ABSTRACT

Subcutaneous adipose tissue diseases involving adipose tissue and its fascia, also known as adipofascial disorders, represent variations in the spectrum of obesity. The adipofascia diseases discussed in this chapter can be localized or generalized and include a common disorder primarily affecting women, lipedema, and four rare diseases, familial multiple lipomatosis, angiolipomatosis, Dercum disease, and multiple symmetric lipomatosis. The fat in adipofascial disorders is difficult to lose by standard weight loss approaches, including lifestyle (diet, exercise), pharmacologic therapy, and even bariatric surgery, due in part to tissue fibrosis. In the management of obesity, healthcare providers should be aware of this difficulty and be able to provide appropriate counseling and care of these conditions. Endocrinologists and primary care providers alike will encounter these conditions and should consider their occurrence during workup for bariatric surgery or hypothyroidism (lipedema) and in those that manifest, or are referred for, dyslipidemia or diabetes (Dercum disease). People with angiolipomas should be worked up for Cowden’s disease where a mutation in the gene PTEN increases their risk for thyroid and breast cancer. This chapter provides details on the pathophysiology, prevalence, genetics and treatments for these adipofascial disorders along with recommendations for the care of people with these diseases. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

People with subcutaneous adipose tissue (SAT) diseases have fat within this compartment that grows abnormally in amount or structure, often causing pain and other discomfort. Subcutaneous adipose tissue is loose connective tissue, or adipofascia, which is the most common type of connective tissue in vertebrates. The focus of this chapter is on abnormal SAT that has within it changes in blood vessels, lymphatic vessels, immune cells, mesenchymal stem cells, fascia, interstitial matrix organ, or other components that make up loose connective tissue.

The SAT diseases discussed here include lipedema, which commonly occurs in women, and four rare adipose tissue diseases (RAD): familial multiple lipomatosis, angiolipomatosis, Dercum disease, and Madelung disease (1). Adipose tissue in SAT diseases is resistant to loss by usual measures including extreme dietary changes (both hypocaloric and in macronutrient content) and exercise. Because of this, it is often referred to persistent fat tissue. People with diabetes and/or obesity may have a mixture of normal and persistent fat, making the understanding of SAT diseases by clinicians important in the care of these patients. Persistent fat may also be found in conditions where adipose tissue proliferation occurs, such as during infection, in autoimmune diseases, in those with hypermobile joint disorders, or with exposure to environmental toxins. Information on subcutaneous adipose tissue diseases not discussed here can be found in recent reviews and other Endotext chapters, including those covering lipodystrophies (2-4), cellulite (5), obesity (6,7), and other fat depots such visceral fat (abdominal, perirenal, pericardial), and perivascular fat (8).

Along with the gut (9), subcutaneous adipose tissue is thought to be one of the largest endocrine organs in the body (10). Subcutaneous adipose tissue houses immune cells including monocytes/macrophages, mast cells, and lymphocytes, which produce some of the hormones secreted by fat tissue (11,12). Greater amounts of fat and immune cells result in an inflammatory process that can lead to insulin resistance and slow intrinsic pumping of lymphatic vessels, which, in turn, may prolong inflammation in this tissue (13).

Patients, most often women with swelling, have slow blood flow in, and lymph flow out of, depots of increased fat on the abdomen (14,15) or the gynoid area (hips, thighs and buttocks) (16). Poor blood and lymph flow through fat tissue results in accumulation of fluid, cell waste material, proteins, cells and other metabolic products in the extracellular matrix (ECM) around adipocytes and other components of adipofascia, resulting in a hypoxic environment, especially in adipocytes furthest from their nutrient and oxygen sources. These adipocytes then send signals that recruit more immune cells, resulting in a state of sustained inflammation and tissue degradation. Connective tissue then replaces degraded tissue in a process called fibroplasia or fibrosis. When tissue ischemia occurs or ECM accumulation outpaces its degradation, fibrosis may become unchecked and lead to widespread pathological remodeling of the ECM culminating in permanent scar tissue that completely inhibits flow through the adipose tissue (17).

