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Original Studies |
Developmental Endocrinology Branch (J.A.Y., T.C.F., G.P.C., T.K., C.T.), National Institute of Child Health and Human Development; the Department of Critical Care, Warren Grant Magnuson Clinical Center (K.D.M.); and the Laboratory of Immunoregulation (J.F.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; and the Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical Center Burns and Allen Research Institute, University of California School of Medicine (T.C.F.), Los Angeles, California 90048
Address all correspondence and requests for reprints to: Jack A. Yanovski, M.D., Ph.D., National Institutes of Health, 10 Center Drive, MSC 1862, Building 10, Room 10N262, 9000 Rockville Pike, Bethesda, Maryland 20892-1862. E-mail: jy15i{at}nih.gov
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Abstract |
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Spontaneous plasma cortisol showed normal diurnal variation in PIAL. Cortisol levels were similar in CON and PIAL, and levels in these groups were less than those in CS at all times of the night or day (P < 0.005). Ovine CRH-stimulated morning plasma cortisol levels were similar in PIAL and CON. ACTH was significantly greater in PIAL than CON (P < 0.05) at 0, 15, and 30 min after CRH stimulation. Urinary free cortisol in PIAL (mean ± SD, 76 ± 51 nmol/day) was significant lower than those in CON (165 ± 64 nmol/day; P < 0.001) and CS (1715 ± 1203 nmol/day; P < 0.001). However, 17-hydroxycorticosteroid excretion was significantly greater in PIAL (43 ± 23 µmol/day) than in CON (17 ± 8 µmol/day; P < 0.001), although lower than that in CS (74 ± 47 µmol/day; P < 0.01). Scatchard analysis revealed normal glucocorticoid receptor number and affinity in PIAL. Serum triglycerides were significantly greater in PIAL (6.57 ± 5.63 mmol/L) than in CS (1.78 ± 0.83 mmol/L; P < 0.001) or CON (1.36 ± 0.84 mmol/L; P < 0.001). Although triglyceride levels were significantly correlated with body mass index for CON and CS, these were not correlated for PIAL. During an oral glucose tolerance test, similar glucose and insulin values were found in PIAL and CS that were greater (P < 0.05) than CON values at 30, 60, 90, and 120 min.
We conclude that the lipodystrophy associated with use of HIV-1 protease inhibitors is a syndrome of increased intraabdominal adiposity with concomitant dyslipidemia and insulin resistance, but without total body weight gain and is distinct from any known form of hypercortisolism. Although urinary cortisol disposition seems to be altered in HIV-infected patients who are being treated with multidrug regimens that include protease inhibitors, the decreased free cortisol and increased 17-hydroxycorticosteroid excretion appear to be unlikely explanations for the observed lipodystrophy. The cause remains to be elucidated.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As survival with HIV-1 has improved, attention has been directed toward the adverse consequences of HIV treatment regimens. Numerous side-effects have been reported with protease inhibitor use, including abnormalities in glucose homeostasis, hyperlipidemia, and changes in body composition including redistribution of body adipose tissue (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19). In HIV-1-infected patients treated with indinavir with such symptoms, we have previously reported increased triglyceride concentrations and disproportionate amounts of intraabdominal adipose tissue, without increased amounts of sc abdominal adipose tissue (18).
A number of reports in other conditions have found greater hypothalamic-pituitary-adrenal (HPA) axis activity in those with greater amounts of intraabdominal adipose tissue (20, 21, 22, 23, 24, 25). We hypothesized that the greater intraabdominal adipose tissue of HIV-infected patients treated with protease inhibitors might be related to abnormalities of adrenal function. We therefore studied the HPA axis of HIV-1-infected men and women with protease inhibitor-associated lipodystrophy (PIAL), using patients with Cushing’s syndrome (CS) and control volunteers as comparison groups. To elucidate the metabolic consequences of the observed lipodystrophy, we also studied plasma lipid concentrations and assessed glucose tolerance in study participants.
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Subjects and Methods |
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We studied 12 HIV-1-infected patients who were identified as having protease inhibitor-associated lipodystrophy (PIAL), 28 patients with CS, and 43 healthy control volunteers (CON) believed to have normal HPA axis activity.
The diagnosis of PIAL was based on the presence of characteristic
changes in body fat distribution that have been associated with PIAL
(Fig. 1
). These changes include increased
visceral abdominal fat, loss of facial fat, development of
dorsocervical and supraclavicular fat pads, and breast enlargement in
women (11, 12, 13, 14, 15, 16, 17, 18, 19). Patients with signs or symptoms of visceral abdominal
fat accumulation were evaluated by computed tomography scan (18) for
evidence of visceral abdominal adipose accumulation (Fig. 1).
