| Summary: | <p>Primary sclerosing cholangitis (PSC) affects the biliary tree and liver. Magnetic resonance imaging (MRI) with cholangiopancreatography (MRCP) is used to diagnose and follow-up patients. Its current use and applications, however, are not standardised and relies on qualitative assessments susceptible to inter-observer variability. The aim of this thesis was to identify standardised and objective imaging metrics derived from quantitative MRI techniques that could potentially be used in future clinical assessment of patients with PSC, longitudinal studies, and interventional drug trials. </p>
<p>The quantitative techniques used in this thesis include (i) MRCP+™, a three-dimensional (3D) biliary tree model computed from MRCP data to derive biliary metrics; (ii) T1 and T2* mapping to compute the iron-corrected T1 (cT1) using LiverMultiScan™; and (iii) co-registration of MRCP+ biliary tree model with LiverMultiScan cT1 maps to calculate periductal cT1. Patients with PSC were categorised into either high-risk or low-risk group for disease progression based on published thresholds of revised Mayo Risk Score (MRS), Amsterdam-Oxford Model (AOM), upper limit of normal (ULN) alkaline phosphatase (ALP), transient elastography liver stiffness (LS), enhanced liver fibrosis score (ELF), modified Amsterdam intrahepatic stricture severity score (ISSS), Anali score, presence of extrahepatic disease, and presence of dominant stricture. Patient reported outcomes were collected using generic SF-36 and disease-specific PSC-PRO questionnaires. </p>
<p>The intrahepatic sum of the relative severity of dilatations (SumRelSevDilat) was consistently higher in the high-risk compared to the low-risk PSC group (MRS: p<0.0001; AOM: p=0.0017; 2.2x ULN ALP: p=0.0007; 1.5x ULN ALP: p=0.0025; LS: p=0.0022; ELF: p=0.0189; ISSS: p<0.0001; Anali: p=0.0299). It identified the high-risk MRS > 0 group (AUC=0.77, 95% CI 0.66–0.88) numerically better than other non-invasive markers and was an independent predictor of this high-risk group (OR: 29.2, p=0.038). SF-36 bodily pain (rs=-0.26, p=0.025) and PSC-PRO activities of daily living (rs=0.29, p=0.014) showed the strongest correlations with intrahepatic SumRelSevDilat.</p>
<p>Two liver cT1 metrics, interquartile range of cT1 (IQR cT1) and mean superpixel variance cT1, were identified as potential markers of liver parenchymal heterogeneity in PSC. IQR cT1 had the best performance to detect the high-risk PSC group stratified by LS (AUC=0.84, 95% CI 0.75–0.93, p<0.0001). Mean superpixel variance cT1 differentiated PSC from every other liver disease (p<0.0001) but did not differentiate between the other liver diseases. Median cT1 correlated with all the domains of SF-36 with the strongest being mental health (rs=-0.37, p=0.001) and social functioning: rs=-0.32, p=0.005). </p>
<p>The periductal mean cT1 1.5–3.5mm surrounding the bile ducts were higher than regions further away from the bile duct (p<0.0001) in PSC but not in healthy controls. Patients with LS > 9.6kPa (AUC=0.74, 95% CI 0.60–0.88, p=0.0021) and AOM > 2 (AUC=0.72, 95% CI 0.59–0.85, p=0.0031) had higher values than those with LS ≤ 9.6kPa and AOM ≤ 2, respectively. The mental health (rs=0.38, p=0.002) and role emotional (rs=0.37, p=0.010) components of SF-36 showed the strongest correlations with periductal mean cT1.</p>
<p>Temporal changes in mean values of IQR cT1 showed a significant interaction with time and baseline risk categorisation by AOM (p<0.001), LS (p=0.010), ELF (p=0.004), ISSS (p=0.039) and Anali (p<0.001). The diagnostic performances of single baseline measurements were numerically better than temporal changes to detect the high-risk group. </p>
<p>Validation against clinical endpoints is warranted before these metrics can be tested in multicentre prospective studies and considered as surrogate endpoints in clinical trials.</p>
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