Cellulite: nature and aetiopathogenesis

International Journal of Cosmetic Science, 2006, 28, 157–167 F. Terranova*, E. Berardesca  and H. Maibachà *International School of Aesthetic Medicine, Fatebenefratelli Foundation Rome,  Department of Clinical Dermatology,San Gallicano Dermatological Institute, Rome, Italy and àDepartment of Dermatology, University of California, San Received 25 January 2006, Accepted 15 February 2006 Keywords: cellulite, subcutaneous adipose tissue, ipodermis These theories must all now be updated in the light of recent advances on the sophisticated and Only a limited number of studies on cellulite have composite physiopathology of the adipose organ – been published in the international literature and which acts not only as a control device which many of them reach somewhat antithetical conclu- regulates the systematic equilibrium of energy sions. Consequently, it is not yet possible to recon- and modulates the food intake and the meta- cile the extreme differences of opinion which have bolism of other tissue substrate through a mul- lingered on for years concerning the nature of this disorder, as well as its origin and even the most basic aspects of its histopathological classification. Itdoes not even have a recognized name: in fact, the term ‘cellulitis’ is used in scientific English to indi-cate a spreading gangrenous infection of the subcu- Seulement un nombre limite´ d’e´tudes sur la cel- taneous cellular tissue. The other terms used from lulite a e´te´ publie´ dans la litte´rature internation- time to time [panniculitis, lipodystrophy, edematofi- ale et beaucoup de ces articles arrivent a` des brosclerotic panniculitis (EFP), liposclerosis, lipoede- conclusions plutoˆt antithe´tiques. Par conse´quent, ma, etc.] have quite different morphological and actuellement il est impossible de reconcilier les pathogenetic connotations in general. Over the last opinions extre`mement diffe´rentes concernant la few decades, three major conflicting theories have nature de ce de´sordre, ainsi que son origine, de emerged in relation to the ethiopathogenesis of cellu- meˆme que les aspects les plus basilaires de sa lite. These indicate, respectively, the following causes: 1. Oedema caused by excessive hydrophilia of the de cette affection n’est pas reconnu: en fait le terme ‘‘ cellulite ’’est utilise´ dans le language sci- 2. A homeostatic alteration on a regional microcir- entifique pour indiquer une inflammation du tis- culatory level; this pathogenetic theory is sum- su cellulaire sous-cutane´, d’origine infectieuse.
marized in a synthetic and self-explanatory Les autres termes employe´s de temps an temps tels que panniculopathie, lipodystrophie, pannicu- 3. A peculiar anatomical conformation of the subcu- taneous tissue of women, different from male lipoede`me etc. ont en general des connotations morphologiques e pathoge´ne´tiques tout a` faitdiffe´rentes.
Correspondence: Enzo Berardesca, Department of Clinical nies, trois principales the´ories contradictoires ont Dermatology, San Gallicano Dermatological Institute, Via e´merge´ pour ce qui concerne l’etiopathologie dela cellulite. Chacune the´orie indique respective- 52666157; fax: +39 06 52666158; e-mail: berardesca@berardesca.it ª 2006 Society of Cosmetic Scientists and the Socie´te´ Franc¸aise de Cosme´tologie 1. Oede`me cause´ par excessive hydrophilie de la ences in opinion which for years have lingered on the nature of this disorder, as well as on the origin 2. Alte´ration parcellaire de l’homeostase au niveau and even on the most basic elements of its histo- microcirculatoire ; cette the´orie pathoge´ne´tique pathological aspects. It is still lacking a recognized est re´sume´e a` l’inte´rieur de la synthe´tique et name: in fact, the term ‘cellulitis’ [2] is used in sci- explicite de´nomination: panniculopathie oede´ma- entific English to indicate an altogether different condition: a spreading gangrenous infection of the 3. Particulie`re conformation anatomique du tissu subcutaneous cellular tissue. The definitions of sous-cutane´ chez la femme, diffe´rente par rap- panniculitis [3] and lipodystrophy [4] include mor- bid forms which are clearly in a different category Ces the´ories doivent toutes eˆtre mises a` jour, a` to common cellulite. In short, the other terms used la lumie`re des recents de´veloppements concernant from time to time [edematofibrosclerotic panniculi- la sophistique´e et compose´e physiopathologie de tis (EFP), liposclerosis, lipoedema, etc.] have quite l’adipocyte, qui n’agit pas seulement comme entre- different morphological and pathogenic connota- poˆt de stockage du mate´riel calorique en exce`s mais aussi comme dispositif de re´gulation de There are many possible reasons for the lack of l’e´quilibre e´nergetique syste´mique, avec la capacite` thorough investigation on the subject. On the one de moduler l’ingestion d’aliments et le me´tabolisme hand, the huge amount of pseudo-scientific non- d’autres substrats tissutaires. La re´vision de ces sense circulating in relation to cellulite makes the the´ories doit eˆtre faite aussi sur la base des nouve- subject less than attractive to any serious study lles acquisitions concernant la modalite` attravers group. On the other hand, in Anglo-Saxon coun- laquelle cet organe re`gle les multiples se´cre´tions tries, where a large proportion of biomedical research is carried out, a theory has prevailed thatdoes not consider cellulite worthy of nosologicalstudy, considering it to be a ‘normal’ expression of Cellulite affects millions of women over the world.
