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Excess Visceral and Hepatic Adipose Tissue in Turner Syndrome Determined by Magnetic Resonance Imaging: Estrogen Deficiency Associated with Hepatic Adipose Content

Department of Endocrinology, University College London Hospitals (J.E.O., M.J.H.A., G.S.C.), London W1T 3AA, United Kingdom; and Robert Steiner Magnetic Resonance Unit, Imaging Sciences Department, Medical Research Council Clinical Sciences Center, Hammersmith Hospital, Imperial College (E.L.T., G.H., J.D.B.), London W12 0HS, United Kingdom

Address all correspondence and requests for reprints to: Dr. Gerard S. Conway, Department of Endocrinology, Middlesex Hospital, Mortimer Street, London W1T 3AA, United Kingdom. E-mail: g.conway{at}ucl.ac.uk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Obesity, predominantly centrally distributed, is common in women with Turner syndrome (TS) and is thought to contribute to the increased risk of atherosclerosis; however, insulin concentrations are unexpectedly low. To explore this discrepancy, we assessed fat content and distribution by magnetic resonance imaging (MRI) and bioelectrical impedance (BI). Six nondiabetic, estrogen-treated women with TS were compared with six age-matched normal controls of similar body mass index. Clinical history, anthropometric measurements, biochemical markers, and MRI and BI measures of adiposity were assessed. TS women had increased intrahepatocellular lipids (IHCL) on MRI. After height adjustment, they also had an excess of total and visceral compared with sc adipose tissue (AT) than controls, without elevated insulin concentrations. BI and MRI measures correlated strongly for total and sc, but not visceral, AT in TS. IHCL was associated with cumulative estrogen-deficient years (r = 0.928; P = 0.008). Women with TS depart from the classical picture of metabolic syndrome despite an excess of total and visceral AT on MRI. Elevated IHCL in TS is associated with estrogen deficiency. BI may be useful to estimate total body fat, but does not reliably localize fat depots in TS.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
WOMEN WITH TURNER syndrome (TS) have an increased risk of ischemic heart disease (IHD) (1), with mortality due to IHD being increased up to 7-fold (2). Diabetes mellitus, a well-established risk factor for IHD, has been reported as the underlying cause of death in 25% of TS patients (3). Type II diabetes is four times more prevalent in TS than in the general population (1).

Obesity is thought to contribute to the cardiovascular risk in TS and has been associated with an adverse lipid profile (4, 5) and hypertension (5). Women with TS are commonly obese (5, 6), and their adiposity appears to have a predominantly central distribution (6). This is in the context, however, of unexpectedly low circulating insulin concentrations (6, 7).

Various techniques are available to assess obesity and fat distribution. These include anthropometric measures, magnetic resonance imaging (MRI), and bioelectrical impedance. MRI is being increasingly used to localize fat depots in different populations (8), whereas bioelectrical impedance has been shown to correlate well with other markers of obesity in the general population (9). On MRI, the most sensitive markers of insulin resistance are abdominal adipose tissue (AT), intrahepatocellular lipids (IHCL), and intramyocellular lipids (IMCL) in the soleus muscle (10, 11).

The aim of this study was to characterize body fat content and distribution in TS subjects by various physical and imaging techniques and to compare these to biochemical markers of obesity to gain a greater understanding of the unusual metabolic profile of TS.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Six nondiabetic, estrogen-treated women with TS were recruited from the Adult Turner Syndrome Clinic at Middlesex Hospital. They were compared with six age-matched normal control women of similar body mass index who were taking no medication and had regular spontaneous menstrual cycles. The study was approved by the University College London Hospitals ethics committee, and participants gave written informed consent.

Clinical history and case notes were reviewed for previous medical history. History of estrogen replacement, previous GH and oxandrolone administration, smoking, exercise, and current medication use were determined. Clinical parameters were recorded, including anthropometric assessments such as height, weight, and waist measurements. Recumbent blood pressure was recorded at the right artery using an automated sphymomanometer (Dinamap, Critikon, Tampa, FL) after subjects had rested for at least 15 min. Five readings were taken, and mean systolic and diastolic blood pressures were calculated. A large cuff was used for obese individuals.

Subjects attended after a 12-hr overnight fast, although they were allowed to drink water until 3 h before the test. A blood sample was taken for analysis of lipids, glucose, insulin, leptin, high sensitivity C-reactive protein (CRP), IL-6, liver function, and karyotype. The homoeostasis model insulin resistance index was calculated as the product of insulin and glucose concentrations divided by 22.5.

