Dr. Melissa Palmer's
Guide to Hepatitis & Liver Disease
received exceptional reviews from both the medical and consumer media. Your writing style makes the
material accessible and interesting to the lay person and provides
clinicians and other healthcare professionals with a refreshing update and
overview on many of the clinical management challenges of
hepatitis C and a wide
spectrum of liver diseases. Are some of your colleagues using the book
as part of their patient education programs?
Palmer: Thank you. Many of my
colleagues have given the book to their physician extenders- i.e. nurse
practitioners, physician assistants, nurses, and medical assistants to
assist them in the care of patients with hepatitis and other liver diseases.
The feedback that I have received is that my book is extremely helpful,
especially when dealing with the side effect management of interferon.
I have devoted an entire chapter to this specific issue. Other doctors have
either given the book or suggested the purchase of the book to their
patients to use as a reference guide. For example, if a patient is
suffering from hair loss on interferon therapy – they may use the index to
look up “hair loss interferon induced” and then refer to the chapter for
MASJ: The chapters
‘Herbs and Other Alternative Therapies’ and “Diet, Nutrition and Exercise’
provide an important professional assessment of adjunct therapies that are
often not well integrated into some medical practices. As you point
out, recent surveys indicate that more people are visiting alternative
medicine professionals than those who practice conventional medicine. What
are the obstacles to physicians discussing and possibly monitoring these
alternate therapies with patients who may choose to supplement traditional
medicine with some of these alternatives?
amount of information and research concerning herbs is increasing, there are
still two important matters that have not been clearly defined as to herbs.
First, due to the lack of controlled research on herbal remedies, the exact
extent of drug-herb interaction is not entirely known. Thus, an herb that a
person may be taking in an attempt to prevent liver damage may have a
negative interaction with the medication that he or she is taking to control
high blood pressure. For example, licorice—proclaimed to be beneficial in
the treatment of viral hepatitis—might cause fluid retention and worsen high
blood pressure. Furthermore, licorice may cause a decrease of libido in men,
which is a potential side effect of interferon therapy, in addition to being
a side effect of many antidepressants which are often used during interferon
therapy for hepatitis C. Many herbs may increase or decrease the action of
conventional medicines. For example, the herb cannabis sativa (marijuana)
has been demonstrated to diminish the effectiveness of interferon and to
suppress the immune system. Though potential adverse drug-herb interactions
can be looked up in the PDR for Herbal Medicines, this list may be
incomplete. An example of such an interaction includes the death of women
who was taking St. Johns Wort at the time she underwent anesthesia with the
drug Demerol. Due to an adverse drug-herb interaction, this patient
experienced fatal cardiac arrest. This also resulted in the filing of a
large lawsuit against the herb manufacturer.
Furthermore, the noted side effects of an herb, in general,
may be incomplete. This is due to the fact that it can be very difficult to
trace side effects to a particular herb. It may take weeks, months, or even
years for problems to show up. By that point, people don’t always remember
that they have taken an herbal remedy or they have become so accustomed to a
particular side effect that they dismiss it. Complicating matters even
further, many natural remedies contain dozens of active ingredients
depending on exactly how they were prepared by the manufacturer. The
composition of these ingredients may vary greatly (even among bottles of the
same type of herb). Finally, there are no regulatory laws mandating that the
manufacturer or distributor of an herbal preparation report possible adverse
reactions of the herb to the FDA or other government agency. So, in all
likelihood, all the possible drug-herb interactions and other side effects
associated with a given herb are not listed in the PDR for Herbal Medicine.
This is made clear by reports which appear on a regular basis alerting the
public to the danger of an herb that was once thought to be safe. Usually
the herb –in-question has caused some unsuspecting consumer to suffer
severe, or even fatal, side effects including cancer, kidney failure and
liver failure, thereby necessitating the removal of the herb from the market
or at least stronger warning labels on the bottle. Examples of such herbs
include kava and ephredra respectively.
