Obesity and Chronic Inflammation in Phlebological and Lymphatic Diseases

Review 55

Obesity and chronic inflammation in phlebological and lymphatic diseases

G. Faerber Centre for Vascular Medicine, Hamburg

Keywords increase in intra-abdominal and intertriginous ten mit venösen oder lymphatischen Erkran- Obesity-associated functional venous insuffi- pressure, which in turn leads to an increase in kungen, die gleichzeitig schwer adipös und ciency, obesity-associated lymphoedema, vis- venous pressure in leg vessels, these relation- häufig multimorbide sind, überproportional ceral obesity, chronic inflammation, insulin ships are mainly caused by the metabolic, an. Die Adipositas, vor allem die viszerale, resistance chronic inflammatory and prothrombotic pro- verschlechtert alle Ödemerkrankungen, er- cesses that result from the increase of visceral höht das Risiko für thromboembolische Er- Summary adipose tissue. These processes can be ident- krankungen und postthrombotisches Syn- The prevalence of obesity has continued to ified by low levels of adiponectin and high lev- drom und kann alleinige Ursache sein für die increase considerably during the past 15 els of leptin, insulin, intact proinsulin, PAI-1 Adipositas-assoziierte funktionelle Venenin- years. Particularly noticeable is the marked and proinflammatory cytokines (IL-6, IL-8, suffizienz ohne Nachweis von Obstruktion increase in morbid obesity, which is in turn TNF-α). Therapeutic measures must therefore oder Reflux. Das Adipositas-assoziierte particularly pronounced among the elderly. be aimed primarily at reducing visceral obesity Lymphödem stellt inzwischen den größten Since the prevalence of venous thromboem- and with it hyperinsulinemia or insulin resis- Anteil unter den sekundären Lymphödemen. bolism, chronic venous insufficiency and sec- tance as well as at fighting chronic inflam- Mehr als 50 Prozent der Lipödempatientin- ondary lymphoedema also increases with mation. nen sind adipös, die bei ihnen im Verlauf zu age, the number of patients with venous or beobachtenden sekundären Lymphödeme in lymphatic diseases, who are also severely der Regel Folge der Adipositas, nicht des Lip- obese and often multimorbid, rises dispro- ödems. Die Symptomatik wird bei allen portionately. Obesity, especially of the vis- Schlüsselwörter Krankheitsbildern durch Gewichtsreduktion ceral type, exacerbates all oedema diseases, Adipositas-assoziierte funktionelle Venenin- gebessert. Neben mechanischen Faktoren increases the risk of thromboembolic dis- suffizienz, Adipositas-assoziiertes Lymph- wie der Erhöhung des intraabdominalen und eases and post-thrombotic syndrome and ödem, viszerale Adipositas, chronische Inflam- intertriginösen Drucks, der wiederum zu ei- may be the sole cause of obesity-associated mation, Insulinresistenz ner venösen Drucksteigerung in den Beinge- functional venous insufficiency without evi- fäßen führt, sind es vor allem die durch die dence of obstruction or reflux. Obesity-as- Zusammenfassung Zunahme des viszeralen Fettgewebes verur- sociated lymphoedema now accounts for the Die Prävalenz der Adipositas ist in den letzten sachten metabolischen, chronisch inflamma- largest share of secondary lymphoedemas. 15 Jahren weiter stark angestiegen. Dabei fällt torischen und prothrombotischen Prozesse, More than 50 percent of patients are obese, besonders die deutliche Zunahme der morbi- die für diese Zusammenhänge verantwortlich with their subsequent secondary lymphoede- den Adipositas auf, die wiederum bei den Älte- sind, erkennbar an niedrigen Spiegeln von ma usually resulting from obesity rather than ren besonders ausgeprägt ist. Da mit dem Al- Adiponektin und hohen von Leptin, Insulin, the lipoedema. Weight reduction improves ter auch venöse Thromboembolien, chronisch intaktem Proinsulin, PAI-1 sowie proinflam- the symptomatology in all clinical presenta- venöse Insuffizienz und sekundäre Lymph- matorischen Zytokinen (Il-6, Il-8, TNF-α). The- tions. Beside mechanical factors, such as an ödeme zunehmen, steigt die Zahl der Patien- rapeutische Maßnahmen müssen also in ers- ter Linie auf die Reduktion der viszeralen Adi- Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. positas und damit der Hyperinsulinämie bzw. Correspondence to: Adipositas und chronische Inflammation bei phle- der Insulinresistenz sowie auf die Bekämp- Dr. med. Gabriele Faerber bologischen und lymphologischen Erkrankungen Zentrum für Gefäßmedizin Phlebologie 2018; 47: 55–65 fung der chronischen Entzündung abzielen. Paul-Dessau-Str. 3e https://doi.org/10.12687/phleb2413-2-2018 22761 Hamburg Submitted: 08 February 2018. Tel. 0049 40 460039 24 Accepted: 12 February 2018 [email protected]

