HIV-associated lipodystrophy syndrome: an accelerated form of the metabolic syndrome of insulin resistance due to altered fat distribution.

Highly active antiretroviral therapy (HAART) has greatly reduced AIDS-related morbidity and mortality. However, its widespread use has been associated with a marked rise in the frequency of insulin resistance, a metabolic syndrome that increases cardiovascular risk in these patients. (1) Some HIV-positive patients receiving HAART also develop "lipodystrophic" features, that is, loss of fat in some parts of the body (especially the face, arms, and legs) (2,3) as well as accumulation of fat in other parts of the body (such as the dorsocervical area, (4,5) trunk, and abdomen. (6,7))

Altered fat distribution may affect 14% to 32% of the HIV-positive population. Features of metabolic syndrome (abdominal obesity, reduced high-density lipoprotein [HDL] cholesterol, hypertension, and elevated triglycerides and glucose) are even more frequent, affecting as many as 69% of men receiving HAART. (8) An important issue, hitherto unresolved, is whether the so-called "metabolic" complications (features of the metabolic syndrome) are linked to the body fat alterations, or indeed if the various aspects of fat "redistribution" (lipoatrophy and lipohypertrophy) are due to the same or different pathophysiologic processes. (9)

HOW CAN WE DEFINE HIV-ASSOCIATED LIPODYSTROPHY?

There is as yet no widely accepted and practical case definition for HIV-associated lipodystrophy. (10) Numerous reports of widely varying descriptions of body habitus changes and of their frequencies have used different methods of measuring total body fat (as well as specific fat depots), and have largely relied on cross-sectional analyses, self-reports of body changes, or less than objective measurements by clinical observers. (11) In 2003, an HIV Lipodystrophy Case Definition Study Group developed a multifactorial statistical model to improve accuracy in diagnosing HIV-associated lipodystrophy. (12) However, this model has limitations in that it emphasizes lipoatrophy rather than fat accumulation as the chief manifestation of altered fat distribution; it also relies on imaging techniques to quantify fat in different regions of the body, making it less than practical for routine medical practice.

There has been a general bias in reporting peripheral fat loss (lipoatrophy) over central fat accumulation as clinical evidence of HIV-associated lipodystrophy. To some extent, this is because visceral abdominal obesity is markedly on the rise worldwide in virtually all populations, hence it is difficult to impute increases in abdominal fat to specific effects of HIV infection or its treatment. Nevertheless, several cohort studies have noted that a significant proportion of HIV-infected patients develop increased abdominal fat following HAART. (6,13-19) The Fat Redistribution and Metabolic Changes in HIV Infection (FRAM) Study set out to examine rigorously, albeit with a cross-sectional design, the relative contributions of peripheral lipoatrophy and central fat accumulation to the phenotype of HIV-associated lipodystrophy. The investigators found, both by self-report and detailed examination, that HIV-positive men had peripheral fat loss, but observed equivalent increases in central fat in both HIV-positive men and HIV-negative controls, as well as an absence of correlation between changes in central fat accumulation and peripheral fat loss in the HIV-positive men. (3) Hence, peripheral fat loss and central fat "gain" may not be pathophysiologically linked.

HOW COULD FAT DISTRIBUTION CHANGES BE LINKED TO THE DEVELOPMENT OF METABOLIC SYNDROME?

In many populations, increase in visceral fat is linked to the development of insulin resistance and the metabolic syndrome, in turn leading to greater cardiovascular risk. Increased visceral fat is associated with further deposition of fat in the liver and muscle, causing local tissue insulin resistance, as well as a rise in circulating factors that are atherogenic and thrombogenic (eg, free fatty acids, tumor necrosis factor-[alpha] [TNF-[alpha]], interleukin-6 [IL-6], and plasminogen activator inhibitor type-1 [PAI-1]), and a decline in factors linked to insulin sensitivity (eg, adiponectin, leptin). The question in regard to HIV-associated lipodystrophy is if and how peripheral fat loss is also linked to the development of insulin resistance and the metabolic syndrome, and whether these effects are linked to those of visceral fat accumulation.