The first attempt to define cellulite and the ori- All the media channels targeting the young female gin of the term itself both date back to the French population concentrate heavily on this problem and doctors Alquier and Pavot who, in 1922, described its various remedies: numerous methods and proce- a dystrophy of the mesenchymal tissues, without dures (surgical, pharmacological, phytotherapeutic, any phlogistic elements, which was characterized homeopathic, electro-medical, cosmetological, phy- by interstitial fluid retention. Alquier and Pavot sio-massotherapeutic, etc.) have all achieved a fleet- considered the disorder to be an elementary reac- tion of the connective tissue resulting from noxae ineffective. Of course, this does not prevent beauty of various natures (traumatic, toxic, infective and clinics and health farms from continuing to gain astronomical sums of money based on their relent- Over the last few decades, three main contrasting theories have emerged on the aethiopathogenesis of Given such a heartfelt problem, medical science cellulite, with mixed fortunes. These theories indicate, appears to have made incredibly mediocre progress respectively, the following causes of the problem: in resolving it: a search of Medline reveals that 1. oedema resulting from excessive hydrophilia of international journals have published only a small number of studies on the subject, all of which reach rather antithetical conclusions. Even more 3. a different anatomical conformation of the sub- surprising is the disinterest displayed towards the cutaneous tissue in women compared to men.
‘cellulite problem’ not only by University Insti- These are discussed in greater detail below.
tutes, but also by the research laboratories belong-ing to the major companies within the cosmetics sector, which nonetheless provide a valuable con- tribution to our increasing knowledge in relationto the physiopathy of the skin. Consequently, it is In 1964, Bassas-Grau and Bassas-Grau [5] des- not yet possible to reconcile the substantial differ- cribed the phenomena of hyperpolymerization of ª 2006 International Journal of Cosmetic Science, 28, 157–167 acid mucopolysaccharides in the connective matrix are mobile and painful, varying in diameter of the subcutaneous tissue of patients suffering between 1 and 5–6 mm; histological sections indi- from cellulite. They attributed the cause to an cate a profound subversion of the subcutaneous tis- abnormal increase in tissue hydrophilia, provoking sue, with connective bands encircling adipose Although not confirmed by other authors [6–8], become sclerotic; there are also haemorrhagic or this observation exerted a lengthy influence over therapeutic approaches, justifying the topical or linked these regressive processes in a pathogenetic mesotherapeutic administration of hyaluronidase interpretation which identifies the primum movens and other agents known to have a lithic action on in the compromission of the delicate homeostasis at a microcirculatory level [13–18].
More recently, Lotti et al. [9], using ruthenium Curri takes the cue for his observations from a thorough anatomical–physiological study of the ter- examined the dermis of the skin covering the areas minal branches of the circulatory system: the func- of adipose tissue affected by cellulite; there was a tional base element is the microvascular-tissue unit marked increase in the presence of glucosaminog- [19], formed by the regional distal vessels (afferent lycans, together with signs of fibroblast activation, arteriole, metarteriole, precapillary sphinters, arterio- alterations in microvessel walls, as well as rarefac- venous anastomosis, capillary network, efferent tion of subepidermal collagen and elastic fibres.
venules and initial lymphatics) and by the perivas- According to the authors’ theory, repeated in a more recent re-evaluation [10], the histochemical mechanical support to the delicate capillary wall (mucopolysaccharide sleeve [20]), and also acts as a response which, through the retention of liquids in dynamic filter in the metabolic exchanges between the interstitial matrix, can result in new collagen deposition in the subcutaneous tissue.
