January 20, 2011
The rate of stroke diagnoses increased significantly between 1997 and 2006 in people living with HIV, while simultaneously falling in HIV-negative people, according to a study published online January 19 in the journal Neurology and reported by the Los Angeles Times.
Researchers have been reporting for years that cardiovascular disease (CVD) rates are on the rise in people with HIV, looking mostly at the number of heart attacks and clogged arteries in various cohorts. Less is known about the rate of stroke, which is another major form of CVD. It occurs when there is an interruption of the blood supply to any part of the brain. It can cause disability and, in many cases, death.
To explore this matter, Bruce Ovbiagele, MD—from the University of California at San Diego—and Avindra Nath, MD—from Johns Hopkins University in Baltimore—examined the medical records of HIV-positive and HIV-negative individuals from a national database of hospitalized patients who were treated for stroke between 1997 and 2006.
Ovbiagele and Nath found that while the risk of stroke in HIV-negative study participants had fallen by 7 percent over that time period, the risk had actually increased by 60 percent in people with HIV. Moreover, the researchers found that the higher stroke risk was from an increase in ischemic strokes—those caused by blood clots in the brain—rather than strokes caused by ruptured arteries (hemorrhagic stroke).
The authors concede that some of the increased risk might be tied to the fact that more people with HIV are simply living into old age, when strokes become more prevalent. They also point out, however, that the age at which HIV-positive patients experienced a stroke—the majority of whom were in their 50s—remained largely the same over the course of the study, and that this more likely points to both HIV and antiretroviral treatment as causes.
As the LA Times story concluded, “The researchers cautioned HIV physicians to be particularly alert to symptoms that might indicate that a patient is at above-normal risk for a stroke…[but that] the absolute risk of stroke was still very low, less than 0.2 percent.”
Source
January 20, 2011
In-vitro antiviral activity of Solanum nigrum against Hepatitis C Virus
Published on: 2011-01-19
Hepatitis C is a major health problem causes liver cirrhosis, hepatocellular carcinoma and death. The current treatment of standard interferon in combination with ribavirin, has limited benefits due to emergence of resistant mutations during long-term treatment, adverse side effects and high cost.
Hence, there is a need for the development of more effective, less toxic antiviral agents.
Results: The present study was designed to search anti-HCV plants from different areas of Pakistan. Ten medicinal plants were collected and tested for anti-HCV activity by infecting the liver cells with HCV 3a innoculum.
Methanol and chloroform extracts of Solanum nigrum (SN) seeds exhibited 37% and more than 50% inhibition of HCV respectively at non toxic concentration. Moreover, antiviral effect of SN seeds extract was also analyzed against HCV NS3 protease by transfecting HCV NS3 protease plasmid into liver cells.
The results demonstrated that chloroform extract of SN decreased the expression or function of HCV NS3 protease in a dose- dependent manner and GAPDH remained constant.
Conclusion: These results suggest that SN extract contains potential antiviral agents against HCV and combination of SN extract with interferon will be better option to treat chronic HCV.
Author: Tariq JavedUsman AshfaqSana RiazSidra RehmanSheikh Riazuddin
Credits/Source: Virology Journal 2011, 8:26
Source
Hepatitis C is a major health problem causes liver cirrhosis, hepatocellular carcinoma and death. The current treatment of standard interferon in combination with ribavirin, has limited benefits due to emergence of resistant mutations during long-term treatment, adverse side effects and high cost.
Hence, there is a need for the development of more effective, less toxic antiviral agents.
Results: The present study was designed to search anti-HCV plants from different areas of Pakistan. Ten medicinal plants were collected and tested for anti-HCV activity by infecting the liver cells with HCV 3a innoculum.
Methanol and chloroform extracts of Solanum nigrum (SN) seeds exhibited 37% and more than 50% inhibition of HCV respectively at non toxic concentration. Moreover, antiviral effect of SN seeds extract was also analyzed against HCV NS3 protease by transfecting HCV NS3 protease plasmid into liver cells.
The results demonstrated that chloroform extract of SN decreased the expression or function of HCV NS3 protease in a dose- dependent manner and GAPDH remained constant.
Conclusion: These results suggest that SN extract contains potential antiviral agents against HCV and combination of SN extract with interferon will be better option to treat chronic HCV.
Author: Tariq JavedUsman AshfaqSana RiazSidra RehmanSheikh Riazuddin
Credits/Source: Virology Journal 2011, 8:26
Source
Science Center awards 3 research grants
Philadelphia Business Journal - by John George , Staff Writer
Date: Wednesday, January 19, 2011, 4:36pm EST.
The University City Science Center said Wednesday it has awarded three $200,000 grants to area researchers studying cancer, hepatitis C, and microRNA molecules through its QED proof-of-concept program.
The research and development funding includes $100,000 from the Science Center and a $100,000 match from each of three supporting institutions: The Children’s Hospital of Philadelphia, Temple University and the University of Pennsylvania.
In addition to the financial award, each of the three principal investigators will receive one year of continued business guidance to help them bring their technologies to market.
The grant recipients were:
• Linda B. Couto, associate director in the Center for Cellular and Molecular Therapeutics at Children's Hospital of Philadelphia, who is working on a novel treatment for people infected with hepatitis C virus that uses microRNA technology to overcome the problem of drug resistance;
• George P. Tuszynski, a professor of Neuroscience at Temple University’s School of Medicine, who is working on a protein-based therapy for acute myeloid leukemia that shows promise in reverting cultured leukemic cells to normal cells; and
• Marija Drndic, an associate professor at the University of Pennsylvania, who is leading a group of Penn researchers developing a “lab-on-a-chip tool” for measuring microRNA molecules, which regulate gene activity in normal and disease states.
The Science Center reviewed 45 applications for its third round of QED program grants before selecting the three recipients.
Source
Date: Wednesday, January 19, 2011, 4:36pm EST.
The University City Science Center said Wednesday it has awarded three $200,000 grants to area researchers studying cancer, hepatitis C, and microRNA molecules through its QED proof-of-concept program.
The research and development funding includes $100,000 from the Science Center and a $100,000 match from each of three supporting institutions: The Children’s Hospital of Philadelphia, Temple University and the University of Pennsylvania.
In addition to the financial award, each of the three principal investigators will receive one year of continued business guidance to help them bring their technologies to market.
The grant recipients were:
• Linda B. Couto, associate director in the Center for Cellular and Molecular Therapeutics at Children's Hospital of Philadelphia, who is working on a novel treatment for people infected with hepatitis C virus that uses microRNA technology to overcome the problem of drug resistance;
• George P. Tuszynski, a professor of Neuroscience at Temple University’s School of Medicine, who is working on a protein-based therapy for acute myeloid leukemia that shows promise in reverting cultured leukemic cells to normal cells; and
• Marija Drndic, an associate professor at the University of Pennsylvania, who is leading a group of Penn researchers developing a “lab-on-a-chip tool” for measuring microRNA molecules, which regulate gene activity in normal and disease states.
The Science Center reviewed 45 applications for its third round of QED program grants before selecting the three recipients.
Source
Hepatitis C Information Growing Among Veterans
By Mike Bowersock
Published: January 19, 2011
BEXLEY, Ohio -- Hepatitis C is striking Vietnam-era veterans at a rate five times the general public and a local man is working to get the word out.
NBC4 reported about the effort Monday, and since then, the man has received several calls, emails and inquiries.
Hepatitis C can remain undetected for 10, 20, 30 years or more.
So some veterans are just finding out that the reason they're always tired or perhaps have abdominal pains is hepatitis C.
NBC4 has featured Dennis Agin in stories regarding Agent Orange, but he's also discovered he has hepatitis C and has been researching it among veterans.
Agin performed oral surgery while in the Navy in Vietnam and many of the veterans who are discovering they have the virus were medics or somehow came in contact with blood.
After the story on veterans and hepatits C aired on NBC4, several veterans and families of veterans contacted Agin, wanting more information.
"From people who saw the video that you did and they happened to be doing something also and all of a sudden they look and they say that's what I have. That's my problem," said Agin.
He's meeting with some of the veterans, helping them fill out paperwork to see if they're eligible for benefits.
One of the calls Agin received was from a woman's whose father died of hepatitis C and was part of the first Marines to go into Vietnam.
NBC4 will continue to follow the story and provide updates as available.
To contact Dr. Agin, call 877-OHIO-VET or email n8iln@att.net.
Source
Also See: Hepatitis C Cases Appearing More In Vietnam Veterans
Published: January 19, 2011
BEXLEY, Ohio -- Hepatitis C is striking Vietnam-era veterans at a rate five times the general public and a local man is working to get the word out.
NBC4 reported about the effort Monday, and since then, the man has received several calls, emails and inquiries.
Hepatitis C can remain undetected for 10, 20, 30 years or more.
So some veterans are just finding out that the reason they're always tired or perhaps have abdominal pains is hepatitis C.
NBC4 has featured Dennis Agin in stories regarding Agent Orange, but he's also discovered he has hepatitis C and has been researching it among veterans.
Agin performed oral surgery while in the Navy in Vietnam and many of the veterans who are discovering they have the virus were medics or somehow came in contact with blood.
After the story on veterans and hepatits C aired on NBC4, several veterans and families of veterans contacted Agin, wanting more information.
"From people who saw the video that you did and they happened to be doing something also and all of a sudden they look and they say that's what I have. That's my problem," said Agin.
He's meeting with some of the veterans, helping them fill out paperwork to see if they're eligible for benefits.
One of the calls Agin received was from a woman's whose father died of hepatitis C and was part of the first Marines to go into Vietnam.
NBC4 will continue to follow the story and provide updates as available.
To contact Dr. Agin, call 877-OHIO-VET or email n8iln@att.net.
Source
Also See: Hepatitis C Cases Appearing More In Vietnam Veterans
Vertex Pharma's Hep C drug gets priority review
Thu Jan 20, 2011 8:08am EST
* Drug gets priority review status from FDA, Health Canada
* FDA sets action date for May 23
Jan 20 (Reuters) - Vertex Pharmaceuticals Inc (VRTX.O) said its experimental treatment for Hepatitis C got priority review status from health regulators in the United States and Canada.
Cambridge, Massachusetts-based Vertex, which had asked the U.S. Food and Drug Administration for a priority review of data from telaprevir in November, said the agency set an action date for May 23 to decide on the approval.
Priority review status from the FDA reduces the review period by four month, the company said. The same status from Canadian health regulator Health Canada cuts short the review period to six to nine months, compared to a review period of 18 months or more.
Vertex is developing telaprevir in collaboration with Tibotec Pharmaceuticals, a unit of Johnson & Johnson (JNJ.N), and Mitsubishi Tanabe Pharma (4508.T).
Vertex holds rights to market the drug in North America while Tibotec has rights to market it in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe has rights in Japan and certain Far East countries.
Shares of Vertex have risen 15 percent since it applied for the priority review. They closed at $39.45 Wednesday on Nasdaq. (Reporting by Vidya L Nathan in Bangalore)
StocksRegulatory NewsGlobal MarketsHealthcare
Source
Also See: U.S. FDA and Health Canada Grant Priority Reviews for Telaprevir for the Treatment of Hepatitis C
* Drug gets priority review status from FDA, Health Canada
* FDA sets action date for May 23
Jan 20 (Reuters) - Vertex Pharmaceuticals Inc (VRTX.O) said its experimental treatment for Hepatitis C got priority review status from health regulators in the United States and Canada.
Cambridge, Massachusetts-based Vertex, which had asked the U.S. Food and Drug Administration for a priority review of data from telaprevir in November, said the agency set an action date for May 23 to decide on the approval.
Priority review status from the FDA reduces the review period by four month, the company said. The same status from Canadian health regulator Health Canada cuts short the review period to six to nine months, compared to a review period of 18 months or more.
Vertex is developing telaprevir in collaboration with Tibotec Pharmaceuticals, a unit of Johnson & Johnson (JNJ.N), and Mitsubishi Tanabe Pharma (4508.T).
Vertex holds rights to market the drug in North America while Tibotec has rights to market it in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe has rights in Japan and certain Far East countries.
Shares of Vertex have risen 15 percent since it applied for the priority review. They closed at $39.45 Wednesday on Nasdaq. (Reporting by Vidya L Nathan in Bangalore)
StocksRegulatory NewsGlobal MarketsHealthcare
Source
Also See: U.S. FDA and Health Canada Grant Priority Reviews for Telaprevir for the Treatment of Hepatitis C
HCV+ Kidneys Safely Go to HCV+ Recipients?
Ron Shapiro, MD
Posted: 01/20/2011
View Video here
Hi. My name is Ron Shapiro. I am a transplant surgeon at the University of Pittsburgh. Today I want to talk about a recent study that provides long-term outcomes in organ recipients who were hepatitis C-positive and received organs from either hepatitis C-positive donors or hepatitis C-negative donors.
This study from Spain[1] has been published with shorter follow-ups than in the past, and this is the most recent study, now with 5- and 10-year outcomes. Patient survival was unchanged, according to the donor hepatitis C serology. Graft survival at 10 years was inferior in the hepatitis C-positive-to-positive group, but the demographics were different in that both the donors and the recipients were older in the positive-to-positive group, and this could explain a great deal of the inferior 10-year outcomes. When a multivariate analysis was performed, hepatitis C serology was not a significant factor.
This study has, in the past, provided us with some reassurance that for hepatitis C-positive recipients, it did not matter whether the donor was positive or negative. We have been able to use these kidneys in hepatitis C-positive recipients. The study now provides 10-year data confirming the safety of this approach.
One of the holes in this study is that the subtypes of hepatitis C were never characterized, and the serologies in the Spanish donors have generally been related to a single subgroup. However, it is reassuring to know that with long-term follow-up, hepatitis C-positive kidneys can be used in hepatitis C-positive recipients.
Thank you.
Source
Posted: 01/20/2011
View Video here
Hi. My name is Ron Shapiro. I am a transplant surgeon at the University of Pittsburgh. Today I want to talk about a recent study that provides long-term outcomes in organ recipients who were hepatitis C-positive and received organs from either hepatitis C-positive donors or hepatitis C-negative donors.
This study from Spain[1] has been published with shorter follow-ups than in the past, and this is the most recent study, now with 5- and 10-year outcomes. Patient survival was unchanged, according to the donor hepatitis C serology. Graft survival at 10 years was inferior in the hepatitis C-positive-to-positive group, but the demographics were different in that both the donors and the recipients were older in the positive-to-positive group, and this could explain a great deal of the inferior 10-year outcomes. When a multivariate analysis was performed, hepatitis C serology was not a significant factor.
This study has, in the past, provided us with some reassurance that for hepatitis C-positive recipients, it did not matter whether the donor was positive or negative. We have been able to use these kidneys in hepatitis C-positive recipients. The study now provides 10-year data confirming the safety of this approach.
One of the holes in this study is that the subtypes of hepatitis C were never characterized, and the serologies in the Spanish donors have generally been related to a single subgroup. However, it is reassuring to know that with long-term follow-up, hepatitis C-positive kidneys can be used in hepatitis C-positive recipients.
Thank you.
Source
DNA Test for Hep B May Find Infections in Donor Blood
By Kristina Fiore, Staff Writer, MedPage Today
Published: January 19, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Nucleic acid testing for hepatitis B virus (HBV) in blood donors may catch potential infection during transfusion, researchers said.
The screen picked up nine cases of the virus in a sample of 3.7 million donors -- more than triple the expected infection rate in this population, Susan Stramer, PhD, of the American Red Cross in Rockville, Md., and colleagues reported in the Jan. 20 issue of the New England Journal of Medicine.
"This study showed a higher-than-expected rate of HBV infection with the use of triplex nucleic acid testing, mainly in donors who had been vaccinated against HBV and who would not have been identified by routine screening," they wrote.
Yet they noted that the acute infections resolved quickly, and their clinical significance in terms of transmission potential isn't clear.
Hepatitis B screening in donors currently tests for disease-specific surface antigen (HBsAg) or for antibodies against hepatitis B core antigen (anti-HBc).
Yet not all donors who have hepatitis B DNA are identified during the period before seroconversion.
So the researchers hypothesized that combination nucleic acid testing for hepatitis B and C as well as HIB in a single triplex assay may provide additional safety.
They performed nucleic acid testing on 3.7 million blood donations and further evaluated the hepatitis B DNA-positive samples that were negative for HBsAg and anti-HBc.
They found nine donors who had hepatitis B DNA, which translated to an overall rate of one in 410,540 donations -- far larger than the two to four expected based on modeling studies, the researchers said.
Six of the samples came from donors who'd received the hepatitis B vaccine and had subclinical infections that developed and resolved.
The investigators said the blood of donors with acute infection during the window period is likely to be highly infectious in transfusion recipients, although the significance of infection in vaccinated donors is less clear.
"These acute HBV infections rapidly resolved and are of inconsequential significance, but their potential for transmission remains unresolved," they wrote.
Three patients who weren't vaccinated and tested positive in nucleic acid screening for hepatitis B had acute infection with subgenotype A2, which is the most frequent genotype in the U.S. and is the parent strain of the HBV vaccine.
On the other hand, only one of the six vaccinated donors were infected with the A2 subtype. The others had non-A2 strains.
The researchers said the findings "emphasize the protective effect of the vaccine, since the observed infections were transient, blunted, and without effect on liver function," but noted that it is less effective for non-A2 infections.
Overall, only two cases of liver injury occurred among those nine hepatitis B DNA-positive patients, and they were in unvaccinated donors.
The researchers attributed infection in four of the DNA-positive donors to a chronically infected sexual partner.
They noted that the infrequent detection of transfusion-transmitted infection contributes to the low cost-effectiveness of nucleic acid testing. Yet in their sample, they found that of 75 reactive nucleic acid tests in seronegative blood samples, 25 were confirmed as positive for either hepatitis B, hepatitis C, or HIV.
Thus, they called for the development of new tests in order to get around the high cost of introducing new screening assays for blood donors and concluded that their findings "may be relevant to decisions about the need to implement screening for HBV DNA among blood donors."
The researchers reported relationships with MacoPharma, Novartis, Abbott Diagnostics, Novartis Vaccines and Diagnostics, Abbott, Roche, Siemens, and Gen-Probe.
Primary source: New England Journal of Medicine
Source reference:
Stramer SL, et al "Nucleic acid testing to detect HBV infection in blood donors" N Engl J Med 2011; 364: 236-247.
