Cosmeceutical Critique - Phosphatidylcholine

Because of the seemingly endless array of topics to cover in this column, I have never directly revisited a subject here (although some botanical ingredients have received individual attention as well as some focus as members of a class of compounds). But much has changed since I last covered phosphatidylcholine in 2003. In this month’s column, I will review recent research and discuss new safety concerns regarding the use of phosphatidylcholine in mesotherapy.

Emerging about 50 years ago and popular in Europe and South America (J. Cosmet. Laser Ther. 2005;7:17-9), mesotherapy entails the subcutaneous injection of pharmaceutical, homeopathic, botanical, vitamin, or other agents with the intention of initiating localized lipolysis in cellulite or other areas with undesired fat deposits. While this is considered a noninvasive alternative to liposuction or lipectomy, the use of phosphatidylcholine for this purpose has not been approved by the U.S. Food and Drug Administration.

Off-Label Use of Phosphatidylcholine Products 

The practice of using a formulation containing soybean-derived phosphatidylcholine in mesotherapy (also called lipo-dissolve, lipotherapy, or injection lipolysis) became popular in the mid-1990s in Brazil. The substance, known as Lipostabil, is a drug that was first used to reduce triglyceride and cholesterol levels in patients with coronary artery disease. However, lipo-dissolve products are marketed in the United States as natural compounds, even though the FDA considers such substances drugs and has not approved of their use for fat removal (http://www.npr.org/templates/story/story.php?storyId=11487499). Off-label use has become increasingly common in Europe and the United States. Given a spate of complications seen after the use of Lipostabil in Brazil, ANVISA, the Brazilian equivalent of the FDA, banned the phosphatidylcholine-containing product. This should give us all pause, since it is very rare for Brazil to ban medical drugs or devices.

Phosphatidylcholine, a component of lipoproteins, is a purified extract from lecithin. It was originally used in the medical setting for emergencies and treating atheroma plaques in cardiac disease (J. Drugs Dermatol. 2003;2:511-8). This phospholipid is a major component of all cell membranes and is the primary phospholipid in plasma. Composed of choline, phosphoric acid, and fatty acids, the phosphatidylcholine molecule occurs naturally in humans (especially in nerve tissue, the liver, and semen), and is obtained through consumption of soybeans, egg yolks, meat, and, rarely, vegetables. The consumption or injection of phosphatidylcholine is believed to augment phosphatidylcholine in lipoproteins, thereby enhancing their ability to mobilize fat and cholesterol. Further, phosphatidylcholine has been demonstrated to lower systemic levels of cholesterol and triglycerides and is believed to induce lipolysis (Dermatol. Surg. 2001;27:391-2).

 Promising Findings for Use in Lipolysis

In the first paper that sparked the craze around this procedure, Rittes reported on the technique that she had begun using in 1995, with fellow Brazilian doctors. The procedure was introduced at the Dermatologic Brazilian Congress in 1999, and published in 2001 as a treatment of lower eyelid bulging caused by prominent fat pads (Dermatol. Surg. 2001;27:391-2). In the 2001 study, which featured subjective assessments of improvement and was not placebo controlled, Rittes concluded that phosphatidylcholine injections (250 mg/5 mL) into periorbital fat pads could postpone the need for or possibly substitute for lower eyelid blepharoplasty. (These findings on the use of phosphatidylcholine for correction of infraorbital fat pads were recently duplicated in an open-label study of 21 subjects conducted by Treacy and Goldberg [J. Cosmet. Laser Ther. 2006;8:129-32]).

In a 2003 study, Rittes continued to suggest that this in-office procedure was a suitable alternative to surgery, in this case lipectomy or liposuction. Specifically, 50 patients received injections of phosphatidylcholine (250 mg/5 mL) into fat deposits in the abdomen, neck, arms, or thighs in an 80-cm² area using a 30G 1/2-inch insulin needle. Rittes observed clear improvement in all patients, with a significant decline in fat deposits and no recurrence or weight gain over a 2-year follow-up (Aesthetic Plast. Surg. 2003;27:315-8).

The next year, Hexsel et al. reported on their clinical experience using 250-mg/mL phosphatidylcholine injections to treat subcutaneous fat deposits in volunteers whose injections, in various localized fat deposits, were separated by a minimum interval of 1 week and mean interval of 15 days. They found that phosphatidylcholine was efficacious in diminishing the treated fatty areas, and was accompanied by minimal side effects. The investigators concluded that this noninvasive, off-label use of phosphatidylcholine was safe, effective, and inexpensive (J. Drugs Dermatol. 2003;2:511-8).

