Pathophysiological dilemmas of lipedema
Introduction
More than 1.4 billion adults were overweight and more than half a billion were obese according to the WHO public data in 2008 [1]. Differential diagnostic purposes demand the discussion of obesity-related masquerading diseases. Regarding the physical and psychological conditions of patients suffering from altered subcutaneous fat deposition, these problems may be as severe as obesity. Large and continuously increasing efforts are made to help obese patients to regain their normal body weight, unlike in case of masquerading diseases, where the underlying pathomechanisms are poorly understood and effective treatments are not or hardly available. The etiology and pathophysiology of conditions with disproportional fatty deposits like lipodystrophies, multiple symmetric lipomatosis, Dercum’s disease and lipedema have not been clearly elucidated. Among these disorders, lipedema is likely to be one of the most common but often underdiagnosed conditions [2]. This review aims to outline the current knowledge and to give insightful ideas and theoretical clues regarding the presumed pathomechanism of lipedema.
Epidemiology of lipedema has been barely investigated. Child AH et al. estimated the minimum value of prevalence within the population as 1:72,000 [3].Besides, according to a study of Foldi et al., prevalence of lipedema was up to 11% among women and postpubertal girls in their test group [4]. Forner-Cordero et al. reported 18.8% of the patients in their unit with enlargement of the lower limbs between 2005 and 2012 [5]. Among patients hospitalized for lymphatic disease, the proportion is estimated as 8–17% [6]. Lipedema is extremely rare in the male population, however, few cases with testosterone or growth hormone deficiency, or liver disease have been reported [3], [7]. Children can also be affected. According to a recent study, 6.5% of infants with the referral diagnosis of lymphedema actually suffered from lipedema [8].
For a proper diagnosis, Wold, Hines and Allen proposed the following six diagnostic criteria in 1951 [9] (Table 1).
Based on the involved body parts, five types of lipedema can be differentiated [10] (Table 2).
Lipedema can progress through four stages [2], [11] (Table 3).
Primary options comprise lymphatic decongestive therapy, physiotherapeutic exercises, pain control, psychological support and liposuction. Occasionally, medications can also be considered: beta-adrenergic agonist for capillary leak syndrome, glucocorticosteroids for swelling and pain, cimetidine and beta glucan to improve the impaired local immune response due to edema [12], short-course of diuretics or selenium for lipedema with concomitant lymphedema [13]. Decongestive lymphatic therapy including manual lymphatic drainage, physical exercise, multilayered and multicomponent compression bandaging and meticulous skin care is the standard conservative approach for lipedema treatment [5]. Complex form of this decongestive lymphatic therapy has also been shown to decrease bruising, one of the hallmarks of lipedema [14]. Physiotherapy can also be combined with intermittent pneumatic compression (IPC) improving venous flow and decreasing lymph production [15]. However, it is doubtful whether IPC leads to additional improvement [16]. Another physiotherapeutical method, shock wave therapy has been found to reduce girth circumference and oxidative stress and to reshape body contour [17]. Liposuction is usually a temporal solution [18], [19] A precise summary of recommended treatments has been reported by Herbst [2].
Section snippets
Hypothesis of the pathomechanism of lipedema
Lipedema is a severe but often underdiagnosed disease [2], however, according to our recent knowledge, generally accepted, evidence based theory for the pathomechanism does not exist, which evoked urgent need for hypothetic issues. In the background of lipedema, polygenetic susceptibility is suspected, which may manifest in parallel with feminine hormonal changes. Several gene candidates playing a role in vasculo-or lymphangiogenesis and being under the influence of estrogen are supposed to be
Genetic background: is lipedema an inherited condition?
A suspected genetic background was reviewed by Herbst [2]. In up to 60% of patients, lipedema was suggested to be an inherited condition [20]. Based on a clinical report, studying 330 family members, a possible autosomal dominant inheritance with incomplete penetrance was suspected, however, exact genes involved in lipedema were not identified here [3]. Nevertheless, several studies on different animal models provided many possible genes, which could potentially be involved in the manifestation
Is the pathogenesis of lipedema hormonally influenced?
Estrogen has a direct effect on white adipose tissue through its estrogen receptors (ERα,β and G protein-coupled estrogen receptors) [31]. Considering the difference of androgenic and gynoid adiposity, this effect is likely to be body region-specific. The background mechanism was discussed in a study where an intravenous bolus of conjugated estrogen led to a lower level of decrease in basal lipolysis of the abdominal than of the femoral region [32]. A study of Gavin and coworkers may explain
Vasculopathy
Microangiopathy is one of the early histological features of the lipedemic pathomechanism [4], which may be due to the primary defect of the endothelial barrier function. Alternatively, hypoxia may result in increased fragility similarly to diabetic retinopathy [44]. Angiogenesis have several stimulators, including VEGF, Ang-1 and Ang-2 among others. In breast cancer, it has been suggested that VEGF generates leaky, hemorrhagic, immature vessels [45]. As tissue expansion requires imbalanced
Neuropathy in lipedema
As a part of the diagnostic criteria (Table 1), the affected subcutaneous regions are often tender and painful, which may cause difficulties in the application of bandaging, however, this pain is improved after mild manual lymphatic drainage [70] and liposuction [64].
In a single case report, reduced amplitude of sensory nerve action potential shown by nerve conduction study was attributed to: (1) mechanical forces (presence of serious edema and increased amount of subcutaneous adipose tissue)
Further ideas
Lipid composition is another barely investigated feature in lipedema. Stallworth et al. revealed altered fatty acid pattern and significant amounts of lipids in plasma and adipose tissue studying fourteen patients [84], but no further information has been found about this issue in the literature until now.
Regarding several features, lipedema may also have an etiological connection with another relatively rare disease, lipedematous alopecia. Only 24 cases were reported until 2007, including
Conclusion
As a summarized concept of the pathomechanism of lipedema has not existed until now even on hypothetic level, we attempted to find causal relationships relying on currently available literature data. If any experimental evidence supports this theory, it will lead to the better understanding of the development of lipedema and be able to provide effective, long-lasting therapy for patients.
Conflict of interest
All authors have approved the manuscript and agreed with submission to the Medical Hypotheses. The authors have no conflicts of interest to declare.
Acknowledgements
Creation of this manuscript was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4. A/2-11-1-2012-0001 ‘National Excellence Program’.
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Groma G., PhD and Szolnoky G., M.D., PhD have contributed equally to this work.