ORIGINAL ARTICLES
METABOLIC SYNDROME AND RELATED DISORDERS Volume 12, Number 3, 2014 Mary Ann Liebert, Inc. Pp. 159–164 DOI: 10.1089/met.2013.0075
Metabolic Syndrome in Turner Syndrome and Relation Between Body Composition and Clinical, Genetic, and Ultrasonographic Characteristics Valeria Calcaterra, MD,1 Paola Brambilla, MD,1 Gabriella Carnevale Maffe`, MD,2 Catherine Klersy, MD,3 Riccardo Albertini, MD,4 Francesca Introzzi, MD,1 Elena Bozzola, MD,5 Mauro Bozzola, MD,6 and Daniela Larizza, MD1
Abstract
Background: An increased relative risk of diabetes, ischemic heart disease, atherosclerosis, and hypertension have been reported in Turner syndrome (TS) patients. No data are currently available on the prevalence of metabolic syndrome in TS subjects. We evaluated the frequency of metabolic syndrome in obese and nonobese patients with TS. Patients and Methods: We evaluated 85 TS patients (27.05 – 11.17 years). Obesity was defined as standard deviation score body mass index (SDS-BMI) ‡ 2 or BMI ‡ 30 kg/m2 in adult patients. We classified metabolic syndrome according to the International Diabetes Federation (IDF). Hepatic ultrasound was performed in all girls. Results: The prevalence of metabolic syndrome was 4.7% (12.5% obese and 4.3% nonobese, P = 0.16) and associated with visceral adiposity (P = 0.008). Abnormalities in glucose metabolism and hypertension were not associated with genetic or therapeutic factors. The karyotype 45,X was associated with atherogenic profile. Pathological waist circumference was more frequent in girls treated with estro-progestin (P = 0.03). Evidence of fatty liver was associated with metabolic syndrome (P = 0.03) and insulin resistance (P = 0.05). Elevated liver enzymes were found in 15 subjects and were not related to treatment or ultrasound abnormalities. Conclusions: Prevalence of each component of metabolic syndrome in TS patients is partially influenced by genetic makeup and treatment. Hepatosteatosis was associated with metabolic syndrome and insulin resistance, but not to elevated liver enzymes.
Introduction
M
etabolic syndrome is a pathological condition that includes a combination of visceral adiposity, abnormalities in glucose metabolism, hypertension, and dyslipidemia and increases the risk of developing diabetes mellitus and cardiovascular disease.1–3 Turner syndrome (TS) is a genetic syndrome caused by the complete or partial absence of an X chromosome. It is one of the more common chromosomal abnormalities in females,
affecting 1/2000–2500 female live births and is usually associated with retarded growth, reduced adult height, and gonadal dysgenesis. Morbidity and mortality are clearly increased in this syndrome, and an increased relative risk of diabetes, ischemic heart disease, atherosclerosis, and hypertension have been reported. Turner patients are also prone to becoming overweight and obese.4–11 No data are currently available on the prevalence of metabolic syndrome in TS subjects. The aim of this study was to estimate the prevalence of metabolic syndrome in obese and nonobese TS patients and
1 Department of Internal Medicine University of Pavia and Department of the Mother and Child Health, Pediatric Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 2 Biometry & Clinical Epidemiology, Scientific Direction, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 3 First Department of Medicine, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 4 Laboratory of Clinical Chemistry, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 5 Pediatric and Infectious Disease Unit, Department of Pediatrics, Bambino Gesu` Children’s Hospital, Rome, Italy. 6 Department of Internal Medicine University of Pavia and Department of the Mother and Child Health, Auxologic Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
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to evaluate the relationship between body composition traits and clinical, genetic, and ultrasonographic characteristics, assuming the hypothesis that not just obesity might increase frequencies of the parameters of metabolic syndrome in TS.
Patients and Methods Patients The study included 85 patients with TS (mean age 27.05 – 11.17 years, range 8.11–46.57 years) attending regular follow-up evaluations at the Endocrine Unit of the Department of Pediatrics. Forty-five girls had a 45,X karyotype and 40 had a structurally abnormal X chromosome or X mosaicism. TS subjects were divided into obese and nonobese patients; obesity was defined as a standard deviation score body mass index (SDS-BMI) ‡ 2 in girls 2–18 years old12 or a BMI ‡ 30 kg/m2 in adult patients. During the study, 62 girls (72.9%) were being treated with growth hormone (GH), 64 (75.3%) with estro-progestin, and 20 (23.5%) with l-thyroxine. Two patients were on treatment with anti-hypertensive agents (these patients were included in the hypertensive group). Except for GH, no drugs that could alter insulin sensitivity were used by patients. The study was performed according to the recommendations of the ethics committee of our Institute. Informed consent was obtained from each patients and/or responsible guardian.
