Radiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online before print October 11, 2001, 10.1148/radiol.2213010106
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2213010106v1
221/3/740    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cho, S. G.
Right arrow Articles by Suh, C. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cho, S. G.
Right arrow Articles by Suh, C. H.
(Radiology. 2001;221:740-746.)
© RSNA, 2001

Gastrointestinal Imaging

Chronic Hepatitis: In Vivo Proton MR Spectroscopic Evaluation of the Liver and Correlation with Histopathologic Findings1

Soon Gu Cho, MD, Mi Young Kim, MD, Hyung Jin Kim, MD, Young Soo Kim, MD, Won Choi, MD, Seok Hwan Shin, MD, Ki Cheon Hong, MD, Young-Bae Kim, MD, Jung Hee Lee, PhD and Chang Hae Suh, MD

1 From the Departments of Radiology (S.G.C., M.Y.K., H.J.K., C.H.S.), Internal Medicine (Y.S.K., W.C.), Surgery (S.H.S., K.C.H.), and Pathology (Y.B.K.), Inha University College of Medicine, 7-206 3rd St, Shinheung-Dong, Choong-Gu, Inchon 400-711, Korea; and Nuclear Magnetic Resonance Laboratory, Asan Institute for Life Sciences, Seoul, Korea (J.H.L.). From the 1999 RSNA scientific assembly. Received December 4, 2000; revision requested January 24, 2001; revision received April 16; accepted May 14. Supported by Inha University research grant INHA-21074. Address correspondence to S.G.C. (e-mail: soongucho@netsgo.com).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To correlate the in vivo hydrogen 1 (1H) magnetic resonance (MR) spectroscopic features of the chronic hepatitis–involved liver with the histopathologic stages of fibrosis.

MATERIALS AND METHODS: Seventy-five patients with chronic hepatitis were examined with 1H MR spectroscopy, which was performed in the right hepatic lobe. The peak areas of glutamine and glutamate complex (Glx), phosphomonoesters (PME), glycogen and glucose complex (Glyu), and lipid were measured on the liver spectra. The histopathologic features were correlated with the in vivo 1H MR spectroscopic findings at each stage of chronic hepatitis. Fifteen healthy volunteers also were included as a control group.

RESULTS: 1H MR spectroscopy depicted Glx, PME, Glyu, and lipid in all livers. In the normal livers, the calculated mean (± SD) relative metabolite-to-lipid ratios of Glx, PME, and Glyu were 0.14 ± 0.04, 0.03 ± 0.01, and 0.21 ± 0.04, respectively. The mean value of each metabolite-to-lipid ratio was significantly different between all stages of chronic hepatitis, and with the exception of the mean ratio at the interval between stages 0 and 1 (P > .05), the mean value increased significantly with increasing stage (P < .05). A pronounced peak was demonstrated at 3.9–4.1 ppm at 1H MR spectroscopy of all stages of chronic hepatitis except stage 0.

CONCLUSION: The increased Glx, PME, and Glyu levels relative to the lipid content with chronic hepatitis indicated the severity of fibrosis and thus were concordant with the histopathologic stages. In vivo 1H MR spectroscopy might be a substitute for liver biopsy in the diagnosis and staging of chronic hepatitis.

Index terms: Hepatitis, 761.291 • Liver, cirrhosis, 761.794 • Liver, diseases, 761.291, 761.794 • Magnetic resonance (MR), spectroscopy, 761.12145


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Various chronic liver diseases, regardless of their causes, may lead to liver cirrhosis in the late stages, and once cirrhosis develops, hepatic fibrosis proceeds slowly and gradually toward decompensated cirrhosis with a risk of several complications (1–3). With liver cirrhosis, the risk of developing hepatocellular carcinoma is elevated relative to this risk with chronic hepatitis. The cumulative rates of hepatocellular carcinoma development in patients with a clinical diagnosis of chronic B or C viral hepatitis are 4.0%, 3.4%–7.0%, 10.5%–14.0%, and 22.4% at 3, 5, 10, and 15 years after diagnosis, respectively (3,4). The results of one study (5) demonstrated a higher 5-year probability of hepatocellular carcinoma occurrence: approximately 25% of nontreated Asian patients with compensated cirrhosis type C. These results suggest that improved surveillance schedules are needed for the early detection of hepatocellular carcinoma in patients with liver cirrhosis. Therefore, accurate evaluation of the current status of the liver is essential to treating patients with chronic hepatitis.

Indirect evaluation parameters, such as clinical symptoms and signs (6,7); radiologic features, including abdominal ultrasonographic (US) (8–12), computed tomographic (CT) (13,14), and magnetic resonance (MR) imaging findings (15,16); and biochemical serum markers (7), are being used widely to assess the status of chronic liver disease, including liver cirrhosis. However, to our knowledge, no single noninvasive method has proved to be sufficient for diagnosing the correct stages of chronic hepatitis. The most accurate and reliable diagnostic method for staging chronic hepatitis is liver biopsy. Histopathologic analysis of chronic hepatitis reveals progressive necroinflammation of piecemeal necrosis associated with collagenization of the spaces of Disse and deposition of basement membrane material, a process termed capillarization (17).

