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MEDICATIONS AND THE LIVER/HEPATITIS
There are over 1,000 drugs and chemicals that are capable of causing
injury to the liver. The terms drug-induced liver disease, drug
hepatotoxicity, and drug-induced hepatitis are used to describe those
instances in which a medication or chemical substance has caused injury to
the liver. Drug-induced liver injury may account for as many as 10 percent
of hepatitis cases in adults overall, 40 percent of hepatitis cases in
adults over fifty years old, and 25 percent of cases of fulminant liver
failure.
There is a rigorous process - known as clinical trials, that a drug
must go through before it is determined to be safe for the public. These
clinical trails are conducted on a carefully selected group of people who
have met a long list of criteria in order to be able to participate in the
testing of the medication. However, after the FDA has approved a particular
drug, a larger and more varied group of people will be taking the drug.
This more diverse group of people may have additional medical problems that
were not encountered during the testing of the medication. This is why
occasionally, a drug originally thought to be safe, may be discovered to
cause severe liver injury. In fact, drug-induced liver injury is the most
common reason for the withdrawal from the market of an already FDA approved
drug. Two examples of drugs withdrawn from the market due to severe liver
injury include Duract (bromfenac), a nonsteroidal anti-inflammatory
medication, and Rezulin (troglitasone) a diabetic medication.
Since all medications are processed through the liver at least to some
degree, people with liver disease must become aware of which medications can
cause liver damage, which medications can worsen preexisting liver disease,
and which medications are safe to take. It is the liver’s job to detoxify
any substances that are potentially harmful to the body. An already damaged
and weakened liver must work much harder than a healthy liver in order to
accomplish this task. When a person with liver disease ingests a potentially
hepatotoxic drug, this puts an additional strain on the liver and can result
in further liver injury or possibly even liver failure. Even people with a
healthy liver can develop liver disease as a consequence of ingesting a
toxic medication or drug.
In general, people with liver disease should avoid medications known to
be hepatotoxic. People who must be treated with a medication that is
potentially hepatotoxic should have their LFTs closely monitored by their
doctors. If a person’s LFTs become greater than three times baseline values,
the medication causing these elevations should be discontinued. Also, it is
essential that people with liver disease inform their liver specialists of
every medication or drug that they are taking—including herbs,
over-the-counter drugs and/or recreational drugs. There is no reason for the
patient to expect the doctor to be judgmental. Her goal is the same as the
patient’s. Therefore, complete information should be provided to the doctor
concerning prescription medications, over-the-counter medications, and
herbal and alternative therapies. Remember, a doctor’s objective is to help
her patient get better and to help protect her patient from unintentional
additional liver damage.
People with cirrhosis must be particularly aware of which drugs are
hepatotoxic, as they are typically more sensitive to drugs side effects due
to the inability of the liver to clear the drug from the body ( excretion
rate). Even drugs that are not known to be hepatotoxic may have a prolonged
excretion rate. This means that the drug and its metabolites will stay in
the body longer. Therefore, usual dosages of these drugs should not be
taken - the dosage of these drugs should be decreased. Examples of such
drugs that require a decrease in the dosage when used for a prolonged period
of time in people with cirrhosis include
How Drugs Cause Liver Disease
A particular drug may cause liver damage for many reasons. First, there
are some drugs that are intrinsically toxic to the liver. These drugs can
cause liver injury when the drug is taken in a dosage that exceeds the
recommended dosage. This form of drug hepatotoxicity is what is known as
“dose-dependent.” The greater the amount by which the dosage taken exceeds
the recommended dose, the more likely it is that the drug will cause liver
injury. Drugs in this category are usually broken down by the cytochrome
P450 enzyme system, discussed in Chapter 1. Under normal circumstances, the
cytochrome P450 enzyme system usually converts toxic substances into
nontoxic ones. However, in situations of drug hepatotoxicity, the reverse
happens. A nonhepatotoxic drug is broken down into hepatotoxic byproducts.
These byproducts cause liver damage as they begin to accumulate. An example
of a drug in this category is the headache and minor pain reliever
acetaminophen (Tylenol), which is discussed on page xx. The drugs in this
category may also cause liver injury if taken in excess in combination with
another hepatotoxic substance, such as alcohol.
