November 4, 2010

AASLD: Liver Graft Quality Significantly Poorer With Female Vs Male Donors

From Reuters Health Information

By Anne Harding

NEW YORK (Reuters Health) Nov 03 - Gender mismatch between donor and recipient does not promote liver transplant rejection, a new analysis including nearly 25,000 patients confirms. However, female donors tend to be older, heavier and shorter than their male counterparts, lowering the quality of their livers for grafting.

Dr. Jennifer C. Lai of the University of California, San Francisco and her colleagues found that while female-to-male transplants were more likely to be rejected, once they accounted for gender differences in donor quality, the effect of gender mismatch disappeared. "The message really is that donor quality is key," Dr. Lai told Reuters Health. She presented her findings at this week's annual meeting of the American Association for the Study of Liver Diseases in Boston.

Previous research had suggested that donor-recipient gender mismatches might make liver transplant rejection more likely, Dr. Lai explained in an interview. However, she added, the importance of donor quality as measured by factors like the donor's cause of death, age, height and race has only relatively recently been recognized. She pointed to her UCSF colleague Dr. Sandy Feng's 2006 report describing a quantitative donor risk index, which has since been validated by other researchers.

To investigate the influence of gender mismatch on graft rejection risk, Dr. Lai, Dr. Feng and their colleagues looked at 24,544 adults who received liver transplants between 2002 and 2007. The recipient cohort contained 16,633 males (68%) and 7,911 females (32%). The donors consisted of 14,568 males (59%) and 9,976 females (41%).

Thirty-six percent of men and 51% of women received a gender-mismatched graft. The risk of graft loss was 1.11 times greater overall with a gender mismatch. But while giving a male donor graft to a female recipient didn't significantly increase the risk of graft loss, female-male mismatches raised the risk by 18% (P<0.001).

The researchers found "clinically relevant" differences in graft quality between male and female donors on six of the 15 characteristics that they evaluated. For example, the average age for female donors was 47, compared to 39 for men, while females' average height was 165 centimeters compared to 178 centimeters for men. Fifty-six percent of the women died of stroke, compared to 34% of men. And 26% of female donors had BMIs above 30, while 20% of males did. The donor risk index was 1.6 for women and 1.3 for men, a 20% difference that Dr. Lai said was "a huge surprise."

Once the researchers took these factors into account, the increased risk of rejection seen with female-male mismatch disappeared. The most important factors were donor age, with a 12% increased risk of rejection for every additional 10 years, and height, with a 6% reduced risk of rejection with every additional 10 cm of height.

"The conversation kind of is over about donor gender mismatch and donor gender, at least for non-hepatitis C infected patients," Dr. Lai concluded.


Also See: AASLD: Men Make Better Liver Donors

AASLD: More Evidence Coffee May Slow Liver Disease

From Reuters Health Information

By Anne Harding

NEW YORK (Reuters Health) Nov 03 - Drinking coffee could help slow the progression of fibrosis in patients with fatty liver disease, according to new research presented at the American Association for the Study of Liver Diseases' annual meeting in Boston.

And a separate study presented at the same meeting found that patients with chronic hepatitis C who drank the most coffee and had failed standard treatment fared much better with retreatment.

Since the early 1990s, several studies have suggested benefits of coffee drinking for liver health, Dr. Jeffrey W. Molloy and Dr. Stephen A. Harrison and their colleagues at Brooke Army Medical Center in San Antonio, Texas, note in their report. In 2009, Dr. Harrison noted in an interview, two studies showed drinking about 2.5 cups of coffee daily reduced the risk of hepatic steatosis in patients with hepatitis C.

For the current study, the Texas researchers used a group of asymptomatic individuals whom they had initially screened for liver disease with ultrasound, giving them a "nice clean cohort of patients" with no liver disease who served as controls, Dr. Harrison told Reuters Health. Patients with ultrasound tests suggesting fatty liver disease underwent percutaneous liver biopsies.

Their analysis included 177 controls, 89 patients with simple steatosis, 31 patients with nonalcoholic steatohepatitis (NASH) and stage 0-1 fibrosis, and nine patients with NASH and stage 2-4 fibrosis.

Among the NASH patients, the researchers found, those with less severe disease drank significantly more coffee than those with more severe fibrosis. The patients with NASH stage 0-1 fibrosis consumed an average of 413 mg of caffeine and 312 mg of coffee, compared to 189 mg of caffeine (p=0.035) and 79 mg of coffee (p=0.03) for the NASH stage 2-4 fibrosis patients.

