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Investigation of liver cirrhosis using 31P-MRS at 7T

Lucian A. B. Purvis¹, William T. Clarke¹, Ladislav Valkovic¹, Christina Levick¹, Michael Pavlides², Eleanor Barnes², Jeremy F. Cobbold², Stefan Neubauer¹, Matthew D. Robson¹, and Christopher T. Rodgers¹

¹OCMR, Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom, ²Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom

Synopsis

Phosphorus (³¹P) metabolites have potential value as markers in liver disease. The increase in field strength from 3 to 7T allows more accurate quantitation of the liver ³¹P-MRS spectrum. Ten volunteers and eleven patients with liver cirrhosis were scanned using a 16-channel array and a 3D UTE-CSI sequence. Metabolite concentrations were calculated using an endogenous 2.5mM ATP reference. Significant reductions in inorganic phosphate and phosphoenolpyruvate/phosphatidylcholine concentrations were seen, as well as an increase in glycerophosphoethanolamine (P<0.05). The splitting of PDE into its constituent peaks allows more insight into changes in metabolism.

Purpose

The burden of hepatic disease is increasing¹. Phosphorus (³¹P) metabolites have potential value as markers for diseases including non-alcoholic fatty liver disease (NAFLD)², and cirrhosis³. The increase in field strength from 3T to 7T increases SNR⁴ and allows increased spectral resolution⁵. In addition, using a 16-channel array at 7T increases the coverage and precision of metabolite peak fitting⁶. These allow more accurate quantitation of the liver ³¹P-MRS spectrum, especially the phosphodiester (PDE) region⁷. This study investigates the effect of this improved quantification on measuring metabolites in the cirrhotic liver.

Methods

Ten volunteers (six male and four female, 27 ± 5 years, BMI 22.5 ± 1.5 kg.m^-2) and eleven patients with cirrhosis of the liver (seven male and four female, 61 ± 6 years, BMI 29.5 ± 6.9 kg.m^-2) were scanned supine after an overnight fast using a whole-body Siemens Magnetom 7T (Siemens Healthcare, Germany) and a 16-channel ³¹P receive array coil (Rapid Biomedical, Germany)⁸. The patients were recruited based on cirrhosis established using clinical, biochemical or radiological criteria. Five patients had been previously diagnosed with hepatitis C, three with non-alcoholic fatty liver disease, two with alcoholic steatohepatitis, and one with autoimmune hepatitis. Data were acquired as previously described⁶. In short, a 1s TR, UTE-CSI sequence was used to acquire a 16 × 16 × 8 matrix of liver spectra over a 270 x 240 x 200 mm³ field of view. Whitened singular value decomposition (WSVD)⁹ was used for channel combination. The CSI data were then analysed as previously described⁶, giving a mean and standard deviation for each subject. Concentrations were calculated using γ-ATP (adenosine triphosphate) as a 2.5mM endogenous reference¹⁰.

Results

The average γ-ATP linewidth in cirrhosis was 43.25 ± 10.65Hz compared to 44.02 ± 18.86 Hz in normal volunteers. The average γ-ATP SNR was 19.58 ± 3.64 in cirrhosis compared to 20.77 ± 6.15. Average metabolite concentrations for both normal and cirrhotic livers are given in Table 1, and the concentrations for individual patients are given in Table 2 with their diagnoses. Figure 2 shows the concentrations for each volunteer and patient. There are significant reduction in inorganic phosphate (P = 0.005), and phosphoenolpyruvate/phosphatidylcholine (PEP/PtdC) concentrations (P = 0.016), and a trend to a reduction in phosphocholine (P = 0.08). There was a significant increase in glycerophosphoethanolamine concentrations (P = 0.04). Only nicotinamide dinucleotide has a significantly larger variance in patients than in healthy volunteers (F-test, P = 0.003). There was no significant difference in residual phosphocreatine signal.