Second, there are some drugs that can trigger an idiosyncratic reaction
(an abnormal, unexpected hypersensitivity), to a normal dose of the drug
similar to an allergic reaction, even though a normal dose may have been
taken. Such a reaction is not related to the quantity of the drug ingested,
and, furthermore, the ensuing liver injury is unpredictable. This type of
drug hepatotoxicity is often accompanied by fatigue, fever, and rash. It
usually develops after a person has already been taking the drug for a few
weeks. An example of a drug in this category is the anticonvulsant phenytoin
(Dilantin).
Finally, a person’s susceptibility to a potentially hepatotoxic drug is
enhanced by many factors. Some of these factors are within the person’s
control, such as cigarette smoking and excessive alcohol intake. But other
factors cannot be altered. These include advancing age and being of the
female gender. Many of the relevant factors, both alterable as well as
permanent, are listed below. (See Table 24.1 on page 380 for more
information concerning most of the medications mentioned in this list.)
• Age. Adults are more prone to liver
injury from certain hepatotoxic drugs. such as isoniazide (INH), a drug used
to treat tuberculosis.
• Gender. Females are more
susceptible than males are to most forms of drug-induced liver
disease—especially drugs that can cause chronic hepatitis, such as
methyldopa (Aldomet)- a drug used to treat hypertension (high blood
pressure).
• Genetics. Some people have a
genetically based impaired ability to break down potentially hepatotoxic
drugs into safe byproducts, such as phenytoin (Dilantin)—a drug used to
treat seizures.
• Dose. The higher the dose the
greater the risk of liver toxicity. This applies to drugs, such as
acetaminophen (Tylenol), which are by nature, potentially toxic to the
liver.
• Duration. For some drugs, such as
methotrexate (a type of chemotherapy), the longer it is used, the greater
the likelihood of liver damage or even cirrhosis.
• Kidney damage. People with poorly
functioning kidneys are more prone to the hepatotoxicity of some drugs, such
as tetracycline- an antibiotic.
• Alcohol. Alcohol consumption
enhances the hepatotoxicity of certain drugs, such as acetaminophen.
• Cigarettes. Cigarette smoking
enhances the hepatotoxicity of certain drugs, such as acetaminophen.
• Drug interactions. Taking two
hepatotoxic drugs in combination can greatly increase the likelihood of
liver damage compared with taking one hepatotoxic drug alone.
- Hepatitis C. The presence of
hepatitis C may increase the hepatotoxic potential of certain drugs such as
the nonsteroidal anti-inflammatory (NSAID) ibuprofen (Motrin), and certain
medications used in the treatment of HIV.
• HIV. The presence of HIV (the virus
which causes AIDS), increases the likelihood of hepatotoxicity from certain
drugs, such as sulfamethoxazole-trimethoprim (Septra).
• Rheumatoid arthritis (RA) and systemic lupus
erythematosus (SLE). People with these autoimmune disorders are
more prone to the hepatotoxic effects of aspirin than people without these
disorders.
• Obesity. Obesity increases the
susceptibility of halothane-induced liver injury. (Halothane is a type of
anesthesia.)
• Nutritional status. Either fasting
or a high protein diet can increase a person’s susceptibility to
acetaminophen-induced liver injury.
Characteristics of Drug-Induced Liver
Disease
Many drugs have the ability to cause any form of liver disease, including
acute and chronic hepatitis as well as a fatty liver and nonalcoholic fatty
liver disease (NAFLD). And, many drugs can cause cirrhosis, liver failure,
or even liver tumors. People with drug-induced liver disease may be
asymptomatic with only mildly elevated LFTs, or they may be severely ill
with liver failure and consequently in need of a liver transplant. Or they
may be somewhere in between. Drug-induced liver disease can result in
exactly the same symptoms and signs as those that characterize the same
disease when not induced by drugs. It is essential for both the patient and
the doctor to consider the potential hepatotoxicity of all drugs that the
patient is taking and to promptly discontinue the use of such medications
whenever an adverse effect on the liver is suspected. Continuing to use a
drug after liver-related symptoms and signs have appeared greatly increases
the chances of serious liver damage.