Obesity is a main cause of densification of fascia and fibrosis development in loose connective tissue (18). The result is a fibrotic mesh around adipocytes and fat lobules which has been well described (19). This sick fat, or adisopathy, increases the risk of metabolic disease (20). In addition, more fibrotic adipose tissue is less responsive to mobilization and reduction attempts through diet, exercise, use of weight loss medications, or bariatric surgery (19,21,22). All the SAT disorders in this chapter have a component of fibrosis in the tissue that prevents loss by usual measures. An important goal is to determine why the loose connective tissue in SAT diseases becomes fibrotic and adisopathic to prevent its occurrence and progression and treat when identified.

LIPEDEMA

Lipedema is a common SAT disease that was first described in 1940 at the Mayo clinic by Drs. Allen and Hines (23). A second seminal paper in 1951 provided a description of lipedema that is still commonly used for clinical diagnosis. Lipedema occurs almost exclusively in women but has been reported rarely in men (24-26).

Lipedema fat is located just under the skin on the limbs including upper arms, hips, buttocks, thighs, lower legs, generally sparing the trunk and feet. It feels nodular when palpated, may be painful to touch, and often has prominent superficial veins. Lipedema tissue can be found under the umbilicus and in some woman, a deeper nodular adipofascia is found in the lateral abdomen. This inner nodularity may reflect changes in the ECM that may be a precursor to lipedema fat if abdominal obesity develops. Disease defining key questions and physical examination characteristics can help to establish the diagnosis of lipedema (Figure 1).

Figure 1.

Characteristics of lipedema that aid in establishment of diagnosis are listed, and many can be seen in the accompanying photo. This patient was diagnosed with Stage 3, type III and IV lipedema without lymphedema (see below). A quick and easy set of questions and exam findings are included to help in diagnosis of women with lipedema.

Classification of Lipedema

Lipedema is classified by stages and types (27). In Stage 1 (Figure 2) the skin surface is normal over an enlarged hypodermis that already has palpable pea-sized nodules in the fat. These pea-sized nodules represent enlargement of and fibrosis in the ECM and in the connective tissue surrounding the fat lobule. Stage 2 skin is uneven with indentations (like cellulite) representing thickening and contraction of underlying connective tissue fibers over increased fat with small to larger hypodermal masses. Lobular extrusions of skin, fat and fascia tissue in Stage 3 represent significant loss of elasticity in the adipofascia drastically inhibiting mobility; blood flow in and lymph flow out of the lobules is reduced resulting in inflammation followed by fibrosis; it is in this stage that fibrosis in the tissue becomes prominent and clearly palpable; fibrosis may or may not affect the skin and the skin may develop thinning and a looser connection to the underlying hypodermis (Figure 1). Modifications of diagnostic criteria for lipedema have been suggested (28).

Lymphedema can occur at any stage, but is more often found in women with Stage 3 lipedema when it is often called lipo-lymphedema or Stage 4 (26). Rather than use this combined term, however, it is preferable to identify the lipemia stage and state whether lymphedema is also present or not. Lymphedema can be identified in women with lipedema by visible swelling of the hands or feet, pitting edema, asymmetry between the size of one limb versus the other, and/or a positive Stemmer sign. A positive Stemmer sign occurs when edema in the limb makes it difficult to pinch skin on the great toe, top of the foot, finger, or dorsal hand. A negative Stemmer sign occurs when only skin is pinched. Other differences between lipedema and lymphedema include symmetry (lipedema tissue occurs symmetrically versus lymphedema, which is usually unilateral), sparing of the hands and feet in lipedema, and report by patients of pain in lipedematous but not lymphedematous tissue.

Figure 2.

Three stages of legs of women with lipedema with subcategories of types. In Stage 1, the skin is smooth, and the legs can appear normal but there is pain, easy bruising and a nodular feel to the fat tissue. In Stage 2, the lipedema fat exhibits a mattress-like pattern indicating fibrosis under the skin that tethers on the skin that can be found on the upper legs (Type II) or extend down to the ankles (Type III). In lipedema Stage 3, there are folds of tissue and the lipedema fat usually extends down to the ankles. For description of the types of lipedema, see Figure 3.