On the basis of kinetic metabolic studies in the fasting and fed states in patients with HIV-associated lipodystrophy, Sekhar et al (20,21) identified basic defects in adipocyte function that result in a marked acceleration of lipolysis, or hydrolysis of stored triglycerides leading to a net release of free fatty acids into the circulation. This causes a decrease in the size of some fat depots, and increases the flow of fatty acids to the liver where they undergo increased re-esterification, leading to high levels of very-low-density lipoprotein (VLDL)-triglyceridemia. Furthermore, a profound defect in the clearance of dietary triglycerides leads to hyperchylomicron triglyceridemia. This scenario explains the typical dyslipidemia observed in patients with HIV-associated lipodystrophy, as well as their tendency to develop fatty liver, fatty muscle, and insulin resistance. However, it does not explain why they might develop visceral adiposity, but this could be due to differential turnover rates of lipids in visceral adipocytes (higher) compared to peripheral adipocytes (lower). As to the mechanisms underlying adipocyte dysfunction, they are likely complex and multifactorial, and probably include one or more HAART agents, increased proinflammatory cytokine activity, (22) or proteins expressed by HIV itself.

An altered milieu of endocrine or paracrine hormones in the setting of HIV infection or its treatment may also contribute to adipocyte dysfunction. Proinflammatory cytokines (eg, TNF-[alpha], IL-6) released by HIV-infected immunocytes, or by the adipocytes themselves when exposed to these HIV-infected cells, may lead to increased apoptosis (programmed cell death). Mitochondrial toxicity due to drugs of the nucleoside reverse transcriptase inhibitor (NRTI) class may add to this effect, (23) resulting in lipoatrophy. The mechanisms leading to central fat accumulation are more difficult to rationalize, but attention is turning to dysregulation of the enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-[beta]-HSD1), which is expressed more in visceral than peripheral fat. 11-[beta]-HSD1 converts inactive cortisone to the active glucocorticoid hormone cortisol. There is evidence that 11-[beta]-HSD 1 activity is increased in many forms of visceral obesity, leading to a localized "Cushing's syndrome of the abdomen," with its attendant insulin resistance, fatty liver, and dyslipidemia. (24)

A well-documented hormonal defect that is linked with HIV-associated lipodystrophy is partial or complete growth hormone (GH) deficiency, and this may contribute to its pathophysiology of the syndrome overall. Indeed, this condition may occur in about a third of patients with HIV lipodystrophy. (25) Rietschel et al assessed the function of the growth hormone axis through careful analysis of the pulse-frequency of GH release, and they observed reductions in basal GH concentration and GH pulse amplitude, associated with normal insulin-like growth factor-1 (IGF-1) and increased visceral fat. Levels of IGF-binding protein 3 (IGF-BP3), the chief IGF-l-specific binding protein, are also high relative to the low GH concentrations in these patients. (26) While the reasons for this "disconnect" between GH levels/kinetics and IGF-1 levels remain unclear, these data do imply that GH sensitivity is retained in patients with HIV-associated lipodystrophy, suggesting a rationale for treatment of the condition with GH. Although treatment approaches are beyond the scope of this review, it is worth mentioning that high-dose GH treatment has resulted in significant (if temporary) improvement in the lipodystrophic features, (27) and similar benefits, with fewer side effects, have been noted with treatments aimed at restoration of plasma GH levels to a physiologic range. (28)