According to the Ludwig classification system (18), there are five histopathologic stages of chronic hepatitis. These stages correspond to the degree of fibrosis subsequent to necroinflammatory insults. However, liver biopsy has limitations, such as a high false-negative rate—up to 24% (19)—high hospitalization costs, physical and mental discomfort for patients, and a mortality rate of up to 0.3% (20). Therefore, the need for a noninvasive diagnostic method for the precise staging of chronic hepatitis and the early detection of liver cirrhosis is increasing.

MR spectroscopy enables the noninvasive measurement of biochemical information in vivo (21). In many previously published studies (22–26), it has been reported that liver cirrhosis can be detected with phosphorous 31 MR spectroscopy. Study results have demonstrated that the normal liver and liver cirrhosis have different hydrogen 1 (1H) MR spectroscopic features (27). To our knowledge, no studies involving the correlation between in vivo 1H MR spectroscopic findings and histopathologic stages of chronic hepatitis have been performed to date.

The purpose of this study was to correlate the in vivo 1H MR spectroscopic features of chronic hepatitis–involved livers in humans with the histopathologic stages of fibrosis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Classification of Disease Severity
Eighty-three consecutive patients with chronic B or C viral hepatitis underwent 1H MR spectroscopy at Inha University College of Medicine, Inchon, Korea, from March 1998 to September 1999. Seventy-five (16 women, 59 men; mean age ± SD, 35 years ± 11; age range, 18–64 years) of these patients underwent liver biopsy with US guidance. The remaining patients did not undergo biopsy because of their poor clinical condition: five had a large amount of ascites, and three had a tendency for bleeding. Of the 75 patients, 10 had stage 1 chronic hepatitis; 25, stage 2; 24, stage 3; and 16, stage 4, according to the Ludwig classification system (5). All of these 75 patients were included in the study. Fifteen healthy volunteers (five women, 10 men; mean age ± SD, 29 years ± 2; age range, 28–32 years), who had no previous medical history or current liver morbidity (stage 0), also were included as a control group. In two of these control subjects, cholecystectomy was performed for acute cholecystitis and small liver specimens were obtained with informed consent.

All subjects underwent serologic testing for viral markers; liver function testing, including serum cholesterol, total protein, albumin, total and direct bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase level measurements; and US. All of the healthy volunteers had normal liver function test results. Of the 75 patients with chronic viral hepatitis, 45 had results that were positive for hepatitis B surface antigen and 30 had results that were positive for anti–hepatitis C virus antibodies at serologic testing. All 75 patients had elevated serum aspartate aminotransferase and alanine aminotransferase levels of at least 1.5 times the upper limit of normal of more than 6 months duration. The intervals between all examinations were less than 2 days, and 1H MR spectroscopy was performed 1 or 2 days before the clinical and histopathologic examinations.

Informed consent for 1H MR spectroscopy was obtained from all subjects, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval from the human research committee of Inha University College of Medicine.

MR Spectroscopy
All MR spectroscopic examinations were performed with a 1.5-T whole-body system (MRI/MRS, version 5.5; GE Medical Systems, Milwaukee, Wis) equipped with actively shielded gradients. For all spectra, a stimulated echo acquisition method, or STEAM, localization sequence, in conjunction with a three-pulse chemical shift selective, or CHESS, sequence to suppress the water signal, was used with the following acquisition parameters: 3,000/30 (repetition time msec/echo time msec), 13.7-msec mixing time, 2,500-Hz sweep width, 2,048 data points, and 128 images.

In all patients, a localization voxel of 8 cm3 was placed in the right hepatic lobe at spectroscopy, with care taken to avoid the large intrahepatic vessels. To diminish tissue contamination from the adjacent structures and to maintain proper localization, all voxels were positioned by an individual (S.G.C.) experienced in abdominal radiology. Restricting the edge of voxels to positions more than 10 mm from the inner margin of the abdominal wall helped to prevent the spectrum from being contaminated by strong signals originating from the subcutaneous fat, which can mask resonance from hepatic parenchymal fat. STEAM spectra were acquired in all subjects in the supine position. The subjects breathed in quiet regular respiration without respiratory interruption during signal acquisition.