Drug-induced liver injury may be diagnosed through blood work. Some
medications may cause hepatocellular liver injury. This is manifested by
elevations in the transaminases AST and ALT. Other medications may cause
cholestatic liver injury. This is manifested by elevations in AP and GGTP.
And some medications may cause both types of liver injury. In addition,
there are medications that may cause elevated bilirubin levels. Patients
with elevated bilirubin levels exhibit signs of jaundice, including
yellowing of the skin and eyes, and a darkening of the urine.
Drug-induced liver disease can be expected to occur in most, but not all
cases, within the time frame of between five and ninety days from initial
exposure to the hepatotoxic drug. Thus, people taking potentially
hepatotoxic drugs should be monitored with blood tests during this time
period. If a greater than threefold increase from baseline LFT levels
occurs, the medication should be discontinued. LFTs should improve within
two to four weeks from when the medication was discontinued.
Since more than 1,000 drugs are potentially hepatotoxic, a comprehensive
list detailing every hepatotoxic drug is beyond the scope of this book.
However, Table 24.1 on page xx lists some commonly used medications that may
cause liver injury in some people. It is important to remember that not
everyone will sustain liver injury as a result of using one of these drugs.
And it is important to keep in mind that, as discussed on page xx, there are
numerous variables that increase a person’s susceptibility to the
hepatotoxicity of these medications. Still, any person with liver disease
who is using one or more of these medications needs to be carefully
monitored. Careful monitoring is particularly crucial when such a person is
using two or more hepatotoxic drugs in combination with alcohol. People with
liver disease are best advised to use an alternative to one of these
potentially hepatotoxic medications whenever possible.
http://liverdisease.com/medications_hepatitis.html
The offices of
Melissa Palmer, M.D. are located at:
1097 Old
Country Road Suite 104
Plainview, N.Y
11803
or
500 Portion
Road
Lake
Ronkonkoma, N.Y. 11779
To arrange an
appointment with Dr. Palmer, call
(516) 939-2626
Return
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Tobacco
Docs Warn Smokers with Hep C of Cancer Risk
by John C. Martin
Article Date: 07-14-05
Doctors in Italy are issuing a warning to heavy smokers
diagnosed with hepatitis C that they face a significantly greater risk of
developing a form of cancer known as non-Hodgkin's lymphoma (NHL).1
HCV Infection Complicates the Risk
While smoking by itself isn't necessarily thought to be a major risk factor
for NHL,2 smokers with hepatitis C face about 4 times the risk,
warn Renato Talamini, ScD, of the Istituto Nazionale Tumori (National Cancer
Institute) in Aviano, Italy and his colleagues in the International Journal
of Cancer.
"Tobacco smoking is a well-documented risk factor for
several cancers, but the role of cigarette smoking in the [origins] of
non-Hodgkin lymphoma is inadequately understood," the Italian study team
wrote.
While HCV is linked with non-Hodgkin's lymphoma,3,4
the interactions between the virus and this form of cancer hasn't been
studied much either, Talamini and his colleagues added. So, they set out to
evaluate the link between the two diseases.
NHL: Many Forms Exist
Non-Hodgkin's lymphoma is a form of cancer that begins in your lymphatic
system. This is part of the body's immune system, whose role is to fight
infections and other diseases. In the lymphatic system, a network of lymph
vessels carries clear fluid known as lymph. These vessels lead to small,
round organs known as lymph nodes, which are filled with white blood cells
that trap bacteria and other substances that may be in the lymph. Lymph
nodes are found in the neck, underarms, chest, abdomen, and groin.
There are many forms of non-Hodgkin's lymphoma, which
infects the cells of the lymphatic system. The cancer begins when a
lymphocyte (a B-cell or T-cell) becomes abnormal. This abnormal cell divides
to make copies of itself, and the process repeats over and over, making more
abnormal cancer cells. These cells can then spread to other parts of the
body.5
Common risk factors for NHL include a weak immune system;
certain infections like
HIV, Epstein-Barr virus and Helicobacter
pylori, which are bacteria that cause stomach ulcers; and older age.
