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Thursday, September 30, 2010
David A. Johnson, MD
Authors and Disclosures
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23 September 2010 09:57 GMT
Researchers at Oregon Health and Science University have discovered that a form of cell division typically associated with cancer called multipolar mitosis can yield diverse, viable cells capable of protecting the liver from injury and poisonous substances, such as pesticides, carcinogens or drugs. Their findings are published online in the journal Nature.
'Our findings show that the liver, which is known to have a tremendous capacity for regeneration, also has an amazing degree of diversity. A better understanding of this process may reveal why some individuals are more susceptible to different forms of liver injury than others, which could lead to new therapies for the treatment of liver disease,' said Andrew Duncan, Ph.D., principal investigator and postdoctoral researcher in the lab of Markus Grompe, M.D., Pape Family Pediatric Institute, OHSU Doernbecher Children's Hospital; and the Oregon Stem Cell Centre at OHSU.
The liver comprises a pool of genetically distinct hepatocytes, the primary functional cell type in the liver. Duncan and colleagues' work suggests that in response to liver injury that is toxic to most hepatocytes, a subset of select hepatocytes may respond favourably, thereby preventing liver failure and ensuring survival of the organism.
Unique among other cells in the body, hepatocytes in humans and rodents contain either a single nucleus with one set of DNA, called diploid hepatocytes, or one-two nuclei with multiple sets of DNA, called polyploid hepatocytes, explained Duncan. The functional significance of hepatic polyploidy is unknown.
Duncan and colleagues endeavoured to study the function of mouse polyploid hepatocytes using multiple approaches, including therapeutic liver repopulation, live cell imaging and cytogenetic analysis. While most polyploid hepatocytes underwent normal cell division to generate two identical daughter cells, approximately 4 percent of polyploid hepatocytes underwent specialised cell divisions, or multipolar mitosis, generating genetically distinct daughter cells. These unique daughter hepatocytes contained either chromosomal gains/losses, known as aneuploidy, or one-half DNA content of the parental polyploid hepatocyte.
The research team characterised the extent of hepatocyte aneuploidy in livers from healthy adult mice and found chromosomal gains and/or losses in more than 60 percent of hepatocytes. Together, the data show that hepatocyte proliferation involves a cycle of polyploidisation, 'ploidy reversal' - the opposite of polyploidisation - and aneuploidy. The researchers call this dynamic process the 'ploidy conveyor.'
'Aneuploidy is most often associated with cancer, therefore our finding of pervasive aneuploidy in the liver is very surprising. Despite the high prevalence of numerical chromosome abnormalities, spontaneous liver cancer is rare in wild-type mice. We believe aneuploidy is a normal characteristic of hepatocytes. Furthermore, we speculate aneuploidy may be common in many different tissues. Studies are currently under way to characterise aneuploidy in human hepatocytes and other normal tissues in rodents and humans,' said Duncan.
Although it is well known that hepatocytes become polyploid, the function of polyploid hepatocytes has been unknown. Andrew and colleagues suggest that proliferating hepatocytes polyploidise and undergo ploidy reversal, that is the ploidy conveyor, to specifically generate unique hepatocytes with different mixtures of chromosomes. This genetic diversity may operate as an adaptive mechanism, serving as a substrate for selection of those hepatocytes most resistant to foreign compounds, Duncan explained. In response to liver injury that is toxic to most hepatocytes, a subset of select hepatocytes may respond favourably, thereby preventing liver failure and ensuring survival of the organism.
Source: Oregon Health and Science University
Main Category: Liver Disease / Hepatitis
In recent human trials for a promising new class of drug designed to target the hepatitis C virus (HCV) without shutting down the immune system, some of the HCV strains being treated exhibited signs of drug resistance.
In response, an interdisciplinary team of Florida State University biologists, chemists and biomedical researchers devised a novel genetic screening method that can identify the drug-resistant HCV strains and the molecular-level mechanisms that make them that way -- helping drug developers to tailor specific therapies to circumvent them.
The potentially life-saving technology also works when screening other viruses with drug-resistance issues, notably human immunodeficiency virus (HIV) and influenza.
More than 170 million people worldwide are infected with HCV, which leads to both acute and chronic liver diseases.
"In collaboration with pharmaceutical firm Gilead Sciences and researchers from the University of Heidelberg (Germany), what our research team discovered was how the latest drug for HCV works and what changes in the virus that makes it resistant to this unique therapy," said Hengli Tang, a Florida State University molecular biologist.