Methods The physical examination of patients included evaluation of height, weight, body composition, waist circumference, BMI, and blood pressure. Height measurement was performed using a Harpenden stadiometer, with patients in an upright position, without shoes, with their heels together, arms extended down the sides of the body, and head positioned parallel to the floor. Weight and body composition was determined using bioelectrical impedance analysis (Tanita BC 420 s MA) with the girls barefoot and wearing light clothes, standing upright in the center of the scale platform with their arms extended down the sides of the body. Waist circumference was obtained at the midpoint between the lowest rib and the iliac crest. BMI was calculated as body weight in kilograms divided by body height in meters squared. Systolic (SBP) and diastolic (DBP) blood pressure was taken on both arms twice using a mercury sphygmomanometer, after the patient had been sitting comfortably for 5 min, with an appropriately sized cuff on the right arm slightly flexed at heart level. The second blood pressure measurement on the right arm was used for analysis. Liver ultrasound was performed to check for the presence of hepatosteatosis. Transabdominal sonography was performed using an Esaote MyLab 70X V G machine, with a 1–8 MHz curvilinear ultrasound probe. In all patients, fasting blood measures included glucose [fasting blood glucose (FBG)], insulin, total cholesterol, highdensity lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Insulin resistance was calculated by the homeostasis model assessment for insulin resistance (HOMA-IR).13 Reproducibility has been investigated in the past and was satisfying although not optimal.14 Euglycemic–hyperinsulinemic clamp is the gold standard for measuring insulin resistance,
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but this method is invasive, time consuming, and difficult to apply to children. For these reasons, we used HOMA-IR as surrogate marker of insulin resistance/sensitivity. Serum glucose was measured using the hexokinase– glucose-6-phosphate dehydrogenase (G-6-PDH) method (Abbott Diagnostics, Wiesbaden, Germany) with a chemistry analyzer (Architect c-16000); intra- and interassay coefficients of variation (CVs) were 1.98% and 2.15%, respectively, at 4.4 mmol/L and 0.65% and 1.51% at 15.5 mmol/L. Total cholesterol was determined by enzymatic method (Abbott Diagnostics, Wiesbaden, Germany); intra- and interassay CVs were 0.8% and 1.5%, respectively, at 6.7 mmol/L and 0.6% and 1.6% at 3.3 mmol/L. HDL-C was measured by the accelerator selective detergent method (Abbott Diagnostics, Wiesbaden, Germany), intra- and interassay CVs were 1.7% and 5.5%, respectively, at 0.5 mmol/L and 1% and 1.4% at 2 mmol/L. TG concentration was measured by the glycerol phosphatase oxidase method (Abbott Diagnostics, Wiesbaden, Germany); intraand interassay CVs were 0.7% and 1.7%, respectively, at 3.2 mmol/L and 0.8% and 2% at 1.5 mmol/L. Serum insulin was determined by a solid-phase, two-site chemiluminescent immunometric assay with an immunochemistry analyzer (Immulite 2000, Siemens Medical Solutions Diagnostics, Los Angeles, CA); intra- and interassay CVs were 5.5% and 7.3%, respectively, at 7.67 mIU/mL and 3.8% and 4.2% at 100 mIU/mL. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and g-glutamyltransferase (GGT) were measured with a chemistry analyzer (Architect c-16000) equipped with dedicated reagents; the method for transaminase assay is based on nicotinamide adenine dinucleotide (NADH) monitoring by ultraviolet (UV) detection without the addition of P-5¢-P. The method for the GGT assay is based on transfer of the gamma-glutamyl group from l-gamma-glutamyl-3-carboxy-4-nitroaniline to the glycylglycine acceptor, to yield 3-carboxy-4-nitroaniline, whose absorbance is detected at 416 nm. Intra- and interassay CVs were 1% and 1.5 % for AST, ALT, and GGT. Impaired insulin sensitivity (ISI) was defined as a HOMA-IR ‡ 4. According to the International Diabetes Federation,15,16 we defined subjects with metabolic syndrome as having central obesity and two or more of following parameters: High SBP or DBP, high TGs, low HDL-C, and impaired fasting glucose using the cutoff in the IDF criteria according to age. A positive family history, assessed by interviewing the parents, was determined when obesity, diabetes mellitus, and hypertension in parents and grandparents were reported.
Statistical analysis Continuous variables were described as mean and standard deviation (SD) or median and interquartile range (IQR), and categorical variables as counts and percentages. Data were compared between groups with the Student t-test or the Mann–Whitney U-test if continuous and the Fisher exact test if categorical. A two-group t-test with a 0.050 two-sided significance level will have 80% power to detect and affect a size of 0.787 when the sample sizes in the two groups are 16 and 69, respectively (a total sample size of 85). According to Cohen, this is a medium-large effect size.17,18 Stata 11
METABOLIC SYNDROME IN TURNER SYNDROME
Table 1. Characteristics Age (years [range]) Karyotype 45,X (%) BMI (kg/m2) SDS-BMI Birthweight (grams) Fat body mass (%) Fat rating Lean body mass (%) Water body mass (%) Waist circumference (cm) Triglycerides (mg/dL) HDL-C (mg/dL) Systolic blood pressure (mmHg) SDS-systolic blood pressure Diastolic blood pressure (mmHg) SDS-diastolic blood pressure Blood glucose (mg/dL) Fasting insulin (mIU/mL) HOMA-IR
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Characteristics of Turner Syndrome Patients Obese TS (n = 16)
Nonobese TS (n = 69)
p
23.29 – 11.6 [8.1–34.3] 10 (62.6) 28.54 – 4.56 2.8 – 0.65 2521.87 – 554.58 33.60 – 3.74 5.14 – 1.95 66.41 – 3.74 19.90 – 2.84 84.05 – 11.5 96.87 – 51.21 64.87 – 14.66 115.31 – 14.31 1.26 – 1.12 69.37 – 9.93 0.81 – 0.92 81.62 – 13.2 7.41 – 5.87 1.57 – 1.2
27.92 – 11.7 [8.3–46.57] 35 (50.7) 21.75 – 4.35 0.26 – 0.9 2626.85 – 555.19 20.49 – 7.86 2.06 – 1.32 79.50 – 7.86 15.99 – 1.45 71.04 – 11.17 77.33 – 52.43 65.53 – 14.43 114.63 – 14.27 1.19 – 1.48 71.05 – 9.96 0.96 – 0.91 75.63 – 6.7 5.07 – 1.16 0.95 – 1.16
0.16 0.56 < 0.001 < 0.001 0.41 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.18 0.86 0.86 0.52 0.54 0.55 0.01 0.002 0.005
TS, Turner syndrome; BMI, body mass index; SDS, standard deviation score; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance.
