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Rheumatology Advance Access originally published online on April 4, 2007
Rheumatology 2007 46(7):1102-1106; doi:10.1093/rheumatology/kem062
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Corticosteroid-induced lipodystrophy is associated with features of the metabolic syndrome

L. Fardet1,2, J. Cabane1, A. Kettaneh1, C. Lebbé3 and A. Flahault2

1Département de médecine interne, hôpital Saint-Antoine, 184 rue du Fbg Saint-Antoine, 2Département de santé publique, hôpital Tenon, INSERM U707, 4 rue de la Chine and 3Département de dermatologie, hôpital Saint-Louis, 1 av Claude Vellefaux, Paris, France.

Correspondence to: L. Fardet, Department of Internal Medicine, Hopital Saint-Antoine, 184 rue du faubourg Saint-Antoine, 75012 Paris, France. E-mail: laurence.fardet{at}sat.aphp.fr


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. Familial and HIV-associated lipodystrophies are associated with metabolic disorders and elevated blood pressure. Whether corticosteroid-induced lipodystrophy (CIL) is also associated with features of the metabolic syndrome is unknown.

Methods. We conducted a prospective study in two French tertiary centres and enrolled all consecutive patients starting long-term (≥3 months), high dosage (≥20 mg/day) systemic corticosteroid therapy. Three investigators assessed the development of CIL from standardized head and neck photographs. Arterial blood pressure and fasting blood glucose levels were assessed at baseline and then every three months until month 12. Total, HDL- and LDL-cholesterol and triglycerides were recorded at baseline, month 3 and month 12.

Results. Eighty-eight patients were enrolled (women: 75%, mean age: 57.4 ± 17.9 yrs, mean baseline dosage of prednisolone: 56 ± 15 mg/day). Sixty-four patients still received corticosteroids at month 12 (mean prednisolone dosage: 11 ± 4 mg/day). In intention-to-treat analysis, the cumulative incidence rate of CIL at months 3 and 12 was 61 ± 8% and 69 ± 9%, respectively. Baseline characteristics were similar in patients who developed CIL and patients who did not develop CIL during follow-up except with regard to baseline body mass index, which was higher in patients who develop CIL (24.3 ± 3.7 kg/m2 vs 21.4 ± 3.2 kg/m2, P= 0.02). Blood pressure was significantly higher in CIL+ patients at month 9 (135/78 mmHg vs 127/73 mmHg) and month 12 (141/81 mmHg vs 128/72 mmHg) visits. Moreover, compared with CIL– patients, CIL+ patients had significantly higher plasma concentrations of fasting blood glucose, triglycerides and total cholesterol and lower HDL-cholesterol concentration during follow-up.

Conclusions. CIL is associated with features of the metabolic syndrome and should then not be considered only as an aesthetic challenge. Further studies are required to test the relation between CIL and cardiovascular events.

KEY WORDS: Corticosteroids, Lipodystrophy, Metabolic syndrome, Hypertension


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Corticosteroids are the treatment of choice for numerous immunological, neoplastic and allergic diseases. However, their use is limited by frequent adverse effects and, particularly metabolic changes. Morphological changes, creating a ‘Cushingoid’ aspect, are often observed during chronic systemic therapy. Clinically, adipose tissue accumulates in the facial (‘moon face’), dorsocervical (‘buffalo hump’, accumulation of fat in the supraclavicular area) and abdominal regions, whereas subcutaneous fat thickness is reduced in the limbs. Abdominal visceral fat accumulation is suspected but few radiological studies have been conducted to confirm this point [1, 2]. We prefer to use the term ‘corticosteroid-induced lipodystrophy’ (CIL) to refer to these morphological changes. More than 50 yrs after the introduction of corticosteroids, few studies focused on CIL. Owing to the lack of a consensus in the definition for this syndrome, its exact prevalence is not known and varies between 15 and 83% [3–7] after more than 2 months of therapy. Moreover, if increased risks of hypertension and metabolic disorders have been linked to other forms of lipodystrophy (e.g. HIV-associated or familial lipodystrophies) [8–11], similar data are not available in the field of CIL. Interestingly, we have recently identified in CIL patients, demographical, clinical and nutritional risk factors, similar to those previously reported in HIV-associated or familial forms of lipodystrophy [12]. Moreover, common pathophysiological mechanisms have been hypothesized between CIL and HIV-associated lipodystrophy [13, 14]. For all these reasons, we hypothesized that, as other forms of lipodystrophy, CIL may be associated with some metabolic abnormalities and an increase of arterial blood pressure. We designed this study to answer this hypothesis.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Participants
Subjects were recruited in two French centres between June 2003 and May 2005. All consecutive patients who were prescribed long-term systemic corticosteroid therapy for chronic disorders were invited to participate. The following inclusion criteria were applied: age over 18 yrs, systemic corticosteroid therapy planned to last more than 3 months, initial dosage over 20 mg/day and inclusion within 15 days of treatment outset. The following exclusion criteria were applied: Cushing's disease, HIV infection, inflammatory bowel disease (because of the risk of malabsorption), pregnancy and systemic corticosteroid therapy ending less than 6 months prior to inclusion. Moreover, patients who stated they had lost more than 5% of their initial body weight owing to their underlying health disorder were not eligible for the study.

