show reduction in galectin-3 expression and other inflammatory biomarkers. The PLOS ONE article can be found online at http://dx.plos.org/10.1371/journal.pone.0083481

"There are currently no approved treatments for fatty liver disease with fibrosis, a major health problem in the United States. These preclinical findings add to our scientific understanding of the role galectin inhibitors play in the treatment of fatty liver disease," said Peter G. Traber, M.D., Chief Executive Officer, President and Chief Medical Officer, Galectin Therapeutics. "The results support our current Phase 1 clinical trial of GR-MD-02 and our long-term development programs for GM-CT-01 and GR-MD-02."

GM-CT-01 and GR-MD-02 are proprietary molecules that bind to and inhibit galectin proteins, predominantly galectin-3. Six of eight patients have been enrolled and infused in cohort 1 of a blinded Phase 1 clinical trial of GR-MD-02 for patients with NASH with advanced fibrosis. Enrollment continues and no serious adverse events have been reported. The Phase 1 first-in-man study is evaluating the safety, tolerability, pharmacokinetics and exploratory biomarkers for efficacy for single and multiple doses of GR-MD-02 when administered to patients with fatty liver disease with advanced fibrosis. Clinical data from the first cohort is expected early in 2014.

About Fatty Liver Disease with Advanced Fibrosis

Non-alcoholic steatohepatitis (NASH), also known as fatty liver disease, has become a common disease of the liver with the rise in obesity rates, estimated to affect nine to 15 million people, including children, in the U.S. Fatty liver disease is characterized by the presence of fat in the liver along with inflammation and damage in people who drink little or no alcohol. Over time, patients with fatty liver disease can develop fibrosis, or scarring of the liver, and it is estimated that as many as three million individuals will develop cirrhosis, a severe liver disease where liver transplantation is the only current treatment available. Approximately 6,300 liver transplants are done on an annual basis in the U.S. There are no drug therapies approved for the treatment of liver fibrosis.

About Galectin Therapeutics

Galectin Therapeutics GALT +4.65% is developing promising carbohydrate-based therapies for the treatment of fibrotic liver disease and cancer based on the Company's unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at www.galectintherapeutics.com .

Forward Looking Statements

This press release contains, in addition to historical information, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as "may," "estimate," "could," "expect" and others. They are based on our current expectations and are subject to factors and uncertainties which could cause actual results to differ materially from those described in the statements. These statements include those regarding preclinical data and the potential role for GR-MD-02 and GM-CT-01 in the treatment of liver fibrosis and cirrhosis in humans. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others, that our plans, expectations and goals regarding any preclinical data and potential therapeutic uses and benefits of our drugs and any future pre-clinical or clinical studies are subject to factors beyond our control. Future clinical studies may not begin or produce positive results in a timely fashion, if at all, and could prove time consuming and costly. Plans regarding development, approval and marketing of any of our drugs are subject to change at any time based on the changing needs of our company as determined by management and regulatory agencies. Regardless of the results of current or future studies, we may be unsuccessful in developing partnerships with other companies or obtaining capital that would allow us to further develop and/or fund any studies or trials. To date, we have incurred operating losses since our inception, and our ability to successfully develop and market drugs may be impacted by our ability to manage costs and finance our continuing operations. For a discussion of additional factors impacting our business, see our Annual Report on Form 10-K for the year ended December 31, 2012, and our subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements.

Source

Galectin Therapeutics Announces First Patient Dosed in Phase 1 Trial of GR-MD-02, a Potential First-in-Class Treatment for Fatty Liver Disease with Advanced Fibrosis

NORCROSS, Ga., July 24, 2013 /PRNewswire-USNewswire/ -- Galectin Therapeutics (NASDAQ:GALT), the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, announced today that the first patient has been successfully dosed in a Phase 1 clinical trial of GR-MD-02. The first-in-man study will evaluate the safety, tolerability, and exploratory biomarkers for efficacy for single and multiple doses of GR-MD-02 when administered to patients with fatty liver disease with advanced fibrosis.

GR-MD-02 is a complex carbohydrate drug that targets galectin-3, a critical protein in the pathogenesis of fatty liver disease and fibrosis. Galectin proteins play a major role in diseases that involve scaring of organs such as cancer, and inflammatory and fibrotic disorders. The drug binds to galectin proteins and disrupts their function. Preclinical data has shown that GR-MD-02 has robust treatment effects in reversing fibrosis and cirrhosis.

"The successful first patient dosing in the clinical trial of GR-MD-02 is a critical milestone in Galectin's development program. There are currently no treatments for fatty liver disease with advanced fibrosis; this milestone takes us one step closer to bringing a first-in-class treatment to the millions of Americans suffering from this silent epidemic," said Dr. Peter G. Traber, President, Chief Executive Officer, and Chief Medical Officer of Galectin Therapeutics Inc. "We anticipate that enrollment of the first cohort of eight patients in the Phase 1 trial will be complete by late summer with initial safety and tolerability results available following the 70 day study period and analysis of the data."

The Phase 1 multi-center, partially-blinded clinical trial will be conducted in 24 patients with fatty liver disease and advanced fibrosis who will receive four weekly doses of GR-MD-02. The study, which includes a dose escalation design, will be conducted at six US centers with extensive experience in clinical trials in liver disease. This first patient dosing took place at Indiana University under the direction of the Principal Investigator Dr. Naga Chalasani, a world-renowned expert in NASH.

The trial is titled, "A Multi-Center, Partially Blinded, Maximum Tolerated Multiple Dose Escalation, Phase 1 Clinical Trial to Evaluate the Safety of GR-MD-02 in Subjects with Non-Alcoholic Steatohepatitis (NASH) with Advanced Hepatic Fibrosis." Trial design details can be found at http://clinicaltrials.gov/ct2/show/NCT01899859?term=gt-020&rank=1.

An estimated 9 to 15 million Americans, including children, are affected by fatty liver disease. Without an available therapeutic treatment, the only alternative for patients with fatty liver disease is a transplant but there are limited donors available and the procedure is costly.

Recently, Galectin submitted a Fast Track application to the FDA to help expedite its clinical development program of GR-MD-02 in fatty liver disease with advanced fibrosis. FDA grants Fast Track designation to help expedite review and approval of drugs in development that treat serious or life threatening diseases and fill an unmet medical need.

About NASH
NASH has become a common disease of the liver with the rise in obesity rates, affecting 9 to 15 million people, including children, in the United States. NASH is characterized by the presence of fat in the liver along with inflammation and damage in people who drink little or no alcohol. Over time, patients with NASH can develop fibrosis, or scarring of the liver, and it is estimated that as many as 3,000,000 will develop cirrhosis, a severe liver disease where transplantation is the only current treatment available. Approximately 6,300 liver transplants are done on an annual basis in the United States.

About Galectin Therapeutics Inc.
Galectin Therapeutics (NASDAQ: GALT) is developing promising carbohydrate-based therapies for the treatment of fibrotic liver disease and cancer based on the Company's unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at www.galectintherapeutics.com. Follow us on Twitter @GalectinGALT.

Forward Looking Statements
This press release contains, in addition to historical information, statements that look forward in time or that express management's beliefs, expectations or hopes. Such statements are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as "may," "estimate," "could," "expect" and others. They are based on our current expectations and are subject to risks and uncertainties that could cause actual results to differ materially from those described in the statements. These statements include those regarding our plans, expectations and goals regarding the clinical trial, our Fast Track submission and the potential benefits of a Fast Track designation, and our estimates regarding those impacted by NASH. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others, that our plans, expectations and goals regarding the clinical trial are subject to factors beyond our control. Our clinical trial may not produce positive results in a timely fashion, if at all, and any necessary changes during the course of the trial could prove time consuming and costly. Also, receipt of a Fast Track designation from the FDA is beyond our control and the FDA may not approve our application. In regard to our clinical trial, we may have difficulty in enrolling candidates for testing, which would impact our estimates regarding timing, and we may not be able to achieve the desired results. Upon receipt of FDA approval, we may face competition with other drugs and treatments that are currently approved or those that are currently in development, which could have an adverse impact on our ability to achieve revenues from this proposed indication. Plans regarding development, approval and marketing of any of our drugs, including GR-MD-02, are subject to change at any time based on the changing needs of our company as determined by management and regulatory agencies. To date, we have incurred operating losses since our inception, and our ability to successfully develop and market drugs may be impacted by our ability to manage costs and finance our continuing operations. For a discussion of additional factors impacting our business, see our Annual Report on Form 10-K for the year ended December 31, 2012, and our subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements.