"This is knowledge that is essential to drug developers focused on HCV," said Tang, "but equally important is that our method, which we call 'CoFIM' (Cofactor-independent mutant) screening, can also be applied to other drug targets and other viruses.
"And, since we now understand how this latest class of drug works and what causes resistance to it, we can better select other classes of drugs with distinct mechanisms -- in other words, those that target other parts of the virus -- in order to craft a combination therapy, which is the future of HCV therapy and the key to overcoming drug resistance."
The groundbreaking research is described in a paper published online in the September 2010 issue of the journal PLoS Pathogens.
Florida State biology doctoral student Feng Yang led the research team. The award-winning scholar earned her Ph.D. in August 2010 and is now a postdoctoral associate at Yale University. Yang designed the CoFIM screening methodology with fellow FSU graduate students, postdoctoral associates and distinguished faculty colleagues -- including Associate Professor Tang; chemistry/biochemistry Professor Timothy M. Logan, director of FSU's Institute of Molecular Biophysics; and Research Assistant Professor Ewa A. Bienkiewicz, of the FSU College of Medicine, where she directs the Biomedical Proteomics Laboratory.
Driving the team's development of CoFIM screening was the need to identify key "cellular cofactors" and their mechanisms of action -- a fundamental aspect of virus-host interaction research.
'Cellular cofactors' are proteins that normally exist in host cells that have been hijacked by viruses to facilitate viral replication." Tang said. "They became accomplices to the invading viruses.
"Our research team was the first to show that 'cyclophilin A' (CyPA) is an essential cellular cofactor for hepatitis C virus infection and the direct target of a new class of clinical anti-HCV compounds, which include cyclosporine A (CsA)-based drugs that are devoid of immunosuppressive function," Tang said.
"In addition, we went a step further than other research teams by employing our newly developed CoFIM screening method, which we used to demonstrate not only HCV's dependence on cellular cofactor cyclophilin A and susceptibility to cyclosporine A drugs but also to uncover the molecular-level regulators that determine those two traits in the virus."
Those molecular-level regulators are known as "small interfering RNA libraries" -- collections of molecules so named for their size and ability to suppress gene expression. They act to individually suppress every gene in the cell, resulting in different consequences depending upon which gene is suppressed by a given member in the library.
The CoFIM screening method involves inducing or "coaxing" the HCV virus to mutate by itself, in vitro, absent the replication assistance it normally receives from a particular cellular cofactor. Then, CoFIM tracks the changes in the virus's response both to CsA-based drugs and any other drug designed to inhibit the cofactor.
Funding for the research conducted at Florida State University came in largest part from a $1.4 million grant awarded by the National Institutes of Health (NIH). And, because chronic liver disease caused by HCV can lead to liver cancer, a grant from the American Cancer Society provided additional support.
In addition to now-doctoral alumna Feng Yang and faculty members Hengli Tang, Timothy M. Logan and Ewa A. Bienkiewicz, the Florida State University co-authors of the PLoS Pathogen paper ("A Major Determinant of Cyclophilin Dependence and Cyclosporine Susceptibility of Hepatitis C Virus Identified by a Genetic Approach") are current biology doctoral students Henry Grise and Stephen Frausto and postdoctoral associates Anita Nag and Jason M. Robotham. Co-authors from the University of Heidelberg Department of Infectious Diseases are Vanesa Madan, Margarita Zayas and Ralf Bartenschlager, and from Gilead Sciences (Foster City, Calif.), Andrew E. Greenstein and Margaret Robinson.
Florida State University
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In the United States
Hepatitis C infection is the most common chronic blood borne infection in the U.S. Approximately 4.1 million persons, or 1.6% of the total U.S. population, are infected with hepatitis C
Alan Franciscus, Editor-in-Chief
(HCV) is highly variable, which means that it is difficult to tell
who will and who will not have severe HCV disease progression.In general about 80% of people with chronic hepatitis C will have a slow rate ofdisease progression that may not lead to serious complication.
severe disease progression that could lead to complications such
as severe fibrosis, cirrhosis, liver failure, liver cancer and death.
The question that has vexed us all is why some people with HCV
have serious disease progression while others only have mild progression.
Although we are far from completely understanding and
answering this important question there is information available about
some of the factors that will likely increase the risk for serious HCV
disease progression. This article will discuss the various factors that
increase the likelihood of disease progression and steps we can all
take to minimize these effects – at least for those factors over which
we have some control.
Alanine aminotransferase or ALT (previously called SGPT) is
a chemical produced in the liver.
