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DOI:10.2214/AJR.07.2418
AJR 2007; 189:819-823
© American Roentgen Ray Society

Original Research

31P MR Spectroscopy in Assessment of Response to Antiviral Therapy for Hepatitis C Virus–Related Liver Disease

Adrian K. P. Lim1, Nayna Patel1,2, Gavin Hamilton1,2, Kailash Mylvahan1,2, Yu-Ting Kuo1,3, Robert D. Goldin4 and Simon D. Taylor-Robinson1,2

1 Department of Imaging Sciences, Faculty of Medicine, Imperial College London, Robert Steiner MRI Unit, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Rd., London W12 0HS, United Kingdom.
2 Liver Unit, Division of Medicine, Imperial College London, St. Mary's Hospital, London, United Kingdom.
3 Department of Medical Imaging, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Taiwan.
4 Department of Histopathology, Faculty of Medicine, Imperial College London, St. Mary's Hospital, London, United Kingdom.

Received September 28, 2006; accepted after revision April 23, 2007.

 
Supported by the British Medical Research Council (grant G99000178) and the United Kingdom Department of Health.

A. K. P. Lim was supported by a Kodak Scholarship from the Royal College of Radiologists, UK.

Address correspondence to A. K. P. Lim (a.lim{at}ic.ac.uk).


Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
OBJECTIVE. An increase in the ratio of phosphomonoester (PME) to phosphodiester (PDE) during 31P MR spectroscopy of the liver has been observed with increasing severity of hepatitis C–related liver disease. The purpose of this study was to investigate the utility of 31P MR spectroscopy as a biomarker of response to interferon and ribavirin treatment.

SUBJECTS AND METHODS. Forty-seven patients with biopsy-proven hepatitis C undergoing viral eradication treatment with interferon and ribavirin underwent hepatic 31P MR spectroscopy at 1.5 T (voxel size, 70 x 70 x 70 mm; TR, 10,000; number of signals averaged, 48). All underwent baseline imaging before treatment and repeated imaging at 6-month intervals after the start of treatment.

RESULTS. All patients underwent follow-up imaging 6 months after the start of treatment; 25 patients, 12 months; and 10 patients, 18 months after the start of treatment. According to the Ishak histologic scoring system, nine patients had mild hepatitis; 30 patients, moderate to severe hepatitis; and eight patients, cirrhosis. Thirty-two patients responded to antiviral treatment. Among these patients, 25 had a decrease in PME/PDE ratio on follow-up imaging. Among responders the mean baseline PME/PDE ratio decreased from 0.27 ± 0.02 (standard error) to 0.16 ± 0.01 after treatment (paired Student's t test, p < 0.001). Among the 15 virologic nonresponders, the ratios were similar in six patients; six other patients had an increase on follow-up imaging. In the latter nonresponder group, the mean baseline PME/PDE ratio was 0.21 ± 0.03 compared with 0.31 ± 0.08 after treatment (paired Student's t test, p =0.24).

CONCLUSION. The in vivo hepatic PME/PDE ratio decreased in patients with hepatitis C who responded to antiviral treatment and remained similar or increased in patients without a virologic response. These results suggest that PME and PDE can be used as biomarkers in a noninvasive test of response to treatment.

Keywords: hepatitis C • phospholipids • 31P MR spectroscopy


Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
It is estimated that approximately 3% of the global population has chronic infection with the hepatitis C virus (HCV) and that approximately 4 million persons are newly infected each year [1]. There is a great degree of variation in prevalence, ranging from less than 1% in the United Kingdom to more than 20% in Egypt [1]. In 55–85% of persons the infection develops into chronic liver disease, which in many cases remains asymptomatic. In the other cases, the primary symptom is chronic fatigue [2]. In approximately 20% of cases, fibrosis develops into cirrhosis, which leads to hepatocellular cancer in 5% of cases each year [3].

