Abstract
Background:
Lipedema is a chronic condition characterized by abnormal deposition of subcutaneous adipose tissue, leading to pain. The lack of internationally recognized diagnostic criteria complicates the characterization of pain. Physiological parameters such as pain pressure threshold (PPT) represent promising prognostic markers for diagnosing lipedema, yet they remain understudied. This study aimed to evaluate the reliability and validity of two pain pressure measurements, PPT and the hand-held sphygmomanometer (HHS) in lipedema.
Methods:
A total of 28 adult females diagnosed with lipedema were recruited. Both PPT, using a digital algometer, and HHS, using a manual aneroid HHS, were performed to assess pain in the lower limbs. The testing was performed in a standing position with PPT and HHS placed on the calf. Intraclass correlation coefficient (ICC) and coefficient of variation (CV) were employed to assess the within session reliability, while the validity between PPT and HHS was analyzed using R2 in a linear regression model.
Results:
The results showed excellent reliability for both PPT and HHS, with ICC indicating high consistency (ICC = 0.93 to 0.97) and CV showing acceptable scores (CV = 3.62% to 9.06%). In addition, good validity between PPT and HHS was also observed (R2 = 0.69 to 0.74), suggesting that HHS can be a reliable alternative to PPT for pain assessment in lipedema.
Conclusion:
These findings have important clinical implications, as they expand the knowledge of pain characterization in people with lipedema, potentially aiding in diagnostic refinement. In addition, a cost-effective and accessible method for assessing pain was examined (i.e., HHS), showing promising findings and providing an objective method to help diagnose lipedema.
Introduction
Lipedema is a chronic condition characterized by bilateral and symmetric deposition of subcutaneous adipose tissue in the lower limbs and, to a lesser extent, in the upper limbs, excluding feet, hands, and trunk.1–4 From an epidemiological perspective, the prevalence of lipedema in females is estimated to be around 11%, with onset occurring before the age of 25 in 77% of the cases. 5 To date, the etiology of lipedema is not yet clear; however, it has been postulated that the hormonal system may play a crucial role in developing lipedema. 6 Indeed, lipedema appears to progress during specific phases of the female lifespan, such as puberty, pregnancy, and menopause, suggesting a potential association with circulating estrogen levels and, presumably, a genetic predisposition. 7 In addition, lipedema transmission may also occur on a genetic basis (i.e., autosomal dominant pattern with incomplete penetrance), despite the responsible gene has not been identified yet.8,9 However, despite recommendations for physical activity and a healthy lifestyle (e.g., diet), lipedema does not typically respond to these interventions.4,10
Although the growing body of evidence about lipedema, current diagnostic criteria in clinical practice are based on two points: the degree of subcutaneous adipose tissue proliferation and its anatomical distribution. 10 Such criteria may lead to confusing lipedema with other conditions such as lymphedema, obesity, or other adipose tissue disorders like lipohypertrophy.5,7 Despite observable signs and symptoms during physical examination, differentiating these conditions remains challenging. 11 Indeed, lipedema, unlike lymphedema, always presents bilaterally with soft subcutaneous tissue and no primary lymphatic damage. 6 Unlike obesity, lipedema affects limbs rather than the trunk and resists dietary interventions. 12 Gynoid lipohypertrophy differs from lipedema by lacking spontaneous or palpation-evoked pain.5,7 The absence of internationally recognized diagnostic criteria complicates the differential diagnosis process, meaning that new and objective criteria are needed to diagnose lipedema.
