Commentary on: Paradoxical Adipose Hypertrophy (PAH) After Cryolipolysis

Commentary on: Paradoxical Adipose Hypertrophy (PAH) After Cryolipolysis Paradoxical adipose hypertrophy (PAH) after cryolipolysis is a common and concerning complication associated with cryolipolysis body contouring. Body contouring, or body sculpting, procedures are the fastest growing procedures in aesthetic medicine. According to the American Society for Dermatologic Surgery (ASDS), approximately 387,000 body sculpting treatments were performed in the United States in 2016.1 The number of body sculpting treatments has risen 68% since 2015, which was the largest year-to-year growth of all cosmetic procedures.1 Within body sculpting procedures, cryolipolysis, or “fat-freezing,” accounted for 177,000 treatments or 45.7% of all body contouring treatments. In fact, cryolipolysis surpassed the growth rate of body sculpting treatments by increasing 76% from 2015 to 2016.1 While cryolipolysis has grown in popularity as a noninvasive approach to body contouring, it also has common potential adverse effects (eg, erythema, edema, and neuralgia). Most of these common side effects are mild to moderate and transient, often lasting several weeks to months. However, a fraction of patients in clinical studies and clinical practice have developed firm, nontender, well-demarcated areas of increased fat volume in treated areas approximately two to six months after cryolipolysis. This side effect is termed paradoxical adipose hypertrophy (PAH). PAH is a concerning, clinically significant complication because patients undergo cryolipolysis to remove fat, but instead the volume of fat increases at a treatment site, resulting in a completely opposite, undesirable outcome. From the patient’s perspective, not only can PAH affect patients psychologically, including quality of life and self-esteem, but it can also affect patients financially as the initial cryolipolysis treatment is paid for out-of-pocket by the patient. Additionally, after the initial wave of side effects, PAH subjects the patient to a second round of an unexpected delayed side effect several months postrecovery that does not spontaneously resolve and requires surgical treatment for correction. There are also additional hidden costs to the patients, including time required to correct PAH, downtime associated with PAH treatment recovery, and lost time from work and other activities. Currently, the treatment of choice for PAH is liposuction, but liposuction is not always curative. A case of PAH recurring after liposuction has been described, highlighting that PAH may represent an ongoing concern for some patients.2 The occurrence rate of PAH has been a subject of discussion amongst physicians and patients, as the manufacturer’s reported rate seems to be incongruent with clinical experience. In the study “Paradoxical Adipose Hypertrophy After Cryolipolysis,” Stroumza et al attempt to address this issue by investigating the incidence rate of PAH in their practice.3 Herein, a single center retrospective review reported the incidence of PAH in 398 patients treated with cryolipolysis over a period of 3 years (36 months). This case series by Stroumza et al described four of the 398 patients (1.0%) who developed PAH within 2 to 4 months after cryolipolysis. Overall, this case series adds to and supports the growing body of literature which suggests that the incidence of PAH is underreported. Underreporting of PAH may be due to the highest volumes of cryolipolysis treatments occurring at medical spas or body contouring centers with patients who are not closely supervised by physicians or well-trained medical professionals who can identify PAH and report cases of PAH to the manufacturer. Also, PAH may be subtle so detection can be difficult depending on the degree of PAH. We predict that as the number of cryolipolysis procedures increases over time and becomes widely available, the incidence of PAH may also increase as increased awareness among medical providers and patients may lead to diagnosis and reporting. When PAH was first reported in the literature in 2014, the incidence rate was estimated to be less than 0.0051%.4 Based upon the manufacturer’s postmarket consumer reports, the incidence of PAH has since been increasing annually (2013: 0.0032%, 2014: 0.021%-0.026%, and 2015: 