In 2004, Rotunda et al. assessed the mechanism of action and characteristics of the active components of a clinically used, injectable fat-dissolution formulation containing phosphatidylcholine and sodium deoxycholate, a bile salt incorporated to solubilize in water the natural phospholipid. In this experiment, the investigators performed cell viability and cell membrane lysis assays on cell cultures and porcine skin after treatment with the phosphatidylcholine product, isolated sodium deoxycholate, or common laboratory detergents. In comparing the results with phosphatidylcholine and isolated sodium deoxycholate, they found a significant and comparable loss of cell viability, cell membrane lysis, and disruption of fat and musculature in cell cultures and tissue specimens. The effects generated from the laboratory detergents were similar. The investigators concluded that the popular fat-dissolution formula based on phosphatidylcholine works mainly as a detergent, inducing nonspecific cell membrane lysis. Notably, they also suggested that sodium deoxycholate was the major active constituent causing the cell lysis, and urged caution for physicians regarding this procedure pending the availability of sufficient safety data (Dermatol. Surg. 2004;30:1001-8).

In 2005, Rose and Morgan took skin biopsies, 1 and 2 weeks after mesotherapy, from a patient who had undergone the procedure with phosphatidylcholine and deoxycholate. Both biopsies revealed normal epithelium and dermis, with a mixed septal and lobular panniculitis. The investigators noted that the fat lobules were infiltrated by an elevated number of lymphocytes and macrophages, the latter of which consisted of conventional forms, foam cells, and multinucleated fat-containing giant cells. Serous atrophy and microcyst development was linked to inflammation. In this first histologic study to illustrate the mechanism of action of phosphatidylcholine and deoxycholate, the authors concluded that mesotherapy with these compounds clearly impacted subcutaneous fat. They speculated that inflammatory-mediated necrosis and resorption likely accounted for the decrease in subcutaneous fat (J. Cosmet. Laser Ther. 2005;7:17-9).

In 2007, Sasaki et al. conducted a study in nine healthy female volunteers with grade II-III thigh cellulite to determine the safety and efficacy of a phosphatidylcholine-based cosmeceutical anticellulite gel combined with light-emitting diode (LED) treatment at 660 nm (red) and 950 nm (near-infrared). In this double-blind, controlled study, volunteers were randomly treated twice daily for 3 months with an active gel on one thigh and a placebo gel on the control thigh. Each thigh underwent a 15-minute treatment with LED light twice weekly (totaling 24 treatments).

At the end of the 3-month study period, investigators found alterations in cellulite warranting a downgrade in cellulite grade, based on clinical examinations, digital photography, and pinch test assessments, in eight of nine thighs treated with the phosphatidylcholine-based anticellulite gel and LED. A statistically significant decrease in immediate hypodermal depth and echolike intrusions into the dermal layer in the treated thighs was determined using digital ultrasound at the dermal-adiposal interface. Few clinical alterations were noted in the nine thighs treated with placebo and LED. Edema, erythema, and pruritus were among the rare and transient adverse effects from treatment. Follow-up at month 18 for eight response thighs revealed that five thighs regressed to their initial cellulite grade, and three thighs maintained the improvement from therapy, suggesting the need for repeated treatments (J. Cosmet. Laser Ther. 2007;9:87-96).

Given the dearth of published studies on mesotherapy with phosphatidylcholine and other ingredients, in 2007, Co et al. sought to ascertain the efficacy of phosphatidylcholine alone vs. phosphatidylcholine and organic silicium in reducing submental fat. Twelve healthy patients (of whom 1 was lost to follow-up) with submental fat received one to five treatments, with 2 weeks as the average between-treatment interval. Baseline fat measurements were taken at each session. Both treatment options were found to be equally effective, with no findings of ultrasound or histopathologic changes. Significant decreases in fat were observed after three treatment sessions in both groups, and only rare side effects (mild and fleeting) were noted. The authors identified the small sample size and the lack of a double-blind, placebo-controlled design as important limitations of the study. The researchers concluded that while the supportive evidence for using phosphatidylcholine or phosphatidylcholine with organic silicium is sparse and the mechanisms of action still poorly understood, both regimens appeared in this small study to be safe, efficacious, and inexpensive alternatives to invasive fat removal surgery (J. Cosmet. Dermatol. 2007;6:250-7).

In 2008, Salti et al. sought to assess the clinical efficacy and safety of phosphatidylcholine and sodium deoxycholate in chemical lipolysis and to characterize the roles of the agents in this nonsurgical procedure, based on reports that sodium deoxycholate, the intended excipient, was actually the active ingredient, rather than phosphatidylcholine. In the double-blind, randomized study, 37 consecutive female patients seeking treatment for cellulite received injections of a phosphatidylcholine/sodium deoxycholate preparation on one side and sodium deoxycholate on the contralateral side, for a total of four treatments every 8 weeks. The investigators recorded an overall local fat reduction of 91.9%, with no significant differences between the treatments. Side effects were local and rare, though manifested more on the sides treated with sodium deoxycholate. Both treatments were deemed safe in the short term. The authors concluded that the slower postoperative resolution associated with sodium deoxycholate suggests that this compound alone may be adequate for achieving the destruction of fat cells, while phosphatidylcholine could be used subsequently to emulsify the adipose tissue (Dermatol. Surg. 2008;34:60-6).