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) was 911 ± 357 (mean ±
SD). All but two had HIV-1 viral loads below 500 copies/mL,
the lower limit of detection of a branched HIV-1 DNA assay
(Chiron Corp., Emeryville, CA). No patient had an active
opportunistic or other infection at the time of evaluation. Nine of the
12 patients with PIAL were participating in ongoing trials of
intermittent interleukin-2 therapy in the treatment of HIV-1 infection
(Table 1). No subject had received treatment with interleukin-2 more
recently than 4 weeks before evaluation. All subjects with PIAL were
prescribed antiretroviral regimens that included a protease inhibitor
at the time of evaluation (Table 1). Subjects with PIAL had been
treated with protease inhibitors for an average of 17.4 ± 7.5
(mean ± SD) months. The single patient (no. 5) not
prescribed indinavir at the time of study had discontinued it 8 months
previously and had been treated since then with Ritonavir
and saquinavir. Three other patients who were taking indinavir at the
time of evaluation had taken saquinavir, and two had taken
Ritonavir in the past.
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Protocol
Subjects were admitted to the Warren Grant Magnuson Clinical Center for study. In all subjects, the 24-h excretion of UFC, 17-hydroxycorticosteroids (17-OHCS), and creatinine was measured for 1 day. An oral glucose tolerance test was performed in 11 PIAL, 18 CS, and 11 CON. Each subject ingested 75 mg dextrose by mouth, and serum glucose and insulin concentrations were measured at 0, 30, 90, and 120 min. Serum for the measurement of cortisol was collected from an indwelling iv catheter in 10 PIAL, 13 CS, and 12 CON at the following times: 0600, 0700, 0800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2300, 2400, 0100, 0300, 0500, 0600, and 0700 h. Samples for cortisol from an additional 15 CS and 14 CON were obtained only from 0600–0800 h and from 2300–0100 h. Fasting samples were obtained for triglycerides, total cholesterol, and HDL cholesterol from all subjects. In 11 PIAL, 28 CS, and 35 CON, a CRH stimulation test was performed. Ovine CRH (Bachem California, Inc., Torrance, CA) was administered as an iv bolus injection at a dose of 1 µg/kg between 0800–0810 h. Plasma samples were assayed for cortisol and ACTH 1 min before CRH stimulation and then 15, 30, and 60 min after CRH.
Hormonal analyses
UFC, 17-OHCS, and creatinine excretion were measured as previously described (29). Plasma ACTH, cortisol, and cortisol-binding globulin were measured as previously described (30) by Covance Laboratories, Inc. (Vienna, VA).
Glucose, triglyceride, total cholesterol, and high density lipoprotein cholesterol assays were performed at the NIH’s Warren Grant Magnuson Clinical Center Clinical Pathology Laboratory using standard colorimetric methods on a Hitachi 736–30 analyzer (Boehringer Mannheim, Indianapolis, IN). High density lipoprotein cholesterol was measured after precipitation with phosphotungstic acid. Insulin was measured by RIA at Covance Laboratories, Inc.
Glucocorticoid receptor binding affinity and number
Glucocorticoid receptor binding affinity and number were determined by standard methods (31). Briefly peripheral blood mononuclear cells were isolated using Ficoll-Isopaque and were seeded at 2 x 106 cells/well in 500 µL incubation medium (RPMI 1640 supplemented with 50 µg/mL streptomycin and 50 U/mL penicillin) in 24-well tissue culture plates. 3H-Labeled dexamethasone, in six different concentrations ranging from 1.5–50 nmol/L, was then added. Nonspecific binding was determined in the presence of a 200-fold excess of cold dexamethasone. Binding capacity and Kd values were determined by Scatchard analysis.
Statistical analyses
Data were analyzed on a Macintosh PowerPC using SuperAnova 1.11 and StatView 4.5 software (Abacus Concepts, Inc., Berkeley, CA). ANOVA, with repeated measures where appropriate, was used to compare the hormone concentrations during the ovine CRH and glucose tolerance tests, followed by preplanned, paired and unpaired Fisher’s least significant difference tests, corrected for multiple comparisons. Due to heteroscadasticity of variance, hormone measurements were subjected to logarithmic transformation before analysis. For the ovine CRH test, the 21 patients with CD were compared to CON and PIAL, although results were not significantly altered when all patients with CS were included in the analysis (data not shown).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Body mass index
was significantly lower in PIAL (26.1 ± 3.9 kg/m2)
and CON (25.8 ± 4.7 kg/m2) than in CS (33.4 ±
8.0 kg/m2; P < 0.005 vs. CON or
PIAL).