Second, there is a lack of standardization among herbal
products. It is important to be aware that not all parts of the herb contain
the active ingredient proclaimed to produce the beneficial effect. For
example, one study compared ten different brands of the herb ginseng and
found that the active ingredient ginsenoside varied drastically among
different brands, although all were essentially similar in their
descriptions of ingredients contained in the bottle. In fact, some pills or
capsules contained almost none of the active ingredient. A different study
found that up to one-quarter of the products on health food store shelves
did not contain any of the listed ingredients.
Due to the absence of
regulation, it is possible that a totally different herb can be substituted
for the one on the label. Furthermore, there have been reports that some
herbs have been spiked with steroids, painkillers, tranquilizers, thyroid
extracts or other substances to improve their effectiveness. Toxic metals,
including lead and arsenic and even powerful heart stimulants (such as
digitalis), the blood thinner warfarin, and the diabetic medication
glyburide have been discovered mixed in with herbal preparations. And, some
herbs have been found to contain dangerous microorganisms, such as
staphylococcus aureus, escherichia coli (E. coli), salmonella, and shigella,
each of which can make a person quite ill. Of course, the product labels,
did not mention the addition of any of these adulterants, and all labels
claimed to contain only “natural” ingredients.
The chapter ‘Pregnancy, Sex, Medications, and Prevention”
includes a comprehensive discussion of drug-induced liver disease that
appears to be alarmingly high in my age category - with 40 percent of
hepatitis cases in people over fifty years old. Would you comment on the
factors contributing to this high incidence and what actions physicians and
patients can take to reduce the incidence of drug-induced hepatitis in
general and especially in this age group?
Palmer: 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.
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 Benadryl (diphenhydramine), morphine, Demerol (meperidine) and
A person’s susceptibility
to a potentially hepatotoxic drug is enhanced by many factors. Some of these
factors may be within the person’s control, such as cigarette smoking ,
excessive alcohol intake, and obesity. So, it is important for all
individuals with liver disease, especially older people to discontinue
cigarette smoking, alcohol use and to loose weight when required.
IV drug use
accounting for 70 percent of new HCV infections, could you comment on the options
for and obstacles to accessing appropriate treatment for HCV in this
Palmer: Recent studies have
demonstrated that people with HCV who actively use intravenous drugs - a
condition previously considered to be a contraindication to treatment with
interferon, may be successfully treated with interferon. Since intravenous
drug use is currently the most common mode of transmission of new HCV
infections, treatment of these individuals is important as it may
potentially reduce the spread of HCV. Ideally, these individuals should be
enrolled in a methadone maintenance drug treatment program. The use of
methadone is not a contraindication to interferon treatment. Furthermore,
the decision of the
Statement of 2002 concluded that active
intravenous drug use should not be considered a contraindication to
treatment with interferon.
MASJ: What is the risk of organ transplants as a potential
source of HCV transmission?
Palmer: Since 1992, extremely
accurate testing for HCV has been available. Thus the current risk of
infection with HCV from a transplant is probably less than that of receiving
a blood transfusion - less then 0 .001 percent – i.e. miniscule. The reason
that a small risk still may exist is that when a person initially becomes
infected with HCV, there is a short period of time that neither HCVRNA or
HCVAb is detectable. Once somebody has tested positive for HCV he or she is
prohibited from donating organs ( see exception to this rule in question
13). Anyone who received an organ transplant prior to 1992 and especially
prior to 1990, are advised to be checked for HCV.
A recent article by
al in the August 19, 2004 New England Journal of Medicine (NEJM) states
that the risk of transmission of HCV by a blood transfusion is now only 1 in
2 million blood units. Another article by
Zou et al.
in the same issue of NEJM states
that the prevalence rates of HBV, HCV, and HIV are lower in individuals who
donate organs compared with the prevalence in the general population, but
may be higher compared to first-time blood donors.
MASJ: Has HCV superinfection with multiple HCV genotypes been noted
in this population as has HIV superinfection?