The motor of the haematic microcirculatory cur- rent is known as vasomotion, the rhythmic con-tracting action of the arteriolar myocells [22], with a frequency varying between three and The most popular theory, at least in Europe, 20 cycles per minute, in relation to local condi- explains cellulite as the consequence of a primitive tions (interstitial pressure, PO2, etc.). The vasomo- dysfunction of the tissue microcirculation. Indeed European researchers have mainly contributed undulatory variations of the flow (flowmotion) substantially towards the development of this Recent advances have clarified that endothelium Binazzi [11] set a milestone in the interpretation is key to the microcirculatory homeostasis. Endothe- of the histopathological aspects of cellulite thanks lium does not just perform a purely mechanical role to a series of observations which enabled him to function of endoluminal coating; it also modulates develop a pathogenetic theory which is still blood–tissue exchanges and, through a complex adhered to today, and to summarize it with a syn- biosynthesis action resembling a diffuse glandular thetic and self-explanatory term: EFP [12].
function, manages the equilibrium between many According to Binazzi, the initial stage is often phenomena (pro and anti-coagulant, fibrinolitic associated with adiposity and is clinically charac- and anti-fibrinolitic, vasodilatory and vasoconstric- terized by irregularity of the cutaneous surface on tive) in order to regulate, in real time, the local the buttocks, thighs, abdomen and shoulders, the functionality of the microcirculation according to so-called ‘mattress’ effect. Histological examination the changeable demands of the cells [24].
reveals only an extreme variability in the size and Curri and Merlen [25] clarified the morphologi- cal peculiarities of the microvascular-tissue unit of together with oedema of the dermis, dilation of the the subcutaneous tissue, which is characterized lymphatic vessels and patches of follicular hyper- The subsequent stage is distinguished by the branches, in near proximity to adipocytes and presence of nodular lesions on palpation, which reducing the ‘diffusion space’ to the minimum; ª 2006 International Journal of Cosmetic Science, 28, 157–167 • absence of arterio-venous anastomosis: it leads tonic phlebopathy (the preclincal stage of venous to the deduction that the continuity of apidocyte perfusion is a condition which cannot be sacri- • branches connecting the arteries and veins of • compromission of the hydrostatic capillary equi- adipose tissue to the vascular plexus of the der- mis and muscular tissue: these form cylindrical • reduced parietal and tissue oxidation; units, arranged perpendicularly to the surface of • endothelial damage (endothelial swelling, mic- the skin and reaching from the latter to the hypodermis [26]. This justifies the fact that the • abnormal capillary-venular permeability; microcirculatory deficits of panniculopathy are • increase in the hydrostatic pressure of the inter- often associated with alterations in the blood stitial liquid and in its protein content [35]; flow extending to the skin and regional muscu- • recurring episodes of inter-adipocyte oedema.
lature, where they cause both clinical (hyper- The damage caused to the adipocytes manifests itself initially with an anisopoichilocytosis, followed by ruptures of the plasmatic membrane and leak- The presence of oestrogen receptors in the age of lipidic material. The fine interweaving of endothelial cells and smooth muscle [30] explains delicate fibrils which serve as the framework for the functional differences of the female microcircu- the adipose lobule, enveloping each individual cell lation [31, 32], especially in relation to vascular (we now know that each adipocyte is coated with a basement membrane [36]), thickens due to hyp- On the basis of these suppositions, together with oxia and the consequent oxidative stress [37].
a thorough analysis of histological and clinical– Bands of young connective tissue form, creating instrumental data, Curri constructed his theory on the lobule by encircling clusters of degenerate adi- pose cells [38, 39]. Subsequently, the micronod- The causal factor is identified as a chronic ules formed in this way tend to merge due to the microcirculatory maldistribution, which is in turn further apposition of collagen material which due to a primitive defect of the arterial device becomes sclerotic, leading to the production of pal- modulating the blood flow or to an inadequacy of pable macro nodules, which cause the irregularity vasomotion. The consequences of this condition, which can be classified within the sphere of hypo- Curri identifies four stages to this process [40]: massive microvessal dilatation, fibrillopoiesis Neoflibrillogenesis, degenerate adipocytes surrounding macronodules. Local dystrophic phenomena of the dermis and the epidermis ª 2006 International Journal of Cosmetic Science, 28, 157–167 Bartoletti et al. have provided significant contri- accessible by means of bioptic examination. If cel- butions to the definition of cellulitic dystrophy.
lulite is simply the expression of a localized excess The first contribution was of a nosological nature.