Liver biopsy is the reference standard for staging and grading chronic liver disease, but this invasive procedure is not without risk. There is a small mortality rate but a high error rate, predominantly ow ing to undersampling, whereby typically less than 1/50,000 of the liver volume is obtained for histologic evaluation [4–7]. As a result of the problems associated with biopsy, a steady drive to find an effective noninvasive method of evaluating liver damage has led to developments both in testing with serologic biomarkers of disease and in imaging. For ethical reasons and because most patients are unwilling to undergo repeated procedures, treatment algorithms in the United Kingdom rarely allow serial liver biopsy. The impetus to find a reliable and repeatable biomarker of disease activity and response to treatment thus has renewed focus [8].

One particular noninvasive technique for characterizing chronic liver disease is 31P MR spectroscopy, the results of which were found to be a useful indicator of disease severity in one of our previous studies [9]. In that study we found that the phosphomonoester to phosphodiester (PME/PDE) ratio increased with increasing severity of chronic liver disease and that this ratio was highly sensitive for the presence of cirrhosis. With noninvasive imaging, we used PME/PDE to assess the severity of precirrhotic HCV-related liver disease. The initial study had a cross-sectional design, but whether PME/PDE ratio changes in response to viral eradication treatment was left for further, longitudinal studies. The aim of the current study was to investigate the utility of 31P MR spectroscopy as a noninvasive test for biomarkers of response to interferon and ribavirin treatment. These drugs have been shown to eradicate the virus in at least 50% of cases, preventing progression of HCV infection to cirrhosis [10–13].


Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients
In a period beginning in December 1999, after institutional and ethics board review and approval and after providing informed consent, 47 patients with biopsy-proven HCV-related liver disease undergoing viral eradication treatment with interferon and ribavirin were enrolled in a prospective study. As part of routine clinical protocols in the United Kingdom [12], all patients underwent baseline liver biopsy for assessment of the severity of hepatic inflammation before the decision was made to embark on antiviral treatment. The group comprised 29 men and 18 women with a mean age of 47.5 years (range, 31–67 years). Thirteen patients had genotype 1 or 4, and 12 patients had genotype 2 or 3. Because genotyping was not universally requested before commencement of HCV antiviral treatment in the United Kingdom at the time, 22 patients did not undergo genotype characterization by a referring clinician. None of the patients drank more than 20 g/d of alcohol, and none had a history of alcohol excess. All were abstinent from IV drug use. No patient had coinfection with either hepatitis B virus or HIV.

Each patient underwent baseline pretreatment31P MR spectroscopy within 3 months of starting viral eradication treatment. After the start of treatment, all patients underwent repeated imaging every 6 months for up to 18 months. All patients underwent interferon {alpha} and ribavirin or pegylated interferon {alpha} and ribavirin treatment for a minimum of 12 weeks.

31P MR Spectroscopy
The method for obtaining the hepatic 31P MR spectra was as previously described [8]. A 1.5-T MRI unit (Eclipse, Philips Medical Systems) was used. All imaging was conducted after an overnight fast. An enveloping transmitter coil and separate surface receiver coil were used. Both coils were double-tuned for protons at 64 MHz and phosphorus at 26 MHz. The proton signal was used to obtain a T1-weighted image (TR/TE, 800/16) in the axial plane to confirm patient positioning. The 31P MR spectra were localized to a centrally placed voxel within the liver by use of an image-selected in vivo spectroscopy sequence; voxel size, 70 x 70 x 70 mm; TR, 10,000; number of signals averaged, 48. A voxel location within the right liver away from major vessels was used for each patient and was consistent for all baseline and follow-up images. The total examination time was 40 minutes with a 10-minute acquisition time for the 31P MR spectroscopic sequences. All patients underwent baseline 31P MR spectroscopy before the start of antiviral treatment, and all underwent follow-up imaging 6 months after baseline. Twenty-five patients underwent imaging 12 months after baseline, and 10 patients underwent imaging 18 months after baseline.