As there is no consensus definition of long-term corticosteroid therapy, we assumed a period of at least 3 months, as in previous studies [15].

All the participants provided written consent to be included in the study and the study protocol has been approved by the local ethics committee.

Study design and data collection
After enrollment the patients were seen every 3 months until month 12. At baseline visit demographic and clinical data were recorded and photographs of the face and dorsocervical region were taken. Arterial blood pressure was assessed with an automatic blood pressure device (Omron M4) after 10 min of rest. During subsequent visits (M3, M6, M9, M12), body weight and the steroid dosage were recorded. Photographs were taken of the face and dorsocervical region (lighting, camera, practitioner and patient position kept standard). Arterial blood pressure was assessed with the same automatic blood pressure device after 10 min of rest. Hypertension was defined as a newly developed systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg. Fasting blood glucose and C-reactive protein (CRP) levels were recorded at baseline and at the M3, M6, M9 and M12 visits. Total plasma cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides were recorded at baseline, and at the M3 and M12 visits. Type II diabetes was defined as two or more fasting blood glucose concentration higher than 126 mg/dl (normal <110 mg/l). Because alcohol may influence lipid measurements, patients were asked to record on a standardized questionnaire all their alcohol intakes during one week of the first and third months of treatment. The M0–M3 mean value was calculated for each patient.

Lipodystrophy assessment
At the end of the study, three senior physicians independently and simultaneously examined the M0, M3, M6, M9 and M12 photographs of each patient and evaluated the presence of morphological changes between two consecutive photographic evaluations (apparition of moon face, double chin or buffalo neck or attenuation or disappearance of facial wrinkles). They completed a standard questionnaire on which they noted (1) clear facial and cervical CIL (presence of at least two morphological changes), (2) possible facial and cervical CIL or (3) no facial and cervical CIL (no morphological changes). Judgements agreed by at least two of the three physicians were recorded. If the three scores were discordant, the opinion of a fourth expert was requested. Patients were then classified as CIL+ or CIL–.

Statistical analysis
Groups were compared by the Wilcoxon test for continuous variables and the chi-square or Fisher's exact test (as appropriate) for categorical variables. The cumulative incidence rates of CIL were assessed by Kaplan–Meyer curves. Performance of photographs to diagnose CIL have been described elsewhere [16]. Differences were considered statistically significant when P < 0.05. All statistical analyses were tested at the significance threshold {alpha} = 0.05 and were two-tailed. Analyses were performed using SAS software (version 8.2, SAS Institute, Cary, NC, USA). Values are reported as mean ± S.D.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Patients
During the 2-yr inclusion period, 91 patients fulfilled the inclusion criteria. Three of them refused to take part in the study and 88 were enrolled. Their characteristics are reported in Table 1. At month 3, month 6, month 9 and month 12, data were available for 85, 80, 75 and 73 patients, respectively. Eighty-one, 77, 68 and 64 of them still received corticosteroids (mean daily prednisolone dosages: 32 ± 15 mg, 19 ± 6 mg, 15 ± 6 mg and 11 ± 4 mg, respectively). In intention-to-treat analysis, cumulative incidence rate of CIL was 61 ± 8% at month 3, 65 ± 7% at month 6, 68 ± 9% at month 9 and 69 ± 9% at month 12. Most patients classified as CIL+ developed CIL soon in the course of therapy (i.e. within the first 3 months). Among the 73 patients with a complete follow-up (i.e. 1 yr), 53 developed lipodystrophy under treatment and 20 did not. Their baseline characteristics are reported in Table 2. Baseline body mass index (BMI) of patients who developed CIL was significantly higher than this of patients who did not.


