cardiorespiratory fitness (CRF) by exercise based prevention interventions is a ... from body fat reduction by a sharp nutritional intervention in first place thus ... in daily life [21, 26, 31-34]. ..... At baseline, the mean VO2peak was 27.2 ml/kg/min. ..... chronic liver disease. BMC Medicine, 2011. 9(70): p. 1 - 7. PMID:21645344.
1
Original Paper
2 A Web-based exercise intervention for effective complementary treatment of patients with 3
NAFLD - First results of the HELP-Study
4Pfirrmann, D.1, Huber, Y.2, Schattenberg JM.2, Simon P.1 51Institute of Sports Science, Department of Sports Medicine, Johannes Gutenberg University 62University Medical Center of the Johannes Gutenberg University, Department of Internal Medicine 7Abstract 8Background 9Physical inactivity is a major risk factor for non-alcoholic fatty liver disease (NAFLD). Improvement of 10cardiorespiratory fitness (CRF) by exercise based prevention interventions is a recommended 11complementary treatment for NAFLD. Enabling patients to achieve minimally effective physical 12activity recommendations to improve CRF, typically requires high personal and financial expenses in 13face-to-face settings. Here we designed an eHealth approach for patients with NAFLD to overcome 14typical intrinsic and extrinsic barriers for the improvement of CRF (HELP-Study). 15Objective 16We assessed the effectiveness of an 8-week tailored Web-based exercise intervention for the 17improvement of CRF, expressed as VO2peak, in patients with histologically confirmed NAFLD. 18Methods 19In a 24-month period, 44 patients were enrolled into an 8-week prospective, single-arm study. After a 20medical examination and performance diagnostics, a sports therapist introduced the patients to a 21Web-based platform for individualized training support. Regular individual patient feedback, was used 22to systematically adapt the weekly exercise schedule. This enabled to monitor and warrant patient 23adherence to strength and endurance training and to optimize the step-wise progressive exercise 24load. Exercise progression was based on an a priori algorithm taking the subjective rate for both, 25perceived exhaustion and general physical discomfort into account. VO 2peak was assessed at baseline 26and at the end of the study by spiroergometry. 27 28
29Results 30Forty-three patients completed the intervention with no adverse events reported. VO 2peak significantly 31increased 8.5 % by 2.4 ml/kg/min (95% CI: 1.48 - 3.27, P < .0001) accompanied by a 1.0 kg (95% CI: 320.33 – 1.58, P = .004) body weight reduction and a 1.3 kg (95% CI: 0.27 – 2.27, P = .01) body fat mass 33reduction. In an exploratory analysis step-wise logistic regression analysis revealed low body fat and 34low VO2peak at baseline as well as the total minutes of endurance training during the intervention as 35main contributors to a positive change in VO 2peak. Our predictive model indicated that the average 36NAFLD patient needed 223 min for stabilization of VO 2peak, while 628 min were required to achieve 37average improvement in VO2peak. However, in patients with a roughly 20 % higher than average VO 2peak 38these 628 min were only sufficient to stabilize VO 2peak and a more than 40 % lower than average fat 39mass would be required for such subjects with high VO 2peak to achieve an average outcome. 40Conclusions 41Here we show for the first time that patients with NAFLD can be effectively supported by a Web42based approach enabling similar increases in VO 2peak as face-to-face interventions. Patients with low 43body fat and low VO2peak turned out to profit the most from our intervention. In terms of future 44treatment strategies, this implies that NAFLD patients with high body fat may particularly benefit 45from body fat reduction by a sharp nutritional intervention in first place thus enabling a more 46effective exercise intervention, subsequently. 47 48Trial Registration: Clinicaltrials.gov: NCT02526732 49https://clinicaltrials.gov/ct2/show/NCT02526732 (Archived by WebCite at 50http://www.webcitation.org/6Nch4ldcL) 51Keywords: Web-based, exercise, NAFLD, fatty liver, treatment, lifestyle 52 53 54 55 56Introduction 57
58Sedentary behavior and an unhealthy diet are common in western industrialized countries [1, 2]. 59Modern lifestyle increases the risk for chronic diseases such as the metabolic syndrome [2-5]. In 60accordance to the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in 61adults, the metabolic syndrome is defined by the presence of abdominal obesity, 62hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension, and impaired fasting 63glycaemia [6]. In the last years, the nonalcoholic fatty liver disease (NAFLD) has been moving into the 64spotlight, since it has the highest increase in the incidence among chronic liver diseases worldwide [3, 654, 7-9]. Some researchers describe NAFLD as a part (hepatic manifestation of metabolic syndrome) or 66at least a partial result of the metabolic syndrome [3, 10-13]. Independent of age or ethnicity, 20 to 6730 % show fatty changes in the liver with an increasing tendency [8, 11, 14-17] and the prevalence is 68still higher in patients with diabetes [18]. NAFLD is seen as a benign preliminary stage with the 69potential to progress: from simple steatosis towards non-alcoholic steatohepatitis (NASH), cirrhosis 70and finally hepatocellular carcinoma (HCC) [9, 19-22]. The pathways driving this progression are 71numerous and complex, [22, 23] and not every patient with NAFLD develops cirrhosis related 72complications [9, 24]. However, patients have a higher mortality rate, when compared to the