Source
Published: January 19, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Nucleic acid testing for hepatitis B virus (HBV) in blood donors may catch potential infection during transfusion, researchers said.
The screen picked up nine cases of the virus in a sample of 3.7 million donors -- more than triple the expected infection rate in this population, Susan Stramer, PhD, of the American Red Cross in Rockville, Md., and colleagues reported in the Jan. 20 issue of the New England Journal of Medicine.
"This study showed a higher-than-expected rate of HBV infection with the use of triplex nucleic acid testing, mainly in donors who had been vaccinated against HBV and who would not have been identified by routine screening," they wrote.
Yet they noted that the acute infections resolved quickly, and their clinical significance in terms of transmission potential isn't clear.
Hepatitis B screening in donors currently tests for disease-specific surface antigen (HBsAg) or for antibodies against hepatitis B core antigen (anti-HBc).
Yet not all donors who have hepatitis B DNA are identified during the period before seroconversion.
So the researchers hypothesized that combination nucleic acid testing for hepatitis B and C as well as HIB in a single triplex assay may provide additional safety.
They performed nucleic acid testing on 3.7 million blood donations and further evaluated the hepatitis B DNA-positive samples that were negative for HBsAg and anti-HBc.
They found nine donors who had hepatitis B DNA, which translated to an overall rate of one in 410,540 donations -- far larger than the two to four expected based on modeling studies, the researchers said.
Six of the samples came from donors who'd received the hepatitis B vaccine and had subclinical infections that developed and resolved.
The investigators said the blood of donors with acute infection during the window period is likely to be highly infectious in transfusion recipients, although the significance of infection in vaccinated donors is less clear.
"These acute HBV infections rapidly resolved and are of inconsequential significance, but their potential for transmission remains unresolved," they wrote.
Three patients who weren't vaccinated and tested positive in nucleic acid screening for hepatitis B had acute infection with subgenotype A2, which is the most frequent genotype in the U.S. and is the parent strain of the HBV vaccine.
On the other hand, only one of the six vaccinated donors were infected with the A2 subtype. The others had non-A2 strains.
The researchers said the findings "emphasize the protective effect of the vaccine, since the observed infections were transient, blunted, and without effect on liver function," but noted that it is less effective for non-A2 infections.
Overall, only two cases of liver injury occurred among those nine hepatitis B DNA-positive patients, and they were in unvaccinated donors.
The researchers attributed infection in four of the DNA-positive donors to a chronically infected sexual partner.
They noted that the infrequent detection of transfusion-transmitted infection contributes to the low cost-effectiveness of nucleic acid testing. Yet in their sample, they found that of 75 reactive nucleic acid tests in seronegative blood samples, 25 were confirmed as positive for either hepatitis B, hepatitis C, or HIV.
Thus, they called for the development of new tests in order to get around the high cost of introducing new screening assays for blood donors and concluded that their findings "may be relevant to decisions about the need to implement screening for HBV DNA among blood donors."
The researchers reported relationships with MacoPharma, Novartis, Abbott Diagnostics, Novartis Vaccines and Diagnostics, Abbott, Roche, Siemens, and Gen-Probe.
Primary source: New England Journal of Medicine
Source reference:
Stramer SL, et al "Nucleic acid testing to detect HBV infection in blood donors" N Engl J Med 2011; 364: 236-247.
Source
U.S. FDA and Health Canada Grant Priority Reviews for Telaprevir for the Treatment of Hepatitis C
- Six-month review date of May 23, 2011 set by FDA-
CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) announced today that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for telaprevir and granted the company's request for six-month Priority Review. Telaprevir is Vertex's lead medicine in development for people with genotype 1 chronic hepatitis C. The FDA grants Priority Review to medicines that offer major advances in treatment or provide a treatment where no adequate therapy exists. A target review date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA) for the FDA's approval decision, which is four months earlier than the standard review time of 10 months.
Additionally, Vertex today announced the completion of a New Drug Submission (NDS) to the Therapeutic Product Directorate (TPD) of Health Canada seeking approval for telaprevir in Canada. Telaprevir was also granted Priority Review in Canada, which allows for faster review for promising medicines that address life-threatening or severely debilitating conditions and for which there are few effective therapies already available. Standard review in Canada takes 18 months or more and Priority Review typically shortens the review time to approximately six to nine months.
In December 2010, Janssen-Cilag International NV announced that the European Medicines Agency (EMA) accepted telaprevir for accelerated assessment in Europe, which is granted to new medicines of major public health interest.
"Data from Phase 3 studies showed that when compared to currently available medicines, telaprevir-based combination therapy nearly doubled viral cure rates and cut treatment time in half for the majority of patients new to treatment," said Peter Mueller, Ph.D., Chief Scientific Officer and Executive Vice President of Global Research and Development at Vertex. "We look forward to working with the FDA and Health Canada to make telaprevir available as quickly as possible for people with hepatitis C."
Data to Support the Telaprevir Submissions
The regulatory submissions in the United States, Canada and Europe are supported by data from three Phase 3 studies, known as ADVANCE, ILLUMINATE and REALIZE, which evaluated up to 12 weeks of telaprevir in combination with Pegasys® (pegylated-interferon alfa-2a) and Copegus® (ribavirin) in people chronically infected with genotype 1 hepatitis C virus (HCV) who were new to treatment as well as those who were treated before with currently available medicines but did not achieve a sustained viral response (SVR, or viral cure). In these studies, treatment with telaprevir-based combination therapy resulted in significantly higher viral cure rates compared to approved medicines, regardless of prior treatment experience, race or stage of liver disease. Up to 75 percent of people new to treatment achieved a viral cure with telaprevir-based therapy. The majority of these people were able to complete their course of treatment at six months — half the time needed with currently available medicines. Among those who did not achieve a viral cure with a prior treatment course of currently available medicines, Phase 3 data showed that telaprevir-based combination therapy resulted in viral cure rates three to five times higher compared to re-treatment with currently available medicines. The safety and tolerability results of telaprevir-based combination therapy were consistent across the Phase 3 studies. The most common adverse events regardless of treatment regimen were rash, fatigue, pruritis, headache, nausea, anemia, insomnia, diarrhea, flu-like symptoms and pyrexia, with the majority being mild or moderate in severity.
Vertex provided a summary of Phase 3 results, including SVR and safety data for telaprevir, in its November 23, 2010 press release announcing the NDA submission.
About Telaprevir
Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with genotype 1 hepatitis C have received telaprevir in Phase 2 and Phase 3 studies.
Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1 Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved medicines, do not achieve SVR,2,3,4 or viral cure.5 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.6,7,8.9,10
Hepatitis C in the United States
Up to 3.9 million people in the United States have chronic hepatitis C and 75 percent of them are unaware of their infection.11 The majority of people with hepatitis C in the U.S. were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the U.S. and is reported to contribute to 4,600 to 12,000 deaths annually.7 By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.10
Hepatitis C in Canada
Approximately 250,000 people in Canada have chronic hepatitis C and more than a third of them do not know they are infected.12 Three provinces account for 80 percent of hepatitis C infections in Canada: Ontario (42 percent), British Columbia (22 percent) and Quebec (16 percent).13 Each year up to 5,000 people are newly infected with hepatitis C and in 2007 alone, nearly 8,000 people were infected.12, 13 In 2010, the annual cost of hepatitis C due to medical treatment and lost productivity in Canada was estimated to reach $1 billion.14 By 2022, the number of hepatitis C-related deaths is expected to increase by one-third.15
Additional resources for media are available at: http://investors.vrtx.com/press.cfm.
PEGASYS® and COPEGUS® are registered trademarks of Hoffman-LA Roche.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements, including statements regarding (i) the FDA's target review date for the telaprevir NDA, (ii) Priority Review in Canada allowing for faster review of New Drug Submissions, typically shortening the review time to approximately six to nine months and (iii) Vertex working with the FDA and Health Canada to make telaprevir available as quickly as possible for people with hepatitis C. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
About Vertex
Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.
About Vertex in Canada
In 2009, Vertex established a research and development site in Laval, Quebec through the acquisition of Virochem Pharma, Inc. Vertex is expanding its existing research and development infrastructure with the addition of commercial and medical teams to support the potential launch of telaprevir in Canada.
For more information and to view Vertex's press releases, please visit http://www.vrtx.com/.
(VRTX - GEN)
References:
1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010.
2 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
3 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
4 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
5 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
6 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
7 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
8 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
9 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
10 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc.
11 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010.
12 Public Health Agency of Canada. Hepatitis C: Get the facts. You could have it and not know it. http://www.phac-aspc.gc.ca/hepc/pubs/getfacts-informezvous/index-eng.php. Updated September 21, 2010. Accessed January 18, 2011.
13 Public Health Agency of Canada. Modeling the incidence of prevalence of hepatitis C infection and its sequelae in Canada, 2007. http://www.phac-aspc.gc.ca/sti-its-surv-epi/model/results-eng.php. Updated October 20, 2010. Accessed January 18, 2011.
14 Public Health Agency of Canada. A renewed public health response to address hepatitis C: A summary report of the priority-setting process and strategic framework to action. http://www.phac-aspc.gc.ca/hepc/sr-rs/pdf/srhepc-eng.pdf. Updated June 2009. Accessed January 2011.
15 Sherman M, Sharfran S, Burak K, et al. Management of chronic hepatitis C consensus guidelines. Can J Gastroenterol. 2007;21 (Suppl C):25C-34C.
Vertex Pharmaceuticals Incorporated
Media:
Amy Pasqua, 617-444-6992
or
Dawn Kalmar, 617-444-6992
or
Zachry Barber, 617-444-6992
mediainfo@vrtx.com
or
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755
or
Matthew Osborne, 617-444-6057
Source: Vertex Pharmaceuticals Incorporated
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CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) announced today that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for telaprevir and granted the company's request for six-month Priority Review. Telaprevir is Vertex's lead medicine in development for people with genotype 1 chronic hepatitis C. The FDA grants Priority Review to medicines that offer major advances in treatment or provide a treatment where no adequate therapy exists. A target review date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA) for the FDA's approval decision, which is four months earlier than the standard review time of 10 months.
Additionally, Vertex today announced the completion of a New Drug Submission (NDS) to the Therapeutic Product Directorate (TPD) of Health Canada seeking approval for telaprevir in Canada. Telaprevir was also granted Priority Review in Canada, which allows for faster review for promising medicines that address life-threatening or severely debilitating conditions and for which there are few effective therapies already available. Standard review in Canada takes 18 months or more and Priority Review typically shortens the review time to approximately six to nine months.
In December 2010, Janssen-Cilag International NV announced that the European Medicines Agency (EMA) accepted telaprevir for accelerated assessment in Europe, which is granted to new medicines of major public health interest.
"Data from Phase 3 studies showed that when compared to currently available medicines, telaprevir-based combination therapy nearly doubled viral cure rates and cut treatment time in half for the majority of patients new to treatment," said Peter Mueller, Ph.D., Chief Scientific Officer and Executive Vice President of Global Research and Development at Vertex. "We look forward to working with the FDA and Health Canada to make telaprevir available as quickly as possible for people with hepatitis C."
Data to Support the Telaprevir Submissions
The regulatory submissions in the United States, Canada and Europe are supported by data from three Phase 3 studies, known as ADVANCE, ILLUMINATE and REALIZE, which evaluated up to 12 weeks of telaprevir in combination with Pegasys® (pegylated-interferon alfa-2a) and Copegus® (ribavirin) in people chronically infected with genotype 1 hepatitis C virus (HCV) who were new to treatment as well as those who were treated before with currently available medicines but did not achieve a sustained viral response (SVR, or viral cure). In these studies, treatment with telaprevir-based combination therapy resulted in significantly higher viral cure rates compared to approved medicines, regardless of prior treatment experience, race or stage of liver disease. Up to 75 percent of people new to treatment achieved a viral cure with telaprevir-based therapy. The majority of these people were able to complete their course of treatment at six months — half the time needed with currently available medicines. Among those who did not achieve a viral cure with a prior treatment course of currently available medicines, Phase 3 data showed that telaprevir-based combination therapy resulted in viral cure rates three to five times higher compared to re-treatment with currently available medicines. The safety and tolerability results of telaprevir-based combination therapy were consistent across the Phase 3 studies. The most common adverse events regardless of treatment regimen were rash, fatigue, pruritis, headache, nausea, anemia, insomnia, diarrhea, flu-like symptoms and pyrexia, with the majority being mild or moderate in severity.
Vertex provided a summary of Phase 3 results, including SVR and safety data for telaprevir, in its November 23, 2010 press release announcing the NDA submission.
About Telaprevir
Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with genotype 1 hepatitis C have received telaprevir in Phase 2 and Phase 3 studies.
Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1 Approximately 60 percent of genotype 1 patients who undergo an initial 48-week regimen with pegylated-interferon and ribavirin, the currently approved medicines, do not achieve SVR,2,3,4 or viral cure.5 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.6,7,8.9,10
Hepatitis C in the United States
Up to 3.9 million people in the United States have chronic hepatitis C and 75 percent of them are unaware of their infection.11 The majority of people with hepatitis C in the U.S. were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the U.S. and is reported to contribute to 4,600 to 12,000 deaths annually.7 By 2029, total annual medical costs in the U.S. for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.10
Hepatitis C in Canada
Approximately 250,000 people in Canada have chronic hepatitis C and more than a third of them do not know they are infected.12 Three provinces account for 80 percent of hepatitis C infections in Canada: Ontario (42 percent), British Columbia (22 percent) and Quebec (16 percent).13 Each year up to 5,000 people are newly infected with hepatitis C and in 2007 alone, nearly 8,000 people were infected.12, 13 In 2010, the annual cost of hepatitis C due to medical treatment and lost productivity in Canada was estimated to reach $1 billion.14 By 2022, the number of hepatitis C-related deaths is expected to increase by one-third.15
Additional resources for media are available at: http://investors.vrtx.com/press.cfm.
PEGASYS® and COPEGUS® are registered trademarks of Hoffman-LA Roche.
Special Note Regarding Forward-looking Statements
This press release contains forward-looking statements, including statements regarding (i) the FDA's target review date for the telaprevir NDA, (ii) Priority Review in Canada allowing for faster review of New Drug Submissions, typically shortening the review time to approximately six to nine months and (iii) Vertex working with the FDA and Health Canada to make telaprevir available as quickly as possible for people with hepatitis C. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
About Vertex
Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.
About Vertex in Canada
In 2009, Vertex established a research and development site in Laval, Quebec through the acquisition of Virochem Pharma, Inc. Vertex is expanding its existing research and development infrastructure with the addition of commercial and medical teams to support the potential launch of telaprevir in Canada.
For more information and to view Vertex's press releases, please visit http://www.vrtx.com/.
(VRTX - GEN)
References:
1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed May 25, 2010.
2 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
3 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
4 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
5 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
6 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
7 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
8 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
9 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
10 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. This report was commissioned by Vertex Pharmaceuticals, Inc.
11 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed May 25, 2010.
12 Public Health Agency of Canada. Hepatitis C: Get the facts. You could have it and not know it. http://www.phac-aspc.gc.ca/hepc/pubs/getfacts-informezvous/index-eng.php. Updated September 21, 2010. Accessed January 18, 2011.
13 Public Health Agency of Canada. Modeling the incidence of prevalence of hepatitis C infection and its sequelae in Canada, 2007. http://www.phac-aspc.gc.ca/sti-its-surv-epi/model/results-eng.php. Updated October 20, 2010. Accessed January 18, 2011.
14 Public Health Agency of Canada. A renewed public health response to address hepatitis C: A summary report of the priority-setting process and strategic framework to action. http://www.phac-aspc.gc.ca/hepc/sr-rs/pdf/srhepc-eng.pdf. Updated June 2009. Accessed January 2011.
15 Sherman M, Sharfran S, Burak K, et al. Management of chronic hepatitis C consensus guidelines. Can J Gastroenterol. 2007;21 (Suppl C):25C-34C.
Vertex Pharmaceuticals Incorporated
Media:
Amy Pasqua, 617-444-6992
or
Dawn Kalmar, 617-444-6992
or
Zachry Barber, 617-444-6992
mediainfo@vrtx.com
or
Investors:
Michael Partridge, 617-444-6108
or
Lora Pike, 617-444-6755
or
Matthew Osborne, 617-444-6057
Source: Vertex Pharmaceuticals Incorporated
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Source
January 18, 2011
Increased risk of parkinsonism among patients with cirrhosis: a 7-year follow-up study
Liver International
Early View (Articles online in advance of print)
Jiunn-Horng Kang 1,2,†, Ming-Chieh Tsai 3,4,†, Ching-Chun Lin 5, Hsiu-Li Lin 6, Herng-Ching Lin 5
Article first published online: 11 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02432.x
© 2011 John Wiley & Sons A/S
Author Information
1 Neuroscience Research Center, Taipei Medical University Hospital, Taipei, Taiwan
2 School of Medicine, Taipei Medical University, Taipei, Taiwan
3 School of Health Care Administration, Taipei Medical University, Taipei, Taiwan
4 Department of Internal Medicine, Division of Gastroenterology, General Cathay Hospital, Sijhih Branch, Taipei, Taiwan
5 School of Health Care Administration, Taipei Medical University, Taipei, Taiwan
6 Department of Neurology, General Cathay Hospital, Sijhih Branch, Taipei, Taiwan
* Correspondence: Correspondence Herng-Ching Lin, School of Health Care Administration, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan Tel: +886 2 2736 1661x3613 Fax: +886 2 2378 9788 e-mail: henry11111@tmu.edu.tw
†* Contributed equally.
Keywords: cirrhosis;epidemiology;parkinsonism
Abstract
Background/Aims: Previous studies have suggested that hepatic (toxic-metabolic) encephalopathy, the major complication of cirrhosis, is a neuropsychiatric disorder typically seen in patients with liver dysfunction after exclusion of other known brain disease. This study aims to investigate the risk for parkinsonism during a 7-year follow-up period after a diagnosis of cirrhosis.
Methods: In total, 1361 patients with cirrhosis and 6805 comparison patients without cirrhosis were included in this study. Each patient was then individually tracked for 7 years from the time of their initial diagnosis of cirrhosis to identify those who developed parkinsonism during the follow-up period. Stratified Cox proportional hazard regressions were conducted to calculate the hazard of parkinsonism for the two groups during the follow-up period, after adjusting for patient's age, monthly income, level of urbanization and geographic location.