Symptoms include swollen, painless lymph
nodes; unexplained weight loss; fever; soaking night sweats; coughing,
difficulty breathing, or chest pain; sustained weakness or fatigue; and
pain, swelling, or a feeling of fullness in the abdomen.5
HCV and NHL: Investigating their
Relationship
For the study, the researchers followed 225 consecutive patients who had
been hospitalized with a diagnosis of NHL, and compared their prognoses with
a group of 504 patients admitted to the same hospitals for conditions not
related to cancer or tobacco use.
In this study, which ran from 1999 to 2002, it was found
that patients who smoked at least 20 cigarettes per day faced twice the risk
of NHL, on average, compared to those who had never smoked. This was true
for all age groups and both sexes. However, some patients faced only a
slightly higher risk.
The researchers then analyzed the risk of developing
certain types of NHL—B-cell-low-grade, B-cell-intermediate and high-grade,
and T-cell—related to smoking. The risk of developing B-cell NHL was
inconclusive (some patients actually faced a lower risk while others faced
more than a four-fold risk). However, heavy smokers faced more than 25 times
the risk of developing T-cell NHL, on average, Talamini's team noted.
HCV's Impact on Cancer Risk
When the investigators evaluated the risk of developing the cancer in people
with
hepatitis C, they found it was four times
higher.
"Our study confirms that tobacco is related to NHL, and
reports on the combined effect of tobacco smoking and HCV," they wrote.
"Infection acted together according to a multiplicative model, leading to a
4-fold elevated risk in current [smoking] HCV-positive subjects."
While the cause of this increased risk in those with HCV isn't yet known, it
appears that cigarette smoking and hepatitis C infection act independently
of one another in increasing the risk of non-Hodgkin's lymphoma, Talamini
stated.
Physicians can play a key role in preventing NHL in
smokers, he said, such as encouraging healthy lifestyles, engaging in
anti-smoking campaigns, providing support for those giving up the smoking
habit, and endorsing certain interventions against risky behaviors such as
IV drug use and unprotected sexual intercourse, the researchers wrote.
1. Talamini R, Polesel J, Montella M et al. Smoking and
non-Hodgkin lymphoma: case-control study in Italy. Int J Cancer
2005 Jul 1;115(4):606-10.
2. Zahm SH, Weisenburger DD, Holmes FF, Cantor KP, Blair A. Tobacco and
non-Hodgkin's lymphoma: combined analysis of three case-control studies
(United States). Cancer Causes Control 1997 Mar;8(2):159-66.
3. Libra M, Gasparotto D, Gloghini A, Navolanic PM, De Re V, Carbone A.
Hepatitis C virus (HCV) I hepatitis C virus (HCV) infection and
lymphoproliferative disorders. Front Biosci 2005 Sep 1;10:2460-71.
4. Bianco E, Marcucci F, Mele A et al. Prevalence of hepatitis C virus
infection in lymphoproliferative diseases other than B-cell non-Hodgkin's
lymphoma, and in myeloproliferative diseases: an Italian Multi-Center
case-control study. Haematologica 2004 Jan;89(1):70-6.
5. National Cancer Institute. National Institutes of Health. What is
non-Hodgkin's lymphoma? Available at: http://www.cancer.gov/cancertopics/wyntk/non-hodgkins-lymphoma/page3.
Accessed July 7, 2005.
John Martin is a long-time health journalist and an
editor for Priority Healthcare. His credits include overseeing health news
coverage for the website of Fox Television's The Health Network, and
articles for the New York Post and other consumer and trade publications.
http://www.hepatitisneighborhood.com/content/in_the_news/archive_2425.aspx
Frequent Cannabis Use is Associated with Worse Liver
Fibrosis Progression in Hepatitis C Patients
 Daily
marijuana use may contribute to the progression of
liver fibrosis in people with
chronic hepatitis C, according to a report
published in the January 2008 issue of Clinical
Gastroenterology & Hepatology;
the study was previously presented at the 57th
meeting of the American Association for the Study of
Liver Disease (AASLD) in October 2006.
Researchers from the University of California at San Francisco interviewed 204 patients with
chronic hepatitis C between 2001 and 2004, assessing
demographic characteristics, HCV risk factors, and
use of cannabis and alcohol. Participants underwent
virological testing and
liver biopsies, which were scored according to the
Ishak system (stages F0
to F6).