ALT levels are elevated when liver cells are inflamed, damaged, or
destroyed by HCV, HBV, alcohol and certain drugs.Persistently elevated ALT levels are more of a sign that there is ongoing damage to the liver,and, if elevated over a long period of time, indicate ongoing fibrosis progression. But it is important to know that people with
persistently normal ALT levels can also have fibrosis progression, although
the risk is much lower.
The amount or degree of inflammation in the liver roughly
correlates with the development of fibrosis and cirrhosis. The amount
of inflammation can be reduced by taking HCV medical treatment
and avoiding any substance that causes harm to the liver, such as
lead to even more severe scarring of the liver called cirrhosis.
The damage caused by hepatitis C is not linear – this means that once
fibrosis and cirrhosis start to develop, the progression of liver disease
speeds up. In other words, it may take 10 years to progress
from one degree or stage of liver damage to another, but the next
increase in the amount of damage may take less time – say 7 years.
Progression to the next stage may only take 5 years and so forth.
HCV treatment can help to reduce, slow down or stop the disease
progression progress especially if HCV treatment is successful.
Lifestyle changes can also help the liver to stay healthy by maintaining
a healthy weight, eating a healthy diet, avoiding alcohol and drugs,
moderate exercise, stress reduction, etc.
Age plays a critical role in HCV disease progression. The age at
the time that someone acquired HCV plays an important role in
disease progression – so the older you are when you acquire HCV
the faster the disease progression.
This is because the body’s immune system doesn’t work
as well to minimize the damage HCV causes. On the other hand,
if someone acquires HCV at an early age, as they get older the
greater the chances of more severe disease progression due to the accumulation
of damage over time.
For instance, some studies have found that people over 60 years old
have a quicker disease progression and other studies have found that
having HCV for 25 years or longer increases the chances of disease
Fatty liver or steatosis can contribute to lower HCV treatment
response and a faster rate of HCV disease progression. The cause
of steatosis in most people with HCV is a synergistic effect of thevirus,
poor diet and lack of exercise. If you are HCV genotype 3,
however, steatosis is most likely caused by the hepatitis C virus.
For example, in people with genotype 3 who are successfully treated
with HCV medications steatosis has been found to be decreased
or eliminated. This is not true of steatosis in people with HCV non-3
the simple, but not so easy, methods that we all struggle with – a
healthy diet and exercise program.
We recommend that anyone who undertakes a diet and exercise
program consult with a medical provider and experts in the field of
diet and exercise.
Unfortunately,these tools are not available to
everyone; but there are still many avenues and resources open to
become even healthier. On the internet there is a wealth of diet
and exercise sites to help.
There have been some studies that have found that regular daily
use of marijuana can significantly increase the risk of fibrosis progression.
There is a caveat, however, about the data that has surfaced.
The studies have been self-disclosure studies that are typically extremely
difficult to gauge as to how truthful people may answer questions
about how much they smoke.
But the most important factor is that it is impossible to measure the
concentrations of THC (the active ingredient in marijuana) that the
participants were smoking. Interestingly,
the studies that report that daily marijuana causes significant
fibrosis progression also report that non-daily use of marijuana did not
accelerate fibrosis progression. The bottom line – more is not better
when it comes to many issues including using marijuana.
I don’t think anyone these days would be surprised to learn that
smoking cigarettes causes many health-related problems including
increasing the chances of fibrosis progression and liver cancer.
Another no-brainer is that alcohol consumption can increase
fibrosis and cirrhosis progression.
Excessive alcohol consumption – in and of itself – can lead to cirrhosis,
liver failure and liver cancer. If both of the negative effects, alcohol and
HCV, were combined I think it’s easy to see why people with HCV
should avoid alcohol. If someone has trouble stopping, they should
cut back on the amount of alcohol they drink and get help to stop.
There are many effective programs to help people stop drinking.
In the last decade the relationship between metabolic disorders
and fibrosis progression has been well-documented. Metabolic disorders
are a group of conditions that increase the likelihood for
cardiovascular disease and other health problems.Components of
metabolic syndrome include:
• Abdominal obesity
• High blood cholesterol and
• High blood pressure
• Insulin resistance
• State of inflammation caused
by obesity, insulin resistance,
• Prothrombotic state – increased
Although there are different components that define metabolic
syndrome they are also interconnected interconnected
especially with obesity.
Obesity and insulin resistance are the two factors that stand out as
factors that increase fibrosis progression.
A simple tool to measure insulin resistance is the HOMA-IR
– the higher the score, the higher the degree of insulin resistance.
