| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Diagnostic Radiology and Organ Imaging, Faculty of Medicine, The
Chinese University of Hong Kong, Prince of Wales Hospital, Ngan Shing St.,
Shatin, Hong Kong SAR, China.
2 Department of Surgery, The Chinese University of Hong Kong, Prince of Wales
Hospital, Shatin, Hong Kong SAR, China.
3 Department of Clinical Oncology, Medical Physics Division, The Chinese
University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR,
China.
Received May 6, 2004;
accepted after revision September 9, 2004.
Address correspondence to W. C. W. Chu
(winnie{at}med.cuhk.edu.hk).
Abstract
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
MATERIALS AND METHODS. Eleven pediatric transplant recipients (eight with good graft function, two with chronic hepatitis, and one with acute rejection) and four healthy control subjects were studied with in vivo 31P MR spectroscopy. Ratios of phosphomonoesters (PME) to total phosphorus (TP), phosphodiester (PDE) to TP, nucleotide triphosphates (NTP), inorganic phosphate (Pi), and intracellular acid–base status (pH) were measured. Liver function test (n = 11) and biopsy (n = 3) results were obtained for correlation with spectroscopic findings.
RESULTS. The eight patients with good graft function displayed spectral profiles similar to those of the healthy subjects, and no significant difference in the metabolic ratios of these patients compared with the control subjects was detected. Three patients with abnormal liver function and biopsy-proven hepatic complications showed elevated PME/TP ratios when compared with those of both the control subjects and the group with good graft function.
CONCLUSION. Phosphorus-31 MR spectroscopy is a feasible technique for the noninvasive assessment of host-related complications in pediatric patients after liver transplantation. Our preliminary data suggest that the technique may be integrated with MRI for the investigation of impaired liver function in transplant recipients when neither a biliary complication nor a vascular complication is identified.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The aims of this preliminary study were to document the phosphorous-31 spectra of the liver of pediatric patients in vivo after liver transplantation and to compare the spectra obtained from healthy control subjects, transplanted patients with good graft function, and those with persistently deranged liver function of more than 6 months. Identifiable spectral changes were further correlated with histologic findings from liver biopsy that was performed within 1 month after MR examination.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
All patients were under close follow-up with blood tests to monitor their liver function. Biochemical analysis included alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and albumin levels. When an abnormality in the liver function test results persisted for more than 6 months, a sonographically guided liver biopsy was performed for tissue diagnosis. The time interval between the blood test and MR examination was within 2 weeks. When indicated, liver biopsy was performed within 1 month with respect to MR examination.
In our study group, all 11 children with a liver transplant were clinically asymptomatic at the time of MR examination. Three patients were found to have abnormal liver function test results that persisted for more than 6 months on serial blood tests; therefore, liver biopsy was performed. One child was found to have chronic viral hepatitis (patient 7 in Table 1) in the allograft; she had hepatitis B before the transplantation. Two children were found to have early acute rejection (patients 1 and 4). The remaining eight children with normal liver function had normal serial blood test results and normal findings on sonography examinations in the following 6 months. Among them, one child (patient 3) had an episode of chronic rejection 3 years earlier; however, liver function returned to normal by the time of this study after increment of cyclosporin A therapy. The demographic data of the subjects and transplantation details are summarized in Table 1.
|
The control group consisted of one female and three male volunteers with a mean age of 13 years. They were average-sized children with no history of metabolic or liver disease. No blood tests were performed for this group because they were volunteers. Consents from both the children and their parents were obtained. The control subjects underwent sonography examination of the liver to exclude hepatobiliary abnormalities and diseases before 31P MR spectroscopy was performed.
