Paradoxical Adipose Hyperplasia

Etiology

The exact etiology of PAH is unknown, but identifying potential risk factors is crucial for setting patient expectations and fully understanding the risks. Unfortunately, the risk factors for PAH are also poorly understood; however, some reports suggest a correlation with certain factors, such as Hispanic background, male gender, use of a single large applicator, and treatment of the abdominal region.[3] However, many individuals affected by PAH have no known risk factors.

A set of twins has been identified that developed PAH following cryolipolysis at separate practices, indicating a potential genetic predisposition to the condition.[3] Kelly et al also proposed that increased levels of testosterone may increase the risk of PAH.[3] Interestingly, a study by Nikolis et al found that newer cryolipolysis models and applicators demonstrated a 75% decrease in PAH occurrence, indicating that mechanical defects in older models may have contributed to the higher incidence of PAH.[4]

Epidemiology

The incidence of PAH is likely underreported and may be significantly higher than initially predicted. Originally estimated at approximately 0.0051% or 1 in 20,000 treatments when first described in 2014, the reported incidence has increased as awareness of this complication has grown.[2] 

PAH reporting is typically measured per treatment or cycle, which can obscure the true risk for patients undergoing multiple treatments. Many patients receive several cycles in a single session targeting different body areas and may have repeat sessions within 4 to 8 weeks. Consequently, the cumulative risk of developing PAH may be higher than reported figures suggest. Per-cycle reporting could underestimate the overall incidence of PAH in patients undergoing multiple procedures, highlighting the need for more comprehensive risk assessments and patient counseling that account for the total number of treatments received.

The most recent manufacturer-reported incidence in 2021 estimated PAH at 0.033% or 1 in 3000 treatments. However, a 2020 systematic review by Hedayati et al found the incidence to be approximately 0.91% or 1 in 110 treatments, over 27 times higher than the manufacturer's estimate.[5] Despite the wide range of PAH incidence reported, some estimates suggest the actual rate may be as high as 2%.[1]

Pathophysiology

Cryolipolysis is a noninvasive "fat-freezing" procedure that uses controlled cooling and negative pressure to selectively target adipocytes while sparing surrounding tissue.[6] This process occurs secondary to the crystallization of cytoplasmic lipids within the adipocytes, leading to apoptosis, panniculitis, and eventual loss of the fat cells.[2] 

Although the exact pathophysiology of PAH is unknown, researchers have proposed several mechanisms that may lead to its development. These mechanisms include hypoxic injury, hypertrophy of preexisting adipocytes, sympathetic denervation, recruitment of preadipocytes, modifications in the expression of receptors and/or signaling factors involved in adipocyte metabolism, and/or secondary to negative pressure suction.[2] 

Hypoxic injury may cause adipocyte hypertrophy through various mechanisms. Stefani hypothesized that cooling adipocytes without rupturing the cell wall might result in rebound hypertrophy and hyperplasia due to hypoxic injury.[7] Hypoxic injury is also known to stimulate the release of hypoxia-inducible factors, which can lead to angiogenesis and potentially contribute to adipocyte hypertrophy and hyperplasia.[8]

Reduced sympathetic innervation, recruitment of preadipocytes, and modifications in the expression of receptors and/or signaling factors involved in adipocyte metabolism may also contribute to the development of PAH. Multiple animal studies have suggested that sympathetic denervation of adipose tissue can inhibit lipolysis and may lead to an increase in adipocyte proliferation.[9][10][11] Additionally, local inflammation stimulates the release of inflammatory cytokines, such as tumor necrosis factor-α, which can further promote the recruitment of cells for adipose tissue growth and may contribute to PAH.