general 73population [9, 24, 25]. Most of patients with NAFLD are asymptomatic [16, 19, 26]. Some suffer from 74unspecific symptoms, such as fatigue [26, 27] and depression [28], which additionally affects the 75health related quality of life (HRQOL) [29, 30]. If left untreated, most patients will develop diabetes as 76a long-term result [9]. In order to improve the condition of the liver and to reduce additional risk 77factors, changes towards a balanced nutrition and a more physically active lifestyle are recommended 78in daily life [21, 26, 31-34]. The Practice Guideline by the American Association for the Study of Liver 79Diseases (AASLD) recommend a loss of at least 3-5 % of body weight, in order to improve steatosis 80[35]. Current recommendation for adult patients with NAFLD or NASH is a physical activity target of at 81least 150 minutes exercise per week of moderate intensity or at least 75 minutes per week of 82vigorous intensity [36]. In addition strengthening exercises should be performed twice a week [36]. 83Most people with NAFLD do not know about the presence of the disease, because of the absence of 84any specific symptom. Therefore, NAFLD is occasionally self-caused [37], and develops and progresses 85over years. Studies showed a reduced physical activity level (intensity and amount) in patients with 86NAFLD compared to healthy individuals [12, 27, 38] and a suboptimal cardiorespiratory fitness with 87fewer than 20 % of patients meeting recommended physical activity guidelines [39]. In a survey 88conducted by Kistler, 54 % mentioned to be inactive, while 57 % of them reported no recreational 89activity. The remaining 43 % stated some activity, which was, however, not enough to achieve the 90goals set in the recommendations [40]. Besides the decreased activity level, prolonged sitting time is 91associated with a higher prevalence of NAFLD [41, 42]. At the point of diagnosis, patients are 92encouraged to immediately change many aspects in their daily routine. Here, different barriers and
93obstacles have to be overcome. Time and place constraints, for instance, are common problems for a 94regular activity [4, 37, 43, 44]. Changing one’s lifestyle is not easy, especially for patients with highly 95sedentary habits [45]. Consequently, regular motivational support from experts is needed [45]. Thus, 96advances in modern technologies should be taken into account for promoting health-conscious 97behavior [43]. In a survey conducted by Pew Research Center in 2015, 84 % of American adults have 98access to a computer and regularly use the internet [46]. In 2005, 75 % of internet users searched for 99health information and 42 % of them searched for specific information about exercise and training 100[47]. The possibility to reach and support large numbers of patients via the internet [48] can thus be 101seen as a cost-effective possibility to improve and maintain an active lifestyle [49]. Web-based 102interventions with cancer patients produced first promising results [50, 51]. The aim of our 103prospective, non-randomized pilot study, was to find out, whether online support aids patients with 104NAFLD or NASH in establishing and maintaining a regular level of physical activity and whether the 105individualized training recommendations improve the overall physical fitness determined as VO 2peak 106and body composition. 107Methods 108 109The HELP study is a prospective, single arm study in patients with histologically confirmed NALFD and 110explored the feasibility and effectivity of an individualized exercise intervention. A total of 46 patients 111were recruited from August 2015 to December 2017. The study was registered at (clinicaltrials.gov 112(NCT02526732)). 113Patient Selection 114Inclusion criteria were (1) age between 18 and 70; (2) histologically proven NAFLD. Subjects were 115excluded if they had (1) bariatric operation in the past five years; (2) body mass index (BMI) below 11618.5 kg/m2 or higher than 45 kg/m2; (3) instable coronary heart disease; (4) coronary interventions in 117the past six months; (5) stroke in the past six months; (6) higher grade of coronary artery disease (II118IV); (7) chronic obstructive pulmonary disease (COPD); (8) renal or metabolic abnormalities; (9) 119uncontrolled hypertension; (10) presence of other liver diseases, such as hepatitis; (11) presence of 120decompensated liver cirrhosis; (12) presence of HCC; (13) alcohol consumption >30g / day in men and 121>20g / day in women; (14) pregnancy; (15) medications that can cause secondary NASH (for example 122corticosteroids); (16) presence of other immunological or inflammatory diseases (e.g. systemic lupus 123erythematosus (SLE)); (17) musculoskeletal disorders; (18) Marcumar therapy. 124The primary outcome was defined as a change in VO 2peak from the baseline. The secondary outcome 125measures included changes in body composition, and feasibility as well as safety of the Web-based