Quantitation
Quantitation of the 31P signals was performed in the time domain with the advanced method for accurate, robust, and efficient spectral fitting (AMARES) algorithm [14] included in the Magnetic Resonance User Interface–MRUI software program (www.mrui.uab.es/mrui) [15]. This technique has been described in detail previously [16]. Anonymity was assured and MR spectra were analyzed by one blinded observer, and the spectra were rechecked by another blinded observer. Peak areas for PME, PDE, inorganic phosphate, and the three nucleoside triphosphate moieties ({gamma}, {alpha}, and ß) were obtained with respect to the total phosphorus signal intensity [9, 16]. Because of previous findings highlighting the utility of the PME/PDE ratio, this index was used for further statistical analysis. Data from a bank of 15 age-matched healthy volunteers without a history of liver disease were used for comparison.

Histologic Staging and Grading
Baseline liver biopsies were performed up to 12 months (median, 3 months) before the start of antiviral treatment. One liver pathologist assessed all liver biopsy specimens for necroinflammation and fibrosis. The specimens were scored according to the Ishak system (modified histologic activity index) [17]. Subdivision into mild and moderate disease was based on the Ishak fibrosis and necroinflammation scoring system. Mild hepatitis was a fibrosis score of 2 or less and a necroinflammation score of 3 or less. Moderate hepatitis was a fibrosis score between 3 and 6 or a necroinflammation score of 4 or greater. Cirrhosis had a fibrosis score of 6. This system is based on current treatment algorithms in the United Kingdom [3]. According to the Ishak histologic scoring system, nine patients had mild hepatitis, 30 had moderate to severe hepatitis, and eight patients had cirrhosis.

Virologic Response to Treatment
For data analysis, patients were classified as responders to viral eradication treatment on the basis of sustained viral clearance obtained from quantitative HCV RNA polymerase chain reaction studies. A sustained virologic response was defined as repeatedly undetectable HCV RNA measured a minimum of 6 months after completion of antiviral treatment.

Data and Statistical Analysis
For virologic responders to antiviral treatment who underwent imaging 6, 12, and 18 months after baseline, data analysis was conducted with the PME/PDE ratio on 31P MR spectroscopy that first corresponded to treatment response. For the virologic nonresponders (and those without a sustained virologic response), the chronologically latest PME/PDE ratio was used for statistical analysis. Comparison of the PME/PDE ratios of the virologic responders with those of the virologic nonresponders before and after treatment with interferon and ribavirin was performed with a paired Student's t test. A value of p < 0.05 was considered statistically significant.


Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Thirty-two patients responded to antiviral treatment with a sustained viral response. In 25 of these patients, the PME/PDE ratio had decreased toward normal on follow-up MR spectroscopy. Figure 1 is the graph of a responder whose spectra changed after treatment, showing a decrease in PME/PDE ratio. Six of the 15 virologic nonresponders had PME/PDE ratios on follow-up imaging similar to the baseline values. Another six nonresponders had an increase in PME/PDE ratio on follow-up imaging (Table 1). An unchanged PME/PDE ratio was defined as a difference of not more than 0.03 in comparison with the baseline ratio. An increase was defined as a greater than 0.03 increase in PME/PDE ratio in comparison with baseline. A decrease in PME/PDE ratio was defined as more than 0.03 reduction in the ratio compared with baseline.


Figure 1
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  		Fig. 1 —40-year-old woman with cirrhosis secondary to hepatitis C virus infection. Graph shows change in 31P MR spectra 1 year after treatment. Patient successfully cleared virus after antiviral treatment. Red indicates baseline spectrum; blue, spectrum 12 months after treatment. PME = phosphomonoester, PDE = phosphodiester.

 

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  		TABLE 1: Changes in Hepatic Phosphomonoester to Phosphodiester (PME/PDE) Ratio in Virologic Responders and Nonresponders After Antiviral Treatment

 

Analysis of the mean baseline PME/PDE ratio showed that in the 32 virologic responders, the PME/PDE ratio decreased from 0.27 ± 0.02 (standard error) to 0.16 ± 0.01 after treatment. This finding is shown in Figure 2 and was statistically significant (paired Student's t test, p < 0.001). Previous studies showed that a PME/PDE ratio greater than 0.3 was highly sensitive for cirrhosis and that a PME/PDE ratio less than 0.2 was a good indicator of mild hepatitis [9]. By comparison, the mean PME/PDE ratio among the virologic nonresponders remained much the same as the baseline value (Fig. 3). The mean baseline PME/PDE ratio was 0.21 ± 0.03 compared with 0.31 ± 0.08 after treatment, and there was no statistically significant difference (paired Student's t test, p = 0.24). A statistically significant difference also was found when the number of patients who were responders and had a subsequent reduction in PME/PDE ratio was compared with the number of patients whose ratios remained the same or increased (chi-square, p < 0.001).