The median age of the study participants was 47
years, 69% were men, 49% were white, 21% were
coinfected with HIV,
most were low income, and for 70% the presumed route of HCV infection
was injection drug use. The median lifetime duration
of alcohol use was 29 years, with a median of about
2 drinks per day.
Results
• 13.7% of the
participants reported daily cannabis use within the
past 12 months, 45.1% reported occasional use, and
41.2% said they never used marijuana.
• Fibrosis stage
distribution was as follows:
o
F0
(absent): 27.5%;
o
F1-F2 (minimal to mild): 55.4%;
o
F3-F6 (moderate to severe): 17.2%.
• Daily cannabis use (compared with occasional or no use) was strongly
associated with moderate to severe (F3-F6) fibrosis
(univariate analysis OR
3.21, P = 0.020; multivariate analysis OR 6.78, P =
0.003).
• Other independent
predictors of moderate to severe fibrosis were:
o
Greater lifetime duration of moderate to heavy
alcohol use (1.72 per 10 years; P = 0.044)
o
>
11 portal tracts (compared to < 5; OR 6.92; P = 0.021).
o
Age was of borderline significance (OR 2.19 per 10
years; P = 0.064).
• Daily cannabis use
was not strongly associated with mild (F1-F2)
fibrosis compared with absent (F0) fibrosis in
univariate or
multivariate analyses.
• Independent
predictors of mild fibrosis were:
o
Higher HCV viral load (OR 1.86 per log increase; P =
0.009);
o
5-11 or
>
11
portal tracts (compared to < 5) (OR 3.43, P = 0.002 and OR 10.4, P <
0.001, respectively);
• Age, sex, race,
duration of HCV infection, HCV genotype, HIV status,
body weight, tobacco use, and lifetime alcohol use
were not significantly associated with mild
fibrosis.
Conclusion
In conclusion, the researchers wrote, “Daily
cannabis use is strongly associated with moderate to
severe fibrosis.”
They recommended
that, “HCV-infected individuals should be counseled
to reduce or abstain from cannabis use.”
This data supports
previous studies showing that
frequent cannabis use is associated with more severe
fibrosis, faster fibrosis progression, and advanced
liver steatosis (fat
accumulation).
While long-term frequent cannabis use may be
detrimental to people with chronic hepatitis C,
other research has shown that
medicinal use of cannabis during interferon-based
therapy can relieve side effects and help patients
stay on treatment, thereby improving their chances
of sustained response.
01/25/08
References
JH Ishida, MG Peters, C Jin, and others.
Influence of cannabis use on severity of hepatitis C
disease. Clinical Gastroenterology &
Hepatology 6(1):
69-75. January 2008.
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Daily cannabis smoking as a risk factor for progression of fibrosis in
chronic hepatitis C
....we show a significant relationship between
daily cannabis use and fibrosis progression in patients with ongoing CHC. We
believe that patients with ongoing CHC should be strongly advised to abstain
from daily cannabis use.....
Hepatology
July 2005
Christophe Hézode 1 6, Françoise Roudot-Thoraval 2 6, Son Nguyen 1 5,
Pascale Grenard 5, Boris Julien 5, Elie-Serge Zafrani 3 5, Jean-Michel
Pawlostky 4 6, Daniel Dhumeaux 1, Sophie Lotersztajn 5, Ariane Mallat 1 5 *
1Department of Hepatology and Gastroenterology, Hôpital Henri Mondor,
Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France
2Department of Public Health, Hôpital Henri Mondor, Assistance
Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France
3Department of Pathology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux
de Paris, Université Paris XII, Créteil, France
4Department of Virology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux
de Paris, Université Paris XII, Créteil, France
5INSERM, U581, Université Paris XII, Hôpital Henri Mondor, Créteil, France;
and
6INSERM, U635, Hôpital Henri Mondor, Créteil, France
ABSTRACT
Cannabinoids present in Cannabis sativa (marijuana) exert biological effects
via cannabinoid receptors CB1 and CB2. We recently demonstrated that CB1 and
CB2 receptors regulate progression of experimental liver fibrosis.
We therefore investigated the impact of cannabis smoking on fibrosis
progression rate in patients with chronic hepatitis C (CHC).
Two hundred seventy consecutive untreated patients with CHC of known
duration undergoing liver biopsy were studied.