Introduction with a first thrombosis a doubling of the overweight as an independent risk factor risk of thrombosis at a BMI of 30 kg/m2 for CVI-typical skin lesions. Over 50% of In Germany, men with a normal body- and higher (CI95: 1.5 vs. 3.4) as well as an the obese patients had oedema and a florid weight are already a minority from the age increase in factors VIII and IX. The relative or healed ulcer. In a study of ulcers, Ober- of 30 to 35 years, while overweight women risk was similar for both sexes and all age mayer et al. also described a share of 46% do not dominate until the age of 55 years. groups; in absolute terms, the effect was of obese and 35% of overweight patients At the end of their working life, 74.2% of greatest among the elderly (13). A prospec- (19). Overall, the proportion of the so- men and 56.3% of women are overweight. tive cohort study by Ageno et al. involving called venous hydrostatic ulcers without re- While the number of overweight individu- 83 consecutive thrombosis patients showed flux is reported to be between 20 and over als has been stagnant for several years, the that a BMI > 28 kg/m2 is already a predic- 60%, depending on the degree of obesity proportion of obese people increased from tor for the early development of a post- (16, 20). The skin lesions improve after 12% in 2000 to 15% in 2009 and up to thrombotic syndrome. After 12 months, weight loss (21, 22). 23.6% in 2015. Most notably, the propor- PTS was observed in 24.1 percent; the CVI-typical symptoms occurring in the tion of people with morbid obesity (BMI ≥ mean BMI was significantly higher in this context of obesity are summarised under 40) aged over 65 increased between 1999 group (29.6 vs. 27.2 kg/m2, p = 0.022). The the term „obesity-associated dependency and 2013 by 300% for men and by 175% for authors concluded that thrombosis pa- syndrome,“ analogous to “immobility-in- women (1). Since the prevalence of throm- tients should avoid weight gain and that a duced dependency syndrome” in paralysed boembolic events, chronic venous insuffi- reduction could possibly help to prevent individuals (23, 24). Garzon and Ober- ciency (2) and secondary lymphoedema PTS (14). mayer were able to demonstrate that the also increases with age, the number of pa- intertriginous pressure in the groin already tients with these conditions, who are also correlates with the leg vein pressure at a severely obese, is steadily increasing. The CVI and ulcus cruris BMI as low as 25 kg/m2 and that in obese development of overweight and obesity is patients it causes, in addition to the result- favoured by family predisposition or gen- The influence of body weight on the sever- ing obstruction of the leg veins due to the etic causes (3, 4), medications, endocrine ity of CVI has been the subject of contro- weight on the groin, a complete inacti- and mental illnesses as well as by a low so- versial debate in the literature, mainly be- vation of the calf muscle pump when sit- cial and educational status (5). The rapid cause both CVI and BMI increase with age ting, thereby preventing the relief of the in spread of the obesity epidemic is above all (2). In a large epidemiological study invol- itself healthy, venous system, thus causing caused by today‘s lifestyle, which is charac- ving over 16,000 subjects, Chiesa et al. de- the venous pressure to increase. The au- terized by the constant availability of scribed a relationship between BMI, visible thors see this as a possible explanation for mostly unhealthy food, frequent „snack- signs of CVI and increase in venous reflux the formation of hydrostatic ulcers (23). ing“ (6), lack of exercise due to a sedentary (15). In contrast, a retrospective study by Since it is most likely that additional, par- lifestyle in a closed environment, chronic Padberg et al in 2003 (20 men, 39 legs, ticularly metabolic interrelationships con- stress (7) and lack of sleep (8–10). CEAP C4 to C6, BMI ≥ 40 kg/m2) found tribute to the pathogenesis, the clinical pic- no evidence of venous reflux on duplex ture is better described as secondary func- examination in two thirds of the patients tional venous insufficiency without evi- Obesity-associated despite typical skin changes (hyperpigmen- dence of reflux or obstruction (11). tation, lipodermatosclerosis up to hydro- diseases of veins and static ulcus cruris). With respect to the lymphatics clinical findings (VCSS, venous clinical se- Lymphoedema and verity score), no differences were observed lipoedema Obesity aggravates any existing oedema dis- between patients with or without reflux eases or may cause them in the first place (16). In a cross-sectional study from Serbia Compared to the general population with a (11). It increases the risk of thromboembolic in 2013, the authors also described a strong proportion of obesity of around 20%, pa- diseases and post-thrombotic syndrome correlation between obesity and CEAP-C tients with lymphatic diseases are far more Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. (PTS) as well as the severity of chronic ve- stages that was independent of age, gender often overweight or obese (see also nous insufficiency (CVI), postthrombotic and other risk factors, but not between Bertsch, Tobias in this issue). In a study of syndrome (PTS) and ulcus cruris (12). obesity and venous reflux (17). With the 72 patients attending consultations at the aid of duplex ultrasound examinations on Lymphatic Outpatient Clinic of the Venous more than 400 legs, Danielsson et al. also Centre of the Ruhr University Bochum, Thromboembolism and demonstrated that obese patients may ex- Reich-Schupke observed a mean BMI of 38 post-thrombotic syndrome hibit CVI-typical skin changes even with- kg/m2, whith the proportion of obesity dif- out venous reflux (18). They found a strong fering greatly depending on the lympho- In the Netherlands, in 2008, Abdollahi et correlation between BMI and the severity logical diagnosis (25). In a lymphological al. observed in 454 consecutive patients of the clinical symptoms and described population, Flaggl et al. found 24% of pa-