Quantification of Metabolite Ratios
Postprocessing was carried out on a workstation (SUN SPARC 20; Sun Microsystems, Mountain View, Calif) by using computer software (Spectral Analysis/General Electric; GE Medical Systems) incorporated with low-frequency filtering of residual water signal removal, apodization by means of 0.5 Hz of exponential line broadening, zero filling of 8 K, Fourier transformation, and Lorentzian-to-Gaussian transformation, according to the method described by Kreis et al (28). Two authors (S.G.C., J.H.L.) analyzed the 1H MR spectroscopic signal intensities of various metabolites on the basis of findings demonstrated in the normal liver of humans in studies conducted by Barany et al (29,30), in which the peak metabolite levels were fitted by the Lorentzian line shape at known frequencies of glutamine and glutamate complex (Glx) of 2.10–2.49 ppm, phosphomonoesters (PME) of 3.00–3.21 ppm, and glycogen and glucose complex (Glyu) of 3.35–3.90 ppm. The peak lipid frequency was integrated at 1.22–1.62 ppm.

MR Spectrum Analyses and Statistical Methods
We obtained the relative metabolite-to-lipid ratios by dividing the peak areas of Glx, PME, and Glyu by the peak area of lipid. The means (± SD) of each metabolite-to-lipid ratio were calculated at various stages of chronic hepatitis. One-way analysis of variance was performed to compare the mean metabolite-to-lipid ratios at various stages of chronic hepatitis. Multiple comparisons of the metabolite-to-lipid ratios at various stages of chronic hepatitis were performed with the Scheffé method (31). A P value of less than .05 was considered to indicate a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
In all cases, we successfully obtained 1H MR spectra of the liver. These spectra exactly revealed the peak metabolite ratios at the expected ranges of frequency, as observed in previous studies (29,30,32). Overall, the largest peak at 1H MR spectroscopy occurred at 1.22–1.62 ppm, where the chemical shift of the lipid occurs (Figs 1–4). In normal liver, the calculated mean (± SD) relative metabolite-to-lipid ratios of Glx, PME, and Glyu were 0.14 ± 0.04, 0.03 ± 0.01, and 0.21 ± 0.04, respectively (Table 1).



View larger version (161K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1a. Typical (a) histopathologic features of and (b) 1H MR spectrum from liver of healthy volunteer without previous medical history or current liver morbidity (stage 0). (a) Photomicrograph shows normal architecture of hepatic lobule: Normal contours of central vein (small arrows) and porta hepatis (large arrows) are seen. (Masson trichrome stain; original magnification, x100.) (b) 1H MR spectrum shows largest peak from lipid and minor peaks from various other metabolites. No peak is demonstrated at the frequency of 3.9-4.1 ppm. Glu + Glm = glutamine and glutamate complex, Glyc + Gluc = glycogen and glucose complex.

 


View larger version (21K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1b. Typical (a) histopathologic features of and (b) 1H MR spectrum from liver of healthy volunteer without previous medical history or current liver morbidity (stage 0). (a) Photomicrograph shows normal architecture of hepatic lobule: Normal contours of central vein (small arrows) and porta hepatis (large arrows) are seen. (Masson trichrome stain; original magnification, x100.) (b) 1H MR spectrum shows largest peak from lipid and minor peaks from various other metabolites. No peak is demonstrated at the frequency of 3.9-4.1 ppm. Glu + Glm = glutamine and glutamate complex, Glyc + Gluc = glycogen and glucose complex.

 


View larger version (143K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2a. (a) Histopathologic features of and (b) 1H MR spectrum from liver of patient with stage 2 chronic hepatitis. (a) Photomicrograph shows fibrosis of portal triad (small arrows), with mild periportal fibrotic infiltration (large arrows). (Masson trichrome stain; original magnification, x100.) (b) 1H MR spectrum shows increases in sizes of various metabolite peaks compared with increases in size of lipid peak. A peak from an unknown source is demonstrated at frequency of 3.9-4.1 ppm. Glu + Glm = glutamine and glutamate complex, Glyc + Gluc = glycogen and glucose complex.

 


View larger version (26K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2b. (a) Histopathologic features of and (b) 1H MR spectrum from liver of patient with stage 2 chronic hepatitis. (a) Photomicrograph shows fibrosis of portal triad (small arrows), with mild periportal fibrotic infiltration (large arrows). (Masson trichrome stain; original magnification, x100.) (b) 1H MR spectrum shows increases in sizes of various metabolite peaks compared with increases in size of lipid peak. A peak from an unknown source is demonstrated at frequency of 3.9-4.1 ppm. Glu + Glm = glutamine and glutamate complex, Glyc + Gluc = glycogen and glucose complex.

 


View larger version (163K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3a. (a) Histopathologic features of and (b) 1H MR spectrum from liver of patient with stage 3 (septal fibrosis, early cirrhosis) chronic hepatitis. (a) Photomicrograph shows septal fibrosis (arrows) between adjacent portal triads. (Masson trichrome stain; original magnification, x100.) (b) 1H MR spectrum shows greater increase in size of various metabolite peaks compared with increased size of these peaks with stage 2 chronic hepatitis (Figure 2). The increase in peak from an unknown source at 3.9-4.1 ppm also is greater than that with stage 2 chronic hepatitis. Glu+Glm = glutamine and glutamate complex, Glyc+Gluc = glycogen and glucose complex.

