The main results from this study show that more than half of the patients with chronic leg oedema/lymphoedema are affected by obesity, and the severity of oedema increases with each weight category. The most advanced stage of lymphoedema with fibrotic tissue (ISL III) affected 14% of patients with normal weight, 18% with class I-II obesity, and 39% with class III obesity (p = 0.001). The clinical observation of the challenges of managing chronic oedema in obesity was confirmed, with fewer patients reaching good oedema control compared to normal weight. These findings build on previous research reporting the unfavorable influence of obesity on the lymphatics and oedema management [2,3,4, 6, 8, 16, 21], with the advantage of being a large multicenter international study involving over 7000 clinically evaluated patients.

Obesity-induced oedema is a newly recognized condition, described by some to affect those at a BMI over 40. With increased BMI the oedema worsens and at BMI > 60 lymphoedema is almost inevitable, when determined by lymphoscintigraphy [22]. However, clinical obesity guidelines/comorbidity studies rarely mention lymphoedema as a complication [23,24,25,26] or suggest it as a standard part of a physical examination [27]. The prevalence of obesity-induced lymphoedema is yet to be determined but could be expected to be high, taking the above mentioned findings into account together with the notion that obesity affects every third US citizen and 8% of the population have a BMI ≥ 40 [28]. Increased awareness of this complication may increase the chance of early diagnosis and treatment, before the development of advanced lymphoedema – preventing complications such as wounds and bacterial cellulitis. The identification of chronic oedema can be performed at the bedside or in the patient’s home, with either the pitting oedema test or a positive Stemmer’s sign (see methods for how this is performed), used in this study. If in doubt, a lymphoscintigraphy can be performed.

In the study we aimed to investigate the impact/association of obesity on the characteristics of people with chronic oedema. People with increased obesity class had decreased mobility (walking with aids or being chair bound), which by itself contributes to oedema development due to gravitational forces and less activation of the calf muscle pump. Importantly, the risk of cellulitis/erysipelas within 12 months increased with each weight category, affecting every fifth patient with class III obesity. Similar findings have been reported by others [4, 21], including our previous publication [29]. Surprisingly, a significantly lower presentation of peripheral arterial disease (PAD) was seen with increased weight. The diagnosis of PAD was made by the investigator without formal definitions. Therefore, we cannot exclude that this finding may be biased by oedema/obesity itself, masking the presence of peripheral palpable foot pulses (if this was used for the diagnosis).

The high prevalence of advanced lymphoedema in obesity, identified in this and other studies [4, 8] may explain why we found a high accumulation of these patients in specialist lymphoedema services. Our finding that compression usage was associated with increased weight, is likely a reflection that these patients have more advanced forms of lymphoedema and are recruited from specialist services who routinely use compression in all patients. Less surprisingly, increased weight was associated with diabetes, secondary lymphoedema, bilateral swelling, and increased swelling duration. All these factors may explain the lower quality of life with increased weight, identified by both a disease-specific and a general quality of life tool. The level of class III obesity varied greatly among the countries ranging from 1% in Italy to 47% in Canada, this is likely to reflect the site of recruitment but may also reflect the different level of obesity among countries.

There is a gap in our knowledge surrounding why obesity causes lymphoedema [13, 22, 30]. One hypothesis is that the lymphatics are normal but the production of lymph is increased, overwhelming the lymphatic system. Compressed lymphatic vessels impacting lymphatic drainage due to pressure from the weight, has also been suggested [3]. Other theories involve inflammation from adipose tissue causing lymphatic destruction [22]. Studies of mice with obesity show reduced lymphatic pumping capacity, decreased lymphatic vessel density, increased lymphatic leakiness and infiltration of inflammatory cells around lymphatics compared to normal weight [31, 32]. Conversely, stagnant lymphatic fluid also stimulates adipogenesis. Animal models show lipid accumulation by lymphstasis, being associated with an upregulation of adiponectin and adipogenic transcription factors [7, 12]. These lipid factors, including free fatty acids, have adipogenic properties in vitro [33]. Inflammation may also play a part stimulating adipogenesis, e.g. T-cell inhibition/depletion of CD4+ cells decrease the severity of lymphoedema in animals with obesity [9, 34, 35]. The human lymphoedema fat tissue appear different compared to normal adipose tissue, with 24% larger [36] and highly variable adipocytes in size [10] compared to adipose tissue. Larger lobules, more collagen and a decreased number of M2 macrophages is also seen in lymphoedema adipose tissue [10]. As obesity may damage the lymphatics, and stagnant lymph may stimulate adipogenesis, a vicious loop has been created [4].