Phlebologie 2/2018 © Schattauer 2018 G. Faerber: Obesity and chronic inflammation 57 tients with normal weight (26). Obesity flammatory. Adiponectin is decreased in leads to a deterioration of primary lymp- insulin resistance and obesity. High levels hoedema (27), while secondary postoper- have an anti-inflammatory effect: CRP, ative lymphoedemas are more prevalent, TNF-α, IL-6, IL-8 and Plasminogen-Acti- occur earlier and are more severe in obese vator-Inhibitor-1 (PAI-1) decrease. In- persons (28). Most importantly, morbid creasing levels are associated with decreas- obesity (BMI above 40 kg/m2) is now the ing insulin resistance and improvement of most common cause of secondary lymp- cardiovascular risk factors. hoedema, and forms its own entity as obes- Overall, abdominal obesity increases the ity-associated lymphoedema (29). It typi- risk of thrombosis through the increased cally develops in the second half of life par- activity of the coagulation cascade, de- allel to weight gain, particularly at the creased activity of the fibrinolytic cascade, thighs, the genital region and abdominally increased inflammatory processes, elevated in the area of fat folds, while the fibrosis on oxidative stress and endothelial dysfunc- the lower legs is mildly pronounced and tion. This is further accompanied by dis- the Stemmer sign often only weakly detect- orders of lipid metabolism and glucose tol- able (29). Obesity-associated lymphoede- erance in the context of metabolic syn- ma is often associated with skin lesions Fig. 1 Obesity-associated lymphoedema with drome (insulin resistance, increased trig- typical of secondary venous insufficiency secondary functional venous insufficiency. BMI 61 lycerides, low HDL), which also have (▶ Fig. 1). kg/m2 (162cm, BMI 61. WHtR 0.88). Hyperpig- proinflammatory effects and enhance en- For lipoedema, Schmeller et al. reported mentation, dermatoliposclerosis, ulcus cruris on dothelial dysfunction. These thrombogenic a proportion of patients with normal the right 0.5x0.5 cm, lymphorrhoea; diabetes risk factors can invariably be improved by weight of 29% (30). The real proportion of mell. type II, art. hypertension. weight reduction (35). In their meta-analy- adipose lipoedema patients is likely to be sis, Ageno et al. also concluded that visceral well over 50% (31). The secondary lymp- adipose tissue, as an endocrine organ, is re- hoedema, which often develops in these not mutually exclusive, but rather comple- sponsible for chronic inflammation and patients over the further clinical course, is ment each other. thus for a thrombogenic condition that in- the result of obesity, not the lipoedema. creases the risk of venous thromboembol- Transitions appear to exist in both direc- ism (36). Chronic inflammation increases tions between the asymptomatic lipohyper- Visceral obesity, fibrinogen, tissue factor (factor III) and trophy and the symptomatic, painful li- thrombosis and secondary factor VII, activating thereby the coagu- poedema, usually in phases of weight or venous insufficiency lation cascade. Moreover, patients with vis- hormonal changes (32, 33). Because of the ceral obesity were often found to exhibit additional fat masses at the thighs, obesity Willenberg and colleagues observed an en- elevated levels of PAI-1 and low levels of deteriorates axial malalignment, gait and larged diameter of the femoral vein and a tissue-specific plasminogen activator mobility, which further increases weight. deterioration of venous flow parameters in (t-PA), which is released from endothelial obese patients. They saw this as a confir- cells of vascular walls and acts as an endo- mation that abdominal adipose tissue genous activator of fibrinolysis by convert- Influence of visceral could mechanically increase the risk of ve- ing plasminogen directly into plasmin. The nous thromboembolism and CVI by in- PAI-1 level correlates positively with the adipose tissue on hyperco- creasing intra-abdominal pressure (34). BMI and with the plasma insulin and trig- agulability, chronic Darvall et al., on the other hand, described lyceride levels. If insulin levels are lowered inflammation and insulin in a review that visceral obesity in particu- by fasting or metformin, PAI-1 (37) also lar is associated with an increased inci- decreases, suggesting that hyperinsuline- resistance dence and prevalence of arterial and ve- mia increases the hepatic synthesis of Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. nous thromboembolism (35). Visceral adi- PAI-1 and thus contributes to a hypofibri- The relationship between obesity and the pose tissue is not only an energy store, but nolytic condition (38). clinical pictures described above can be ex- also a production site for numerous hor- There is much to suggest that in addi- plained by mechanical mechanisms (in- mones and cytokines that influence the tion to the mechanical factors described crease of intra-abdominal, intertriginous glucose and lipid metabolism and clotting above, chronic inflammatory and pro- and subsequently venous pressure) and (▶ Tab. 1). The secretion of leptin is in- thrombotic processes caused by visceral those that emphasize the role of chronic increased by TNF-α and hyperinsulinemia. obesity also play a role in skin changes in flammation and metabolic changes associ- Leptin promotes platelet aggregation, en- the context of secondary venous insuffi- ated with obesity. These mechanisms are hances the synthesis of CRP via activation ciency up to hydrostatic ulcers, since these of the IL-6 receptors and thus acts proin- increase, among other things, capillary per-

