FDA NEWS RELEASE
For Immediate Release: June 21, 2010
Media Inquiries: Shelly Burgess, 301-796-4651, shelly.burgess@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
Test advances ability to detect HIV infection earlier
The U.S. Food and Drug Administration today approved the first assay to detect both antigen and antibodies to Human Immunodeficiency Virus (HIV). This assay is approved for use as an aid in the diagnosis of HIV-1/HIV-2 infection in adults including pregnant women. It is also the first assay for use as an aid in the diagnosis of HIV-1/HIV-2 infection in children as young as two years old.
The highly sensitive assay is intended to be used as an aid in the diagnosis of HIV-1/HIV-2 infection, including acute or primary HIV-1 infection. Since it actually detects the HIV-1 virus (specifically the p24 antigen) in addition to antibodies to HIV, the ARCHITECT HIV Ag/Ab Combo assay can be used to diagnose HIV infection prior to the emergence of antibodies. Most tests used today in the diagnostic setting detect HIV antibodies only. Although direct detection of the virus itself by nucleic acid testing is available, it is not widely used in diagnostic settings.
HIV is the virus that can lead to acquired immune deficiency syndrome, or AIDS. HIV damages a person’s body by destroying specific blood cells, called CD4+ T cells, which are crucial to helping the body fight diseases. Two types of HIV have been identified: HIV-1 and HIV-2. HIV-1 is responsible for most HIV infections throughout the world. HIV-2 is found primarily in West Africa; however, cases of HIV-2 infection have been reported in North America and Europe.
The Centers for Disease Control and Prevention report that approximately 18 million people in the United States are tested for HIV each year. Most recent CDC estimates are that there are about 56,000 new HIV infections in the United States each year. In addition, there are more than 1 million people living with HIV in the United States, according to CDC.
“The approval of this assay represents an advancement in our ability to better diagnose HIV infection in diagnostic settings where nucleic acid testing to detect the virus itself is not routinely used,” said Karen Midthun, M.D., acting director of FDA’s Center for Biologics Evaluation and Research. “It provides for more sensitive detection of recent HIV infections compared with antibody tests alone.”
The ARCHITECT HIV Ag/Ab Combo assay is not intended to be used for routine screening of blood donors. However, it is approved as a donor screening assay for HIV-1/HIV-2 infection in urgent situations where licensed blood donor screening tests are unavailable or their use is impractical.
The ARCHITECT HIV Ag/Ab Combo assay will be used in clinical laboratories and in public health laboratories, and is the first assay approved in the United States to detect HIV antigen and antibodies simultaneously.
The ARCHITECT HIV Ag/Ab Combo assay is manufactured by Abbott Laboratories, Abbott Park, Illinois.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm216375.htm
June 22, 2010
Liver at Risk in Diabetes
By Crystal Phend, Senior Staff Writer, MedPage Today
Published: June 21, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Although the liver is often overlooked in diabetes, even newly-diagnosed cases carry a substantial risk of serious hepatic damage, researchers found.
In a population-based study, newly-diagnosed diabetes was associated with a near doubling in the rate of liver cirrhosis, liver failure, or liver transplant compared with people in the general population who did not have diabetes, according to Gillian Booth, MD, MSc, of St. Michael's Hospital in Toronto, and colleagues.
After adjusting for important contributors to liver disease, the association remained significant with a 77% increased risk for newly-diagnosed diabetes patients (95% confidence interval 68% to 86%), they reported online in CMAJ.Action Points
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Note that the retrospective study could not determine whether diabetes caused the liver disease seen during follow-up.
Note that diabetes guidelines do not recommend screening for liver disease.
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"The negative impact of diabetes on the retinal, renal, nervous, and cardiovascular systems is well recognized, yet little is known about its effect on the liver," they wrote.
Although much still remains to be discovered about the mechanisms and cause of the link between diabetes and liver disease, nonalcoholic steatohepatitis (NASH) is almost certainly involved, according to Kenneth Cusi, MD, who has been studying this condition at the University of Texas Health Science Center in San Antonio.
Steatosis is known to arise in relationship to insulin resistance in obesity, and most people with the condition do have some degree of glucose abnormality, he explained in an interview.
The two seem to "feed on each other," Cusi said.
Unlike with eye disease, cardiovascular disease, and kidney disease, guidelines for diabetes care don't recommend screening for liver disease.
"However, when the liver fails," Booth's group cautioned in the paper, "there is no equivalent form of management, such as hemodialysis or retinal photocoagulation."
They suggested that liver disease "may be appropriate for addition to the list of target-organ conditions related to diabetes," with annual screening by means of a blood test, such as for the liver enzyme alanine aminotransferase.
But the sensitivity of blood tests and even ultrasound aren't great for identifying fatty liver disease that is the precursor to more serious liver problems and liver biopsy is not a feasible screening method, Cusi noted.
Also, it would first have to be shown that preventive measures such as weight loss and glycemic and lipid control are effective in diabetes, as they are in isolated fatty liver without diabetes, the researchers said.
To expand evidence for the link, the researchers retrospectively examined the administrative databases of the universal healthcare system in the province of Ontario from 1994 through 2006.
They compared 438,069 adults with newly diagnosed diabetes and an age-, sex-, and regionally-matched control group of 2,059,708 individuals without known diabetes. Preexisting liver or alcohol-related disease were cause for exclusion.
During a median of 6.4 years of follow-up, serious liver disease -- liver cirrhosis, liver failure, or liver transplant -- developed in 2,463 newly-diagnosed diabetes cases and 5,902 controls.
Thus, unadjusted liver disease incidence was 92% higher with diabetes (8.19 per 10,000 person-years with diabetes and 4.17 without it).
This difference remained significant across mutually-adjusted patient subgroups by age, gender, urban versus rural residence, and income level.
Diabetes appeared to have the most pronounced link with liver cirrhosis (adjusted hazard ratio 2.55, 95% CI 2.35 to 2.76) and the least with liver transplantation (adjusted HR 1.31, 95% CI 1.05 to 1.64).
Hypertension and obesity didn't appear to entirely account for the relationship with diabetes. The risk of serious liver disease in nondiabetic individuals with preexisting hypertension or obesity was elevated but less so than among those with diabetes.
But the researchers cautioned that it is difficult to separate out the effects of these related conditions.
"Although our findings and those of the U.S. study [which found elevated chronic NASH risk in veterans with diabetes] edge forward the idea that diabetes may be harmful to the liver, the question remains of whether this effect extends beyond the metabolic syndrome," they wrote.
Another question that remains to be answered is causality.
Booth's group pointed out that hepatic fat content rises in parallel with insulin resistance and glucose dysregulation and that diabetes as a complication of cirrhosis typically doesn't arise until cirrhosis reaches an advanced stage.
However, they noted, they couldn't rule out the pre-existence of subclinical liver disease before study entry.
The study was funded by the Banting and Best Diabetes Centre at the University of Toronto and by the Institute for Clinical Evaluative Sciences, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care
The researchers reported no conflicts of interest.
Cusi reported support from the American Diabetes Association and the Boris Welcome Fund and an award from the VA. Takeda provided the study drug for research he is doing in NASH but no personal renumeration to Cusi.
Primary source: CMAJ
Source reference:
Porepa L, et al "Newly diagnosed diabetes mellitus as a risk factor for serious liver disease" CMAJ 2010
Thought rare, virus strikes twice in S.A.
By Don Finley - Express-News
Web Posted: 06/22/2010 12:00 CDT
Two local cases — one of them fatal — of a form of hepatitis once thought to be rare in the United States have captured the attention of state and local health officials.
Hepatitis E, a viral infection of the liver, was long considered a problem mainly in developing countries — and to a handful of Americans who traveled there — spread by contaminated food and water.
While the infection clears up on its own in most people, it causes severe illness in some and can be fatal in pregnant women.
Large outbreaks of hepatitis E have taken place in Mexico, Asia and Africa.
The Metropolitan Health District was notified late last year that three people in one San Antonio hospital had tested positive for the infection between September and November 2009. A more sophisticated test later found one of the three was not infected.
Of the two others, one was a 21-year-old woman who died while undergoing a liver transplant. An earlier home pregnancy test had been positive, but she wasn't pregnant when admitted to the hospital, health officials said. The other patient, a 44-year-old nurse's aide, had also suffered some liver damage.
“We couldn't figure out how they acquired it,” said Roger Sanchez, senior epidemiologist with Metro Health, who presented a paper on the cases at a public health meeting in Austin recently. “None of them had any (foreign) travel history. They were previously healthy. Which begs the question — how did they get it?”
But some American researchers who study hepatitis E are finding it more common in the U.S. than previously thought. In fact, the infection seems to be everywhere. What remains a mystery is why some people get sick from the virus but most don't.
“It appears to be a relatively common infection. But clinical symptoms following infection appear to be quite rare,” said Mark Kuniholm, an instructor of epidemiology and population health at the Albert Einstein College of Medicine in New York.
In a study published last July in the Journal of Infectious Diseases, Kuniholm and colleagues tested 18,695 blood samples that had been collected across the country through the National Health and Nutrition Examination Survey, which is conducted every few years by the federal government. He found one in every five people had antibodies to hepatitis E, suggesting a previous infection.
Setting aside those born in another country, the highest infection rates were in Anglo men living in the Midwest. Those who ate liver more than once a month were more likely to have antibodies.
Hepatitis E is commonly found in U.S. pigs, with one study showing 63 percent of commercially raised swine carried antibodies to the virus and 35 percent had signs of active infection. Another study found the virus in 11 percent of pig livers sold in a sample of grocery stores.
“But this virus doesn't make pigs very sick,” Kuniholm said. “And for the most part it doesn't make humans very sick. It appears that we get the virus, we develop an immune response, but the vast majority of us never get sick.”
Sanchez and Kuniholm stressed that proper cooking kills the virus.
Of the three common forms of hepatitis in the United States, A, B and C, the infection most resembles hepatitis A — which is also often spread through fecally contaminated food and water. Patients who get sick usually recover without treatment. But it's also different from hepatitis A in that person-to-person transmission isn't common with hepatitis E, and outbreaks are usually linked to water supplies contaminated by sewage. Adults are more likely to get sick from E, while children seem more susceptible to A.
And hepatitis E can be passed from animals to humans. A study found that American veterinarians who specialized in swine had higher rates of hepatitis E exposure. Antibodies also have been found in other animals, including rodents, dogs and cats.
Sanchez said there's too little information about the disease to draw any conclusions about whether more people are getting infected. It might be that the commercially available antibody test is prone to false positives. Hepatitis E isn't part of the standard panel of hepatitis tests given to liver patients. It must be specially ordered from certain labs.
Web Posted: 06/22/2010 12:00 CDT
Two local cases — one of them fatal — of a form of hepatitis once thought to be rare in the United States have captured the attention of state and local health officials.
Hepatitis E, a viral infection of the liver, was long considered a problem mainly in developing countries — and to a handful of Americans who traveled there — spread by contaminated food and water.
While the infection clears up on its own in most people, it causes severe illness in some and can be fatal in pregnant women.
Large outbreaks of hepatitis E have taken place in Mexico, Asia and Africa.
The Metropolitan Health District was notified late last year that three people in one San Antonio hospital had tested positive for the infection between September and November 2009. A more sophisticated test later found one of the three was not infected.
Of the two others, one was a 21-year-old woman who died while undergoing a liver transplant. An earlier home pregnancy test had been positive, but she wasn't pregnant when admitted to the hospital, health officials said. The other patient, a 44-year-old nurse's aide, had also suffered some liver damage.
“We couldn't figure out how they acquired it,” said Roger Sanchez, senior epidemiologist with Metro Health, who presented a paper on the cases at a public health meeting in Austin recently. “None of them had any (foreign) travel history. They were previously healthy. Which begs the question — how did they get it?”
But some American researchers who study hepatitis E are finding it more common in the U.S. than previously thought. In fact, the infection seems to be everywhere. What remains a mystery is why some people get sick from the virus but most don't.
“It appears to be a relatively common infection. But clinical symptoms following infection appear to be quite rare,” said Mark Kuniholm, an instructor of epidemiology and population health at the Albert Einstein College of Medicine in New York.
In a study published last July in the Journal of Infectious Diseases, Kuniholm and colleagues tested 18,695 blood samples that had been collected across the country through the National Health and Nutrition Examination Survey, which is conducted every few years by the federal government. He found one in every five people had antibodies to hepatitis E, suggesting a previous infection.
Setting aside those born in another country, the highest infection rates were in Anglo men living in the Midwest. Those who ate liver more than once a month were more likely to have antibodies.
Hepatitis E is commonly found in U.S. pigs, with one study showing 63 percent of commercially raised swine carried antibodies to the virus and 35 percent had signs of active infection. Another study found the virus in 11 percent of pig livers sold in a sample of grocery stores.
“But this virus doesn't make pigs very sick,” Kuniholm said. “And for the most part it doesn't make humans very sick. It appears that we get the virus, we develop an immune response, but the vast majority of us never get sick.”
Sanchez and Kuniholm stressed that proper cooking kills the virus.
Of the three common forms of hepatitis in the United States, A, B and C, the infection most resembles hepatitis A — which is also often spread through fecally contaminated food and water. Patients who get sick usually recover without treatment. But it's also different from hepatitis A in that person-to-person transmission isn't common with hepatitis E, and outbreaks are usually linked to water supplies contaminated by sewage. Adults are more likely to get sick from E, while children seem more susceptible to A.
And hepatitis E can be passed from animals to humans. A study found that American veterinarians who specialized in swine had higher rates of hepatitis E exposure. Antibodies also have been found in other animals, including rodents, dogs and cats.
Sanchez said there's too little information about the disease to draw any conclusions about whether more people are getting infected. It might be that the commercially available antibody test is prone to false positives. Hepatitis E isn't part of the standard panel of hepatitis tests given to liver patients. It must be specially ordered from certain labs.
Family man Leigh fought illness with a smile on his face
smile with ease
Jun 22 2010 by Alex Terrell, South Wales Echo
WHEN Leigh David Sugar passed away aged 44, it marked the departure of a beloved husband, a father and a loving son.
An entrepreneur, he established and grew the Tynant Garage in Beddau, near Pontypridd, into a respected business in the community.
It is testament to his positivity that Leigh – a beloved son to parents Margaret and Graham – held the business until recently.
Those closest to Leigh will say that he had the alchemy to make people around him laugh and smile with ease.
He would go out of his way to make a witty remark and it provided family, friends and acquaintances with a unique feeling of assurance.
His wife Barbara and daughters Kayleigh and Jodie have always been Leigh’s muse, a source of love and a reason for action, even when illness took hold. They loved to holiday, jetting off to the sunshine of the Dominican Republic, Mexico and Cuba. Leigh beamed at both his daughters’ ambition at school and university.
A keen horseman, Leigh rode hunts in his youth throughout the Pontypridd area.
It was here that Leigh met his sweetheart Barbara. Her father employed Leigh in their stables and they dated until their marriage in 1990.
Younger cousin David recalled how Leigh would always make him the butt of the jokes, teasing but including those around him in the fun. Leigh once repaired the car of David’s brother in a matter of hours, so nobody could tell that David had earlier driven it into a bollard – such was Leigh’s way with cars and generosity to his family.
A haemophiliac, Leigh died from liver cancer, a complication from Hepatitis C which he was given through contaminated blood products then prescribed to improve his condition. Haemophilia reduces the blood’s ability to clot and can result in internal and external bleeding without warning from a bump or bruise.
Leigh was one of 4,800 haemophiliacs in the UK to be given Hepatitis C through defective blood products, drawn from the blood of American prisoners, prostitutes and homeless patients to fuel a private enterprise.
These were injected into British patients in the 1970s and ’80s, people are still dying as a result.
Aged 26 when he discovered he had Hepatitis C, his relatives remembered how it forced him to seize what was left of his life. He refused to let it stand in the way of securing a future for his family and business. He was still fun to be around, still cracking jokes and lightening the mood, despite the uncomfortable side effects of his treatment plan.
In the pursuit for better treatments, Leigh’s family rallied, searching all over the world for advice. They even managed to get him a pioneering drug from America, and he shared his treatment experiences with other contaminated blood victims.
Barbara told relatives she recently received a letter from an elderly widow, a Tynant Garage customer, thanking Leigh for his fantastic personal service. Nothing was too much trouble for Leigh in his business, nor in his life.
Tainted Blood is a campaign for victims of contaminated blood products. The group will be conducting a protest for the campaign on June 30 in front of Parliament to urge the Government to address the issue and remember those who have passed away.
For more information visit http://www.taintedblood.info/
http://www.walesonline.co.uk/news/wales-news/2010/06/22/family-man-leigh-fought-illness-with-a-smile-on-his-face-91466-26696766/
Transplanted organs are often far from perfect
Donors often have pre-existing conditions
June 22, 2010
By MONIFA THOMAS Staff Reporter/mjthomas@suntimes.com
The death of a 28-year-old British woman who contracted pneumonia after receiving a lung transplant from a donor who had smoked for 30 years sparked an uproar.
But the practice of transplanting organs from donors with less-than-ideal medical histories, such as smokers and cancer survivors, isn't unusual and is, in fact, a necessity, given the shortage of donor organs, transplant specialists say.
"In a perfect world, if we were able to build organs from scratch . . . everyone would get a perfect organ," says Dr. Giuliano Testa, director of liver transplantation at the University of Chicago Medical Center. "But those perfect organs in nature are only in a minority of cases."