126support. Assessment of the outcome was performed before and after the 8-week intervention, as 127described. 128Clinical examination 129All eligible patients were screened and recruited at the outpatient hepatology clinic of the University 130Medical Center Mainz. 131Sports medical examination 132After informed consent, patients underwent clinical examination and were referred for a 133cardiopulmonary exercise test until exhaustion at the Department of Sports Medicine, University 134Mainz. A standard 12-lead resting electrocardiogram (ECG) and a pulmonary function test 135(Spirometry); (Body Box 5500, Medisoft) were performed. In addition, the body composition was 136measured by Bio-Impedance Analysis (BIA), (InBody 3.0, Biospace). After the exercise test each 137patient was registered and trained by the administrator on the webpage. In addition to a detailed 138explanation, a manual for the homepage, a heart rate monitor and three elastic tapes were provided. 139For more detailed information on study flow, a video clip is available. (see Multimedia Appendix 1). 140Cardiopulmonary exercise test 141All study participants performed a stepwise exercise test on a treadmill until volitional exhaustion 142(subjective) or until meeting an objective criterion (i.e. inappropriate blood pressure response or 143changes in ECG). Each stage of the modified walking protocol lasted for 3 minutes and intensity was 144increased by speed and elevation of the treadmill (Saturn, HP Cosmos) [52]. Continuous expired gas 145analysis (breath by breath) was performed (Ergostik, Geratherm) and heart rate was monitored 146during the test. Blood samples from the earlobe were taken at the end of each stage to determine 147lactate concentration and blood pressure was measured in every second stage. The subjective 148condition was measured utilizing the BORG scale (6-20) 30 seconds before the end of each stage. 149Follow-up assessment 150All participants performed the clinical and sports medical examination described above at study start 151and again after eight weeks. The clinical examination was additionally performed 12 weeks after the 152end of the intervention (Fig. 1).
153 154Figure 1 Study flow. 155Intervention 156Patients received exercise recommendations via system internal messages on a weekly basis [53]. 157Depending on the initial exercise test and the subjective feedback from the patients during the 158intervention period of eight weeks, the exercise program was adjusted for each patient. In order to 159avoid early dropouts, moderate exercise intensity with three sessions per week was chosen (2x 160endurance training (walking/ running) and 1x strength training (major muscle groups)). The program 161was intensified after a four-week familiarization to reach a frequency of five sessions per week (3x 162endurance training and 2x strength training) for the remaining four weeks. Beside the frequent 163interaction with a counselor, peer support is considered as a cornerstone in the concept. Therefore, a 164discussion board and a chatroom were implemented, in order to improve social support and 165adherence [54]. 166Strength training 167A program of ten strength exercises should be carried out in a prescribed sequence, to stimulate 168muscular strength in the major muscle groups. A detailed, illustrated instruction and video files for 169the exercises were available on the website. Training individualization was achieved by varying the 170number of repetitions or number of sets. 171Endurance training 172The individualized endurance training was based on lactate measurements. The intensity of the 173jogging program was controlled by a heart rate (HR) measurement (FT1, Polar). After an initial 174continuous method with a HR at the lactate threshold (LT), the training followed the interval method 175(e. g. 2 x 4 min, 2 x 3 min, 2 x 2min with 2 min. at rest) at a higher HR. The intensity of training was 176achieved by adjusting the interval time or by adding additional intervals.
177Training process 178Endurance training and strength training, consisting of bodyweight exercises and exercises with 179elastic tapes, were the main content of the training recommendations. Each training started with a 5180minute warm up and was followed by a 5-minute cool-down phase. A selection of relaxation and 181breathing exercises were also available on the website. At the end of each week, the patients sent in 182a filled schedule with important information such as average heart rate, resting heart rate, and 183training time. In addition, two values were asked to allow the modification the training intensity and 184duration for the following week. First, the patient’s individual assessment of pain and assessment of 185training load was determined as modified BORG value (1-10), after each training session. Second, a 186traffic light principle was used to regulate the intensity of the next week’s training. Depending on the 187individual feedback an increase or decrease of the training recommendations were possible, whereby 188the pain value was dominant for the decision [53]. The weekly feedback should ensure an 189appropriate load according to individual abilities and assess the compliance. In addition, a group 190training was offered biweekly at the sports center of the University Mainz. 191Statistical Procedures 192Statistical analysis was performed by using SPSS Statistics version 23 and JMP. Descriptive statistics 193were used for the presentation of baseline characteristics and the using behavior of the website. 194Variables were described by using mean, median, and standard deviation (SD). Normal distribution 195was tested with Shapiro-Wilk-Test due to the small sample size. In case of normal distribution, the 196paired students t-test was used in order to determine within group differences before and after eight 197weeks’ intervention. Intention to treat analysis was performed and the data were processed 198according to the last observation carried forward method. A P-value of P < .05 was considered 199statistically significant. For the investigation of the factors that contribute to changes in VO 2peak, we 200employed a two-step procedure. Fold-Change in VO 2peak had to be normalized by a normalization 201procedure using the inverse of the squared values, as suggested by box-cox analysis. First, we 202computed a step-wise feed-forward logistic regression analysis. In order to warrant stringent inclusion 203criteria, we fed the model on the one hand with the baseline data on anthropometrics including body 204composition and performance data, as presented in Table 1, and with the data on endurance training 205(for the 8 weeks) and the total exercise time (strength and endurance training in minutes for 8 206weeks). Only 3 factors emerged that reached a significance level set at .05 for entering a single 207variable into the regression equation. These factors were used to compute a logistic regression 208analysis. 209