Tab. 1 Metabolic and inflammatory markers and cytokines compared to lean individuals (42, 43). In- Marker, site of formation terestingly, gender differences were also observed in this context. A higher increase of Adiponectin Low values associated with: VEGF-C and D as well as of angiopoietin 2 Peptide hormone, fat cells; visceral obesity (suppresses secretion) was observed among overweight women antiatherogenic, antiin- insulin resistance and hyperinsulinemia flammatory dyslipidaemia (high triglycerides, low HDL) compared to overweight men. inflammation VEGF-A mainly stimulates the prolifer- stress ation and migration of vascular endothelial increased risk of type 2 diabetes mellitus, CHD cells. Overexpression of VEGF-A in trans- Intact proinsulin High values associated with: genic mice resulted in an increased number Precursor of insulin pan- advanced dysfunction of β cells and size of blood vessels. However, these creatic -cells prediabetes mice were also protected from developing a increased cardiovascular risk (stimulates PAI-I, blocks fibrinolysis) high-fat-diet-induced obesity and from in- further weight gain sulin resistance (44). In this respect, en- Leptin High values associated with: hanced levels of VEGF-A appear to be an Proteohormone, adipo- leptin resistance immune response to counter adipose tissue cytes regulation of body visceral obesity hypoxia and to regulate hypoxia-related in- weight hyperinsulinemia, β-cell dysfunction, high triglycerides, low HDL flammatory processes. inflammation The obesity-enhanced expression of hs-CRP High values associated with: VEGF-C, the most important growth fac- acute-phase protein chronic inflammation tor for lymphangiogenesis, appears, how- liver, vascular muscle cells insulin resistance, increased risk of type II diabetes ever, to result in a lymphatic dysfunction. hypertension, metabolic syndrome This finding is supported by the observa- increased risk of vascular events tion that a blockade of the VEGFR-3 ligand Plasminogen Activator High values associated with: VEGF-C in the mouse model leads to a re- Inhibitor-1 visceral obesity duction of oedema formation as well as to a (PAI-1) inflammation and oxidative stress significant improvement of insulin sensi- especially visceral adipose tissue tivity and decreased hepatic steatosis (39). Elevated levels of VEGF-C mRNA were Inhibition of fibrinolysis Increased risk of thromboembolic events, atherosclerosis insulin resis- observed in mouse adipose tissue in both tance, metabolic syndrome, type II diabetes mellitus genetically and diet-induced obesity, sug- Inflammatory cytokines: High values associated with: gesting that inflamed adipose tissue itself is IL-6, IL-8, TNF-α chronic inflammation one of the sources of the elevated VEGF-C visceral adipose tissue visceral obesity levels (39, 40). Obesity leads to increased stimulation of inflamma- insulin resistance, type II diabetes mellitus tory processes vascular events migration of M1-polarized macrophages into adipose tissue. A feature of these M1 macrophages is, in addition to the release of proinflammatory cytokines, the en- meability, extravasation and consecutively liver (39). In a mouse model, Karaman et hanced expression of VEGFR-3. the lymphatic burden (24). al. showed that the VEGFR-3 receptor and Initially, VEGFR-3 stimulates lymphan- its ligands VEGF-C and D, which are im- giogenesis. However, several research portant for lymphangiogenesis, not only groups have shown that obesity leads to re- Obesity, chronic inflam- play a role in inflammation of adipose tis- duced lymphatic flow and to a reduced up- mation and lymphoedema sue and the development of metabolic syn- take of lymphatic fluid into the lymph drome, but are also of importance for the nodes. This seems to be caused by imma- Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. Obesity and metabolic syndrome are as- development of obesity-associated lymp- ture, increasingly permeable (“leaky”) lym- sociated with elevated levels of proinflam- hoedema (39, 40). This influence is me- phatic vessels (45, 46). In addition, the re- matory cytokines, detected not only sys- diated by macrophages, which, along with lease of inducible nitric oxide synthase temically, but also in adipose tissue, in the T cells, play a major role in the obesity-as- (iNOS) by macrophages leads to a dila- liver and in skeletal muscle. Numerous sociated inflammatory response (41). tation of the lymphatic vessels and a con- studies have shown that an increase of It has long been known that the expan- comitant decrease in contraction intensity. proinflammatory cytokines such as TNF-α, sion of adipose tissue requires increased Finally, the frequency of contraction of the IL-6, and MCP-1 (macrophage chemotac- neoangiogenesis. Various studies have re- lymph collectors is also reduced (45, 46). tic protein 1) leads to insulin resistance in ported elevated serum levels of VEGF-A, C This results in lymphatic stasis. In the adipose tissue, increased lipolysis and fatty and D in overweight and obese patients as long term, as with other secondary lymp-