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). There were no
significant differences between PIAL and CON at any time point. After
CRH stimulation (Fig. 3), cortisol
responses of PIAL and CON were similar. ACTH was significantly greater
in PIAL than CON at baseline, 15 min, and 30 min (P <
0.05). Both PIAL and CON had significantly lower plasma ACTH and
cortisol levels than CS at all times examined (P <
0.01).
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) of free cortisol in PIAL (mean ±
SD, 76 ± 51 nmol/day) was within the normal range,
but significantly lower than those in CON (165 ± 64 nmol/day;
P < 0.001) and CS (1715 ± 1203 nmol/day;
P < 0.001). However, excretion of 17-OHCS was
significantly greater in PIAL (43 ± 23 µmol/day) than in CON
(17 ± 8 µmol/day; P < 0.0001), but was still
significantly lower than that in CS (74 ± 47 µmol/day;
P < 0.01). When urinary excretion of 17-OHCS was
expressed per g creatinine, and free cortisol was expressed per
m2 surface area (Table 2), the comparisons were unchanged;
UFC excretion was significantly lower in PIAL than in CON
(P < 0.001) or CS (P < 0.001),
whereas 17-OHCS excretion was greater in PIAL than in CON
(P < 0.01), but lower than that in CS
(P < 0.005). The morning plasma cortisol-binding globulin level in PIAL was 716.2 ± 155.7 nmol/L, comparable to results in CON (652.3 ± 132.2) and well within the published normal range for cortisol-binding globulin (27, 32). The glucocorticoid receptor number and affinity of patients with PIAL were within the range reported as normal (33). As determined by Scatchard analysis, patients with PIAL had 2702 ± 865 glucocorticoid receptors/mononuclear cell, and the Kd was 4.4 ± 1.7 nmol.
During an oral glucose tolerance test, glucose and insulin values were
significantly higher (P < 0.05) in PIAL and CS than in
CON at 30, 60, 90, and 120 min and were similar in PIAL and CS (Fig. 4). Total serum cholesterol was similar
in PIAL and CS and was significantly greater in both than in CON. Serum
triglycerides were significantly greater in PIAL (6.57 ± 5.63
mmol/L) than in CS (1.78 ± 0.83 mmol/L; P <
0.02) or CON (1.36 ± 0.84 mmol/L; P < 0.01).
Although triglyceride levels were significantly correlated with body
mass index for CON and CS, these were not correlated in patients with
PIAL (Fig. 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We also observed that basal and CRH-stimulated plasma ACTH and 24-h urinary 17-OHCS excretion were significantly greater, whereas UFC excretion was significantly lower, in PIAL than in CON. These results were quite distinct from those observed in CS, where plasma ACTH, cortisol, urinary 17-OHCS, and UFC were all increased to a significantly greater extent. Others have reported UFC levels within the normal range for patients with PIAL (19), but did not compare them to levels in body mass index-matched controls. We do not believe that interleukin-2 therapy affected these results, because most subjects had not received interleukin-2 within several months of evaluation.
The increased plasma ACTH in concert with greater 17-OHCS and lower UFC lead us to conclude that the metabolism of cortisol is altered by the medication regimens employed in HIV-positive patients with PIAL, but in a manner that allows for normal plasma cortisol concentrations. Many medications interfering with cortisol metabolism induce hepatic cytochrome P-450 enzymes that enhance the metabolism of cortisol to 6ß-hydroxycortisol and 6ß-hydroxycortisone, but such medications would not produce the observed findings, because these steroids do not form Porter-Silber chromogens measured as 17-OHCS (34). Others, such as spironolactone or hydroxyzine, may increase apparent 17-OHCS values because they may also produce a yellow color (35). Spectrophotometric analysis at three wavelengths was performed in the present study to avoid including such interfering substances; no such substances were identified in any of the samples.
The most parsimonious hypothesis for these findings is that the metabolism of cortisol is altered in PIAL by one or more of the anti-HIV medications taken by these individuals, such that one or more of the steroids measured as 17-OHCS, but not as free cortisol, is increased. The Porter Silber chromogens include 11-deoxycortisol, cortisol, cortisone, 11-deoxytetrahydrocortisol, tetrahydrocortisol, tetrahydrocortisone, and their glucuronidated forms. The UFC assay employed in this study is specific, measuring only cortisol. Greater activity of the renal 11-ketosteroid reductase enzyme, which catalyzes the conversion of cortisol to cortisone, or partial inhibition of the adrenal 11-hydroxylase enzyme, which catalyzes the conversion of 11-deoxycortisol to cortisol, are explanations consistent with the available data.