Results: Of the total 8166 sampled patients, 141 (1.7%) developed parkinsonism during the follow-up period, 48 from the study group (3.5% of the patients with cirrhosis) and 93 from the comparison group (1.4% of patients in the comparison group). Stratified Cox proportional hazard regressions show that the hazard for parkinsonism for patients with cirrhosis was 2.65 times as high (95% confidence interval=1.85–3.80, P<0.001) as the patients in the comparison group over the 7-year follow-up period, after adjusting for patient's age, monthly income, level of urbanization and the geographic location of the community in which the patient resided.
Conclusions: We concluded that cirrhosis significantly increased the risk of parkinsonism.
Source
Early View (Articles online in advance of print)
Jiunn-Horng Kang 1,2,†, Ming-Chieh Tsai 3,4,†, Ching-Chun Lin 5, Hsiu-Li Lin 6, Herng-Ching Lin 5
Article first published online: 11 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02432.x
© 2011 John Wiley & Sons A/S
Author Information
1 Neuroscience Research Center, Taipei Medical University Hospital, Taipei, Taiwan
2 School of Medicine, Taipei Medical University, Taipei, Taiwan
3 School of Health Care Administration, Taipei Medical University, Taipei, Taiwan
4 Department of Internal Medicine, Division of Gastroenterology, General Cathay Hospital, Sijhih Branch, Taipei, Taiwan
5 School of Health Care Administration, Taipei Medical University, Taipei, Taiwan
6 Department of Neurology, General Cathay Hospital, Sijhih Branch, Taipei, Taiwan
* Correspondence: Correspondence Herng-Ching Lin, School of Health Care Administration, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan Tel: +886 2 2736 1661x3613 Fax: +886 2 2378 9788 e-mail: henry11111@tmu.edu.tw
†* Contributed equally.
Keywords: cirrhosis;epidemiology;parkinsonism
Abstract
Background/Aims: Previous studies have suggested that hepatic (toxic-metabolic) encephalopathy, the major complication of cirrhosis, is a neuropsychiatric disorder typically seen in patients with liver dysfunction after exclusion of other known brain disease. This study aims to investigate the risk for parkinsonism during a 7-year follow-up period after a diagnosis of cirrhosis.
Methods: In total, 1361 patients with cirrhosis and 6805 comparison patients without cirrhosis were included in this study. Each patient was then individually tracked for 7 years from the time of their initial diagnosis of cirrhosis to identify those who developed parkinsonism during the follow-up period. Stratified Cox proportional hazard regressions were conducted to calculate the hazard of parkinsonism for the two groups during the follow-up period, after adjusting for patient's age, monthly income, level of urbanization and geographic location.
Results: Of the total 8166 sampled patients, 141 (1.7%) developed parkinsonism during the follow-up period, 48 from the study group (3.5% of the patients with cirrhosis) and 93 from the comparison group (1.4% of patients in the comparison group). Stratified Cox proportional hazard regressions show that the hazard for parkinsonism for patients with cirrhosis was 2.65 times as high (95% confidence interval=1.85–3.80, P<0.001) as the patients in the comparison group over the 7-year follow-up period, after adjusting for patient's age, monthly income, level of urbanization and the geographic location of the community in which the patient resided.
Conclusions: We concluded that cirrhosis significantly increased the risk of parkinsonism.
Source
Serum B12 levels predict response to treatment with interferon and ribavirin in patients with chronic HCV infection
Journal of Viral Hepatitis
Volume 18, Issue 2, pages 129–134, February 2011
P. Rosenberg 1,2, K. Hagen 2
Article first published online: 19 FEB 2010
DOI: 10.1111/j.1365-2893.2010.01288.x
© 2010 Blackwell Publishing Ltd
Author Information
1 Department of Medicine, Karolinska Institute
2 Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden
* Correspondence: Peter Rosenberg, MD, PhD, Department of Gastroenterology and Hepatology, Karolinska University Hospital, S-17176 Stockholm, Sweden. E-mail: peter.rosenberg@karolinska.se
Abstract
Keywords: B12;hepatitis C;infection;interferon;ribavirin;treatment
Summary. Vitamin B12 is stored in hepatocytes and inhibits hepatitis C virus (HCV) RNA translation. The implication of B12 in the setting of antiviral treatment is unknown. This study aims to retrospectively evaluate the discriminative efficacy of pretreatment B12 serum levels (s-B12) on end-of-treatment response (ETR) in patients with chronic HCV. Ninety-nine treatment naïve HCV patients, treated with interferon and ribavirin were studied. Serum B12 (s-B12) was analysed in samples collected before treatment start. Pretreatment s-B12 levels were correlated to ETR using univariate analysis. S-B12 and clinical data were evaluated in a multivariate logistic regression model. Mean pretreatment s-B12 was 331 pm in ETR and 260 pm in nonresponders (NR) (P = 0.012). In patients with s-B12 levels ≤ 360 pm, 23 (31.5%) were NR and 50 (68.5%) had ETR. In patients with s-B12 > 360 pm, one (3.8%) was NR and 25 (96.2%) had ETR (P = 0.0034). The results of the multivariate analysis were as follows: Pretreatment s-B12 > 360 vs≤360 pm: OR 28.6 CI 2.31–354, P = 0.008. Fibrosis stage 3–4 vs 0–2: OR 0.29 CI 0.074–1.12, P = 0.068. Genotype 2/3 vs 1/4/5: OR 15.5 CI 2.87–83.9, P = 0.0012. Dose reduction vs no dose reduction: OR 0.21, CI 0.048–0.91 P = 0.034. Standard interferon vs pegylated-interferon: OR 0.079, CI 0.0091–0.68 P = 0.019. Age and gender were not correlated to ETR. S-B12 > 360 pm is independently correlated to ETR in HCV patients treated with interferon and ribavirin. This suggests that B12 is involved in suppression of viral replication during anti-HCV treatment
Source
Volume 18, Issue 2, pages 129–134, February 2011
P. Rosenberg 1,2, K. Hagen 2
Article first published online: 19 FEB 2010
DOI: 10.1111/j.1365-2893.2010.01288.x
© 2010 Blackwell Publishing Ltd
Author Information
1 Department of Medicine, Karolinska Institute
2 Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden
* Correspondence: Peter Rosenberg, MD, PhD, Department of Gastroenterology and Hepatology, Karolinska University Hospital, S-17176 Stockholm, Sweden. E-mail: peter.rosenberg@karolinska.se
Abstract
Keywords: B12;hepatitis C;infection;interferon;ribavirin;treatment
Summary. Vitamin B12 is stored in hepatocytes and inhibits hepatitis C virus (HCV) RNA translation. The implication of B12 in the setting of antiviral treatment is unknown. This study aims to retrospectively evaluate the discriminative efficacy of pretreatment B12 serum levels (s-B12) on end-of-treatment response (ETR) in patients with chronic HCV. Ninety-nine treatment naïve HCV patients, treated with interferon and ribavirin were studied. Serum B12 (s-B12) was analysed in samples collected before treatment start. Pretreatment s-B12 levels were correlated to ETR using univariate analysis. S-B12 and clinical data were evaluated in a multivariate logistic regression model. Mean pretreatment s-B12 was 331 pm in ETR and 260 pm in nonresponders (NR) (P = 0.012). In patients with s-B12 levels ≤ 360 pm, 23 (31.5%) were NR and 50 (68.5%) had ETR. In patients with s-B12 > 360 pm, one (3.8%) was NR and 25 (96.2%) had ETR (P = 0.0034). The results of the multivariate analysis were as follows: Pretreatment s-B12 > 360 vs≤360 pm: OR 28.6 CI 2.31–354, P = 0.008. Fibrosis stage 3–4 vs 0–2: OR 0.29 CI 0.074–1.12, P = 0.068. Genotype 2/3 vs 1/4/5: OR 15.5 CI 2.87–83.9, P = 0.0012. Dose reduction vs no dose reduction: OR 0.21, CI 0.048–0.91 P = 0.034. Standard interferon vs pegylated-interferon: OR 0.079, CI 0.0091–0.68 P = 0.019. Age and gender were not correlated to ETR. S-B12 > 360 pm is independently correlated to ETR in HCV patients treated with interferon and ribavirin. This suggests that B12 is involved in suppression of viral replication during anti-HCV treatment
Source
First liver transplant patients receive experimental drug to prevent hepatitis C infection
Public release date: 18-Jan-2011
Contact: Michael Cohen
michael.cohen@umassmed.edu
508-868-4778
University of Massachusetts Medical School
Phase 2 clinical trial begins for a novel monoclonal antibody
Boston, Mass. — Following a successful Phase 1 study for safety, researchers at MassBiologics of the University of Massachusetts Medical School (UMMS) today announced the beginning of a Phase 2 clinical trial testing the ability of a human monoclonal antibody they developed to prevent hepatitis C virus (HCV) infection of a donor liver in transplant patients.
The first patients were enrolled in the study in December. The primary goal of this randomized, double-blind, placebo-controlled study is to test if the monoclonal antibody, designated MBL-HCV1, prevents re-infection of patients chronically infected with HCV who are undergoing liver transplantation.
MassBiologics plans to enroll 16 patients in the first part of the study. "We are hopeful that positive results from this study will meet an important public health need, and we could not take this important step without the willing and thoughtful participation of these volunteers," said Donna Ambrosino, MD, executive director of MassBiologics and a professor of pediatrics at the Medical School.
There are currently five hospitals participating in the trial—Massachusetts General Hospital, Beth Israel Deaconess Medical Center, both in Boston, Lahey Clinic in Burlington, Massachusetts, Yale-New Haven Hospital in Connecticut and Mount Sinai Hospital in New York City—and others may join in the coming months. The first six patients enrolled have come from three of these sites.
HCV damages the liver and is the leading indication for liver transplantation, diagnosed in about half of the 6,000 patients who receive liver transplants each year in the United States. According to the US Centers for Disease Control and Prevention, 3.2 million Americans are chronically infected with HCV and approximately 10,000 die annually of the disease. Globally, as many as 170 million people are estimated to suffer from HCV infection.
For patients with end-stage liver disease from HCV infection, liver transplantation is the only option. While it can be a life-saving treatment, transplantation does not cure the disease. In nearly all cases, the patient's new liver is eventually infected by HCV because the virus remains in the patient's bloodstream during surgery. The course of recurrent HCV disease is accelerated after transplantation and up to 20 percent of transplant patients develop cirrhosis within five years. Unfortunately, the standard antiviral drugs currently used to treat HCV prior to the onset of end-stage liver disease are poorly tolerated after liver transplantation, leaving these patients with few options.
To address this unmet medical need, the team at MassBiologics, working in collaboration with investigators Gyongyi Szabo, MD, PhD, professor of medicine, and Robert Finberg, MD, professor and chair of the Department of Medicine at UMMS, set out to develop a human monoclonal antibody that could clear HCV from a patient's bloodstream and protect the donated liver from infection. In pre-clinical studies, MBL-HCV1 successfully neutralized the virus in cell culture and animal models of infection. A Phase 1 study in 31 healthy volunteers completed in 2009 showed the antibody was well tolerated, with no serious side effects. The Phase 1 study also measured the levels of the antibody in the bloodstream and its ability to bind and inactivate the virus, thereby helping to establish the dosage and protocol for the Phase 2 study now under way.
In the current study, patients will be randomized to receive an infusion of either the antibody or placebo between one and four hours prior to surgery. Then, during the phase of surgery when the diseased liver is removed, but before the donor liver is implanted, patients will receive a second infusion of either the antibody or placebo. After the surgery is completed, the patients will receive a third infusion, and then daily infusions during the first week of recovery. A final infusion is administered on the 14th day after liver transplantation.
"The liver is the main reservoir for the hepatitis C virus," said Brett Leav, MD, senior director of clinical affairs at MassBiologics. "The virus circulates in the blood, but only resides and replicates in the liver. So the idea here is to clear the virus from the bloodstream before it has an opportunity to re-infect the new liver."
After transplantation, patients' blood will be tested on a regular basis to screen for reemergence of HCV, which is usually detected within the first week after transplantation. The primary goal of the Phase 2 trial is to see if the patients who received the antibody are free of HCV at 42 days after transplantation. An interim analysis is planned after the first 16 patients have been enrolled in the trial, and a Data Safety and Monitoring Board overseeing the study will assess the effectiveness and safety of MBL-HCV1.
###
About MassBiologics
MassBiologics, also known as the Massachusetts Biologic Laboratories, is the only non-profit FDA- licensed manufacturer of vaccines and other biologic products in the United States. MassBiologics produces 30 percent of the US tetanus/diphtheria vaccine supply. In addition to the HCV program, MassBiologics has discovered and developed human monoclonal antibodies to severe acute respiratory syndrome (SARS), and to Clostridium difficile (C. difficile), which has shown efficacy in a Phase 2 clinical trial, and to rabies which will be starting Phase 2 clinical trial soon in collaboration with the Serum Institute of India. MassBiologics traces its roots to 1894, and since then has maintained a mission to improve public health through applied research, development and production of biologic products. MassBiologics has been a part of the University of Massachusetts Medical School since 1997.
About the University of Massachusetts Medical School
The University of Massachusetts Medical School has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $255 million in research funding annually, 80 percent of which comes from federal funding sources. The work of UMMS researcher Craig Mello, PhD, an investigator of the prestigious Howard Hughes Medical Institute (HHMI), and his colleague Andrew Fire, PhD, then of the Carnegie Institution of Washington, toward the discovery of RNA interference was awarded the 2006 Nobel Prize in Physiology or Medicine and has spawned a new and promising field of research, the global impact of which may prove astounding. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information, visit http://www.umassmed.edu/.
Source
Contact: Michael Cohen
michael.cohen@umassmed.edu
508-868-4778
University of Massachusetts Medical School
Phase 2 clinical trial begins for a novel monoclonal antibody
Boston, Mass. — Following a successful Phase 1 study for safety, researchers at MassBiologics of the University of Massachusetts Medical School (UMMS) today announced the beginning of a Phase 2 clinical trial testing the ability of a human monoclonal antibody they developed to prevent hepatitis C virus (HCV) infection of a donor liver in transplant patients.
The first patients were enrolled in the study in December. The primary goal of this randomized, double-blind, placebo-controlled study is to test if the monoclonal antibody, designated MBL-HCV1, prevents re-infection of patients chronically infected with HCV who are undergoing liver transplantation.
MassBiologics plans to enroll 16 patients in the first part of the study. "We are hopeful that positive results from this study will meet an important public health need, and we could not take this important step without the willing and thoughtful participation of these volunteers," said Donna Ambrosino, MD, executive director of MassBiologics and a professor of pediatrics at the Medical School.
There are currently five hospitals participating in the trial—Massachusetts General Hospital, Beth Israel Deaconess Medical Center, both in Boston, Lahey Clinic in Burlington, Massachusetts, Yale-New Haven Hospital in Connecticut and Mount Sinai Hospital in New York City—and others may join in the coming months. The first six patients enrolled have come from three of these sites.
HCV damages the liver and is the leading indication for liver transplantation, diagnosed in about half of the 6,000 patients who receive liver transplants each year in the United States. According to the US Centers for Disease Control and Prevention, 3.2 million Americans are chronically infected with HCV and approximately 10,000 die annually of the disease. Globally, as many as 170 million people are estimated to suffer from HCV infection.
For patients with end-stage liver disease from HCV infection, liver transplantation is the only option. While it can be a life-saving treatment, transplantation does not cure the disease. In nearly all cases, the patient's new liver is eventually infected by HCV because the virus remains in the patient's bloodstream during surgery. The course of recurrent HCV disease is accelerated after transplantation and up to 20 percent of transplant patients develop cirrhosis within five years. Unfortunately, the standard antiviral drugs currently used to treat HCV prior to the onset of end-stage liver disease are poorly tolerated after liver transplantation, leaving these patients with few options.
To address this unmet medical need, the team at MassBiologics, working in collaboration with investigators Gyongyi Szabo, MD, PhD, professor of medicine, and Robert Finberg, MD, professor and chair of the Department of Medicine at UMMS, set out to develop a human monoclonal antibody that could clear HCV from a patient's bloodstream and protect the donated liver from infection. In pre-clinical studies, MBL-HCV1 successfully neutralized the virus in cell culture and animal models of infection. A Phase 1 study in 31 healthy volunteers completed in 2009 showed the antibody was well tolerated, with no serious side effects. The Phase 1 study also measured the levels of the antibody in the bloodstream and its ability to bind and inactivate the virus, thereby helping to establish the dosage and protocol for the Phase 2 study now under way.
In the current study, patients will be randomized to receive an infusion of either the antibody or placebo between one and four hours prior to surgery. Then, during the phase of surgery when the diseased liver is removed, but before the donor liver is implanted, patients will receive a second infusion of either the antibody or placebo. After the surgery is completed, the patients will receive a third infusion, and then daily infusions during the first week of recovery. A final infusion is administered on the 14th day after liver transplantation.
"The liver is the main reservoir for the hepatitis C virus," said Brett Leav, MD, senior director of clinical affairs at MassBiologics. "The virus circulates in the blood, but only resides and replicates in the liver. So the idea here is to clear the virus from the bloodstream before it has an opportunity to re-infect the new liver."
After transplantation, patients' blood will be tested on a regular basis to screen for reemergence of HCV, which is usually detected within the first week after transplantation. The primary goal of the Phase 2 trial is to see if the patients who received the antibody are free of HCV at 42 days after transplantation. An interim analysis is planned after the first 16 patients have been enrolled in the trial, and a Data Safety and Monitoring Board overseeing the study will assess the effectiveness and safety of MBL-HCV1.
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About MassBiologics
MassBiologics, also known as the Massachusetts Biologic Laboratories, is the only non-profit FDA- licensed manufacturer of vaccines and other biologic products in the United States. MassBiologics produces 30 percent of the US tetanus/diphtheria vaccine supply. In addition to the HCV program, MassBiologics has discovered and developed human monoclonal antibodies to severe acute respiratory syndrome (SARS), and to Clostridium difficile (C. difficile), which has shown efficacy in a Phase 2 clinical trial, and to rabies which will be starting Phase 2 clinical trial soon in collaboration with the Serum Institute of India. MassBiologics traces its roots to 1894, and since then has maintained a mission to improve public health through applied research, development and production of biologic products. MassBiologics has been a part of the University of Massachusetts Medical School since 1997.
