Of 41 HIV-infected patients with facial lipoatrophy who underwent autologous fat transplantation, disfiguring facial lipohypertrophy at the graft site occurred at the same time as recurrent fat accumulation at the tissue harvest site in 4 patients who had had fat transferred from the dorsocervical fat pad or from subcutaneous abdominal tissue

De Fazio D.

ESPOSITO, Roberto

GUARALDI, Giovanni

GUARALDI, Pietro

Murri R.

Orlando G.

Wu A.

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BRIEF REPORT • CID 2005:40 (15 January) • e13B R I E F R E P O R TFacial Lipohypertrophy in HIV-InfectedSubjects Who Underwent AutologousFat Tissue TransplantationGiovanni Guaraldi,1 Domenico De Fazio,3 Gabriella Orlando,1Rita Murri,4 Albert Wu,5 Pietro Guaraldi,2 and Roberto Esposito11Clinica delle Malattie Infettive and 2Clinica Neurologica, Universita` degli Studidi Modena e Reggio Emilia, Modena, and 3Chirurgia Plastica, Ospedale SanRaffaele, Milan, and 4Clinica delle Malattie Infettive, Universita` Cattolicadel “Sacro Cuore,” Rome, Italy; and 5Johns Hopkins School of Public Health,Johns Hopkins University, Baltimore, MarylandOf 41 HIV-infected patients with facial lipoatrophy who un-derwent autologous fat transplantation, disfiguring facial li-pohypertrophy at the graft site occurred at the same time asrecurrent fat accumulation at the tissue harvest site in 4patients who had had fat transferred from the dorsocervicalfat pad or from subcutaneous abdominal tissue.Lipodystrophy associated with HAART includes subcutaneousfat loss (i.e., lipoatrophy) in the face, limbs, or buttocks and/or fat accumulation (i.e., lipohypertrophy) in the abdomen, inthe breast, and/or on the dorsocervical spine (resulting in adorsocervical fat pad or “buffalo hump”) [1]. In patients withlipodystrophy, switching from treatment with either of the thy-midine nucleoside analogues, stavudine or zidovudine, to treat-ment with the nonthymidine analogue abacavir resulted in amild increase in peripheral fat mass; however, facial lipoatrophydid not improve [2]. The only currently available clinical in-terventions to treat facial lipoatrophy are fat transplantion sur-gery or injection with inert colloidal preparations.Patients and methods. At our Metabolic Clinic in Modena,Italy, 41 HIV-infected patients with facial lipoatrophy under-went autologous fat transplantation to treat facial-fat wasting[3, 4]. Surgery was performed using the technique describedby Coleman [3]. Intact fat-tissue parcels were harvested, andthe nonviable components were removed; mechanical trauma,exposure to infectious agents, and direct contact with air wereReceived 23 July 2004; accepted 23 August 2004; electronically published 21 December2004.Reprints or correspondence: Dr. Giovanni Guaraldi, Dept. of Medicine and MedicineSpecialities, Infectious Diseases Clinic, University of Modena and Reggio Emilia School ofMedicine, Via del Pozzo 71, 41100 Modena, Italy (g.guaraldi@unimo.it).Clinical Infectious Diseases 2005; 40:e13–5 2004 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2005/4002-00E2$15.00avoided to allow the graft to remain metabolically active. Thegraft was implanted with small cannulae in the subcutaneousspace to allow nutrition and cell anchoring. The source of thegraft was the subcutaneous abdominal region in 27 patients,the dorsocervical fat pad in 14 patients, the breast in 2 patients,and the pubis region in 2 patients. Few patients had multipleharvest sites as the graft source.Results. Of the 41 patients, 32.1% were women, and 21%had Centers for Disease Control and Prevention (CDC) stageC HIV disease. At baseline, the mean values (SD) for clinicalcharacteristics and laboratory values were as follows: age,years; nadir CD4 cell count, cells/mL; dura-43 6 191 151tion of exposure to HAART, months; and duration of65 17exposure to stavudine, months. At the time of surgery,44 19the patients’ mean (SD) CD4 cell count was cells/582 248mL, and the median HIV load was copies/mL.9621 24,867Surgery resulted in a safe, effective, and durable aestheticresult in all patients, with a mean increase in the subcutaneousthickness of the cheeks of 5.5 mm ( mm). After aSD 2.4median of 17.5 months postsurgery, 4 patients who had fattissue harvested from a single site developed renewed fat ac-cumulation at the harvest site. All 4 of these patients developedsimultaneous facial graft hypertrophy. For 3 patients, the graftsource had been the dorsocervical fat pad, and, for 1 patient,the graft source had been subcutaneous abdominal fat tissue.Patients described themselves as looking like “hamsters,” be-cause of the prominence of their cheeks.During the follow-up period, the 4 patients had their treat-ment switched from stavudine to abacavir or tenofovir andfrom a protease inhibitor to a nonnucleoside reverse-transcrip-tase inhibitor or multiple nucleoside reverse-transcriptase in-hibitors. None of the patients received steroids. The mean in-crease in body weight was 2 kg.Progressive facial lipohypertrophy of the cheeks after surgerywas documented by ultrasonography that was performed, inall cases, by the same operator with a high-frequency (7.5 MHz)transducer (3-GE Medical System; LOGIQ).The mean increase in the subcutaneous thickness of thecheeks from the time of surgery to the evaluation at month 24was 14.6 mm ( mm; ) in the 4 patients. FigureSD 2.1 Pp .071 shows the increase in the subcutaneous thickness of the cheeksin the 4 patients, compared with that of the overall cohort, andalso shows the morphological