Gay Men's Health Crisis "Treatment Issues", Vol. 8, No. 8 - September 1994
Donald Kotler

Diagnosing GI Disorders

TI: Are there things that concern you about how people are being treated for HIV-related gastrointestinal disorders?

Kotler: Yes. If a doctor says, "You have malabsorption," and the doctor was smart enough to test for it specifically and find it, then I think the patient should listen to whatever the doctor says. Most doctors don't know malabsorption from hemorrhoids, and diarrhea becomes a common wastebasket designation. Diarrhea comes from the small intestine or the large intestine. And when it comes from the small intestine, it may well be malabsorption. When it comes from the large intestine, it may well not be malabsorption. If you're trying to feed someone, it is absolutely important to know whether the small intestine is working or not. Most doctors ignore that. If you have a doctor who ignores it, then you probably can't trust what he or she is going to say in terms of nutritional advice. If you have a doctor who does not ignore it and actually makes that determination, that's probably a doctor who will refer you to a good nutritionist.

The biggest mistake that I've seen is that patients with malabsorption are told to eat as much as they want of anything that they want to try, to maximize the calories that go in.

TI: Why is that bad?

Kotler: Usually you maximize the symptoms that occur and in maximizing the symptoms, there is a big push to not eat. So patients are left in a horrible situation of being very hungry, but knowing that whatever they eat is going to give really bad symptoms. In fact, if you look at the typical malabsorption syndromes, the amount of calories that are malabsorbed are not huge. People should just be able to eat a little bit more and overcome that. But they do not, either because the symptoms prevent the eating, or there are unconscious signals not related to symptoms which prevent food intake.

So in fact, the typical malabsorber doesn't eat enough. And the richer the diet you give them, the less they end up eating, especially of calories that will be absorbed. Someone who has a malabsorption syndrome and who starts the day with a big ice cream soda because it has a lot of calories is probably going to have great difficulty eating lunch at all and may not get any appetite back until late at night.

TI: So, often people are not getting proper workups?

Kotler: Right. And if they do have an assessment which shows malabsorption, they need to be treated with a special diet, and even that might not even work. For that, I often have to resort to intravenous feeding, but I'm now doing a study to see if I can get away from intravenous feeding.

TI: What does a patient need to know about getting a good GI workup?

Kotler: The workup has to lead to some answer. If it doesn't, then it's not an actual workup. A patient who has a problem and goes for an evaluation and is told simply, that it is not A, B, or C - that patient hasn't finished their evaluation. It's very important to know what or at least where it is. There must be an explanation for the symptoms whether or not it can be treated.

Sometimes, there is damage and you can't find the causative organism, but you can at least localize the damage. And you treat based upon localizing the damage because you might not be able to cure the underlying process -

TI: What does "localize the damage" mean?

Kotler: Cryptosporidiosis affects the small intestine and is causing malabsorption. Since we can't cure cryptosporidiosis, we try to treat the malabsorption to minimize the symptoms and improve the nutrition. There are people who have small intestinal damage that's as bad as you'd see by cryptosporidiosis, but there's no bug. The evaluation ends up saying, "You don't have crypto." Well, that's not good enough. The evaluation should end up saying, "You have no cryptosporidiosis, but you have damage to your small intestine that gives malabsorption, just as if you did have crypto." The patient can be treated nutritionally, just as if he had cryptosporidiosis because the damage has been localized in the small intestine.

TI: So the idea is to correct for the malabsorption?

Kotler: If the damage is such that it prevents the proper digestion of lactose and fat, the idea is to remove lactose and fat from your diet. It's not to add lactose and fat just because they are great sources of calories and you should at least absorb something - that doesn't work. And it is certainly not enough to say, "Well, there's no cryptosporidiosis. Good bye."

TI: You have said that you try to get people off of IV feeding. How do you do that?

Kotler: By adjusting the diet. If somebody has intestinal damage and can't deal with food given the regular way, the two possibilities to get around the problem are to give food in a different way - intravenously - or to give a different food.

To give a different food means to give medium chain triglyceride, rather than long chain fats; less complex carbohydrates rather than more complex carbohydrates; no lactose and use sugars that are much easier to digest and absorb. And then see if this changed diet is as good as feeding intravenously. We know that feeding intravenously can improve nutrition.

Inflammation and HIV

TI: What behavioral things can people do to really extend their life?

Kotler: Oh, I would look at it the other way around. Patients should avoid certain things - like being reinfected over and over again.

TI: Do we know for a fact that "reinfection" [with HIV] occurs? Kotler: No, we don't know anything. We don't know the effect of inflammation. But the guy who gets gonorrhea twenty times in the course of a year-and-a-half and each time inflames his intestine, which happens to have HIV in it, and the inflammation stimulates the intestine and drives the T-cells into the intestine to fight the inflammation where they get lost - I truly think that that sped the disease along in the past. Do I know that? No.

TI: Is the inflammation of the intestines central to HIV progression?