of adipose tissue, then why is the appearance of Curri, attributing to the pannicular perfusion defi- this unsightly problem limited almost exclusively cit the capacity to increase the lipidic deposit [41], to the female gender, and only to certain areas of associated the pathogenesis of EFP with that of regional subcutaneous tissue thickening. Bartoletti made a more clear-cut distinction between panni- [62], referring to the results of histological exami- culopathy and localized peritrochanteric adiposity nations carried out on a wide range of cases (150 in females, and reclassified the latter within the samples from corpses and 30 from live subjects), sphere of morphological and physiological normal- ity, albeit without negating the possibility of inter- oedema or of fibrosis. In fact, they attribute the manifestation of cutaneous irregularity in typicalfemale areas to the combination of two causal In fact, the presence of oestrogen receptors on adipocytes [43, 44] explains the typical female fat • excessive lipidic deposit (there is no cellulite distribution, which is a consequence of the modu- lation exerted by these hormones on the lipase • the peculiar architecture which, in women, [45, 46] and lipoprotein-lipase [47, 48] activities.
characterizes the subcutaneous tissue in these Furthermore, Bartoletti et al. [49, 50] completely areas, where fibrous branches perpendicular the re-examined the semiological and clinical classifi- skin’s surface separate voluminous lobules in cation, codified the diagnostic procedure[51] (iden- rectangular sections; their peaks press against dermis and push outwards, in the form of ‘adi- examination, the phlebological study, the postural The dermo-hypodermic border is therefore char- [52–55]) and developed the most followed thera- acterized, in ‘cellulitic areas’, by a ‘hill’ profile peutic protocols at the present time [56, 57].
which, in the case of perfect normality, can beproved with the ‘pinch test’. This action, whichplaces in traction the non-stretchable connective tissue bands, highlights surface undulations even in very slim subjects. Women who develop a thicken- Numerous authors, such as Cambar et al. [58], ing of the subcutaneous panniculus in the areas Braun-Falco and Scherwitz [6], Ribuffo et al. [59] typical of gynoid adiposity have enlarged lobules.
and Calvieri et al. [60], have denied that, in areas These are held back along the sides by the bands, where the clinical aspects of cellulite appear, it is however, at the centre they stretch out into the der- possible to discern, with an optical and electronic mis, with hypertrophic adipose lobes, thus creating microscope, histological modifications different to an unattractive alternation of bumps and troughs those commonly observed in the zones of macro- which are first evident only when standing upright, scopically ‘normal’ adipose tissue accumulation.
but are subsequently also visible when lying down.
These observations lead to the widely held con- On the other hand, in male subcutaneous tissue, ception, especially in Anglo-Saxon countries that the bands take a different course, crisscrossing and views cellulite as a simple manifestation of lipidic accumulation [61]. This provides a stark contrast which, even in cases of lipidic hyper-accumulation, do not tend to protrude towards the dermis. In Clearly, the existence of differing opinions within hypogonadic males, the adipose tissue assumes a the realms of science is not unusual. However, the fact that this controversy is based on the expres- activity is the causal factor of any gender-related differences. Numerous reviews on the subject of assumptions produces a certain amount of perplex- cellulite have confirmed the opinions expressed by ity: it seems surprising the persisting of such wide margins of disagreement on the definition of mor- Amongst these, Marenus theorized that the pro- phological aspects in structures which are easily jection of the adipose lobes towards the dermis is ª 2006 International Journal of Cosmetic Science, 28, 157–167 brought about by the degeneration of the collagen In short, on the basis of the study of 39 post- component of the latter, resulting from the action mortem samples, Pierard et al. [70], although con- firming the presence of adipose lobes in the female Rosenbaum et al. [66] also noted an individual sex, concluded that these formations were too variability in addition to gender-related differences; small to be capable of producing the coarse combi- the subcutaneous tissue in women with cellulite is nation of convexity and depression typical of cellu- characterized by a more irregular and broken sub- lite. However, this case would be due to the dermal layer, which is the factor enabling the adi- progress of the adiposity, which cause a stretching of the interlobular branches; some of these would Querleux et al. [67] employed, in over 70 sub- undergo to retraction phenomena (due to reactive jects, magnetic nuclear resonance (MNR), using thickening and to the appearance of myofibro- both imaging and spectroscopy techniques. The blasts), whilst others would suffer partial lacera- former recorded the indented profile which the adi- tions, similar to stretch marks, causing irregular pose lobes make on the dermo-epidermic border, protrusions of adipose lobules. This observation led and confirmed the different orientation of the con- the authors to try a therapeutic approach with ret- nective bands in males compared with females inol, although this produced only a modestly bene- (although the difference did not appear to be as ¨ ller). According to the authors, the MNR spectrometry data ruled out the possibility of an inter-adipocytary oedema occurring in cellulite.