(StataCorp, College Station, TX, USA) was used for computations. All tests were two-sided.
Results According to BMI, 16 TS subjects (18.8%) were obese and 69 (81.2%) nonobese. In Table 1, we describe the characteristics of the TS girls. BMI, fat body mass, fat rating, waist circumference, blood glucose, fasting insulin, and HOMA-IR were significantly higher in obese than in nonobese subjects. No significant differences were found in TG, HDL-C, and blood pressure between the two groups. The prevalence of metabolic syndrome in TS patients was 4.7%; in particular, metabolic syndrome occurred in 12.5% of obese girls and in 4.3% of nonobese subjects (P = 0.16). All girls were over 16 years old. The prevalence of each component of metabolic syndrome in the groups is shown in Table 2. Abnormalities in glucose metabolism and hypertension were not associated with genetic or therapeutic factors. Karyotype 45,X was associated with an atherogenic profile (Table 3). Pathological waist circumference was more frequent in girls treated with estro-progestin (P = 0.03). Association between low birth weight and structurally abnormal X chromosome or X mosaicism was found (P = 0.0003), without significant differences in girls with or without each pathological component of metabolic syndrome (P = 0.41) (Tables 1 and 3). Parameters of adiposity are reported in Table 4. Metabolic syndrome was positively correlated with visceral adiposity (P = 0.008). There were no significant differences in birth weight (P = 0.13), karyotype (P = 0.3), and therapy with GH (P = 0.4), estro-progestin (P = 0.3), or l-thyroxine (P = 1) between metabolic syndrome and non–metabolic syndrome groups A family history of obesity and hypertension was not significantly reported in obese and hypertensive TS girls (P = 0.09 and P = 0.3, respectively). Metabolic syndrome
occurrence was not associated with a family history of obesity (P = 1), diabetes (P = 0.64), hypertension (P = 0.13), and dyslipidemia (P = 1) ISI was present in 37.5% of the obese TS subjects and in 5.8% of non-obese subjects (P = 0.002). Insulin-resistant patients had a higher visceral index compared to girls with a normal insulin sensitivity (5 – 3.44 versus 2.40 – 1.58, P = 0.01); no difference in treatment was found. No significant association was found between metabolic syndrome and insulin resistance. We found evidence of fatty liver in 14 (16.5%) patients; 4 (25%) were obese TS and 10 (14.5%) nonobese TS patients (P = 0.5). Patients with steatosis presented pathological waist circumference (P = 0.03), hyperglycemia or diabetes (P = 0.01), and insulin resistance (P = 0.05); no significant difference in TGs, HDL-C, and blood pressure, with respect to girls without fatty liver, was present. A significant association between steatosis and metabolic syndrome (P = 0.03) was found. Elevation of liver enzymes was noted in 15 subjects, with no significant association with metabolic syndrome, treatment, or ultrasound abnormalities.
Table 2. Prevalence of Each Component of Metabolic Syndrome in Obese and Nonobese Turner Syndrome Patients Components of metabolic syndrome
Obese TS Nonobese TS (n = 16) (n = 69)
Pathological waist 15 (96.9) circumference (%) Hypertriglyceridemia (%) 2 (12.5) Low HDL-C (%) 2 (12.5) Hypertension (%) 2 (12.5) Hyperglycemia 2 (12.5) or diabetes (%)
16 (23.1) 4 9 10 2
(5.8) (13) (14.5) (2.8)
p < 0.001 0.69 0.72 0.73 0.31
TS, Turner syndrome; HDL-C, high-density lipoprotein cholesterol.
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Table 3.
Characteristics of Turner Syndrome Patients According to Karyotype
Characteristics Age (years [range]) BMI (kg/m2) SDS-BMI Birth weight (grams) Fat body mass (%) Fat rating Lean body mass (%) Water body mass (%) Waist circumference (cm) Triglycerides (mg/dL) HDL-C (mg/dL) Systolic blood pressure (mmHg) SDS-systolic blood pressure Diastolic blood pressure (mmHg) SDS-diastolic blood pressure Blood glucose (mg/dL) Fasting insulin (mIU/mL) HOMA-IR
45,X (n = 45)
Other karyotype (n = 40)
p
28.54 – 11.45 23.56 – 4.48 0.86 – 1.38 2811.34 – 545.44 22.72 – 9.57 2.72 – 2.11 77.27 – 9.57 19.4 – 3.25 74.34 – 12.7 92.0 – 50.05 63.01 – 12.0 117.33 – 13.78 1.45 – 1.31 72.17 – 9.23 1.06 – 0.84 78.28 – 15.48 4.71 – 3.94 0.93 – 0.83
25.36 – 10.75 22.44 – 4.17 0.64 – 1.31 2392.05 – 475.29 22.98 – 6.92 2.3 – 1.33 77.01 – 6.92 19.15 – 2.79 72.53 – 9.56 70.65 – 51.0 68.24 – 12.0 111.87 – 14.44 0.93 – 1.37 69.12 – 10.61 0.78 – 0.96 75.05 – 9.72 6.44 – 7.15 1.21 – 1.44
0.19 0.23 0.45 0.0003 0.88 0.28 0.88 0.70 0.46 0.05 0.04 0.07 0.07 0.16 0.15 0.25 0.16 0.26
TS, Turner syndrome; BMI, body mass index; SDS, standard deviation score; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance.