MRI
MRI and spectroscopy were performed on a 1.5-T whole-body system (Gyroscan
ACS-N, Philips Medical Systems). All children were required to fast overnight
to standardize the MR spectroscopy examinations. Conventional MRI was
performed for all children with a liver transplant using the body coil and
consisted of an axial spin-echo T1-weighted sequence (TR/TE, 550/15) and an
axial fat-saturated turbo spin-echo T2-weighted sequence (1,800/80). MR
cholangiograms were obtained from 3D volume maximum-intensity-projection
images, reformatted from the T2-weighted fat-suppressed inversion recovery
(3,600/600; inversion time, 25 msec) images, to show the morphology of the
biliary tree. MR angiography was performed using a coronal
respiratory-triggered 3D interpolated spoiled gradient-echo sequence (3/1.13;
flip angle, 25°) before and after IV administration of gadodiamide (0.4
mmol/kg body weight [Omniscan, Nycomed]). Images were acquired during both the
arterial phase and portal venous phase to show the best anatomy of hepatic
arterial, portal venous, and vena caval anastomoses. The image acquisitions
were timed on the basis of a 1-mL test bolus of contrast material. Multiplanar
reformatted and 3D reconstruction images obtained with
maximum-intensity-projection and volume-rendering algorithms were
analyzed.
Phosphorus-31 MR Spectroscopy
Conventional axial and coronal MR images obtained with the body coil were
used for voxel positioning in spectroscopic acquisition. A 14-cm
31P transmit–receive surface coil was used for both
excitation and signal acquisition. Phosphorus-31 MR spectra were obtained from
a central region of the transplanted liver that had no major vessels. The
selected volume of interest was positioned at least 2 cm away from the edge of
the liver to minimize the likelihood of the selected volume falling outside
the liver caused by breathing. Spectra were also acquired from the thigh
muscle and were used for the correction of muscle contamination during liver
spectroscopy. With the use of imaging guidance, the coil was positioned over
the thigh quadriceps muscle and subsequently over the liver with the center of
the coil as close as possible to the region of interest. Magnetic field
shimming was performed automatically at the proton (water) resonance frequency
of 63.9 MHz.
The volume of interest used was 40 x 30 x 50 mm3 (60 mL) for the liver and 40 x 60 x 100 mm3 (240 mL) for muscle. Volume selection was performed using a modified image selected in vivo spectroscopy protocol. The surface coil was manually matched and tuned to the operating frequency of phosphorus (25.9 MHz). Both proton decoupling and nuclear Overhauser effect spectral enhancement techniques were used for signal acquisition. Radiofrequency irradiation to enable broadband proton decoupling and nuclear Overhauser effect was generated using the body coil and the specific absorption rate values, which were within safety limits and were calculated automatically from the power levels based on the results of the proton power optimization.
Data were acquired at 512 points with a spectral bandwidth of 1,500 Hz and a TR of 2 sec. For the liver, 256 free induction decay signals were averaged to produce each in vivo spectrum, and 64 signal averages were used for muscle. Subjects were instructed to perform quiet breathing, and respiratory restrainers were placed over the thoracic region to limit chest wall movement when spectroscopy of the liver was performed. The duration of the spectroscopy sequence for the liver and the thigh was 9 min and 2.5 min, respectively. The total examination time for both imaging and spectroscopy examinations, including positioning and tuning of the coil, was approximately 60 min.
Spectral Processing
All spectra were analyzed by a single physicist who was blinded to the
medical history and biochemical and histology findings of the subjects. The
averaged free induction decay signals from the liver were initially filtered
using a convolution difference procedure (50 Hz) and apodization (gaussian
filter with 6-Hz line broadening) using the manufacturer's software to reduce
noise and remove broad signals from less mobile phospholipids; no prior
processing was required for the muscle. The filtered free induction decay
signal was processed in the time domain using an MR user interface (MRUI)
software package and a variable projection (VARPRO) subroutine, running on an
offline workstation (UNIX, The Open Group). The resonance frequencies and line
widths for phosphomonoesters (PMEs), inorganic phosphate (Pi), phosphodiesters
(PDEs), phosphocreatine (PCr), and nucleotide triphosphates (NTPs),
(
-NTP, 
-NTP, and ß-NTP) were selected manually in the
frequency domain as the initial values in the fitting process. No prior
knowledge was imposed on the line width of individual peaks and their
respective resonance frequencies. The zero-order phase correction was
estimated by VARPRO, and the first-order phase was fixed to zero.
