and excerpts from review of lipodystrophy in recent AIDS article (2001, 15: 1917-1930) by Don Kotler et al.
 
Lisa A. Kosmiski; Daniel R. Kuritzkesa; Kenneth A. Lichtensteinb; Deborah H. Glueckc; Patrick J. Gourleyd; Elizabeth R. Stamme; Ann L. Scherzingere; Robert H. Eckel
 
From the Division of Endocrinology, Metabolism and Diabetes, the aDivision of Infectious Disease, Department of Medicine, University of Colorado Health Sciences Center, the bDepartment of Medicine, Rose Medical Center, the cDepartment of Preventative Medicine and Biometrics, University of Colorado Health Sciences Center, the dDepartment of Medicine, Division of Infectious Diseases, Denver Health Medical Center, and the eDepartment of Radiology, University of Colorado Health Sciences Center, Denver, Colorado, USA.
 
AIDS 2001;15:1993-2000
 
Objective: To examine the relationships between protease inhibitor (PI) therapy, body fat distribution and metabolic disturbances in the HIV lipodystrophy syndrome.
 
Design: Cross-sectional study.
 
Setting: HIV primary care practices.
 
Patients: PI-treated patients with lipodystrophy (n= 14) and PI-treated (n= 13) and PI-naive (n= 5) patients without lipodystrophy.
 
Main outcome measures: Body composition was assessed by physical examination, dual-energy X-ray absorptiometry and computed tomography. Insulin sensitivity (SI) was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. Lipid profiles, other metabolic parameters, duration of HIV infection, CD4 lymphocyte counts, HIV-1 RNA load and resting energy expenditure (REE) were also assessed.
 
Results: PI-treated patients with lipodystrophy were significantly less insulin sensitive than PI-treated patients and PI-naive patients without any changes in fat distribution (SI(22) ? 10-4 (min-1/U/ml) versus 3.2 ? 10-4 and 4.6 ? 10-4 (min-1/U/ml), respectively; P < 0.001). Visceral adipose tissue area and other measures of central adiposity correlated strongly with metabolic disturbances as did the percent of total body fat present in the extremities; visceral adipose tissue was an independent predictor of insulin sensitivity and high density lipoprotein cholesterol levels. REE per kg lean body mass was significantly higher in the group with lipodystrophy compared to the groups without lipodystrophy (36.9 versus 31.5 and 29.4 kcal/kg lean body mass; P < 0.001), and SI was strongly correlated with and was an independent predictor of REE in this population.
 
Conclusions: Body fat distribution and metabolic disturbances are strongly correlated in the HIV lipodystrophy syndrome and REE is increased.
 
`Insulin resistance' refers to an impaired ability of insulin-sensitive tissues (such as liver, muscle, and subcutaneous adipose tissue) to respond appropriately to increased levels of insulin in the post-prandial phase (following a meal). Insulin coordinates post-prandial metabolism, stimulating the uptake and utilization of carbohydrates as metabolic fuel, while directing fats towards uptake and storage, for later use in the Œfasted' state. Release of fatty acids from adipose (fat) stores (lipolysis) is inhibited by insulin, whereas fatty acid and triglyceride synthesis is stimulated. Hence, insulin resistance is associated with defects in post-prandial metabolism in which there is impaired uptake of fatty acids by adipocytes (fat cells) and other sites of fat storage, and inappropriate release of fatty acids in the fed state. Insulin resistance is associated with a characteristic dyslipidemia (abnormal cholesterol, triglycerides) in which triglyceride-rich lipoproteins are abundant, a phenotype that is also seen in the familial partial lipodystrophy syndrome as well as in HIV lipodystrophy.
 
Editorial notes from Jules Levin:
 
there are 2 important points from this study--1. although the authors found an association between lipodystrophy (body changes) & insulin insensitivity, central adiposity (belly paunch) & metabolic abnormality, fat loss in the extremeties & metabolic abnormalities, we don't know which causes which. For example, does lipodystrophy cause insulin resistance or does insulin resistance cause lipodystrophy. The authors do not answer this question. 2. Persons with lipodystrophy were found to have higher resting energy expenditure (REE). The authors reported that increased REE has also been found in otherwise healthy subjects with impaired glucose tolerance and diabetes mellitus. They also reported that increased REE has been noted in several but not all studies of HIV-infected men and women with and without weight loss in both the pre-highly active antiretroviral therapy (HAART) and HAART eras, but the mechanism of this increase is not known. In the pre-HAART era, increased REE may have been secondary to high levels of inflammatory cytokines associated with uncontrolled HIV infection. In the HAART era, increased REE probably has a different etiology. An earlier study showed that HAART administration is independently associated with increased REE in HIV-infected patients. The present study confirms that increased REE in HIV infection persists in the HAART era, and suggests that it may be a feature of the HIV lipodystrophy syndrome even in patients with good virologic control.
 