Discussion Metabolic syndrome is a constellation of physiological and biochemical abnormalities characterized by diabetes or high fasting glucose, central obesity, abnormal cholesterol and TG levels, and hypertension.1,2 The incidence of this syndrome has been estimated to increase with age in patients over 50 years of age. In recent years, metabolic syndrome has been reported to affect nearly 30% of the general population in Europe2 and more than 40% in the United States.3 Metabolic syndrome has been accepted worldwide as a clinical marker for earlier detection of cardiovascular disease and type 2 diabetes diabetes mellitus (T2DM). People with metabolic syndrome are estimated to have twice the risk of developing cardiovascular disease compared to healthy individuals and a five-fold increased risk of T2DM.19 We report metabolic syndrome in 4.7% of our patients. This incidence is lower than that in the Italian population, which was reported to be 10% in girls20 and 18% in adult women.21 Even though abnormalities in carbohydrate and
Table 4. Parameters of Adiposity in Turner Syndrome Patients With or Without Metabolic Syndrome
Parameters BMI (kg/m2) Fat body mass (%) Visceral fat index Lean body mass (%) Water body mass (%) Waist circumference (cm) Waist circumference/ height
TS with metabolic syndrome
TS without metabolic syndrome
p
28.71 – 4.33 32.70 – 2.99 5.25 – 1.70 77.84 – 8.22 19.44 – 3.04 85.83 – 4.50
22.75 – 4.18 21.73 – 8.60 2.30 – 1.63 67.30 – 2.99 16.63 – 0.76 72.77 – 11.13
0.006 0.01 0.001 0.01 0.07 0.05
0.57 – 0.05
0.50 – 0.06
0.02
TS, Turner syndrome; BMI, body mass index.
lipid metabolism and hypertension are important clinical aspects of TS, our overall frequency suggests that dysmetabolic diseases cannot be considered to significantly increase cardiovascular risk reported in TS subjects. Results in a long-term follow-up study are required to confirm this suggestion. It is generally accepted that metabolic syndrome increases with obesity. Even though nonobese TS subjects showed a more favorable metabolic profile compared to obese patients, the frequency of metabolic syndrome in our study did not differ in the two groups. BMI alone is not a good predictor of metabolic risk in subjects with TS because it is not correlated with the visceral lipid depot, even taking into consideration the particular anthropometric composition of TS patients. BMI and fat mass have been found to be higher in adult TS patients compared with agematched controls, and free-fat mass is lower, implying a higher incidence of adiposity. In addition, distinct differences in regional body composition in young TS girls were reported,22 and this was accounted for by an increased fat mass in the arms and trunk. In view of our results, it is possible that in TS a good predictor of metabolic risk is the set of parameters of adiposity (BMI, fat body mass, visceral fat index, waist circumference, waist circumference/ height). Visceral fat depot in TS is linked to metabolic syndrome, but the presence of pathological parameters is also correlated with genetic and therapeutic factors. In particular, in accordance with Van et al.,23 atherogenic profile is associated with monosomy X in our patients. This finding confirms that the second X chromosome may contribute to a more salutary lipid panel and, as described by Giordano,24 patients treated with hormonal replacement therapy are connoted by higher frequency of central obesity. The most common feature of TS patients is prenatal and postnatal growth retardation. Clinical studies have related the dysmetabolic syndrome to abnormal fetal and neonatal growth patterns.25–29 Special attention should be given to children born prematurely or small for gestational age. Low
METABOLIC SYNDROME IN TURNER SYNDROME
birth weight has been associated with a higher prevalence of metabolic syndrome in adult life because accelerated growth during the first months of life by means of centile crossing might have an unfavorable effect in the long term.30–32 In our study, birth weight in TS girls with and without metabolic syndrome does not differ, and this data might be justified by growth retardation during early infancy without catch-up. According to Louzada Strufaldi et al.,33 the presence of metabolic syndrome in TS subjects is not associated with a family history of risk factors for metabolic syndrome, and, in fact, we did not find a significant association between obesity and a positive family history of obesity, diabetes, and hypertension. The metabolic derangement may be dependent on the syndrome. In our TS population, impaired insulin sensitivity is significantly higher in obese than in nonobese subjects, and this data confirms that obesity, specifically visceral adiposity, is directly linked to insulin resistance,34,35 but IR is not significantly associated with metabolic syndrome. The biological variability of HOMA is influenced by that of its components, which can be high; this variability may have influenced our result.36 In addition, in TS patients, IR may not predispose to other metabolic abnormalities, confirming that the causative role of insulin in the development of metabolic syndrome is still questionable, and underlining the complexity and synergism of genetic and environmental factors in the etiology of this disease.37 Impaired hepatic function in the form of raised liver enzymes is overrepresented in TS. It is often detected on routine investigation and is not accompanied by signs or symptoms of liver disease.38–40 Several studies have reported that hormone replacement therapy41–45 and growth hormone43,44,46 treatment may improve hepatic function in women with TS and that obesity is related to liver abnormalities in most cases.47,48 In our study, elevation of liver enzymes was not correlated to treatment and liver steatosis; the significance of liver dysfunction is not fully understood. In conclusion, the frequency of metabolic syndrome in TS patients is low and associated with visceral adiposity, and the prevalence of each component of metabolic syndrome is partially influenced by genetic factors and treatment. Hepatosteatosis was associated with metabolic syndrome and insulin resistance, but not to elevated liver enzymes.
Acknowledgment We thank Dr. Karen Doyle for revising the English manuscript.
Author Disclosure Statement No competing financial interests exist.