Organ donors who are HIV-positive or who have actively spreading cancer are automatically ruled out for transplants. But transplants involving donors who have just about any other chronic medical condition are still possible, according to the United Network for Organ Sharing.
Transplant centers make decisions on whether to use organs from donors with pre-existing medical conditions based on factors such as how ill the would-be recipient is, how likely it is another organ would be found for that person and whether there's a risk of disease transmission from the donor, says Dr. Michael Ison, a specialist in transplant infections at Northwestern Memorial Hospital who chairs the organ-sharing organization's Ad Hoc Disease Transmission Advisory Committee.
Disease transmission from donated organs is extremely rare, occurring in 0.2 percent of cases, Ison says. The United Network for Organ Sharing requires organ donors to be tested for HIV, hepatitis B and C and the Epstein-Barr virus.
The transmission of HIV and hepatitis C to four transplant recipients in Chicago from a single donor in 2007 were the first known cases in two decades.
A far greater risk for people on the transplant waiting list is dying because they didn't get a transplant. There are currently more than 100,000 people on the waiting list for an organ transplant. About 25,000 people receive transplants each year, while on average 18 people a day die waiting.
"All of transplantation is a cost-benefit ratio," says Dr. Howard Sankary, chief of intra-abdominal transplantation at Loyola University Medical Center in Maywood. "If a liver patient is going to die from their liver disease, and there's no other organ available, you would take the less-than-perfect organ because they have a chance of living."
People in need of organs are usually informed of the potential risk of disease transmission from donors when they join the transplant waiting list, Ison says. If a potential problem with a donor is identified, it's also standard policy for recipients to be notified of these issues at the time an offer is made. Ison says patients usually have one hour to decide if they'll accept the organ, though Testa says he gives his patients longer to decide.
"The majority of patients that are offered this are more than willing to accept that organ, and even in many of the disease transmission cases . . . many people still say they don't regret accepting the organ," says Ison, who is conducting a study on the subject.
http://www.suntimes.com/lifestyles/2417424,CST-NWS-transplants22.article#
Disease transmission from donated organs is extremely rare.
(AP File)
June 22, 2010
By MONIFA THOMAS Staff Reporter/mjthomas@suntimes.com
The death of a 28-year-old British woman who contracted pneumonia after receiving a lung transplant from a donor who had smoked for 30 years sparked an uproar.
But the practice of transplanting organs from donors with less-than-ideal medical histories, such as smokers and cancer survivors, isn't unusual and is, in fact, a necessity, given the shortage of donor organs, transplant specialists say.
"In a perfect world, if we were able to build organs from scratch . . . everyone would get a perfect organ," says Dr. Giuliano Testa, director of liver transplantation at the University of Chicago Medical Center. "But those perfect organs in nature are only in a minority of cases."
Organ donors who are HIV-positive or who have actively spreading cancer are automatically ruled out for transplants. But transplants involving donors who have just about any other chronic medical condition are still possible, according to the United Network for Organ Sharing.
Transplant centers make decisions on whether to use organs from donors with pre-existing medical conditions based on factors such as how ill the would-be recipient is, how likely it is another organ would be found for that person and whether there's a risk of disease transmission from the donor, says Dr. Michael Ison, a specialist in transplant infections at Northwestern Memorial Hospital who chairs the organ-sharing organization's Ad Hoc Disease Transmission Advisory Committee.
Disease transmission from donated organs is extremely rare, occurring in 0.2 percent of cases, Ison says. The United Network for Organ Sharing requires organ donors to be tested for HIV, hepatitis B and C and the Epstein-Barr virus.
The transmission of HIV and hepatitis C to four transplant recipients in Chicago from a single donor in 2007 were the first known cases in two decades.
A far greater risk for people on the transplant waiting list is dying because they didn't get a transplant. There are currently more than 100,000 people on the waiting list for an organ transplant. About 25,000 people receive transplants each year, while on average 18 people a day die waiting.
"All of transplantation is a cost-benefit ratio," says Dr. Howard Sankary, chief of intra-abdominal transplantation at Loyola University Medical Center in Maywood. "If a liver patient is going to die from their liver disease, and there's no other organ available, you would take the less-than-perfect organ because they have a chance of living."
People in need of organs are usually informed of the potential risk of disease transmission from donors when they join the transplant waiting list, Ison says. If a potential problem with a donor is identified, it's also standard policy for recipients to be notified of these issues at the time an offer is made. Ison says patients usually have one hour to decide if they'll accept the organ, though Testa says he gives his patients longer to decide.
"The majority of patients that are offered this are more than willing to accept that organ, and even in many of the disease transmission cases . . . many people still say they don't regret accepting the organ," says Ison, who is conducting a study on the subject.
http://www.suntimes.com/lifestyles/2417424,CST-NWS-transplants22.article#
June 21, 2010
Fatty Liver Associated with Lipids/Metabolics/VAT
"Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of VAT. These findings highlight the specificity of fat accumulation in particular depots and the presence of metabolic disease."
"The most compelling and unique finding in our study was the association of fatty liver with lipid and glucose traits independent of VAT......we found that VAT is the strongest correlate of fatty liver, and after adjusting for VAT, fatty liver remains associated with dyslipidemia and dysglycemia. Given the cross-sectional, observational nature of our measures, our findings must be considered in light of the fact that association does not prove causality......After adjustment for other fat depots, fatty liver remained associated with diabetes, hypertension, impaired fasting glucose, metabolic syndrome, HDL, triglycerides, and adiponectin levels (all P < 0.001), whereas associations with SBP and DBP were attenuated (P > 0.05). Conclusion: Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of visceral adipose tissue and other obesity measures. This work begins to dissect the specific links between fat depots and metabolic disease......The liver is the main source of lipid regulation in the body, plays an important role in glucose metabolism, and overall is known to play a little-known role in blood pressure regulation. Fat accumulation in the liver is predominantly in the form of triglycerides......Delivery of nonesterified fatty acids from VAT has been shown to be as high at 20% of the total delivery of fatty acids to the liver compared with just 5% in lean individuals without visceral fat.[29] In our population-based study, we show that even though VAT was the strongest correlate of fatty liver, the correlation is at best modest (-0.34), suggesting that VAT is only one component in the pathogenesis of fatty liver.....we found that the second-best correlate of fatty liver is insulin resistance"
Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: The Framingham heart study
Hepatology June 2010
Elizabeth K. Speliotes 1 5 *, Joseph M. Massaro 6 7, Udo Hoffmann 2, Ramachandran S. Vasan 6 8, James B. Meigs 4, Dushyant V. Sahani 2, Joel N. Hirschhorn 5 10 11, Christopher J. O'Donnell 3 6, Caroline S. Fox 6 9 1Departments of Gastroenterology, Massachusetts General Hospital, Boston MA 2Radiology, Massachusetts General Hospital, Boston MA 3Cardiology, Massachusetts General Hospital, Boston MA 4General Medicine, Massachusetts General Hospital, Boston MA 5Department of Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 6National Heart, Lung, and Blood Institute's The Framingham Heart Study, Framingham, MA 7Department of Biostatistics, Boston University, Boston, MA 8Departments of Cardiology, Preventive Medicine, and Medicine, Boston University School of Medicine, Boston, MA 9Departments of Medicine and Endocrinology, Brigham and Women's Hospital, Boston, MA 10Departments of Endocrinology and Genetics, Children's Hospital, Boston, MA 11Department of Genetics, Harvard Medical School, Boston, MA email: Elizabeth K. Speliotes (espeliotes@partners.org)
*Correspondence to Elizabeth K. Speliotes, Department of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 Potential conflict of interest: D. V. S. has a research agreement with General Electric and is on the Speakers' Bureau of Bracco Diagnostics. J. B. M. currently has research grants from GlaxoSmithKline and sanofi-aventis, and has consulting agreements with Eli Lilly and Interleukin Genetics. Dr. Hirshhorn advises Correlagen Diagnostics, Inc. fax: 617-724-1685
Funded by: National Institutes of Health; Grant Number: T32 DK07191-32 Department of Gastroenterology at Massachusetts General Hospital; Grant Number: F32 DK079466-01, K23 DK080145-01 Framingham Heart Study; Grant Number: N01-HC25195 American Diabetes Association Career Development Award General Clinical Research Centers Program; Grant Number: M01-RR-01066 National Institute of Diabetes and Digestive and Kidney Diseases; Grant Number: K24 DK080140
Abstract
Obesity is not uniformly associated with the development of metabolic sequelae. Specific patterns of body fat distribution, in particular fatty liver, may preferentially predispose at-risk individuals to disease. In this study, we characterize the metabolic correlates of fat in the liver in a large community-based sample with and without respect to visceral fat. Fatty liver was measured by way of multidetector computed tomography of the abdomen in 2,589 individuals from the community-based Framingham Heart Study. Logistic and linear regression were used to determine the associations of fatty liver with cardio-metabolic risk factors adjusted for covariates with and without adjustment for other fat depots (body mass index, waist circumference, and visceral adipose tissue). The prevalence of fatty liver was 17%. Compared with participants without fatty liver, individuals with fatty liver had a higher adjusted odds ratio (OR) of diabetes (OR 2.98, 95% confidence interval [CI] 2.12-4.21), metabolic syndrome (OR 5.22, 95% CI 4.15-6.57), hypertension (OR 2.73, 95% CI 2.16-3.44), impaired fasting glucose (OR 2.95, 95% CI 2.32-3.75), insulin resistance (OR 6.16, 95% CI 4.90-7.76); higher triglycerides, systolic blood pressure (SBP), and diastolic blood pressure (DBP); and lower high-density lipoprotein (HDL) and adiponectin levels (P < 0.001 for all). After adjustment for other fat depots, fatty liver remained associated with diabetes, hypertension, impaired fasting glucose, metabolic syndrome, HDL, triglycerides, and adiponectin levels (all P < 0.001), whereas associations with SBP and DBP were attenuated (P > 0.05). Conclusion: Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of visceral adipose tissue and other obesity measures. This work begins to dissect the specific links between fat depots and metabolic disease.
Article Text
Obesity is a global epidemic. In the United States, more than 66% of individuals are overweight or obese and more than 33% are obese.[1] Obesity affects more than 1 billion people worldwide and is expected to increase to 1.5 billion by 2115.[2] Obesity is associated with metabolic complications, although not all obese individuals develop medical sequelae.[3] Why some people develop obesity-related illnesses and others do not has not been well-characterized.
One hypothesis for why some individuals develop medical problems from obesity is that specific fat depots may predispose some individuals to getting particular ailments. Abdominal obesity, as estimated by waist circumference, has been associated with the metabolic syndrome, insulin resistance, and cardiovascular complications.[4] Subcutaneous and visceral adipose tissue as well as fat in liver are all correlated with waist circumference,[5][6] but how these depots selectively contribute to the development of metabolic complications is not clear. One possibility is that these depots produce adipocytokines - including adiponectin and resistin - that can affect steatosis as well as metabolic traits. Adiponectin in rodents, for example, can alleviate steatosis and improve insulin sensitivity,[7][8] whereas resistin may promote steatosis and insulin resistance.[9][10] Furthermore, fatty liver has been considered by some to be a by-product of fat deposition in the viscera, blood from which drains to the liver, where it is deposited.[11] Alternatively, fat in the liver may confer independent metabolic consequences above and beyond the effects of visceral fat.
The goal of this study was to examine the correlation of fatty liver with metabolic risk factors for cardiovascular disease, and in particular to assess the association of metabolic risk factors for cardiovascular disease with fatty liver above and beyond standard anthropometric measures and visceral abdominal fat. We report the measurement, prevalence, and metabolic and anthropometric correlates of fatty liver in The Framingham Heart Study.
Discussion
Fatty liver is observed in 17% of participants in an unselected community-based sample. Individuals with fatty liver are characterized by a high-risk metabolic profile. After adjustment for other fat depots, including VAT, fatty liver remained associated with lipid and glucose traits.
The most compelling and unique finding in our study was the association of fatty liver with lipid and glucose traits independent of VAT. Not all obese individuals develop metabolic disease from their obesity. Understanding how individuals that develop metabolic sequelae from their obesity differ from those that do not may help target at-risk individuals and guide development of novel therapeutics to combat disease. In the present study, we extend previous reports[6][22-27] and illustrate how fatty liver associates with the metabolic syndrome components in the largest study to date of Caucasian individuals that have not been selected for the presence of fatty liver, obesity, or metabolic disease. The association of liver fat with lipid, glucose, and blood pressure traits may be indirect and due to generalized adiposity, or to the presence of fat in particular depots, including VAT. The size of our cohort and the richness of the covariates and traits measured - including VAT - gave us the unique opportunity to assess the association of liver fat with these cardiometabolic traits above and beyond VAT. In particular, we found that VAT is the strongest correlate of fatty liver, and after adjusting for VAT, fatty liver remains associated with dyslipidemia and dysglycemia. Given the cross-sectional, observational nature of our measures, our findings must be considered in light of the fact that association does not prove causality.
The liver is the main source of lipid regulation in the body, plays an important role in glucose metabolism, and overall is known to play a little-known role in blood pressure regulation. Fat accumulation in the liver is predominantly in the form of triglycerides. Fifteen percent of this fat comes from dietary cholymicrons, 60% from nonesterified fatty acids that come from lipolysis from adipose tissue or from lipoproteins hydrolyzed above a rate that can be taken up by adipose tissue, and 25% from newly synthesized fatty acids.[28] Delivery of nonesterified fatty acids from VAT has been shown to be as high at 20% of the total delivery of fatty acids to the liver compared with just 5% in lean individuals without visceral fat.[29] In our population-based study, we show that even though VAT was the strongest correlate of fatty liver, the correlation is at best modest (-0.34), suggesting that VAT is only one component in the pathogenesis of fatty liver. It has been shown that in the absence of peripheral fat stores or in insulin-resistant states where peripheral tissues are impaired in their ability to accumulate energy stores, there can be an increase in nonesterified fatty acid delivery to the liver and increased fat accumulation in mice and humans.[30-32] Indeed, we found that the second-best correlate of fatty liver is insulin resistance. Delivery of excess fatty acids to the liver in energy excess states due to differences in fat storage ability and/or insulin resistance peripherally in the population may result in de novo lipogenesis, fatty acid esterification, and storage of esterified fatty acids as cytoplasmic triglycerides or to formation of very low-density lipoprotein (VLDL) particles.[33][34] These VLDL particles can be secreted and can lead to the formation of atherogenic small dense lipoprotein particles, cholesterol-rich VLDL remnants, and triglyceride-rich HDL particles that can be cleared by the kidney, leading to lower levels of HDL.[33] In this way, fatty liver may be specifically related to hypertriglyceridemia, low HDL, and impaired glucose use above and beyond other fat depots, consistent with what we found in our analyses. Furthermore, the lack of peripheral fat storage capacity may be indirectly indicated by low levels of adipokines such as adiponectin, which is inversely corrected with fatty liver. Alternatively, low levels of adiponectin may be related directly to the excess storage of energy in the liver.
The conjoint associations of fatty liver and VAT in association with lipid and glucose traits highlights the independent roles of different metabolic fat depots. Furthermore, our findings that fatty liver was mostly associated with lipid and glucose traits may help explain in part why these abnormalities are often seen together. In addition, understanding why some, but not all individuals, develop fatty liver can offer insight into why certain individuals develop metabolic complications of obesity while others do not. Finally, it will be of great interest to determine whether the presence of fat in the liver prospectively is an independent predictor of the development not only of metabolic disease in the form of dysglycemia or dyslipidemia but also of cardiovascular disease.
The strength of the present study is the large, well-characterized cohort of individuals with a wealth of metabolic traits and covariates measured. Furthermore, our sample is unselected for obesity-related traits, reducing selection bias. Indeed, we establish that fatty liver is prevalent at 17%, affects more men than women, and peaks in women at later ages than in men in the largest Caucasian population-based study to date. Our study directly measured fatty liver on CT scans, which allowed us to quantify it more precisely compared with indirect measures of fatty liver disease, such as elevated liver function tests, which have a low sensitivity to detect the presence of the condition. We also measured both liver phantom ratio and liver spleen ratio and found that our results were comparable between these two measures, suggesting that these results can be compared with studies that have just the liver spleen ratio. The distribution was skewed with most people having little or no fatty liver. The peak of the distribution may represent a point at which people have no fat in their liver or alternatively low levels of fat that can be considered normal for the population. Because high water, glycogen, or iron concentrations in the liver increase the attenuation of the liver, confounding by these deposits would - if anything - lead to underestimation of fatty liver; individuals to the left of the peak likely do have high liver fat. Our study was limited by including only individuals of European ancestry and thus cannot be generalized to other ethnicities. Also, these individuals were initially from one geographic area and were part of a health outcomes study that may not be generalizable. Furthermore, covariates were measured at times separate from the CT scans, and CT can only indirectly measure fat in the liver; these effects may result in misclassification. However, misclassification would only serve to bias our results toward the null, and would not lead to a positive association, as we have observed. Furthermore, a general limitation of the diagnosis of diabetes in population-based studies is that it is dependent on a one-time assessment of glucose and self-reported medication use, which may include metformin. In particular, metformin might be used for both polycystic ovary syndrome and impaired fasting glucose. The exposure and covariate data were measured from 1998 to 2005, and may not reflect current trends. Lastly, these data are cross-sectional and derived from an observational study; therefore, we cannot draw conclusions.
Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of VAT. These findings highlight the specificity of fat accumulation in particular depots and the presence of metabolic disease.
Results
Study Sample Characteristics.