The type of lipedema is defined by its anatomical location (29). Women with Type I lipedema have affected fat on the pelvis, buttocks and hips (saddle bag phenomenon). Women with Type II have affected fat from the buttocks to knees with formation of a tender deposits of fat around the inner side of and below the knee. Women with Type III lipedema have affected fat from the buttocks to ankles where a prominent “cuff,” or ledge, of fat tissue develops. Women with Type IV lipedema fat have affected arms and women with Type V lipedema, a rare type, have only affected lower legs. The most common phenotype of women with lipedema are combinations of II and IV or III and IV (Figure 3).

Figure 3.

Types of lipedema fat. Lipedema fat may be located from the umbilicus down to the bottom of the hips (Type I), down to the medial knees usually including a pad of fat on the inner knee and below the knee (Type II), and down to the ankle (Type III) where a “cuff” of fat develops but spares the dorsal foot. Rarely only the lower legs are affected (Type V). Lipedema affecting the arms alone is rare (Type IV) and, instead, usually is found in combination with Type II or III lipedema. The arms can be variably affected with nodular lipedema fat around the cubit nodes, over the brachioradialis, down the medial arm to the wrist in line with the thumb or 5^th digit, the entire lower arm, or the entire arm.

Conditions Associated with Lipedema

Obesity

Women with lipedema are often are often thought of as having common obesity whether or not they meet BMI criteria for this condition. The two striking differences between women with lipedema and women with obesity are that women with lipedema often have tenderness of the affected tissue and/or easy bruising of the skin overlying the lipedema fat, which is not found in women with common obesity (Table 1). However, some women with lipedema do not have pain in their tissues. It is unclear if women with lipedema with pain have the same disease as women without pain. Of note, women with lipedema may have no pain in their lipedema fat tissue when they are well-controlled under treatment regimens, however, they should still be considered to have lipedema. For example, women with lipedema who eat low inflammatory foods, avoiding processed starch and sugar, who exercise most days of the week and wear compression garments on their legs can have minimal to no pain. Therefore, a good history is important to identify a history of pain in the tissue that would be indicate the presence of lipedema. As described above, helpful measures to differentiate women with lipedema from women with common obesity include the disproportionate distribution of their adipose tissue between the trunk and legs, any family history of lipedema, as well as a historical inability to lose much fat from the lipedema-affected areas. On the other hand, when women with obesity and lipedema lose more substantial weight through medical or surgical interventions, they can lose some fat from the areas with lipedema, which can then leave them with rolls of excess skin along in the areas of remaining lipedema fat tissue (Figure 4).

Table 1.

Clinical Similarities and Differences Between Lipedema and Obesity

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Sign/Symptom	Lipedema	Obesity
Sex affected	Females	Females and Males
Onset	Puberty	Any age
Increased fat	Common	Common
Gynoid disproportion	Common	Possible
Influenced by lifestyle	No	Yes
Tenderness of the tissue	Common	Absent
Easy bruising	Common	Absent
Pitting edema	Uncommon	Uncommon
Stemmer sign	Negative	Negative
Able to lose fat from the legs/hips	Minimal	Common

Obesity (especially abdominal/visceral obesity) and/or polycystic ovary syndrome can worsen lipedema severity. This is thought to be mediated by increases in adipokines, tumor necrosis factor alpha (TNFα) and leptin that often accompany these conditions, which are associated with venous disease (83). Venous dysfunction that can lead to leakage of fluid back into tissue due to reflux may also be an important contributor to worsening of both lipedema and lymphedema, when present (84,85).

Figure 4.

Fat due to obesity and fat due to lipedema can be intermixed on the legs. With weight loss, the obesity fat can be lost resulting in excess skin and lipedema fat tissue remaining on the legs.

