|Year : 2019 | Volume
| Issue : 4 | Page : 165-169
Saad Sami AlSogair
Department of Dermatology, Consultant Dermatologist, Elite Derma Care Clinic, Dr. Layla Al-Onaizi Polyclinic, Khobar, Saudi Arabia
|Date of Submission||10-Feb-2019|
|Date of Acceptance||05-Mar-2019|
|Date of Web Publication||11-Nov-2019|
Saad Sami AlSogair
Elite Derma Care Clinic, Dr. Layla Al-Onaizi Polyclinic, Khobar 31952
Source of Support: None, Conflict of Interest: None
Cold-based therapies have been used in the skin in the past due to its minimal damage of skin tissues. Cryolipolysis is a type of non-invasive body contouring technology that makes use of the ability of cold applications to create an inflammatory reaction within adipose tissues which may later on lead to apoptotic adipocyte cell death. Human and animal studies have revealed that cryolipolysis can significantly decrease subcutaneous fat and change body contour without causing damage to the overlying skin and surrounding structures or deleterious changes in blood lipids. Cryolipolysis has been described as a safe and effective procedure by previous studies. A thorough medical history and physical examination is done before the performance of this method to ensure its optimal efficacy. This method can either be used alone or in combination with other treatments such as shock wave treatment. More studies should be done to investigate further how cryolipolysis leads to adipocyte apoptosis so that new methods may be discovered that may enhance subcutaneous fat reduction.
Keywords: Apoptotic adipocyte cell death, blood lipids, cryolipolysis, non-invasive body contouring
|How to cite this article:|
AlSogair SS. Cryotherapy-induced lipolysis. Hamdan Med J 2019;12:165-9
| Introduction|| |
Excess fat in the body has negative consequences. Not only does it affect physical appearance and self-esteem but also it makes a person prone to various life-threatening health problems such as hypertension, diabetes, atherosclerosis, heart disease and stroke. Excess fat can decrease a person's life span and can lower quality of life over the years. This is why numerous methods have been developed to manage fat in a non-invasive way and to contour the body.
Non-invasive body contouring technology is said to be the fastest growing segment of aesthetic medicine. These technologies are in the form of suction or massage devices, thermal devices, radiofrequency energy devices, high-frequency focused ultrasound energy devices, low-level light laser therapy devices and cryolipolysis energy devices. Among these techniques, cryolipolysis is one of the most novel methods that use cold exposure to reduce subcutaneous fat.
This review aims to discuss the origins of cryolipolysis as well as its safety and efficacy in subcutaneous fat reduction.
| History of Cryolipolysis|| |
Cryolipolysis is a technique adapted from the older method cryotherapy, a method which has been used in dermatology since the ancient times. Cold-based therapies have been used in the skin in the past due to its minimal damage of skin tissues. Cryotherapy has been employed in the destruction of superficial skin tumours, verrucae, actinic keratoses and other skin lesions. In 1902, Hoschinger reported on the sensitivity of adipose tissue to cold injury by observing an acute freezing reaction on firm nodules under the chin in young children. It was then in 1941 that Haxthausen published a case series of 4 young children and a teenager who had developed what he termed 'adiponecrosis e frigore' or lesions that occur after exposure to cold. These lesions are created by cold-induced panniculitis and appear as red indurated nodules with transient fat necrosis after exposure to cold. These findings have led experts to believe that fatty tissues are more susceptible to cold injury than other tissues. These results also conform to the fact that saturated fats are more solid at room temperature while less saturated fats are more liquid at room temperature. The colder it gets, the more solid saturated fats are.
