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Why
Triple Antioxidants Relieve the Symptoms of Chronic Hepatitis C,
by
George D. Henderson, 5 - 10 - 2007
Just
because you have a positive test for Hep C, a bad
outcome is far from inevitable. Many people with Hepatitis C never develop
symptoms. Even if you’re already sick with chronic Hepatitis C you can turn
your life around, by making healthier diet, exercise and drug choices and by
using the appropriate dietary supplements to replace the body’s depleted
antioxidants and assist the recovering liver. This article describes how
antioxidants are depleted in hepatitis C, the methods of antioxidant repletion,
and the results of antioxidant protocols in hepatitis C. It’s important to
realize that antioxidants are not an antiviral therapy; viral levels will only
decline slowly. The benefit of antioxidants is that they can prevent lipid
peroxidation (the mechanism of liver damage in cirrhosis) and reduce or prevent
the disabling symptoms of hepatitis: fatigue, nausea, pain, depression,
tiredness, irritability. They improve liver function by protecting existing
liver cells and protecting the DNA in new cells (formed to replace the liver
cells destroyed by immune attack) from the damage that causes the decline in
liver function seen in long-term cirrhosis [1. Berkson 1997]
I know these methods work because I use
them myself. In four years I have gone from being very sick, depressed and
addicted to being healthy, happy and productive, with liver enzymes well inside
the normal range.
Tests,
studies and trials involving hepatitis C
populations all over the world show the same results; compared to healthy
populations, people with chronic hepatitis C (CHC) have depleted levels of
antioxidants (both dietary, e.g. beta-carotene, vitamin E, lycopene, and
endogenous, e.g. glutathione, alpha-lipoic acid), antioxidant enzymes, and most
vitamins and minerals used in antioxidant synthesis (e.g. selenium, zinc,
magnesium). The only minerals whose levels are regularly found to be normal or
elevated in hepatitis C are iron and copper, transition elements which are a
source of free radicals.
This systemic antioxidant depletion is
characteristic of CHC, and the depletion is more marked in patients with
cirrhosis. The wide-ranging consequences of this antioxidant depletion syndrome
account for most of the unpleasant, disabling and life-threatening symptoms of
CHC, including muscle fatigue, depression, and liver damage. There are no
longer enough antioxidants being produced to quench the free radicals that are
generated in the course of the liver cells performing their normal duties, let
alone deal with the reactive peroxides that are generated by the immune
system’s attack on the infected liver cells, and this shortfall is what allows
the lipid peroxidation process that causes hepatocellular fibrosis and leads to
cirrhosis.
Antioxidant
precursors include the amino acid l-methionine,
which is in demand for the production of immunoglobulins (antibodies) and the
antioxidants l-cysteine, glutathione (GSH), alpha-lipoic acid (ALA), Co-enzyme
Q10 (CoQ10), carnitine, taurine, and creatine. Given a limited supply of
l-methionine the body will supply its essential systems first; the immune
system has priority, and the needs of the muscles come last. In order for the
limited intake of l-methionine to supply l-cysteine for antibody production and
GSH for immune cell function and liver cell protection (and the production of
liver GSH in CHC is often inadequate to provide such protection), the muscles
become starved of taurine, creatine, carnitine, GSH, and ALA. Antioxidants are
needed by muscle cells both to produce energy and to recover after exertion,
and this explains why fatigue and muscle pain (myalgia) so often result from a
liver infection (because immune cells exist in the blood, they are able to
absorb nutrients before they can nourish muscle cells). Parallel processes play
a role in depression and insomnia; l-methionine is also the precursor for the
methyl-donor S-adenosylmethionine (SAMe) which plays a vital role in serotonin
synthesis (methyl donors including SAMe, B6, B12, folic acid and betaine act in
the methylation cycle, which metabolises dietary l-methionine and l-cysteine;
these being depleted or the cycle being otherwise blocked can also deplete
glutathione [2. Von Konynenburg, 2004]). The increasing demand for
l-methionine’s many metabolites in chronic hepatitis C creates a bottleneck in
the body’s antioxidant and methyl-donor supply lines.