0.025%).5 Most recently, the manufacturer’s 2016 report to the FDA indicated that the incidence of serious adverse events was 0.13%, which included 4 cases of PAH and 2 cases of contour irregularity in 4,792 cryolipolysis treatments of all sites.6 If the manufacturer listed the risk of PAH by treatment area and treatment handpiece, this would provide more clinically relevant information as the abdominal region or a specific applicator may be a risk factor for PAH. Similarly, the incidence of PAH in the medical literature has also been on the rise and exceeding the manufacturer’s reported rates. Others have demonstrated incidence rates of 0.47%7 and, more recently, an incidence of 0.78%.8 This case series by Stroumza et al shows the highest incidence rate of PAH reported yet (1.0%), which is 40 times greater than the device manufacturer’s most recent reported incidence and about 200 times greater than the initially reported incidence. While the manufacturer may disclose an incidence of PAH to be a fraction of a percent, some clinical practices may experience greater than 1% of their patients developing PAH. This incidence rate is impressive and concerning given that the frequency of this adverse event was initially reported as rare but has been increasing steadily. According to the World Health Organization (WHO), any adverse event greater than 0.01% and less than 0.1% is classified “rare” whereas any adverse event greater than 0.1% and less than 1.0% is classified as “uncommon” or “infrequent.”9 Similarly, any adverse event equal to or greater than 1.0% but less than 10.0% is classified as “common” or “frequent.” As we are now seeing that PAH occurrence rates reported from clinical settings are trending upwards and have reached a rate of 1.0%, we recommend that PAH should be reclassified as “common” or “frequent” instead of as a “rare” adverse event. Another important finding from this case series is that three of the four cases of PAH occurred in women. The incidence of PAH in women in this study was 0.94% (3/318) compared to the incidence of PAH in men of this study was 1.25% (1/80). This is particularly interesting because it demonstrates a disproportionate PAH incidence between genders and is consistent with previous reports of male gender being a risk factor for PAH, along with Hispanic or Latino descent.5 However, it is important to note that these small numbers of affected patients make it challenging to draw firm conclusions. Interestingly, one of the PAH cases occurred in the submental region with a small applicator, which is noteworthy for two reasons: the first occurrence of PAH in the submental region and occurrence of PAH with a small applicator. Of the 9 FDA-approved treatment sites, PAH has been previously reported to affect many treatment sites, including upper and lower abdomen, flanks, posterior trunk, inner thighs, and pectoral regions.5 To our knowledge, this is the first occurrence of PAH in the submental region. To reduce double chin fat in the submental region, Stroumza et al used a recently released small handpiece designed to fit in the submental region. Initially, large applicators were believed to play a role in causing PAH, so the newer applicators that replaced the previous applicators were hoped to help limit PAH. Currently, there are limited data substantiating this claim, so additional clinical trials and observations reporting the incidence of PAH in these newer applicators are needed. Unfortunately, the pathophysiology for PAH has not yet been identified. Several hypotheses have been proposed, including hypoxia, local sympathetic denervation, and natural selection of adipocytes.5 Further basic science or translation research should be done to elucidate the mechanism of the paradoxical response of cold-induced injury to adipocytes so that PAH can be prevented and/or corrected. As a method to identify what causes PAH, some have histologically analyzed tissue samples from patients after liposuction or surgery. Stroumza et al points out that the results of their histological analysis of the adipose tissue in one patient with PAH differed from the histological analysis of Jalian et al4 and Seaman et al.10 The conflicting findings are about vascularization and the number of live interstitial cells. For example, Jalian et al4 noted increased vascularization while