210Results 211 212Baseline characteristics 21346 patients were screened and after exclusion of two patients were 44 patients included in the study 214(see Fig. 2). One patient dropped out (2.3 %) during the intervention period. 215 216 217 218 219 220 221Figure 2 Patient flow. 222Among patients, three (6.8 %) had a normal weight status, 15 (34.1 %) were overweight, and 26 (59.1 223%) were obese. Characteristics at study start are summarized in Table 1. 30 patients (68.2 %) were 224male, with a mean age of 42 years. 41 (93.2 %) had a BMI above 25 and more than 27 % percent of 225body fat. In total, 1166 exercise recommendations (729 endurance; 437 strength) were performed 226and 222 recommended workouts were cancelled due to different reasons. 227 228Table 1 Baseline characteristics of patients enrolled in the HELP study characteristics (N: 44) age (y) 42,0 (SD 10.9) < 30 years 5 (11.4%) 30-60 years 38 (86.4%) > 60 years 1 (2.3%) male, n (%) 30 (68.2%) height (cm) 175 (SD 10.3) weight (kg) 95.9 (SD 17.4) BMI (kg/m²) 31.2 (SD 4.3) overweight (BMI > 25 < 30) 15 (34.1%) obese (BMI > 30) 26 (59.1%) body composition body fat (kg) 26.7 (SD 8.2) body fat (%)
27.9 (SD 7.4) lean body mass (kg) 64.8 (SD 14.1) spirometry forced vital capacity (FVC) (%norm) 107.5 (SD 13.3) forced expiratory volume (FEV1) (%norm) 96.3 (SD 16.3) spiroergometry resting heart rate (bpm) 79 (SD 10.2) VO2peak (ml/kg/min) 27.2 (SD 5.1) watt max 135.1 (SD 42.9) watt IAT 96.1 (SD21.5) BORG value max (6-20) 18.5 (1.5) heart frequency (HF) max 172 (SD 16)
229 230Primary Outcome 231At baseline, the mean VO2peak was 27.2 ml/kg/min. After eight weeks of intervention, the VO 2peak 232significantly increased by 8.8 % (from 27.2 ml/kg/min (SD 5.1) to 29.6 ml/kg/min (SD 5.4); (95% CI: 233-3.27 – -1.48, P < .0001); (Fig. 3). 234 235 236 237 238 239 240 241 242 243 244Figure 3. Individual changes in VO2peak from baseline to end of the study. Peak VO2 improved by 2.4 ml/kg/min. 245We employed logistic regression analysis to assess the combined effects of the variables shown in 246Table 1 on the fold-change in VO2max by step-wise feed-forward logistic regression analysis. A multiple 247linear regression model with three independent predictors emerged based on a total of 43 248observations (df =3; F = 8.03, r2 = 0.38; P < .001). All predictors had a significant influence and a
249corrected power of more than 80 % with VO 2peak at baseline (t = -3,77; std. effect size = -0,12; 95% CI: 250-0,18 - -0,05; P < .001, total minutes of endurance training during the intervention period of eight 251weeks (t = 3,27; std. effect size = 0,09; 95% CI: 0,04 - 0,15; P = .002), and body fat (%) at baseline (t = 252-3,22
std. effect size = -0,10; 95% CI:-0,17 - -0,04; P = .003) . The model indicated that participants
253in the program with average body fat percentage (27.9 %) and average VO 2peak at baseline (27.1 254ml/kg/min) would need roughly 223 hours of training within the intervention period to maintain their 255baseline VO2peak (Fig. 4a), while 628 hours of training are required to reach the average improvement 256of basal VO2peak of roughly 8 % (Fig. 4b). However, a high VO 2peak at baseline with average fat mass 257would lead to a significantly lower outcome (Fig. 4c) that can principally be compensated, if 258candidates with higher baseline VO2peak also have a lower fat mass (Fig. 4d). 259 260 261 262 263 264 265 266 267 268 269Figure 4 Predictive analysis for fold-change (FC) in VO2max. The linear effect of VO2peak at study start, total minutes of 270endurance training during the intervention period of eight weeks and body fat in percent at study start is presented as solid 271black regression lines and dashed blue lines indicate the respective upper and lower 95% CIs for the regressions . (a) 272According to this model 222 minutes endurance training are needed to stabilize VO 2max in the collective for a person with 273average VO2peak of 27 ml/kg/min and average body fat of 27.9 %. (b) For an improvement of roughly 8 % VO 2max an endurance 274training load of at least 600 minutes over eight weeks is necessary. (c) A higher initial VO 2peak leads to a reduced effect of the 275628 minutes endurance training within eight weeks on the primary outcome VO 2max. (d) In principal, a lower body fat (%) 276could compensate for the higher VO2peak at baseline (33.67) and still enable an eight percent improvement in VO 2max. with the 277same training load. 278 279Secondary Outcomes 280Significant changes could be observed in body weight and Body Mass Index (BMI) (95% CI: 0.33 – 2811.58, P = .004), (95% CI: 0.14 – 0.54, P = .001) respectively. With regard to the body composition, 282there is a significant reduction in body fat (95% CI: 0.27 – 2.27, P = .01) and thus the percentage of 283body fat (95% CI: 0.26 – 2.11, P = .01) and a slight, but not significant increase in lean body mass (Tab.