There
has been considerable research and experimentation
done to learn which combination and dosage of antioxidants is most effective at
reversing the depletion that occurs in hepatitis C and relieving the symptoms
of CHC, including protecting against cirrhosis and liver cancer. A consensus
has developed favouring a combination of Alpha-lipoic acid (lipoic acid),
Selenium, Silymarin (milk thistle), and vitamins E and C, the so-called “triple
antioxidant” method. Other antioxidants used include SAMe and glycyrrhizin from
liquorice and a number of Japanese trials have successfully used an IV product
called Stronger Neo-Minophagen C, which is a compound of glycyrrhizin,
l-cysteine, l-glycine and dl-methionine [5: H Kumada 2002], but the
advantage of Triple Antioxidants is that they are safe enough, and convenient
and effective enough, to be taken by people who are not lucky enough to have a
doctor willing to study, diagnose and treat the antioxidant depletion caused by
CHC. Although this treatment was developed through the study and treatment of
CHC by doctors and scientists working in world-renowned hospitals and
universities, and cannot be called an “alternative therapy”, many doctors in
this country (N.Z.) seem content to wait for new treatments to arrive via the
drug companies and the government drug purchasing agency Pharmac and are
embarrassed about standing out from the herd. New Zealand is a very small
country (c. 4.5 million); waiting for a sophisticated new treatment to appear
in mainstream health care here is analogous to waiting for a sophisticated food
product to appear on the shelves of a small town “Four Square” store, when it
has long been on the shelves of the big city supermarkets.
Triple antioxidants interact to enhance one another’s antioxidant activity. For
example, both Sylimarin and ALA promote GSH synthesis and reduce oxidised glutathione;
ALA also reduces oxidised vitamin C and vitamin E. Selenium, in the glutathione
peroxidase enzyme, catalyses both the synthesis of GSH and its antioxidant
activity, and enhances the lipo-protective activity of vitamin E (in other
words, vitamin E prevents lipid peroxidation at lower doses in the presence of
adequate selenium). In thioredoxin reductase, selenium reduces oxidised vitamin
C, and possibly restores the activity of other antioxidants. HCV itself encodes
for selenium and HCV infection can worsen selenium depletion, which has the
effect of making any mercury present more toxic as mercury can form a safe
intrametallic compound with selenium or conjugate safely with glutathione; as
GSH depletion and selenium deficiencies are linked, relatively low levels of
mercury can become problematic when either Se or GSH is depleted. Some viruses,
e.g. Cocksackie viruses, mutate more virulently when selenium is
deficient, and mutation of HCV helps the virus avoid immune attack.
Triple
Antioxidants as developed by Burt Berkson MD, and
the similar mixed antioxidants (not including selenium) recently trialed in
Israel provide benefits in the following parameters; [1: Berkson 1997, 3:
Melhen et al. 2005]
Liver
Enzymes: are rapidly reduced, tending to become
normal. In most cases where ALT is normalized it stays normal once treatment is
stopped; however it is recommended that antioxidant therapy be maintained as
long as the disease persists, or renewed if liver enzymes rise or symptoms
recur. ALT levels are an indication of ongoing liver damage, not of viral load,
but the destruction of infected liver cells accelerates the spread of HCV. The
normalization of liver enzymes is indicative of a low rate of hepatocellular
necrosis.
Fatigue: Alpha-lipoic acid is able to replete GSH, and consquently elevates
taurine, carnitine and creatine in muscles. ALA increases glutathione synthesis
and glutathione transports cysteine into cells, where it acts as a precursor
for intracellular GSH and other antioxidants. ALA also reactivates GSH and
other antioxidants from the oxidized to the (active) reduced phase.
Glutathione, N-acetyl l-cysteine (NAC), l-methionine, whey protein and other
precursors have also been used. Ascorbic acid plays an essential role in
l-carnitine synthesis. In the Israeli trial 58% of patients had improved scores
in the SF-36 quality of life questionnaire after treatment. The ability of
triple antioxidants to restore normal, pre-disease energy levels is usually the
first benefit to be appreciated by the patient.