Seaman et al10 found decreased vascularization and Stroumza et al found no hypervascularization. Regarding live interstitial cells, Seaman et al10 found a statistically significant decrease in total interstitial cells while Stroumza et al did not find a decrease in live interstitial cells. It is critical, however, to note that each of these case reports analyzed one tissue sample only and histological analysis occurred at different time points postcryolipolysis (3 months,4 5 months, and 7 months10 postcryolipolysis treatment). Rather than conflicting findings, perhaps these varied histological findings reflect the evolution of PAH over time. Therefore, future histological studies with a large sample size are necessary to confirm the histological findings of PAH and may also give clues for the underlying mechanism of PAH. Conceptually, deoxycholic acid may treat PAH by dissolving fat associated with post-cryolipolysis PAH. However, there is a lack of data on treating PAH with deoxycholic acid and there are several limitations to this approach. First, the amount and volume of deoxycholic acid required to treat PAH is cost prohibitive to the physician and patient. Second, the practical number of treatment sessions to induce a reduction in fat would prolong the patient’s discomfort and recovery. Finally, it is unknown if deoxycholic acid is able to dissolve PAH, as deoxycholic acid in our experience does not dissolve all types of fat deposits and is not effective in treating other forms of fat hypertrophy such as lipomas. Overall, this retrospective study demonstrates the concerning complication of PAH after cryolipolysis that interests physicians and patients alike. We recommend that, prior to every treatment session, the risk of PAH as a common, not rare, potential complication and the possibility of elective surgical intervention for PAH if it occurs should be discussed thoroughly with every patient. Also, it is of the utmost importance that follow up occurs for at least 6 months posttreatment for timely detection of PAH. Follow up for up to 9 months may be needed to monitor for PAH as the longest time reported for PAH to develop was 9 months postcryolipolysis.4 Disclosures Dr Jagdeo is a scientific consultant for Zeltiq (Pleasanton, CA). Drs Wang and Kaur declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. ASDS Survey: Nearly 10.5 Million Treatments Performed in 2016 [press release]. May 30, 2017. https://www.asds.net/2016-procedures-survey.aspx. Accessed August 17, 2017. 2. Friedmann DP, Buckley S, Mishra V. Paradoxical adipose hyperplasia after cryoadipolysis refractory to tumescent liposuction. Dermatol Surg . 2017; 43( 8): 1103- 1105. Google Scholar CrossRef Search ADS PubMed  3. Stroumza N, Gauthier N, Senet P, Moguelet P, Barthelemy RN, Atlan M. Paradoxical Adipose Hypertrophy (PAH) after cryolipolysis. Aesthet Surg J . 2018; 38( 4): 411- 417. 4. Jalian HR, Avram MM, Garibyan L, Mihm MC, Anderson RR. Paradoxical adipose hyperplasia after cryolipolysis. JAMA Dermatol . 2014; 150( 3): 317- 319. Google Scholar CrossRef Search ADS PubMed  5. Ho D, Jagdeo J. A Systematic Review of Paradoxical Adipose Hyperplasia (PAH) Post-Cryolipolysis. J Drugs Dermatol . 2017; 16( 1): 62- 67. Google Scholar PubMed  6. ZELTIQ™ Aesthetics I. 510(K) Summary of Safety and Effectiveness . March 14, 2016. 7. Singh SM, Geddes ER, Boutrous SG, Galiano RD, Friedman PM. Paradoxical adipose hyperplasia secondary to cryolipolysis: An underreported entity? Lasers Surg Med . 2015; 47( 6): 476- 478. Google Scholar CrossRef Search ADS PubMed  8. Kelly E, Rodriguez-Feliz J, Kelly ME. Paradoxical Adipose Hyperplasia after Cryolipolysis: A Report on Incidence and Common Factors Identified in 510 Patients. Plast Reconstr Surg . 2016; 137( 3): 639e- 640e. Google Scholar CrossRef Search ADS PubMed  9. World Health Organization. Definitions. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/trainingcourses/definitions.pdf. Accessed August 13, 2017. 10. Seaman SA, Tannan SC, Cao Y, Peirce SM, Gampper TJ. Paradoxical Adipose Hyperplasia and Cellular Effects After Cryolipolysis: A Case Report. Aesthet Surg J . 2016; 36( 1): NP6- N13. Google Scholar CrossRef Search ADS PubMed  © 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aesthetic Surgery Journal Oxford University Press

Commentary on: Paradoxical Adipose Hypertrophy (PAH) After Cryolipolysis