2842). There is a trend towards a lower resting heart rate (95% CI: -0.18 – 7.22, P = .06) and no changes in 285lung function expressed as FEV1 (95% CI: -4.11 – 1.38, P = .32) and vital capacity (95% CI: -1.09 – 3.41, 286P = .31) could be observed. 287Table 2 study results characteristics (n:44)
pre
post
Difference (%)
P value
weight (kg) 95,9 (SD 17.4)
95.0 (SD 17.8)
0.9 (0.9)
0.004
31.2 (SD 4.3)
30.8 (SD 4.4)
0.4 (1.3)
0.001
15 (34.1)
14 (32.6)
1 (6.7)
26 (59.1)
26 (59.1)
0 (0)
26.7 (SD 8.2)
25.5 (SD 9.0)
1.2 (4.5)
0.01
27.9 (SD 7.4)
26.8 (SD 8.4)
1.1 (3.9)
0.01
64.8 (SD 14.1)
65.2 (SD 14.2)
0.4 (0.6)
0.31
107.5 (SD 13.3)
106.3 (SD 14.2)
1.2 (1.1)
0.31
96.3 (SD 16.3)
97.6 (SD 13.3)
1.3 (1.3)
0.32
79 (SD 10.2)
75 (SD 11.5)
4 (5)
0.06
27.2 (SD 5.1)
29.6 (SD 5.4)
2.4 (8.8)
< 0.001
135.1 (SD 42.9)
149.5 (SD 49.5)
14.4 (10.7)
< 0.001
96.1 (SD 21.5)
100.6 (24.6)
4.5 (4,7)
0.001
18.5 (1.5)
18 (1.8)
0.5 (2.7)
0.03
172 (SD 16)
172 (SD 14.8)
0 (0)
BMI (kg/m²) overweight (BMI > 25 < 30) (%) obese (BMI > 30) (%) body composition body fat (kg) body fat (%) lean body mass (kg) spirometry
forced vital capacity (FVC) (%norm) forced expiratory volume (FEV1) (%norm) spiroergometry
resting heart rate (bpm) VO2peak (ml/kg/min) watt max watt IAT BORG value max (6-20) heart frequency (HF max)
288 289Further, significant changes in the power, expressed as Watt max (95% CI: -18.46 – -10.17, P < .001), 290and Watt at the individual anaerobic threshold (IAT) (95% CI: -7.00 – -2.05, P = .001) were observed 291(Fig. 5). The maximum heart frequency remains unchanged and the subjective perception of 292exhaustion, expressed as BORG-value, decreased significantly from baseline to post intervention (95% 293CI: -0.05 – 0.95, P = .02), as shown in Table 2. 294 295 296
297 298 299 300 301 302 303 304 305 306 307 308Figure 5. Fold changes for maximum Watt, VO2max, body fat, and Watt at the individual anaerobic threshold. 309 310Website Use 311All study participants were registered on the homepage at study start. The registration- and 312explanation process took about one hour and was integrated between the end of the treadmill test 313and the last blood sampling at 90 minutes post-test. During the intervention period, regular 314communication and feedback were easily achieved using the webpage. In some cases, the patients 315did not send the exercise feedback on time. Therefore, 120 reminders were sent in total to the 316participants in order to ask for the exercise feedback. The average user behavior in terms of log-in 317duration and frequency is presented in Table 3. The participants’ average length of a visit was about 31812 minutes and the average log-in frequency was 13 times during the intervention period of eight 319weeks. 320Table 3 Using behavior of the homepage during the intervention period of eight weeks. characteristics (N:43) total number of log-ins (sum; mean) 557 (13.0) total log-in duration in minutes (sum; mean) 6548 (152.3) reminder (sum; mean) 120 (2.8) using e-mail instead of the website for exercise feedback (sum; mean) 165 (3.8)
321 322However, there is a descending trend in registration frequency and duration over time, as shown in 323Figure 6 and 7. Nevertheless, a timely response was still achieved, also in patients who did not 324continue to use the webpage, by interacting via conventional e-mail (Tab. 3).
