Increased bile excretion of Gd-EOB-DTPA in diffuse liver disease : mechanistic modeling of qDCE-MRI in patients with severe fibro-sis

• IntroductionOver the past decades, several different non-invasive methods for staging hepatic fibrosis have been proposed. One such method is dynamic contrast enhanced MRI (DCE-MRI) using the contrast agent (CA) Gd-EOB-DTPA. Gd-EOB-DTPA is liver specific, which means that it is taken up specifically by the hepatocytes via the OATP3B1/B3 transporters and excreted into the bile via the MRP2 transporter. Several studies have shown that DCE-MRI and Gd-EOBDTPA can separate patients with advanced (F3-F4) from mild (F0-F2) hepatic fibrosis by measuring the signal intensity, where patients with advanced fibrosis have a lower signal intensity than the mild fibrosis cases.1 However, none of the studies up to date have been able to differentiate if the reduced signal intensity in the liver is because of an decreased uptake of CA or an increased excretion. Analyzing the DCE-MRI data with mechanistic mathematical modelling has the possibility of investigating such a differentiation.Subjects and methods88 patients with diffuse liver disease were examined using DCE-MRI (1.5 T Philips Achieva, two-point Dixon, TR=6.5 ms, TE=2.3/4.6 ms, FA=13) after a bolus injection of Gd-EOB-DTPA, followed by a liver biopsy. Regions of interest were placed within the liver, spleen and veins and a whole-body mechanistic pharmacokinetic model2 was fitted to the data. The fitted parameters in the model correspond to the rate of CA transport between different compartments, e.g. hepatocytes, blood plasma, and bile (Fig. 1).ResultsAs can be seen in Fig. 2, the parameter corresponding to the transport of CA from the blood plasma to the hepatocytes, kph, is lower for patients with advanced fibrosis (p=0.01). Fig. 3 shows that the parameter corresponding to the CA excretion into the bile, khb, is higher for patients with advanced fibrosis (p<0.01).Discussion/ConclusionThis work shows that the decreased signal intensity in DCE-MRI images in patients with advanced fibrosis depends on both a decreased uptake of CA in the hepatocytes and an increased excretion into the bile. Similar results have also been observed in a rat study3. In that study, rats with induced cirrhosis had a higher MRP2-activity than the healthy control rats.References1Norén et al: Eur. Radiol, 23(1), 174-181, 2013.2Forsgren et al: PloS One, 9(4): e95700, 2014.3Tsuda & Matsui: Radiol, 256(3): 767-773, 2010.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Gastroenterologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Anestesi och intensivvård (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Anesthesiology and Intensive Care (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

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