Viral
Load: A decrease in viral load (one log) was seen
in 25% of the Israeli subjects (few of whom received all of the triple
antioxidants) after 20-40 weeks and a significant decrease was seen in all
three of Berkson’s patients over a longer period. A steady decrease in viral
load can be expected throughout long-term treatment, but the decrease does not
account for the beneficial effects of triple antioxidants, which can still
occur when the viral load stays more or less constant. In no case so far has
viral load increased during antioxidant treatment.
In subjects with seriously depleted antioxidant levels, antioxidant repletion
(like combination therapy) may cause HCV and other infective organisms to die
off so rapidly that the consequent toxic load causes distress – this is known
as the Herxheimer reaction, and may last for a few days. For this reason
Berkson advised drinking 8 glasses of water daily, to protect the kidneys as
the toxins are flushed out. Because viral load tends to decrease slowly in
antioxidant therapy, and because people with high HCV loads are used to feeling
bad, the Herxheimer reaction is seldom recognized, but its possiblility needs
to be borne in mind.
Histology: histological improvement was noted in 36.1% of the Israeli
subjects. In a separate study, high dose Vitamin E (d-alpha tocopherol) alone
stopped the progress of fibrosis, preventing cirrhosis, for as long as
treatment lasted [4: Houglum et al. 1977]. Alpha-lipoic acid
increases the antioxidant activity of vitamin E. Antioxidants have the
potential to prevent lipid peroxidation, the disease process that causes
fibrosis. That neither selenium nor any other mineral was included in the
Israeli trial may account for the failure of some participants to respond to mixed
antioxidants as selenium is needed for the synthesis of antioxidant enzymes and
for the formation of glutathione itself.
In a Chinese population study selenium supplementation (200mcg) reduced the
rate of hepatocellular cancer (HCC) in subjects with cirrhosis due to chronic
HBV to zero, and in a population study involving subjects with both HBV and/or
HCV a similar protective effect of high selenium levels was seen in both
groups. Selenium is needed for the glutathione peroxidase family of antioxidant
enzymes. At high doses excess selenium becomes methylated and this methylation
product is believed to have a pharmacological action that protects against many
cancers.
Summary: Antioxidants do not act as
potent antivirals, but do tend to restrain HCV replication. Triple antioxidants
are effective at preventing cirrhosis and cancer in CHC, and are also effective
against fatigue, depression, pain, and GI disturbance (most bile-producing
reactions in the liver depend on GSH and taurine is an important constituent of
bile salts). Patients are most likely to respond when doses of ALA, ascorbic
acid, and glutathione or its precursors can be increased on a PRN basis and
when B vitamins including methylation factors [2: R. A. Van Konynenburg
2004] and essential minerals, especially selenium but also magnesium, zinc and
manganese, are supplemented.
Many
people who have CHC do not develop serious symptoms
and stay healthy without treatment. We can hypothesize that a combination of
influences may be at play in these individuals: a healthy lifestyle low in
oxidative stressors such as alcohol, cigarettes and drugs, a diet low in iron,
calories, saturated fats and toxic chemical additives and high in antioxidants
and easily assimilable protein, and a genetic predisposition to avoid
accumulation of iron and copper, and to produce higher than normal levels of
endogenous antioxidants (e.g. GSH, GR, ALA, CoQ10), as well as a genetic
tendency against high levels of autoimmune and inflammatory activity. To such
an individual life-long infection with hepatitis C might be largely benign, and
such habits and genetic tendencies might account for the variable but
significant percentage of persons with CHC who never become ill.
It
seems it is not always essential to clear the virus
to control or eliminate the symptoms of CHC, and in any case viral clearance by
chemotherapeutic intervention is not always possible. In developed countries
most people with CHC are IVDU, and in Australia, for example, 95% of IVDU will
not access combination therapy (interferon plus Ribavirin). In most of these
cases antivirals will be medically contraindicated for these individuals due to
alcohol or intravenous drug use, mood disorders, autoimmune syndromes etc. It
may be thought possible to manage these symptoms in some cases, but this means
accepting an increased risk of unwanted outcomes. In any case, antivirals are
only effective in approximately half of cases, they are often blamed for
causing lasting health problems, and have unpleasant side effects that can seem
counterproductive, leading to patients dropping out of treatment. Viral clearance, both spontaneous and
chemotherapeutic, is associated with a decreased rate of cirrhosis and
hepatocellular cancer, but on long term follow up the other, extrahepatic
symptoms of hepatitis C can persist: fatigue, depression, upper right quadrant
pain, arthralgia (joint pain) and autoimmune disease have been seen at the same
rates, for example nine years after spontaneous clearance, and the picture
after chemotherapeutic clearance is often worse, due to the longer period of
infection pre-clearance and the effects of the antivirals. Thus antioxidants
may be of value to anyone who has ever had Hepatitis C and is in less than
perfect health as a result.
