31P magnetic resonance spectroscopy of the liver: Correlation with standardized serum, clinical, and histological changes in diffuse liver disease

31p Magnetic Resonance Spectroscopy of the Liver: Correlation With Standardized Serum, Clinical, and Histological Changes in Diffuse Liver Disease HESTER N. VAN WASSENAER-VAN HALL, 1 J E R O E N VAN DER GROND, 1 J A N VAN HATTUM, 2 CAROLE KOOIJMAN, 3 TJAARD U . HOOGENRAAD, 4 AND W I L L E M P . TH. M . M A L I ~

The goal o f this s t u d y w a s to a n a l y z e t h e possibilities of 31p MR s p e c t r o s c o p y to detect a b n o r m a l h e p a t i c histological c h a n g e s in p a t i e n t s w i t h diffuse liver disease. 31p MR s p e c t r o s c o p y w a s performed, o n a 1.5 T w h o l e - b o d y s p e c t r o m e t e r u s i n g a n i m a g e g u i d e d l o c a l i z a t i o n techn i q u e (ISIS), o n 38 p a t i e n t s w i t h v a r i o u s diffuse liver diseases, w h o all u n d e r w e n t h i s t o l o g i c a l a n d s e r u m analysis, a n d 22 h e a l t h y v o l u n t e e r s . P h o s p h o m o n o e s t e r e x p r e s s e d as a fraction o f total p h o s p h o r u s (PME/P) s h o w e d a c o r r e l a t i o n w i t h a b n o r m a l s e r u m aspartate t r a n s a m i n a s e (AST), h i s t o l o g i c a l intralobular degeneration/focal necrosis, portal i n f l a m m a t i o n , a n d p i e c e m e a l necrosis. We f o u n d a l o w e r c o r r e l a t i o n for PME/P w i t h fibrosis. It w a s n o t possible to differentiate b e t w e e n fibrosis a n d cirrhosis. In s u m m a r y , 3~p MR s p e c t r o s c o p y is a t e c h n i q u e to detect intralobular d e g e n e r a t i o n , inf l a m m a t i o n a n d n e c r o s i s a n d to a less e x t e n t fibrosis. N o d i a g n o s t i c v a l u e w a s f o u n d w i t h r e s p e c t to steatosis a n d cholangitis. F u r t h e r m o r e , 31p MR s p e c t r o s c o p y is a p o o r m e t h o d for classifying patients into d i a g n o s t i c categories. (HEPATOLOGY 1995;21:443-449.)

3~p magnetic resonance spectroscopy (MRS) has been shown to be a useful method for studying metabolism in normal liver and in the liver with diffuse liver abnormalities. M1 However, relatively little is known about the potential of MRS for diagnosing patients with diffuse liver disease into clinical and histological categories. Because experimental conditions (field strength, repetition time, acquisition technique, and quantification routine used) are often different between studies and patient inclusion criteria are not the same or are described poorly, it is difficult to compare individual studies with each other. Abbreviations: MRS, mag~netic resonance spectroscopy; PME, phosphomonoester; AST, aspartate transaminase; ALT, alanine transaminase; Pi, inorganic phesphoi'us; VOI, volume of interest; PCr, phosphocreatine. From the 1Department of Radiodiagnosis, 2Department of Gastroenterology, 3Department of Pathology, and 4Department of Neurology of the University Hospital Utrecht, the Netherlands. Received January 10, 1994; accepted September 14, 1994. Address reprint requests to: Jeroen van der Grond, MD, Academic Hospital Utrecht, Department of Radiology, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. Copyright © 1995 by the American Association for the Study of Liver Diseases.