SOURCE Galectin Therapeutics

Source

Many Livers 'Too Fat' For Transplant

By Kristina Fiore, Staff Writer, MedPage Today

Published: May 24, 2012

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

SAN DIEGO -- Increases in factors associated with fatty liver disease may be leading clinicians to discard more donated organs, researcher found.

In an analysis of data from the United Organ Sharing Network (UNOS), age, obesity, diabetes, and hypertension were associated with an increased risk of a liver being discarded, Eric Orman, MD, of the University of North Carolina at Chapel Hill, and colleagues reported during a press briefing at Digestive Disease Week here.

"We're actually throwing out livers that in the past may have been able to be used ... [because] of all these factors associated with fatty liver disease," Orman explained.

Orman said that over the past few years, there's been a decline in the number of liver transplants done, but that drop isn't explained by flat donation rates alone.

"Although donation rates have decreased overall, they haven't decreased to the same extent as the decline in the number of livers transplanted," he said, adding that one explanation may be an increase in discard rates due to poor quality of organs.

So he and colleagues conducted a retrospective study of data from UNOS between 1994 and 2010 totaling 93,232 organ donors. Living donors, split livers, and donors with a body mass index of less than 14 or more than 50 kg/m were excluded.

Among the nearly 94,000 donors, 75% of livers were transplanted and a quarter of livers were not used.

They found that the number of discarded organs was stable until 2003 (with a total of 1,058 organs discarded in that last year), and then rose to 1,828 by 2010.

In a bivariate analysis, they found that discarded livers more often came from donors who were older (median 49 versus 43 years), obese (35% verses 22% of non-obese donors), diabetic (35% versus 24% of nondiabetics), and hypertensive (31% versus 22% of normotensive patients).

Discard rates were also higher in donation after cardiac death, which is different from standard procurement. In the latter, a patient is declared brain dead but kept on a ventilator to keep the organs perfused (65% versus 22%). In donation after cardiac death, perfusion of blood to the organs is disrupted.

In multivariate analysis, the researchers found that all of the previous factors were associated with a liver being discarded:

• Age (OR 1.03 for each year increase, 95% CI 1.03­ to 1.04)
• Obesity (OR 1.92, 95% CI 1.82 to ­2.03)
• Diabetes (OR 1.42, 95% CI 1.32 to ­1.53)
• Hypertension (OR 1.15, 95% CI 1.08­ to 1.22)
• Donation after cardiac death (OR 12.3, 95% CI 11.3 to ­13.4)

The researchers also saw significant increases in median donor age (40 to 46) and the prevalence of obesity (13% to 31%) during the study period, along with significant increases in diabetes (3% to 13%), hypertension (22% to 39%), and donation after cardiac death (2% to 12%).

They estimated that in 2010, 44% of discards were due to increased age, 9% to obesity, 5% to diabetes, and 5% to hypertension. These proportions were stable over time, they said.

On the other hand, the proportion of livers discarded due to donation after cardiac death rose from 0.2% in 2000 to 26% in 2010, suggesting an increasing reluctance to use these grafts, they reported.

Orman said that, overall, the findings are important "because if these trends continue, we're going to see further declines in liver transplant."

Kenneth Andreoni, MD, a UNOS committee member, said the increasing prevalence of comorbidities in donors is a "double-edged sword" because it reflects the fact that public health messages about safety are getting through to younger people, even though that may mean fewer quality donors.

"We're seeing fewer young people dying in traumas, but we're getting less high-quality, excellent organs," Andreoni told MedPage Today. "The question is, how can we make the best use of more middle-age and older donors?"

When it comes to organs with fatty liver disease, some researchers have been trying to better quantify the type of fat in the liver so that surgeons can have a better idea of what's usable and what's not, said Andreoni, who is from Ohio State University in Columbus.

Improvements on the pathology side may also be needed, he said. For instance, pathologists may need to offer a more specific range in terms of the percentage of fat in the organ, so clinicians can more easily recognize if an organ needs to be discarded or not.

Other work has focused on whether there are better ways to protect a fatty liver so it has a better chance of working after it's transplanted. "Is there something you can put in during reperfusion, like an antioxidant, that will lead to better outcomes?" Andreoni said.

A co-author reported a relationship with Salix Pharmaceuticals.

Primary source: Digestive Disease Week
Source reference:
Orman ES, et al "The number of grafts available for liver transplantation is decreasing as a result of increasing age, metabolic syndrome, and donation after cardiac death" DDW 2012; Abstract 841.

Source

Increased fructose consumption may deplete cellular energy in patients with obesity and diabetes

Public release date: 2-May-2012

Contact: Mary Jane Gore
mary.gore@duke.edu
919-660-1309
Duke University Medical Center

DURHAM, N.C. -- Obese people who consume increased amounts of fructose, a type of sugar that is found in particular in soft drinks and fruit juices, are at risk for nonalcoholic fatty liver disease (NFALD) and more its more severe forms, fatty inflammation and scarring.

Now researchers at Duke University Medical Center believe they better understand what mechanism may account for fructose-related liver injury.

Chronic fructose consumption in a diet puts people at risk for depleting their store of critically important molecules called ATP, which provide liver cells (and other body cells) energy for important cellular processes, including metabolism.

"The stores of liver ATP are decreased in obese and/or diabetic individuals who chronically consume increased amounts of fructose-containing beverages," said lead author Manal Abdelmalek, M.D., MPH, Associate Professor of Gastroenterology & Hepatology at Duke.

The study was published online at the Hepatology journal site on May 2.

Nonalcoholic fatty liver disease is currently the leading cause of chronic liver disease in the United States. This condition can lead to elevated liver enzymes, inflammation and rarely even advanced scarring (cirrhosis) in individuals who do not drink alcohol. In obesity and/or diabetes, the ability of the cells to optimally make ATP may already be impaired.

Unlike other simple sugars, fructose requires ATP for its metabolism. The inability to optimally generate cellular energy as well and the continued consumption of ATP from chronic fructose ingestion can result in the liver's depletion of energy. ATP depletion may increase risk for inflammation and scarring in the liver.

"The state of being insulin resistant impairs the ability of a vital enzyme, AMP kinase, to make new ATP molecules," Abdelmalek explained. "Increased fructose consumption, and excess utilization of ATP favors the increase in molecules that lead to increased fatty acid synthesis as well as increased uric acid."

The researchers also noted that more uric acid is produced in the body when excess fructose is consumed. Too much uric acid is associated with conditions that include gout, high blood pressure, cardiovascular disease, type 2 diabetes, metabolic syndrome and uric acid stones, a form of kidney stones.

The silver lining is that measuring the amount of uric acid in these individuals may help doctors predict the presence and monitor the severity of nonalcoholic fatty liver disease, Abdelmalek said.

Research Abdelmalek published in the Journal of Hepatology in 2008 showed that, within a small subset of patients, fructose-containing beverages were associated with NAFLD compared to patients with comparable weight, age, and gender. Her 2010 research, published in Hepatology, went further and linked fructose with the liver injury and scarring (fibrosis).

The current study evaluated adults enrolled in the NIH-sponsored Look Ahead Fatty Liver Disease Ancillary Study headed by senior author Jeanne M.Clark, M.D., MPH, at Johns Hopkins University. The researchers analyzed dietary questionnaires collected in patients who underwent a magnetic resonance imaging to measure liver fat as well as an intravenous fructose challenge to evaluate the liver's ATP stores and response to ATP depletion.

Patients enrolled in the Look Ahead study had been counseled on lower dietary sugar consumption for the management of diabetes. Despite the overall lower levels of fructose use in this study population, the researchers found evidence of liver ATP depletion in those who consumed more fructose.

