Cryolipolysis for Reduction of Excess Adipose Tissue C A F c U t o r t v V r a a m * † ‡ D D A 2 ryolipolysis for Reduction of Excess Adipose Tissue ndrew A. Nelson, MD,* Daniel Wasserman, MD,† and Mathew M. Avram, MD, JD‡ Controlled cold exposure has long been reported to be a cause of panniculitis in cases such as popsicle panniculitis. Cryolipolysis is a new technology that uses cold exposure, or energy extraction, to result in localized panniculitis and modulation of fat. Presently, the Zeltiq cryolipolysis device is FDA cleared for skin cooling, as well as various other indications, but not for lipolysis. There is, however, a pending premarket notification for noninvasive fat layer reduction. Initial animal and human studies have demonstrated significant reductions in the superficial fat layer thickness, ranging from 20% to 80%, following a single cryolipolysis treatment. The decrease in fat thickness occurs gradually over the first 3 months following treatment, and is most pronounced in patients with limited, discrete fat bulges. Erythema of the skin, bruising, and temporary numbness at the treatment site are commonly observed following treatment with the device, though these effects largely resolve in approximately 1 week. To date, there have been no reports of scarring, ulceration, or alterations in blood lipid or liver function profiles. Cryolipolysis is a new, noninvasive treatment option that may be of benefit in the treatment of excess adipose tissue. Semin Cutan Med Surg 28:244-249 © 2009 Elsevier Inc. All rights reserved. KEYWORDS cryolipolysis, Zeltiq, non-invasive, body contouring, fat removal, cold panniculitis e c r n q a t k o c a k a e p a n P T s f at treatment and removal is a worldwide, billion-dollar cosmetic industry, and liposuction remains the most ommon surgical cosmetic procedure performed in the nited States.1 Although liposuction is an effective therapeu- ic option for the removal of fat and can be safely performed n an outpatient basis, it remains an invasive procedure. In ecent years, there has been a dramatic trend toward effec- ive, noninvasive procedures. Unfortunately, current nonin- asive fat treatments such as Endermologie (LPG Systems, alence, France), radiofrequency treatment, and lasers have esulted in only modest clinical improvements in the appear- nce of fat and cellulite.2-8 There is, therefore, a great demand nd need for an effective, selective, and noninvasive treat- ent option for excess adipose tissue. Division of Dermatology, UCLA Medical Center, Los Angeles, CA. Total Skin and Beauty Dermatology Center, Birmingham, AL. Dermatology Laser and Cosmetic Center, Wellman Center of Photomedi- cine, Massachusetts General Hospital, Boston, MA. r. Avram has received research grants from Candela Corporation and is a stock holder in Zeltiq Aesthetics, Inc. r. Nelson and Dr. Wasserman have no conflicts to disclose. ddress reprint requests to Mathew M. Avram, MD, JD, Dermatology Laser and Cosmetic Center, Wellman Center of Photomedicine, Massachusetts General Hospital, 50 Staniford St, Suite 250, Boston, MA 02114. E-mail: nmavram@partners.org 44 1085-5629/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.sder.2009.11.004 Cryolipolysis is based on clinical observations that cold xposure, under the proper circumstances, can result in lo- alized panniculitis; this panniculitis ultimately results in the eduction and clearance of adipose tissue. Cold-induced pan- iculitis was initially described in infants, where it is fre- uently known as popsicle panniculitis.9,10 However, it has lso been observed in adult patients; for example, panniculi- is occurring after horseback riding in cold environments is nown as equestrian panniculitis.11 Exogenous application f cold, particularly with aggressive cryosurgery, is known to ause epidermal damage as well as damage to the underlying dipose tissue. Cryolipolysis attempts to use controlled fat cooling, also nown as energy extraction, to cause localized panniculitis nd fat reduction. By controlling and modulating the cold xposure, it could be possible to selectively damage the adi- ocytes, while avoiding damage to the overlying epidermis nd dermis. This would result in an effective, localized, and oninvasive treatment for excess adipose tissue. roposed Pathogenesis he exact pathogenesis by which cold results in adipose tis- ue removal is unknown. Case reports of infants suffering rom popsicle panniculitis and adults with equestrian pan- iculitis demonstrate that a perivascular inflammatory infil- mailto:mavram@partners.org t p i c l u r s l m o d p t o t c e b i c w p a c c i w a e a s b f T t u d o r f m t u t a s a i t d t t n C M c t a l t d a t i t o a P e v c p T c “ p b i c m d i l t t l f a d m 3 w b m s m n 3 t i w b