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Many 31p MRS liver studies are assigned to determine T1 values and absolute concentrations of hepatic metabolites or to test the diagnostic value in monitoring hepatic cirrhosis or hepatitis. Although most studies agree on relaxation time values, because these are independent of the method used, it is still not clear which hepatic metabolic processes are responsible for the observed spectroscopic changes in the liver of patients with hepatitis or fibrosis/cirrhosis. Meyerhoff et al 2 showed that the phosphomonoester (PME) concentration is increased in viral hepatitis b u t not in alcoholic hepatitis, whereas Angus et al e showed that the PME concentration in alcoholic hepatitis was also increased and even was correlated with the severity of alcoholic hepatitis. Also, the description of spectroscopic changes in the liver of patients with liver fibrosis or cirrhosis is unclear: Angus et al e suggested that hepatic PME concentration was not correlated to the severity of cirrhosis. This suggestion is supported by Raj a n a y a g a m et al ~ and Meyerhoff et al, 2 who both showed that hepatic PME is not significantly increased in alcoholic cirrhosis. However, other studies 3'5 demonstrated that the hepatic PME was increased in patients with liver cirrhosis. These contradicting results in the potential of MRS in detecting hepatitis or cirrhosis may be caused by the fact that in a limited number of patients histological information was present. Because in these studies no, or only limited, information is provided about the results of biopsy or serum analysis, it cannot be excluded that other hepatic abnormalities, or more specific hepatic abnormalities, may influence the PME concentration. The goal of this study was to find possible correlations between MR spectroscopic results and standardized serum, clinical, and biopsy values, to detect hepatic abnormalities in patients with diffuse liver disease. SUBJECTS AND METHODS

Subjects. 3~p MR spectra of the liver were obtained from 22 healthy control subjects (21 to 65 years of age) and 38 patients (17 to 64 years) with diffuse liver disease (Table 1). Only patients of whom biopsies were performed within 1 year before the spectroscopic examination were included in this

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TABLE 2. N u m e r i c a l S c o r i n g o f L i v e r B i o p s y S p e c i m e n s Periportal and Bridging Necrosis

0 None 1 Mild piecemeal necrosis

3 Moderate piecemeal necrosis (less than 50% of the circumference of most portal tracts) 4 Marked piecemeal necrosis (more than 50% of the circumference of most portal tracts) 5 Moderate piecemeal necrosis plus bridging necrosis 6 Marked piecemeal necrosis plus bridging necrosis 10 Multilobular necrosis

Intralobular Degeneration and Focal Necrosis

0 None 1 Mild (acidophilic bodies, ballooning degeneration, or scattered loci of hepatonuclear necrosis 1 in <3 of lobule or nodules) 3 Moderate involvement of <2 of lobules or nodules Marked involvement of >2 of lobules or nodules

Portal Inflammation

Fibrosis

0 None 1 Mild (sprinkling of inflammatory cells in <~ of portal tracts)

0 None 1 Fibrous portal expansion

3 Moderate (increased inflammatory cells in <2 of portal tracts)

3 Bridging fibrosis (portal-portal or portal-central linkage)

4 Marked dense packing of inflammatory cells in >~ of portal tracts

4 Cirrhosis

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study. This study was limited to patients having diffuse liver disease with a stable course. Therefore the kind of disease and severity obtained from the biopsy specimen is likely to be representative for the whole liver and also representative for at least on year. Patients showing abnormalities on MRI or biopsy specimens indicating malignancy were excluded from this study. Biopsy specimens were scored for periportal and bridging necrosis, intralobular degeneration and focal necrosis, portal inflammation, and fibrosis according to Knodell et a112 (Table 2). Histological steatosis was scored 0, 1, and 2 for absent, mild, and severe, respectively, and for cholangitis, we scored 0 or 1 (absent or present, respectively). Liver tests (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase, gamma-glutamyltranspepsidase, bilirubin, albumin, and lactate dehydrogenase) were measured in all patients within 3 days of the study. We correlated biopsy scores, liver tests, and the ChildPugh 13 classification with phosphomonoester expressed as a fraction of total phosphorus (PME/P), inorganic phosphate expressed as a fraction of total phosphorus (Pi/P), phosphodiester expressed as a fraction of total phosphorus (PDE/P), and nucleoside triphosphate (NTP) expressed as a fraction of total phosphorus (~-P NTP/P). The hepatic NTP signal mainly (_+80%) consists of adenosine triphosphate (ATP). Spectroscopic ratios are expressed as percentage metabolite of total phosphorus signal, in which total phosphorus was defined as the signal of PME + Pi + PDE + fl-P NTP. Patients and volunteers participated in this study after their informed consent was obtained. All subjects fasted for at least 6 hours before MR spectroscopy examination. ~lp MR Spectroscopy. MRS was performed on a 1.5 Tesla Philips whole-body system. A switchable (1H-alP) surface coil with a diameter of 15 cm was placed to the right side of the liver. The coil position was identified by coronal proton images, made with the body coil. The volume of interest (VOI) was selected on the basis of the anatomic information of the coronal as well as axial images. The VOI varied from 200 to