Thus, the method of cryolipolysis became widely known afterwards. This method makes use of the ability of cold applications to create an inflammatory reaction within adipose tissues which may later on lead to apoptotic adipocyte cell death. The cold stimulus applied is above the freezing point but below body temperature. Manstein et al. have previously performed cryolipolysis experiments in pigs using a copper plate that was cooled and regulated to −7°C by an attached heat exchanger chamber. This plate was then applied to multiple sites in animals for about 5–21 min. The pigs were then observed after 3½ months. There were no significant skin changed observed; however, there was selective fat absorption in the treatment sites as evidenced by contour indentations. There was also an observed 40% reduction in fat thickness and a reduction in distance between fat septae on histological examination. This study has further led to human applications later. The device was further developed into that consisting of a control console and an umbilical cable connecting the cooling applicator cup or paddles to the console. This device is to be applied on sites such as lower abdominal tissues or love handles so that mild suctioning can be done for about 30–60 min.
In 2010, a cryolipolytic device (CoolSculpting ®; ZELTIQ Aesthetics, Inc., Pleasanton, CA, USA) was given Food and Drug Administration (FDA) clearance for reduction of flank and abdominal fat. Later in 2014, it received clearance for the treatment of subcutaneous fat in the thighs. This particular device is made up of a cup-shaped applicator with two cooling panels that is applied to the treatment area. Under moderate vacuum, tissue is drawn into the handpiece and the temperature is regulated by thermoelectric elements and controlled by sensors that monitor the heat flux out of the tissue. The area should be treated for 45 min, and massage should be done for 2 min after each therapy to maximise effects. The patient is then discharged after treatment. The number of treatment cycles depends on the area being treated. While flanks require only one treatment session, the back and the inner and outer thighs require more than two treatment cycles. Treatment cycles are spaced 8 weeks apart from each other.
| Mechanism of Action|| |
The exact way by which cold stimuli removes fat in tissues is quite unknown; however, earlier studies have described that the responsible mechanism would be the development of a perivascular inflammatory infiltrate consisting of histiocytes and lymphocytes about 24 h after cold exposure. The infiltrate further results into a lobular panniculitis and further leads to rupture of the adipocytes aggregation of the lipids and the formation of small cystic spaces. This gradually resolves over the next few weeks further leading to reduction of fat with no tissue damage or scarring.
In animal studies, there was observed inflammation and damage to fat cells with phagocytosis of the adipocytes. After treatment, there may be no fat damage observed; however, adipocyte damage may be evident after 2 days until the next month. Adipocyte apoptosis is said to stimulate the inflammatory infiltrate consisting of neutrophils and mononuclear cells. This infiltrate later on becomes denser as panniculitis develops. Inflammation appears within 14 days following treatment wherein adipocytes are surrounded by lymphocytes, neutrophils, histiocytes and other mononuclear cells. The macrophages envelope and take in adipocytes that have undergone apoptosis, making the adipocytes decrease in size, and widening the fibrous septae of the fat layer. All these occur within the next 90 days and thus further explain the mechanism behind cryolipolysis. Apoptosis may be due to possible cold-induced reperfusion injury of temperature-sensitive adipocytes, resulting in free radical damage, oxidative stress and subsequent cell death.
Zelickson et al. in 2009 determined whether cryolipolysis can selectively damage subcutaneous fat without causing damage to the overlying skin or rise in lipid levels. In their study, three Yucatan pigs underwent cryolipolysis at 22 sites: 20 at cooling intensity factor (CIF) index 24.5 (43.8 mW/cm 2), one at CIF 24.9 (44.7 mW/cm 2) and one at CIF 25.4 (45.6 mW/cm 2). The result revealed that there was a significant reduction in the superficial fat layer without damage to the overlying skin. An inflammatory response triggered by cold-induced apoptosis of adipocytes preceded the reduction in the fat layer. Evaluation of lipids over a 3-month period following treatment demonstrated that cholesterol and triglyceride values remained normal. Thus, it was noted by the researchers that cryolipolysis can significantly decrease subcutaneous fat and changes body contour without causing damage to the overlying skin and surrounding structures or deleterious changes in blood lipids.
