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Behind the Scenes of MRI-based Liver Disease Diagnostics
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Liver disease is a major global health concern, accounting for approximately 2 million deaths per year worldwide1. The most common causes include alcohol misuse, obesity or viral hepatitis and in the UK, about 90% of these cases are preventable2. Liver disease is often undetectable until it is in its later stages, as damage can occur without the appearance of any symptoms3.
Early diagnosis can be life-saving, particularly because the liver has an amazing capacity to regenerate4 – so it is possible to curb highly prevalent diseases such as fatty liver disease by making lifestyle changes.
One company working to address this issue is Perspectum Diagnostics, a spin-out from the University of Oxford. By taking advantage of magnetic resonance imaging (MRI), they are developing ways to improve diagnosis in the clinic and accelerate drug discovery.
Filling an unmet need for non-invasive liver diagnostics in the clinic and drug trials
At present, liver biopsy is the “gold standard” for assessing liver disease. While methods for collecting liver tissue have improved in recent years, the process has significant drawbacks which make the technique less than perfect. Liver biopsy takes an extremely small tissue sample from the liver. Discordance in sample interpretation can occur between different pathologists and results may take several days to come back. Lastly, a liver biopsy is invasive with a small but significant risk of morbidity with pain occurring in 20% and major complications such as bleeding in 0.5%5. Developing an alternative to biopsy is highly appealing to help clinicians make therapeutic decisions and predict clinical outcomes non-invasively.
Clinical trials are currently underway to assess pharmacological treatments for non-alcoholic steatohepatitis (NASH). However, these trials are limited as serial liver biopsies are needed to assess changes in liver fibrosis and disease activity. Non-invasive biomarkers can help accelerate trials and bring new treatment options to patients.
What does LiverMultiScan® do?
LiverMultiScan is a non-invasive test which characterizes liver tissue — using multiparametric MRI and digital image processing to generate accurate and quantitative measures that are delivered within hours. Its metrics include:
· PDFF (proton density fat fraction) as a measure of liver fat
· T2* as a measure of liver iron
· cT1 (corrected T1) as a measure of fibrosis and inflammation in the liver
This video provides an overview of LiverMultiScan and shows examples of images that can be obtained.
Following the heart — how did LiverMultiScan come about?
Perspectum Diagnostics came about when its founder and CEO, Dr. Rajarshi Banerjee was doing his doctoral studies at the University of Oxford. He used a multiparametric MRI approach that exploited T1 mapping to characterize myocardial fibrosis and inflammation. When considering other organs where T1 mapping could be applied, the liver was an obvious choice. However, Dr. Banerjee and the team had to overcome significant complexities, including the impact of iron deposition and its interference with the MRI signal, which does not occur in the heart.
Iron is stored in the liver, in varying quantities for different people. Following a multidisciplinary effort, an algorithm that corrected T1 for the variable effect of iron was developed and is now a crucial marker in LiverMultiScan.
Dr. Matt Kelly, Chief Innovation Officer at Perspectum Diagnostics, elaborates, “The team performed a validation study where they first scanned patients who were undergoing a liver biopsy and then looked at how well corrected T1 corresponded to biopsy results. That data was very promising. They looked into grants to fund more work, but the most appealing option to take this technology from a research lab into a clinic — where it can be used to improve patient care — was to start a company. So, they decided to spin out a company from the university.”
Every hurdle has a silver lining
When asked about hurdles along the way, Dr. Kelly and Ross Stewart (Senior Business Development Manager), agreed that one particular challenge stood out — upscaling.
According to Dr. Kelly, “The technology had initially been validated on a small set of scanners, but in order to build wider clinical adoption, we had to support all major scanner models. We also had to make sure that our technology was standardized across scanners, and I think we underestimated the amount of effort required. However, we enjoy a challenge, and the result is metrics that are consistent across all major scanner models.”
Overcoming the big hurdle of standardization is now working in their favor. “The flipside of all this effort to standardize is that we’ve set a high bar for other technologies, because we know how hard it is to standardize these measures from MRI. It’s a hard problem to solve and we put a lot of resources into solving it — I would say that is one big challenge that has turned into a benefit for us.”
Standardization has been a selling point for LiverMultiScan to pharmaceutical companies. Dr. Kelly added, “We can say to them, ‘These measures are equivalent no matter what system you use, the FDA has cleared the technology and agrees that the test shows good reproducibility, so you can be confident when evaluating change.’”
Insights gathered from patients (and clinicians)
As patients would be the end consumers of LiverMultiScan reports, the team looked to patients to help them optimize their technology. The team designed a qualitative interview and questionnaire to gain insights into patient experience and their understanding of the results.
“As this technology rolls out more widely in the clinic, we want to empower patients with the information that they receive,” Dr. Kelly shared. “We invited 100 people with various kinds of liver disease for a scan. We went through the report with them and got their feedback. We wanted to make sure that the information was clear, not misleading, and easy-to-understand.”
“The feedback we’ve had from clinicians is that they find it makes the conversation with patients easier, because rather than just telling them ‘Your blood test is X’ or ‘Your fibrosis score is 2 out of 4’, they can say, ‘Here’s a picture of your liver, this is what it looks like and it doesn’t look healthy.’”
Recent progress points towards a promising future
Collaboration with UK Biobank6,7, which follows the health and well-being of 500,000 participants, has led to new discoveries. As published in PLoS One, screening for liver fat8 and iron9 with LiverMultiScan could be an effective method to better inform patient treatment and stratification.
Better legislation would accelerate diagnostic development
An inconvenient irony exists, which is a by-product of the industry. While the goal of Perspectum Diagnostics is to reduce the number of unnecessary liver biopsies, the team has had to demonstrate that LiverMultiScan is comparable to liver biopsies for regulatory approval and market access.
“That’s what the field has said, ‘We understand the pathology and the histology. Biopsy is the standard.’” Mr Stewart explains. “While we have published evidence showing LiverMultiScan’s prognostic value, that we can stratify patients, and with some certainty predict what happens to them and their outcomes – that data tends to be overlooked because we have to address the question, ‘How does that correlate with biopsy?’”
The team remains optimistic that over time, the field will eventually transition away from needing biopsies.
References
1. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70(1):151-171. doi:10.1016/j.jhep.2018.09.014
2. https://britishlivertrust.org.uk/about-us/media-centre/statistics/
3. https://britishlivertrust.org.uk/wp-content/uploads/The-alarming-impact-of-liver-disease-FINAL-June-2019.pdf
4. Forbes SJ, Newsome PN. Liver regeneration — mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol. 2016;13(8):473-485. doi:10.1038/nrgastro.2016.97
5. Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology. 2000 Sep;32(3):477-81. doi:10.1053/jhep.2000.16602
6. https://www.ukbiobank.ac.uk/
7. Mojtahed, A., Kelly, C. J., Herlihy, A. H., et al. Reference range of liver corrected T1 values in a population at low risk for fatty liver disease-a UK Biobank sub-study, with an appendix of interesting cases. Abdom Radiol (NY). 2019;44(1):72–84. doi:10.1007/s00261-018-1701-2
8. Wilman HR, Kelly M, Garratt S, et al. Characterisation of liver fat in the UK Biobank cohort. PLoS ONE. 2017;12(2):e0172921. doi:10.1371/journal.pone.0172921
9. McKay A, Wilman HR, Dennis A, et al. Measurement of liver iron by magnetic resonance imaging in the UK Biobank population. PLoS One. 2018;13(12). doi:10.1371/journal.pone.0209340