Total body AT content

Rapid T₁-weighted MR images (repetition time, 36 msec; echo time, 14 msec) were acquired as previously described (8). Subjects lay in the magnet in a prone position with arms straight above the head and were moved through the magnet on a purpose-built platter. They were scanned from fingertips to toes by acquiring 10-mm-thick transverse images with 30-mm gaps between slices in the arms and legs and 10-mm gaps between slices in the trunk. Images were analyzed for fat and nonfat components using SliceOmatic (Tomovision, Montréal, Canada) (12). Total body AT, sc, total internal, sc abdominal, and intraabdominal AT volumes were measured (8). The coefficient of variation varies between different depots, but the data analysis method is generally highly reproducible: 3% for internal fat, 5% for visceral fat, and less than 1% for total, sc, and sc abdominal fat (13).

MRI of the liver

¹H magnetic resonance spectra were acquired on a 1.5T Eclipse multinuclear system (Phillips Medical Systems, Cleveland, OH) using a flexible body coil. Spectra were obtained from the right lobe of the liver using a PRESS sequence (repetition time, 1500 msec; echo time, 135 msec) without water saturation and with 128 signal averages. Transverse images of the liver were used to ensure accurate positioning of the 20 x 20 x 20 mm voxel in the liver, avoiding blood vessels, gall bladder, and fatty tissue. Spectra were analyzed as previously described, with IHCL measured relative to liver water content after correcting for relative variations in T1 and T2 components. The coefficient of variation for repeated determinations of this measurement was 7% (14).

MRI of muscle

Subjects were supine with the left leg immobilized in a 30-cm diameter quadrature bird cage coil. ¹H magnetic resonance spectra were obtained from the soleus and tibialis muscles with repetition time of 1500 msec, echo time of 135 msec, and 256 averages (15). IMCL were measured relative to the total muscle creatine signal after correcting for relative variations in T1 and T2 components. The coefficient of variation for repeated determinations of this measurement was 13.6 ± 3.5% (15).

Bioelectrical impedance for body fat composition

Bioelectrical impedance was assessed using a Tanita BC-418MA body fat analyzer (Tanita Corp., Tokyo, Japan) according to the manufacturer’s protocol.

Statistical analysis

Statistical Analysis was performed using SPSS version 11.0 for Windows (SPSS, Inc., Chicago, IL). For the cross-sectional analyses, continuous variables were compared by ANOVA, log transformation, and cofactor adjustment where appropriate, whereas categorical variables were compared by ² test. Associations between variables were assessed using Spearman’s correlation coefficients.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subject characteristics

Table 1 compares clinical characteristics between the two groups of subjects. Women with TS were shorter and had greater systolic blood pressure and waist circumference. All but one woman in each group were nonsmokers, and there was no difference between the groups with regard to exercise taken (three vs. four women in TS and control groups, respectively, took no regular exercise). TS women had a median estrogen start age of 14 yr (range, 11–19 yr), with 2 cumulative yr (range, 0–8 cumulative yr) of estrogen deficiency (defined as the number of years after the age of 11 during which estrogen-deficient women were not treated with estrogen). Total cholesterol, CRP, and IL-6 concentrations were greater in the TS women compared with the controls.

With regard to absolute values for MRI and bioelectrical impedance, the only difference between the two groups was the excess of IHCL in the TS women (Table 2). There was, however, a strong correlation between visceral AT and height (r = 0.886; P = 0.019), and height adjustment was therefore performed for all physical parameters of fat distribution. After correction for height differences, women with TS still had an excess of IHCL, but, in addition, they were shown to have greater ratios of total and visceral fat to sc and sc abdominal fat, and a lower ratio of total to internal (all nonsubcutaneous, nonhepatic) fat (Table 2). Height correction had no effect on the comparisons of bioelectrical impedance measures between the two groups.

MRI and bioelectrical impedance. In TS women, there were strong correlations between bioelectrical impedance measures of total and trunk fat mass and MRI measures of total and sc AT on MRI (r > 0.800; P < 0.05 for all; Fig. 1). There was no association, however, between bioelectrical impedance trunk fat mass and MRI internal or visceral AT (Fig. 2). In the control group there were strong associations between bioelectrical impedance total and trunk fat mass and MRI total, sc, visceral, and internal AT and also waist circumference (r > 0.800; P < 0.05 for all; Fig. 1). In particular, and in contrast to the TS group, the relationship between bioelectrical impedance trunk fat mass and MRI visceral and internal AT was very strong in the control group (r > 0.900; P < 0.01; Fig. 2), although there was no association with IHCL.

View larger version (10K): [in this window] [in a new window]   FIG. 1. Comparison of total body fat measurements in TS and normal control women. •, TS; , controls.