The 75th quartile for daily coffee consumption was 343 mg, or about 2.5 cups, the researchers found. Ten percent of patients who consumed this much coffee had NASH stage 2-4 disease, compared to roughly half of the patients who didn't drink coffee at all. Logistic regression analysis showed that the risk of severe fibrosis declined as caffeine and coffee consumption rose (p=0.023 for both).

"There's definitely a relationship, we don't know exactly what it is yet," between coffee and fibrosis, Dr. Harrison said. He called the findings "provocative" and "hypothesis-generating," noting that a prospective interventional study would be needed to determine a causal relationship.

Nevertheless, he and his colleagues conclude, "moderate caffeine and/or coffee consumption may be a benign adjunct to the comprehensive management of NASH patients."

In the second study, Dr. Neal D. Freeman of the National Cancer Institute and his colleagues found that among 885 patients with chronic hepatitis C who failed standard treatment with interferon, those who drank more coffee responded better to retreatment with peg interferon alfa 2a and ribavirin.

The median log10 drop from baseline to week 12 of retreatment was 1.7 among non-coffee drinkers, compared to 3.7 for those who drank three cups or more daily (p for trend across categories < 0.0001).

There also were "highly statistically significant trends" in early virologic response (EVR, defined as a two log10 drop in HCV RNA at week 12), undetectable HCV RNA at week 20 of treatment, and sustained virologic response (SVR, at week 72, 24 weeks after the end of treatment).

For example, 11.3% of non-coffee drinking patients had an SVR, compared to 25.8% of patients who drank at least three cups a day. The EVR rate was 45.7% in non-coffee drinkers and 72.7% in the heaviest coffee drinkers. And among the non-coffee drinkers, 26.3% had undetectable levels of HCV RNA at week 20 of the study, compared to 52.3% of people who drank three or more cups daily (p for trend in all three categories <0.0001).


AASLD 2010/Echosens Continues to Push the Boundaries of Innovation With CAPTM: the First, Non-Invasive Solution for the Measurement of Hepatic Steatosis

Nov 04, 2010 12:22 ET

PARIS, FRANCE--(Marketwire - Nov. 4, 2010) - At the 2010 meeting of the American Association for the Study of Liver Disease (AASLD), which took place in Boston from October 29 to November 2, Echosens, a pioneer and major player in the field of non-invasive hepatic diagnostics, presented its latest research and development focus: the CAP™ (Controlled Attenuation Parameter).

Echosens is innovating and diversifying its research

Echosens, the inventor of the first medical device for measuring liver elasticity (the FibroScan® 502), is pushing innovation even further in 2010 with the development of the CAP™.

In recent years, the prevalence of metabolic illnesses (type 2 diabetes and obesity) has been on the rise in France and elsewhere in the world. These illnesses have given rise to numerous complications including NAFLD (Non Alcoholic Fatty Liver Disease).

CAP™ was developed to enable physicians to detect liver steatosis. With this new application, Echosens meets the needs of health professionals who, in most cases, are unable to diagnose patients suffering from metabolic steatosis. The usual technique for diagnosing this liver disease is hepatic biopsy but hepatic biopsy cannot be used to diagnose at-risk patients who are, more often than not, asymptomatic. Other diagnostic techniques do exist but abdominal ultrasound scans are favoured in clinics for the detection of steatosis. This method has significant limitations: the results are operator- and machine-dependent, it is impossible to quantify the steatosis and steatosis detection is only possible if more than 30% of liver cells are affected, while its pathological threshold is around 5-10%. CAP™ is a new tool for diagnosing liver steatosis and can be an alternative to liver biopsy.

Based on VCTE™ and the measurement of ultrasonic attenuation, CAP™ has been proven provide effective diagnosis of steatosis levels above 10%. To date, its clinical performance has been tested on more than 1,200 patients. On par with the ability of FibroScan® to diagnose fibrosis via elasticity measurements, CAP™ is poised to become the standard in detecting and quantifying steatosis.

Echosens is expanding again - this time in Brazil

Echosens just recently obtained ANVISA approval in Brazil for the FibroScan® 502 and its dedicated S, M and XL probes. Already present in more than 50 countries, Echosens is broadening its international distribution network.