Phlebologie 2/2018 © Schattauer 2018 G. Faerber: Obesity and chronic inflammation 59

Average HOMA index 10 5,2+/‐ 3,23 8 evolution HOMA (%) start –end 6 3,5 +/‐ 1,11 2,7+/‐ 1,72 4 1,9+/‐ 1 control ‐48,46 2

0 with lipoedema ‐42,85 STARTEND

patients without lipoedema (control) patients with lipoedema

Average Weight 160 116,9+/‐ 26,7 KG 140 110,5 +/‐ 21,89KG evolution weight (%) 93,6+/‐ 18,1KG 94,3,+/‐ 19,44 KG 120 start –end 100 80 control ‐14,92 60 40 20 with lipoedema ‐18,17 0 STARTEND

patients without lipoedema (control) patients with lipoedema

Fig. 2 Average HOMA index and weight before and after nutritional therapy. Female lipoedema patients had a higher starting weight along with a lower HOMA index.

hoedemas, this leads – at least in subcu- not clear whether and in what way these investigations, it is striking that insulin re- taneous adipose tissue – to an M2 macro- are the primary cause or the consequence sistance in a population of obese lipoedema phage shift and to a TH2-dominated in- of other physical changes such as obesity or patients is less pronounced than in a con- flammatory response, which is responsible hormonal imbalances. It has long been trol group of obese patients without li- for further lymphoedema-associated, local known that obesity worsens symptoms in poedema, despite a higher average weight, adipose tissue formation, fibrosis of the patients with a verified diagnosis of li- with this difference disappearing with in- surrounding tissue and sclerosis of the poedema (48, 49). However, there are also creasing abdominal obesity (▶ Fig. 2) (51). lymphatic vessels (47). A vicious circle de- disease progressions, in which an asympto- In addition, insulin directly stimulates velops. matic lipohypertrophy only develops into a the aromatase activity in adipose tissue and symptomatic lipoedema in the course of thus the conversion of androstenedione Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. life, usually in a phase of marked weight and testosterone to estrone and estradiol Obesity and lipoedema – gain. In both cases, this development may (52). It also reduces the sex hormone-bind- be reversible after weight loss and change ing globulin (SHBG) and thus further in- inflammation, insulin and in diet (50). It is understandable that in li- creases free estradiol (53, 54). Hyperinsu- oestradiol poedema too, the vicious circle of obesity linemia thus promotes a shift in the hor- and gradually increasing hyperinsulinemia monal balance between estradiol and pro- Although the pathogenesis of lipoedema is not only leads to a further increase in adi- gesterone in favour of estradiol, which in still largely unknown, there is much to sug- pose tissue, but also to the described proin- turn has pro-inflammatory, oedema-en- gest the involvement of inflammatory pro- flammatory and oedema-promoting effects hancing and lipogenic effects. The role of cesses in addition to hormonal factors. It is of the visceral adipose tissue. In our own adipose tissue as an alternative site of estra-

Hyperinsulinemia Insulin resistance Adiponectin Hyperglycaemia

Insulin ++

Proinsulin Adipocyte

+ + + Beta cell dysfunction +

Insulin Cytokines Angiotensin Intact proinsulin IL 6, IL 8, TNF α Blood pressure Fig. 3 hs CRP Free fatty acids Relationships between PAI‐I adipogenesis, insulin Dyslipidaemia resistance and inflam- HDL Inflammation, arteriosclerosis, thrombosis mation (modified ac- Triglycerides cording to Pfützner 2005).

