Figure 2 shows the prevalence of overweight and obesity in the posttransplant population over time compared with the general pediatric population of the United States from 2003 to 2004 (2). At 1 and 3 years after LT, patients were statistically more likely to be overweight or obese, as compared with the general pediatric population. At 5 years after transplant, however, the degree of overweight and obesity was similar to the general pediatric population.
The prevalence of obesity in the LT population was compared with NHANES data for 3 time periods (1999–2000, 2001–2002, and 2003–2004). According to NHANES data, 13.9% of children ages 2 to 19 years were obese in 1999 to 2000, 15.4% in 2001 to 2002, and 17.1% in 2003 to 2004 (2,9). As seen in Table 2, a similar proportion of the overall LT patients and the general pediatric population were obese across all of the periods studied. However, there was a significantly increased prevalence of obesity in 2- to 5-year-olds in transplant follow-up compared with the general population across all of the periods studied. The percentage of obese blacks, Hispanics, and whites were similar in the posttransplant and NHANES population.
A univariate analysis was conducted to identify risk factors for obesity after liver transplantation, at a significance level of ≤0.1. Identified factors included ALT, age younger than 2 years or 2 to 5 years at transplant, Hispanic ethnicity, Medicaid insurance, overweight, obese or severely obese weight status at the time of transplant, height deficit (height z score <−2) at transplant, steroid use at follow-up, and elapsed time interval between transplant and follow-up. Children who were 5 years old or younger when receiving transplant did not, however, have shorter lengths of follow-up, P = NS. Nonsignificant factors included sex, primary diagnosis, year of transplant, primary immunosuppression (cyclosporine versus tacrolimus) at transplant, early rejection after transplant, donor organ type, and AST, total bilirubin, and INR at time of BMI measurement. The present study had insufficient power to determine the effect steroid use at transplant had on obesity because 93% of all of the individuals received steroids at transplant.
Significant risk factors identified on univariate analysis were entered into a stepwise logistic regression model to further understand predictors of obesity after LT. Three time invariant factors were identified as potential risk factors for obesity on univariate analysis: age at transplant, ethnicity, and insurance status. No significant interaction was noted between these factors and time on GEE analyses with repeated measures, and therefore, an interaction term was not included in the multivariate analysis. The results of this multivariate analysis (Table 3) demonstrate that patients of Hispanic ethnicity, those using steroids at follow-up, those 3 or fewer years after transplant, and those who were overweight or obese at the time of transplant are at increased risk of posttransplant obesity.
A subgroup analysis was conducted on individuals who were obese 3 and/or 5 years after transplant, because these individuals were unlikely to be affected by postoperative factors and were judged by the authors of the present study to be at increased risk for persistent obesity. Follow-up BMI data were available at 3 and/or 5 years after transplant for 564 patients, 117 (20.7%) of whom were obese 3 and/or 5 years after transplant. These patients were predominantly girls (52%), white (56%), and received transplants for biliary atresia (61%), primarily before 2001 (79%). Triglycerides were available for 475 patients (84%) at 3 years after transplant. The mean levels of triglycerides were as follows: 77 ± 12 mg/dL in 12 underweight patients, 82 ± 3 mg/dL in 287 healthy weight patients, 81 ± 4 mg/dL in 100 overweight patients, 105 ± 20 mg/dL in 40 obese patients, and 88 ± 7 mg/dL in 36 morbidly obese patients (P = NS). Cholesterol values were available for 496 patients (88%) at 3 years after transplant. The mean cholesterol values were as follows: 108 ± 12 mg/dL in 12 underweight patients, 132 ± 2 mg/dL in 301 healthy weight patients, 134 ± 4 mg/dL in 105 overweight patients, 127 ± 6 mg/dL in 40 obese patients, and 134 ± 4 mg/dL in 38 morbidly obese patients (P = NS).
A univariate analysis was conducted to identify risk factors for obesity at 3 and/or 5 years after LT, at a significance of P ≤ 0.1. Identified factors included Hispanic ethnicity, metabolic disease requiring transplant, and obesity or severe obesity at transplant. Nonsignificant risk factors for chronic obesity included age at transplant, sex, choice of primary immunosuppression, insurance coverage, year of transplant, steroid use at the time of transplant or at follow-up, early rejection after transplant, height deficit (height z score <−2) at transplant, and AST, ALT, INR, and total bilirubin at time of BMI measurement.
The risk factors identified on univariate analysis were entered into a stepwise logistic regression model to further understand predictors of obesity 3 and/or 5 years after LT. The results of this multivariate analysis (Table 3) show that Hispanic patients and those who were obese or morbidly obese at transplant are at increased risk of obesity 3 and/or 5 years after LT.
We have shown in a large, nationally representative cohort of pediatric LT recipients that the prevalence of obesity after transplant is extremely high. In the first year after LT, 19.2% of pediatric LT recipients were obese. Three years after transplant, 17.5% of individuals were obese and 5 years after transplant, 10.9% of individuals remained obese. Surprisingly, we report a higher prevalence of obesity among post-LT patients who are 2 to 5 years old as compared with a cohort of similar age among the general pediatric population of the United States. The prevalence of obesity after LT in children 6 to 19 years old, however, is similar to a comparable age group in the general pediatric population. More important, the prevalence of obesity in children 5 years after transplant, a sufficient duration after transplant to minimize the effect of factors such as posttransplant medications and activity, is similar to that in the general pediatric population. Therefore, these findings reveal a disturbing trend in pediatric obesity in a special pediatric population typically perceived as underweight.