The management of obesity-induced lymphoedema is largely based on expert opinion and involves good skin care to ensure an intact skin barrier, compression, weight loss and exercise. These patients are therefore treated like most other lymphoedema patients receiving complex decongestive therapy (CDT) [4, 17] – but there are many challenges. Due to the deep skin folds the skin may be compromised, wet and therefore often affected by mycosis. Applying a therapeutic level of compression is also challenging, especially in those with ISL stage III, with fibroadipose tissue. The level of compression is effected by the increased size of the limb and it is complex to apply in those with deep skin folds and limb shape distortions [37]. Some patients develop massive localized lymphoedema, with large lobules, frequently affecting the thigh, that are difficult to apply compression to. A lot of padding may be required to prevent pressure injuries in a limb with severe shape distortion such as this. The effect of increased padding causes a large limb circumference in which applying a therapeutic level of pressure is challenging. To achieve compression the application technique must be adapted which includes using more layers of bandage. The cumulative effect is a bulky limb which in turn reduces mobility and limb function and may cause difficulty in maintaining personal hygiene. Furthermore, the oedema may be reaching the genitals and abdomen, and in reality, these areas cannot be easily compressed. Full leg compression may itself move fluid into the genital area thus compounding the problem. Comorbidities such as severe heart failure may also limit the compression, due to the risk of complications such as pulmonary oedema. Severe diabetic neuropathy may likewise increase the risk of pressure injuries from compression, and polypharmacy is also an issue with calcium channel blockers aggravating oedema. While compression bandages lead to one problem a second is the transition to compression garments used to maintain the effects of the CDT. Finding a correct type of garment is associated with many challenges and may require a combination of hosiery and compression wraps to prevent rebound oedema. While the clinical presentation of the swelling may indicate that a full leg garment or tights are required this may be practically impossible to achieve. Due to obesity, some patients may not be able to apply or remove the garments themselves or to perform exercise. All these factors may explain why control of swelling was less likely to be achieved in our patients with higher weight categories (OR 0.8). Understanding the quality of life and psychosocial impact of these patients (e.g. living alone, not being able to walk, maintaining personal hygiene, addressing pain) needs to be integrated into the treatments plans to enable improved adherence. Clinicians may be obsessed with limb volume reduction, whereas the patient priorities may be completely different. Although compression therapy is central to alleviating symptoms and complications, chronic oedema/lymphoedema is often a symptom/consequence of severe obesity. Addressing the real cause of the problem is the obesity issue. Weight loss would seem intuitive to prevent further lymphatic damage and/or to reverse the lymphatic function but would need further confirmation in clinical studies. Studies of mice with obesity have shown that diet-induced weight loss can reverse the lymphatic damage [32], including aerobic exercise that is independent of weight loss [31]. Preliminary results in humans have suggested that if BMI is reduced below 50 there is a 50% chance that the lymphatic dysfunction is normalized on lymphscintrography [17]. A meta-analysis of four RCT’s with patients with breast-cancer-related lymphoedema found that weight loss decreased the volume of both arms (affected by lymphoedema and not) but the treatment did not reduce the severity of lymphoedema as determined by interlimb difference in arm volume. The authors concluded that effect of weight loss as a preventative measure needs to be investigated [38]. The effect of bariatric surgery on limb volumes is promising but based on case-series [39]. Taken together, a collaboration between lymphoedema services and a bariatric weight loss center may prove to be essential [17]. Future encouraging treatment modalities include an evaluation of new weight loss drugs.

Limitations to our study include the following: 1. Weight categories were classified as either normal weight, class I-II obesity or class III obesity, using BMI when this was available. This was a pragmatic decision based on the complexity of the different study sites, including community care when e.g. weight scales are not available or patients are not able to stand up. Also, patients with overweight were included in the normal weight category which may have influenced the effect on increased weight categories. 2. Chronic oedema/lymphoedema was diagnosed with either a positive pitting oedema test and/or Stemmer’s sign. Stemmer’s sign holds high sensitivity and specificity for the diagnosis of lymphoedema (reference being lymphscintrography), but may produce false positive results in obesity [40]. As the majority of the patients with class III obesity were mainly recruited from specialized lymphoedema centers, we feel confident that these patients had true chronic oedema/lymphoedema. 3. Extrapolation of the results to a more general population cannot be concluded from this data, due to the dominant recruitment from specialist lymphoedema services.

To conclude, the results from this study confirm the negative impact of obesity, and especially class III obesity, on chronic oedema/lymphoedema. More than half of the patients with chronic leg oedema have concomitant obesity, and the severity of oedema is worsened with increasing weight. Likewise, lymphoedema-related complications such as cellulitis/erysipelas is increased in patients with obesity. Despite these and previous findings, clinical guidelines rarely mention lymphoedema as a comorbidity to obesity. Future studies would need to assess the prevalence and impact of each weight category on chronic oedema, and whether weight loss interventions can prevent and/or reverse the lymphatic damage.