There
are many cases where antioxidants and antivirals
have been combined and in none of these has the antiviral clearance rate
suffered. The ability of antioxidants to improve viral clearance rates from
combination therapy varies and seems to depend, naturally enough, on the
combination and doses of antioxidants; iron levels and the availability of
dietary methionine and selenium are other factors that could be critical.
Magnesium deficiency is widespread in CHC and magnesium is involved in 350
enzyme reactions, including antioxidant enzymes and the conversion of serotonin
into the sleep-promoting and neuroprotective antioxidant melatonin.
A reductionist approach to medicine is
singularly unrewarding when dealing with nutrients. The action of any single
nutrient depends on its context in the matrix of all nutrients; whether its
co-factors are present in sufficient quantity, whether competitive nutrients
are present, amongst other things, may be critical. Diet, exercise, water,
sunlight are just some of the possible influences. Berkson’s approach [1:
Berkson 1997], which can scarcely be bettered, was to supplement the action of
the triple antioxidants (alpha lipoic acid 600 mg, selenium 400 mcg, silymarin
900 mg daily in two doses) with moderately high doses of Vitamin E (400 iu
d-alpha tocopherol) and vitamin C (4 g ascorbic acid in divided doses), as well
as a high dose B complex pill (B100, 2x daily) and a multimineral supplement
(including adequate magnesium, zinc, molybdenum, chromium and manganese). He
also recommended his patients eat a diet with only moderate calories, eat 5+
fruit and veges, drink 8 glasses of water daily, and get exercise and sunlight.
Because the extra-hepatic HCV syndromes
tend to persist even after the desired SVR result of combination therapy, there
is a need for antioxidants to be used by these patients, as well as in the
conservative management of hepatitis C. For the patient the disease does not
end when the virus dies, but when their health is restored to normal. There is
no reason to accept continued disability or discomfort due to a past or current
infection with HCV when this safe, cheap and convenient treatment yields such a
high rate of improvement. “If it’s so good why doesn’t everyone use it?” is the
standard question at this juncture, to which the response is two-fold; one,
they do: many thousands of HCV sufferers are already using antioxidants. And
two: although antioxidant treatment of CHC is safe, convenient, effective, and
relatively cheap it is not simple. It is not a one-pill, magic bullet fix. To
apply it properly in a given case can take some understanding of antioxidant
metabolism, which can be gained by reading, and some awareness of one’s own
antioxidant status, which depends on the ability to analyze one’s diet, or on
diagnostic tests that, apart from iron levels, are not part of everyday medical
practice in N.Z. Many people imagine that antioxidant treatment of Hep C
requires the co-operation of a doctor, and if their doctor fobs them off they
do nothing, or make a half-hearted attempt, for example taking silymarin or
selenium but nothing else, and stopping once there is no further improvement.
My
experience with Triple Antioxidants was typical;
for years I told my doctors I wanted to try N-acetylcysteine, showing them
papers etc. without generating any interest. At that time the only NAC I knew
of in New Zealand was being used by hospitals. I went to study NAC in the
medical library and discovered the importance of l-methionine and selenium to
GSH synthesis. I now knew I could find all I needed in heath shops and
pharmacies. I began with selenium, silymarin, vitamin E, vitamin C, and a gram
a day of l-cysteine, later switching to NAC or l-methionine. The depression
associated with CHC lifted immediately, the abdominal pain ceased, my digestion
improved, and my energy levels increased rapidly. After two years I learned the
importance of the iron connection and stopped using the foods (Milo, Marmite,
most breakfast cereals) and multivitamins that are fortified with non-heme iron;
after a few weeks my heath improved further. Four years after beginning daily
antioxidants my liver enzymes, which had reduced sharply at the start, became
normal. However, switching to Berkson’s triple antioxidants (in the form of a
product called Hep C Complete) a few months ago was a great improvement even
over my previous regime, and all residual fatigue disappeared. I now seem to
have normal levels of physical and mental energy and I no longer tire easily.