Concerns About Tissue Fibrosis/Necrosis

A few months later, Schuller-Petrovic et al. reported on their investigation of the subcutaneous tissue effects of phosphatidylcholine solubilized with deoxycholate in rats and one human volunteer. In a 30-day study, the rats were treated subcutaneously on the abdomen three times with 50, 300, or 600 mcL of the combination formula. The human volunteer, scheduled for elective liposuction, was treated in the same fashion. The investigators noted dose-dependent decreases in membrane integrity and cell viability in the rats, as well as histologic changes such as fibroplasia, bandlike fibrosis near the cutaneous muscle, and partial muscle loss. Fat necrosis, fat cyst development, and necrotic alterations in the walls of small blood vessels were associated with the highest dose. In the human volunteer, dose-dependent panniculitis, fat cysts, and vessel necrosis were noted in histologic sections of subcutaneous tissue. The researchers concluded that tissue fibrosis and necrosis of adipose and vascular tissues result from injection lipolysis with phosphatidylcholine/deoxycholate, and that the long-term safety profile for this nonsurgical subcutaneous fat treatment is consequently murky (Dermatol. Surg. 2008;34:529-42).

In a 2009 study of 42 patients, Rotunda et al. assessed the safety and efficacy of subcutaneously injected deoxycholate alone compared with a conventionally used phosphatidylcholine/deoxycholate combination in patients with unwanted submental fat. In this single-center, randomized, double-blind study, 28 subjects received 1-mL injections of one of the test compounds into submental fat, and 14 received 2-mL injections, with up to five treatments administered every 4 weeks. Patients completed diaries at home as well as post-treatment self-assessments. Modest changes (ranging from none to mild) in submental profiles based on photographic assessment were reported for both groups. No significant differences between the groups were seen based on patient self-assessment; physical examination; or incidence, duration, and severity of adverse events (e.g., burning, edema, erythema, and pain). The investigators reported that minimal aesthetic improvement was observed from the injection of either deoxycholate or phosphatidylcholine/deoxycholate into submental fat. They also suggested that further study is warranted based on the belief that proof of concept was supported by improved neck profiles in multiple participants. In particular, they suggested that additional work is needed to establish a validated submental profile grading scale and optimal doses and techniques (Dermatol. Surg. 2009;35:792-803).

Conclusions

Clearly, new research is slowly emerging on the use of phosphatidylcholine injections for the in-office reduction of fat deposits. The weight of this new evidence, particularly in light of the Brazilian ban on Lipostabil, strongly suggests continued optimism for the eventual use of phosphatidylcholine for fat reduction, but much more research is necessary to develop safer applications.

I would like to see larger sample sizes in randomized, placebo-controlled trials. At this point, I strongly advise against the use of Lipostabil, which, unfortunately, is available in kits sold over the Internet (lecithin and phosphatidylcholine are not regulated as drugs, though they should be, and are even sold as supplements). Several companies are working to develop safer versions of Lipostabil. I recommend that physicians advise their patients to wait until such products are vetted and validated.

Because of the seemingly endless array of topics to cover in this column, I have never directly revisited a subject here (although some botanical ingredients have received individual attention as well as some focus as members of a class of compounds). But much has changed since I last covered phosphatidylcholine in 2003. In this month’s column, I will review recent research and discuss new safety concerns regarding the use of phosphatidylcholine in mesotherapy.

Emerging about 50 years ago and popular in Europe and South America (J. Cosmet. Laser Ther. 2005;7:17-9), mesotherapy entails the subcutaneous injection of pharmaceutical, homeopathic, botanical, vitamin, or other agents with the intention of initiating localized lipolysis in cellulite or other areas with undesired fat deposits. While this is considered a noninvasive alternative to liposuction or lipectomy, the use of phosphatidylcholine for this purpose has not been approved by the U.S. Food and Drug Administration.

Off-Label Use of Phosphatidylcholine Products 

The practice of using a formulation containing soybean-derived phosphatidylcholine in mesotherapy (also called lipo-dissolve, lipotherapy, or injection lipolysis) became popular in the mid-1990s in Brazil. The substance, known as Lipostabil, is a drug that was first used to reduce triglyceride and cholesterol levels in patients with coronary artery disease. However, lipo-dissolve products are marketed in the United States as natural compounds, even though the FDA considers such substances drugs and has not approved of their use for fat removal (http://www.npr.org/templates/story/story.php?storyId=11487499). Off-label use has become increasingly common in Europe and the United States. Given a spate of complications seen after the use of Lipostabil in Brazil, ANVISA, the Brazilian equivalent of the FDA, banned the phosphatidylcholine-containing product. This should give us all pause, since it is very rare for Brazil to ban medical drugs or devices.