Discussion

The average γ-ATP linewidths indicates that the shim was also not significantly different from in healthy volunteers. Only nicotinamide dinucleotide has a significantly larger variance than in healthy volunteers (F-test, P = 0.003), and the residual phosphocreatine signal is not significantly higher. Our protocol is therefore still effective in patients with cirrhotic livers. We saw a significant 12% reduction in inorganic phosphate (P = 0.005), which agrees with the 18% change reported by Dezortova et al. in patients with cirrhosis³. A reduction in inorganic phosphate has been correlated with an increase in hepatic inflammation¹¹. Dezortova et al. also found a significant 34% reduction in PDE, whereas we saw a significant 21% increase in GPE (P = 0.04). The two PDE metabolites are cell degradation products, so this study would indicate an increase in cell turnover rate, which has been previously found in hepatitis-C induced cirrhosis¹². There are two contaminating factors in the PDE signal at low field strength: signal from the PEP/PtdC peak, and a broad underlying peak from phospholipids in the membrane⁷. The PEP/PtdC signal was reduced by 23% (P = 0.02). This signal reduction is likely due to a reduction of bile in the liver. The remaining change in PDE, and the increase in PME at 3T might be explained by a variation in the underlying phospholipid signal.

Conclusion

We report comparable quality of data in patients with cirrhosis and in healthy volunteers. 7T ³¹P spectroscopy with a receive array is a powerful tool for studying metabolism in the diseased liver. A reduction in inorganic phosphate indicates an increase in inflammation in the cirrhotic liver. The splitting of PDE into its constituent peaks allows more insight into changes in metabolism.

Acknowledgements

Funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (Grant Number 098436/Z/12/Z). LABP has a DPhil studentship from the Medical Research Council (UK).

References

1. Blachier M, et al. J Hepatol. 2013

2. Abrigo JM, et al. J Hepatol. 2014

3. Dezortova M, et al. World J Gastroenterol. 2005

4. Runge JH, et al. Magn Reson Imaging. 2016

5. Chmelik M, et al. NMR Biomed. 2014

6. Purvis LAB, et al. Proc. ISMRM p.0838, 2015

7. Purvis LAB, et al. Proc. ISMRM p.3691, 2016;

8. Rodgers CT, et al., Proc ISMRM p.2896, 2014;

9. Rodgers CT, Robson MD. Magn Reson Med. 2016

10. Sijens PE, et al. Magn Reson Imaging. 1998

11. van Wassenaer-van Hall HN, et al. Hepatology. 1995

12. Karidis NP, et al. Gastroenterology Research and Practice. 2015

Figures

Figure 1: Spectra taken from normal (top) and cirrhotic (bottom) livers. Both were acquired at 7T using our 3D UTE-CSI protocol.

Figure 2: A scatter plot of the concentrations of nine different peaks in normal volunteers and patients. Each red ‘+’ marks a subject. The blue line shows the mean ± SD of each group. P_i and PtdC/PEP are significantly lower in cirrhosis than in normal volunteers, and GPE is significantly higher (P < 0.05).

Table 1: Mean ± SD of concentrations for 10 normal volunteers and 11 patients with cirrhotic livers from a 28min 3D CSI acquisition. The concentrations are based on a 2.5mM γ-ATP concentration. This assumption is reasonable for the normal volunteers, but does not necessarily hold for cirrhosis. The PDE concentration is the sum of the GPC and GPE concentrations, and the PME concentration is the sum of the PC and PE concentrations. Significant differences between healthy and cirrhotic concentrations are marked with stars: * P < 0.05, ** P < 0.01.

Table 2: Metabolite concentrations of 11 patients with liver cirrhosis (mean ± inter-voxel SD). Five have been diagnosed with Hepatitis C (HCV), three with non-alcoholic fatty liver disease (NAFL), two with alcoholic steatohepatitis (ASH), and one with auto-immune hepatitis (AIH). Inter-subject means are given in Table 1.

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)

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