The characteristics of the study subjects are shown in Table 1. Fifty-one percent of the sample were women, with an average age of 51 years and a BMI of 27.6 kg/m2. Using a liver phantom ratio
Prevalence.
The overall prevalence of fatty liver was 17%. Age-specific and sex-specific prevalence was higher for men (19%) compared with women (15%), and peaked for men between ages 55 and 64 and for women between ages 75 and 84 (Table 2). There was little difference in prevalence using liver spleen ratio instead of liver phantom ratio as a measure of fatty liver (data not shown).
Correlations Between Fatty Liver and Metabolic/Anthropometric Traits.
Fatty liver as measured using liver phantom ratio and liver spleen ratio was associated with all tested metabolic and fat depot variables. Decreases in liver phantom ratio and liver spleen ratio (reflecting more fat in the liver) were associated with higher levels of VAT, waist circumference, BMI, triglycerides, weight, SAT, fasting plasma glucose, HOMA-IR, SBP, DBP, and lower adiponectin and HDL (P < 0.001 for all) (Table 3).
Multivariable-Adjusted Correlations Between Fatty Liver and Metabolic/Anthropometric Traits.
Fatty liver (as both continuous and dichotomous measures) was significantly associated with all glucose, lipid, and blood pressure traits (P < 0.001) except resistin levels in multivariable analyses (Table 4). Compared to participants without fatty liver, individuals with fatty liver had a higher adjusted odds ratio of prevalent diabetes (odds ratio [OR] 2.98, 95% confidence interval [CI] 2.12-4.21), insulin resistance (OR 6.16, 95% CI 4.90-7.76), metabolic syndrome (OR 5.22, 95% CI 4.15-6.57), hypertension (OR 2.73, 95% CI 2.16-3.44), and impaired fasting glucose (OR 2.95, 95% CI 2.32-3.75) than individuals without fatty liver (P < 0.001 for all).
After further adjustment for BMI, waist circumference, and VAT, there remained statistically significant associations of fatty liver with prevalent diabetes (OR 1.64, 95% CI 1.11-2.41), impaired fasting glucose (OR 1.58, 95% CI 1.21-2.07), insulin resistance (OR 2.79, 95% CI 2.14-3.65), metabolic syndrome (OR 1.95, 95% CI 1.48-2.56), log HOMA-IR (beta 0.14, 95% CI 0.17-0.2), adiponectin (beta -1.59 mg/dL, 95% CI -2.57 to -0.62), log triglycerides (beta 0.22 mg/dL, 95% CI 0.17-0.28 mg/dL), HDL (beta -2.48, 95% CI -3.89 to -1.06), and hypertension (OR 1.52, 95% CI 1.17-1.97), whereas SBP and DBP were no longer associated with fatty liver (P = 0.09 and 0.19, respectively) (Table 4).
Similar associations were observed when we examined decreasing liver phantom ratio as a continuous measure of fatty liver (Table 4). Similar results were also observed after additional adjustment for physical activity and education (data not shown). There was no evidence for an interaction by age or sex in the association of fatty liver with continuous or dichotomous metabolic risk factors - except with adiponectin, where women had a slightly higher effect than men, and in HOMA-IR, where individuals >50 years of age had a higher HOMA-IR values than those <50 years of age. However, in all cases, the effect in these classes was directionally consistent with the overall effect (data not shown).
The median glucose, triglycerides, HDL, SBP, and DBP values in participants above and below the 90th percentile cut-point for VAT derived from a healthy referent sample[21] (Fig. 1) show that lipid and glucose traits were associated with fatty liver (P < 0.0001), whereas SBP and DBP were associated to a lesser extent (P = 0.0002 and 0.004, respectively) with fatty liver high and low levels of VAT. When fatty liver and VAT were jointly considered in the multivariate models, VAT remained associated with all metabolic correlates (all P < 0.0001) (data not shown) whereas fatty liver was not associated with SBP and DBP (P = 0.06 and 0.16, respectively). However, fatty liver remained associated with all other metabolic traits (P < 0.004) (data not shown).
Subjects and Methods
Subjects.
Subjects were drawn from The Framingham Heart study, a prospective cohort study initiated to evaluate risk factors for the development of cardiovascular disease. The selection criteria for this cohort have been reported.[12] The study was initiated in 1948, enrolling 5,209 residents of Framingham, Massachusetts. These individuals have been followed since then with multiple serial examinations and collection of risk factor data. In 1971, 5,124 offspring and their spouses were recruited into the Offspring Study and have been followed every 4-8 years since then.[13] In 2002, 4,095 Third Generation members and their spouses were enrolled.[14] Between 2002 and 2005, multidetector computed tomography (CT) examinations of the chest and abdomen were performed in 3,529 individuals drawn from families including both Offspring and Third Generation participants.
Multidetector CT Scan Cohort.
A total of 3,529 individuals underwent multidetector CT scanning, 1,418 from the Offspring Study and 2,111 from the Third Generation. Inclusion criteria for the study favored individuals who still resided in the greater New England area and included 755 families. The minimum age cutoffs were 35 years in men and 40 years in women. All women of child-bearing age completed a pregnancy screening, and pregnant women (for risk to the fetus) and individuals weighing >160 kg were excluded from examination. Individuals undergoing scans were excluded from this analysis if their multidetector CT scans were not interpretable for fatty liver (n = 323), did not attend Offspring Examination 7 (n = 23) or if individuals reported greater than seven drinks for men or 14 drinks for women per week (n = 487). Of these, 107 were missing a complete covariate profile and were further excluded, resulting in a total sample size of 2,589.
Multidetector CT Scan Protocol and Measurement of Fatty Liver, Visceral Adipose Tissue, and Subcutaneous Adipose Tissue.
Multidetector CT scanning was conducted as reported.[5][15][16] A calibration phantom (Image Analysis, Lexington, KY) with a water equivalent compound (CT-Water, Light Speed Ultra; General Electric, Milwaukee, WI) and calcium hydroxyapatite at 0, 75, and 150 mg/cm3 was placed under each participant.[16]
Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured[5][15]; briefly, 25 contiguous 5-mm-thick sections (120 kVP, 400 mA, gantry rotation time 500 ms, table feed 3:1 were acquired covering 125 mm above S1). Fat was identified using an image display window of -195 to -45 HU and a window center of -120 HU. After manually tracing the abdominal muscular wall separating the visceral from the subcutaneous compartment, high-resolution volumetric measurements of SAT and VAT were defined as the volumetric fat content outside and inside of this dividing line. The intraclass correlation coefficient was 0.992 for VAT and 0.997 for SAT.
Fatty liver was measured on multidetector CT scans of the abdomen and has been described elsewhere.[16] Briefly, three areas from the liver - two from the spleen and one from the external phantom - were measured. The average of the liver and spleen measurements were then calculated and used to create liver spleen ratios and liver phantom ratios. The intraclass correlation coefficient was 0.99.[16] Given that the phantom but not the spleen was visualized on all scans, primary analyses were conducted with a liver phantom ratio as the indexed standard; secondary analyses were conducted on the liver spleen ratio. Only participants with abdominal scans were used in the current analysis, because data from the abdominal scans had better reproducibility than chest scans.[16]
Distribution of the Fatty Liver Phenotype.
The distributions of liver phantom ratio and liver spleen ratio were left skewed with a median (lower-upper quartile) of 0.37 (0.34-0.39) and 1.21 (1.13-1.28), respectively (Supporting Fig. 1A). The 95th percentiles were 0.41 and 1.37 for the liver phantom ratio and liver spleen ratio, respectively. In the literature, a liver spleen ratio of 1.1 corresponds to the presence of 30% fatty liver.[17] We found that a liver phantom ratio cutoff of 0.33 had a 98% sensitivity and 70% specificity using liver spleen ratio cut-point of 1.1 as the gold standard (Supporting Fig. 1B).
Measurement of Covariates.
Risk factors used in analyses in this study were measured at the seventh examination cycle of the Offspring Study cohort (1998-2001) or the first examination of the Third Generation cohort (2002-2005). Body mass index (BMI) was defined as weight (kg)/height (m)2; waist circumference was measured at the level of the umbilicus; diabetes was defined as a fasting plasma glucose of at least 126 mg/dL at examination or treatment with either insulin or a hypoglycemic agent; impaired fasting glucose was defined as fasting plasma glucose of 100-125 mg/dL among those not treated for diabetes; and hypertension was defined as systolic blood pressure (SBP) >/=140 mm Hg or diastolic blood pressure (DBP) >/=90 mm Hg or on antihypertensive treatment. Triglycerides and high-density lipoprotein (HDL) levels are measured on fasting morning samples. Participants are considered current smokers if they had smoked at least one cigarette per day in the year preceding The Framingham Heart Study examination. Alcohol use was assessed through a series of physician-administered questions. Physical activity, assessed with a questionnaire, is a score based on the average daily number of hours of sleep and sedentary, slight, moderate, and heavy activity of the participant. Women were considered menopausal if their periods had stopped for at least 1 year. Metabolic syndrome is defined from modified Adult Treatment Panel criteria. Obesity is defined as BMI 30 kg/m2. Insulin resistance was determined as the top quartile of the homeostasis model homeostasis model assessment of insulin resistance (HOMA-IR) (fasting glucose x fasting insulin/22.5) distribution among individuals without diabetes.[18][19] Circulating adiponectin and resistin were measured by way of enzyme-linked immunoassay after an 8-hour fast as described.[20]
Determination of Fatty Liver Phantom Ratio Dichotomous Cutoff and Continuous Distribution.
The distributions of liver phantom ratios and liver spleen ratios were characterized. Because the liver phantom ratio and liver spleen ratio are likely measures of more than just fat in the liver (water content, iron, and so forth), the top 5% of points in the liver phantom ratio were winsorized for analyses with fatty liver as a continuous variable.
Prior to winsorization, to determine the liver phantom ratio cutoff that mirrored a liver spleen ratio of 1:1, the cutoff that best discriminates the presence of 30% fat in the liver,[17] we minimized misclassification of subjects at various cutoffs for liver phantom ratio. From a receiver operating curve analysis of liver phantom ratio compared with a gold standard of liver spleen ratio of 1.1, we determined the sensitivity and specificity of various cutoffs of liver phantom ratio and established a liver phantom ratio cutoff of 0.33 or lower as our working definition of fatty liver.
Statistical Analyses.
Differences in participant characteristics between those with (liver phantom ratio 0.33) were determined using a t test for normally distributed traits, Wilcoxon rank sum test for nonnormally distributed continuous variables or ordinal variables, and a chi-square test for dichotomous variables. Because the liver phantom ratio was not normally distributed, Spearman correlation coefficients were used to determine age-adjusted and sex-adjusted correlations of continuous metabolic traits with liver phantom ratio.
Primary multivariable analyses focused on fatty liver (yes/no) as the exposure and individual metabolic risk factors and fat depot measures as the dependent (outcome) variables. For dichotomous outcomes, odds ratios (calculated fatty liver yes versus fatty liver no) are reported; for continuous outcomes, the regression coefficients for the presence of fatty liver are reported. We also modeled continuous fatty liver as the exposure and odds ratios and regression coefficients for a 1 standard deviation decrease in liver phantom ratio are reported for dichotomous and continuous outcomes, respectively. The following modeling structures were used. In model 1, age, sex, alcohol consumption (after exclusions mentioned above), menopausal status, hormone replacement therapy, smoking (three-level variable: current/former/never smoker) were included as covariates. In addition, lipid treatment, hypertension treatment, and diabetes treatment were included as covariates in models for HDL cholesterol, log triglycerides, SBP and DBP, and fasting plasma glucose, respectively. In model 2, we additionally adjusted for BMI, waist circumference, and VAT. SAT was not included in these multivariate models because it was highly collinear with BMI.
In secondary analyses, we added physical activity and education to the models. Assessment of the significance of sex and age interactions with fatty liver on metabolic risk factors was also assessed. Analyses were performed using SAS version 9.1; a two-sided 0.05 alpha was used to declare statistical significance.
http://www.natap.org/2010/HCV/062010_01.htm
"The most compelling and unique finding in our study was the association of fatty liver with lipid and glucose traits independent of VAT......we found that VAT is the strongest correlate of fatty liver, and after adjusting for VAT, fatty liver remains associated with dyslipidemia and dysglycemia. Given the cross-sectional, observational nature of our measures, our findings must be considered in light of the fact that association does not prove causality......After adjustment for other fat depots, fatty liver remained associated with diabetes, hypertension, impaired fasting glucose, metabolic syndrome, HDL, triglycerides, and adiponectin levels (all P < 0.001), whereas associations with SBP and DBP were attenuated (P > 0.05). Conclusion: Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of visceral adipose tissue and other obesity measures. This work begins to dissect the specific links between fat depots and metabolic disease......The liver is the main source of lipid regulation in the body, plays an important role in glucose metabolism, and overall is known to play a little-known role in blood pressure regulation. Fat accumulation in the liver is predominantly in the form of triglycerides......Delivery of nonesterified fatty acids from VAT has been shown to be as high at 20% of the total delivery of fatty acids to the liver compared with just 5% in lean individuals without visceral fat.[29] In our population-based study, we show that even though VAT was the strongest correlate of fatty liver, the correlation is at best modest (-0.34), suggesting that VAT is only one component in the pathogenesis of fatty liver.....we found that the second-best correlate of fatty liver is insulin resistance"
Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: The Framingham heart study
Hepatology June 2010
Elizabeth K. Speliotes 1 5 *, Joseph M. Massaro 6 7, Udo Hoffmann 2, Ramachandran S. Vasan 6 8, James B. Meigs 4, Dushyant V. Sahani 2, Joel N. Hirschhorn 5 10 11, Christopher J. O'Donnell 3 6, Caroline S. Fox 6 9 1Departments of Gastroenterology, Massachusetts General Hospital, Boston MA 2Radiology, Massachusetts General Hospital, Boston MA 3Cardiology, Massachusetts General Hospital, Boston MA 4General Medicine, Massachusetts General Hospital, Boston MA 5Department of Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 6National Heart, Lung, and Blood Institute's The Framingham Heart Study, Framingham, MA 7Department of Biostatistics, Boston University, Boston, MA 8Departments of Cardiology, Preventive Medicine, and Medicine, Boston University School of Medicine, Boston, MA 9Departments of Medicine and Endocrinology, Brigham and Women's Hospital, Boston, MA 10Departments of Endocrinology and Genetics, Children's Hospital, Boston, MA 11Department of Genetics, Harvard Medical School, Boston, MA email: Elizabeth K. Speliotes (espeliotes@partners.org)
*Correspondence to Elizabeth K. Speliotes, Department of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 Potential conflict of interest: D. V. S. has a research agreement with General Electric and is on the Speakers' Bureau of Bracco Diagnostics. J. B. M. currently has research grants from GlaxoSmithKline and sanofi-aventis, and has consulting agreements with Eli Lilly and Interleukin Genetics. Dr. Hirshhorn advises Correlagen Diagnostics, Inc. fax: 617-724-1685
Funded by: National Institutes of Health; Grant Number: T32 DK07191-32 Department of Gastroenterology at Massachusetts General Hospital; Grant Number: F32 DK079466-01, K23 DK080145-01 Framingham Heart Study; Grant Number: N01-HC25195 American Diabetes Association Career Development Award General Clinical Research Centers Program; Grant Number: M01-RR-01066 National Institute of Diabetes and Digestive and Kidney Diseases; Grant Number: K24 DK080140
Abstract
Obesity is not uniformly associated with the development of metabolic sequelae. Specific patterns of body fat distribution, in particular fatty liver, may preferentially predispose at-risk individuals to disease. In this study, we characterize the metabolic correlates of fat in the liver in a large community-based sample with and without respect to visceral fat. Fatty liver was measured by way of multidetector computed tomography of the abdomen in 2,589 individuals from the community-based Framingham Heart Study. Logistic and linear regression were used to determine the associations of fatty liver with cardio-metabolic risk factors adjusted for covariates with and without adjustment for other fat depots (body mass index, waist circumference, and visceral adipose tissue). The prevalence of fatty liver was 17%. Compared with participants without fatty liver, individuals with fatty liver had a higher adjusted odds ratio (OR) of diabetes (OR 2.98, 95% confidence interval [CI] 2.12-4.21), metabolic syndrome (OR 5.22, 95% CI 4.15-6.57), hypertension (OR 2.73, 95% CI 2.16-3.44), impaired fasting glucose (OR 2.95, 95% CI 2.32-3.75), insulin resistance (OR 6.16, 95% CI 4.90-7.76); higher triglycerides, systolic blood pressure (SBP), and diastolic blood pressure (DBP); and lower high-density lipoprotein (HDL) and adiponectin levels (P < 0.001 for all). After adjustment for other fat depots, fatty liver remained associated with diabetes, hypertension, impaired fasting glucose, metabolic syndrome, HDL, triglycerides, and adiponectin levels (all P < 0.001), whereas associations with SBP and DBP were attenuated (P > 0.05). Conclusion: Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of visceral adipose tissue and other obesity measures. This work begins to dissect the specific links between fat depots and metabolic disease.
Article Text
Obesity is a global epidemic. In the United States, more than 66% of individuals are overweight or obese and more than 33% are obese.[1] Obesity affects more than 1 billion people worldwide and is expected to increase to 1.5 billion by 2115.[2] Obesity is associated with metabolic complications, although not all obese individuals develop medical sequelae.[3] Why some people develop obesity-related illnesses and others do not has not been well-characterized.
