Assessing Severity of Liver Cirrhosis with Extracellular Volume Fraction MRI – Scientific Reports

The aim of this study was to evaluate the diagnostic utility of MRI-derived hepatic ECV for the assessment of cirrhosis severity and discrimination of different Child-Pugh classes in patients with liver cirrhosis of different etiologies. The key findings of our study are: (1) liver-native T1, as well as MRI-derived ECV, showed significant correlations with Child-Pugh score and (2) MRI-derived hepatic ECV showed high diagnostic performance for the discrimination of different Child-Pugh grades, which was higher than that of the liver-native T1 and MELD score.

The assessment of the severity of liver cirrhosis is currently mainly based on clinical and laboratory studies, with the calculation of various scores, including the Child-Pugh score, being the most well known. Over the past decade, several imaging modalities, including MRI, have evolved rapidly and are now an important pillar of clinical management, risk stratification, prognosis estimation, and procedural planning in patients with CLD and cirrhosis. Elastography methods, including ultrasound and MR-based elastography, have become important diagnostic tools in patients with CLD, mainly for the assessment of the fibrosis stage21† However, since the stage of liver fibrosis in cirrhosis patients is already definitive, assessment of fibrosis stage alone seems insufficient to draw conclusions about liver function and disease severity. There are also studies demonstrating the ability of baseline liver stiffness measurements, as well as the dynamics of changes in liver stiffness, for the prediction of liver compensation222324† In a cross-sectional setting, different MRI techniques have been tried to assess the functional aspect of liver cirrhosis/disease, e.g. using DWI extended to intravoxel incoherent movement, contrast enhanced T1 techniques using different techniques and contrast media (e.g. hepatocytes). -specific vs. extracellular), and even T1 rho mapping. However, these techniques suffer from a lack of standardization (e.g., DWI and contrast-enhanced MRI) and availability across institutions (e.g., T1 rho mapping). Quantitative MRI mapping using T1 mapping techniques with calculation of ECV may overcome these limitations and allow assessment of liver function and disease severity. A representative liver T1 map can be obtained during a single breather and T1 values ​​can be obtained quickly and directly from the parametric map. Therefore, the technique can be implemented cost-effectively in the clinical routine. Fibrosis is known to be associated with prolongation of T1 relaxation times (which can also be caused by intra- and extracellular edema in inflammatory environments). Also, fibrosis is associated with an expansion of the extracellular space and, as a consequence, with an increased accumulation of extracellular contrast in the extracellular space, which is reflected in elevated ECV values13141516

In our study, we extended the applicability of mapping techniques to assess the severity of liver cirrhosis. We found a significant correlation between liver-native T1 and Child-Pugh score (r = 0.45). This is consistent with some previous studies, which showed that cirrhotic changes lead to prolongation of T1 relaxation times compared to healthy subjects and increase with increasing stage of liver cirrhosis in patients with Child-Pugh A to C2526† However, there are other studies that show no significant differences in natural T1 relaxation times between healthy volunteers and cirrhotic patients.1127† These conflicting results have been controversially discussed. On the one hand, the prolongation of the liver-native T1 relaxation times can be explained by the tissue remodeling, on the other hand, the shortening of the T1 relaxation times in patients with liver cirrhosis can be explained by the presence of paramagnetic molecules (e.g. iron) as well as the presence of macromolecules with increased amounts of bound water1125262829303132† Liver function may also be correlated with post-contrast hepatic T1 relaxation times in patients with liver cirrhosis. However, hepatic post-contrast T1 relaxation times are highly variable, as they depend on the time and flow rate of contrast application, as well as on the contrast medium used (e.g., hepatocyte-specific vs. extracellular). In addition, post-contrast values ​​may vary depending on contrast agent dose, renal clearance rate, time and hematocrit level. These factors would limit the general applicability and comparability of research results.

In contrast to native and post-contrast T1 relaxation times, ECV appears to be a physiologically normalized and more robust parameter as it does not depend on magnetic field and acquisition parameters. Expansion of the extracellular matrix caused by chronic liver injury leads to enlargement of the extracellular space and consequently to elevated ECV values151633† According to histopathological studies, the proportional collagen area increases proportionally in all stages of cirrhosis, which can be explained by the fact that thicker cirrhotic septa contain more collagen34† Elevated liver ECV values ​​in liver cirrhosis may reflect increased synthesis and deposition of extracellular matrix proteins, which are higher in advanced stages. For the same reason, ECV is a well-known parameter in cardiac MRI and can be used for non-invasive assessment of myocardial fibrosis353637† There are also studies in animals and humans showing that ECV correlates better with portal pressure measurements than native T11638† In our study, we showed significant differences in ECV values ​​between all Child-Pugh classes, which also differed from those in the healthy subjects. ECV correlated more strongly with Child-Pugh score than liver-native T1 (r = 0.64 vs. 0.45). Our study results also support previous data in terms of diagnostic utility of ECV to diagnose liver cirrhosis1213143940† However, none of the previous studies focused solely on cirrhosis patients, nor on the ability of MRI-derived ECV to discriminate between different classes of cirrhosis.

Finally, we showed a high diagnostic performance of parameter mapping to distinguish between different cirrhosis classes, which was also higher than that of the MELD score. This can be explained by the fact that different laboratory and clinical markers are used to calculate clinical scores for the severity of liver disease. On the one hand, it may reduce the specificity of these markers, as changes outside the liver and also co-morbidities, not primarily related to liver disease, contribute to the final score. On the other hand, ECV appears to be mainly liver specific as all variables for ECV calculation are obtained directly from the liver parenchyma.41 and then normalized for hematocrit. In addition, approaches for automated calculation of ECV, even without hematocrit sampling, already exist and can be further developed using machine learning4142† However, because clinical information and laboratory markers are critical to assessing liver function and disease severity, the intent of this study was not to discourage the use of clinical scores and laboratory markers, but to assess the potential diagnostic value of a quantitative imaging approach. to show. †

Despite the advantages of MRI-derived ECV as a potential non-invasive biomarker for liver cirrhosis severity, our study has several limitations. First, the small sample size with a limited number of controls and Child-Pugh class C patients limit the generalizability of the study results. Second, we included patients with CLD and cirrhosis of different etiologies. This may affect liver T1 values, as the pattern of liver fibrosis and cirrhosis depends on the underlying etiology of CLD. Another limitation is the absence of liver biopsy as a reference standard at the time of MRI examination. Larger prospective studies focusing on the etiology of liver disease in correlation with histopathological findings are needed to further investigate the diagnostic utility of MRI-derived ECV.

In conclusion, this is the first study to investigate the diagnostic utility of MRI-derived ECV for assessing the severity of cirrhosis. MRI-derived ECV may provide valuable diagnostic information beyond standard morphologic imaging for the assessment of liver fibrosis and could be a novel non-invasive imaging-based biomarker for the assessment and follow-up of liver cirrhosis severity. Our research findings may also motivate future studies to evaluate whether quantitative liver MRI can be used in conjunction with clinical scores to improve severity assessment and outcome prediction in patients with liver cirrhosis.

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