Abundant questions, scarce answers
A year has passed since I reported from the World AIDS Conference in Geneva about "lipodystrophy syndrome."
Much has happened since then. Within the last year, four conferences have been held where researchers have addressed lipodystrophy and presented some data. But we still have not agreed on a name or definition of the condition, nor do we understand the mechanism causing it, and we certainly have no clear idea about how to treat it.
What is lipodystrophy?
Lipodystrophy, defined as any disturbance of fat metabolism, is associated in some variation with many medical conditions, including HIV/AIDS.
While the term "lipodystrophy" is not accurate in its current usage in regard to HIV drug complications, it is widely used since no better word or definition of the condition has yet come along to replace it.
The condition is sometimes referred to as lipoatrophy (loss of fat), fat redistribution or fat maldistribution syndrome, among other things.
We do know we are seeing a variety of physical and biochemical changes in people with HIV infection. Speculation that these changes may not be related to each other appears to be gaining validity. What we have been observing over the last two years may be more than one syndrome.
Regardless of what may be the ultimate cause and mechanism, monitoring changes is very important. Be sure that you and your doctor fully document any changes on your medical record and as best as possible clearly identify the underlying cause of each of these changes.
Physical changes associated with lipodystrophy syndrome are related to body shape and body composition, mostly body fat losses and fat gains. No consensus yet exists on the best way to measure body changes.
BIA (bio-electric impedance analysis), CAT (computerized axial tomography) scan, DEXA (dual x-ray absorptiometry), and anthropometric, which includes skinfold measurements and waist-hip ratio, are ways currently being used. You and your physician should routinely look at the areas of your body that may potentially change to at least visually monitor them.
Parts of the body where changes in body fat may occur include:
- Buccal (cheek)
- Limbs (arms & legs) with prominent leg veins
- Abdominal girth (waist), also called visceral adiposity
- Interscapular fat pad ("buffalo hump")
- Lipomas (fat tissue deposits) in other locations
- Face (under jawline, neck)
A set of researchers at the First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV held in June in San Diego reported that they had documented rates of body fat changes, with abdominal obesity being the most common.
The order of less common changes seen were thinning of the extremities, buttocks, sunken cheeks, developing a moon face and buffalo hump. Others reported that overweight individuals were more likely to experience fat accumulation, while those who are underweight were more likely to experience fat loss under the skin.
Risk of fat redistribution was found to be greater among older individuals, those who had lived a long time with HIV and those who had been using long-term combination antiretroviral therapy.
Trends in gender differences were reported. Women were more likely to experience fat accumulation (98 percent) than men (76 percent), and men were more likely to experience fat loss under the skin (80 percent) than women (73 percent).
It seems that gender, age and pre-therapy weight all play roles in the types of fat changes that occur.
Hemophiliacs were reported to be at greater risk of experiencing changes in fat distribution. (Because hemophiliacs who are living were usually infected before 1985, they are older and likely to be on medications longer.)
Biochemical effects associated with lipodystrophy are metabolic changes: the way that nutrients are processed. Changes that have been seen include the following:
Blood glucose (sugar)
- High glucose
- Increase insulin resistance
Blood lipids (fat)
- High total Cholesterol
- High LDL cholesterol
- Lower HDL cholesterol
- High VLDL cholesterol
- High triglycerides
Trends in gender differences have been seen. Men are more likely to have increased blood fats, triglycerides (84 percent) and cholesterol (53 percent), when compared to women (32 percent, 28 percent, respectively).
Abnormal lab values may require modifications in diet and exercise. Additional medications may be prescribed to control and avoid further complications. Problems associated with these metabolic abnormalities are numerous and pose life-compromising and threatening conditions: coronary artery disease, stroke, diabetes mellitus, renal failure, and death.
Every individual with HIV infection should have his or her fasting blood sugar and lipid panel monitored quarterly, after fasting for 8 to 12 hours.
P.I.s and lipodystrophy
Lipodystrophy syndrome appears to occur in 35 to 50 percent of those with more than three years of use of protease inhibitors. It appears to occur somewhat less frequently among those on combination therapy that does not include a protease inhibitor. Until a consensus emerges on a lipodystrophy definition, these percentages will vary greatly.
Morris Schambelan, M.D., from the University of California at San Francisco reported on data from the Third International Conference on Nutrition in HIV Infection, held in Cannes, France in April. According to Schambelan, fasting triglyceride and cholesterol rise and insulin sensitivity decreases after the starting of protease inhibitors before any body composition changes are identified. This finding means that metabolic changes occur first and may cause body fat composition changes, and that it is unlikely that body fat changes cause metabolic abnormalities.
However, a report by Donald Kotler, M.D., from St. Lukes-Roosevelt Medical Center in New York City found that changes of body fat are not necessarily associated with high lipid levels. Thierry St. Marc of Lyons, France, reported that body fat changes may be significantly associated with changes in serum insulin concentration, which is a laboratory test usually not measured or obtained in typical clinical practices. St. Marc also showed that high triglyceride levels were significantly associated with losses of fat.
