Objectives: Metabolic syndrome components, such as being overweight or having hypertension, hyper­lipidemia, or diabetes mellitus, are common com­plications after liver transplant in pediatric patients with probable multifactorial causes and increase the risk of cardiovascular complications in adulthood. In this study, our aim was to evaluate the prevalence of these components both before and after transplant surgery.

Materials and Methods: Our study included all children having liver transplant at our institution over a period of 20 years who were under 18 years old and had at least 6 months of posttransplant follow-up. Prevalence of metabolic syndrome components and pretrans­plant and posttransplant laboratory data of patients were evaluated.

Results: Over the 20-year study period, 391 liver transplant patients were included in our study, in which 167 were girls (42.7%) and 224 were boys (57.3%). Patients showed a posttransplant hyperlipidemia rate of 7.5%, hyperglycemia rate of 22%, hypertension rate of 9.6%, and metabolic syndrome rate of 50.2%. Pretransplant, the rate of patients with metabolic syndrome was 10.5%.

Conclusions: Our study confirmed that the prevalence of metabolic syndrome in patients after liver trans­plant increases dramatically and should be explored with further research.

Key words : Diabetes mellitus, Dyslipidemia, Hypertension, Insulin resistance, Obesity

Introduction

Patient quality of life and survival rates after liver transplant have improved vigorously over recent years.¹ A return to ordinary lifestyle activities with normalized hypermetabolic state (versus that seen with liver insufficiency) and normal diet can cause progressive weight gain in these patients.^2-4 Determination of the predisposing factors contri­buting to mortality in patients with progressive liver insufficiency remains a challenging issue. In addition, determining the optimal time for transplant and the effective factors on short-term and long-term survival are debatable topics in this field.¹

Excess weight, hypertension, hyperlipidemia, and diabetes mellitus (DM) are common complications after liver transplant most likely due to multiple causes. These components of metabolic syndrome can increase the risk of cardiovascular disease.^1-4 As shown in a cross-sectional survey on adult liver transplant, 53% of patients had hypertension, 51% had hyperlipidemia, 37% had hyperglycemia, and 32% of patients had increased waist circumference at least 6 months after operation, with metabolic syndrome observed in 44.5%.¹

Some predisposing factors of metabolic syndrome after liver transplant are immunosuppressive drugs, higher age at time of operation, being male, higher body mass index (BMI) before transplant, pre­transplant DM, underlying liver disease, and higher BMI in donors.⁵

Pediatric patients have historically shown great improvements with liver transplant.¹ This procedure was first attempted in pediatric patients in 1963, with the first successful transplant occurring in 1967.¹

Organ preservation, improvements in immuno­suppressive drug treatment, and well-chosen donors have given clinicians more confidence about rapid survival postoperation. Nevertheless, posttransplant complications with vascular origin can cause transplant rejection or retransplant.³

In long-term follow-up of pediatric liver transplant recipients, preoperation obesity has correlated with high mortality rate after transplant.⁶ Fifteen to 21% of children are overweight or have severe obesity before transplant. Posttransplant, these statistics are 18% to 67%, with variability according to age and preoperation weight.⁷ Compared with that shown in children, adults have similar prevalence of posttransplant obesity (21%); moreover, 43% to 58% of adults develop metabolic syndrome.⁸ In addition, some cohort studies on pediatric patients have shown that metabolic syndrome in childhood increases the risk of cardiovascular disease in adulthood.⁹

Obesity in childhood, hypertension, and glucose intolerance correlate with premature death,¹⁰ whereas immediate diagnosis and treatment of these complications will prevent other similar long-term problems.^11,12

Throughout Iran, Shiraz city has the best active center for liver transplant procedures for pediatric patients. Metabolic syndrome is an important concern in this age group; therefore, we performed this study to survey the prevalence of this syndrome, as well as rates of obesity, hyperlipidemia, hyper­glycemia, and hypertension after transplant. Our goal was to determine the age groups most likely to get metabolic syndrome, the postoperative complications, and the correlations between metabolic syndrome and age, sex, and preoperation laboratory data.