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Address correspondence to: Valeria Calcaterra, MD Department of Pediatrics IRCCS Policlinico San Matteo Foundation P.le Golgi n.2 27100 Pavia Italy E-mail: [email protected]
METABOLIC SYNDROME AND RELATED DISORDERS Volume 12, Number 3, 2014 Mary Ann Liebert, Inc. Pp. 159–164 DOI: 10.1089/met.2013.0075
Metabolic Syndrome in Turner Syndrome and Relation Between Body Composition and Clinical, Genetic, and Ultrasonographic Characteristics Valeria Calcaterra, MD,1 Paola Brambilla, MD,1 Gabriella Carnevale Maffe`, MD,2 Catherine Klersy, MD,3 Riccardo Albertini, MD,4 Francesca Introzzi, MD,1 Elena Bozzola, MD,5 Mauro Bozzola, MD,6 and Daniela Larizza, MD1
Abstract
Background: An increased relative risk of diabetes, ischemic heart disease, atherosclerosis, and hypertension have been reported in Turner syndrome (TS) patients. No data are currently available on the prevalence of metabolic syndrome in TS subjects. We evaluated the frequency of metabolic syndrome in obese and nonobese patients with TS. Patients and Methods: We evaluated 85 TS patients (27.05 – 11.17 years). Obesity was defined as standard deviation score body mass index (SDS-BMI) ‡ 2 or BMI ‡ 30 kg/m2 in adult patients. We classified metabolic syndrome according to the International Diabetes Federation (IDF). Hepatic ultrasound was performed in all girls. Results: The prevalence of metabolic syndrome was 4.7% (12.5% obese and 4.3% nonobese, P = 0.16) and associated with visceral adiposity (P = 0.008). Abnormalities in glucose metabolism and hypertension were not associated with genetic or therapeutic factors. The karyotype 45,X was associated with atherogenic profile. Pathological waist circumference was more frequent in girls treated with estro-progestin (P = 0.03). Evidence of fatty liver was associated with metabolic syndrome (P = 0.03) and insulin resistance (P = 0.05). Elevated liver enzymes were found in 15 subjects and were not related to treatment or ultrasound abnormalities. Conclusions: Prevalence of each component of metabolic syndrome in TS patients is partially influenced by genetic makeup and treatment. Hepatosteatosis was associated with metabolic syndrome and insulin resistance, but not to elevated liver enzymes.
Introduction
M
etabolic syndrome is a pathological condition that includes a combination of visceral adiposity, abnormalities in glucose metabolism, hypertension, and dyslipidemia and increases the risk of developing diabetes mellitus and cardiovascular disease.1–3 Turner syndrome (TS) is a genetic syndrome caused by the complete or partial absence of an X chromosome. It is one of the more common chromosomal abnormalities in females,
affecting 1/2000–2500 female live births and is usually associated with retarded growth, reduced adult height, and gonadal dysgenesis. Morbidity and mortality are clearly increased in this syndrome, and an increased relative risk of diabetes, ischemic heart disease, atherosclerosis, and hypertension have been reported. Turner patients are also prone to becoming overweight and obese.4–11 No data are currently available on the prevalence of metabolic syndrome in TS subjects. The aim of this study was to estimate the prevalence of metabolic syndrome in obese and nonobese TS patients and
1 Department of Internal Medicine University of Pavia and Department of the Mother and Child Health, Pediatric Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 2 Biometry & Clinical Epidemiology, Scientific Direction, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 3 First Department of Medicine, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 4 Laboratory of Clinical Chemistry, IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 5 Pediatric and Infectious Disease Unit, Department of Pediatrics, Bambino Gesu` Children’s Hospital, Rome, Italy. 6 Department of Internal Medicine University of Pavia and Department of the Mother and Child Health, Auxologic Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
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to evaluate the relationship between body composition traits and clinical, genetic, and ultrasonographic characteristics, assuming the hypothesis that not just obesity might increase frequencies of the parameters of metabolic syndrome in TS.
Patients and Methods Patients The study included 85 patients with TS (mean age 27.05 – 11.17 years, range 8.11–46.57 years) attending regular follow-up evaluations at the Endocrine Unit of the Department of Pediatrics. Forty-five girls had a 45,X karyotype and 40 had a structurally abnormal X chromosome or X mosaicism. TS subjects were divided into obese and nonobese patients; obesity was defined as a standard deviation score body mass index (SDS-BMI) ‡ 2 in girls 2–18 years old12 or a BMI ‡ 30 kg/m2 in adult patients. During the study, 62 girls (72.9%) were being treated with growth hormone (GH), 64 (75.3%) with estro-progestin, and 20 (23.5%) with l-thyroxine. Two patients were on treatment with anti-hypertensive agents (these patients were included in the hypertensive group). Except for GH, no drugs that could alter insulin sensitivity were used by patients. The study was performed according to the recommendations of the ethics committee of our Institute. Informed consent was obtained from each patients and/or responsible guardian.