Demographic, epidemiological, metabolic, and virological data were recorded,
and detailed histories of cannabis, alcohol, and tobacco use over the span
of hepatitis C virus infection were obtained. Fibrosis stage, steatosis, and
activity grades were scored according to Metavir system.
Patients were categorized as noncannabis users (52.2%), occasional users
(14.8%), or daily users (33.0%), and the relationship between cannabis use
and fibrosis progression rate (FPR) or fibrosis stage was assessed.
On multivariate analysis, six factors were independently related to a FPR
greater than 0.074 (median value of the cohort):
--daily cannabis use (OR = 3.4 [1.5-7.4]),
--Metavir activity grade A2 or higher (OR = 5.4 [2.9-10.3]),
--age at contamination of more than 40 years (OR = 10.5 [3.0-37.1]),
--genotype 3 (OR = 3.4 [1.5-7.7]),
--excessive alcohol intake (OR = 2.2 [1.1-4.5]), and steatosis (OR = 2.0
[1.0-4.1]).
Daily cannabis use was also an independent predictor of a rapid FPR (>0.15)
(OR = 3.6 [1.5-7.5]).
Finally, severe fibrosis (F3) was also predicted by daily cannabis use (OR =
2.5 [1.1-5.6]; P = .034), independently of Metavir activity grade, excessive
alcohol intake, age at liver biopsy, steatosis, and tobacco smoking.
In conclusion, daily cannabis smoking is significantly associated with
fibrosis progression during CHC. Patients with ongoing CHC should be advised
to refrain from regular cannabis use.
INTRODUCTION
Cannabis (Cannabis sativa, marijuana), the most common recreational drug
used in the Western world,[13] is the source of more than 60 cannabinoid
compounds that bind two G protein-coupled receptors, CB1 and CB2.[14][15]
CB1 receptors predominate in the brain and are responsible for the
psychoactive effects of -9-tetrahydrocannabinol, the main active component
of cannabis, whereas CB2 receptors are mainly expressed in cells of the
immune system.[14][15] Expression of both receptors has also been
demonstrated in a variety of peripheral tissues.[16] We recently found that
CB1 and CB2 receptor expression undergo marked induction in the human liver
with cirrhosis.[17-19] We also demonstrated that CB1 receptors strongly
enhance experimental liver fibrogenesis, while CB2 receptors exert opposite
antifibrogenic effects.[17-19] The present study was therefore undertaken to
determine the clinical relevance of these experimental findings. To this
aim, we investigated the impact of cannabis smoking on fibrosis progression
in patients with CHC.
AUTHOR DISCUSSION
The present study investigates the impact of cannabis use on the natural
history of CHC in a large series of patients with untreated CHC and known
disease duration. Using multivariate analysis, we identify daily cannabis
smoking as an independent predictor of FPR, in contrast to occasional
cannabis use. In keeping with these results, severe fibrosis (F3) is also
independently related to daily cannabis use.
Major factors previously incriminated in fibrosis progression during CHC
were identified as predictors of FPR and fibrosis stage, in addition to
daily cannabis smoking, as expected. Older age at infection and chronic
excessive alcohol intake are consistently considered primary determinants of
fibrosis progression,[4][6][7][20][23][24] and the relationship between
fibrosis stage and necroinflammatory grade has been documented in both
longitudinal and cross-sectional studies.[3][12][25][26] Steatosis is also a
recognized factor associated with severe fibrosis[11][27][28] and emerged as
an independent predictor of FPR in our study, while being close to
significance for the prediction of severe fibrosis. An impact of genotype 3
was found in analyses based on FPR, independently of steatosis, and was
absent when considering fibrosis stage. This finding is rather unusual,
because the majority of previous studies found no effect of viral genotype
on fibrosis progression.[29] We considered the possibility of a confounding
effect related to an interaction between daily cannabis use and genotype 3.
However, in daily users of cannabis, the proportion of patients with a FPR
greater than 0.074 or greater than 0.15 was not significantly different in
patients with genotype 3 compared with patients who had other genotypes
(data not shown; P = .411 and .583, respectively). In addition, there was no
impact of genotype 3 on the prevalence of severe fibrosis in daily cannabis
users (P = .411). Overall, discrepant results obtained with respect to viral
genotype deserve additional investigation in further studies.