Palmer: Interesting question. HCV
superinfection with multiple HCV genotypes may occur, however, the
predominant genotype will prevail. This predominant genotype will typically
be the only genotype to appear on blood test results – usually being
genotype 1a or 1b.
MASJ: . Your book provides a comprehensive overview of the
principal drugs used in the management of the various forms of hepatitis and
liver diseases, their side effects, and the management of these
side effects. Please comment on the current standard of care for
coinfected with HIV and HCV and the impact of the APRICOT (AIDS PEGASYS
Ribavirin International CO-infection Trial) data reported in the July 29,
2004 New England Journal of Medicine on such care?
Palmer: Approximately 200,000 people in the United
States are infected with both HCV and HIV. The incidence of death for
people with HIV has dramatically declined since 1996 due to the
implementation of highly active antiretroviral therapy. Since this time,
hepatitis C has emerged as a major cause of illness and death in coinfected
people. People infected with both viruses have been shown to have a more a
rapid progression to cirrhosis, liver failure and liver cancer. Thus,
people in whom HIV infection is well-controlled should undergo treatment for
HCV. Two studies recently published in NEJM (Chung
et al and
confirm that the current
standard of care for coinfected people is the combination of peginterferon
plus ribavirin[. Sustained virological responses were reported as 40%
(APRICOT) and 27% (Chung et al.) In fact, in the Chung study, even in
patients who did not clear HCV with this regimen, histological improvement
was seen on repeat liver biopsy specimens in 35%. Thus, therapy should not
be discontinued prematurely in patients with advanced liver disease (stage 3
or 4) even if an early virological response is not achieved.
MASJ: What current trials of investigational drugs hold
significant promise for the management of hepatitis?
improved drugs with a similar structure to ribavirin (known as ribavirin
analogues) but less side effects are in the process of being developed. The
most promising of these analogues is viramidine. The major advantage of
these ribavirin analogues is their decreased incidence of associated
Thymosin alfa-1 is a group of linked amino acids that is produced by the
thymus gland, a gland located in the neck. Thymosin alfa-1 is an important
component of the body’s immune system and helps fight off viral infections.
Studies have shown that synthetic thymosin alfa-1 (known as
manufactured by SciClone Pharmaceuticals, can stimulate the immune system to
fight off viruses. Used by itself to treat people with chronic hepatitis C,
Zadaxin, produces no significant improvements. However, preliminary studies
suggest that when used in combination with pegylated interferon, Zadaxin may
lower or eradicate hepatitis C viral levels, in addition to improving
inflammation and damage in the liver. Preliminary studies pairing Zadaxin
with pegylated interferon alpha 2a (Pegasys) for those who fail to respond
to interferon/ribavirin combination therapy look promising. In a recent
study, 20-36 percent of people with hepatitis C who failed previous
interferon treatment experienced significant decreases in viral load after 3
months of Zadaxin/Pegasys combination therapy. Therefore, Zadaxin used in
combination with Pegasys may be of benefit to people with chronic hepatitis
C who were nonresponders to previous interferon regimens. Further studies
involving larger groups of people are underway. Zadaxin is administered at a
dose of 1.6 mg, twice a week, by subcutaneous injection. So far, it appears
that Zadaxin causes little, if any, side effects.
major advance for potential future treatment strategies for hepatitis C was
the discovery of the actual structure of two of the key enzymes involved in
HCV replication by researchers from Vertex Pharmaceuticals. These enzymes
are known as the NS3 protease and the NS3 helicase. Vertex is attempting to
develop a drug that will inhibit these specific enzymes—an HCV-protease and
a HCV-helicase inhibitor. The development of a drug that would inhibit these
enzymes in the HCV life cycle would be a powerful weapon in the treatment of
Clinical trials are ongoing to evaluate the drug
which is manufactured by Vertex Pharmaceuticals. VX-497 is an inhibitor of
the enzyme inosine monophosphate dehydrogenase (IMPDH). This enzyme is
essential for the production of a nucleotide—a compound that forms the
building blocks of DNA and RNA. Therefore, blocking the production of IMPDH
may slow or block HCV viral replication. In experimental trials, VX-497 has
shown to be a potent antiviral, much more potent than ribavirin. And,
VX-497’s antiviral activity appears to be even greater when it is combined
is another inhibitor of the enzyme IMPDH. This drug is
currently used to prevent rejection of a newly transplanted liver (see
chapter 22). In one study it was combined with Pegasys and some patients
achieved sustained eradication. Further study is needed on this combination
therapy before it can be recommended.