Lymphedema

Women with lipedema are at risk for developing lymphedema, which may happens in lipedema Stage 3 > Stage 2 > Stage 1 (26). The presence of lymphatic disease or lymphedema increases the risk of cellulitis and wounds, which can be difficult to manage and disfiguring. Women with heavy limbs and swelling should be considered for manual lymphatic drainage and deeper tissue therapies such as instrument assisted soft tissue therapies (e.g., Astym therapy, Graston technique) or manual therapies (e.g., myofascial therapies or other deep tissue therapies (86)), followed by compression plus reduction of obese adipofascia to reduce the risk of developing lymphedema.

Psychosocial

Psychosocial issues are prominent in women with lipedema including appearance-related distress and depression (87), which can result in eating disorders (88). This is not surprising in the United States where very thin women or photos of women that have been photoshopped to accentuate the appearance of leanness are posted on the internet and on television. Imagine how a woman in today’s society might feel who developed lipedema at puberty and is told to diet and exercise by friends, family and healthcare providers to lose weight, something that she has done for years to no avail. One author polled women in Germany and found a high rate of suicide attempts in women with lipedema (89). Lower mobility associated with lipedema and obesity were also found to affect quality of life in women living with lipedema (87) and may contribute to social isolation. Prevention and management of obesity in women with lipedema becomes paramount to maintain their quality of life. High anxiety is associated with hypermobile joint disorders (90), and because hypermobile joint disorders are associated with lipedema (25), anxiety should be assessed and treated to help women living with lipedema.

Dercum Disease (painful lipomas)

Lipedema can be present in the same individual who also has Dercum disease (see below), and in this instance, would be considered a mixed disorder. Authors have tried to differentiate women with lipedema from those with Dercum disease by examining populations and finding that people with Dercum disease tend to have other pain disorders including higher pain scores, fibromyalgia, abdominal pain, and migraines, and more often have lipomas, cognitive dysfunction and shortness of breath; whereas women with lipedema have more often fibrotic tissue, easy bruising, hypermobile joints, venous disease and edema of the feet (25).

Numerous other conditions apart from those described above have been associated with lipedema (Table 2). Of note, hypothyroidism is found in 27% of women with lipedema (25,26). In one case, a woman with lipedema was described as having lymphedema and multiple symmetric lipomatosis (91).

Table 2.

Co-morbidities and Complications of Associated with Lipedema (60, 92-94)

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Musculoskeletal	Soft Tissue	Vascular	Other
Gait disturbance	Obesity; fat deposits	Lymphedema/Idiopathic Edema	Pain
Change in posture (e.g., lordosis)	Loss of skin elasticity	Dilated Capillaries Microangiopathy	Psychological distress/anxiety
Genu valgum and arthritis of the knees	Thinning of the skin	Bruising	Shortness of breath
Ankle pronation	Lipomas	Varicose veins Venous insufficiency	Cellulitis
Hypermobile joints (Hypermobile Ehlers Danlos?)	Cellulite; fibrosis	Cherry angiomas	Slow metabolic rate

FAMILIAL MULTIPLE LIPOMATOSIS

Familial multiple lipomatosis (FML) is a rare adipose disorder (RAD) of multiple lipomas in subcutaneous fat (OMIM 151900). Some members in an FML family may have only a few lipomas whereas others may have hundreds to thousands; it is not understood why there is unequal penetrance in families. Lipomas usually are not painful or tender to the touch except while growing; they may also cause a slight feeling of itching or burning when forming. Some lipomas can be tender if they develop in areas of pressure such as on the back of the legs, the lower back (pressure from a chair), or the lateral wrist due to repetitive stress such as comes from using a computer mouse (150,151). Another example of trauma-induced lipomatous growth includes movement of the xiphoid process (152).

According to older FML literature (153), "pain may suddenly develop in one of the lipomas (called lipoma dolorosa), and will gradually extend to involve more and more of the discrete lipomas.” The authors state that lipoma dolorosa syndrome in families with FML is not the same as Dercum disease (see below) (154). This is confusing as individuals with painful lipomas in an FML family have been described as having Dercum disease. While painful lipomas in a person with FML may also be on the spectrum of Dercum disease, a more precise name is FML with painful lipomas, especially when a family history of FML is known.