f a a Cryolipolysis for reduction of excess adipose tissue 245 rate consisting of histiocytes and lymphocytes develops ap- roximately 24 hours after cold exposure. The inflammatory nfiltrate results in a lobular panniculitis. The inflammatory ells cause a rupture of the adipocytes, aggregation of the ipids, and the formation of small cystic spaces. This pannic- litis slowly resolves over the next several weeks, ultimately esulting in modulation of the fat without any persistent tis- ue damage or scarring. A similar mechanism of action has been proposed for cryo- ipolysis. In animal models, cold exposure results in inflam- ation, damage to the fat cells, and ultimately phagocytosis f the adipocytes.12 Immediately after the treatment, no fat amage is observed and the adipocytes are intact. Initial adi- ocyte damage is noted histologically at day 2, and increases hroughout the next month. It is believed that adipocyte ap- ptosis stimulates the initial inflammatory infiltrate, though he exact mechanism is not fully characterized; pig adipo- ytes in culture undergo apoptosis and necrosis following xposure to cool temperatures.13 At day 2 after treatment, pig iopsy samples demonstrate localized subcutaneous mixed nflammation, consisting of neutrophils and mononuclear ells, and the adipocytes remain unchanged. Over the next eek, the infiltrate becomes denser and an intense lobular anniculitis develops. The inflammation appears to peak at pproximately 14 days following treatment when the adipo- ytes are surrounded by histiocytes, neutrophils, lympho- ytes, and other mononuclear cells. During 14-30 days, the nflammatory infiltrate becomes more monocytic, consistent ith a phagocytic process. Macrophages begin to envelop nd digest the apoptotic adipocytes, thereby facilitating their limination from the body. As this process occurs, the aver- ge size of the adipocytes decrease, a wider range of adipocyte izes are observed, and the fibrous septae of the fat layer ecome widened. The actual elimination of the adipocytes rom the body occurs slowly over at least the next 90 days. he exact mechanism and pathway by which the phagocy- osed adipocytes are eliminated from the body are not fully nderstood at present. Ultimately, the lobules of fat cells ecrease in size, and the fibrous septae constitute a majority f the volume of the subcutaneous layer. Clinically, this cor- esponds to a decrease in the thickness of the subcutaneous at layer.12,14 These initial animal studies have helped to shape the likely echanism of cryolipolysis. However, it should be stressed hat the exact mechanism has not been fully elucidated. It is nclear why adipocytes are more sensitive to cold tempera- ure than other cell lines. It is also not fully established why dipocyte apoptosis occurs and how this leads to the ob- erved inflammatory infiltrate. Finally, once the adipocytes re phagocytosed and mobilized, the full mechanism of elim- nation is not well characterized. The adipocytes are thought o be mobilized via the lymphatic system, but it remains to be etermined how they are then eliminated or redistributed hroughout the body in response to cryolipolysis. As the echnology continues to be developed, future studies will eed to further investigate these issues. s linical Animal Studies anstein et al12 performed the initial exploratory studies of ryolipolysis in Yucatan pigs. In their article, they described he results of 3 different studies: an initial exploratory study, dosimetry study, and a study of treatment effect on serum ipid levels. The initial exploratory study used a cold copper applica- or, chilled by circulating antifreeze solution. The cooling evice was maintained at a constant temperature of �7°C, nd was applied to the Yucatan pig for times ranging from 5 o 21 minutes. The highest degree of clinical effect was noted n a treatment area on the buttock; 3.5 months after the single reatment, 80% of the superficial fat layer was removed (40% f total fat layer). Following the demonstration of efficacy with the copper pplicator, a prototype clinical device (Zeltiq Aesthetics Inc., leasanton, CA) was developed, which contained a thermo- lectric cooling element. This device allowed for the use of ariable, present plate temperatures during treatments; the old temperature was maintained at a constant level via tem- erature sensors imbedded within the treatment plates. reatments were performed with this device in either a “flat onfiguration” with a flat panel cooling the skin or in a folded configuration” in which the excess tissue was inched between 2 cooling panels, allowing for cooling on oth sides of the tissue. The tissue was exposed to cold rang- ng from 20°C to �7°C for 10 minutes. All sites treated with old exposure less than �1°C