View larger version (9K): [in this window] [in a new window]   FIG. 2. Comparison of trunk and visceral fat measurements in TS and normal control women. •, TS; , controls.

Within the control group, MRI visceral AT was strongly correlated with insulin, homoeostasis model insulin resistance index, and CRP concentrations (r > 0.800; P < 0.05 for all). There were no associations between soleus IMCL or IHCL and biochemical markers of obesity.

Previous estrogen, GH, and oxandrolone therapy in TS women. Within the TS cohort there was an association between both estrogen start age and cumulative years of estrogen deficiency and IHCL (r = 0.900; P = 0.037 and r = 0.928; P = 0.008, respectively; Fig. 3). Previous history of GH and oxandrolone therapy or karyotype had no association with physical or biochemical markers of adiposity.

View larger version (6K): [in this window] [in a new window]   FIG. 3. The relationship between IHCL on MR spectroscopy and estrogen-deficient years in women with TS.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Bioelectrical impedance measures of adiposity did not reflect the excess trunk mass in TS detected by MRI, even after height adjustment, although there were good correlations with total and sc AT on MRI. This contrasted with the findings in the control group, in whom visceral and trunk measures of adiposity were well correlated between the two techniques. Our findings suggest that although bioelectrical impedance may be useful to gain an overall impression of total adiposity, fat localization is poor in women with TS. MRI, however, which has been well validated in patient and control groups (8), is a useful method of assessing different fat depots in TS.

Women with TS had not only physical, but also biochemical, markers of excess adiposity, with greater total cholesterol, CRP, and Il-6 concentrations than controls. The excess central adiposity in TS was associated with triglyceride concentrations. There is thus a discrepancy between the finding of increased visceral AT and IHCL on MRI, two of the three measures most associated with insulin resistance (10), in the context of some elevated markers of obesity, but an absence of hyperinsulinemia. A possible explanation for this is that the centrally distributed AT in TS is predominantly sc, but our findings have ruled this out. The excess visceral AT shown here infers an abnormality of adipose function/deposition, although the present study does not explain the mechanism. Another possibility is the existence of an insulin secretory defect in TS, which has been previously suggested (6, 7), and our findings are consistent with this.

Perhaps the most remarkable finding in this study was the association between estrogen deficiency and IHCL. Women with TS are known to have an increased prevalence of abnormal liver function (16, 17), and it has been suggested that this may be related to estrogen deficiency (17, 18). It is possible that estrogen deficiency in childhood years may affect AT lipolysis and/or alter adipocyte differentiation and function, which, in turn, would lead to increased liver fat content later in life (19). Accumulation of ectopic fat, especially in muscle and liver has been implicated in the development of type II diabetes (20). Liver biopsies have revealed a variety of abnormalities, including fatty infiltration, fibrosis, and cirrhosis (21). It is therefore interesting to note the excess of IHCL in women with TS compared with controls in this study and the association with estrogen deficiency in the context of elevated liver enzymes in TS women. The sample size may have been too small to demonstrate a relationship between serum liver function biochemistry and hepatic fat (14).

In conclusion, this study has confirmed that the central obesity seen in women with TS on anthropometric measurements is reflected by excess total, internal, and visceral AT on MRI, best demonstrated by adjustment for height. This fat distribution is associated with established biochemical markers of central adiposity, but not hyperinsulinemia. IHCL are elevated in TS, and this is associated with history of estrogen deficiency, which may explain the beneficial effect of estrogen therapy on liver function. Bioelectrical impedance may be useful to estimate total body fat, but does not reliably localize fat depots in women with TS. Larger studies are now required to explore these relationships.

	Acknowledgments

 
We thank the British Heart Foundation, the Turner Syndrome Support Society, and the Medical Research Council (United Kingdom) for funding the research and Marcelo Salinas-Eytel por inspiratio.

	Footnotes

 
This work was supported by grants from the British Heart Foundation, London, United Kingdom (PG/02/025, to J.E.O.), and the Turner Syndrome Support Society, United Kingdom (to J.E.O.); the Medical Research Council, United Kingdom (to E.L.T., G.H., and J.D.B.); and a grant from the Iranian Ministry of Health and Medical Education (M.J.H.A.).

First Published Online February 15, 2005

Abbreviations: AT, Adipose tissue; BI, bioelectrical impedance; CRP, C-reactive protein; IHCL, intrahepatocellular lipid; IHD, ischemic heart disease; IMCL, intramyocellular lipid; MRI, magnetic resonance imaging; TS, Turner syndrome.

Received September 30, 2004.

Accepted February 7, 2005.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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