Histamine is a natural substance made by the body. It may reverse the
oxidative stress and free radical damage to the liver caused by HCV.
Furthermore, and may enhance the body’s response to interferon. When
histamine (manufactured by Maxim pharmaceuticals as
Ceplene) is combined
with interferon, additional antiviral effects occur. Histamine is in
combination with peginterferon and ribavirin is being studied in ongoing
Vaccines given to treat chronic hepatitis C – known as therapeutic HCV
vaccines, and HCV antibody immunoglobulins given - alone or in combination
with interferon, are in the preliminary stages of investigation.
Heptazyme (Ribozyme Pharmaceuticals, Inc.) is a type of ribozyme—a kind of
RNA molecule with the unique ability to cut targeted genetic material. In
the case of Heptazyme, the targeted genetic material is contained within
HCV. Thus Heptazyme seeks to incapacitate HCV so that it can no longer
replicate. When part of its key genetic material is severed, HCV dies and,
therefore, no further virus particles can be produced. Unfortunately initial
studies have shown that blindness may be a possible side effect of Heptazyme.
Further study is currently ongoing to determine if the benefits of this drug
outweigh its risks. Other less toxic ribozymes are in the process of being
enzymes that are essential to HCV’s replication - proteases, polymerases and
helicases, are all potential targets for drug therapy. So far, the protease
inhibitor BILN 2016 appears to be the most promising investigational drug
utilizing this approach. Preliminary results in people with genotype 1 have
been impressive. Further studies on this promising new drug are ongoing,
and the results are being eagerly anticipated.
ISIS-14803 is a synthetic antisense oligonucleotide that binds HCVRNA
thereby resulting in decreased viral replication. Initial studies have
shown that ISIS-14803 (given intravenously) significantly reduces the level
of HCV RNA in people who did not respond to previous interferon therapy.
Studies are underway combining ISIS -14803 with peginterferon and ribavirin
in people with genotype 1 who failed previous combination therapy.
MASJ: You included information in your book on the cost of drugs, blood tests,
medical care, and medical insurance including Medicare. Are there any
programs for the medically indigent to access any of the current drugs?
Palmer: Yes. Reimbursement
assistance programs exist for both pegylated interferons. The
program (1-877-734-2797) is sponsored by Roche and the
Commitment to Care
program is sponsored by Schering-Plough to assist patients with HCV receive
PegIntron (respectively) free of charge or at a significantly
reduced fee. Forms do need to be filled out and some tax information also
needs to be submitted. Also, both pharmaceutical companies are conducting
phase four or “post-marketing” trials of Pegasys and PegIntron. When a
patient enters into a trial study, all medication, blood testing and medical
visits are typically free-of-charge. Finally, Medicaid typically covers the
cost of these medications.
MASJ: Please explain the factors contributing to
the increased prevalence of HBV and HCV in African-Americans and the impact
of this higher prevalence data on screening recommendations.
Palmer: African Americans with
HCV appear to have poorer prognostic factors than Caucasians. They have a
higher prevalence of hepatitis C than Caucasians. In fact, the prevalence
among AA is approximately 2X as great as that of Caucasians. AA, especially
males, are more likely to progress to chronic disease than are Caucasians
(86% versus 68%). Approximately 90% of AA are infected with genotype 1 as
compared to 70-75% of Caucasians. While
African Americans appear to have a slower rate of
progression of HCV, once cirrhosis develops they are more likely to suffer
from complications such as liver cancer and death. Finally, the response
rate to treatment is poorer for AA than for Caucasians. Factors that have
been suggested to contribute to this decreased response rate include –
genotype 1, viral kinetics, interferon resistance and body mass index.
