Assessing treatment effects in liver cirrhosis and portal hypertension with an integrated imaging approach
Liver cirrhosis is a global health care burden and accounts for around 2 million deaths per year worldwide (GBD 2017 Cirrhosis Collaborators, 2020). Today, there are no specific therapies available and treating late-stage liver fibrosis remains a huge unmet need with an increasing focus for drug development. Liver cirrhosis is the result of different causes of chronic liver injury including metabolic dysfunction-associated steatohepatitis (MASH; previously called non-alcoholic steatohepatitis or NASH), alcohol related liver disease, hepatitis B and C. Even though the aetiologies are diverse, the resulting pathophysiology is the same – hepatocyte injury induces inflammation and activates differentiation of hepatic stellate cells to collagen-producing myofibroblasts, which in turn leads to fibrosis. The progressive fibrogenesis combined with intrahepatic vasoconstriction leads to an increased intrahepatic resistance resulting in portal hypertension.
Portal hypertension – a hallmark of cirrhosis
Portal hypertension is a hallmark of liver cirrhosis present in both compensated and decompensated cirrhotic stages. In compensated cirrhosis, mild and sub-clinical portal hypertension is present. Increased portal pressure increases the risk for decompensation and severe complications such as variceal bleeding and ascites. Today, portal hypertension is defined using thresholds of hepatic venous pressure gradient (HVPG), a considered gold standard technique. However, HVPG is limited by its complexity, extreme invasiveness, and operator-dependence. There is a need for effective, non-invasive biomarkers of portal hypertension for use in clinical trials, not only to reduce the burden of the HVPG measurements but also to provide richer and more informative data that better reflects pathophysiological processes and the impact of novel treatments.
What imaging can do
Magnetic resonance imaging (MRI) provides a powerful platform to assess pathophysiological features that represent the dynamic and static nature of portal hypertension as well as liver fibrosis and cirrhosis. This includes the structure, composition and stiffness of the liver and spleen, hemodynamics of the portal vein and hepatocyte function. Further, the non-invasive, non-radiating characteristics of MRI allows for repeated examinations to follow long-term treatment effects.
MRI to assess pathophysiological features of cirrhosis and portal hypertension
Due to the linked blood supply between the liver and the spleen, an increased pressure in the portal vein forces the blood back into the splenic vein, causing the spleen to become congested and increase in volume. The enlarged spleen seen with increased pressure in the portal vein is not only caused by congestion, but also tissue hyperplasia and fibrosis. Spleen volume, extracellular volume and stiffness reflect these pathophysiological processes and can be measured with MRI to provide a way of assessing treatment effects in clinical trials as an indicator of reduced portal venous pressure (Mesropyan et al, 2021, Yoo et al, 2021, Colecchia et al, 2012). In addition, hemodynamic measurements including portal vein flow, velocity and resistance can be assessed for additional insight of the treatment effects and mode of action of potential new drugs.
To add to the overall understanding of cirrhosis and portal hypertension in clinical trials, MRI measurements of liver stiffness and liver function can be used to assess treatment effects in liver fibrosis and functioning hepatocytes. Further, assessing liver volume provides a control measurement of the changes seen in other, both imaging and non-imaging, data to build confidence in the trial outcome. In decompensated cirrhosis where ascites is present, MRI can also be used to accurately quantify abdominal fluid, as well as assessment of the kidneys for potential hepatorenal effects.
An integrated MRI approach for decision-making in drug development
Our integrated MRI approach yields a rich non-invasive biomarker data set for a comprehensive view of disease assessing cirrhosis and its downstream effects including portal hypertension. The precision and sensitivity of these measures allow for small sample sizes to get early answers on drug effects and understanding of mode and mechanism of action. Further, the approach is scalable for large multi-centre trials. Overall, using this integrated MRI approach to assess changes in pathophysiology in cirrhosis and portal hypertension will support decision-making throughout all stages of a drug development programme.
GBD 2017 Cirrhosis Collaborators, Lancet Gastroenterol Hepatol. 2020 Mar;5(3):245-266 (doi: 10.1016/S2468-1253(19)30349-8.)
Mesropyan et al. Eur Radiol. 2021 Jan;31(1):85-93. (doi: 10.1007/s00330-020-07080-5.)
Yoo et al. Eur Radiol. 2021 Mar;31(3):1432-1442. (doi: 10.1007/s00330-020-07209-6.)
Colecchia et al. Gastroenterology. 2012 Sep;143(3):646-654. (doi: 10.1053/j.gastro.2012.05.035.)