Obesity in adult LT recipients has been reported in 17% to 43% of patients, depending on the definition of obesity used and the duration from transplant captured (3–7). The present study illustrates that obesity after pediatric LT, although less prevalent than in adults, is remarkably common. High recipient BMI at the time of transplant influences posttransplant obesity in adults (3,4,10). Similarly, in this large pediatric cohort, we have demonstrated that the most prominent predictor of obesity after LT was body habitus at the time of transplant. LT recipients who were obese were 10 times as likely and those who were severely obese were 14 times more likely, to be obese after transplant compared with children who were of healthy weight at the time of transplant. SPLIT does not, however, collect data on pretransplant medical therapies, such as steroid use, which have the potential to affect pretransplant BMI. It is also possible that some children were misclassified as obese at the time of transplant due to the presence of ascites or anasarca. Unfortunately, SPLIT does not collect data on ascites or anasarca at transplant, nor does it collect anthropometric data such as triceps skinfold or mid-arm circumference, which may allow insight into this potential problem. Clinically, the majority of children at risk of such misclassification are infants or toddlers, and age at transplant (including younger than 2 years) was not found to be predictive of obesity. Therefore, body habitus at the time of transplant remains a crucial risk factor for post-LT obesity. In addition, these findings highlight the opportunity for primary care and subspecialty providers to collaboratively improve the posttransplant health of pediatric patients by focusing on pretransplant weight optimization when possible.
Conflicting data exist regarding the affect of calcineurin inhibitor choice on obesity in adult transplant recipients (3,4,10–12). We did not find that choice of calcineurin inhibitor affected the presence of posttransplant obesity in pediatric LT recipients. Both steroid use at the time of transplant and cumulative prednisone dose have been shown to affect obesity in adult LT recipients (3,4,10). The nearly universal use of steroids at transplant in this population precluded our ability to assess their affect on obesity. The SPLIT database also does not capture data on cumulative steroid dose immediately after transplant. Children who were 3 years or younger at transplant, however, were at increased risk for obesity, suggesting a potential role for steroid-related weight gain. In addition, the use of steroids in the posttransplant period was noted to be a risk factor for obesity. Therefore, particularly in overweight or obese patients, transplant teams should consider prioritizing a rapid wean of steroids into therapeutic paradigms. Further investigation is necessary to determine optimal immunosuppressive regimens for overweight and obese pediatric patients in the posttransplant period, including steroid-free protocols.
In the present study, Hispanic ethnicity was also a significant risk factor for posttransplant obesity. This parallels racial trends in obesity seen in 2003 to 2004 NHANES data, in which 19.2% of Hispanics were obese compared with 16.3% of whites (2). In addition to ethnic disparities, geographic disparities in pediatric obesity exist, with the highest rates seen in the southeastern United States (13). Although SPLIT does not collect data on the geographic area from which patients originate, this too may be an important risk factor. Recognition of these demographic risk factors may allow primary care providers and transplant teams to collectively focus intensive nutritional and exercise counseling into the routine care of high-risk groups. In addition, high-risk demographic groups may particularly benefit from steroid minimization.
Adults with obesity after transplant are at increased risk for the long-term complications of cardiovascular disease, type 2 diabetes, and the metabolic syndrome. In addition, they may have lower overall survival after transplant (14). Children who are obese before transplant are reported to have decreased long-term survival compared with normal weight or underweight children (15). Our study shows that children who are overweight or obese at transplant are likely to remain so after transplant. As such, it is possible that decreased long-term survival in obese patients may be related to obesity-related comorbidities. Transplant teams and primary care providers together must remain cognizant of the long-term cardiovascular and metabolic risks in these overweight and obese patients (1,16). We suggest incorporating screening of overweight and obese children for type 2 diabetes mellitus, hypertension, and hyperlipidemia into routine transplant follow-up as recommended in the 2007 summary report of the Expert Committee on Prevention, Assessment, and Treatment of Child and Adolescent Overweight and Obesity (1,17,18). Such screening may be best facilitated by a partnership between primary care providers and transplant teams. Unfortunately, the SPLIT study lacks robust data on these obesity-related comorbidities. Systematic study of these parameters in the future may enhance our ability to understand the affect these potential risk factors have on posttransplant outcomes.
The prevalence of obesity after pediatric liver transplant is high and similar to that in the general pediatric population. Obesity at the time of liver transplant, a potentially modifiable factor, confers a high risk of posttransplant obesity. These findings suggest a need to broaden standard care to include obesity assessment and intervention in routine pre- and posttransplant care. Pediatric transplant teams are accustomed to the malnourished state that is commonplace in many children listed for liver transplant. As such, well-accepted treatment algorithms exist to improve nutritional health and BMI in undernourished patients. Our study demonstrates the critical nature of focused attention on the nutritional status of children who are overweight or obese before transplant as well. A carefully devised weight loss program, with interventions by both nutritionists and exercise therapists may stimulate pretransplant weight loss in a rigorous and safe manner. In addition, families should be educated and empowered to make good nutritional choices with their children and emphasize active lifestyles, even as they move forward with transplant.
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Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
liver transplant; obesity; pediatric; risk factors