Phosphatidylcholine, a component of lipoproteins, is a purified extract from lecithin. It was originally used in the medical setting for emergencies and treating atheroma plaques in cardiac disease (J. Drugs Dermatol. 2003;2:511-8). This phospholipid is a major component of all cell membranes and is the primary phospholipid in plasma. Composed of choline, phosphoric acid, and fatty acids, the phosphatidylcholine molecule occurs naturally in humans (especially in nerve tissue, the liver, and semen), and is obtained through consumption of soybeans, egg yolks, meat, and, rarely, vegetables. The consumption or injection of phosphatidylcholine is believed to augment phosphatidylcholine in lipoproteins, thereby enhancing their ability to mobilize fat and cholesterol. Further, phosphatidylcholine has been demonstrated to lower systemic levels of cholesterol and triglycerides and is believed to induce lipolysis (Dermatol. Surg. 2001;27:391-2).

 Promising Findings for Use in Lipolysis

In the first paper that sparked the craze around this procedure, Rittes reported on the technique that she had begun using in 1995, with fellow Brazilian doctors. The procedure was introduced at the Dermatologic Brazilian Congress in 1999, and published in 2001 as a treatment of lower eyelid bulging caused by prominent fat pads (Dermatol. Surg. 2001;27:391-2). In the 2001 study, which featured subjective assessments of improvement and was not placebo controlled, Rittes concluded that phosphatidylcholine injections (250 mg/5 mL) into periorbital fat pads could postpone the need for or possibly substitute for lower eyelid blepharoplasty. (These findings on the use of phosphatidylcholine for correction of infraorbital fat pads were recently duplicated in an open-label study of 21 subjects conducted by Treacy and Goldberg [J. Cosmet. Laser Ther. 2006;8:129-32]).

In a 2003 study, Rittes continued to suggest that this in-office procedure was a suitable alternative to surgery, in this case lipectomy or liposuction. Specifically, 50 patients received injections of phosphatidylcholine (250 mg/5 mL) into fat deposits in the abdomen, neck, arms, or thighs in an 80-cm² area using a 30G 1/2-inch insulin needle. Rittes observed clear improvement in all patients, with a significant decline in fat deposits and no recurrence or weight gain over a 2-year follow-up (Aesthetic Plast. Surg. 2003;27:315-8).

The next year, Hexsel et al. reported on their clinical experience using 250-mg/mL phosphatidylcholine injections to treat subcutaneous fat deposits in volunteers whose injections, in various localized fat deposits, were separated by a minimum interval of 1 week and mean interval of 15 days. They found that phosphatidylcholine was efficacious in diminishing the treated fatty areas, and was accompanied by minimal side effects. The investigators concluded that this noninvasive, off-label use of phosphatidylcholine was safe, effective, and inexpensive (J. Drugs Dermatol. 2003;2:511-8).

In 2004, Rotunda et al. assessed the mechanism of action and characteristics of the active components of a clinically used, injectable fat-dissolution formulation containing phosphatidylcholine and sodium deoxycholate, a bile salt incorporated to solubilize in water the natural phospholipid. In this experiment, the investigators performed cell viability and cell membrane lysis assays on cell cultures and porcine skin after treatment with the phosphatidylcholine product, isolated sodium deoxycholate, or common laboratory detergents. In comparing the results with phosphatidylcholine and isolated sodium deoxycholate, they found a significant and comparable loss of cell viability, cell membrane lysis, and disruption of fat and musculature in cell cultures and tissue specimens. The effects generated from the laboratory detergents were similar. The investigators concluded that the popular fat-dissolution formula based on phosphatidylcholine works mainly as a detergent, inducing nonspecific cell membrane lysis. Notably, they also suggested that sodium deoxycholate was the major active constituent causing the cell lysis, and urged caution for physicians regarding this procedure pending the availability of sufficient safety data (Dermatol. Surg. 2004;30:1001-8).

In 2005, Rose and Morgan took skin biopsies, 1 and 2 weeks after mesotherapy, from a patient who had undergone the procedure with phosphatidylcholine and deoxycholate. Both biopsies revealed normal epithelium and dermis, with a mixed septal and lobular panniculitis. The investigators noted that the fat lobules were infiltrated by an elevated number of lymphocytes and macrophages, the latter of which consisted of conventional forms, foam cells, and multinucleated fat-containing giant cells. Serous atrophy and microcyst development was linked to inflammation. In this first histologic study to illustrate the mechanism of action of phosphatidylcholine and deoxycholate, the authors concluded that mesotherapy with these compounds clearly impacted subcutaneous fat. They speculated that inflammatory-mediated necrosis and resorption likely accounted for the decrease in subcutaneous fat (J. Cosmet. Laser Ther. 2005;7:17-9).

