Effect of a ketogenic diet on pain and quality of life in patients with lipedema: The LIPODIET pilot study

Abstract Background Lipedema is an underdiagnosed condition in women, characterized by a symmetrical increase in subcutaneous adipose tissue (SAT) in the lower extremities, sparing the trunk. The lipedema SAT has been found to be resistant to diet, exercise and bariatric surgery, in regard to both weight loss (WL) and symptom relief. Current experience indicates that a low carbohydrate and high fat (LCHF‐diet) might have a beneficial effect on weight and symptom management in lipedema. Objective To assess the impact of an eucaloric low carbohydrate, high fat (LCHF)‐diet on pain and quality of life (QoL) in patients with lipedema. Methods Women diagnosed with lipedema, including all types and stages affecting the legs, (age 18–75 years, BMI 30–45 kg/m2) underwent 7 weeks of LCHF‐diet and, thereafter 6 weeks of a diet following the Nordic nutrition recommendations. Pain (visual analog scale) and QoL (questionnaire for lymphedema of the limbs), weight and body composition were measured at baseline, week seven and 13. Results Nine women (BMI: 36.7 ± 4.5 kg/m2 and age: 46.9 ± 7 years) were recruited. The LCHF diet induced a significant WL −4.6 ± 0.7 kg (−4.5 ± 2.4%), p < 0.001 for both, and reduction in pain (−2.3 ± 0.4 cm, p = 0.020). No correlation was found between WL and changes in pain at week seven (r = 0.283, p = 0.460). WL was maintained between week seven and 13 (0.3 ± 0.7 kg, p = 0.430), but pain returned to baseline levels at week 13 (4.2 ± 0.7 cm, p = 0.690). A significant increase in general QoL was found between baseline and week seven (1.0 (95% CI (2.0, 0.001)), p = 0.050) and 13 (1.0 95% CI (2.0, 0.001) p = 0.050), respectively. Conclusion A LCHF‐diet is associated with reduction in perceived pain and improvement in QoL, in patients with lipedema. Larger randomized clinical trials are needed to confirm these findings.

Women on the ketogenic WOE report reduction or elimination of swelling and pain, and weight loss (WL). 13,18 However, these reports came from patients' experiences, not clinical trials, therefore more research is needed to confirm these findings and to investigate if KD is a possible treatment option for lipedema. Recently, Renzo et al (2021) reported a reduction in fat mass (FM) and an improvement in QoL with a Mediterranean diet in patients with lipedema. 19 The main objective of this study was to assess if an eucaloric LCHF-diet lead to change in pain and QoL in patients with lipedema.
The second aim was to assess if a LCHF diet led to change in body composition in patients with lipedema. The hypothese of the study were that a LCHF-diet would lead to a reduction in pain and increase in QoL, independently of WL, in lipedema patients.

| Participants
Women (18-75 years old) with obesity (BMI: 30-45 kg/m 2 ) and diagnosed with lipedema, including all types and stages affecting the legs, were included in the study. The participants had to be weight stable (<2 kg variation within the last 3 months) and not currently dieting to lose weight or on a KD. Exclusion criteria was pregnancy or breast feeding, history of infectious diseases, medication known to affect body weight and enrollment in any other obesity treatment.
Moreover, those with a history of psychological disorders, not mastering a Scandinavian language, having a malign disease or any disease that leads to dietary advice that is not consistent with the intervention, or difficulties following the instructions, were not accepted into the study. Participants were recruited via announcement at obesity treatment facilities and Internet, (Lipedema-groups on Facebook and the intranet at the University Hospital in Trondheim), posters in the region, and through the Norwegian lymphedema-and lipedema association. All participants provided a written informed consent before commencement.

| Study design
This was a repeated measures study, where females with lipedema underwent 7 weeks of an eucaloric LCHF-diet, followed by 6 weeks of an isocaloric diet in line with the Nordic Nutrition Recommendations.
The study design is illustrated in Figure 1.
Dietary plans were based on individual calculated energy needs (resting energy expenditure (REE) x physical activity levels (PAL)) aiming at maintaining baseline weight. REE was measured in the fasting state by indirect calorimetry (Vmax Encore 29N; CareFusion), at baseline, using a canopy system and following standard procedures. 20

| Nordic nutrition recommendations-phase
During week 8, the participants were gradually introduced to a 6-week eucaloric diet (dietary plans and a recipe booklet as for the LCHF-phase) based on the Nordic nutrition recommendations (NNR).
The control diet used in this study was based on the NNR that constitutes the scientific basis for national nutrient recommendations and dietary guidelines in Norway. The purpose is to help prevent chronic diet-related diseases in the population. 21

| Compliance
The participants had 30-min weekly follow-ups with the dietitian aiming to ensure compliance with the diets. Moreover, patients were asked to fill out daily food records throughout the study period. Food records from baseline, weeks 6 and 11 were then analyzed for macro-and micronutrient composition using Kostholdsplanleggeren (Norwegian Food Safety Authority and Norwegian Directorate of Health, 2016). 22 Acetoacetate (AcAc) was measured in the first urine of the day at the weekly follow-ups, using ketostix (Bayer Corp.), as a measure of compliance during the LCHF diet. Participants were asked not to change their activity throughout the study and armbands (SenseWear, Body Media) were used for 7 days, at prebaseline, week six and week 12, to check for compliance. For data to be considered valid, participants had to wear the armbands for <7 days, including at least 1 weekend day, and more than 95% of data needed to be available over a 24 h period. PAL-value and number of steps/day were analyzed. 23

| Data collection
The following variables were measured at baseline, week seven and week 13.