325 326 327 328 329 330 331 332Figure 6 Log-in frequency during the intervention period of eight weeks. 333 334 335 336 337 338 339 340 341Figure 7 Log-in duration in minutes during the intervention period of eight weeks. 342 343Physical activity development 344As illustrated in Figure 8, the physical activity level increased steadily over the period of eight weeks. 345After an initial familiarization period, the exercise recommendations increased progressively. In the 346second half of the intervention, the patients reached and exceeded the recommended activity goal of 347the world health organization (WHO) [55]. The study participants performed 72 additional workouts 348(e.g. hiking, playing volleyball or badminton) (Tab. 4). However, the participants were not obliged to 349record other leisure time activities, and therefore the additional exercises were not further examined. 350The adherence to the Web-based exercise concept, expressed as 80 % or more of the endurance 351workouts, was pretty good. 33 participants (77 %) performed 80 % or more of the recommended 352endurance workouts. Common reasons for breaks were due to deadlines (e.g. congress participation, 353or workshops), medical reasons (e.g. cold, inflammation, blisters, headache, or food poisoning), 354external conditions (e.g. high temperature or heavy rain), or private reasons. In total 222 exercise 355recommendations were not performed as recommended (Tab. 4).
356 357 358 359 360 361 362 363 364Figure 8 Development of the physical activity level, expressed as weekly endurance training in minutes. The dashed line 365indicates the recommended vigorous activity goal of 75 minutes per week from the WHO. 366 367Table 4 Presentation of the exercise profile characteristics (N:43) total physical activity within eight weeks in minutes (sum; mean) 52373 (1218) endurance training within eight weeks in minutes (sum; mean) 29104 (677) interruption of exercise training (sum; mean) 222 (5) additional workouts (sum; mean) 72 (1.7)
368 369Adverse events 370The online exercise concept was well-accepted by the patients. The intervention in this group of 371patients with liver disease was safe. No serious adverse events occurred during the study period. 372Discussion 373 374Current guidelines recommend lifestyle changes as the primary approach to treat obesity and NAFLD, 375however few studies, focusing on physical activity, have been published. Neither the type nor the 376intensity of exercise has been defined. Also, it has been suggested that physical deconditioning of 377patients with NAFLD leads to the inability to adhere to exercise recommendations. The HELP study 378explored the feasibility and the efficiency of a Web-based and patient-centered exercise support 379concept. 380The role of weight loss 381Weight loss is a major topic in the treatment of NAFLD [56]. The guidelines and experts in field 382recommend a weight loss of at least 3-5 % to improve steatosis [35, 57]. Anyway, there are critical
383limits mentioned, below the weight loss must not fall. [58] A weight loss of 1.6 kg per week should 384not be exceeded due to potentially provoked portal inflammation or portal fibrosis [57, 58]. 385Furthermore, three study participants in this investigation showed a normal weight status and a 386weight reduction is therefore not needed. The term weight management is more accurate instead of 387weight loss. We were able to show a significant but extremely low weight change, and this is in 388accordance to other exercise studies [59-61]. Weight gain is a result of a higher energy intake and a 389reduced energy expenditure [62]. Weight reduction is only possible if the energy expenditure 390persistently exceeds the energy intake [31]. Therefore, diet is a necessary aspect in weight reduction. 391Further, with reference to the above described prediction model (Fig. 4), the reduction of the fat 392mass percentage is crucial in order to significantly improve the cardiorespiratory fitness with an 393achievable amount of physical activity. Regular exercise supports energy expenditure, but conscious 394nutrition is essential for energy intake control. Furthermore, the absence of weight loss might partly 395be explained by a moderate shift from fat mass to fat free mass. Regular activity reduces body fat, 396however, lean body mass increases. Another explanation for not observing a weight loss during the 397intervention is an insufficient negative energy balance due to a low starting intensity [63]. For an 398effective weight loss, a longer duration and accordingly an increased intensity is required. 399Nevertheless, exercise studies show, irrespective of nutrition, promising results in terms of decreased 400insulin and homeostasis model assessment index (HOMA-IR) [60, 64], improved cardiorespiratory 401fitness, [59, 65] reduced hepatic and visceral lipids [60, 66], reduced liver enzymes and modulated 402liver fat [34]. Exercise combined with an adjusted diet shows strong interaction effects in relation to 403weight change, but exercise has also independent modes of action. Thus, physical activity or 404structured exercise recommendations should be strongly promoted due to additional benefits in the 405absence of a weight loss. 406The improvement of the fitness 407In the short intervention period of eight weeks, the results of this study are comparable to those of 408face to face interventions [34, 60, 61, 64, 67, 68], with respect to changes in body composition and 409VO2peak. Takahashi (2015) already assessed the efficiency and safety of two simple resistance exercises 410in 53 patients with NAFLD [64]. After a 12-week period, patients in the intervention group had a 411significantly increased mean level of fat-free mass (-0.24 ± 0.88 vs. 0.30 ± 0.67 kg, P = .01) and muscle 412(-0.24 ± 0.82 vs. 0.25 ± 0.70 kg, P = .02) compared to the control group [64]. This changes are similar 413to our findings. Further, a change of nearly 9 % in VO 2peak could be also shown in an investigation by 414Sullivan [67]. Participants in the intervention group trained five times per week for 16 weeks [67]. The 415subjects exercised under supervision once a week, and were encouraged to perform the remaining 416four sessions in their home environment. The endurance training was controlled by heart rate 417measurement [67]. In our study a combination of the heart rate, as objective measure and the Borg
