BALANCE - Promoting energy balance related behavior after liver transplantation : development of a behavioral intervention based on physical activity and diet to support effective weight management and a healthy lifestyle – a multiphase mixed method research program

Obesity has become a global health concern not only in the general population but also among liver transplant (Tx) recipients. For more than 2 decades, rates of obesity in liver Tx candidates have been rising;1 and post-Tx weight gain is contributing to a rising prevalence of post-Tx obesity in this group compared to pre-Tx measurements.2-4
While obesity predicts morbidity and mortality in the general population,5-8 this rela-tionship has not been reported consistently in liver Tx recipients. Regarding the impact of pre- and post-Tx obesity on metabolic or cardiovascular comorbidities, current evidence is mixed.9-11 However, the few studies examining post-Tx weight gain found that it increased the burden of disease and predicted both nonalcoholic fatty liver disease12,13 and metabolic syndrome.12,14
Metabolic syndrome occurs in 44% to 58% of liver Tx recipients,12 contributing to an increased risk of cardiovascular disease and mortality.12 Indeed, cardiovascular events (CVEs) are a leading cause of mortality after liver Tx.15-18 And while first-year post-Tx patient and graft survival rates have been increasing steadily for decades, long-term outcomes have not echoed these improvements.19 This progress gap is attributed partly to the post-Tx development of comorbidities such as hypertension, diabetes, and dyslipidemia–due largely to the side effects of long-term immunosuppressive medication intake accompanied by life-style factors (e.g., physical inactivity, unhealthy eating).12,14,20-22
To reduce post-Tx morbidity risks, the Tx community has called for action to tackle weight gain and obesity via lifestyle interventions.22-25 Expressed as a deceptively simple equation, weight gain most commonly results from an energy imbalance whereby energy intake surpasses energy expenditure.26 Although a web of interconnected variables are involved, behavioral factors related to energy balance, such as physical activity and diet, are among the most influential and can be targeted via interventions. Intervention research on this topic is rare regarding the liver Tx population. To date, only one study has tested an intervention using individual counseling on exercise and diet after liver Tx;27 however, its authors did not examine the intervention’s impact in relation to weight gain prevention.
The systematic development of a behavioral weight management intervention is no easy task: such interventions are typically complex, and should be informed by a theoretical model.28,29 However, the crucial first step in developing any behavioral intervention is to build a sound understanding and definition of the problem in behavioral terms. Also, in the con-text of weight gain after liver Tx, two clinical questions remain unanswered: “How important is the prevention of weight gain after Tx?” and “Which factors are related to weight gain and obesity after Tx?”
Aims
The overall aim of this dissertation was to generate evidence that would facilitate the devel-opment of a behavioral intervention focusing on physical activity and diet to support effec-tive weight management and a healthy lifestyle after liver Tx. The specific aims were as fol-lows:
1) To examine the evolution of body weight parameters up to 3 years after Tx within and among adult kidney, liver, lung, and heart Tx patients in the STCS (Chapter 3).
2) To summarize and synthesize the current literature in view of risk factors for post-Tx BMI, weight gain and obesity in the liver Tx population (Chapter 4).
3) To examine weight gain in the first year after solid organ Tx in the STCS from a genomic perspective (Chapter 5).
4) To determine clinical and psychosocial risk factors for post-liver Tx new-onset obesity and examine its impact on outcomes including patient survival and CVEs in the STCS (Chapter 6).
This dissertation was designed as a multiphase mixed method research project in-cluding three data analyses of the prospective nationwide Swiss Transplant Cohort Study (STCS), and one systematic review with meta-analysis. The results (summarized below) promise to facilitate evidence-based decision-making towards the development of a behav-ioral intervention to prevent post-Tx weight gain.
Chapter 3: Evolution of body weight parameters up to 3 years after solid organ transplantation: the prospective Swiss Transplant Cohort Study.