Methods The physical examination of patients included evaluation of height, weight, body composition, waist circumference, BMI, and blood pressure. Height measurement was performed using a Harpenden stadiometer, with patients in an upright position, without shoes, with their heels together, arms extended down the sides of the body, and head positioned parallel to the floor. Weight and body composition was determined using bioelectrical impedance analysis (Tanita BC 420 s MA) with the girls barefoot and wearing light clothes, standing upright in the center of the scale platform with their arms extended down the sides of the body. Waist circumference was obtained at the midpoint between the lowest rib and the iliac crest. BMI was calculated as body weight in kilograms divided by body height in meters squared. Systolic (SBP) and diastolic (DBP) blood pressure was taken on both arms twice using a mercury sphygmomanometer, after the patient had been sitting comfortably for 5 min, with an appropriately sized cuff on the right arm slightly flexed at heart level. The second blood pressure measurement on the right arm was used for analysis. Liver ultrasound was performed to check for the presence of hepatosteatosis. Transabdominal sonography was performed using an Esaote MyLab 70X V G machine, with a 1–8 MHz curvilinear ultrasound probe. In all patients, fasting blood measures included glucose [fasting blood glucose (FBG)], insulin, total cholesterol, highdensity lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Insulin resistance was calculated by the homeostasis model assessment for insulin resistance (HOMA-IR).13 Reproducibility has been investigated in the past and was satisfying although not optimal.14 Euglycemic–hyperinsulinemic clamp is the gold standard for measuring insulin resistance,
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but this method is invasive, time consuming, and difficult to apply to children. For these reasons, we used HOMA-IR as surrogate marker of insulin resistance/sensitivity. Serum glucose was measured using the hexokinase– glucose-6-phosphate dehydrogenase (G-6-PDH) method (Abbott Diagnostics, Wiesbaden, Germany) with a chemistry analyzer (Architect c-16000); intra- and interassay coefficients of variation (CVs) were 1.98% and 2.15%, respectively, at 4.4 mmol/L and 0.65% and 1.51% at 15.5 mmol/L. Total cholesterol was determined by enzymatic method (Abbott Diagnostics, Wiesbaden, Germany); intra- and interassay CVs were 0.8% and 1.5%, respectively, at 6.7 mmol/L and 0.6% and 1.6% at 3.3 mmol/L. HDL-C was measured by the accelerator selective detergent method (Abbott Diagnostics, Wiesbaden, Germany), intra- and interassay CVs were 1.7% and 5.5%, respectively, at 0.5 mmol/L and 1% and 1.4% at 2 mmol/L. TG concentration was measured by the glycerol phosphatase oxidase method (Abbott Diagnostics, Wiesbaden, Germany); intraand interassay CVs were 0.7% and 1.7%, respectively, at 3.2 mmol/L and 0.8% and 2% at 1.5 mmol/L. Serum insulin was determined by a solid-phase, two-site chemiluminescent immunometric assay with an immunochemistry analyzer (Immulite 2000, Siemens Medical Solutions Diagnostics, Los Angeles, CA); intra- and interassay CVs were 5.5% and 7.3%, respectively, at 7.67 mIU/mL and 3.8% and 4.2% at 100 mIU/mL. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and g-glutamyltransferase (GGT) were measured with a chemistry analyzer (Architect c-16000) equipped with dedicated reagents; the method for transaminase assay is based on nicotinamide adenine dinucleotide (NADH) monitoring by ultraviolet (UV) detection without the addition of P-5¢-P. The method for the GGT assay is based on transfer of the gamma-glutamyl group from l-gamma-glutamyl-3-carboxy-4-nitroaniline to the glycylglycine acceptor, to yield 3-carboxy-4-nitroaniline, whose absorbance is detected at 416 nm. Intra- and interassay CVs were 1% and 1.5 % for AST, ALT, and GGT. Impaired insulin sensitivity (ISI) was defined as a HOMA-IR ‡ 4. According to the International Diabetes Federation,15,16 we defined subjects with metabolic syndrome as having central obesity and two or more of following parameters: High SBP or DBP, high TGs, low HDL-C, and impaired fasting glucose using the cutoff in the IDF criteria according to age. A positive family history, assessed by interviewing the parents, was determined when obesity, diabetes mellitus, and hypertension in parents and grandparents were reported.
Statistical analysis Continuous variables were described as mean and standard deviation (SD) or median and interquartile range (IQR), and categorical variables as counts and percentages. Data were compared between groups with the Student t-test or the Mann–Whitney U-test if continuous and the Fisher exact test if categorical. A two-group t-test with a 0.050 two-sided significance level will have 80% power to detect and affect a size of 0.787 when the sample sizes in the two groups are 16 and 69, respectively (a total sample size of 85). According to Cohen, this is a medium-large effect size.17,18 Stata 11
METABOLIC SYNDROME IN TURNER SYNDROME
Table 1. Characteristics Age (years [range]) Karyotype 45,X (%) BMI (kg/m2) SDS-BMI Birthweight (grams) Fat body mass (%) Fat rating Lean body mass (%) Water body mass (%) Waist circumference (cm) Triglycerides (mg/dL) HDL-C (mg/dL) Systolic blood pressure (mmHg) SDS-systolic blood pressure Diastolic blood pressure (mmHg) SDS-diastolic blood pressure Blood glucose (mg/dL) Fasting insulin (mIU/mL) HOMA-IR
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Characteristics of Turner Syndrome Patients Obese TS (n = 16)
Nonobese TS (n = 69)
p
23.29 – 11.6 [8.1–34.3] 10 (62.6) 28.54 – 4.56 2.8 – 0.65 2521.87 – 554.58 33.60 – 3.74 5.14 – 1.95 66.41 – 3.74 19.90 – 2.84 84.05 – 11.5 96.87 – 51.21 64.87 – 14.66 115.31 – 14.31 1.26 – 1.12 69.37 – 9.93 0.81 – 0.92 81.62 – 13.2 7.41 – 5.87 1.57 – 1.2
27.92 – 11.7 [8.3–46.57] 35 (50.7) 21.75 – 4.35 0.26 – 0.9 2626.85 – 555.19 20.49 – 7.86 2.06 – 1.32 79.50 – 7.86 15.99 – 1.45 71.04 – 11.17 77.33 – 52.43 65.53 – 14.43 114.63 – 14.27 1.19 – 1.48 71.05 – 9.96 0.96 – 0.91 75.63 – 6.7 5.07 – 1.16 0.95 – 1.16
0.16 0.56 < 0.001 < 0.001 0.41 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.18 0.86 0.86 0.52 0.54 0.55 0.01 0.002 0.005
TS, Turner syndrome; BMI, body mass index; SDS, standard deviation score; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance.
