This prospective study demonstrated that a simplified one bolus-only MRI technique for quantifying the hepatic ECV is accurate to diagnose and grade fibrosis in an animal model. This is based on the main findings that show stable hepatic ECV values over time after contrast agent administration. ECV values at 5, 15, and 25 min after contrast injection were all equally suitable to detect hepatic fibrosis.
The calculation of the ECV was initially introduced for quantifying the myocardial extracellular fractional distribution volume  and was subsequently validated in histopathologic studies of myocardial fibrosis . Although liver parenchyma with its dual blood supply, portal triad and parenchymal organisation has a more complex anatomy compared to the myocardium, hepatic ECV was also associated with severity fibrosis in the liver in an experimental animal model and correlated with different histopathologic parameters of liver fibrosis . Furthermore, ECV mapping techniques have recently been adopted for liver imaging in humans. A proof-of-concept study has described ECV to be correlated with Sirius red staining in patients with diffuse liver disease . Furthermore, bolus-only ECV measurements were independently correlated with different fibrosis stages in patients with chronic hepatitis B . Also, ECV was shown to be superior to serum fibrosis indices in staging liver fibrosis in these patients . Another study reported that hepatic ECV measured with equilibrium computed tomography (CT) imaging is associated with biopsy-derived collagen-proportionate area . However, in comparison to MRI, the use of CT has some drawbacks, as it requires ionising radiation exposure and iodinated contrast agent administration, which is contraindicated in patients with reduced kidney function.
Beside that ECV has been validated against specific reference standards of disease severity in liver, heart and amyloid disease [2, 20, 21], recent data has shown that ECV was also strongly related to the fractional extracellular cellular volume of a three-dimensional engineered tissue model which was measured directly during its manufacture . These results further support the principles underlying ECV estimation.
The calculation of ECV values is based on the assumption of a two-compartment model. After the application of an extracellular contrast agent, a steady state is achieved due to a rapid exchange with equal contrast concentrations between the blood and the extracellular space . As ECV is calculated from the ratio of change in hepatic T1 relaxation time relative to blood-pool T1 after and before contrast administration, an adequate equilibrium is necessary to obtain valid results . Several cardiac magnetic resonance studies focusing on myocardial ECV already discussed about whether equilibrium can only be achieved by a continuous contrast infusion technique or if a single bolus is sufficient to establish equilibrium within a certain time after contrast injection [9, 12, 24].
The results of this study showed that ECV assessment in the liver can be achieved using a bolus-only technique only, as measurements of ECV were quite constant over time. The data support the thesis of a dynamic equilibrium, which approximates the contrast equilibrium of a slow primed infusion of contrast media. Our results are concordant with previously published data on myocardial ECV. A cardiac magnetic resonance study, which compared bolus-only and primed infusion ECV assessment, reported that bolus-only ECV measurements are sufficient for ECV measurements across a range of cardiac disease. Both obtained ECV values correlated with histological collagen volume fraction . Kawel et al.  described only slightly higher myocardial ECV values measured between 5 and 45 min. Miller et al.  described a linear increase of myocardial ECV over time, although the total mean difference between the measured ECV after 2 and 20 min was lower than 1.6%.
In our current study on liver ECV, the mean difference in hepatic ECV at 5 and 25 min in all three groups was lower than 2.1%. The slight increase was not statistically significant. There was also a strong linear relationship between hepatic ECV and Sirius red staining across a wide spectrum of liver fibrosis severity in this study. This strong relationship was independent of the time point of ECV assessment. Therefore, the results indicate that bolus-only hepatic ECV assessment is feasible. In practice, ECV value might likely be obtained at only one time point after contrast media injection.
Our study has several limitations. The T1 maps were acquired in a single transverse section and may therefore have missed more pronounced fibrotic disease that occurred in other planes. Also, the measurements were not corrected for hepatic steatosis or hepatic iron content because they are not expected in animal models. In humans, especially iron overload can influence quantitative measurements (e.g., T1 relaxation times). However, when an iron-correction is applied, T1 values can grade hepatic fibrosis . Finally, the results of this study have to be transferred to patients with chronic liver disease.
In conclusion, in this experimental animal study, we found that hepatic MRI-derived ECV using a bolus-only contrast injection technique is constant over time indicating a dynamic equilibrium. In clinical routine, post-contrast T1 relaxation times for ECV calculation might be obtained at only one time point during routine liver MRI, which might enhance and accelerate ECV assessment in the clinical workup of chronic liver disease. ECV values obtained at 5, 15, and 25 min after contrast administration were suitable to detect diffuse hepatic fibrosis.