Kotler: Well, this is my personal and speculative view of disease progression:

Take it from the intestine and to a different, but similar group of structures - the mucous membranes. They have facets that are different than any place else in the body. They're an interface between a very clean and pristine, internal environment and a filthy, contaminated, external environment. Think about the rectum, the vagina, especially the cervix. The mouth isn't so much better. It's a very fine membrane separating an immune system from bugs of all types.

The body, over millennia, has learned to react promptly to any type of invasion of organisms. Membranes of bacteria or other organisms are perhaps the strongest immune stimulators you could ever find. Any break in the lining of a mucous membrane will tend to bring those bugs in direct contact with the immune system. So the inflammation would be prompt and strong. That wouldn't happen in the kidney or the adrenal gland because there's no bugs around to cause that rapid stimulation. But in the intestine, in the other mucous membranes, they are there all the time.

So if anything like gonorrhea - or a cold - breaks the lining and opens up its pores for permeability and schmutz gets in and the body responds with a very strong inflammatory response, that inflammatory response will, at the same time, recruit lymphocytes that activate each other. It becomes self-perpetuating. So the inflammation reproduces the initial insult - weakening of the barrier. As long as the inflammation is there, the barrier will continue to be weakened. Stuff will continue to get in. The inflammation will continue to go on. So having bugs around and a weak barrier becomes like an amplifier.

Now, the normal immune system has shut-off mechanisms. For every yin there's a yang. For everything that turns something on, there is something that will turn it off again. And early in the disease, this may happen - the immune system is intact enough so that it will limit [its reaction] and localize it and shut it off. There may come a point during the weakening of the immune system where the turnoff switch is missing, and then there's nothing to hold it back. Think of it. You salivate because you get some stimulus. Unless there was something to shut that off, once you started salivating, you would just continue to salivate until you dehydrated yourself and died. You need the shut-off valve to make you stop salivating.

TI: So you want to avoid getting any additional bugs that survive. Which raises the common question, should people not be drinking water in major urban areas, such as New York City?

Kotler: I'm not sure that bottled waters are better. I recommend a good filter that gets changed often. You usually won't see chronic cryptosporidiosis unless the CD4 cells fall below 200.

Boiling is okay [but] difficult to do, to make big boiled water tanks. I suspect that most bottled water is free of contamination. But it is insufficient if you wash your lettuce or make your ice from tap water.

TI: What about salad bars and fresh vegetables?

Kotler: Stay away, unless you're going to clean them with a water source that's okay.

There's a lot of stuff written. And it's best coming from dietitians. Your cutting board shouldn't be wood, so that stuff gets caught in it. If you're cutting raw meat, use different cutting boards for other foods.

Therapies for HIV-Wasting

TI: What role do anabolic hormones, like testosterone and oxandrolone [a synthetic testosterone-like steroid with reduced masculininzing effects], have in therapy?

Kotler: It seems clear that anabolic agents, under certain circumstances, can allow people to build back their protein and muscle stores, and in doing so, feel a whole lot better. Low testosterone levels have to be looked at as a natural response to chronic inflammation.

Anabolic steroids shunt the amino acids back to the muscles to make them grow. The body can't be asked to do two things at once - to give up its protein [to support the inflammatory response] and at the same time make bigger pecs. Now, it may not be so important any more, since God's Love We Deliver [a New York City meal delivery group] can give you all the amino acids you need. But the body's metabolic machinery was set up in a different millennium [when protein and energy sources were scarce].

TI: What about exercise?

Kotler: Absolutely. You can perhaps maximize the effect of an anabolic steroid by using resistance-training exercise. On the other hand, you might be able to get pretty far without using any anabolics at all and just using resistance-training exercise.

TI: And what role can recombinant human growth hormone play?

Kotler: That's another anabolic. I think in both cases, the more you use, the better response you get, and that you're going to have to supply the energy and the nutrients along with it to have them work. Then after that, I don't know.

TI: Can women use anabolic steroids?

Kotler: There's only one that's ever been recommended in women because the others appear to have too much androgen activity, but I'm not really sure. Estrogen and progesterone do not seem to act as anabolic steroids in women. It's really unclear what is an analogous anabolic agent for women.

In fact, it may go back to a chemical that was bandied around in AIDS circles years ago and then pretty much neglected recently - that's DHEA [dehydroepiandrosterone]. DHEA is a precursor to the anabolics and it may be that one of the reasons the anabolic levels fall is because DHEA metabolism is diverted to something else rather than anabolics. Perhaps, if you're given DHEA, you can overcome that.

The people who did DHEA studies did nothing to see if it had an anabolic effect. Although some people taking DHEA looked pretty good, it was all being looked at as an antiretroviral agent or an immune modulator. It didn't really show very much that way, but it's conceivable that it is an anabolic agent. And it might well be that early on, that might be the best one to use, but no one studied it that way.