(StataCorp, College Station, TX, USA) was used for computations. All tests were two-sided.
Results According to BMI, 16 TS subjects (18.8%) were obese and 69 (81.2%) nonobese. In Table 1, we describe the characteristics of the TS girls. BMI, fat body mass, fat rating, waist circumference, blood glucose, fasting insulin, and HOMA-IR were significantly higher in obese than in nonobese subjects. No significant differences were found in TG, HDL-C, and blood pressure between the two groups. The prevalence of metabolic syndrome in TS patients was 4.7%; in particular, metabolic syndrome occurred in 12.5% of obese girls and in 4.3% of nonobese subjects (P = 0.16). All girls were over 16 years old. The prevalence of each component of metabolic syndrome in the groups is shown in Table 2. Abnormalities in glucose metabolism and hypertension were not associated with genetic or therapeutic factors. Karyotype 45,X was associated with an atherogenic profile (Table 3). Pathological waist circumference was more frequent in girls treated with estro-progestin (P = 0.03). Association between low birth weight and structurally abnormal X chromosome or X mosaicism was found (P = 0.0003), without significant differences in girls with or without each pathological component of metabolic syndrome (P = 0.41) (Tables 1 and 3). Parameters of adiposity are reported in Table 4. Metabolic syndrome was positively correlated with visceral adiposity (P = 0.008). There were no significant differences in birth weight (P = 0.13), karyotype (P = 0.3), and therapy with GH (P = 0.4), estro-progestin (P = 0.3), or l-thyroxine (P = 1) between metabolic syndrome and non–metabolic syndrome groups A family history of obesity and hypertension was not significantly reported in obese and hypertensive TS girls (P = 0.09 and P = 0.3, respectively). Metabolic syndrome
occurrence was not associated with a family history of obesity (P = 1), diabetes (P = 0.64), hypertension (P = 0.13), and dyslipidemia (P = 1) ISI was present in 37.5% of the obese TS subjects and in 5.8% of non-obese subjects (P = 0.002). Insulin-resistant patients had a higher visceral index compared to girls with a normal insulin sensitivity (5 – 3.44 versus 2.40 – 1.58, P = 0.01); no difference in treatment was found. No significant association was found between metabolic syndrome and insulin resistance. We found evidence of fatty liver in 14 (16.5%) patients; 4 (25%) were obese TS and 10 (14.5%) nonobese TS patients (P = 0.5). Patients with steatosis presented pathological waist circumference (P = 0.03), hyperglycemia or diabetes (P = 0.01), and insulin resistance (P = 0.05); no significant difference in TGs, HDL-C, and blood pressure, with respect to girls without fatty liver, was present. A significant association between steatosis and metabolic syndrome (P = 0.03) was found. Elevation of liver enzymes was noted in 15 subjects, with no significant association with metabolic syndrome, treatment, or ultrasound abnormalities.
Table 2. Prevalence of Each Component of Metabolic Syndrome in Obese and Nonobese Turner Syndrome Patients Components of metabolic syndrome
Obese TS Nonobese TS (n = 16) (n = 69)
Pathological waist 15 (96.9) circumference (%) Hypertriglyceridemia (%) 2 (12.5) Low HDL-C (%) 2 (12.5) Hypertension (%) 2 (12.5) Hyperglycemia 2 (12.5) or diabetes (%)
16 (23.1) 4 9 10 2
(5.8) (13) (14.5) (2.8)
p < 0.001 0.69 0.72 0.73 0.31
TS, Turner syndrome; HDL-C, high-density lipoprotein cholesterol.
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Table 3.
Characteristics of Turner Syndrome Patients According to Karyotype
Characteristics Age (years [range]) BMI (kg/m2) SDS-BMI Birth weight (grams) Fat body mass (%) Fat rating Lean body mass (%) Water body mass (%) Waist circumference (cm) Triglycerides (mg/dL) HDL-C (mg/dL) Systolic blood pressure (mmHg) SDS-systolic blood pressure Diastolic blood pressure (mmHg) SDS-diastolic blood pressure Blood glucose (mg/dL) Fasting insulin (mIU/mL) HOMA-IR
45,X (n = 45)
Other karyotype (n = 40)
p
28.54 – 11.45 23.56 – 4.48 0.86 – 1.38 2811.34 – 545.44 22.72 – 9.57 2.72 – 2.11 77.27 – 9.57 19.4 – 3.25 74.34 – 12.7 92.0 – 50.05 63.01 – 12.0 117.33 – 13.78 1.45 – 1.31 72.17 – 9.23 1.06 – 0.84 78.28 – 15.48 4.71 – 3.94 0.93 – 0.83
25.36 – 10.75 22.44 – 4.17 0.64 – 1.31 2392.05 – 475.29 22.98 – 6.92 2.3 – 1.33 77.01 – 6.92 19.15 – 2.79 72.53 – 9.56 70.65 – 51.0 68.24 – 12.0 111.87 – 14.44 0.93 – 1.37 69.12 – 10.61 0.78 – 0.96 75.05 – 9.72 6.44 – 7.15 1.21 – 1.44
0.19 0.23 0.45 0.0003 0.88 0.28 0.88 0.70 0.46 0.05 0.04 0.07 0.07 0.16 0.15 0.25 0.16 0.26
TS, Turner syndrome; BMI, body mass index; SDS, standard deviation score; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance.