In 2007, Sasaki et al. conducted a study in nine healthy female volunteers with grade II-III thigh cellulite to determine the safety and efficacy of a phosphatidylcholine-based cosmeceutical anticellulite gel combined with light-emitting diode (LED) treatment at 660 nm (red) and 950 nm (near-infrared). In this double-blind, controlled study, volunteers were randomly treated twice daily for 3 months with an active gel on one thigh and a placebo gel on the control thigh. Each thigh underwent a 15-minute treatment with LED light twice weekly (totaling 24 treatments).

At the end of the 3-month study period, investigators found alterations in cellulite warranting a downgrade in cellulite grade, based on clinical examinations, digital photography, and pinch test assessments, in eight of nine thighs treated with the phosphatidylcholine-based anticellulite gel and LED. A statistically significant decrease in immediate hypodermal depth and echolike intrusions into the dermal layer in the treated thighs was determined using digital ultrasound at the dermal-adiposal interface. Few clinical alterations were noted in the nine thighs treated with placebo and LED. Edema, erythema, and pruritus were among the rare and transient adverse effects from treatment. Follow-up at month 18 for eight response thighs revealed that five thighs regressed to their initial cellulite grade, and three thighs maintained the improvement from therapy, suggesting the need for repeated treatments (J. Cosmet. Laser Ther. 2007;9:87-96).

Given the dearth of published studies on mesotherapy with phosphatidylcholine and other ingredients, in 2007, Co et al. sought to ascertain the efficacy of phosphatidylcholine alone vs. phosphatidylcholine and organic silicium in reducing submental fat. Twelve healthy patients (of whom 1 was lost to follow-up) with submental fat received one to five treatments, with 2 weeks as the average between-treatment interval. Baseline fat measurements were taken at each session. Both treatment options were found to be equally effective, with no findings of ultrasound or histopathologic changes. Significant decreases in fat were observed after three treatment sessions in both groups, and only rare side effects (mild and fleeting) were noted. The authors identified the small sample size and the lack of a double-blind, placebo-controlled design as important limitations of the study. The researchers concluded that while the supportive evidence for using phosphatidylcholine or phosphatidylcholine with organic silicium is sparse and the mechanisms of action still poorly understood, both regimens appeared in this small study to be safe, efficacious, and inexpensive alternatives to invasive fat removal surgery (J. Cosmet. Dermatol. 2007;6:250-7).

In 2008, Salti et al. sought to assess the clinical efficacy and safety of phosphatidylcholine and sodium deoxycholate in chemical lipolysis and to characterize the roles of the agents in this nonsurgical procedure, based on reports that sodium deoxycholate, the intended excipient, was actually the active ingredient, rather than phosphatidylcholine. In the double-blind, randomized study, 37 consecutive female patients seeking treatment for cellulite received injections of a phosphatidylcholine/sodium deoxycholate preparation on one side and sodium deoxycholate on the contralateral side, for a total of four treatments every 8 weeks. The investigators recorded an overall local fat reduction of 91.9%, with no significant differences between the treatments. Side effects were local and rare, though manifested more on the sides treated with sodium deoxycholate. Both treatments were deemed safe in the short term. The authors concluded that the slower postoperative resolution associated with sodium deoxycholate suggests that this compound alone may be adequate for achieving the destruction of fat cells, while phosphatidylcholine could be used subsequently to emulsify the adipose tissue (Dermatol. Surg. 2008;34:60-6).

Concerns About Tissue Fibrosis/Necrosis

A few months later, Schuller-Petrovic et al. reported on their investigation of the subcutaneous tissue effects of phosphatidylcholine solubilized with deoxycholate in rats and one human volunteer. In a 30-day study, the rats were treated subcutaneously on the abdomen three times with 50, 300, or 600 mcL of the combination formula. The human volunteer, scheduled for elective liposuction, was treated in the same fashion. The investigators noted dose-dependent decreases in membrane integrity and cell viability in the rats, as well as histologic changes such as fibroplasia, bandlike fibrosis near the cutaneous muscle, and partial muscle loss. Fat necrosis, fat cyst development, and necrotic alterations in the walls of small blood vessels were associated with the highest dose. In the human volunteer, dose-dependent panniculitis, fat cysts, and vessel necrosis were noted in histologic sections of subcutaneous tissue. The researchers concluded that tissue fibrosis and necrosis of adipose and vascular tissues result from injection lipolysis with phosphatidylcholine/deoxycholate, and that the long-term safety profile for this nonsurgical subcutaneous fat treatment is consequently murky (Dermatol. Surg. 2008;34:529-42).