In the current literature, lipedema is considered a disorder that affects the connective tissue, particularly the subcutaneous adipose tissue. 12 In detail, this proliferative phenomenon, characterized by hyperplasia and hypertrophy of adipocyte cells, is associated with a chronic inflammatory process, resulting in spontaneous or palpation-evoked pain which differentiates lipedema from other pathologies (e.g., lymphedema), 11 and leading to consider pain a major distinct trait for people suffering from lipedema.6,13,14 The characteristics of lipedema-related pain have a negative impact on psychosocial well-being, including a reduced quality of life, physical activity, social participation, and alterations in body image.5,9,15,16 Pain is defined as a physiological sensory and psychological emotional experience, 17 and current evaluation of pain in people with lipedema includes the visual analog scale,18–20 the numeric rating scale, 21 or questionnaires such as PainDETECT. 22 Despite this, physiological pain characteristics have not been investigated in depth in people suffering from lipedema, especially when referring to the characterization of pain pressure. Recently, Chakraborty et al. 13 explored the mechanical sensitivity in people with lipedema compared to healthy controls, using von Frey filament stimulation on the thigh, calf, and arm. Interestingly, people with lipedema showed significantly higher sensitivity in the calf and arm, compared to controls. Subsequently, Dinnendahl et al. 23 observed that people with lipedema showed significantly reduced pain pressure threshold (PPT) at the lateral thigh compared to healthy controls, indicating hyperresponsiveness to pain pressure. Considering these findings, the authors of the aforementioned studies suggested that mechanical sensitivity as well as pain pressure assessment could be employed to categorize pain and help to improve the diagnosis of lipedema. However, to date, no other studies have been performed to characterize pain in lipedema, meaning that further research is necessary.
To the best of our knowledge, alternative devices to assess PPTs for lipedema-related pain have not been performed. For this reason, we hypothesized that measuring stimulus-evoked pain in people with lipedema may expand not only the understanding of pain in this cohort but also potentially provide new methods to assess and diagnose lipedema-related pain. In this regard, a digital algometer, measuring the PPT, has been used in only one study, 23 with no prior investigations examining pain in the calf among individuals affected by lipedema. In addition, taking into account not only the high cost of von Frey filaments and digital algometer but also the skills to correctly use such instruments, this may represent a barrier in clinical practice and limit their applications. Therefore, we also proposed the adoption of an inexpensive tool available in varied clinical settings which can be used for the same purpose, as the hand-held sphygmomanometer (HHS). 24 Thus, the aims of the current study were: 1) to examine the reliability of both PPT and HHS in measuring pain in the calf in people with lipedema; 2) to compare pain testing procedures of PPT and HHS.
Methods
Subjects
Adult females were recruited voluntarily from a private clinic in Italy. To be included in the current study subjects had to meet the following inclusion criteria: (1) older than 18 years of age; (2) diagnosed with lipedema from stage 1 to 3, confirmed through clinical and instrumental assessments (including medical history, observation, palpation, anthropometric measurements, ultrasound, bioimpedance analysis, and venous doppler);25–27 (3) diagnosed with lipedema type 3 or 5, characterized by fat distribution involving the lower limbs, particularly the calves;9,10,15 and (4) no lipedema-related surgical interventions (e.g., liposuction or other surgical treatments targeting lipedema) in the last 12 months.
Exclusion criteria were: (1) neurological disorders and (2) discomfort affecting their ability to perform PPT and HHS testing. All subjects were informed about the purpose of the study and informed consent was obtained before the start of the experimental study according to the Declaration of Helsinki. Ethical approval was also granted by the ethics committee.
Procedure
Demographic data were collected before the testing procedure. Subjects performed two familiarization sessions with both the PPT and HHS one week before the actual test. Then, PPT and HHS were performed in a random order with a 72-hour rest period between each test. Subjects were required to perform three tests on each leg with a 120-second rest between. Order selection of the limb (i.e., right or left) was randomly chosen using digital software. The average values were taken for subsequent analysis. Assessments were conducted by a trained clinician at the same time of the day and room temperature to minimize confounding variables.