"The fact we found a difference in liver ATP stores at lower levels of dietary fructose intake does suggest that higher fructose consumption (as would occur with the consumption of processed food and sweetened beverages) could deplete the liver of energy and thus risk causing worse metabolic problems and potentially even liver injury," Abdelmalek said. In the past 30 years, Abdelmalek and authors wrote, fructose consumption has more than doubled.

###

Other authors include Dr. Anna Mae Diehl, chief of the Duke Division of Gastroenterology and Hepatology in the Department of Medicine; Mariana Lazo, Alana Horska, Susanne Bonekamp and Jeanne M. Clark, Departments of Epidemiology, Russel H. Morgan Department of Radiology and Radiological Science and Medicine, at Johns Hopkins University, Baltimore; Division of Metabolism, Edward W. Lipkin, Endocrinology & Nutrition, University of Washington, Seattle; Ashok Balasubramanyam, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, Houston; John P. Bantle, Division of Endocrinology & Diabetes. University of Minnesota, Minneapolis; and Richard J. Johnson, Division of Nephrology, University of Colorado, Denver.

The study was supported by NIH/NIDDK grants and the Johns Hopkins University School of Medicine General Clinical Research Center, plus a NIH/NIDDK Career Development Award.

Source

Fibrosis and fatty liver disease increase risk of early atherosclerosis

Public release date: 24-Apr-2012

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell 

Italian researchers report that severe fibrosis increases the early atherosclerosis risk in patients with genotype 1 chronic hepatitis C virus (HCV) infection. A second study found that fatty liver disease also increases risk of developing atherosclerosis at an earlier period. Both studies appear in the May issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

In the first study, researchers led by Dr. Salvatore Petta from the Di.Bi.M.I.S. University of Palermo in Italy evaluated 174 patients with chronic HCV (genotype 1) along with 174 controls from an outpatient cardiology unit for signs of atherosclerosis. Ultrasonography was used to measure thickening of the carotid artery. Severity of fibrosis was determined for all HCV patients.

The team found carotid plaques in 42% of HCV patients compared to 23% of patients in the control group. Older age and severe liver fibrosis were independently associated with the presence of carotid plaque according to the authors. In patients 55 years or younger who had less sever fibrosis (stage F0-F2) only 22% had plaques in their artery compared to 52% with more sever fibrosis (stage F3-F4). Patients older the 55 years of age had similar prevalence of carotid lesions for those with or without severe fibrosis at 58% and 51% respectively.

"Our findings suggest that severe liver fibrosis places chronic HCV patients at higher risk of early atherosclerosis," said Dr. Petta. "This patient group should be carefully monitored to prevent progression of cardiovascular disease that is independent of their metabolic profile." The authors also caution that a majority of the European study participants were overweight, which should be considered in applying results to other patient populations.

A second study by Dr. Michaela Kozakova and colleagues from the University of Pisa further explored whether the association between fatty liver disease and early atherosclerosis is a consequence of shared conventional risk factors or is it determined by a specific circulating factor originating from liver or adipose tissue. For this purpose the researches investigated the association between the presence of early carotid plaques and the fatty liver index (FLI), which is an established surrogate marker for fatty liver disease based on body mass index (BMI), waist circumference, triglycerides and gamma glutamyltransferase (GGT), in subjects who were part of the multicenter European RISC (Relationship between Insulin Sensitivity and Cardiovascular risk) study group. For the present study, a subgroup of 1.012 RISC subjects who were free of hypertension, diabetes, cardiovascular diseases, chronic hepatic, inflammatory and neoplastic diseases, abnormal lipid levels, and metabolic syndrome were included.

In such a healthy population, only about 5% of subjects had small carotid plaques, and these subjects were older, had a FLI of 60 or more, and had higher blood pressure, LDL cholesterol, glucose, GGT and C-reactive protein than participants without plaques. In logistic regression model, after adjustment for conventional cardiovascular risk factors, family history, liver transaminase and alcohol consumption, the independent predictors of plaque presence were age, FLI of 60 or more and smoking habit. However, when FLI in the model was replaced by variables used in its equation the predictors of early atherosclerosis were age, GGT and smoking.

"Our cross-sectional study indicates that GGT may represent a link between fatty liver disease and development of early atherosclerosis," concludes Dr. Kozakova. On the basis of these results the authors suggest the GGT levels in the blood could be used as a biomarker of atherosclerosis.

###

Full Citations:Carotid Atherosclerosis and Chronic Hepatitis C: A Prospective Study of Risk Associations." Salvatore Petta, Daniele Torres, Giovanni Fazio, Calogero Cammà, Daniela Cabibi, Vito Di Marco, Anna Licata, Giulio Marchesini, Alessandra Mazzola,Gaspare Parrinello, Salvatore Novo, Giuseppe Licata and Antonio Craxì. Hepatology; April 4, 2012 (DOI: 10.1002/hep.25508); Print Issue Date: May 2012. http://onlinelibrary.wiley.com/doi/10.1002/hep.25508/abstract.

"Fatty Liver Index, Gamma-glutamyltransferase and Early Carotid Plaques." Michaela Kozakova, Carlo Palombo, Marco Paterni Eng, Jacqueline Dekker, Allan Flyvbjerg, Asimina Mitrakou, Amalia Gastaldelli, Ele Ferrannini and the RISC Investigators. Hepatology; Published Online: April 19, 2012 (DOI: 10.1002/hep.25555); Print Issue Date: May 2012. http://onlinelibrary.wiley.com/doi/10.1002/hep.25555/abstract.

Author Contact: Media representative at the University of Pisa is Dr. Roberta Filidei who can be reached at R.Filidei@adm.unipi.it. or 804-827-0890 begin_of_the_skype_highlighting 804-827-0890 end_of_the_skype_highlighting. Contacts at the University Hospital are Dr. Del Mauro and Dr. Zanotto who can be reached at ufficio.stampa@ao-pisa.toscana.it.

These studies are published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Hepatology's current impact factor is 10.885.Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350.

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com or our new online platform, Wiley Online Library (http://www.wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

Source

U of I study: Soy protein alleviates symptoms of fatty liver disease

Public release date: 22-Apr-2012

Contact: Phyllis Picklesimer
p-pickle@illinois.edu
217-244-2827
University of Illinois College of Agricultural, Consumer and Environmental Sciences

URBANA – University of Illinois scientists report that soy protein may significantly reduce fat accumulation and triglycerides in the livers of obese persons. And they've discovered why it happens: soy restores partial function of that organ's key signaling pathway.

"Almost a third of American adults have fatty liver disease, many of them without symptoms. Obesity is a key risk factor for this condition, which can lead to liver failure," said Hong Chen, a U of I assistant professor of food science and human nutrition.

Fat is metabolized in the liver, and in obese persons, the transport of fat to adipose tissue can slow down to the point that the liver becomes a dumping ground for excess fat, she said.

"When fat accumulates in an organ that's not supposed to store fat—like the liver, that organ's vital function can be dangerously compromised," she noted.

Adding soy protein, in such sources as tofu and soy yogurt, appears to alleviate some of the stress on fatty livers, she said.

Chen's study compared fat accumulation in the livers of lean and obese rats, which were assigned to either a diet containing casein, a milk-based protein, or a diet containing soy protein isolate, for 17 weeks after weaning. The researchers found that diet had no effect on the liver profiles of lean animals.

But obese rats fed soy showed a 20 percent reduction in triglycerides and overall fat accumulation in the liver, leading Chen to believe that soy protein could be used to alleviate the symptoms of fatty liver disease.

Further, the scientists discovered that soy protein isolate partially restored the Wnt/β-catenin signaling pathway, a crucial player in fat metabolism.

"In many obese persons, there's a sort of traffic problem, and when more fat can make its way out of the liver, there is less pressure on that organ," she said.

The scientists verified the involvement of this pathway by doing in vitro cell culture studies.

Graduate student Dan Zhou found the results especially interesting because of their practical implications. "It's exciting to think that adding soy protein to their diets might help people who have fatty liver disease," she said.