About the University of Massachusetts Medical School
The University of Massachusetts Medical School has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $255 million in research funding annually, 80 percent of which comes from federal funding sources. The work of UMMS researcher Craig Mello, PhD, an investigator of the prestigious Howard Hughes Medical Institute (HHMI), and his colleague Andrew Fire, PhD, then of the Carnegie Institution of Washington, toward the discovery of RNA interference was awarded the 2006 Nobel Prize in Physiology or Medicine and has spawned a new and promising field of research, the global impact of which may prove astounding. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information, visit http://www.umassmed.edu/.
Source
Studies: New treatments may increase cure rates of hepatitis C
By Jade Walker – Tue Jan 18, 9:14 am ET
The Starting Point is a snapshot of the news that occurred overnight and a preview of the stories we expect to cover today.
Featured story
People suffering from hepatitis C, a disease caused by a blood-born virus that attacks the liver, may soon have access to a cure.
Most people get the disease by using dirty needles, either to inject illegal drugs or while obtaining a tattoo or piercing. Others contracted hepatitis C from an infected blood transfusion or organ transplant that was performed before the U.S. began screening for the disease in 1992. You cannot get hepatitis C from casual contact such as hugging, kissing, sneezing, coughing or sharing food or drink.
About 3.2 million Americans, and 170 million people worldwide, have chronic hepatitis C, which is the leading cause of liver transplants. According to the Mayo Clinic, many patients may have the disease and not even realize it because they either show no symptoms (tiredness, joint and belly pain and jaundice) or the symptoms don't manifest for many years. Yet hepatitis C is a serious illness, one that kills about 12,000 Americans a year. Medical experts say that number is expected to triple over the next two decades.
The two-drug method currently used to treat the disease --ribavirin pills plus injections of interferon-alpha -- only cures about 40 percent of patients. However, new major studies show that adding a third drug, either Vertex Pharmaceuticals' telaprevir or Merck & Co.'s boceprevir, can increase cure rates by as high as 75 percent because they can block an enzyme the virus needs to reproduce. When taken in conjunction with the standard medications, these new drugs may also allow some patients to cut treatment time in half to six months.
The side effects of existing treatments include: sleeplessness, fever, muscle and body aches, anxiety, mouth sores, dehydration, irritability, headaches, depression, dry mouth, sore throat, nausea, vomiting, diarrhea and hair loss. And the new drugs may cause additional side effects, such as a rash and/or anemia. The drugmakers haven't announced what the drugs will cost either; the price of treatment can already cost $30,000 (before a liver transplant).
The Food and Drug Administration is expected to approve the drugs this summer, a move that is prompting some newly diagnosed patients to hold off on treatment until the new drug therapy is available.
"We're entering a whole new era of therapy," Dr. John Ward, hepatitis chief at the Centers for Disease Control and Prevention, told The Associated Press. "We really want to begin that clarion call for action for this population who's at risk."
Who should be tested for hepatitis C?
* Anyone who has ever injected illegal drugs
* Recipients of clotting factor concentrates made before 1987
* People who received blood transfusions or organ transplants before July 1992
* Patients who have ever received long-term hemodialysis treatment
* People who have HIV
* People with signs or symptoms of liver disease
* Children born to mothers who have hepatitis C
Source
Also See: New Hope For Hepatitis C, An Often Hidden Disease
The Starting Point is a snapshot of the news that occurred overnight and a preview of the stories we expect to cover today.
Featured story
People suffering from hepatitis C, a disease caused by a blood-born virus that attacks the liver, may soon have access to a cure.
Most people get the disease by using dirty needles, either to inject illegal drugs or while obtaining a tattoo or piercing. Others contracted hepatitis C from an infected blood transfusion or organ transplant that was performed before the U.S. began screening for the disease in 1992. You cannot get hepatitis C from casual contact such as hugging, kissing, sneezing, coughing or sharing food or drink.
About 3.2 million Americans, and 170 million people worldwide, have chronic hepatitis C, which is the leading cause of liver transplants. According to the Mayo Clinic, many patients may have the disease and not even realize it because they either show no symptoms (tiredness, joint and belly pain and jaundice) or the symptoms don't manifest for many years. Yet hepatitis C is a serious illness, one that kills about 12,000 Americans a year. Medical experts say that number is expected to triple over the next two decades.
The two-drug method currently used to treat the disease --ribavirin pills plus injections of interferon-alpha -- only cures about 40 percent of patients. However, new major studies show that adding a third drug, either Vertex Pharmaceuticals' telaprevir or Merck & Co.'s boceprevir, can increase cure rates by as high as 75 percent because they can block an enzyme the virus needs to reproduce. When taken in conjunction with the standard medications, these new drugs may also allow some patients to cut treatment time in half to six months.
The side effects of existing treatments include: sleeplessness, fever, muscle and body aches, anxiety, mouth sores, dehydration, irritability, headaches, depression, dry mouth, sore throat, nausea, vomiting, diarrhea and hair loss. And the new drugs may cause additional side effects, such as a rash and/or anemia. The drugmakers haven't announced what the drugs will cost either; the price of treatment can already cost $30,000 (before a liver transplant).
The Food and Drug Administration is expected to approve the drugs this summer, a move that is prompting some newly diagnosed patients to hold off on treatment until the new drug therapy is available.
"We're entering a whole new era of therapy," Dr. John Ward, hepatitis chief at the Centers for Disease Control and Prevention, told The Associated Press. "We really want to begin that clarion call for action for this population who's at risk."
Who should be tested for hepatitis C?
* Anyone who has ever injected illegal drugs
* Recipients of clotting factor concentrates made before 1987
* People who received blood transfusions or organ transplants before July 1992
* Patients who have ever received long-term hemodialysis treatment
* People who have HIV
* People with signs or symptoms of liver disease
* Children born to mothers who have hepatitis C
Source
Also See: New Hope For Hepatitis C, An Often Hidden Disease
Review of liver injury associated with dietary supplements
Liver International
Early View (Articles online in advance of print)
Felix Stickel 1, Kerstin Kessebohm 2, Rosemarie Weimann 3, Helmut K. Seitz 4
Article first published online: 11 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02439.x
© 2011 John Wiley & Sons A/S
Author Information
1 Department of Visceral Surgery and Medicine, Institute of Clinical Pharmacology and Visceral Research, Inselspital, University of Berne, Berne, Switzerland
2 Institute of Clinical Pharmacology and Visceral Research, University of Berne, Berne, Switzerland
3 Institute of Pathology, University of Berne, Berne, Switzerland
4 Department of Medicine, Center of Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg, Germany
* Correspondence: Correspondence Felix Stickel, MD, Department of Visceral Surgery and Medicine, Institute of Clinical Pharmacology and Visceral Research, Inselspital, University of Bern, Murtenstr. 35, 3010 Bern, Switzerland Tel: +41 31 632 87 28 Fax: +41 31 632 49 97 e-mail: felix.stickel@ikp.unibe.ch
Keywords:
anabolic steroids; Camellia sinensis; cholestasis; hepatitis; retinoid toxicity; toxic liver injury
Abstract
Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms ‘dietary/nutritional supplements’, ‘adverse hepatic reactions’, ‘liver injury’; ‘hepatitis’, ‘liver failure’, ‘vitamin A’ and ‘retinoids’, and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife® and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks.
Abbreviations
ALF, acute liver failure; DILI, drug-induced liver injury; DS, dietary supplements; FDA, Food and Drug Administration; HSC/MFB, hepatic stellate cells/portal myofibroblasts
The use of dietary supplements (DS) containing vitamins, anti-oxidants, fibre, trace elements, proteins, amino acids and herbal constituents has become a major health trend in affluent societies (1, 2). Consumption of DS in the USA has doubled to 18.9% of adults admitting their use only between 1999 and 2004 (3, 4); some investigations report their consumption up to 47% in certain subgroups such as among elder, non-smoking females with higher education (5). The rising popularity of DS is probably because of an increased awareness of consumers towards health in general and the desire to prevent diseases by an optimized nutritional status, and the persuasion that these treatments are safe (1, 2, 5, 6). Further, DS do not require prescriptions from health professionals allowing largely unrestricted access to relatively cheap products. Consequently, marketing such products has become a multibillion business largely unregulated by official health authorities (6–8).
In the USA, DS are expected to meet the standards outlined in the Dietary Supplement and Health Education Act published in 1994, which allows distribution without prior approval of their efficacy and safety by the Food and Drug Administration (FDA) (9). This simplified licensing practice does not ensure efficacy and safety in the same strict way as with the approval of conventional medications and treatments. Similarly, the European Union has set forth legislative measures for the distribution and marketing of DS and functional foods that are outlined in the European Commission 2000 White Paper on Food Safety (10, 11). This set of legislation pays tribute to the fact that DS may harbour specific problems because of their complex composition, particularly with respect to quality aspects, and defines guidelines for conducting premarketing in vitro and in vivo studies.
While adverse hepatic reactions from xenobiotics are well documented by pre- and post-marketing pharmacovigilance, the situation for DS is less well depicted as widespread and uncontrolled use and under-reporting prevent the determination of their true incidence. Additionally, a low awareness of users and providers towards their potential harms impedes their recognition as the causative agent in incidents of hepatotoxicity. Consequently, estimates of the frequency of DS-associated hepatic injury are likely imprecise and, possibly, too low. The proportion of hepatotoxicity ascribed to DS varies from 2% in a Spanish study (12) describing 531 cases of drug-induced liver injury (DILI) to approximately 10% in a series from the US Drug-Induced Liver Injury Network (DILIN) (13). Figures were as high as 35% in a small series of 20 patients developing acute liver failure with DS exposure as the only identifiable cause of liver damage (14).
Our article aimed to review and describe the literature on liver injury because of DS, delineate patterns and mechanisms of injury and to increase the awareness towards this possible cause of acute and chronic liver damage.
Literature search methodology
In February 2010, case reports and series thereof on liver injury specifically occurring following the consumption of DS published between 1990 and 2010 were searched in PubMed and EMBASE data bases using the terms ‘adverse hepatic reactions’, ‘anabolic steroids’, ‘Camellia sinensis’, ‘dietary/nutritional supplements’, ‘Herbalife’, ‘hepatitis’, ‘Hydroxycut’, ‘green tea’, ‘liver failure’, ‘liver injury’, ‘Noni’, ‘retinoids’, ‘vitamin A’ and critically reviewed. Retrieved publications were searched for yet unidentified publications. Remedies were considered DS if consumed as an aid to improve nutritional status, to loose weight or to treat constipation. Cases of liver injury from preparations taken for other causes than nutritional purposes were not included. No language restriction was used.
While hepatotoxicity from herbal medicines in general has been addressed in several reviews (15–18), summaries specifically devoted to liver-related risks along with DS are scarce (19). In the following, a panel of rather distinct DS preparations associated with liver injury are described (Table 1).
Specific dietary supplements associated with liver injury
Herbalife® (Los Angeles, CA, USA) sells nutritional and herbal supplements as tablets, capsules, drinks and energy bars for weight control, improvement of nutrition, ‘well-being’ and cosmetics. In 2006, the stock market quoted that Herbalife® company had a revenue of US$3.1 billion via online marketing or through independently operating sales agents.
There are so far six published reports on liver damage following the intake of Herbalife® products since 2007 describing 34 cases from five countries (Switzerland, Israel, Spain, Argentina and Iceland), although Herbalife® products are sold in at least 60 countries worldwide (20–25). Individual data of all reports are displayed in Table 2. Pattern of injury was mostly hepatocellular, but mixed and cholestatic enzyme patterns were also observed. Severity ranged from mild to severe hepatic damage including cirrhosis and acute liver failure requiring liver transplantation, which was successful in one patient while the second died because of post-operative complications. Causality between intake of Herbalife® products and the evolution of liver injury was assessed by widely used scores (26, 27) in five of the six reports and considered ‘certain’ in at least five patients by a positive rechallenge reaction and ‘probable’ in the majority of the remaining cases (20, 21).
Camellia sinensis (green tea)
Green tea is among the most frequently consumed drinks in the USA and often used as a DS. The first report on liver injury following the ingestion of green tea extracts and preparations thereof was published in 1999 (31), and since then, numerous consecutive cases were reported to regulatory agencies worldwide. With effect of April 2003, the manufacturer of Exolise® (Arkopharma, Carros, France), a hydro-alcoholic extract of C. sinensis, has revocated all of their products after altogether 13 cases of acute liver damage following its intake were reported to the French pharmacovigilance authorities (Agence Francaise de Securité Sanitaire de Produits de Sanité; http://www.afssaps.sante.fr/). As a reaction to these accumulating reports, the US Pharmacopeia performed a systematic review of all cases accessible from PubMed, EMBASE and pharmacovigilance data bases in the USA, Canada, UK and Australia reporting on 34 single cases of liver injury following the ingestion of numerous different green tea preparations (32). Herein, case reports were retrospectively evaluated according to the Naranjo causality algorithm scale (33), and 27 reports pertaining to liver damage were labelled as ‘possibly’ and the remaining seven cases as ‘probably’ linked to green tea. Another Medline search review of cases on green tea liver injury from the same year also retrieved 34 published reports and described two further yet unpublished cases (34). On histological examination, livers of patients revealed inflammatory reactions, cholestasis, occasionally steatosis and necrosis. Although there was some overlap of single reports between these two review articles, collected case reports were not identical and jointly provided details on 58 cases of hepatotoxicity along with the intake of green tea extracts, powdered leaves, green tea infusions and hydro-alcoholic and aqueous extracts. In Mazzanti's summary, no causality re-evaluation was performed, but information on de- and rechallenge is provided for every case indicating a positive rechallenge response with accelerated recurrence of liver injury in seven of 36 incidents, which strongly suggests a causal relationship between the observed liver injury and green tea consumption. Of concern is that there was one reported death. However, a note of caution is warranted in many of the cases regarding an exclusive assignment of causality to green tea, because many patients who experienced adverse hepatic reactions also took numerous other products with a published record of hepatotoxicity, such as Cassia angustifolia, Hydroxycut and Ephedra sinica (for all three, please see below). Since these two review articles, additional cases have been published from Belgium reporting on a 42-year-old female patient who developed cholestatic hepatitis 6 months after starting Densitive® (Kerastase Nutritients, L'Oréal, Paris), which contains C. sinensis (35). Upon dechallenge, a full recovery was recorded. Other causes of liver injury were carefully excluded, but formal causality assessment using an established score was not performed. In the second case, jaundice, weight loss and subacute hepatitis developed in a 76-year-old man who regularly drank green tea infusions (36). Histology showed marked necro-inflammation, and transiently elevated antismooth muscle auto-antibodies were suggestive of autoimmunity induced by green tea constituents.
The mode of toxicity derived from green tea still remains incompletely understood but could be because of (−)-epigallocatechin gallate or its metabolite (−)-epicatechin gallate, which, under certain conditions such as fasting, can induce oxidative stress-related liver damage (37). Interestingly, in vitro and in vivo experimental studies have demonstrated both hepatoprotective as well as hepatotoxic properties (37–40). Along this line, support for potentially hepatoprotective activity from green tea extracts comes from clinical studies studying its therapeutic effects in humans with liver diseases including liver cancer, cirrhosis and steatosis. Four randomized-controlled clinical trials, two cohort, one case–control and three cross-sectional studies from China, Japan and the USA were recently subjected to a systematic review and found overall favourable effects from green tea as reflected by reduced mortality, attenuated steatosis and reduced incidence of primary liver cancer (41).
Whether the risks from green tea consumption outweigh their benefits remains open, but current evidence as outlined above suggests a causal relationship between intake of green tea-containing products and hepatotoxicity. Consequently, in their systematic review, the US Pharmacopeia included a cautionary statement on green tea indicating this possibility (32).
Usnic acid
Some years ago, several cases of acute liver failure requiring liver transplantation following the intake of LipoKinetix®, a product extracted from lichens and fungi and sold as DS capsules, were reported (42–45). Onset of liver injury was usually acute with a maximum latency of 3 months and the injury pattern hepatocellular with massive elevations of ALT and AST. Lipokinetix contained usnic acid and was marketed as a weight-loss remedy. Efficacy for this indication was postulated based on its function as an uncoupler of the respiratory chain, which in principle can augment weight loss (46). Apart from usnic acid, LipoKinetix® contained norephedrine hydrochloride, diiodothyronine, yohimbine hydrochloride and caffeine, which were confirmed by analysing the used LipoKinetix® lots. None of the ingredients were associated previously with liver damage and inadvertent contamination was excluded. These serious events caused the withdrawal of LipoKinetix® from the market.
Hydroxycut
Only recently, several Hydroxycut products were retracted by the manufacturer following a warning posted by the FDA in May 2009 because of 23 reports of liver injury including cases with acute hepatic failure and subsequent liver transplantation (47–49). Hydroxycut preparations were sold as powder, capsules and tablets by conventional retailers, through Internet sources and via direct television marketing. Hydroxycut was used to support weight loss and by body builders. The manufacturer had been charged previously with several lawsuits for unfounded health claims. Before May 2009, its primary ingredients included Garcinia cambogia, Gymnema sylvestre, chromium polynicotinate, caffeine and green tea. Published cases were recently reviewed and showed acute onset after several weeks of intake with high levels of serum aminotransferases in the majority of cases, while others presented with a more insidious, usually cholestatic course (50).
Miscellaneous
Various other DS have been associated with acute and subacute liver damage such as Senna (C. angustifolia), which is used as a powder, tea or suppository to treat constipation. According to our search, a total of five reports with altogether five individual cases describe the evolution of variable liver pathologies including acute cytolytic hepatitis, subacute cholestatic hepatitis, acute liver failure and portal vein thrombosis upon consumption of Senna products (51–55). In some reports, Senna preparations were self-made or ingested excessively such as in a young woman taking approximately 10 times the recommended dose who developed cytolytic hepatitis, which completely subsided after stopping Senna (51). The causal relationship between the preparation and hepatitis was confirmed through a positive rechallenge in two cases (51, 52). Senna is biotransformed via intestinal bacteria to rhein anthrone, which is highly reactive and requires binding to glucuronide and sulphate via phase I oxidation for renal excretion (56). Rhein anthrone is suspected to function as an uncoupler of the respiratory chain, and can therefore possibly affect hepatocyte integrity under certain circumstances, such as in genetically predisposed individuals. Seybold et al. (52) describe a case of increased toxicity of Senna tea in a homozygous carrier of a genetic cytochrome P450 2D6 variant rendering the individual a poor metabolizer for phase I hepatic detoxification reactions.