500 mL according to the size of the particular liver. Field homogeneity was optimized by shimming on the proton signal. Volume-selective 31p spectra were recorded using the ISIS technique with a repetition time of 1,500 msec and 256 measurements. The total duration of the examination was 30 minutes: 7 to 8 minutes patient preparation and positioning of the surface coil, 7 to 8 minutes MR imaging, 7 minutes shimming, tuning/matching and RF optimization, and 7 minutes MR spectroscopy acquisition time. The averaged free induction decays were zero filled to 4,096 data points and processed with a convolution difference procedure (150 Hz) to remove broad signals from less mobile phospholipids. After exponential multiplication (4 Hz) and Fourier transformation, a linear phase correction was applied. Subsequent to baseline correction, quantification of the metabolites was achieved by integrating peaks of interest. Phosphocreatine (PCr) was seen in almost all of the MR spectra. Although PCr is not present in the liver, 3 it can sometimes be observed because of muscle contamination in the VOI in the ISIS experiment, pH was derived from the chemical shift of inorganic phosphate measured relative to the chemical shift of a-P NTP (referenced at -7.50 ppm). 14 Statistical Analysis. All spectroscopic data are presented as mean _+ SD. To analyze the differences in mean PME/P, Pi/ P PDE/P, and ~-P NTP/P among groups (grouped according to serum value, biopsy score or Child-Pugh score), analysis of variance (ANOVA) was used. If the result of ANOVA was significant for PME/P, Pi/P PDE/P, or p-P NTP/P, we analyzed this metabolite ratio within the group using the unpaired Student's t-test, which was corrected for repeated measures. Furthermore, these ratios were compared with control values using the same test. We performed ANOVA in which patient groups were defined as follows: For the biopsy scores we used the numerical scoring of liver biopsy specimens (Table 2), 1~for steatosis we used 0, 1, and 2 for absent, mild, and marked, respectively, for cholangitis, we scored 0 or 1 (absent or present, respec-

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tively). The liver tests bilirubin and albumin we scored two categories; below or above the upper limit of the reference range for undiseased controls, for alkaline phosphatase, gamma-glutamyl transpepsidase, AST, and ALT we scored three categories; below the upper limit of the reference range for undiseased controls, below 3 times the upper limit of the reference range for undiseased controls, and above 3 times the upper limit of the reference range for undiseased controls. All normal values used are indicated in Table 1. The ChildPugh classification was scored in categories A, B, or C.13 RESULTS

Diagnostic Categories Typical MR spectra of a healthy volunteer and of a patient showing increased PME/P ratio are shown in Fig. 1A and 1B, respectively. The results of the biopsies and the serum analyses and corresponding metabolite ratios obtained with MR spectroscopy are summarized in Table 1. In this table, the spectroscopic results of the control subjects are expressed as a range extending 2 SD below and above the mean. Figure 2 shows the distribution of the MR data grouped to diagnostic categories. The shaded area represents the mean metabolite ratios of the control subjects _+ 2 × SD. There was no significant difference in metabolic ratios or pH between any of the diagnostic categories with control subjects or other diagnostic groups. Biopsies and Serum Values

We found a statistically significant difference (ANOVA) (P < .05) among the means of the subcategories of periportal bridging necrosis, intralobular degeneration, portal inflammation, fibrosis, and AST with the PME/P ratio. This difference was not statistically significant for Pi/P, PDE/P, or/~-P NTP/P. No statistically significant difference (ANOVA) was found in any of the metabolite ratios among the means of the subcategories of steatosis, cholangitis, bilirubin, alkaline phosphatase, gamma-glutamyl transpepsidase, alanine transferase, albumin, and the ChildPugh score. Periportal and Bridging Necrosis. Figure 3A shows