 


View larger version (28K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3b. (a) Histopathologic features of and (b) 1H MR spectrum from liver of patient with stage 3 (septal fibrosis, early cirrhosis) chronic hepatitis. (a) Photomicrograph shows septal fibrosis (arrows) between adjacent portal triads. (Masson trichrome stain; original magnification, x100.) (b) 1H MR spectrum shows greater increase in size of various metabolite peaks compared with increased size of these peaks with stage 2 chronic hepatitis (Figure 2). The increase in peak from an unknown source at 3.9-4.1 ppm also is greater than that with stage 2 chronic hepatitis. Glu+Glm = glutamine and glutamate complex, Glyc+Gluc = glycogen and glucose complex.

 


View larger version (137K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4a. (a) Histopathologic features of and (b) 1H MR spectrum from liver of patient with stage 4 (liver cirrhosis) chronic hepatitis. (a) Photomicrograph shows massive fibrosis (arrows). (Masson trichrome stain; original magnification, x100.) (b) 1H MR spectrum shows marked decrease in size of lipid peak compared with change in size of peak of other metabolites. Glu+Glm = glutamine and glutamate complex, Glyc+Gluc = glycogen and glucose complex.

 


View larger version (22K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4b. (a) Histopathologic features of and (b) 1H MR spectrum from liver of patient with stage 4 (liver cirrhosis) chronic hepatitis. (a) Photomicrograph shows massive fibrosis (arrows). (Masson trichrome stain; original magnification, x100.) (b) 1H MR spectrum shows marked decrease in size of lipid peak compared with change in size of peak of other metabolites. Glu+Glm = glutamine and glutamate complex, Glyc+Gluc = glycogen and glucose complex.

 

View this table:
[in this window]
[in a new window]

  		TABLE 1. Metabolite-to-Lipid Ratios at 1H MR Spectroscopy of Various Stages of Chronic Hepatitis

 
The most significant change with chronic hepatitis that was demonstrated at 1H MR spectroscopy was a decrease in the lipid peak compared with the lipid level in the normal liver (Figs 1 –4). As the stage of chronic hepatitis became higher—that is, as the degree of fibrosis increased—all of the metabolite-to-lipid ratios increased (Table 1). The relative Glx-to-lipid ratios at stages 0, 1, 2, 3, and 4 of chronic hepatitis were 0.14 ± 0.04, 0.16 ± 0.06, 0.26 ± 0.04, 0.40 ± 0.06, and 0.61 ± 0.10, respectively. The corresponding relative PME-to-lipid ratios were 0.03 ± 0.01, 0.07 ± 0.03, 0.14 ± 0.03, 0.23 ± 0.04, and 0.40 ± 0.06, respectively. Scheffé test results revealed that the mean ratios of Glx to lipid and PME to lipid were significantly different between all stages of chronic hepatitis (P < .05) except stages 0 and 1 (P > .05) (Table 1, Fig 5a, 5b). The Glyu-to-lipid ratios at stages 0, 1, 2, 3, and 4 of chronic hepatitis were 0.21 ± 0.04, 0.21 ± 0.04, 0.30 ± 0.05, 0.43 ± 0.04, and 0.66 ± 0.08, respectively. The results of Scheffé tests to compare these ratios also revealed a significant difference between all stages of chronic hepatitis (P < .05) except stages 0 and 1 (P > .05) (Fig 5c).



View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5a. Graphs illustrate ratios of (a) Glx to lipid, (b) PME to lipid, and (c) Glyu to lipid on 1H MR spectra at various stages of chronic hepatitis. The graphs show distribution of each variable ({square}; may refer to more than one data point), the mean ({blacksquare}), and the SD (error bars) at each stage of chronic hepatitis. The numbers of patients with each stage of chronic hepatitis are cited above the stages.

 


View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5b. Graphs illustrate ratios of (a) Glx to lipid, (b) PME to lipid, and (c) Glyu to lipid on 1H MR spectra at various stages of chronic hepatitis. The graphs show distribution of each variable ({square}; may refer to more than one data point), the mean ({blacksquare}), and the SD (error bars) at each stage of chronic hepatitis. The numbers of patients with each stage of chronic hepatitis are cited above the stages.

 


View larger version (19K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5c. Graphs illustrate ratios of (a) Glx to lipid, (b) PME to lipid, and (c) Glyu to lipid on 1H MR spectra at various stages of chronic hepatitis. The graphs show distribution of each variable ({square}; may refer to more than one data point), the mean ({blacksquare}), and the SD (error bars) at each stage of chronic hepatitis. The numbers of patients with each stage of chronic hepatitis are cited above the stages.