Avram et al. has described in detail the changes in the subcutaneous fat and in the adipocytes after cryolipolysis. They noted that immediately after treatment, there are no discernible changes in the subcutaneous fat without the presence of inflammatory cells and with intact cell membranes. Within 3 days after treatment, the inflammatory process brought about by apoptosis of adipocyte begins and peaks at about 14 days after treatment, during which the adipocytes are surrounded by histiocytes, neutrophils, lymphocytes and other mononuclear cells. Within 14–30 days, there is phagocytosis of fat as macrophages and other phagocytes surround, envelope and digest the contents of dead adipocytes as a natural response of the body to injury. After 30 days, there may be a decrease in the inflammatory response with remarkable thickening of the interlobular septae and a decrease in fat cell volume. This decrease in inflammation further continued up to 90 days; the resorption of digested adipocytes took place with the displacement of lipids. There is also a clear reduction in fat layer thickness. Further studies are needed to ascertain the cause of the apoptotic injury of adipocytes.
| Pre-Clinical and Clinical Studies|| |
One pilot pre-clinical study sought to determine the effects of cryolipolysis on fat using a single Yucatan pig exposed to a copper plate cooled to 7°C with circulating antifreeze solution. Firm pressure was used to ensure contact as well as to decrease perfusion, facilitating a more rapid rate of cooling. After 3 months, all 10 sites demonstrated visible indentation with a measurable decrease in superficial fat layer thickness. The conclusions were further confirmed by a subsequent study with 3 swine which revealed a 30% reduction in the thickness of the superficial fat layer in the treatment area, as measured by ultrasonography. There was decreased occurence of transient hyperpigmentation in these two studies, which further resolved within 1 week. There were neither ulcerations nor hypopigmentations that were noted, nor were significant changes in serum lipids or liver function observed.
There were also in vitro studies on adipocyte cell cultures which have showed that, indeed, cold-induced adipocyte apoptosis was responsible for cryolipolysis effects. Some studies have also implicated reperfusion injury of cryosensitised adipocytes, leading to inflammation, generation of reactive oxygen species and cell death.
Manstein et al. was the first to perform initial exploratory studies of cryolipolysis in Yucatan pigs. In their article, they described the results of 3 different studies: an initial exploratory study, a dosimetry study and a study of treatment effect on serum lipid levels. The initial exploratory study used a cold copper applicator, chilled by circulating antifreeze solution. The cooling device was maintained at a constant temperature of 7°C and was applied to the Yucatan pig for times ranging from 5 to 21 min. The highest degree of clinical effect was noted in a treatment area on the buttock; 3.5 months after the single treatment, 80% of the superficial fat layer was removed (40% of total fat layer).
A follow-up animal study was then performed by Zelickson et al. In this study, 4 pigs were treated with the cryolipolysis device. About 25%–30% of the total body surface of each animal was treated. Ultrasound assessments demonstrated a 33% reduction in the thickness of the superficial fat layer following cryolipolysis. Pathologic specimens revealed an approximate reduction of 50% in the thickness of the superficial fat layer. Erythema lasting approximately 30 min developed in treatment areas. The skin became cool, though not frozen, after treatment. There was no oedema, bruising, purpura or scarring observed in the trial. There were no significant variations in the lipid profiles of the animals throughout the study. In the above animal studies, the cryolipolysis treatments were well tolerated by the animals.
Clinical studies have also confirmed the efficacy of cryolipolysis for improvement in localised adiposity according to Jalian et al. in 2013. These clinical studies have also demonstrated improvement in adiposity of the flanks, so-called 'love handles', in 32 individuals. There was both subjective and objective improvement in adiposities. Ten individuals who underwent ultrasonography examination demonstrated a 22.4% average reduction of fat-layer thickness. A subsequent larger prospective study of 50 individuals confirmed this subjective improvement. All these data were made basis by FDA clearance for cryolipolysis to be applied on non-invasive fat removal in the flanks. Later in 2012, cryolipolysis gained FDA clearance for use on the abdomen.