Minor contamination of liver spectra from the body wall
musculature—that is, liver PCr / total visible phosphate, which is
typically less than 5%—was corrected by subtraction of the relative
phosphate compound (Pc peak) contribution derived from the muscle
spectra using the following formula to calculate the liver Pc
peakcorrected:
 |
-NTP, -NTP, and
ß-NTP. Calculated positions and intensities of the peaks were then used
to calculate the following peak intensity ratios: PME/PDE, PME/TP, PDE/TP,
Pi/TP, and NTP/TP. Liver intracellular pH was derived from the chemical shift
difference between inorganic phosphate (Pi) and -NTP according to the
supplied calibration curves provided with the MRUI software package.
Statistical Analysis
A nonparametric Kruskal-Wallis test was used to compare MR spectroscopy
metabolite ratios among the three groups: healthy control subjects, transplant
recipients with good graft function, and transplant recipients with abnormal
graft function on the basis of the results from standard biochemical liver
function tests. The Mann-Whitney test was used to compare the metabolic ratios
between cadaveric livers and those from living related donors in children with
normal graft function. Spearman's rank correlation was calculated to determine
the relationship between measured biochemical variables and metabolite ratios.
These tests were performed using the SPSS Chicago version 10.0 (Statistical
Package for the Social Sciences) for Windows (Microsoft). Two-tailed
probability values that were less than 0.05 were considered significant.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
|
There was no significant difference in the mean PME/TP, PDE/TP, and PME/PDE ratios between the control subjects and the eight pediatric transplant recipients with good graft function. No significant difference in those ratios for children with good graft function from either cadaveric or living related donors was found (Mann-Whitney test, p > 0.05). However, the mean PME/TP ratio (0.13 ± 0.02) was significantly elevated in the three children with abnormal liver function compared with the control subjects and group with good graft function (Kruskal-Wallis test, p = 0.044). No statistically significant difference in the mean Pi/TP, NTP/TP, and pH values was found among pediatric transplant recipients with good graft function, those with abnormal liver function, and control subjects (Kruskal-Wallis test, p > 0.05).
Patients with normal results on liver function tests had 31P MR spectral patterns that were similar to those of the healthy control subjects (Fig. 2). The child with biopsy-proven chronic viral hepatitis (patient 7) had markedly elevated ALT and ALP. The 31P MR spectra for patient 7 showed marked elevation in PME and reduction in PDE signals, which gave rise to a significantly elevated PME/PDE ratio, as shown by the bottom spectrum in Figure 2. The two children with acute rejection (patients 1 and 4) also showed elevated PME resonance. Patient 1 had reduced PDE and, hence, a significantly elevated PME/PDE ratio. Patient 4, however, had unchanged PDE resonance, which gave rise to a PME/PDE ratio that was not significantly increased compared with that for the group with normal liver function.
|
There was a significant correlation between the PME/TP ratio and serum bilirubin (Spearman's rho, 0.74; p < 0.01) in the patient group. However, there was no significant correlation between serum ALP or ALT activity and the other 31P MR spectroscopy metabolite ratios.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Our results are in agreement with those of a previous adult study by Taylor-Robinson and colleagues [11] that liver transplantation patients with good graft function displayed no spectral abnormalities and that their spectra were similar to those of healthy volunteers. In our study, the patient with chronic viral hepatitis had a significantly elevated PME/PDE ratio. This finding can be explained by the increase in turnover of cell membrane synthesis and degradation products in patients with hepatitis. Our findings are in agreement with the previous study of in vivo 31P MR spectra in patients with hepatitis C virus–related liver disease [12]. In that study, there was statistically significant difference in the PME/PDE ratios among patients with mild hepatitis, moderate hepatitis, and cirrhosis.
In the study of Taylor-Robinson et al. [11], adult liver transplant recipients with chronic ductopenia and graft failure showed a significantly elevated PME/NTP ratio. In that study, the mean PME/NTP ratio in healthy adult volunteers was 0.77 and that in adults with a diseased transplant liver was 1.11 [11], suggesting an elevation of PME. The mean value of PME/TP in our cohort of healthy control subjects (0.08) was in good agreement with the reported values for normal adult livers (mean, 0.10; range, 0.08–0.11) [13]. However, for the children with a diseased transplant liver, the PME/TP ratio was much higher (0.13), and that increase in the PME/TP ratio may be attributed to an elevation of PME [11]. Despite a small series, the two patients with acute rejection in our study also showed significantly raised PME/TP (0.11 and 0.13, respectively) when compared with the nondiseased and control groups.