Materials and Methods

Study population
All children seen from July 1992 to July 2012 at the Shiraz Transplantation Center who were under 18 years old and had at least 6 months of follow-up after liver transplant were included in our study. Individuals who died before the 6-month follow-up and those with familial hypercholesterolemia were excluded. Our center is the primary center for transplant in Iran, children requiring liver transplant are only seen at our center, and all patients seen at our center were followed in related clinics. Therefore, periodic laboratory data were complete for these patients. The study was approved by the Shiraz University of Medical Sciences Ethics Committee, and all participants’ families gave their written consents. The protocol of the study was approved by our Institutional Review Board.

Study protocol
Weight was measured by Seca balance (Seca, Hamburg, Germany) while patients wore thin clothing; vertical height was measured without shoes using a metal stadiometer. Body mass index was calculated as weight in kilograms divided by height in meters (kg/m²). Mercury sphygmomanometer was the best choice for measuring blood pressure with a proportionate arm cuff. Fasting blood sugar, triglyceride, total cholesterol, high-density lipo­protein (HDL), and low-density lipoprotein levels were periodically tested in every patient.

Metabolic syndrome consists of a combination of metabolic abnormalities that increase the risk of cardiovascular disease and DM. The criteria for metabolic syndrome have been mentioned since the original definition by the World Health Organization in 1998. The major features of metabolic syndrome include hypertriglyceridemia, central obesity, low HDL cholesterol, hyperglycemia, and hypertension.¹³ Some definitions for metabolic syndrome in children have also been defined and updated by other groups, such as the National Cholesterol Education Program/Adult Treatment Panel III and the International Diabetes Foundation, most recently in 2003.

Regardless of sex or ethnic background, there is a single definition for adult patient populations at high risk.¹⁴ However, a single definition for children and adolescents has been difficult. Hypertension, triglyceride titers, and anthropometric data change as children grow and change during puberty. Puberty has a great influence on fat distribution, and hence there is decreased insulin sensitivity; also 30% insulin secretion is noticed during puberty.¹⁵ Therefore, small changes are not good for children. However, there is no global agreement for metabolic syndrome criteria in children. One of the most accepted criteria is from the National Cholesterol Education Program/Adult Treatment Panel III, described here in Table 1 and used in our survey.

Both elevated systolic blood pressure and BMI in the upper 95th percentile are considered as hyper­tension and obesity for all ages, both sexes, and all heights. Fasting triglyceride levels ≥ 100 mg/dL and HDL levels ≤ 50 mg/dL (except for boys between 15 and 18 years old, who have a cutoff point of 45 mg/dL for HDL) are considered as hyper­lipidemia. Fasting blood sugar ≥ 110 mg/dL are considered abnormal. According to the National Cholesterol Education Program/Adult Treatment Panel III criteria, for children, existence of 3 or more of these factors will establish a diagnosis of metabolic syndrome6 (Table 1).

The prevalences of metabolic syndrome, hyper­lipidemia, hypertension, and hyperglycemia were our main survey goals. Comparisons before and after transplant regarding liver and kidney function tests (albumin, bilirubin, and total protein) were other goals of this study.

In this study, Pediatric End-Stage Liver Disease scores according to age, growth disturbance, albumin and bilirubin levels, and the international nor­malized ratio were measured for every patient less than 12 years old, whereas Model for End-Stage Liver Disease scores based on bilirubin, international normalized ratio, and creatinine levels were measured in children greater than 12 years old.