In a 2009 study of 42 patients, Rotunda et al. assessed the safety and efficacy of subcutaneously injected deoxycholate alone compared with a conventionally used phosphatidylcholine/deoxycholate combination in patients with unwanted submental fat. In this single-center, randomized, double-blind study, 28 subjects received 1-mL injections of one of the test compounds into submental fat, and 14 received 2-mL injections, with up to five treatments administered every 4 weeks. Patients completed diaries at home as well as post-treatment self-assessments. Modest changes (ranging from none to mild) in submental profiles based on photographic assessment were reported for both groups. No significant differences between the groups were seen based on patient self-assessment; physical examination; or incidence, duration, and severity of adverse events (e.g., burning, edema, erythema, and pain). The investigators reported that minimal aesthetic improvement was observed from the injection of either deoxycholate or phosphatidylcholine/deoxycholate into submental fat. They also suggested that further study is warranted based on the belief that proof of concept was supported by improved neck profiles in multiple participants. In particular, they suggested that additional work is needed to establish a validated submental profile grading scale and optimal doses and techniques (Dermatol. Surg. 2009;35:792-803).

Conclusions

Clearly, new research is slowly emerging on the use of phosphatidylcholine injections for the in-office reduction of fat deposits. The weight of this new evidence, particularly in light of the Brazilian ban on Lipostabil, strongly suggests continued optimism for the eventual use of phosphatidylcholine for fat reduction, but much more research is necessary to develop safer applications.

I would like to see larger sample sizes in randomized, placebo-controlled trials. At this point, I strongly advise against the use of Lipostabil, which, unfortunately, is available in kits sold over the Internet (lecithin and phosphatidylcholine are not regulated as drugs, though they should be, and are even sold as supplements). Several companies are working to develop safer versions of Lipostabil. I recommend that physicians advise their patients to wait until such products are vetted and validated.

Because of the seemingly endless array of topics to cover in this column, I have never directly revisited a subject here (although some botanical ingredients have received individual attention as well as some focus as members of a class of compounds). But much has changed since I last covered phosphatidylcholine in 2003. In this month’s column, I will review recent research and discuss new safety concerns regarding the use of phosphatidylcholine in mesotherapy.

Emerging about 50 years ago and popular in Europe and South America (J. Cosmet. Laser Ther. 2005;7:17-9), mesotherapy entails the subcutaneous injection of pharmaceutical, homeopathic, botanical, vitamin, or other agents with the intention of initiating localized lipolysis in cellulite or other areas with undesired fat deposits. While this is considered a noninvasive alternative to liposuction or lipectomy, the use of phosphatidylcholine for this purpose has not been approved by the U.S. Food and Drug Administration.

Off-Label Use of Phosphatidylcholine Products 

The practice of using a formulation containing soybean-derived phosphatidylcholine in mesotherapy (also called lipo-dissolve, lipotherapy, or injection lipolysis) became popular in the mid-1990s in Brazil. The substance, known as Lipostabil, is a drug that was first used to reduce triglyceride and cholesterol levels in patients with coronary artery disease. However, lipo-dissolve products are marketed in the United States as natural compounds, even though the FDA considers such substances drugs and has not approved of their use for fat removal (http://www.npr.org/templates/story/story.php?storyId=11487499). Off-label use has become increasingly common in Europe and the United States. Given a spate of complications seen after the use of Lipostabil in Brazil, ANVISA, the Brazilian equivalent of the FDA, banned the phosphatidylcholine-containing product. This should give us all pause, since it is very rare for Brazil to ban medical drugs or devices.

Phosphatidylcholine, a component of lipoproteins, is a purified extract from lecithin. It was originally used in the medical setting for emergencies and treating atheroma plaques in cardiac disease (J. Drugs Dermatol. 2003;2:511-8). This phospholipid is a major component of all cell membranes and is the primary phospholipid in plasma. Composed of choline, phosphoric acid, and fatty acids, the phosphatidylcholine molecule occurs naturally in humans (especially in nerve tissue, the liver, and semen), and is obtained through consumption of soybeans, egg yolks, meat, and, rarely, vegetables. The consumption or injection of phosphatidylcholine is believed to augment phosphatidylcholine in lipoproteins, thereby enhancing their ability to mobilize fat and cholesterol. Further, phosphatidylcholine has been demonstrated to lower systemic levels of cholesterol and triglycerides and is believed to induce lipolysis (Dermatol. Surg. 2001;27:391-2).

 Promising Findings for Use in Lipolysis

In the first paper that sparked the craze around this procedure, Rittes reported on the technique that she had begun using in 1995, with fellow Brazilian doctors. The procedure was introduced at the Dermatologic Brazilian Congress in 1999, and published in 2001 as a treatment of lower eyelid bulging caused by prominent fat pads (Dermatol. Surg. 2001;27:391-2). In the 2001 study, which featured subjective assessments of improvement and was not placebo controlled, Rittes concluded that phosphatidylcholine injections (250 mg/5 mL) into periorbital fat pads could postpone the need for or possibly substitute for lower eyelid blepharoplasty. (These findings on the use of phosphatidylcholine for correction of infraorbital fat pads were recently duplicated in an open-label study of 21 subjects conducted by Treacy and Goldberg [J. Cosmet. Laser Ther. 2006;8:129-32]).