One hypothesis for why some individuals develop medical problems from obesity is that specific fat depots may predispose some individuals to getting particular ailments. Abdominal obesity, as estimated by waist circumference, has been associated with the metabolic syndrome, insulin resistance, and cardiovascular complications.[4] Subcutaneous and visceral adipose tissue as well as fat in liver are all correlated with waist circumference,[5][6] but how these depots selectively contribute to the development of metabolic complications is not clear. One possibility is that these depots produce adipocytokines - including adiponectin and resistin - that can affect steatosis as well as metabolic traits. Adiponectin in rodents, for example, can alleviate steatosis and improve insulin sensitivity,[7][8] whereas resistin may promote steatosis and insulin resistance.[9][10] Furthermore, fatty liver has been considered by some to be a by-product of fat deposition in the viscera, blood from which drains to the liver, where it is deposited.[11] Alternatively, fat in the liver may confer independent metabolic consequences above and beyond the effects of visceral fat.
The goal of this study was to examine the correlation of fatty liver with metabolic risk factors for cardiovascular disease, and in particular to assess the association of metabolic risk factors for cardiovascular disease with fatty liver above and beyond standard anthropometric measures and visceral abdominal fat. We report the measurement, prevalence, and metabolic and anthropometric correlates of fatty liver in The Framingham Heart Study.
Discussion
Fatty liver is observed in 17% of participants in an unselected community-based sample. Individuals with fatty liver are characterized by a high-risk metabolic profile. After adjustment for other fat depots, including VAT, fatty liver remained associated with lipid and glucose traits.
The most compelling and unique finding in our study was the association of fatty liver with lipid and glucose traits independent of VAT. Not all obese individuals develop metabolic disease from their obesity. Understanding how individuals that develop metabolic sequelae from their obesity differ from those that do not may help target at-risk individuals and guide development of novel therapeutics to combat disease. In the present study, we extend previous reports[6][22-27] and illustrate how fatty liver associates with the metabolic syndrome components in the largest study to date of Caucasian individuals that have not been selected for the presence of fatty liver, obesity, or metabolic disease. The association of liver fat with lipid, glucose, and blood pressure traits may be indirect and due to generalized adiposity, or to the presence of fat in particular depots, including VAT. The size of our cohort and the richness of the covariates and traits measured - including VAT - gave us the unique opportunity to assess the association of liver fat with these cardiometabolic traits above and beyond VAT. In particular, we found that VAT is the strongest correlate of fatty liver, and after adjusting for VAT, fatty liver remains associated with dyslipidemia and dysglycemia. Given the cross-sectional, observational nature of our measures, our findings must be considered in light of the fact that association does not prove causality.
The liver is the main source of lipid regulation in the body, plays an important role in glucose metabolism, and overall is known to play a little-known role in blood pressure regulation. Fat accumulation in the liver is predominantly in the form of triglycerides. Fifteen percent of this fat comes from dietary cholymicrons, 60% from nonesterified fatty acids that come from lipolysis from adipose tissue or from lipoproteins hydrolyzed above a rate that can be taken up by adipose tissue, and 25% from newly synthesized fatty acids.[28] Delivery of nonesterified fatty acids from VAT has been shown to be as high at 20% of the total delivery of fatty acids to the liver compared with just 5% in lean individuals without visceral fat.[29] In our population-based study, we show that even though VAT was the strongest correlate of fatty liver, the correlation is at best modest (-0.34), suggesting that VAT is only one component in the pathogenesis of fatty liver. It has been shown that in the absence of peripheral fat stores or in insulin-resistant states where peripheral tissues are impaired in their ability to accumulate energy stores, there can be an increase in nonesterified fatty acid delivery to the liver and increased fat accumulation in mice and humans.[30-32] Indeed, we found that the second-best correlate of fatty liver is insulin resistance. Delivery of excess fatty acids to the liver in energy excess states due to differences in fat storage ability and/or insulin resistance peripherally in the population may result in de novo lipogenesis, fatty acid esterification, and storage of esterified fatty acids as cytoplasmic triglycerides or to formation of very low-density lipoprotein (VLDL) particles.[33][34] These VLDL particles can be secreted and can lead to the formation of atherogenic small dense lipoprotein particles, cholesterol-rich VLDL remnants, and triglyceride-rich HDL particles that can be cleared by the kidney, leading to lower levels of HDL.[33] In this way, fatty liver may be specifically related to hypertriglyceridemia, low HDL, and impaired glucose use above and beyond other fat depots, consistent with what we found in our analyses. Furthermore, the lack of peripheral fat storage capacity may be indirectly indicated by low levels of adipokines such as adiponectin, which is inversely corrected with fatty liver. Alternatively, low levels of adiponectin may be related directly to the excess storage of energy in the liver.
The conjoint associations of fatty liver and VAT in association with lipid and glucose traits highlights the independent roles of different metabolic fat depots. Furthermore, our findings that fatty liver was mostly associated with lipid and glucose traits may help explain in part why these abnormalities are often seen together. In addition, understanding why some, but not all individuals, develop fatty liver can offer insight into why certain individuals develop metabolic complications of obesity while others do not. Finally, it will be of great interest to determine whether the presence of fat in the liver prospectively is an independent predictor of the development not only of metabolic disease in the form of dysglycemia or dyslipidemia but also of cardiovascular disease.
The strength of the present study is the large, well-characterized cohort of individuals with a wealth of metabolic traits and covariates measured. Furthermore, our sample is unselected for obesity-related traits, reducing selection bias. Indeed, we establish that fatty liver is prevalent at 17%, affects more men than women, and peaks in women at later ages than in men in the largest Caucasian population-based study to date. Our study directly measured fatty liver on CT scans, which allowed us to quantify it more precisely compared with indirect measures of fatty liver disease, such as elevated liver function tests, which have a low sensitivity to detect the presence of the condition. We also measured both liver phantom ratio and liver spleen ratio and found that our results were comparable between these two measures, suggesting that these results can be compared with studies that have just the liver spleen ratio. The distribution was skewed with most people having little or no fatty liver. The peak of the distribution may represent a point at which people have no fat in their liver or alternatively low levels of fat that can be considered normal for the population. Because high water, glycogen, or iron concentrations in the liver increase the attenuation of the liver, confounding by these deposits would - if anything - lead to underestimation of fatty liver; individuals to the left of the peak likely do have high liver fat. Our study was limited by including only individuals of European ancestry and thus cannot be generalized to other ethnicities. Also, these individuals were initially from one geographic area and were part of a health outcomes study that may not be generalizable. Furthermore, covariates were measured at times separate from the CT scans, and CT can only indirectly measure fat in the liver; these effects may result in misclassification. However, misclassification would only serve to bias our results toward the null, and would not lead to a positive association, as we have observed. Furthermore, a general limitation of the diagnosis of diabetes in population-based studies is that it is dependent on a one-time assessment of glucose and self-reported medication use, which may include metformin. In particular, metformin might be used for both polycystic ovary syndrome and impaired fasting glucose. The exposure and covariate data were measured from 1998 to 2005, and may not reflect current trends. Lastly, these data are cross-sectional and derived from an observational study; therefore, we cannot draw conclusions.
Fatty liver is a prevalent condition and is characterized by dysglycemia and dyslipidemia independent of VAT. These findings highlight the specificity of fat accumulation in particular depots and the presence of metabolic disease.
Results
Study Sample Characteristics.
The characteristics of the study subjects are shown in Table 1. Fifty-one percent of the sample were women, with an average age of 51 years and a BMI of 27.6 kg/m2. Using a liver phantom ratio
Prevalence.
The overall prevalence of fatty liver was 17%. Age-specific and sex-specific prevalence was higher for men (19%) compared with women (15%), and peaked for men between ages 55 and 64 and for women between ages 75 and 84 (Table 2). There was little difference in prevalence using liver spleen ratio instead of liver phantom ratio as a measure of fatty liver (data not shown).
Correlations Between Fatty Liver and Metabolic/Anthropometric Traits.
Fatty liver as measured using liver phantom ratio and liver spleen ratio was associated with all tested metabolic and fat depot variables. Decreases in liver phantom ratio and liver spleen ratio (reflecting more fat in the liver) were associated with higher levels of VAT, waist circumference, BMI, triglycerides, weight, SAT, fasting plasma glucose, HOMA-IR, SBP, DBP, and lower adiponectin and HDL (P < 0.001 for all) (Table 3).
Multivariable-Adjusted Correlations Between Fatty Liver and Metabolic/Anthropometric Traits.
Fatty liver (as both continuous and dichotomous measures) was significantly associated with all glucose, lipid, and blood pressure traits (P < 0.001) except resistin levels in multivariable analyses (Table 4). Compared to participants without fatty liver, individuals with fatty liver had a higher adjusted odds ratio of prevalent diabetes (odds ratio [OR] 2.98, 95% confidence interval [CI] 2.12-4.21), insulin resistance (OR 6.16, 95% CI 4.90-7.76), metabolic syndrome (OR 5.22, 95% CI 4.15-6.57), hypertension (OR 2.73, 95% CI 2.16-3.44), and impaired fasting glucose (OR 2.95, 95% CI 2.32-3.75) than individuals without fatty liver (P < 0.001 for all).
After further adjustment for BMI, waist circumference, and VAT, there remained statistically significant associations of fatty liver with prevalent diabetes (OR 1.64, 95% CI 1.11-2.41), impaired fasting glucose (OR 1.58, 95% CI 1.21-2.07), insulin resistance (OR 2.79, 95% CI 2.14-3.65), metabolic syndrome (OR 1.95, 95% CI 1.48-2.56), log HOMA-IR (beta 0.14, 95% CI 0.17-0.2), adiponectin (beta -1.59 mg/dL, 95% CI -2.57 to -0.62), log triglycerides (beta 0.22 mg/dL, 95% CI 0.17-0.28 mg/dL), HDL (beta -2.48, 95% CI -3.89 to -1.06), and hypertension (OR 1.52, 95% CI 1.17-1.97), whereas SBP and DBP were no longer associated with fatty liver (P = 0.09 and 0.19, respectively) (Table 4).
Similar associations were observed when we examined decreasing liver phantom ratio as a continuous measure of fatty liver (Table 4). Similar results were also observed after additional adjustment for physical activity and education (data not shown). There was no evidence for an interaction by age or sex in the association of fatty liver with continuous or dichotomous metabolic risk factors - except with adiponectin, where women had a slightly higher effect than men, and in HOMA-IR, where individuals >50 years of age had a higher HOMA-IR values than those <50 years of age. However, in all cases, the effect in these classes was directionally consistent with the overall effect (data not shown).
The median glucose, triglycerides, HDL, SBP, and DBP values in participants above and below the 90th percentile cut-point for VAT derived from a healthy referent sample[21] (Fig. 1) show that lipid and glucose traits were associated with fatty liver (P < 0.0001), whereas SBP and DBP were associated to a lesser extent (P = 0.0002 and 0.004, respectively) with fatty liver high and low levels of VAT. When fatty liver and VAT were jointly considered in the multivariate models, VAT remained associated with all metabolic correlates (all P < 0.0001) (data not shown) whereas fatty liver was not associated with SBP and DBP (P = 0.06 and 0.16, respectively). However, fatty liver remained associated with all other metabolic traits (P < 0.004) (data not shown).
Subjects and Methods
Subjects.
Subjects were drawn from The Framingham Heart study, a prospective cohort study initiated to evaluate risk factors for the development of cardiovascular disease. The selection criteria for this cohort have been reported.[12] The study was initiated in 1948, enrolling 5,209 residents of Framingham, Massachusetts. These individuals have been followed since then with multiple serial examinations and collection of risk factor data. In 1971, 5,124 offspring and their spouses were recruited into the Offspring Study and have been followed every 4-8 years since then.[13] In 2002, 4,095 Third Generation members and their spouses were enrolled.[14] Between 2002 and 2005, multidetector computed tomography (CT) examinations of the chest and abdomen were performed in 3,529 individuals drawn from families including both Offspring and Third Generation participants.
Multidetector CT Scan Cohort.
A total of 3,529 individuals underwent multidetector CT scanning, 1,418 from the Offspring Study and 2,111 from the Third Generation. Inclusion criteria for the study favored individuals who still resided in the greater New England area and included 755 families. The minimum age cutoffs were 35 years in men and 40 years in women. All women of child-bearing age completed a pregnancy screening, and pregnant women (for risk to the fetus) and individuals weighing >160 kg were excluded from examination. Individuals undergoing scans were excluded from this analysis if their multidetector CT scans were not interpretable for fatty liver (n = 323), did not attend Offspring Examination 7 (n = 23) or if individuals reported greater than seven drinks for men or 14 drinks for women per week (n = 487). Of these, 107 were missing a complete covariate profile and were further excluded, resulting in a total sample size of 2,589.
Multidetector CT Scan Protocol and Measurement of Fatty Liver, Visceral Adipose Tissue, and Subcutaneous Adipose Tissue.
Multidetector CT scanning was conducted as reported.[5][15][16] A calibration phantom (Image Analysis, Lexington, KY) with a water equivalent compound (CT-Water, Light Speed Ultra; General Electric, Milwaukee, WI) and calcium hydroxyapatite at 0, 75, and 150 mg/cm3 was placed under each participant.[16]
Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured[5][15]; briefly, 25 contiguous 5-mm-thick sections (120 kVP, 400 mA, gantry rotation time 500 ms, table feed 3:1 were acquired covering 125 mm above S1). Fat was identified using an image display window of -195 to -45 HU and a window center of -120 HU. After manually tracing the abdominal muscular wall separating the visceral from the subcutaneous compartment, high-resolution volumetric measurements of SAT and VAT were defined as the volumetric fat content outside and inside of this dividing line. The intraclass correlation coefficient was 0.992 for VAT and 0.997 for SAT.
Fatty liver was measured on multidetector CT scans of the abdomen and has been described elsewhere.[16] Briefly, three areas from the liver - two from the spleen and one from the external phantom - were measured. The average of the liver and spleen measurements were then calculated and used to create liver spleen ratios and liver phantom ratios. The intraclass correlation coefficient was 0.99.[16] Given that the phantom but not the spleen was visualized on all scans, primary analyses were conducted with a liver phantom ratio as the indexed standard; secondary analyses were conducted on the liver spleen ratio. Only participants with abdominal scans were used in the current analysis, because data from the abdominal scans had better reproducibility than chest scans.[16]
Distribution of the Fatty Liver Phenotype.
The distributions of liver phantom ratio and liver spleen ratio were left skewed with a median (lower-upper quartile) of 0.37 (0.34-0.39) and 1.21 (1.13-1.28), respectively (Supporting Fig. 1A). The 95th percentiles were 0.41 and 1.37 for the liver phantom ratio and liver spleen ratio, respectively. In the literature, a liver spleen ratio of 1.1 corresponds to the presence of 30% fatty liver.[17] We found that a liver phantom ratio cutoff of 0.33 had a 98% sensitivity and 70% specificity using liver spleen ratio cut-point of 1.1 as the gold standard (Supporting Fig. 1B).
Measurement of Covariates.
Risk factors used in analyses in this study were measured at the seventh examination cycle of the Offspring Study cohort (1998-2001) or the first examination of the Third Generation cohort (2002-2005). Body mass index (BMI) was defined as weight (kg)/height (m)2; waist circumference was measured at the level of the umbilicus; diabetes was defined as a fasting plasma glucose of at least 126 mg/dL at examination or treatment with either insulin or a hypoglycemic agent; impaired fasting glucose was defined as fasting plasma glucose of 100-125 mg/dL among those not treated for diabetes; and hypertension was defined as systolic blood pressure (SBP) >/=140 mm Hg or diastolic blood pressure (DBP) >/=90 mm Hg or on antihypertensive treatment. Triglycerides and high-density lipoprotein (HDL) levels are measured on fasting morning samples. Participants are considered current smokers if they had smoked at least one cigarette per day in the year preceding The Framingham Heart Study examination. Alcohol use was assessed through a series of physician-administered questions. Physical activity, assessed with a questionnaire, is a score based on the average daily number of hours of sleep and sedentary, slight, moderate, and heavy activity of the participant. Women were considered menopausal if their periods had stopped for at least 1 year. Metabolic syndrome is defined from modified Adult Treatment Panel criteria. Obesity is defined as BMI 30 kg/m2. Insulin resistance was determined as the top quartile of the homeostasis model homeostasis model assessment of insulin resistance (HOMA-IR) (fasting glucose x fasting insulin/22.5) distribution among individuals without diabetes.[18][19] Circulating adiponectin and resistin were measured by way of enzyme-linked immunoassay after an 8-hour fast as described.[20]
Determination of Fatty Liver Phantom Ratio Dichotomous Cutoff and Continuous Distribution.
The distributions of liver phantom ratios and liver spleen ratios were characterized. Because the liver phantom ratio and liver spleen ratio are likely measures of more than just fat in the liver (water content, iron, and so forth), the top 5% of points in the liver phantom ratio were winsorized for analyses with fatty liver as a continuous variable.
Prior to winsorization, to determine the liver phantom ratio cutoff that mirrored a liver spleen ratio of 1:1, the cutoff that best discriminates the presence of 30% fat in the liver,[17] we minimized misclassification of subjects at various cutoffs for liver phantom ratio. From a receiver operating curve analysis of liver phantom ratio compared with a gold standard of liver spleen ratio of 1.1, we determined the sensitivity and specificity of various cutoffs of liver phantom ratio and established a liver phantom ratio cutoff of 0.33 or lower as our working definition of fatty liver.
Statistical Analyses.