| Pain
To measure the perceived pain, a visual analog scale (VAS) was used. 24,25 Participants were asked to place a perpendicular line on the VAS-scale to represent their current pain-intensity at baseline, W7 and W13. The question used was: "In how much pain are you right now?" (0 = No pain at all 10 = As much pain you can possibly imagine).

| Quality of life
The Norwegian version of the QoL questionnaire for lymphedema of the legs, a validated health-related QoL questionnaire 26

| Weight and body composition
Height was measured following standard procedures, 27 using a measuring tape installed on the wall. Bioelectrical impedance analysis (BIA) was used (InBody 720 (BIA)) at baseline, week seven and week 13 to measure body weight (BW) and to analyze body composition. [28][29][30] Waist, hip, thigh, and calf circumference were measured at baseline, week seven and week 13 using a measuring tape. The waist was defined as the midway between the lower rib and the iliac crest. 31 The participants were asked to breathe normally, and the measurement was taken as they exhaled. Hip circumference was measured over the largest part of the buttocks. [31][32][33] The thigh and calf circumferences were measured as the participants were lying on a bench and measured where the circumference of the thigh/calf apparently was largest. To ensure that the thigh and calf circumference was measured at approximately the same place each time, the length (cm) from the foot to the point, was measured and recorded for the next measurement.
These circumference measures were taken only wearing underwear.

| Blood samples
Blood samples were collected in fasting at baseline, week seven and week 13, at the laboratory of the University Hospital in Trondheim, F I G U R E 1 Timeline of data collection throughout the LIPODIET-study SØRLIE ET AL.
-485 to ensure that the participants tolerated the diet and that the diet did not lead to elevated blood lipids and/or deteriorated kidney function. 17,34 The parameters measured in the blood were C-reactive protein (CRP), high-density lipoprotein (HDL) cholesterol, lowdensity protein (LDL) cholesterol, triglycerides, glucose, glycated hemoglobin (HbA1c), alanine transaminase (ALAT), gamma-glutamyl transferase (GT), alkaline phosphatase (ALP), natrium and potassium.

| Statistical analyses
Statistical analysis was carried out using IBM SPSS Statistics 26 (SPSS Inc.) and statistical significance assumed at 5%, unless otherwise stated, and data presented as mean � SEM, except for baseline anthropometric data, where mean � SD was used. Data was analyzed using linear mixed models (LLM) and Bonferroni adjustment were used for comparison between timepoints (baseline, week seven and week 13). Correlation analysis between WL at week seven and week 13 and change in perceived pain was performed using Spearman r correlation.

| RESULTS
Nine participants met study entry criteria and were included in the study with an average age of 46.9 � 9.0 years and with a BMI of 36.7 � 4.5 kg/m 2 . One participant did not show up for testing at week 13, due to illness, but was included in the analysis. Mean attendance of weekly follow-up meetings throughout the study period was 85.7% (range: 71.4%-100.0%).

| Body weight and composition
Changes in body weight and composition overtime can be seen in Table 1

| Diet
All participants achieved ketosis, as positive AcAc (>0.5 mmol/L) was detected in urine during the LCHF-diet, according to objective observations of color change on the ketostix. AcAc increased from baseline to week 7 (>0.05-8 mmol/L) and returned to baseline levels at week 13 (<0.03).
Changes in energy, macro-and micronutrients intake over time are shown in Table 2. There was no significant change in median total energy intake between any of the three time points. The total fat intake increased significantly from baseline to week 6 (88.0 � 8.6 vs. 146.0 � 8.6 g/day, p < 0.001), and decreased significantly from week 6 to week 11 (146.0 � 8.6 vs. 73.0 � 8.6 g/day, p < 0.001). Simultaneously the total intake of carbohydrates decreased significantly from baseline to week 6 (182.0 � 21.6 vs. 28.0 � 21.6 g/day, p < 0.001) and increased from week six to week 11 (28.0 � 21.6 vs. 197 � 21.6 g/day, p < 0.001).
There were no significant differences between baseline and week 11 in any of the nutrients.
There was a significant increase in the intake of main carbohydrate sources and a decreased intake of meat and eggs between weeks six and 11, when changing from the ketogenic to the NNR diet.

| Physical activity
There were no significant differences in PAL or number of steps per day over time. These data are presented in Table 4.