African Americans have been found to have a lower neutrophil count than Caucasians, which has
traditionally excluded them from enrolling in many trials and from
maintaining a therapeutic dose of interferon. An abundance of research is
currently ongoing concerning these issues in
African Americans with HBV have been
found to have higher rates of fibrosis and cirrhosis than Caucasians in
spite of having lower levels of hepatitis B viral replication (HBVDNA). Currently, this higher
prevalence data has not effected screening recommendations. However, with
greater amounts of research specifically targeting these issues in AA,
guidelines for screening may be impacted in the future.
MASJ: How effective are the
current treatment options for Non-Alcoholic Fatty Liver Disease (NAFLD) and
what have been the obstacles to the development of effective drugs for the
management of NAFLD?
There is no specific therapy for NAFLD that has clearly been proven
effective. Treatment has focused on weight reduction and hepatoprotective
medications. As with all liver diseases, avoidance of alcohol, before,
during, and after treatment, is essential. This is especially true for
people with NAFLD, as alcohol may worsen the severity of fat deposits, fatty
inflammation, and fatty scarring in the liver. NAFLD is an evolving disease
and much research is going on in connection with it. Thus, there is some
disagreement within the medical community as to the characteristics of NAFLD,
which may have been an obstacle to the development of effective drugs for
Could you provide a brief summary of
some of the more promising investigational drugs for NAFLD?
promising medication for the treatment appears to be
UDCA, also known by the brand names Actigall, URSO, and Ursodiol, is a
naturally occurring bile acid, that, unlike many other bile acids in the
body, is not toxic to the liver. It is found in a small quantity in the
human body, but in a large quantity in a bear’s body. UDCA was initially
used to dissolve gallstones, but is now commonly used to treat many
different liver diseases, specifically primary biliary cirrhosis. Initial
studies involving people with NASH have shown that treatment with UDCA can
lead to improvements in liver enzymes and to a reduction in the severity of
fatty deposits in the liver. UDCA may possibly decrease the risk of
developing gallstones during weight reduction. Further studies are ongoing
as to the effects of UDCA on NAFLD.
Metformin (Glucophage) and rosiglitazone (Avandia) are oral glucose-lowering
(also known as hypoglycemic) medications used to treat type II diabetes.
These medications work by correcting insulin resistance. Therefore, these
types of drugs may potentially benefit people with NAFLD and insulin
resistance. In fact, preliminary studies have shown that treatment with
metformin can improve liver enzyme elevations in people with NAFLD.
However, improvement in the amount of fat and inflammation in the liver have
thus far been established only in studies involving animals. Studies on
humans will be required before these medications can be recommended for
people with NAFLD.
Clofibrate, a triglyceride-lowering drug, has been tested as a treatment but
has not shown to be beneficial. Gemfibrozil, another triglyceride-lowering
medication was able to improve liver enzyme elevations in a small group of
people with NAFLD, but its effects on liver fat and scarring was not
tested. Further study is needed on gemfibrozil. Polymixin B is an
antibiotic that can reduce the amount of bacteria in the intestines. This
medication may be characterized as a form of “bowel decontaminate.” Studies
have shown that administering polymixin B to people on intravenous feedings
(total parenteral nutrition (TPN)) can reduce the amount of fat in their
livers. This treatment option needs further study before definite
conclusions can be drawn about its effectiveness in treating people with
Betaine is a precursor of S-adenosyl methionine (SAMe), a derivative of the
amino acid methionine. S-AMe is purported to promote the health of the
liver. In two studies, some patients who were treated with betaine
experienced decreased liver enzyme elevations and a decreased amount of
fatty deposits in their livers. The mechanism by which betaine exerts its
beneficial effect on the liver, is not clear, but it is believed that it may
assist in transporting fat away from the liver. More research is needed in
Certain nutritional deficiencies which are common among people with NAFLD
may provide a clue in the search for a successful treatment. Some people who
receive intravenous feedings for prolonged periods of time develop fatty
liver in addition to a choline deficiency. (Choline is a B vitamin.)