Statistical analysis
All required data were extracted from patient medical records and examinations; gathered data were collected by a checklist and entered into a computer database. All statistical analyses were performed using the Statistical Package for the Social Sciences, version 15.0 (SPSS Inc., Chicago, IL, USA). Descriptive results are presented as mean values ± standard deviation for 95% confidence interval with or without proportions. Independent sample t tests and chi-square tests were used to compare findings before and after transplant. A 2-sided P value < .05 was considered statistically significant with power of 90%.

Results

Our study included 391 patients who had liver transplant over the 20-year study period, including 167 female (42.7%) and 224 male (57.3%) patients. We excluded 32 patients who died before the 6-month follow-up and 57 patients with familial hyper­cholesterolemia; therefore, the total number of individuals included was 302. Mean age of children was 8.8 ± 6.5 years at time of enrollment (range, 0.5 to 14 years) and 10 ± 7.4 at time of transplant surgery (range, 1 to 18 years). Mean age of donors was 24 ± 11.6 (range, 2 to 55 years). The most common reasons for transplant were biliary atresia (15.4%), cirrhosis without finding cause (13.5%), and Wilson disease (13.3%), with the less common being hepatic carcinoma (0.8%). Mean Pediatric End-Stage Liver Disease score was 16.3 ± 11.1, and mean Model for End-Stage Liver Disease score was 20.6 ± 7.7.

After transplant, hyperlipidemia rate was 7.5%, hyperglycemia rate was 22%, hypertension rate was 9.6%, and metabolic syndrome rate was 50.2%; rate of metabolic syndrome was 10.5% before surgery. Mean BMI for patients was calculated as 16.9 ± 4.3 kg/m² (range, 8.09 to 36 kg/m2) before transplant. This quantity postoperation was 17.6 ± 7.1 kg/m² (range, 7.7 to 61.6 kg/m²).

The prevalence of metabolic syndrome in 359 individuals before transplant (total patients but excluding 32 patients with familial hypercho­lesterolemia) was 10.5% (38 patients). In the 302 study patients (also excluding 57 patients who died before the 6-month follow-up), 50.2% (152 patients) had metabolic syndrome posttransplant. We found that 183 patients had preoperational hyperlipidemia. In this group of patients, prevalence of metabolic syn­drome was 46.6% (85/183 patients) before transplant and 64.5% (118/183 patients) after transplant.

According to our findings, metabolic syndrome had a high prevalence after transplant (5 times more than pretransplant). These results show that multiple risk factors for this syndrome along with other predisposing factors increase the risk of its occurrence. This fact is more obvious in hyper­lipidemic patients, as there are additional factors to enhance the risk of this syndrome after transplant. These findings are shown in Table 2.

We found no statistically significant correlations between age and metabolic syndrome before (P = .21) and after (P = .98) transplant. Table 3 shows the prevalence of hyperlipidemia, hyperglycemia, and hypertension in our study patients. As shown in Table 3, the most prevalent posttransplant com­plication was hyperglycemia, whereas the most prevalent complication before transplant was hyperlipidemia, which gradually decreased after transplant. Also shown is the increase of blood pressure after transplant.

We also considered prophylaxis, rapid diagnosis and treatment of risk factors, and postoperation complications in our study patients. Fasting blood sugar and lipid profiles before and after transplant are presented in Table 4. As shown, we found no statistically significant correlations in fasting blood sugar and lipid profiles versus metabolic syndrome before and after transplant.

Mortality rate in children after liver transplant was 23.2% (91/391 patients) in this study. Deaths mainly occurred during the first month and first 3 months postoperation (54.2% and 45.8%). Death rate during the 6 months after transplant, one of the exclusion criteria for our study, was 14.6% (57/391 patients). After elimination of deaths during the first trimester, survival rate was 84% and varied according to original liver disease.