Differences in participant characteristics between those with (liver phantom ratio 0.33) were determined using a t test for normally distributed traits, Wilcoxon rank sum test for nonnormally distributed continuous variables or ordinal variables, and a chi-square test for dichotomous variables. Because the liver phantom ratio was not normally distributed, Spearman correlation coefficients were used to determine age-adjusted and sex-adjusted correlations of continuous metabolic traits with liver phantom ratio.
Primary multivariable analyses focused on fatty liver (yes/no) as the exposure and individual metabolic risk factors and fat depot measures as the dependent (outcome) variables. For dichotomous outcomes, odds ratios (calculated fatty liver yes versus fatty liver no) are reported; for continuous outcomes, the regression coefficients for the presence of fatty liver are reported. We also modeled continuous fatty liver as the exposure and odds ratios and regression coefficients for a 1 standard deviation decrease in liver phantom ratio are reported for dichotomous and continuous outcomes, respectively. The following modeling structures were used. In model 1, age, sex, alcohol consumption (after exclusions mentioned above), menopausal status, hormone replacement therapy, smoking (three-level variable: current/former/never smoker) were included as covariates. In addition, lipid treatment, hypertension treatment, and diabetes treatment were included as covariates in models for HDL cholesterol, log triglycerides, SBP and DBP, and fasting plasma glucose, respectively. In model 2, we additionally adjusted for BMI, waist circumference, and VAT. SAT was not included in these multivariate models because it was highly collinear with BMI.
In secondary analyses, we added physical activity and education to the models. Assessment of the significance of sex and age interactions with fatty liver on metabolic risk factors was also assessed. Analyses were performed using SAS version 9.1; a two-sided 0.05 alpha was used to declare statistical significance.
http://www.natap.org/2010/HCV/062010_01.htm
Hepatic Encephalopathy Linked to Chronic Cognitive Effects
Last Updated: June 18, 2010
Among patients with cirrhosis, episodes of overt hepatic encephalopathy may be associated with lingering and cumulative problems with learning, working memory, and response inhibition, according to research published in the June issue of Gastroenterology.
FRIDAY, June 18 (HealthDay News) -- Among patients with cirrhosis, episodes of overt hepatic encephalopathy (OHE) may be associated with lingering and cumulative problems with learning, working memory, and response inhibition, according to research published in the June issue of Gastroenterology.
Jasmohan S. Bajaj, M.D., of the Virginia Commonwealth University in Richmond, and colleagues analyzed data from a cross-sectional arm with 226 patients with hepatic cirrhosis, with or without history of OHE; a cross-sectional arm with 50 patients with cirrhosis and a history of OHE; and a prospective arm with 59 cirrhotic patients without prior OHE at entry. Patients underwent testing of cognitive function.
The researchers found that patients with a history of OHE had more severe cognitive impairment, with severity increasing with the number of previous episodes of OHE. In those followed prospectively, a single episode of OHE was associated with a new defect in learning of response inhibition, and multiple OHE episodes were linked to defects in reaction time, set shifting, divided attention, response inhibition, and working memory, the authors write.
"In conclusion, this study demonstrates that there are residual effects on cognitive function, especially executive functions, that result in learning impairment and working memory problems in patients with OHE, even after their first episode despite adequate therapy and the attainment of normal mental status. This psychometric performance deterioration continues and expands to the more basic cognitive domains of psychomotor speed, set shifting, and divided attention with increasing numbers of episodes and hospitalizations for OHE," the authors conclude.
Two co-authors disclosed financial relationships with Salix and/or Ocera.
Abstract
Full Text (subscription or payment may be required)
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Among patients with cirrhosis, episodes of overt hepatic encephalopathy may be associated with lingering and cumulative problems with learning, working memory, and response inhibition, according to research published in the June issue of Gastroenterology.
FRIDAY, June 18 (HealthDay News) -- Among patients with cirrhosis, episodes of overt hepatic encephalopathy (OHE) may be associated with lingering and cumulative problems with learning, working memory, and response inhibition, according to research published in the June issue of Gastroenterology.
Jasmohan S. Bajaj, M.D., of the Virginia Commonwealth University in Richmond, and colleagues analyzed data from a cross-sectional arm with 226 patients with hepatic cirrhosis, with or without history of OHE; a cross-sectional arm with 50 patients with cirrhosis and a history of OHE; and a prospective arm with 59 cirrhotic patients without prior OHE at entry. Patients underwent testing of cognitive function.
The researchers found that patients with a history of OHE had more severe cognitive impairment, with severity increasing with the number of previous episodes of OHE. In those followed prospectively, a single episode of OHE was associated with a new defect in learning of response inhibition, and multiple OHE episodes were linked to defects in reaction time, set shifting, divided attention, response inhibition, and working memory, the authors write.
"In conclusion, this study demonstrates that there are residual effects on cognitive function, especially executive functions, that result in learning impairment and working memory problems in patients with OHE, even after their first episode despite adequate therapy and the attainment of normal mental status. This psychometric performance deterioration continues and expands to the more basic cognitive domains of psychomotor speed, set shifting, and divided attention with increasing numbers of episodes and hospitalizations for OHE," the authors conclude.
Two co-authors disclosed financial relationships with Salix and/or Ocera.
Abstract
Full Text (subscription or payment may be required)
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Advanced Telaprevir Trial Cures 75 Percent of HCV
June 21, 2010
Data from a Phase III trial examining telaprevir's safety and efficacy for Hepatitis C has just been released - and it is great news!
by Nicole Cutler, L.Ac.
One of the most promising drugs in development continues to prove itself as the leading contender for improving Hepatitis C antiviral treatment. Currently in Phase III clinical trials, Vertex's telaprevir is in the last stage before obtaining FDA approval. The likelihood of telaprevir becoming widely available soon has just grown since Vertex's recent announcement that telaprevir plus the current standard of treatment substantially increases Hepatitis C treatment's success rate.
Consisting of pegylated interferon and ribavirin, the currently approved Hepatitis C antiviral treatment is only about 50 percent effective for those with the most common genotype in America - Hepatitis C genotype 1. With an estimated four to five million Americans at risk of advanced liver disease because of chronic infection with the Hepatitis C virus, a 50 percent success rate is far too low. Also referred to as combination therapy, experts have been predicting for a while that pegylated interferon and ribavirin need a third medication to increase the chance for curing Hepatitis C.
Telaprevir's readiness for the Hepatitis C market is currently being evaluated by three Phase III trials, one of which is known as the ADVANCE study. The specifics of the three studies differ slightly from one another. The three Phase III trials designed to test telaprevir, include:
1. ADVANCE - In October 2008, Vertex completed enrollment in ADVANCE, the first Phase III clinical trial of telaprevir. ADVANCE is evaluating 24-week telaprevir-based treatment regimens in those with Hepatitis C genotype 1 who have never attempted treatment before. These individuals are known as treatment naïve.
2. ILLUMINATE - In January 2009, Vertex completed enrollment in ILLUMINATE. This trial is evaluating 24-week and 48-week telaprevir-based regimens in those with Hepatitis C genotype 1 who are treatment naïve.
3. REALIZE - In February 2009, Vertex and its collaborator, Tibotec, completed enrollment in REALIZE. This trial is evaluating telaprevir-based treatment regimens for those with Hepatitis C genotype 1 who were previously unsuccessful with pegylated-interferon and ribavirin. These individuals are also known as previous non-responders.
For the purpose of defining what successful Hepatitis C treatment entails, investigators and clinicians use a sustained viral response (SVR) as their determination of success. SVR is considered to be attained if zero Hepatitis C genetic material is detectable immediately following the end of treatment and 24 weeks after the end of treatment.
During the last week of May 2010, Vertex announced results from ADVANCE. The announcement included:
· After 12 weeks of dosing with telaprevir, pegylated interferon and ribavirin was followed by another 12 weeks of just pegylated interferon and ribavirin, 75 percent of treatment naïve patients with Hepatitis C genotype 1 achieved SVR.
· After just 8 weeks of dosing with telaprevir, pegylated interferon and ribavirin was followed by another 16 weeks of just pegylated interferon and ribavirin, 69 percent of treatment naïve patients with Hepatitis C genotype 1 achieved SVR.
· After 48 weeks of treatment with the currently approved regimen of pegylated-interferon and ribavirin, 44 percent of treatment naïve patients with Hepatitis C genotype 1 achieved SVR. As this is the currently recommended medication combination and time frame used to treat Hepatitis C, this was the control group.
Since the addition of telaprevir to the current standard Hepatitis C treatment yields far better results in about half the time, many currently infected people are eagerly anticipating this treatment being available to the public. According to Ira Jacobson, MD, Chief of the Division of Gastroenterology and Hepatology, Weill Cornell Medical College and an Investigator for the ADVANCE trial, "The ADVANCE results confirm findings seen in earlier trials of telaprevir and highlight that telaprevir-based combination regimens may increase viral eradication rates and shorten treatment time for many patients."
With such good news coming from the ADVANCE trial, Vertex has indicated that it expects to request FDA approval for telaprevir in the second half of 2010. That means that the long wait for an improved Hepatitis C treatment could finally be right around the corner.
References:
http://www.vrtx.com/current-projects/drug-candidates/telaprevir-VX-950.html , Telaprevir (TX-950), Retrieved June 19, 2010, Vertex Pharmaceuticals, 2010.
http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=54657 , First Phase III Data on Vertex's Telaprevir: 75% HCV Viral Cure, Trista Morrison, Retrieved June 18, 2010, BioWorld, 2010.
http://www.hivandhepatitis.com/hep_c/news/2010/0608_2010_a.html , 75% of Treatment-naive Genotype 1 Hepatitis C Patients Achieve Sustained Response with Telaprevir Combination, Most with 24 Weeks of Therapy, Retrieved June 18, 2010, hivandhepatitis.com, June 2010.
http://www.webmd.com/hepatitis/news/20100526/hepatitis-c-drug-telaprevir-ups-cure-rate?ecd=wnl_hep_061710 , Hepatitis C Drug Telaprevir Raises Cure Rate, Daniel J. DeNoon, Retrieved June 18, 2010, WebMD, LLC, 2010.
http://www.hepatitis-central.com/mt/archives/2010/06/advanced_telapr.html
Data from a Phase III trial examining telaprevir's safety and efficacy for Hepatitis C has just been released - and it is great news!
by Nicole Cutler, L.Ac.
One of the most promising drugs in development continues to prove itself as the leading contender for improving Hepatitis C antiviral treatment. Currently in Phase III clinical trials, Vertex's telaprevir is in the last stage before obtaining FDA approval. The likelihood of telaprevir becoming widely available soon has just grown since Vertex's recent announcement that telaprevir plus the current standard of treatment substantially increases Hepatitis C treatment's success rate.
Consisting of pegylated interferon and ribavirin, the currently approved Hepatitis C antiviral treatment is only about 50 percent effective for those with the most common genotype in America - Hepatitis C genotype 1. With an estimated four to five million Americans at risk of advanced liver disease because of chronic infection with the Hepatitis C virus, a 50 percent success rate is far too low. Also referred to as combination therapy, experts have been predicting for a while that pegylated interferon and ribavirin need a third medication to increase the chance for curing Hepatitis C.
Telaprevir's readiness for the Hepatitis C market is currently being evaluated by three Phase III trials, one of which is known as the ADVANCE study. The specifics of the three studies differ slightly from one another. The three Phase III trials designed to test telaprevir, include:
1. ADVANCE - In October 2008, Vertex completed enrollment in ADVANCE, the first Phase III clinical trial of telaprevir. ADVANCE is evaluating 24-week telaprevir-based treatment regimens in those with Hepatitis C genotype 1 who have never attempted treatment before. These individuals are known as treatment naïve.
2. ILLUMINATE - In January 2009, Vertex completed enrollment in ILLUMINATE. This trial is evaluating 24-week and 48-week telaprevir-based regimens in those with Hepatitis C genotype 1 who are treatment naïve.
3. REALIZE - In February 2009, Vertex and its collaborator, Tibotec, completed enrollment in REALIZE. This trial is evaluating telaprevir-based treatment regimens for those with Hepatitis C genotype 1 who were previously unsuccessful with pegylated-interferon and ribavirin. These individuals are also known as previous non-responders.
For the purpose of defining what successful Hepatitis C treatment entails, investigators and clinicians use a sustained viral response (SVR) as their determination of success. SVR is considered to be attained if zero Hepatitis C genetic material is detectable immediately following the end of treatment and 24 weeks after the end of treatment.
During the last week of May 2010, Vertex announced results from ADVANCE. The announcement included:
· After 12 weeks of dosing with telaprevir, pegylated interferon and ribavirin was followed by another 12 weeks of just pegylated interferon and ribavirin, 75 percent of treatment naïve patients with Hepatitis C genotype 1 achieved SVR.
· After just 8 weeks of dosing with telaprevir, pegylated interferon and ribavirin was followed by another 16 weeks of just pegylated interferon and ribavirin, 69 percent of treatment naïve patients with Hepatitis C genotype 1 achieved SVR.
· After 48 weeks of treatment with the currently approved regimen of pegylated-interferon and ribavirin, 44 percent of treatment naïve patients with Hepatitis C genotype 1 achieved SVR. As this is the currently recommended medication combination and time frame used to treat Hepatitis C, this was the control group.
Since the addition of telaprevir to the current standard Hepatitis C treatment yields far better results in about half the time, many currently infected people are eagerly anticipating this treatment being available to the public. According to Ira Jacobson, MD, Chief of the Division of Gastroenterology and Hepatology, Weill Cornell Medical College and an Investigator for the ADVANCE trial, "The ADVANCE results confirm findings seen in earlier trials of telaprevir and highlight that telaprevir-based combination regimens may increase viral eradication rates and shorten treatment time for many patients."
With such good news coming from the ADVANCE trial, Vertex has indicated that it expects to request FDA approval for telaprevir in the second half of 2010. That means that the long wait for an improved Hepatitis C treatment could finally be right around the corner.
References:
http://www.vrtx.com/current-projects/drug-candidates/telaprevir-VX-950.html , Telaprevir (TX-950), Retrieved June 19, 2010, Vertex Pharmaceuticals, 2010.
http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=54657 , First Phase III Data on Vertex's Telaprevir: 75% HCV Viral Cure, Trista Morrison, Retrieved June 18, 2010, BioWorld, 2010.
http://www.hivandhepatitis.com/hep_c/news/2010/0608_2010_a.html , 75% of Treatment-naive Genotype 1 Hepatitis C Patients Achieve Sustained Response with Telaprevir Combination, Most with 24 Weeks of Therapy, Retrieved June 18, 2010, hivandhepatitis.com, June 2010.
http://www.webmd.com/hepatitis/news/20100526/hepatitis-c-drug-telaprevir-ups-cure-rate?ecd=wnl_hep_061710 , Hepatitis C Drug Telaprevir Raises Cure Rate, Daniel J. DeNoon, Retrieved June 18, 2010, WebMD, LLC, 2010.
http://www.hepatitis-central.com/mt/archives/2010/06/advanced_telapr.html
June 20, 2010
DDW: Researchers Make Advances In Understanding Causes, Treatments And Outcomes Of Liver Disease
Health Outcomes Explored at DDW® 2010
NEW ORLEANS, LA (May 2, 2010) – Non-alcoholic fatty liver disease (NAFLD), which may soon be the leading indication for liver transplant, is found to be significantly associated with worse transplant outcomes. In addition, a new tool for diagnosing NAFLD represents an alternative to liver biopsy, which is more expensive and prone to complications, and ultrasound and alfafeprotein blood test screening are an effective alternative to CT scan and MRI for patients with cirrhosis at high risk for hepatocellular cancer. These are among the research findings being presented at Digestive Disease Week® (DDW®) 2010. DDW is the largest international gathering of physicians and researchers in the field of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
“NAFLD is a growing concern in the U.S. and the research presented here gives us a better understanding of its influence on transplant outcomes as well as alternatives in diagnosing the condition,” said Frank Anania, MD, AGAF, Emory University School of Medicine, associate professor of medicine, director of hepatology.
The Influence of NAFLD and Its Associated Comorbidities on Liver Transplant Outcomes (Abstract #S1858)
NAFLD is significantly associated with worse transplant outcomes (death and graft failure) within the first 30 days after transplant, according to new research from the University of North Carolina (UNC), Chapel Hill.
NAFLD is a rising epidemic in the U.S., fueled in part by the dual epidemics of obesity and diabetes. As NAFLD increases in incidence and prevalence, researchers say they expect it to become the leading indication for liver transplantation in the next two decades. Unfortunately, the same risk factors for NAFLD — diabetes, obesity, high blood pressure and high cholesterol — are also risk factors for heart disease.
Researchers used a retrospective cohort study design to analyze 118 liver transplants over a three-year period. Besides NAFLD, diabetes was also associated with worse outcome and having poorer survival at three years after transplant. High blood pressure, high cholesterol and obesity were not independently associated with death or graft failure.
The study builds on previous research published in 2009, which reached similar conclusions. However, the group at UNC was able to use a stronger study design with a more extensive accounting of donor, operative and patient characteristics.
"Patients with NAFLD may need a more thorough pre-operative assessment prior to listing for liver transplant," said A. Sidney Barritt IV, MD, MSCR, fellow in advanced hepatology and liver transplant, UNC, Chapel Hill. "Future work should determine strategies to decrease perioperative mortality among patients with NAFLD."
That said, the study is a single center experience with a relatively small number of patients, so the researchers are actively building a consortium of transplant centers to research liver transplant outcomes. They aim to repeat a similar study on a much larger scale to validate their findings.