Stevens et al. in 2013 made a retrospective chart review on 528 consecutive patients who underwent cryolipolysis treatment (performed by L. K. P.) from January 2010 to December 2012. Over the study period, 1785 anatomic sites were treated with 2729 cycles. (Multiple cycles were often delivered to the same treatment site.) Treatments were delivered primarily to the lower abdomen (28%, n = 490), upper abdomen (11%, n = 189), left flank (19%, n = 333), right flank (19%, n = 333), inner thigh (6%, n = 111), outer thigh (5%, n = 87) and back (6%, n = 99). The commercially available applicators used in the study period were the CoolCurve (eZ App 6.2), CoolCore (eZ App 6.3) and CoolMax (eZ App 8.0). The review found that the typical side effects of cryolipolysis procedures reported in clinical studies include erythema, oedema, bruising and transient neuralgia. These were typically reported to resolve spontaneously within 2-week post-treatment.
| Candidates|| |
Patient selection is important in any procedure. This is why a thorough medical history and physical examination are done before any procedure. Areas with focal adiposity should be lifted from the underlying musculature and examined. There should be a sufficient fat layer; otherwise, the device may not attach correctly with the vacuum applicator. Patients with hernias should be excluded, as there may be a potential for hernia incarceration with the vacuum suctioning in these patients. Contraindications for this procedure include cold-sensitive disorders, including Raynaud's phenomenon, cold urticaria, cryoglobulinemia and paroxysmal nocturnal haemoglobinuria. Caution should also be exercised in those with known neurologic disease (for example, multiple sclerosis) since there are temporary neurologic effects.
Good candidates for cryolipolysis are those within their ideal weight range and those who engage in regular exercise, eat a healthy diet, have noticeable fat bulges on the trunk, are realistic in their expectations and are willing to maintain the results of cryolipolysis with a healthy, active lifestyle.
| Safety and Adverse Effects|| |
Immediately after treatment, there may be oedema and erythema which may persist for up to 72 h. There may also be ecchymosis secondary to the vacuum applicator, especially in those who are on anticoagulation medications. There may also be a decreased cutaneous sensation, which is common yet transient. There may also be dysthesia which may be transient, only lasting for a week. However, in very few patients, this decrease in sensation may continue up to 2 months. There were no reports of permanent sensory alteration after cryolipolysis treatment. There were also no reports of significant changes in triglyceride levels or liver function tests in humans after treatment. Rarely, there may be severe pain after treatments which may be shooting and stabbing in character and may last for about a week. This may be controlled by oral or topical analgesics and may resolve spontaneously within 1–4 weeks.
Coleman et al. in 2009 have studied the clinical efficacy of non-invasive cryolipolysis and its effects on peripheral nerves. In their study, 10 individuals were treated with a prototype cooling device. Cryolipolysis resulted to a normalised fat layer reduction of 20.4% at 2 months and 25.5% at 6 months after treatment. Transient reduction in sensation occurred in six of nine individuals assessed by neurologic evaluation. However, all sensation returned by a mean of 3.6 weeks after treatment. Biopsies showed no long-term change in nerve fibre structure. There were no lasting sensory alterations or observations of skin damage in any of the individuals evaluated. These side effects were all modest reversible short-term changes in the function of peripheral sensory nerves.
Klein et al. in 2009 studied whether cryolipolysis affects serum lipid levels or liver function tests. Forty individuals with fat bulges on their flanks ('love handles') were treated bilaterally with a non-invasive device (Zeltiq Aesthetics, Pleasanton, CA) that precisely cools tissue to achieve a reduction in the fat layer. Serum lipid levels and liver function test results were measured before treatment and at 1 day and 1, 4, 8 and 12 weeks' post-treatment. There were no meaningful changes in mean values for any blood lipid level or liver test at any point over the 12-week follow-up period.