###

The research will be presented at April's Experimental Biology meeting. Co-authors are Dan Zhou and Huan Wang of the U of I and Jeremy Davis and William Banz of Southern Illinois University. The study was funded by the Illinois Soybean Association and Solae, Inc.

Source

EASL 2012: Gut Microbiota Transplantation may Prevent Development of Diabetes and Fatty Liver Disease

PRESS RELEASE

April 19, 2012, 5:00 a.m. EDT

BARCELONA, Spain, April 19, 2012 /PRNewswire via COMTEX/ -- Exciting new data presented today at the International Liver Congress™ 2012 shows the gut microbiota's causal role in the development of diabetes and non-alcoholic fatty liver disease (NAFLD), independent of obesity[1]. Though an early stage animal model, the French study highlights the possibility of preventing diabetes and NAFLD with gut microbiota transplantation - the engrafting of new microbiota, usually through administering faecal material from a healthy donor into the colon of a diseased recipient.[2]

To view the Multimedia News Release, please click:

http://multivu.prnewswire.com/mnr/prne/easl/53808/

In the 16 week study, two groups of germ free mice received gut microbiota transplants; one set from donor mice displaying symptoms of insulin resistance and liver steatosis (responders), the other from normal mice (non responders). The donor mice were selected due to their response to being fed a high fat diet.

The germ free group that received microbiota from symptomatic mice (responder receivers - RR) showed higher levels of fat concentration in the liver as well as being insulin resistant. The germ free group that received microbiota from healthy mice (non-responder-receivers - NRR) maintained normal glucose levels and sensitivity to insulin.

EASL Scientific Committee Member Dr Frank Lammert said: "The factors leading to Non-Alcoholic Fatty Liver Disease (NAFLD) are poorly understood, but it is known that NAFLD and Type 2 diabetes are characterised, respectively, by liver inflammation and metabolic disorders like insulin resistance."

"This study shows that different microbiota cause different metabolic responses in animals. By implanting microbiota from healthy mice, the study authors prevented the development of liver inflammation and insulin resistance, both indications of liver disease and diabetes. Thus, gut microbiota transplants could have a therapeutic role in the development of these diseases."

The RR mice also showed lower levels of microorganisms than usually found in the healthy gut. Lachnospiraceae was identified as the species most important in developing fatty liver and insulin resistance.

At present, the intestinal microbiota is considered to constitute a "microbial organ": one that has pivotal roles in the body's metabolism as well as immune function. Therefore transplantation aims to restore gut functionality and re-establish a certain state of intestinal flora.

Notes to Editors

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL's main focus on education and research is delivered through numerous events and initiatives, including:

The International Liver Congress™ which is the main scientific and professional event in hepatology worldwide

Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year

Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology

Journal of Hepatology published monthly

Participation in a number of policy initiatives at European level

iLiver iPhone app - a free medical app developed by EASL, with content fully authored, validated and accredited by 42 independent liver specialists

About The International Liver Congress™ 2012

The International Liver Congress™ 2012, the 47th annual meeting of the European Association for the study of the Liver, is being held at the Centre Convencions Internacional (CCIB) in Barcelona from April 18 - 22, 2012. The congress annually attracts over 8,300 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

References

1. Le Roy T et al. Gut microbiota transplantation demonstrates its causal role in the development of type 2 diabetes and fatty liver. Abstract presented at the International Liver Congress™ 2012

2. Khoruts A and Sadowsky MJ, Therapeutic transplantation of the distal gut microbiota. Mucosal Immunology 2011;4:4-7

For further information on the studies, or to request an interview, please do not hesitate to contact the EASL Press Office on: Email: easlpressoffice@cohnwolfe.com  Travis Taylor +44(0)7894-386-422 Vicky O'Connor +44(0)7894-386-428

Video: http://multivu.prnewswire.com/mnr/prne/easl/53808/

SOURCE European Association for the Study of the Liver

Source

Galectin Therapeutics to Present Promising New Therapeutic Approach for Fatty Liver Disease at Digestive Disease Week 2012

PRESS RELEASE

April 16, 2012, 9:01 a.m. EDT

NEWTON, Mass., Apr 16, 2012 (BUSINESS WIRE) -- Galectin Therapeutics, the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, today announced that it will present at Digestive Disease Week May 19-22, 2012, in San Diego, CA. Peter G Traber, MD, President, CEO and CMO of Galectin, will present "Galectin Inhibition: a Promising New Strategy to Treat NASH and Liver Fibrosis" at the Product Theater on May 21, 2012, at 2 pm PT. Dr. Traber will discuss the role of galectins in the pathogenesis of non-alcoholic steatohepatitis (NASH), also known as fatty liver disease, and how the Company's galectin inhibitor compounds have been efficacious in preclinical models of disease. The broad effect of galectin inhibitors in preclinical models on all parameters of NASH liver injury, including fat deposition, liver cell death, inflammation and fibrosis makes this class of compounds particularly attractive drug candidates. In addition, Galectin Therapeutics will host Booth #3424 in Exhibit Hall E.

"We believe that our preclinical results suggest that galectin inhibition may be a robust and novel therapy for NASH and liver fibrosis, conditions for which there are no currently approved therapies," said Dr. Traber. "Presentation of our preclinical results at DDW provides exposure to the world's largest gathering of physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery."

About NASH NASH is a common disease of the liver, affecting 9 to 15 million people in the United States and is characterized by the presence of fat in the liver along with inflammation and damage in people who drink little or no alcohol. Over time, patients with NASH can develop fibrosis, or scarring of the liver, that can lead to cirrhosis, a severe liver disease where transplantation is the only current treatment available. Galectin Therapeutics is developing drug candidates as an alternative to transplantation and lead candidates have reversed fibrosis in preclinical disease models.

About Galectin Therapeutics Galectin Therapeutics is developing promising carbohydrate-based therapies for the treatment of fibrotic liver disease and cancer based on the Company's unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at www.galectintherapeutics.com .

Forward Looking Statements This press release contains, in addition to historical information, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as "may," "estimate," "could," "expect" and others. They are based on our current expectations and are subject to factors and uncertainties which could cause actual results to differ materially from those described in the statements. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others: incurrence of operating losses since our inception, uncertainty as to adequate financing of our operations, extensive and costly regulatory oversight that could restrict or prevent product commercialization, inability to achieve commercial product acceptance, inability to protect our intellectual property, dependence on strategic partnerships, product competition, and others stated in risk factors contained in our SEC filings. We cannot assure that we have identified all risks or that others may emerge which we do not anticipate. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements.

SOURCE: Galectin Therapeutics

Source

What can I do for a fatty liver?

By Howard LeWine, M.D., Tribune Media Services The Medicine Cabinet

March 28, 2012

Q: A recent blood test revealed abnormally high liver enzymes. My doctor says I have fatty liver disease. I've started eating artichokes (after reading these were good for your liver), as well as cutting back on my food intake. I'm also eating lots of vegetables and beans, and plan to exercise more and drink less alcohol. Do you think these measures might help?

A: Yes, you're off to a great start

Having a fatty liver means that an excess of triglycerides (one type of fat) have accumulated inside liver cells. This condition is also known as steatosis. When the fat causes the liver to be inflamed, liver enzymes are released into the blood. Doctors call this steatohepatitis.

The primary causes of fatty liver are weight gain, overuse of alcohol, diabetes, and insulin resistance. Insulin resistance means that the body has become less responsive to rising blood sugar levels. To compensate, the pancreas has to make more insulin and send it into the blood stream. Higher blood levels of insulin slow down the normal turnover of triglycerides in liver cells, so they build up.

Most often, people with fatty livers don't have any symptoms. Like you, many people are diagnosed when a blood test shows elevated liver enzymes. Or a doctor detects an enlarged liver during a physical exam. Sometimes, a large fatty liver is seen on an ultrasound or CT scan of the abdomen when the test is ordered for some other reason.

Untreated steatohepatitis can progress to cirrhosis of the liver -- a serious condition where the liver becomes unable to do its job of cleaning toxins out of the bloodstream.