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  		TABLE 1. Baseline characteristics of the 88 enrolled patients

 

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  		TABLE 2. Baseline characteristics and M0–M3 mean alcohol intakes with regard to occurrence of CIL during 1-yr follow-up

 
At each follow-up visit (Table 3), CRP levels and cumulative steroid dosage did not differ between CIL+ and CIL– corticosteroid-treated patients, whereas BMI was significantly higher in CIL+ patients.


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  		TABLE 3. Follow-up data of patients receiving corticosteroids

 
Arterial blood pressure
Mean baseline systolic and diastolic blood pressures (BP) were not different between patients who developed and patients who did not develop CIL during the follow-up (Table 2). In the CIL+ group, 6 out of 40 (15%) patients with no past history of hypertension at baseline developed hypertension during follow-up vs 1 out of 13 (8%) in the CIL– group (P = 0.67). At M9 and M12 visits (Fig. 1), CIL+ patients had significantly higher mean systolic and diastolic BP than CIL– patients (135/78 mmHg vs 127/73 mmHg at month 9 and 141/81 mmHg vs 128/72 mmHg at month 12).


Figure 1
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  		FIG. 1. Comparison of systolic and diastolic blood pressure (BP) between patients classified as CIL+ and patients classified as CIL–.

 
Metabolic disorders
At months 3, 9 and 12, blood glucose concentration of CIL+ patients was significantly higher than this of CIL– patients (Fig. 2). Two patients in the CIL+ group and none in the CIL– group developed type II diabetes during follow-up. Lipids parameters were evaluated at month 3 and 12 visits (Figs 3 and 4). In both periods, mean triglycerides concentration was significantly higher in CIL+ patients than in CIL– patients. Plasma concentrations of total, HDL- and LDL-cholesterol were similar in both groups at month 3, whereas at month 12, plasma concentration of total cholesterol was significantly higher (5.81 vs 5.17 mmol/l, P = 0.01) and HDL-cholesterol significantly lower (1.91 vs 2.24 mmol/l, P = 0.02) in CIL+ patients.


Figure 2
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  		FIG. 2. Comparison of mean fasting blood glucose between patients classified as CIL+ and patients classified as CIL–.

 

Figure 3
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  		FIG. 3. Comparison of mean triglycerides plasma concentrations between patients classified as CIL+ and patients classified as CIL–.

 

Figure 4
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  		FIG. 4. Comparison of mean total, HDL- and LDL-cholesterol plasma concentrations between patients classified as CIL+ and patients classified as CIL–.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
In this cohort of 88 adult patients starting long-term treatment with prednisolone at an initial mean dosage of 56 mg/day, occurrence of CIL was common and was associated with a higher arterial blood pressure after 9 and 12 months of therapy. During follow-up, mean blood glucose, total cholesterol and triglyceride concentrations were higher and HDL-cholesterol concentration lower in patients who developed CIL+ than in patients who did not. These metabolic characteristics are consistent with the assumption of a complete corticosteroid-induced lipodystrophic syndrome (centripetal fat redistribution with abdominal lipohypertrophy and visceral fat accumulation) associated with facial and cervical lipodystrophy.

Because there is no standard method to assess the presence or absence of CIL, we chose to use standardized photographs. Using this method, a classification bias is possible but unlikely, given the good agreement among the three independent experts [16]. Nevertheless, there is no healthy or untreated control group for body shape changes over the same period of time. We thus cannot assert that the body shape changes we classified as lipodystrophy were not in fact morphological changes secondary to a weight gain. Nevertheless, we think this hypothesis is unlikely. On one hand, because the three experts did not evaluate only the presence or absence of lipodystrophy but also assessed the body shape changes between baseline and follow-up, our study was designed to control potential bias related to the presence of lipodystrophic features at inclusion. On the other hand, because most patients developed CIL during the first three months of therapy, we think that major morphological changes on face and neck secondary to a weight gain were unlikely during this short period.