In a 2003 study, Rittes continued to suggest that this in-office procedure was a suitable alternative to surgery, in this case lipectomy or liposuction. Specifically, 50 patients received injections of phosphatidylcholine (250 mg/5 mL) into fat deposits in the abdomen, neck, arms, or thighs in an 80-cm² area using a 30G 1/2-inch insulin needle. Rittes observed clear improvement in all patients, with a significant decline in fat deposits and no recurrence or weight gain over a 2-year follow-up (Aesthetic Plast. Surg. 2003;27:315-8).

The next year, Hexsel et al. reported on their clinical experience using 250-mg/mL phosphatidylcholine injections to treat subcutaneous fat deposits in volunteers whose injections, in various localized fat deposits, were separated by a minimum interval of 1 week and mean interval of 15 days. They found that phosphatidylcholine was efficacious in diminishing the treated fatty areas, and was accompanied by minimal side effects. The investigators concluded that this noninvasive, off-label use of phosphatidylcholine was safe, effective, and inexpensive (J. Drugs Dermatol. 2003;2:511-8).

In 2004, Rotunda et al. assessed the mechanism of action and characteristics of the active components of a clinically used, injectable fat-dissolution formulation containing phosphatidylcholine and sodium deoxycholate, a bile salt incorporated to solubilize in water the natural phospholipid. In this experiment, the investigators performed cell viability and cell membrane lysis assays on cell cultures and porcine skin after treatment with the phosphatidylcholine product, isolated sodium deoxycholate, or common laboratory detergents. In comparing the results with phosphatidylcholine and isolated sodium deoxycholate, they found a significant and comparable loss of cell viability, cell membrane lysis, and disruption of fat and musculature in cell cultures and tissue specimens. The effects generated from the laboratory detergents were similar. The investigators concluded that the popular fat-dissolution formula based on phosphatidylcholine works mainly as a detergent, inducing nonspecific cell membrane lysis. Notably, they also suggested that sodium deoxycholate was the major active constituent causing the cell lysis, and urged caution for physicians regarding this procedure pending the availability of sufficient safety data (Dermatol. Surg. 2004;30:1001-8).

In 2005, Rose and Morgan took skin biopsies, 1 and 2 weeks after mesotherapy, from a patient who had undergone the procedure with phosphatidylcholine and deoxycholate. Both biopsies revealed normal epithelium and dermis, with a mixed septal and lobular panniculitis. The investigators noted that the fat lobules were infiltrated by an elevated number of lymphocytes and macrophages, the latter of which consisted of conventional forms, foam cells, and multinucleated fat-containing giant cells. Serous atrophy and microcyst development was linked to inflammation. In this first histologic study to illustrate the mechanism of action of phosphatidylcholine and deoxycholate, the authors concluded that mesotherapy with these compounds clearly impacted subcutaneous fat. They speculated that inflammatory-mediated necrosis and resorption likely accounted for the decrease in subcutaneous fat (J. Cosmet. Laser Ther. 2005;7:17-9).

In 2007, Sasaki et al. conducted a study in nine healthy female volunteers with grade II-III thigh cellulite to determine the safety and efficacy of a phosphatidylcholine-based cosmeceutical anticellulite gel combined with light-emitting diode (LED) treatment at 660 nm (red) and 950 nm (near-infrared). In this double-blind, controlled study, volunteers were randomly treated twice daily for 3 months with an active gel on one thigh and a placebo gel on the control thigh. Each thigh underwent a 15-minute treatment with LED light twice weekly (totaling 24 treatments).

At the end of the 3-month study period, investigators found alterations in cellulite warranting a downgrade in cellulite grade, based on clinical examinations, digital photography, and pinch test assessments, in eight of nine thighs treated with the phosphatidylcholine-based anticellulite gel and LED. A statistically significant decrease in immediate hypodermal depth and echolike intrusions into the dermal layer in the treated thighs was determined using digital ultrasound at the dermal-adiposal interface. Few clinical alterations were noted in the nine thighs treated with placebo and LED. Edema, erythema, and pruritus were among the rare and transient adverse effects from treatment. Follow-up at month 18 for eight response thighs revealed that five thighs regressed to their initial cellulite grade, and three thighs maintained the improvement from therapy, suggesting the need for repeated treatments (J. Cosmet. Laser Ther. 2007;9:87-96).