 
There was a pronounced peak at 3.9–4.1 ppm from an unknown source at 1H MR spectroscopy at stages 1–4 of chronic hepatitis (Figs 2–4). This peak was not demonstrated at stage 0 and was detected during stage 1 as a small peak. The mean unknown source–to-lipid ratios were significantly different at stages 1, 2, and 3 (P < .05). However, these ratios were not significantly different between stages 3 and 4 (P > .05) (Table 2).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Results of 3.9-4.1-ppm Peak-to-Lipid Ratios at 1H MR Spectroscopy of Various Stages of Chronic Hepatitis

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
Attempts to diagnose various diseases with MR spectroscopy began in the middle 1980s (33–35). However, the use of MR spectroscopy in the abdominal organs has lagged behind that in the central nervous system because of artifacts caused by physiologic motion such as respiratory movement and intestinal peristalsis. The major problem in obtaining signals from moving organs is the introduction of noise into the spectroscopic signals. Various methods of reducing the noise introduced by physiologic movement, such as respiratory holding and placing patients in the prone position during signal acquisition, have been used in previous studies (30,36). In our study, 1H MR spectra were successfully obtained from the liver in all subjects without respiratory interruption. We used a relatively long repetition time, so patients were able to adapt their respiratory cycle to the repetition time interval, and, thus, the time of signal acquisition occurred approximately at maximal inspiration or expiration.

Other investigators (29,30,32) have reported the frequencies of chemical shift from the metabolites in the liver. Barany et al (29,30) reported the peaks of various metabolites on 1H MR spectra in the normal liver of humans. These metabolites were glutamate at 2.36 ppm; glutamine at 2.49 ppm; phosphocreatine and creatine at 3.00 ppm; choline at 3.09 ppm; phosphocholine, {alpha}-glycerophosphorylcholine, and taurine at 3.21 ppm; carnitine at both 3.28 ppm and 3.48 ppm; and water signal at 4.77 ppm as a standard signal. According to Bell et al (32), the signals from glycogen were demonstrated in a wide range, 3.2–4.0 ppm, on 1H MR spectra in the liver of humans. These frequencies correlated well with our results, and various metabolites were expressed as distinguishable peaks on 1H MR spectra.

In the Ludwig classification system, chronic hepatitis is classified into five histopathologic stages on the basis of the severity of fibrosis: Stage 0 indicates a normal histopathologic architecture of the liver; stages 1 and 2, portal and periportal fibrosis without architectural distortion; stage 3, septal fibrosis with architectural distortion (including early-stage cirrhosis); and stage 4, obvious cirrhosis with bridging fibrosis and nodular regeneration (18). The relative signal intensity of lipid at 1H MR spectroscopy is substantially lower in the cirrhotic liver than in the normal liver, according to Stanka et al (27). In our study, we had similar results, which demonstrated that all of the relative ratios of Glx to lipid, PME to lipid, and Glyu to lipid increased as the stage of chronic hepatitis became higher. This was one of the most prominent changes in 1H MR spectroscopic features as the stage of chronic hepatitis changed.

There are several explanations for these results. First, it may be that the amount of lipid in the liver parenchyma actually decreases as the stage of disease becomes higher. However, the lipid peak also decreases in cases of parenchymal fatty infiltration, and this may imply that the relative signal intensity of the lipid peak depends not only on the absolute amount of parenchymal lipid content but also on the influences of unknown compounds, such as metallic substances that accumulate in the liver parenchyma at T2 shortening of lipid.

Second, it may be that the relative amounts of other metabolites, such as Glx, PME, and Glyu, increase as the stage of chronic hepatitis becomes higher. This phenomenon is possible when the affected liver shows stromal collapse and fibrosis of many portal triads (37) with distortion of lobular architectures, including hemodynamic derangement, to result in disturbed excretion of the intracellular metabolites. In addition, various metabolic changes can occur with chronic hepatitis. However, chronic hepatitis is a diffuse parenchymal disease that results in decreased liver function by destroying the hepatocytes. Therefore, there is little chance for the actual amount of various metabolites to increase with chronic hepatitis.

Third, 1H MR spectroscopic features may be directly influenced by the increase in fibrotic tissue as the stage of chronic hepatitis becomes higher. This may be an unknown effect of increased collagen fibers in the liver parenchyma that modulates 1H MR spectroscopic expression.

Fourth, increased parenchymal accumulation of metallic substances, such as iron or copper, may cause local magnetic field inhomogeneity. It has been reported that iron (38,39) or copper (39,40) can accumulate with chronic hepatitis and liver cirrhosis. To our knowledge, so far, there has been no study on the effect of metallic substances on the expression of local magnetic field inhomogeneity. We think that the decreasing relative signal intensity of lipid with chronic hepatitis might be a result of the combined effect of the various described phenomena.

The results of our study indicate that area ratios of Glx to lipid, PME to lipid, and Glyu to lipid were significantly different between various stages of chronic hepatitis. This means that one might be able to distinguish various stages of chronic hepatitis by analyzing changes in these metabolic ratios. There was no significant difference in the metabolic ratios between stages 0 and 1. This may imply that chronic hepatitis in its early stage cannot be distinguished from normal liver. Our results correlated well with the results of Stanka et al (27), who reported that the peak levels of Glyu with liver cirrhosis were significantly different from those in the normal liver. However, these results were not correlated with the other results in that study—namely, that there were no statistically significant differences in peak levels of Glx between the normal and cirrhotic liver.

