Interesting info.
What Is Glutamine?
Glutamine, like NAC and carnitine, is an amino acid. It is the most
abundant amino acid in the human body, mostly found in the muscle.
Some aver that glutamine should be considered "conditionally
essential," but since it can be synthesized in healthy bodies of
healthy individuals, it is considered "nonessential." Cirrhosis is a
liver disease that causes tissues to break down (known as a catabolic
state). When the liver is damaged in this way, its ability to
synthesize new glutamine is severely hampered. Glutamine is also
extremely important for gut functioning (Teran, 1995). Since both the
gut and the liver are often compromised in people with HIV, there is a
strong argument in support of glutamine being conditionally essential.
Glutamine is used to help break down proteins during digestion and to
treat "leaky gut," which results when intestinal tissues are damaged.
Glutamine is taken up in cells of the intestine (enterocytes) and then
oxidized, strengthening the overall structure. It stimulates skeletal
muscle protein synthesis (Varnier, 1995), and researchers at Case
Western feel it may help lower elevated levels of cytokines like IL-1,
IL-6 and TNF that often occur in HIV infection, especially along the
GI tract. Glutamine is also a primary respiratory fuel for activated
macrophages and lymphocytes (Hannigan, 1994).
(See the Information Sheets on Glutathione and NAC.)
Are There Deficiencies in HIV Infection?
There is some evidence for a deficiency (Shabert, 1996). Shabert
postulates that the body is rapidly using large amounts of glutamine
in its ongoing struggle to control HIV. She points to the evidence of
lean tissue loss, which she says is indicative of stores being given
up by the muscles. One study noted that PWAs' glutamine levels were
30% lower than those of the controls or those at early stages of
infection (Althoff, 1989).
Lymphocytes and macrophages use glutamine as a fuel source, consuming
it at high rates even when no infection is present (Newsholme, 1985).
As one might anticipate, chronic HIV infection results in an active
consumption of many bodily stores. Simultaneously, the body's use of
glutamine increases during infection. As other papers have discussed
in greater detail, this is underscored by the hyperimmune activation
of the immune system-parts of it go into overdrive, rapidly and
chronically depleting bodily stores of nutrients (European Cytokine
Network, 1995).
In addition, the intestines depend on glutamine to function
effectively because certain intestinal cells called enterocytes
produce prodigious quantities of ATP from the breakdown of glutamine.
ATP is the "energy" molecule and assists in the transport of nutrients
from the intestines to the bloodstream and off to the liver for
further breakdown, storage or transport to other organs. These
enterocytes can be damaged by chemotherapy (drugs like AZT, ddI, d4T,
etc.). While studies show that enterocytes themselves do not appear to
be infected, the process of HIV itself has been shown to dysregulate
the immune environment of the intestines (Choquet-Kastylevsky, 1993).
Other studies suggest that HIV does infect enterocytes, finding
evidence in both humans with HIV and macaques with SIV (Dandekar,
1990).
One study suggested that the amount of glutamine found in the duodenum
(where the stomach connects to the small intestine) was much higher in
PWAs than in other patients undergoing endoscopy. They also found
increased levels of glutamate, ornithine and valine. However, the
amounts in the small intestine differed from those found in the colon
(Ollenschlager, 1990).
Studies (Laboratory, Animal, Human)
Various animal studies have shown the value of glutamine
supplementation under various conditions. One study looked at rats who
were either malnourished and/or had their intestine perforated
(laparotomy). When they were given glutamine, their absorption ability
was increased as was the area of tissue used in the intestine to
absorb (Wiren, 1995).
Prevention of disease seems to be another important contribution of
glutamine. Mice challenged with bacteria that could result in sepsis
were spared when orally fed glutamine (Gianotti, 1995). Rats with
tumors saw steady decreases in liver glutamine levels; they were
replenished with oral administration of glutamine (Inoue, 1995).
Glutamine also offsets the negative effects of glucocorticoids, which
can reduce muscle mass. When rats were fed glutamine, the effects of
glucocorticoids on muscle mass were counteracted (Hickson, 1995).
In another study of chemotherapy in rats, glutamine offset toxicities
(Rouse, 1995). The authors concluded that not only does oral glutamine
supplementation help restore supplies in tissues depleted by
chemotherapy but it may also sensitize tumor cells to the effects of
the drugs (thereby minimizing toxicity while maximizing benefits). The
way this works is that the glutamine increases levels of intracellular
glutathione, replenishing that which was lost in the rats fed
methotrexate. Additionally, rather than feed the tumor, as some fear
happens when upregulating intracellular glutathione, supplementation
appears to depress levels in the tumor cells, enhancing their
susceptibility to the tumor cell-killing effects of the chemotherapy.
