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Liz Highleyman
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In This Issue:
Hepatitis C
Risk Factors for Ribavirin:
Anemia
Herbal Remedies for HCV Patients
Liver Toxicity Related to Acetaminophen
Most Common Causes of Drug-Related Liver Failures
Risk Factors for Ribavirin: Anemia
In many patients with hepatitis C, hemolytic
anemia necessitates dose reduction or discontinuation of ribavirin,
which increases the chances of HCV relapse after interferon-based
therapy. In the July issue of the Journal of Gastroenterology,
Shintaro Takaki and colleagues examined factors associated
with an increased risk of developing anemia. Their study included
123 patients with chronic HCV (85 male, 38 female; mean age
50 years [range 20-70]); patients were treated with standard
interferon plus 600-800 mg daily ribavirin. During the study,
about 28% required ribavirin dose reduction and about 16%
discontinued ribavirin. In a multivariate analysis, ribavirin
dose reduction was associated with lower pretreatment hemoglobin
levels (less than 14 g/dL) and age older than 55. In a univariate
analysis, female sex was also linked to dose reduction, but
this variable was not statistically significant in the multivariate
analysis. (Women typically have lower normal hemoglobin levels
than men.) According to the researchers, more careful monitoring
during combination therapy is indicated for older patients
and those with lower pretreatment hemoglobin levels.
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Herbal Remedies for HCV Patients
Herbal remedies are being used by a growing
number of people with hepatitis C, and are increasingly being
studied in clinical trials. At this year’s Digestive
Disease Week conference in May, for example, German researchers
reported that an herbal combination containing mistletoe extract,
green tomato extract, and Hepatodoron (extracts of Fragaria
vesca and Tritis vinifer) produced SVR rates
of 18% after one year of treatment and 44% after two years,
as well as decreased liver inflammation and fibrosis.
In the August 1 issue of the Journal of Hepatology,
Yukihiro Imanishi and colleagues reported on a study of a
Kampo (traditional Japanese medicine) herbal preparation called
inchin-ko-to (TJ-135), which is used in Japan to treat hepatitis
C, cirrhosis, and cholestasis. They found that inchin-ko-to
down-regulates the proliferation and activity of hepatic stellate
cells, which produce substances that contribute to fibrosis.
Inchin-ko-to attenuated the development of fibrosis in rat
livers induced by a toxic chemical. The preparation suppressed
collagen and fibronectin synthesis, reduced expression of
alpha-actin (a smooth muscle protein), and decreased blood
levels of hyaluronic acid (a component of connective tissue).
It also interfered with stellate cell signaling pathways.
Among the various ingredients in inchin-ko-to, a phytochemical
called emodin, derived from the rhizomes of the Rheum palmatum
plant (Chinese rhubarb or Da Huang), was the most active.
In past research, another ingredient, genipin (derived from
Gardenia jasminoides), was shown to reduce hepatocyte
apoptosis (cell death).
In the July supplement of the Journal of Clinical Gastroenterology,
Filomena Morisco and colleagues reported that a tomato-based
“functional food” reduces anemia in HCV patients
taking ribavirin. The researchers created a functional food
high in natural antioxidants and carotenoids. Because oxidative
stress appears to play a role in ribavirin-related hemolytic
anemia, they hoped the antioxidants in the food would help
prevent anemia. The study included 92 patients with chronic
HCV receiving pegylated interferon plus ribavirin. Half also
received a daily dose of the functional food. After three
months, about 9% of patients in the functional food group
reduced their ribavirin dose due to side effects, compared
with about 30% in the group not receiving the antioxidant
product. Subjects in the functional food group had higher
hemoglobin levels measured at 15, 30, and 90 days. The new
product “reduces the severity of ribavirin-related anemia
and improves the tolerance to the full dose of ribavirin in
patients with chronic hepatitis C,” the authors concluded.