Dr. Barritt said despite the findings, patients with NAFLD will continue to be considered for liver transplant. "Our intent is to find ways to improve transplant outcomes for this population and to ensure that liver transplantation remains a viable, cost-effective intervention for all people with liver disease," he said.
Dr. Barritt will present these data on Sunday, May 2 at 8 a.m. CT in Hall F, Ernest N. Morial Convention Center.
Can the NAFLD Fibrosis Score be used as a Prognostic Predictor for Poor Outcomes of NAFLD Patients? (Abstract #S1848)
Researchers from Chulalongkorn University, Bangkok, Thailand, and the Mayo Clinic have developed a scoring system that for the first time appears to predict liver complications or even death in patients with NAFLD.
NAFLD is one of the most common causes of chronic liver disease and its prevalence is rising, in part because of the increasing incidence of obesity. Liver biopsy is widely considered the gold standard to diagnose the severity of NAFLD, but it is expensive, invasive and associated with a number of complications. Currently, there are no medications to treat fatty liver effectively.
To address this issue, researchers developed a simple tool, the "NAFLD fibrosis score," a composite score of variables, including medical history, age, high blood sugar and body mass index, as well as variables from blood tests including platelet count, albumin and AST/ALT ratio (liver tests). These factors were found to be an indicator for separating NAFLD patients with and without advanced or severe liver fibrosis at the initial NAFLD diagnosis. Participants were predominantly middle-aged (47 years; range 21 to 86 years), were white (95 percent) and 44 percent were male. Obesity was present in 73 percent of the population. History of high blood sugar and high blood pressure were found in 16 percent and 41 percent respectively.
Researchers used data from a cohort study of fatty liver patients diagnosed from 1980 to 2000 including 302 patients with an average follow-up of 12 years and found: the NAFLD fibrosis score change per year in patients who died was significantly higher than in those who survived; intermediate to high probability of advanced liver fibrosis assessed by NAFLD fibrosis score were found in 40 percent of patients; and higher NAFLD fibrosis score at baseline, less often use of metformin and higher creatinine at the end of follow up significantly predicted death or development of liver complication in patients with fatty liver. Results also showed that 40 percent of patients with fatty liver were in an intermediate or high probability of advanced liver fibrosis at baseline and most of them (94 percent) were still in advanced liver fibrosis group at the end of follow up.
"This quantitative scoring system should be calculated for all patients with NAFLD at initial consultation to estimate the probability of advanced liver fibrosis without additional costs," said Sombat Treeprasertsuk, MD, a gastroenterologist from Chulalongkorn University, Bangkok, Thailand, and the Mayo Clinic, Rochester, MN. "Once providers identify patients with fatty liver who have a high score or high risk of poor outcomes, they can set up a customized follow-up regimen for these patients." The test can then be recalculated to monitor progress.
Dr. Treeprasertsuk cautioned that when the tool shows a high risk of death or development of liver complications, be mindful that every diagnostic test has a true positive or a false positive result. He also encouraged people to improve their liver health through lifestyle, diet and regular exercise.
Dr. Treeprasertsuk will present these data on Sunday, May 2 at 8 a.m. CT in Hall F, Ernest N. Morial Convention Center.
Use of Ultrasound as the Initial Imaging Exam for Hepatocellular Carcinoma in High Risk Population (Abstract #S1278)
Patients with cirrhosis who are at high risk for developing heptatocellular cancer (HCC) can be effectively screened via ultrasound and alfa fetoprotein (AFP) blood test screening, rather than more costly CT or MRI scans. Researchers from the University of Texas Medical Branch at Galveston found that results from ultrasound and AFP screenings were accurate in detecting HCC. High levels of AFP are considered a biomarker for HCC.
To test the accuracy and sensitivity of standard monitoring procedures for patients with cirrhosis for the development of HCC, researchers retrospectively compared standard monitoring of ultrasound with AFP screening to subsequent results from CT or MRI scans performed within six months of the initial screening. Researchers found ultrasound alone was 99 percent specific and 76 percent sensitive in the detection of HCC. When elevated AFP was screened, specificity increased to 100 percent and the sensitivity to 87.5 percent.
"These findings emphasize the importance of using ultrasound, together with alfa fetoprotein, as the initial screening protocol, and provide a road map for when additional screening procedures, like CT and MRI scans should be undertaken," said Roger D. Soloway, MD, Marie B. Gale Centennial professor of internal medicine, University of Texas Medical Branch, gastroenterology, hepatology and nutrition division, department of internal medicine. "This data can lead to decreased use of CT without sacrificing detection rate significantly."
This retrospective analysis of demographic and laboratory data included 160 cases in which an initial ultrasound was performed followed by a CT or MRI within six months; this group included 34 cases of suspected HCC. From these suspected cases, 26 patients were correctly identified as having HCC by ultrasound. In eight cases in which ultrasound was falsely negative and CT found a lesion, the average AFP level was 32,325 ng/mL. In the 125 patients with a true negative ultrasound, the average AFP was 17.14 ng/mL. This group had only 12 patients, with an AFP greater than 20 ng/mL, and only one who had an AFP greater than 400 ng/mL.
For the entire population of patients, the positive predictive value of ultrasound for detecting HCC was 96.3 percent, while the negative predictive value was 94 percent. Only two patients had a negative ultrasound, with a normal AFP level and still had HCC.
These findings demonstrate that even with high risk patients, if ultrasound does not show a focal lesion and the AFP is normal, these standard monitoring tests should be repeated in six months. If the ultrasound does not show a focal lesion but the AFP is elevated (> 20 ng/mL), a CT and AFP should be obtained in three months as follow up.
"Ultrasound can eliminate more expensive imaging studies until confirmation is necessary, helping to reduce the overall cost of medical monitoring for patients in heptatocellular cancer screening populations," said Dr. Soloway. He cautioned that, while ultrasound is an effective screening for this group, it is not as sensitive as CT for detecting HCC.
Dr. Soloway will present these data on Sunday, May 2 at 8 a.m.. CT in Hall F, Ernest N. Morial Convention Center.
The Significance of Buprenorphine Use and Adherence in AntiHCV Treatment Outcome in Drug Users (Abstract # M1883)
A new study shows successful treatment of intravenous drug users (IVDUs) with hepatitis C virus (HCV) when treated concurrently with anti-viral and opioid substitution therapies. Intravenous drug use is a main cause of HCV transmission in Western countries, and IVDU patients with HCV are generally treated on a case-by-case basis according to current guidelines because of concerns regarding low adherence and response rates in treatment.
Investigators from The Greek Organisation Against Drugs (OKANA) and the Medical Schools of Athens and Thessaloniki evaluated common anti-HCV treatment outcomes in IVDUs receiving methadone or buprenorphine. Patients were evaluated on their adherence to treatment and the sustained virologic response (SVR) to medication, meaning no HCV RNA was detectectable by blood tests for an extended period of time following treatment.
From 2002 to 2008, 95 IVDUs with chronic HCV infection started antiviral treatment. All of them were treated with opioid-substitution therapy, 46 with methadone and 49 with buprenorphine. More than 82 percent of patients completed the treatment schedule, while seven patients discontinued treatment due to side effects and nine patients due to their own decision. SVR was observed in 66.3 percent of patients with six months post-treatment data available; 15 patients were non-responders or relapsed and 17 had not completed the treatment schedule or were lost to follow up.
SVR was higher in patients who were adherent to treatment (adherent versus discontinuation side effects versus discontinuation by own decision: 77.9 percent versus 28.6 percent versus 0 percent). Buprenorphine was also found to be associated with higher rates of fulfilling treatment schedule compared to methadone (8.1 percent discontinuation versus 27.3 percent).
"Our research demonstrates that patients with hepatitis C virus infection can be effectively treated as long as they are kept adherent," said Olga Anagnostou, MD, OKANA. "Intravenous drug users with hepatitis C infection should not be excluded from treatment — especially when they are on substitution treatment."
The results of the Greek study suggest the reconsideration of eligibility criteria for initiation of an anti-viral treatment in IVDUs and revealed the crucial role that buprenorphine may play on improving adherence and response rates.
Dr. Anagnostou will present these data on Monday, May 3 at 8 a.m. CT in Ballroom C, Ernest N. Morial Convention Center.
http://www.ddw.org/wmspage.cfm?parm1=912
NEW ORLEANS, LA (May 2, 2010) – Non-alcoholic fatty liver disease (NAFLD), which may soon be the leading indication for liver transplant, is found to be significantly associated with worse transplant outcomes. In addition, a new tool for diagnosing NAFLD represents an alternative to liver biopsy, which is more expensive and prone to complications, and ultrasound and alfafeprotein blood test screening are an effective alternative to CT scan and MRI for patients with cirrhosis at high risk for hepatocellular cancer. These are among the research findings being presented at Digestive Disease Week® (DDW®) 2010. DDW is the largest international gathering of physicians and researchers in the field of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
“NAFLD is a growing concern in the U.S. and the research presented here gives us a better understanding of its influence on transplant outcomes as well as alternatives in diagnosing the condition,” said Frank Anania, MD, AGAF, Emory University School of Medicine, associate professor of medicine, director of hepatology.
The Influence of NAFLD and Its Associated Comorbidities on Liver Transplant Outcomes (Abstract #S1858)
NAFLD is significantly associated with worse transplant outcomes (death and graft failure) within the first 30 days after transplant, according to new research from the University of North Carolina (UNC), Chapel Hill.
NAFLD is a rising epidemic in the U.S., fueled in part by the dual epidemics of obesity and diabetes. As NAFLD increases in incidence and prevalence, researchers say they expect it to become the leading indication for liver transplantation in the next two decades. Unfortunately, the same risk factors for NAFLD — diabetes, obesity, high blood pressure and high cholesterol — are also risk factors for heart disease.
Researchers used a retrospective cohort study design to analyze 118 liver transplants over a three-year period. Besides NAFLD, diabetes was also associated with worse outcome and having poorer survival at three years after transplant. High blood pressure, high cholesterol and obesity were not independently associated with death or graft failure.
The study builds on previous research published in 2009, which reached similar conclusions. However, the group at UNC was able to use a stronger study design with a more extensive accounting of donor, operative and patient characteristics.
"Patients with NAFLD may need a more thorough pre-operative assessment prior to listing for liver transplant," said A. Sidney Barritt IV, MD, MSCR, fellow in advanced hepatology and liver transplant, UNC, Chapel Hill. "Future work should determine strategies to decrease perioperative mortality among patients with NAFLD."
That said, the study is a single center experience with a relatively small number of patients, so the researchers are actively building a consortium of transplant centers to research liver transplant outcomes. They aim to repeat a similar study on a much larger scale to validate their findings.
Dr. Barritt said despite the findings, patients with NAFLD will continue to be considered for liver transplant. "Our intent is to find ways to improve transplant outcomes for this population and to ensure that liver transplantation remains a viable, cost-effective intervention for all people with liver disease," he said.
Dr. Barritt will present these data on Sunday, May 2 at 8 a.m. CT in Hall F, Ernest N. Morial Convention Center.
Can the NAFLD Fibrosis Score be used as a Prognostic Predictor for Poor Outcomes of NAFLD Patients? (Abstract #S1848)
Researchers from Chulalongkorn University, Bangkok, Thailand, and the Mayo Clinic have developed a scoring system that for the first time appears to predict liver complications or even death in patients with NAFLD.
NAFLD is one of the most common causes of chronic liver disease and its prevalence is rising, in part because of the increasing incidence of obesity. Liver biopsy is widely considered the gold standard to diagnose the severity of NAFLD, but it is expensive, invasive and associated with a number of complications. Currently, there are no medications to treat fatty liver effectively.
To address this issue, researchers developed a simple tool, the "NAFLD fibrosis score," a composite score of variables, including medical history, age, high blood sugar and body mass index, as well as variables from blood tests including platelet count, albumin and AST/ALT ratio (liver tests). These factors were found to be an indicator for separating NAFLD patients with and without advanced or severe liver fibrosis at the initial NAFLD diagnosis. Participants were predominantly middle-aged (47 years; range 21 to 86 years), were white (95 percent) and 44 percent were male. Obesity was present in 73 percent of the population. History of high blood sugar and high blood pressure were found in 16 percent and 41 percent respectively.
Researchers used data from a cohort study of fatty liver patients diagnosed from 1980 to 2000 including 302 patients with an average follow-up of 12 years and found: the NAFLD fibrosis score change per year in patients who died was significantly higher than in those who survived; intermediate to high probability of advanced liver fibrosis assessed by NAFLD fibrosis score were found in 40 percent of patients; and higher NAFLD fibrosis score at baseline, less often use of metformin and higher creatinine at the end of follow up significantly predicted death or development of liver complication in patients with fatty liver. Results also showed that 40 percent of patients with fatty liver were in an intermediate or high probability of advanced liver fibrosis at baseline and most of them (94 percent) were still in advanced liver fibrosis group at the end of follow up.
"This quantitative scoring system should be calculated for all patients with NAFLD at initial consultation to estimate the probability of advanced liver fibrosis without additional costs," said Sombat Treeprasertsuk, MD, a gastroenterologist from Chulalongkorn University, Bangkok, Thailand, and the Mayo Clinic, Rochester, MN. "Once providers identify patients with fatty liver who have a high score or high risk of poor outcomes, they can set up a customized follow-up regimen for these patients." The test can then be recalculated to monitor progress.
Dr. Treeprasertsuk cautioned that when the tool shows a high risk of death or development of liver complications, be mindful that every diagnostic test has a true positive or a false positive result. He also encouraged people to improve their liver health through lifestyle, diet and regular exercise.
Dr. Treeprasertsuk will present these data on Sunday, May 2 at 8 a.m. CT in Hall F, Ernest N. Morial Convention Center.
Use of Ultrasound as the Initial Imaging Exam for Hepatocellular Carcinoma in High Risk Population (Abstract #S1278)
Patients with cirrhosis who are at high risk for developing heptatocellular cancer (HCC) can be effectively screened via ultrasound and alfa fetoprotein (AFP) blood test screening, rather than more costly CT or MRI scans. Researchers from the University of Texas Medical Branch at Galveston found that results from ultrasound and AFP screenings were accurate in detecting HCC. High levels of AFP are considered a biomarker for HCC.
To test the accuracy and sensitivity of standard monitoring procedures for patients with cirrhosis for the development of HCC, researchers retrospectively compared standard monitoring of ultrasound with AFP screening to subsequent results from CT or MRI scans performed within six months of the initial screening. Researchers found ultrasound alone was 99 percent specific and 76 percent sensitive in the detection of HCC. When elevated AFP was screened, specificity increased to 100 percent and the sensitivity to 87.5 percent.
"These findings emphasize the importance of using ultrasound, together with alfa fetoprotein, as the initial screening protocol, and provide a road map for when additional screening procedures, like CT and MRI scans should be undertaken," said Roger D. Soloway, MD, Marie B. Gale Centennial professor of internal medicine, University of Texas Medical Branch, gastroenterology, hepatology and nutrition division, department of internal medicine. "This data can lead to decreased use of CT without sacrificing detection rate significantly."
This retrospective analysis of demographic and laboratory data included 160 cases in which an initial ultrasound was performed followed by a CT or MRI within six months; this group included 34 cases of suspected HCC. From these suspected cases, 26 patients were correctly identified as having HCC by ultrasound. In eight cases in which ultrasound was falsely negative and CT found a lesion, the average AFP level was 32,325 ng/mL. In the 125 patients with a true negative ultrasound, the average AFP was 17.14 ng/mL. This group had only 12 patients, with an AFP greater than 20 ng/mL, and only one who had an AFP greater than 400 ng/mL.
For the entire population of patients, the positive predictive value of ultrasound for detecting HCC was 96.3 percent, while the negative predictive value was 94 percent. Only two patients had a negative ultrasound, with a normal AFP level and still had HCC.
These findings demonstrate that even with high risk patients, if ultrasound does not show a focal lesion and the AFP is normal, these standard monitoring tests should be repeated in six months. If the ultrasound does not show a focal lesion but the AFP is elevated (> 20 ng/mL), a CT and AFP should be obtained in three months as follow up.
"Ultrasound can eliminate more expensive imaging studies until confirmation is necessary, helping to reduce the overall cost of medical monitoring for patients in heptatocellular cancer screening populations," said Dr. Soloway. He cautioned that, while ultrasound is an effective screening for this group, it is not as sensitive as CT for detecting HCC.
Dr. Soloway will present these data on Sunday, May 2 at 8 a.m.. CT in Hall F, Ernest N. Morial Convention Center.
The Significance of Buprenorphine Use and Adherence in AntiHCV Treatment Outcome in Drug Users (Abstract # M1883)
A new study shows successful treatment of intravenous drug users (IVDUs) with hepatitis C virus (HCV) when treated concurrently with anti-viral and opioid substitution therapies. Intravenous drug use is a main cause of HCV transmission in Western countries, and IVDU patients with HCV are generally treated on a case-by-case basis according to current guidelines because of concerns regarding low adherence and response rates in treatment.
Investigators from The Greek Organisation Against Drugs (OKANA) and the Medical Schools of Athens and Thessaloniki evaluated common anti-HCV treatment outcomes in IVDUs receiving methadone or buprenorphine. Patients were evaluated on their adherence to treatment and the sustained virologic response (SVR) to medication, meaning no HCV RNA was detectectable by blood tests for an extended period of time following treatment.