PPT
A trained tester (L.F.) measured calf pain evocation using a digital algometer (JTECH Commander wireless, PowerTrack, Utah). The PPT testing was performed in a standing position with both hands lying on the table at 90° elbow flexion. The PPT was placed on the calf at a standardized location identified based on the literature. 28 A consistent pressure of 0.5 mm/second was applied perpendicular to the marked point until the subjects first experienced an unpleasant feeling. 29 Participants were instructed to keep their eyes closed and were not allowed to view the algometer monitor display. Results were recorded in Newton (N).
HHS
A trained tester (L.F.) measured calf pain evocation using a manual aneroid HHS (Boso Clinicus II, Vitamed, Germany). The HHS testing was performed in a standing position with both hands lying on the table at 90° elbow flexion. The HHS was placed and wrapped around the calf, ensuring that the marked reference point used for the PPT assessment was centered within the cuff. The HHS was pressured at 0 mmHg before the test and unordinary variation of the contact area between the cuff and the participant was checked during the test. Increments of 2 mmHg (minor lines) are displayed on the sphygmomanometer scale (major lines are displayed every 10 mmHg), with 300 mmHg being the maximum value. A gradual increment of the pressure, inflating the HHS, was applied to the calf until the subjects first experienced an unpleasant feeling. Participants were instructed to keep their eyes closed and were not allowed to view the HHS monitor display. Results were recorded in mmHg.
Statistical analyses
All data were initially recorded as mean and standard deviation (SD) in Microsoft Excel and later transferred to SPSS (version 25.0; SPSS, Inc., Armonk, NY). Normality was analyzed using the Shapiro–Wilk test. An average-measures two-way random intraclass correlation coefficient (ICC) with an absolute agreement and 95% confidence intervals, and coefficient of variation (CV) were used to assess the within session reliability of the test. ICC values were interpreted as follows: > 0.9 = excellent, 0.75–0.9 = good, 0.5–0.75 = moderate, and < 0.5 poor. 30 The CV was calculated using the formula: (SD [trials 1–3]/average [trials 1–3] × 100), with values < 10% deemed acceptable. 31
The validity between PPT and HHS testing was analyzed using unstandardized coefficients and R2 in a linear regression model. The significance level was established at p < 0.05.
Results
Twenty-eight adult females (40.7 ± 10.5 years; 75.5 ± 15.7 kg; 163.7 ± 6.2 cm; body mass index [BMI] = 28.2 ± 5.9 kg/m2; stage 3, n = 24; stage 5, n = 4) volunteered to participate in this study. All data were normally distributed (p > 0.05). Raw PPT scores (reported as mean ± SD) were 35.43 ± 14.47 N and 36.15 ± 15.16 N on the right and left sides, respectively. Raw HHS scores (reported as mean ± SD) were 166.53 ± 45.13 mmHg and 170.21 ± 42.46 mmHg on the right and left sides, respectively.
Reliability
Within the session, reliability data is reported in Table 1. Pain-evoked assessment using PPT showed “excellent” reliability with ICC ranging from 0.93 to 0.97, and CV between 3.62% and 3.71% (Table 1). Pain-evoked assessment using HHS showed “excellent” reliability with ICC ranging from 0.96 to 0.97, and CV between 7.94% and 9.06% (Table 1).
Relative and Absolute Reliability Using Coefficient of Variation and Intra-Class Correlation Coefficients of Pain Pressure Threshold and Hand-Held Sphygmomanometer Testing
CV, coefficient of variation; HHS, hand-held sphygmomanometer; ICC, intra-class correlation coefficients; PPT, pain pressure threshold.
Validity
Linear relationships between the right PPT and HHS were found, with coefficients of determination (R2) 0.74, indicating that at least 74% of the pain evoked during HHS was explained by the measures collected by the PPT (Table 2).
Linear Regression Model for Right Pain Pressure Threshold and Hand-Held Sphygmomanometer Testing (n = 28) (R2 = 0.74)
HHS, hand-held sphygmomanometer.
