Observed paradoxical perfusion fraction elevation in steatotic liver: An example of intravoxel incoherent motion modeling of the perfusion component constrained by the diffusion component

Intravoxel incoherent motion (IVIM) theory in MRI was proposed by Le Bihan et al to account for the effect of vessel/capillary perfusion on the aggregate diffusion weighted MR signal. The fast component of diffusion is related to microperfusion, whereas the slow component is linked to molecular diffusion. Three parameters can be computed. Dslow (or D) is the diffusion coefficient representing the slow “pure” molecular diffusion (unaffected by perfusion). The perfusion fraction (PF, or f ) represents the fraction of the compartment related to (micro)circulation, which can be understood as the proportional “incoherently flowing fluid” (ie blood) volume. Dfast (or D*) is the perfusion-related diffusion coefficient representing the incoherent microcirculation within the voxel, which contains information on blood perfusion speed. Within the IVIM research community, it has been generally assumed that the perfusion component and the diffusion component can be separately determined. However, in NMR in Biomedicine we recently published that, at least for the liver, IVIM modeling of the perfusion component is constrained by the diffusion component, and a reduced Dslow measure leads to artificially higher PF and Dfast measures. 1 Our results may have important implications for interpreting previously published literature on IVIM and for designing future IVIM studies. For one example, many previous works have reported that liver steatosis is associated with an increased PF. I argue that the increased PF is a measurement artifact caused by the decreased Dslow due to liver steatosis. Guiu et al reported that Dslow was significantly lower in steatotic livers compared with nonsteatotic livers (mean 1.03 versus 1.24 × 10 mm, p < 0.0001), while PF was significantly higher in steatotic livers compared with nonsteatotic livers (mean 0.33 versus 0.27; p = 0.0003). Lefebvre et al reported that Dslow was negatively correlated with steatosis (Spearman's ρ = −0.25, p < 0.001), while PF was positively correlated with steatosis (ρ = 0.35, p = 0.001). Sandrasegaran et al reported that their study subjects with “no steatosis,” “mild steatosis,” and “moderate/severe steatosis” had mean PFs of 0.151, 0.163, and 0.286 respectively. França et al reported that their subjects without steatosis had a median PF of 0.28, while their subjects with steatosis had a median PF of 0.35 or more. Observations of positive correlation between liver steatosis and PF have also been reported by other authors, such as Shin et al. It has been well established that liver steatosis induces Dslow reduction. The presence of fat may decrease the diffusion coefficient of water in tissue by restricting the diffusion of water within hepatocytes. Moreover, lipid signal peaks near water are often incompletely suppressed by the fat suppression techniques, and the measured diffusivity may incorporate the diffusion constant of lipid, which is much lower than that of water, with higher b-values leading to even lower observed diffusion coefficient. Echo planar image acquisition commonly uses spatial-spectral pulses for fat suppression (ie water-only excitation). Water excitation pulses have a spectral bandwidth centered on the water peak (located at 4.7 ppm), while the NMR spectrum of triglycerides in liver fat has several peaks (between 4.2 and 5.3 ppm) close to the water peak. Water excitation pulses, even in the absence of B0 inhomogeneities, will excite about 9% of the triglyceride proton magnetization. On the other hand, it is well known that liver steatosis reduces hepatic microcirculation regardless of underlying etiology. Studies with human fatty donor livers and experimental models of hepatic steatosis demonstrated an inverse correlation between the degree of fat infiltration and both total hepatic blood flow and flow in microcirculation. The increase of hepatocyte cell volume due to steatosis can result in partial or complete obstruction of the hepatic sinusoid space. Metabolically, hepatic fat accumulates negligible F-fluorodeoxyglucose (FDG). Thus, PF in the literature noted above was likely artificially promoted by IVIM modeling due to an actually decreased Dslow. Note that, in cases when the livers with steatosis had been contaminated with steatohepatitis pathology, it has been established that steatohepatitis decreases, instead of increases, PF. The point discussed will also have implications for tumor characterization by IVIM. For example, most malignant liver tumors have low diffusion (due to higher cellularity etc) and high perfusion. It has well documented that most liver tumors have low Dslow and high PF. 7,17,18 In these cases, there is the possibility that PF is artificially further promoted. With effective chemical or biological treatments tumorDslow would increase 7, ; this may lead to an artificially lower PFmeasure. Finally, PF and Dfast are highly and positively correlated. In a study evaluating IVIM measure of liver fibrosis, we reported a Pearson correlation coefficient r of 0.865 between PF and Dfast. 19 Although it is more difficult to measure Dfast precisely, 18,20 the point mentioned above is also likely to have implications for interpreting Dfast results, as a reduced Dslow measure can lead to an artificially higher Dfast measure as well . Received: 29 December 2020 Revised: 20 January 2021 Accepted: 24 January 2021