We observed a peak at 3.9–4.1 ppm from an unknown source at 1H MR spectroscopy of stages 1–4 of chronic hepatitis in the current series. This peak was not observed in the spectra at stage 0. The mean unknown source–to-lipid ratios were significantly different from each other at stages 1, 2, and 3. However, the ratios were not significantly different between stages 3 and 4 (Table 2). These results suggest that stage 0 of chronic hepatitis can be distinguished from the other stages by the absence of the peak from the unknown source. The unknown peak at 3.9–4.1 ppm is thought to be produced by double or triple bonds of hydrocarbon groups in the collagen fibers included in increased fibrotic tissue, and this peak from the unknown source could be one of the standards for evaluating the early stages of chronic hepatitis.

There were limitations in this study. Respiratory movement can prevent adequate signal acquisition owing to the inconstant position of a voxel. However, chronic hepatitis is a diffuse parenchymal disease, and we carefully located the voxel within the liver. Thus, the minimal change in the location of a voxel was thought to be acceptable when obtaining MR spectra of the liver with chronic hepatitis and therefore was not a serious problem in this study. Overlapping the peaks made it difficult to discriminate all metabolite peaks at 1H MR spectroscopy of the liver. This is thought to be a common limitation of current commercial machines with low magnetic field strength because of their low discrimination power, which may be improved by using high-field-strength machines. 1H MR spectroscopic analysis of only the known metabolites of the liver was performed in this study. However, several peaks from an unknown source also were demonstrated on the spectrum. Thus, further investigations with metabolic extracts with use of a solution nuclear MR spectroscopic method are needed to disclose the peaks of unknown sources.

We did not try to determine the cutoff value for each metabolite-to-lipid ratio or to assess other criteria to sensitively predict each stage of chronic hepatitis because of the small sample size. Although the results of this study show that the mean metabolite-to-lipid ratios were significantly different between various stages of chronic hepatitis, there was an overlap in the distribution of ratios between various stages. This means that a misclassification should have existed. Further studies with larger sample sizes are needed to determine more specific criteria to predict each stage of chronic hepatitis.

In summary, the results of this study show that Glx-to-lipid, PME-to-lipid, and Glyu-to-lipid ratios increased as the stage of chronic hepatitis became higher. A peak from an unknown source was observed at 3.9–4.1 ppm with chronic hepatitis; this finding also had a positive correlation with the stages of chronic hepatitis. We conclude that the normal liver can be distinguished from different stages of chronic hepatitis at in vivo 1H MR spectroscopy of the liver. In this study, the increased contents of Glx, PME, and Glyu relative to the lipid content with chronic hepatitis indicated the severity of fibrosis and thus were concordant with the histopathologic stages. In vivo 1H MR spectroscopy is a potential substitute for liver biopsy in the diagnosis and staging of chronic hepatitis.


   FOOTNOTES
 
Abbreviations: Glx = glutamine and glutamate complex, Glyu = glycogen and glucose complex, PME = phosphomonoesters

Author contributions: Guarantor of integrity of entire study, S.G.C.; study concepts and design, S.G.C.; literature research, S.G.C., W.C., M.Y.K.; clinical studies, Y.S.K., W.C., S.H.S., K.C.H.; experimental studies, Y.B.K.; data acquisition and analysis/interpretation, S.G.C.; statistical analysis, S.G.C.; manuscript preparation, S.G.C.; manuscript definition of intellectual content, S.G.C., C.H.S.; manuscript editing, M.Y.K.; manuscript revision/review, H.J.K., J.H.L., S.G.C.; manuscript final version approval, S.G.C., C.H.S.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 