diol production thus enhances the physio- proved solely by changes in dietary habits fasting days (intermittent or periodic fast- logically present estradiol dominance in and lifestyle. ing) not only seem to favourably influence the pre- or perimenopausal phase and thus Increased physical activity, especially weight and insulin sensitivity, but would contributes to the late manifestation of li- endurance training in the aerobic range, also appear to have anti-inflammatory ef- poedema in this phase of life (51). promotes fat burning and serves primarily fects (57–59). to increase the insulin sensitivity of muscle This and a significant reduction of cal- cells, rather than to burn calories, the im- orie intake can result in non-diabetic fast- Reducing hyperinsulinemia, portance of which is anyway usually over- ing blood glucose levels after eight weeks in fighting inflammation estimated (55). In cases of severe obesity, 87% of patients, who have been suffering the various forms of water exercises (Aqua from diabetes for a short period of time, Hyperinsulinemia increases adipogenesis Cycling, Aqua Jogging etc.) are particularly and in 50% of patients, who have had dia- and reduces lipolysis, leading thereby to an suitable to avoid excess strain of the joints. betes for a longer period of time, and can increase of visceral adipose tissue and thus In terms of nutrition, importance must significantly improve blood pressure and to a formation of proinflammatory and co- be given, on the one hand, to its composi- blood lipids irrespective of the duration of agulation-activating hormones and cyto- tion, as blood glucose and insulin peaks the diabetes (60, 61). These results are kines. The formation of oedema increases, should be avoided in the context of a diet therefore comparable to those after bariat- on the one hand, as a result of the inflam- with low glycaemic load by abstaining from ric surgery, in which a rapid normalization matory-mediated increase of capillary per- sugar and refined carbohydrates (56), but of the metabolism is also achieved in type meability and the increased retention of perhaps even more decisive is a reduction II diabetes, but which is neither possible water and sodium and, on the other hand, in the frequency of meals and abstaining nor desirable for all patients and is not Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. as a result of the insulin-mediated increase from between-meal snacking. This is a rad- without risks. In addition to the immediate of estradiol. ical turning away from the recommen- risk of surgery, these include long-term Therapeutic options should therefore dation to eat many small, especially carbo- malnutrition, osteoporosis, oesophagitis, target primarily the reduction of hyperin- hydrate-dense meals. The awarding of the dumping syndrome and blood sugar fluc- sulinemia and the resolution of insulin re- Nobel Prize in Medicine to Y. Ohsumi for tuations in diabetes, increased suicide and sistance as well as fighting chronic inflam- his research on autophagy has once again accident rates compared to non-operated mation (▶ Fig. 3; ▶ Tab. 2) brought the various forms of fasting and patients, increased drug use and a failure In cases of low to moderate insulin re- their effects on the metabolism into focus. rate of up to 20% (62–64). Long-term fol- sistance, insulin sensitivity can be im- Here an extension of the nocturnal fasting low-up care and supervision is imperative period or the introduction of individual after both bariatric surgery and nutritional