418value [69] as subjective measure were used for the determination of the intensity. Borg values are 419considered as an appropriate measure for monitoring and regulating exercise intensity [34, 70, 71]. To 420clarify whether the intensity or the volume is more effective, Keating (2015) aimed to determine the 421more important training parameter in inactive overweight adults [61]. 47 obese adults trained for 422eight weeks either with low intensity and high volume (LO:HI), or high intensity and low volume 423(HI:LO), or low intensity and low volume (LO:LO), or were prescribed a stretching and self-massage 424program (placebo = PLA). The investigators came to the conclusion, that volume as well as intensity 425were both efficient [61]. However, with a view to adherence, an investigation by Perri found out, that 426a higher exercise frequency is more accepted, compared to a higher exercise intensity [72]. 427Furthermore, high exercise intensity conditions resulted in a higher percentage of exercise-related 428injuries [72]. Beside the positive effects of regular physical activity, independent of intensity and 429volume, the most important challenge is, to face the adherence to exercise [73]. 430The importance of regular support 431It is recommended to be physically active on five days a week. In addition a resistance training on at 432least two days a week should be performed. In contrast to the findings of Perri, [72] many study 433participants in this trial reported at the end of the study, that they struggled with the integration of 434the demanding volume in the second half of the intervention. Berzagotti (2016) summarized the 435beneficial effects of exercise on the health of NAFLD patients, but also discuss high dropout rates in 436physical activity trials in these patients [3]. There is an urgent need to counteract with the sedentary 437habits of NAFLD patients. Besides all the proven positive effects of regular physical activity and a 438healthy diet, many people are still lacking in long-term motivation [74]. Engaging in less physical 439activity increases the risk of fatty changes in the liver [41, 75, 76]. In the investigation of Hsieh (1998), 440the physical inactive group showed a significantly higher prevalence of fatty liver changes [76]. This 441statement is supported by the results of a study by Perseghin (2007). They showed an association 442between habitual physical activity and intrahepatic fat content [77]. Furthermore, a large cross 443sectional study by Ryu (2015) fully supports this statement, that prolonged sitting times are positively 444associated with the prevalence of NAFLD [42]. Therefore, supporting patients to achieve and sustain 445regular activity is a key issue in NAFLD management [12]. Due to the pronounced sedentary lifestyle, 446starting with a low training volume and intensity is indicated because of motivational reasons. Self447chosen sitting times should be reduced and barriers for regular exercise should be identified and 448eliminated [78]. Intensive exercise interventions, carried out under supervision in hospitals or fitness 449centers, [32, 34, 65, 67] impose an unnatural lifestyle on the patients for a short period of time. After 450the intervention, patients very quickly lose motivation and fall back into their old habits [45]. There is 451a strong need and a high potential for Web-based intervention designs [79, 80]. Web-based 452interventions are essential to bridge the treatment gap between demand and supply [81, 82]. In a
453study conducted by Casey, patients with diabetes stated that they need a better transition strategy to 454subsequent post-intervention realities of less support [83]. Furthermore, from the patient’s point of 455view, scheduling flexibility and geographical proximity are important factors that should be taken into 456account [83]. Even the most powerful individualized exercise program enhances the patient’s 457situation sustainably only, if patients are able to transfer the regular activity into their daily routine 458[84]. Therefore, the main focus is to incorporate an exercise program into the daily routine of NALFD 459patients to promote long-term changes [85] and reverse sedentariness [86]. Regular feedback from a 460counselor seems to be an important aspect for patients to stay motivated [87, 88]. Furthermore, it is 461important to integrate the patient in the decision process [84]. Thus, a change from compliance 462(implementation of prescription) to adherence (mutual agreement between patient and caregiver) 463should be achieved [80, 84]. Growing interest in utilization of modern technologies such as computer 464and smartphone could for this purpose represent feasible ways to transport knowledge and care in a 465home based setting. Web-based support allows a flexible scheduling of training and still transport 466proper guidance through regular counseling and tailored feedback. In the study presented here, 467common obstacles like time constraints (e.g. shift work or family responsibilities) or no access to a 468fitness center (e.g. distance, high costs, or lack of sound advice) [37, 43, 45] could be circumvented 469using additional training equipment like pulse watches and elastic bands. Furthermore, a regular, 470close communication with a team of experts was realized by the communication via the specially 471designed website. This approach reduced the mentioned geographical and time-related barriers. In 472contrast to print-based interventions and face-to-face counseling, the Web-based communication 473lowers costs and has a higher potential to reach a wide range of target groups with tailored support 474[43, 49, 89]. Individualized recommendations based on heart frequency and personal feedback, 475expressed as RPE values seem to be useful in this context [34]. 