Eating healthier and decreasing alcohol use should help. But in my mind, it's not enough. I recommend complete abstinence from alcohol and cutting calories to lose weight.

Exercise is a must. You can start slow, but you do want to progress to a minimum of 30 minutes of dedicated aerobic exercise daily. An hour of moderate intensity exercise most days of the week would be best.

I'm not sure if eating artichokes will help. But they surely won't hurt as long as you don't dip them in butter or mayonnaise.

(Howard LeWine, M.D., is a practicing internist at Brigham and Women's Hospital, Boston, Mass., and Chief Medical Editor of Internet Publishing at Harvard Health Publications, Harvard Medical School.)

(For additional consumer health information, please visit www.health.harvard.edu.)

Source

The Medicine Cabinet-Ask the Harvard Experts: What can I do for a fatty liver?

By Howard LeWine, M.D., Tribune Media Services Premium Health News Service

March 28, 2012

Q: A recent blood test revealed abnormally high liver enzymes. My doctor says I have fatty liver disease. I've started eating artichokes (after reading these were good for your liver), as well as cutting back on my food intake. I'm also eating lots of vegetables and beans, and plan to exercise more and drink less alcohol. Do you think these measures might help?

A: Yes, you're off to a great start.

Having a fatty liver means that an excess of triglycerides (one type of fat) have accumulated inside liver cells. This condition is also known as steatosis. When the fat causes the liver to be inflamed, liver enzymes are released into the blood. Doctors call this steatohepatitis.

The primary causes of fatty liver are weight gain, overuse of alcohol, diabetes, and insulin resistance. Insulin resistance means that the body has become less responsive to rising blood sugar levels. To compensate, the pancreas has to make more insulin and send it into the blood stream. Higher blood levels of insulin slow down the normal turnover of triglycerides in liver cells, so they build up.

Most often, people with fatty livers don't have any symptoms. Like you, many people are diagnosed when a blood test shows elevated liver enzymes. Or a doctor detects an enlarged liver during a physical exam. Sometimes, a large fatty liver is seen on an ultrasound or CT scan of the abdomen when the test is ordered for some other reason.

Untreated steatohepatitis can progress to cirrhosis of the liver -- a serious condition where the liver becomes unable to do its job of cleaning toxins out of the bloodstream.

Eating healthier and decreasing alcohol use should help. But in my mind, it's not enough. I recommend complete abstinence from alcohol and cutting calories to lose weight.

Exercise is a must. You can start slow, but you do want to progress to a minimum of 30 minutes of dedicated aerobic exercise daily. An hour of moderate intensity exercise most days of the week would be best.

I'm not sure if eating artichokes will help. But they surely won't hurt as long as you don't dip them in butter or mayonnaise.

(Howard LeWine, M.D., is a practicing internist at Brigham and Women's Hospital, Boston, Mass., and Chief Medical Editor of Internet Publishing at Harvard Health Publications, Harvard Medical School.)

(For additional consumer health information, please visit www.health.harvard.edu.)

Source

Researchers unravel genetic mechanism of fatty liver disease in obese children

Public release date: 26-Mar-2012

Contact: Karen N. Peart
karen.peart@yale.edu
203-432-1326
Yale University

Obese youths with particular genetic variants may be more prone to fatty liver disease, a leading cause of chronic liver disease in children and adolescents in industrialized countries, according to new findings by Yale School of Medicine researchers.

The study, which focused on three ethnic groups, is published in the March issue of the journal Hepatology.

Led by Nicola Santoro, M.D., associate research scientist in the Department of Pediatrics at Yale School of Medicine, the authors measured the hepatic, or liver, fat content of children using magnetic resonance imaging. The study included 181 Caucasian, 139 African-American and 135 Hispanic children who were, on average, age 13.

"We observed that a common genetic variant known as Patatin-like phospholipase domain containing protein-3 (PNPLA3) working with a regulatory protein called glucokinase (GCKR), was associated with increased triglycerides, very low-density lipoproteins levels, and fatty liver," said Santoro.

Santoro explained that his observations could help unravel the genetic mechanisms that contribute to liver fat metabolism. "This may drive the decisions about future drug targets to treat hypertriglyceridemia and non-alcoholic fatty liver disease," he said.

Childhood obesity is a global health concern. Experts say nonalcoholic fatty liver disease is now the leading cause of chronic liver disease in children and adolescents in industrialized countries.

"Our findings confirm that obese youths with genetic variants in the GCKR and PNPLA3 genes may be more susceptible to fatty liver disease," said Santoro, who is cautious about automatically extending this observation to the overall population.

"Our data refer to a population of obese children and adolescents," he said. "I think that further studies in a larger sample size involving lean subjects and adults may help to further define in more details these associations."

###

Other authors on the study included Clarence K. Zhang, Hongyu Zhao, Andrew J. Pakstis, Grace Kim, Romy Kursawe, Daniel J. Dykas, Allen E. Bale, Cosimo Giannini, Bridget Pierpont, Melissa M. Shaw, Leif Groop, and Sonia Caprio.

The work was also funded, in part, by the Yale Clinical and Translational Science Award grant from the National Center for Research Resources at the National Institutes of Health.

Citation: Hepatology Vol. 55, No. 3 (March 2012)
http://onlinelibrary.wiley.com/doi/10.1002/hep.24806/abstract.

Source

Coffee consumption reduces fibrosis risk in those with fatty liver disease

February 2, 2012

Caffeine consumption has long been associated with decreased risk of liver disease and reduced fibrosis in patients with chronic liver disease. Now, newly published research confirms that coffee caffeine consumption reduces the risk of advanced fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Findings published in the February issue of Hepatology, a journal of the American Association for the Study of Liver Diseases, show that increased coffee intake, specifically among patients with nonalcoholic steatohepatitis (NASH), decreases risk of hepatic fibrosis.

The steady increase in rates of diabetes, obesity, and metabolic syndrome over the past 20 years has given rise to greater prevalence of NAFLD. In fact, experts now believe NAFLD is the leading cause of chronic liver disease in the U.S., surpassing both hepatitis B and C. The majority of patients will have isolated fatty liver which has a very low likelihood of developing progressive liver disease. However, a subset of patients will have NASH, which is characterized by inflammation of the liver, destruction of liver cells, and possibly scarring of the liver. Progression to cirrhosis (advanced scarring of the liver) may occur in about 10-11% of NASH patients over a 15 year period, although this is highly variable.

To enhance understanding of the correlation between coffee consumption and the prevalence and severity of NAFLD, a team led by Dr. Stephen Harrison, Lieutenant Colonel, U.S. Army at Brooke Army Medical Center in Fort Sam Houston, Texas surveyed participants from a previous NAFLD study as well as NASH patients treated at the center's hepatology clinic. The 306 participants were asked about caffeine coffee consumption and categorized into four groups: patients with no sign of fibrosis on ultrasound (control), steatosis, NASH stage 0-1, and NASH stage 2-4.

Researchers found that the average milligrams in total caffeine consumption per day in the control, steatosis, Nash 0-1, and Nash 2-4 groups was 307, 229, 351 and 252; average milligrams of coffee intake per day was 228, 160, 255, and 152, respectively. There was a significant difference in caffeine consumption between patients in the steatosis group compared to those with NASH stage 0-1. Coffee consumption was significantly greater for patients with NASH stage 0-1, with 58% of caffeine intake from regular coffee, than with NASH stage 2-4 patients at only 36% of caffeine consumption from regular coffee.

Multiple analyses showed a negative correlation between coffee consumption and risk of hepatic fibrosis. "Our study is the first to demonstrate a histopatholgic relationship between fatty liver disease and estimated coffee intake," concludes Dr. Harrison. "Patients with NASH may benefit from moderate coffee consumption that decreases risk of advanced fibrosis. Further prospective research should examine the amount of coffee intake on clinical outcomes."

More information: "Association of Coffee and Caffeine Consumption with Fatty Liver Disease, Non-alcoholic Steatohepatitis, and Degree of Hepatic Fibrosis." Jeffrey W Molloy, Christopher J Calcagno, Christopher D Williams, Frances J Jones, Dawn M Torres, Stephen A Harrison. Hepatology; December 22, 2011 (DOI: 10.1002/hep.24731); Print Issue Date: February 2012.