Not all studies of herbal remedies
have found a beneficial effect, however. In the June 28 issue
of the Archives of Internal Medicine, Mrudula Jakkula
and colleagues reported on a double-blind trial in which 45
HCV patients with fatigue were randomly assigned to receive
a Chinese herbal combination or placebo for 12 weeks. The
herbal preparation “had no effect on any quality-of-life
variables,” nor did it have a significant effect on
ALT levels or HCV viral load. “Patients and practitioners
should remain cautious about the use of herbal medicines for
HCV, because studies have not shown a clear benefit of these
agents,” the authors concluded. Clearly, this is an
area that requires more research.
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Liver Toxicity
Related to Acetaminophen
The July issue of Hepatology
included two “point/counterpoint” articles on
liver toxicity related to acetaminophen (e.g., Tylenol). Acetaminophen,
like many drugs, is metabolized by the liver. If the normal
processing pathway is overwhelmed, the cytochrome P450 enzyme
system comes into play, producing a toxic metabolite called
NAPQI. Liver damage can be prevented by administering N-acetylcysteine,
which detoxifies NAPQI. Acetaminophen overdose accounts for
more than 56,000 emergency room visits and 450 deaths due
to acute liver failure annually. Data from the U.S. Acute
Liver Failure Study (ALFS) registry implicates acetaminophen
in half of all cases of acute liver failure. Although liver
toxicity usually occurs when people take too much acetaminophen,
hepatotoxicity is sometimes seen at recommended doses. Emphasizing
the drug’s risks, ALFS principal investigator William
Lee asks, “Is this amount of injury and death really
acceptable for an over-the-counter pain reliever?”
Barry Rumack of the University of Colorado’s Rocky Mountain
Poison and Drug Center argues that normal therapeutic doses
of acetaminophen are generally safe, and that alcohol consumption
or fasting “do not place patients at a greater risk.”
He contends that most acetaminophen-related injuries and deaths
are due to intentional overdose, such as suicide attempts.
“Glucuronidation capacity [ability to metabolize acetaminophen]
in humans is not a factor except in massively overdosed patients,”
Rumack concludes.
In September 2002, an FDA advisory panel recommended that
acetaminophen should carry a warning about the potential for
liver toxicity, and that all medications that contain acetaminophen
should be clearly labeled as such. Nearly two years later,
however, the agency has not yet implemented these recommendations.
“For a pain reliever with only mild-to-moderate efficacy,
it would seem prudent to move toward limiting these needless
deaths,” Lee argues. It is unclear whether people with
chronic liver disease (including viral hepatitis) are at greater
risk for acetominophen-related hepatotoxicity, but Lee suggests
it would be prudent for such individuals to limit themselves
to half the maximum recommended adult dose of 4,000 mg within
a 24-hour period.
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Most Common
Causes of Drug-Related Liver Failures
In related news, Mark Russo and
colleagues reported on liver transplantation due to acute
drug-related liver failure in the August issue of Liver
Transplantation. Analyzing data from the United Network
for Organ Sharing (UNOS) liver transplant database from 1990
to 2002, the researchers identified 270 patients diagnosed
with acute drug-related hepatic necrosis (tissue death). Overall,
drug toxicity accounted for 15% of all transplants due to
acute liver failure. Acetaminophen, alone or in combination
with other drugs, accounted for 49% of all such cases. The
other drugs implicated most frequently were isoniazid (for
tuberculosis) at 17.5%, propylthiouracil (for hyperthyroidism)
at 9.5%, and phenytoin (Dilantin) and valprioc acid (Depakene),
both used for seizures, at 7.3% each. After transplantation,
the overall one-year survival rate was 77%. Liver failure
due to acetaminophen alone was more common among Caucasians
(53%) compared with African Americans (25%), while African
Americans were more likely to develop liver failure related
to other drugs (75% vs 47% ). Overall, 76% of the acute drug-related
hepatotoxicity cases requiring transplants were seen in women.
(Other research indicates that women are at greater risk for
hepatotoxicity related to HIV medications.) The researchers
concluded that more study is needed to explain the different
rates of liver toxicity in women and people of different races.
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