Veteran Uptown Metabolic Trouble Shooter Argues Crix Belly, Buffalo Hump Are Not What They Seem
The RU-486 fix
As part of TAG’s new monthly meeting format (first Tuesday of each month at the Michael Callen/Audrey Lourde Community Health Center, 356 West 18th Street), St. Luke/Roosevelt’s Dr. Donald Kotler was invited to share with us his latest thoughts on the fat redistribution phenomenon showing up in HIV-infected individuals on HAART. Just when you thought you’d heard it all before, Don arrives on the scene to challenge the conventional wisdom — and turn the whole paradigm on its head. Mike Barr prepared this summary for TAGline.
The basis for Kotler’s new hypotheses come from two recently completed studies he has conducted up at St. Luke’s. (One’s “sitting at AIDS”; the other’s three-quarters completed and will be an oral presentation in Geneva.) Following his hunch that the “new” reports of strange fat redistribution in people on protease inhibitors were something we’ve seen since the early days of the epidemic — just not paid much attention to (“When someone comes in with sunken cheeks or a pot belly and sight-threatening or gastric CMV, you tend to focus on the immediately life-threatening condition,” he explains.), Kotler went back into his computer database of MRI scans of dozens and dozens of patients from the past year and carefully matched them to MRI scans of HIV-negative controls. What he unearthed was telling: some 40% of patients — none of them on protease inhibitors — exhibited what we now commonly refer to as “truncal obesity.” In women, the syndrome manifested itself more often as increased breast size and loss of fat in the upper thighs, but it was there — regardless of gender. And, interestingly, it was more evident in people with higher CD4+ T cell counts than in those with lower ones.
In a second, less high-tech study, Kotler used simple calipers and a tape measure to perform anthropometric assessments of patients’ waist size and skin thickness. Of some 300 patients, Kotler divided them up into what he called the “old HIV” era (pre-1996) and the “new HIV” era (1996 to the present). (Of the “new HIV” patients, about 50 were taking protease inhibitors, 20 were taking non-protease inhibitor-containing antiretroviral regimens and another 20 or so were receiving no therapy at all.) He then matched these to a group of HIV negative controls.
In a multivariate analysis, taking into account treatment or no treatment, protease or no protease, CD4+ cell count, plasma viral load, age, sex, weight and height, the effect of plasma viral load was significantly predictive of the presence of truncal obesity — even after controlling for all other parameters. Use of protease inhibitors and CD4+ T cell count were not. And the correlation was an inverse one: the patients with the lowest plasma HIV RNA levels were the most likely to exhibit truncal obesity!
So what’s going on here? Kotler asks his compact audience rhetorically. First of all, let me say that “lipodystrophy” is a misnomer — because it means “loss of fat.” What we’re seeing is not a loss of fat, but rather a redistribution of fat — away from the peripheral and subcutaneous fat and towards the viscera. What can, all at the same time, cause hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hypertension, hyperglycemia, lowered testosterone levels, lowered progesterone levels, high uric acid levels and gout? The answer, in word: cortisol.
Cortisol, which the body converts from the naturally occurring hormone cortisone, is responsible for the metabolism of glucose, protein and fats. It also regulates the immune system and affects many other bodily functions. Cortisol levels in the body typically display a diurnal patter: elevated in the early morning and then dropping gradually but steadily throughout the day. Cortisol levels are lowest at night. Cortisol and its competitor hormone, adrenaline (a/k/a epinephrine), are produced by the body in response to stress — be it outside stress (such as loud noise or the threat of bodily harm) or internal stress (such as anxiety or disease). Cortisol also causes resistance to insulin, which can lead to a kind of diabetes.
As Kotler tells it, these elevated cortisol levels (“hypercortisolism,” if you will) are one of the last remaining legacies of a life-threatening condition which has become less life-threatening. (“I’m not saying this is hypercortisolism, just that that’s certainly what it looks like.”) “You see the same thing in women who have survived breast cancer, children who have survived childhood leukemia. I even had a Vietnam vet who had survived agent orange. They all had chronically elevated cortisol levels. They were all people with life-threatening illnesses who got better. It’s the body’s natural response to stress.” “We’re just seeing [a big wave of this] in HIV right now because everything’s synchronized,” Kotler exclaims. “Everybody started AZT at the same time. Then everybody ‘failed’ at the same time. Now everybody has started protease inhibitors at the same time.”
But woe to s/he who would order a simple “fasting serum cortisol” and, upon receiving a reasonable level on the lab print-out, proclaim all is well. “The only accurate way to measure cortisol,” Kotler cautions, “is a 24-hour urine cortisol.” But you have to be willing to collect your urine for a 24-hour period and take it to the lab. (In a study of his own which examined the 24-hour urine cortisol levels of 9 HIV+ patients, 7 of 9 were above normal.)
What of the Sydney (Carr, Cooper et al. AIDS 1998, 12:F51-8) study at last February’s retrovirus conference that declared a full 64% of protease patients to suffer from various manifestations of “lipodystrophy” you ask? And what of the knee-jerk reaction to categorically link the lipid problem to the protease inhibitors? About the Australian study, Kotler states matter-of-factly that the data were simply “over-interpreted.” (“All the patients took protease inhibitors. All the patients’ viral load fell dramatically. And they attributed it to the use of protease inhibitors — rather than to the rapid and sustained reduction in plasma virus.”)
As for the Falloon study (an NIH study published in the March 21, 1998 issue of The Lancet which unequivocally linked the fat redistribution problem to protease inhibitors — indinavir in particular), her team analyzed a random sample of patients which included 10 individuals on indinavir who had evidence of truncal obesity, another 10 individuals on indinavir who had no evidence of truncal obesity and 10 controls. “Even though fully half of the patients taking indinavir had no evidence of truncal obesity, the NIH team concluded that the truncal obesity was caused by indinavir!” “It’s possible that protease inhibitors are doing something on top of this,” Kotler concedes, “but I really don’t believe this is anything new.”
A letter is due to come out soon in The Lancet describing “early onset cardiovascular disease” in individuals living with HIV. With more and more HIV-infected individuals walking around with elevated triglyceride and cholesterol levels, Kotler warns that we’re looking at “heart attack city.” He thinks a Clinical Alert is warranted. Or a letter to patients:
“As the prospects for long-term health have changed, so have the potential complications. If you have noticed any of the following, you should talk to your health care provider:
- a sudden increase in waist size;
- diabetes;
- high total or low HDL cholesterol;
- increased blood pressure.
At the very least, the activist community (or NIH?) should convene a summit of sorts composed of leading HIV physicians. But what therapeutic interventions exist? Lipid lowering drugs abound (lovastatin, pravastatin, simvastatin, gemfibrozil), and have been met with mixed results. A year or so ago, Kotler recommended steroids and regular exercise. That didn’t seem to work. (“So I was wrong,” he bats back.) Testosterone supplementation, effective in the non-HIV arena, has also seen little success in HIV. Then there’s human growth hormone (at $20,000-30,000 a year). Kotler says he’s heard good things about it for the treatment of buffalo hump and truncal obesity but doubts it will help to replace fat lost peripherally. (It could also lead to diabetes.)
Arguably the most efficient mechanism would be to block the cortisol receptor itself. To date, the most effective agent for this is the controversial French “abortion pill,” RU-486. “You’ll have to put together that old AL-721 train again — this time from France,” Kotler notes wryly but half serious. “Maybe you should just eat more fish, less French fries and (as he fingers the Marlboro reds in the pocket of his dungarees) stop smoking.”