Linear relationships between left PPT and HHS were found, with coefficients of determination (R2) 0.69, indicating that at least 69% of the pain evoked during HHS was explained by the measures collected by the PPT (Table 3).
Linear Regression Model for Left Pain Pressure Threshold and Hand-Held Sphygmomanometer Testing (n = 28) (R2 = 0.69)
HHS, hand-held sphygmomanometer.
Discussion
The present study aimed to evaluate the reliability and validity of PPT and HHS, for measuring pain in the calf of adult females suffering from lipedema. Our results indicate that both methods demonstrated excellent reliability and good validity, providing valuable insights into new objective measures to assess and diagnose lipedema-related pain.
Reliability
Our findings showed that both PPT and HHS revealed excellent relative and absolute reliability. Specifically, PPT showed ICC values ranging from 0.93 to 0.97 and CV values between 3.62% and 3.71%, while HHS demonstrated ICC values ranging from 0.96 to 0.97 and CV values between 7.94% and 9.06%. Although HHS reports higher CV scores compared to PPT, these results suggest that both methods are consistent and reproducible for pain assessment in people with lipedema. Indeed, it should be noted that the lower reliability observed with HHS may be attributed to the manual nature of the HHS method, which may induce greater variability.
Validity
The study also examined the validity of HHS in comparison to PPT, with R2 values ranging from 0.69 to 0.74 for the left and right sides, respectively. Such findings suggest that a significant proportion of pain measured by PPT can be explained by the pain evoked during HHS testing. This relationship supports the use of HHS as a valid tool for assessing pain in individuals with lipedema, offering a cost-effective alternative to the digital algometer, whose cost may represent a barrier in daily clinical practice.
Clinical implications
To the best of our knowledge, this is the first study to assess the reliability and validity of pain pressure measurements in lipedema using PPT and HHS. Findings from our study deepen the knowledge pertaining to pain assessment in people with lipedema. Furthermore, our results corroborate similar findings observed in Dinnendahl et al. 23 The authors not only observed reduced PPT in the lower limb in people with lipedema compared with healthy controls but they also found that PPT was promising in its diagnostic ability (receiver operating characteristic > 90%). The underlying reasons are not fully understood; however, it appears that pain pressure is mediated by C and A-δ fibers, 32 and therefore, lipedema may affect such fibers as postulated by Dinnendahl et al. 23 Although anatomical sites differ from our study (i.e., thigh vs. calf), we deliberately chose the calf owing to deposition of subcutaneous adipose tissue in such area in people affected by lipedema recruited according to our inclusion criteria (i.e., lipedema stage and type). Our results are worth mentioning especially when considering the promising ability of PPT in predicting a diagnosis of lipedema. 23 To further expand this, we also observed that the PPT ranged from 35.43N to 36.15 N in our cohort, which is lower than values typically found in healthy individuals in the calf, with a mean of 48 N. 28 In addition, Chakraborty et al. 13 identified a significantly higher mechanical sensitivity (using von Frey filament) in the calf, when comparing people with lipedema with controls. It is worth noting that mechanical sensitivity engages primarily A-β fibers and to a lesser extent A-δ fibers. 33 While our study differs in methodology (pain pressure vs. mechanical sensitivity), both studies reinforce altered physiological characteristics of pain in the lower limbs in people affected by lipedema. Taken together, our results further support previous findings, 23 as evidenced by the presence of reduced PPT in people with lipedema.