I recommend in some cases using 600mg of
NAC or l-methionine with the triple antioxidants (or using whey protein or
spirulina as a source of readily assimilable protein), using omega-3 fish oil
and vitamin D to lessen auto-immune activity, and I emphasize the importance of
ensuring adequate magnesium, folate, B6, choline, and Vitamin D, from diet or
supplements (it is especially important to sustain vitamin D intake in winter
or times of low sun exposure, and an intake of 800-1,200iu is recommended).
There is a complementary liver-protecting approach that involves supplying
specialised nutrients to rebuild and strengthen the phospholipid cell
membranes, and I intend to address this and the needs of the regenerating liver
in my next article. Berkson treated each patient individually according to their
symptoms, but his basic “Triple Antioxidants” regime is still the gold standard
of treatment for preventing and alleviating the symptoms of hepatitis C and
protecting the liver, just as combination therapy, for all its faults, is still
the gold standard of treatment for killing the hepatitis C virus.
References
and Links:
1: Burt
Berkson MD’s Triple Antioxidant paper: http://allinone-nutrition.com/6.html The company that maintains this site also sells a triple antioxidant formula,
Hep C Complete. This product is good value compared to similar NZ products.
It supplies 600mg Alpha-lipoic acid, 400mcg
selenium and 900mg Silymarin per day and should be used with an iron-free
multivitamin-and-mineral product high in B complex vitamins and high doses of
vitamin C and vitamin E, as Berkson describes.
2: R. A. Van Konynenburg Ph D. Glutathione Depletion – Methylation
Cycle Block: A Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome.
Based on “Is glutathione depletion an important part of the pathogenesis of
chronic fatigue syndrome?”, the poster paper at the Seventh International AACFS
Conference 2004. Available online at Phoenix Rising: a guide to ME/CFS
treatment. http://phoenix-cfs.org/GSH%20Methylation%20Van%20Konynenburg.htm
3: Mehlen et al. Journal of Clinical Hepatology, September 2005, Treatment of Chronic Hepatitis
C Infection via Antioxidants: Results of a Phase 1 Clinical Trial, Melhen et
al. “Fifty chronic HCV patients were treated orally on a daily basis for 20
weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra,
silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol),
along with four different intravenous preparations (glycyrrhizin, ascorbic
acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and
followed up for an additional 20 weeks. Patients were monitored for HCV-RNA
levels, liver enzymes, and liver histology. Assessment of quality of life was
performed using the SF-36 questionnaire.”
4: Houglum K et al. A pilot study of the effects of d-alpha-tocopherol on
hepatic stellate cell activation in chronic hepatitis C. Gastroenterology.
1977;113(4):1069-1073, cited with related papers in http://hepcchallenge.org/choices/supplements.htm
5: Kumada H. Long-term treatment for chronic
hepatitis C with glycyrrhizin (stronger neo-minophagen C) for preventing liver
cirrhosis and hepatocellular carcinoma. Oncology 2002; 62:94-100
General resource: Life Extension Foundation hepatitis C protocol (with
references) :http://www.lef.org/protocols/infections/hepatitis_c_01.htm This protocol is more extensive than Berkson’s. The Green Tea polyphenols and
high dose Calcium mentioned are no longer recommended; adverse reactions caused
by green tea polyphenols are under investigation, and 2,000 mg doses of calcium
are associated with an elevated risk of heart attacks in the elderly. In any
case, these two supplements were only intended to block the absorption of
non-heme iron. A cup of tea with a meal will have this effect (reducing
absorption of non-heme iron by 70%) and iron-rich foods are easily avoided in
any case. NAC is recommended (1,200 mg
daily) where Alpha-lipoic acid (one of the triple antioxidants) is too
expensive, or (600 mg) where triple antioxidants alone do not completely
relieve fatigue; SAMe and lipoic acid are recommended when liver damage does
not allow the full metabolism of dietary methionine (protein syndrome).
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