| Pain
Changes in pain overtime can be seen in Table 5. The LCHF-diet induced a significant reduction in pain from baseline to week seven

| Quality of life
Changes in QoL can be seen in Table 6. There was a significant in-

| Markers of glucose, lipid and electrolyte metabolism in the blood
Changes in glucose, lipid and electrolyte markers in the blood can be seen in Table 7. The LCHF-diet induced a significant reduction in -489 are needed to elucidate this. 18 The pain reduction may also be explained by the anti-inflammatory effects of an LCHF-diet, given the inflammation present in the lipedema fat. 8,9 Nutrients affects our immune system, and various macronutrients can be either pro-or antiinflammatory. 35 Omega-6, refined carbohydrates (white bread, pasta, and ultra-processed food) and saturated fats are nutrients with pro-inflammatory effects, while omega-3, polyphenols (fruits and vegetables) and whole-grain products have anti-inflammatory properties. 36 The intake of omega-3 fatty acids increased during the LCHFperiod and decreased in the NNR-phase. Simultaneously the intake of sugar decreased in the LCHF-period. These findings may indicate that a decreased intake of refined carbohydrates, and increased intake of omega-3 fatty acids may be part of the explanation of the reduction in pain in these patients, due to their anti-inflammatory effects. Therefore, the Mediterranean diet could be more appropriate for lipedema patients, also allowing the consumption of more whole-grain products and some fruits. 37 This is in line with a recent study by Renzo et al, showing improvements in antioxidant capacity with a Mediterranean diet in patients with lipedema. 19 This is one of the few studies investigating the effect of diet on pain in patients with lipedema, which is the dominating symptom in lipedema and the one with the strongest negative impact on QoL.
Liposuction has been shown to induce a reduction in pain (assessed with VAS), with a concomitant improvement in psychological stress 38 In an experimental study by Rapprich et al., 25 patients diagnosed with lipedema were examined before and after liposuction. These patients reported a significant reduction in pain from 7.2 to 2.1 cm on VAS-score, six months after liposuction. 38 Liposuction is a highly invasive treatment, not suitable to or affordable by all patients. The participants in our study reported a lower VAS-score initially, and therefore the reduced pain reported after 6 weeks on a LCHF-diet illustrates a great significant and clinical effect on pain.
The KD did induce a small, but significant reduction in BW (−4.6 kg CI (3.2,6.2 kg)). Loss of total body water (TBW), due to depletion of glycogen in the muscles and liver, is likely to account to some of the weight reduction seen (approximately 1.5 to 2 kg). 39,40 Similarly, the small, although not significant, weight gain during the NNR-phase, is likely due to hydration of the lean tissue, which accompanies glycogen storage. Crescenzi R. et al. found that tissue sodium content is elevated in the skin and SAT in women with lipedema, and that the relative fat-to-water volume in the calf was elevated in lipedema, and skin sodium content was directly correlated with fat-to-water volume. 1 This indicates that the water volume in the legs of women with lipedema may be elevated.  -491 The reduction in waist-and hip-circumference being the most significantly compared to thigh-or calf-circumference during LCHF indicate that these was the areas mostly affected by the WL. This is in line with a review article by Herbst et al. (2012) that lipedema fat in the lower extremities of the body in lipedema patients is resistant to WL. 3 Child et al. presented the hypothesis that adipocyte proliferation induce hypoxia due to a pressure on the capillaries, resulting in adipocyte necrosis followed by macrophage infiltration and inflammatory responses. 2 A LCHF-diet may reduce pain by reducing the amount of non-lipidemic fat in the legs, which then relieves the pressure on the blood vessels. 41 The lack of change in tight circumference in the present study is in contrast to the findings of another KD intervention study conducted in a mixed sample of patients with either lip-and/or lymphedema, which found a reduction in volume of the lower limbs. 15 The diversity in findings could be due to differences in methods of assessment, participant characteristics (sex, age, disease type and stage), and sample size.
The early diagnosis of Lipedema followed by WL and dietary changes may reduce non-lipidemic fat and inflammation. This may also potentially slow down the progression of the condition. However, even with strict diet and exercise regimens, the disease may progress, and further treatment may be necessary. 11 People with obesity only need a modest WL of 5%-10% of initial weight to have a significant impact on health. 9  There might be an increase in number of women diagnosed with lipedema in the future, as the awareness among health care providers is increasing, and lipedema is underdiagnosed. To identify these patients, a physical examination is important. Therefore, the physical examination of all patients with overweight and obesity should be performed as a regular part of the clinical practice in obesity.
In summary, this study showed that there was a reduction in pain in patients with lipedema after 7 week on a KD. Even though the exact mechanisms mediating this effect remain unknown, several hypotheses have been proposed, namely ketosis per se, 35 the antiinflammatory effects of a LCHF-diet or a potential effect of a reduction in TBW or WL.

| CONCLUSION
A LCHF-diet leads to a reduction in perceived pain and improvement in general QoL, independently of WL. Randomized clinical trials are needed to confirm these findings and explore the potential mechanisms involved.