developed perivascular inflam- ation, panniculitis, and ultimately fat layer reduction. Fat amage was significantly greater at lower temperatures, and ncreased over time. In Manstein’s lipid study, no significant changes in the ipid profiles of the animals were noted immediately or at any ime point through 3 months post treatment. There was a emporary decrease in serum triglycerides immediately fol- owing the cold exposures, though this was attributed to asting before and during general anesthesia. A follow-up animal study was performed by Zelickson et l.14 In this study, 4 pigs were treated with the cryolipolysis evice. Three animals underwent a single cryolipolysis treat- ent, while the fourth pig underwent 7 treatments (90, 60, 0, 14, 7, and 3 days, as well as 30 min before euthanasia) ith the cryolipolysis device. About 25%-30% of the total ody surface of each animal was treated. Ultrasound assess- ents demonstrated a 33% reduction in the thickness of the uperficial fat layer following cryolipolysis. Pathologic speci- ens revealed an approximate reduction of 50% in the thick- ess of the superficial fat layer. Erythema lasting approximately 0 minutes developed in treatment areas. The skin became cool, hough not frozen, after treatment. There was no edema, bruis- ng, purpura, or scarring observed in the trial. Lipid panels ere performed for each animal at multiple time points; the aseline profile was after a 12 hour fast before treatment, with ollow-up lipid profiles performed 1 day, 1 week, and 1, 2, nd 3 months after treatment. There were no significant vari- tions in the lipid profiles of the animals throughout the tudy. w a e n c i t t H F ( d c t T e c t t i c 6 i t c t t m t Z o c i t e t c t l c h w s a m o p a o 2 t a b t a g p T g T t 246 A.A. Nelson, D. Wasserman, and M.M. Avram In the above animal studies, the cryolipolysis treatments ere well tolerated by the animals. Erythema of the treated reas was common. In the initial animal studies by Manstein t al,12 whitening, hardening, and freezing of the skin was oted in 30% of the treated areas. Superficial epidermal ne- rosis was observed in some of the frozen areas, with result- ng transient hypopigmentation following re-epithelializa- ion. However, no scarring or ulceration was noted in any of he animal studies. uman Clinical Studies ollowing the promising animal studies, the Zeltiq System Zeltiq Aesthetics Inc, Pleasanton, CA) was developed. This evice consists of a control console, with a treatment appli- ator attached by a cable. A thermal coupling gel is placed on he area to be treated, and the applicator is then applied. issue is drawn into the cup-shaped applicator with a mod- rate vacuum to optimally positioning the tissue between 2 ooling panels; this allows for more efficient cooling of the issue. A cooling intensity factor (CIF) is then selected by he treating clinician. The CIF is an index value represent- ng the rate of heat flux into or out of tissue opposite the ooling device. Treatment with the cold exposure for up to 0 minutes then begins. The energy extraction rate, or cool- ng, is controlled by sensors that monitor the heat flux out of he treated areas and is modulated by thermoelectric cooling ells. Following completion of the treatment, the system au- omatically stops the cold exposure and the clinician releases he vacuum. Depending on the surface area to be treated, ultiple applications may be necessary to effectively expose he entire area to cryolipolysis. It is important to note that the eltiq device is presently FDA cleared for skin cooling and Figure 1 A representative example of clinical improve reduction of the flanks (ie, love handles). The patient’s le control. The top pictures show the baseline, while the bo after treatment. The patient’s weight on the baseline an obtained and used with permission of Flor Mayoral, MD.15 ther various indications. However, the Zeltiq device is not urrently FDA cleared for lipolysis, although there is a pend- ng premarket notification for noninvasive fat layer reduc- ion. A multicenter, prospective, nonrandomized clinical study valuating the use of cryolipolysis for fat layer reduction of he flanks (ie, love handles) and back (ie, back fat pads) was onducted at 12 sites.15 Patients underwent cryolipolysis reatment to 1 area, while a symmetric, contralateral area was eft untreated to serve as a control for observing clinical effi- acy. An interim subgroup analysis of all patients in the “love andle” group, 32 patients, was performed. Clinical efficacy as determined at 4 months post-treatment using visual as- essment with digital photography, physician assessment, nd subject satisfaction. Most patients had a clinical improve- ent with a visible contour change, as assessed by physician