Noni juice (Morinda citrifolia) has become increasingly popular in Western countries as a health tonic. Consumption of Noni was the presumed cause of acute hepatitis in a 45-year-old man who drank a glass of this tropical fruit over several weeks for preventive reasons and for ‘strengthening the immune system’ (57). Other possible aetiologies of acute hepatitis were ruled out and liver tests rapidly turned normal after the cessation of Noni intake. Since this first report in 2005, five additional cases have been published from Austria, Germany and Spain (58–61). Remarkably, two patients experienced liver failure of which one required liver transplantation. The pattern of liver injury was hepatocellular in all cases and occurred rapidly within a few weeks of exposure. Causality was formally assessed in two publications, but not considered ‘certain’ in any of the cases because no rechallenge was used. Also, at least two of totally six patients had concomitant medication with known hepatotoxic potential, such as interferon-β (62) and a Chinese herbal mixture (63) respectively. Responsibility of Noni preparations as the cause of liver injury in these cases is challenged by one of the manufacturers of Noni products (64, 65) by demonstrating experimental evidence of no dose-dependent hepatotoxicity and even hepatoprotective properties in some animal models of chronic liver injury (66, 67). However, a lack of dose-dependent hepatotoxicity does not exclude idiosyncratic drug toxicity, e.g. by inducing autoimmune reaction as shown by Yuce et al. (59) who found excessively high liver–kidney microsomal antibodies of 1:3840 in a patient drinking Noni juice for 4 weeks. Nevertheless, the true underlying pathophysiology of Noni-associated liver injury remains elusive because active components within Noni extracts such as flavonoids, glycosides, vitamins, anthraquinones and polyunsaturated fatty acids are not known to be hepatotoxic.
Chinese herbs have become highly popular among consumers in Western countries because of a prevailing belief in their efficacy and safety. Among many others, Ma huang (E. sinica) is marketed in the USA as a nasal decongestant and bronchodilator, and more recently as a weight-loss remedy. The first report of Ma huang-associated liver injury was about a woman developing acute hepatitis together with elevated antinuclear antibodies (ANA) and smooth muscle antibodies (SMA) after only 3 weeks of intake of Ma huang, but liver abnormalities resolved after its discontinuation (68). Another report suggested that intake of Ma huang was the cause of acute liver failure in a 58-year-old patient initiating her listing for high-urgency liver transplantation who also presented with elevated titres of SMA (69). Another report suggested an association of Ma huang-related liver injury with compound heterozygosity for the C282Y and H63D mutation in the haemochromatosis gene, proposing that excess hepatic iron could aggravate hepatotoxicity, possibly via enhancing oxidative stress (70). The largest series on severe liver injury because of the intake of Ma huang by Neff et al. (71) describes 10 cases of acute cytolytic hepatitis of which two subjects required liver transplantation and one died, while the remaining seven patients recovered spontaneously. These cases of severe liver damage and others referring to cardiac toxicity have prompted a warning by the FDA for the use of Epedra-containing DS such as Ma huang (72).
In 1986, Germander (Teucrium chamaedrys) was approved as a drug for the supportive treatment of obesity in France. Its subsequent widespread use precipitated numerous reports on acute, chronic and even fulminant hepatitis to the French pharmacovigilance authorities in 1992 (73–75). Within a median of 2 months, intake of daily doses between 600 and 1600 mg/day precipitated acute cytolytic hepatitis or chronic hepatitis with fibrosis and even cirrhosis (74, 76). All patients recovered after the discontinuation of treatment, but some relapsed under re-exposure. Germander contains saponins, glycosides, flavonoids and neoclerodane diterpenoids, which were shown to be converted into diterpenoid toxic metabolites by cytochrome P450 3A in mice (77). In conditions of glutathione depletion – such as during fasting – or after induction of cytochrome P450 3A, toxic diterpenoids are potent inducers of hepatocyte apoptosis (78, 79). Hence, in 1992, the license for Germander-containing products was withdrawn.
‘Onshidou-Genbi-Kounou’, another herbal marketed for weight loss, seemed the likely cause of chronic hepatitis in a 52-year-old Japanese woman who took this preparation for 2 months (80). Serum levels of liver enzymes were elevated to >1500 IU/l and ANA were positive with 1:160. All other possible causes for chronic hepatitis were excluded, and liver histology was compatible with drug-induced autoimmune hepatitis. The patient recovered completely without intervention on cessation of ‘Onshidou-Genbi-Kounou’ intake. In a larger series from Japan describing 12 patients with acute hepatitis after taking ‘Onshidou-Genbi-Kounou’ and ‘Chaso’ for weight loss, two patients developed liver failure of which one survived after successful liver transplantation and the other one died (81). ‘Onshidou-Genbi-Kounou’ contains several natural compounds (amachazuru, tea leaf, barbaloin, total saponin and polyphenols) and N-nitroso-fenfluramine. The latter demonstrated induction of mitochondrial permeability transition and hepatocyte apoptosis following uncoupling of oxidative phosphorylation and intracellular ATP depletion (82, 83).
Vitamin A-associated liver injury
DS fortified with vitamin A are used to prevent night blindness, to increase immune function and to promote health in general. Liver injury related to hypervitaminosis A is well known for many decades and comprises mild elevations of serum liver enzymes, cholestatic hepatitis, non-cirrhotic portal hypertension, progressive fibrosis and cirrhosis (84–87). Toxicity does not usually occur with standard doses below 50 000 IU/day as contained in common multivitamin preparations, but individual tolerability may vary (88). Pre-existing liver lesions including steatosis, chronic alcohol consumption, comedication with other potentially hepatotoxic drugs and young age may predispose certain individuals to develop vitamin A hepatotoxicity (89, 90). Several case reports have demonstrated significant hepatotoxicity with vitamin A doses as low as 20 000 IU/day (91), and upper limits of tolerability may even be lower in regular alcohol consumers (92).
Toxicity is mediated to the dose-dependent effect of retinoids on hepatic stellate cells/portal myofibroblasts (HSC/MFB), which are the key effector cells in the evolution of fibrosis and cirrhosis (93). Upon excessive vitamin A exposure, HSC/MFB start to produce collagens, downregulate collagenase activity and acquire the ability of contraction leading to elevation of blood pressure in the portal vein. In addition to this direct impact on HSC/MFB function and activity, retinoids can be transformed into metabolites that affect mitochondrial function and hepatocyte viability with resulting liver cell apoptosis (94, 95). This was shown to occur particularly when co-administered with alcohol. Dan and colleagues showed that retinoids can be transformed via alcohol-induced cytochrome P450 2E1 into highly reactive and toxic polar metabolites, which cause hepatocyte apoptosis upon caspase 3 activation (Fig. 2). Hence, health professionals should consult users carefully about the potential dangers of vitamin A, particularly when intended for longer period, in children and regular alcohol consumers.
Anabolic steroids
Anabolic steroids are an integral part of the nutritional concept of many athletes to improve fitness, muscle gain and exercise performance. Their use is widespread although anabolics are classified as class III substances and therefore subdued to strict rules (96). However, access via inofficial and sometimes illegal sources is easy, and therefore, in spite of tight rules, further adverse hepatic reactions following the consumption of anabolic steroids can be expected. Hepatotoxicity has been frequently described and patterns of injury delineated. Liver lesions include intrahepatic cholestasis, hepatitis, adenoma and hepatocellular carcinoma and rare malformations such as peliosis hepatis, a rare pathological entity characterized by the gross appearance of multiple cyst-like, blood-filled cavities within the liver (97, 98). A recent case series demonstrated the evolution of cholestasis 2 weeks after the intake of anabolic steroids had been stopped. All patients recovered fully after intake had been terminated (99). Even more worrisome is the observation that some DS may contain anabolic steroids sufficient to precipitate liver injury, as demonstrated by a recent case report showing cholestasis in two young men who took DS to enhance their body-building performance (100). Another case presented with a less favourable course as prolonged intrahepatic cholestasis and subsequent kidney failure developed (101). The precise mechanism underlying toxicity is yet unclear, but experimental data indicate direct hepatocellular toxicity from steroids via increased oxidative stress and subsequent impairment of function of the canalicular bile salt export pump (100).
A recent case–control study from Brazil suggested that anabolic steroids could be a cause of toxicant-associated non-alcoholic fatty liver disease (TAFLD) by comparing 95 recreational body builders using anabolic steroids with 85 non-users. In those consuming anabolic steroids, 12.6% of subjects revealed criteria compatible with TAFLD such as steatosis on ultrasound imaging, elevated serum transaminases and exclusion of relevant alcohol intake or concomitant medication, but no overweight or insulin resistance suggestive of metabolic NAFLD. In turn, 2.4% of body builders not using anabolic steroids showed clinical signs and findings suggestive of NAFLD. The authors concluded that the intake of anabolic steroids could be a cause of non-metabolic, but toxicant-associated NAFLD (102).
Conclusion
Hepatic injury secondary to consumption of DS is recognized, although its exact frequency remains unclear, mostly because evidence relies exclusively on case reports. Lack of stringent diagnostic criteria, poor awareness of consumers and prescribers, easy and uncontrolled access and under-reporting account for this epidemiological gap of knowledge. Diagnostic assessment of DS-associated should be made more consistent, and customized specifically to DS. Although causality categories reached in many of the published reports suggest a causal relationship between liver injury and the intake of certain DS products, pitfalls exist related to the used diagnostic scales, which have all been criticized for variable reasons and of which none is unequivocally accepted as being suitable for the evaluation of DS as a cause of liver injury. While the WHO score is not specifically designed to evaluate DILI (103), the Naranjo adverse drug reaction probability scale (33) was recently found to have low sensitivity (54%), poor negative predictive value (29%) and to lack reproducibility in a large series of cases of suspected hepatotoxicity (104) when compared with the Roussel Uclaf Causality Assessment Method (RUCAM) (26, 105). A clinical diagnostic scale has been suggested as a simple tool to assess adverse hepatic drug reactions and showed good correlation with RUCAM in one study (106), but not in another (107). To conclude, all used scores reveal merits and limitations, but a common consensus on which one is the best to apply in causality assessment of DS-associated liver damage has never been reached. In an approach to compensate for this lack of common agreement, recently, the DILIN was established to advance our understanding and research into DILI by initiating a prospective registry of patients with DILI for future studies into host clinical, genetic, environmental and immunological risk factors, and to develop standardized nomenclature, terminology and causality assessment instruments (108). Patients with liver injury because of herbal products are also eligible to be included. Herein, a causality score ranging from 1 (definite) to 5 (unlikely) as well as a severity score ranging from 1 (mild) to 5 (fatal) is applied by three hepatologists of the DILIN study group, thereby minimizing individual biases. In addition to accounting for the input of the reporting investigator who took the history, performed the physical examination and supervised the data collection, a prospective evaluation of other potential causes of liver injury and serial laboratory data through at least 6 months of follow-up are offered. However, the DILIN expert opinion is limited by its lack of generalizability and a low level of agreement between the three hepatologists (109). Hence, a certain degree of inaccuracy in assigning causality remains until better diagnostic measures are established.
Apart from diagnostic measures, better regulatory measures to assure safety and timely recognition of potentially harmful products require improvement and, thus, efforts of pharmacovigilance authorities and healthcare providers must jointly act to minimize risks and protect consumers. Manufactures must spend utmost care in providing users with clean and unadulterated products and should be held liable if this accidentally or carelessly fails. Finally, consumers should develop a more critical attitude towards the expectations and hopes associated with DS use in largely healthy individuals, and turn to measures for which safety data are known, and efficacy is proven.
References
1 Radimer K, Bindewald B, Hughes J, et al. Dietary supplement use by US adults: data from the national health and nutrition examination survey, 1999–2000. Am J Epidemiol 2004; 160: 339–49.
2 Landström E, Hursti UK, Becker W, Magnusson M. Use of functional food among Swedish consumers is related to health-consciousness and perceived effect. Br J Nutr 2007; 98: 1058–69.
3 Ni H, Simile C, Hardy AM. Utilization of complementary and alternative medicine by United States adults: results from the 1999 national health interview survey. Med Care 2002; 40: 353–8.
4 Kessler RC, Davis RB, Foster DF, et al. Long-term trends in the use of complementary and alternative medical therapies in the United States. Ann Intern Med 2001; 135: 262–8.
5 Reinert A, Rohrmann S, Becker N, Linseisen J. Lifestyle and diet in people using dietary supplements. Eur J Nutr 2007; 46: 165–73.
6 Michels Blanck H, Serdula MK, Gillespie C, et al. Use of nonprescription dietary supplements for weight loss is common among Americans. J Am Diet Assoc 2007; 107: 441–7.
7 Brevoort P. The booming US botanical market: a new overview. HerbalGram 1998; 44: 33–46.
8 Dorsch KD, Bell A. Dietary supplement use in adolescents. Curr Opin Pediatr 2005; 17: 653–7.
9 US Food and Drug Administration. Guidance, compliance and regulatory information. Available at http://www.fda.gov/food/dietarysupplements/GuidanceComplianceRegulatoryInformation (accessed 31 May 2009).
10 Coppens P, da Silva MF, Pettman S. European regulations on neutraceuticals, dietary supplements and functional foods: a framework based on safety. Toxicology 2006; 221: 59–74.
11 Gulati OP, Berry Ottaway P. Legislation relating to nutraceuticals in the European Union with a particular focus on botanical-sourced products. Toxicology 2006; 221: 75–87.
12 GarcÃa-Cortés M, Borraz Y, Lucena MI, et al. Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry. Rev Esp Enferm Dig 2008; 100: 688–95.
13 Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924–34.
14 Estes JD, Stolpman D, Olyaei A, et al. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003; 138: 852–8.
15 De Smet PAGM. Herbal remedies. N Engl J Med 2002; 347: 2046–56.
16 Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol 2005; 43: 901–10.
17 Seeff LB. Herbal hepatotoxicity. Clin Liv Dis 2007; 11: 577–96.
18 Chitturi S, Farrell GC. Hepatotoxic slimming aids and other herbal hepatotoxins. J Gastroenterol Hepatol 2008; 23: 366–73.
19 Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373–82.
20 Elinav E, Pinsker G, Safadi R, et al. Association between consumption of Herbalife® nutritional supplements and acute hepatotoxicity. J Hepatol 2007; 47: 514–20.
21 Schoepfer AM, Engel A, Fattinger K, et al. Herbal does not mean innocuous: 10 cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products. J Hepatol 2007; 47: 521–6.
22 Duque JM, Ferreiro J, Salgueiro E, Manso G. Hepatotoxicity associated with the consumption of herbal slimming products. Med Clin (Barcelona) 2007; 128: 238–9.
23 Chao S, Anders M, Turbay M, et al. Toxic hepatitis by consumption Herbalife products a case report. Acta Gastroenterol Latinoam 2008; 38: 274–7.
24 Stickel F, Droz S, Patsenker E, et al. Severe hepatotoxicity following ingestion of Herbalife® nutritional supplements contaminated with Bacillus subtilis. J Hepatol 2009; 50: 111–7.
25 Johannsson M, Ormarsdottir S, Olafsson S. Hepatotoxicity associated with the use of Herbalife. Laeknabladid 2010; 96: 167–72.
26 Benichou C. Criteria of drug-induced liver disorders: report of an international consensus meeting. J Hepatol 1990; 11: 272–6.
27 Available at http://www.who-umc.org/DynPage.aspx?id=22682 (accessed 27 December 2010).
28 Hoffmann M, Marbet UA, Hurni A, Bianchi L, Göldi H. Rezidiv einer medikamentös-toxischen Hepatitis. Schweiz Med Forum 2005; 5: 147–8 (in German).
29 Manso G, Lopez-Rivas L, Duque JM, Salgueiro E. Spanish reports of hepatotoxicity associated with Herbalife® products. J Hepatol 2008; 49: 289–90.
30 Ignarro L, Heber D, Henig YS, Bejar E. Herbalife nutritional products and liver injury revisited. J Hepatol 2008; 49: 291–3.
31 Gavilan JC, Bermudez FJ, Salgado F, Pena D. Phytotherapy and hepatitis. Rev Clin Esp 1999; 199: 693–4.
32 Sarma DN, Barrett ML, Chavez ML, et al. Safety of green tea extracts. A systematic review by the US pharmacopeia. Drug Saf 2008; 31: 469–84.
33 Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–45.
34 Mazzanti G, Menniti-Ippolito F, Moro PA, et al. Hepatotoxicity from green tea: a review of the literature and two unpublished cases. Eur J Clin Pharmacol 2009; 65: 331–41.
35 Verhelst X, Burvenich P, Van Sassenbroeck D, et al. Acute hepatitis after treatment for hair loss with oral green tea extracts (Camellia sinensis). Acta Gastroenterol Belg 2009; 72: 262–4.
36 Vanstraelen S, Rahier J, Geubel AP. Jaundice as a misadventure of a green tea (Camellia sinensis) lover. Acta Gastroenterol Belg 2008; 71: 409–12.
37 Galati G, Lin A, Sultan AM, O'Brien PJ. Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. Free Radic Biol Med 2006; 40: 570–80.
38 Lin BR, Yu CJ, Chen WC, et al. Green tea extract supplement reduces D-galactosamine-induced acute liver injury by inhibition of apoptotic and proinflammatory signaling. J Biomed Sci 2009; 16: 35.
39 Kobayashi H, Tanaka Y, Asagiri K, et al. The antioxidant effect of green tea catechin ameliorates experimental liver injury. Phytomedicine 2010; 17: 197–202.
40 Zhong Z, Froh M, Lehnert M, et al. Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats. Am J Physiol Gastrointest Liver Physiol 2003; 285: G1004–13.
41 Jin X, Zheng RH, Li YM. Green tea consumption and liver disease: a systematic review. Liver Int 2008; 28: 990–6.
42 Durazo FA, Lassman C, Han SB, et al. Fulminant liver failure due to usnic acid for weight loss. Am J Gastroenterol 2004; 99: 950–2.
43 Favreau JT, Ryu ML, Braunstein G, et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002; 136: 590–5.
44 Neff GW, Reddy KR, Durazo FA, et al. Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid. J Hepatol 2004; 41: 1062–4.