Furthermore, we explored a cost-effective method such as HHS for pain assessment, which could significantly enhance the ability to characterize pain in lipedema. To further corroborate this, the use of HHS has recently gained attention in different clinical populations (e.g., musculoskeletal disorders) not only to measure pain but also muscle strength.34–36 The reasons can be attributed to its ease of use, low-cost, and availability, making it an attractive method for future investigations, which is in contrast with the use of digital algometer or von Frey filament used in studies involving lipedema.13,23 We observed that 69% to 74% of pain evoked using HHS was explained by the measures taken with PPT, which have been shown to be relevant in lipedema. 23 Simply put, HHS appears to possess an acceptable capacity to determine pain in people with lipedema. Although some limitations should be taken into account, the fact that the HHS can be wrapped around the calf and gradually inflated potentially allows a similar response in pain perception. Indeed, when considering the characteristics of lipedema, it should be noted that the deposition of subcutaneous adipose tissue affects the entire anatomical sites (e.g., thigh or calf), and not only a defined point (as per the PPT), leading to altered pain perception in the whole anatomical area. We could not speculate which types of fibers (e.g., A-β or A-δ) may be involved in such assessment; however, it can be assumed that a form of pain pressure was exerted when adopting the HHS. It is worth noting that more research is needed to precisely clarify the assessment of the HHS for people with lipedema; however, the novelty of our findings is promising.
From a practical point of view, the chronic inflammatory process associated with lipedema, characterized by hyperplasia and hypertrophy of adipocytes and subsequent tissue fibrosis, necessitates reliable pain assessment tools.11,12 Indeed, palpation-evoked pain has been commonly reported in people suffering from lipedema, yet comprehensive pain assessments remain underexplored in this population. Our study was the first investigation into the reliability of pain pressure assessments in lipedema, which is of utmost importance when considering the lack of knowledge pertaining to pain characteristics in lipedema. This may improve the characterization of pain in lipedema. Furthermore, considering the lack of internationally recognized diagnostic criteria, such findings may guide future investigations and help objective measures (i.e., PPT) to diagnose lipedema, based on the assessment of pain. Furthermore, the novelty of our results also demonstrated strong concordance between PPT and HHS. This suggests that future studies may consider its implementation to further expand new and objective measures to characterize and diagnose lipedema-related pain.
Limitations and directions for future research
Despite the promising findings, our study is not without limitations. Firstly, the sample size was relatively small and focused on a specific demographic, potentially limiting the generalizability of our results. Future studies should include larger and more diverse cohorts, possibly incorporating healthy controls for comparative analysis to better understand pain characteristics in lipedema. In addition, our study primarily assessed pain in the calf using HHS, which restricts the applicability of our findings to other body regions affected by lipedema. Therefore, future research should aim to explore pain responses across various anatomical sites to provide a more comprehensive understanding of pain patterns in lipedema.
From a future research perspective, considering the nature of pain and the uncertainties related to pain in lipedema, assessments at different time points may expand the confidence in the results given. Furthermore, assessing pain at different stages of the condition could enhance the reliability and clinical relevance of our findings. Moreover, further exploration of the interplay between psychological and physiological domains with pain traits in lipedema is crucial. Understanding these correlations, alongside their associations with physical parameters such as lower limb volume, fat mass, BMI, and muscle strength, will contribute to a more holistic approach to pain diagnosis in lipedema.5,15,16
Conclusion
In conclusion, our study demonstrated that both PPT and HHS are reliable and valid methods for assessing pain in people with lipedema. Our findings expand the knowledge pertaining to the physiological characterization of pain in lipedema. In addition, the excellent reliability and good validity of HHS make it a valuable and promising tool for pain assessment in clinical practice, offering a cost-effective method of assessment. Incorporating these validated tools is essential for enhancing diagnostic accuracy for lipedema. Future research should further investigate these methods across diverse stages of lipedema and anatomical sites to strengthen their reliability and validity, as well as relate these measurements to also psychological and physical domains. Overall, implementing reliable pain measurement methods is essential for improving the diagnosis of people with lipedema.
Footnotes
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Authors’ Contributions
F.B. drafted the article. L.F. and S.M. collected data. F.B. and L.M. ran statistical analysis. L.F., L.M., D.A., and S.M. edited and revised the article. All authors approved the final version before submission.
Author Disclosure Statement
The authors declare that they have no conflicts of interest relevant to the content of this study.
Funding Information
No funding was received for this project.