Our study closely investigated possible confounders of cannabis impact.
Arguably, the shorter duration of HCV infection in cannabis users compared
with nonusers may result in overestimation of FPR in daily cannabis users.
However, daily cannabis use was also independently related to fibrosis
stage. Moreover, occasional cannabis smoking did not emerge as an
independent predictor of FPR, although this group of patients had similar
disease duration compared with daily users. As reported in several studies,
prevalence of excessive alcohol intake was high in cannabis users.[13]
Nevertheless, it should be noted that there was a significant relationship
between fibrosis stage and daily cannabis use in the subgroup of patients
with low disease-time alcohol intake. This finding therefore allows us to
rule out a confounding effect of alcohol on cannabis impact. Ongoing use of
illicit drugs other than cannabis is another potential confounding factor
that was excluded at enrollment. An influence of maintenance treatment by
methadone or buprenorphine in former IVDU was investigated and ruled out via
univariate analysis. Finally, tobacco smoking was also taken into account,
given the conflicting results of recent studies.[12][30]
Several limitations of the study must be acknowledged. As in several
previous reports,[6][9][24][31] fibrosis progression rate was calculated
from a single liver biopsy and estimated disease duration. Potential
inaccuracy in the presumed date of infection[32] was limited by exclusive
enrollment of patients with a previous history of a single, well-identified
route of exposure. The assumption of linearity of FPR has recently been
disputed in a report suggesting late acceleration of fibrogenesis.[23]
However, our findings are strongly supported by the fact that daily cannabis
use was also identified as an independent predictor of fibrosis stage.
Disease-time cannabis history recording is also subject to potential
inaccuracy. Therefore, this possible bias was minimized by categorizing
patients according to the pattern of cannabis use (none, occasional, or
daily) rather than a quantitative estimation of usage. Uncertainties in
quantification of disease-time alcohol intake were also controlled by
grouping patients according to two types of behavior.
Life prevalence of cannabis use has increased steadily over the past 30
years in the Western world.[33][34] A recent survey from the National
Institutes of Health also shows that within a period of 10 years, there has
been a significant increase in cannabis use among 45- to 64-year-old men and
women.[35] In our study, cannabis use was recorded using a standardized
questionnaire covering the span of HCV infection. Daily and occasional use
of cannabis was reported in 32% and 17% of patients, respectively, and
predominantly involved former IVDU, as expected. These findings are in
keeping with the notion that prolonged cannabis use for up to 20 years
predominantly occurs in near-daily and daily users.[36-38]
There have been great advances in the understanding of mechanisms of action
of plant-derived cannabinoids in recent years. Biological effects are
elicited by two G protein-coupled cannabinoid receptors, CB1 and CB2, that
also bind endogenous lipidic cannabinoid ligands with autocrine and
paracrine effects.[14][15] Although the central properties of cannabinoids
such as mood regulation, stimulation of appetite, and analgesia are best
known, the peripheral effects of the compounds are becoming increasingly
recognized.[16] In this respect, it has been shown that endogenous
activation of the cannabinoid system plays a role in the pathogenesis of
portal hypertension associated with cirrhosis via CB1-dependent splanchnic
vasodilation.[39][40] We recently demonstrated that the cannabinoid system
is involved in experimental liver fibrogenesis.[17-19] Along this line,
results of the present study are in keeping with our experimental data
demonstrating the profibrogenic role of CB1 receptors.[18][19] Indeed, we
found a strong induction of CB1 receptor expression in samples of human
livers with cirrhosis, predominating in liver fibrogenic cells. Moreover, we
showed that mice genetically invalidated for the CB1 receptor display
reduced fibrosis following chronic intoxication with carbon tetrachloride
compared with wild-type littermates. These data suggest that CB1-receptor
antagonism may open new therapeutic avenues in the treatment of liver
fibrosis.[19]
In conclusion, we show a significant relationship between daily cannabis use
and fibrosis progression in patients with ongoing CHC. We believe that
patients with ongoing CHC should be strongly advised to abstain from daily
cannabis use. This recommendation might be particularly beneficial in
difficult-to-treat
patients
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