Echosens is meeting the needs of developing countries with its diagnostic and monitoring solution for patients with chronic liver disease. The international figures for the prevalence of hepatitis B and C (400 and 180 million chronic cases, respectively) and for Non-Alcoholic Steatohepatitis (NASH) illustrate the huge potential of these types of investigative methods.

Brazil is the largest medical-device market in South America.

The FibroScan® 402: an addition to the FibroScan® line

This version of FibroScan® meets the need for a lightweight, compact device with a smaller envelope.

The FibroScan® 402 is designed for use in the offices of hepato-gasteroenterology specialists, community hospitals and clinics as well as institutions that do not yet have access such as prisons and specialized health care centres.

The FibroScan® 402 is a tactile device with software that has been completely re-designed. It is used in conjunction with the M probe and has an integrated printer. Naturally, it uses the specific FibroScan® algorithm that has been widely and clinically validated for measuring liver elasticity.

This unique tool makes FibroScan ® so easily-available it can be used in everyday practice.

FibroScan® technology, along with its related latest developments, have been the subject of more than 50 scientific papers.

About Echosens and FibroScan®

FibroScan® is a non invasive method for quantifying liver elasticity when testing for chronic liver diseases such as viral hepatitis B and C.

Founded in 2001, Echosens focuses a large part of its effort on research and development in order to develop new medical devices and open up new medical perspectives. The company works in close collaboration with health professionals and patient associations to facilitate patient care and therapeutic follow-up.

For more information, please contact

Philippe Garabedian
Mobile: +33 6 24 60 47 24
Sophie Baumont
Phone: 01 53 83 81 49


Isentress Might Reduce Risk of a “Fatty” Liver From Protease Inhibitors

November 4, 2010

A new laboratory study suggests that the integrase inhibitor Isentress (raltegravir) could prevent the accumulation of excess fat in the liver (steatosis) that results from protease inhibitor (PI) therapy. These data were presented at the 61st Annual Meeting of the American Association for the Study of Liver Diseases, held October 29 to November 2 in Boston.

Several antiretroviral (ARV) drugs used to treat HIV have been implicated in steatosis. These include older drugs such as Zerit (stavudine) and several drugs from the PI class. While steatosis is not immediately harmful, and is usually reversible, it can ultimately lead to lasting health problems if it is not addressed right away. What’s more, with HIV drugs, steatosis is intricately tied to other blood fat disorders, including increases in trigylcerides and “bad” types of cholesterol and the risk for developing diabetes, as well as accumulation of fat in the gut. Such disorders can significantly increase a person’s risk for developing cardiovascular disease.

Unfortunately, people with HIV who take ARVs must remain on them for life—at least for now—and many don’t have the option to stop taking a PI. This means that steatosis must be addressed. However, researchers are getting close to understanding why these HIV drug–induced disruptions in fat metabolism occur, and there have been some hints that Isentress might actually be able to counteract the accumulation of liver fat from PIs.

To test this theory, Min Liang, PhD, from the Virginia Commonwealth University in Richmond, and her colleagues examined the behavior of liver cells in the presence of the various drugs. Previously, Liang’s team found that PIs can put stress on a type of cell known as the endoplasmic reticulum (ER), which aids in the healthy formation of other types of cells and structures in the liver. ER stress has been shown to contribute to liver steatosis.

Liang and her colleagues proceeded with their studies based on a hunch that Isentress actually protects against ER stress, and their hunch appears to be correct. When PIs were added to liver cells alone, they caused the accumulation of fat in those cells. When Isentress was added to this mix, however, the cells did not take on additional fat.

Further research will be needed to duplicate these results and to document that these effects can be seen in living animals before extrapolating them to humans. Nevertheless, these do offer hope that people who must take a PI may be able to avoid steatosis—and possibly other fat disorders.


CRP Level Predicts Short-Term Mortality Better Than MELD Score in End-Stage Liver Disease: Presented at AASLD

By Cheryl Lathrop

BOSTON -- November 3, 2010 -- In patients with end-stage liver disease (ESLD), the C-reactive protein (CRP) level predicts short-term mortality better than, and independently of, the Model for End-Stage Liver Disease (MELD) score, researchers said here at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

This is important because the determination of patients with the highest risk of mortality is crucial to optimise the allocation of liver grafts, according to Jean-Paul Cervoni, MD, Service d'Hépatologie, CHU Jean Minjoz, Besançon, France, and colleagues.