The higher the HOMA-IR score, the more rapid fibrosis progression
Many of the factors of metabolic syndrome can be treated with
lifestyle changes (diet, exercise, stress reduction) and medications
to control diabetes, high blood pressure, cholesterol, etc.
-Blood and blood product transfusions;
-Sharing needles and syringes (IV drug abuse);
-Other possible risk behaviors: tattoos, body piercing, living and medical care in a developing country, folk medicine, intranasal cocaine;
-Extensive surgical procedures
-Unknown--up to 5% of patients have no identifiable risk factors;
-Sexual transmission is rare; the risk of sexual transmission to an individual is probably less than 3% when a person is in a stable monogamous relationship;
-Vertical transmission from mother to baby;
-Reused needles in a medical or health care setting.
According to studies in the Journal of the American Medical Association, a low sexual transmission rate of hepatitis C was suggested. Of the 62 patients studied, none of the monogamous heterosexual partners had developed the hepatitis C antibody. In general, the probable risk of heterosexual transmission of hepatitis C is less than 3%.
It is recommend that all patients in a non-monogamous relationship use a condom or spermicide and patients in a monogamous relationship use a barrier method only if they are anxious or concerned about transmission.
For patients with hepatitis C, testing of spouses, babies and significant others is recommended by Centers for Disease Control(CDC). Please discuss these issues with your physician.
There is no substantial evidence that hepatitis C is transmitted through breast milk, however, a few studies have been performed that tested breast milk and very rarely is hepatitis C found in the breast milk--even using the most sensitive tests such as PCR. The CDC has issued a statement explaining that mothers who have HCV can breast feed, but should avoid it if there are sores around the nipple.
Can hepatitis C be transmitted to other members of my family (household contacts)?
There is a slight risk of hepatitis C transmission among household contacts, so family members should not share items such as razors or toothbrushes that may transmit blood or secretions. Women who have hepatitis C and are menstruating as well as men or women with hepatitis C and sores in the genital area should avoid sexual contact. The CDC recommends that spouses or partners of a hepatitis C patient be tested for hepatitis C.
Can a pregnant woman give hepatitis C to her baby?
A report in New England Journal of Medicine suggested a 7% transmission rate of hepatitis C from mother to child at birth. Though this is a high estimate, the possibility of transmission must be considered when a woman with hepatitis C is deciding whether to have children.
For infants who have received the hepatitis C virus from their mother, brief elevations of liver enzymes may occur, but no chronic liver disease has been reported. There have been no reports of cirrhosis in newborns, infants or child due to mother-to-child hepatitis C infection. It is recommended that all babies born to mothers with HCV be tested annually until age three with antibody tests.
Women with AIDS and hepatitis C are at high risk for transmitting the virus to their babies, and research has shown that these women consistently transmit the virus to their babies at birth.
There is no documented transmission of hepatitis C through insects. The virus, however, is related to a group of viruses including yellow fever and Dengue, and those are known to have been spread by insects.
Exams and Tests »
The following tests are done to help diagnose hepatitis C:
ELISA assay to detect hepatitis C antibody
Hepatitis C genotype. Six genotypes exist. Most Americans have genotype 1 infection, which is the most difficult to treat.
Hepatitis C RNA assays to determine virus levels (called viral load)
Liver function tests
The fourth component indicates the amount of scarring in the liver and is scored from 0 (no scarring) to 4 (extensive scarring or cirrhosis).
In 70 to 80 percent of people, the infection becomes chronic. The word "chronic" implies that the infection will be prolonged, or even lifelong, unless you get treatment that cures the infection.
Many people with chronic hepatitis C have no symptoms, even if there is serious liver damage. Of those who do develop symptoms, the most common symptom is fatigue; other less common symptoms include nausea, lack of appetite, muscle or joint aches, weakness, and weight loss.
Also See :Symptoms
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Video/Treating With Standard Of Care
Talking To Your Doctor
This drug is giving genotype 1 a 70 percent or higher success rate.Your chances of an effective response to FDA current treatment SOC= (Pegylated+Ribavirin) can be up to 40% in the more difficult-to-treat type of the virus, genotype 1, and nearly 70% in the easier-to-treat type of the virus.
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The FAQ List WILL answer evey question
you may have about Hepatiitis C.
FAQ English (PDF) 881 KB
It's important to keep an open dialogue with your doctor, especially when it comes to understanding your treatment options, and how your body is responding to the therapy.
What is my genotype and how does it impact my therapy?
What is my viral load and how does it impact my therapy?
What are my expected outcomes with treatment?
What are my expected outcomes without treatment?
Do I have any other conditions that will complicate treatment?