Discussion Metabolic syndrome is a constellation of physiological and biochemical abnormalities characterized by diabetes or high fasting glucose, central obesity, abnormal cholesterol and TG levels, and hypertension.1,2 The incidence of this syndrome has been estimated to increase with age in patients over 50 years of age. In recent years, metabolic syndrome has been reported to affect nearly 30% of the general population in Europe2 and more than 40% in the United States.3 Metabolic syndrome has been accepted worldwide as a clinical marker for earlier detection of cardiovascular disease and type 2 diabetes diabetes mellitus (T2DM). People with metabolic syndrome are estimated to have twice the risk of developing cardiovascular disease compared to healthy individuals and a five-fold increased risk of T2DM.19 We report metabolic syndrome in 4.7% of our patients. This incidence is lower than that in the Italian population, which was reported to be 10% in girls20 and 18% in adult women.21 Even though abnormalities in carbohydrate and
Table 4. Parameters of Adiposity in Turner Syndrome Patients With or Without Metabolic Syndrome
Parameters BMI (kg/m2) Fat body mass (%) Visceral fat index Lean body mass (%) Water body mass (%) Waist circumference (cm) Waist circumference/ height
TS with metabolic syndrome
TS without metabolic syndrome
p
28.71 – 4.33 32.70 – 2.99 5.25 – 1.70 77.84 – 8.22 19.44 – 3.04 85.83 – 4.50
22.75 – 4.18 21.73 – 8.60 2.30 – 1.63 67.30 – 2.99 16.63 – 0.76 72.77 – 11.13
0.006 0.01 0.001 0.01 0.07 0.05
0.57 – 0.05
0.50 – 0.06
0.02
TS, Turner syndrome; BMI, body mass index.
lipid metabolism and hypertension are important clinical aspects of TS, our overall frequency suggests that dysmetabolic diseases cannot be considered to significantly increase cardiovascular risk reported in TS subjects. Results in a long-term follow-up study are required to confirm this suggestion. It is generally accepted that metabolic syndrome increases with obesity. Even though nonobese TS subjects showed a more favorable metabolic profile compared to obese patients, the frequency of metabolic syndrome in our study did not differ in the two groups. BMI alone is not a good predictor of metabolic risk in subjects with TS because it is not correlated with the visceral lipid depot, even taking into consideration the particular anthropometric composition of TS patients. BMI and fat mass have been found to be higher in adult TS patients compared with agematched controls, and free-fat mass is lower, implying a higher incidence of adiposity. In addition, distinct differences in regional body composition in young TS girls were reported,22 and this was accounted for by an increased fat mass in the arms and trunk. In view of our results, it is possible that in TS a good predictor of metabolic risk is the set of parameters of adiposity (BMI, fat body mass, visceral fat index, waist circumference, waist circumference/ height). Visceral fat depot in TS is linked to metabolic syndrome, but the presence of pathological parameters is also correlated with genetic and therapeutic factors. In particular, in accordance with Van et al.,23 atherogenic profile is associated with monosomy X in our patients. This finding confirms that the second X chromosome may contribute to a more salutary lipid panel and, as described by Giordano,24 patients treated with hormonal replacement therapy are connoted by higher frequency of central obesity. The most common feature of TS patients is prenatal and postnatal growth retardation. Clinical studies have related the dysmetabolic syndrome to abnormal fetal and neonatal growth patterns.25–29 Special attention should be given to children born prematurely or small for gestational age. Low
METABOLIC SYNDROME IN TURNER SYNDROME
birth weight has been associated with a higher prevalence of metabolic syndrome in adult life because accelerated growth during the first months of life by means of centile crossing might have an unfavorable effect in the long term.30–32 In our study, birth weight in TS girls with and without metabolic syndrome does not differ, and this data might be justified by growth retardation during early infancy without catch-up. According to Louzada Strufaldi et al.,33 the presence of metabolic syndrome in TS subjects is not associated with a family history of risk factors for metabolic syndrome, and, in fact, we did not find a significant association between obesity and a positive family history of obesity, diabetes, and hypertension. The metabolic derangement may be dependent on the syndrome. In our TS population, impaired insulin sensitivity is significantly higher in obese than in nonobese subjects, and this data confirms that obesity, specifically visceral adiposity, is directly linked to insulin resistance,34,35 but IR is not significantly associated with metabolic syndrome. The biological variability of HOMA is influenced by that of its components, which can be high; this variability may have influenced our result.36 In addition, in TS patients, IR may not predispose to other metabolic abnormalities, confirming that the causative role of insulin in the development of metabolic syndrome is still questionable, and underlining the complexity and synergism of genetic and environmental factors in the etiology of this disease.37 Impaired hepatic function in the form of raised liver enzymes is overrepresented in TS. It is often detected on routine investigation and is not accompanied by signs or symptoms of liver disease.38–40 Several studies have reported that hormone replacement therapy41–45 and growth hormone43,44,46 treatment may improve hepatic function in women with TS and that obesity is related to liver abnormalities in most cases.47,48 In our study, elevation of liver enzymes was not correlated to treatment and liver steatosis; the significance of liver dysfunction is not fully understood. In conclusion, the frequency of metabolic syndrome in TS patients is low and associated with visceral adiposity, and the prevalence of each component of metabolic syndrome is partially influenced by genetic factors and treatment. Hepatosteatosis was associated with metabolic syndrome and insulin resistance, but not to elevated liver enzymes.
Acknowledgment We thank Dr. Karen Doyle for revising the English manuscript.
Author Disclosure Statement No competing financial interests exist.
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Address correspondence to: Valeria Calcaterra, MD Department of Pediatrics IRCCS Policlinico San Matteo Foundation P.le Golgi n.2 27100 Pavia Italy E-mail: [email protected]