The increase in PME resonance can be explained by rapid cell turnover in hepatic graft failure contributing to an increase in cell membrane precursors [11]. In the child (patient 3) with a history of chronic rejection who recovered with therapy, liver function test results were normal when MR spectroscopy was performed. For patient 3, the MR spectroscopy result displayed no spectral abnormalities; instead MR spectroscopy showed a pattern similar to those from healthy control subjects.
Our results seem to support the previously suggested hypothesis that chronic rejection may be reversible consequent to antirejection chemotherapy [14] and might be reflected by a normal MR spectroscopy examination. This finding suggests a role for serial in vivo MR spectroscopy examinations in monitoring the response of chronic rejection to immunosuppressive agents. In our study, one major limitation was the small number of transplant recipients who had abnormal graft function (rejection or hepatitis). This was an intrinsic problem because only a few children receive a liver transplant each year in our locality. The small sample size made it difficult to draw definitive conclusions at the present stage of study. Nevertheless, a multicenter longitudinal study would allow better assessment of the sensitivity and specificity shown in our study.
Phosphorus-31 MR spectroscopy can provide information about hepatic metabolism from a large volume within the liver noninvasively, and the procedure can be performed within 30 min. However, as shown by other studies, the change in PME and PDE metabolites was observed in a number of other hepatic diseases [8–12, 15]. Therefore, these metabolic changes are sensitive but not specific to liver transplantation issues. Phosphorus-31 MR spectroscopy is therefore unlikely to be useful in making a specific clinical diagnosis in patients with deranged liver function, and it is unlikely that the technique could replace liver biopsy in establishing histologic diagnosis.
So what is the role of MR spectroscopy then? As a noninvasive tool to assess the liver function, 31P MR spectroscopy can be performed as a screening tool for early detection of liver parenchymal injury. Phosphorus-31 MR spectroscopy also has a potential advantage over liver function tests by giving additional information about the energy status of the liver. Previous studies have shown improvement in hepatic energy after biliary decompression in patients with obstructive jaundice [13]. In pediatric liver transplant recipients who have persistent graft function disorder, MR spectroscopy can be used to assess in vivo hepatic graft energy metabolism and phospholipid biochemistry and to monitor treatment response, hence obviating repeated traumatic liver biopsies after the first histologic diagnosis has been established. Taylor-Robinson et al. [11] have shown the potential role of 31P MR spectroscopy in adult hepatic transplant patients by identifying patients with chronic ductopenia and graft rejection with a significantly elevated PME resonance.
Although 31P MR spectroscopy is a well-established technique, the fact that it is not available on most clinical scanners and its relatively long scanning time might be limiting factors for its wider application. To the best of our knowledge, our study is the first attempt to use 31P MR spectroscopy in the assessment of pediatric liver transplant recipients. All our patients managed to complete the spectroscopic examination, which took approximately 30 min on average, and all spectra acquired in this study were successful despite potential shimming difficulties as a result of liver excursion. A previous study showed that the diaphragmatic excursion in healthy adults on maximal inspiration and expiration in the supine position is approximately 10 cm [16]. In our study, the likelihood of the voxel border falling outside the edge of the liver was minimized by placing the region of interest in the central region of the liver—at least 2 cm away from the liver margin. In addition, our subjects were instructed to perform quiet breathing, and respiratory restrainers were placed over their thoracic region to minimize their chest wall motion. The estimated liver excursion in our subjects was 1–2 cm.
Our results suggest that 31P MR spectroscopy has a potential role in the assessment of host-related nonanatomic complications in pediatric patients after liver transplantation. It can be implemented as part of the MRI study for investigation of impaired liver function in transplant recipients when neither a biliary complication nor a vascular complication is identified. Phosphorus-31 MR spectroscopy as a baseline measure of liver function in conjunction with the first liver biopsy may be useful for long-term monitoring of graft function.
Acknowledgments
We thank E. Wong for statistical assistance in the preparation of the
manuscript.
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