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Abstract

Paradoxical adipose hypertrophy (PAH) after cryolipolysis is a common and concerning complication associated with cryolipolysis body contouring. Body contouring, or body sculpting, procedures are the fastest growing procedures in aesthetic medicine. According to the American Society for Dermatologic Surgery (ASDS), approximately 387,000 body sculpting treatments were performed in the United States in 2016.1 The number of body sculpting treatments has risen 68% since 2015, which was the largest year-to-year growth of all cosmetic procedures.1 Within body sculpting procedures, cryolipolysis, or “fat-freezing,” accounted for 177,000 treatments or 45.7% of all body contouring treatments. In fact, cryolipolysis surpassed the growth rate of body sculpting treatments by increasing 76% from 2015 to 2016.1 While cryolipolysis has grown in popularity as a noninvasive approach to body contouring, it also has common potential adverse effects (eg, erythema, edema, and neuralgia). Most of these common side effects are mild to moderate and transient, often lasting several weeks to months. However, a fraction of patients in clinical studies and clinical practice have developed firm, nontender, well-demarcated areas of increased fat volume in treated areas approximately two to six months after cryolipolysis. This side effect is termed paradoxical adipose hypertrophy (PAH). PAH is a concerning, clinically significant complication because patients undergo cryolipolysis to remove fat, but instead the volume of fat increases at a treatment site, resulting in a completely opposite, undesirable outcome. From the patient’s perspective, not only can PAH affect patients psychologically, including quality of life and self-esteem, but it can also affect patients financially as the initial cryolipolysis treatment is paid for out-of-pocket by the patient. Additionally, after the initial wave of side effects, PAH subjects the patient to a second round of an unexpected delayed side effect several months postrecovery that does not spontaneously resolve and requires surgical treatment for correction. There are also additional hidden costs to the patients, including time required to correct PAH, downtime associated with PAH treatment recovery, and lost time from work and other activities. Currently, the treatment of choice for PAH is liposuction, but liposuction is not always curative. A case of PAH recurring after liposuction has been described, highlighting that PAH may represent an ongoing concern for some patients.2 The occurrence rate of PAH has been a subject of discussion amongst physicians and patients, as the manufacturer’s reported rate seems to be incongruent with clinical experience. In the study “Paradoxical Adipose Hypertrophy After Cryolipolysis,” Stroumza et al attempt to address this issue by investigating the incidence rate of PAH in their practice.3 Herein, a single center retrospective review reported the incidence of PAH in 398 patients treated with cryolipolysis over a period of 3 years (36 months). This case series by Stroumza et al described four of the 398 patients (1.0%) who developed PAH within 2 to 4 months after cryolipolysis. Overall, this case series adds to and supports the growing body of literature which suggests that the incidence of PAH is underreported. Underreporting of PAH may be due to the highest volumes of cryolipolysis treatments occurring at medical spas or body contouring centers with patients who are not closely supervised by physicians or well-trained medical professionals who can identify PAH and report cases of PAH to the manufacturer. Also, PAH may be subtle so detection can be difficult depending on the degree of PAH. We predict that as the number of cryolipolysis procedures increases over time and becomes widely available, the incidence of PAH may also increase as increased awareness among medical providers and patients may lead to diagnosis and reporting. When PAH was first reported in the literature in 2014, the incidence rate was estimated to be less than 0.0051%.4 Based upon the manufacturer’s postmarket consumer reports, the incidence of PAH has since been increasing annually (2013: 0.0032%, 2014: 0.021%-0.026%, and 2015: 0.025%).5 Most recently, the manufacturer’s 2016 