Provided by Wiley (news : web)

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NIH study to test treatment for fatty liver disease in children

For Immediate Release
Wednesday, January 11, 2012

Contact:
Leslie Curtis
Amy F. Reiter
301-496-3583

With the launch of a new clinical trial supported by the National Institutes of Health, researchers are working to determine whether treating children diagnosed with the most severe form of fatty liver disease with a drug called cysteamine will help improve the liver.

The trial, called Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease in Children (CyNCh),will enroll 160 boys and girls ages 8 to 17 with nonalcoholic fatty liver disease (NAFLD). The participants will receive cysteamine or placebo by mouth twice a day for a year. There are no weight cutoffs or percentiles for the children participating in CyNCh. However, more than 90 percent of the children are expected to be overweight or obese. Participants need a baseline biopsy that confirms severe NAFLD to be eligible for the study. Children with poorly managed diabetes, heart disease, and other chronic liver diseases will be excluded.

NAFLD covers a range of severity from simple liver disease without injury, called steatosis, to the more concerning nonalcoholic steatohepatitis, or NASH, which includes fat accumulation, inflammation, and liver injury. Most children with fatty liver disease are overweight and resistant to insulin, a hormone that regulates energy. The only way to distinguish NASH from other forms of fatty liver disease is with a liver biopsy.

"We did not see fatty liver disease in children until recently," said Edward Doo, M.D., NASH Clinical Research Network project scientist and director of the Liver Diseases Program at NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is funding the study in collaboration with Raptor Pharmaceutical of Novato, Calif., which makes the drug and will provide it to the trial. "Fatty liver disease affects about 17 percent of children in the United States. This rise in the number of children with NAFLD most likely mirrors the increase in obesity, which affects more than 16 percent of American children and teens," Dr. Doo said.

Results from a small pilot study using cysteamine in 11 children with NASH suggest that it improves liver enzymes by reducing toxins that can damage the liver. Cysteamine is approved to treat cystinosis, a genetic disease that causes the amino acid cystine to accumulate in the kidneys, liver, eyes, brain, and white blood cells. Modest weight loss through diet and physical activity may help some children with fatty liver disease, but it is a treatment option that seldom helps people meet their goals. "We know that following a weight loss plan for many children and adults can be daunting, especially if they have limited access to healthy food options that are low in fat, added sugars, and calories, and infrequent opportunities for physical activity," said Joel E. Lavine, M.D., Ph.D., a CyNCh principal investigator and professor of pediatrics at Columbia University, New York City. "Hopefully, this trial will move us closer to finding a safe and effective treatment that helps children with fatty liver disease."

NAFLD can be a precursor to NASH, which may progress to cirrhosis, liver failure and liver cancer. NAFLD may also increase a patient’s risk of developing heart disease. A healthy liver helps the body remove harmful chemicals from the blood, fight infection and digest food. If too much scar tissue forms, the liver could fail. Then a liver transplant is required. "We are concerned that the disease may advance as children become adults and increase their risk for cirrhosis, liver failure, liver transplantation, and death as adults," said Stephen P. James, M.D., director of the NIDDK’s Digestive Diseases and Nutrition Division. "This multicenter, double-blind trial offers researchers and NIDDK an opportunity to rigorously assess how safe and effective cysteamine is in treating children with NASH, as well as to reveal new avenues worthy of scientific study."

The following clinical centers are conducting the CyNCh trial:

• Children's Memorial Hospital, Chicago
• Cincinnati Children’s Hospital Medical Center
• Columbia University, New York City
• Indiana University, Indianapolis
• Mount Sinai Medical Center, New York City
• St. Louis University
• Texas Children's Hospital, Houston
• University of California, San Diego
• University of California, San Francisco
• University of Washington, Seattle

For more information:

• NIDDK's NASH Clinical Research Network: https://jhuccs1.us/nash/open/centers/centers.htm
• NIDDK's Action Plan for Liver Disease Research: www.liverplan.niddk.nih.gov
• National Digestive Diseases Information Clearinghouse: http://digestive.niddk.nih.gov
• Weight-control Information Network: www.win.niddk.nih.gov
• ClinicalTrials.gov: www.clinicaltrials.gov

The NIDDK, a component of the NIH, conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe and disabling conditions affecting Americans. For more information about the NIDDK and its programs, see www.niddk.nih.gov. Education programs for diabetes and kidney disease offer information and resources for patients and health professionals.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Source

Us Fda Clears Investigational New Drug (Ind) Application & Phase 2b Trial for Immuron’s Nash/Fatty Liver Therapeutic

· Phase IIb NASH/Fatty Liver trial cleared without FDA raising concern

· Unmet medical need provides large global opportunity

· Immuron’s NASH/Fatty Liver therapeutic derives from the same platform as Travelan®

Melbourne, Australia, 10 January 2012: Australian biopharmaceutical company Immuron Limited (ASX: IMC), manufacturer of Travelan®, today announced that the United States Food and Drug Administration (US FDA) had cleared an Investigational New Drug (IND) submission to commence a Phase 2b clinical trial of its bovine colostrum-derived therapeutic (IMM-124E) for the treatment of Non-Alcoholic Steatohepatitis (NASH) and Fatty Liver.

The trial has been designed as a double-blind, placebo-controlled and dose ranging multi-centre trial with sites in the United States, Australia and Israel. Its principal aims are to determine the safety and efficacy of Immuron’s orally administered IMM-124E in patients with biopsy- confirmed NASH.

As previously announced Dr Arun J Sanyal, Professor of Medicine at Virginia Commonwealth University, has been appointed global principal investigator for the upcoming clinical trial.

Immuron’s Chief Executive Officer Joe Baini said: “This is a major milestone for Immuron with global significance for an unmet and rapidly growing disease. The FDA has cleared Immuron’s IND submission, without raising any concerns.”

“Based on the encouraging results generated to date, IMM-124E could be the first available and approved treatment for NASH patients in the world and the only product candidate to date that addresses the pathogenesis of the disease. From a commercial perspective it represents an extremely lucrative opportunity for Immuron. We are very excited to commence the trial, which is pending financing."

The potential NASH market is estimated to be a multi-billion dollar market and there are no effective treatments.

NASH (non-alcoholic steatohepatitis) is one of the most common liver diseases in the western world. It is associated with obesity, diabetes and hyperlipidaemia. It affects approximately 5% of the lean population, 20% of the obese population and 50% of morbidly obese people. It resembles alcoholic liver disease but occurs in people who drink little or no alcohol. The major feature in NASH is fat in the liver (hence another of its names ‘Non-alcoholic Fatty Liver Disease’ along with inflammation and damage. NASH can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to function properly.

Contact

Joe Baini – Chief Executive Officer Rudi Michelson

+61 3 8637 1107 Monsoon Communications

+ 61 3 9620 3333

+ 61 411 402 737

About Immuron Limited

Immuron is a biopharmaceutical company focused on oral immunotherapy treatments using dairy-derived antibody products for humans. Immuron is uniquely positioned with a versatile technology platform capable of generating a wide range of products with a high safety profile. This high safety profile makes it possible to complete pre-clinical studies relatively quickly and increases the prospect that the clinical development of Immuron’s products will be expedited. Immuron’s current products and product candidates target infectious diseases of the gastrointestinal tract, chronic diseases such as fatty liver (NASH), and the prevention of influenza. Immuron has one product in the market, Travelan, for preventing travellers’ diarrhoea. Immuron’s main scientific alliances are with Hadassah Medical Center (Israel), the University of Melbourne and Monash University (Australia).

Monsoon Communications
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Melbourne VIC 3000
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Fatty livers are in overdrive

Public release date: 6-Dec-2011

Contact: Elisabeth (Lisa) Lyons
elyons@cell.com
617-386-2121
Cell Press

When our livers become loaded with fat, it isn't because they are slacking. A new study of human patients in the December Cell Metabolism shows that fatty livers actually burn more fat, not less. All that "hard work" may be at the root of the organ damage that comes with nonalcoholic fatty liver disease (NAFLD), a condition associated with insulin resistance that affects about one in three in the U.S. population.