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the distribution of the PME/P ratio for all diagnostic categories grouped according to the biopsy score for periportal and bridging necrosis (Table 2). For periportal and bridging necrosis, we did not find a statistically significant difference in PME/P between patients with a biopsy score of 0 and 1 (0.13 _+ 0.04, n -- 18, and 0.15 _+ 0.04, n - 14, respectively). We found a significant difference in the PME/P ratio between patients with a biopsy score 0 and 3 and up (0.13 _+ 0.04 versus 0.18 _+ 0.05, n = 9, P < .01). Intralobular Degeneration and Focal Necrosis. Figure 3B shows the distribution of the PME/P ratio for all diagnostic categories grouped according to the biopsy score for intralobular degeneration and focal necrosis (Table 2). For intralobular degeneration and focal necrosis, we found a significant difference in the hepatic PME/P ratio between patients with a biopsy score of 0 and 1 (P < .0005, PME/P = 0.13 +_ 0.04, n = 26, and 0.19 ± 0.04, n --- 10, respectively. Because of the low number of patients with a biopsy score of 2 (n = 2), we did not perform statistical tests with the spectroscopic data from this biopsy score (PME/P = 0.18 +_ 0.04). Portal Inflammation. Figure 3C shows the distribution of the PME/P ratio for all diagnostic categories grouped according to the biopsy score for portal inflammation (Table 2). For portal inflammation we did not find a statistically significant difference in the PME/P ratio between patients with a biopsy score of 0 and 1 in PME/P (0.11 _+ 0.02, n = 7, and 0.13 _+ 0.04, n = 9, respectively), whereas the mean PME/P ratio for patients with biopsy scores 3 and 4 were significantly increased compared to biopsy score 0 (0.17 +_ 0.04, n = 12, P < .005, and 0.16 _+ 0.05, n = 10, P < .05, respectively). Fibrosis. Figure 3D shows the distribution of the PME/P ratio for all diagnostic categories grouped according to the biopsy score for fibrosis (Table 2). For fibrosis we did not find a statistically significant difference in the hepatic PME/P ratio between patients with a biopsy score of 0 and 1 (0.13 _+ 0.04, n = 13, and 0.12 _+ 0.03, n = 11, respectively). Between patients with a biopsy score 0 and 3 we found a significant difference in the PME/P ratio (0.13 _+ 0.04 versus 0.18 _ 0.06, n = 6, P < .05). We also found a significant difference in PME/P between patients with a biopsy score 0 and 4 (cirrhosis) (0.13 _+ 0.04 versus 0.18 _ 0.06, n = 8, P < .05). AST For AST we found a significant difference in PME/P between category 1 (n = 13) and 2 (n = 20) (1 = normal value and 2 = 1 to 3 times normal value, 0.13 +_ 0.03 and 0.16 ___0.05, P < .02, respectively). Between category 1 and 3 (n = 5) (more t h a n three times normal value PME/P = 0.17 +_ 0.08), we did not find a statistically significant difference. We only found a significant difference in the hepatic PME/P ratio (P < .02) between control subjects and category 2. Figure 4 shows the distribution of the PME/P ratio for all diagnostic categories grouped according to the AST concentration. In

HEPATOLOGY Vol. 21, No. 2, 1995

VAN WASSENAER-VAN HALL ET AL

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this figure we excluded 2 AST values as outlyer who were far outside the normal range. The correlation coefficient between the PME/P ratio and serum AST was 0.45 (P < .005). DISCUSSION Clinical. The most important finding of this report is that hepatic ~IP MRS can detect pathologic processes such as beginning necrosis and moderate inflammation but to a less extent for detecting fibrosis. On the contrary, 31p MRS is a poor method for classifying patients into diagnostic categories. The increase in PME/P, which is in most literature attributed to hepatitis alone, is in our study for the most part associated with histological intralobular degeneration/focal necrosis, periportal and bridging necrosis, moderate portal inflammation, and abnormal serum AST. The finding of a correlation of PME/P with a combination of these three hepatic histological abnormalities m a y indicate a correlation with what they have in common, i.e., tissue damage. Increased serum levels of AST, a mitochondrial and cytosolic enzyme

