Dermatology Online Journal
Iatrogenic lipomatosis: A rare manifestation of treatment with a peroxisome proliferator-activated receptor gamma agonist
- Author(s): Femia, Alisa
- Klein, Peter A
- et al.
Letter: Iatrogenic lipomatosis: A rare manifestation of treatment with a peroxisome proliferator-activated receptor gamma
agonistDepartment of Dermatology, Stony Brook University Medical Center, Stony Brook, New York. firstname.lastname@example.org
Alisa Femia MD, Peter A Klein MD
Dermatology Online Journal 16 (4): 15
Lipomas are common benign neoplasms of adipose tissue. Lipomatosis, the progressive appearance of multiple lipomas, is most often associated with specific congenital, familial, or idiopathic syndromes. In one reported case, the development of multiple lipomas occurred as a result of treatment with rosiglitazone, a peroxisome proliferator-activated receptor (PPAR) gamma agonist. We report a second case of lipomatosis occurring as a result of treatment with a PPAR gamma agonist. This case occurred in a 77-year-old woman who developed multiple lipomas two years after beginning treatment with pioglitazone, a PPAR gamma agonist. Histopathologic examination confirmed these lesions to be lipomas. Within four weeks of discontinuation of pioglitazone, regression of the lipomas began. We describe a case of PPAR agonist-induced lipoma formation, review relevant literature, and provide a molecular mechanism for this side effect.
Peroxisome proliferator-activated receptor (PPAR) gamma agonists are a relatively new class of drugs used in the treatment of type II diabetes mellitus. We present the second case of lipomatosis induced by a PPAR gamma agonist.
|Figure 1. Distal left arm lipoma, measuring 22.9 cm|
A 77-year-old woman with type II diabetes mellitus was seen for evaluation of non-tender masses on her bilateral dorsal arms and thighs. The patient’s past medical history included nonmelanoma skin cancer, pancreatitis, and osteoarthritis. The patient had no personal or family history of similar masses and no history of alcohol abuse. At the time of presentation, the patient had been taking pioglitazone, a PPAR gamma agonist, for two years. On exam, doughy, nontender, subcutaneous masses were present on the patient’s bilateral hips, dorsal arms, and distal dorsal thighs. The masses on the left and right forearm had a greatest circumference of 22.9 cm and 21.6 cm, respectively (Figure 1). A six mm deep punch biopsy of the left forearm confirmed the diagnosis of lipoma and pioglitazone was subsequently discontinued. At the four-week follow-up, the greatest circumference of the left and right arm lipomas measured 21 cm and 20.3 cm, respectively; at the ten-week follow-up, 20.3 cm and 19.1 cm, respectively. The discontinuation of pioglitazone had been the only interval intervention. The patient also reported losing 4.5 kg since discontinuing pioglitazone.
Lipomatosis induced by a PPAR gamma agonist has been previously reported in only one case. In 2004, Mafong et al.  described a patient who developed multiple lipomas on his bilateral arms and thighs following three months of treatment with rosiglitazone. Biopsy of one mass confirmed the diagnosis of lipoma and a stain for PPAR gamma was positive. All but five lipomas resolved completely within three months of discontinuation of rosiglitzone. In 2005, at the 14th Congress of the European Academy of Dermatology and Venereology, Gonzalez et al. presented the case of a 50-year-old woman who developed symmetric lipomatosis after six months of treatment with rosiglitazone for type II diabetes mellitus. Rosiglitazone was discontinued and the patient was referred for excision of the lipomas. Additional medications shown to have the potential to induce lipomas are listed in Table 1.
The mechanism of PPAR-gamma agonist-induced lipomas can be deduced. PPAR-gamma is most abundantly expressed in adipose tissue and directly affects the transcription of genes regulating glucose and lipid metabolism . PPAR-gamma promotes fatty acid uptake and storage in subcutaneous adipose tissue [3, 4], increases adipocyte proliferation [3, 5], and redistributes adipose tissue from visceral fat to subcutaneous fat [4, 6]. Pioglitazone has been shown to increase lipin-beta, a gene product that increases adiposity 
The effect of PPAR agonists on adipose tissue has previously been recognized in rodent studies. In two-year mouse and rat carcinogenicity studies, three of six PPAR gamma agonists induced the development of lipomas in rats, albeit at doses much higher than clinical human doses [8, 9]. In these trials, muraglitazar, a dual PPAR agonist with effects on both PPAR alpha and PPAR gamma, was found to increase the incidence of subcutaneous malignant liposarcoma in male rats and subcutaneous lipoma in female rats . These effects again were seen at doses much higher than human clinical doses .
Given their benign nature, the treatment of lipomas is usually not necessary. However, if lipomas are disfiguring, painful, or rapidly growing, treatment with a variety of modalities are available. In our patient, lipomas began regressing within one month of discontinuation of the PPAR gamma agonist. In Mafong et al., dramatic regression of lipomas occurred within a short period of time. In these cases, withdrawal of the PPAR agonist was sufficient to at least partially treat the lipomas. Other available treatment modalities include excision, enucleation, liposuction, steroid injections, and injection of phosphatidylcholine and subcutaneous deoxycholate [11, 12, 13]. For complete eradication of a lipoma, surgical excision or liposuction are the most effective, but may result in scarring, seroma, and hematoma formation .
We report a second case of PPAR gamma agonist-induced lipomatosis, and review the relevant literature. In both cases, withdrawal of the PPAR gamma agonist was sufficient to at least partially treat the lipomas. We suggest that lipomatosis be considered a potential side effect of PPAR gamma agonists.