It is interesting that by observation in some families with FML, the men will develop lipomas and the women often develop obesity in line with lipedema. This suggests an overlap between the development of one fat disorder (FML) and another (lipedema) and should prompt more detailed questions regarding other potentially affected family members.

Treatment of FML

The current management of FML includes screening for associated conditions such as cancer (Table 7) and consideration of a referral to genetics for tumor suppressor gene workups as needed. A healthy diet and an exercise plan to avoid or reduce obesity is important as obesity in families with FML can be associated with pain (154) and, anecdotally, triathletes notice a reduction in lipoma size during high intensity training. A statin has been shown to reduce a lipoma in a case report (177). Painful lipomas or those that interfere with activities of daily living can be excised as needed but these procedures can cause numerous scars (Figure 5). Massive amounts of lipomas can occur on the arms, hips/flanks, buttocks and thighs. Therefore, this condition can be psychologically devastating and people with severe FML do not consider it benign.

Figure 5.

Multiple scars after excision of lipomas in FML.

Liposuction is an option to excision of lipomas in people with FML as it provides good results in terms of skin appearance, and there is reported lack of recurrence or growth or development of other lipomas in the same area for at least 12 months (178). Injections of collagenase have been shown to shrink or destroy lipomas with minimal pain and good cosmetic result in a published abstract (179). Similar data were found for the detergent, deoxycholic acid (180), but anecdotally care should be taken not to inject too much detergent that can remain in the tissue requiring excision to remove. Additional treatments such as cryotherapy have been suggested and reviewed (181). More data is needed for the efficacy of injections and other therapies for the lipomas in FML as they are preferable to more invasive and scarring surgical techniques.

ANGIOLIPOMATOSIS

Angiolipomatosis also known as angiolipoma microthromboticum (OMIM 206550) is a rare disease of multiple angiolipomas and connective tissue that occurs commonly in men and usually begins after puberty; one case of a child with an angiolipoma in a family in which the father also had angiolipomatosis has been reported (182). Angiolipomas have been described as vascular malformations or vascular lipomas where blood vessels occupy between 10-90% of the angiolipoma. In families with familial angioliopomatosis, lipomas and angiolipomas can exist in the same person. Subcutaneous angiolipomas usually occur on the trunk and limbs, rarely on the head, hands, or feet (183). The angiolipomas can be the size of a rice grain, pea, a marble or much larger and are tender to the touch and can be associated with intense pain. Angiolipomas may or may not be visible and may be palpable or non-palpable depending on their location and size. Numerous case reports describe epidural or extradural spinal angiolipomas, and rare cases report colonic (184), bronchial (185), joint (186), and testicular angiolipomas (187). Angiolipomas are known to be painful, although not always, and should be distinguished from other painful neoplasms (188). One case of angiolipomatosis was reported to occur after treatment with corticosteroids (189).

The loose connective tissue of angiolipomas contains adipose cells, fibrotic tissue, vessels with fibrin clots, and mast cells as salient features (Figure 6). Due to the large number of vessels, angiolipomas are bluish in color through the skin. Interestingly, the vessels in angiolipomas can grow from the dermis into the territory of the epidermis making the vessels palpable as small raised areas on the skin (Figure 7). A plethora of capillary “cherry” angiomas where a capillary grows and dilates through the epidermis may be found on the skin in areas of angiolipomas (Figure 8).

Figure 6.

Angiolipoma with mast cell with enlarged multiple vessel lumens and degraded tissue. The black arrow points to a classic fried egg appearance of a mast cell stained with Alcian Blue in angiolipoma tissue. Red arrows point to small fat cell remnants likely non-functional as evidenced by the absence of nuclei. Blood vessels are numerous and large for location. The green arrow demonstrates the remnant of a capillary. Connective tissue is evident especially in the area surrounding the mast cell as bluish fibers. Magnification 100X.

Figure 7.