Weight gain is frequently observed in long-term corticosteroid-treated patients, either with high- or low- (i.e. ≤10 mg/day) dosages [17–19]. In a meta-analysis of four rheumatoid arthritis trials using ≤10 mg/day of prednisolone, corticosteroid therapy was associated with an increase of mean body weight over 2 yrs, in the range of 4–8% [20]. Moreover, the fear of weight gain is firstly cited by patients suffering from rheumatoid arthritis who are unwilling to consider treatment with corticosteroids [21]. In our study, weight gain was important in patients who developed CIL whereas weight tended to be stable in patients who did not develop CIL.

In our study, baseline BMI was significantly higher in patients who develop CIL during follow-up. It suggests that patients with higher BMI at outset are more likely to develop CIL (and features of the metabolic syndrome). This has therapeutic implications—if such patients need high dose corticosteroids for long periods, they perhaps need close monitoring for and treatment of elevated blood pressure, lipids and glucose.

We hypothesized that patients who did not develop CIL were in fact non-compliant patients. Nevertheless, this is unlikely because CRP levels improved in the same way in both groups.

Other forms of lipodystrophy are associated with elevated blood pressure and metabolic disorders. Patients suffering from familial forms (e.g. Dunnigan- or Kobberling-type lipodystrophy) are at high risk of developing hypertension, insulin resistance/diabetes or dyslipidaemia [10, 11]. In HIV-infected patients, abnormalities in body composition are frequent (i.e. 40–50% of ambulatory patients [22] and most studies describe an association between fat redistribution and a cluster of metabolic abnormalities, including insulin resistance, impaired glucose tolerance, hypertriglyceridemia and low serum levels of HDL-C [8, 9, 23–26]. These associated metabolic changes can be responsible for the increased cardiovascular risk [27, 28]. Moreover, HIV-associated lipodystrophy increases the risk of hypertension [29–31]. Lastly, for these patients, lipodystrophy related symptoms may negatively affect quality of life [32], and may be responsible for a negative adherence to therapy [33, 34]. For all these reasons, lipodystrophy is now considered as a major problem in HIV-infected patients and many studies focused on it since its first descriptions in 1998 [35]. In our study, we showed that, as other forms of lipodystrophy, CIL was associated with an increase of arterial blood pressure and with metabolic disorders. Through our results, we cannot assert that CIL was associated with insulin resistance. However, fasting blood glucose was higher at M3, M9 and M12 visits among patients with CIL, whereas inflammatory markers, known to be associated with glycaemia [36–38], were not different between the two groups. We assume that this early-elevated blood glucose concentration would be predictive of later glucose intolerance, but longer follow-up is required. The rise in total plasma cholesterol was rapid and marked in both groups soon after the initiation of corticosteroids but at M12 visit, CIL+ patients had higher total cholesterol and lower HDL-cholesterol than CIL– patients. Moreover, patients with CIL had significant higher triglycerides levels at M3 and M12 visits. Alterations of lipid metabolism have been reported in non-transplant populations treated with corticosteroids [39–41], but these studies were usually retrospective and described only lipid disorders occurring after several years of corticosteroid therapy. Moreover, the results were somewhat discordant, probably because of large differences in the dosages and treatment periods. We hypothesize that these metabolic disorders are much more frequent in patients developing lipodystrophy during corticosteroid-therapy than in other patients. Given the very large number of patients receiving long-term systemic corticosteroid therapy worldwide [15] and because a two- to threefold risk of cardiovascular events has been reported in corticosteroid-treated population [42, 43], we think that prospective studies testing the link between CIL and cardiovascular events are urgently needed.

Formula


   Acknowledgment
 
We would like to thank the SNFMI (French National Society of Internal Medicine) for its financial support for this work.

Flahault has declared conflict of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 8 November 2006; revised version accepted 8 February 2007.
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