The occurrence of systemic inflammatory response syndrome (SIRS) was reported to affect the survival of patients with ESLD, but it is not considered by the MELD score. The aim of this study was to improve the prediction of short-term mortality in patients with ESLD by evaluating CRP as a possible surrogate marker of SIRS.

This was a prospective study of 155 consecutive cirrhotic patients with a Child-Pugh score >8, admitted between January 2007 and June 2010. The median age of the patients was 58 years; 86% were male; 83% had alcoholic cirrhosis; 42% had a comorbidity; 29% had SIRS; 15.5% had hepatocellular carcinoma; the median MELD score was 22.5; the median CRP was 26.5 mg/L; and the median procalcitonin was 0.28 ng/mL.

The researchers recorded 170 demographic, clinical, biochemical, and histological variables at admission, and during follow-up on day 15, month 3, and month 6. The primary endpoint was survival at month 3.

The following key events occurred during follow-up (median 2.9 months): 41% got a bacterial infection, 7% had hepatorenal syndrome, 8% had a liver transplant, 26% died at month 3, and 30% died at month 6.

The 3-month survival according to CRP level was as follows: >100 mg/L, 0%; 70 to 100 mg/L, 59%; 40 to 70 mg/L, 64%; 10 to 40 mg/L, 75% and <10 mg/L, 87%.

Variables associated with month 3 mortality were hepatocellular carcinoma, extrahepatic carcinoma, a high MELD score, a high CRP level (>26 mg/L), elevated blood lactate, and renal failure. Variables associated with month 3 mortality were a high CRP level (>26 mg/L), the MELD score, extrahepatic comorbidities, and hepatocellular carcinoma.

Multivariate analysis identified 3 predictors of mortality: extrahepatic comorbidities (P =.021), a high CRP level (P =.013), and MELD score (P =.023). The performance of the 3 variables taken together for predicting death was 0.74 (Area Under the Receiver Operating Characteristic [AUROC]). The performance of the MELD score was 0.61 (AUROC), and the performance of the CRP level alone for the same prediction was 0.66 (AUROC) -- better than the performance of the MELD score.

"This finding suggests that we should build a new MELD-CRP prognosis score," said Dr. Cervoni on November 1.

[Presentation title: CRP Predicts Short-Term Mortality in Patients With End-Stage Liver Disease (ESLD) Independently of MELD Score: A Prospective Study. Abstract 1209]


Increased Risk of Hip, Wrist Fracture in Patients With Cirrhosis: Presented at AASLD

By Cheryl Lathrop

BOSTON -- November 3, 2010 -- Studying a representative population, patients with cirrhosis were found to be at a considerably higher risk for hip and wrist fracture than age- and sex-matched controls in the general population, according to results presented here at the 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD).

Joe West, PhD, Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom, and colleagues reported findings from their study at the poster session here on November 1.

While numerous studies have shown an association between chronic liver disease and osteoporosis, few have accurately documented the risks of osteoporotic fracture in these patients and none have compared incidence rates to the general population.

The researchers undertook a UK population-based study using the General Practice Research Database (GPRD) to quantify the excess fracture risk in people with cirrhosis.

The researchers obtained all records of patients with a diagnostic or therapeutic code for cirrhosis, oesophageal varices, and/or portal hypertension within the GPRD between June 1987 and April 2002, as well as records of up to 10 age-, sex-, and practice-matched controls for each.

A total of 4,787 patients with cirrhosis and 46,789 matched patients without cirrhosis were included in the study.

Patients with cirrhosis had a higher hazard of hip and wrist fracture. Patients with alcoholic cirrhosis had a higher hazard ratio for fracture than those with non-alcoholic cirrhosis (however, this is mediated by the increased risk of fracture in the older control population of non-alcoholic cirrhosis).

The adjusted (age, sex) hazard ratios were as follows:

· Compensated cirrhosis (vs controls): hip 4.0, wrist 1.6
· Decompensated cirrhosis (vs controls): hip 8.4, wrist 2.9
· Alcoholic cirrhosis (vs controls): hip 9.5, wrist 3.0
· Non-alcohol-related cirrhosis (vs controls): hip 3.1, wrist 1.3

"Consideration should be given to interventions in this group to reduce fracture risk," said Dr. West.