Visceral adiposity may represent an effort to retain fat within adipocytes, rather than permit fatty acids and triglycerides to accumulate in energetic tissues such as muscle and liver, as well as in triglyceride-rich lipoproteins. Unger has suggested that the lipotoxicity associated with "ectopic" accumulation of fat is greatly increased when the synthesis and secretion of the adipocyte hormone leptin is inadequate to meet the challenge of increased flow of fatty acids from the periphery or the gut. (29) Thus, in a low-leptin state that occurs in HIV-positive patients with marked peripheral lipoatrophy, (30) a kind of "systemic steatosis" occurs. (31) Increased lipolysis, the key biochemical marker of lipodystrophy, causes increased flow of fatty acids to the liver, promoting the synthesis of triglycerides, reducing degradation of apolipoprotein B, and causing increased synthesis and secretion of VLDL-triglycerides. Lipid uptake within the central fat depots is higher than in peripheral fat depots (specifically the femoral-gluteal regions), perhaps because of increased sensitivity to lipoprotein lipase (LPL)-activating hormones (eg, cortisol in omental adipocytes), so that fatty acids transported to this site are consequently taken up and stored as diglycerides and triglycerides. The result is preferential deposition of fat in abdominal visceral fat depots, central obesity, and the clinical picture of HIV-associated lipodystrophy.

Perhaps because of a "spillover" from intra-abdominal fat depots (possibly caused by leptin deficiency or leptin resistance), fat accumulates "ectopically" in patients with HIV-associated lipodystrophy. Both total abdominal fat and intra-hepatic lipid content were greater in HIV-positive men than in healthy controls, and were associated with dyslipidemia. (32) This reflects insulin resistance at the level of the liver, as shown in a detailed study by Sutinen et al (33) The severity of insulin resistance was related to the accumulation of fat in the liver rather than to the accumulation of intra-abdominal fat; the same relationship between liver fat and dyslipidemia has also been found in HIV-negative men. (34) The data of Sekhar et al (20,21) would suggest that the source of the fat that accumulates in the liver is from excessive lipolysis; indeed Hadigan et al showed that blocking lipolysis acutely with acipimox improved insulin sensitivity in patients with HIV-associated lipodystrophy and visceral obesity. (35) Fatty infiltration of muscle also occurs and is linked to insulin resistance at the level of skeletal muscle. (36)

WHAT ARE THE ETIOLOGIC FACTORS THAT LEAD TO ADIPOCYTE DYSFUNCTION, AND HENCE TO HIV-ASSOCIATED LIPODYSTROPHY?

Although much attention has been focused on one or more HAART drugs as the inciting cause of HIV-associated lipodystrophy, its etiology is very likely muhifactorial. Intrinsic host factors and disease status, as well as treatment duration and type, probably play key roles. (37) Multivariate analyses of data from the HIV Out-Patient Study (HOPS) cohort (23) indicate that the following are risk factors for lipoatrophy: exposure to and duration of thymidine analogs (particularly stavudine and zidovudine), age, CD4 T-cell count, viral load, duration of therapy in general, and White race. Risk factors for fat accumulation are: duration of therapy, CD4 T-cell count, viral load, age, exposure to HIV protease inhibitors (PIs), and female sex. While such epidemiologic risk factor assessments are helpful in understanding the heterogeneity and multiplicity of possible causes of HIV-associated lipodystrophy, they cannot serve to define etiologies or mechanisms. Regarding fat distribution abnormalities and their relation to the development of the metabolic syndrome, it is unfortunate that few mechanistic hypotheses have been tested to date.

WHAT ARE THE PATHOLOGIC CONSEQUENCES OF HIV-ASSOCIATED LIPODYSTROPHY?

Patients with HIV-associated lipodystrophy frequently complain of cosmetic alterations in more noticeable parts of the body such as the face. This may lead patients to attempt cosmetic surgery or to discontinue some or all of their antiretroviral medications in the belief that the drugs are chiefly responsible for the disfiguration. Severe, sometimes rapid, accumulation of fat in the abdomen may lead to abdominal discomfort or respiratory difficulty, umbilical herniation, or gastro-esophageal reflux. (38) Most significantly, in relation to long-term metabolic morbidity and cardiovascular risk, the lipid kinetic and fat storage abnormalities that underlie fat maldistribution are strongly associated with rapid development of the metabolic syndrome. (39) Components of the metabolic syndrome are increased waist circumference, increased triglycerides, reduced HDL-cholesterol, high blood pressure, and elevated fasting glucose. This cluster of cardiovascular risk factors predisposes HIV-positive patients receiving HAART, and especially patients with HIV-associated lipodystrophy, to premature cardiovascular disease. (40,41)