Glutamine does have an impact on immune function, but whether it
helps, has no effect or is harmful to people with HIV has not yet been
studied. It has long been observed that after strenuous exercise,
immune function is temporarily compromised. One study showed that rats
who exercised on a treadmill suffered a reduction in the
responsiveness of their immune system to stimulation by mitogens. When
glutamine was added to the diet, responsiveness normalized (Moriguchi,
1995).
Interestingly, in one study, 2 grams of glutamine were dissolved in a
cola drink. Forty-five minutes after a light breakfast, this mixture
was ingested over a 20 minute period. Ninety minutes after this, the
researchers noted elevations in both plasma bicarbonate (demonstrating
increased alkaline reserves) and circulating plasma growth hormone
concentrations (Welbourne, 1995). Does this suggest viable competition
for Serono and their outrageously priced growth hormone?
One of the body's immune defenses in the intestines is an antibody
called secretory immunoglobulin A (sIgA). This is important for
fending off a wide range of pathogens and is also found in the linings
of the respiratory and genitourinary tracts. Supplementation with
L-glutamine may help restore sIgA production in a way that will
improve the immune defense of the gut lining and help prevent
infections (Pastores, 1994; Souba, 1993). Adequate sIgA production is
crucial for the immune defense of the genital and urinary tracts. As
Lark Lands points out in the section on glutamine (more of which is
quoted below and from which the discussion on sIgA is largely
derived): "In a study of HIV+ women, it has been shown that secretion
rates of sIgA are sharply reduced in later disease stages (Belec,
1995). The levels of sIgA in cervicovaginal secretions were found to
be markedly lower than would be optimal for proper immune defense in
the genital tract. For all these reasons, giving the body sufficient
L-glutamine to help restore adequate amounts of sIgA to the linings of
the body could significantly boost immune defenses."
Other human studies have shown unequivocal results. Burn victims used
to not be fed, which resulted in wasting. When given a glutamine
enriched diet, recovery was faster. Similarly, patients with diseases
like Crohn's who have significant amounts of their intestines removed
(from its original 21-foot length to mere inches) saw a marked
reduction in frequency of diarrhea and even formation of stools as a
result of glutamine supplementation. People undergoing massive
chemotherapy and radiation followed by a bone marrow transplant are
kept in germ-free isolation until the bone marrow starts to
proliferate-but they still get sick. This is thought to be due to
bacterial infection against which the gut normally works. However,
chemo and radiation destroy the gut mucosa. Those fed glutamine in
contrast to those on standard therapy had a significantly faster
recovery (to the tune of some $21,000 in savings). These studies used
doses up to 40 grams.
This suggests a possible cure for cryptosporidiosis made up of 40
grams of glutamine and allicin, the garlic extract. The glutamine will
improve gut function; the allicin will kill the parasite. The
glutamine will make it easier to take the allicin because gut function
will be improved, diarrhea reduced and nausea limited. It is important
to include other therapies supporting the liver to assure that the
production of ammonia is appropriately dealt with. This is PURELY
THEORETICAL but seems more than worth a try. Acidophilus/bifidus to
help restore helpful flora along the GI tract may be a good idea as
well.
What Does Glutamine Do? How Does It Work in HIV Infection?
Although more studies need to be conducted to determine this fully,
glutamine aids in three areas. First, it is one of the amino acids the
body uses to make the peptide glutathione. As suggested in the study
noted above, it may help offset chemotherapy effects and inhibit tumor
growth (Rouse, 1995). In addition, after cysteine, glutamine is the
next "rate-limiting" step in the production of glutathione. If you
have all the cysteine you need but insufficient stores of glutamine
(which are being rapidly used up in the fight against HIV), you will
still be unable to produce needed amounts of glutathione. This will
also help the liver in its job of detoxifying drug products (please
see the Information Sheet on Glutathione).
Second, it helps heal and promote gut function. Given that
malabsorption is a common feature of HIV infection, glutamine is
"conditionally essential" to assure that the lining inside the
intestines-the gut mucosa-are kept in a state of better health by
feeding the enterocytes and helping the villi to stand tall. The villi
are the little finger-like extensions found inside the intestines that
help draw nutrients from digested foods into the bloodstream. People
with HIV often suffer "villous atrophy," or stunting of these hairlike
projections (Elia, 1992). To the extent this can further inhibit other
pathogens from getting a foothold in the guts, it may also help speed
recovery and prevent or shorten hospital stays. Also, please see the
next section on limiting side effects of protease inhibitors as well.