[Presentation title: Increased Risk of Hip and Wrist Fracture in Patients With Cirrhosis Compared With the General Population: A Population-Based Cohort Study. Abstract 1180]


Metformin, Vitamin E Do Not Significantly Improve NAFLD in Children

Bob Roehr

November 4, 2010 (Boston, Massachusetts) — The first randomized controlled trial to use histology as a measure for treating nonalcoholic fatty liver disease (NAFLD) in children has found that neither metformin nor vitamin E provide a statistically significant sustained reduction in alanine transaminase (ALT) levels, the primary end point of the study, compared with placebo.

Results of the TONIC study by the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network, presented here at The Liver Meeting 2010: American Association for the Study of Liver Diseases 61st Annual Meeting, by Joel Lavine, MD, from the Department of Gastroenterology, Hepatology, and Nutrition at Columbia University in New York City, "reinforce the PIVENS [trial] findings in adults with NASH."

The rise of childhood obesity has helped make NAFLD the most common cause of chronic liver disease in American children. "NASH-related cirrhosis has been described in children as early as 7 years," and it is also a risk factor for metabolic syndrome, Dr. Lavine said. There is no established pharmacologic treatment for NAFLD or NASH in children, in part because no pediatric study of liver disease has ever used histology as an end point.

The researchers enrolled 173 children 8 to 17 years of age with biopsy-confirmed NAFLD and elevated serum alanine aminotransferase (ALT > 60 U/L). Diabetes, cirrhosis, significant alcohol use, ALT above 400 U/L, and a recent pharmaceutical course of therapy for fatty liver disease were exclusionary factors. Most of the 229 children screened but not enrolled had insufficiently high ALT levels to meet the entry criteria.

Patients were randomized in a 1:1:1 manner to receive 400 IU of the natural form of vitamin E twice a day (58 subjects), 500 mg of metformin in gel capsules twice a day (57 subjects), or placebo (58 subjects) for 96 weeks, with 24 weeks of follow-up to ascertain durability. They also were counseled on diet and lifestyle changes to improve their health.

The primary end point was a sustained reduction in ALT to either below 40 IU/L or below 50% from baseline ALT from weeks 48 to 96. In light of the 2 separate interventions being evaluated in the study, the floor for statistical significance was established as P < .025.

Dr. Lavine said that "ALT [levels] decreased in all 3 groups," primarily because of changes in diet and exercise. The vitamin E group showed an early (week 24) statistically significant sharp decline in ALT levels, "but by the time 96 weeks came around, they all converged, to a decline of about 40 IU/L."

There was a sustained 25.9% reduction in serum ALT levels in the vitamin E group, a 15.8% reduction in the metformin group, and a 17.2% reduction in the placebo group. The decline seen with vitamin E, compared with placebo, was just shy of significance (P = .26); with metformin, the significance was more distant (P = .83).

There were statistically significant improvements in hepatocellular ballooning: 44%, 44%, and 21% in the vitamin E, metformin, and placebo groups, respectively. Improvement was also seen in patients with NASH or borderline NASH at baseline: 58% in the vitamin E group and 28% in the placebo group (P = .006). There was no significant impact on fibrosis or inflammation with either intervention.

"There also was no change in insulin resistance, which was somewhat surprising in light of the fact that metformin is used to treat type 2 diabetes in children," said Dr. Lavine.

Diet and activity questionnaires were administered at baseline and at weeks 48 and 96. Analysis of the way changes in these parameters affected metabolic responses will be published in the future.

One audience member noted the significant improvement on all measures in the placebo group, and wondered if that might not mask some of the contributions of vitamin E and metformin.

Dr. Lavine would not speculate on that. He added: "I think that lifestyle advice works in the context of having frequent follow-up and the amount of attention these children received, and the investment by their families in making considerable changes in terms of the type of foods they were eating and activities they pursued." But such an intense intervention probably is not possible to implement on a broader population basis.

Ronald J. Sokol, MD, from the University of Colorado in Aurora, praised the study for its completeness. He was surprised by the ALT data that showed a convergence of all 3 groups at the end of the study. He wondered if there are follow-on data.

Dr. Lavine responded that "this is not a durable response. ALT will rise again once vitamin E and placebo are discontinued, but it doesn't rise back to its baseline. That is probably because of the adoption and maintenance of lifestyle changes."

The study was totally supported by the National Institutes of Health. Dr. Lavine has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract 110. Presented November 1, 2010.


Also See: AASLD: Vitamin E Resolves NASH in Children