At baseline, 14 children (12%) had a systolic blood pressure of >130 mmHg and 1 had a diastolic blood pressure of >85 mmHg. These blood pressures were decreased during the camp and increased again after 12 months.
Transaminases and Other Parameters
At baseline, 58 of 117 (50%) of the children had increased ALT (>25 U/L) (Fig. 2), which decreased during the camp in all of the children (P < 0.05) with no further change 12 months later. There were no age or sex differences for ALT levels or changes. Among the 50% of the children with normal ALT at baseline, 12 (12%) developed elevated ALT during the camp, which normalized 12 months later. At baseline, the children's ALT values and their liver ultrasound changes were correlated with echogenicity (r = 0.23, P = 0.01), liver texture (r = 0.26, P < 0.01), plump liver sign (r = 0.36, P < 0.001), and total liver score (r = 0.32, P < 0.001). There were no correlations between their ALT values and the measures of insulin sensitivity, waist circumference, triglycerides, HDL-cholesterol, or blood pressure levels.
Apart from the transaminases, all of the children had normal routine liver tests at baseline (Table 2). After the camp, alkaline phosphatases (P < 0.05), coagulation factors II, VII, X, and γ-glutamyltransferase were decreased (P < 0.05). The coagulation factors increased again after 12 months.
At baseline, 43% of the children had increased liver echogenicity, 21% had plump liver sign, and 18% had changed liver texture. Boys had more frequently increased liver fat echogenicity compared with girls (P = 0.04) at baseline; however, there was no sex effect on liver fat changes during the study period. These frequencies were reduced to 30%, 8%, and 4%, respectively, after the camp and did not change after 12 months. The scores for all 3 measures and their sum decreased during the camp (P < 0.05). At the 12-month follow-up, echogenicity, liver texture, and total liver score significantly improved from baseline (P < 0.05) (Table 3).
At baseline, the children's liver echogenicity score correlated positively with their body fat component (r = 0.19, P = 0.05), waist–hip ratio (r = 0.21, P = 0.03), and their insulin levels after the OGTT (r = 0.19, P = 0.04). There were no correlations between echogenicity and waist circumference, triglycerides, HDL-cholesterol, or blood pressure.
The children's fasting plasma glucose concentrations were unchanged throughout the study, whereas both their insulin and HOMA values decreased markedly during the camp (P < 0.05) (Table 4). Similarly, their OGTT 2-hour glucose and insulin levels decreased (P < 0.05). After 12 months, glucose, insulin, and HOMA were higher than baseline (P < 0.05). No child developed diabetes, but 3 (3%) had an OGTT plasma glucose between 7.8 and 8.5 mol/L, that is, impaired glucose tolerance. There was no effect of age or sex on the above parameters.
The insulin levels at baseline correlated with glucose (r = 0.41, P < 0.001), fat component (r = 0.43, P < 0.001), BMI (r = 0.49, P < 0.001), waist (r = 0.43, P < 0.001), hip (r = 0.30, P < 0.001), systolic (r = 0.29, P = 0.05) and diastolic (r = 0.27, P < 0.005) blood pressure, but not the waist–hip ratio. There were correlations among baseline insulin and triglycerides (r = 0.71, P < 0.001), total cholesterol (r = 0.46, P < 0.001), HDL-cholesterol (r = −0.32, P < 0.001), and low-density lipoprotein (LDL) -cholesterol (r = 0.42, P < 0.001).
During the camp, triglycerides and total and LDL-cholesterol levels decreased significantly (P < 0.05), followed by an increase after 12 months (P < 0.05) (Table 5). There was no change in the HDL-cholesterol fraction (Table 5). There was no effect of age or sex on the above parameters. At baseline, 19 (16%) children had low HDL-cholesterol (boys >1.03 and girls >1.29 mmol/L (9). Nine children (8%) had increased triglycerides at baseline (>1.7 mmol/L) and 4 (3%) had both triglycerides and HDL-cholesterol abnormalities. Two children had an increased total cholesterol (>6.0 mmol/L), and 1 child had an increased LDL-cholesterol (>4.5 mmol/L).
The present study is the first study to investigate the effects of a weight loss camp on NAFLD, body composition, and insulin sensitivity in obese children with a 12-month follow-up. Furthermore, these are the first data on the prevalence of NAFLD and reduced insulin sensitivity in obese Nordic children. Our study shows that this simple and short-term change in lifestyle had profound positive effects on the children's metabolic status.
The main findings were the improvement in the prevalence and severity of NAFLD along with improvements in body composition, insulin, and other aspects of the metabolic syndrome. Twelve months after return to their spontaneous lifestyle, these improvements were maintained in 24% of the children, but 76% had increased their BMI-SDS again. This shows that long-term measures must be implemented in most children so that the positive effects that are readily obtained with the short-term intervention are maintained.
A recommended standard treatment of childhood NAFLD/NASH has not yet been established, and pharmacological interventions in children have not been adequately investigated through appropriate clinical trials (7). Because NAFLD is associated with obesity and reduced insulin sensitivity, specific regimens aimed at reducing body weight and improving insulin sensitivity are recommended. In adults, this has recently proven to be efficient in a randomized clinical trial (11).