The findings represent a paradigm shift in the connection between metabolism and fatty liver disease, as it was previously thought that fatty livers burned less fat.

"Our overwhelming goal is to try to understand what happens in those with fatty liver," says Jeffrey Browning of the University of Texas Southwestern Medical Center. "By understanding what leads to the onset and progression of the disease, we hope we can come up with therapies that actually work."

Most studies of people with insulin resistance have focused on the more accessible skeletal muscle. Those studies show that the mitochondria that power skeletal muscle cells work at a slower pace in the context of metabolic syndrome, including insulin resistance and fatty liver. Browning and his colleague Shawn Burgess weren't so sure that muscle could tell you much about what might be happening in other organs, including the liver.

"Unless skeletal muscle is working, it doesn't have much of an energy requirement," Browning explained. "The liver is always working." The liver breaks down fat and makes glucose and ketone bodies that fuel the rest of our bodies, including our hearts and our brains.

In the new study, the researchers used a special method that allowed them to trace metabolic inputs and outputs in the human liver in people with low and high levels of triglyceride fats in their livers. Those studies show that people with fatty livers are breaking down lipids 50 percent faster and producing glucose 30 percent faster in comparison to those with healthy livers.

That increased demand on the liver suggests a link between fatty liver, oxidative stress, and liver damage. Browning says that means therapies including antioxidants like vitamin E might help protect the liver.

The researchers now hope to explore how metabolism shifts over the course of the disease. One day the tracer technique they have developed might even help to identify those patients at the greatest risk of progressing to the point of liver transplantation.

"A third of the population has fatty liver, and it is difficult to look at them and tell anything without a liver biopsy," Browning says. The trouble is all those biopsies would simply overwhelm the health care system.

Perhaps most important, the findings show that researchers need to rethink what insulin resistance means for the functioning of mitochondria throughout the body. "Skeletal muscle is very different from the liver," he says.

Source

Fatty liver disease associated with cardiovascular risk in patients with HIV

Michael Carter
Published: 24 January 2011

Hardening of the arteries is common in HIV-positive patients, and is associated with fatty liver disease, US investigators report in the online edition of HIV Medicine.

“HIV-infected persons with fatty liver disease may warrant early cardiovascular assessment and institution of risk reduction methods,” comment the researchers.

Cardiovascular disease is an increasingly important cause of illness and death in patients with HIV. Studies conducted in HIV-negative individuals have shown that the presence of a fatty liver is associated with hardening of the coronary artery (atherosclerosis), an important risk factor for heart disease.

A team of investigators lead by Dr Nancy Crum-Cianflone wished to see if this was also the case for HIV-infected individuals.

They write: “Given that liver test abnormalities and fatty liver disease are common in among HIV infected persons, determining their relationship with coronary artery atherosclerosis may be helpful in the development of screening guidelines and risk stratification for underlying cardiovascular risk in this population.”

Between 2008 and 2010 they undertook a cross sectional study involving 223 HIV-positive adults. All the patients had a CT scan which checked for hardening, or calcification, of the coronary artery and fatty liver disease.

Atherosclerosis in the coronary artery was diagnosed if any calcification was detected (a score above 0), and a score above 100 was considered clinicially significant. Fatty liver was defined as a liver-to-spleen ratio < 0.1.

Information was also gathered on the patients’ demographics, CD4 cell count and viral load, use of antiretroviral drugs, lipid levels, and medical histories. A series of statistical analyses were then performed to see which factors were associated with hardening of the coronary artery.

With a median age of 43 years (range 36-50), the patients were relatively young. Risk factors for cardiovascular disease were common, and 39% had hypertension and 6% diabetes. Fatty liver can be a complication of viral hepatitis, but only 3% of the study population were co-infected with hepatitis C.

Most patients (83%) were taking antiretroviral therapy, 70% had an undetectable viral load and median CD4 cell count was 586 cells/mm3.

CT scanning showed that 34% of individuals had some hardening of the coronary artery, and that this was clinically significant for 8% of patients. Fatty liver was diagnosed in 13% of individuals.

Prevalence of fatty liver for patients with no evidence of hardening of the coronary artery was 8%. But this increased to 18% for individuals with a calcification score between 1-100, and was 41% for patients with clinically significant arterial hardening.

Overall, 59% of patients with fatty liver also had coronary atherosclerosis, and the correlation between the two conditions was significant (p = 0.02).

Statistical analysis that controlled for potentially confounding factors showed that three factors were significantly associated with calcification of the coronary artery: older age (each ten year increase, p < 0.01); fatty liver disease (p < 0.01), and hypertension (p < 0.01).

The relationship between hardening of the coronary artery and fatty liver disease was extremely robust, and was unaltered when the investigators excluded the small number of patients with hepatitis C, or those with metabolic syndrome. It was also present when patients with alcohol use were excluded from analysis.

“In our study, HIV-infected persons, despite their relatively young age, had a high prevalence of subclinical heart disease,” write the authors. They believe rheir results “emphasize the importance of cardiovascular disease among HIV-infected patients and suggest that addressing underlying heart disease may be an important component of further normalizing the life expectancy of this group.”

Inflammation could, the authors believe, be causing both the hardening of the arteries and the fatty liver disease observed in their patients.

Dr Crum-Cianflone and her colleagues conclude: “Fatty liver disease is associated with underlying cardiovascular disease and should be considered as a novel marker for risk stratification among HIV-infected persons.”

Reference

Crum-Cianflone N et al. Fatty liver disease is associated with underlying cardiovascular disease in HIV-infected persons. HIV Med, online edition (DOI: 10.1111/j.1468-1293.2010.00904.x), 2011 (click here for the free abstract).

Source

Liver Disease a Possible Predictor of Stroke

ScienceDaily (Jan. 7, 2011) — People suffering from fatty liver disease may be three times more likely to suffer a stroke than individuals without fatty liver, according to a study by researchers at St. Michael's Hospital and the London Health Sciences Centre. The study is the first to find a link between nonalcoholic fatty liver disease -- a disease characterized by the accumulation of fat in the liver in non drinkers -- and stroke.

In a research letter to the editor in the journal Epidemiology released January 6, Drs. Joel Ray, Ivan Ying and colleagues explain they found high levels of enzymes known to be markers of liver disease in adults who had an acute stroke. Between 2005 and 2009, they reviewed 103 consecutive adults who had an MRI-proven acute stroke between 2005 and 2009 and compared them to 200 adults with suspected acute stroke, but whose MRI was normal, thereby ruling out acute stroke.

"The risk of stroke in relation to fatty liver disease has never been tested," Dr. Ray says. "Our study shows a strong link between the two and the possibility in future that currently available blood liver enzyme tests, or novel markers of fatty liver, may be used to predict the risk of stroke and help us better care for and treat at risk patients."

Nonalcoholic fatty liver disease is a common condition that often has no symptoms or complications. Risk factors include obesity, high cholesterol, diabetes and, especially, insulin resistance.

While the findings are promising, additional research is needed to validate the study's findings, Dr. Ray said.

Source

Fatty Liver Disease Soars in U.S.

January 7, 2011

There's a fair amount of guesswork to the estimates, but perhaps as many as 20% of American adults have some degree of fatty liver disease, a condition that used to occur almost exclusively in people who drink excessively. The epidemics of obesity and diabetes are to blame. Fatty liver affects between 70% and 90% of people with those conditions, so as obesity and diabetes have become more common, so has fatty liver disease.

Fatty liver disease isn't confined to any one group, and there don't seem to be pronounced gender differences, but studies suggest that Latinos are disproportionately affected. It's primarily a condition of middle age, although children may get it, too. Fatty liver disease is rapidly becoming more common in Asia, and some research suggests that men in India may be especially susceptible.