From 2002 to 2008, 95 IVDUs with chronic HCV infection started antiviral treatment. All of them were treated with opioid-substitution therapy, 46 with methadone and 49 with buprenorphine. More than 82 percent of patients completed the treatment schedule, while seven patients discontinued treatment due to side effects and nine patients due to their own decision. SVR was observed in 66.3 percent of patients with six months post-treatment data available; 15 patients were non-responders or relapsed and 17 had not completed the treatment schedule or were lost to follow up.
SVR was higher in patients who were adherent to treatment (adherent versus discontinuation side effects versus discontinuation by own decision: 77.9 percent versus 28.6 percent versus 0 percent). Buprenorphine was also found to be associated with higher rates of fulfilling treatment schedule compared to methadone (8.1 percent discontinuation versus 27.3 percent).
"Our research demonstrates that patients with hepatitis C virus infection can be effectively treated as long as they are kept adherent," said Olga Anagnostou, MD, OKANA. "Intravenous drug users with hepatitis C infection should not be excluded from treatment — especially when they are on substitution treatment."
The results of the Greek study suggest the reconsideration of eligibility criteria for initiation of an anti-viral treatment in IVDUs and revealed the crucial role that buprenorphine may play on improving adherence and response rates.
Dr. Anagnostou will present these data on Monday, May 3 at 8 a.m. CT in Ballroom C, Ernest N. Morial Convention Center.
http://www.ddw.org/wmspage.cfm?parm1=912
DDW: New Drug Treatments Hold Promise for Hepatitis C Patients
Dr. Andrew Muir was my Hepatologist at Duke who
treated me in 2005. When all other Drs told me I could never do
treatment again, he gave me the chance to retreat.
treated me in 2005. When all other Drs told me I could never do
treatment again, he gave me the chance to retreat.
I have been SVR now since May 2006.
2010 Press Releases
Health Outcomes Explored at DDW® 2010
NEW ORLEANS, LA (May 4, 2010) – Research being presented at Digestive Disease Week® (DDW®) shows that using telaprevir in the treatment regimen for hepatitis C virus (HCV) is highly effective, particularly in difficult-to-treat cases. Further studies show that aspirin may be a factor in the development of inflammatory bowel disease. DDW is the largest international gathering of physicians and researchers in the field of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
"Treatment for hepatitis C has historically been challenging, with available treatment options being uncomfortable for the patient and sometimes ineffective, but the science presented here offers hope for the patients living with the infection and the doctors who treat them," said Philip S. Schoenfeld, MD, MSEd, MSc (Epi), associate professor of medicine University of Michigan School of Medicine. "Inflammatory bowel disease, including Crohn’s disease, has been historically difficult to treat, partly because we’re still learning how the disease occurs. These data will help us better understand this debilitating disease."
Final Results of A Rollover Study Assessing Telaprevir in Combination with Peginterferon Alfa-2A and Ribavirin in Chronic Hepatitis C Patients with Well-Characterized Null Response, Partial Response, Virtual Breakthrough, or Relapse After Prior PR Treatment (Abstract #311)
Researchers at Duke Clinical Research Institute found that patients who had not improved with standard HCV treatment significantly improved response rates when telaprevir was added to the standard treatment regimen.
A previous study had suggested that patients who had failed prior treatments benefited from telaprevir, but the Duke researchers did not have records from these patients to know the full details of their previous treatment. In this study, researchers studied patients from previous telaprevir trials during which patients received standard treatment with peginterferon and ribavirin, but placebo instead of telaprevir, a drug frequently used in the treatment of HCV.
Researchers looked at 117 patients, all of whom received treatment with the combination of pegylated interferon alfa, ribavirin and telaprevir. All patients received 12 weeks of the triple combination and then 12 to 36 more weeks of pegylated interferon alfa and ribavirin.
Telaprevir was discontinued after 12 weeks, and the patients continued for 12 or 36 more weeks of peginterferon alfa and ribavirin. Results showed that null responders — patients who did not respond to previous treatment (<1-log10 decrease in HCV RNA at week four or <2-log10 at week 12) — needed 48 weeks of treatment, but 57 percent of null responders were cured with this regimen.
The other groups received the 12 weeks of triple combination therapy plus 12 more weeks of peginterferon alfa and ribavirin. For patients who were partial responders to previous therapy, 60 percent were cured with the triple combination. For patients who relapsed with previous therapy, 92 percent were cured with the triple combination.
"The results seen in this trial were encouraging for all patient groups studied," said Andrew J. Muir, MD, director of GI/hepatology research at Duke Clinical Research Institute, Duke University. "This study is yet another indication that telaprevir is consistently showing potential efficacy as a new treatment option for patients who have failed treatment, but also reinforces the additional side effects that come with adding this drug to standard treatments."
The study was funded by Vertex Pharmaceuticals, which is developing telaprevir.
Dr. Muir will present these data on Monday, May 3 at 9 a.m. CT in 383-385, Ernest N. Morial Convention Center.
Improved Sustained Virologic Response (SVR) in “Difficult to Cure” Patients Treated with Telaprevir (T) in Combination with Peginterferon Alfa-2a (P) and Ribavirin (R): An Analysis from the PROVE3 Study (Abstract #T2002)
A new study from Duke Clinical Research Institute shows that telaprevir is effective in difficult-to-treat populations with HCV. Researchers focused on populations traditionally referred to as difficult to treat, including patients with a high viral load (very severe infection), cirrhosis, older or obese patients, or African Americans, and found they all experienced improved response rates. The findings are significant because previous studies have not achieved such high response rates.
This research was a secondary analysis of a large prospective, randomized, controlled trial, PROVE3, which enrolled patients who did not respond to previous standard treatment with peginterferon alfa and ribavirin. Patients (453) were assigned to one of four treatment approaches, which included varying combinations of telaprevir in combination with peginterferon alfa and ribavirin, as well as peginterferon alfa, ribavirin and placebo.
"These findings, if confirmed in larger phase III studies, could provide a meaningful treatment option for clinicians to consider when dealing with patients who have failed an initial standard of care treatment regimen," said Andrew J. Muir, MD, director of GI/hepatology research at Duke Clinical Research Institute, Duke University.
Dr. Muir cautioned that this study is a secondary analysis, and the numbers in each subgroup are small; they need to be further confirmed in larger trials. The study was funded by Vertex Pharmaceuticals, which is developing telaprevir.
Dr. Muir will present these data on Tuesday, May 4 at from 8:00 a.m. CT in Hall F, Ernest N. Morial Convention Center.
http://www.ddw.org/wmspage.cfm?parm1=920
India needs 20,000 cadaver livers a year: Mohamed Rela
Deepa Suryanarayan / DNA
Monday, June 21, 2010 1:05
Beginning his career as a surgeon in Chennai, professor Mohamed Rela has worked over 15 years in the field of hepatobiliary (HPB) surgery and liver transplantation, and has personally performed around 1,300 liver transplants. He has even performed a successful liver transplant on the youngest patient ever (a five-day-old), a feat that earned him a place in the Guinness Book of World Records 2000 Edition.
Having worked in the largest liver transplant programme in Europe at King’s College Hospital, London, UK, since 1991, Dr Rela will now head the liver transplant and HPB surgery of Global Hospitals. DNA spoke to Dr Rela on the need for a liver transplant programme in the city.
Has liver transplant surgery changed over the years?
I performed India’s first liver transplant 14 years ago at Jaslok Hospital. Unfortunately, the child died five or six years later due to pneumonia and some complications that arose due to immuno-suppressants. Fifteen years ago, people had only heard of kidney transplant. But today, liver transplant surgeries are being performed at all leading metros. Earlier the problem was a lack of expertise, commitment and team-building. But, the situation has changed now. In the seven months that I have spent in India, I have already performed 52 liver transplants. I have also pioneered some major technical advances such as split liver transplantation — where a cadaver donor liver is divided into two for transplantation into two patients and auxiliary liver transplantation, which will soon be available in Mumbai.
How can liver transplant be made affordable to the common man?
The cost of a liver transplant — about Rs20 lakh, plus a lifelong commitment to immuno-suppressants, which cost Rs10,000 per month — is prohibitive and out of reach of the common man. One way to make it affordable is to rope in the government to subsidise it or to offer it free of cost at public hospitals. Liver transplantation is a complex procedure. It requires high infrastructure, an expert medical team, preserving the organs, expensive drugs, prolonged stay in the ICU — all of which add to the cost. But, it is still cheaper in India because the cost of the personnel and hospital fees is comparatively low. In the US, a liver transplant would cost $2,50,000 (Rs1.15 crore).
What is the biggest hurdle as far as organ donation is concerned?
According to me, lack of understanding of brain death condition is a big hurdle. You need a huge amount of public awareness about the concept of brain death as well as organ donation in order to make the organ donation programme a success. Government initiatives through legislative changes can also help. At the moment only an authorised transplant centre is allowed to retrieve organs, as a result of which the patient’s body has to be transported to the centre. This could be changed to permit any hospital with ICU facility and an equipped team of surgeons and neurologists to perform organ retrieval.
What is the need for a liver transplant programme?
Given the high incidence of Hepatitis-B and Hepatitis-C in India, as well as the prevalence of fatty liver disease which ultimately causes liver cirrhosis and cancer, a large number of people in the country are in need of transplants. In fact, India requires up to 20,000 liver transplants per year. Even if 1/10th of these patients can afford to pay for a liver transplant surgery, then 2,000 liver transplants are needed. However, currently, we are doing just 200-300 transplants. The need is huge.
http://www.dnaindia.com/mumbai/report_india-needs-20000-cadaver-livers-a-year-mohamed-rela_1399127
Monday, June 21, 2010 1:05
Beginning his career as a surgeon in Chennai, professor Mohamed Rela has worked over 15 years in the field of hepatobiliary (HPB) surgery and liver transplantation, and has personally performed around 1,300 liver transplants. He has even performed a successful liver transplant on the youngest patient ever (a five-day-old), a feat that earned him a place in the Guinness Book of World Records 2000 Edition.
Having worked in the largest liver transplant programme in Europe at King’s College Hospital, London, UK, since 1991, Dr Rela will now head the liver transplant and HPB surgery of Global Hospitals. DNA spoke to Dr Rela on the need for a liver transplant programme in the city.
Has liver transplant surgery changed over the years?
I performed India’s first liver transplant 14 years ago at Jaslok Hospital. Unfortunately, the child died five or six years later due to pneumonia and some complications that arose due to immuno-suppressants. Fifteen years ago, people had only heard of kidney transplant. But today, liver transplant surgeries are being performed at all leading metros. Earlier the problem was a lack of expertise, commitment and team-building. But, the situation has changed now. In the seven months that I have spent in India, I have already performed 52 liver transplants. I have also pioneered some major technical advances such as split liver transplantation — where a cadaver donor liver is divided into two for transplantation into two patients and auxiliary liver transplantation, which will soon be available in Mumbai.
How can liver transplant be made affordable to the common man?
The cost of a liver transplant — about Rs20 lakh, plus a lifelong commitment to immuno-suppressants, which cost Rs10,000 per month — is prohibitive and out of reach of the common man. One way to make it affordable is to rope in the government to subsidise it or to offer it free of cost at public hospitals. Liver transplantation is a complex procedure. It requires high infrastructure, an expert medical team, preserving the organs, expensive drugs, prolonged stay in the ICU — all of which add to the cost. But, it is still cheaper in India because the cost of the personnel and hospital fees is comparatively low. In the US, a liver transplant would cost $2,50,000 (Rs1.15 crore).
What is the biggest hurdle as far as organ donation is concerned?
According to me, lack of understanding of brain death condition is a big hurdle. You need a huge amount of public awareness about the concept of brain death as well as organ donation in order to make the organ donation programme a success. Government initiatives through legislative changes can also help. At the moment only an authorised transplant centre is allowed to retrieve organs, as a result of which the patient’s body has to be transported to the centre. This could be changed to permit any hospital with ICU facility and an equipped team of surgeons and neurologists to perform organ retrieval.
What is the need for a liver transplant programme?
Given the high incidence of Hepatitis-B and Hepatitis-C in India, as well as the prevalence of fatty liver disease which ultimately causes liver cirrhosis and cancer, a large number of people in the country are in need of transplants. In fact, India requires up to 20,000 liver transplants per year. Even if 1/10th of these patients can afford to pay for a liver transplant surgery, then 2,000 liver transplants are needed. However, currently, we are doing just 200-300 transplants. The need is huge.
http://www.dnaindia.com/mumbai/report_india-needs-20000-cadaver-livers-a-year-mohamed-rela_1399127
New kids on the block
By Penni Crabtree, SPECIAL TO THE UNION-TRIBUNE
Sunday, June 20, 2010 at 12:01 a.m
A decade after the Human Genome Project, which provided new insights into genes and novel tools to explore them, biotechnology companies are using that knowledge to develop cutting-edge therapies and technologies.
Here are some of the newest and most innovative leaders on San Diego’s biotech block:
REGULUS THERAPEUTICS
Founded: 2007
Employees: 45
Product: Potential treatments for inflammatory disease, hepatitis C
What happens when two venerable biotech players in the field of RNA research come together to create something new?
You get Regulus Therapeutics, the decidedly precocious offspring of Carlsbad’s Isis Pharmaceuticals and joint-venture partner Alnylam Pharmaceuticals of Cambridge, Mass.
RNA, the genetic material crucial in the production of proteins, has spawned several biotech companies over the years.
But Regulus is cutting its baby teeth on a relatively new discovery — microRNA — and has already signed major deals to develop drugs to treat hepatitis C and inflammatory diseases.
MicroRNA, tiny strands of RNA that regulate gene expression, weren’t discovered in humans until 2001. Nearly 700 microRNAs have been identified in the human genome, and more than one-third of all human genes are believed to be regulated by them, said Regulus Chief Executive Kleanthis Xanthopoulos.
MicroRNAs can affect one gene or protein, or entire networks of genes. That makes them the “master maestros” of the human genome, holding sway like a conductor over an orchestra, Xanthopoulos said.
But in a disease, the maestro microRNA — like any sensitive conductor — can get into a huff, erratically blocking some musicians or occasionally disemboweling them with the genetic baton.
“When the maestro gets out of whack and overdoes the job, there are severe consequences,” Xanthopoulos said with a laugh. “We want to develop drugs to get the maestro to return to normal so the musicians can get back on key.”
At least one major pharmaceutical company is already tapping its feet to the beat. In 2008, Regulus signed a deal with GlaxoSmithKline for $20 million, and as much as $600 million in future milestone and development fees, to create microRNA drugs for inflammatory diseases.
And GlaxoSmithKline came to the table again in February, this time paying as much as $150 million for a collaboration to develop drugs for hepatitis C.
Xanthopoulos says drug companies are jumping at microRNA because it has the same potential for blockbuster therapies that monoclonal antibodies showed 20 years ago.
“MicroRNA is one of the most innovative discoveries of the decade,” Xanthopoulos said. “The science is exploding right now.”
http://www.signonsandiego.com/news/2010/jun/20/new-kids-on-the-block/
Sunday, June 20, 2010 at 12:01 a.m
A decade after the Human Genome Project, which provided new insights into genes and novel tools to explore them, biotechnology companies are using that knowledge to develop cutting-edge therapies and technologies.
Here are some of the newest and most innovative leaders on San Diego’s biotech block:
REGULUS THERAPEUTICS
Founded: 2007
Employees: 45
Product: Potential treatments for inflammatory disease, hepatitis C
What happens when two venerable biotech players in the field of RNA research come together to create something new?
You get Regulus Therapeutics, the decidedly precocious offspring of Carlsbad’s Isis Pharmaceuticals and joint-venture partner Alnylam Pharmaceuticals of Cambridge, Mass.
RNA, the genetic material crucial in the production of proteins, has spawned several biotech companies over the years.
But Regulus is cutting its baby teeth on a relatively new discovery — microRNA — and has already signed major deals to develop drugs to treat hepatitis C and inflammatory diseases.
MicroRNA, tiny strands of RNA that regulate gene expression, weren’t discovered in humans until 2001. Nearly 700 microRNAs have been identified in the human genome, and more than one-third of all human genes are believed to be regulated by them, said Regulus Chief Executive Kleanthis Xanthopoulos.
MicroRNAs can affect one gene or protein, or entire networks of genes. That makes them the “master maestros” of the human genome, holding sway like a conductor over an orchestra, Xanthopoulos said.
But in a disease, the maestro microRNA — like any sensitive conductor — can get into a huff, erratically blocking some musicians or occasionally disemboweling them with the genetic baton.
“When the maestro gets out of whack and overdoes the job, there are severe consequences,” Xanthopoulos said with a laugh. “We want to develop drugs to get the maestro to return to normal so the musicians can get back on key.”
At least one major pharmaceutical company is already tapping its feet to the beat. In 2008, Regulus signed a deal with GlaxoSmithKline for $20 million, and as much as $600 million in future milestone and development fees, to create microRNA drugs for inflammatory diseases.
And GlaxoSmithKline came to the table again in February, this time paying as much as $150 million for a collaboration to develop drugs for hepatitis C.
Xanthopoulos says drug companies are jumping at microRNA because it has the same potential for blockbuster therapies that monoclonal antibodies showed 20 years ago.
“MicroRNA is one of the most innovative discoveries of the decade,” Xanthopoulos said. “The science is exploding right now.”
http://www.signonsandiego.com/news/2010/jun/20/new-kids-on-the-block/
June 19, 2010
Organ transplant across blood groups now a reality
Published: June 19, 2010 23:37 IST
Updated: June 20, 2010 01:54 IST
Questioning the basic rules of science is responsible for some of the more fantastic cures in medical history. Performing organ transplantation across blood groups will probably fit into this category.