Multiple cherry angiomas present on the legs and arms of a woman with angiolipomatosis.

Figure 8.

Histological features of angiolipomas. A. Small area of hypervascularity in an angiolipoma (40X). B. Blood vessels in an angiolipoma grow up and through the epidermis and are palpable on the skin (40X). C. Empty and presumed dead and non-functional vessel on the left containing an eosinophil next to two functional blood vessel lumens containing red blood cells (100X). Microthrombi can be seen as pale areas especially between the right side of the dead vessel and the lumen of the active vessel. Dead vessels may result in hypoxia and ischemia causing pain. D. Non-functioning blood vessel to the right and smaller fat cells surrounded by an enlarged interstitial organ (40X).

DERCUM DISEASE

Dercum disease (DD; OMIM 103200) is a term used to describe extremely painful adipofascial tissue that is resistant to loss by diet and exercise and poorly responsive to analgesics. Other names include adiposis dolorosa (a term that is also used to describe women with lipedema) and Morbus Dercum. While Dercum disease is defined as painful fatty masses accompanied by other signs and symptoms of a chronic healing cycle disorder (25) (213), there remains a lot of confusion in the literature as to what exactly Dercum disease is. One review article stated that people with Dercum disease have obesity and chronic pain (214), which can easily be confused with people who have obesity and chronic pain for a variety of reasons including fibromyalgia. The old classification of Dercum disease and a new classification remain inadequate to differentiate the overlapping disorders that are bundled together as Dercum disease (65,215,216) because they describe only the phenotype and not the history (Table 8).

A better classification of painful adipofascia considers the history of the disease (Table 9). For example, women with lipedema who become obese and/or develop lymphedema can metabolically become toxic or ill leading to the growth of painful masses in fat tissue. The etiology of these masses is likely due to the presence of inflammation known to slow lymphatic pumping leaving more pre-lymph fluid in the ECM, inducing adipogenesis, as lymph (even pre-lymph) makes fat grow. Women with lipedema, obesity, and painful fatty masses have dominated some studies on Dercum disease leading the authors to describe women with Dercum disease as having obesity and chronic pain (214). The masses that develop in women with lipedema and metabolic syndrome are similar to those that develop on the abdomens of people who have obesity and do not have lipedema. These tender masses resolve with weight loss and have been called Ander’s disease or adiposis tuberosa simplex (217). A good history taken from a woman with lipedema and the label Dercum disease, may reveal the development of lipedema earlier in life and additional weight gain later in life with development of tender masses, allowing treatment to be focused on lipedema and obesity rather than on Dercum disease.

Signs and symptoms of Dercum disease include chronic pain, fatigue, brain fog, insomnia, cardiac arrhythmia most often tachycardia (palpitations), gastrointestinal distress often similar to irritable bowel syndrome, muscle weakness, tremor or jerking of muscles (myoclonus), joint pains, insulin resistance and diabetes, hypothyroidism, and other autoimmune disorders (219). The signs and symptoms of Dercum disease have been suggested to be in the spectrum of fibromyalgia (220).

Dr. Dercum’s first patient was a woman with obesity with fat similar to a woman with Stage 3 lipedema (221). Dr. Dercum and his medical resident described rapid changes in fat tissue shape and size in real time suggestive of edema or fluid shifts. Therefore, involvement of the lymphatic system is likely in Dercum disease. Irregular and thickened lymphatic vessels have been described in Dercum disease suggesting that an altered lymphatic system can contribute to changes in the adipofascial tissue that found by palpation (222). Once people with Dercum disease are more accurately described by phenotype, there will be a better chance of finding a gene or biomarkers.

Genetics of Dercum Disease

There is(are) currently no known gene(s) for Dercum disease. Continuing to include people with angiolipomas, FML, and lipedema under the same moniker of Dercum disease will make it very difficult to discover genes important for these diseases when examining populations. The study of genes for specific families may be more helpful to find gene mutations that can then be assessed in individuals with painful adipofascia.