Plumped-up liver cells

The prevailing theory is that the condition gets started because of insulin resistance, which is, in turn, frequently a consequence of obesity and excess fat tissue in the abdomen. When people are insulin resistant, their muscle, fat, and liver cells don't respond normally to insulin, so levels of the hormone — and the blood sugar it ushers into cells — build up in the blood. As a result, the risk of developing diabetes and heart disease increases. But insulin resistance is a complicated metabolic state that also includes an increase in the amount of free fatty acids circulating in the blood.

Fatty liver disease occurs when some of those fat molecules accumulate inside liver cells. The presence of those fattened cells can then lead to inflammation in the liver and damage to surrounding liver tissue. Once that happens, if excess alcohol is not involved, the condition is called nonalcoholic steatohepatitis (steato- for fat and –hepatitis because the liver is inflamed). Fortunately, that unwieldy name boils down to a handier acronym, NASH. Estimates vary quite a bit, but it seems that 5% to 10% of people with fatty liver disease go on to develop NASH.

NASH is often a relatively stable, low-grade condition that people live with for years, with few if any symptoms. But it can also start a cascade of serious damage to the liver and attempts by the organ to regenerate itself that culminate in an abundance of scar tissue and impaired liver function — a condition called cirrhosis. Cirrhosis is irreversible and can lead to total failure of the liver. It also is associated with an increased risk for developing liver cancer.

Some studies have shown as few as 3% of people with NASH developing cirrhosis, while others have shown as many as 26% doing so. There's no test or risk factor that predicts who will develop cirrhosis and who won't, although one study did find that people who are older or whose initial liver biopsies showed more inflammation were at greater risk. It's clear, though, that the prognosis for NASH is far better than it is for steatohepatitis that's the result of heavy alcohol consumption. Perhaps as many as half of all those with alcoholic steatohepatitis (which lacks a handy acronym) go on to develop cirrhosis.

It's just a theory at this point, but people with fatty liver disease and NASH may need to be more worried about heart disease and stroke than about serious liver problems. An article published in The New England Journal of Medicine in late 2009 argued that the inflammatory and other factors pumped out by a fat-afflicted liver promote the atherosclerotic process that damages the insides of arteries and makes blood more likely to clot, a combination that can lead to heart attack or stroke. The evidence the authors cited is intriguing, if circumstantial. They pointed to a study showing that people with NASH are twice as likely to die from heart attack or stroke as people without it. And NASH seems to add to the risks that come with excess weight. Overweight men with NASH have higher levels of C-reactive protein, an inflammatory factor, and fibrinogen, a clotting factor, than overweight men without NASH. Moreover, the levels of those and other factors go up as NASH gets more severe.

Diagnosis requires a biopsy

Most people with fatty liver disease don't have symptoms, and that's true even if it has developed into NASH. Only occasionally do people feel run-down, or they have an achy feeling in the upper right side of the abdomen, where the liver is located. So, more often than not, fatty liver disease and NASH are discovered incidentally, starting with higher than normal levels of liver enzymes on a routine blood test. Ultrasound imaging, the same technology used to get pictures of developing fetuses, can be informative: the liver looks bright because the fat shows up as white on the image. But neither an ultrasound nor a CT or MRI scan is completely reliable for making a diagnosis. The fat in the liver is visible, but not the NASH-related inflammation. Some researchers have developed formulas that use a simple blood test and measurements of various hormones, inflammatory factors, and liver enzymes to arrive at a diagnosis, but this work is at a preliminary stage.

Currently, a liver biopsy is the only way to make a definitive diagnosis of fatty liver or NASH. Liver biopsies involve inserting a long needle into the right side of the abdomen and extracting a small piece of liver tissue that can be examined under a microscope. Liver biopsies are an invasive procedure, so they aren't entirely free of risk and complications, but they're also fairly routine these days and can be done on an outpatient basis.

Whether a doctor will order a biopsy to nail down a diagnosis depends on many factors, including whether the person is obese or has diabetes or shows other signs of liver trouble.

Weight loss is the treatment

There's been a fair amount of research into using diabetes drugs to treat NASH, even in people who don't have diabetes. Rosiglitazone (sold as Avandia) and pioglitazone (sold as Actos) have been the leading candidates because they reduce insulin resistance, the root cause of fatty livers. They're not looking so promising these days. The FDA has moved to sharply curtail the use of Avandia because it seems to cause heart problems. The results of an important trial published in 2010 in The New England Journal of Medicine showed Actos to be no better than a placebo in improving NASH in people without diabetes.

Another diabetes drug, metformin (Glucophage), might prove to be an effective treatment, but there isn't enough evidence yet. Vitamin E is a possibility: the same trial that showed Actos wasn't effective showed some improvement in the livers of people who took large doses (800 IU daily) of the vitamin. But many doctors are wary about prescribing large doses of vitamin E because they've been associated with an increased risk of bleeding. Besides, the improvements in the liver were limited. Fish oil has produced some favorable results, and clinical trials are under way, but it can't be endorsed yet.

These setbacks and uncertainties have left weight loss (ideally from changes in diet and an increase in physical activity) as the only recommended treatment for most cases of fatty liver disease and NASH. In many cases, weight loss seems to have a very direct effect: as people lose weight, the fatty liver becomes less fatty. Crash dieting is a bad idea, though, because rapid weight loss (losing 4 pounds a week or more) can wind up damaging the liver. Of course, if sustained weight loss were easy, a lot of today's health problems would be solved, not just fatty liver disease and NASH.

In addition to encouraging people to lose weight, doctors will often advise people with diabetes who have fatty liver disease or NASH to be vigilant about controlling their blood sugar.

The bottom line Many parts of the body come to grief once people become obese or develop diabetes. It's not surprising that our livers do too, given how central they are to a whole suite of metabolic processes. There's some evidence that a fatty liver may add to the already high risk of heart disease among people who are obese or have diabetes. Fatty livers can also develop into cirrhotic ones if the inflammatory processes take off.

But there are two bright spots in the take-home message about fatty livers. First, most cases stay relatively stable and don't result in serious liver disease. Second, the treatment is not an expensive drug with side effects, but losing weight — and that will benefit many other parts of the body besides the liver.

Source: Harvard Univ.
 
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The Fatty Liver Dilemna

By Carolyn Salazar
Published November 20, 2010
Fox News Latino

Hispanics children and adolescents are genetically predisposed to developing fatty liver disease, which could trigger cirrhosis, cardiovascular problems and diabetes, two recent studies show.

The study found that Hispanic children who carry a gene variant have increased liver fat and are susceptible to developing liver fat when they have a diet high in sugar, according to the studied published in the journals Diabetes and the American Journal of Clinical Nutrition.

Fatty liver is a disease mostly seen among those who consume excessive alcohol or are obese and can lead to a form of hepatitis. It is a major cause of illness and death in the United States.

Previous reports have shown Hispanics are particularly susceptible to accumulation of fat in the liver, and reports suggest that nearly four of 10 obese Hispanic children have nonalcoholic fatty liver disease.

“Collectively these findings demonstrate that Hispanics are genetically susceptible to the negative health effects of high sugar consumption, and that this effect is manifested early in life,” said Michael I. Goran, director of the University of Southern California’s Childhood Obesity Research Center at the Keck School of Medicine. “This is a major public health concern, especially in the face of massive marketing of sugary beverages to children.”

The researchers studied more than 300 Hispanic youth – ages 8-18 – in the Los Angeles. It found that carriers have almost double the amount of liver fat content as non-carriers.

The effects are strongest among Hispanics because the variant is higher (49 percent) than in whites (23 percent) or African Americans (17 percent), said Jaimie Davis, assistant professor of preventive medicine at the Keck School of Medicine, and a lead author on the studies.

The findings suggest that obese Hispanic children with the variant have an increased capacity for fat storage and a smaller breakdown of stored fats among those whose diets are high in sugar, she said.

Sugar intake is high among youth in Los Angeles, and accounts for nearly half of all daily carbohydrate intake and 25 percent of energy intake, the study shows.

“Specific dietary interventions based on the genetic predisposition may lead to more effective therapeutic outcomes in children with fatty liver disease,” she said. “I think the studies really highlight the need to test such diet and genotyping interventions.”

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