Three months ago, Rajan Ravichandran, Director, MIOT Institute of Nephrology, and his team, pulled off such a feat as they used a kidney from a donor with ‘B' blood group on a recipient with ‘O' blood group. Normally, that would have killed the patient on the operating table. Not this time though. Using a special procedure called Double Filtration Plasmapheresis (DFPP) evolved by the Japanese, the team had the patient, S, discharged in a week, and back at his software job in three months' time.
Dr. Ravichandran says: “The most essential requirement in transplantation is a blood group match. Ideally, the patient's own blood group, or, in the event it is not available, any group for which his blood does not carry antibodies.” Antibodies are used to detect and neutralise foreign bodies, being the base for both allergy and immunity in the human body.
While ‘O' is a universal donor, it has antibodies to ‘A' and ‘B' groups; similarly, ‘A' has antibodies to ‘B'; and ‘B'group, antibodies to ‘A'. Only the ‘AB' group, a universal recipient, has no antibodies. The Rhesus factor (+ve, –ve) is irrelevant in the transplantation process. Tissue matching is also not done for most ‘cadaver transplants' and the availability of new generation immunosuppressant drugs has helped patients tide over that mismatch, Dr. Ravichandran clarifies.
If the right blood group is not chosen, the moment the recipient's blood begins to flow into the transplanted organ (which will continue to harbour micro red blood corpuscles from the differently matched donor's kidney), it will turn blue and will be rejected by the body. Patient S (with blood group ‘O') had a donor in his father, who was in ‘B' group. Thanks to the Japanese technology, the team removed the specific antibody (in this case, ‘B') in the patient's blood through the DFPP process over three sittings.
Meanwhile, titres to measure the presence of antibodies in the blood were done periodically. At the right time, the transplantation surgery was fixed. Post transplantation, the patient received special monoclonal antibody rejection injection to prevent new antibody formation. This process does not compromise the health of the patient in any way, Dr. Ravichandran adds.
The MIOT team comprising Ashok Shakthivel, transplant surgeon; A. Kanakaraj, nephrologist; C.N. Srinivas – Head, Immunlogy Department; N.K. Ganesh Prasad, nephrologist, headed by Dr. Ravichandran completed this procedure, which costs about Rs.3.5 lakh (against the conventional transplantation cost of Rs.2.5 lakh) on patient S.
In Japan, where the technology was evolved, over 450 successful cross-blood-group transplantations have been perfomed, he explains. The success at a 10-year survival rate is equal to that of any regular kidney transplantation. At the Mayo Clinic in the United States, over 40 such transplants have been performed using a different technique. Closer home, while several attempts at cross-blood-group transplantation have been made over the years (including by Dr. Ravichandran), success was noted only six months ago at Christian Medical College, Vellore.
This process can be used across various organ transplants, Dr. Ravichandran says, adding that it could also help people who have rejected a transplanted organ many years later because of antibody formation. With lakhs of people with end stage kidney disease in India, there are only 5,000 transplantations that occur in a year. While efforts are being made to increase the donor pool, strategies such as DFPP would increase the chances of saving lives, Dr. Ravichandran states.
P.V.A. Mohandas, managing director, MIOT Hospitals, stresses on the need to communicate the tremendous possibilities of such procedures to the public. With a high burden of diabetes and hypertension in the population and the consequent impact in the number of people with kidney disease, efforts must be taken to make transplantation available to more people, he adds.
http://beta.thehindu.com/news/cities/Chennai/article474537.ece
Updated: June 20, 2010 01:54 IST
Questioning the basic rules of science is responsible for some of the more fantastic cures in medical history. Performing organ transplantation across blood groups will probably fit into this category.
Three months ago, Rajan Ravichandran, Director, MIOT Institute of Nephrology, and his team, pulled off such a feat as they used a kidney from a donor with ‘B' blood group on a recipient with ‘O' blood group. Normally, that would have killed the patient on the operating table. Not this time though. Using a special procedure called Double Filtration Plasmapheresis (DFPP) evolved by the Japanese, the team had the patient, S, discharged in a week, and back at his software job in three months' time.
Dr. Ravichandran says: “The most essential requirement in transplantation is a blood group match. Ideally, the patient's own blood group, or, in the event it is not available, any group for which his blood does not carry antibodies.” Antibodies are used to detect and neutralise foreign bodies, being the base for both allergy and immunity in the human body.
While ‘O' is a universal donor, it has antibodies to ‘A' and ‘B' groups; similarly, ‘A' has antibodies to ‘B'; and ‘B'group, antibodies to ‘A'. Only the ‘AB' group, a universal recipient, has no antibodies. The Rhesus factor (+ve, –ve) is irrelevant in the transplantation process. Tissue matching is also not done for most ‘cadaver transplants' and the availability of new generation immunosuppressant drugs has helped patients tide over that mismatch, Dr. Ravichandran clarifies.
If the right blood group is not chosen, the moment the recipient's blood begins to flow into the transplanted organ (which will continue to harbour micro red blood corpuscles from the differently matched donor's kidney), it will turn blue and will be rejected by the body. Patient S (with blood group ‘O') had a donor in his father, who was in ‘B' group. Thanks to the Japanese technology, the team removed the specific antibody (in this case, ‘B') in the patient's blood through the DFPP process over three sittings.
Meanwhile, titres to measure the presence of antibodies in the blood were done periodically. At the right time, the transplantation surgery was fixed. Post transplantation, the patient received special monoclonal antibody rejection injection to prevent new antibody formation. This process does not compromise the health of the patient in any way, Dr. Ravichandran adds.
The MIOT team comprising Ashok Shakthivel, transplant surgeon; A. Kanakaraj, nephrologist; C.N. Srinivas – Head, Immunlogy Department; N.K. Ganesh Prasad, nephrologist, headed by Dr. Ravichandran completed this procedure, which costs about Rs.3.5 lakh (against the conventional transplantation cost of Rs.2.5 lakh) on patient S.
In Japan, where the technology was evolved, over 450 successful cross-blood-group transplantations have been perfomed, he explains. The success at a 10-year survival rate is equal to that of any regular kidney transplantation. At the Mayo Clinic in the United States, over 40 such transplants have been performed using a different technique. Closer home, while several attempts at cross-blood-group transplantation have been made over the years (including by Dr. Ravichandran), success was noted only six months ago at Christian Medical College, Vellore.
This process can be used across various organ transplants, Dr. Ravichandran says, adding that it could also help people who have rejected a transplanted organ many years later because of antibody formation. With lakhs of people with end stage kidney disease in India, there are only 5,000 transplantations that occur in a year. While efforts are being made to increase the donor pool, strategies such as DFPP would increase the chances of saving lives, Dr. Ravichandran states.
P.V.A. Mohandas, managing director, MIOT Hospitals, stresses on the need to communicate the tremendous possibilities of such procedures to the public. With a high burden of diabetes and hypertension in the population and the consequent impact in the number of people with kidney disease, efforts must be taken to make transplantation available to more people, he adds.
http://beta.thehindu.com/news/cities/Chennai/article474537.ece
'Presumed consent' legislative proposal for organ donations sparks debate
By Cara Matthews •Albany Bureau • June 19, 2010, 7:20 pm
ALBANY -- A proposal to flip New York's organ-donation system on its head by presuming people are donors unless they indicate otherwise has the state Legislature buzzing.
Polls have found that the majority of New Yorkers would like to be donors, yet just 13 percent of residents 18 and older are on the state Donate Life Registry. More than 9,600 people in the state need organ transplants, according to the New York Organ Donor Network. Last year, there were just 423 deceased organ donors in New York.
"What we have in New York is a completely failed system," said Assemblyman Richard Brodsky, D-Greenburgh, whose daughter is a two-time kidney transplant recipient and who proposed the legislation.
"People are dying in New York this week because we have failed to create a system that maximizes the opportunities to keep them alive," Brodsky said.
Brodsky said his bills to implement "presumed consent" and prohibit family members from overriding donors' wishes have sparked a lot of interest. People approach him about it everywhere he goes, and individuals and religious groups have raised legitimate concerns.
Because of that, he's not pushing the proposal this session, he said.
"What I've said to anybody, whether they like it or they don't like it, we can't sustain the current system," said Brodsky, whose daughter, Julianne "Willie," received her second transplant four years ago and has become an advocate for changing the system.
He is working on other reforms on organ donations, such as requiring the state Department of Motor Vehicles to provide information on organ donations and creating an organ donation tax credit.
Brodsky, a candidate for state attorney general, co-sponsored legislation this session that would let people consent for giving an anatomical gift through an electronic signature. It passed both houses and goes to Gov. David Paterson for his consideration. Forty-five states allow electronic signatures for donor registries, the New York Organ Donor Network said.
Other states with low donor-registration rates are Texas (an estimated 2 percent), South Carolina (9 percent) and New Hampshire (10 percent), compared to 73 percent in Alaska, an April Donate Life America report found.
No states have "presumed consent" laws, although there have been attempts in several of them, including Maryland and Pennsylvania. Legislation is under consideration in Illinois. A bill was introduced in the Delaware Legislature two years ago.
A number of European nations, including France, Austria and Spain, have this kind of system in place, and they have seen an increase in organ availability, said Arthur Caplan, a bioethics professor at the University of Pennsylvania School of Medicine.
Polla have found that the majority of New Yorkers and Americans want to donate organs and tissues when they die, so the burden should be on the minority to opt out, Caplan said. A recent survey by the New York Alliance for Donation found 67 percent of state residents strongly support organ and tissue donation.
The use of the term "presumed consent" can make some people angry because they don't want presumptions made about what happens to their bodies after they die, Caplan said. He prefers to call it "default to donation."
To get traction in this country, "It's going to take one state to sort of jump out there and show that it works," said Caplan, who has been working on the issue since 1983.
Organ-donation groups report that common objections to presumed consent are a belief that physicians may not work as hard to save them and the government and health care systems would have too much power.
The Long Island Coalition for Life Inc. opposes Brodsky's legislation, which is sponsored in the Senate by Senate Health Committee Chairman Thomas Duane, D-Manhattan.
"This legislation opens up the door to abuse via hastened death of vulnerable people and overriding of family concerns," Jerome Higgins, chairman of the coalition, wrote in a memo to lawmakers. "It also goes a step further toward turning human organs into commodities. The sick and disabled need to be protected, not exploited for their body parts."
The Rev. Jason McGuire of New Yorkers for Constitutional Freedoms, an evangelical Christian group, said organ donation should be voluntary. There are personal-privacy and big-government issues involved. In general, evangelical Christians don't oppose organ donations, although they are not permitted in certain religions, he said.
It's "bizarre" to think presumed consent would go over well with ordinary Americans, said Mary Ann Baily, a fellow of the Hastings Center, a bioethics research group in Garrison, Putnam County, and a graduate faculty member at Sarah Lawrence College in Yonkers. They are frustrated with taxes, and the idea that government would have control over their organs likely is even less popular with them.
"The problem is it's quite easy not to even notice that box that says, 'I don't want to donate my organs,"' she said, referring to a driver's license form. "You should only presume consent when it really is clear that everybody would consent if they thought about it."
One of the major reasons for not having enough organs is people have to die in a certain way and in a hospital for their organs to be viable for use by others. Most families will give consent if they are asked in the right way, said Baily, who once sat on an Institute of Medicine committee that looked at how to boost organ donations.
But even if all available organs were taken, it wouldn't eliminate waiting lists, Baily said. Hospitals may not get the maximum number of organs possible if they and organ banks aren't well organized, she said.
"This law, it seems to me ... is going to stir everybody up and probably not increase organ donations," she said.
Physicians who conduct transplants "don't hope for somebody to die to be a donor," said Dr. Luca Cicalese, chairman and director of the Texas Transplant Center and surgery professor at the University of Texas Medical Branch.
"The reality of the system is that we don't have anything to do with donors," he said.
Transplant staff don't talk to the family of someone who is dying, Cicalese said. That's done by organ-bank staff members, he said.
"There is a system that is very careful in keeping things separate and avoiding conflicts of interest," he said.
Under presumed consent, the family would still be asked whether they wanted the relative's organs to be donated, Cicalese said.
"I think the education is very important. Many people don't understand that one donor can actually save many, many people's lives," he said.
http://www.pressconnects.com/article/20100619/NEWS01/6190348/1112/-Presumed-consent--legislative-proposal-for-organ-donations-sparks-debate
ALBANY -- A proposal to flip New York's organ-donation system on its head by presuming people are donors unless they indicate otherwise has the state Legislature buzzing.
Polls have found that the majority of New Yorkers would like to be donors, yet just 13 percent of residents 18 and older are on the state Donate Life Registry. More than 9,600 people in the state need organ transplants, according to the New York Organ Donor Network. Last year, there were just 423 deceased organ donors in New York.
"What we have in New York is a completely failed system," said Assemblyman Richard Brodsky, D-Greenburgh, whose daughter is a two-time kidney transplant recipient and who proposed the legislation.
"People are dying in New York this week because we have failed to create a system that maximizes the opportunities to keep them alive," Brodsky said.
Brodsky said his bills to implement "presumed consent" and prohibit family members from overriding donors' wishes have sparked a lot of interest. People approach him about it everywhere he goes, and individuals and religious groups have raised legitimate concerns.
Because of that, he's not pushing the proposal this session, he said.
"What I've said to anybody, whether they like it or they don't like it, we can't sustain the current system," said Brodsky, whose daughter, Julianne "Willie," received her second transplant four years ago and has become an advocate for changing the system.
He is working on other reforms on organ donations, such as requiring the state Department of Motor Vehicles to provide information on organ donations and creating an organ donation tax credit.
Brodsky, a candidate for state attorney general, co-sponsored legislation this session that would let people consent for giving an anatomical gift through an electronic signature. It passed both houses and goes to Gov. David Paterson for his consideration. Forty-five states allow electronic signatures for donor registries, the New York Organ Donor Network said.
Other states with low donor-registration rates are Texas (an estimated 2 percent), South Carolina (9 percent) and New Hampshire (10 percent), compared to 73 percent in Alaska, an April Donate Life America report found.
No states have "presumed consent" laws, although there have been attempts in several of them, including Maryland and Pennsylvania. Legislation is under consideration in Illinois. A bill was introduced in the Delaware Legislature two years ago.
A number of European nations, including France, Austria and Spain, have this kind of system in place, and they have seen an increase in organ availability, said Arthur Caplan, a bioethics professor at the University of Pennsylvania School of Medicine.
Polla have found that the majority of New Yorkers and Americans want to donate organs and tissues when they die, so the burden should be on the minority to opt out, Caplan said. A recent survey by the New York Alliance for Donation found 67 percent of state residents strongly support organ and tissue donation.
The use of the term "presumed consent" can make some people angry because they don't want presumptions made about what happens to their bodies after they die, Caplan said. He prefers to call it "default to donation."
To get traction in this country, "It's going to take one state to sort of jump out there and show that it works," said Caplan, who has been working on the issue since 1983.
Organ-donation groups report that common objections to presumed consent are a belief that physicians may not work as hard to save them and the government and health care systems would have too much power.
The Long Island Coalition for Life Inc. opposes Brodsky's legislation, which is sponsored in the Senate by Senate Health Committee Chairman Thomas Duane, D-Manhattan.
"This legislation opens up the door to abuse via hastened death of vulnerable people and overriding of family concerns," Jerome Higgins, chairman of the coalition, wrote in a memo to lawmakers. "It also goes a step further toward turning human organs into commodities. The sick and disabled need to be protected, not exploited for their body parts."
The Rev. Jason McGuire of New Yorkers for Constitutional Freedoms, an evangelical Christian group, said organ donation should be voluntary. There are personal-privacy and big-government issues involved. In general, evangelical Christians don't oppose organ donations, although they are not permitted in certain religions, he said.
It's "bizarre" to think presumed consent would go over well with ordinary Americans, said Mary Ann Baily, a fellow of the Hastings Center, a bioethics research group in Garrison, Putnam County, and a graduate faculty member at Sarah Lawrence College in Yonkers. They are frustrated with taxes, and the idea that government would have control over their organs likely is even less popular with them.
"The problem is it's quite easy not to even notice that box that says, 'I don't want to donate my organs,"' she said, referring to a driver's license form. "You should only presume consent when it really is clear that everybody would consent if they thought about it."
One of the major reasons for not having enough organs is people have to die in a certain way and in a hospital for their organs to be viable for use by others. Most families will give consent if they are asked in the right way, said Baily, who once sat on an Institute of Medicine committee that looked at how to boost organ donations.
But even if all available organs were taken, it wouldn't eliminate waiting lists, Baily said. Hospitals may not get the maximum number of organs possible if they and organ banks aren't well organized, she said.
"This law, it seems to me ... is going to stir everybody up and probably not increase organ donations," she said.
Physicians who conduct transplants "don't hope for somebody to die to be a donor," said Dr. Luca Cicalese, chairman and director of the Texas Transplant Center and surgery professor at the University of Texas Medical Branch.
"The reality of the system is that we don't have anything to do with donors," he said.
Transplant staff don't talk to the family of someone who is dying, Cicalese said. That's done by organ-bank staff members, he said.
"There is a system that is very careful in keeping things separate and avoiding conflicts of interest," he said.
Under presumed consent, the family would still be asked whether they wanted the relative's organs to be donated, Cicalese said.
"I think the education is very important. Many people don't understand that one donor can actually save many, many people's lives," he said.
http://www.pressconnects.com/article/20100619/NEWS01/6190348/1112/-Presumed-consent--legislative-proposal-for-organ-donations-sparks-debate
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