Frank Goebel, Ph.D. from Ludwig-Maximillians-University in Munich, Germany, reported that insulin resistance ranges from zero for people not on combination antiretroviral therapy, to 25 percent for people taking a nucleoside reverse transciptase inhibitor (NRTI), to 50 percent when taking an NRTI in combination with an non-NRTI (NNRTI). The rate rises to 55 percent for those taking the triple combination of NRTI, NNRTI and protease inhibitor.
Goebel reported one study that identified the risk for insulin resistance was highest for indinivir (Crixivan®), followed by ritonavir (Norvir®), invirase (Fortovase®) and nelfinavir (Viracept®).
Many drugs implicated
Numerous reports at the lipodystrophy conference confirmed that all NRTI drugs are associated with some body fat changes.
One study reported that 14 percent of patients who had never taken protease inhibitors experienced fat loss compared to 51 percent of patients who were or had taken protease inhibitors.
Further, studies have indicated some combinations to be more strongly associated in these changes. d4T (Zerit®) has been associated with fat changes that are two- to three times the rate of other NRTIs. The longer time on d4T was statistically associated with the amounts of lower leg subcutaneous fat (fat right under the skin). According to M. Galli, M.D. and others from University of Milan, Italy, the highest associated incidence rates of fat redistribution were d4T (26 percent), 3TC (18 percent), ddC (15 percent), and both AZT and ddI (9 percent).
Over the last few years there have been reports of mitochondrial toxicity by NRTIs.
In your gut, food gets mechanically cut into smaller pieces, mixed with water and enzymes to be chemically digested breaking down the complicated larger nutrients of carbohydrates, protein and fats into much smaller molecules of glucose, amino acids and triglycerides. These molecules are then carried through the bloodstream to be used or stored after a series of further metabolic processes.
With the help of insulin, glucose enters the cell and then through a series of systematic steps uses oxygen to further break down and produce energy, by-products and waste products. These last steps, called electron-transport or oxidation, take place in the mitochondria, the "power plant" of the cell.
What seems to be occurring is that NRTIs and the nucleotide adefovir (not yet approved by the Food and Drug Administration), adversely affects mitochondrial DNA, which is important in the maintaining mechanics of the mitochondria that produces energy. One of the adverse results is the production of excess by-product, lactic acid, which normally would be further oxidized and not accumulate.
Symptoms of lactic acidosis are nausea, vomiting, abdominal pain and hyperventilation. In the extreme, lactic acidosis can be fatal. Other conditions that may be related to mitochondrial toxicity include polyneuropathy, myopathy, steatosis, pancreatitis, pancytopenia and proximal tubal dysfunction. Co-existing nutrient deficiencies of riboflavin and acetyl-carnitine and other factors may further contribute to NRTI toxicity.
Nutritional sources of riboflavin (vitamin B2) are eggs, lean meat, milk, broccoli and enriched breads and cereals. We usually recommend a routine vitamin and mineral supplement and an additional B-complex vitamin supplement. Riboflavin is the vitamin that turns urine that vivid yellow color. Five to 10 times the recommended daily allowance (RDA) has been sufficient in other conditions to correct riboflavin deficiency. Many typical multiple vitamin-mineral supplements or B-complex preparations are more than adequate to correct the condition if it exists.
Nutritional sources for carnitine are red meat, pork, chicken, fish, milk and cheese. Fruits, vegetables and grains are a much poorer source. If supplementing, L-carnitine should be chosen and absolutely not R-carnitine. Many nutritionists prefer to recommend the pharmaceutical grade Carnitor rather than an over-the-counter supplement.
While some trends are beginning to appear, no clear treatment recommendations exist. Any steps people take are still experimental. Constant reminders through all the conference reports urge caution against reaching premature conclusions.
The role of protease inhibitors and NRTIs in lipodystrophy syndrome, and the syndrome itself, has been very distressing to many. Researchers, clinicians and nutrition and treatment advocates urge clients not to stop taking medications without a full discussion with the treating physician. It is clear that stopping medications quickly leads to viral rebound and an increase in the risk of developing drug resistance to medications.
Body image is an important part of maintaining one's self esteem and determining one's health behaviors. Some people may prefer a larger body size normally and more so to avoid any possible hint of HIV infection. Some may strive for an underweight body size and even refuse therapy to maintain it.
Being overweight or underweight have negative health effects. Daily, we must make decisions to eat healthful foods and avoid unhealthful ones, to exercise, and, if you are doing so, take steps to stop smoking. Optimizing your body's health is still your first and foremost priority.
Marcy Fenton, M.S., R.D. is a registered dietitian and HIV nutrition advocate for AIDS Project Los Angeles. She can be reached at (323)993-1612 and firstname.lastname@example.org.