Correcting the choline deficiency in these people has been shown to resolve
the fatty liver as well. Choline supplementation in people with NAFLD is a
promising treatment option, but is one which requires further study.
Coenzyme A is a substance that is essential for the metabolism of
carbohydrates, fats, and certain amino acids. It contains pantothenic acid,
a B vitamin which is necessary for growth. In some studies, people with
NAFLD were supplemented with a form of coenzyme A, and this caused the
extent of fat deposits in the liver to decrease. More research must be done
to confirm the efficacy of this type of nutritional supplementation.
Preliminary studies have shown that another B vitamin - , may decrease
insulin resistance. Thus, biotin supplementation may be beneficial for
people with nonalcoholic fatty liver disease (NAFLD). However, this needs
to be confirmed by further studies.
preliminary study has indicated that vitamin E (alpha-tocopherol)
supplementation may be a beneficial adjunctive treatment for people with
NAFLD, but more research is needed in this area. Biotin, a B vitamin has
been shown to decrease insulin resistance. Studies on people with NAFLD
have not been conducted at this time, but biotin supplementation would be an
interesting area of exploration for people with NAFLD.
MASJ: There are
more than 17,000 people in the US on waiting lists for liver transplants.
What steps are being taken
to increase liver donations?
Palmer: In an
effort to increase the number of suitable donor livers available for
transplantation some of the criteria for donation have become less
stringent. Livers from donors over the age of fifty, and sometimes from
those as old as seventy, are now being used – and generally with favorable
results. Livers from donors who have hepatitis C are being utilized in cases
where the patient undergoing the transplant also has hepatitis C. Similar
with hepatitis B.
liver donation involves the removal of one lobe of the liver from a donor,
(typically the right lobe in adult-to-adult transplantation), and its
transplantation into the recipient with liver disease. This technique offers
an additional means of expanding the existing liver donor pool. Furthermore,
waiting time on the transplant list is eliminated, and transplantation may
be performed at a time when the patient is not exceedingly ill. And,
not only does living donor transplantation diminish the waiting time for the
living donor recipient, it also reduces the waiting time for those on the
Sometimes, one viable donor liver is split in two, with each half being
transplanted into a separate person. This procedure, known as split-liver
transplantation, obviously has the capacity to double the number of livers
available for donation. Usually, an adult receives the larger right side of
the liver, and a child or small adult receives the smaller left side of the
liver. However, new techniques are enabling a more even split, so that one
donor liver can be utilized for two adult patients. Some experts are
lobbying to have liver-splitting mandated as the first option in the
transplantation of cadaver livers.
Hepatocyte transplantation involves the infusion of a small number of liver
(hepatocytes) from a donor liver into a person who has either a genetic
defect of the liver (such as Crigler-Najjar syndrome) or fulminant liver
failure. The use of hepatocyte transplantation might even eliminate the need
for transplantation in some people with fulminant liver failure by promoting
spontaneous recovery. While there have been only limited attempts to
implement this procedure in humans, the results in animal-based studies
Another exciting procedure that is still in the experimental stage is one
that involves taking samples of one’s liver cells, altering the genetic and
then reconstituting it back into the person’s genetically defective liver.
Known as gene therapy, this procedure is also being evaluated for use in
preventing the rejection of a transplanted liver, thereby eliminating the
need for post-transplant immunosuppressant medications. This promising
technique is undergoing extensive testing.
MASJ: Thank you for insights into the challenges in the management
of hepatitis C and other liver diseases which will be of
great interest to physicians, other healthcare professionals, and those
affected by these diseases.
Gordon Nary is executive director of Medical Advocates for Social