Because we did not study a group of HIV-infected individuals who had not been treated with protease inhibitors, we cannot specifically ascribe these alterations in cortisol metabolism to the use of protease inhibitors. However, as laboratory alterations and symptoms coincided with the onset of protease inhibitor treatment, we believe that it is most likely that the increased plasma ACTH and urinary 17-OHCS and decreased UFC are side-effects of protease inhibitors. Aspartic acid proteases may be important in the processing of many different biological molecules, possibly including enzymes important in cortisol metabolism. Thus, protease inhibitors may have a number of biological effects not easily predicted ex vivo. We are currently attempting to determine which urinary steroids are increased by the administration of protease inhibitors. Nevertheless, because plasma cortisol is unaltered, we cannot ascribe the signs of PIAL to these alterations in steroid metabolism. One remaining possibility is that protease inhibitors specifically alter the sensitivity to glucocorticoids of particular adipose tissue depots, including visceral abdominal adipose tissue, without action at other fat depots, thus leading to increased visceral abdominal adipose tissue deposition and the metabolic derangements observed without leading to a generalized Cushingoid habitus or abnormalities in circadian cortisol secretion.
Because the catalytic HIV-1 aspartic acid protease has approximately 60% homology with the low density lipoprotein receptor-related protein and the cytoplasmic retinoic acid-binding protein type 1 or 2, one group has proposed that incomplete inhibition of the actions of these proteins could change serum lipid concentrations and increase rates of apoptosis in peripheral adipocytes. This, in turn, might stimulate visceral abdominal adipose tissue accumulation, because fewer peripheral adipocytes would be available to process circulating fatty acids (36). It also remains possible that PIAL is due at least in part to a reactive change that occurs in response to the marked changes in viral load that occur after initiation of protease inhibitor treatment or is an ongoing process that may predate the onset of protease inhibitor therapy, but be exacerbated by it. Future studies are needed in this area to determine both the cause of PIAL and the best approach for treating this complication of protease inhibitor therapy.
We also confirm previously reported findings of elevated triglycerides and insulin resistance in patients treated with HIV protease inhibitors (6, 7, 8, 9, 10). Carr et al. described significantly greater fasting insulin and triglyceride levels in HIV-positive patients treated with protease inhibitors compared either to healthy men or to HIV-positive men not treated with protease inhibitors, and greater fasting insulin in those with PIAL compared to HIV-positive patients without PIAL (17). Two of their protease inhibitor-treated patients developed new-onset type II diabetes. In the present study, cholesterol and insulin levels were elevated to a similar extent in PIAL and CS, whereas triglyceride values were significantly greater in PIAL than in either CS or CON. The uncoupling of the relationship between body mass and triglyceride levels in PIAL is evidence that the antiretroviral regimens of patients with PIAL induce a unique syndrome that is distinct from either simple body fat gain or even gain of intraabdominal adipose tissue, as is seen in CS, although as we have reported previously (18), triglyceride concentrations in PIAL remain correlated with the degree of trunkal obesity and intraabdominal adipose tissue.
Carr et al. reported that 64% of HIV-positive patients treated with a protease inhibitor developed PIAL, with an estimated median time to lipodystrophy of 10 months after starting protease inhibitor treatment (17). As determined by dual energy x-ray absorptiometry, patients with PIAL have less fat than HIV-positive men not treated with protease inhibitors in body regions other than the central abdomen (17), where we have previously found greater intraabdominal adipose tissue in such patients (18). One feature of PIAL that is decidedly different from CS is wasting of facial fat. This has been a striking feature in our patients taking protease inhibitors and has been described previously (12, 15, 17). Although PIAL shares some characteristics of known lipodystrophies, such as Barraquer-Simmons lipodystrophy (37), it appears to be distinct from all previously described syndromes (38).
We conclude that the lipodystrophy found with protease inhibitor treatment is a syndrome of increased intraabdominal adiposity with associated dyslipidemia and insulin resistance, but without total body weight gain, and is distinct from any known form of hypercortisolism. Although cortisol metabolism is altered by anti-HIV treatment such that plasma ACTH levels are increased and a significantly greater amount of cortisol is excreted as 17-hydroxycorticosteroids, abnormalities in the HPA axis do not affect either plasma cortisol or glucocorticoid receptor number and affinity. The observed alterations in glucocorticoid clearance appear unlikely to explain the observed lipodystrophy. The underlying mechanism by which protease inhibitors induce the lipodystrophy observed in HIV-1-infected patients remains to be elucidated.
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Footnotes |
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2 Current address: Division of Basic Research, Hellenic National
Diabetes Center, 3 Ploutarchou Street, 106 75 Athens, Greece.
Received July 17, 1998.
Revised January 12, 1999.
Accepted February 24, 1999.
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,
P < 0.05, CON vs. PIAL and
vs. CS.