Reducing the Inflammatory Response

TI: Let's talk more about inflammation. Is there anything that patients could do to cut down on inflammation in a beneficial way? Kotler: You can cut down on inflammation with an anti-inflammatory agent - we're doing a study right now with aspirin. The rationale is that several of the inflammatory signals directly stimulate HIV. Tumor necrosis factor [TNF] and interleukin-1 [IL-1], which are the messengers of the inflammatory response, happen to activate HIV. A number of compounds, like aspirin and thalidomide, inhibit inflammatory signals. There are many anti-inflammatories, some may be perfect, some awful. There's a difference between the aspirin-type and the Motrin-type agents.

Another consequence of inflammation is what's called "oxidative stress," which uses up the body's naturally available antioxidants. There are people who are using antioxidants in an attempt to compensate for that loss.

It may be that the body's oxidative balance relates directly to how HIV grows, so that people who take salicylate [aspirin] or antioxidant therapies - vitamin E or C - may inhibit the virus to some extent.

TI: What is your present research with anti-inflammatory therapies?

Kotler: Our anti-inflammatory agent study originally was related to inflammation and HIV expression in the gut. We found that aspirin- like anti-inflammatories seemed to dampen both the inflammation and its symptoms and decrease the expression of HIV viral proteins in the GI tract.

I was unable to get further funding to study this in the gut and instead got funding to do the systemic study of aspirin in a group of HIV-infected people. That's being done at Community Research Initiative on AIDS [CRIA] in New York.

TI: When do you expect to have some data from the aspirin study?

Kotler: Don't know. The techniques we were using were insufficient to show the changes that we were looking for. We are now using a much more sensitive assay to measure viral load (the branched chain DNA), but only a few people have started the study and we want at least 50. We've already screened 35. With a more sensitive assay we probably would have needed 25 or 35 in the study. Once the study accrues, it's only a two-month study.

It's very difficult to get funding for an aspirin study. There's no patent at the end of the road. Nobody's going to make a lot of money, so the research money is limited.

TI: The dose being used is equivalent to how many aspirin per day?

Kotler: Twelve, like the arthritis dose. It's big-time aspirin as a drug, leading to [high] blood levels, not aspirin as a headache remedy.

TI: What do you think aspirin does, specifically? What's its mode of action?

Kotler: A recent paper in Science says it inhibits a cellular activity promoter - NFkappaB - that is turned on by TNF and other signals. It also may be a free radical scavenger and act as an antioxidant. Certain salicylates do that. But in fact, I really don't know how it might work. People have been using aspirin for hundreds of years, and the mechanism of action was worked out, I believe, in the early seventies.

Reforming Research

TI: Let's talk about antiretroviral therapy. What do you tell your patients?

Kotler: My own feeling is that people should be on therapy early, that if they're willing, an antiviral therapy can be part of that, and that consideration of a combination therapy should come up early rather than late.

TI: What other therapy would be part of the combination, if not an antiviral?

Kotler: Besides behavior modification, good diet, and lots of sleep and stress reduction, I often use NAC [n-acetyl cysteine, a precursor to the cellular antioxidant molecule glutathione] and moderate doses of vitamins and minerals, including the antioxidants. There's a little bit too much "either/or" in AIDS treatment these days. You know people are put on AZT and just kept on it until they turn terrible and their doctors are virtually forced to change therapy out of embarrassment and shame.

TI: Where should we be putting our AIDS research dollars?

Kotler: Alternate hypotheses for pathogenesis. The hypotheses of the effects of inflammation. The effects of oxidative stress. They're here. There are drugs on the shelf that can be used right now if we knew they were good. These therapies took the back seat to the antiretrovirals. So a huge amount of data was, and still is, being generated about antiretrovirals in ways that're unbelievably confusing.

We've been let down. After all this time, what's the proper dose of AZT? What's the blood level you really need? Do you really need a blood level or do you need a level in CD4 lymphocytes? If so, what is that level? Basic answers aren't known.

TI: Why is it so hard to get studies funded?

Kotler: They're expensive. Somebody has to lay out the money for them. And the people who were making the decisions, came down hard on the side of the chemotherapeutic agent and antiretroviral agents, seeking the precise molecule to take out HIV altogether and bring about a cure.

They're still looking at new single agents that will hold HIV off altogether, indefinitely. And every new drug that comes out, it seems like it's being looked at in exactly the same way. Can you imagine a baseball game where the home team is down three to two in the sixth inning, and everybody tries to hit a home run, but they all strike out? Nobody tries to get to first base. That's my view of AIDS drug development. Everybody is looking for a $2-billion a year drug and nobody is looking for things that might just help.

TI: Whose responsibility is it to change that - private industry or government?

Kotler: I don't know. Probably the patients. You've been pushing things along pretty well up to now. If there's a change, you're probably going to have to be the ones to force the change. I wouldn't leave it to the people who are now in charge because they benefit from the status quo. From their point of view, things might be going okay. But from a different point of view, things are not going so well at all.

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