bservation and digital photography (Fig. 1). A subset of 10 atients underwent pre- and post-treatment ultrasound im- ging. Of these 10 patients, all had a decrease in the thickness f their fat layer, with an average reduction in thickness of 2.4%. Importantly, regardless of the assessment protocol, he best cosmetic results were achieved in those patients with modest, discrete fat bulge. The treatment was well tolerated y patients with no adverse events related to the device or reatment. Kaminer et al,16 demonstrated that cryolipolysis results in visible cosmetic improvement in the flank/love handle re- ion. A blinded comparison of preprocedure and 6 month ostprocedure photographs was performed on 50 subjects. hree physicians specializing in dermatology, cosmetic sur- ery, or plastic surgery performed the photographic review. he physicians were able to accurately differentiate between he pre- and post-photographs in 89% of the cases. When the ollowing 1 treatment with cryolipolysis for fat layer was treated, while the right side served as an untreated ictures demonstrate the clinical improvement 4 months nth follow-up day remained unchanged. This figure is ment f ft side ttom p d 4 mo e t c T c s o i e i c m c d p l a f i t c p i b a f a S A w I t o c e a a c r s t C fl i u l s i d s r f h n t Cryolipolysis for reduction of excess adipose tissue 247 valuation was limited to those subjects who maintained heir original weight, �5 lb after the procedure, the physi- ians were able to accurately differentiate 92% of the cases. his study demonstrates that the improvement following ryolipolysis treatment is clinically apparent on visual in- pection, further documenting the usefulness of this technol- gy. A feasibility study of using cryolipolysis to reduce abdom- nal fat is currently ongoing.17 A total of 42 subjects were nrolled in this study. Symmetric abdominal fat bulges, typ- cally to the left and right of the umbilicus, were treated with ryolipolysis. An interim analysis of the subjects’ self-assess- ents indicated that 79% (31 of 39) subjects reported clini- al improvement within the first 2-4 months after the proce- ure (Fig. 2). Further clinical end points, including blinded hysician assessments and ultrasound measurements of fat ayer thickness, have not been reported as of yet. The interim nalysis appears to support that cryolipolysis may be effective or noninvasive contouring of abdominal fat and body sculpt- ng. Cryolipolysis seems to be an effective treatment option for he reduction of excess adipose tissue, as shown in these linical studies. It is important to note that the clinical im- rovements were most pronounced in patients with local- zed, discrete fat bulges. The technology does not appear to e as effective in patients with significant skin laxity or who re obese. Thus, cryolipolysis is an effective treatment option or the reduction of fat, particularly when the proper patients re selected for treatment. Figure 2 A representative example of clinical improve reduction of the abdomen. The patient underwent a s application to the right and 1 application to the left side surface area. The top pictures show the baseline, while months after treatment. The patient’s weight at the 4 m day. This figure is obtained and used with permission of Ivan afety Profile s with any new technology, it is important to establish hether the device results in any significant adverse events. n the previous clinical studies, the device has been well olerated by the subjects. Patients typically develop erythema f the treatment area, lasting up to a few hours following ryolipolysis. As the device uses a vacuum to increase clinical fficacy, patients may also develop bruising of the treatment rea, which may last approximately 1 week. The treated skin lso becomes cold and firm following cryolipolysis. In all linical studies to date, no ulceration or scarring has been eported. Cryolipolysis has been reported by human subjects to re- ult in a temporary dulling of sensation and numbness in reated areas. To better characterize this phenomenon, oleman et al18 performed cryolipolysis on 10 subjects with ank fat bulges. Following cryolipolysis, a 20.4% reduction n the thickness of the fat layer was observed, as assessed by ltrasound. Thus, the patients had achieved an effective cryo- ipolysis treatment. These subjects underwent neurologic as- essment by a board-certified neurologist during the study, ncluding light touch evaluated with a soft tissue, two-point iscrimination, temperature sensitivity (cold temperature ense), and pain sensitivity (assessed with a pinprick). Neu- ologic assessments were performed at baseline and weekly ollowing treatment. One subject underwent skin biopsy for istologic analysis of nerve-fibers. Patients