What changes should I make in my everyday life?
What is the most important information I need to know before starting treatment?
What should I do next?
A specialist can help determine whether treatment is right for you. Ask your doctor to recommend one today; your chances for recovery may be better than you think.
With time and experience, studies have showed that people treating hepatitis C can tolerate a lower white count on treatment than originally thought. If they are able to keep the neutrophil count (ANC) above 750, people do not typically develop infections.
Departments of Gastroenterology and Hepatology, University Medical Center Rotterdam, Rotterdam, The Netherlands.
PMID: 20830784 [PubMed - in process]LinkOut - more resourcesk
Lymphocytes are made in lymphoid tissue in the spleen, lymph nodes, and thymus gland. There are different kinds of lymphocytes. Lymphocytes identify foreign substances from germs (bacteria or viruses) in the body and produce antibodies and cells that specifically target them. It takes from several days to weeks for lymphocytes to recognize and attack a new foreign substance.
Neutrophils are also major players in the body's defense against bacterial infections. Neutrophils are made in the bone marrow and circulate in the bloodstream. Neutrophils move out of the blood vessels into the infected tissue to attack the bacteria. The pus in a boil (an abscess) is made up largely of neutrophils. Normally a serious bacterial infection causes the body to produce an increased number of neutrophils, resulting in a higher than normal white blood cell count (WBC). When the WBC is low, there may not be enough neutrophils to defend against bacterial infections.
The white blood cell count is done by counting the number of white blood cells in a sample of blood. A normal WBC is in the range of 4,000 to 11,000 cells per microliter. A low WBC is called leukopenia. A high WBC is termed leukocytosis.
A normal absolute neutrophil count (ANC) is in the range of 1,500 to 8,000 cells per microliter. If the ANC is below 500 for an extended period of time, the risk of serious bacterial infection may increase significantly. A low neutrophil count is called neutropenia.
SOURCE: Digestive Diseases and SciencesReduction in Neutrophil Count During Hepatitis C Treatment:
Bone marrow suppression is a well-recognized toxicity of the treatment of hepatitis C virus (HCV). Reduction of the peginterferon dose because of neutropenia is common in clinical practice. However, reduction of peginterferon dose during the first weeks of HCV treatment is associated with failure to achieve sustained virological response. AIMS: The objective of this study is to investigate whether the fall of neutrophil count during hepatitis C treatment is associated with achieving sustained virological response.
We performed an observational study of patients who completed peginterferon and ribavirin treatment in an Infectious Diseases Department in Manchester, UK.
DEFINITIONThese are WBC that play a key role in inflammation, allergic reactions, pus formation, and in destroying bacteria and parasites.
Low neutrophil can mean infection or inflammation. Interferon treatment is associated with low neutrophil levels. Therefore, you must have normal levels of neutrophils to start interferon.
Article first published online: 11 FEB 2009DOI: 10.1111/j.1365-2893.2009.01079.x
Diagnosing Neutropenia During Chemo (Not HCV Treatment)
When discussing your CBC results, your doctor may talk about specific numbers in relation to your results. Of course, he or she will explain them in detail, but the summary below will help you get see the "bigger picture" in relation to ANC values:
Normal ANC Values: Normal ANC values range from 2,500 to 6,000 neutrophils per cubic millimeter. Ranges vary on a number of factors, from someone just getting over being sick; the presence of infection, diseases and other conditions that may influence count; and even race.
Treating NeutropeniakIf your ANC reveals a low neutrophil count, treatment may be necessary to prevent infection. Mild cases of neutropenia may only require monitoring at home for signs of infection while more severe cases may need hospitalization.
In some cases, your doctor may recommend a course of antibiotics to prevent infection before it develops. This is called prophylactic antibiotic therapy.
Other medications, called growth factors or granulocyte-colony stimulating factors (G-CSF), are often used to increase white blood cell production in the bone marrow. Commonly used growth factors include:
Leukine (sargramostim)Neulasta (pegfilgrastim)Neupogen (filgrastim)
In conclusion, neutropenia is frequent during treatment of hepatitis C with .... The changes in neutrophil and lymphocyte counts during treatment are shown in Fig. 1. .... Among the exclusion criteria for therapy, low white blood cell and ... Bacterial infections did not occur in neutropenic patients, and the only ...
is important for achieving a sustained virological response
(SVR) so some medical providers will prescribe an injectable
growth factor, granulocyte colony-stimulating factor (G-CSFfilgrastim),
brand name Neupogen
Hepatitis C Support Project • www.hcvadvocate.org ...