Insulin resistance is increased in patients with HIV-associated lipodystrophy

The basis of the metabolic syndrome is insulin resistance, and central fat accumulation is the primary consequence of insulin resistance, acting as the driving force for other risk factors. (6,42-44) About 30% to 90% of HIV-positive patients treated with PIs develop insulin resistance; the incidence of frank diabetes is about 10%. (45) PIs induce insulin resistance in muscle by inhibiting the function of the Glut 4 transporter. (46) Among non-diabetic, HIV-positive patients receiving HAART (PIs in particular), fasting glucose levels are not elevated, but levels of fasting insulin, 2-hour insulin, and 2-hour glucose on-challenge are elevated. (47) NRTIs, especially the thymidine analogs, may also induce lipotoxic insulin resistance in muscle and liver by disrupting mitochondrial function; this is linked to the inability of these tissues to oxidize fat. These effects of PIs and NRTIs, together with those of adipocyte lipolysis causing visceral adiposity and increased intrahepatic and intramyocellular fat deposition, may account for the insulin resistance observed in HIV-positive patients. (48)

Cardiovascular risk is increased because of the metabolic syndrome resulting from insulin resistance

HIV-positive patients receiving HAART and patients with HIV-associated lipodystrophy have an elevated risk of cardiovascular disease. (40,49) Patients receiving HAART may be at increased risk of myocardial infarction (MI) or coronary heart disease compared with the general population or with HIV-positive patients not receiving HAART. Insulin resistance and diabetes mellitus, hypertension, and the presence of a chronic inflammatory state (such as seen in HIV disease) could predispose a patient to accelerated atherosclerosis, endothelial dysfunction, and a chronic prothrombotic state. The degree of cardiovascular risk induced by HIV infection or its treatment remains controversial. The largest data set to date is that of the prospective D:A:D Study, a clinical study of more than 23,000 patients, in which 207 patients had a total of 968 cardiovascular or cerebrovascular events. There was a gradual increase in the incidence of MI with duration on therapy. Combination therapy was associated with a small annual increase (5 events per 1000 patient years) in the risk of myocardial infarction. (50,51)

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CONCLUSIONS

The precise pathophysiologic mechanisms underlying the heterogeneous manifestations of HIV-associated lipodystrophy remain unclear. Much data have been acquired from human epidemiologic and metabolic studies; but these now need to be translated into mechanistic studies in animal or cellular models. Meanwhile, there is a pressing need to diagnose and treat patients for the lipodystrophic changes and the attendant dyslipidemia, if only to alleviate the metabolic syndrome and its associated cardiovascular risks. In this regard, the lack of a reliable and practical case definition of HIV-associated lipodystrophy is a problem, as it leads to marked variability in estimates of prevalence and risk factors, and difficulties in interpreting results of clinical trials in heterogeneous patients. Important future developments in the area of HIV-associated lipodystrophy should include a more thorough comprehension of the molecular pathogenesis, as well as the availability of rational treatment options. Until then, clinicians should continue to use best practice guidelines for the treatment of the metabolic syndrome and reduction of cardiovascular risk factors, utilizing both lifestyle (diet and exercise) and pharmacologic approaches. Nevertheless, the latter must be based on a good understanding of their interactions with HAART agents and effects on other medical conditions that are common in patients with HIV infection.

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By Ashok Balasubramanyam, MD and Rajagopal V. Sekhar, MD

Ashok Balasubramanyam, MD is Associate Professor of Medicine in the Translational Metabolism Unit within the Division of Diabetes, Endocrinology and Metabolism, at Baylor College of Medicine. He is also the Principal Investigator for the Heart Positive Study (heartpositive.org), which is currently enrolling subjects for the treatment of HIV-associated lipodystrophy and lipid disorders (see page 12 for additional information).

Rajagopal V. Sekhar, MD is Assistant Professor of Medicine and the Director of the Translational Metabolism Unit within the Division of Diabetes, Endocrinology and Metabolism, at Baylor College of Medicine.