Figure 2
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  		Fig. 2 —Graph shows significant decrease in mean phosphomonoester/phosphodiester (PME/PDE) ratio for group of responders. SE = standard error.

 

Figure 3
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  		Fig. 3 —Graph shows nonresponders had no difference in phosphomonoester/phosphodiester (PME/PDE) ratios before and after treatment. SE = standard error.

 
Table 2 outlines the breakdown of patients by severity of disease according to the Ishak histologic scoring criteria. We found it interesting that in all four patients with cirrhosis in the virologic responder group, the PME/PDE ratio decreased toward the normal range. This result contrasted to the finding that three of four patients with cirrhosis in the virologic nonresponder group had an increase in PME/PDE ratio beyond the normal range for healthy volunteers.


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  		TABLE 2: Breakdown of Patients by Disease Severity According to Ishak Histologic Scoring System [17]

 


Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Evaluating and treating the increasing numbers of patients with HCV infection is a major clinical problem. The consensus statement [18] of the National Institutes of Health and Centers for Disease Control and Prevention continues to recommend liver biopsy as the reference standard for the staging and grading of most cases of HCV-related liver disease. However, the risk of liver biopsy, although small, is prevalent. Increasing evidence shows that biopsy is significantly less accurate than once perceived, particularly with respect to sampling error from what are essentially tiny pieces of liver tissue that may not be representative of the liver as a whole [4–7]. This problem is particularly true when liver disease is not uniform in its involvement. There has thus been a drive to develop noninvasive and potentially more accurate techniques of assessment of most of the liver parenchyma rather than a small biopsy sample, which by its nature leaves most of the liver unassessed [4–7].

Assessment of the severity of hepatic involvement is required before antiviral regimens are considered in the treatment of patients with hepatitis C. In addition, owing to the variable disease progression, the potentially life-threatening complications of end-stage liver disease, and the development of hepatocellular carcinoma, it is imperative to monitor patients with HCV infection and established cirrhosis.

Treatment with interferon-{alpha} or pegylated interferon-{alpha} and ribavirin is of proven value as viral eradication therapy in the case of patients with HCV-related liver disease. Sustained viral clearance occurs in at least 50% of patients, depending on the underlying genotype [10–12]. Successful treatment is by no means universal, however, and much work is being invested into newer therapies that halt or reverse liver fibrosis, although they are not as yet in routine clinical use [19]. In many trials of the efficacy of these drugs, viral load or clearance is used as an outcome measure [10, 11], but this value unfortunately does not provide information on underlying liver status. Liver biopsy would provide this information but is not ideal, particularly for serial monitoring, owing to the attendant morbidity and small mortality rates. A noninvasive test in which a large volume of liver is sampled and that can be repeated in a longitudinal manner would be optimal. Evaluation of 31P MR spectroscopy for this purpose thus was the impetus of this study.

The PME/PDE ratio obtained with hepatic 31P MR spectroscopy has been shown in previous studies [9, 20, 21] to be a good indicator of cirrhosis. This index has been reported to delineate the severity of precirrhotic liver disease in patients with hepatitis C. The advantages of 31P MR spectroscopy over liver biopsy are its non-invasive nature and significantly larger sampling of the liver, the sample being many times larger than that of liver biopsy. Similar results with 31P MR spectroscopy have been reported by researchers [22] who reported on the utility of the PDE to adenosine triphosphate (nucleoside triphosphate) ratio in differentiating hepatitis C patients with cirrhosis from those with varying grades of precirrhotic disease.