appearance of patient 1.Discussion. The reasons for fat depletion and accumulationin HIV-infected patients receiving antiretroviral therapy remainunexplained. Microscopic examination of adipocytes in patients at Universitàdegli Studi di Modenae Reggio Emilia on November 8, 2012http://cid.oxfordjournals.org/Downloaded from e14 • CID 2005:40 (15 January) • BRIEF REPORTFigure 1. Top panel, Subcutaneous increase in cheek thickness, as measured by ultrasonography, in the 4 patients with facial lipohypertrophy (pt1–4), as well as the mean thickness for the overall cohort (whiskers indicate SDs). Bottom panel, Photographs show lipohypertrophy of the dorsocervicalfat pad (upper row) and simultaneous hypertrophy of the facial fat graft (lower row). Written permission for use of the photographs was obtainedfrom the patient.with lipoatrophy shows remodeling that involves a combinationof apoptosis, defective lipogenesis, and increased metabolic ac-tivity in different areas [5]. Antiretroviral drugs may impairlipid metabolism enzymes, which may result in hyperlipidemia,insulin resistance, and apoptosis of adipocytes, because of thegreat similarity between the low-density lipoprotein-receptor–related protein and the cytoplasmic retinoic acid-binding pro-tein type I. Several of the commonly used nucleoside analoguesinhibit mitochondrial enzymes (e.g., g-polymerase), producinga progressive loss of mtDNA, with impairment of the oxidativephosphorylation pathway.Antiretroviral drugs may cause downregulation of TNF-ahomeostasis, altering transcriptional regulation, glucose levels,fatty acid metabolism, and hormone receptor signaling. Hy-pertrophy of the subcutaneous, denervated fat that was trans-planted in the cheeks clearly suggests that the abnormal dis-tribution of adipose tissue in HIV-infected patients cannot beentirely explained as a selective neuropathy mediated via theCNS but that some other circulating or humoral factor, as yetunknown, should be taken into account to explain the path-ogenesis of HIV-associated adipose redistribution syndrome[6].Our observations do not provide evidence for any patho-genetic mechanism. The syndrome is unlikely to depend onlyon paracrine factors, such as cytokine signals. In fact, paracrinefactors were present where the lipid alteration appeared, butrelapse occurred in a different area. Adipocyte receptors andmitochondrial toxicity–related mechanisms could explain howreceptor expression, as well as mtDNA, could be transferredfrom the harvest site to the graft site and remain sensitive to at Universitàdegli Studi di Modenae Reggio Emilia on November 8, 2012http://cid.oxfordjournals.org/Downloaded from BRIEF REPORT • CID 2005:40 (15 January) • e15lipohypertrophy determinants. Another hypothesis is that li-pohypertrophy of the cheeks may be the result of the expansionof brown fat that is transferred with the intervention. Ultra-structural observation suggests that dorsocervical fat consistsmainly of brown fat, and its expansion has been demonstratedin areas undergoing white-fat atrophy, such as subcutaneousabdominal tissue. Our data suggests that brown fat, which hasa higher mitochondria content, could be more prone to lipo-hypertrophy and that it may be a mechanism that compensatesfor fat atrophy.The influence of genetic factors is suggested, as only a mi-nority of the patients (21% of patients who received a graftfrom the dorsocervical fat pad and 4% of patients who receiveda graft from other sites) developed lipohypertrophy at the graftsite. A clinical implication is that, when autologous fat trans-plantation is chosen for the treatment of facial lipoatrophy, thepreferred subcutaneous harvest site should be the abdomen orpubis region.AcknowledgmentsWe thank A. Grisotti, M. Callegari, M. De Lorenzi, I. Pecorari, and M.Blini, for their active contribution in the surgery activities; G. Nardini andB. Beghetto, for their assistance in the project; and G. Amorico, for per-forming ultrasonography.Potential conflicts of interest. All authors: no conflicts.References1. Lichtenstein K, Delaney KM, Armon C, et al. Incidence and risk factorsfor lipoatrophy (abnormal fat loss) in ambulatory HIV-1–infected pa-tients. J Aquir Immune Defic Syndr 2003; 32:48–56.2. Moyle GJ, Baldwin C, Langroudi B, Mandalia S, Gazzard BG. A 48-week, randomized, open-label comparison of three abacavir-based sub-stitutions approaches in the management of dyslipidemia and peripherallipoatrophy. J Aquir Immune Defic Syndr 2003; 33:22–8.3. Coleman SR. Structural fat graft: the ideal filler? Clinic Plastic Surg2001; 28:111–9.4. Guaraldi G, De Fazio D, Orlando G, et al. Autologous fat transfer fortreating facial wasting in HIV body fat redistribution syndrome [abstract722]. In: Program and abstracts of the 10th Conference on Retrovirusesand Opportunistic Infections (Boston). 2003. Available at: http://www.retroconference.org/2003/. Accessed 19 December 2004.5. Lloreta J, DOmingo P, Pujol RM, et al. Ultrastructural feature of highlyactive antiretroviral therapy–associated partial lipodystrophy. VirchowsArchives 2002; 441:599–604.6. Fliers E, Sauerwein HP, Romijn JA, et al. HIV-associated adipose re-distribution syndrome as a selective autonomic neuropathy. Lancet2003; 362:1758–60. at Universitàdegli Studi di Modenae Reggio Emilia on November 8, 2012http://cid.oxfordjournals.org/Downloaded from 

Facial lipohypertrophy in HIV-infected subjects who underwent autologous fat tissue transplantation.

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