Tab. 2 Laboratory Lifestyle recommen- Dietary recommendations Recommendations on nutritional Therapy recommen- marker dations supplements dations for insulin resistance and inflam- Inflammation Elimination/treatment of in- Avoiding: • Fish oil mation markers: flammatory diseases • Sugar, fructose, refined carbohy- • Vitamins D, C, B • hs-CRP drates, trans fats, • IL 6, IL8 Increase of insulin sensitiv- • Omega-6 rich oils If required: • TNF- α ity by: • Preservatives and additives, pro- • Zinc, magnesium, chromium, • More exercise (especially cessed meat products selenium Metabolic aerobic) • Meat from intensive rearing • Green tea extract (EGCG) markers: • Sufficient sleep • Wheat • Resveratrol • HOMA-IR • Stress reduction • Reduction of sweeteners • Curcumin • Adiponectin • Weight loss • Garlic, ginger • Proinsulin • Reduction of the number Increasing healthy fats: • Rosemary, basil of meals • Omega-3 fatty acids (cold-water • Gymnema silvestre • Intermittent fasting fish) where appropriate • Olive oil, nuts and seeds, Hormones: • Ketogenic diet where ap- • Meat and dairy products (full fat) • If necessary, DHEA (if decreased) propriate preferably from pasture raised ani- • If necessary, progesterone (transder- mals mal) • High fibre diet, lots of fresh veg- etables, moderate amount of fruit (preferably berries) therapy; only then are satisfactory long- 6 and 8, TNF-α) is reduced, diuresis and formation of ketones takes place via lipoly- term results possible (65). natriuresis are increased and the blood sis. In this context, attention should be paid Numerous studies have already demon- concentration of arachidonic acid and to the quality of the dietary fats: Desirable strated a reduction in inflammatory pa- omega-6 fatty acids decreases. Beta-hy- is the highest possible share of anti-inflam- rameters and cardiovascular risk factors as- droxybutyrate has a direct anti-inflamma- matory omega-3 fatty acids from plant and sociated with a ketogenic diet (very low tory effect in that it blocks a part of the im- marine origins and the lowest possible carb ketogenic diet (VLCKD) (66–68); fa- mune system involved in various inflam- share of proinflammatory omega-6 fatty vourable effects are also evident in neur- matory diseases (71). In contrast to the ex- acids. In contrast to industrial trans fats, odegenerative diseases (69, 70). The reduc- tremely high-fat, ketogenic diet in other the natural trans fats contained in dairy tion in carbohydrate intake below the indi- diseases, in which a weight loss is undesir- products were found to have positive ef- vidual ketogenic threshold normalizes glu- able (epilepsy, tumours), a calorie deficit fects on HDL, inflammatory markers and cose and insulin at low levels. The secretion can be induced in overweight individuals vascular health. Because of their higher of proinflammatory enzymes (Interleukins by a low to moderate fat intake, since the content of omega-3 fatty acids and conju- Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages.