We found the PME/PDE ratio decreased significantly toward normal in the sustained virologic responder group. This ratio remained static or increased in patients who were virologic nonresponders (Figs. 2 and 3). PME resonance contains contributions from cell membrane precursors, and PDE resonance contains contributions from cell membrane degradation products [23–25]. The PME/PDE ratio thus gives information on cell turnover within the liver [19, 20, 24]. It is therefore interesting that this ratio is reduced after effective viral eradication treatment [20–23]. It is also of interest that three of four responders in the cirrhosis group had a reduction in PME/PDE ratio. Previous findings [9] of good correlation between PME/PDE ratio and degree of liver fibrosis suggest that liver fibrosis can regress in patients with cirrhosis. The number of patients in our sample was too small for an absolute conclusion, but the findings fuel this controversial area. Overall, the results are highly encouraging and show that 31P MR spectroscopy can be used as a completely noninvasive imaging indicator of response to treatment in a population of patients who may be undergoing imaging anyway, that is, patients with established cirrhosis undergoing screening for the development of hepatocellular carcinoma.

Like all imaging techniques that have gained acceptance, such as transient elastography, assessment of the PME/PDE ratio is not 100% sensitive or specific [26]. For example, in our study three patients had a reduction in PME/PDE ratio, suggesting abatement of liver disease, but these patients were ultimately found not to have a sustained response on the basis of results of longer-term follow-up virologic studies. Similarly, two patients in the sustained virologic responder group had a worsening PME/PDE ratio but subsequently were found clear of the virus on longer-term virologic follow-up studies. It may be that with further follow-up, the PME/PDE ratio will provide more information on resolution of fibrosis. Given the course of development of fibrosis, it may be appropriate to conduct follow-up with repeated imaging 3–5 years after completion of antiviral therapy. Future studies should take this factor into account. If the protocol is proved ethically appropriate, permission for repeated liver biopsy should be sought for ultimate histologic correlation. Without initial pilot data, we were unable to obtain this permission from our local ethics committee, but repeated biopsy will be a focus of further research for future validation. It is possible that an aggregate score from the various noninvasive techniques for assessing liver disease, such as transient elastography and microbubble sonography, together with the PME/PDE ratio, can be used for accurate analysis of the true status of disease [26, 27].

Another potential weakness of this study was that correlative serologic biomarkers of fibrosis were not used. When this longitudinal MR spectroscopy study was started in 1999, many of the markers that have gained favor were not available or were not discussed in the literature, to our knowledge [28–31]. The cohort over this period was relatively small, but it is indicative of the difficult nature of follow-up of this group of patients, who were predominantly current or previous IV drug users. Therefore, a larger cohort of patients is needed for future studies to delineate the true role of 31P MR spectroscopy with prospective correlation with other imaging techniques, such as sonographic elastography (FibroScan, EchoSens) and microbubble sonography [26–27, 32] and the use of tests with serologic biomarkers (e.g., FibroTest, Biopredictive) [30]. Although our cohort in this study underwent liver biopsy before antiviral therapy, none of the patients underwent repeated liver biopsy after cessation of treatment. The study design was observational, and follow-up biopsy was not in accordance with current or previous treatment algorithms in the United Kingdom [12]. Ultimately, correlation with histologic findings at least 24 months after treatment is required for evaluation of the accuracy and reliability of 31P MR spectroscopy in noninvasive assessment of response to treatment.

These preliminary results are encouraging and indicate that the PME/PDE ratio can be used as an indicator of response to treatment and may obviate repeated biopsy. The MR spectroscopic sequence can be easily added to a standard MR liver imaging protocol. Most modern MR systems have the capability for MR spectroscopy. The sequence lengthens the imaging protocol by approximately 10 minutes but provides useful data on metabolites in patients with hepatitis C.


Acknowledgments
 
We are indebted to Howard Thomas and Jo Hajnal for advice on the protocols and technique used this study. We are grateful to the staff of the liver unit at St. Mary's Hospital, London, and the gastroenterology unit at the Hammersmith Hospital, London, who referred patients for this study.


References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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