Discussion About the Study
 
The authors conclude that the results of this study have several implications. First, the strong associations between body fat distribution and insulin resistance in the HIV lipodystrophy syndrome suggest causality - but in which direction? Central adiposity in this syndrome may lead to insulin resistance via accelerated release of FFA. On the other hand, insulin resistance with hyperinsulinemia may lead to visceral fat accumulation. The rapid development of insulin resistance on PI therapy described in the studies mentioned above suggests that the development of insulin resistance precedes visceral lipohypertrophy in the HIV lipodystrophy syndrome and may therefore contribute to accumulation of lipid in this depot. Prospective studies in patients initiating PI-based therapy are needed to understand better the link between insulin resistance and visceral fat accumulation. The strong associations between fat redistribution and metabolic changes also suggest that the metabolic disturbances associated with PI therapy may not reverse completely if PI are discontinued but body composition remains altered. Given the strong correlations between both central fat accumulation and peripheral lipoatrophy and metabolic disturbances, patients with peripheral lipoatrophy alone and with central obesity alone need to be included in future studies in order to determine the individual influences of fat atrophy and fat hypertrophy on metabolic parameters.
 
Both visceral lipohypertrophy and peripheral lipoatrophy are strongly associated with metabolic disturbances in the HIV lipodystrophy syndrome. The accumulation of central abdominal fat and the loss of peripheral subcutaneous fat may each have important metabolic consequences in patients on antiretroviral therapy. However, there is evidence that PI also have independent effects on metabolic parameters. The finding that PI-naive subjects tend to be more insulin sensitive than PI-treated subjects without lipodystrophy lends further support to this idea. Finally, resting energy expenditure is increased in HIV lipodystrophy and is highly correlated with insulin sensitivity.
 
In an editorial in the same issue of AIDS, David Nolan & Simon Malal of Australia say the findings of Kosmiski et al. may provide a new way of looking at the interaction between NRTI and PI in the pathogenesis of subcutaneous fat wasting. There is increasing evidence from longitudinal clinical studies that the development of fat wasting is greatly enhanced when NRTI and PI are used in combination, compared to when either class is used alone, suggesting that the interaction between these drug classes is the most powerful determinant of this outcome. The role of NRTI in the pathogenesis of fat wasting is beyond the scope of this article, and has been reviewed elsewhere. However, given that mitochondrial dysfunction appears to play a prominent role in long-term toxicities associated with NRTI use, the in vivo demonstration that PI-associated insulin resistance and increased fatty acid flux may substantially affect mitochondrial function by decreasing the efficiency of oxidative metabolism provides a possible mechanism to explain the overlapping toxicities of NRTI and PI. These findings move us one step closer to elucidating the proximal pathogenic mechanisms of the metabolic syndrome induced by the PI class, which in turn will clarify the relationship between NRTI and PI in the pathogenesis of the lipodystrophy syndrome as a whole.
 
Editorial notes from Jules Levin--
 
What Causes Lipodystrophy (body changes)
 
A number of leading researchers in this field hold varying and at times similar opinions about the causes. Although researchers are unsure about it, It is generally accepted by these researchers based on evidence accumulated so far that more than one syndrome or condition is involved in causing body changes and metabolic abnormalities (cholesterol, triglycerides, sugar). Don Kotler et al discuss this and lipodystrophy in general nicely in the October issue of the journal AIDS. Following are excerpts. The cause of HIV-associated lipodystrophy syndrome remains to be elucidated. Understanding what causes the changes seen in patients with HIV-associated lipodystrophy syndrome is hampered by disparity in the methods used to assess various manifestations of the syndrome and the need for studies designed to distinguish causative factors among risk factors. (It is difficult to conduct these types of studies). Antiretroviral agents are thought to play a primary role, but so far, most studies implicating these agents show associations rather than causation. Numerous non-drug factors also appear to contribute to HIV-associated lipodystrophy. Understanding the cause is further complicated by diffculties in determining relationships among different aspects of the syndrome. For example, available evidence shows that metabolic changes precede fat redistribution; it is not clear whether metabolic changes cause fat redistribution or, conversely, whether fat redistribution promotes metabolic changes. As mentioned above, PIs have been implicated most strongly in both metabolic and fat distribution abnormalities. However, evidence is accumulating to support a role for NRTI (in particular, stavudine and dideoxyinosine) in lipodystrophy syndrome. It is also possible that PI and NRTI drugs act together to produce changes associated with lipodystrophy (one study found some PIs may increase blood or intracellular levels of NRTIs).
 