report to the FDA indicated that the incidence of serious adverse events was 0.13%, which included 4 cases of PAH and 2 cases of contour irregularity in 4,792 cryolipolysis treatments of all sites.6 If the manufacturer listed the risk of PAH by treatment area and treatment handpiece, this would provide more clinically relevant information as the abdominal region or a specific applicator may be a risk factor for PAH. Similarly, the incidence of PAH in the medical literature has also been on the rise and exceeding the manufacturer’s reported rates. Others have demonstrated incidence rates of 0.47%7 and, more recently, an incidence of 0.78%.8 This case series by Stroumza et al shows the highest incidence rate of PAH reported yet (1.0%), which is 40 times greater than the device manufacturer’s most recent reported incidence and about 200 times greater than the initially reported incidence. While the manufacturer may disclose an incidence of PAH to be a fraction of a percent, some clinical practices may experience greater than 1% of their patients developing PAH. This incidence rate is impressive and concerning given that the frequency of this adverse event was initially reported as rare but has been increasing steadily. According to the World Health Organization (WHO), any adverse event greater than 0.01% and less than 0.1% is classified “rare” whereas any adverse event greater than 0.1% and less than 1.0% is classified as “uncommon” or “infrequent.”9 Similarly, any adverse event equal to or greater than 1.0% but less than 10.0% is classified as “common” or “frequent.” As we are now seeing that PAH occurrence rates reported from clinical settings are trending upwards and have reached a rate of 1.0%, we recommend that PAH should be reclassified as “common” or “frequent” instead of as a “rare” adverse event. Another important finding from this case series is that three of the four cases of PAH occurred in women. The incidence of PAH in women in this study was 0.94% (3/318) compared to the incidence of PAH in men of this study was 1.25% (1/80). This is particularly interesting because it demonstrates a disproportionate PAH incidence between genders and is consistent with previous reports of male gender being a risk factor for PAH, along with Hispanic or Latino descent.5 However, it is important to note that these small numbers of affected patients make it challenging to draw firm conclusions. Interestingly, one of the PAH cases occurred in the submental region with a small applicator, which is noteworthy for two reasons: the first occurrence of PAH in the submental region and occurrence of PAH with a small applicator. Of the 9 FDA-approved treatment sites, PAH has been previously reported to affect many treatment sites, including upper and lower abdomen, flanks, posterior trunk, inner thighs, and pectoral regions.5 To our knowledge, this is the first occurrence of PAH in the submental region. To reduce double chin fat in the submental region, Stroumza et al used a recently released small handpiece designed to fit in the submental region. Initially, large applicators were believed to play a role in causing PAH, so the newer applicators that replaced the previous applicators were hoped to help limit PAH. Currently, there are limited data substantiating this claim, so additional clinical trials and observations reporting the incidence of PAH in these newer applicators are needed. Unfortunately, the pathophysiology for PAH has not yet been identified. Several hypotheses have been proposed, including hypoxia, local sympathetic denervation, and natural selection of adipocytes.5 Further basic science or translation research should be done to elucidate the mechanism of the paradoxical response of cold-induced injury to adipocytes so that PAH can be prevented and/or corrected. As a method to identify what causes PAH, some have histologically analyzed tissue samples from patients after liposuction or surgery. Stroumza et al points out that the results of their histological analysis of the adipose tissue in one patient with PAH differed from the histological analysis of Jalian et al4 and Seaman et al.10 The conflicting findings are about vascularization and the number of live interstitial cells. For example, Jalian et al4 noted increased vascularization while Seaman et al10 found decreased vascularization and