Fig. 4 Lipoedema case study: Grade I obesity (BMI 31.1), 91.2kg; WHtR 0.55; lipoedema of the arms (Stage I) and legs (Stage II); contact sensitivity, sponta- neous pain, 3–4 Ibu 400/day; retired early „because of her legs and the pain“; rheumatology and muscle biopsy without pathological findings; HOMA-IR 1.3; CRP 2.3; right photos: ketogenic diet, omega 3 supplementation; weight loss 19 kg in 3 months. Free of complaints, no more pain medication; practices sports again

Fig. 5 Lipoedema case study: Lipoedema stage II; weight 141 kg; 178cm; BMI 44.5; ketogenic, high-protein diet; symptom improvement already after 1 week (subjectively and objectively by lymph therapist)

For patients, ketosis has the immediate benefit of physical and mental well-being, as ketone bodies have a satiating effect (75–77) and are slightly mood enhancing. In terms of weight loss and symptomatology, the ketogenic diet seems to be particularly effective for lipoedema (▶ Fig. 5, ▶ Fig. 6). It not only leads to weight loss and degradation of visceral fat, but also to a reduction of the alimentary, i.e. not exclus- ively lipoedema-related, subcutaneous adipose tissue at the extremities. According to our own investigations, typical symptoms such as sensation of tension, oedema, often tenderness to palpation as well, are improved in more than 80% of cases, so that a Fig. 6 Lipoedema case study: Weight loss; 104kg (-36.5 kg), Circumference reduction of 10–18cm: Still massive lipohypertrophy. No complaints, lymphoedema no longer present. reduction of the therapeutic measures is often possible (50). Interestingly, even patients with normal weight often experience a relief of their complaints by avoiding re- gated linoleic acid, full-fat, pasture raised mass-farmed animals. A study of 37 pa- fined carbohydrates and sugars. Hence, dairy products are recommended (72). tients with type II diabetes showed that a this improvement is not only a conse- A qualitatively and quantitatively ad- high-normal protein intake reduces liver quence of weight loss, but most likely of the equate protein intake, as is necessary for fat content, liver enzymes, inflammatory anti-inflammatory and anti-oedematous the protection of the lean mass and for parameters and insulin resistance (73). An effects of the metabolic readjustment as Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. saturation (73), can also be modified with amount of 1 to 1.2 grams of protein per well. regard to pro- or anti-inflammatory prop- kilogram of the normal weight is recom- erties: fish, especially high-fat, cold-water mended, which is usually enough to pro- Additional dietary recommen- fish such as herring, mackerel and wild tect lean mass (74) and, as the brain is good dations salmon are recommended because of their at using the ketones as an alternative ener- content of omega-3 fatty acids. Meat from gy source, but depends on glucose to about Even though they do not contain usable pasture raised livestock (lamb, cattle) or 15 to 20 %, to maintain the necessary glu- carbohydrates, sugar-free sweeteners game contains more omega-3 fatty acids coneogenesis. Insulin secretion increases should also be avoided or consumed in and significantly less arachidonic acid than only at a significantly higher protein intake only small quantities, as they can also in- pork and turkey or meat from industrially (>2g/kg) due to increased gluconeogenesis. crease the insulin secretion via the sense of

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