reported numb- ess in 24 of the 25 treated sites (96% of treated sites), hough by 1 week following treatment the numbness had ollowing 1 treatment with cryolipolysis for fat layer reatment with cryolipolysis, though 2 applications (1 required to treat the entire abdomen due to the larger ttom pictures demonstrate the clinical improvement 4 llow-up day had increased by 3.5 lb from the baseline ment f ingle t ) were the bo onth fo Rosales-Berber, MD. l p a t w t w l s m b d t i p d t l l Z i n f 4 h o b w o l s b n m d i f 9 a t i l d c o p t f i b d o I i c s t w D C c i a s a t a p a o m t s o o h t f e a i p e u o t s l i h w p s t m o f s a f i s c f a t t i 248 A.A. Nelson, D. Wasserman, and M.M. Avram argely resolved. Transient reductions in sensation were re- orted in 6 of 9 patients (67%), most commonly manifested s reductions in pain sensitivity. However, reductions in light ouch, 2 point discrimination, and temperature sensitivity ere also reported by a minority of patients. These reduc- ions in neurologic sensation lasted between 1 and 6 weeks, ith a mean duration of 3.6 weeks. All reductions in neuro- ogic sensation had resolved by 2 months after the cryolipoly- is treatment. No changes were noted in the nerve biopsy 3 onths after the cryolipolysis compared with the baseline iopsy. These results indicate that cryolipolysis results in a ecrease in sensation of treated areas, but this altered sensa- ion is transient and appears to resolve without any further ntervention. As previously discussed, the exact mechanism of cryoli- olysis is not well understood. It is possible that as the fat is estroyed and phagocytosed, the fat could be released into he blood. Many of the clinical studies have therefore ana- yzed the patient’s lipid profiles and liver function tests fol- owing cryolipolysis. In the animal studies by Manstein and elickson, no significant changes in the lipid profiles follow- ng cryolipolysis were observed. In all human studies to date, o clinically significant alterations in lipid profiles or liver unction tests have been observed. Klein et al,19 reported on 0 patients with bilateral fat bulges on their flanks (ie, love andles) treated with cryolipolysis. The patients were treated n 1 or 2 sites on each flank, depending on the size of the fat ulge, to a maximum of 4 treatment applications. Patients ere treated at a CIF of 42 for 30 minutes. Lipid values were btained, including triglycerides; total cholesterol; and very- ow-density lipoprotein, low-density lipoprotein, and high-den- ity lipoprotein (HDL) cholesterol. Additionally, liver-related lood tests, including: aspartate aminotransferase, alanine ami- otransferase, alkaline phosphatase, total bilirubin, and albu- in were obtained before treatment. Follow-up values were etermined 1, 4, 8, and 12 weeks after treatment. Triglycer- de values were noted to increase slightly in the 12 weeks ollowing cryolipolysis, from a mean of 82.1 to a mean of 3.2; this increase was not statistically significant (P � 0.22) nd the mean value remained well below the upper limit of he reference range. There was, however, a statistically signif- cant decrease in HDL cholesterol in the first few weeks fol- owing cryolipolysis (P � 0.0296), though the HDL values id return to baseline by 12 weeks. No statistically significant hanges from baseline for any of the liver function tests were bserved following cryolipolysis. These initial safety reports support that the Zeltiq cryoli- olysis device results in a significant reduction in fat layer hickness with no significant adverse events. During the in- ormed consent process before cryolipolysis treatment, it is mportant to emphasize known risks including erythema, ruising, and temporary altered sensation. To date, there oes not appear to be significant risk of altered lipid profiles r liver function tests associated with cryolipolysis treatment. t remains to be determined whether patients with rare, cold- nduced dermatologic conditions, such as cryoglobulinemia, old urticaria, or paroxysmal cold hemoglobinuria, can be afely treated with cryolipolysis. Patients with a known his- n ory of cold-induced disease should probably not be treated ith the cryolipolysis device until further data are available. iscussion ryolipolysis is a novel procedure, which uses controlled old exposure, known as energy extraction, to produce non- nvasive, effective, and selective damage to adipocytes. In nimal and human clinical studies, cryolipolysis has been hown to result in significant improvement in the clinical ppearance of fat. Additionally, reductions in the thickness of he subcutaneous fat layer of up to 50% can occur following single cryolipolysis treatment. Clinical studies have shown otential efficacy in the