References1. Mafong DD, Lee GA, Yu S, Tien P, Mauro T, Grunfeld C. Development of multiple lipomas during treatment with rosiglitazone in a patient with HIV-associated lipoatrophy. AIDS. 2004 Aug 20;18(12):1742-1744. [PubMed]
2. Boyd AS. Thiazolidinediones in dermatology. Int J Dermatol. 2007 Jun;46(6):557-563. [PubMed]
3. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004 Sept 9;351(11):1106-1118. [PubMed]
4. Laplante M, Festuccia WT, Soucy G. Mechanisms of the depot specificity of peroxisome proliferator-activated receptor gamma action on adipose tissue metabolism. Diabetes. 2006 Oct; 55(10):2771-2778. [PubMed]
5. Ohsumi J, Sakakibara S, Yamaguchi J, Miyadai K, Yoshioka S, Fujiwara T, Horikoshi H, Serizawa N. Troglitazone prevents the inhibitory effects of inflammatory cytokines on insulin-induced adipocyte differentiation in 3T3-L1 cells. Endocrinology. 1994 Nov;135(5):2279-2282. [PubMed]
6. Nakamura T, Funahashi T, Yamashita S, Nishida M, Nishida Y, Takahashi M, Hotta K, Kuriyama H, Kihara S, Ohuchi N, Nishimura T, Kishino BI, Ishikawa K, Kawamoto T, Tokunaga K, Nakagawa C, Mineo I, Watanabe F, Tarui S, Matsuzawa Y. Thiazolidinedione derivative improves fat distribution and multiple risk factors in subjects with visceral fat accumulation - double-blind placebo-controlled trial. Diabetes Res Clin Pract. 2001 Dec;54(3):181-190. [PubMed]
7. Yao-Borengasser A, Rasouili N, Varma V, Miles LM, Phanavanh B, Starks TN, Phan J, Spencer HJ 3rd, McGehee RE Jr, Reue K, Kern PA. Lipin expression is attenuated in adipose tissue of insulin-resistant human subjects and increases with peroxisome proliferators-activated receptor gamma activation. Diabetes. 2006 Oct;55(10):2811-2818. [PubMed]
8. U.S. Food and Drug Administration [homepage on the Internet]. Maryland: Hage JE. [updated 2005 Aug 4; cited 2007 Sep 24]. Animal Toxicology Summary, Advisory committee briefing document: Preclinical pharmacology and toxicology summary. [12 page pdf document].
9. U.S. Food and Drug Administration [homepage on the Internet]. Maryland: The Administration. [2005 Sep 9; cited 2007 Sep 24]. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research: Endocrinologic and Metabolic Drugs Advisory Committee Volume II. [245 page pdf document]
10. Tannehill-Gregg SH, Sanderson TP, Minnema D, Voelker R, Ulland B, Cohen SM, Arnold LL, Schilling BE, Waites CR, Dominick MA. Rodent carcinogenicity profile of the antidiabetic dual PPAR alpha and gamma agonist muraglitazar. Toxicol Sci. 2007 Jul;98(1):258-270. [PubMed]
11. Salam GA. Lipoma excision. Am Fam Physician. 2002 Oct 15;65(5):901-904. [PubMed]
12. Hexsel D, Serra M, Mazzuco R, Dal’Forno T, Zechmeister D. Phosphatidylcholine in the treatment of localized fat. J Drugs Dermatol. 2003 Oct;2(5):511-518. [PubMed]
13. Rotunda AM, Ablon G, Kolodney MS. Lipomas treated with subcutaneous deoxycholate injections. J Am Acad Dermatol. 2005 Dec;53(6):973-978. [PubMed]
14. Tranquada RE. Subcutaneous lipomas at sites of insulin injection: report of a case. Diabetes. 1966 Nov;15(11): 807-809. [PubMed]
15. Garfinkel HA. A massive lipoma in a patient receiving chlorpropamide therapy. Postgrad Med J. 1971 Feb;47(544):137-138. [PubMed]
16. Burkhardt N, Hamann GF. Extradural lipomatosis after long-term treatment with steroids. Nervenarzt. 2006 Dec;77(12):1477-1479. [PubMed]
17. Roy-Camille R, Mazel C, Husson JL, Saillant G. Symptomatic spinal epidural lipomatosis induced by a long-term steroid treatment. Review of the literature and report of two additional cases. Spine. 1991 Dec;16(12):1365-1371. [PubMed]
18. Poulet FM, Berardi MR, Halliwell W, Hartman B, Auletta C, Bolte H. Development of hibernomas in rats dosed with phentolamine mesylate during the 24-month carcinogenicity study. Toxicol Pathol. 2004 Sep-Oct;32(5):558-566. [PubMed]
19. National Toxicology Program, Public Health Service, National Institutes of Health, US Department of Health and Human Services. Toxicology and carcinogenesis studies of o-nitrotoluene sulfone (CAS no. 88-72-2) in F344/N rats and B6C3F(1) mice (feed studies). Natl Toxicol Program Tech Rep Ser. 2002 May;(504):1-357. [PubMed]
20. Balestreire E, Haught JM, English JC 3rd. Multiple subcutaneous lipomas induced by HAART in the absence of protease inhibitors. Arch Dermatol. 2007;143(12):1596-1597. [PubMed]
21. Bornhovd E, Sakrauski AK, Bruhl H, Walli R, Plewig G, Röcken M. Multiple circumscribed subcutaneous lipomas associated with use of human immunodeficiency virus protease inhibitors. Br J Dermatol. 2000;143(5):1113-1114. [PubMed]
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