  1. Chevallier M, Guerret S, Chossegros P, Gerard F, Grimaus JA. A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies. Hepatology 1994; 20:349-355.
  2. Saunders JB, Walters JRF, David P, Paton A. A 20-year prospective study of cirrhosis. Br Med J 1981; 282:263-266.
  3. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997; 112:463-472.
  4. Ikeda K, Saitoh A, Suzuki Y, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol 1998; 28:930-938.
  5. Nishiguchi S, Kuroki T, Nakatani S, et al. Randomized trial of effects of interferon alfa on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995; 346:1051-1055.
  6. Espinoza P, Ducot B, Pelletier G, et al. Interobserver agreement in the physical diagnosis of alcoholic liver disease. Dig Dis Sci 1987; 32:244-247.
  7. Di Bisceglie AM, Hoofnagle JH. Chronic viral hepatitis. In: Zakim D, Boyer TD, eds. Hepatology: a textbook of liver disease. 3rd ed. Philadelphia, Pa: Saunders, 1996; 1299-1301.
  8. Ajello A, Freni MA, Spadaro A, et al. Ten year follow-up of patients with chronic hepatitis C treated with interferon. Hepatogastroenterology 1999; 46:2447-2450.
  9. Di Lelio A, Cestari C, Lomazzi A, Beretta L. Cirrhosis: diagnosis with sonographic study of the liver surface. Radiology 1989; 172:389-392.
  10. Goyal AK, Pokharna DS, Sharma SK. Ultrasonic diagnosis of cirrhosis: reference to quantitative measurements of hepatic dimensions. Gastrointest Radiol 1990; 15:32-34.
  11. Ferral H, Male R, Cardiel M, Munoz L, Ferrari FQ. Cirrhosis: diagnosis by liver surface analysis with high-frequency ultrasound. Gastrointest Radiol 1992; 17:74-78.
  12. Hess CF, Schmiedl U, Koelbel G, Knecht R, Kurtz B. Diagnosis of liver cirrhosis with US: receiver operating characteristic analysis of multidimensional caudate lobe indexes. Radiology 1989; 171:349-351.
  13. Torres WE, Whitmire LF, Gedgaudas-McClees K, Bernardino ME. Computed tomography of hepatic morphologic changes in cirrhosis of the liver. J Comput Assist Tomogr 1986; 11:47-50.
  14. Harbin WP, Robert NJ, Ferrucci JT, Jr. Diagnosis of cirrhosis based on regional changes in hepatic morphology: a radiological and pathological analysis. Radiology 1980; 135:273-283.
  15. Mitchell DG, Lovett KE, Hann HWL, Ehrlich S, Palazzo J, Rubin R. Cirrhosis: multiobserver analysis of hepatic MR imaging findings in a heterogeneous population. J Magn Reson Imaging 1993; 3:313-321.
  16. Goldberg HI, Moss AA, Stark DD, McKerrow J, Engelstad B, Brito A. Hepatic cirrhosis: magnetic resonance imaging. Radiology 1984; 153:737-739.
  17. Ishak KG, Markin RS. Liver. In: Damjanov I, eds. Linder J Anderson’s pathology. 10th ed. St Louis, Mo: Mosby–Year Book, 1996; 1800-1801.
  18. Batts KP, Ludwig J. Chronic hepatitis: an update on terminology and reporting. Am J Surg Pathol 1995; 19:1409-1417.
  19. Nord HJ. Biopsy diagnosis of cirrhosis: blind percutaneous versus guided direct vision techniques: a review. Gastrointest Endosc 1982; 28:102-104.
  20. Reddy KR, Schiff ER. Complications of liver biopsy. In: Taylor MB, Gollan JL, Steer ML, Wolfe MM, eds. Gastrointestinal emergencies. 2nd ed. Baltimore, Md: Williams & Wilkins, 1997; 959-968.
  21. Henriksen O. MR spectroscopy in clinical research. Acta Radiol 1994; 35:96-116.
  22. Kiyono K, Shibata A, Sone S, et al. Relationship of 31P MR spectroscopy to the histopathological grading of chronic hepatitis and response to therapy. Acta Radiol 1998; 39:309-314.
  23. Taylor-Robinson SD, Sargentoni J, Bell JD, et al. In vivo and in vitro hepatic 31P magnetic resonance spectroscopy and electron microscopy of the cirrhotic liver. Liver 1997; 17:198-209.
  24. Jalan R, Sargentoni J, Coutts GA, et al. Hepatic phosphorus-31 magnetic resonance spectroscopy in primary biliary cirrhosis and its relation to prognostic models. Gut 1996; 39:141-146.
  25. Menon DK, Sargentoni J, Taylor-Robinson SD, et al. Effect of functional grade and etiology on in vivo hepatic phosphorus-31 magnetic resonance spectroscopy in cirrhosis: biochemical basis of spectral appearances. Hepatology 1995; 21:417-427.
  26. Munakata T, Griffiths RD, Martin PA, Jenkins SA, Shields R, Edwards RH. An in vivo 31P MRS study of patients with liver cirrhosis: progress towards a non-invasive assessment of disease severity. NMR Biomed 1993; 6:168-172.
  27. Stanka M, Rummeny E, Reimer P, et al. Characterization of chronic liver diseases by localized 1H-MR-STEAM-spectroscopy (abstr) In: Proceedings of the Fifth Meeting of the International Society for Magnetic Resonance in Medicine. Berkeley, Calif: International Society for Magnetic Resonance in Medicine, 1997; 1272.
  28. Kreis R, Ross BD, Farrow NA, Ackerman Z. Metabolic disorders of the brain in the chronic hepatic encephalopathy detected with 1H MR spectroscopy. Radiology 1992; 182:19-27.
  29. Barany M, Spigos DG, Mok E, Venkatasubramanian PN, Wilbur AC, Langer BG. High resolution proton magnetic resonance spectroscopy of human brain and liver. Magn Reson Imaging 1987; 5:393-398.
  30. Barany M, Langer BG, Glick RP, Venkatasubramanian PN, Wilbur AC, Spigos DG. In vivo H-1 spectroscopy in humans at 1.5 T. Radiology 1988; 167:839-844.
  31. Dawson-Saunders B, Trapp RG. Posteriori, or post hoc, comparisons. In: Dawson-Saunders B, Trapp RG, eds. Basic and clinical biostatistics. Norwalk, Conn: Appleton & Lange, 1990; 133-135.
  32. Bell JD, Cox IJ, Sargentoni J, et al. A 31P and 1H-NMR investigation in vitro of normal and abnormal human liver. Biochim Biophys Acta 1993; 1225:71-77.
  33. Weiner MW, Adam WR. Magnetic resonance spectroscopy for evaluation of renal function. Semin Urol 1985; 3:34-42.
  34. McIntosh TK, Faden AI, Bendall MR, Vink R. Traumatic brain injury in the rat: alterations in brain lactate and pH as characterized by 1H and 31P nuclear magnetic resonance. J Neurochem 1987; 49:1530-1540.
  35. Keller AM, Sorce DJ, Sciacca RR, Barr ML, Cannon PJ. Very rapid lactate measurement in ischemic perfused hearts using 1H MRS continuous negative echo acquisition during steady-state frequency selective excitation. Magn Reson Med 1988; 7:65-78.
  36. Thomsen C, Becker U, Winkler K, Christoffersen P, Jensen M, Henriksen O. Quantification of liver fat using magnetic resonance spectroscopy. Magn Reson Imaging 1994; 12:487-495.
  37. Podolsky DK, Isselbacher KJ. Cirrhosis of the liver. In: Wilson JD, Braunwald E, Isselbacher KJ, et al., eds. Harrison’s principles of internal medicine. 12th ed. New York, NY: McGraw-Hill, 1991; 1340-1350.
  38. Ohtomo K, Itai Y, Ohtomo Y, Shiga J, Iio M. Regenerating nodules of liver cirrhosis: MR imaging with pathologic correlation. AJR Am J Roentgenol 1990; 154:505-507.
  39. Ishida M, Nakagawara G, Imamura Y, Fukuda M. Iron and copper deposition in chronic active hepatitis and liver cirrhosis: pathogenetic role in progressive liver cell damage. Eur J Histochem 1995; 39:221-236.
  40. Thornburg LP, Rottinghaus G, Dennis G, Crawford S. The relationship between hepatic copper content and morphologic changes in the liver of West Highland White Terriers. Vet Pathol 1996; 33:656-661.