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distributed throughout the ]iver, can imply disturbed integrity of hepatocytic membranes (leakage) or cellular necrosis. Although generally ALT, a cytosolic enzyme predominantly in the periportal zone, is a better indicator of hepatitis than AST, we did not find a significant correlation between ALT and the PME/P ratio. However, in acute hepatocellular necrosis due to chemical or vascular injury, the elevation of AST is often greater than the elevation of ALT. 15 We expected a correlation between AST and ALT, both serum markers for all forms of acute and chronic hepatitis, with histological portal inflammation. The absence of this correlation can be explained by the fact that biopsy and serum analysis was not performed at the same time. Furthermore, although we limited our study to diffuse liver disease and did not include focal liver disease, it should be realized that conclusions based on biopsy specimens only should be interpreted with care, because of the well-known possibility of sampling errors. Fig. 3A through 3D shows that the 31p MRS is a good method to detect pathological processes as periportal and bridging necrosis, intralobular degeneration and

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focal necrosis, a n d p o r t a l i n f l a m m a t i o n , b u t less for d e t e c t i n g fibrosis. T h e s e findings a r e in a g r e e m e n t w i t h e a r l i e r studies, L2'~ t h a t s u g g e s t e d t h a t a n i n c r e a s e d P M E w a s m a i n l y c o r r e l a t e d to v i r a l h e p a t i t i s a n d not to fibrosis. Cox et al 4 d e m o n s t r a t e d t h a t t h e r e w a s no c h a n g e in t h e P M E / A T P r a t i o in p a t i e n t s w i t h liver cirrhosis only. H o w e v e r , w h e n cirrhosis w a s a c c o m p a n i e d b y h e p a t i t i s , a significant i n c r e a s e in P M E / A T P w a s observed. N e v e r t h e l e s s , o t h e r s t u d i e s s h o w t h a t b o t h h e p a t i t i s a n d cirrhosis c o n t r i b u t e to a n i n c r e a s e d P M E . 8'5 T h e differences for M R s p e c t r o s c o p y to diagnose l i v e r a b n o r m a l i t i e s in t h e s e s t u d i e s m a y be c a u s e d b y t h e v e r y b r o a d p a t i e n t inclusion criteria. A l t h o u g h we also f o u n d a s t a t i s t i c a l difference (P < .005) in P M E / P b e t w e e n h e p a t i t i s p a t i e n t s a n d control subjects (0.16 _+ 0.03 a n d 0.13 + 0.04, respectively), o u r s t u d y s h o w s t h a t h e p a t i c 3~p M R S is also a t e c h n i q u e to d e t e c t diff e r e n c e s b e t w e e n mild, m o d e r a t e or s e v e r e i n f l a m m a tion, a n d also b e t w e e n differences b e t w e e n m i l d a n d s e v e r e fibrosis. T h e r e f o r e , p a t i e n t selection t h a t is only b a s e d on t h e p r e s e n c e or a b s e n c e of i n f l a m m a t i o n (hepatitis) m a y i n t r o d u c e a lot of p a t i e n t bias.

Fibrosis

FIG. 3. The distribution of the PME/P ratios for all diagnostic categories grouped according to the biopsy score for periportal and bridging necrosis (A), intralobular degeneration and focal necrosis (B), portal inflammation (C), and fibrosis (D). The two horizontal lines represent the control range for the PME/P ratio _+2 × SD (n = 22). A = autoimmune chronic active hepatitis, • = hepatitis B, O = hepatitis C, • = cryptogene chronic hepatitis, [] = graft versus host immune disease, • = primary biliary cirrhosis, (} = primary sclerosing cholangitis, • = Wilson's disease. Statistical indices represent the significance between each histological subgroup and the normal control values; * = P < .05, ** = P < .005, *** = P < .0005. In A, the biopsy scores from category 2-6 were treated as one group.