Body weight parameters vary considerably among solid organ Tx populations and geo-graphical regions. However, a rigorous comparison of these parameters’ evolution between organ groups and throughout the course of Tx is limited due to methodological and termino-logical differences between the relevant studies (e.g., single center versus database stud-ies, different timeframes for follow up measures, diverse operational definitions). Therefore, to compare all solid organ Tx populations concurrently, we conducted a descriptive longitu-dinal study using data from the STCS, a prospective nationwide cohort study. The STCS’s long-term prospective design allowed comparison of weight change patterns among organ groups and among patients in different body mass index (BMI) categories to assess weight parameters in relation to settings and patient groups. Changes in weight and BMI category were compared to the reference values at 6 months post-Tx.
We included 1359 adult kidney (58.3%), liver (21.7%), lung (11.6%), and heart (8.4%) recipients. Compared to data on international Tx groups, the majority of our Swiss Tx recipients had lower post-Tx weight gain. However, their cumulative incidence of obesity at 3 years after kidney, liver, lung, and heart Tx was 18.1%, 38.1%, 15.3%, and 13.3%, respec-tively. At 3 years post-Tx, in relation to their BMI categories at 6 months, normal weight and obese liver Tx patients, followed by underweight kidney, lung and heart Tx patients, showed the greatest weight gains. Compared to all other organ groups, liver Tx recipients showed both the greatest weight gain (mean 4.8 ± 10.4 kg), with 57.4% gaining >5% of their body weight, and the highest incidence of obesity (38.1%). Although weight gain patterns varied both within and across organ Tx groups, long-term monitoring of weight is indicated in all solid organ Tx populations to prevent weight gain leading to obesity.
Chapter 4: Pre- and post-transplant factors associated with body weight parameters after liver transplantation – a systematic review and meta-analysis.
Weight gain and obesity are the result of complex interactions between genetic, sociodem-ographic, behavioral, biomedical, psychological, and environmental factors. Therefore, a clear knowledge of factors influencing weight gain and other body weight parameters in Tx is important in view of tailoring interventions to avoid or modify these factors. As weight gain in this group has never been the subject of a systematic review, though, evidence on risk factors in the liver Tx population remains non-explicit. In our systematic review then, we summarized the available evidence in view of factors associated with post-liver Tx BMI, obe-sity, and weight gain. Meta-analysis techniques were applied to relationships investigated at least 5 times. Of the 16495 articles retrieved, 43 assessed risk factors for body weight pa-rameters. These identified a total of 82 separate factors, most of which either biomedical (e.g., etiology of liver disease, metabolic comorbidities before liver Tx) or sociodemographic (e.g., age, gender, pre- and post-Tx education).
In view of energy balance-related behaviors, not one of the 43 retrieved studies ex-amined eating behavior; but 4 examined physical activity in relation to BMI or obesity after liver Tx. Overall, extensive variation in risk factor definitions limited the combination of factors to groups of at least 5 studies. The final meta-analyses focused on two risk factors–tacrolimus and cyclosporine–in 6 studies (median sample size: n = 171 (range: 63–455); 3 from Europe, 3 from the United States; publication era: 1997 – 2015). Post-Tx obesity was neither significantly associated with tacrolimus (odds ratio (OR), 0.75; 95% confidence inter-val (CI), 0.47-1.21; p = 0.24) nor cyclosporine (OR, 1.40; 95% CI, 0.89-2.18; p = 0.14). Evi-dence on factors related to post-liver Tx body weight parameters is still limited and warrants further investigation. It is recommended that future research be guided by theoretical frameworks to facilitate a systematic examination of interrelationships among selected fac-tors.
Chapter 5: Weighted genetic risk scores and prediction of weight gain in solid organ transplant populations.
Genetic factors also interact with clinical and psychosocial variables. To examine associa-tions between weighted genetic risk scores and BMI up to 1 year after Tx, we studied 2 patient samples. Sample A (n = 995) consisted of kidney, liver, heart, lung and multi-organ Tx patients from the STCS; sample B (n = 156) included only kidney, liver and lung Tx pa-tients enrolled between 2003 and 2005 from the Tx center of the University Hospital of Lau-sanne. Calculation of genetic risk scores used data on Tx candidate genes and single nu-cleotide polymorphisms (SNPs) associated with BMI in genome-wide association studies. Classified by the number of BMI risk alleles identified (range: 0 – 2), the genotypes were coded as 0, 1 or 2. Based on the assumption that each SNP effects BMI separately, SNPs were then weighted by allele effect (β-coefficient), leading to the calculation of the final weighted genetic risk score.