treatment of excess back fat, flank fat, nd abdominal fat; the potential efficacy of cryolipolysis in ther treatment areas and for the treatment of cellulite re- ains to be determined. In these initial studies, cryolipolysis reatments have been well tolerated by patients with tran- ient, mild adverse events such as erythema and bruising ccurring in treated patients. No cases of ulceration, scarring, r significant changes in lipid profiles and liver function tests ave been reported following cryolipolysis. Cryolipolysis herefore appears to be a safe and effective treatment option or reduction of excess adipose tissue. The exact mechanism of cryolipolysis remains to be fully lucidated. It has been shown that cold exposure results in poptosis of the adipocytes, followed by an inflammatory nfiltrate. Ultimately, the inflammatory infiltrate results in hagocytosis and mobilization of the treated adipocytes. The xact mechanism and pathway for this fat elimination are nclear. No significant alterations in blood lipid profiles, ther than transient decreases in HDL values, or liver func- ion tests have been observed following cryolipolysis. Further tudies to determine the exact mechanism of action for cryo- ipolysis remains an active area of research. Although cryolipolysis is a promising new technology, it is mportant to bear in mind a few potential limitations. In the uman clinical studies, results were most visible in patients ith discrete, localized fat bulges. Cryolipolysis does not ap- ear to be as effective in obese patients or patients with excess kin laxity. It is unclear whether the device itself is less effec- ive in these patients, or whether the potential improve- ent associated with cryolipolysis treatment is harder to bserve in these patients. Additionally, the improvement ollowing cryolipolysis is not immediate, but rather occurs lowly over the course of 2-3 months. Finally, the currently vailable data seem to support that cryolipolysis is most ef- ective for localized, discrete fat bulges. Thus, patients seek- ng large scale fat removal, which can be achieved with lipo- uction, may not achieve their desired outcomes with ryolipolysis. It is therefore important for physicians to care- ully select potential cryolipolysis treatment patients, as well s educate them regarding their expected outcomes and po- ential limitations. Cryolipolysis is a new, selective, effective, and noninvasive reatment option for excess adipose tissue. While the device s currently FDA cleared only for skin cooling, a premarket otification application for lipolysis is pending. The device is p n a c e i m R 1 1 1 1 1 1 1 1 1 1 Cryolipolysis for reduction of excess adipose tissue 249 articularly appealing given that it is noninvasive, requires ot much or no downtime for patients following treatment, nd does not require local or regional anesthesia. Ongoing linical studies will help to determine the full potential and fficacy of this device. Cryolipolysis appears to be a promis- ng new technology for safe, effective, and noninvasive treat- ent of fat. eferences 1. American Society for Aesthetic Plastic Surgery Annual Statistics. Available at: http://www.cosmeticplasticsurgerystatistics.com/statistics. html#2007-NEWS. Accessed November 15, 2009 2. Gulec AT: Treatment of cellulite with LPG endermologie. Int J Derma- tol 48:265-270, 2009 3. Moreno-Moraga J, Valero-Altés T, Riquelme AM, et al: Body contouring by non-invasive transdermal focused ultrasound. Lasers Surg Med 39: 315-323, 2007 4. Goldberg DJ, Fazeli A, Berlin AL: Clinical, laboratory, and MRI analysis of cellulite treatment with a unipolar radiofrequency device. Dermatol Surg 34:204-209, 2008 5. Trelles MA, van der Lugt C, Mordon S, et al: Histological findings in adipocytes when cellulite is treated with a variable-emission radiofre- quency system. 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Rosales-Berber IA, Diliz-Perez E: Controlled cooling of subcutaneous fat for body reshaping. Presented at the 15th World Congress of the International Confederation for Plastic, Reconstructive and Aesthetic Surgery, 2009, New Delhi, India 8. Coleman SR, Sachdeva K, Egbert BM, et al: Clinical efficacy of nonin- vasive cryolipolysis and its effects on peripheral nerves. Aesthet Plast Surg 33:482-488, 2009 9. Klein K, Zelickson B, Riopelle J, et al: Non-invasive cryolipolysis for subcutaneous fat reduction does not affect serum lipid levels or liver function tests. Lasers Surg Med (in press) http://www.cosmeticplasticsurgerystatistics.com/statistics.html http://www.cosmeticplasticsurgerystatistics.com/statistics.html Cryolipolysis for Reduction of Excess Adipose Tissue Proposed Pathogenesis Clinical Animal Studies Human Clinical Studies Safety Profile Discussion References