Brightman et al. hypothesised that a second treatment given before completion of apoptosis of cells could lead to greater inflammatory response and a greater reduction in fat over the long term. Greater reduction in fat is also dependent on other factors such as appropriate patient selection, reasonable expectations and technique. Appropriate candidates for this technique are those who are generally fit with localised and persistent fat pockets which cannot be reduced by diet and exercise. This procedure is not fit for people who want to reduce large volumes of fat and who have visceral fat.
Cryolipolysis has been described as a safe and effective procedure by previous studies. Animal models were able to prove a reduction of up to 1 cm or 40% of the total fat layer thickness after a single exposure without harming the overlying skin. A study by Manstein et al. has demonstrated changes such as lipid-laden mononuclear inflammatory cells and local thickening of fibrous septae at 2-week post-procedure. In another study in 2009 described by Nils et al., ten individuals reported a 20.4% and 25.5% reduction in the fat layer 2 months and 6 months after treatment, respectively. One retrospective multicenter study has reported that 86% of 518 individuals showed improvement after cryolipolysis. The body sites at which cryolipolysis were most effective were the abdomen, back and flank. Patients completed a satisfaction questionnaire, with 73% reporting being satisfied and 82% being prepared to recommend cryolipolysis to a friend. The majority described minimal to tolerable discomfort during the procedure. Another study by Garibyan et al. used a three-dimensional camera to evaluate the amount of fat loss after cryolipolysis. Mean fat loss between baseline and the 2-month follow-up visit was 56.2 ± 25.6 cc on the treated side and 16.6 ± 17.6 cc on the control side. Two-month post-treatment, the mean difference in fat loss between the treated and untreated sides was 39.6 cc. In another study by Ferraro et al., cryolipolysis was combined with acoustic waves to achieve possible synergistic effects. These authors reported significant reductions of up to 6.7 cm in circumference and up to 4.5 cm in thickness of the fat layer 12 weeks after 3–4 treatments.
Nils et al. also noted that several publications including two systematic literature reviews have failed to identify any significant adverse events that could be attributed to cryolipolysis, including scarring, ulceration or disfigurement. Although cold temperatures are known to induce subcutaneous panniculitis, no cases of nodule formation have been reported.
Nelson et al. remarked in 2009 that, in previous clinical studies, the device has been well tolerated by the individuals. In all clinical studies to date, no ulceration or scarring has been reported. In all human studies to date, no clinically significant alterations in lipid profiles or liver function tests have been observed. Klein et al. reported on 40 patients with bilateral fat bulges on their flanks (i.e., love handles) treated with cryolipolysis. The patients were treated on 1 or 2 sites on each flank, depending on the size of the fat bulge, to a maximum of 4 treatment applications. No statistically significant changes from baseline for any of the cholesterol and triglyceride tests as well as the liver function tests were observed following cryolipolysis.
A study by Dierickx et al. in 2013 investigated the clinical outcomes of cryolipolysis in European individuals. This was a retrospective study performed at clinical sites in Belgium and France and evaluated safety, tolerance and patient satisfaction. A total of 518 patients were studied. No significant side effects or adverse events were reported. The procedure was well-tolerated, with 89% of respondents reporting a positive perception of treatment duration and 96% reporting minimal to tolerable discomfort. Survey results demonstrated 73% patient satisfaction, and 82% of patients would recommend the cryolipolysis procedure to a friend. Caliper measurements demonstrated 23% reduction in fat layer thickness at 3 months. Abdomen, back and flank treatment sites were most effective, with 86% of individuals showing improvement per investigator assessment. The authors concluded that cryolipolysis is a safe, well-tolerated and effective treatment method for reduction of subcutaneous fat.