This article has been cited by other articles:


Home page
 Am. J. Roentgenol.Home page
A. Orlacchio, F. Bolacchi, M. Cadioli, A. Bergamini, V. Cozzolino, M. Angelico, and G. Simonetti
Evaluation of the Severity of Chronic Hepatitis C with 3-T1H-MR Spectroscopy
Am. J. Roentgenol., May 1, 2008; 190(5): 1331 - 1339.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Roentgenol.Home page
C. G. Lall, A. M. Aisen, N. Bansal, and K. Sandrasegaran
Nonalcoholic Fatty Liver Disease
Am. J. Roentgenol., April 1, 2008; 190(4): 993 - 1002.
[Abstract] [Full Text] [PDF]

Home page
 RadiologyHome page
C.-Y. Chen, C.-W. Li, Y.-T. Kuo, T.-S. Jaw, D.-K. Wu, J.-C. Jao, J.-S. Hsu, and G.-C. Liu
Early Response of Hepatocellular Carcinoma to Transcatheter Arterial Chemoembolization: Choline Levels and MR Diffusion Constants--Initial Experience
Radiology, May 1, 2006; 239(2): 448 - 456.
[Abstract] [Full Text] [PDF]

Home page
 RadiologyHome page
A. Qayyum, J. S. Goh, S. Kakar, B. M. Yeh, R. B. Merriman, and F. V. Coakley
Accuracy of Liver Fat Quantification at MR Imaging: Comparison of Out-of-Phase Gradient-Echo and Fat-saturated Fast Spin-Echo Techniques--Initial Experience
Radiology, November 1, 2005; 237(2): 507 - 511.
[Abstract] [Full Text] [PDF]

Home page
 RadiologyHome page
A. K. P. Lim, G. Hamilton, N. Patel, J. D. Bell, and S. D. Taylor-Robinson
1H MR Spectroscopy in the Evaluation of the Severity of Chronic Liver Disease
Radiology, January 1, 2003; 226(1): 288 - 289.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2213010106v1
221/3/740    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cho, S. G.
Right arrow Articles by Suh, C. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cho, S. G.
Right arrow Articles by Suh, C. H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
RADIOLOGY RADIOGRAPHICS RSNA JOURNALS ONLINE