The weighted genetic risk scores were associated with BMI increase for each addi-tional risk allele in both samples (p-values < 0.008). Additionally, compared to the models incorporating no genetic factors, those using genetic risk scores better predicted weight gain at 1 year post-Tx. This result highlights the complexity of weight gain and the im-portance of incorporating a range of factors that influence post-Tx weight gain. Further re-search will be necessary to examine the genetic risk score and post-Tx body weight parame-ters in relation to patient outcomes.
Chapter 6: New-onset obesity after liver transplantation - outcomes and risk factors. The Swiss Transplant Cohort Study.
In addition to studying weight gain per se, we examined the impact of new-onset obesity on cardiovascular events (CVEs) and patient survival to identify related post-liver Tx sociodem-ographic, behavioral, biomedical, psychological and genetic risk factors. Based on STCS data on 253 liver Tx patients, the cumulative incidence of new-onset obesity was 21.3%, while that of CVE was 28.1%. Independent of the CVE status at liver Tx, risk factors for post-Tx CVEs were new-onset obesity (Hazard Ratio (HR) 2.95; 95% CI, 1.47-5.95; p = 0.002) and higher age at liver Tx (HR, 1.05; 95% CI, 1.02-1.08; p < 0.001). In patients with-out pre-Tx CVEs (n = 214), risk factors for post-Tx CVEs also included new-onset obesity (HR, 2.59; 95% CI, 1.21-5.53; p = 0.014) and higher age (HR, 1.04; 95% CI, 1.02-1.07; p = 0.001). However, survival itself was not associated with new-onset obesity (HR, 0.84; 95% CI, 0.34-2.04; p = 0.696). Independent predictors of new-onset obesity were male gender (HR, 0.39; 95% CI, 0.16-0.93; p = 0.034) and alcoholic liver disease (HR, 3.37; 95% CI, 1.17-9.71; p = 0.025). The genetic risk score was available in a subsample of 114 patients. In this analysis, alcoholic liver disease (HR, 12.82; 95% CI, 1.66-98.94; p = 0.014) and hepatocellular carcinoma (HR, 10.02; 95% CI, 1.03-97.94; p = 0.048) predicted new-onset obesity. Given the link between new-onset obesity and CVEs, the prevention of new-onset obesity by effective early weight management programs could probably lead to improved post-Tx cardiovascular outcomes.
Chapter 7: Development of the BALANCE intervention with the COM-B model and the behavior change wheel.
In conjunction with the existing evidence, the findings of this dissertation contributed to the development of a behavioral weight management intervention. The COM-B model and the behavior change wheel served as theoretical guidance.28,29 While COM-B is an explanatory model, characterizing the sources of behavior (i.e., capability, opportunity, and motivation), the behavior change wheel informed the intervention’s systematic development and evalua-tion. Beginning with a theoretical introduction, follows the three stages of the behavior change wheel, leading to the suggestion of the BALANCE intervention in the liver Tx popu-lation.
Conclusion
This dissertation contributed to the evidence base regarding weight gain and obesity after solid organ Tx. For the first time, we simultaneously compared the evolution of body weight parameters up to 3 years after kidney, liver, heart and lung Tx to identify patterns of interest among these four populations. By studying the impact of new-onset obesity on cardiovascu-lar morbidity and patient survival after liver Tx, we increased the limited evidence on the impact of post-Tx body weight parameters on patient health outcomes. In 3 studies, all guided by our theoretical framework, we systematically examined biomedical, behavioral, sociodemographic, psychological and genetic risk factors leading to weight gain, obesity and new onset obesity after Tx, thereby highlighting the cross-category interplay of factors. These studies’ findings highlighted various implications for future research and clinical prac-tice. Based on these findings, we recommend organizing post-Tx follow-up care based on a chronic care model, supported by eHealth technology. Such a care model has the potential not only to support effective weight management, but also to improve long-term patient out-comes.