In the present study, we observed striking improvements in all of the parameters of liver fat, transaminases, obesity, insulin sensitivity, and parameters of the metabolic syndrome. We previously reported that a moderate increase in exercise and change in diet resulted in marked changes toward normality in sex hormones in the same children during their stay at the weight loss camp (12); however, the rapid weight loss may cause an increase in ALT levels as observed in 12 children with normal ALT levels at baseline. This has been observed in adults during rapid weight loss (13,14).
Unfortunately, in the present study, most changes were lost during follow-up, and it is likely that a steady long-term weight loss program is superior for preserving initial improvements. This trend has been shown with lifestyle changes, such as low-fat and low-glycemic index diet and weight loss reduction, in observational studies of childhood NAFLD/NASH (15,16). A large prospective study of lifestyle intervention in NAFLD children demonstrated significant reductions in ALT levels and NAFLD based on ultrasound for up to 2 years (17). Studies by Reinehr et al (18) and Nobili et al (16) included intervention programs that consisted of physical activity, nutrition education, and behavior therapy, that is, individual psychological care of the child and family.
Twenty-four percent of the children in our intervention program maintained their weight loss induced at the camp; however, we have no data on effect of lifestyle changes after the weight-loss camp stay but speculate that in this subgroup the short-term intervention leads to a sustained change in lifestyle and food habits. The poor long-term effects in the 76% of children in the present study may be multifactorial conditioned. The heritability of NAFLD and obesity must be considered, as recently demonstrated (19). Similarly, we found a high prevalence of obesity and features of the metabolic syndrome among the children's parents (data not shown). When there are obesity issues among the parents, maintaining weight loss or sustaining a stable weight is a difficult task; in childhood, the management of NAFLD and/or obesity may require counseling with the entire family. Our data support the notion that long-term measures must be implemented to maintain the effects of the weight loss camp, and we suggest continuous intervention in the local community using local schools, health authorities, and sports clubs. Long-term effects in the coming years will be interesting to study in this cohort.
The true prevalence of pediatric NAFLD is unknown and depends on the population that is studied, the ALT cutoff values that are used, and the imaging methods that are used (20). In the clinical setting, the NAFLD diagnosis is considered in an obese child with elevated ALT levels and increased liver echogenicity based on ultrasound. Just recently, the ALT cutoff value has been debated in the United States, and it was concluded that an ALT value >25 IU/L (95th percentile) is abnormal in children (21). We observed increased ALT levels in 50% of obese Danish children using this cutoff, which is similar to the 43% prevalence of children with fatty liver based on ultrasound. The discrepancy between ALT levels and liver fat accumulation has been shown by Franzese et al (22) using ultrasound but was also demonstrated with more specific magnetic resonance imaging (23).
The prevalence of transaminasemia and fatty liver based on ultrasound in our study is similar to previous data from obese children in other parts of the world (20,21). In the general population, NAFLD identified by ALT or ultrasound is in the range of 3% in the United States (NHANES III, ALT) (24), Korea (ALT in 3.2%), and Japan (2.6%) using ultrasound (25,26). An autopsy study observed NAFLD in 10% of US children; NAFLD is increasing with age and is associated with obesity (27).
Obesity and reduced insulin sensitivity are critical factors in the pathogenesis of NAFLD/NASH, and previous studies have shown hyperinsulinemia to be strongly associated with transaminasemia in children with biopsy-proven NAFLD (28,29). Thus, a HOMA-insulin resistance index >3 is greatly suggestive of childhood NAFLD/NASH (30,31). In the present study, however, HOMA values were lower, which implied that children in our study showed fewer metabolic derangements than the other studies mentioned above. This may explain the lower prevalence of metabolic abnormalities compared with previous studies, in which most children with biopsy-proven NAFLD/NASH are dyslipidemic; up to 40% were hypertensive, 10% had impaired glucose tolerance, and a few manifest diabetes (28,30,32,33). Because the children in the present study are less metabolically deranged and only showed modestly increased ALT levels, we were unable to demonstrate significant correlations between ALT and the parameters of both insulin sensitivity and the metabolic syndrome; however, ALT levels correlated with ultrasound-based signs of fatty liver. The increase in insulin levels at 12 months may be caused by the return of obesity, but it may also partly be explained by the physiological pubertal decrease in insulin sensitivity (9).
The strength of the present study lies in the validated methods using ultrasound and transaminasemia for NAFLD detection. A weakness of the present study is the dropout rate of 39% at 12 months compared with a previous study by Reinehr et al (17), in which the dropout rate was only 16%. There were no significant differences, however, between children who did or did not complete the 12-month follow-up in terms of baseline characteristics, which indicates no major selection bias.
In conclusion, in obese Danish children with reduced insulin sensitivity, we found the same prevalence of NAFLD determined by ultrasound and ALT levels as in the southern parts of Europe, the United States, and the East, which indicates the universal association between obesity, reduced insulin sensitivity, and NAFLD. We demonstrated that NAFLD and insulin resistance were effectively treated with physical exercise and weight loss during the weight loss camp residency. Twenty-two percent of children maintained weight loss at 12-month follow-up. Long-term actions must be implemented to increase this percentage to counter the long-term complications of obesity, such as NAFLD, reduced insulin sensitivity, and vascular complications.
We thank laboratory technician Jane Hansen, Aarhus University Hospital, Skejby, for helping to collect and process all of the blood samples. We thank the staff at Julemærhjemmet Hobro for collaboration during the study.
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Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
fatty liver; insulin sensitivity; obesity; transaminasemia; ultrasound; weight loss