45 Sanchez W, Maple JT, Burgart LJ, Kamath PS. Severe hepatotoxicity associated with use of a dietary supplement containing usnic acid. Mayo Clin Proc 2006; 81: 541–4.
46 Han D, Matsumaru K, Rettori D, Kaplowitz N. Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress. Biochem Pharmacol 2004; 67: 439–51.
47 US Food and Drug Administration. Warning on Hydroxycut products. Available at http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm152152.htm (accessed 31 May 2009).
48 Dara L, Hewett J, Lim JK. Hydroxycut hepatotoxicity: a case series and review of liver toxicity from herbal weight loss supplements. World J Gastroenterol 2008; 14: 6999–7004.
49 Fong TL, Klontz KC, Canas-Coto A, et al. Hepatotoxicity due to Hydroxycut: a case series. Am J Gastroenterol 2010; 105: 1561–6.
50 Lobb A. Hepatoxicity associated with weight-loss supplements: a case for better post-marketing surveillance. World J Gastroenterol 2009; 15: 1786–7.
51 Beuers U, Spengler U, Pape G. Hepatitis after chronic abuse of senna. Lancet 1991; 337: 372–3.
52 Seybold U, Landauer N, Hillebrand S, Goebel FD. Senna-induced hepatitis in a poor metabolizer. Ann Intern Med 2004; 141: 650–1.
53 Vanderperren B, Rizzo M, Angenot L, et al. Acute liver failure with renal impairment related to the abuse of senna anthraquinone glycosides. Ann Pharmacother 2005; 39: 1353–7.
54 Sonmez A, Yilmaz MI, Mas R, et al. Subacute cholestatic hepatitis likely related to the use of senna for chronic constipation. Acta Gastroenterol Belg 2005; 68: 385–7.
55 Soyuncu S, Cete Y, Nokay AE. Portal vein thrombosis related to Cassia angustifolia. Clin Toxicol (Philadelphia) 2008; 46: 774–7.
56 de Witte P, Lemli L. The metabolism of anthranoid laxatives. Hepatogastroenterology 1990; 37: 601–5.
57 Millonig G, Stadelmann S, Vogel W. Herbal hepatotoxicity: acute hepatitis caused by a Noni preparation (Morinda citrifolia). Eur J Gastroenterol Hepatol 2005; 17: 45–7.
58 Stadlbauer V, Fickert P, Lackner C, et al. Hepatotoxicity of NONI juice: report of two cases. World J Gastroenterol 2005; 11: 4758–60.
59 Yuce B, Gulberg V, Diebold J, Gerbes AL. Hepatitis induced by Noni juice from Morinda citrifolia: a rare cause of hepatotoxicity or the tip of the iceberg? Digestion 2006; 73: 167–70.
60 López-Cepero Andrada JM, Lerma Castilla S, Fernández Olvera MD, Amaya Vidal A. Hepatotoxicity caused by a Noni (Morinda citrifolia) preparation. Rev Esp Enferm Dig 2007; 99: 179–81 (in Spanish).
61 Stadlbauer V, Weiss S, Payer F, Stauber RE. Herbal does not at all mean innocuous: the sixth case of hepatotoxicity associated with Morinda citrifolia (noni). Am J Gastroenterol 2008; 103: 2406–7.
62 Duchini A. Autoimmune hepatitis and interferon beta-1a for multiple sclerosis. Am J Gastroenterol 2002; 97: 767–8.
63 Kamiyama T, Nouchi T, Kojima S, et al. Autoimmune hepatitis triggered by administration of an herbal medicine. Am J Gastroenterol 1997; 92: 703–4.
64 West BJ. Hepatotoxicity from interferon-beta, not noni juice. Digestion 2006; 74: 47–8.
65 West BJ, Jensen CJ, Westendorf J. Noni juice is not hepatotoxic. World J Gastroenterol 2006; 12: 3616–9.
66 West BJ, Su CX, Jensen CJ. Hepatotoxicity and subchronic toxicity tests of Morinda citrifolia (noni) fruit. J Toxicol Sci 2009; 34: 581–5.
67 Wang MY, Anderson G, Nowicki D, Jensen J. Hepatic protection by noni fruit juice against CCl(4)-induced chronic liver damage in female SD rats. Plant Foods Hum Nutr 2008; 63: 141–5.
68 Nadir A, Agrawal S, King PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, Ma-Huang. Am J Gastroenterol 1996; 91: 1436–8.
69 Borum ML. Fulminant exacerbation of autoimmune hepatitis after the use of Ma huang. Am J Gastroenterol 2001; 96: 1654–5.
70 Bajaj J, Knox JF, Komorowski R, Saeian K. The irony of herbal hepatitis: Ma-Huang-induced hepatotoxicity associated with compound heterozygosity for hereditary hemochromatosis. Dig Dis Sci 2003; 48: 1925–8.
71 Neff GW, Reddy KR, Durazo FA, et al. Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid. J Hepatol 2004; 41: 1062–4.
72 Nelson R. FDA issues alert on ephedra supplements in the USA. Lancet 2004; 363: 135.
73 Diaz D, Ferroudji S, Heran B. Hépatite aigue à la Germandrée petit-chene. Gastroenterol Clin Biol 1993; 16: 1006–7.
74 Larrey D, Vial T, Pauwels A, et al. Hepatitis after Germander (Teucrium chamaedrys) administration: Another instance of herbal medicine hepatotoxicity. Ann Int Medicine 1992; 117: 129–32.
75 Mostefa-Kara N, Pauwels A, Pines E, et al. Fatal hepatitis after herbal tea. Lancet 1992; 340: 674.
76 Dao T, Peytier A, Galateau F, Valla A. Hépatite chronique cirrhogene a la germandrée petit-chene. Gastroenterol Clin Biol 1993; 17: 609–10.
77 Piozzi F, Rodriguez B, Savona G. Advances in the chemistry of the furanoditerpenoids from Teucrium species. Heterocycles 1987; 25: 807–41.
78 Lekehal M, Pessayre D, Lereau JM, et al. Hepatotoxicity of the herbal medicine, germander. Metabolic activation of its furano diterpenoids by cytochrome P450 3A depletes cytoskeleton-associated protein thiols and forms plasma membrane blebs in rat hepatocytes. Hepatology 1996; 24: 212–8.
79 Fau D, Lekehal M, Farrell G, et al. Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes. Gastroenterology 1997; 113: 1334–46.
80 Kanda T, Yokosuka O, Tada M, et al. N-nitroso-fenfluramine hepatotoxicity resembling chronic hepatitis. J Gastroenterol Hepatol 2003; 18: 999–1000.
81 Adachi M, Saito H, Kobayashi H, et al. Hepatic injury in 12 patients taking the herbal weight loss aids Chaso or Onshido. Ann Intern Med 2003; 139: 488–92.
82 Nakagawa Y, Tayama S, Ogata A, Suzuki T, Ishii H. ATP-generating glycolytic substrates prevent N-nitrosofenfluramine-induced cytotoxicity in isolated rat hepatocytes. Chem Biol Interact 2006; 164: 93–101.
83 Nakagawa Y, Suzuki T, Kamimura H, Nagai F. Role of mitochondrial membrane permeability transition in N-nitrosofenfluramine-induced cell injury in rat hepatocytes. Eur J Pharmacol 2006; 529: 33–9.
84 Minuk GY, Kelly JK, Hwang WS. Vitamin A hepatotoxicity in multiple family members. Hepatology 1988; 8: 272–5.
85 Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology 1991; 100: 1701–9.
86 Becker P, Maurer B, Schirmacher P, et al. Vitamin A-induced cholestatic hepatitis: a case report. Z Gastroenterol 2007; 45: 1063–6.
87 Ramanathan VS, Hensley G, French S, et al. Hypervitaminosis A inducing intra-hepatic cholestasis – a rare case report. Exp Mol Pathol 2010; 88: 324–5.
88 Penniston KL, Tanumihardjo SA. The acute and chronic effects of vitamin A. Am J Clin Nutr 2006; 83: 191–201.
89 Carpenter TO, Pettifor JM, Russell RM, et al. Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake. J Pediatr 1987; 111: 507–12.
90 Krasinski SD, Russell RM, Otradovec CL, et al. Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinol-binding protein, retinyl esters, carotene, alpha-tocopherol, and cholesterol among elderly people and young adults: increased plasma retinyl esters among vitamin A-supplement users. Am J Clin Nutr 1989; 49: 112–20.
91 Kowalski TE, Falestiny M, Furth E, Malet PF. Vitamin A hepatotoxicity: a cautionary note regarding 25.000 IU supplements. Am J Med 1994; 97: 523–8.
92 Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotine: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr 1999; 69: 1071–85.
93 Nollevaux MC, Guiot Y, Horsmans Y, et al. Hypervitaminosis A-induced liver fibrosis: stellate cell activation and daily dose consumption. Liver Int 2006; 26: 182–6.
94 Liu C, Russell RM, Seitz HK, Wang XD. Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P4502E1. Gastroenterology 2001; 120: 179–89.
95 Dan Z, Popov Y, Patsenker E, et al. Hepatotoxicity of alcohol-related polar retinoid metabolites involves apoptosis via loss of mitochondrial membrane potential. FASEB J 2005; 19: 845–7.
96 US Department of Justice, Drug Enforcement Administration (DEA). Rules 2005-Implementation of the Anabolic Steroid Control Act of 2004. Available at http://www.deadiversion.usdoj.gov/fed_regs/rules/2005/fr1216.htm(accessed 27 December 2010).
97 Ishak KG. Hepatic lesions caused by anabolic and contraceptive steroids. Semin Liver Dis 1981; 1: 116–28.
98 Erlinger S. Drug-induced cholestasis. J Hepatol 1997; 2 (Suppl. 1): 1–4.
99 Shah NL, Zacharias I, Khettry U, Afdhal N, Gordon FD. Methasteron-associated cholestatic liver injury: clinicopathologic findings in 5 cases. Clin Gastroenterol Hepatol 2008; 6: 255–8.
100 Kafrouni MI, Anders RA, Verma S. Hepatotoxicity associated with dietary supplements containing anabolic steroids. Clin Gastroenterol Hepatol 2007; 5: 809–12.
101 Krishnan PV, Feng ZZ, Gordon SC. Prolonged intrahepatic cholestasis and renal failure secondary to anabolic steroid-enriched dietary supplements. J Clin Gastroenterol 2009; 43: 672–5.
102 Schwingel PA, Cotrim HP, Salles BR, et al. Anabolic-androgenic steroids: a possible new risk factor of toxicant-associated fatty liver disease. Liver Int 2010. DOI: DOI: 10.1111/j.1478-3231.2010.02346.x.
103 WHO. WHO Guidelines on Safely Monitoring of Herbal Medicines in Pharmacovigilance Systems. Geneva: WHO, 2004.
104 Garcia-Cortés M, Lucena MI, Pachkoria K, et al. Evaluation of Naranjo adverse drug reactions probability scale in causality assessment of drug-induced liver injury. Aliment Pharmacol Ther 2008; 27: 780–9.
105 Danan G, Benichou C. Causality assessment of adverse reactions to drugs I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993; 46: 1323–30.
106 Aithal GP, Rawlins MD, Day CP. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic reactions. J Hepatol 2000; 33: 949–52.
107 Lucena MI, Camargo R, Andrade RJ, et al. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001; 33: 123–30.
108 Fontana RJ, Watkins PB, Bonkovsky HL, et al. Drug-induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf 2009; 32: 55–68.
109 Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology 2010; 52: 730–42.
Source
Early View (Articles online in advance of print)
Felix Stickel 1, Kerstin Kessebohm 2, Rosemarie Weimann 3, Helmut K. Seitz 4
Article first published online: 11 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02439.x
© 2011 John Wiley & Sons A/S
Author Information
1 Department of Visceral Surgery and Medicine, Institute of Clinical Pharmacology and Visceral Research, Inselspital, University of Berne, Berne, Switzerland
2 Institute of Clinical Pharmacology and Visceral Research, University of Berne, Berne, Switzerland
3 Institute of Pathology, University of Berne, Berne, Switzerland
4 Department of Medicine, Center of Alcohol Research, Liver Disease and Nutrition, Salem Medical Center, University of Heidelberg, Heidelberg, Germany
* Correspondence: Correspondence Felix Stickel, MD, Department of Visceral Surgery and Medicine, Institute of Clinical Pharmacology and Visceral Research, Inselspital, University of Bern, Murtenstr. 35, 3010 Bern, Switzerland Tel: +41 31 632 87 28 Fax: +41 31 632 49 97 e-mail: felix.stickel@ikp.unibe.ch
Keywords:
anabolic steroids; Camellia sinensis; cholestasis; hepatitis; retinoid toxicity; toxic liver injury
Abstract
Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms ‘dietary/nutritional supplements’, ‘adverse hepatic reactions’, ‘liver injury’; ‘hepatitis’, ‘liver failure’, ‘vitamin A’ and ‘retinoids’, and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife® and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks.
Abbreviations
ALF, acute liver failure; DILI, drug-induced liver injury; DS, dietary supplements; FDA, Food and Drug Administration; HSC/MFB, hepatic stellate cells/portal myofibroblasts
The use of dietary supplements (DS) containing vitamins, anti-oxidants, fibre, trace elements, proteins, amino acids and herbal constituents has become a major health trend in affluent societies (1, 2). Consumption of DS in the USA has doubled to 18.9% of adults admitting their use only between 1999 and 2004 (3, 4); some investigations report their consumption up to 47% in certain subgroups such as among elder, non-smoking females with higher education (5). The rising popularity of DS is probably because of an increased awareness of consumers towards health in general and the desire to prevent diseases by an optimized nutritional status, and the persuasion that these treatments are safe (1, 2, 5, 6). Further, DS do not require prescriptions from health professionals allowing largely unrestricted access to relatively cheap products. Consequently, marketing such products has become a multibillion business largely unregulated by official health authorities (6–8).
In the USA, DS are expected to meet the standards outlined in the Dietary Supplement and Health Education Act published in 1994, which allows distribution without prior approval of their efficacy and safety by the Food and Drug Administration (FDA) (9). This simplified licensing practice does not ensure efficacy and safety in the same strict way as with the approval of conventional medications and treatments. Similarly, the European Union has set forth legislative measures for the distribution and marketing of DS and functional foods that are outlined in the European Commission 2000 White Paper on Food Safety (10, 11). This set of legislation pays tribute to the fact that DS may harbour specific problems because of their complex composition, particularly with respect to quality aspects, and defines guidelines for conducting premarketing in vitro and in vivo studies.
While adverse hepatic reactions from xenobiotics are well documented by pre- and post-marketing pharmacovigilance, the situation for DS is less well depicted as widespread and uncontrolled use and under-reporting prevent the determination of their true incidence. Additionally, a low awareness of users and providers towards their potential harms impedes their recognition as the causative agent in incidents of hepatotoxicity. Consequently, estimates of the frequency of DS-associated hepatic injury are likely imprecise and, possibly, too low. The proportion of hepatotoxicity ascribed to DS varies from 2% in a Spanish study (12) describing 531 cases of drug-induced liver injury (DILI) to approximately 10% in a series from the US Drug-Induced Liver Injury Network (DILIN) (13). Figures were as high as 35% in a small series of 20 patients developing acute liver failure with DS exposure as the only identifiable cause of liver damage (14).
Our article aimed to review and describe the literature on liver injury because of DS, delineate patterns and mechanisms of injury and to increase the awareness towards this possible cause of acute and chronic liver damage.
Literature search methodology
In February 2010, case reports and series thereof on liver injury specifically occurring following the consumption of DS published between 1990 and 2010 were searched in PubMed and EMBASE data bases using the terms ‘adverse hepatic reactions’, ‘anabolic steroids’, ‘Camellia sinensis’, ‘dietary/nutritional supplements’, ‘Herbalife’, ‘hepatitis’, ‘Hydroxycut’, ‘green tea’, ‘liver failure’, ‘liver injury’, ‘Noni’, ‘retinoids’, ‘vitamin A’ and critically reviewed. Retrieved publications were searched for yet unidentified publications. Remedies were considered DS if consumed as an aid to improve nutritional status, to loose weight or to treat constipation. Cases of liver injury from preparations taken for other causes than nutritional purposes were not included. No language restriction was used.
While hepatotoxicity from herbal medicines in general has been addressed in several reviews (15–18), summaries specifically devoted to liver-related risks along with DS are scarce (19). In the following, a panel of rather distinct DS preparations associated with liver injury are described (Table 1).
Specific dietary supplements associated with liver injury
Herbalife® (Los Angeles, CA, USA) sells nutritional and herbal supplements as tablets, capsules, drinks and energy bars for weight control, improvement of nutrition, ‘well-being’ and cosmetics. In 2006, the stock market quoted that Herbalife® company had a revenue of US$3.1 billion via online marketing or through independently operating sales agents.
There are so far six published reports on liver damage following the intake of Herbalife® products since 2007 describing 34 cases from five countries (Switzerland, Israel, Spain, Argentina and Iceland), although Herbalife® products are sold in at least 60 countries worldwide (20–25). Individual data of all reports are displayed in Table 2. Pattern of injury was mostly hepatocellular, but mixed and cholestatic enzyme patterns were also observed. Severity ranged from mild to severe hepatic damage including cirrhosis and acute liver failure requiring liver transplantation, which was successful in one patient while the second died because of post-operative complications. Causality between intake of Herbalife® products and the evolution of liver injury was assessed by widely used scores (26, 27) in five of the six reports and considered ‘certain’ in at least five patients by a positive rechallenge reaction and ‘probable’ in the majority of the remaining cases (20, 21).
Figure 1. Liver histology from a patient with secondary biliary cirrhosis following long-term intake of numerous Herbalife® nutritional supplements contaminated with Bacillus subtilis. (A) Enlargement of portal tracts with fibrosis, chronic inflammation and porto-lobular interface activity as well as ductular proliferation of the bile ducts with reactive changes of the epithelium (HE staining). (B) Immunohistochemistry with anticytokeratin 7 indicating bile duct such as loss of biliary lumina and significant lympho-epithelial infiltration (see arrow).