One family with familial multiple lipomatosis was found to have members that developed pain in the lipomas consistent with Dercum disease (adiposis dolorosa). While many of the family members with FML and pain also had obesity, not all were. Therefore the authors concluded that “adiposis dolorosa may in fact be an expression of familial multiple lipomas” (154). It remains unclear, however, why some individuals would develop pain and some not in a family with FML. Fascia can become inflamed for a variety of reasons including surgery, trauma, infection, toxin or drug exposure, and development of obesity. Lipomas in people with FML are often connected by a tail of connective tissue to solid fascial structures in the body, and fascia is a source of preadipocytes (Figure 9). It may be that lipomas in FML are a marker of fascial disease and that pain in and around the lipomas depends on the amount and extent of inflammation present. Other genes may modify susceptibility to prolonged inflammation including those yet to be identified in fibromyalgia (224).

Figure 9.

Lipomas with fascial component. A. Lipoma with obvious tail of connective tissue. Removal of the fascia is important along with the lipoma to reduce additional growth in the area of removal. B. Long piece of connective tissue weaving amongst multiple lipomas during resection.

MULTIPLE SYMMETRIC LIPOMATOSIS

Multiple symmetric lipomatosis (MSL; OMIM#151800) also known as Madelung disease, Launois-Bensaude syndrome, cephalothoracic lipodystrophy, and benign symmetric lipomatosis is a rare disease first described by Brodie in 1846.This disorder is clearly not benign. Madelung reported data on 33 cases, but the classical description of the disease is attributed to Launois and Bensaude who published a detailed account of 65 cases in 1898. The literature on MSL was initially dominated by research on men with alcoholism; however, people who do not consume alcohol (252), women, and children are also affected (253).

There are different types of MSL described initially by two different groups and reclassified in 2018 based on a German cohort of 45 patients (Table 11 and Figure 10) (91).

Figure 10.

Two different presentations of MSL. The man has MSL with a Charcot Marie Tooth presentation with increased fat on the upper body even after multiple resections, and the woman on the right has increased fat on the arms and upper back consistent with the old classification of MSL Type II.

Women tend to have Type II MSL and the authors state that it is difficult to differentiate women with lipedema from women with MSL type II. Criteria the authors used to distinguish the two are “the hips and bottom are affected [in Type II MSL] which are not affected in patients suffering from lipedema.” Lipedema, however, does affect the hips and buttocks in Types I-III lipedema (Figure 3). Finding a gene or biomarker for lipedema and MSL will be ultimately be helpful in distinguishing these adipofascial disorders.

In rare cases, MSL SAT can invade the muscles of the tongue (256,257), vocal cords (258), and periorbital area (259). Tracheal or esophageal compression can occur resulting in superior vena cava syndrome (260).

Disorders Associated with MSL

Associated disorders include liver disease, dyslipidemia, metabolic syndrome, hypertriglyceridemia, hypothyroidism, diabetes mellitus, and peripheral and autonomic neuropathy (Figure 11).

Figure 11.

Disorders often associated with MSL (Madelung disease). Copyright © 2018 Szewc et al. (286). This work is published and licensed by Dove Medical Press Limited. Full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/).

Morbidity and mortality in MSL is thought to be high with sudden non-coronary death accounting for a large percentage of deaths in one series of primarily men (254). The neuropathology of MSL is a distal axonal demyelination different from that associated with alcohol intake and impairment of autonomic function has been suggested as a possible cause of sudden death; this impairment seems to prevalently involve the autonomic nervous system and not related to a high alcohol intake.

OVERALL CONCLUSIONS ON ADIPOFASCIAL DISEASES

Aipofascial diseases occur when there is an increase in adipofascial tissue on the body that becomes fibrotic and is resistant to loss by lifestyle change. Until such time that better understanding of the pathophysiology of these disorder hints at other treatment modalities, these disorders often require removal by surgical means. Many of the diseases overlap, making identification difficult and will remain so until additional genes or biomarkers are clinically available. A comparison table of the five adipofascial disorders presented in this chapter can be helpful (Table 12).

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