Evaluation of hepatic fibrosis with portal pressure gradient in rats

Abstract

MRI has the potential of providing a noninvasive assessment of liver pathology. This work introduces a portal pressure gradient (PPG) model derived from fluid mechanics, where the PPG is proportional to the average velocity and inversely proportional to the vessel area in the upper part of portal vein. Using a phase-contrast spoiled gradient echo sequence, the PPG model was verified in a phantom study and was tested in an animal study using 35 rats with various degrees of hepatic fibrosis induced by carbon tetrachloride (CCl(4)). Histological examination was conducted to determine the severity of hepatic fibrosis. The fibrosis score monotonically increased with the duration of CCl(4) treatment. The PPG was highly correlated with nonzero fibrosis scores (r(2) = 0.90, P < 0.05). There was a significant difference between control and cirrhosis groups (P < 0.0006, alpha < 0.0018). The difference between control and fibrosis (noncirrhosis) groups (P < 0.002, alpha < 0.006) was also significant. Without the administration of any contrast agent, the MRI-PPG approach shows promise as a noninvasive means of evaluating liver fibrosis.

FIG. 1.

Graph shows the setup of the phantom.

FIG. 2.

Bars: standard deviation (STD). a: Graph shows one example of the velocity profile in the phantom (diameter D = 8 mm) acquired using PC-MRI with TR/TE = 61/11 ms, flip angle = 15°, resolution = 0.5 × 0.5 mm², NEX = 3, slice thickness = 5 mm, Venc = 10/50 cm/s, total scan time ≈25 sec. The MRI-measured average velocity v_MRI = 9 cm/s with the repeatability error ≈5%; flow meter measured average velocity v_real = 8.8 cm/s (< the 5% repeatability error of the MRI measurement). b: Phase velocity images for Venc = 10 cm/s, Venc = 50 cm/s, and the three-point method (Venc = 10/50 cm/s) of the phantom in color using the same scan parameters as (a). v_MRI = 19 cm/s and v_real = 21.0 cm/s. Phase wrapping is observed in the low Venc image (b1), large noise is observed in high Venc image (b2), and three-point image has lower noise than high-Venc image and no phase wrapping (b3). c: Graph shows one example of the velocity profile in the rat’s PV (diameter D = 2 mm) acquired using PC-MRI with TR/TE = 45/9.7 ms, flip angle = 15°, resolution = 0.25 × 0.25 mm², NEX = 12, slice thickness = 2.6 mm, Venc = 10/50 cm/s, total scan time ≈5 min. The MRI-measured average velocity v = 6 cm/s with the repeatability error ≈8%.

FIG. 3.

Phantom data shows the pressure gradient was proportional to (v/A). The slope of D = 8 mm and D = 6 mm was approximately equal to 8πμ, which verified the PPG model in Eq. [1]. Bars = STD.

FIG. 4.

a: The sagittal view of a rat: the liver, PV, and inferior vena cava (IVC) are clearly shown; the landmark was the upper part of PV (≈10 mm), where the flow satisfied the laminar, steady-state, and fully developed conditions. A single slice was chosen perpendicular to PV within the landmark. b: The reconstructed magnitude image where the vessel area was measured. c: The reconstructed phase image using the three-point phase unwrapping method where the velocity was measured. The IVC and PV were bright and the aorta was dark, which meant the flow direction was opposite to each other.

FIG. 5.

Graphs show the histology of the rats’ liver in the control, 2–3-week, 6–8-week, and 11–16-week groups, respectively: Masson’s trichrome-stained sections of liver for collagen (blue/green) from CCl₄-induced injury. The degree of fibrosis increases from normal in control rats (upper left) to minimal in the 2–3-week group (upper right), to mild and moderate in the 6–8-week group (bottom left), and finally to marked and severe in the 11–16-week group (bottom right). Rats in the 6–8-week group (bottom left) had the most significant fatty change (steatosis) within hepatocytes. Rats in the 11–16-week group (bottom right) had nodular hepatocellular regeneration (NR), marked fibrosis (*) that bridged hepatic lobules and pronounced biliary hyperplasia (BH), which indicate cirrhosis. Scale bars = 200 μm.

FIG. 6.

Bars: standard error of the mean (SEM). a: Graph shows the fibrosis score monotonically increased with the time of CCl₄ treatment in rats and the fibrosis score was highly correlated with the duration of the treatment (r = 0.99, P < 0.01). b: Graph shows the PPG monotonically decreased with the duration of the CCl₄ treatment in rats. c: Graph shows the PPG of control, fibrosis (noncirrhosis), and cirrhosis group: the PPG in the control group was significantly higher than the fibrosis (noncirrhosis) group (P < 0.0006, α < 0.0018); the PPG in the control group was also significantly higher than the cirrhosis group (P < 0.0002, α < 0.0006). However, the difference between fibrosis and cirrhosis groups was not very significant (α ≈0.05).

FIG. 7.

a: Graph shows a linear relationship between PPG and nonzero fibrosis scores in fibrosis rats (r² = 0.90, P < 0.05, with 95% confidence interval). b: Graph shows the PPG of early fibrosis (FS = 1 and 2) and moderate fibrosis (FS = 3) was significantly different from that of severe fibrosis (FS = 5). Bars: SEM.