| Concomitant Treatments|| |
Ferraro et al. in 2012 studied the effects of a combination of acoustic wave treatment and cryolipolysis in subcutaneous fat reduction. This method is known as ice-shock lipolysis and is a new non-invasive procedure for reducing subcutaneous fat volume and fibrous cellulite in areas that normally would be treated by liposuction. Shock waves have been previously used in the treatment of renal calculi and musculoskeletal disorders and are focused on the collagen structure of cellulite-afflicted skin. The combination of the two procedures causes the programmed death and slow resorption of destroyed adipocytes. In this study, 50 patients with localised fat and cellulite were treated with a selective protocol for the simultaneous use of two transducers: A Freezing Probe for localised fatty tissue and a Shock Probe for fibrous cellulite. The procedure significantly reduced the circumference in the treated areas, significantly diminishing fat thickness. The mean reduction in fat thickness after treatments was 3.02 cm. Circumference was reduced by a mean of 4.45 cm. Weight was unchanged during the treatment, and no adverse effects were observed. Histologic and immunohistochemical analysis confirmed a gradual reduction of fat tissue by programmed cell death. Moreover, the reduction in fat thickness was accompanied by a significant improvement in microcirculation, and thus, the cellulite. The safety of the method also has been highlighted because it is accompanied by no significant increase in serum liver enzymes or serum lipids.
| Conclusion|| |
Cryolipolysis, a method which makes use of the ability of cold applications to create an inflammatory reaction within adipose tissues which later on leads to apoptotic adipocyte cell death, is a safe and effective procedure for the reduction of subcutaneous fat. Proper patient selection is needed for it to be more effective. This method can either be used alone or in combination with other treatments such as shock wave treatment. More studies should be done to investigate further how cryolipolysis leads to adipocyte apoptosis so that new methods may be discovered that may enhance subcutaneous fat reduction.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Mulholland RS, Paul MD, Chalfoun C. Noninvasive body contouring with radiofrequency, ultrasound, cryolipolysis, and low-level laser therapy. Clin Plast Surg 2011;38:503-20, vii-iii.
Jalian HR, Avram MM. Cryolipolysis: A historical perspective and current clinical practice. Semin Cutan Med Surg 2013;32:31-4.
Krueger N, Mai SV, Luebberding S, Sadick NS. Cryolipolysis for noninvasive body contouring: Clinical efficacy and patient satisfaction. Clin Cosmet Investig Dermatol 2014;7:201-5.
Nelson AA, Wasserman D, Avram MM. Cryolipolysis for reduction of excess adipose tissue. Semin Cutan Med Surg 2009;28:244-9.
Jalian HR, Avram MM. Body contouring: The skinny on noninvasive fat removal. Semin Cutan Med Surg 2012;31:121-5.
Zelickson B, Egbert BM, Preciado J, Allison J, Springer K, Rhoades RW, et al.
Cryolipolysis for noninvasive fat cell destruction: Initial results from a pig model. Dermatol Surg 2009;35:1462-70.
Avram MM, Harry RS. Cryolipolysis for subcutaneous fat layer reduction. Lasers Surg Med 2009;41:703-8.
Stevens WG, Pietrzak LK, Spring MA. Broad overview of a clinical and commercial experience with CoolSculpting. Aesthet Surg J 2013;33:835-46.
Coleman SR, Sachdeva K, Egbert BM, Preciado J, Allison J. Clinical efficacy of noninvasive cryolipolysis and its effects on peripheral nerves. Aesthetic Plast Surg 2009;33:482-8.
Klein KB, Zelickson B, Riopelle JG, Okamoto E, Bachelor EP, Harry RS, et al.
Non-invasive cryolipolysis for subcutaneous fat reduction does not affect serum lipid levels or liver function tests. Lasers Surg Med 2009;41:785-90.
Brightman L, Geronemus R. Can second treatment enhance clinical results in cryolipolysis? Cosmet Dermatol 2011;24:85-8.
Dierickx CC, Mazer JM, Sand M, Koenig S, Arigon V. Safety, tolerance, and patient satisfaction with noninvasive cryolipolysis. Dermatol Surg 2013;39:1209-16.
Ferraro GA, De Francesco F, Cataldo C, Rossano F, Nicoletti G, D'Andrea F, et al.
Synergistic effects of cryolipolysis and shock waves for noninvasive body contouring. Aesthetic Plast Surg 2012;36:666-79.