Hepatic enzymes and bilirubin levels (direct and indirect) increased by 100 and 20 times after versus before transplant. Kidney function tests, including serum urea nitrogen and creatinine levels, showed that some patients displayed renal failure secondary to hepatic insufficiency. These comparisons are shown in Table 5. As shown, alterations in laboratory results became balanced after transplant. Nevertheless, these quantities had risen rapidly after transplant before decreasing gradually. Table 5 shows that the pretransplant alanine aminotransferase and alkaline phosphatase levels were correlated with metabolic syndrome; albumin levels also correlated with metabolic syndrome but just posttransplant (P ˂ .001). Other diagnostic criteria did not have any significant correlation. Total bilirubin, alanine aminotransferase, and cholesterol levels had the least association with this syndrome.

Discussion

The rate of liver transplant has recently increased dramatically. When we consider the depletion in the number of available livers and the large numbers of patients on transplant wait lists, it is important to monitor patients for severe complications. The most common causes of liver failure in children are cholestatic and metabolic diseases. Considering the increased life expectancy after liver transplant, mainly due to better hospital care and immuno­suppressive drugs, it is important to diagnose complications early after transplant. One of these complications is metabolic syndrome, diagnosed as hypertension, hyperlipidemia, DM, and being overweight. A positive correlation between over­weight and cardiovascular problems leading to death has been shown in pediatric patients. Multiple studies have shown that metabolic syndrome increases after transplant, especially in adult patients.^1,4

Reasons for increased rates of metabolic syndrome in transplant patients include being overweight and the adverse effects of immunosuppressive drugs. Multiple studies have shown the effects of metabolic syndrome on adulthood diseases, with increased cardiovascular complications (increased by 10 times) and type 2 DM (increased by 4 times). Childhood obesity and hypertension are also related to early death.¹⁰ Several studies have explained the increased rates of metabolic syndrome in posttransplant patients; however, most of these were conducted in adult patients. Because Nemazee Hospital is the 4th largest liver transplant center in the world and a massive number of transplants are done every year in this center, we conducted a survey to find the incidence of metabolic syndrome in children after liver transplant in our center.

Similar to that shown in Broering and associates,3 we found that the most common cause of liver failure in children was biliary atresia and Wilson disease, suggesting the important role of early diagnosis to diminish the incidence of liver failure. Regarding cause of liver failure, we found no differences between children older or younger than 2 years. Studies by Klenman and associates and Leonard and associates^5,8 showed a similar prevalence of pos­t­operation obesity in both children and adults; obesity increases the risk of cardiovascular complications and is an important component of metabolic syndrome. In our study, we measured BMI and found an increase in mean range of BMI posttransplant, although these results were not significant (P = .21). Measurement of BMI is important, as obesity is a “sine qua non” of metabolic syndrome in adults and children.^16-19 In other laboratory changes after transplant, both alkaline phosphatase and alanine aminotransferase levels changed and albumin levels changed significantly after transplant. These laboratory data may help predict prognosis of transplanted liver.

In this study, hypertension rate was 10.6%, hyperlipidemia rate was 6.7%, and blood sugar rate was 22.3% posttransplant, which are similar to those shown in Everhart and associates and Laish and associates.^11,12 These findings strongly confirm the main goal of our study. The most common age for metabolic syndrome before transplant was 15 years, whereas this age decreased by 5 to 10 years after transplant.

In a larger 30-year study from Cook and associates²⁰ from the Lipidi-prinston Research Center, risk of cardiovascular disease and type 2 DM was 9 times and 4 times more likely in patients with meta­bolic syndrome versus individuals without this disease.

In a recent study from Malatack and associates,⁶ 252 liver recipients between 54.5 and 62.8 years old were analyzed for metabolic syndrome components. The group found that the prevalence of this syndrome was 2 times greater than in the general population, which also agreed with our findings.

We found that the rate of metabolic syndrome was significantly increased in children after versus before transplant. Metabolic syndrome may increase due to lack of physical activity, complications of drugs, and diet. Therefore, early diagnosis and stopping further complications would be helpful so that patients could have a high quality life. This study guides the researchers to pay more attention to symptoms of metabolic syndrome and its complications.

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