Technical. T h e P M E p e a k is c o m p o s e d m a i n l y f r o m r e s o n a n c e s t h a t a r i s e f r o m p h o s p h o r y l c h o l i n e (PC) a n d p h o s p h o r y l e t h a n o l a m e (PE), w h i c h a r e b o t h p r e c u r s o r s in p h o s p h o l i p i d b i o s y n t h e s i s . I n s m a l l a m o u n t s , s u g a r phosphates and adenosine monophosphate contribute to t h e P M E p e a k . 16 I n c r e a s e d levels of p h o s p h o l i p i d p r e c u r s o r s in g e n e r a l p o i n t a t a n i n c r e a s e d p h o s p h o lipid b i o s y n t h e s i s , a n d t h e i n c r e a s e in P M E / P in hep a t i c i n f l a m m a t i o n p r o b a b l y reflects h e p a t o c y t e r e g e n eration, w h i c h is likely to occur in i n f l a m m a t i o n a n d necrosis. A l t h o u g h we realize t h a t p r e s e n t a t i o n of a b s o l u t e m e t a b o l i t e c o n c e n t r a t i o n s is p r e f e r r e d , in t h i s s t u d y m e t a b o l i t e r a t i o s r a t h e r t h a n a b s o l u t e m e t a b o l i c concentrations are measured. Measurements involving the c a l c u l a t i o n of a b s o l u t e c o n c e n t r a t i o n s r e q u i r e individual T1 m e a s u r e m e n t s . To c a l c u l a t e s a t u r a t i o n factors, t h e M R S e x p e r i m e n t s n e e d to be r e p e a t e d w i t h a t l e a s t one different r e p e t i t i o n time. U n f o r t u n a t e l y , b e c a u s e of t h e p h y s i c a l a n d m e n t a l condition of t h e p a t i e n t s , t h e y would n o t s t a n d s u c h a l o n g - l a s t i n g effort. H o w ever, e s p e c i a l l y b e c a u s e t h e T1 v a l u e s of liver m e t a b o -

HEPATOLOGYVol. 21, No. 2, 1995

VAN WASSENAER-VAN HALL ET AL REFERENCES

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FIG. 4. Cartesian plot showing the correlation between the PME/ P ratio and serum AST. The correlation coefficient between the PME/ P ratio and serum AST was 0.45 (P < .005). A = autoimmune chronic active hepatitis, • = hepatitis B, © = hepatitis C, • = cryptogene chronic hepatitis, [] = graft versus host immune disease, • = primary biliary cirrhosis, ~ = primary sclerosing cholangitis, $ = Wilson's disease.

l i t e s a r e e x p e c t e d to b e i n f l u e n c e d b y d e p o s i t i o n o f p a r a m a g n e t i c F e o r C u , 17i9 i n d i v i d u a l T1 r e l a x a t i o n measurements may be very useful. Munakata et al 5 determined that there was a trend of a prolongation of T~ for a l l m e t a b o l i t e s i n c i r r h o t i c p a t i e n t s c o m p a r e d w i t h n o r m a l s u b j e c t s . A p r o l o n g e d T~ v a l u e , i n g e n e r a l , causes a reduced signal intensity using the same repetition time. Using the data of Munukata et al also a reduced PME/P ratio would exist in the cirrhotic liver c o m p a r e d w i t h n o r m a l l i v e r , b a s e d on t h e r e d u c e d T~ only. Therefore, the observed increase in PME/P with increased periportal and bridging necrosis, intralobular degeneration and focal necrosis, portal inflammat i o n , f i b r o s i s a n d A S T is p r o b a b l y c a u s e d b y a n i n creased concentration of PME components, because a p r o l o n g e d T1 o n l y w o u l d d e c r e a s e t h e P M E / P r a t i o . Nevertheless, even if saturation factors are known, c o m p a r i s o n b e t w e e n d i f f e r e n t s t u d i e s w o u l d s t i l l b e difficult. D i f f e r e n c e s i n f i e l d s t r e n g t h , t e c h n i c a l m e t h o d s (Spectroscopic Imaging or ISIS), and quantification methods are of great influence on the final ratios. Furthermore, age-related changes in the PME/P ratio cann o t b e e x c l u d e d , 2° a l t h o u g h o u r a d u l t c o n t r o l g r o u p d i d not show an age-related correlation with spectral data. CONCLUSION T h i s s t u d y s h o w s t h a t ~lp M R S o f t h e l i v e r is a p o o r m e t h o d for c l a s s i f y i n g p a t i e n t s i n t o d i a g n o s t i c c a t e g o r i e s , b u t m i g h t b e u s e f u l to d e t e c t m a r k e r s o f l i v e r tissue damage, being abnormal serum AST, intralobular degeneration, piecemeal necrosis, and portal inflammation.

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