An even more recent study, using magnetic nuc- Clearly, the debate surrounding the topic of lear resonance imaging (MRI) to examine the mor- provided further evidence of the structural differ- ences relating to gender [68]. It proved once again Moreover, the impasse which still exists due to the pathogenetic significance of the ‘herniation’ of the lack of solutions to relatively basic questions adipose lobes in the reticular dermis in female sub- runs the risk of being overtaken by the advances of by other branches of medicine in relation to brought to light two interesting pieces of data: the the comprehension of the physiology of the adi- first relates to the absence of a direct correlation pose tissue and endothelium, the two key cellu- between the body mass index (BMI) and the lar elements associated with the development of appearance of irregularities of the cutaneous sur- face: amongst the women whose BMI is over 30, In particular, new developments are bringing to it is possible to distinguish women with no signs light a limitation which is shared by the two main of cellulite and subjects who are more or less theories on the origin of cellulite. According to the severely affected by this dysmorphism. This dem- onstrates that other factors, in addition to localized ¨ ller, adipose tissue, the area of distortion, does excess adipose tissue, play a part in the dislocation not play a significant role in the onset of cellulite: of adipose hernias. The second piece of data relates it participates only with a purely physical function, to the fibrous component of the subcutaneous tis- producing mechanical tension through its hyper- sue affected by cellulite: the MRI showed that its trophy. Such claims carry traces of an idea which overall size did not increase but, on the contrary, is now outmoded, which sees within the adipose appeared to have reduced substantially in compar- tissue a cellular element with limited capacities, ison with the controls. The authors therefore iden- used only for the storage of excess calorific sub- tify one of the pathogenic elements of cellulite as a strates. Given the illogical aspect of attributing constitutional thinness and laxity in the fibrous extensive pathogenetic ‘responsibilities’ to such an interlobular bands [68]. Further confirmation of apparently banal cytotype, the causal factors of this theory is provided by a recent study in which the visco-elastic properties of skin affected by cellu- Today we know that the adipose organ performs lite were compared with those of unaffected skin sophisticated and composite functions[72], acting ª 2006 International Journal of Cosmetic Science, 28, 157–167 • device controlling the systemic energy balance, of far more dynamic connections, with a bidirec- able to modulate the food intake and the meta- tional course [109, 110]. In fact, we know that bolism of the substrata of other tissues; adipose tissue is able to modulate, directly or indi- • glandular system for multiple hormonal and rectly, the blood flow which passes through it in para-hormonal secretions[73–76], not only cap- accordance with the demands exerted on it [111].
able of carrying out the bio-conversion of circu- Furthermore, the adipocytes secrete neoangio- genetic elements [112] and numerous other sub- synthesize de novo regulation elements of a pro- stances with the ability to regulate the activity of The following substances released by the adipose The most recent studies inform us that, in obese tissue are known to have an endocrine and/or encountered by the adipocytes, as they become hypertrophic, is an increase in the release of phlogo- genic cytokines [113, 114]. This cause systemic effects and at the same time induce, in the appar- ently ‘normal’ adipose tissue as a whole, a macro- • tumour necrosis factor (TNF)-a [84–87] and sol- phagic infiltration proportional in size to the average adipocytaric volume[115–117]. Therefore, adiposity entails the activation, on a regional level, of biochemical–cellular mechanisms of a phlogistic nature. Paradoxically, these remain subclinical in the area of production, whilst causing metabolic repercussions from a distance, on the organism as a • angiotensinogen and angiotensin II [94]; whole, contributing to the development of insulin resistance and cardiovascular diseases [118, 119].
• transforming growth factor-beta [96]; At this point, it is not unreasonable to hypothes- • plasminogen activator inhibitor-1 [97]; ize that inflammatory processes (similar or differ- • vascular endothelial growth factor [98, 99].
The apparent significance assumed by excess accumulations of cellulite, where they could play adipose tissue, especially the visceral type, in the quite a plausible role in its pathogenesis, rendering pathogenesis of insulin resistance and diabetes them responsible, for example, for the endothelial [100, 101], similarly to that of atherosclerosis alterations and the oedema described by Curri. Cel- [102] and cardiovascular diseases in general lulite could therefore prove worthy of its name, [103], explains the huge amount of studies devo- rightfully winning back its distinguishing features ted in recent years to the biology of adipose tissue.
as a disorder originating primarily from inflamma- Amongst other observations, one factor which has tion. Unfortunately, no studies have been published been highlighted is the significant plasticity of the to date to prove or disprove this theory. Similarly, adipose tissue, due to the presence of undifferenti- on a more general level, no data are available to ated mesenchymal elements which are capable, clarify whether, and if so in what way, the recently when necessary, of converting themselves into adi- identified functional properties of the adipose tissue pocytes [104, 105]. Apoptosis phenomena coun- are involved in the pathogenesis of this problem.
teract the neoadipogenesis; these can reduce thenumber of adipocytes in a certain area [106–108].
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