Third, glutamine may help to increase soluble immunoglobulin A (sIgA),
which is an important gut-associated immune defender, as discussed
above. Incidentally, it may help curb alcohol intake.
Droge's group hypothesizes that there are two stages to wasting
(cachexia) as is seen in cancer and AIDS. Wasting causes a particular
destruction of the lean tissue or skeletal muscle. The first stage is
a "pre-cachectic" condition described as a "pull," in which the
liver's need for more glutathione to deal with the oxidative stress
draws more glutamate and other amino acids from tissues (or
conversely, inhibits the transport of glutamate from the plasma into
the skeletal muscle tissues where they are needed to make glutamine,
thus further draining the levels of ATP as more glutamine is
synthesized: glutamine levels have also been found to be low in PWHIV;
Droge, 1996). The ability of the mitochondria to produce the amount of
ATP needed is overwhelmed by conditions of chronic stress produced by
HIV infection (or AZT use). In this "pull" stage, there is no overt
manifestation of loss in body cell mass, but various biological
markers are triggered, notably reductions in plasma amino acid levels.
As this process progresses, there is a "push" phase, where the body's
skeletal muscle pushes out more amino acids for utilization as energy
sources. This model effectively clarifies the observations of greater
amounts of plasma levels of some amino acids seen in later stages
(Kinscherf, 1996; Droge, 1996).
Special Note for Those Taking Protease Inhibitors
We also ask that you review the Personal Protocols Section of the
DAAIR MOP (Member Outreach Pack) for further information on the
following.
Protease inhibitors inhibit the HIV protease enzyme, which is a type
of protease known as an aspartate protease. Proteases are generally
used by the body to cut up proteins. They can be endopeptidases like
pepsin, cathepsins and papain, or exopeptidases (like carboxy- or
aminopeptidases, dipeptidases) which chop off pieces of amino acids.
Aspartate proteases are a class involved in numerous critical GI tract
functions, and they include digestive enzymes, pepsin and gastricsin.
Aspartate protease is also critical in two enzymes known as cathepsin
D and E, which have numerous functions. Judging from the numerous and
frequent GI tract disturbances reported by PWHIV using proteases,
these drugs appear to be inhibiting multiple GI-tract functions as
well as HIV. Ritonavir (Norvir), in particular, is a hands-down
nightmare of negative GI-tract effects. Varying doses of glutamine
(see MOP and How Should I Take section below) appear to be reversing
most of these negative effects. We suggest that people using protease
inhibitors supplement with moderate doses of glutamine to prophylax
against negative effects along the GI tract.
Historical/Traditional Use
Glutamine's use is fairly recent. However, it is often incorporated
into a more successful formula of total (or partial) parenteral
nutrition. People sometimes suffer diseases (like Crohn's disease)
that result in a section of their intestines being removed (resected).
The two ends are then sown together. This often results in the people
having to take long-term intravenous feeding (total parenteral
nutrition or TPN). One study of long term use of glutamine, growth
hormone and special diet indicated a much reduced need for TPN in 40%,
while another 40% completely eliminated their need for TPN (Byrne TA,
1995).
Anecdotal/Informal Community Use
As is mentioned above, numerous negative GI-tract effects
(particularly horrible diarrhea) in people using protease inhibitors
have been reversed with varying doses of glutamine. There is also
considerable community evidence to suggest using high doses (30 to 40
grams per day) of glutamine to reverse muscle wasting as well.
Is It Toxic?
Generally, no. However, one study showed that 2 of 5 people using
0.285 g/kg in a TPN solution saw an elevation of liver enzymes after 2
to 3 weeks. This disappeared after glutamine was stopped. These were
people who were doing TPN at home, preparing solutions weekly. They
also found that it didn't improve their ability to absorb nutrients
using a D-xylose test (Hornsby-Lewis, 1994). This certainly argues in
favor of closely monitoring liver enzyme levels. Glutamine is
transformed in enterocytes into glutamate and ammonia. The ammonia is
detoxified in the liver. Why they found no increased absorptive
capacity by using glutamine is not clear and contradicts other studies
that show significant benefit.
Other studies have shown glutamine to be safe. Some concern that
ammonia or plasma glutamate levels may increase with glutamine
supplementation were allayed in one study that saw no such
metabolites. This study looked at 7 healthy volunteers (Lowe, 1990).