Given the dearth of published studies on mesotherapy with phosphatidylcholine and other ingredients, in 2007, Co et al. sought to ascertain the efficacy of phosphatidylcholine alone vs. phosphatidylcholine and organic silicium in reducing submental fat. Twelve healthy patients (of whom 1 was lost to follow-up) with submental fat received one to five treatments, with 2 weeks as the average between-treatment interval. Baseline fat measurements were taken at each session. Both treatment options were found to be equally effective, with no findings of ultrasound or histopathologic changes. Significant decreases in fat were observed after three treatment sessions in both groups, and only rare side effects (mild and fleeting) were noted. The authors identified the small sample size and the lack of a double-blind, placebo-controlled design as important limitations of the study. The researchers concluded that while the supportive evidence for using phosphatidylcholine or phosphatidylcholine with organic silicium is sparse and the mechanisms of action still poorly understood, both regimens appeared in this small study to be safe, efficacious, and inexpensive alternatives to invasive fat removal surgery (J. Cosmet. Dermatol. 2007;6:250-7).

In 2008, Salti et al. sought to assess the clinical efficacy and safety of phosphatidylcholine and sodium deoxycholate in chemical lipolysis and to characterize the roles of the agents in this nonsurgical procedure, based on reports that sodium deoxycholate, the intended excipient, was actually the active ingredient, rather than phosphatidylcholine. In the double-blind, randomized study, 37 consecutive female patients seeking treatment for cellulite received injections of a phosphatidylcholine/sodium deoxycholate preparation on one side and sodium deoxycholate on the contralateral side, for a total of four treatments every 8 weeks. The investigators recorded an overall local fat reduction of 91.9%, with no significant differences between the treatments. Side effects were local and rare, though manifested more on the sides treated with sodium deoxycholate. Both treatments were deemed safe in the short term. The authors concluded that the slower postoperative resolution associated with sodium deoxycholate suggests that this compound alone may be adequate for achieving the destruction of fat cells, while phosphatidylcholine could be used subsequently to emulsify the adipose tissue (Dermatol. Surg. 2008;34:60-6).

Concerns About Tissue Fibrosis/Necrosis

A few months later, Schuller-Petrovic et al. reported on their investigation of the subcutaneous tissue effects of phosphatidylcholine solubilized with deoxycholate in rats and one human volunteer. In a 30-day study, the rats were treated subcutaneously on the abdomen three times with 50, 300, or 600 mcL of the combination formula. The human volunteer, scheduled for elective liposuction, was treated in the same fashion. The investigators noted dose-dependent decreases in membrane integrity and cell viability in the rats, as well as histologic changes such as fibroplasia, bandlike fibrosis near the cutaneous muscle, and partial muscle loss. Fat necrosis, fat cyst development, and necrotic alterations in the walls of small blood vessels were associated with the highest dose. In the human volunteer, dose-dependent panniculitis, fat cysts, and vessel necrosis were noted in histologic sections of subcutaneous tissue. The researchers concluded that tissue fibrosis and necrosis of adipose and vascular tissues result from injection lipolysis with phosphatidylcholine/deoxycholate, and that the long-term safety profile for this nonsurgical subcutaneous fat treatment is consequently murky (Dermatol. Surg. 2008;34:529-42).

In a 2009 study of 42 patients, Rotunda et al. assessed the safety and efficacy of subcutaneously injected deoxycholate alone compared with a conventionally used phosphatidylcholine/deoxycholate combination in patients with unwanted submental fat. In this single-center, randomized, double-blind study, 28 subjects received 1-mL injections of one of the test compounds into submental fat, and 14 received 2-mL injections, with up to five treatments administered every 4 weeks. Patients completed diaries at home as well as post-treatment self-assessments. Modest changes (ranging from none to mild) in submental profiles based on photographic assessment were reported for both groups. No significant differences between the groups were seen based on patient self-assessment; physical examination; or incidence, duration, and severity of adverse events (e.g., burning, edema, erythema, and pain). The investigators reported that minimal aesthetic improvement was observed from the injection of either deoxycholate or phosphatidylcholine/deoxycholate into submental fat. They also suggested that further study is warranted based on the belief that proof of concept was supported by improved neck profiles in multiple participants. In particular, they suggested that additional work is needed to establish a validated submental profile grading scale and optimal doses and techniques (Dermatol. Surg. 2009;35:792-803).

Conclusions

Clearly, new research is slowly emerging on the use of phosphatidylcholine injections for the in-office reduction of fat deposits. The weight of this new evidence, particularly in light of the Brazilian ban on Lipostabil, strongly suggests continued optimism for the eventual use of phosphatidylcholine for fat reduction, but much more research is necessary to develop safer applications.

I would like to see larger sample sizes in randomized, placebo-controlled trials. At this point, I strongly advise against the use of Lipostabil, which, unfortunately, is available in kits sold over the Internet (lecithin and phosphatidylcholine are not regulated as drugs, though they should be, and are even sold as supplements). Several companies are working to develop safer versions of Lipostabil. I recommend that physicians advise their patients to wait until such products are vetted and validated.