Stroumza et al found no hypervascularization. Regarding live interstitial cells, Seaman et al10 found a statistically significant decrease in total interstitial cells while Stroumza et al did not find a decrease in live interstitial cells. It is critical, however, to note that each of these case reports analyzed one tissue sample only and histological analysis occurred at different time points postcryolipolysis (3 months,4 5 months, and 7 months10 postcryolipolysis treatment). Rather than conflicting findings, perhaps these varied histological findings reflect the evolution of PAH over time. Therefore, future histological studies with a large sample size are necessary to confirm the histological findings of PAH and may also give clues for the underlying mechanism of PAH. Conceptually, deoxycholic acid may treat PAH by dissolving fat associated with post-cryolipolysis PAH. However, there is a lack of data on treating PAH with deoxycholic acid and there are several limitations to this approach. First, the amount and volume of deoxycholic acid required to treat PAH is cost prohibitive to the physician and patient. Second, the practical number of treatment sessions to induce a reduction in fat would prolong the patient’s discomfort and recovery. Finally, it is unknown if deoxycholic acid is able to dissolve PAH, as deoxycholic acid in our experience does not dissolve all types of fat deposits and is not effective in treating other forms of fat hypertrophy such as lipomas. Overall, this retrospective study demonstrates the concerning complication of PAH after cryolipolysis that interests physicians and patients alike. We recommend that, prior to every treatment session, the risk of PAH as a common, not rare, potential complication and the possibility of elective surgical intervention for PAH if it occurs should be discussed thoroughly with every patient. Also, it is of the utmost importance that follow up occurs for at least 6 months posttreatment for timely detection of PAH. Follow up for up to 9 months may be needed to monitor for PAH as the longest time reported for PAH to develop was 9 months postcryolipolysis.4 Disclosures Dr Jagdeo is a scientific consultant for Zeltiq (Pleasanton, CA). Drs Wang and Kaur declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. ASDS Survey: Nearly 10.5 Million Treatments Performed in 2016 [press release]. May 30, 2017. https://www.asds.net/2016-procedures-survey.aspx. Accessed August 17, 2017. 2. Friedmann DP, Buckley S, Mishra V. Paradoxical adipose hyperplasia after cryoadipolysis refractory to tumescent liposuction. Dermatol Surg . 2017; 43( 8): 1103- 1105. Google Scholar CrossRef Search ADS PubMed  3. Stroumza N, Gauthier N, Senet P, Moguelet P, Barthelemy RN, Atlan M. Paradoxical Adipose Hypertrophy (PAH) after cryolipolysis. Aesthet Surg J . 2018; 38( 4): 411- 417. 4. Jalian HR, Avram MM, Garibyan L, Mihm MC, Anderson RR. Paradoxical adipose hyperplasia after cryolipolysis. JAMA Dermatol . 2014; 150( 3): 317- 319. Google Scholar CrossRef Search ADS PubMed  5. Ho D, Jagdeo J. A Systematic Review of Paradoxical Adipose Hyperplasia (PAH) Post-Cryolipolysis. J Drugs Dermatol . 2017; 16( 1): 62- 67. Google Scholar PubMed  6. ZELTIQ™ Aesthetics I. 510(K) Summary of Safety and Effectiveness . March 14, 2016. 7. Singh SM, Geddes ER, Boutrous SG, Galiano RD, Friedman PM. Paradoxical adipose hyperplasia secondary to cryolipolysis: An underreported entity? Lasers Surg Med . 2015; 47( 6): 476- 478. Google Scholar CrossRef Search ADS PubMed  8. Kelly E, Rodriguez-Feliz J, Kelly ME. Paradoxical Adipose Hyperplasia after Cryolipolysis: A Report on Incidence and Common Factors Identified in 510 Patients. Plast Reconstr Surg . 2016; 137( 3): 639e- 640e. Google Scholar CrossRef Search ADS PubMed  9. World Health Organization. Definitions. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/trainingcourses/definitions.pdf. Accessed August 13, 2017. 10. Seaman SA, Tannan SC, Cao Y, Peirce SM, Gampper TJ. Paradoxical Adipose Hyperplasia and Cellular Effects After Cryolipolysis: A Case Report. Aesthet Surg J . 2016; 36( 1): NP6- N13. Google Scholar CrossRef Search ADS PubMed  © 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com

Journal

Aesthetic Surgery JournalOxford University Press

Published: Apr 1, 2018

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