Stefani also hypothesized that the negative pressure suction used during cryolipolysis may stimulate adipocytes in the treatment area.[7] This mechanical stimulation of the adipocytes can potentially stimulate cell growth and proliferation, similar to the observed effect seen in typical external tissue expansion devices. These devices involve using a suction that is applied to the breasts for several hours per day, mechanically stimulating breast tissue to promote cell growth and increase breast size. Similarly, the negative pressure suction used during cryolipolysis might have a comparable stimulatory effect on adipocytes.[7] However, further research is needed to fully understand the extent of this stimulatory effect.

Histopathology

Histopathological examination typically reveals increased septal thickening and fibrosis, enhanced vascularity, and disorganized adipocytes of varying sizes and shapes.[2][12] Interestingly, a study by Seaman et al reported a decrease in adipocyte size and vascularity when examining the pathological changes of PAH at the cellular level.[13] The authors hypothesized that their findings might be attributed to analyzing PAH tissue at a different stage in its progression, as their study was conducted 7 months after treatment, compared to 3 months in the report by Jalian et al.[2][13]

History and Physical

PAH generally presents within 12 months of cryolipolysis as a painless, firm, and well-demarcated enlargement of adipose tissue confined to the treated area. Tissue growth is gradual and generally stabilizes after several months. PAH has been reported in all approved treatment areas, including the abdomen, submentum, bra fat region, thighs, flanks, and upper arms.

A thorough history and physical examination are essential for accurately diagnosing PAH. During history-taking, clinicians should ask about the patient's cryolipolysis experience, including the treatment timeline, areas treated, and any previous aesthetic procedures. The physical examination should focus on the morphology of the affected tissue, noting the firm, bulging appearance characteristic of PAH. The shape of the affected tissue is often described as a "stick of butter" because it generally reflects the shape of the applied applicator. The affected tissue is generally firmer than the surrounding unaffected areas.

Evaluation

The evaluation of a patient with PAH involves a comprehensive clinical assessment to distinguish it from other postprocedural complications. If PAH is suspected, imaging studies are used to assess the extent of adipose tissue hypertrophy and distinguish PAH from other conditions, such as lipomas or localized fat deposits.

Ultrasound can provide insight into the thickness and density of the adipose tissues. Computed tomography (CT) and magnetic resonance imaging (MRI) of individuals with PAH reveal an increase in subcutaneous adipose tissue with normal signal intensity localized to the previously treated area.[2][12] MRI offers a detailed view of tissue architecture and helps confirm the absence of inflammatory or malignant changes. Although biopsy is rarely needed, it may be considered to rule out other pathologies. 

Treatment / Management

The effectiveness of noninvasive fat loss modalities in treating patients with PAH following cryolipolysis remains unknown. Additional sessions of cryolipolysis are not recommended, as they have been shown to aggravate PAH symptoms and lead to further tissue growth.[1] 

Cytolytic therapy, such as deoxycholic acid (DCA), has been suggested as a possible treatment for PAH. DCA is a nonsurgical alternative for submental fat reduction that received approval from the US Food and Drug Administration (FDA) in 2015 as an injectable drug. DCA is a naturally occurring bile acid produced in the human intestines that emulsifies and solubilizes dietary fats.[14] Ward et al reported a case of an individual with PAH who experienced abdominal volume reduction after three treatments with DCA, highlighting the need for further studies to evaluate its potential as a treatment modality.[15]

A recent report also suggested that combining cryolipolysis with extracorporeal shock wave therapy (ESWT) may decrease the incidence of PAH.[16] ESWT is a noninvasive procedure that utilizes acoustic shock waves to treat various urologic, musculoskeletal, and soft tissue conditions.[17] The use of ESWT in treating cellulite has grown due to its ability to stimulate blood flow, promote collagen synthesis, and enhance tissue elasticity.[17] Michon reported no cases of PAH following 2291 treatment cycles of cryolipolysis, suggesting that ESWT may help prevent PAH by providing antifibrosclerotic effects and reducing oxidative stress in the treated tissue.[16]