Green tea is among the most frequently consumed drinks in the USA and often used as a DS. The first report on liver injury following the ingestion of green tea extracts and preparations thereof was published in 1999 (31), and since then, numerous consecutive cases were reported to regulatory agencies worldwide. With effect of April 2003, the manufacturer of Exolise® (Arkopharma, Carros, France), a hydro-alcoholic extract of C. sinensis, has revocated all of their products after altogether 13 cases of acute liver damage following its intake were reported to the French pharmacovigilance authorities (Agence Francaise de Securité Sanitaire de Produits de Sanité; http://www.afssaps.sante.fr/). As a reaction to these accumulating reports, the US Pharmacopeia performed a systematic review of all cases accessible from PubMed, EMBASE and pharmacovigilance data bases in the USA, Canada, UK and Australia reporting on 34 single cases of liver injury following the ingestion of numerous different green tea preparations (32). Herein, case reports were retrospectively evaluated according to the Naranjo causality algorithm scale (33), and 27 reports pertaining to liver damage were labelled as ‘possibly’ and the remaining seven cases as ‘probably’ linked to green tea. Another Medline search review of cases on green tea liver injury from the same year also retrieved 34 published reports and described two further yet unpublished cases (34). On histological examination, livers of patients revealed inflammatory reactions, cholestasis, occasionally steatosis and necrosis. Although there was some overlap of single reports between these two review articles, collected case reports were not identical and jointly provided details on 58 cases of hepatotoxicity along with the intake of green tea extracts, powdered leaves, green tea infusions and hydro-alcoholic and aqueous extracts. In Mazzanti's summary, no causality re-evaluation was performed, but information on de- and rechallenge is provided for every case indicating a positive rechallenge response with accelerated recurrence of liver injury in seven of 36 incidents, which strongly suggests a causal relationship between the observed liver injury and green tea consumption. Of concern is that there was one reported death. However, a note of caution is warranted in many of the cases regarding an exclusive assignment of causality to green tea, because many patients who experienced adverse hepatic reactions also took numerous other products with a published record of hepatotoxicity, such as Cassia angustifolia, Hydroxycut and Ephedra sinica (for all three, please see below). Since these two review articles, additional cases have been published from Belgium reporting on a 42-year-old female patient who developed cholestatic hepatitis 6 months after starting Densitive® (Kerastase Nutritients, L'Oréal, Paris), which contains C. sinensis (35). Upon dechallenge, a full recovery was recorded. Other causes of liver injury were carefully excluded, but formal causality assessment using an established score was not performed. In the second case, jaundice, weight loss and subacute hepatitis developed in a 76-year-old man who regularly drank green tea infusions (36). Histology showed marked necro-inflammation, and transiently elevated antismooth muscle auto-antibodies were suggestive of autoimmunity induced by green tea constituents.
The mode of toxicity derived from green tea still remains incompletely understood but could be because of (−)-epigallocatechin gallate or its metabolite (−)-epicatechin gallate, which, under certain conditions such as fasting, can induce oxidative stress-related liver damage (37). Interestingly, in vitro and in vivo experimental studies have demonstrated both hepatoprotective as well as hepatotoxic properties (37–40). Along this line, support for potentially hepatoprotective activity from green tea extracts comes from clinical studies studying its therapeutic effects in humans with liver diseases including liver cancer, cirrhosis and steatosis. Four randomized-controlled clinical trials, two cohort, one case–control and three cross-sectional studies from China, Japan and the USA were recently subjected to a systematic review and found overall favourable effects from green tea as reflected by reduced mortality, attenuated steatosis and reduced incidence of primary liver cancer (41).
Whether the risks from green tea consumption outweigh their benefits remains open, but current evidence as outlined above suggests a causal relationship between intake of green tea-containing products and hepatotoxicity. Consequently, in their systematic review, the US Pharmacopeia included a cautionary statement on green tea indicating this possibility (32).
Usnic acid
Some years ago, several cases of acute liver failure requiring liver transplantation following the intake of LipoKinetix®, a product extracted from lichens and fungi and sold as DS capsules, were reported (42–45). Onset of liver injury was usually acute with a maximum latency of 3 months and the injury pattern hepatocellular with massive elevations of ALT and AST. Lipokinetix contained usnic acid and was marketed as a weight-loss remedy. Efficacy for this indication was postulated based on its function as an uncoupler of the respiratory chain, which in principle can augment weight loss (46). Apart from usnic acid, LipoKinetix® contained norephedrine hydrochloride, diiodothyronine, yohimbine hydrochloride and caffeine, which were confirmed by analysing the used LipoKinetix® lots. None of the ingredients were associated previously with liver damage and inadvertent contamination was excluded. These serious events caused the withdrawal of LipoKinetix® from the market.
Hydroxycut
Only recently, several Hydroxycut products were retracted by the manufacturer following a warning posted by the FDA in May 2009 because of 23 reports of liver injury including cases with acute hepatic failure and subsequent liver transplantation (47–49). Hydroxycut preparations were sold as powder, capsules and tablets by conventional retailers, through Internet sources and via direct television marketing. Hydroxycut was used to support weight loss and by body builders. The manufacturer had been charged previously with several lawsuits for unfounded health claims. Before May 2009, its primary ingredients included Garcinia cambogia, Gymnema sylvestre, chromium polynicotinate, caffeine and green tea. Published cases were recently reviewed and showed acute onset after several weeks of intake with high levels of serum aminotransferases in the majority of cases, while others presented with a more insidious, usually cholestatic course (50).
Miscellaneous
Various other DS have been associated with acute and subacute liver damage such as Senna (C. angustifolia), which is used as a powder, tea or suppository to treat constipation. According to our search, a total of five reports with altogether five individual cases describe the evolution of variable liver pathologies including acute cytolytic hepatitis, subacute cholestatic hepatitis, acute liver failure and portal vein thrombosis upon consumption of Senna products (51–55). In some reports, Senna preparations were self-made or ingested excessively such as in a young woman taking approximately 10 times the recommended dose who developed cytolytic hepatitis, which completely subsided after stopping Senna (51). The causal relationship between the preparation and hepatitis was confirmed through a positive rechallenge in two cases (51, 52). Senna is biotransformed via intestinal bacteria to rhein anthrone, which is highly reactive and requires binding to glucuronide and sulphate via phase I oxidation for renal excretion (56). Rhein anthrone is suspected to function as an uncoupler of the respiratory chain, and can therefore possibly affect hepatocyte integrity under certain circumstances, such as in genetically predisposed individuals. Seybold et al. (52) describe a case of increased toxicity of Senna tea in a homozygous carrier of a genetic cytochrome P450 2D6 variant rendering the individual a poor metabolizer for phase I hepatic detoxification reactions.
Noni juice (Morinda citrifolia) has become increasingly popular in Western countries as a health tonic. Consumption of Noni was the presumed cause of acute hepatitis in a 45-year-old man who drank a glass of this tropical fruit over several weeks for preventive reasons and for ‘strengthening the immune system’ (57). Other possible aetiologies of acute hepatitis were ruled out and liver tests rapidly turned normal after the cessation of Noni intake. Since this first report in 2005, five additional cases have been published from Austria, Germany and Spain (58–61). Remarkably, two patients experienced liver failure of which one required liver transplantation. The pattern of liver injury was hepatocellular in all cases and occurred rapidly within a few weeks of exposure. Causality was formally assessed in two publications, but not considered ‘certain’ in any of the cases because no rechallenge was used. Also, at least two of totally six patients had concomitant medication with known hepatotoxic potential, such as interferon-β (62) and a Chinese herbal mixture (63) respectively. Responsibility of Noni preparations as the cause of liver injury in these cases is challenged by one of the manufacturers of Noni products (64, 65) by demonstrating experimental evidence of no dose-dependent hepatotoxicity and even hepatoprotective properties in some animal models of chronic liver injury (66, 67). However, a lack of dose-dependent hepatotoxicity does not exclude idiosyncratic drug toxicity, e.g. by inducing autoimmune reaction as shown by Yuce et al. (59) who found excessively high liver–kidney microsomal antibodies of 1:3840 in a patient drinking Noni juice for 4 weeks. Nevertheless, the true underlying pathophysiology of Noni-associated liver injury remains elusive because active components within Noni extracts such as flavonoids, glycosides, vitamins, anthraquinones and polyunsaturated fatty acids are not known to be hepatotoxic.
Chinese herbs have become highly popular among consumers in Western countries because of a prevailing belief in their efficacy and safety. Among many others, Ma huang (E. sinica) is marketed in the USA as a nasal decongestant and bronchodilator, and more recently as a weight-loss remedy. The first report of Ma huang-associated liver injury was about a woman developing acute hepatitis together with elevated antinuclear antibodies (ANA) and smooth muscle antibodies (SMA) after only 3 weeks of intake of Ma huang, but liver abnormalities resolved after its discontinuation (68). Another report suggested that intake of Ma huang was the cause of acute liver failure in a 58-year-old patient initiating her listing for high-urgency liver transplantation who also presented with elevated titres of SMA (69). Another report suggested an association of Ma huang-related liver injury with compound heterozygosity for the C282Y and H63D mutation in the haemochromatosis gene, proposing that excess hepatic iron could aggravate hepatotoxicity, possibly via enhancing oxidative stress (70). The largest series on severe liver injury because of the intake of Ma huang by Neff et al. (71) describes 10 cases of acute cytolytic hepatitis of which two subjects required liver transplantation and one died, while the remaining seven patients recovered spontaneously. These cases of severe liver damage and others referring to cardiac toxicity have prompted a warning by the FDA for the use of Epedra-containing DS such as Ma huang (72).
In 1986, Germander (Teucrium chamaedrys) was approved as a drug for the supportive treatment of obesity in France. Its subsequent widespread use precipitated numerous reports on acute, chronic and even fulminant hepatitis to the French pharmacovigilance authorities in 1992 (73–75). Within a median of 2 months, intake of daily doses between 600 and 1600 mg/day precipitated acute cytolytic hepatitis or chronic hepatitis with fibrosis and even cirrhosis (74, 76). All patients recovered after the discontinuation of treatment, but some relapsed under re-exposure. Germander contains saponins, glycosides, flavonoids and neoclerodane diterpenoids, which were shown to be converted into diterpenoid toxic metabolites by cytochrome P450 3A in mice (77). In conditions of glutathione depletion – such as during fasting – or after induction of cytochrome P450 3A, toxic diterpenoids are potent inducers of hepatocyte apoptosis (78, 79). Hence, in 1992, the license for Germander-containing products was withdrawn.
‘Onshidou-Genbi-Kounou’, another herbal marketed for weight loss, seemed the likely cause of chronic hepatitis in a 52-year-old Japanese woman who took this preparation for 2 months (80). Serum levels of liver enzymes were elevated to >1500 IU/l and ANA were positive with 1:160. All other possible causes for chronic hepatitis were excluded, and liver histology was compatible with drug-induced autoimmune hepatitis. The patient recovered completely without intervention on cessation of ‘Onshidou-Genbi-Kounou’ intake. In a larger series from Japan describing 12 patients with acute hepatitis after taking ‘Onshidou-Genbi-Kounou’ and ‘Chaso’ for weight loss, two patients developed liver failure of which one survived after successful liver transplantation and the other one died (81). ‘Onshidou-Genbi-Kounou’ contains several natural compounds (amachazuru, tea leaf, barbaloin, total saponin and polyphenols) and N-nitroso-fenfluramine. The latter demonstrated induction of mitochondrial permeability transition and hepatocyte apoptosis following uncoupling of oxidative phosphorylation and intracellular ATP depletion (82, 83).
Vitamin A-associated liver injury
DS fortified with vitamin A are used to prevent night blindness, to increase immune function and to promote health in general. Liver injury related to hypervitaminosis A is well known for many decades and comprises mild elevations of serum liver enzymes, cholestatic hepatitis, non-cirrhotic portal hypertension, progressive fibrosis and cirrhosis (84–87). Toxicity does not usually occur with standard doses below 50 000 IU/day as contained in common multivitamin preparations, but individual tolerability may vary (88). Pre-existing liver lesions including steatosis, chronic alcohol consumption, comedication with other potentially hepatotoxic drugs and young age may predispose certain individuals to develop vitamin A hepatotoxicity (89, 90). Several case reports have demonstrated significant hepatotoxicity with vitamin A doses as low as 20 000 IU/day (91), and upper limits of tolerability may even be lower in regular alcohol consumers (92).
Toxicity is mediated to the dose-dependent effect of retinoids on hepatic stellate cells/portal myofibroblasts (HSC/MFB), which are the key effector cells in the evolution of fibrosis and cirrhosis (93). Upon excessive vitamin A exposure, HSC/MFB start to produce collagens, downregulate collagenase activity and acquire the ability of contraction leading to elevation of blood pressure in the portal vein. In addition to this direct impact on HSC/MFB function and activity, retinoids can be transformed into metabolites that affect mitochondrial function and hepatocyte viability with resulting liver cell apoptosis (94, 95). This was shown to occur particularly when co-administered with alcohol. Dan and colleagues showed that retinoids can be transformed via alcohol-induced cytochrome P450 2E1 into highly reactive and toxic polar metabolites, which cause hepatocyte apoptosis upon caspase 3 activation (Fig. 2). Hence, health professionals should consult users carefully about the potential dangers of vitamin A, particularly when intended for longer period, in children and regular alcohol consumers.
Figure 2. Retinoids are substrates of cytochrome P450 2E1 and may be transformed into toxic polar retinoid metabolites. These can damage mitochondria by disrupting the mitochondrial membrane potential, releasing pro-apoptotic factors (e.g. cytochrome C) and initiating caspase activation and hepatocellular apoptosis.
Anabolic steroids are an integral part of the nutritional concept of many athletes to improve fitness, muscle gain and exercise performance. Their use is widespread although anabolics are classified as class III substances and therefore subdued to strict rules (96). However, access via inofficial and sometimes illegal sources is easy, and therefore, in spite of tight rules, further adverse hepatic reactions following the consumption of anabolic steroids can be expected. Hepatotoxicity has been frequently described and patterns of injury delineated. Liver lesions include intrahepatic cholestasis, hepatitis, adenoma and hepatocellular carcinoma and rare malformations such as peliosis hepatis, a rare pathological entity characterized by the gross appearance of multiple cyst-like, blood-filled cavities within the liver (97, 98). A recent case series demonstrated the evolution of cholestasis 2 weeks after the intake of anabolic steroids had been stopped. All patients recovered fully after intake had been terminated (99). Even more worrisome is the observation that some DS may contain anabolic steroids sufficient to precipitate liver injury, as demonstrated by a recent case report showing cholestasis in two young men who took DS to enhance their body-building performance (100). Another case presented with a less favourable course as prolonged intrahepatic cholestasis and subsequent kidney failure developed (101). The precise mechanism underlying toxicity is yet unclear, but experimental data indicate direct hepatocellular toxicity from steroids via increased oxidative stress and subsequent impairment of function of the canalicular bile salt export pump (100).
A recent case–control study from Brazil suggested that anabolic steroids could be a cause of toxicant-associated non-alcoholic fatty liver disease (TAFLD) by comparing 95 recreational body builders using anabolic steroids with 85 non-users. In those consuming anabolic steroids, 12.6% of subjects revealed criteria compatible with TAFLD such as steatosis on ultrasound imaging, elevated serum transaminases and exclusion of relevant alcohol intake or concomitant medication, but no overweight or insulin resistance suggestive of metabolic NAFLD. In turn, 2.4% of body builders not using anabolic steroids showed clinical signs and findings suggestive of NAFLD. The authors concluded that the intake of anabolic steroids could be a cause of non-metabolic, but toxicant-associated NAFLD (102).
Conclusion
Hepatic injury secondary to consumption of DS is recognized, although its exact frequency remains unclear, mostly because evidence relies exclusively on case reports. Lack of stringent diagnostic criteria, poor awareness of consumers and prescribers, easy and uncontrolled access and under-reporting account for this epidemiological gap of knowledge. Diagnostic assessment of DS-associated should be made more consistent, and customized specifically to DS. Although causality categories reached in many of the published reports suggest a causal relationship between liver injury and the intake of certain DS products, pitfalls exist related to the used diagnostic scales, which have all been criticized for variable reasons and of which none is unequivocally accepted as being suitable for the evaluation of DS as a cause of liver injury. While the WHO score is not specifically designed to evaluate DILI (103), the Naranjo adverse drug reaction probability scale (33) was recently found to have low sensitivity (54%), poor negative predictive value (29%) and to lack reproducibility in a large series of cases of suspected hepatotoxicity (104) when compared with the Roussel Uclaf Causality Assessment Method (RUCAM) (26, 105). A clinical diagnostic scale has been suggested as a simple tool to assess adverse hepatic drug reactions and showed good correlation with RUCAM in one study (106), but not in another (107). To conclude, all used scores reveal merits and limitations, but a common consensus on which one is the best to apply in causality assessment of DS-associated liver damage has never been reached. In an approach to compensate for this lack of common agreement, recently, the DILIN was established to advance our understanding and research into DILI by initiating a prospective registry of patients with DILI for future studies into host clinical, genetic, environmental and immunological risk factors, and to develop standardized nomenclature, terminology and causality assessment instruments (108). Patients with liver injury because of herbal products are also eligible to be included. Herein, a causality score ranging from 1 (definite) to 5 (unlikely) as well as a severity score ranging from 1 (mild) to 5 (fatal) is applied by three hepatologists of the DILIN study group, thereby minimizing individual biases. In addition to accounting for the input of the reporting investigator who took the history, performed the physical examination and supervised the data collection, a prospective evaluation of other potential causes of liver injury and serial laboratory data through at least 6 months of follow-up are offered. However, the DILIN expert opinion is limited by its lack of generalizability and a low level of agreement between the three hepatologists (109). Hence, a certain degree of inaccuracy in assigning causality remains until better diagnostic measures are established.
Apart from diagnostic measures, better regulatory measures to assure safety and timely recognition of potentially harmful products require improvement and, thus, efforts of pharmacovigilance authorities and healthcare providers must jointly act to minimize risks and protect consumers. Manufactures must spend utmost care in providing users with clean and unadulterated products and should be held liable if this accidentally or carelessly fails. Finally, consumers should develop a more critical attitude towards the expectations and hopes associated with DS use in largely healthy individuals, and turn to measures for which safety data are known, and efficacy is proven.
References
1 Radimer K, Bindewald B, Hughes J, et al. Dietary supplement use by US adults: data from the national health and nutrition examination survey, 1999–2000. Am J Epidemiol 2004; 160: 339–49.