Numerous studies have shown that patients taking a PI have higher blood levels of triglycerides, total and LDL cholesterol, certain lipoproteins, insulin, and glucose. Current data suggest that elevated blood levels of glucose or insulin may be a consequence of HIV infection, a result of PI or NRTI treatment, or an indirect consequence of truncal adiposity (belly paunch) or lipoatrophy. Insulin resistance has been demonstrated in patients taking antiretroviral agents, most often with PI treatment but also with NRTI treatment alone. One study has shown that replacing PI with nevirapine partially reverses insulin resistance (editorial notes: one study suggested that replacing PI with abacavir may improve glucose).
 
Fat loss seen in patients with HIV, typically in subcutaneous regions (arms, face, legs), may result from cell atrophy, apoptosis (automatic cell death), or dedifferentiation of fat cells. Fat gain in visceral regions (belly) may result from adipogenesis, lipogenesis, or both (these are processes by which fat is produced and deposited). Because visceral fat drains portally into the liver, it may contribute to the elevation in serum triglycerides and insulin resistance seen in patients with HIV. Factors controlling fat loss and accumulation are complex and thought to be influenced by cytokines such as tumor necrosis factor alpha and interleukin 6, by endocrine factors such as cortisol, testosterone, and growth hormone, and by differential expression of receptors for these factors on adipocytes in different fat depots (Editorial note: it appears that dysregulation of the immune system may play a role in causing body changes. The affect of HIV itself or immune reconsitution by HAART may contribute to this dysregulation).
 
Evidence suggests that both PI and NRTI use are involved. On a cellular and molecular level, PI drugs have been shown to inhibit adipocyte (fat cell) differentiation (production), thereby possibly contributing to morphological (body) changes. In addition, some researchers speculate that toxic effects of NRTIs on mitochondrial function and associated lactic acidosis may be linked to changes in fat distribution.
 
All NRTI drugs can cause mitochondrial toxicity, but to differing degrees and their impact may be worsened by interactions with PIs. For example, when indinavir and stavudine are combined, indinavir can increase plasma stavudine concentrations, thereby potentially increasing or accelerating NRTI-mediated mitochondrial toxicity. When mitochondria do not function properly, lactic acid may accumulate in the cytosol (the fluid compartment of the cytoplasm), with toxic consequences for the cell and surrounding tissues. Fatty acids that normally would be metabolized in mitochondria also may accumulate in the cytosol, possibly explaining the lipid accumulation observed within muscle, liver, and nerve cells in vitro and sometimes in biopsies of patients with other mitochondrial disorders. Ensuing cellular damage can lead to hepatic steatosis, myopathy, cardio- myopathy, peripheral neuropathy, and, possibly, lipodystrophy.
 
NRTI-related mitochondrial toxicity may contribute to the fat redistribution syndrome seen in patients with HIV infection. This relationship is based partly on the resemblance of certain manifestations of the syndrome to other conditions characterized by abnormal fat accumulation and mitochondrial malfunction, such as Madelung's disease and dorsocervical lipoma in the absence of Cushing's disease. But HIV-infected patients have only certain of the changes seen with either condition, so the association may be unrelated to the pathogenesis of HIV-lipodystrophy syndrome. Furthermore, despite the ability of NRTI to inhibit mitochondrial DNA polymerase gamma in vitro, frank lactic acidosis is a rare occurrence in patients taking these agents. Moreover, there are no data to link the manifestations of HIV-associated lipodystrophy syndrome to lactic acidosis or other signs of mitochondrial dysfunction. (editorial note: other researchers feel more strongly that NRTIs play a role in the development of body changes. But so far the evidence implicating NRTIs needs more strength. Associations between NRTIs and lipodystrophy have been seen but actual causation by NRTIs have not been seen).