476The present trial is one of the first to test the feasibility of a Web-based exercise program in a group 477of patients with liver disease. In line with the recommendations of current guidelines, this is also one 478of the first investigations supporting patients with NAFLD with a combined endurance and strength 479training concept. 480Strengths and limitations 481This study has several strengths and limitations. Strengths of this study could be seen in the liver 482biopsy which is the gold standard in determining liver condition [7, 90]. Furthermore, we are the first 483to conduct a Web-based approach for a tailored exercise intervention in this patient collective. In 484contrast to other studies, we had only one (2.3 %) dropout, showing good adherence and tolerance, 485whereas in a recent review the dropout rates ranged between 6 % and 45 % with similar intervention 486content [73]. Possible advantages of the Web-based approach are the flexible design and the exercise 487implementation in the home environment. The main limitation is, that investigators had to rely at
488least partially on subjective feedback for training adherence without the possibility of a visual control 489by the sports physician. Data on training adherence might be prone to social desirability bias as well 490as over- or underestimation. Researchers already discussed this issue of over- or underestimation in 491home-based training settings [91, 92]. To reduce such potential bias, we combined the subjective 492feedback (Borg rating for training sessions) with an objective measurement (average heart rate). A 493person that tended to respond in a socially desirable fashion would at least need some in-depth 494knowledge in exercise physiology to trick the therapist or would most likely submit none-plausible 495data. Another aspect to be considered is the absence of a control group. Because of different 496comorbidities, some patients had to be excluded. Therefore, we do probably not present a typical 497NAFLD collective here. Missing features and confusing page layout of the website could affect the 498using behavior. Most of the patients demanded regular nutritional advices. Some of the participants 499stated, that they neglected their common eating habits, due to diverse changes during the 500intervention period (e.g. marriage, job loss, change of shift). Therefore, minor changes in weight 501status could be explained. Another limitation might be the length of the intervention period. Eight 502weeks were probably too short to show further improvements in weight status or cardiorespiratory 503fitness. 504 505What we know is, that… 506… NAFLD patients are less active. 507… patients have problems to start and maintain an active lifestyle. 508… weight loss is not common in exercise interventions. 509… nevertheless, exercise has many benefits on liver function. 510 511What this study adds, is, that… 512… patients increased their activity level during the tailored intervention period. 513… the Web-based support concept is feasible and save for the patients. 514… the Web-based support significantly improved the cardio respiratory fitness and body composition 515… the Web-based support achieves similar effects like face to face studies 516 517Conclusion 518 519In conclusion, the present findings indicate that 8 weeks of Web-based, highly individualized 520supervised training is save and feasible for patients with NAFLD. In addition, the program improved 521significantly VO2peak and the body composition. In order to influence the risk factor sedentariness 522sustainably and to enable a long-term lifestyle change, an exercise program is needed which can be
523integrated into everyday life. The Web-based communication as connection between patient and 524caregiver might be a useful and cost effective monitoring tool. Close contact to the supervisor can 525immediately reduce sport-related doubts and anxieties as well as motivational barriers. The Web526based design is the first step into a new way of delivering service to a group of patients with NAFLD 527and potentially other diseases. Future studies are needed to find out, whether regular interaction 528between the patient and the study team can be maintained in long-term. Additionally, the 529intervention program, presented here, could be further supplemented with individualized, nutritional 530advices provided by a dietician to further improve the weight status. Finally, an expert should rework 531the page design and integrate missing features for a more pleasant handling of the page. 532Acknowledgment 533We thank all the participants in this study and the staff of the I. Department of Medicine, University 534Medical Center of the Johannes Gutenberg-University, Mainz, Germany and the Department of Sports 535Medicine, Rehabilitation and Disease Prevention at the Johannes Gutenberg-University, Mainz, 536Germany for recruiting, sample processing and support. 537Authors' Contributions 538PS, JMS, YH, and DP developed the individual study concepts. DP designed the website. PS and DP 539designed the exercise components, and YH and JMS revised the manuscript. All authors read and 540approved the final document. 541Conflicts of Interest 542None declared. 543Abbreviations AASLD BIA BMI CRF COPD ECG FEV1 FVC HCC HOMA-IR HR HRQOL IAT LT NAFLD NASH SD SLE WHO
American Association for the Study of Liver Diseases Bio-Impedance Analysis body mass index cardiorespiratory fitness chronic obstructive pulmonary disease electrocardiogram forced expiratory volume forced vital capacity hepatocellular carcinoma homeostasis model assessment index heart rate health related quality of life individual anaerobic threshold lactate threshold non-alcoholic fatty liver disease non-alcoholic steatohepatitis standard deviation systemic lupus erythematosus world health organization
544 545Multimedia Appendix 1 546Video clip of the Web-based exercise support concept.
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