2 Landström E, Hursti UK, Becker W, Magnusson M. Use of functional food among Swedish consumers is related to health-consciousness and perceived effect. Br J Nutr 2007; 98: 1058–69.
3 Ni H, Simile C, Hardy AM. Utilization of complementary and alternative medicine by United States adults: results from the 1999 national health interview survey. Med Care 2002; 40: 353–8.
4 Kessler RC, Davis RB, Foster DF, et al. Long-term trends in the use of complementary and alternative medical therapies in the United States. Ann Intern Med 2001; 135: 262–8.
5 Reinert A, Rohrmann S, Becker N, Linseisen J. Lifestyle and diet in people using dietary supplements. Eur J Nutr 2007; 46: 165–73.
6 Michels Blanck H, Serdula MK, Gillespie C, et al. Use of nonprescription dietary supplements for weight loss is common among Americans. J Am Diet Assoc 2007; 107: 441–7.
7 Brevoort P. The booming US botanical market: a new overview. HerbalGram 1998; 44: 33–46.
8 Dorsch KD, Bell A. Dietary supplement use in adolescents. Curr Opin Pediatr 2005; 17: 653–7.
9 US Food and Drug Administration. Guidance, compliance and regulatory information. Available at http://www.fda.gov/food/dietarysupplements/GuidanceComplianceRegulatoryInformation (accessed 31 May 2009).
10 Coppens P, da Silva MF, Pettman S. European regulations on neutraceuticals, dietary supplements and functional foods: a framework based on safety. Toxicology 2006; 221: 59–74.
11 Gulati OP, Berry Ottaway P. Legislation relating to nutraceuticals in the European Union with a particular focus on botanical-sourced products. Toxicology 2006; 221: 75–87.
12 GarcÃa-Cortés M, Borraz Y, Lucena MI, et al. Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry. Rev Esp Enferm Dig 2008; 100: 688–95.
13 Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924–34.
14 Estes JD, Stolpman D, Olyaei A, et al. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003; 138: 852–8.
15 De Smet PAGM. Herbal remedies. N Engl J Med 2002; 347: 2046–56.
16 Stickel F, Patsenker E, Schuppan D. Herbal hepatotoxicity. J Hepatol 2005; 43: 901–10.
17 Seeff LB. Herbal hepatotoxicity. Clin Liv Dis 2007; 11: 577–96.
18 Chitturi S, Farrell GC. Hepatotoxic slimming aids and other herbal hepatotoxins. J Gastroenterol Hepatol 2008; 23: 366–73.
19 Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373–82.
20 Elinav E, Pinsker G, Safadi R, et al. Association between consumption of Herbalife® nutritional supplements and acute hepatotoxicity. J Hepatol 2007; 47: 514–20.
21 Schoepfer AM, Engel A, Fattinger K, et al. Herbal does not mean innocuous: 10 cases of severe hepatotoxicity associated with dietary supplements from Herbalife® products. J Hepatol 2007; 47: 521–6.
22 Duque JM, Ferreiro J, Salgueiro E, Manso G. Hepatotoxicity associated with the consumption of herbal slimming products. Med Clin (Barcelona) 2007; 128: 238–9.
23 Chao S, Anders M, Turbay M, et al. Toxic hepatitis by consumption Herbalife products a case report. Acta Gastroenterol Latinoam 2008; 38: 274–7.
24 Stickel F, Droz S, Patsenker E, et al. Severe hepatotoxicity following ingestion of Herbalife® nutritional supplements contaminated with Bacillus subtilis. J Hepatol 2009; 50: 111–7.
25 Johannsson M, Ormarsdottir S, Olafsson S. Hepatotoxicity associated with the use of Herbalife. Laeknabladid 2010; 96: 167–72.
26 Benichou C. Criteria of drug-induced liver disorders: report of an international consensus meeting. J Hepatol 1990; 11: 272–6.
27 Available at http://www.who-umc.org/DynPage.aspx?id=22682 (accessed 27 December 2010).
28 Hoffmann M, Marbet UA, Hurni A, Bianchi L, Göldi H. Rezidiv einer medikamentös-toxischen Hepatitis. Schweiz Med Forum 2005; 5: 147–8 (in German).
29 Manso G, Lopez-Rivas L, Duque JM, Salgueiro E. Spanish reports of hepatotoxicity associated with Herbalife® products. J Hepatol 2008; 49: 289–90.
30 Ignarro L, Heber D, Henig YS, Bejar E. Herbalife nutritional products and liver injury revisited. J Hepatol 2008; 49: 291–3.
31 Gavilan JC, Bermudez FJ, Salgado F, Pena D. Phytotherapy and hepatitis. Rev Clin Esp 1999; 199: 693–4.
32 Sarma DN, Barrett ML, Chavez ML, et al. Safety of green tea extracts. A systematic review by the US pharmacopeia. Drug Saf 2008; 31: 469–84.
33 Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–45.
34 Mazzanti G, Menniti-Ippolito F, Moro PA, et al. Hepatotoxicity from green tea: a review of the literature and two unpublished cases. Eur J Clin Pharmacol 2009; 65: 331–41.
35 Verhelst X, Burvenich P, Van Sassenbroeck D, et al. Acute hepatitis after treatment for hair loss with oral green tea extracts (Camellia sinensis). Acta Gastroenterol Belg 2009; 72: 262–4.
36 Vanstraelen S, Rahier J, Geubel AP. Jaundice as a misadventure of a green tea (Camellia sinensis) lover. Acta Gastroenterol Belg 2008; 71: 409–12.
37 Galati G, Lin A, Sultan AM, O'Brien PJ. Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. Free Radic Biol Med 2006; 40: 570–80.
38 Lin BR, Yu CJ, Chen WC, et al. Green tea extract supplement reduces D-galactosamine-induced acute liver injury by inhibition of apoptotic and proinflammatory signaling. J Biomed Sci 2009; 16: 35.
39 Kobayashi H, Tanaka Y, Asagiri K, et al. The antioxidant effect of green tea catechin ameliorates experimental liver injury. Phytomedicine 2010; 17: 197–202.
40 Zhong Z, Froh M, Lehnert M, et al. Polyphenols from Camellia sinenesis attenuate experimental cholestasis-induced liver fibrosis in rats. Am J Physiol Gastrointest Liver Physiol 2003; 285: G1004–13.
41 Jin X, Zheng RH, Li YM. Green tea consumption and liver disease: a systematic review. Liver Int 2008; 28: 990–6.
42 Durazo FA, Lassman C, Han SB, et al. Fulminant liver failure due to usnic acid for weight loss. Am J Gastroenterol 2004; 99: 950–2.
43 Favreau JT, Ryu ML, Braunstein G, et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002; 136: 590–5.
44 Neff GW, Reddy KR, Durazo FA, et al. Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid. J Hepatol 2004; 41: 1062–4.
45 Sanchez W, Maple JT, Burgart LJ, Kamath PS. Severe hepatotoxicity associated with use of a dietary supplement containing usnic acid. Mayo Clin Proc 2006; 81: 541–4.
46 Han D, Matsumaru K, Rettori D, Kaplowitz N. Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress. Biochem Pharmacol 2004; 67: 439–51.
47 US Food and Drug Administration. Warning on Hydroxycut products. Available at http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm152152.htm (accessed 31 May 2009).
48 Dara L, Hewett J, Lim JK. Hydroxycut hepatotoxicity: a case series and review of liver toxicity from herbal weight loss supplements. World J Gastroenterol 2008; 14: 6999–7004.
49 Fong TL, Klontz KC, Canas-Coto A, et al. Hepatotoxicity due to Hydroxycut: a case series. Am J Gastroenterol 2010; 105: 1561–6.
50 Lobb A. Hepatoxicity associated with weight-loss supplements: a case for better post-marketing surveillance. World J Gastroenterol 2009; 15: 1786–7.
51 Beuers U, Spengler U, Pape G. Hepatitis after chronic abuse of senna. Lancet 1991; 337: 372–3.
52 Seybold U, Landauer N, Hillebrand S, Goebel FD. Senna-induced hepatitis in a poor metabolizer. Ann Intern Med 2004; 141: 650–1.
53 Vanderperren B, Rizzo M, Angenot L, et al. Acute liver failure with renal impairment related to the abuse of senna anthraquinone glycosides. Ann Pharmacother 2005; 39: 1353–7.
54 Sonmez A, Yilmaz MI, Mas R, et al. Subacute cholestatic hepatitis likely related to the use of senna for chronic constipation. Acta Gastroenterol Belg 2005; 68: 385–7.
55 Soyuncu S, Cete Y, Nokay AE. Portal vein thrombosis related to Cassia angustifolia. Clin Toxicol (Philadelphia) 2008; 46: 774–7.
56 de Witte P, Lemli L. The metabolism of anthranoid laxatives. Hepatogastroenterology 1990; 37: 601–5.
57 Millonig G, Stadelmann S, Vogel W. Herbal hepatotoxicity: acute hepatitis caused by a Noni preparation (Morinda citrifolia). Eur J Gastroenterol Hepatol 2005; 17: 45–7.
58 Stadlbauer V, Fickert P, Lackner C, et al. Hepatotoxicity of NONI juice: report of two cases. World J Gastroenterol 2005; 11: 4758–60.
59 Yuce B, Gulberg V, Diebold J, Gerbes AL. Hepatitis induced by Noni juice from Morinda citrifolia: a rare cause of hepatotoxicity or the tip of the iceberg? Digestion 2006; 73: 167–70.
60 López-Cepero Andrada JM, Lerma Castilla S, Fernández Olvera MD, Amaya Vidal A. Hepatotoxicity caused by a Noni (Morinda citrifolia) preparation. Rev Esp Enferm Dig 2007; 99: 179–81 (in Spanish).
61 Stadlbauer V, Weiss S, Payer F, Stauber RE. Herbal does not at all mean innocuous: the sixth case of hepatotoxicity associated with Morinda citrifolia (noni). Am J Gastroenterol 2008; 103: 2406–7.
62 Duchini A. Autoimmune hepatitis and interferon beta-1a for multiple sclerosis. Am J Gastroenterol 2002; 97: 767–8.
63 Kamiyama T, Nouchi T, Kojima S, et al. Autoimmune hepatitis triggered by administration of an herbal medicine. Am J Gastroenterol 1997; 92: 703–4.
64 West BJ. Hepatotoxicity from interferon-beta, not noni juice. Digestion 2006; 74: 47–8.
65 West BJ, Jensen CJ, Westendorf J. Noni juice is not hepatotoxic. World J Gastroenterol 2006; 12: 3616–9.
66 West BJ, Su CX, Jensen CJ. Hepatotoxicity and subchronic toxicity tests of Morinda citrifolia (noni) fruit. J Toxicol Sci 2009; 34: 581–5.
67 Wang MY, Anderson G, Nowicki D, Jensen J. Hepatic protection by noni fruit juice against CCl(4)-induced chronic liver damage in female SD rats. Plant Foods Hum Nutr 2008; 63: 141–5.
68 Nadir A, Agrawal S, King PD, Marshall JB. Acute hepatitis associated with the use of a Chinese herbal product, Ma-Huang. Am J Gastroenterol 1996; 91: 1436–8.
69 Borum ML. Fulminant exacerbation of autoimmune hepatitis after the use of Ma huang. Am J Gastroenterol 2001; 96: 1654–5.
70 Bajaj J, Knox JF, Komorowski R, Saeian K. The irony of herbal hepatitis: Ma-Huang-induced hepatotoxicity associated with compound heterozygosity for hereditary hemochromatosis. Dig Dis Sci 2003; 48: 1925–8.
71 Neff GW, Reddy KR, Durazo FA, et al. Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid. J Hepatol 2004; 41: 1062–4.
72 Nelson R. FDA issues alert on ephedra supplements in the USA. Lancet 2004; 363: 135.
73 Diaz D, Ferroudji S, Heran B. Hépatite aigue à la Germandrée petit-chene. Gastroenterol Clin Biol 1993; 16: 1006–7.
74 Larrey D, Vial T, Pauwels A, et al. Hepatitis after Germander (Teucrium chamaedrys) administration: Another instance of herbal medicine hepatotoxicity. Ann Int Medicine 1992; 117: 129–32.
75 Mostefa-Kara N, Pauwels A, Pines E, et al. Fatal hepatitis after herbal tea. Lancet 1992; 340: 674.
76 Dao T, Peytier A, Galateau F, Valla A. Hépatite chronique cirrhogene a la germandrée petit-chene. Gastroenterol Clin Biol 1993; 17: 609–10.
77 Piozzi F, Rodriguez B, Savona G. Advances in the chemistry of the furanoditerpenoids from Teucrium species. Heterocycles 1987; 25: 807–41.
78 Lekehal M, Pessayre D, Lereau JM, et al. Hepatotoxicity of the herbal medicine, germander. Metabolic activation of its furano diterpenoids by cytochrome P450 3A depletes cytoskeleton-associated protein thiols and forms plasma membrane blebs in rat hepatocytes. Hepatology 1996; 24: 212–8.
79 Fau D, Lekehal M, Farrell G, et al. Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes. Gastroenterology 1997; 113: 1334–46.
80 Kanda T, Yokosuka O, Tada M, et al. N-nitroso-fenfluramine hepatotoxicity resembling chronic hepatitis. J Gastroenterol Hepatol 2003; 18: 999–1000.
81 Adachi M, Saito H, Kobayashi H, et al. Hepatic injury in 12 patients taking the herbal weight loss aids Chaso or Onshido. Ann Intern Med 2003; 139: 488–92.
82 Nakagawa Y, Tayama S, Ogata A, Suzuki T, Ishii H. ATP-generating glycolytic substrates prevent N-nitrosofenfluramine-induced cytotoxicity in isolated rat hepatocytes. Chem Biol Interact 2006; 164: 93–101.
83 Nakagawa Y, Suzuki T, Kamimura H, Nagai F. Role of mitochondrial membrane permeability transition in N-nitrosofenfluramine-induced cell injury in rat hepatocytes. Eur J Pharmacol 2006; 529: 33–9.
84 Minuk GY, Kelly JK, Hwang WS. Vitamin A hepatotoxicity in multiple family members. Hepatology 1988; 8: 272–5.
85 Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C. Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases. Gastroenterology 1991; 100: 1701–9.
86 Becker P, Maurer B, Schirmacher P, et al. Vitamin A-induced cholestatic hepatitis: a case report. Z Gastroenterol 2007; 45: 1063–6.
87 Ramanathan VS, Hensley G, French S, et al. Hypervitaminosis A inducing intra-hepatic cholestasis – a rare case report. Exp Mol Pathol 2010; 88: 324–5.
88 Penniston KL, Tanumihardjo SA. The acute and chronic effects of vitamin A. Am J Clin Nutr 2006; 83: 191–201.
89 Carpenter TO, Pettifor JM, Russell RM, et al. Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake. J Pediatr 1987; 111: 507–12.
90 Krasinski SD, Russell RM, Otradovec CL, et al. Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinol-binding protein, retinyl esters, carotene, alpha-tocopherol, and cholesterol among elderly people and young adults: increased plasma retinyl esters among vitamin A-supplement users. Am J Clin Nutr 1989; 49: 112–20.
91 Kowalski TE, Falestiny M, Furth E, Malet PF. Vitamin A hepatotoxicity: a cautionary note regarding 25.000 IU supplements. Am J Med 1994; 97: 523–8.
92 Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotine: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr 1999; 69: 1071–85.
93 Nollevaux MC, Guiot Y, Horsmans Y, et al. Hypervitaminosis A-induced liver fibrosis: stellate cell activation and daily dose consumption. Liver Int 2006; 26: 182–6.
94 Liu C, Russell RM, Seitz HK, Wang XD. Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P4502E1. Gastroenterology 2001; 120: 179–89.
95 Dan Z, Popov Y, Patsenker E, et al. Hepatotoxicity of alcohol-related polar retinoid metabolites involves apoptosis via loss of mitochondrial membrane potential. FASEB J 2005; 19: 845–7.
96 US Department of Justice, Drug Enforcement Administration (DEA). Rules 2005-Implementation of the Anabolic Steroid Control Act of 2004. Available at http://www.deadiversion.usdoj.gov/fed_regs/rules/2005/fr1216.htm(accessed 27 December 2010).
97 Ishak KG. Hepatic lesions caused by anabolic and contraceptive steroids. Semin Liver Dis 1981; 1: 116–28.
98 Erlinger S. Drug-induced cholestasis. J Hepatol 1997; 2 (Suppl. 1): 1–4.
99 Shah NL, Zacharias I, Khettry U, Afdhal N, Gordon FD. Methasteron-associated cholestatic liver injury: clinicopathologic findings in 5 cases. Clin Gastroenterol Hepatol 2008; 6: 255–8.
100 Kafrouni MI, Anders RA, Verma S. Hepatotoxicity associated with dietary supplements containing anabolic steroids. Clin Gastroenterol Hepatol 2007; 5: 809–12.
101 Krishnan PV, Feng ZZ, Gordon SC. Prolonged intrahepatic cholestasis and renal failure secondary to anabolic steroid-enriched dietary supplements. J Clin Gastroenterol 2009; 43: 672–5.
102 Schwingel PA, Cotrim HP, Salles BR, et al. Anabolic-androgenic steroids: a possible new risk factor of toxicant-associated fatty liver disease. Liver Int 2010. DOI: DOI: 10.1111/j.1478-3231.2010.02346.x.
103 WHO. WHO Guidelines on Safely Monitoring of Herbal Medicines in Pharmacovigilance Systems. Geneva: WHO, 2004.
104 Garcia-Cortés M, Lucena MI, Pachkoria K, et al. Evaluation of Naranjo adverse drug reactions probability scale in causality assessment of drug-induced liver injury. Aliment Pharmacol Ther 2008; 27: 780–9.
105 Danan G, Benichou C. Causality assessment of adverse reactions to drugs I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993; 46: 1323–30.
106 Aithal GP, Rawlins MD, Day CP. Clinical diagnostic scale: a useful tool in the evaluation of suspected hepatotoxic reactions. J Hepatol 2000; 33: 949–52.
107 Lucena MI, Camargo R, Andrade RJ, et al. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001; 33: 123–30.
108 Fontana RJ, Watkins PB, Bonkovsky HL, et al. Drug-induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf 2009; 32: 55–68.
109 Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology 2010; 52: 730–42.
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