Surgical management is the primary treatment for PAH, typically involving liposuction and/or direct excision, such as abdominoplasty. A customized treatment plan should be developed for each patient. Liposuction can be performed independently or in conjunction with one or more additional techniques, such as power-assisted, ultrasound-assisted, or radiofrequency-assisted methods.[18] Vibration amplification of sound energy at resonance (VASER) liposuction is often used to treat PAH by precisely targeting and breaking down the dense, fibrous fat tissue characteristic of this condition. This advanced technique can help achieve smoother contours and more effective fat removal in PAH-affected areas compared to traditional liposuction methods. However, without understanding the exact mechanism of PAH, it remains uncertain whether the added stress of invasive procedures might increase the risk of relapse.[19] The treatment plan should also include considerations for postoperative care and the potential need for additional procedures to achieve optimal results. Effective treatment planning requires close collaboration with a skilled plastic surgeon and ongoing patient education to ensure a comprehensive approach to managing the original complication.

Local inflammation may influence the timing of definitive surgical correction for PAH. A recent study by Kelly et al recommends waiting at least 6 months after diagnosing PAH before proceeding with the surgical correction to ensure complete resolution of local inflammation.[20] Performing invasive procedures before the inflammation resolves may increase the risk of relapse. A study by Khan in 2019 reviewed 4 PAH cases, finding that early treatments with ultrasonic liposuction, laser lipolysis, and radiofrequency skin tightening had failed in 3 cases.[21] The authors concur that liposuction and direct excision are effective treatments for PAH but should not be performed until 6 months after diagnosis to ensure that local inflammation has resolved.

Differential Diagnosis

The differential diagnoses of PAH include seroma, hematoma, lipomas, postprocedural edema or fibrosis, panniculitis, lymphoceles, hypertrophic scarring, hernias, and weight gain. Accurately distinguishing PAH from these conditions is crucial, as PAH requires specific management approaches.

Prognosis

PAH is generally considered benign and does not pose a direct danger to the patient. However, there have been no documented cases of PAH resolving spontaneously without intervention, suggesting that patients typically require invasive procedures, such as liposuction or direct excision, to address the resulting deformity.

Patients diagnosed with PAH often need multiple surgical interventions to effectively address the affected areas. Initial treatment typically involves liposuction to remove the hypertrophic fat. However, due to the firm and fibrous nature of the tissue, results can be inconsistent, often necessitating additional surgeries. In some cases, direct excision of the tissue may be required, which can result in scarring and may necessitate further cosmetic revisions. The complex nature of PAH and its resistance to nonsurgical treatments often require patients to undergo multiple procedures over an extended period to achieve satisfactory aesthetic results. Additionally, affected individuals frequently face significant out-of-pocket expenses, as insurance typically does not cover these corrective cosmetic procedures.

A diagnosis of PAH can have significant emotional consequences for patients. The condition often leads to distress and frustration, especially as cryolipolysis is intended to reduce fat and enhance appearance. Patients may experience a loss of self-esteem and body confidence due to the disfiguring nature of PAH, which can be particularly challenging for those who sought the procedure to improve their appearance. The extended timeline for diagnosis and the potential need for corrective surgery can heighten feelings of anxiety, regret, and dissatisfaction. Increased public awareness of PAH, including high-profile cases, may also contribute to feelings of isolation or misunderstanding, further intensifying the emotional burden of the condition.

Complications

PAH can lead to several physical and psychological complications. Physically, the primary complication is the unexpected and localized increase in fat tissue, which resists further noninvasive treatments and often requires surgical intervention. The fibrous nature of the hypertrophic tissue complicates treatment with liposuction alone, sometimes necessitating more invasive procedures such as direct excision, which can result in scarring, contour irregularities, and extended recovery times. Multiple surgeries may be needed, increasing the risk of complications such as infection, hematoma, and poor wound healing.

Psychologically, the disfiguring nature of PAH can cause significant emotional distress, including anxiety, depression, and diminished self-esteem. The condition’s unpredictability and resistance to treatment further exacerbate these issues, impacting the overall quality of life for those affected.