In follow-up studies done in catabolic patients (wasting) using the
same dose as Hornsby-Lewis's group (0.570 g/kg/day), they found an
increase in nitrogen retention and no toxic metabolites (i.e., ammonia
or glutamate). Lower doses (0.285 g/kg/day) showed little effect on
nitrogen balance in comparison to those on a standard formulation of
TPN (Ziegler, 1990).
What Are the Best Forms?
The powder form is probably absorbed the best, although tablets and
capsules are also useful. The powered forms should be mixed with water
or juice and consumed immediately so they don't have a chance to break
down.
What Questions Remain?
What is the best dose of glutamine? To what extent does the dosage
depend on a person's condition? Is the glutamine getting to where it
is needed? Is it converting to glutamic acid and thence to
glutamate-i.e., is there a possibility that extensive glutamine use
may reduce intracellular glutathione levels (although the Lowe study
seems to discount this)? Are levels of arginine increased by glutamine
supplementation (Ziegler, 1990)-and if so, (a) are herpes outbreaks
increased in frequency or severity and/or (b) would supplementation
with lysine be advisable?
[snip]
How Should I Take Glutamine?
If at all possible it is very important that you take this amino acid
three or more times per day before/after or at the very beginning of
meals for it to work effectively along your GI tract. Some PWAs are
using anywhere from 1.5 (prophylactic) to over 30 grams (muscle
wasting/severe GI tract-protease problems) per day, either between
meals or before the beginning of a meal. Suggested use is a quarter
teaspoon (700 mg) in juice 1 to 3 times a day between meals. However,
some PWAs are using a loading dose of up to 9 grams per day for a
month to six weeks and then tapering it down by 50% in the hopes of
reducing infections, increasing absorption and lessening severe
inflammation by enhancing glutathione production along the GI tract.
Higher doses-up to 30 or more grams per day-are being used for weight
gain and very severe intestinal inflammation. Many mix their amino
acid powders together or put them in their protein powder. Also note
Dr. Lands's recommendations below as well.
From Chapter 6 of Lark Lands's forthcoming, Positively Well: Living
with HIV as a Chronic, Manageable, Survivable Disease:
"Dr. Shabert believes that the combination of all these needs for
glutamine results in a demand for it that is well beyond what the body
can possibly provide for itself. Thus, supplementation with sufficient
amounts of L-glutamine to provide the body what it needs for all these
important functions is very crucial. The L-glutamine can be given
either orally or intravenously to accomplish this. Glutamine normally
makes up 5 to 8% of dietary protein, so the average person eating
approximately 100 grams of protein per day is getting around 5 to 8
grams daily. However, this level appears to be inadequate even for
maintenance of glutamine levels in someone living with HIV who is
asymptomatic. For someone in more advanced disease stages or in need
of intestinal repair or muscle rebuilding, it is hopelessly
insufficient. It appears that even those in early, asymptomatic
disease stages may need approximately 10 grams per day to protect
their bodies. As the disease progresses, moving toward 15 grams per
day is probably appropriate. When there are already existing problems,
increasing to even higher doses may be necessary.
"Charlie Smigelski, RD, a registered dietitian and researcher at
Harvard University, has suggested that doses of 40 grams per day may
be useful for those who need to repair the intestines or gain weight
and muscle tissue. Based on his work and that of other researchers, it
appears that doses of 30-40 grams per day (30,000-40,000 mg), spread
out over five doses of 6 to 8 grams each (6,000-8,000 mg), continued
for at least 7 to 10 days may be helpful. Lengthier periods on this
higher dosage may be necessary for some, especially if the need for
intestinal repair coincides with the need to restore wasted muscles.
Substantial amounts of L-glutamine are necessary for both of these so
when these two problems coincide, it may be necessary to continue
higher dosage levels until both the intestines and the muscles are
well restored. It is only when all the extraordinary demands for
glutamine needed to effect intestinal and muscle repair are met that
the body will be able to return to meeting day-to-day needs for
maintenance of those tissues and of proper antioxidant status in the
body with lower levels of L-glutamine."
How Do I Find Out More? General Comments Section:
By and large, glutamine appears to be a safe, sane and sensible
supplement. The protection it affords in "leaky gut" syndrome and the
potential beneficial weight gain are important considerations. Whether
you need to use over 30 grams is a personal choice, but 7 to 8 grams a
day seems to be a reasonable amount to consider. Talk to your health
care provider.
-------------------------------------------------------------
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